The European Medicines Agency (EMA) has granted orphan status to Atir, a product consisting of T-cell-depleted donor immune cells, for the treatment of acute myeloid leukemia (AML).

The EMA and the US Food and Drug Administration previously granted Atir orphan status for the prevention of acute graft-vs-host-disease (GVHD) following hematopoietic stem cell transplant (HSCT).

The EMA’s orphan designation provides incentives to support drug development. This includes fee reductions and a 10-year period of market exclusivity in the European Union after product approval.

About Atir

Atir consists of donor immune cells from which the alloreactive T-cells that would otherwise attack the patient’s body have been selectively eliminated.

The product is produced using a molecule known as TH9402 to selectively remove those T cells from the donor graft, while preserving other immune cells. To activate patient-reactive T cells, the graft is mixed (ex vivo) with patient cells.

Then, TH9402 is added. As this phototoxic compound selectively accumulates in activated T cells, the cells can be eliminated by exposing the cell mixture to light of a specific wavelength. The resulting Atir product can be frozen and stored and is infused into the patient in a scheduled procedure.

Trial data

Researchers said Atir proved safe and effective in a phase 1/2 study in which high-risk leukemia patients with very poor prognosis were treated with escalating doses of Atir after a haploidentical HSCT.

The overall survival of 19 patients who received an optimal dose of Atir was 78% at 1 year and 67% at 5 years, rates that compare favorably to outcomes of HSCTs from fully matched donors. The data also suggest that immune cells responsible for the graft-vs-leukemia effect are retained in Atir.

Five-year follow-up data show that none of the 19 patients developed acute grade 3/4 GVHD, compared to an incidence of 30% in matched unrelated HSCTs. In the 9 patients who received an optimal dose of Atir, there was no transplant-related mortality.

Researchers are currently testing Atir in a phase 2 study of patients with AML, acute lymphoblastic leukemia, and myelodysplastic syndrome, to corroborate and extend the safety and efficacy results from the phase 1/2 study. Data from this trial are expected in the second half of 2014.

Atir is under development by Kiadis Pharma. For more information, visit the company’s website.

The European Medicines Agency (EMA) has granted orphan status to Atir, a product consisting of T-cell-depleted donor immune cells, for the treatment of acute myeloid leukemia (AML).

The EMA and the US Food and Drug Administration previously granted Atir orphan status for the prevention of acute graft-vs-host-disease (GVHD) following hematopoietic stem cell transplant (HSCT).

The EMA’s orphan designation provides incentives to support drug development. This includes fee reductions and a 10-year period of market exclusivity in the European Union after product approval.

About Atir

Atir consists of donor immune cells from which the alloreactive T-cells that would otherwise attack the patient’s body have been selectively eliminated.

The product is produced using a molecule known as TH9402 to selectively remove those T cells from the donor graft, while preserving other immune cells. To activate patient-reactive T cells, the graft is mixed (ex vivo) with patient cells.

Then, TH9402 is added. As this phototoxic compound selectively accumulates in activated T cells, the cells can be eliminated by exposing the cell mixture to light of a specific wavelength. The resulting Atir product can be frozen and stored and is infused into the patient in a scheduled procedure.

Trial data

Researchers said Atir proved safe and effective in a phase 1/2 study in which high-risk leukemia patients with very poor prognosis were treated with escalating doses of Atir after a haploidentical HSCT.

The overall survival of 19 patients who received an optimal dose of Atir was 78% at 1 year and 67% at 5 years, rates that compare favorably to outcomes of HSCTs from fully matched donors. The data also suggest that immune cells responsible for the graft-vs-leukemia effect are retained in Atir.

Five-year follow-up data show that none of the 19 patients developed acute grade 3/4 GVHD, compared to an incidence of 30% in matched unrelated HSCTs. In the 9 patients who received an optimal dose of Atir, there was no transplant-related mortality.

Researchers are currently testing Atir in a phase 2 study of patients with AML, acute lymphoblastic leukemia, and myelodysplastic syndrome, to corroborate and extend the safety and efficacy results from the phase 1/2 study. Data from this trial are expected in the second half of 2014.

Atir is under development by Kiadis Pharma. For more information, visit the company’s website.

The European Medicines Agency (EMA) has granted orphan status to Atir, a product consisting of T-cell-depleted donor immune cells, for the treatment of acute myeloid leukemia (AML).

The EMA and the US Food and Drug Administration previously granted Atir orphan status for the prevention of acute graft-vs-host-disease (GVHD) following hematopoietic stem cell transplant (HSCT).

The EMA’s orphan designation provides incentives to support drug development. This includes fee reductions and a 10-year period of market exclusivity in the European Union after product approval.

About Atir

Atir consists of donor immune cells from which the alloreactive T-cells that would otherwise attack the patient’s body have been selectively eliminated.

The product is produced using a molecule known as TH9402 to selectively remove those T cells from the donor graft, while preserving other immune cells. To activate patient-reactive T cells, the graft is mixed (ex vivo) with patient cells.

Then, TH9402 is added. As this phototoxic compound selectively accumulates in activated T cells, the cells can be eliminated by exposing the cell mixture to light of a specific wavelength. The resulting Atir product can be frozen and stored and is infused into the patient in a scheduled procedure.

Trial data

Researchers said Atir proved safe and effective in a phase 1/2 study in which high-risk leukemia patients with very poor prognosis were treated with escalating doses of Atir after a haploidentical HSCT.

The overall survival of 19 patients who received an optimal dose of Atir was 78% at 1 year and 67% at 5 years, rates that compare favorably to outcomes of HSCTs from fully matched donors. The data also suggest that immune cells responsible for the graft-vs-leukemia effect are retained in Atir.

Five-year follow-up data show that none of the 19 patients developed acute grade 3/4 GVHD, compared to an incidence of 30% in matched unrelated HSCTs. In the 9 patients who received an optimal dose of Atir, there was no transplant-related mortality.

Researchers are currently testing Atir in a phase 2 study of patients with AML, acute lymphoblastic leukemia, and myelodysplastic syndrome, to corroborate and extend the safety and efficacy results from the phase 1/2 study. Data from this trial are expected in the second half of 2014.

Atir is under development by Kiadis Pharma. For more information, visit the company’s website.

Topical steroid therapy improved some indicators of mucosal integrity in patients with eosinophilic esophagitis, but proton pump inhibitor therapy did not, according to two studies reported in the November issue of Clinical Gastroenterology and Hepatology.

The first study found that topical fluticasone therapy at a dose of 880 mcg twice daily for 2 months helped correct esophageal spongiosis, or dilated intercellular space, in patients with eosinophilic esophagitis (EoE). Spongiosis scores for treated patients were significantly lower than for untreated patients (0.4 vs. 1.3; P = .016), said Dr. David Katzka at the Mayo Clinic in Rochester, Minn. and his associates (Clin. Gastroenterol. Hepatol. 2014 [doi:10.1016/j.cgh.2014.02.039]).

In the study, histologic analyses also showed that improved spongiosis scores in treated patients correlated with increased density of two tight junction proteins, filaggrin (P = .001) and zonula occludens-3 (P = .016), said the investigators. These proteins might help regulate antigenic penetration of the esophageal mucosa and also could permit migration of white blood cells, they said. “Loss of tight junction regulators and dilation of intercellular spaces appear to be involved in the pathophysiology of EoE and could be targets for treatment,” the researchers concluded. But they also noted that their study did not examine the same patients before and after steroid therapy and did not look at desmosomes, intercellular junctions that past research has suggested might be affected in EoE.

For the second study, Dr. Bram van Rhijn and his associates at the Academic Medical Center in the Netherlands compared endoscopies of 16 patients with dysphagia and suspected (unconfirmed) EoE with 11 controls, both at baseline and after 8 weeks of high-dose esomeprazole treatment. Esophageal mucosal integrity was “severely impaired” in patients with confirmed EoE and in those with proton pump inhibitor–responsive eosinophilia (PPRE), the researchers said (Clin. Gasteroenterol. Hepatol. 2014 [doi:10.1016/j.cgh.2014.02.037]).

In both forms of disease, molecules as large as 40,000 daltons were able to pass through the compromised esophageal mucosa, Dr. Bram van Rhijn and his associates reported. “This size is similar to the size of most plant and animal food allergens to which EoE patients are sensitized,” they added. Esophageal permeability might increase the rate of immune exposure to allergens, thereby mediating EoE and PPRE, they said.

On mucosal functional tests, both EoE and PPRE were associated with reduced transepithelial electrical resistance and lower electrical tissue impedance, most notably in patients with EoE (P less than .001 for both, compared with controls), the investigators reported. Proton pump inhibitor treatment partially reversed these changes in patients with PPRE but showed no effect for patients with EoE, they said. This finding suggests that acid reflux might play a role in PPRE, but not in EOE, they concluded.

Dr. Katzka and his associates disclosed no funding sources and reported having no conflicts of interest. Dr. Rhijn and his associates were supported by the Netherlands Organization for Scientific Research. Two of Dr. Rhijn’s coauthors reported financial relationships with AstraZeneca, Endostim, Medical Measurement Systems, Shire, and GlaxoSmithKline.

Topical steroid therapy improved some indicators of mucosal integrity in patients with eosinophilic esophagitis, but proton pump inhibitor therapy did not, according to two studies reported in the November issue of Clinical Gastroenterology and Hepatology.

The first study found that topical fluticasone therapy at a dose of 880 mcg twice daily for 2 months helped correct esophageal spongiosis, or dilated intercellular space, in patients with eosinophilic esophagitis (EoE). Spongiosis scores for treated patients were significantly lower than for untreated patients (0.4 vs. 1.3; P = .016), said Dr. David Katzka at the Mayo Clinic in Rochester, Minn. and his associates (Clin. Gastroenterol. Hepatol. 2014 [doi:10.1016/j.cgh.2014.02.039]).

In the study, histologic analyses also showed that improved spongiosis scores in treated patients correlated with increased density of two tight junction proteins, filaggrin (P = .001) and zonula occludens-3 (P = .016), said the investigators. These proteins might help regulate antigenic penetration of the esophageal mucosa and also could permit migration of white blood cells, they said. “Loss of tight junction regulators and dilation of intercellular spaces appear to be involved in the pathophysiology of EoE and could be targets for treatment,” the researchers concluded. But they also noted that their study did not examine the same patients before and after steroid therapy and did not look at desmosomes, intercellular junctions that past research has suggested might be affected in EoE.

For the second study, Dr. Bram van Rhijn and his associates at the Academic Medical Center in the Netherlands compared endoscopies of 16 patients with dysphagia and suspected (unconfirmed) EoE with 11 controls, both at baseline and after 8 weeks of high-dose esomeprazole treatment. Esophageal mucosal integrity was “severely impaired” in patients with confirmed EoE and in those with proton pump inhibitor–responsive eosinophilia (PPRE), the researchers said (Clin. Gasteroenterol. Hepatol. 2014 [doi:10.1016/j.cgh.2014.02.037]).

In both forms of disease, molecules as large as 40,000 daltons were able to pass through the compromised esophageal mucosa, Dr. Bram van Rhijn and his associates reported. “This size is similar to the size of most plant and animal food allergens to which EoE patients are sensitized,” they added. Esophageal permeability might increase the rate of immune exposure to allergens, thereby mediating EoE and PPRE, they said.

On mucosal functional tests, both EoE and PPRE were associated with reduced transepithelial electrical resistance and lower electrical tissue impedance, most notably in patients with EoE (P less than .001 for both, compared with controls), the investigators reported. Proton pump inhibitor treatment partially reversed these changes in patients with PPRE but showed no effect for patients with EoE, they said. This finding suggests that acid reflux might play a role in PPRE, but not in EOE, they concluded.

Dr. Katzka and his associates disclosed no funding sources and reported having no conflicts of interest. Dr. Rhijn and his associates were supported by the Netherlands Organization for Scientific Research. Two of Dr. Rhijn’s coauthors reported financial relationships with AstraZeneca, Endostim, Medical Measurement Systems, Shire, and GlaxoSmithKline.

Topical steroid therapy improved some indicators of mucosal integrity in patients with eosinophilic esophagitis, but proton pump inhibitor therapy did not, according to two studies reported in the November issue of Clinical Gastroenterology and Hepatology.

The first study found that topical fluticasone therapy at a dose of 880 mcg twice daily for 2 months helped correct esophageal spongiosis, or dilated intercellular space, in patients with eosinophilic esophagitis (EoE). Spongiosis scores for treated patients were significantly lower than for untreated patients (0.4 vs. 1.3; P = .016), said Dr. David Katzka at the Mayo Clinic in Rochester, Minn. and his associates (Clin. Gastroenterol. Hepatol. 2014 [doi:10.1016/j.cgh.2014.02.039]).

In the study, histologic analyses also showed that improved spongiosis scores in treated patients correlated with increased density of two tight junction proteins, filaggrin (P = .001) and zonula occludens-3 (P = .016), said the investigators. These proteins might help regulate antigenic penetration of the esophageal mucosa and also could permit migration of white blood cells, they said. “Loss of tight junction regulators and dilation of intercellular spaces appear to be involved in the pathophysiology of EoE and could be targets for treatment,” the researchers concluded. But they also noted that their study did not examine the same patients before and after steroid therapy and did not look at desmosomes, intercellular junctions that past research has suggested might be affected in EoE.

For the second study, Dr. Bram van Rhijn and his associates at the Academic Medical Center in the Netherlands compared endoscopies of 16 patients with dysphagia and suspected (unconfirmed) EoE with 11 controls, both at baseline and after 8 weeks of high-dose esomeprazole treatment. Esophageal mucosal integrity was “severely impaired” in patients with confirmed EoE and in those with proton pump inhibitor–responsive eosinophilia (PPRE), the researchers said (Clin. Gasteroenterol. Hepatol. 2014 [doi:10.1016/j.cgh.2014.02.037]).

In both forms of disease, molecules as large as 40,000 daltons were able to pass through the compromised esophageal mucosa, Dr. Bram van Rhijn and his associates reported. “This size is similar to the size of most plant and animal food allergens to which EoE patients are sensitized,” they added. Esophageal permeability might increase the rate of immune exposure to allergens, thereby mediating EoE and PPRE, they said.

On mucosal functional tests, both EoE and PPRE were associated with reduced transepithelial electrical resistance and lower electrical tissue impedance, most notably in patients with EoE (P less than .001 for both, compared with controls), the investigators reported. Proton pump inhibitor treatment partially reversed these changes in patients with PPRE but showed no effect for patients with EoE, they said. This finding suggests that acid reflux might play a role in PPRE, but not in EOE, they concluded.

Dr. Katzka and his associates disclosed no funding sources and reported having no conflicts of interest. Dr. Rhijn and his associates were supported by the Netherlands Organization for Scientific Research. Two of Dr. Rhijn’s coauthors reported financial relationships with AstraZeneca, Endostim, Medical Measurement Systems, Shire, and GlaxoSmithKline.

Series Editor: Arthur T. Skarin, MD, FACP, FCCP

Each year approximately 228,000 Americans will be diagnosed with lung cancer, and 159,000 will die of this disease. An estimated 85% of lung cancer cases are non–small cell lung cancer (NSCLC), more than 50% of NSCLC is comprised of adenocarcinoma, the median age at diagnosis is 71 years, and 25% of patients with this diagnosis present with stage III disease. In 2010 the seventh edition of the American Joint Committee on Cancer (AJCC) TNM staging system for lung cancer was released, and several changes were made which affect the patient population designated as having stage III disease.

To read the full article in PDF:

Click here

Series Editor: Arthur T. Skarin, MD, FACP, FCCP

Each year approximately 228,000 Americans will be diagnosed with lung cancer, and 159,000 will die of this disease. An estimated 85% of lung cancer cases are non–small cell lung cancer (NSCLC), more than 50% of NSCLC is comprised of adenocarcinoma, the median age at diagnosis is 71 years, and 25% of patients with this diagnosis present with stage III disease. In 2010 the seventh edition of the American Joint Committee on Cancer (AJCC) TNM staging system for lung cancer was released, and several changes were made which affect the patient population designated as having stage III disease.

To read the full article in PDF:

Click here

Series Editor: Arthur T. Skarin, MD, FACP, FCCP

Each year approximately 228,000 Americans will be diagnosed with lung cancer, and 159,000 will die of this disease. An estimated 85% of lung cancer cases are non–small cell lung cancer (NSCLC), more than 50% of NSCLC is comprised of adenocarcinoma, the median age at diagnosis is 71 years, and 25% of patients with this diagnosis present with stage III disease. In 2010 the seventh edition of the American Joint Committee on Cancer (AJCC) TNM staging system for lung cancer was released, and several changes were made which affect the patient population designated as having stage III disease.

To read the full article in PDF:

Click here

More than 30 years into the human immunodeficiency virus (HIV) epidemic, our understanding of the needs of women living with this virus continues to evolve. In the early years of the epidemic, managing HIV was all about preventing death and treating opportunistic infections. But now it is also about enabling patients to live long, healthy, and productive lives and preventing new HIV infections. In women, these goals can only be achieved by paying careful attention to sex-specific issues.

See related editorial

As a result of longer survival, HIV-infected persons are increasingly developing common health problems that also affect the general population and that require screening, management, and monitoring by primary care providers. Because people infected with HIV are typically seen by both an HIV specialist and a primary care provider, HIV specialists need to be familiar with primary care issues and primary care providers need to be familiar with HIV care recommendations in order to provide optimal care.

AFRICAN AMERICAN WOMEN BEAR A DISPROPORTIONATE BURDEN

In the United States, HIV was first reported in women in 1983 among those who had been steady sexual partners of males with acquired immune deficiency syndrome.¹ Although men with HIV still outnumber women, the number of women with HIV has increased rapidly. At the end of 2010 an estimated one in four people with HIV in the United States was female.²

African American women bear a disproportionate burden of the disease (Table 1).³ In 2010, women accounted for an estimated 9,500 (20%) of the approximately 45,000 new infections occurring in the United States. Of these newly infected women, 64% were black, 18% were white, and 15% were Hispanic. Yet blacks make up only about 12% of the US population, whites make up 68%, and Hispanics 14%.

