Plasmodium parasite

infecting a red blood cell

Photo courtesy of St. Jude

Children’s Research Hospital

Researchers say they have gained a better understanding of how the antimalarial drug artemisinin kills the Plasmodium falciparum parasite.

A chemical proteomics analysis revealed more than 120 protein targets of artemisinin and the mechanism that activates its killing effect.

Given the emergence of artemisinin resistance, the team believes their findings could aid the design of new treatments against drug-resistant parasites.

They reported the findings in Nature Communications.

Previously, only 2 targets of artemisinin had been identified, and their correlation with the parasite-killing effect of the drug had been questioned.

Lin Qingsong, PhD, of the National University of Singapore, and his colleagues identified 124 protein targets of artemisinin in P falciparum. Many of these newly identified protein targets are involved in essential biological processes in the parasite, thus explaining artemisinin’s potent killing effect.

The research suggests that, through its promiscuous targeting mechanism, artemisinin targets the blood-eating nature of the malaria parasite, binding to a broad spectrum of targets simultaneously and fatally disrupting the biochemistry of the parasite.

The study also showed that the main activator of artemisinin is heme, an iron-containing compound that is either biosynthesized by the parasite at its early developmental ring stage or derived from hemoglobin digestion in the later stages.

The drug activation level was found to be much lower in ring-stage parasites, given that artemisinin activation requires heme, which is of much lower abundance and is biosynthesized by the parasite.

In comparison, during the late stages of its life cycle, the parasite actively digests the hemoglobin in infected blood cells as its primary energy source. This releases large amounts of heme, and the drug is able to specifically respond to parasite-infected cells and effectively attack the disease-causing parasites.

“The current findings not only provide a more complete picture of how artemisinin and its derivatives work but also suggest new ways of using the drug,” Dr Lin said. “For instance, to improve drug activation at ring stage, we can explore enhancing the level of heme biosynthesis in the parasite.”

“By understanding that hemoglobin digestion releases huge amounts of heme, which brings about the effective killing mechanism in the later stages, we can also consider prolonging the treatment time to ensure that the drug can effectively kill the parasite through multiple cycles.”

In addition, the researchers are planning to develop novel artemisinin analogues with more specific targeting properties.

Plasmodium parasite

infecting a red blood cell

Photo courtesy of St. Jude

Children’s Research Hospital

Researchers say they have gained a better understanding of how the antimalarial drug artemisinin kills the Plasmodium falciparum parasite.

A chemical proteomics analysis revealed more than 120 protein targets of artemisinin and the mechanism that activates its killing effect.

Given the emergence of artemisinin resistance, the team believes their findings could aid the design of new treatments against drug-resistant parasites.

They reported the findings in Nature Communications.

Previously, only 2 targets of artemisinin had been identified, and their correlation with the parasite-killing effect of the drug had been questioned.

Lin Qingsong, PhD, of the National University of Singapore, and his colleagues identified 124 protein targets of artemisinin in P falciparum. Many of these newly identified protein targets are involved in essential biological processes in the parasite, thus explaining artemisinin’s potent killing effect.

The research suggests that, through its promiscuous targeting mechanism, artemisinin targets the blood-eating nature of the malaria parasite, binding to a broad spectrum of targets simultaneously and fatally disrupting the biochemistry of the parasite.

The study also showed that the main activator of artemisinin is heme, an iron-containing compound that is either biosynthesized by the parasite at its early developmental ring stage or derived from hemoglobin digestion in the later stages.

The drug activation level was found to be much lower in ring-stage parasites, given that artemisinin activation requires heme, which is of much lower abundance and is biosynthesized by the parasite.

In comparison, during the late stages of its life cycle, the parasite actively digests the hemoglobin in infected blood cells as its primary energy source. This releases large amounts of heme, and the drug is able to specifically respond to parasite-infected cells and effectively attack the disease-causing parasites.

“The current findings not only provide a more complete picture of how artemisinin and its derivatives work but also suggest new ways of using the drug,” Dr Lin said. “For instance, to improve drug activation at ring stage, we can explore enhancing the level of heme biosynthesis in the parasite.”

“By understanding that hemoglobin digestion releases huge amounts of heme, which brings about the effective killing mechanism in the later stages, we can also consider prolonging the treatment time to ensure that the drug can effectively kill the parasite through multiple cycles.”

In addition, the researchers are planning to develop novel artemisinin analogues with more specific targeting properties.

Plasmodium parasite

infecting a red blood cell

Photo courtesy of St. Jude

Children’s Research Hospital

Researchers say they have gained a better understanding of how the antimalarial drug artemisinin kills the Plasmodium falciparum parasite.

A chemical proteomics analysis revealed more than 120 protein targets of artemisinin and the mechanism that activates its killing effect.

Given the emergence of artemisinin resistance, the team believes their findings could aid the design of new treatments against drug-resistant parasites.

They reported the findings in Nature Communications.

Previously, only 2 targets of artemisinin had been identified, and their correlation with the parasite-killing effect of the drug had been questioned.

Lin Qingsong, PhD, of the National University of Singapore, and his colleagues identified 124 protein targets of artemisinin in P falciparum. Many of these newly identified protein targets are involved in essential biological processes in the parasite, thus explaining artemisinin’s potent killing effect.

The research suggests that, through its promiscuous targeting mechanism, artemisinin targets the blood-eating nature of the malaria parasite, binding to a broad spectrum of targets simultaneously and fatally disrupting the biochemistry of the parasite.

The study also showed that the main activator of artemisinin is heme, an iron-containing compound that is either biosynthesized by the parasite at its early developmental ring stage or derived from hemoglobin digestion in the later stages.

The drug activation level was found to be much lower in ring-stage parasites, given that artemisinin activation requires heme, which is of much lower abundance and is biosynthesized by the parasite.

In comparison, during the late stages of its life cycle, the parasite actively digests the hemoglobin in infected blood cells as its primary energy source. This releases large amounts of heme, and the drug is able to specifically respond to parasite-infected cells and effectively attack the disease-causing parasites.

“The current findings not only provide a more complete picture of how artemisinin and its derivatives work but also suggest new ways of using the drug,” Dr Lin said. “For instance, to improve drug activation at ring stage, we can explore enhancing the level of heme biosynthesis in the parasite.”

“By understanding that hemoglobin digestion releases huge amounts of heme, which brings about the effective killing mechanism in the later stages, we can also consider prolonging the treatment time to ensure that the drug can effectively kill the parasite through multiple cycles.”

In addition, the researchers are planning to develop novel artemisinin analogues with more specific targeting properties.

Illustrative case

A 28-year-old gravida 2, para 1001 at 10 weeks gestation presents to your clinic for a routine first-trimester prenatal visit. Her first child has no known chromosomal abnormalities and she has no family history of aneuploidy. She asks you which tests are available to screen her fetus for chromosomal abnormalities.

Pregnant women have traditionally been offered some combination of serum biomarkers and nuchal translucency to assess the risk of fetal aneuploidy. Cell-free DNA testing (cfDNA) is a form of noninvasive prenatal testing that uses maternal serum samples to conduct massively parallel sequencing of cell-free fetal DNA fragments. It has been offered to pregnant women as a screening test to detect fetal chromosomal abnormalities since 2011 after multiple clinical studies found high sensitivities, specificities, and negative predictive values (NPVs) for detecting aneuploidy.^3-6 However until 2015, practice guidelines from the American Congress of Obstetricians and Gynecologists (ACOG) recommended that standard aneuploidy screening or diagnostic testing be offered to all pregnant women and cfDNA be reserved for women with pregnancies at high risk for aneuploidy (strength of recommendation: B).⁷

CARE (Comparison of Aneuploidy Risk Evaluation) and NEXT (Noninvasive Examination of Trisomy) are 2 large studies that compared cfDNA and standard aneuploidy screening methods in pregnant women at low risk for fetal aneuploidy. Based on new data from these and other studies, ACOG and the Society for Maternal-Fetal Medicine (SMFM) released a new consensus statement in June 2015 that addressed the use of cfDNA in the general obstetric population. The 2 groups still recommend conventional first- and second-trimester screening by serum chemical biomarkers and nuchal translucency as the first-line approach for low-risk women who want to pursue aneuploidy screening; however, they also recommend that the risks and benefits of cfDNA should be discussed with all patients.⁸

STUDY SUMMARIES

CARE was a prospective, blinded, multicenter (21 US sites across 14 states) study that compared the aneuploidy detection rates of cfDNA to those of standard screening. Standard aneuploidy screening included assays of first- or second-trimester serum biomarkers with or without fetal nuchal translucency measurement.

This study enrolled 2042 pregnant patients ages 18 to 49 (mean: 29.6 years) with singleton pregnancies. The population was racially and ethnically diverse (65% white, 22% black, 11% Hispanic, 7% Asian). This study included women with diabetes mellitus, thyroid disorders, and other comorbidities. cfDNA testing was done on 1909 maternal blood samples for trisomy 21 and 1905 for trisomy 18.

cfDNA and standard aneuploidy screening results were compared to pregnancy outcomes. The presence of aneuploidy was determined by physician-documented newborn physical exam (97%) or karyotype analysis (3%). In both live and non-live births, the incidence of trisomy 21 was 5 of 1909 cases (0.3%) and the incidence of trisomy 18 was 2 of 1905 cases (0.1%).

The NPV of cfDNA in this study was 100% (95% confidence interval, 99.8%-100%) for both trisomy 21 and trisomy 18. The positive predictive value (PPV) was higher with cfDNA compared to standard screening (45.5% vs 4.2% for trisomy 21 and 40% vs 8.3% for trisomy 18). This means that approximately 1 in 25 women with a positive standard aneuploidy screen actually has aneuploidy. In contrast, nearly one in 2 women with a positive cfDNA result has aneuploidy.

Similarly, false positive rates with cfDNA were significantly lower than those with standard screening. For trisomy 21, the cfDNA false positive rate was 0.3% compared to 3.6% for standard screening (P<.001); for trisomy 18, the cfDNA false positive rate was 0.2% compared to 0.6% for standard screening (P=.03).

NEXT was a prospective, blinded cohort study that compared cfDNA testing with standard first-trimester screening (with measurements of nuchal translucency and serum biochemical analysis) in a routine prenatal population at 35 centers in 6 countries.

This study enrolled 18,955 women ages 18 to 48 (mean: 31 years) who underwent traditional first-trimester screening and cfDNA testing. Eligible patients included pregnant women with a singleton pregnancy with a gestational age between 10 and 14.3 weeks. Prenatal screening results were compared to newborn outcomes using a documented newborn physical examination and, if performed, results of genetic testing. For women who had a miscarriage or stillbirth or chose to terminate the pregnancy, outcomes were determined by diagnostic genetic testing.

The primary outcome was the area under the receiver-operating-characteristic (ROC) curve for trisomy 21. Area under the ROC curve is a measure of a diagnostic test’s accuracy that plots sensitivity against 1-specificity; <.700 is considered a poor test, whereas 1.00 is a perfect test. A secondary analysis evaluated cfDNA testing in low-risk women (ages <35 years).

cfDNA can't detect neural tube or ventral wall defects, so women who choose this method should be offered maternal serum alpha-fetoprotein or ultrasound evaluation.

The area under the ROC curve was 0.999 for cfDNA compared with 0.958 for standard screening (P=.001). For diagnosis of trisomy 21, cfDNA had a higher PPV than standard testing (80.9% vs 3.4%; P<.001) and a lower false positive rate (0.06% vs 5.4%; P<.001). These findings were consistent in the secondary analysis of low-risk women.

Both the CARE and NEXT trials also evaluated cfDNA testing vs standard screening for diagnosis of trisomy 13 and 18 and found higher PPVs and lower false positive rates for cfDNA compared with traditional screening.

WHAT'S NEW

Previously, cfDNA was recommended only for women with high-risk pregnancies. The new data demonstrate that cfDNA has substantially better PPVs and lower false positive rates than standard fetal aneuploidy screening for the general obstetrical population.

So while conventional screening tests remain the most appropriate methods for aneuploidy detection in the general obstetrical population, according to ACOG and SMFM, the 2 groups now recommend that all screening options—including cfDNA—be discussed with every woman. Any woman may choose cfDNA but should be counseled about the risks and benefits.⁸

CAVEATS

Both the CARE and NEXT studies had limitations. They compared cfDNA testing with first- or second-trimester screening and did not evaluate integrated screening methods (sequential first- and second-trimester biomarkers plus first-trimester nuchal translucency), which have a slightly higher sensitivity and specificity than first-trimester screening alone.

Multiple companies offer cfDNA, and the test is not subject to Food and Drug Administration approval. The CARE and NEXT studies used tests from companies that provided funding for these studies and employ several of the study authors.

Although cfDNA has increased specificity compared to standard screening, there have been case reports of false negative results. Further testing has shown that such false negative results could be caused by mosaicism in either the fetus and/or placenta, vanishing twins, or maternal malignancies.^8-10

In the CARE and NEXT trials, cfDNA produced no results in 0.9% and 3% of women, respectively. Patients for whom cfDNA testing yields no results have higher rates of aneuploidy, and therefore require further diagnostic testing.

Many insurance companies do not yet cover cfDNA for women with low-risk pregnancies, and the test may cost up to $1,700.

Because the prevalence of aneuploidy is lower in the general obstetric population than it is among women whose pregnancies are at high risk for aneuploidy, the PPV of cfDNA testing is also lower in the general obstetric population. This means that there are more false positive results for women at lower risk for aneuploidy. Therefore, it is imperative that women with positive cfDNA tests receive follow-up diagnostic testing such as chorionic villus sampling or amniocentesis before making a decision about termination.

All commercially available cfDNA tests have high sensitivity and specificity for trisomy 21, 18, and 13. Some offer testing for sex chromosome abnormalities and microdeletions. However, current cfDNA testing methods are unable to detect up to 17% of other clinically significant chromosomal abnormalities,¹¹ and cfDNA cannot detect neural tube or ventral wall defects. Therefore, ACOG and SMFM recommend that women who choose cfDNA as their aneuploidy screening method should also be offered maternal serum alpha-fetoprotein or ultrasound evaluation.

CHALLENGES TO IMPLEMENTATION

cfDNA testing is validated only for singleton pregnancies. Physicians should obtain a baseline fetal ultrasound to confirm the number of fetuses, gestational age, and viability before ordering cfDNA to ensure it is the most appropriate screening test. This may add to the overall number of early pregnancy ultrasounds conducted.

Counseling patients about aneuploidy screening options is time-consuming, and requires discussion of the limitations of each screening method and caution that a negative cfDNA result does not guarantee an unaffected fetus, nor does a positive result guarantee an affected fetus. However, aneuploidy screening is well within the scope of care for family physicians who provide prenatal care, and referral to genetic specialists is not necessary or recommended.

Some patients may request cfDNA in order to facilitate earlier identification of fetal sex. In such cases, physicians should advise patients that cfDNA testing also assesses trisomy risk. Patients who do not wish to assess their risk for aneuploidy should not receive cfDNA testing.

Finally, while cfDNA is routinely recommended for women with pregnancies considered at high risk for aneuploidy, many insurance companies do not cover the cost of cfDNA for women with low-risk pregnancies, and the test may cost up to $1,700.¹² The overall cost-effectiveness of cfDNA for aneuploidy screening in low-risk women is unknown.

ACKNOWLEDGEMENT 
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative case

A 28-year-old gravida 2, para 1001 at 10 weeks gestation presents to your clinic for a routine first-trimester prenatal visit. Her first child has no known chromosomal abnormalities and she has no family history of aneuploidy. She asks you which tests are available to screen her fetus for chromosomal abnormalities.

