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1.  The Safety of Adult Male Circumcision in HIV-Infected and Uninfected Men in Rakai, Uganda 
PLoS Medicine  2008;5(6):e116.
Background
The objective of the study was to compare rates of adverse events (AEs) related to male circumcision (MC) in HIV-positive and HIV-negative men in order to provide guidance for MC programs that may provide services to HIV-infected and uninfected men.
Methods and Findings
A total of 2,326 HIV-negative and 420 HIV-positive men (World Health Organization [WHO] stage I or II and CD4 counts > 350 cells/mm3) were circumcised in two separate but procedurally identical trials of MC for HIV and/or sexually transmitted infection prevention in rural Rakai, Uganda. Participants were followed at 1–2 d and 5–9 d, and at 4–6 wk, to assess surgery-related AEs, wound healing, and resumption of intercourse. AE risks and wound healing were compared in HIV-positive and HIV-negative men. Adjusted odds ratios (AdjORs) were estimated by multiple logistic regression, adjusting for baseline characteristics and postoperative resumption of sex. At enrollment, HIV-positive men were older, more likely to be married, reported more sexual partners, less condom use, and higher rates of sexually transmitted disease symptoms than HIV-negative men. Risks of moderate or severe AEs were 3.1/100 and 3.5/100 in HIV-positive and HIV-negative participants, respectively (AdjOR 0.91, 95% confidence interval [CI] 0.47–1.74). Infections were the most common AEs (2.6/100 in HIV-positive versus 3.0/100 in HIV-negative men). Risks of other complications were similar in the two groups. The proportion with completed healing by 6 wk postsurgery was 92.7% in HIV-positive men and 95.8% in HIV-negative men (p = 0.007). AEs were more common in men who resumed intercourse before wound healing compared to those who waited (AdjOR 1.56, 95% CI 1.05–2.33).
Conclusions
Overall, the safety of MC was comparable in asymptomatic HIV-positive and HIV-negative men, although healing was somewhat slower among the HIV infected. All men should be strongly counseled to refrain from intercourse until full wound healing is achieved.
Trial registration: http://www.ClinicalTrials.gov; for HIV-negative men, #NCT00047073 and for HIV-positive men, #NCT00047073.
Ron Gray and colleagues report on complications of circumcision in HIV-infected and HIV-uninfected men from two related trials in Uganda, finding increased risk with intercourse before wound healing.
Editors' Summary
Background
Worldwide over 33 million people are thought to be living with HIV, and in the absence of a vaccine, preventing its spread is a major health issue. The World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS (UNAIDS) estimate that 68% of 2.5 million new infections worldwide in 2007 took place in sub-Saharan Africa, where 76% of 2.1 million AIDS-related deaths also took place.
One of the principal means of person-to-person transmission of HIV is through sex without the protection of a condom. In parts of Africa, male circumcision is performed in infancy or childhood for religious or cultural reasons or is a traditional rite of passage that marks the transition from child to man. Three trials, in South Africa, Kenya, and Uganda, each found that circumcised men were around half as likely as uncircumcised men to contract HIV from HIV-positive female partners. After reviewing the results, WHO and UNAIDS issued joint advice that male circumcision should be promoted for preventing HIV infection in heterosexual men. As male circumcision does not provide complete protection against HIV infection, they advised that it should be promoted in addition to existing strategies of promoting condom use, abstinence, and a reduction in the number of sexual partners.
Why Was This Study Done?
Although earlier studies had shown that adult male circumcision, when performed in Africa under optimal conditions, is a safe procedure for HIV-negative men, it was not known whether it would also be a safe procedure for HIV-positive men. WHO guidelines recommend that HIV-positive men who request the procedure or have a medical need and no contraindications for it should be circumcised. Also, exclusion of HIV-positive men from circumcision programs may result in stigmatization of these men, and discourage participation by men who do not wish to be tested for HIV. Therefore, it is important to know whether the procedure is safe for HIV-positive men.
What Did the Researchers Do and Find?
The authors compared results from two separate clinical trials carried out with identical procedures in rural Rakai, Uganda. The first, which compared the effect of circumcision with no circumcision in HIV-negative men, was one of the three trials that persuaded the WHO and UNAIDS to promote male circumcision as an HIV prevention strategy. The second Rakai trial did the same comparison but in men who were HIV positive and without symptoms. In this present study, the authors used data from both trials to compare the likelihood of surgery-related complications following circumcision for HIV-negative and HIV-positive men.