Regardless of race or ethnicity, unprotected heterosexual contact is the most common mode of transmission of HIV in women.²

Although the overall rates of HIV infection in the United States are relatively low, certain areas of the country have rates similar to those in sub-Saharan Africa, where most HIV-infected people reside.⁴ The HIV Prevention Trials Network found that the incidence of HIV infection in US women living in these “hot spots,” with high rates of poverty and HIV, was 0.32% per year. Compare this with the 2009 estimate of HIV incidence in the general population of US black women of similar age (0.05% per year) and the adult incidence rates in Congo (0.28% per year) and Kenya (0.53% per year).⁵ To better understand the epidemiology of HIV infection in women and concentrate our prevention efforts, we need to focus on these hot spots.

Misinformation abounds in these hot spots, as does disease. In a survey of residents of the South Side Chicago Housing Authority facilities,⁶ many were aware that effective antiretroviral therapy existed, but one-fourth thought that there was an effective HIV vaccine, and 13% thought there was a cure.

In the early years, an HIV diagnosis was essentially a death sentence. Samji et al⁷ estimated that life expectancy of patients who were prescribed antiretroviral therapy in the United States and Canada increased from 36.1 years in 2000–2002 to 51.4 years in 2006–2007, with the greatest increases in those who started with a baseline CD4 count above 350 cells/mm³. Now, a 20-year-old HIV-positive person with a CD4 count greater than 350 cells/mm³ can expect to live into his or her early 70s.

But not all patients achieve these benefits. In 2009, despite major advances in diagnosis and treatment, HIV was the fourth leading cause of death among African American women ages 25 to 44, causing about 800 deaths, or 9% of all deaths in this group.⁸

TEST ALL, UNLESS THEY OPT OUT

Testing is vital in efforts to prevent and treat HIV infection. In 2006, the US Centers for Disease Control and Prevention (CDC) recommended that everyone between the ages of 13 and 64 be screened for HIV regardless of risk.⁹

The CDC recommends an opt-out strategy.⁹ Rather than ask a patient whether he or she wants to be tested for HIV, the provider says something like, “I advise all of my patients to have an HIV test; as long as you have no objection, we will send you to the lab to have it done.” This approach reduces barriers to HIV testing by eliminating pretest counseling and by making HIV testing routine and the standard of care. Separate consent is not required—clinicians just need to document whether the patient has accepted or declined the test.

Testing should be offered at least once and can be done in any health care setting, including primary care offices and clinics, emergency rooms, health departments, and urgent care centers.⁹ Patients at higher risk (injection drug users and their sex partners; people who exchange sex for money or drugs; sex partners of HIV-infected people; men who have sex with men; and heterosexuals who themselves or whose sex partners have had more than one sex partner since their most recent HIV test) should receive repeat screening annually.

HIV testing should also be offered to all pregnant women at entry into care and again in the third trimester. This strategy is cost-effective even in areas of low prevalence.⁹ Since 2006, other professional organizations have made HIV testing recommendations as well (Table 2).^9–12

A cost-effectiveness analysis suggested that routine opt-out testing is economically justified if the prevalence of HIV is greater than 0.2%.¹³

HIV-POSITIVE WOMEN NEED ROUTINE GYNECOLOGIC CARE

It is important for women with HIV to receive routine gynecologic care. Women with HIV have gynecologic problems similar to those of all women; however, they may be more vulnerable to certain conditions such as human papillomavirus (HPV) infection, which may be related to HIV disease or associated immunosuppression. In addition, pregnancy and family planning pose special challenges in this group.¹⁴

Cervical cancer screening

Effective screening and timely treatment of precancerous cervical lesions are key in preventing cervical cancer in women with or without HIV.

Persistent infection with HPV is necessary for the development of precancerous lesions as well as invasive cervical cancer. Most new cases of HPV infection in the general population resolve spontaneously within 2 years. However, in HIV-infected women, HPV infection is more likely to persist and progress to precancerous lesions of the cervix. This association is strongest in women with more compromised immune function as reflected by low CD4 cell counts and high viral loads.¹⁴ Women with HIV have higher rates of infection with high-risk HPV strains and of cervical intraepithelial neoplasia compared with their HIV-negative counterparts.¹⁴ The incidence of cervical cancer is five to six times higher in HIV-infected women in the United States than in the general population.¹⁵

According to guidelines from the Infectious Diseases Society of America,¹⁶ the American College of Obstetricians and Gynecologists,¹⁰ the CDC,¹⁷ and the American Cancer Society,¹⁸ all HIV-infected women should undergo cervical Papanicolaou (Pap) screening upon initiation into care, and this test should be repeated at 6 months and then annually if the results are normal. Patients with abnormalities on the Pap test should undergo colposcopy and, possibly, also biopsy. These abnormalities include atypical squamous cells of unknown significance and higher-grade lesions.¹⁶

Nearly one-fourth of HIV-positive women do not receive annual Pap smears despite engagement in care.¹⁹ This is unacceptable, because half of the cases of cervical cancer diagnosed in the United States are in women who never received appropriate screening, and an additional 10% are in women who have not been screened in the previous 5 years.¹⁹

In HIV-infected women who have had a total hysterectomy, whether to continue Pap testing depends on their history before the surgery. Continued vaginal Pap smear screening is recommended after hysterectomy (including removal of the cervix) in HIV-infected women who have a history of cervical intraepithelial neoplasia grades 2 or 3 or invasive cancer.^10,17,20

TREATING HIV IN WOMEN: SPECIAL CONSIDERATIONS

Because it is not yet possible to eradicate the HIV virus, the goals of antiretroviral therapy are to reduce HIV-associated morbidity and mortality, to restore and preserve immune function, to suppress viral load, and to prevent sexual and, in women, perinatal transmission of the virus.²¹

Antiretroviral therapy is recommended for all HIV-infected patients regardless of the CD4 count, although the strength of recommendation is weaker with higher CD4 counts (Table  3).²¹ The recommendations for starting antiretroviral therapy and the goals of treatment are the same for men and women. Table 4 summarizes the recommendations for adolescents and adults who are new to treatment.²¹ For women, additional factors that should be taken into account when considering a regimen include pregnancy potential and whether the drugs chosen for the regimen are considered safe in pregnancy.

Since the early years of the HIV epidemic, researchers have debated whether women attain the same benefits from antiretroviral therapy as men. US Food and Drug Administration investigators performed a meta-analysis of the efficacy outcomes in women in studies of antiretroviral drugs published between 2000 and 2008. They included randomized clinical trials reporting at least 48-week efficacy outcomes, with viral suppression defined as HIV RNA less than 50 copies/mL. The combined database included 40 trials of 16 drugs from 7 drug classes with a total of 20,328 HIV-positive participants. Overall, there were no clinically or statistically significant differences between the sexes in 48-week efficacy outcomes or in rates of trial discontinuation due to adverse events, loss to follow-up, or death.²²

Antiretroviral therapy may, however, cause different adverse effects in women than in men. For example:

Nevirapine, a nonnucleoside reverse transcriptase inhibitor, has been associated with the development of a rash and potentially life-threatening hepatotoxicity, more commonly in women than in men and at lower CD4 counts in women. This resulted in recommendations²¹ to avoid starting a nevirapine-containing regimen in women with CD4 counts greater than 250 cells/mm³ and in men with CD4 counts greater than 400 cells/mm³.

Ritonavir has been observed to cause a higher incidence of nausea and vomiting in women and a higher incidence of diarrhea in men. These are thought to be due to differences between men and women in weight and pharmacokinetics.²³

PRECONCEPTION COUNSELING FOR HIV-POSITIVE WOMEN

Preconception counseling is an essential component of both primary and preventive care and should be considered the standard of care for all women of reproductive age who have HIV.²⁴ Health care providers who fully understand the impact of HIV infection and associated comorbidities upon a woman’s reproductive health, fertility desires, and family planning needs are better prepared to assist in their patients’ reproductive health decisions.

The first few weeks of pregnancy are the most critical period in fetal development. During this time, a woman should be healthy and avoid any activities or substances that could cause adverse maternal or fetal outcomes. However, most patients present for prenatal care after this critical time period—thus the need for preconception counseling. Both the Infectious Diseases Society of America and the HIV Medicine Association recommend that all HIV-infected women of childbearing age be asked about their pregnancy plans and desires at the start of care and routinely thereafter.¹⁶

The goals of preconception care in women with HIV are to prevent unintended pregnancy, optimize maternal health before pregnancy, optimize pregnancy outcomes for mother and fetus, prevent perinatal HIV transmission, and prevent HIV transmission to an HIV-negative partner when trying to conceive.²⁴

Goal 1: Prevent unintended pregnancy

Nearly half of all pregnancies in the United States are unintended.²⁵ Moreover, the Women’s Interagency HIV Study²⁶ showed that women with HIV are underusing effective contraception. In the Medical Monitoring Project, 85% of the women who had been pregnant since being diagnosed with HIV said that at least one pregnancy was unplanned.²⁷

The consequences of unintended and unplanned pregnancies are serious and add significant burden to women, men, and families. Women who do not wish to become pregnant should be advised to use an effective method of contraception.

Contraception

Contraception use varies worldwide. Factors affecting its use include the methods available, patient choice, current health conditions, religious beliefs, perception of method effectiveness, and side effects.²⁴

The Women’s Interagency HIV Study evaluated trends in contraception use from 1998 to 2010. Condoms were the most common form of contraception, and their use changed little over time. Fewer than 15% of women with HIV used no contraception. The use of long-acting reversible contraception, including injectable progestins, implants, and intrauterine devices, which minimize the need for user adherence, increased among HIV-negative women but not among HIV-positive women.²⁸

The World Health Organization states that all available methods are safe for women with HIV except for spermicides with or without a diaphragm, as there is evidence linking the use of spermicides to an increased risk of HIV transmission (Table 5).²⁹

Some antiretroviral drugs may reduce the effectiveness of some contraceptives (Table 6); however, recommendations are based on pharmacokinetic studies, not on outcome studies. Condoms should be recommended not only to protect against pregnancy, but also to protect against sexually transmitted infections.

Goal 2: Optimize maternal health before pregnancy

Maternal health should be optimized before conceiving to reduce the risk of pregnancy-related morbidities and poor birth outcomes. This includes screening for other infections and ensuring that other comorbidities, such as hypertension, diabetes, substance abuse, and mental illness, are well managed with medications that are safe to use in pregnancy (Table 7).

Goal 3: Prevent perinatal HIV transmission

Educating the patient about perinatal transmission is a fundamental component of preconception counseling. Topics that need to be addressed are transmission risk and methods to reduce the risk, including not breastfeeding after delivery.

Goal 4: Prevent HIV transmission to an uninfected partner when trying to conceive

HIV-discordant couples who desire pregnancy should receive appropriate counseling about methods to minimize risk of transmission to the uninfected partner while trying to conceive. There are a number of effective methods and techniques, which are beyond the scope of this review. Key components of all methods are to screen for and treat sexually transmitted infections in both partners and to use effective antiretroviral therapy and attain maximal viral suppression in the HIV-positive partner.

Antiretroviral therapy for the HIV-infected partner significantly reduced the risk of HIV transmission by 96% in the HIV Prevention Trials Network 052 trial.³⁰ Of note: this reduction was the result of both risk-reduction counseling and antiretroviral therapy. This was the first randomized clinical trial to demonstrate that antiretroviral therapy in those with some preserved immune function (CD4 counts 350–500 cells/mm³) in conjunction with risk-reduction counseling can reduce HIV transmission to an uninfected partner.

Vaginal insemination without intercourse is another option for female-positive couples. The man ejaculates into a condom without spermicide, and the contents are introduced with a non-needle syringe or turkey baster. This can be done at home and confers no risk to the uninfected male partner.³¹ Chances of pregnancy can be maximized by insemination during the most fertile days of the menstrual cycle.

Preexposure prophylaxis combined with timed intercourse. In a study in Switzerland, the infected male partner was given antiretroviral therapy to suppress his viral load to less than 50 copies/mL for at least 6 months, and luteinizing hormone was measured every day in the urine of the noninfected female partner. When the urinary luteinizing hormone level reached a peak, the woman received a dose of tenofovir in the morning, the couple had unprotected intercourse, and the woman took a second dose the next morning. In 53 cases, none of the female partners seroconverted for HIV.³²

Health care providers need to document and update the relationship status, partner HIV status, and fertility desires of their HIV patients, both men and women, on a regular basis. Patient education should include awareness of referrals and options to help safely conceive when desired and achieve effective contraception when not.³³

WHEN HIV-POSITIVE WOMEN BECOME PREGNANT

Screening for HIV during pregnancy

The CDC recommends prenatal screening for HIV in the first trimester or at entry into prenatal care. A repeat HIV test should be offered in the third trimester for women at risk of acquiring HIV, for women who have signs or symptoms of early HIV infection, in health care settings where prenatal testing yields at least 1 case of HIV infection per 1,000 women screened, and in areas of high HIV incidence. If women present to labor and delivery with unknown HIV status, rapid HIV testing should be done.⁹

If a woman acquires HIV during pregnancy, the infection may not be detected and may be transmitted to the infant at birth. From 2002 to 2006 in New York State, 3,396 HIV-exposed babies were born. Of these, 9 (22%) of 41 infants born to mothers who acquired HIV during pregnancy became infected, compared with 1.8% of those born to mothers who acquired HIV before pregnancy. Maternal acquisition of HIV during pregnancy was documented in only 1.3% of perinatal HIV exposures, but it was associated with 9 (13.8%) of the 65 perinatal transmission cases.³⁴

Providers should be aware of the signs and symptoms of acute HIV infection and should have a low threshold for repeating HIV testing at any time during pregnancy. It has been estimated that 40% to 90% of patients with acute HIV infection experience fever, lymphadenopathy, pharyngitis, skin rash, myalgia, arthralgia, or other symptoms.³⁵ Providers often do not recognize acute HIV infection, however, because the symptoms are similar to those of other common illnesses. Also, some individuals with the condition have no symptoms.

Antiretroviral therapy during pregnancy

In a landmark study, AIDS Clinical Trial Group 076 demonstrated that zidovudine monotherapy given during pregnancy, labor, and delivery and to the newborn reduced the risk of HIV transmission to the infant by 67%, from 25% to 8%.³⁶ Other studies demonstrated that combination therapy further decreased the risk of HIV transmission to 1% to 2%.³⁷

The US Department of Health and Human Services recommends that all HIV-positive women who are pregnant receive effective combination antiretroviral therapy regardless of CD4 count to minimize the risk of mother-to-child transmission.³⁷

The goals of HIV treatment during pregnancy are to maintain the woman’s health, restore her immune system, suppress viral replication, and decrease the risk of perinatal transmission. The preferred antiretroviral therapy for pregnant women differs from that for nonpregnant women and is based on evolving experience and information about safety, efficacy, and tolerability in pregnancy (Table 8). A woman who presents for prenatal care on a suppressive regimen should continue that regimen as long as she can tolerate it because there is a risk of losing virologic control when switching regimens, and this may increase the risk of perinatal transmission.³⁷

Physiologic changes that occur during pregnancy may alter drug disposition, which could potentially lead to decreased drug exposure. Some of the changes include an increase in total body water, decreased protein binding, induction of hepatic metabolic pathways, and increased clearance of drugs eliminated by the kidneys.³⁸ These changes may be associated with incomplete virologic suppression, virologic failure, or development of drug resistance, so altered doses of some antiretroviral drugs or careful monitoring of viral load should be considered, particularly in the second and third trimester.

Delivery

Women who have a viral load greater than 1,000 copies/mL near the end of pregnancy should undergo a cesarean delivery at 38 weeks and, before surgery, should receive intravenous zidovudine to reduce the risk of perinatal transmission. For women with viral loads below the threshold of 1,000 copies/mL, there is no proven added benefit to cesarean delivery, and in this situation it should be performed only for standard obstetric indications. Antiretroviral regimens should be continued during labor.³⁷

HIV IN OLDER ADULTS

By 2015, approximately 50% of people with HIV will be over age 50.³⁹ Unfortunately, older people and their providers often underestimate their risk of acquiring HIV. Many older people are newly single and may engage in sexual activity with new partners. Also, older people may be reluctant to use condoms as the need for contraception is past.^40,41

Baseline HIV RNA levels tend to be higher and CD4 cell counts lower in patients diagnosed with HIV at older ages. These observations support previous ones that older HIV-infected patients may have advanced HIV disease at the time of diagnosis, perhaps in part due to delayed testing.⁴² Other possible factors are limited income, comorbid illness, polypharmacy, and insufficient data on drug interactions in the elderly.^41,42

A prompt diagnosis is important for older patients because HIV may accelerate aging, and aging may speed up HIV progression. Studies have shown that aging is associated with more rapid progression to AIDS, particularly among people who are older than 40 at seroconversion.⁴³ Other studies have reported that older patients have better virologic responses to antiretroviral therapy but have a blunted immune response, more AIDS-defining events, and a higher mortality rate than younger patients.⁴²

More than 30 years into the human immunodeficiency virus (HIV) epidemic, our understanding of the needs of women living with this virus continues to evolve. In the early years of the epidemic, managing HIV was all about preventing death and treating opportunistic infections. But now it is also about enabling patients to live long, healthy, and productive lives and preventing new HIV infections. In women, these goals can only be achieved by paying careful attention to sex-specific issues.

See related editorial

As a result of longer survival, HIV-infected persons are increasingly developing common health problems that also affect the general population and that require screening, management, and monitoring by primary care providers. Because people infected with HIV are typically seen by both an HIV specialist and a primary care provider, HIV specialists need to be familiar with primary care issues and primary care providers need to be familiar with HIV care recommendations in order to provide optimal care.

AFRICAN AMERICAN WOMEN BEAR A DISPROPORTIONATE BURDEN

In the United States, HIV was first reported in women in 1983 among those who had been steady sexual partners of males with acquired immune deficiency syndrome.¹ Although men with HIV still outnumber women, the number of women with HIV has increased rapidly. At the end of 2010 an estimated one in four people with HIV in the United States was female.²

African American women bear a disproportionate burden of the disease (Table 1).³ In 2010, women accounted for an estimated 9,500 (20%) of the approximately 45,000 new infections occurring in the United States. Of these newly infected women, 64% were black, 18% were white, and 15% were Hispanic. Yet blacks make up only about 12% of the US population, whites make up 68%, and Hispanics 14%.

