HIV cure in children?

At the Conference on Retroviruses and Opportunistic Infection in March, investigators presented the case of a child born to an HIV-infected mother who received highly active antiretroviral therapy (HAART) beginning at 30 hours of age. The child was demonstrated to have plasma viremia on day 2 of life and a positive qualitative DNA polymerase chain reaction. The child received triple-drug therapy and declining plasma viremia was documented on three additional occasions during the first month of life. The child was treated with three drugs for approximately 18 months and was lost to follow-up; no HAART was administered beyond that time. At age 26 months, after months without antiretroviral therapy, HIV DNA was detected at 4 copies/million peripheral blood mononuclear cell (PBMC). Plasma viral load, PBMC DNA, and HIV-specific antibodies remained undetectable with standard clinical assays. Does this child represent a functional cure as the investigators suggest? Will early, multidrug therapy cure HIV in infants with intrauterine or perinatal acquisition of HIV?

The functional cure of HIV in this newborn builds on the already successful experiences in prevention of HIV transmission by administration of antiretroviral therapy within the first 48 hours of life or after exposure, most often in health care workers after needle stick. Since the 1990s, postexposure prophylaxis against HIV infection has been used after occupational exposures, most often after needle sticks. A case-control study supported the efficacy of this approach in that health care workers who received zidovudine after needle stick exposures were 81% less likely to develop HIV infection (N. Eng. J. Med. 1997;337:1485-90). The success of postexposure prophylaxis appears to be related to the inoculum of virus as represented by visible blood and large bore needles being more often associated with transmission. This evidence suggests that when administered early enough after a challenge dose, infection can be prevented.

Similarly, New York State’s mandatory HIV testing for all newborns has identified that when administration of zidovudine was initiated within the first 48 hours after birth to neonate whose mothers did not receive prior antiretroviral treatment, the rate of HIV infection was reduced from about 18% to about 9%. (N. Engl. J. Med. 1998;339:1409-14) A large study furthered these observations demonstrating that ART administered within 48 hours of birth reduces rates of infection in infants born to HIV infected women who did not receive prior treatment during pregnancy (N. Engl. J. Med. 2012;366:2368-79). Evidence has also accumulated that concurrent administration of ART to breast feeding infants of HIV infected mothers (N. Engl. J. Med. 2008;359:119-29) or to HIV uninfected sexually partners of HIV infected men decreases virus transmission substantially (MMWR 2011;60:65-8).

What is different in our newborn is the documentation of increasing plasma viral replication in the first month of life, signifying infection, not simply exposure. First, most newborn infection arises from exposure shortly before or at the time of birth. Studies demonstrating a lower transmission rate in twin B, compared with twin A, are thought to relate to the time in the birth canal and exposure in to genital tract secretions or blood. Once the infant is exposed, the immune system will respond with an array of immune cellular mechanisms hoping to prevent replication, dissemination, and development of latency [infection of primarily resting-memory T lymphocytes in which the virus is "silent"]. Current concepts suggest that this battle between the virus and the immune system occurs over several days, and the virus is either cleared or infection is established. In this infant, viremia was documented at 30 hours of age, which makes it less certain when infection occurred (intrauterine vs. perinatal) and therefore at what sequence in the pathogenesis antiretroviral therapies were initiated. The outcome, however, suggests that it was before latency was established, permitting a long term functional cure as evidenced by the fact that replicating virus could not be detected some 8 months off treatment.

Is this a one-of-a-kind event, where infection and functional cure was exquisitely demonstrated? Is this more common than we have documented and explains some of the success of strategies that initiate prophylaxis within the first 48 hours?

Did this child fail to develop latent infection because triple-drug therapy was initiated at less than 30 hours of age? It would perhaps be more puzzling if this child were infected in utero as suggested by the early detection of viremia. If intrauterine infection occurred, then why wasn’t latent infection established prior to initiation of therapy? What conclusion can we draw from this experience? First, there is still a significant amount of biology about newborn transmission that requires further study. While our approach to prevention of mother to child transmission incorporating maternal, peripartum, and postpartum prophylaxis has been hugely successful, now we have further evidence that early initiation of ARTs to infants born to HIV-infected women who had not received prophylaxis/treatment can still be effective in either prevention or possible cure.

Recent data of functional cure in adults when HAART is initiated in the early stages of infection raises new hope that current ART may be sufficiently powerful to rapidly clear viremia and prevent infection of a complete array of resting cells that perpetuate infection. I think it is premature to conclude we understand the time sequence of exposure to infection well enough to predict in whom we might achieve a cure, but it is not premature to imagine that we are moving the football down the field.

Dr. Pelton is chief of pediatric infectious disease and coordinator of the maternal-child HIV program at Boston Medical Center. He said he had no relevant financial disclosures.