Pregnant women have traditionally been offered some combination of serum biomarkers and nuchal translucency to assess the risk of fetal aneuploidy. Cell-free DNA testing (cfDNA) is a form of noninvasive prenatal testing that uses maternal serum samples to conduct massively parallel sequencing of cell-free fetal DNA fragments. It has been offered to pregnant women as a screening test to detect fetal chromosomal abnormalities since 2011 after multiple clinical studies found high sensitivities, specificities, and negative predictive values (NPVs) for detecting aneuploidy.^3-6 However until 2015, practice guidelines from the American Congress of Obstetricians and Gynecologists (ACOG) recommended that standard aneuploidy screening or diagnostic testing be offered to all pregnant women and cfDNA be reserved for women with pregnancies at high risk for aneuploidy (strength of recommendation: B).⁷

CARE (Comparison of Aneuploidy Risk Evaluation) and NEXT (Noninvasive Examination of Trisomy) are 2 large studies that compared cfDNA and standard aneuploidy screening methods in pregnant women at low risk for fetal aneuploidy. Based on new data from these and other studies, ACOG and the Society for Maternal-Fetal Medicine (SMFM) released a new consensus statement in June 2015 that addressed the use of cfDNA in the general obstetric population. The 2 groups still recommend conventional first- and second-trimester screening by serum chemical biomarkers and nuchal translucency as the first-line approach for low-risk women who want to pursue aneuploidy screening; however, they also recommend that the risks and benefits of cfDNA should be discussed with all patients.⁸

STUDY SUMMARIES

CARE was a prospective, blinded, multicenter (21 US sites across 14 states) study that compared the aneuploidy detection rates of cfDNA to those of standard screening. Standard aneuploidy screening included assays of first- or second-trimester serum biomarkers with or without fetal nuchal translucency measurement.

This study enrolled 2042 pregnant patients ages 18 to 49 (mean: 29.6 years) with singleton pregnancies. The population was racially and ethnically diverse (65% white, 22% black, 11% Hispanic, 7% Asian). This study included women with diabetes mellitus, thyroid disorders, and other comorbidities. cfDNA testing was done on 1909 maternal blood samples for trisomy 21 and 1905 for trisomy 18.

cfDNA and standard aneuploidy screening results were compared to pregnancy outcomes. The presence of aneuploidy was determined by physician-documented newborn physical exam (97%) or karyotype analysis (3%). In both live and non-live births, the incidence of trisomy 21 was 5 of 1909 cases (0.3%) and the incidence of trisomy 18 was 2 of 1905 cases (0.1%).

The NPV of cfDNA in this study was 100% (95% confidence interval, 99.8%-100%) for both trisomy 21 and trisomy 18. The positive predictive value (PPV) was higher with cfDNA compared to standard screening (45.5% vs 4.2% for trisomy 21 and 40% vs 8.3% for trisomy 18). This means that approximately 1 in 25 women with a positive standard aneuploidy screen actually has aneuploidy. In contrast, nearly one in 2 women with a positive cfDNA result has aneuploidy.

Similarly, false positive rates with cfDNA were significantly lower than those with standard screening. For trisomy 21, the cfDNA false positive rate was 0.3% compared to 3.6% for standard screening (P<.001); for trisomy 18, the cfDNA false positive rate was 0.2% compared to 0.6% for standard screening (P=.03).

NEXT was a prospective, blinded cohort study that compared cfDNA testing with standard first-trimester screening (with measurements of nuchal translucency and serum biochemical analysis) in a routine prenatal population at 35 centers in 6 countries.

This study enrolled 18,955 women ages 18 to 48 (mean: 31 years) who underwent traditional first-trimester screening and cfDNA testing. Eligible patients included pregnant women with a singleton pregnancy with a gestational age between 10 and 14.3 weeks. Prenatal screening results were compared to newborn outcomes using a documented newborn physical examination and, if performed, results of genetic testing. For women who had a miscarriage or stillbirth or chose to terminate the pregnancy, outcomes were determined by diagnostic genetic testing.

The primary outcome was the area under the receiver-operating-characteristic (ROC) curve for trisomy 21. Area under the ROC curve is a measure of a diagnostic test’s accuracy that plots sensitivity against 1-specificity; <.700 is considered a poor test, whereas 1.00 is a perfect test. A secondary analysis evaluated cfDNA testing in low-risk women (ages <35 years).

cfDNA can't detect neural tube or ventral wall defects, so women who choose this method should be offered maternal serum alpha-fetoprotein or ultrasound evaluation.

The area under the ROC curve was 0.999 for cfDNA compared with 0.958 for standard screening (P=.001). For diagnosis of trisomy 21, cfDNA had a higher PPV than standard testing (80.9% vs 3.4%; P<.001) and a lower false positive rate (0.06% vs 5.4%; P<.001). These findings were consistent in the secondary analysis of low-risk women.

Both the CARE and NEXT trials also evaluated cfDNA testing vs standard screening for diagnosis of trisomy 13 and 18 and found higher PPVs and lower false positive rates for cfDNA compared with traditional screening.

WHAT'S NEW

Previously, cfDNA was recommended only for women with high-risk pregnancies. The new data demonstrate that cfDNA has substantially better PPVs and lower false positive rates than standard fetal aneuploidy screening for the general obstetrical population.

So while conventional screening tests remain the most appropriate methods for aneuploidy detection in the general obstetrical population, according to ACOG and SMFM, the 2 groups now recommend that all screening options—including cfDNA—be discussed with every woman. Any woman may choose cfDNA but should be counseled about the risks and benefits.⁸

CAVEATS

Both the CARE and NEXT studies had limitations. They compared cfDNA testing with first- or second-trimester screening and did not evaluate integrated screening methods (sequential first- and second-trimester biomarkers plus first-trimester nuchal translucency), which have a slightly higher sensitivity and specificity than first-trimester screening alone.

Multiple companies offer cfDNA, and the test is not subject to Food and Drug Administration approval. The CARE and NEXT studies used tests from companies that provided funding for these studies and employ several of the study authors.

Although cfDNA has increased specificity compared to standard screening, there have been case reports of false negative results. Further testing has shown that such false negative results could be caused by mosaicism in either the fetus and/or placenta, vanishing twins, or maternal malignancies.^8-10

In the CARE and NEXT trials, cfDNA produced no results in 0.9% and 3% of women, respectively. Patients for whom cfDNA testing yields no results have higher rates of aneuploidy, and therefore require further diagnostic testing.

Many insurance companies do not yet cover cfDNA for women with low-risk pregnancies, and the test may cost up to $1,700.

Because the prevalence of aneuploidy is lower in the general obstetric population than it is among women whose pregnancies are at high risk for aneuploidy, the PPV of cfDNA testing is also lower in the general obstetric population. This means that there are more false positive results for women at lower risk for aneuploidy. Therefore, it is imperative that women with positive cfDNA tests receive follow-up diagnostic testing such as chorionic villus sampling or amniocentesis before making a decision about termination.

All commercially available cfDNA tests have high sensitivity and specificity for trisomy 21, 18, and 13. Some offer testing for sex chromosome abnormalities and microdeletions. However, current cfDNA testing methods are unable to detect up to 17% of other clinically significant chromosomal abnormalities,¹¹ and cfDNA cannot detect neural tube or ventral wall defects. Therefore, ACOG and SMFM recommend that women who choose cfDNA as their aneuploidy screening method should also be offered maternal serum alpha-fetoprotein or ultrasound evaluation.

CHALLENGES TO IMPLEMENTATION

cfDNA testing is validated only for singleton pregnancies. Physicians should obtain a baseline fetal ultrasound to confirm the number of fetuses, gestational age, and viability before ordering cfDNA to ensure it is the most appropriate screening test. This may add to the overall number of early pregnancy ultrasounds conducted.

Counseling patients about aneuploidy screening options is time-consuming, and requires discussion of the limitations of each screening method and caution that a negative cfDNA result does not guarantee an unaffected fetus, nor does a positive result guarantee an affected fetus. However, aneuploidy screening is well within the scope of care for family physicians who provide prenatal care, and referral to genetic specialists is not necessary or recommended.

Some patients may request cfDNA in order to facilitate earlier identification of fetal sex. In such cases, physicians should advise patients that cfDNA testing also assesses trisomy risk. Patients who do not wish to assess their risk for aneuploidy should not receive cfDNA testing.

Finally, while cfDNA is routinely recommended for women with pregnancies considered at high risk for aneuploidy, many insurance companies do not cover the cost of cfDNA for women with low-risk pregnancies, and the test may cost up to $1,700.¹² The overall cost-effectiveness of cfDNA for aneuploidy screening in low-risk women is unknown.

ACKNOWLEDGEMENT 
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative case

A 28-year-old gravida 2, para 1001 at 10 weeks gestation presents to your clinic for a routine first-trimester prenatal visit. Her first child has no known chromosomal abnormalities and she has no family history of aneuploidy. She asks you which tests are available to screen her fetus for chromosomal abnormalities.

Pregnant women have traditionally been offered some combination of serum biomarkers and nuchal translucency to assess the risk of fetal aneuploidy. Cell-free DNA testing (cfDNA) is a form of noninvasive prenatal testing that uses maternal serum samples to conduct massively parallel sequencing of cell-free fetal DNA fragments. It has been offered to pregnant women as a screening test to detect fetal chromosomal abnormalities since 2011 after multiple clinical studies found high sensitivities, specificities, and negative predictive values (NPVs) for detecting aneuploidy.^3-6 However until 2015, practice guidelines from the American Congress of Obstetricians and Gynecologists (ACOG) recommended that standard aneuploidy screening or diagnostic testing be offered to all pregnant women and cfDNA be reserved for women with pregnancies at high risk for aneuploidy (strength of recommendation: B).⁷

CARE (Comparison of Aneuploidy Risk Evaluation) and NEXT (Noninvasive Examination of Trisomy) are 2 large studies that compared cfDNA and standard aneuploidy screening methods in pregnant women at low risk for fetal aneuploidy. Based on new data from these and other studies, ACOG and the Society for Maternal-Fetal Medicine (SMFM) released a new consensus statement in June 2015 that addressed the use of cfDNA in the general obstetric population. The 2 groups still recommend conventional first- and second-trimester screening by serum chemical biomarkers and nuchal translucency as the first-line approach for low-risk women who want to pursue aneuploidy screening; however, they also recommend that the risks and benefits of cfDNA should be discussed with all patients.⁸

STUDY SUMMARIES

CARE was a prospective, blinded, multicenter (21 US sites across 14 states) study that compared the aneuploidy detection rates of cfDNA to those of standard screening. Standard aneuploidy screening included assays of first- or second-trimester serum biomarkers with or without fetal nuchal translucency measurement.

This study enrolled 2042 pregnant patients ages 18 to 49 (mean: 29.6 years) with singleton pregnancies. The population was racially and ethnically diverse (65% white, 22% black, 11% Hispanic, 7% Asian). This study included women with diabetes mellitus, thyroid disorders, and other comorbidities. cfDNA testing was done on 1909 maternal blood samples for trisomy 21 and 1905 for trisomy 18.

cfDNA and standard aneuploidy screening results were compared to pregnancy outcomes. The presence of aneuploidy was determined by physician-documented newborn physical exam (97%) or karyotype analysis (3%). In both live and non-live births, the incidence of trisomy 21 was 5 of 1909 cases (0.3%) and the incidence of trisomy 18 was 2 of 1905 cases (0.1%).

The NPV of cfDNA in this study was 100% (95% confidence interval, 99.8%-100%) for both trisomy 21 and trisomy 18. The positive predictive value (PPV) was higher with cfDNA compared to standard screening (45.5% vs 4.2% for trisomy 21 and 40% vs 8.3% for trisomy 18). This means that approximately 1 in 25 women with a positive standard aneuploidy screen actually has aneuploidy. In contrast, nearly one in 2 women with a positive cfDNA result has aneuploidy.

Similarly, false positive rates with cfDNA were significantly lower than those with standard screening. For trisomy 21, the cfDNA false positive rate was 0.3% compared to 3.6% for standard screening (P<.001); for trisomy 18, the cfDNA false positive rate was 0.2% compared to 0.6% for standard screening (P=.03).

NEXT was a prospective, blinded cohort study that compared cfDNA testing with standard first-trimester screening (with measurements of nuchal translucency and serum biochemical analysis) in a routine prenatal population at 35 centers in 6 countries.

This study enrolled 18,955 women ages 18 to 48 (mean: 31 years) who underwent traditional first-trimester screening and cfDNA testing. Eligible patients included pregnant women with a singleton pregnancy with a gestational age between 10 and 14.3 weeks. Prenatal screening results were compared to newborn outcomes using a documented newborn physical examination and, if performed, results of genetic testing. For women who had a miscarriage or stillbirth or chose to terminate the pregnancy, outcomes were determined by diagnostic genetic testing.

The primary outcome was the area under the receiver-operating-characteristic (ROC) curve for trisomy 21. Area under the ROC curve is a measure of a diagnostic test’s accuracy that plots sensitivity against 1-specificity; <.700 is considered a poor test, whereas 1.00 is a perfect test. A secondary analysis evaluated cfDNA testing in low-risk women (ages <35 years).

cfDNA can't detect neural tube or ventral wall defects, so women who choose this method should be offered maternal serum alpha-fetoprotein or ultrasound evaluation.

The area under the ROC curve was 0.999 for cfDNA compared with 0.958 for standard screening (P=.001). For diagnosis of trisomy 21, cfDNA had a higher PPV than standard testing (80.9% vs 3.4%; P<.001) and a lower false positive rate (0.06% vs 5.4%; P<.001). These findings were consistent in the secondary analysis of low-risk women.

Both the CARE and NEXT trials also evaluated cfDNA testing vs standard screening for diagnosis of trisomy 13 and 18 and found higher PPVs and lower false positive rates for cfDNA compared with traditional screening.

WHAT'S NEW

Previously, cfDNA was recommended only for women with high-risk pregnancies. The new data demonstrate that cfDNA has substantially better PPVs and lower false positive rates than standard fetal aneuploidy screening for the general obstetrical population.

So while conventional screening tests remain the most appropriate methods for aneuploidy detection in the general obstetrical population, according to ACOG and SMFM, the 2 groups now recommend that all screening options—including cfDNA—be discussed with every woman. Any woman may choose cfDNA but should be counseled about the risks and benefits.⁸

CAVEATS

Both the CARE and NEXT studies had limitations. They compared cfDNA testing with first- or second-trimester screening and did not evaluate integrated screening methods (sequential first- and second-trimester biomarkers plus first-trimester nuchal translucency), which have a slightly higher sensitivity and specificity than first-trimester screening alone.

Multiple companies offer cfDNA, and the test is not subject to Food and Drug Administration approval. The CARE and NEXT studies used tests from companies that provided funding for these studies and employ several of the study authors.

Although cfDNA has increased specificity compared to standard screening, there have been case reports of false negative results. Further testing has shown that such false negative results could be caused by mosaicism in either the fetus and/or placenta, vanishing twins, or maternal malignancies.^8-10

In the CARE and NEXT trials, cfDNA produced no results in 0.9% and 3% of women, respectively. Patients for whom cfDNA testing yields no results have higher rates of aneuploidy, and therefore require further diagnostic testing.

Many insurance companies do not yet cover cfDNA for women with low-risk pregnancies, and the test may cost up to $1,700.

Because the prevalence of aneuploidy is lower in the general obstetric population than it is among women whose pregnancies are at high risk for aneuploidy, the PPV of cfDNA testing is also lower in the general obstetric population. This means that there are more false positive results for women at lower risk for aneuploidy. Therefore, it is imperative that women with positive cfDNA tests receive follow-up diagnostic testing such as chorionic villus sampling or amniocentesis before making a decision about termination.

All commercially available cfDNA tests have high sensitivity and specificity for trisomy 21, 18, and 13. Some offer testing for sex chromosome abnormalities and microdeletions. However, current cfDNA testing methods are unable to detect up to 17% of other clinically significant chromosomal abnormalities,¹¹ and cfDNA cannot detect neural tube or ventral wall defects. Therefore, ACOG and SMFM recommend that women who choose cfDNA as their aneuploidy screening method should also be offered maternal serum alpha-fetoprotein or ultrasound evaluation.

CHALLENGES TO IMPLEMENTATION

cfDNA testing is validated only for singleton pregnancies. Physicians should obtain a baseline fetal ultrasound to confirm the number of fetuses, gestational age, and viability before ordering cfDNA to ensure it is the most appropriate screening test. This may add to the overall number of early pregnancy ultrasounds conducted.

Counseling patients about aneuploidy screening options is time-consuming, and requires discussion of the limitations of each screening method and caution that a negative cfDNA result does not guarantee an unaffected fetus, nor does a positive result guarantee an affected fetus. However, aneuploidy screening is well within the scope of care for family physicians who provide prenatal care, and referral to genetic specialists is not necessary or recommended.