Regardless of race or ethnicity, unprotected heterosexual contact is the most common mode of transmission of HIV in women.²

Although the overall rates of HIV infection in the United States are relatively low, certain areas of the country have rates similar to those in sub-Saharan Africa, where most HIV-infected people reside.⁴ The HIV Prevention Trials Network found that the incidence of HIV infection in US women living in these “hot spots,” with high rates of poverty and HIV, was 0.32% per year. Compare this with the 2009 estimate of HIV incidence in the general population of US black women of similar age (0.05% per year) and the adult incidence rates in Congo (0.28% per year) and Kenya (0.53% per year).⁵ To better understand the epidemiology of HIV infection in women and concentrate our prevention efforts, we need to focus on these hot spots.

Misinformation abounds in these hot spots, as does disease. In a survey of residents of the South Side Chicago Housing Authority facilities,⁶ many were aware that effective antiretroviral therapy existed, but one-fourth thought that there was an effective HIV vaccine, and 13% thought there was a cure.

In the early years, an HIV diagnosis was essentially a death sentence. Samji et al⁷ estimated that life expectancy of patients who were prescribed antiretroviral therapy in the United States and Canada increased from 36.1 years in 2000–2002 to 51.4 years in 2006–2007, with the greatest increases in those who started with a baseline CD4 count above 350 cells/mm³. Now, a 20-year-old HIV-positive person with a CD4 count greater than 350 cells/mm³ can expect to live into his or her early 70s.

But not all patients achieve these benefits. In 2009, despite major advances in diagnosis and treatment, HIV was the fourth leading cause of death among African American women ages 25 to 44, causing about 800 deaths, or 9% of all deaths in this group.⁸

TEST ALL, UNLESS THEY OPT OUT

Testing is vital in efforts to prevent and treat HIV infection. In 2006, the US Centers for Disease Control and Prevention (CDC) recommended that everyone between the ages of 13 and 64 be screened for HIV regardless of risk.⁹

The CDC recommends an opt-out strategy.⁹ Rather than ask a patient whether he or she wants to be tested for HIV, the provider says something like, “I advise all of my patients to have an HIV test; as long as you have no objection, we will send you to the lab to have it done.” This approach reduces barriers to HIV testing by eliminating pretest counseling and by making HIV testing routine and the standard of care. Separate consent is not required—clinicians just need to document whether the patient has accepted or declined the test.

Testing should be offered at least once and can be done in any health care setting, including primary care offices and clinics, emergency rooms, health departments, and urgent care centers.⁹ Patients at higher risk (injection drug users and their sex partners; people who exchange sex for money or drugs; sex partners of HIV-infected people; men who have sex with men; and heterosexuals who themselves or whose sex partners have had more than one sex partner since their most recent HIV test) should receive repeat screening annually.

HIV testing should also be offered to all pregnant women at entry into care and again in the third trimester. This strategy is cost-effective even in areas of low prevalence.⁹ Since 2006, other professional organizations have made HIV testing recommendations as well (Table 2).^9–12

A cost-effectiveness analysis suggested that routine opt-out testing is economically justified if the prevalence of HIV is greater than 0.2%.¹³

HIV-POSITIVE WOMEN NEED ROUTINE GYNECOLOGIC CARE

It is important for women with HIV to receive routine gynecologic care. Women with HIV have gynecologic problems similar to those of all women; however, they may be more vulnerable to certain conditions such as human papillomavirus (HPV) infection, which may be related to HIV disease or associated immunosuppression. In addition, pregnancy and family planning pose special challenges in this group.¹⁴

Cervical cancer screening

Effective screening and timely treatment of precancerous cervical lesions are key in preventing cervical cancer in women with or without HIV.

Persistent infection with HPV is necessary for the development of precancerous lesions as well as invasive cervical cancer. Most new cases of HPV infection in the general population resolve spontaneously within 2 years. However, in HIV-infected women, HPV infection is more likely to persist and progress to precancerous lesions of the cervix. This association is strongest in women with more compromised immune function as reflected by low CD4 cell counts and high viral loads.¹⁴ Women with HIV have higher rates of infection with high-risk HPV strains and of cervical intraepithelial neoplasia compared with their HIV-negative counterparts.¹⁴ The incidence of cervical cancer is five to six times higher in HIV-infected women in the United States than in the general population.¹⁵

According to guidelines from the Infectious Diseases Society of America,¹⁶ the American College of Obstetricians and Gynecologists,¹⁰ the CDC,¹⁷ and the American Cancer Society,¹⁸ all HIV-infected women should undergo cervical Papanicolaou (Pap) screening upon initiation into care, and this test should be repeated at 6 months and then annually if the results are normal. Patients with abnormalities on the Pap test should undergo colposcopy and, possibly, also biopsy. These abnormalities include atypical squamous cells of unknown significance and higher-grade lesions.¹⁶

Nearly one-fourth of HIV-positive women do not receive annual Pap smears despite engagement in care.¹⁹ This is unacceptable, because half of the cases of cervical cancer diagnosed in the United States are in women who never received appropriate screening, and an additional 10% are in women who have not been screened in the previous 5 years.¹⁹

In HIV-infected women who have had a total hysterectomy, whether to continue Pap testing depends on their history before the surgery. Continued vaginal Pap smear screening is recommended after hysterectomy (including removal of the cervix) in HIV-infected women who have a history of cervical intraepithelial neoplasia grades 2 or 3 or invasive cancer.^10,17,20

TREATING HIV IN WOMEN: SPECIAL CONSIDERATIONS

Because it is not yet possible to eradicate the HIV virus, the goals of antiretroviral therapy are to reduce HIV-associated morbidity and mortality, to restore and preserve immune function, to suppress viral load, and to prevent sexual and, in women, perinatal transmission of the virus.²¹

Antiretroviral therapy is recommended for all HIV-infected patients regardless of the CD4 count, although the strength of recommendation is weaker with higher CD4 counts (Table  3).²¹ The recommendations for starting antiretroviral therapy and the goals of treatment are the same for men and women. Table 4 summarizes the recommendations for adolescents and adults who are new to treatment.²¹ For women, additional factors that should be taken into account when considering a regimen include pregnancy potential and whether the drugs chosen for the regimen are considered safe in pregnancy.

Since the early years of the HIV epidemic, researchers have debated whether women attain the same benefits from antiretroviral therapy as men. US Food and Drug Administration investigators performed a meta-analysis of the efficacy outcomes in women in studies of antiretroviral drugs published between 2000 and 2008. They included randomized clinical trials reporting at least 48-week efficacy outcomes, with viral suppression defined as HIV RNA less than 50 copies/mL. The combined database included 40 trials of 16 drugs from 7 drug classes with a total of 20,328 HIV-positive participants. Overall, there were no clinically or statistically significant differences between the sexes in 48-week efficacy outcomes or in rates of trial discontinuation due to adverse events, loss to follow-up, or death.²²

Antiretroviral therapy may, however, cause different adverse effects in women than in men. For example:

Nevirapine, a nonnucleoside reverse transcriptase inhibitor, has been associated with the development of a rash and potentially life-threatening hepatotoxicity, more commonly in women than in men and at lower CD4 counts in women. This resulted in recommendations²¹ to avoid starting a nevirapine-containing regimen in women with CD4 counts greater than 250 cells/mm³ and in men with CD4 counts greater than 400 cells/mm³.

Ritonavir has been observed to cause a higher incidence of nausea and vomiting in women and a higher incidence of diarrhea in men. These are thought to be due to differences between men and women in weight and pharmacokinetics.²³

PRECONCEPTION COUNSELING FOR HIV-POSITIVE WOMEN

Preconception counseling is an essential component of both primary and preventive care and should be considered the standard of care for all women of reproductive age who have HIV.²⁴ Health care providers who fully understand the impact of HIV infection and associated comorbidities upon a woman’s reproductive health, fertility desires, and family planning needs are better prepared to assist in their patients’ reproductive health decisions.

The first few weeks of pregnancy are the most critical period in fetal development. During this time, a woman should be healthy and avoid any activities or substances that could cause adverse maternal or fetal outcomes. However, most patients present for prenatal care after this critical time period—thus the need for preconception counseling. Both the Infectious Diseases Society of America and the HIV Medicine Association recommend that all HIV-infected women of childbearing age be asked about their pregnancy plans and desires at the start of care and routinely thereafter.¹⁶

The goals of preconception care in women with HIV are to prevent unintended pregnancy, optimize maternal health before pregnancy, optimize pregnancy outcomes for mother and fetus, prevent perinatal HIV transmission, and prevent HIV transmission to an HIV-negative partner when trying to conceive.²⁴

Goal 1: Prevent unintended pregnancy

Nearly half of all pregnancies in the United States are unintended.²⁵ Moreover, the Women’s Interagency HIV Study²⁶ showed that women with HIV are underusing effective contraception. In the Medical Monitoring Project, 85% of the women who had been pregnant since being diagnosed with HIV said that at least one pregnancy was unplanned.²⁷

The consequences of unintended and unplanned pregnancies are serious and add significant burden to women, men, and families. Women who do not wish to become pregnant should be advised to use an effective method of contraception.

Contraception

Contraception use varies worldwide. Factors affecting its use include the methods available, patient choice, current health conditions, religious beliefs, perception of method effectiveness, and side effects.²⁴

The Women’s Interagency HIV Study evaluated trends in contraception use from 1998 to 2010. Condoms were the most common form of contraception, and their use changed little over time. Fewer than 15% of women with HIV used no contraception. The use of long-acting reversible contraception, including injectable progestins, implants, and intrauterine devices, which minimize the need for user adherence, increased among HIV-negative women but not among HIV-positive women.²⁸

The World Health Organization states that all available methods are safe for women with HIV except for spermicides with or without a diaphragm, as there is evidence linking the use of spermicides to an increased risk of HIV transmission (Table 5).²⁹

Some antiretroviral drugs may reduce the effectiveness of some contraceptives (Table 6); however, recommendations are based on pharmacokinetic studies, not on outcome studies. Condoms should be recommended not only to protect against pregnancy, but also to protect against sexually transmitted infections.

Goal 2: Optimize maternal health before pregnancy

Maternal health should be optimized before conceiving to reduce the risk of pregnancy-related morbidities and poor birth outcomes. This includes screening for other infections and ensuring that other comorbidities, such as hypertension, diabetes, substance abuse, and mental illness, are well managed with medications that are safe to use in pregnancy (Table 7).

Goal 3: Prevent perinatal HIV transmission

Educating the patient about perinatal transmission is a fundamental component of preconception counseling. Topics that need to be addressed are transmission risk and methods to reduce the risk, including not breastfeeding after delivery.

Goal 4: Prevent HIV transmission to an uninfected partner when trying to conceive

HIV-discordant couples who desire pregnancy should receive appropriate counseling about methods to minimize risk of transmission to the uninfected partner while trying to conceive. There are a number of effective methods and techniques, which are beyond the scope of this review. Key components of all methods are to screen for and treat sexually transmitted infections in both partners and to use effective antiretroviral therapy and attain maximal viral suppression in the HIV-positive partner.

Antiretroviral therapy for the HIV-infected partner significantly reduced the risk of HIV transmission by 96% in the HIV Prevention Trials Network 052 trial.³⁰ Of note: this reduction was the result of both risk-reduction counseling and antiretroviral therapy. This was the first randomized clinical trial to demonstrate that antiretroviral therapy in those with some preserved immune function (CD4 counts 350–500 cells/mm³) in conjunction with risk-reduction counseling can reduce HIV transmission to an uninfected partner.

Vaginal insemination without intercourse is another option for female-positive couples. The man ejaculates into a condom without spermicide, and the contents are introduced with a non-needle syringe or turkey baster. This can be done at home and confers no risk to the uninfected male partner.³¹ Chances of pregnancy can be maximized by insemination during the most fertile days of the menstrual cycle.

Preexposure prophylaxis combined with timed intercourse. In a study in Switzerland, the infected male partner was given antiretroviral therapy to suppress his viral load to less than 50 copies/mL for at least 6 months, and luteinizing hormone was measured every day in the urine of the noninfected female partner. When the urinary luteinizing hormone level reached a peak, the woman received a dose of tenofovir in the morning, the couple had unprotected intercourse, and the woman took a second dose the next morning. In 53 cases, none of the female partners seroconverted for HIV.³²

Health care providers need to document and update the relationship status, partner HIV status, and fertility desires of their HIV patients, both men and women, on a regular basis. Patient education should include awareness of referrals and options to help safely conceive when desired and achieve effective contraception when not.³³

WHEN HIV-POSITIVE WOMEN BECOME PREGNANT

Screening for HIV during pregnancy

The CDC recommends prenatal screening for HIV in the first trimester or at entry into prenatal care. A repeat HIV test should be offered in the third trimester for women at risk of acquiring HIV, for women who have signs or symptoms of early HIV infection, in health care settings where prenatal testing yields at least 1 case of HIV infection per 1,000 women screened, and in areas of high HIV incidence. If women present to labor and delivery with unknown HIV status, rapid HIV testing should be done.⁹

If a woman acquires HIV during pregnancy, the infection may not be detected and may be transmitted to the infant at birth. From 2002 to 2006 in New York State, 3,396 HIV-exposed babies were born. Of these, 9 (22%) of 41 infants born to mothers who acquired HIV during pregnancy became infected, compared with 1.8% of those born to mothers who acquired HIV before pregnancy. Maternal acquisition of HIV during pregnancy was documented in only 1.3% of perinatal HIV exposures, but it was associated with 9 (13.8%) of the 65 perinatal transmission cases.³⁴

Providers should be aware of the signs and symptoms of acute HIV infection and should have a low threshold for repeating HIV testing at any time during pregnancy. It has been estimated that 40% to 90% of patients with acute HIV infection experience fever, lymphadenopathy, pharyngitis, skin rash, myalgia, arthralgia, or other symptoms.³⁵ Providers often do not recognize acute HIV infection, however, because the symptoms are similar to those of other common illnesses. Also, some individuals with the condition have no symptoms.

Antiretroviral therapy during pregnancy

In a landmark study, AIDS Clinical Trial Group 076 demonstrated that zidovudine monotherapy given during pregnancy, labor, and delivery and to the newborn reduced the risk of HIV transmission to the infant by 67%, from 25% to 8%.³⁶ Other studies demonstrated that combination therapy further decreased the risk of HIV transmission to 1% to 2%.³⁷

The US Department of Health and Human Services recommends that all HIV-positive women who are pregnant receive effective combination antiretroviral therapy regardless of CD4 count to minimize the risk of mother-to-child transmission.³⁷

The goals of HIV treatment during pregnancy are to maintain the woman’s health, restore her immune system, suppress viral replication, and decrease the risk of perinatal transmission. The preferred antiretroviral therapy for pregnant women differs from that for nonpregnant women and is based on evolving experience and information about safety, efficacy, and tolerability in pregnancy (Table 8). A woman who presents for prenatal care on a suppressive regimen should continue that regimen as long as she can tolerate it because there is a risk of losing virologic control when switching regimens, and this may increase the risk of perinatal transmission.³⁷

Physiologic changes that occur during pregnancy may alter drug disposition, which could potentially lead to decreased drug exposure. Some of the changes include an increase in total body water, decreased protein binding, induction of hepatic metabolic pathways, and increased clearance of drugs eliminated by the kidneys.³⁸ These changes may be associated with incomplete virologic suppression, virologic failure, or development of drug resistance, so altered doses of some antiretroviral drugs or careful monitoring of viral load should be considered, particularly in the second and third trimester.

Delivery

Women who have a viral load greater than 1,000 copies/mL near the end of pregnancy should undergo a cesarean delivery at 38 weeks and, before surgery, should receive intravenous zidovudine to reduce the risk of perinatal transmission. For women with viral loads below the threshold of 1,000 copies/mL, there is no proven added benefit to cesarean delivery, and in this situation it should be performed only for standard obstetric indications. Antiretroviral regimens should be continued during labor.³⁷

HIV IN OLDER ADULTS

By 2015, approximately 50% of people with HIV will be over age 50.³⁹ Unfortunately, older people and their providers often underestimate their risk of acquiring HIV. Many older people are newly single and may engage in sexual activity with new partners. Also, older people may be reluctant to use condoms as the need for contraception is past.^40,41

Baseline HIV RNA levels tend to be higher and CD4 cell counts lower in patients diagnosed with HIV at older ages. These observations support previous ones that older HIV-infected patients may have advanced HIV disease at the time of diagnosis, perhaps in part due to delayed testing.⁴² Other possible factors are limited income, comorbid illness, polypharmacy, and insufficient data on drug interactions in the elderly.^41,42

A prompt diagnosis is important for older patients because HIV may accelerate aging, and aging may speed up HIV progression. Studies have shown that aging is associated with more rapid progression to AIDS, particularly among people who are older than 40 at seroconversion.⁴³ Other studies have reported that older patients have better virologic responses to antiretroviral therapy but have a blunted immune response, more AIDS-defining events, and a higher mortality rate than younger patients.⁴²

More than 30 years into the human immunodeficiency virus (HIV) epidemic, our understanding of the needs of women living with this virus continues to evolve. In the early years of the epidemic, managing HIV was all about preventing death and treating opportunistic infections. But now it is also about enabling patients to live long, healthy, and productive lives and preventing new HIV infections. In women, these goals can only be achieved by paying careful attention to sex-specific issues.

See related editorial

As a result of longer survival, HIV-infected persons are increasingly developing common health problems that also affect the general population and that require screening, management, and monitoring by primary care providers. Because people infected with HIV are typically seen by both an HIV specialist and a primary care provider, HIV specialists need to be familiar with primary care issues and primary care providers need to be familiar with HIV care recommendations in order to provide optimal care.

AFRICAN AMERICAN WOMEN BEAR A DISPROPORTIONATE BURDEN

In the United States, HIV was first reported in women in 1983 among those who had been steady sexual partners of males with acquired immune deficiency syndrome.¹ Although men with HIV still outnumber women, the number of women with HIV has increased rapidly. At the end of 2010 an estimated one in four people with HIV in the United States was female.²

African American women bear a disproportionate burden of the disease (Table 1).³ In 2010, women accounted for an estimated 9,500 (20%) of the approximately 45,000 new infections occurring in the United States. Of these newly infected women, 64% were black, 18% were white, and 15% were Hispanic. Yet blacks make up only about 12% of the US population, whites make up 68%, and Hispanics 14%.