At the Conference on Retroviruses and Opportunistic Infection in March, investigators presented the case of a child born to an HIV-infected mother who received highly active antiretroviral therapy (HAART) beginning at 30 hours of age. The child was demonstrated to have plasma viremia on day 2 of life and a positive qualitative DNA polymerase chain reaction. The child received triple-drug therapy and declining plasma viremia was documented on three additional occasions during the first month of life. The child was treated with three drugs for approximately 18 months and was lost to follow-up; no HAART was administered beyond that time. At age 26 months, after months without antiretroviral therapy, HIV DNA was detected at 4 copies/million peripheral blood mononuclear cell (PBMC). Plasma viral load, PBMC DNA, and HIV-specific antibodies remained undetectable with standard clinical assays. Does this child represent a functional cure as the investigators suggest? Will early, multidrug therapy cure HIV in infants with intrauterine or perinatal acquisition of HIV?

The functional cure of HIV in this newborn builds on the already successful experiences in prevention of HIV transmission by administration of antiretroviral therapy within the first 48 hours of life or after exposure, most often in health care workers after needle stick. Since the 1990s, postexposure prophylaxis against HIV infection has been used after occupational exposures, most often after needle sticks. A case-control study supported the efficacy of this approach in that health care workers who received zidovudine after needle stick exposures were 81% less likely to develop HIV infection (N. Eng. J. Med. 1997;337:1485-90). The success of postexposure prophylaxis appears to be related to the inoculum of virus as represented by visible blood and large bore needles being more often associated with transmission. This evidence suggests that when administered early enough after a challenge dose, infection can be prevented.

Similarly, New York State’s mandatory HIV testing for all newborns has identified that when administration of zidovudine was initiated within the first 48 hours after birth to neonate whose mothers did not receive prior antiretroviral treatment, the rate of HIV infection was reduced from about 18% to about 9%. (N. Engl. J. Med. 1998;339:1409-14) A large study furthered these observations demonstrating that ART administered within 48 hours of birth reduces rates of infection in infants born to HIV infected women who did not receive prior treatment during pregnancy (N. Engl. J. Med. 2012;366:2368-79). Evidence has also accumulated that concurrent administration of ART to breast feeding infants of HIV infected mothers (N. Engl. J. Med. 2008;359:119-29) or to HIV uninfected sexually partners of HIV infected men decreases virus transmission substantially (MMWR 2011;60:65-8).

What is different in our newborn is the documentation of increasing plasma viral replication in the first month of life, signifying infection, not simply exposure. First, most newborn infection arises from exposure shortly before or at the time of birth. Studies demonstrating a lower transmission rate in twin B, compared with twin A, are thought to relate to the time in the birth canal and exposure in to genital tract secretions or blood. Once the infant is exposed, the immune system will respond with an array of immune cellular mechanisms hoping to prevent replication, dissemination, and development of latency [infection of primarily resting-memory T lymphocytes in which the virus is "silent"]. Current concepts suggest that this battle between the virus and the immune system occurs over several days, and the virus is either cleared or infection is established. In this infant, viremia was documented at 30 hours of age, which makes it less certain when infection occurred (intrauterine vs. perinatal) and therefore at what sequence in the pathogenesis antiretroviral therapies were initiated. The outcome, however, suggests that it was before latency was established, permitting a long term functional cure as evidenced by the fact that replicating virus could not be detected some 8 months off treatment.

Is this a one-of-a-kind event, where infection and functional cure was exquisitely demonstrated? Is this more common than we have documented and explains some of the success of strategies that initiate prophylaxis within the first 48 hours?

Did this child fail to develop latent infection because triple-drug therapy was initiated at less than 30 hours of age? It would perhaps be more puzzling if this child were infected in utero as suggested by the early detection of viremia. If intrauterine infection occurred, then why wasn’t latent infection established prior to initiation of therapy? What conclusion can we draw from this experience? First, there is still a significant amount of biology about newborn transmission that requires further study. While our approach to prevention of mother to child transmission incorporating maternal, peripartum, and postpartum prophylaxis has been hugely successful, now we have further evidence that early initiation of ARTs to infants born to HIV-infected women who had not received prophylaxis/treatment can still be effective in either prevention or possible cure.

Recent data of functional cure in adults when HAART is initiated in the early stages of infection raises new hope that current ART may be sufficiently powerful to rapidly clear viremia and prevent infection of a complete array of resting cells that perpetuate infection. I think it is premature to conclude we understand the time sequence of exposure to infection well enough to predict in whom we might achieve a cure, but it is not premature to imagine that we are moving the football down the field.

Dr. Pelton is chief of pediatric infectious disease and coordinator of the maternal-child HIV program at Boston Medical Center. He said he had no relevant financial disclosures.