Some patients may request cfDNA in order to facilitate earlier identification of fetal sex. In such cases, physicians should advise patients that cfDNA testing also assesses trisomy risk. Patients who do not wish to assess their risk for aneuploidy should not receive cfDNA testing.

Finally, while cfDNA is routinely recommended for women with pregnancies considered at high risk for aneuploidy, many insurance companies do not cover the cost of cfDNA for women with low-risk pregnancies, and the test may cost up to $1,700.¹² The overall cost-effectiveness of cfDNA for aneuploidy screening in low-risk women is unknown.

ACKNOWLEDGEMENT 
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ANSWER
This ECG is representative of marked sinus bradycardia with second-degree atrioventricular block (Mobitz I) with an occasional junctional escape, left-axis deviation, and poor R-wave progression in the precordial leads.

Marked sinus bradycardia is evidenced by P waves that are regular except where expected, prior to the third QRS complex on the rhythm strip (lead 1).

Second-­degree Mobitz I (Wenckebach) block is indicated by a gradual prolonging of the PR interval until there is loss of conduction from the atria to the ventricle (following the third P wave). Careful inspection of the third QRS complex shows a slight difference in the normally conducted sinus beat, indicative of a junctional escape beat. Left-axis deviation entails an R-wave axis of –78°.

Finally, there is poor R-wave progression in the precordial leads, including the lateral leads.

Although Mobitz I block is not an indication for pacemaker placement, symptomatic bradycardia is. The patient underwent implantation of a dual-chamber permanent pacemaker, with complete resolution of symptoms.

ANSWER
This ECG is representative of marked sinus bradycardia with second-degree atrioventricular block (Mobitz I) with an occasional junctional escape, left-axis deviation, and poor R-wave progression in the precordial leads.

Marked sinus bradycardia is evidenced by P waves that are regular except where expected, prior to the third QRS complex on the rhythm strip (lead 1).

Second-­degree Mobitz I (Wenckebach) block is indicated by a gradual prolonging of the PR interval until there is loss of conduction from the atria to the ventricle (following the third P wave). Careful inspection of the third QRS complex shows a slight difference in the normally conducted sinus beat, indicative of a junctional escape beat. Left-axis deviation entails an R-wave axis of –78°.

Finally, there is poor R-wave progression in the precordial leads, including the lateral leads.

Although Mobitz I block is not an indication for pacemaker placement, symptomatic bradycardia is. The patient underwent implantation of a dual-chamber permanent pacemaker, with complete resolution of symptoms.

ANSWER
This ECG is representative of marked sinus bradycardia with second-degree atrioventricular block (Mobitz I) with an occasional junctional escape, left-axis deviation, and poor R-wave progression in the precordial leads.

Marked sinus bradycardia is evidenced by P waves that are regular except where expected, prior to the third QRS complex on the rhythm strip (lead 1).

Second-­degree Mobitz I (Wenckebach) block is indicated by a gradual prolonging of the PR interval until there is loss of conduction from the atria to the ventricle (following the third P wave). Careful inspection of the third QRS complex shows a slight difference in the normally conducted sinus beat, indicative of a junctional escape beat. Left-axis deviation entails an R-wave axis of –78°.

Finally, there is poor R-wave progression in the precordial leads, including the lateral leads.

Although Mobitz I block is not an indication for pacemaker placement, symptomatic bradycardia is. The patient underwent implantation of a dual-chamber permanent pacemaker, with complete resolution of symptoms.

Despite advances in human immunodeficiency virus (HIV) screening and treatment over the last 30 years, HIV remains a public health concern. In the United States, after an initial decline, total HIV incidence has failed to significantly decrease in the last 25 years. More than 1.2 million people are living with HIV in the United States, and 12.8% of them (156,300) are unaware they are affected.¹ Of those diagnosed with HIV, only 30% are receiving treatment and are virally suppressed.² Due to structural inequalities and psychosocial factors, African American and Latino patients remain disproportionately affected.³ The incidence of HIV infection among men who have sex with men has increased, and the incidence of HIV infection among people who inject drugs has plateaued after years of progressive decline.⁴

HIV prevention strategies are highly effective, but in general are underutilized. This article reviews 3 prevention strategies that can be administered by family physicians: HIV screening, pre-exposure prophylaxis (PrEP), and harm reduction.

Who and how to screen for HIV

Early identification of HIV infection generally leads to reduced transmission because diagnosis is associated with decreases in risky behavior.^5,6 In addition, antiretroviral therapy (ART) is more effective when initiated early, before the development of advanced immunosuppression.^7-9

The “window period” of acute HIV infection (AHI) is the time from when the virus is transmitted to when markers of infection can be detected. Because this window period is associated with high viral transmission rates, family physicians must be familiar with symptoms of AHI (TABLE 1)^10,11 and associated risk factors (eg, recent condomless sex or sharing of drug injection equipment with someone who is HIV-positive or of unknown HIV status).

Screening for HIV solely based on the presence of risk factors or clinical symptoms is not enough, however. The United States Preventive Services Task Force (USPSTF) recommends screening all pregnant women and individuals ages 15 to 65 for HIV.¹² Screening based solely on risk factors or clinical symptoms frequently leads to missed diagnoses and identification of HIV infection at more advanced stages.^13,14 Both the USPSTF and the Centers for Disease Control and Prevention (CDC) recommend universal opt-out screening (patients are informed that HIV screening will be performed and that they may decline testing) because such screening identifies HIV earlier and is associated with higher testing rates than opt-in screening, which requires explicit written consent and extensive pre-test counseling.

Which test to use. HIV screening with a fourth-generation antigen/antibody combination immunoassay—which detects both HIV p24 antigen and HIV antibodies—provides greater diagnostic accuracy than older tests.¹⁵ These newer tests detect HIV approximately 15 days after initial infection, reducing the window period of AHI.^15,16 If you suspect a patient has AHI, consider early repeat HIV testing with a fourth-generation assay, or initial co-testing with a fourth-generation assay and a nucleic acid amplification test for HIV RNA, which makes it possible to detect infection approximately 5 days earlier than fourth-generation assays.¹⁵

Offer pre-exposure prophylaxis to high-risk patients

PrEP is the use of ART prior to HIV exposure to prevent transmission of the virus. It should be used with conventional risk reduction strategies, such as providing condoms, counseling patients about reducing risky behaviors, supporting medication adherence, and screening for and treating other sexually transmitted infections.

Both the USPSTF and the CDC recommend universal opt-out HIV screening because such screening is associated with higher testing rates than opt-in screening.

The US Food and Drug Administration (FDA) has approved only one medication, Truvada (tenofovir disoproxil fumarate/emtricitabine; TDF/FTC), for use as PrEP. Oral tenofovir-based regimens can effectively prevent HIV transmission,^17-20 and strong adherence is associated with a risk reduction of 90% to 100%.^17-23 The protective effect of oral PrEP is particularly strong in high-risk populations (eg, men who have sex with men, people who inject drugs), where the number needed to treat to prevent one HIV infection ranges from 12 to 100, depending on the patients’ risk profile.^24-26 The CDC and Department of Health and Human Services have issued guidelines for using PrEP in high-risk patients.²⁷ 

Barriers to implementing PrEP. Despite being highly effective, PrEP is not routinely prescribed to high-risk patients; modeling suggests that current use of PrEP is insufficient to significantly impact the incidence of HIV.²⁸ Demand for PrEP is high among target groups,^21,29,30 but patients have expressed concerns about adverse effects³¹ and stigma related to ART, HIV, and being at risk for HIV.^32,33 Young age, lack of social support, low perception of risk, and failure to show up for appointments are also barriers to PrEP use.^28,30,34

Some physicians have expressed concern that prescribing PrEP may promote high-risk sexual behavior.³⁵ However, because PrEP is most beneficial in individuals who already engage in high-risk sexual behavior, strategic delivery of PrEP remains an effective risk-reducing strategy.^{17,18,21,26,36,37} Even in instances where PrEP has been associated with higher-risk sexual behavior and higher rates of sexually transmitted infections, it still prevents as much as 100% of new HIV infections.³⁸

Fear of drug resistance also contributes to slow implementation of PrEP. Drug resistance has been observed in clinical trials of PrEP, but it has been exceedingly rare and predominantly limited to patients who had unrecognized AHI when they started PrEP.³⁹ Furthermore, the few cases of drug resistance attributable to PrEP pale in comparison to the large number of estimated HIV infections averted—infections that would require lifelong ART with its own associated risks of drug resistance. By decreasing HIV transmission, PrEP is expected to decrease total drug resistance.⁴⁰

Cost is another obstacle. Truvada costs approximately $1,540 per month.⁴¹ However, analysis has demonstrated that PrEP is cost-effective when targeted to high-risk patients.⁴² Most insurance plans cover PrEP, but often require high deductibles and copays; fortunately, this financial burden for patients can be mitigated or eliminated by co-pay assistance programs. The manufacturer of Truvada offers assistance programs for both insured and uninsured patients who are candidates for PrEP; details are available at http://www.truvada.com/truvada-patient-assistance.

Stigma has historically burdened individuals who seek to protect their sexual health, including HIV-negative individuals who are candidates for PrEP. Stigma surrounding HIV may decrease ART-based HIV prevention in men who have sex with men,⁴³ while increasing high-risk behaviors⁴⁴ and all-cause mortality.⁴⁵

The resources listed in TABLE 2 can help physicians overcome some of the barriers to implementing PrEP.

How to deliver PrEP

Whether HIV specialists or primary care clinicians are best suited to provide PrEP is a subject of debate. HIV specialists are most familiar with ART and routine monitoring of adherence; however, they have less access to HIV-negative patients, who are the target group for PrEP.³⁵ Family physicians tend to work in closer proximity and maintain longitudinal relationships with PrEP target groups, but in general have less experience with ART and evaluating AHI. Some may argue that competing demands may make it impractical to take a detailed sexual history during a primary care visit.⁴⁶ In truth, both HIV specialists and family physicians can be appropriately equipped to provide PrEP.

TABLE 3 outlines the steps necessary to provide a patient with PrEP.⁴⁷ Assessing risk is the initial step; PrEP is beneficial for patients who have one or more risk factors for HIV infection. To be eligible for TDF/FTC, a patient must be HIV-negative, and should be tested for hepatitis B virus (HBV) infection and kidney disease. Because TDF/FTC treats HBV infection, candidates for PrEP who test positive for HBV should be evaluated for treatment of HBV before initiating PrEP. Candidates for PrEP who test negative for HBV infection and immunity should be vaccinated.

Candidates for PrEP should also be screened and monitored for kidney disease. TDF can cause increased serum creatinine due to tubular toxicity. A patient who has an estimated creatinine clearance <60 mL/min should not receive TDF/FTC for PrEP. If a patient’s estimated creatinine clearance falls below 60 mL/min or serum creatinine increases by 0.3 mg/dL above baseline after PrEP is started, TDF/FTC should be discontinued, and the patient should be evaluated for the underlying cause of the kidney disease.²⁷

Before starting PrEP, candidates should be screened for HIV infection and symptoms of AHI. Strongly consider testing for sexually transmitted infections that may increase the risk of HIV transmission, such as syphilis, gonorrhea, or chlamydia.

Strong adherence to pre-exposure prophylaxis for HIV is associated with a risk reduction of 90% to 100%.

Candidates who are eligible for PrEP must be counseled on medication adverse effects, adherence strategies, and symptoms of sexually transmitted infections. To initiate PrEP, candidates may be given a one-month supply of TDF/FTC; adherence, adverse effects, and other risk-reduction strategies are assessed at an office visit 3 to 4 weeks later. Subsequent prescriptions are then dispensed as a 3-month supply, with office visits to monitor PrEP scheduled for at least once every 3 months. During these monitoring visits, evaluate the patient’s HIV status, pregnancy status, adherence, adverse effects, risk-reduction behaviors, and indications for continued PrEP. Every 6 months, renal function and sexually transmitted infection status should be reassessed. 

Reducing risk of harm among patients who inject drugs

Nonsexual transmission of HIV is a route of high infectivity.⁴⁸ It includes transfusion of infected blood, sharing of equipment during injection drug use, and percutaneous needle sticks. Sharing of equipment during injection drug use is estimated to account for 8% of new infections in the United States.⁴

Harm reduction is a collection of strategies meant to reduce complications of illicit drug use, including HIV transmission. These strategies include needle and syringe programs that provide injection drug users with sterile equipment, and opioid substitution therapy.

Needle and syringe programs decrease HIV transmission⁴⁹ and risky behaviors related to injection drug use,⁵⁰ but federal funding of such programs is prohibited. Opioid substitution therapy reduces the incidence of HIV,^50,51 injection drug use, sharing of drug preparation and injection equipment, and drug-related behaviors associated with a high risk of HIV transmission.^50,52 However, in the United States, the quality of these programs varies; a study of opioid substitution therapy delivery found that 22.8% of programs provided doses that were too low to be effective.⁵³

In clinical trials of pre-exposure prophylaxis, drug resistance has been rare and mostly limited to those who had unrecognized acute HIV infection.

FDA-approved medications for opioid substitution therapy include sublingual buprenorphine, sublingual buprenorphine/naloxone tablets or strips (Suboxone), and oral methadone. Buprenorphine-based regimens can be provided by appropriately trained primary care clinicians; methadone requires a referral to a narcotic treatment program. TABLE 4 provides training and support resources for physicians who want to integrate opioid substitution therapy into their clinical practice.

CORRESPONDENCE
Richard Moore II, MD, 250 Smith Church Road, Roanoke Rapids, NC 27870; [email protected].

Despite advances in human immunodeficiency virus (HIV) screening and treatment over the last 30 years, HIV remains a public health concern. In the United States, after an initial decline, total HIV incidence has failed to significantly decrease in the last 25 years. More than 1.2 million people are living with HIV in the United States, and 12.8% of them (156,300) are unaware they are affected.¹ Of those diagnosed with HIV, only 30% are receiving treatment and are virally suppressed.² Due to structural inequalities and psychosocial factors, African American and Latino patients remain disproportionately affected.³ The incidence of HIV infection among men who have sex with men has increased, and the incidence of HIV infection among people who inject drugs has plateaued after years of progressive decline.⁴

HIV prevention strategies are highly effective, but in general are underutilized. This article reviews 3 prevention strategies that can be administered by family physicians: HIV screening, pre-exposure prophylaxis (PrEP), and harm reduction.

Who and how to screen for HIV

Early identification of HIV infection generally leads to reduced transmission because diagnosis is associated with decreases in risky behavior.^5,6 In addition, antiretroviral therapy (ART) is more effective when initiated early, before the development of advanced immunosuppression.^7-9

The “window period” of acute HIV infection (AHI) is the time from when the virus is transmitted to when markers of infection can be detected. Because this window period is associated with high viral transmission rates, family physicians must be familiar with symptoms of AHI (TABLE 1)^10,11 and associated risk factors (eg, recent condomless sex or sharing of drug injection equipment with someone who is HIV-positive or of unknown HIV status).

Screening for HIV solely based on the presence of risk factors or clinical symptoms is not enough, however. The United States Preventive Services Task Force (USPSTF) recommends screening all pregnant women and individuals ages 15 to 65 for HIV.¹² Screening based solely on risk factors or clinical symptoms frequently leads to missed diagnoses and identification of HIV infection at more advanced stages.^13,14 Both the USPSTF and the Centers for Disease Control and Prevention (CDC) recommend universal opt-out screening (patients are informed that HIV screening will be performed and that they may decline testing) because such screening identifies HIV earlier and is associated with higher testing rates than opt-in screening, which requires explicit written consent and extensive pre-test counseling.

Which test to use. HIV screening with a fourth-generation antigen/antibody combination immunoassay—which detects both HIV p24 antigen and HIV antibodies—provides greater diagnostic accuracy than older tests.¹⁵ These newer tests detect HIV approximately 15 days after initial infection, reducing the window period of AHI.^15,16 If you suspect a patient has AHI, consider early repeat HIV testing with a fourth-generation assay, or initial co-testing with a fourth-generation assay and a nucleic acid amplification test for HIV RNA, which makes it possible to detect infection approximately 5 days earlier than fourth-generation assays.¹⁵

Offer pre-exposure prophylaxis to high-risk patients

PrEP is the use of ART prior to HIV exposure to prevent transmission of the virus. It should be used with conventional risk reduction strategies, such as providing condoms, counseling patients about reducing risky behaviors, supporting medication adherence, and screening for and treating other sexually transmitted infections.