Regardless of race or ethnicity, unprotected heterosexual contact is the most common mode of transmission of HIV in women.²

Although the overall rates of HIV infection in the United States are relatively low, certain areas of the country have rates similar to those in sub-Saharan Africa, where most HIV-infected people reside.⁴ The HIV Prevention Trials Network found that the incidence of HIV infection in US women living in these “hot spots,” with high rates of poverty and HIV, was 0.32% per year. Compare this with the 2009 estimate of HIV incidence in the general population of US black women of similar age (0.05% per year) and the adult incidence rates in Congo (0.28% per year) and Kenya (0.53% per year).⁵ To better understand the epidemiology of HIV infection in women and concentrate our prevention efforts, we need to focus on these hot spots.

Misinformation abounds in these hot spots, as does disease. In a survey of residents of the South Side Chicago Housing Authority facilities,⁶ many were aware that effective antiretroviral therapy existed, but one-fourth thought that there was an effective HIV vaccine, and 13% thought there was a cure.

In the early years, an HIV diagnosis was essentially a death sentence. Samji et al⁷ estimated that life expectancy of patients who were prescribed antiretroviral therapy in the United States and Canada increased from 36.1 years in 2000–2002 to 51.4 years in 2006–2007, with the greatest increases in those who started with a baseline CD4 count above 350 cells/mm³. Now, a 20-year-old HIV-positive person with a CD4 count greater than 350 cells/mm³ can expect to live into his or her early 70s.

But not all patients achieve these benefits. In 2009, despite major advances in diagnosis and treatment, HIV was the fourth leading cause of death among African American women ages 25 to 44, causing about 800 deaths, or 9% of all deaths in this group.⁸

TEST ALL, UNLESS THEY OPT OUT

Testing is vital in efforts to prevent and treat HIV infection. In 2006, the US Centers for Disease Control and Prevention (CDC) recommended that everyone between the ages of 13 and 64 be screened for HIV regardless of risk.⁹

The CDC recommends an opt-out strategy.⁹ Rather than ask a patient whether he or she wants to be tested for HIV, the provider says something like, “I advise all of my patients to have an HIV test; as long as you have no objection, we will send you to the lab to have it done.” This approach reduces barriers to HIV testing by eliminating pretest counseling and by making HIV testing routine and the standard of care. Separate consent is not required—clinicians just need to document whether the patient has accepted or declined the test.

Testing should be offered at least once and can be done in any health care setting, including primary care offices and clinics, emergency rooms, health departments, and urgent care centers.⁹ Patients at higher risk (injection drug users and their sex partners; people who exchange sex for money or drugs; sex partners of HIV-infected people; men who have sex with men; and heterosexuals who themselves or whose sex partners have had more than one sex partner since their most recent HIV test) should receive repeat screening annually.

HIV testing should also be offered to all pregnant women at entry into care and again in the third trimester. This strategy is cost-effective even in areas of low prevalence.⁹ Since 2006, other professional organizations have made HIV testing recommendations as well (Table 2).^9–12

A cost-effectiveness analysis suggested that routine opt-out testing is economically justified if the prevalence of HIV is greater than 0.2%.¹³

HIV-POSITIVE WOMEN NEED ROUTINE GYNECOLOGIC CARE

It is important for women with HIV to receive routine gynecologic care. Women with HIV have gynecologic problems similar to those of all women; however, they may be more vulnerable to certain conditions such as human papillomavirus (HPV) infection, which may be related to HIV disease or associated immunosuppression. In addition, pregnancy and family planning pose special challenges in this group.¹⁴

Cervical cancer screening

Effective screening and timely treatment of precancerous cervical lesions are key in preventing cervical cancer in women with or without HIV.

Persistent infection with HPV is necessary for the development of precancerous lesions as well as invasive cervical cancer. Most new cases of HPV infection in the general population resolve spontaneously within 2 years. However, in HIV-infected women, HPV infection is more likely to persist and progress to precancerous lesions of the cervix. This association is strongest in women with more compromised immune function as reflected by low CD4 cell counts and high viral loads.¹⁴ Women with HIV have higher rates of infection with high-risk HPV strains and of cervical intraepithelial neoplasia compared with their HIV-negative counterparts.¹⁴ The incidence of cervical cancer is five to six times higher in HIV-infected women in the United States than in the general population.¹⁵

According to guidelines from the Infectious Diseases Society of America,¹⁶ the American College of Obstetricians and Gynecologists,¹⁰ the CDC,¹⁷ and the American Cancer Society,¹⁸ all HIV-infected women should undergo cervical Papanicolaou (Pap) screening upon initiation into care, and this test should be repeated at 6 months and then annually if the results are normal. Patients with abnormalities on the Pap test should undergo colposcopy and, possibly, also biopsy. These abnormalities include atypical squamous cells of unknown significance and higher-grade lesions.¹⁶

Nearly one-fourth of HIV-positive women do not receive annual Pap smears despite engagement in care.¹⁹ This is unacceptable, because half of the cases of cervical cancer diagnosed in the United States are in women who never received appropriate screening, and an additional 10% are in women who have not been screened in the previous 5 years.¹⁹

In HIV-infected women who have had a total hysterectomy, whether to continue Pap testing depends on their history before the surgery. Continued vaginal Pap smear screening is recommended after hysterectomy (including removal of the cervix) in HIV-infected women who have a history of cervical intraepithelial neoplasia grades 2 or 3 or invasive cancer.^10,17,20

TREATING HIV IN WOMEN: SPECIAL CONSIDERATIONS

Because it is not yet possible to eradicate the HIV virus, the goals of antiretroviral therapy are to reduce HIV-associated morbidity and mortality, to restore and preserve immune function, to suppress viral load, and to prevent sexual and, in women, perinatal transmission of the virus.²¹

Antiretroviral therapy is recommended for all HIV-infected patients regardless of the CD4 count, although the strength of recommendation is weaker with higher CD4 counts (Table  3).²¹ The recommendations for starting antiretroviral therapy and the goals of treatment are the same for men and women. Table 4 summarizes the recommendations for adolescents and adults who are new to treatment.²¹ For women, additional factors that should be taken into account when considering a regimen include pregnancy potential and whether the drugs chosen for the regimen are considered safe in pregnancy.

Since the early years of the HIV epidemic, researchers have debated whether women attain the same benefits from antiretroviral therapy as men. US Food and Drug Administration investigators performed a meta-analysis of the efficacy outcomes in women in studies of antiretroviral drugs published between 2000 and 2008. They included randomized clinical trials reporting at least 48-week efficacy outcomes, with viral suppression defined as HIV RNA less than 50 copies/mL. The combined database included 40 trials of 16 drugs from 7 drug classes with a total of 20,328 HIV-positive participants. Overall, there were no clinically or statistically significant differences between the sexes in 48-week efficacy outcomes or in rates of trial discontinuation due to adverse events, loss to follow-up, or death.²²

Antiretroviral therapy may, however, cause different adverse effects in women than in men. For example:

Nevirapine, a nonnucleoside reverse transcriptase inhibitor, has been associated with the development of a rash and potentially life-threatening hepatotoxicity, more commonly in women than in men and at lower CD4 counts in women. This resulted in recommendations²¹ to avoid starting a nevirapine-containing regimen in women with CD4 counts greater than 250 cells/mm³ and in men with CD4 counts greater than 400 cells/mm³.

Ritonavir has been observed to cause a higher incidence of nausea and vomiting in women and a higher incidence of diarrhea in men. These are thought to be due to differences between men and women in weight and pharmacokinetics.²³

PRECONCEPTION COUNSELING FOR HIV-POSITIVE WOMEN

Preconception counseling is an essential component of both primary and preventive care and should be considered the standard of care for all women of reproductive age who have HIV.²⁴ Health care providers who fully understand the impact of HIV infection and associated comorbidities upon a woman’s reproductive health, fertility desires, and family planning needs are better prepared to assist in their patients’ reproductive health decisions.

The first few weeks of pregnancy are the most critical period in fetal development. During this time, a woman should be healthy and avoid any activities or substances that could cause adverse maternal or fetal outcomes. However, most patients present for prenatal care after this critical time period—thus the need for preconception counseling. Both the Infectious Diseases Society of America and the HIV Medicine Association recommend that all HIV-infected women of childbearing age be asked about their pregnancy plans and desires at the start of care and routinely thereafter.¹⁶

The goals of preconception care in women with HIV are to prevent unintended pregnancy, optimize maternal health before pregnancy, optimize pregnancy outcomes for mother and fetus, prevent perinatal HIV transmission, and prevent HIV transmission to an HIV-negative partner when trying to conceive.²⁴

Goal 1: Prevent unintended pregnancy

Nearly half of all pregnancies in the United States are unintended.²⁵ Moreover, the Women’s Interagency HIV Study²⁶ showed that women with HIV are underusing effective contraception. In the Medical Monitoring Project, 85% of the women who had been pregnant since being diagnosed with HIV said that at least one pregnancy was unplanned.²⁷

The consequences of unintended and unplanned pregnancies are serious and add significant burden to women, men, and families. Women who do not wish to become pregnant should be advised to use an effective method of contraception.

Contraception

Contraception use varies worldwide. Factors affecting its use include the methods available, patient choice, current health conditions, religious beliefs, perception of method effectiveness, and side effects.²⁴

The Women’s Interagency HIV Study evaluated trends in contraception use from 1998 to 2010. Condoms were the most common form of contraception, and their use changed little over time. Fewer than 15% of women with HIV used no contraception. The use of long-acting reversible contraception, including injectable progestins, implants, and intrauterine devices, which minimize the need for user adherence, increased among HIV-negative women but not among HIV-positive women.²⁸

The World Health Organization states that all available methods are safe for women with HIV except for spermicides with or without a diaphragm, as there is evidence linking the use of spermicides to an increased risk of HIV transmission (Table 5).²⁹

Some antiretroviral drugs may reduce the effectiveness of some contraceptives (Table 6); however, recommendations are based on pharmacokinetic studies, not on outcome studies. Condoms should be recommended not only to protect against pregnancy, but also to protect against sexually transmitted infections.

Goal 2: Optimize maternal health before pregnancy

Maternal health should be optimized before conceiving to reduce the risk of pregnancy-related morbidities and poor birth outcomes. This includes screening for other infections and ensuring that other comorbidities, such as hypertension, diabetes, substance abuse, and mental illness, are well managed with medications that are safe to use in pregnancy (Table 7).

Goal 3: Prevent perinatal HIV transmission

Educating the patient about perinatal transmission is a fundamental component of preconception counseling. Topics that need to be addressed are transmission risk and methods to reduce the risk, including not breastfeeding after delivery.

Goal 4: Prevent HIV transmission to an uninfected partner when trying to conceive

HIV-discordant couples who desire pregnancy should receive appropriate counseling about methods to minimize risk of transmission to the uninfected partner while trying to conceive. There are a number of effective methods and techniques, which are beyond the scope of this review. Key components of all methods are to screen for and treat sexually transmitted infections in both partners and to use effective antiretroviral therapy and attain maximal viral suppression in the HIV-positive partner.

Antiretroviral therapy for the HIV-infected partner significantly reduced the risk of HIV transmission by 96% in the HIV Prevention Trials Network 052 trial.³⁰ Of note: this reduction was the result of both risk-reduction counseling and antiretroviral therapy. This was the first randomized clinical trial to demonstrate that antiretroviral therapy in those with some preserved immune function (CD4 counts 350–500 cells/mm³) in conjunction with risk-reduction counseling can reduce HIV transmission to an uninfected partner.

Vaginal insemination without intercourse is another option for female-positive couples. The man ejaculates into a condom without spermicide, and the contents are introduced with a non-needle syringe or turkey baster. This can be done at home and confers no risk to the uninfected male partner.³¹ Chances of pregnancy can be maximized by insemination during the most fertile days of the menstrual cycle.

Preexposure prophylaxis combined with timed intercourse. In a study in Switzerland, the infected male partner was given antiretroviral therapy to suppress his viral load to less than 50 copies/mL for at least 6 months, and luteinizing hormone was measured every day in the urine of the noninfected female partner. When the urinary luteinizing hormone level reached a peak, the woman received a dose of tenofovir in the morning, the couple had unprotected intercourse, and the woman took a second dose the next morning. In 53 cases, none of the female partners seroconverted for HIV.³²

Health care providers need to document and update the relationship status, partner HIV status, and fertility desires of their HIV patients, both men and women, on a regular basis. Patient education should include awareness of referrals and options to help safely conceive when desired and achieve effective contraception when not.³³

WHEN HIV-POSITIVE WOMEN BECOME PREGNANT

Screening for HIV during pregnancy

The CDC recommends prenatal screening for HIV in the first trimester or at entry into prenatal care. A repeat HIV test should be offered in the third trimester for women at risk of acquiring HIV, for women who have signs or symptoms of early HIV infection, in health care settings where prenatal testing yields at least 1 case of HIV infection per 1,000 women screened, and in areas of high HIV incidence. If women present to labor and delivery with unknown HIV status, rapid HIV testing should be done.⁹

If a woman acquires HIV during pregnancy, the infection may not be detected and may be transmitted to the infant at birth. From 2002 to 2006 in New York State, 3,396 HIV-exposed babies were born. Of these, 9 (22%) of 41 infants born to mothers who acquired HIV during pregnancy became infected, compared with 1.8% of those born to mothers who acquired HIV before pregnancy. Maternal acquisition of HIV during pregnancy was documented in only 1.3% of perinatal HIV exposures, but it was associated with 9 (13.8%) of the 65 perinatal transmission cases.³⁴

Providers should be aware of the signs and symptoms of acute HIV infection and should have a low threshold for repeating HIV testing at any time during pregnancy. It has been estimated that 40% to 90% of patients with acute HIV infection experience fever, lymphadenopathy, pharyngitis, skin rash, myalgia, arthralgia, or other symptoms.³⁵ Providers often do not recognize acute HIV infection, however, because the symptoms are similar to those of other common illnesses. Also, some individuals with the condition have no symptoms.

Antiretroviral therapy during pregnancy

In a landmark study, AIDS Clinical Trial Group 076 demonstrated that zidovudine monotherapy given during pregnancy, labor, and delivery and to the newborn reduced the risk of HIV transmission to the infant by 67%, from 25% to 8%.³⁶ Other studies demonstrated that combination therapy further decreased the risk of HIV transmission to 1% to 2%.³⁷

The US Department of Health and Human Services recommends that all HIV-positive women who are pregnant receive effective combination antiretroviral therapy regardless of CD4 count to minimize the risk of mother-to-child transmission.³⁷

The goals of HIV treatment during pregnancy are to maintain the woman’s health, restore her immune system, suppress viral replication, and decrease the risk of perinatal transmission. The preferred antiretroviral therapy for pregnant women differs from that for nonpregnant women and is based on evolving experience and information about safety, efficacy, and tolerability in pregnancy (Table 8). A woman who presents for prenatal care on a suppressive regimen should continue that regimen as long as she can tolerate it because there is a risk of losing virologic control when switching regimens, and this may increase the risk of perinatal transmission.³⁷

Physiologic changes that occur during pregnancy may alter drug disposition, which could potentially lead to decreased drug exposure. Some of the changes include an increase in total body water, decreased protein binding, induction of hepatic metabolic pathways, and increased clearance of drugs eliminated by the kidneys.³⁸ These changes may be associated with incomplete virologic suppression, virologic failure, or development of drug resistance, so altered doses of some antiretroviral drugs or careful monitoring of viral load should be considered, particularly in the second and third trimester.

Delivery

Women who have a viral load greater than 1,000 copies/mL near the end of pregnancy should undergo a cesarean delivery at 38 weeks and, before surgery, should receive intravenous zidovudine to reduce the risk of perinatal transmission. For women with viral loads below the threshold of 1,000 copies/mL, there is no proven added benefit to cesarean delivery, and in this situation it should be performed only for standard obstetric indications. Antiretroviral regimens should be continued during labor.³⁷

HIV IN OLDER ADULTS

By 2015, approximately 50% of people with HIV will be over age 50.³⁹ Unfortunately, older people and their providers often underestimate their risk of acquiring HIV. Many older people are newly single and may engage in sexual activity with new partners. Also, older people may be reluctant to use condoms as the need for contraception is past.^40,41

Baseline HIV RNA levels tend to be higher and CD4 cell counts lower in patients diagnosed with HIV at older ages. These observations support previous ones that older HIV-infected patients may have advanced HIV disease at the time of diagnosis, perhaps in part due to delayed testing.⁴² Other possible factors are limited income, comorbid illness, polypharmacy, and insufficient data on drug interactions in the elderly.^41,42

A prompt diagnosis is important for older patients because HIV may accelerate aging, and aging may speed up HIV progression. Studies have shown that aging is associated with more rapid progression to AIDS, particularly among people who are older than 40 at seroconversion.⁴³ Other studies have reported that older patients have better virologic responses to antiretroviral therapy but have a blunted immune response, more AIDS-defining events, and a higher mortality rate than younger patients.⁴²

In this issue of the Cleveland Clinic Journal of Medicine, Drs. Short and Anderson give an overview of the epidemic of human immunodeficiency virus (HIV) infection in US women and the various aspects of health care of this group, including pregnancy.¹ They introduce a much broader topic and bring to light a number of additional concerns.

HIV PREYS ON THE VULNERABLE

The authors review epidemiologic trends and the evolving demographics of HIV, which deserve specific discussion.

See related article

In the early years of the epidemic, ie, the early 1980s, HIV infection in women was overshadowed by the epidemic in men, particularly men who have sex with men. The epidemic in men who have sex with men remains the larger component of the HIV picture in the United States. But worldwide, HIV is an evenly balanced problem, with nearly half of all infections occurring in women.² Women have received much more attention recently.

In the United States, about 300,000 women are living with HIV, and 10% of them are unaware of it. Between 1985 and 2013, the number of HIV cases in US women tripled.

The epidemic continues to disproportionately affect women of color. Two-thirds of all women with HIV are African American,² and estimates suggest that 1 of every 32 African American women will acquire HIV during her lifetime. On a positive note, there was a 20% reduction in new infections among African American women between 2008 and 2010.³

The epidemic preys on the vulnerable and is fueled by poverty, lack of education (general and health literacy), substance abuse, and restricted access to health care. Major metropolitan areas such as New York, Washington, DC, Miami, and Los Angeles are “hot spots,” where high concentrations of infected people reside.⁴

Many women underestimate or do not perceive their susceptibility. They unknowingly acquire HIV infection from their male partners, many of whom are unaware of their infection. Some of their partners may lead a dual life of bisexuality. In some areas, an estimated 20% of men who have sex with men also engage in sex with women.⁵ If these women contract the disease, they may be diagnosed at a late stage and when they are symptomatic, or coincidentally during pregnancy and childbirth.