At the Conference on Retroviruses and Opportunistic Infection in March, investigators presented the case of a child born to an HIV-infected mother who received highly active antiretroviral therapy (HAART) beginning at 30 hours of age. The child was demonstrated to have plasma viremia on day 2 of life and a positive qualitative DNA polymerase chain reaction. The child received triple-drug therapy and declining plasma viremia was documented on three additional occasions during the first month of life. The child was treated with three drugs for approximately 18 months and was lost to follow-up; no HAART was administered beyond that time. At age 26 months, after months without antiretroviral therapy, HIV DNA was detected at 4 copies/million peripheral blood mononuclear cell (PBMC). Plasma viral load, PBMC DNA, and HIV-specific antibodies remained undetectable with standard clinical assays. Does this child represent a functional cure as the investigators suggest? Will early, multidrug therapy cure HIV in infants with intrauterine or perinatal acquisition of HIV?

The functional cure of HIV in this newborn builds on the already successful experiences in prevention of HIV transmission by administration of antiretroviral therapy within the first 48 hours of life or after exposure, most often in health care workers after needle stick. Since the 1990s, postexposure prophylaxis against HIV infection has been used after occupational exposures, most often after needle sticks. A case-control study supported the efficacy of this approach in that health care workers who received zidovudine after needle stick exposures were 81% less likely to develop HIV infection (N. Eng. J. Med. 1997;337:1485-90). The success of postexposure prophylaxis appears to be related to the inoculum of virus as represented by visible blood and large bore needles being more often associated with transmission. This evidence suggests that when administered early enough after a challenge dose, infection can be prevented.

Similarly, New York State’s mandatory HIV testing for all newborns has identified that when administration of zidovudine was initiated within the first 48 hours after birth to neonate whose mothers did not receive prior antiretroviral treatment, the rate of HIV infection was reduced from about 18% to about 9%. (N. Engl. J. Med. 1998;339:1409-14) A large study furthered these observations demonstrating that ART administered within 48 hours of birth reduces rates of infection in infants born to HIV infected women who did not receive prior treatment during pregnancy (N. Engl. J. Med. 2012;366:2368-79). Evidence has also accumulated that concurrent administration of ART to breast feeding infants of HIV infected mothers (N. Engl. J. Med. 2008;359:119-29) or to HIV uninfected sexually partners of HIV infected men decreases virus transmission substantially (MMWR 2011;60:65-8).

What is different in our newborn is the documentation of increasing plasma viral replication in the first month of life, signifying infection, not simply exposure. First, most newborn infection arises from exposure shortly before or at the time of birth. Studies demonstrating a lower transmission rate in twin B, compared with twin A, are thought to relate to the time in the birth canal and exposure in to genital tract secretions or blood. Once the infant is exposed, the immune system will respond with an array of immune cellular mechanisms hoping to prevent replication, dissemination, and development of latency [infection of primarily resting-memory T lymphocytes in which the virus is "silent"]. Current concepts suggest that this battle between the virus and the immune system occurs over several days, and the virus is either cleared or infection is established. In this infant, viremia was documented at 30 hours of age, which makes it less certain when infection occurred (intrauterine vs. perinatal) and therefore at what sequence in the pathogenesis antiretroviral therapies were initiated. The outcome, however, suggests that it was before latency was established, permitting a long term functional cure as evidenced by the fact that replicating virus could not be detected some 8 months off treatment.

Is this a one-of-a-kind event, where infection and functional cure was exquisitely demonstrated? Is this more common than we have documented and explains some of the success of strategies that initiate prophylaxis within the first 48 hours?

Did this child fail to develop latent infection because triple-drug therapy was initiated at less than 30 hours of age? It would perhaps be more puzzling if this child were infected in utero as suggested by the early detection of viremia. If intrauterine infection occurred, then why wasn’t latent infection established prior to initiation of therapy? What conclusion can we draw from this experience? First, there is still a significant amount of biology about newborn transmission that requires further study. While our approach to prevention of mother to child transmission incorporating maternal, peripartum, and postpartum prophylaxis has been hugely successful, now we have further evidence that early initiation of ARTs to infants born to HIV-infected women who had not received prophylaxis/treatment can still be effective in either prevention or possible cure.

Recent data of functional cure in adults when HAART is initiated in the early stages of infection raises new hope that current ART may be sufficiently powerful to rapidly clear viremia and prevent infection of a complete array of resting cells that perpetuate infection. I think it is premature to conclude we understand the time sequence of exposure to infection well enough to predict in whom we might achieve a cure, but it is not premature to imagine that we are moving the football down the field.

Dr. Pelton is chief of pediatric infectious disease and coordinator of the maternal-child HIV program at Boston Medical Center. He said he had no relevant financial disclosures.