Both the USPSTF and the CDC recommend universal opt-out HIV screening because such screening is associated with higher testing rates than opt-in screening.

The US Food and Drug Administration (FDA) has approved only one medication, Truvada (tenofovir disoproxil fumarate/emtricitabine; TDF/FTC), for use as PrEP. Oral tenofovir-based regimens can effectively prevent HIV transmission,^17-20 and strong adherence is associated with a risk reduction of 90% to 100%.^17-23 The protective effect of oral PrEP is particularly strong in high-risk populations (eg, men who have sex with men, people who inject drugs), where the number needed to treat to prevent one HIV infection ranges from 12 to 100, depending on the patients’ risk profile.^24-26 The CDC and Department of Health and Human Services have issued guidelines for using PrEP in high-risk patients.²⁷ 

Barriers to implementing PrEP. Despite being highly effective, PrEP is not routinely prescribed to high-risk patients; modeling suggests that current use of PrEP is insufficient to significantly impact the incidence of HIV.²⁸ Demand for PrEP is high among target groups,^21,29,30 but patients have expressed concerns about adverse effects³¹ and stigma related to ART, HIV, and being at risk for HIV.^32,33 Young age, lack of social support, low perception of risk, and failure to show up for appointments are also barriers to PrEP use.^28,30,34

Some physicians have expressed concern that prescribing PrEP may promote high-risk sexual behavior.³⁵ However, because PrEP is most beneficial in individuals who already engage in high-risk sexual behavior, strategic delivery of PrEP remains an effective risk-reducing strategy.^{17,18,21,26,36,37} Even in instances where PrEP has been associated with higher-risk sexual behavior and higher rates of sexually transmitted infections, it still prevents as much as 100% of new HIV infections.³⁸

Fear of drug resistance also contributes to slow implementation of PrEP. Drug resistance has been observed in clinical trials of PrEP, but it has been exceedingly rare and predominantly limited to patients who had unrecognized AHI when they started PrEP.³⁹ Furthermore, the few cases of drug resistance attributable to PrEP pale in comparison to the large number of estimated HIV infections averted—infections that would require lifelong ART with its own associated risks of drug resistance. By decreasing HIV transmission, PrEP is expected to decrease total drug resistance.⁴⁰

Cost is another obstacle. Truvada costs approximately $1,540 per month.⁴¹ However, analysis has demonstrated that PrEP is cost-effective when targeted to high-risk patients.⁴² Most insurance plans cover PrEP, but often require high deductibles and copays; fortunately, this financial burden for patients can be mitigated or eliminated by co-pay assistance programs. The manufacturer of Truvada offers assistance programs for both insured and uninsured patients who are candidates for PrEP; details are available at http://www.truvada.com/truvada-patient-assistance.

Stigma has historically burdened individuals who seek to protect their sexual health, including HIV-negative individuals who are candidates for PrEP. Stigma surrounding HIV may decrease ART-based HIV prevention in men who have sex with men,⁴³ while increasing high-risk behaviors⁴⁴ and all-cause mortality.⁴⁵

The resources listed in TABLE 2 can help physicians overcome some of the barriers to implementing PrEP.

How to deliver PrEP

Whether HIV specialists or primary care clinicians are best suited to provide PrEP is a subject of debate. HIV specialists are most familiar with ART and routine monitoring of adherence; however, they have less access to HIV-negative patients, who are the target group for PrEP.³⁵ Family physicians tend to work in closer proximity and maintain longitudinal relationships with PrEP target groups, but in general have less experience with ART and evaluating AHI. Some may argue that competing demands may make it impractical to take a detailed sexual history during a primary care visit.⁴⁶ In truth, both HIV specialists and family physicians can be appropriately equipped to provide PrEP.

TABLE 3 outlines the steps necessary to provide a patient with PrEP.⁴⁷ Assessing risk is the initial step; PrEP is beneficial for patients who have one or more risk factors for HIV infection. To be eligible for TDF/FTC, a patient must be HIV-negative, and should be tested for hepatitis B virus (HBV) infection and kidney disease. Because TDF/FTC treats HBV infection, candidates for PrEP who test positive for HBV should be evaluated for treatment of HBV before initiating PrEP. Candidates for PrEP who test negative for HBV infection and immunity should be vaccinated.

Candidates for PrEP should also be screened and monitored for kidney disease. TDF can cause increased serum creatinine due to tubular toxicity. A patient who has an estimated creatinine clearance <60 mL/min should not receive TDF/FTC for PrEP. If a patient’s estimated creatinine clearance falls below 60 mL/min or serum creatinine increases by 0.3 mg/dL above baseline after PrEP is started, TDF/FTC should be discontinued, and the patient should be evaluated for the underlying cause of the kidney disease.²⁷

Before starting PrEP, candidates should be screened for HIV infection and symptoms of AHI. Strongly consider testing for sexually transmitted infections that may increase the risk of HIV transmission, such as syphilis, gonorrhea, or chlamydia.

Strong adherence to pre-exposure prophylaxis for HIV is associated with a risk reduction of 90% to 100%.

Candidates who are eligible for PrEP must be counseled on medication adverse effects, adherence strategies, and symptoms of sexually transmitted infections. To initiate PrEP, candidates may be given a one-month supply of TDF/FTC; adherence, adverse effects, and other risk-reduction strategies are assessed at an office visit 3 to 4 weeks later. Subsequent prescriptions are then dispensed as a 3-month supply, with office visits to monitor PrEP scheduled for at least once every 3 months. During these monitoring visits, evaluate the patient’s HIV status, pregnancy status, adherence, adverse effects, risk-reduction behaviors, and indications for continued PrEP. Every 6 months, renal function and sexually transmitted infection status should be reassessed. 

Reducing risk of harm among patients who inject drugs

Nonsexual transmission of HIV is a route of high infectivity.⁴⁸ It includes transfusion of infected blood, sharing of equipment during injection drug use, and percutaneous needle sticks. Sharing of equipment during injection drug use is estimated to account for 8% of new infections in the United States.⁴

Harm reduction is a collection of strategies meant to reduce complications of illicit drug use, including HIV transmission. These strategies include needle and syringe programs that provide injection drug users with sterile equipment, and opioid substitution therapy.

Needle and syringe programs decrease HIV transmission⁴⁹ and risky behaviors related to injection drug use,⁵⁰ but federal funding of such programs is prohibited. Opioid substitution therapy reduces the incidence of HIV,^50,51 injection drug use, sharing of drug preparation and injection equipment, and drug-related behaviors associated with a high risk of HIV transmission.^50,52 However, in the United States, the quality of these programs varies; a study of opioid substitution therapy delivery found that 22.8% of programs provided doses that were too low to be effective.⁵³

In clinical trials of pre-exposure prophylaxis, drug resistance has been rare and mostly limited to those who had unrecognized acute HIV infection.

FDA-approved medications for opioid substitution therapy include sublingual buprenorphine, sublingual buprenorphine/naloxone tablets or strips (Suboxone), and oral methadone. Buprenorphine-based regimens can be provided by appropriately trained primary care clinicians; methadone requires a referral to a narcotic treatment program. TABLE 4 provides training and support resources for physicians who want to integrate opioid substitution therapy into their clinical practice.

CORRESPONDENCE
Richard Moore II, MD, 250 Smith Church Road, Roanoke Rapids, NC 27870; [email protected].

Despite advances in human immunodeficiency virus (HIV) screening and treatment over the last 30 years, HIV remains a public health concern. In the United States, after an initial decline, total HIV incidence has failed to significantly decrease in the last 25 years. More than 1.2 million people are living with HIV in the United States, and 12.8% of them (156,300) are unaware they are affected.¹ Of those diagnosed with HIV, only 30% are receiving treatment and are virally suppressed.² Due to structural inequalities and psychosocial factors, African American and Latino patients remain disproportionately affected.³ The incidence of HIV infection among men who have sex with men has increased, and the incidence of HIV infection among people who inject drugs has plateaued after years of progressive decline.⁴

HIV prevention strategies are highly effective, but in general are underutilized. This article reviews 3 prevention strategies that can be administered by family physicians: HIV screening, pre-exposure prophylaxis (PrEP), and harm reduction.

Who and how to screen for HIV

Early identification of HIV infection generally leads to reduced transmission because diagnosis is associated with decreases in risky behavior.^5,6 In addition, antiretroviral therapy (ART) is more effective when initiated early, before the development of advanced immunosuppression.^7-9

The “window period” of acute HIV infection (AHI) is the time from when the virus is transmitted to when markers of infection can be detected. Because this window period is associated with high viral transmission rates, family physicians must be familiar with symptoms of AHI (TABLE 1)^10,11 and associated risk factors (eg, recent condomless sex or sharing of drug injection equipment with someone who is HIV-positive or of unknown HIV status).

Screening for HIV solely based on the presence of risk factors or clinical symptoms is not enough, however. The United States Preventive Services Task Force (USPSTF) recommends screening all pregnant women and individuals ages 15 to 65 for HIV.¹² Screening based solely on risk factors or clinical symptoms frequently leads to missed diagnoses and identification of HIV infection at more advanced stages.^13,14 Both the USPSTF and the Centers for Disease Control and Prevention (CDC) recommend universal opt-out screening (patients are informed that HIV screening will be performed and that they may decline testing) because such screening identifies HIV earlier and is associated with higher testing rates than opt-in screening, which requires explicit written consent and extensive pre-test counseling.

Which test to use. HIV screening with a fourth-generation antigen/antibody combination immunoassay—which detects both HIV p24 antigen and HIV antibodies—provides greater diagnostic accuracy than older tests.¹⁵ These newer tests detect HIV approximately 15 days after initial infection, reducing the window period of AHI.^15,16 If you suspect a patient has AHI, consider early repeat HIV testing with a fourth-generation assay, or initial co-testing with a fourth-generation assay and a nucleic acid amplification test for HIV RNA, which makes it possible to detect infection approximately 5 days earlier than fourth-generation assays.¹⁵

Offer pre-exposure prophylaxis to high-risk patients

PrEP is the use of ART prior to HIV exposure to prevent transmission of the virus. It should be used with conventional risk reduction strategies, such as providing condoms, counseling patients about reducing risky behaviors, supporting medication adherence, and screening for and treating other sexually transmitted infections.

Both the USPSTF and the CDC recommend universal opt-out HIV screening because such screening is associated with higher testing rates than opt-in screening.

The US Food and Drug Administration (FDA) has approved only one medication, Truvada (tenofovir disoproxil fumarate/emtricitabine; TDF/FTC), for use as PrEP. Oral tenofovir-based regimens can effectively prevent HIV transmission,^17-20 and strong adherence is associated with a risk reduction of 90% to 100%.^17-23 The protective effect of oral PrEP is particularly strong in high-risk populations (eg, men who have sex with men, people who inject drugs), where the number needed to treat to prevent one HIV infection ranges from 12 to 100, depending on the patients’ risk profile.^24-26 The CDC and Department of Health and Human Services have issued guidelines for using PrEP in high-risk patients.²⁷ 

Barriers to implementing PrEP. Despite being highly effective, PrEP is not routinely prescribed to high-risk patients; modeling suggests that current use of PrEP is insufficient to significantly impact the incidence of HIV.²⁸ Demand for PrEP is high among target groups,^21,29,30 but patients have expressed concerns about adverse effects³¹ and stigma related to ART, HIV, and being at risk for HIV.^32,33 Young age, lack of social support, low perception of risk, and failure to show up for appointments are also barriers to PrEP use.^28,30,34

Some physicians have expressed concern that prescribing PrEP may promote high-risk sexual behavior.³⁵ However, because PrEP is most beneficial in individuals who already engage in high-risk sexual behavior, strategic delivery of PrEP remains an effective risk-reducing strategy.^{17,18,21,26,36,37} Even in instances where PrEP has been associated with higher-risk sexual behavior and higher rates of sexually transmitted infections, it still prevents as much as 100% of new HIV infections.³⁸

Fear of drug resistance also contributes to slow implementation of PrEP. Drug resistance has been observed in clinical trials of PrEP, but it has been exceedingly rare and predominantly limited to patients who had unrecognized AHI when they started PrEP.³⁹ Furthermore, the few cases of drug resistance attributable to PrEP pale in comparison to the large number of estimated HIV infections averted—infections that would require lifelong ART with its own associated risks of drug resistance. By decreasing HIV transmission, PrEP is expected to decrease total drug resistance.⁴⁰

Cost is another obstacle. Truvada costs approximately $1,540 per month.⁴¹ However, analysis has demonstrated that PrEP is cost-effective when targeted to high-risk patients.⁴² Most insurance plans cover PrEP, but often require high deductibles and copays; fortunately, this financial burden for patients can be mitigated or eliminated by co-pay assistance programs. The manufacturer of Truvada offers assistance programs for both insured and uninsured patients who are candidates for PrEP; details are available at http://www.truvada.com/truvada-patient-assistance.

Stigma has historically burdened individuals who seek to protect their sexual health, including HIV-negative individuals who are candidates for PrEP. Stigma surrounding HIV may decrease ART-based HIV prevention in men who have sex with men,⁴³ while increasing high-risk behaviors⁴⁴ and all-cause mortality.⁴⁵

The resources listed in TABLE 2 can help physicians overcome some of the barriers to implementing PrEP.

How to deliver PrEP

Whether HIV specialists or primary care clinicians are best suited to provide PrEP is a subject of debate. HIV specialists are most familiar with ART and routine monitoring of adherence; however, they have less access to HIV-negative patients, who are the target group for PrEP.³⁵ Family physicians tend to work in closer proximity and maintain longitudinal relationships with PrEP target groups, but in general have less experience with ART and evaluating AHI. Some may argue that competing demands may make it impractical to take a detailed sexual history during a primary care visit.⁴⁶ In truth, both HIV specialists and family physicians can be appropriately equipped to provide PrEP.

TABLE 3 outlines the steps necessary to provide a patient with PrEP.⁴⁷ Assessing risk is the initial step; PrEP is beneficial for patients who have one or more risk factors for HIV infection. To be eligible for TDF/FTC, a patient must be HIV-negative, and should be tested for hepatitis B virus (HBV) infection and kidney disease. Because TDF/FTC treats HBV infection, candidates for PrEP who test positive for HBV should be evaluated for treatment of HBV before initiating PrEP. Candidates for PrEP who test negative for HBV infection and immunity should be vaccinated.

Candidates for PrEP should also be screened and monitored for kidney disease. TDF can cause increased serum creatinine due to tubular toxicity. A patient who has an estimated creatinine clearance <60 mL/min should not receive TDF/FTC for PrEP. If a patient’s estimated creatinine clearance falls below 60 mL/min or serum creatinine increases by 0.3 mg/dL above baseline after PrEP is started, TDF/FTC should be discontinued, and the patient should be evaluated for the underlying cause of the kidney disease.²⁷

Before starting PrEP, candidates should be screened for HIV infection and symptoms of AHI. Strongly consider testing for sexually transmitted infections that may increase the risk of HIV transmission, such as syphilis, gonorrhea, or chlamydia.

Strong adherence to pre-exposure prophylaxis for HIV is associated with a risk reduction of 90% to 100%.

Candidates who are eligible for PrEP must be counseled on medication adverse effects, adherence strategies, and symptoms of sexually transmitted infections. To initiate PrEP, candidates may be given a one-month supply of TDF/FTC; adherence, adverse effects, and other risk-reduction strategies are assessed at an office visit 3 to 4 weeks later. Subsequent prescriptions are then dispensed as a 3-month supply, with office visits to monitor PrEP scheduled for at least once every 3 months. During these monitoring visits, evaluate the patient’s HIV status, pregnancy status, adherence, adverse effects, risk-reduction behaviors, and indications for continued PrEP. Every 6 months, renal function and sexually transmitted infection status should be reassessed. 

Reducing risk of harm among patients who inject drugs

Nonsexual transmission of HIV is a route of high infectivity.⁴⁸ It includes transfusion of infected blood, sharing of equipment during injection drug use, and percutaneous needle sticks. Sharing of equipment during injection drug use is estimated to account for 8% of new infections in the United States.⁴

Harm reduction is a collection of strategies meant to reduce complications of illicit drug use, including HIV transmission. These strategies include needle and syringe programs that provide injection drug users with sterile equipment, and opioid substitution therapy.