Negotiating safe sex practices can be difficult for a woman. She may perceive or lack empowerment to do so, fearing rejection, isolation, or violence. Sexual violence may have been initiated in childhood, through intimate partners, rape, sex trafficking, or prostitution. Patterns vary throughout the world, but sexual violence is more common than perceived.⁶ Because of shame, embarrassment, and isolation, many victims do not seek medical care and so may carry undiagnosed infections. Even when they access care, they are less likely to remain in the HIV care system.⁷ Greater efforts are needed to reach these women, make them feel supported in care, and keep them in the system.

TESTING IS CRUCIAL

Diagnosis remains a weak link in the chain of care for both men and women. Success has been noted in the form of a marked reduction in cases of mother-to-child transmission, thanks to near-universal opt-out screening during pregnancy or at delivery.

If appropriate routine testing were done for all people, as advocated by the US Centers for Disease Control and Prevention guidelines,⁸ more cases could be diagnosed, behaviors changed, and treatment offered. Control of HIV through treatment can lead to a 96% reduction in transmission between serodiscordant partners, as demonstrated in HPTN 052, an ongoing phase 3 trial.⁹ Early diagnosis and treatment offer the potential for improved immune regeneration and healthier lives.

PRE-EXPOSURE PROPHYLAXIS

Pre-exposure prophylaxis (PrEP) is one approach to empowering women and preventing HIV infection. Studies have demonstrated the efficacy of this approach, although some studies have not.^10,11

An important finding in the failed studies appeared to be a lack of adherence to the regimen.¹¹ Unless taken faithfully, PrEP will not succeed. Additionally, there may be inherent differences in outcomes for unknown reasons. Lack of access to the necessary two-drug combination regimen is another barrier.

PrEP is expensive, requires regular monitoring, and requires patients to remain engaged in medical care. Currently, not all medical programs offer PrEP, and not all insurance policies cover it. Further insight into long-term side effects and complications is needed.

Although PrEP is an attractive concept and a reality for some, it is an incomplete solution to prevention at this time.

MEN AND WOMEN ARE DIFFERENT

Men and women are different physiologically and psychologically. Women typically have a lower body mass, lower bone mass, and higher content of body fat. As a result, women may differ from men in their ability to tolerate medications, and long-term side effects may be more pronounced.

Women are also more likely to place family responsibilities above self-preservation and personal health concerns. As a result, providing for and taking care of their children takes precedence over care of their own health.

Providing care to women presents many challenges and opportunities to improve their health. Health care access, transportation, assistance with child care during medical visits, the availability of counseling to deal with shame, guilt, and depression, and maintaining women within the care system are but a few examples.

AGING WITH HIV: STUDY NEEDED

Antiretroviral therapy has enabled patients to survive and often to reach a normal life expectancy if the infection is diagnosed and treated early. As a result, HIV-associated causes of death have been replaced by non-HIV comorbidities typical of aging, such as cardiovascular disease, organ failure (heart, lung, kidney, liver), non-HIV cancers, and bone disease.

Women face unique aspects of aging with menopause, including an accelerated rate of bone loss resulting in osteoporosis. HIV itself and some antiretroviral drugs may increase the loss of bone mineral density. Alcohol abuse, sedentary lifestyle, smoking, hepatitis C co-infection, and poor nutrition also contribute to this problem. Bone disease and many other aspects of aging and HIV in women require more research and intervention.

Other areas that need to be studied are the unique mucosal immune system of the female genital tract, the interplay of sex hormones and the immune system, the role of genital tract inflammation in increasing the risk of HIV acquisition, sexual violence and HIV acquisition, and the safety and efficacy of PrEP for women. This will require prioritization and ongoing funding, which is becoming scarcer. If there is to be hope of containing this disease, our efforts to understand it must not diminish.

In this issue of the Cleveland Clinic Journal of Medicine, Drs. Short and Anderson give an overview of the epidemic of human immunodeficiency virus (HIV) infection in US women and the various aspects of health care of this group, including pregnancy.¹ They introduce a much broader topic and bring to light a number of additional concerns.

HIV PREYS ON THE VULNERABLE

The authors review epidemiologic trends and the evolving demographics of HIV, which deserve specific discussion.

See related article

In the early years of the epidemic, ie, the early 1980s, HIV infection in women was overshadowed by the epidemic in men, particularly men who have sex with men. The epidemic in men who have sex with men remains the larger component of the HIV picture in the United States. But worldwide, HIV is an evenly balanced problem, with nearly half of all infections occurring in women.² Women have received much more attention recently.

In the United States, about 300,000 women are living with HIV, and 10% of them are unaware of it. Between 1985 and 2013, the number of HIV cases in US women tripled.

The epidemic continues to disproportionately affect women of color. Two-thirds of all women with HIV are African American,² and estimates suggest that 1 of every 32 African American women will acquire HIV during her lifetime. On a positive note, there was a 20% reduction in new infections among African American women between 2008 and 2010.³

The epidemic preys on the vulnerable and is fueled by poverty, lack of education (general and health literacy), substance abuse, and restricted access to health care. Major metropolitan areas such as New York, Washington, DC, Miami, and Los Angeles are “hot spots,” where high concentrations of infected people reside.⁴

Many women underestimate or do not perceive their susceptibility. They unknowingly acquire HIV infection from their male partners, many of whom are unaware of their infection. Some of their partners may lead a dual life of bisexuality. In some areas, an estimated 20% of men who have sex with men also engage in sex with women.⁵ If these women contract the disease, they may be diagnosed at a late stage and when they are symptomatic, or coincidentally during pregnancy and childbirth.

Negotiating safe sex practices can be difficult for a woman. She may perceive or lack empowerment to do so, fearing rejection, isolation, or violence. Sexual violence may have been initiated in childhood, through intimate partners, rape, sex trafficking, or prostitution. Patterns vary throughout the world, but sexual violence is more common than perceived.⁶ Because of shame, embarrassment, and isolation, many victims do not seek medical care and so may carry undiagnosed infections. Even when they access care, they are less likely to remain in the HIV care system.⁷ Greater efforts are needed to reach these women, make them feel supported in care, and keep them in the system.

TESTING IS CRUCIAL

Diagnosis remains a weak link in the chain of care for both men and women. Success has been noted in the form of a marked reduction in cases of mother-to-child transmission, thanks to near-universal opt-out screening during pregnancy or at delivery.

If appropriate routine testing were done for all people, as advocated by the US Centers for Disease Control and Prevention guidelines,⁸ more cases could be diagnosed, behaviors changed, and treatment offered. Control of HIV through treatment can lead to a 96% reduction in transmission between serodiscordant partners, as demonstrated in HPTN 052, an ongoing phase 3 trial.⁹ Early diagnosis and treatment offer the potential for improved immune regeneration and healthier lives.

PRE-EXPOSURE PROPHYLAXIS

Pre-exposure prophylaxis (PrEP) is one approach to empowering women and preventing HIV infection. Studies have demonstrated the efficacy of this approach, although some studies have not.^10,11

An important finding in the failed studies appeared to be a lack of adherence to the regimen.¹¹ Unless taken faithfully, PrEP will not succeed. Additionally, there may be inherent differences in outcomes for unknown reasons. Lack of access to the necessary two-drug combination regimen is another barrier.

PrEP is expensive, requires regular monitoring, and requires patients to remain engaged in medical care. Currently, not all medical programs offer PrEP, and not all insurance policies cover it. Further insight into long-term side effects and complications is needed.

Although PrEP is an attractive concept and a reality for some, it is an incomplete solution to prevention at this time.

MEN AND WOMEN ARE DIFFERENT

Men and women are different physiologically and psychologically. Women typically have a lower body mass, lower bone mass, and higher content of body fat. As a result, women may differ from men in their ability to tolerate medications, and long-term side effects may be more pronounced.

Women are also more likely to place family responsibilities above self-preservation and personal health concerns. As a result, providing for and taking care of their children takes precedence over care of their own health.

Providing care to women presents many challenges and opportunities to improve their health. Health care access, transportation, assistance with child care during medical visits, the availability of counseling to deal with shame, guilt, and depression, and maintaining women within the care system are but a few examples.

AGING WITH HIV: STUDY NEEDED

Antiretroviral therapy has enabled patients to survive and often to reach a normal life expectancy if the infection is diagnosed and treated early. As a result, HIV-associated causes of death have been replaced by non-HIV comorbidities typical of aging, such as cardiovascular disease, organ failure (heart, lung, kidney, liver), non-HIV cancers, and bone disease.

Women face unique aspects of aging with menopause, including an accelerated rate of bone loss resulting in osteoporosis. HIV itself and some antiretroviral drugs may increase the loss of bone mineral density. Alcohol abuse, sedentary lifestyle, smoking, hepatitis C co-infection, and poor nutrition also contribute to this problem. Bone disease and many other aspects of aging and HIV in women require more research and intervention.

Other areas that need to be studied are the unique mucosal immune system of the female genital tract, the interplay of sex hormones and the immune system, the role of genital tract inflammation in increasing the risk of HIV acquisition, sexual violence and HIV acquisition, and the safety and efficacy of PrEP for women. This will require prioritization and ongoing funding, which is becoming scarcer. If there is to be hope of containing this disease, our efforts to understand it must not diminish.

In this issue of the Cleveland Clinic Journal of Medicine, Drs. Short and Anderson give an overview of the epidemic of human immunodeficiency virus (HIV) infection in US women and the various aspects of health care of this group, including pregnancy.¹ They introduce a much broader topic and bring to light a number of additional concerns.

HIV PREYS ON THE VULNERABLE

The authors review epidemiologic trends and the evolving demographics of HIV, which deserve specific discussion.

See related article

In the early years of the epidemic, ie, the early 1980s, HIV infection in women was overshadowed by the epidemic in men, particularly men who have sex with men. The epidemic in men who have sex with men remains the larger component of the HIV picture in the United States. But worldwide, HIV is an evenly balanced problem, with nearly half of all infections occurring in women.² Women have received much more attention recently.

In the United States, about 300,000 women are living with HIV, and 10% of them are unaware of it. Between 1985 and 2013, the number of HIV cases in US women tripled.

The epidemic continues to disproportionately affect women of color. Two-thirds of all women with HIV are African American,² and estimates suggest that 1 of every 32 African American women will acquire HIV during her lifetime. On a positive note, there was a 20% reduction in new infections among African American women between 2008 and 2010.³

The epidemic preys on the vulnerable and is fueled by poverty, lack of education (general and health literacy), substance abuse, and restricted access to health care. Major metropolitan areas such as New York, Washington, DC, Miami, and Los Angeles are “hot spots,” where high concentrations of infected people reside.⁴

Many women underestimate or do not perceive their susceptibility. They unknowingly acquire HIV infection from their male partners, many of whom are unaware of their infection. Some of their partners may lead a dual life of bisexuality. In some areas, an estimated 20% of men who have sex with men also engage in sex with women.⁵ If these women contract the disease, they may be diagnosed at a late stage and when they are symptomatic, or coincidentally during pregnancy and childbirth.

Negotiating safe sex practices can be difficult for a woman. She may perceive or lack empowerment to do so, fearing rejection, isolation, or violence. Sexual violence may have been initiated in childhood, through intimate partners, rape, sex trafficking, or prostitution. Patterns vary throughout the world, but sexual violence is more common than perceived.⁶ Because of shame, embarrassment, and isolation, many victims do not seek medical care and so may carry undiagnosed infections. Even when they access care, they are less likely to remain in the HIV care system.⁷ Greater efforts are needed to reach these women, make them feel supported in care, and keep them in the system.

TESTING IS CRUCIAL

Diagnosis remains a weak link in the chain of care for both men and women. Success has been noted in the form of a marked reduction in cases of mother-to-child transmission, thanks to near-universal opt-out screening during pregnancy or at delivery.

If appropriate routine testing were done for all people, as advocated by the US Centers for Disease Control and Prevention guidelines,⁸ more cases could be diagnosed, behaviors changed, and treatment offered. Control of HIV through treatment can lead to a 96% reduction in transmission between serodiscordant partners, as demonstrated in HPTN 052, an ongoing phase 3 trial.⁹ Early diagnosis and treatment offer the potential for improved immune regeneration and healthier lives.

PRE-EXPOSURE PROPHYLAXIS

Pre-exposure prophylaxis (PrEP) is one approach to empowering women and preventing HIV infection. Studies have demonstrated the efficacy of this approach, although some studies have not.^10,11

An important finding in the failed studies appeared to be a lack of adherence to the regimen.¹¹ Unless taken faithfully, PrEP will not succeed. Additionally, there may be inherent differences in outcomes for unknown reasons. Lack of access to the necessary two-drug combination regimen is another barrier.

PrEP is expensive, requires regular monitoring, and requires patients to remain engaged in medical care. Currently, not all medical programs offer PrEP, and not all insurance policies cover it. Further insight into long-term side effects and complications is needed.

Although PrEP is an attractive concept and a reality for some, it is an incomplete solution to prevention at this time.

MEN AND WOMEN ARE DIFFERENT

Men and women are different physiologically and psychologically. Women typically have a lower body mass, lower bone mass, and higher content of body fat. As a result, women may differ from men in their ability to tolerate medications, and long-term side effects may be more pronounced.

Women are also more likely to place family responsibilities above self-preservation and personal health concerns. As a result, providing for and taking care of their children takes precedence over care of their own health.

Providing care to women presents many challenges and opportunities to improve their health. Health care access, transportation, assistance with child care during medical visits, the availability of counseling to deal with shame, guilt, and depression, and maintaining women within the care system are but a few examples.

AGING WITH HIV: STUDY NEEDED

Antiretroviral therapy has enabled patients to survive and often to reach a normal life expectancy if the infection is diagnosed and treated early. As a result, HIV-associated causes of death have been replaced by non-HIV comorbidities typical of aging, such as cardiovascular disease, organ failure (heart, lung, kidney, liver), non-HIV cancers, and bone disease.

Women face unique aspects of aging with menopause, including an accelerated rate of bone loss resulting in osteoporosis. HIV itself and some antiretroviral drugs may increase the loss of bone mineral density. Alcohol abuse, sedentary lifestyle, smoking, hepatitis C co-infection, and poor nutrition also contribute to this problem. Bone disease and many other aspects of aging and HIV in women require more research and intervention.

Other areas that need to be studied are the unique mucosal immune system of the female genital tract, the interplay of sex hormones and the immune system, the role of genital tract inflammation in increasing the risk of HIV acquisition, sexual violence and HIV acquisition, and the safety and efficacy of PrEP for women. This will require prioritization and ongoing funding, which is becoming scarcer. If there is to be hope of containing this disease, our efforts to understand it must not diminish.

Continued progress in understanding the pathophysiology of acute respiratory distress syndrome (ARDS) is translating into changes in the way we diagnose and manage it. Over the past 20 years, low tidal volume,¹ positive end-expiratory pressure (PEEP),² and fluid restriction³ have become the standard of care. A multidisciplinary approach, including targeted use of sedatives, early mobilization, and protocols for weaning from the ventilator, has also brought about substantial changes in ARDS management and its outcomes.^4–6

In this article, we review the most relevant articles about ARDS in the last 5 years. We include the new definition of ARDS and studies of ventilatory and nonventilatory therapies that have implications in managing patients with ARDS.

A STANDARDIZED APPROACH

ARDS is characterized by damage to the alveolar architecture, severe hypoxemia, and bilateral parenchymal opacities.

The working definition of ARDS developed in 1994 by the American-European Consensus Conference (AECC) was the basis for enrollment in most of the landmark trials and observational studies over the past 20 years.^7,8 However, it was limited in its reliability and validity.

An updated definition

In 2011, the ARDS Definition Task Force, using a novel consensus process, updated the ARDS definition,⁹ focusing on its feasibility, reliability, and validity in predicting response to therapies and outcomes in ARDS. This new “Berlin” definition is not substantially different from the old, but defines the criteria more specifically:

• Bilateral opacities, unexplained by nodules, atelectasis, or effusion, on chest radiography or computed tomography
• New or worsening respiratory symptoms, or a clinical insult associated with ARDS within 7 days of diagnosis
• Objective assessment of cardiac function (eg, with echocardiography) to exclude cardiogenic pulmonary edema
• Hypoxemia, with a partial pressure of arterial oxygen divided by the percentage of inspired oxygen (PaO₂/FiO₂ ratio) of 300 mm Hg or less despite noninvasive or invasive mechanical ventilation with PEEP or continuous positive airway pressure (CPAP) of at least 5 cm H₂O.

In addition, the new definition classifies the severity of disease on the basis of the degree of hypoxemia, ie, the PaO₂/FiO₂ ratio:

• Mild: PaO₂/FiO₂ ratio > 200 and ≤ 300 mm Hg
• Moderate: PaO₂/FiO₂ ratio > 100 and ≤ 200 mm Hg
• Severe: PaO₂/FiO₂ ratio ≤ 100 mm Hg.

The term “acute lung injury” has been eliminated, as has the previous criterion of a pulmonary artery wedge pressure of 18 mm Hg or less.

The panel also evaluated four ancillary variables for predicting outcomes in severe ARDS:

• Compliance of the respiratory system less than or equal to 40 mL/cm H₂O
• Radiographic severity (involvement of three or four quadrants on chest radiography)
• PEEP of 10 cm H₂O or greater
• Corrected expired volume 10 L/min or greater.

The task force evaluated the reliability and validity of this definition in a meta-analysis of 4,400 patients previously enrolled in randomized controlled trials or observational studies.

Findings. The Berlin definition predicted the risk of death better than the AECC definition. The mortality rate increased with the severity of ARDS, from 27% with mild disease to 32% with moderate disease to 45% with severe disease. The four ancillary variables did not contribute to the predictive validity of severe ARDS for mortality and were removed from the definition.