Needle and syringe programs decrease HIV transmission⁴⁹ and risky behaviors related to injection drug use,⁵⁰ but federal funding of such programs is prohibited. Opioid substitution therapy reduces the incidence of HIV,^50,51 injection drug use, sharing of drug preparation and injection equipment, and drug-related behaviors associated with a high risk of HIV transmission.^50,52 However, in the United States, the quality of these programs varies; a study of opioid substitution therapy delivery found that 22.8% of programs provided doses that were too low to be effective.⁵³

In clinical trials of pre-exposure prophylaxis, drug resistance has been rare and mostly limited to those who had unrecognized acute HIV infection.

FDA-approved medications for opioid substitution therapy include sublingual buprenorphine, sublingual buprenorphine/naloxone tablets or strips (Suboxone), and oral methadone. Buprenorphine-based regimens can be provided by appropriately trained primary care clinicians; methadone requires a referral to a narcotic treatment program. TABLE 4 provides training and support resources for physicians who want to integrate opioid substitution therapy into their clinical practice.

CORRESPONDENCE
Richard Moore II, MD, 250 Smith Church Road, Roanoke Rapids, NC 27870; [email protected].

In September 2015, the Centers for Medicare & Medicaid Services (CMS) launched a promising 4-year program called the "Transforming Clinical Practice Initiative" to lighten the load for family physicians.¹ The central figures in this program are skilled and trained quality improvement advisors (QIA) who will work directly with physicians and their staffs to assist with the heavy lifting of practice improvement. The Oklahoma Physicians Research and Resources Network has used QIAs, which it calls practice enhancement assistants (PEAs), for more than 20 years to help Oklahoma family physicians improve various aspects of their practices, including testing processes, diabetes care, and preventive services. The PEAs have been enormously helpful.²

For this new CMS program, the feds awarded $685 million to 39 national and regional collaborative health care transformation networks and supporting organizations to develop peer-based learning networks to facilitate practice improvements.¹ The program is designed to help more than 140,000 primary care physicians improve their practices by providing an extra set of skilled hands.

The new CMS initiative is a great opportunity to get that extra set of skilled hands you need to help meet new quality mandates.

The American Board of Family Medicine (ABFM) and the American Academy of Family Physicians (AAFP) have teamed up to assist with this national effort. ABFM will cover the cost for the first 6000 family physicians who enroll in one of the regional Practice Transformation Networks to use their newly developed chronic disease registry called PRIME. This registry will extract clinical quality data from diverse electronic health records and report back to practices. The registry will meet the new federal quality measures reporting requirements and will also be a path for maintenance of certification.

The CMS Transforming Clinical Practice Initiative is a great opportunity to get that extra set of skilled hands you need to help meet new quality mandates and make your office more efficient and enjoyable for you, your staff, and your patients. Contact the ABFM (www.theabfm.org) to find out which organization is running the Practice Transformation Network in your area.

In September 2015, the Centers for Medicare & Medicaid Services (CMS) launched a promising 4-year program called the "Transforming Clinical Practice Initiative" to lighten the load for family physicians.¹ The central figures in this program are skilled and trained quality improvement advisors (QIA) who will work directly with physicians and their staffs to assist with the heavy lifting of practice improvement. The Oklahoma Physicians Research and Resources Network has used QIAs, which it calls practice enhancement assistants (PEAs), for more than 20 years to help Oklahoma family physicians improve various aspects of their practices, including testing processes, diabetes care, and preventive services. The PEAs have been enormously helpful.²

For this new CMS program, the feds awarded $685 million to 39 national and regional collaborative health care transformation networks and supporting organizations to develop peer-based learning networks to facilitate practice improvements.¹ The program is designed to help more than 140,000 primary care physicians improve their practices by providing an extra set of skilled hands.

The new CMS initiative is a great opportunity to get that extra set of skilled hands you need to help meet new quality mandates.

The American Board of Family Medicine (ABFM) and the American Academy of Family Physicians (AAFP) have teamed up to assist with this national effort. ABFM will cover the cost for the first 6000 family physicians who enroll in one of the regional Practice Transformation Networks to use their newly developed chronic disease registry called PRIME. This registry will extract clinical quality data from diverse electronic health records and report back to practices. The registry will meet the new federal quality measures reporting requirements and will also be a path for maintenance of certification.

The CMS Transforming Clinical Practice Initiative is a great opportunity to get that extra set of skilled hands you need to help meet new quality mandates and make your office more efficient and enjoyable for you, your staff, and your patients. Contact the ABFM (www.theabfm.org) to find out which organization is running the Practice Transformation Network in your area.

In September 2015, the Centers for Medicare & Medicaid Services (CMS) launched a promising 4-year program called the "Transforming Clinical Practice Initiative" to lighten the load for family physicians.¹ The central figures in this program are skilled and trained quality improvement advisors (QIA) who will work directly with physicians and their staffs to assist with the heavy lifting of practice improvement. The Oklahoma Physicians Research and Resources Network has used QIAs, which it calls practice enhancement assistants (PEAs), for more than 20 years to help Oklahoma family physicians improve various aspects of their practices, including testing processes, diabetes care, and preventive services. The PEAs have been enormously helpful.²

For this new CMS program, the feds awarded $685 million to 39 national and regional collaborative health care transformation networks and supporting organizations to develop peer-based learning networks to facilitate practice improvements.¹ The program is designed to help more than 140,000 primary care physicians improve their practices by providing an extra set of skilled hands.

The new CMS initiative is a great opportunity to get that extra set of skilled hands you need to help meet new quality mandates.

The American Board of Family Medicine (ABFM) and the American Academy of Family Physicians (AAFP) have teamed up to assist with this national effort. ABFM will cover the cost for the first 6000 family physicians who enroll in one of the regional Practice Transformation Networks to use their newly developed chronic disease registry called PRIME. This registry will extract clinical quality data from diverse electronic health records and report back to practices. The registry will meet the new federal quality measures reporting requirements and will also be a path for maintenance of certification.

The CMS Transforming Clinical Practice Initiative is a great opportunity to get that extra set of skilled hands you need to help meet new quality mandates and make your office more efficient and enjoyable for you, your staff, and your patients. Contact the ABFM (www.theabfm.org) to find out which organization is running the Practice Transformation Network in your area.

THE CASE

An 80-year-old man sought medical advice over the phone because he’d had sharp anal pain for 4 days. The pain increased during sitting and defecation. He was told he most likely had an acute anal fissure and was instructed to treat it with sitz baths, a stool-bulking agent, and a topical anesthetic. Despite these treatments, he continued to have intense anal pain.

Two days later, he presented to our practice complaining of severe anal discomfort and perianal swelling that made it almost impossible to sit. The patient led an active lifestyle and was otherwise healthy. He did not recall any injury to the perianal area.

THE DIAGNOSIS

During examination, we noted tender, erythematous swelling over the right perianal region at the 9 o’clock position without fluctuance, discharge, or ulceration. A digital rectal examination revealed a foreign body lying transversely across the anus about 2.5 cm from the anal verge. A pelvic x-ray confirmed the presence of a foreign body—a pin (FIGURE 1).

DISCUSSION

Anal pain is a common symptom that is usually caused by hemorrhoids, fissures, fistulas, or abscesses.¹ Anal pain is rarely reported to be secondary to the ingestion of sharp foreign bodies, which can produce problems in the lower gastrointestinal tract.

Foreign body ingestion is most common in children ages 6 months to 6 years.² When it occurs in adults, it tends to involve those who are older, patients without teeth, prisoners, patients under the influence of drugs or alcohol, or those with intellectual disabilities or psychiatric disorders.^2,3

The foreign bodies that adults most commonly unintentionally ingest are bones from fish or other animals.^2,4 Most of these pass through the alimentary tract uneventfully within a week.^2,5,6 Swallowed bones have been known to cause perianal abscesses and anal fistulae, which can cause extreme pain.⁷

The presence of foreign bodies is not always easy to spot

In our patient’s case, the diagnosis was made by a careful digital rectal examination; however, a foreign body in an abscess cavity can be missed during a digital exam.⁸ In our patient’s case, a pelvic x-ray confirmed the presence and location of the pin.

Radiography is recommended as an initial screening method and is especially useful for determining the location of radiodense foreign bodies.² However, most swallowed foreign bodies, such as non-radiodense fish bones, wood, thorns, plastic, small aluminum objects, and glass, cannot be detected by this method.³ Non-radiodense foreign bodies can be identified using computed tomography scanning.⁹

Removal is typically straightforward

The best method of removing a foreign body in the perianal region is by dilating the anus and then cutting the object in half. Alternatively, the object can be carefully dislodged from the anal canal by freeing one of the impacted ends. Care must be taken while removing the object to avoid accidental injury.

This procedure can be performed in any primary care setting that is adequately equipped for minor surgical services. Consider referral to a secondary care specialist based on the level of risk involved and the physician’s skills and training.

Our patient. After a complete assessment, we prepared the patient for gentle anal dilatation under intravenous conscious sedation. We carefully transected the 3.5 cm pin using a nail splitter (FIGURE 2). Because there was no abscess cavity, no other procedure was needed. We prescribed oral amoxicillin/clavulanic acid 500/125 mg every 8 hours for 7 days to treat a local infection.

After the procedure, we asked the patient about the pin. He said he had no idea how he could have ingested it and didn’t recall any abdominal pain during the previous month. Follow-up was normal, and he recovered without any complications.

THE TAKEAWAY

Consider the possibility of ingested sharp foreign bodies as a cause of severe anal pain, and perform a local and digital rectal examination. Radiography is recommended as an initial screening method. Following anal dilatation, the object can be removed by cutting it in half or by freeing one of the impacted ends.

THE CASE

An 80-year-old man sought medical advice over the phone because he’d had sharp anal pain for 4 days. The pain increased during sitting and defecation. He was told he most likely had an acute anal fissure and was instructed to treat it with sitz baths, a stool-bulking agent, and a topical anesthetic. Despite these treatments, he continued to have intense anal pain.

Two days later, he presented to our practice complaining of severe anal discomfort and perianal swelling that made it almost impossible to sit. The patient led an active lifestyle and was otherwise healthy. He did not recall any injury to the perianal area.

THE DIAGNOSIS

During examination, we noted tender, erythematous swelling over the right perianal region at the 9 o’clock position without fluctuance, discharge, or ulceration. A digital rectal examination revealed a foreign body lying transversely across the anus about 2.5 cm from the anal verge. A pelvic x-ray confirmed the presence of a foreign body—a pin (FIGURE 1).

DISCUSSION

Anal pain is a common symptom that is usually caused by hemorrhoids, fissures, fistulas, or abscesses.¹ Anal pain is rarely reported to be secondary to the ingestion of sharp foreign bodies, which can produce problems in the lower gastrointestinal tract.

Foreign body ingestion is most common in children ages 6 months to 6 years.² When it occurs in adults, it tends to involve those who are older, patients without teeth, prisoners, patients under the influence of drugs or alcohol, or those with intellectual disabilities or psychiatric disorders.^2,3

The foreign bodies that adults most commonly unintentionally ingest are bones from fish or other animals.^2,4 Most of these pass through the alimentary tract uneventfully within a week.^2,5,6 Swallowed bones have been known to cause perianal abscesses and anal fistulae, which can cause extreme pain.⁷

The presence of foreign bodies is not always easy to spot

In our patient’s case, the diagnosis was made by a careful digital rectal examination; however, a foreign body in an abscess cavity can be missed during a digital exam.⁸ In our patient’s case, a pelvic x-ray confirmed the presence and location of the pin.

Radiography is recommended as an initial screening method and is especially useful for determining the location of radiodense foreign bodies.² However, most swallowed foreign bodies, such as non-radiodense fish bones, wood, thorns, plastic, small aluminum objects, and glass, cannot be detected by this method.³ Non-radiodense foreign bodies can be identified using computed tomography scanning.⁹

Removal is typically straightforward

The best method of removing a foreign body in the perianal region is by dilating the anus and then cutting the object in half. Alternatively, the object can be carefully dislodged from the anal canal by freeing one of the impacted ends. Care must be taken while removing the object to avoid accidental injury.

This procedure can be performed in any primary care setting that is adequately equipped for minor surgical services. Consider referral to a secondary care specialist based on the level of risk involved and the physician’s skills and training.

Our patient. After a complete assessment, we prepared the patient for gentle anal dilatation under intravenous conscious sedation. We carefully transected the 3.5 cm pin using a nail splitter (FIGURE 2). Because there was no abscess cavity, no other procedure was needed. We prescribed oral amoxicillin/clavulanic acid 500/125 mg every 8 hours for 7 days to treat a local infection.

After the procedure, we asked the patient about the pin. He said he had no idea how he could have ingested it and didn’t recall any abdominal pain during the previous month. Follow-up was normal, and he recovered without any complications.

THE TAKEAWAY

Consider the possibility of ingested sharp foreign bodies as a cause of severe anal pain, and perform a local and digital rectal examination. Radiography is recommended as an initial screening method. Following anal dilatation, the object can be removed by cutting it in half or by freeing one of the impacted ends.

THE CASE

An 80-year-old man sought medical advice over the phone because he’d had sharp anal pain for 4 days. The pain increased during sitting and defecation. He was told he most likely had an acute anal fissure and was instructed to treat it with sitz baths, a stool-bulking agent, and a topical anesthetic. Despite these treatments, he continued to have intense anal pain.

Two days later, he presented to our practice complaining of severe anal discomfort and perianal swelling that made it almost impossible to sit. The patient led an active lifestyle and was otherwise healthy. He did not recall any injury to the perianal area.

THE DIAGNOSIS

During examination, we noted tender, erythematous swelling over the right perianal region at the 9 o’clock position without fluctuance, discharge, or ulceration. A digital rectal examination revealed a foreign body lying transversely across the anus about 2.5 cm from the anal verge. A pelvic x-ray confirmed the presence of a foreign body—a pin (FIGURE 1).

DISCUSSION

Anal pain is a common symptom that is usually caused by hemorrhoids, fissures, fistulas, or abscesses.¹ Anal pain is rarely reported to be secondary to the ingestion of sharp foreign bodies, which can produce problems in the lower gastrointestinal tract.

Foreign body ingestion is most common in children ages 6 months to 6 years.² When it occurs in adults, it tends to involve those who are older, patients without teeth, prisoners, patients under the influence of drugs or alcohol, or those with intellectual disabilities or psychiatric disorders.^2,3

The foreign bodies that adults most commonly unintentionally ingest are bones from fish or other animals.^2,4 Most of these pass through the alimentary tract uneventfully within a week.^2,5,6 Swallowed bones have been known to cause perianal abscesses and anal fistulae, which can cause extreme pain.⁷

The presence of foreign bodies is not always easy to spot

In our patient’s case, the diagnosis was made by a careful digital rectal examination; however, a foreign body in an abscess cavity can be missed during a digital exam.⁸ In our patient’s case, a pelvic x-ray confirmed the presence and location of the pin.

Radiography is recommended as an initial screening method and is especially useful for determining the location of radiodense foreign bodies.² However, most swallowed foreign bodies, such as non-radiodense fish bones, wood, thorns, plastic, small aluminum objects, and glass, cannot be detected by this method.³ Non-radiodense foreign bodies can be identified using computed tomography scanning.⁹

Removal is typically straightforward

The best method of removing a foreign body in the perianal region is by dilating the anus and then cutting the object in half. Alternatively, the object can be carefully dislodged from the anal canal by freeing one of the impacted ends. Care must be taken while removing the object to avoid accidental injury.

This procedure can be performed in any primary care setting that is adequately equipped for minor surgical services. Consider referral to a secondary care specialist based on the level of risk involved and the physician’s skills and training.

Our patient. After a complete assessment, we prepared the patient for gentle anal dilatation under intravenous conscious sedation. We carefully transected the 3.5 cm pin using a nail splitter (FIGURE 2). Because there was no abscess cavity, no other procedure was needed. We prescribed oral amoxicillin/clavulanic acid 500/125 mg every 8 hours for 7 days to treat a local infection.

After the procedure, we asked the patient about the pin. He said he had no idea how he could have ingested it and didn’t recall any abdominal pain during the previous month. Follow-up was normal, and he recovered without any complications.

THE TAKEAWAY

Consider the possibility of ingested sharp foreign bodies as a cause of severe anal pain, and perform a local and digital rectal examination. Radiography is recommended as an initial screening method. Following anal dilatation, the object can be removed by cutting it in half or by freeing one of the impacted ends.

In its 2014 report, “The Health Consequences of Smoking—50 Years of Progress,”¹ the US Surgeon General concluded that, while significant improvements have been made since the publication of its landmark 1964 report, cigarette smoking remains a major public health problem. It is the leading cause of preventable death, increasing the risks of such common causes of mortality as cardiovascular disease, pulmonary disease, and malignancy. Cigarette smoking is responsible for an estimated 443,000 deaths annually.²

Overall, 42 million US adults and about 3 million middle and high school students smoke, despite the availability of an array of pharmacologic interventions to help them quit.¹ Half of those who continue to smoke will die from a tobacco-related cause. Stopping before the age of 50 years cuts the risk in half, and quitting before age 30 almost completely negates it.³

The number of cigarettes smoked per day and how long a patient is awake before smoking that first cigarette are important factors in determining which medication to select for smoking cessation.

The most recent comprehensive smoking cessation guideline, sponsored by the US Public Health Service, was published in 2008.⁴ The US Preventive Services Task Force (USPSTF) recommendation that “clinicians ask all adults about tobacco use and provide tobacco cessation interventions” for those who smoke was issued one year later.⁵ Since then, multiple studies have assessed the merits of the various medications, forms of nicotine replacement therapy (NRT), and counseling aimed at helping smokers maintain abstinence from tobacco.

This article reviews the guideline and provides family physicians with an evidence-based update.

The guideline: Treating tobacco use and dependence

Prescribing a first-line medication (bupropion SR, varenicline, nicotine gum, nicotine inhaler, nicotine lozenge, nicotine nasal spray, or nicotine patch) for every patient who seeks to quit smoking is a key component of the 2008 guideline (See TABLE W1).⁴ The only exceptions: patients for whom such agents are medically contraindicated and groups for which there is insufficient evidence of effectiveness, such as pregnant women and adolescents.

The use of any of these medications as a single agent nearly doubles the likelihood of success compared with placebo, with an average cessation rate of 25% (TABLE 1).⁴

Combination therapy (pairing a nicotine patch and an additional agent) was found to be even more effective, with some combinations attaining success rates as high as 65%.⁴

Second-line therapies, including clonidine and nortriptyline, were also cited as effective, with an average cessation rate of 24%.⁴ Although the meta-analyses that these averages were based on did not include head-to-head comparisons, subsequent studies that also showed efficacy did include such comparisons.

Counseling is an essential component

In one of the meta-analyses on which the guideline was based, the combination of counseling and medication proved to be more effective than either intervention alone. Individual, group, and telephone counseling were all effective (odds ratio [OR]=1.7 [1.4-2.0], 1.3 [1.1-1.6], and 1.2 [1.1-1.4], respectively), provided they included practical help that emphasized problem solving and skills training, as well as social support. The benefits of a team-based approach were evident from the finding that counseling provided by more than one type of clinician had higher effect sizes (OR=2.5 [1.9-3.4] when 2 different clinical disciplines were involved and 2.4 [2.1-2.9] for 3 or more disciplines).⁴

The guideline also found state-sponsored quit lines, accessible at no charge via 800-QUIT-NOW, are an effective option. (For more information about this and other resources, see TABLE W2.)

For patients who aren’t ready to stop smoking, the guideline recommends motivational interviewing⁴—a direct, patient-centered technique used to explore and work through ambivalence. Further information about this method is available at motivational interviewing.org/.

In counseling patients considering a quit attempt, it is important to present all options. A smoking history is needed, too, because factors such as the number of cigarettes smoked per day, how long a patient is typically awake before smoking the first cigarette of the day, and level of dependence are important factors in determining medication and dosage. Consider the advantages and disadvantages of the various medications (TABLE 2)^4,6,7 or methods used for prior quit attempts and reasons for relapse, if appropriate; and patient preference.

Evidence update: What's best?

Since 2009, many clinical trials have examined the best way to help smokers quit. Here’s a closer look at the latest evidence.

NRT boosts long-term cessation

Quitting smoking by age 50 cuts the risk of a smoking-related death in half, and quitting by age 30 almost completely negates it.

A 2012 Cochrane review examined 150 trials and found that every type of NRT—gum, lozenge, patch, inhaler, and nasal spray—was associated with long-term cessation (relative risk [RR]=1.60; 95% CI, 1.53-1.68).⁸ This effect was essentially unchanged regardless of the duration, setting, or intensity of supportive therapy offered, and no single type of NRT was more effective than any other. However, combining a short-acting form like a lozenge with a long-acting patch was found to be more effective than either one alone (RR=1.34; 95% CI, 1.18-1.51).

Starting the NRT before the patient quit did not improve cessation rates over traditional start times (RR=1.18; 95% CI 0.98-1.41). Neither was there an added benefit to using NRT beyond the recommended 24-week prescription period,⁹ although doing so was found to be safe. Another 2012 Cochrane review looked specifically at the use of pharmacologic smoking cessation interventions during pregnancy and concluded that there was still not sufficient data to document efficacy for this patient population.¹⁰

Adherence. In deciding on which type of NRT to prescribe, it is important to consider not only patient preference and previous efforts, but also the latest evidence. A study comparing various NRT formulations found patient adherence to be highest with the patch, followed by nicotine gum, which had a higher compliance rate than either the nicotine inhaler or nasal spray.¹¹

Varenicline is still a first-line agent

Among the various types of nicotine replacement therapy, the patch has the highest adherence rate.

Since the 2008 guideline recommended this partial nicotinic receptor agonist/antagonist as a first-line pharmacologic agent, additional meta-analyses have confirmed its long-term efficacy in smokers who are ready to quit.^12,13 A 2012 Cochrane review found varenicline to increase long-term cessation compared with placebo (RR=2.27; 95% CI, 2.02-2.55).¹³ It also showed varenicline to be more effective than bupropion SR (RR=1.52; 95% CI, 1.22-1.88), but about as effective as NRT (RR=1.13; 95% CI, 0.94-1.35).

Newer data suggest that varenicline may also be effective for those who are willing to cut down on smoking but not yet ready to give up cigarettes completely. Used for 24 weeks by those who were initially resistant to quitting, researchers found varenicline nearly tripled the cessation rate at 52 weeks compared with placebo (RR=2.7; 95% CI, 2.1-3.5).¹⁴

Latest evidence on safety. Additional concerns about the safety of varenicline have been raised, however, since the 2008 guideline was published. In 2009, the US Food and Drug Administration (FDA) required that black box warnings be added to the labels of both varenicline and bupropion SR based on post-marketing safety reports showing the risk of neuropsychiatric symptoms, including suicidality.¹⁵ In 2011, a large case control study by the FDA Adverse Event Reporting System also showed an increased risk of suicidality in patients taking these drugs.¹⁶

Follow-up studies, however, including a large prospective cohort study and a large meta-analysis, failed to show an increased association with neuropsychiatric adverse effects.^17,18 A smaller randomized controlled trial (RCT) showed that in smokers diagnosed with schizophrenia and bipolar disorder, maintenance therapy with varenicline was effective in preventing smoking relapse for up to 52 weeks. Abstinence rates were 60% for those in the varenicline group vs 19% for those in the placebo group (OR=6.2; 95% CI, 2.2-19.2). Although no increased risk of adverse psychiatric events was found in this study, it was not powered to detect them.¹⁹ Also of note: a meta-analysis of 14 RCTs showed an increased rate of cardiovascular events associated with varenicline.²⁰ There are concerns about methodologic flaws in this meta-analysis, however, and 2 subsequent meta-analyses failed to find a cardiovascular risk.^21,22

The higher quality studies that have been published since the original concerns about varenicline's safety are reassuring, but it is still essential to carefully weigh the risks and benefits of varenicline. Review cardiac and psychiatric history and conduct a suicidality assessment before prescribing it as a smoking cessation aid, and provide close follow-up.

A closer look at antidepressants

Bupropion SR, an atypical antidepressant, was also listed as a first-line treatment in the 2008 guideline. A 2014 Cochrane review of 90 studies confirmed the evidence for this recommendation.⁶ Monotherapy with this agent was found to significantly increase rates of long-term cessation (RR=1.62; 95% CI, 1.49-1.76). No increased risk of serious adverse events was identified compared with placebo. As already noted, associations with neuropsychiatric symptoms were found, but this risk must be considered with any antidepressant.

Bupropion’s efficacy was not significantly different from that of NRT, but moderate evidence suggests that it is less effective than varenicline, (RR=0.68; 95% CI, 0.56-0.83). Other classes of antidepressants, including selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and monoamine oxidase inhibitors, were found to be ineffective for smoking cessation.⁶

Nortriptyline, a tricyclic antidepressant, was not significantly different from bupropion SR (RR, 1.30; 95% CI, 0.93-1.82) in efficacy for smoking cessation, but it lacks FDA approval for this purpose and is not considered a first-line agent.⁶

Second-line agents

Clonidine is an alpha-2 adrenergic receptor agonist that was originally used to treat hypertension but found to be effective for smoking cessation in a meta-analysis performed for the 2008 guideline.⁴ Like nortriptyline, however, clonidine is not FDA-approved for this purpose and is not considered a first-line agent.⁵ A 2013 Cochrane meta-analysis further showed that clonidine is effective for smoking cessation vs placebo (RR=1.63; 95% CI, 1.22-2.18),⁷ but suggested that its significant dose-related adverse effects, including postural hypotension and sedation, could limit its usefulness.

Combination therapies are highly effective

Evidence for various combinations of smoking cessation pharmacotherapy continues to mount.^23-26 Perhaps the most compelling evidence comes from a comparative effectiveness trial that randomized 1346 patients in 12 primary care clinics to nicotine patches, nicotine lozenges, bupropion SR, a combination of patch plus lozenge, and bupropion SR plus lozenge. The 6-month abstinence rate was 30% for the bupropion SR plus lozenge combination, the most effective option. The combination was superior to either patch or bupropion SR monotherapy (OR, 0.56 and 0.54, respectively).²³ Based on data from the 2008 guideline, similar combinations (eg, nicotine patch plus nicotine gum or bupropion SR plus the patch) are likely to be equally effective. The 2008 guideline also supports a nicotine patch and nicotine inhaler combination.

Another study found varenicline combined with the patch to be highly effective, with a 65% abstinence rate at 24 weeks vs 47% for varenicline alone (number needed to treat [NNT]=6; 95% CI, 4-11).²⁴

In heavy smokers—defined as those who smoke ≥20 cigarettes daily—a varenicline and bupropion SR combination was more effective than varenicline alone (NNT= 9; 95% CI, 4.6-71.6), but the combination can lead to increased anxiety and depression.²⁵ A smaller study found triple therapy using nicotine patch plus inhaler plus bupropion SR to be more effective than the nicotine patch alone (35% abstinence vs 19% abstinence at 26 weeks; NNT=6).²⁶ Consider using these combinations in patients who have high nicotine dependency levels or have been unable to quit using a single first-line agent.

What role do e-cigarettes play?

The use of electronic cigarettes or “vapes”—battery-operated devices that deliver nicotine to the user through vapor—has increased significantly since their US introduction in 2007. A recent study found that “ever use” of e-cigarettes increased from 1.8% in 2010 to 13% in 2013; current use increased from 0.3% to 6.8% in the same time frame.²⁷ “Vaping,” as inhaling on an e-cigarette is sometimes known, causes a sensor to detect airflow and initiate the heating element to vaporize the liquid solution within the cartridge, which contains propylene glycol, flavoring, and nicotine.

Higher quality studies published since initial safety concerns for varenicline were raised are reassuring, but it's still essential to weigh the drug's risks and benefits for each patient.

There is limited evidence of the efficacy of e-cigarettes for smoking cessation, but there is support for their role in reducing the quantity of conventional cigarettes smoked. A 2014 Cochrane review of 2 RCTs evaluating e-cigarette efficacy for smoking cessation or reduction found evidence of increased abstinence at 6 months in users of e-cigarettes containing nicotine compared with placebo e-cigarettes (9% vs 4%; RR=2.29; 95% CI, 1.05-4.96). Additionally, e-cigarette use was associated with >50% decrease in cigarette smoking vs placebo (36% vs 27%; RR=1.31; 95% CI, 1.02-1.68) or patch (61% vs 44%; RR=1.41; 95% CI, 1.20-1.67).²⁸

A survey published after the review also showed a correlation between cigarette reduction (but not cessation) after one year of e-cigarette use.²⁹ A subsequent RCT conducted in a controlled laboratory setting found that e-cigarettes were highly effective in reducing cessation-related cravings.³⁰ And at 8-month follow-up, 44% of those using e-cigarettes were found to have at least a 50% reduction in the use of conventional cigarettes—and complete cessation in some cases.

Concerns about health effects

E-cigarettes have generally been thought to be safer than conventional cigarettes, given that they mainly deliver nicotine and propylene glycol instead of the more toxic chemicals—eg, benzene, carbon monoxide, and formaldehyde—released by conventional cigarettes.³¹ Carcinogens have also been found in e-cigarettes, but at significantly lower levels.³¹ However, a systematic review found wide variation in the toxin content of e-cigarettes.³² In addition, recent reports have detailed incidents in which e-cigarette devices were alleged to have exploded, causing severe bodily harm.³³

Adverse effects of e-cigarettes include minor irritation of the throat, mouth, and lungs. Among cigarette-naive patients, light-headedness, throat irritation, dizziness, and cough were most commonly reported. No serious adverse events have been reported, but the lack of long-term safety data is a source of concern.³²

Additionally, minimal regulatory oversight of the e-cigarette industry exists. Currently, the FDA only has authority to regulate e-cigarettes that are marketed for therapeutic purposes, although the agency is seeking to extend its oversight to all e-cigarettes.

The bottom line: More data on safety and regulatory oversight are needed before recommendations on the use of e-cigarettes as a smoking cessation tool can be made.

Looking ahead

A systematic review found a wide variation in the toxin content of e-cigarettes.

Several novel pharmacotherapies have been evaluated for smoking cessation in recent years. Among them is a nicotine vaccine that several drug companies have been pursuing. In theory, such a vaccine would create an immunologic reaction to nicotine in a smoker, thereby preventing the substance from reaching the brain and providing rewarding stimuli. A 2008 Cochrane review of 4 trials assessing the efficacy of nicotine vaccines for tobacco cessation found that none showed efficacy.³⁴

Naltrexone, an opioid antagonist, has shown efficacy in helping those with opioid or alcohol dependence achieve abstinence from these substances, raising the possibility that it might aid in smoking cessation, as well. A 2013 Cochrane review of 8 trials found that this was not the case: Compared with placebo, naltrexone was not beneficial when used alone (RR=1.00; 95% CI, 0.66-1.51) or as an adjunct to NRT compared with NRT alone (RR=0.95; 95% CI, 0.70-1.30).³⁵

Cytisine, an extract from plants in the Faboideae family, has been used in Eastern Europe for decades for smoking cessation. It appears to work as a nicotine receptor partial agonist similar to varenicline. The extract does not have FDA approval, but the National Institutes of Health’s Center for Complementary and Integrative Health is sponsoring early-stage safety trials that could lead to its approval in the United States.³⁶

A 2012 Cochrane review identified 2 recent RCTs evaluating cytisine and found it to be effective in increasing smoking cessation rates vs placebo (RR=3.98; 95% CI, 2.01-7.87).¹³

CORRESPONDENCE
Paul Bornemann, MD, 3209 Colonial Drive, Columbia, SC 29203; [email protected].

ACKNOWLEDGEMENT
The authors thank Matt Orr, PhD, and Kathryn E. Bornemann for their help with this manuscript.

In its 2014 report, “The Health Consequences of Smoking—50 Years of Progress,”¹ the US Surgeon General concluded that, while significant improvements have been made since the publication of its landmark 1964 report, cigarette smoking remains a major public health problem. It is the leading cause of preventable death, increasing the risks of such common causes of mortality as cardiovascular disease, pulmonary disease, and malignancy. Cigarette smoking is responsible for an estimated 443,000 deaths annually.²

Overall, 42 million US adults and about 3 million middle and high school students smoke, despite the availability of an array of pharmacologic interventions to help them quit.¹ Half of those who continue to smoke will die from a tobacco-related cause. Stopping before the age of 50 years cuts the risk in half, and quitting before age 30 almost completely negates it.³

The number of cigarettes smoked per day and how long a patient is awake before smoking that first cigarette are important factors in determining which medication to select for smoking cessation.