Thille et al¹⁰ retrospectively reviewed autopsy findings from 712 patients and found that the new definition identified a homogeneous group who had severe ARDS.¹⁰

Conclusions. The new definition may overcome some of the limitations of the old one, but it needs to be validated in clinical practice, especially its ability to predict death.

VENTILATORY SUPPORT

Prompt recognition, lung-protective ventilation, and a conservative fluid strategy remain the cornerstones of ARDS management. However, other strategies are being tested.

Prone-position ventilation in severe ARDS: The right therapy in a specific population

Prone-position ventilation was first described almost 30 years ago, but it has been used inconsistently in clinical practice.

Physiologic and observational studies indicated that prone positioning might improve survival in patients with ARDS, but several randomized trials failed to demonstrate any positive effect on outcomes.^11,12 Some trials also reported a higher rate of complications with this intervention.¹³ However, meta-analyses suggested that prone-position ventilation might have a beneficial effect in patients with severe ARDS (defined as a PaO₂/FiO₂ ratio ≤ 100 mm Hg).¹⁴

In view of these findings, investigators conducted a trial of prone-position ventilation exclusively in patients with severe ARDS.

The PROSEVA study

The Proning Severe ARDS Patients (PROSEVA) study was a randomized controlled trial designed to determine whether prone-position ventilation, applied early, would improve outcomes in patients with severe ARDS.¹⁵

In PROSEVA, 466 patients with severe ARDS (defined as a PaO₂/FiO₂ ratio < 150 mm Hg, FiO₂ ≥ 60%, and PEEP ≥ 5 cm H₂O) underwent either at least 16 hours of prone positioning or were left in the supine position after 12 to 24 hours of initial conventional mechanical ventilation. The patients were recruited from centers in France and Spain where prone-position ventilation had been used in daily practice for more than 5 years.

The primary outcome studied was the rate of death at 28 days. The secondary end points were the death rate at day 90, rates of successful extubation, the length of stay in the intensive care unit, and complications.

Findings. At study entry, the patients in the supine group were sicker, more of them required a vasopressor, and fewer of them were receiving neuromuscular blocking agents than those in the prone group. These baseline differences may have influenced the outcomes; the unadjusted 28-day mortality rate was 16.0% in the prone group compared with 32.8% in the supine group (P < .001). However, the hazard ratio for death with prone positioning was 0.39 (95% confidence interval [CI] 0.25–0.63) even after adjusting for severity and the use of vasopressors and neuromuscular blocking agents. Prone-position ventilation was not associated with a higher incidence of complications, and the rate of successful extubation was higher.

Conclusions. In patients with severe ARDS, early use of prolonged prone positioning significantly decreased the 28-day and 90-day mortality rates. This trial has made prone positioning one of the strategies in managing patients with early severe ARDS. To minimize complications such as pressure ulcers and line or tube dislodgement, personnel caring for these patients must follow a protocol and undergo specific training.

These results were corroborated by a meta-analysis by Beitler et al¹⁶ that found a significant decrease in mortality rate with prone-position ventilation even in older studies when lung-protective ventilation strategies were separated from high-tidal-volume ventilation.

High-frequency oscillatory ventilation: No benefit in two trials

Observational data and experimental studies suggested that high-frequency oscillatory ventilation (HFOV) is superior to conventional mechanical ventilation in ARDS patients.^17,18 However, outdated and cumbersome equipment, lack of protocols, and a lack of high-quality evidence led to limited and inconsistent use of HFOV, mainly as a rescue therapy in ARDS.¹⁹

Over the last few years, HFOV has been gaining acceptance, especially earlier in the course of ARDS.²⁰ After preliminary clinical trials reported promising results, two trials conducted in Canada and the United Kingdom compared HFOV vs conventional mechanical ventilation in patients with ARDS.

The OSCAR study

The Oscillation in ARDS (OSCAR) study²¹ was a “pragmatic” trial²² (ie, it had minimal exclusion criteria) of the safety and effectiveness of HFOV as a primary ventilatory strategy for ARDS. It included 795 patients randomized to receive conventional ventilation (n = 397) or HFOV (n = 398). Research centers followed detailed algorithms for HFOV management and adopted their usual practice for conventional ventilation. Medical care was given according to the clinician’s judgment.

The primary outcome studied was survival at 30 days. The secondary outcomes were all-cause mortality in the intensive care unit and the hospital, duration of mechanical ventilation, and use of antimicrobial, sedative, vasoactive, and neuromuscular-blocking drugs.

Findings. The patient baseline characteristics were similar in both groups.

There was no significant difference in intensive care unit mortality rates, hospital mortality rates, or mortality rates at 30 days (41.7% in the HFOV group vs 41.1% in the conventional ventilation group; P = .85, 95% CI 6.1–7.5) even after adjustments for center or severity of illness.

The duration of mechanical ventilation was similar in both groups (14.9 ± 13.3 days in the HFOV group vs 14.1 ± 13.4 days in the conventional ventilation group, P = .41). However, sedatives and neuromuscular-blocking drugs were used more often and longer in the HFOV group than in the conventional ventilation group. There was no difference in the use of vasoactive or antimicrobial medications.

Conclusions. This multicenter randomized control trial did not demonstrate any benefit from using HFOV for routine management of ARDS. Its pragmatic design made it less likely to reach a firm conclusion,²² but it at least made a case against routinely using HFOV in patients with ARDS.

The OSCILLATE study

The Oscillation for Acute Respiratory Distress Syndrome Treated Early (OSCILLATE) study²³ assessed the safety and efficacy of HFOV as a treatment for early-onset moderate-to-severe ARDS.

The inclusion criteria were similar to those in the OSCAR trial except that pulmonary symptoms had to be present less than 2 weeks and ARDS assessment was done under standard ventilator settings. As this was an efficacy trial, it had more exclusion criteria than the OSCAR trial. A total of 548 patients were randomized to receive conventional ventilation (n = 273) or HFOV (n = 275). The baseline characteristics were similar between groups.

Conventional ventilation was given according to a protocol used in an earlier trial² and included recruitment maneuvers. HFOV was given in centers that had experience in this treatment, and there were protocols for ventilation management, hemodynamic optimization, and weaning. All other care was left to the clinician’s choice.

The primary outcome studied was in-hospital mortality. The investigators also evaluated whether there were interactions between the treatment and baseline severity of lung injury and center experience with HFOV.

Findings. The trial was stopped after an interim analysis found that HFOV might be harmful, although the statistical threshold for stopping was not reached. The in-hospital mortality rate was 47% in the HFOV group and 35% in the control group (relative risk of death with HFOV 1.33, 95% CI 1.09–1.64, P = .005). HFOV was worse than conventional ventilation regardless of the severity of disease or center experience. The HFOV group had higher mean airway pressures but similar FiO₂ compared with the conventional ventilation group.

The HFOV group received significantly more vasopressors, sedatives, and neuromuscular blockers. This group’s fluid balance was higher as well, but not significantly so. Refractory hypoxemia (defined as PaO₂ < 60 mm Hg for 1 hour with an FiO₂ of 1.0 and neuromuscular blockade) was more frequent in the conventional ventilation group, but the number of deaths in the subgroup with refractory hypoxemia was similar with either treatment.

Conclusions. This multicenter randomized controlled trial demonstrated that HFOV was harmful when used routinely to manage ARDS. The trial’s protocol was based on the results of a pilot study carried out by the same investigators, which provided the best evidence available regarding the safety of HFOV at that time.

The results of the OSCAR and OSCILLATE trials have quelled enthusiasm for early, routine use of HFOV in ARDS. Although there are concerns that the protocol (ie, the way HFOV was implemented) rather than HFOV itself may have led to worse outcomes, there is no signal to support its routine use. We need further studies to define if it remains a viable rescue therapy.

Extracorporeal membrane oxygenation: Is it a viable option in severe ARDS?

Extracorporeal membrane oxygenation (ECMO) uses cardiopulmonary bypass technology to provide gas exchange. In patients with severe hypoxemia, ECMO can ensure adequate oxygenation and ventilation while ensuring the optimization of lung-protective ventilation. But ECMO was never as successful in adults with ARDS as it was in children and neonates.²⁴

The first two trials of ECMO in ARDS^24,25 reported equal or worse survival rates compared with conventional ventilation, and the overall mortality rate in these studies was staggeringly high. However, these studies were carried out before the era of lung-protective ventilation and at a time when ECMO technology was relatively primitive.

With new technology such as venovenous circuits and smaller cannulas, ECMO has gained more acceptance. It was used in patients with severe or refractory hypoxemia associated with ARDS during the H1N1 pandemic.^26,27

The CESAR trial

The Conventional Ventilatory Support Versus Extracorporeal Membrane Oxygenation for Severe Adult Respiratory Failure (CESAR) trial²⁸ assessed the safety, clinical efficacy, and cost-effectiveness of ECMO in managing severe ARDS. It compared best standard practice vs a protocol that included ECMO. The trial was conducted from 2001 to 2006.

Patients with severe ARDS, as defined by a Murray score²⁹ greater than 3 or uncompensated hypercapnea, were prospectively randomized and recruited from an ECMO center and 148 tertiary intensive care units and referral hospitals in England. This was a pragmatic trial, with minimal exclusion criteria (essentially, mechanical ventilation with high pressures and high FiO₂ for more than 7 days, intracranial bleeding, or contraindication to heparinization).

A total of 180 patients were randomized in a one-to-one ratio to receive ECMO or conventional management. The ventilator management in the conventional treatment group was not done according to a protocol but in general was low-volume and low-pressure. All patients randomized to ECMO were transferred to the ECMO center and treated according to a standardized ventilation protocol. After 12 hours, if predefined goals were not reached, venovenous ECMO was started. Patients assigned to conventional management could not cross over to ECMO.

The primary outcomes were death or severe disability at 6 months after randomization, and cost-effectiveness. The secondary outcomes were hospital resource use (eg, rescue techniques, length of stay, duration of ECMO) and health status after 6 months.

Findings. The groups were similar at baseline. Sixty-eight (75%) of the 90 patients randomized to receive ECMO actually received it. Of the 22 patients who did not receive ECMO, 16 (18% of the 90) improved on conventional therapy, 5 (6%) died during or before transfer, and 1 could not receive heparin.

Two patients had severe complications in the ECMO group: one had an arterial puncture, and one had an oxygen delivery failure during transport. In each case, these events contributed to the death of the patient.

More patients in the ECMO group received lung-protective ventilation, 84 (93%) vs 63 (70%).

The primary outcome, ie, death or severe disability at 6 months, occurred in 33 (37%) of the 90 patients in the ECMO group and in 46 (53%) of the patients in the conventional management group (relative risk 0.69, 95% CI 0.05–0.97, P = .03). More patients in the ECMO group survived, but the difference was not statistically significant (relative risk of death 0.73, 95% CI 0.52–1.03, P = .07). The most common cause of death in the ECMO group was multiorgan failure (42%), whereas in the conventional management group, the most common cause of death was respiratory failure (60%).

Length of stay in the hospital and in the critical care unit and health care costs were double for patients in the ECMO group. There was no difference in quality-of-life markers at 6 months in the survivors.

Conclusions. This pragmatic trial demonstrated that a protocol that includes ECMO could improve survival rates in ARDS.

Of note, the ECMO group got care in regional centers that used protocols. Therefore, in interpreting the results of this trial, we have to consider that being in a center with protocol-specified care for ARDS could drive some of the difference in mortality rates.

Regardless, this trial demonstrated that ECMO is feasible and led to better outcomes than expected. The findings were encouraging, and spurred the use of ECMO in severe ARDS during the 2009 H1N1 pandemic. Two propensity-matched studies and a number of case series reported a survival benefit associated with the use of ECMO in patients with severe ARDS.^27,30

A recent meta-analysis also reported that ECMO might lower the mortality rate in ARDS; however, the patients in the H1N1 pandemic were younger and usually had isolated respiratory failure.³¹

The success of ECMO has opened new possibilities in the management of ARDS. As the technology improves and our experience increases, ECMO will likely gain more acceptance as a treatment for severe ARDS.

Airway pressure release ventilation

The use of airway pressure release ventilation and other ventilator modalities in ARDS is not supported by current evidence, though results of clinical trials may influence our practice in the future.

PHARMACOTHERAPY IN ARDS

The pathogenesis of ARDS includes damage to the alveolar-capillary membrane, with leakage of protein-rich edema fluid into alveoli. This damage is propagated by a complex inflammatory response including but not limited to neutrophil activation, free-radical formation, dysregulation of the coagulation system, and extensive release of inflammatory mediators.^32,33 As a consequence, there are multiple potential targets for pharmacologic therapy in ARDS.

A variety of drugs, including corticosteroids, anti-inflammatory agents, immune-modulating agents, pulmonary vasodilators, antioxidants, and surfactants, have been studied in patients with ARDS.³⁴ But effective pharmacotherapy for ARDS remains extremely limited.

Neuromuscular blockade in early severe ARDS

Mechanical ventilation can result in injurious stretching of the lung parenchyma, either from alveolar overdistention (volutrauma) or from continual recruitment and derecruitment of unstable lung units during the ventilator cycle (atelectrauma).³⁵ Ventilator-induced lung injury can be exacerbated by asynchronous breathing.

In theory, neuromuscular blockers could minimize patient-ventilator asynchrony and provide much better control of tidal volume and pressure in patients with ARDS. This may result in less volutrauma and atelectrauma associated with asynchronous breathing. Data also suggest that cisatracurium (Nimbex), a neuromuscular blocking agent, may have a direct effect on the amount of inflammation in lungs with ARDS.³⁶

The ACURASYS study

The ARDS et Curarisation Systématique (ACURASYS) study³⁷ was a randomized trial in 340 patients undergoing mechanical ventilation for severe ARDS to evaluate the impact of neuromuscular blockade within the first 48 hours in this population.

The primary outcome was the mortality rate before hospital discharge or within 90 days of study entry. Secondary outcomes included the 28-day mortality rate, the rate of intensive care unit-acquired paresis, and the number of ventilator-free days. To be included, patients had to have been mechanically ventilated for less than 48 hours and to meet the AECC criteria for severe ARDS, with a PaO₂/FiO₂ ratio less than 150 mm Hg.

The intervention group received a continuous infusion of cisatracurium for 48 hours, while the control patients received placebo. Muscle strength was evaluated by clinical scoring of strength in different muscle groups.

Findings. The study groups were similar at baseline.

The crude 90-day mortality rate was lower in the cisatracurium group (31.6% vs 40.7%, P = .08). Regression analysis showed an improved 90-day survival rate with the use of this neuromuscular blocker after adjustment for severity of illness and the severity of ARDS (based on degree of hypoxemia and plateau pressures) (hazard ratio for death at 90 days 0.68; 95% CI 0.48–0.98; P = .04). The rate of paresis acquired in the intensive care unit did not differ significantly between the two groups.

Conclusion. In patients with severe ARDS, giving a neuromuscular blocking agent early improved the survival rate and increased the time off the ventilator without increasing muscle weakness.

These data are in line with similar findings from two other studies published by the same group.^38,39 A meta-analysis of 432 patients showed that the use of neuromuscular blockade in early severe ARDS is associated with a statistically significant effect on early mortality (relative risk 0.66, 95% CI 0.50–0.87).⁴⁰ The pooled analysis of these trials did not show any statistically significant critical-illness polyneuropathy.

These results need to be interpreted carefully, as we have inadequate data to see if they generalize to different intensive care units, and the evaluation and categorization of critical-illness polyneuropathy remains to be defined.

Cisatracurium is a promising treatment for moderate to severe ARDS and merits investigation in a large confirmatory randomized controlled trial.

Other pharmacologic agents

A number of other drugs have been studied in ARDS patients, including both inhaled and intravenous beta agonists,^41,42 statins,⁴³ and nutritional supplements.⁴⁴ But as with other drugs previously studied in ARDS such as corticosteroids, N-acetylcysteine, and surfactant,³⁴ these agents showed no effect on outcomes. In fact, a recent trial of intravenous salbutamol in ARDS patients was stopped after an interim analysis because of a higher incidence of arrhythmias and lactic acidosis with this agent.⁴²

These findings reaffirm that pharmacologic therapy needs to be carefully considered, and potential harms associated with these therapies need to be addressed before they are introduced in the care of critically ill patients.

Continued progress in understanding the pathophysiology of acute respiratory distress syndrome (ARDS) is translating into changes in the way we diagnose and manage it. Over the past 20 years, low tidal volume,¹ positive end-expiratory pressure (PEEP),² and fluid restriction³ have become the standard of care. A multidisciplinary approach, including targeted use of sedatives, early mobilization, and protocols for weaning from the ventilator, has also brought about substantial changes in ARDS management and its outcomes.^4–6

In this article, we review the most relevant articles about ARDS in the last 5 years. We include the new definition of ARDS and studies of ventilatory and nonventilatory therapies that have implications in managing patients with ARDS.

A STANDARDIZED APPROACH

ARDS is characterized by damage to the alveolar architecture, severe hypoxemia, and bilateral parenchymal opacities.

The working definition of ARDS developed in 1994 by the American-European Consensus Conference (AECC) was the basis for enrollment in most of the landmark trials and observational studies over the past 20 years.^7,8 However, it was limited in its reliability and validity.

An updated definition

In 2011, the ARDS Definition Task Force, using a novel consensus process, updated the ARDS definition,⁹ focusing on its feasibility, reliability, and validity in predicting response to therapies and outcomes in ARDS. This new “Berlin” definition is not substantially different from the old, but defines the criteria more specifically:

• Bilateral opacities, unexplained by nodules, atelectasis, or effusion, on chest radiography or computed tomography
• New or worsening respiratory symptoms, or a clinical insult associated with ARDS within 7 days of diagnosis
• Objective assessment of cardiac function (eg, with echocardiography) to exclude cardiogenic pulmonary edema
• Hypoxemia, with a partial pressure of arterial oxygen divided by the percentage of inspired oxygen (PaO₂/FiO₂ ratio) of 300 mm Hg or less despite noninvasive or invasive mechanical ventilation with PEEP or continuous positive airway pressure (CPAP) of at least 5 cm H₂O.

In addition, the new definition classifies the severity of disease on the basis of the degree of hypoxemia, ie, the PaO₂/FiO₂ ratio:

• Mild: PaO₂/FiO₂ ratio > 200 and ≤ 300 mm Hg
• Moderate: PaO₂/FiO₂ ratio > 100 and ≤ 200 mm Hg
• Severe: PaO₂/FiO₂ ratio ≤ 100 mm Hg.

The term “acute lung injury” has been eliminated, as has the previous criterion of a pulmonary artery wedge pressure of 18 mm Hg or less.

The panel also evaluated four ancillary variables for predicting outcomes in severe ARDS:

• Compliance of the respiratory system less than or equal to 40 mL/cm H₂O
• Radiographic severity (involvement of three or four quadrants on chest radiography)
• PEEP of 10 cm H₂O or greater
• Corrected expired volume 10 L/min or greater.

The task force evaluated the reliability and validity of this definition in a meta-analysis of 4,400 patients previously enrolled in randomized controlled trials or observational studies.

Findings. The Berlin definition predicted the risk of death better than the AECC definition. The mortality rate increased with the severity of ARDS, from 27% with mild disease to 32% with moderate disease to 45% with severe disease. The four ancillary variables did not contribute to the predictive validity of severe ARDS for mortality and were removed from the definition.

Thille et al¹⁰ retrospectively reviewed autopsy findings from 712 patients and found that the new definition identified a homogeneous group who had severe ARDS.¹⁰

Conclusions. The new definition may overcome some of the limitations of the old one, but it needs to be validated in clinical practice, especially its ability to predict death.

VENTILATORY SUPPORT

Prompt recognition, lung-protective ventilation, and a conservative fluid strategy remain the cornerstones of ARDS management. However, other strategies are being tested.

Prone-position ventilation in severe ARDS: The right therapy in a specific population

Prone-position ventilation was first described almost 30 years ago, but it has been used inconsistently in clinical practice.

Physiologic and observational studies indicated that prone positioning might improve survival in patients with ARDS, but several randomized trials failed to demonstrate any positive effect on outcomes.^11,12 Some trials also reported a higher rate of complications with this intervention.¹³ However, meta-analyses suggested that prone-position ventilation might have a beneficial effect in patients with severe ARDS (defined as a PaO₂/FiO₂ ratio ≤ 100 mm Hg).¹⁴

In view of these findings, investigators conducted a trial of prone-position ventilation exclusively in patients with severe ARDS.

The PROSEVA study

The Proning Severe ARDS Patients (PROSEVA) study was a randomized controlled trial designed to determine whether prone-position ventilation, applied early, would improve outcomes in patients with severe ARDS.¹⁵

In PROSEVA, 466 patients with severe ARDS (defined as a PaO₂/FiO₂ ratio < 150 mm Hg, FiO₂ ≥ 60%, and PEEP ≥ 5 cm H₂O) underwent either at least 16 hours of prone positioning or were left in the supine position after 12 to 24 hours of initial conventional mechanical ventilation. The patients were recruited from centers in France and Spain where prone-position ventilation had been used in daily practice for more than 5 years.

The primary outcome studied was the rate of death at 28 days. The secondary end points were the death rate at day 90, rates of successful extubation, the length of stay in the intensive care unit, and complications.

Findings. At study entry, the patients in the supine group were sicker, more of them required a vasopressor, and fewer of them were receiving neuromuscular blocking agents than those in the prone group. These baseline differences may have influenced the outcomes; the unadjusted 28-day mortality rate was 16.0% in the prone group compared with 32.8% in the supine group (P < .001). However, the hazard ratio for death with prone positioning was 0.39 (95% confidence interval [CI] 0.25–0.63) even after adjusting for severity and the use of vasopressors and neuromuscular blocking agents. Prone-position ventilation was not associated with a higher incidence of complications, and the rate of successful extubation was higher.

Conclusions. In patients with severe ARDS, early use of prolonged prone positioning significantly decreased the 28-day and 90-day mortality rates. This trial has made prone positioning one of the strategies in managing patients with early severe ARDS. To minimize complications such as pressure ulcers and line or tube dislodgement, personnel caring for these patients must follow a protocol and undergo specific training.

These results were corroborated by a meta-analysis by Beitler et al¹⁶ that found a significant decrease in mortality rate with prone-position ventilation even in older studies when lung-protective ventilation strategies were separated from high-tidal-volume ventilation.

High-frequency oscillatory ventilation: No benefit in two trials

Observational data and experimental studies suggested that high-frequency oscillatory ventilation (HFOV) is superior to conventional mechanical ventilation in ARDS patients.^17,18 However, outdated and cumbersome equipment, lack of protocols, and a lack of high-quality evidence led to limited and inconsistent use of HFOV, mainly as a rescue therapy in ARDS.¹⁹

Over the last few years, HFOV has been gaining acceptance, especially earlier in the course of ARDS.²⁰ After preliminary clinical trials reported promising results, two trials conducted in Canada and the United Kingdom compared HFOV vs conventional mechanical ventilation in patients with ARDS.

The OSCAR study

The Oscillation in ARDS (OSCAR) study²¹ was a “pragmatic” trial²² (ie, it had minimal exclusion criteria) of the safety and effectiveness of HFOV as a primary ventilatory strategy for ARDS. It included 795 patients randomized to receive conventional ventilation (n = 397) or HFOV (n = 398). Research centers followed detailed algorithms for HFOV management and adopted their usual practice for conventional ventilation. Medical care was given according to the clinician’s judgment.

The primary outcome studied was survival at 30 days. The secondary outcomes were all-cause mortality in the intensive care unit and the hospital, duration of mechanical ventilation, and use of antimicrobial, sedative, vasoactive, and neuromuscular-blocking drugs.

Findings. The patient baseline characteristics were similar in both groups.

There was no significant difference in intensive care unit mortality rates, hospital mortality rates, or mortality rates at 30 days (41.7% in the HFOV group vs 41.1% in the conventional ventilation group; P = .85, 95% CI 6.1–7.5) even after adjustments for center or severity of illness.

The duration of mechanical ventilation was similar in both groups (14.9 ± 13.3 days in the HFOV group vs 14.1 ± 13.4 days in the conventional ventilation group, P = .41). However, sedatives and neuromuscular-blocking drugs were used more often and longer in the HFOV group than in the conventional ventilation group. There was no difference in the use of vasoactive or antimicrobial medications.

Conclusions. This multicenter randomized control trial did not demonstrate any benefit from using HFOV for routine management of ARDS. Its pragmatic design made it less likely to reach a firm conclusion,²² but it at least made a case against routinely using HFOV in patients with ARDS.

The OSCILLATE study

The Oscillation for Acute Respiratory Distress Syndrome Treated Early (OSCILLATE) study²³ assessed the safety and efficacy of HFOV as a treatment for early-onset moderate-to-severe ARDS.

The inclusion criteria were similar to those in the OSCAR trial except that pulmonary symptoms had to be present less than 2 weeks and ARDS assessment was done under standard ventilator settings. As this was an efficacy trial, it had more exclusion criteria than the OSCAR trial. A total of 548 patients were randomized to receive conventional ventilation (n = 273) or HFOV (n = 275). The baseline characteristics were similar between groups.

Conventional ventilation was given according to a protocol used in an earlier trial² and included recruitment maneuvers. HFOV was given in centers that had experience in this treatment, and there were protocols for ventilation management, hemodynamic optimization, and weaning. All other care was left to the clinician’s choice.

The primary outcome studied was in-hospital mortality. The investigators also evaluated whether there were interactions between the treatment and baseline severity of lung injury and center experience with HFOV.

Findings. The trial was stopped after an interim analysis found that HFOV might be harmful, although the statistical threshold for stopping was not reached. The in-hospital mortality rate was 47% in the HFOV group and 35% in the control group (relative risk of death with HFOV 1.33, 95% CI 1.09–1.64, P = .005). HFOV was worse than conventional ventilation regardless of the severity of disease or center experience. The HFOV group had higher mean airway pressures but similar FiO₂ compared with the conventional ventilation group.

The HFOV group received significantly more vasopressors, sedatives, and neuromuscular blockers. This group’s fluid balance was higher as well, but not significantly so. Refractory hypoxemia (defined as PaO₂ < 60 mm Hg for 1 hour with an FiO₂ of 1.0 and neuromuscular blockade) was more frequent in the conventional ventilation group, but the number of deaths in the subgroup with refractory hypoxemia was similar with either treatment.

Conclusions. This multicenter randomized controlled trial demonstrated that HFOV was harmful when used routinely to manage ARDS. The trial’s protocol was based on the results of a pilot study carried out by the same investigators, which provided the best evidence available regarding the safety of HFOV at that time.

The results of the OSCAR and OSCILLATE trials have quelled enthusiasm for early, routine use of HFOV in ARDS. Although there are concerns that the protocol (ie, the way HFOV was implemented) rather than HFOV itself may have led to worse outcomes, there is no signal to support its routine use. We need further studies to define if it remains a viable rescue therapy.

Extracorporeal membrane oxygenation: Is it a viable option in severe ARDS?

Extracorporeal membrane oxygenation (ECMO) uses cardiopulmonary bypass technology to provide gas exchange. In patients with severe hypoxemia, ECMO can ensure adequate oxygenation and ventilation while ensuring the optimization of lung-protective ventilation. But ECMO was never as successful in adults with ARDS as it was in children and neonates.²⁴

The first two trials of ECMO in ARDS^24,25 reported equal or worse survival rates compared with conventional ventilation, and the overall mortality rate in these studies was staggeringly high. However, these studies were carried out before the era of lung-protective ventilation and at a time when ECMO technology was relatively primitive.

With new technology such as venovenous circuits and smaller cannulas, ECMO has gained more acceptance. It was used in patients with severe or refractory hypoxemia associated with ARDS during the H1N1 pandemic.^26,27

The CESAR trial

The Conventional Ventilatory Support Versus Extracorporeal Membrane Oxygenation for Severe Adult Respiratory Failure (CESAR) trial²⁸ assessed the safety, clinical efficacy, and cost-effectiveness of ECMO in managing severe ARDS. It compared best standard practice vs a protocol that included ECMO. The trial was conducted from 2001 to 2006.

Patients with severe ARDS, as defined by a Murray score²⁹ greater than 3 or uncompensated hypercapnea, were prospectively randomized and recruited from an ECMO center and 148 tertiary intensive care units and referral hospitals in England. This was a pragmatic trial, with minimal exclusion criteria (essentially, mechanical ventilation with high pressures and high FiO₂ for more than 7 days, intracranial bleeding, or contraindication to heparinization).

A total of 180 patients were randomized in a one-to-one ratio to receive ECMO or conventional management. The ventilator management in the conventional treatment group was not done according to a protocol but in general was low-volume and low-pressure. All patients randomized to ECMO were transferred to the ECMO center and treated according to a standardized ventilation protocol. After 12 hours, if predefined goals were not reached, venovenous ECMO was started. Patients assigned to conventional management could not cross over to ECMO.

The primary outcomes were death or severe disability at 6 months after randomization, and cost-effectiveness. The secondary outcomes were hospital resource use (eg, rescue techniques, length of stay, duration of ECMO) and health status after 6 months.

Findings. The groups were similar at baseline. Sixty-eight (75%) of the 90 patients randomized to receive ECMO actually received it. Of the 22 patients who did not receive ECMO, 16 (18% of the 90) improved on conventional therapy, 5 (6%) died during or before transfer, and 1 could not receive heparin.

Two patients had severe complications in the ECMO group: one had an arterial puncture, and one had an oxygen delivery failure during transport. In each case, these events contributed to the death of the patient.

More patients in the ECMO group received lung-protective ventilation, 84 (93%) vs 63 (70%).

The primary outcome, ie, death or severe disability at 6 months, occurred in 33 (37%) of the 90 patients in the ECMO group and in 46 (53%) of the patients in the conventional management group (relative risk 0.69, 95% CI 0.05–0.97, P = .03). More patients in the ECMO group survived, but the difference was not statistically significant (relative risk of death 0.73, 95% CI 0.52–1.03, P = .07). The most common cause of death in the ECMO group was multiorgan failure (42%), whereas in the conventional management group, the most common cause of death was respiratory failure (60%).

Length of stay in the hospital and in the critical care unit and health care costs were double for patients in the ECMO group. There was no difference in quality-of-life markers at 6 months in the survivors.

Conclusions. This pragmatic trial demonstrated that a protocol that includes ECMO could improve survival rates in ARDS.

Of note, the ECMO group got care in regional centers that used protocols. Therefore, in interpreting the results of this trial, we have to consider that being in a center with protocol-specified care for ARDS could drive some of the difference in mortality rates.

Regardless, this trial demonstrated that ECMO is feasible and led to better outcomes than expected. The findings were encouraging, and spurred the use of ECMO in severe ARDS during the 2009 H1N1 pandemic. Two propensity-matched studies and a number of case series reported a survival benefit associated with the use of ECMO in patients with severe ARDS.^27,30

A recent meta-analysis also reported that ECMO might lower the mortality rate in ARDS; however, the patients in the H1N1 pandemic were younger and usually had isolated respiratory failure.³¹

The success of ECMO has opened new possibilities in the management of ARDS. As the technology improves and our experience increases, ECMO will likely gain more acceptance as a treatment for severe ARDS.

Airway pressure release ventilation

The use of airway pressure release ventilation and other ventilator modalities in ARDS is not supported by current evidence, though results of clinical trials may influence our practice in the future.

PHARMACOTHERAPY IN ARDS

The pathogenesis of ARDS includes damage to the alveolar-capillary membrane, with leakage of protein-rich edema fluid into alveoli. This damage is propagated by a complex inflammatory response including but not limited to neutrophil activation, free-radical formation, dysregulation of the coagulation system, and extensive release of inflammatory mediators.^32,33 As a consequence, there are multiple potential targets for pharmacologic therapy in ARDS.

A variety of drugs, including corticosteroids, anti-inflammatory agents, immune-modulating agents, pulmonary vasodilators, antioxidants, and surfactants, have been studied in patients with ARDS.³⁴ But effective pharmacotherapy for ARDS remains extremely limited.

Neuromuscular blockade in early severe ARDS

Mechanical ventilation can result in injurious stretching of the lung parenchyma, either from alveolar overdistention (volutrauma) or from continual recruitment and derecruitment of unstable lung units during the ventilator cycle (atelectrauma).³⁵ Ventilator-induced lung injury can be exacerbated by asynchronous breathing.

In theory, neuromuscular blockers could minimize patient-ventilator asynchrony and provide much better control of tidal volume and pressure in patients with ARDS. This may result in less volutrauma and atelectrauma associated with asynchronous breathing. Data also suggest that cisatracurium (Nimbex), a neuromuscular blocking agent, may have a direct effect on the amount of inflammation in lungs with ARDS.³⁶

The ACURASYS study

The ARDS et Curarisation Systématique (ACURASYS) study³⁷ was a randomized trial in 340 patients undergoing mechanical ventilation for severe ARDS to evaluate the impact of neuromuscular blockade within the first 48 hours in this population.

The primary outcome was the mortality rate before hospital discharge or within 90 days of study entry. Secondary outcomes included the 28-day mortality rate, the rate of intensive care unit-acquired paresis, and the number of ventilator-free days. To be included, patients had to have been mechanically ventilated for less than 48 hours and to meet the AECC criteria for severe ARDS, with a PaO₂/FiO₂ ratio less than 150 mm Hg.

The intervention group received a continuous infusion of cisatracurium for 48 hours, while the control patients received placebo. Muscle strength was evaluated by clinical scoring of strength in different muscle groups.

Findings. The study groups were similar at baseline.

The crude 90-day mortality rate was lower in the cisatracurium group (31.6% vs 40.7%, P = .08). Regression analysis showed an improved 90-day survival rate with the use of this neuromuscular blocker after adjustment for severity of illness and the severity of ARDS (based on degree of hypoxemia and plateau pressures) (hazard ratio for death at 90 days 0.68; 95% CI 0.48–0.98; P = .04). The rate of paresis acquired in the intensive care unit did not differ significantly between the two groups.

Conclusion. In patients with severe ARDS, giving a neuromuscular blocking agent early improved the survival rate and increased the time off the ventilator without increasing muscle weakness.

These data are in line with similar findings from two other studies published by the same group.^38,39 A meta-analysis of 432 patients showed that the use of neuromuscular blockade in early severe ARDS is associated with a statistically significant effect on early mortality (relative risk 0.66, 95% CI 0.50–0.87).⁴⁰ The pooled analysis of these trials did not show any statistically significant critical-illness polyneuropathy.

These results need to be interpreted carefully, as we have inadequate data to see if they generalize to different intensive care units, and the evaluation and categorization of critical-illness polyneuropathy remains to be defined.

Cisatracurium is a promising treatment for moderate to severe ARDS and merits investigation in a large confirmatory randomized controlled trial.

Other pharmacologic agents

A number of other drugs have been studied in ARDS patients, including both inhaled and intravenous beta agonists,^41,42 statins,⁴³ and nutritional supplements.⁴⁴ But as with other drugs previously studied in ARDS such as corticosteroids, N-acetylcysteine, and surfactant,³⁴ these agents showed no effect on outcomes. In fact, a recent trial of intravenous salbutamol in ARDS patients was stopped after an interim analysis because of a higher incidence of arrhythmias and lactic acidosis with this agent.⁴²

These findings reaffirm that pharmacologic therapy needs to be carefully considered, and potential harms associated with these therapies need to be addressed before they are introduced in the care of critically ill patients.

Continued progress in understanding the pathophysiology of acute respiratory distress syndrome (ARDS) is translating into changes in the way we diagnose and manage it. Over the past 20 years, low tidal volume,¹ positive end-expiratory pressure (PEEP),² and fluid restriction³ have become the standard of care. A multidisciplinary approach, including targeted use of sedatives, early mobilization, and protocols for weaning from the ventilator, has also brought about substantial changes in ARDS management and its outcomes.^4–6

In this article, we review the most relevant articles about ARDS in the last 5 years. We include the new definition of ARDS and studies of ventilatory and nonventilatory therapies that have implications in managing patients with ARDS.

A STANDARDIZED APPROACH

ARDS is characterized by damage to the alveolar architecture, severe hypoxemia, and bilateral parenchymal opacities.

The working definition of ARDS developed in 1994 by the American-European Consensus Conference (AECC) was the basis for enrollment in most of the landmark trials and observational studies over the past 20 years.^7,8 However, it was limited in its reliability and validity.