The most recent comprehensive smoking cessation guideline, sponsored by the US Public Health Service, was published in 2008.⁴ The US Preventive Services Task Force (USPSTF) recommendation that “clinicians ask all adults about tobacco use and provide tobacco cessation interventions” for those who smoke was issued one year later.⁵ Since then, multiple studies have assessed the merits of the various medications, forms of nicotine replacement therapy (NRT), and counseling aimed at helping smokers maintain abstinence from tobacco.

This article reviews the guideline and provides family physicians with an evidence-based update.

The guideline: Treating tobacco use and dependence

Prescribing a first-line medication (bupropion SR, varenicline, nicotine gum, nicotine inhaler, nicotine lozenge, nicotine nasal spray, or nicotine patch) for every patient who seeks to quit smoking is a key component of the 2008 guideline (See TABLE W1).⁴ The only exceptions: patients for whom such agents are medically contraindicated and groups for which there is insufficient evidence of effectiveness, such as pregnant women and adolescents.

The use of any of these medications as a single agent nearly doubles the likelihood of success compared with placebo, with an average cessation rate of 25% (TABLE 1).⁴

Combination therapy (pairing a nicotine patch and an additional agent) was found to be even more effective, with some combinations attaining success rates as high as 65%.⁴

Second-line therapies, including clonidine and nortriptyline, were also cited as effective, with an average cessation rate of 24%.⁴ Although the meta-analyses that these averages were based on did not include head-to-head comparisons, subsequent studies that also showed efficacy did include such comparisons.

Counseling is an essential component

In one of the meta-analyses on which the guideline was based, the combination of counseling and medication proved to be more effective than either intervention alone. Individual, group, and telephone counseling were all effective (odds ratio [OR]=1.7 [1.4-2.0], 1.3 [1.1-1.6], and 1.2 [1.1-1.4], respectively), provided they included practical help that emphasized problem solving and skills training, as well as social support. The benefits of a team-based approach were evident from the finding that counseling provided by more than one type of clinician had higher effect sizes (OR=2.5 [1.9-3.4] when 2 different clinical disciplines were involved and 2.4 [2.1-2.9] for 3 or more disciplines).⁴

The guideline also found state-sponsored quit lines, accessible at no charge via 800-QUIT-NOW, are an effective option. (For more information about this and other resources, see TABLE W2.)

For patients who aren’t ready to stop smoking, the guideline recommends motivational interviewing⁴—a direct, patient-centered technique used to explore and work through ambivalence. Further information about this method is available at motivational interviewing.org/.

In counseling patients considering a quit attempt, it is important to present all options. A smoking history is needed, too, because factors such as the number of cigarettes smoked per day, how long a patient is typically awake before smoking the first cigarette of the day, and level of dependence are important factors in determining medication and dosage. Consider the advantages and disadvantages of the various medications (TABLE 2)^4,6,7 or methods used for prior quit attempts and reasons for relapse, if appropriate; and patient preference.

Evidence update: What's best?

Since 2009, many clinical trials have examined the best way to help smokers quit. Here’s a closer look at the latest evidence.

NRT boosts long-term cessation

Quitting smoking by age 50 cuts the risk of a smoking-related death in half, and quitting by age 30 almost completely negates it.

A 2012 Cochrane review examined 150 trials and found that every type of NRT—gum, lozenge, patch, inhaler, and nasal spray—was associated with long-term cessation (relative risk [RR]=1.60; 95% CI, 1.53-1.68).⁸ This effect was essentially unchanged regardless of the duration, setting, or intensity of supportive therapy offered, and no single type of NRT was more effective than any other. However, combining a short-acting form like a lozenge with a long-acting patch was found to be more effective than either one alone (RR=1.34; 95% CI, 1.18-1.51).

Starting the NRT before the patient quit did not improve cessation rates over traditional start times (RR=1.18; 95% CI 0.98-1.41). Neither was there an added benefit to using NRT beyond the recommended 24-week prescription period,⁹ although doing so was found to be safe. Another 2012 Cochrane review looked specifically at the use of pharmacologic smoking cessation interventions during pregnancy and concluded that there was still not sufficient data to document efficacy for this patient population.¹⁰

Adherence. In deciding on which type of NRT to prescribe, it is important to consider not only patient preference and previous efforts, but also the latest evidence. A study comparing various NRT formulations found patient adherence to be highest with the patch, followed by nicotine gum, which had a higher compliance rate than either the nicotine inhaler or nasal spray.¹¹

Varenicline is still a first-line agent

Among the various types of nicotine replacement therapy, the patch has the highest adherence rate.

Since the 2008 guideline recommended this partial nicotinic receptor agonist/antagonist as a first-line pharmacologic agent, additional meta-analyses have confirmed its long-term efficacy in smokers who are ready to quit.^12,13 A 2012 Cochrane review found varenicline to increase long-term cessation compared with placebo (RR=2.27; 95% CI, 2.02-2.55).¹³ It also showed varenicline to be more effective than bupropion SR (RR=1.52; 95% CI, 1.22-1.88), but about as effective as NRT (RR=1.13; 95% CI, 0.94-1.35).

Newer data suggest that varenicline may also be effective for those who are willing to cut down on smoking but not yet ready to give up cigarettes completely. Used for 24 weeks by those who were initially resistant to quitting, researchers found varenicline nearly tripled the cessation rate at 52 weeks compared with placebo (RR=2.7; 95% CI, 2.1-3.5).¹⁴

Latest evidence on safety. Additional concerns about the safety of varenicline have been raised, however, since the 2008 guideline was published. In 2009, the US Food and Drug Administration (FDA) required that black box warnings be added to the labels of both varenicline and bupropion SR based on post-marketing safety reports showing the risk of neuropsychiatric symptoms, including suicidality.¹⁵ In 2011, a large case control study by the FDA Adverse Event Reporting System also showed an increased risk of suicidality in patients taking these drugs.¹⁶

Follow-up studies, however, including a large prospective cohort study and a large meta-analysis, failed to show an increased association with neuropsychiatric adverse effects.^17,18 A smaller randomized controlled trial (RCT) showed that in smokers diagnosed with schizophrenia and bipolar disorder, maintenance therapy with varenicline was effective in preventing smoking relapse for up to 52 weeks. Abstinence rates were 60% for those in the varenicline group vs 19% for those in the placebo group (OR=6.2; 95% CI, 2.2-19.2). Although no increased risk of adverse psychiatric events was found in this study, it was not powered to detect them.¹⁹ Also of note: a meta-analysis of 14 RCTs showed an increased rate of cardiovascular events associated with varenicline.²⁰ There are concerns about methodologic flaws in this meta-analysis, however, and 2 subsequent meta-analyses failed to find a cardiovascular risk.^21,22

The higher quality studies that have been published since the original concerns about varenicline's safety are reassuring, but it is still essential to carefully weigh the risks and benefits of varenicline. Review cardiac and psychiatric history and conduct a suicidality assessment before prescribing it as a smoking cessation aid, and provide close follow-up.

A closer look at antidepressants

Bupropion SR, an atypical antidepressant, was also listed as a first-line treatment in the 2008 guideline. A 2014 Cochrane review of 90 studies confirmed the evidence for this recommendation.⁶ Monotherapy with this agent was found to significantly increase rates of long-term cessation (RR=1.62; 95% CI, 1.49-1.76). No increased risk of serious adverse events was identified compared with placebo. As already noted, associations with neuropsychiatric symptoms were found, but this risk must be considered with any antidepressant.

Bupropion’s efficacy was not significantly different from that of NRT, but moderate evidence suggests that it is less effective than varenicline, (RR=0.68; 95% CI, 0.56-0.83). Other classes of antidepressants, including selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and monoamine oxidase inhibitors, were found to be ineffective for smoking cessation.⁶

Nortriptyline, a tricyclic antidepressant, was not significantly different from bupropion SR (RR, 1.30; 95% CI, 0.93-1.82) in efficacy for smoking cessation, but it lacks FDA approval for this purpose and is not considered a first-line agent.⁶

Second-line agents

Clonidine is an alpha-2 adrenergic receptor agonist that was originally used to treat hypertension but found to be effective for smoking cessation in a meta-analysis performed for the 2008 guideline.⁴ Like nortriptyline, however, clonidine is not FDA-approved for this purpose and is not considered a first-line agent.⁵ A 2013 Cochrane meta-analysis further showed that clonidine is effective for smoking cessation vs placebo (RR=1.63; 95% CI, 1.22-2.18),⁷ but suggested that its significant dose-related adverse effects, including postural hypotension and sedation, could limit its usefulness.

Combination therapies are highly effective

Evidence for various combinations of smoking cessation pharmacotherapy continues to mount.^23-26 Perhaps the most compelling evidence comes from a comparative effectiveness trial that randomized 1346 patients in 12 primary care clinics to nicotine patches, nicotine lozenges, bupropion SR, a combination of patch plus lozenge, and bupropion SR plus lozenge. The 6-month abstinence rate was 30% for the bupropion SR plus lozenge combination, the most effective option. The combination was superior to either patch or bupropion SR monotherapy (OR, 0.56 and 0.54, respectively).²³ Based on data from the 2008 guideline, similar combinations (eg, nicotine patch plus nicotine gum or bupropion SR plus the patch) are likely to be equally effective. The 2008 guideline also supports a nicotine patch and nicotine inhaler combination.

Another study found varenicline combined with the patch to be highly effective, with a 65% abstinence rate at 24 weeks vs 47% for varenicline alone (number needed to treat [NNT]=6; 95% CI, 4-11).²⁴

In heavy smokers—defined as those who smoke ≥20 cigarettes daily—a varenicline and bupropion SR combination was more effective than varenicline alone (NNT= 9; 95% CI, 4.6-71.6), but the combination can lead to increased anxiety and depression.²⁵ A smaller study found triple therapy using nicotine patch plus inhaler plus bupropion SR to be more effective than the nicotine patch alone (35% abstinence vs 19% abstinence at 26 weeks; NNT=6).²⁶ Consider using these combinations in patients who have high nicotine dependency levels or have been unable to quit using a single first-line agent.

What role do e-cigarettes play?

The use of electronic cigarettes or “vapes”—battery-operated devices that deliver nicotine to the user through vapor—has increased significantly since their US introduction in 2007. A recent study found that “ever use” of e-cigarettes increased from 1.8% in 2010 to 13% in 2013; current use increased from 0.3% to 6.8% in the same time frame.²⁷ “Vaping,” as inhaling on an e-cigarette is sometimes known, causes a sensor to detect airflow and initiate the heating element to vaporize the liquid solution within the cartridge, which contains propylene glycol, flavoring, and nicotine.

Higher quality studies published since initial safety concerns for varenicline were raised are reassuring, but it's still essential to weigh the drug's risks and benefits for each patient.

There is limited evidence of the efficacy of e-cigarettes for smoking cessation, but there is support for their role in reducing the quantity of conventional cigarettes smoked. A 2014 Cochrane review of 2 RCTs evaluating e-cigarette efficacy for smoking cessation or reduction found evidence of increased abstinence at 6 months in users of e-cigarettes containing nicotine compared with placebo e-cigarettes (9% vs 4%; RR=2.29; 95% CI, 1.05-4.96). Additionally, e-cigarette use was associated with >50% decrease in cigarette smoking vs placebo (36% vs 27%; RR=1.31; 95% CI, 1.02-1.68) or patch (61% vs 44%; RR=1.41; 95% CI, 1.20-1.67).²⁸

A survey published after the review also showed a correlation between cigarette reduction (but not cessation) after one year of e-cigarette use.²⁹ A subsequent RCT conducted in a controlled laboratory setting found that e-cigarettes were highly effective in reducing cessation-related cravings.³⁰ And at 8-month follow-up, 44% of those using e-cigarettes were found to have at least a 50% reduction in the use of conventional cigarettes—and complete cessation in some cases.

Concerns about health effects

E-cigarettes have generally been thought to be safer than conventional cigarettes, given that they mainly deliver nicotine and propylene glycol instead of the more toxic chemicals—eg, benzene, carbon monoxide, and formaldehyde—released by conventional cigarettes.³¹ Carcinogens have also been found in e-cigarettes, but at significantly lower levels.³¹ However, a systematic review found wide variation in the toxin content of e-cigarettes.³² In addition, recent reports have detailed incidents in which e-cigarette devices were alleged to have exploded, causing severe bodily harm.³³

Adverse effects of e-cigarettes include minor irritation of the throat, mouth, and lungs. Among cigarette-naive patients, light-headedness, throat irritation, dizziness, and cough were most commonly reported. No serious adverse events have been reported, but the lack of long-term safety data is a source of concern.³²

Additionally, minimal regulatory oversight of the e-cigarette industry exists. Currently, the FDA only has authority to regulate e-cigarettes that are marketed for therapeutic purposes, although the agency is seeking to extend its oversight to all e-cigarettes.

The bottom line: More data on safety and regulatory oversight are needed before recommendations on the use of e-cigarettes as a smoking cessation tool can be made.

Looking ahead

A systematic review found a wide variation in the toxin content of e-cigarettes.

Several novel pharmacotherapies have been evaluated for smoking cessation in recent years. Among them is a nicotine vaccine that several drug companies have been pursuing. In theory, such a vaccine would create an immunologic reaction to nicotine in a smoker, thereby preventing the substance from reaching the brain and providing rewarding stimuli. A 2008 Cochrane review of 4 trials assessing the efficacy of nicotine vaccines for tobacco cessation found that none showed efficacy.³⁴

Naltrexone, an opioid antagonist, has shown efficacy in helping those with opioid or alcohol dependence achieve abstinence from these substances, raising the possibility that it might aid in smoking cessation, as well. A 2013 Cochrane review of 8 trials found that this was not the case: Compared with placebo, naltrexone was not beneficial when used alone (RR=1.00; 95% CI, 0.66-1.51) or as an adjunct to NRT compared with NRT alone (RR=0.95; 95% CI, 0.70-1.30).³⁵

Cytisine, an extract from plants in the Faboideae family, has been used in Eastern Europe for decades for smoking cessation. It appears to work as a nicotine receptor partial agonist similar to varenicline. The extract does not have FDA approval, but the National Institutes of Health’s Center for Complementary and Integrative Health is sponsoring early-stage safety trials that could lead to its approval in the United States.³⁶

A 2012 Cochrane review identified 2 recent RCTs evaluating cytisine and found it to be effective in increasing smoking cessation rates vs placebo (RR=3.98; 95% CI, 2.01-7.87).¹³

CORRESPONDENCE
Paul Bornemann, MD, 3209 Colonial Drive, Columbia, SC 29203; [email protected].

ACKNOWLEDGEMENT
The authors thank Matt Orr, PhD, and Kathryn E. Bornemann for their help with this manuscript.

In its 2014 report, “The Health Consequences of Smoking—50 Years of Progress,”¹ the US Surgeon General concluded that, while significant improvements have been made since the publication of its landmark 1964 report, cigarette smoking remains a major public health problem. It is the leading cause of preventable death, increasing the risks of such common causes of mortality as cardiovascular disease, pulmonary disease, and malignancy. Cigarette smoking is responsible for an estimated 443,000 deaths annually.²

Overall, 42 million US adults and about 3 million middle and high school students smoke, despite the availability of an array of pharmacologic interventions to help them quit.¹ Half of those who continue to smoke will die from a tobacco-related cause. Stopping before the age of 50 years cuts the risk in half, and quitting before age 30 almost completely negates it.³

The number of cigarettes smoked per day and how long a patient is awake before smoking that first cigarette are important factors in determining which medication to select for smoking cessation.

The most recent comprehensive smoking cessation guideline, sponsored by the US Public Health Service, was published in 2008.⁴ The US Preventive Services Task Force (USPSTF) recommendation that “clinicians ask all adults about tobacco use and provide tobacco cessation interventions” for those who smoke was issued one year later.⁵ Since then, multiple studies have assessed the merits of the various medications, forms of nicotine replacement therapy (NRT), and counseling aimed at helping smokers maintain abstinence from tobacco.

This article reviews the guideline and provides family physicians with an evidence-based update.

The guideline: Treating tobacco use and dependence

Prescribing a first-line medication (bupropion SR, varenicline, nicotine gum, nicotine inhaler, nicotine lozenge, nicotine nasal spray, or nicotine patch) for every patient who seeks to quit smoking is a key component of the 2008 guideline (See TABLE W1).⁴ The only exceptions: patients for whom such agents are medically contraindicated and groups for which there is insufficient evidence of effectiveness, such as pregnant women and adolescents.

The use of any of these medications as a single agent nearly doubles the likelihood of success compared with placebo, with an average cessation rate of 25% (TABLE 1).⁴

Combination therapy (pairing a nicotine patch and an additional agent) was found to be even more effective, with some combinations attaining success rates as high as 65%.⁴

Second-line therapies, including clonidine and nortriptyline, were also cited as effective, with an average cessation rate of 24%.⁴ Although the meta-analyses that these averages were based on did not include head-to-head comparisons, subsequent studies that also showed efficacy did include such comparisons.

Counseling is an essential component

In one of the meta-analyses on which the guideline was based, the combination of counseling and medication proved to be more effective than either intervention alone. Individual, group, and telephone counseling were all effective (odds ratio [OR]=1.7 [1.4-2.0], 1.3 [1.1-1.6], and 1.2 [1.1-1.4], respectively), provided they included practical help that emphasized problem solving and skills training, as well as social support. The benefits of a team-based approach were evident from the finding that counseling provided by more than one type of clinician had higher effect sizes (OR=2.5 [1.9-3.4] when 2 different clinical disciplines were involved and 2.4 [2.1-2.9] for 3 or more disciplines).⁴

The guideline also found state-sponsored quit lines, accessible at no charge via 800-QUIT-NOW, are an effective option. (For more information about this and other resources, see TABLE W2.)

For patients who aren’t ready to stop smoking, the guideline recommends motivational interviewing⁴—a direct, patient-centered technique used to explore and work through ambivalence. Further information about this method is available at motivational interviewing.org/.

In counseling patients considering a quit attempt, it is important to present all options. A smoking history is needed, too, because factors such as the number of cigarettes smoked per day, how long a patient is typically awake before smoking the first cigarette of the day, and level of dependence are important factors in determining medication and dosage. Consider the advantages and disadvantages of the various medications (TABLE 2)^4,6,7 or methods used for prior quit attempts and reasons for relapse, if appropriate; and patient preference.

Evidence update: What's best?

Since 2009, many clinical trials have examined the best way to help smokers quit. Here’s a closer look at the latest evidence.

NRT boosts long-term cessation

Quitting smoking by age 50 cuts the risk of a smoking-related death in half, and quitting by age 30 almost completely negates it.

A 2012 Cochrane review examined 150 trials and found that every type of NRT—gum, lozenge, patch, inhaler, and nasal spray—was associated with long-term cessation (relative risk [RR]=1.60; 95% CI, 1.53-1.68).⁸ This effect was essentially unchanged regardless of the duration, setting, or intensity of supportive therapy offered, and no single type of NRT was more effective than any other. However, combining a short-acting form like a lozenge with a long-acting patch was found to be more effective than either one alone (RR=1.34; 95% CI, 1.18-1.51).

Starting the NRT before the patient quit did not improve cessation rates over traditional start times (RR=1.18; 95% CI 0.98-1.41). Neither was there an added benefit to using NRT beyond the recommended 24-week prescription period,⁹ although doing so was found to be safe. Another 2012 Cochrane review looked specifically at the use of pharmacologic smoking cessation interventions during pregnancy and concluded that there was still not sufficient data to document efficacy for this patient population.¹⁰

Adherence. In deciding on which type of NRT to prescribe, it is important to consider not only patient preference and previous efforts, but also the latest evidence. A study comparing various NRT formulations found patient adherence to be highest with the patch, followed by nicotine gum, which had a higher compliance rate than either the nicotine inhaler or nasal spray.¹¹

Varenicline is still a first-line agent

Among the various types of nicotine replacement therapy, the patch has the highest adherence rate.

Since the 2008 guideline recommended this partial nicotinic receptor agonist/antagonist as a first-line pharmacologic agent, additional meta-analyses have confirmed its long-term efficacy in smokers who are ready to quit.^12,13 A 2012 Cochrane review found varenicline to increase long-term cessation compared with placebo (RR=2.27; 95% CI, 2.02-2.55).¹³ It also showed varenicline to be more effective than bupropion SR (RR=1.52; 95% CI, 1.22-1.88), but about as effective as NRT (RR=1.13; 95% CI, 0.94-1.35).

Newer data suggest that varenicline may also be effective for those who are willing to cut down on smoking but not yet ready to give up cigarettes completely. Used for 24 weeks by those who were initially resistant to quitting, researchers found varenicline nearly tripled the cessation rate at 52 weeks compared with placebo (RR=2.7; 95% CI, 2.1-3.5).¹⁴

Latest evidence on safety. Additional concerns about the safety of varenicline have been raised, however, since the 2008 guideline was published. In 2009, the US Food and Drug Administration (FDA) required that black box warnings be added to the labels of both varenicline and bupropion SR based on post-marketing safety reports showing the risk of neuropsychiatric symptoms, including suicidality.¹⁵ In 2011, a large case control study by the FDA Adverse Event Reporting System also showed an increased risk of suicidality in patients taking these drugs.¹⁶

Follow-up studies, however, including a large prospective cohort study and a large meta-analysis, failed to show an increased association with neuropsychiatric adverse effects.^17,18 A smaller randomized controlled trial (RCT) showed that in smokers diagnosed with schizophrenia and bipolar disorder, maintenance therapy with varenicline was effective in preventing smoking relapse for up to 52 weeks. Abstinence rates were 60% for those in the varenicline group vs 19% for those in the placebo group (OR=6.2; 95% CI, 2.2-19.2). Although no increased risk of adverse psychiatric events was found in this study, it was not powered to detect them.¹⁹ Also of note: a meta-analysis of 14 RCTs showed an increased rate of cardiovascular events associated with varenicline.²⁰ There are concerns about methodologic flaws in this meta-analysis, however, and 2 subsequent meta-analyses failed to find a cardiovascular risk.^21,22

The higher quality studies that have been published since the original concerns about varenicline's safety are reassuring, but it is still essential to carefully weigh the risks and benefits of varenicline. Review cardiac and psychiatric history and conduct a suicidality assessment before prescribing it as a smoking cessation aid, and provide close follow-up.

A closer look at antidepressants

Bupropion SR, an atypical antidepressant, was also listed as a first-line treatment in the 2008 guideline. A 2014 Cochrane review of 90 studies confirmed the evidence for this recommendation.⁶ Monotherapy with this agent was found to significantly increase rates of long-term cessation (RR=1.62; 95% CI, 1.49-1.76). No increased risk of serious adverse events was identified compared with placebo. As already noted, associations with neuropsychiatric symptoms were found, but this risk must be considered with any antidepressant.

Bupropion’s efficacy was not significantly different from that of NRT, but moderate evidence suggests that it is less effective than varenicline, (RR=0.68; 95% CI, 0.56-0.83). Other classes of antidepressants, including selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and monoamine oxidase inhibitors, were found to be ineffective for smoking cessation.⁶

Nortriptyline, a tricyclic antidepressant, was not significantly different from bupropion SR (RR, 1.30; 95% CI, 0.93-1.82) in efficacy for smoking cessation, but it lacks FDA approval for this purpose and is not considered a first-line agent.⁶

Second-line agents

Clonidine is an alpha-2 adrenergic receptor agonist that was originally used to treat hypertension but found to be effective for smoking cessation in a meta-analysis performed for the 2008 guideline.⁴ Like nortriptyline, however, clonidine is not FDA-approved for this purpose and is not considered a first-line agent.⁵ A 2013 Cochrane meta-analysis further showed that clonidine is effective for smoking cessation vs placebo (RR=1.63; 95% CI, 1.22-2.18),⁷ but suggested that its significant dose-related adverse effects, including postural hypotension and sedation, could limit its usefulness.

Combination therapies are highly effective

Evidence for various combinations of smoking cessation pharmacotherapy continues to mount.^23-26 Perhaps the most compelling evidence comes from a comparative effectiveness trial that randomized 1346 patients in 12 primary care clinics to nicotine patches, nicotine lozenges, bupropion SR, a combination of patch plus lozenge, and bupropion SR plus lozenge. The 6-month abstinence rate was 30% for the bupropion SR plus lozenge combination, the most effective option. The combination was superior to either patch or bupropion SR monotherapy (OR, 0.56 and 0.54, respectively).²³ Based on data from the 2008 guideline, similar combinations (eg, nicotine patch plus nicotine gum or bupropion SR plus the patch) are likely to be equally effective. The 2008 guideline also supports a nicotine patch and nicotine inhaler combination.

Another study found varenicline combined with the patch to be highly effective, with a 65% abstinence rate at 24 weeks vs 47% for varenicline alone (number needed to treat [NNT]=6; 95% CI, 4-11).²⁴

In heavy smokers—defined as those who smoke ≥20 cigarettes daily—a varenicline and bupropion SR combination was more effective than varenicline alone (NNT= 9; 95% CI, 4.6-71.6), but the combination can lead to increased anxiety and depression.²⁵ A smaller study found triple therapy using nicotine patch plus inhaler plus bupropion SR to be more effective than the nicotine patch alone (35% abstinence vs 19% abstinence at 26 weeks; NNT=6).²⁶ Consider using these combinations in patients who have high nicotine dependency levels or have been unable to quit using a single first-line agent.

What role do e-cigarettes play?

The use of electronic cigarettes or “vapes”—battery-operated devices that deliver nicotine to the user through vapor—has increased significantly since their US introduction in 2007. A recent study found that “ever use” of e-cigarettes increased from 1.8% in 2010 to 13% in 2013; current use increased from 0.3% to 6.8% in the same time frame.²⁷ “Vaping,” as inhaling on an e-cigarette is sometimes known, causes a sensor to detect airflow and initiate the heating element to vaporize the liquid solution within the cartridge, which contains propylene glycol, flavoring, and nicotine.

Higher quality studies published since initial safety concerns for varenicline were raised are reassuring, but it's still essential to weigh the drug's risks and benefits for each patient.

There is limited evidence of the efficacy of e-cigarettes for smoking cessation, but there is support for their role in reducing the quantity of conventional cigarettes smoked. A 2014 Cochrane review of 2 RCTs evaluating e-cigarette efficacy for smoking cessation or reduction found evidence of increased abstinence at 6 months in users of e-cigarettes containing nicotine compared with placebo e-cigarettes (9% vs 4%; RR=2.29; 95% CI, 1.05-4.96). Additionally, e-cigarette use was associated with >50% decrease in cigarette smoking vs placebo (36% vs 27%; RR=1.31; 95% CI, 1.02-1.68) or patch (61% vs 44%; RR=1.41; 95% CI, 1.20-1.67).²⁸

A survey published after the review also showed a correlation between cigarette reduction (but not cessation) after one year of e-cigarette use.²⁹ A subsequent RCT conducted in a controlled laboratory setting found that e-cigarettes were highly effective in reducing cessation-related cravings.³⁰ And at 8-month follow-up, 44% of those using e-cigarettes were found to have at least a 50% reduction in the use of conventional cigarettes—and complete cessation in some cases.

Concerns about health effects

E-cigarettes have generally been thought to be safer than conventional cigarettes, given that they mainly deliver nicotine and propylene glycol instead of the more toxic chemicals—eg, benzene, carbon monoxide, and formaldehyde—released by conventional cigarettes.³¹ Carcinogens have also been found in e-cigarettes, but at significantly lower levels.³¹ However, a systematic review found wide variation in the toxin content of e-cigarettes.³² In addition, recent reports have detailed incidents in which e-cigarette devices were alleged to have exploded, causing severe bodily harm.³³

Adverse effects of e-cigarettes include minor irritation of the throat, mouth, and lungs. Among cigarette-naive patients, light-headedness, throat irritation, dizziness, and cough were most commonly reported. No serious adverse events have been reported, but the lack of long-term safety data is a source of concern.³²

Additionally, minimal regulatory oversight of the e-cigarette industry exists. Currently, the FDA only has authority to regulate e-cigarettes that are marketed for therapeutic purposes, although the agency is seeking to extend its oversight to all e-cigarettes.

The bottom line: More data on safety and regulatory oversight are needed before recommendations on the use of e-cigarettes as a smoking cessation tool can be made.

Looking ahead

A systematic review found a wide variation in the toxin content of e-cigarettes.

Several novel pharmacotherapies have been evaluated for smoking cessation in recent years. Among them is a nicotine vaccine that several drug companies have been pursuing. In theory, such a vaccine would create an immunologic reaction to nicotine in a smoker, thereby preventing the substance from reaching the brain and providing rewarding stimuli. A 2008 Cochrane review of 4 trials assessing the efficacy of nicotine vaccines for tobacco cessation found that none showed efficacy.³⁴

Naltrexone, an opioid antagonist, has shown efficacy in helping those with opioid or alcohol dependence achieve abstinence from these substances, raising the possibility that it might aid in smoking cessation, as well. A 2013 Cochrane review of 8 trials found that this was not the case: Compared with placebo, naltrexone was not beneficial when used alone (RR=1.00; 95% CI, 0.66-1.51) or as an adjunct to NRT compared with NRT alone (RR=0.95; 95% CI, 0.70-1.30).³⁵

Cytisine, an extract from plants in the Faboideae family, has been used in Eastern Europe for decades for smoking cessation. It appears to work as a nicotine receptor partial agonist similar to varenicline. The extract does not have FDA approval, but the National Institutes of Health’s Center for Complementary and Integrative Health is sponsoring early-stage safety trials that could lead to its approval in the United States.³⁶

A 2012 Cochrane review identified 2 recent RCTs evaluating cytisine and found it to be effective in increasing smoking cessation rates vs placebo (RR=3.98; 95% CI, 2.01-7.87).¹³

CORRESPONDENCE
Paul Bornemann, MD, 3209 Colonial Drive, Columbia, SC 29203; [email protected].

ACKNOWLEDGEMENT
The authors thank Matt Orr, PhD, and Kathryn E. Bornemann for their help with this manuscript.

An over-the-counter botanical acne regimen outperformed a conventional acne regimen, with improved skin appearance and fewer lesions after 12 weeks of treatment, in a double-blind randomized controlled trial.

Eighty individuals aged 12 years and older with mild to moderate acne were randomized either to a three-step botanical-based acne treatment regimen (Receutics) consisting of a skin cleanser, breakout treatment, and tone and complexion corrector twice daily, or the currently marketed acne treatment kit, Proactiv (Guthy-Renker).

The botanical-based acne treatment contains a range of botanical ingredients, including algae and lentil seed extracts; cranberry seed, grape seed, and pumpkin seed oils; and allantoin; with 3.4% benzoyl peroxide as the active ingredient. The active ingredient in the cleanser is 2% salicylic acid, and niacinamide is the active ingredient in the tone and complexion corrector; both also contain botanical ingredients.

In the study, published in December, the investigator, Dr. Zoe Diana Draelos, reported that the botanical regimen achieved a significantly greater reduction in lesion count, in terms of closed comedones and inflammatory lesions, by week four, compared with the control treatment (J Drugs Dermatol. 2015 Dec; 14 [12]:1418-21).

This effect persisted at 12 weeks, with fewer closed comedones (P = .006). The botanical regimen also achieved greater reductions in pus, erythema, lesion height, and inflammation at weeks 2 and 4; although this difference disappeared by week 12. By week four and onwards, the botanical regimen also outperformed the conventional treatment on all blinded, investigator-assessed cosmetic appearance parameters, including skin tone, blemishes, erythema, and overall appearance.

While both treatments were effective at improving acne, Dr. Draelos, of Dermatology Consulting Services, High Point, N.C., said the botanical three-step regimen had the advantage of cosmetic ingredients such as emollients, anti-inflammatory/antioxidants, and “sensitive skin modulators.”

“This study demonstrates the value of combining monographed acne ingredients with advanced cosmeceutical technology,” she wrote.

The author received a grant from manufacturer Receutics to conduct the study.