An updated definition

In 2011, the ARDS Definition Task Force, using a novel consensus process, updated the ARDS definition,⁹ focusing on its feasibility, reliability, and validity in predicting response to therapies and outcomes in ARDS. This new “Berlin” definition is not substantially different from the old, but defines the criteria more specifically:

• Bilateral opacities, unexplained by nodules, atelectasis, or effusion, on chest radiography or computed tomography
• New or worsening respiratory symptoms, or a clinical insult associated with ARDS within 7 days of diagnosis
• Objective assessment of cardiac function (eg, with echocardiography) to exclude cardiogenic pulmonary edema
• Hypoxemia, with a partial pressure of arterial oxygen divided by the percentage of inspired oxygen (PaO₂/FiO₂ ratio) of 300 mm Hg or less despite noninvasive or invasive mechanical ventilation with PEEP or continuous positive airway pressure (CPAP) of at least 5 cm H₂O.

In addition, the new definition classifies the severity of disease on the basis of the degree of hypoxemia, ie, the PaO₂/FiO₂ ratio:

• Mild: PaO₂/FiO₂ ratio > 200 and ≤ 300 mm Hg
• Moderate: PaO₂/FiO₂ ratio > 100 and ≤ 200 mm Hg
• Severe: PaO₂/FiO₂ ratio ≤ 100 mm Hg.

The term “acute lung injury” has been eliminated, as has the previous criterion of a pulmonary artery wedge pressure of 18 mm Hg or less.

The panel also evaluated four ancillary variables for predicting outcomes in severe ARDS:

• Compliance of the respiratory system less than or equal to 40 mL/cm H₂O
• Radiographic severity (involvement of three or four quadrants on chest radiography)
• PEEP of 10 cm H₂O or greater
• Corrected expired volume 10 L/min or greater.

The task force evaluated the reliability and validity of this definition in a meta-analysis of 4,400 patients previously enrolled in randomized controlled trials or observational studies.

Findings. The Berlin definition predicted the risk of death better than the AECC definition. The mortality rate increased with the severity of ARDS, from 27% with mild disease to 32% with moderate disease to 45% with severe disease. The four ancillary variables did not contribute to the predictive validity of severe ARDS for mortality and were removed from the definition.

Thille et al¹⁰ retrospectively reviewed autopsy findings from 712 patients and found that the new definition identified a homogeneous group who had severe ARDS.¹⁰

Conclusions. The new definition may overcome some of the limitations of the old one, but it needs to be validated in clinical practice, especially its ability to predict death.

VENTILATORY SUPPORT

Prompt recognition, lung-protective ventilation, and a conservative fluid strategy remain the cornerstones of ARDS management. However, other strategies are being tested.

Prone-position ventilation in severe ARDS: The right therapy in a specific population

Prone-position ventilation was first described almost 30 years ago, but it has been used inconsistently in clinical practice.

Physiologic and observational studies indicated that prone positioning might improve survival in patients with ARDS, but several randomized trials failed to demonstrate any positive effect on outcomes.^11,12 Some trials also reported a higher rate of complications with this intervention.¹³ However, meta-analyses suggested that prone-position ventilation might have a beneficial effect in patients with severe ARDS (defined as a PaO₂/FiO₂ ratio ≤ 100 mm Hg).¹⁴

In view of these findings, investigators conducted a trial of prone-position ventilation exclusively in patients with severe ARDS.

The PROSEVA study

The Proning Severe ARDS Patients (PROSEVA) study was a randomized controlled trial designed to determine whether prone-position ventilation, applied early, would improve outcomes in patients with severe ARDS.¹⁵

In PROSEVA, 466 patients with severe ARDS (defined as a PaO₂/FiO₂ ratio < 150 mm Hg, FiO₂ ≥ 60%, and PEEP ≥ 5 cm H₂O) underwent either at least 16 hours of prone positioning or were left in the supine position after 12 to 24 hours of initial conventional mechanical ventilation. The patients were recruited from centers in France and Spain where prone-position ventilation had been used in daily practice for more than 5 years.

The primary outcome studied was the rate of death at 28 days. The secondary end points were the death rate at day 90, rates of successful extubation, the length of stay in the intensive care unit, and complications.

Findings. At study entry, the patients in the supine group were sicker, more of them required a vasopressor, and fewer of them were receiving neuromuscular blocking agents than those in the prone group. These baseline differences may have influenced the outcomes; the unadjusted 28-day mortality rate was 16.0% in the prone group compared with 32.8% in the supine group (P < .001). However, the hazard ratio for death with prone positioning was 0.39 (95% confidence interval [CI] 0.25–0.63) even after adjusting for severity and the use of vasopressors and neuromuscular blocking agents. Prone-position ventilation was not associated with a higher incidence of complications, and the rate of successful extubation was higher.

Conclusions. In patients with severe ARDS, early use of prolonged prone positioning significantly decreased the 28-day and 90-day mortality rates. This trial has made prone positioning one of the strategies in managing patients with early severe ARDS. To minimize complications such as pressure ulcers and line or tube dislodgement, personnel caring for these patients must follow a protocol and undergo specific training.

These results were corroborated by a meta-analysis by Beitler et al¹⁶ that found a significant decrease in mortality rate with prone-position ventilation even in older studies when lung-protective ventilation strategies were separated from high-tidal-volume ventilation.

High-frequency oscillatory ventilation: No benefit in two trials

Observational data and experimental studies suggested that high-frequency oscillatory ventilation (HFOV) is superior to conventional mechanical ventilation in ARDS patients.^17,18 However, outdated and cumbersome equipment, lack of protocols, and a lack of high-quality evidence led to limited and inconsistent use of HFOV, mainly as a rescue therapy in ARDS.¹⁹

Over the last few years, HFOV has been gaining acceptance, especially earlier in the course of ARDS.²⁰ After preliminary clinical trials reported promising results, two trials conducted in Canada and the United Kingdom compared HFOV vs conventional mechanical ventilation in patients with ARDS.

The OSCAR study

The Oscillation in ARDS (OSCAR) study²¹ was a “pragmatic” trial²² (ie, it had minimal exclusion criteria) of the safety and effectiveness of HFOV as a primary ventilatory strategy for ARDS. It included 795 patients randomized to receive conventional ventilation (n = 397) or HFOV (n = 398). Research centers followed detailed algorithms for HFOV management and adopted their usual practice for conventional ventilation. Medical care was given according to the clinician’s judgment.

The primary outcome studied was survival at 30 days. The secondary outcomes were all-cause mortality in the intensive care unit and the hospital, duration of mechanical ventilation, and use of antimicrobial, sedative, vasoactive, and neuromuscular-blocking drugs.

Findings. The patient baseline characteristics were similar in both groups.

There was no significant difference in intensive care unit mortality rates, hospital mortality rates, or mortality rates at 30 days (41.7% in the HFOV group vs 41.1% in the conventional ventilation group; P = .85, 95% CI 6.1–7.5) even after adjustments for center or severity of illness.

The duration of mechanical ventilation was similar in both groups (14.9 ± 13.3 days in the HFOV group vs 14.1 ± 13.4 days in the conventional ventilation group, P = .41). However, sedatives and neuromuscular-blocking drugs were used more often and longer in the HFOV group than in the conventional ventilation group. There was no difference in the use of vasoactive or antimicrobial medications.

Conclusions. This multicenter randomized control trial did not demonstrate any benefit from using HFOV for routine management of ARDS. Its pragmatic design made it less likely to reach a firm conclusion,²² but it at least made a case against routinely using HFOV in patients with ARDS.

The OSCILLATE study

The Oscillation for Acute Respiratory Distress Syndrome Treated Early (OSCILLATE) study²³ assessed the safety and efficacy of HFOV as a treatment for early-onset moderate-to-severe ARDS.

The inclusion criteria were similar to those in the OSCAR trial except that pulmonary symptoms had to be present less than 2 weeks and ARDS assessment was done under standard ventilator settings. As this was an efficacy trial, it had more exclusion criteria than the OSCAR trial. A total of 548 patients were randomized to receive conventional ventilation (n = 273) or HFOV (n = 275). The baseline characteristics were similar between groups.

Conventional ventilation was given according to a protocol used in an earlier trial² and included recruitment maneuvers. HFOV was given in centers that had experience in this treatment, and there were protocols for ventilation management, hemodynamic optimization, and weaning. All other care was left to the clinician’s choice.

The primary outcome studied was in-hospital mortality. The investigators also evaluated whether there were interactions between the treatment and baseline severity of lung injury and center experience with HFOV.

Findings. The trial was stopped after an interim analysis found that HFOV might be harmful, although the statistical threshold for stopping was not reached. The in-hospital mortality rate was 47% in the HFOV group and 35% in the control group (relative risk of death with HFOV 1.33, 95% CI 1.09–1.64, P = .005). HFOV was worse than conventional ventilation regardless of the severity of disease or center experience. The HFOV group had higher mean airway pressures but similar FiO₂ compared with the conventional ventilation group.

The HFOV group received significantly more vasopressors, sedatives, and neuromuscular blockers. This group’s fluid balance was higher as well, but not significantly so. Refractory hypoxemia (defined as PaO₂ < 60 mm Hg for 1 hour with an FiO₂ of 1.0 and neuromuscular blockade) was more frequent in the conventional ventilation group, but the number of deaths in the subgroup with refractory hypoxemia was similar with either treatment.

Conclusions. This multicenter randomized controlled trial demonstrated that HFOV was harmful when used routinely to manage ARDS. The trial’s protocol was based on the results of a pilot study carried out by the same investigators, which provided the best evidence available regarding the safety of HFOV at that time.

The results of the OSCAR and OSCILLATE trials have quelled enthusiasm for early, routine use of HFOV in ARDS. Although there are concerns that the protocol (ie, the way HFOV was implemented) rather than HFOV itself may have led to worse outcomes, there is no signal to support its routine use. We need further studies to define if it remains a viable rescue therapy.

Extracorporeal membrane oxygenation: Is it a viable option in severe ARDS?

Extracorporeal membrane oxygenation (ECMO) uses cardiopulmonary bypass technology to provide gas exchange. In patients with severe hypoxemia, ECMO can ensure adequate oxygenation and ventilation while ensuring the optimization of lung-protective ventilation. But ECMO was never as successful in adults with ARDS as it was in children and neonates.²⁴

The first two trials of ECMO in ARDS^24,25 reported equal or worse survival rates compared with conventional ventilation, and the overall mortality rate in these studies was staggeringly high. However, these studies were carried out before the era of lung-protective ventilation and at a time when ECMO technology was relatively primitive.

With new technology such as venovenous circuits and smaller cannulas, ECMO has gained more acceptance. It was used in patients with severe or refractory hypoxemia associated with ARDS during the H1N1 pandemic.^26,27

The CESAR trial

The Conventional Ventilatory Support Versus Extracorporeal Membrane Oxygenation for Severe Adult Respiratory Failure (CESAR) trial²⁸ assessed the safety, clinical efficacy, and cost-effectiveness of ECMO in managing severe ARDS. It compared best standard practice vs a protocol that included ECMO. The trial was conducted from 2001 to 2006.

Patients with severe ARDS, as defined by a Murray score²⁹ greater than 3 or uncompensated hypercapnea, were prospectively randomized and recruited from an ECMO center and 148 tertiary intensive care units and referral hospitals in England. This was a pragmatic trial, with minimal exclusion criteria (essentially, mechanical ventilation with high pressures and high FiO₂ for more than 7 days, intracranial bleeding, or contraindication to heparinization).

A total of 180 patients were randomized in a one-to-one ratio to receive ECMO or conventional management. The ventilator management in the conventional treatment group was not done according to a protocol but in general was low-volume and low-pressure. All patients randomized to ECMO were transferred to the ECMO center and treated according to a standardized ventilation protocol. After 12 hours, if predefined goals were not reached, venovenous ECMO was started. Patients assigned to conventional management could not cross over to ECMO.

The primary outcomes were death or severe disability at 6 months after randomization, and cost-effectiveness. The secondary outcomes were hospital resource use (eg, rescue techniques, length of stay, duration of ECMO) and health status after 6 months.

Findings. The groups were similar at baseline. Sixty-eight (75%) of the 90 patients randomized to receive ECMO actually received it. Of the 22 patients who did not receive ECMO, 16 (18% of the 90) improved on conventional therapy, 5 (6%) died during or before transfer, and 1 could not receive heparin.

Two patients had severe complications in the ECMO group: one had an arterial puncture, and one had an oxygen delivery failure during transport. In each case, these events contributed to the death of the patient.

More patients in the ECMO group received lung-protective ventilation, 84 (93%) vs 63 (70%).

The primary outcome, ie, death or severe disability at 6 months, occurred in 33 (37%) of the 90 patients in the ECMO group and in 46 (53%) of the patients in the conventional management group (relative risk 0.69, 95% CI 0.05–0.97, P = .03). More patients in the ECMO group survived, but the difference was not statistically significant (relative risk of death 0.73, 95% CI 0.52–1.03, P = .07). The most common cause of death in the ECMO group was multiorgan failure (42%), whereas in the conventional management group, the most common cause of death was respiratory failure (60%).

Length of stay in the hospital and in the critical care unit and health care costs were double for patients in the ECMO group. There was no difference in quality-of-life markers at 6 months in the survivors.

Conclusions. This pragmatic trial demonstrated that a protocol that includes ECMO could improve survival rates in ARDS.

Of note, the ECMO group got care in regional centers that used protocols. Therefore, in interpreting the results of this trial, we have to consider that being in a center with protocol-specified care for ARDS could drive some of the difference in mortality rates.

Regardless, this trial demonstrated that ECMO is feasible and led to better outcomes than expected. The findings were encouraging, and spurred the use of ECMO in severe ARDS during the 2009 H1N1 pandemic. Two propensity-matched studies and a number of case series reported a survival benefit associated with the use of ECMO in patients with severe ARDS.^27,30

A recent meta-analysis also reported that ECMO might lower the mortality rate in ARDS; however, the patients in the H1N1 pandemic were younger and usually had isolated respiratory failure.³¹

The success of ECMO has opened new possibilities in the management of ARDS. As the technology improves and our experience increases, ECMO will likely gain more acceptance as a treatment for severe ARDS.

Airway pressure release ventilation

The use of airway pressure release ventilation and other ventilator modalities in ARDS is not supported by current evidence, though results of clinical trials may influence our practice in the future.

PHARMACOTHERAPY IN ARDS

The pathogenesis of ARDS includes damage to the alveolar-capillary membrane, with leakage of protein-rich edema fluid into alveoli. This damage is propagated by a complex inflammatory response including but not limited to neutrophil activation, free-radical formation, dysregulation of the coagulation system, and extensive release of inflammatory mediators.^32,33 As a consequence, there are multiple potential targets for pharmacologic therapy in ARDS.

A variety of drugs, including corticosteroids, anti-inflammatory agents, immune-modulating agents, pulmonary vasodilators, antioxidants, and surfactants, have been studied in patients with ARDS.³⁴ But effective pharmacotherapy for ARDS remains extremely limited.

Neuromuscular blockade in early severe ARDS

Mechanical ventilation can result in injurious stretching of the lung parenchyma, either from alveolar overdistention (volutrauma) or from continual recruitment and derecruitment of unstable lung units during the ventilator cycle (atelectrauma).³⁵ Ventilator-induced lung injury can be exacerbated by asynchronous breathing.

In theory, neuromuscular blockers could minimize patient-ventilator asynchrony and provide much better control of tidal volume and pressure in patients with ARDS. This may result in less volutrauma and atelectrauma associated with asynchronous breathing. Data also suggest that cisatracurium (Nimbex), a neuromuscular blocking agent, may have a direct effect on the amount of inflammation in lungs with ARDS.³⁶

The ACURASYS study

The ARDS et Curarisation Systématique (ACURASYS) study³⁷ was a randomized trial in 340 patients undergoing mechanical ventilation for severe ARDS to evaluate the impact of neuromuscular blockade within the first 48 hours in this population.

The primary outcome was the mortality rate before hospital discharge or within 90 days of study entry. Secondary outcomes included the 28-day mortality rate, the rate of intensive care unit-acquired paresis, and the number of ventilator-free days. To be included, patients had to have been mechanically ventilated for less than 48 hours and to meet the AECC criteria for severe ARDS, with a PaO₂/FiO₂ ratio less than 150 mm Hg.

The intervention group received a continuous infusion of cisatracurium for 48 hours, while the control patients received placebo. Muscle strength was evaluated by clinical scoring of strength in different muscle groups.

Findings. The study groups were similar at baseline.

The crude 90-day mortality rate was lower in the cisatracurium group (31.6% vs 40.7%, P = .08). Regression analysis showed an improved 90-day survival rate with the use of this neuromuscular blocker after adjustment for severity of illness and the severity of ARDS (based on degree of hypoxemia and plateau pressures) (hazard ratio for death at 90 days 0.68; 95% CI 0.48–0.98; P = .04). The rate of paresis acquired in the intensive care unit did not differ significantly between the two groups.

Conclusion. In patients with severe ARDS, giving a neuromuscular blocking agent early improved the survival rate and increased the time off the ventilator without increasing muscle weakness.

These data are in line with similar findings from two other studies published by the same group.^38,39 A meta-analysis of 432 patients showed that the use of neuromuscular blockade in early severe ARDS is associated with a statistically significant effect on early mortality (relative risk 0.66, 95% CI 0.50–0.87).⁴⁰ The pooled analysis of these trials did not show any statistically significant critical-illness polyneuropathy.

These results need to be interpreted carefully, as we have inadequate data to see if they generalize to different intensive care units, and the evaluation and categorization of critical-illness polyneuropathy remains to be defined.

Cisatracurium is a promising treatment for moderate to severe ARDS and merits investigation in a large confirmatory randomized controlled trial.

Other pharmacologic agents

A number of other drugs have been studied in ARDS patients, including both inhaled and intravenous beta agonists,^41,42 statins,⁴³ and nutritional supplements.⁴⁴ But as with other drugs previously studied in ARDS such as corticosteroids, N-acetylcysteine, and surfactant,³⁴ these agents showed no effect on outcomes. In fact, a recent trial of intravenous salbutamol in ARDS patients was stopped after an interim analysis because of a higher incidence of arrhythmias and lactic acidosis with this agent.⁴²

These findings reaffirm that pharmacologic therapy needs to be carefully considered, and potential harms associated with these therapies need to be addressed before they are introduced in the care of critically ill patients.