The trials recruited men aged 15–49, who were randomly assigned to be circumcised either on enrollment or two years later and were followed up to monitor complications related to the procedure, such as infections, as well as wound healing and when the participant first had sex after the operation. Condom use was recorded at enrollment and six months after enrollment.
The researchers found that most complications were infrequent, mild, and comparable in both groups, with moderate-to-severe complications occurring in only 3%–4% of men in each group. However, delayed wound healing was more frequent in HIV-positive men. Complications were more likely among men who had sex before healing was complete; such men were more likely to be HIV-positive and/or married. Similarly, moderate or severe complications were more likely where men had symptoms of sexually transmitted disease at enrollment, although these were treated before surgery, and these men were more likely to be HIV-positive. Six months after enrollment, similar proportions of HIV-positive and HIV-negative men used condoms consistently, but HIV-positive men were more likely to report using condoms inconsistently than HIV-negative men. However, consistent use of a condom increased among the HIV-positive men compared to when they enrolled.
What Do these Findings Mean?
Circumcision in HIV-positive men without symptoms of AIDS has a low rate of complications, although healing is slower than in HIV-negative men. Because of the greater risk of complications if sex is resumed before full healing, both men and their women partners should be advised to have no sex for at least six weeks after the operation. A separately reported analysis from one of these studies found that women partners are more likely to become HIV infected by HIV-positive men who resume sex prior to complete wound healing. Therefore, for protection of both men and their female partners, it is essential to refrain from intercourse after circumcision until the wound has completely healed.
Because the study found no increased risk of surgical complications in HIV-positive men who undergo circumcision, it should not be necessary to screen men with no symptoms of HIV in future circumcision programs. This should reduce the complexity of implementing such programs and reduce any stigma resulting from exclusion, making it likely that more men will be willing to be circumcised. The rise in consistent condom use among HIV-positive men suggests that messages of safe sex are reaching an important target group and changing their behavior, and that circumcision does not make men less likely to use a condom.
The authors also noted that the rates of complications they observed were low compared with those following traditional circumcision procedures. Others have found that circumcision carried out under unsafe conditions has a high rate of complications. The authors of this study comment that the resources and standards of surgery during the trial represented best practice and that to attain similarly low rates of complications—and the confidence of men in the safety of the procedure—there is a need to ensure sufficient resources and high standards of training.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050116.
WHO and the UNAIDS issued a joint report recommending male circumcision for HIV prevention and another on the HIV epidemic worldwide in December 2007
An information pack here on male circumcision and HIV prevention has also been developed jointly by WHO/UNAIDS, the United Nations International Children's Emergency Fund (UNICEF), the United Nations Population Fund (UNFPA), and the World Bank
The University of California San Francisco's HIV InSite provides information on HIV prevention, treatment, and policy
AEGIS is the world's largest searchable database on HIV and AIDS
The National AIDS Trust provides information on HIV prevention
doi:10.1371/journal.pmed.0050116
PMCID: PMC2408615  PMID: 18532873
2.  Impact of Round-the-Clock, Rapid Oral Fluid HIV Testing of Women in Labor in Rural India 
PLoS Medicine  2008;5(5):e92.
Background
Testing pregnant women for HIV at the time of labor and delivery is the last opportunity for prevention of mother-to-child HIV transmission (PMTCT) measures, particularly in settings where women do not receive adequate antenatal care. However, HIV testing and counseling of pregnant women in labor is a challenge, especially in resource-constrained settings. In India, many rural women present for delivery without any prior antenatal care. Those who do get antenatal care are not always tested for HIV, because of deficiencies in the provision of HIV testing and counseling services. In this context, we investigated the impact of introducing round-the-clock, rapid, point-of-care HIV testing and counseling in a busy labor ward at a tertiary care hospital in rural India.
Methods and Findings
After they provided written informed consent, women admitted to the labor ward of a rural teaching hospital in India were offered two rapid tests on oral fluid and finger-stick specimens (OraQuick Rapid HIV-1/HIV-2 tests, OraSure Technologies). Simultaneously, venous blood was drawn for conventional HIV ELISA testing. Western blot tests were performed for confirmatory testing if women were positive by both rapid tests and dual ELISA, or where test results were discordant. Round-the-clock (24 h, 7 d/wk) abbreviated prepartum and extended postpartum counseling sessions were offered as part of the testing strategy. HIV-positive women were administered PMTCT interventions. Of 1,252 eligible women (age range 18 y to 38 y) approached for consent over a 9 mo period in 2006, 1,222 (98%) accepted HIV testing in the labor ward. Of these, 1,003 (82%) women presented with either no reports or incomplete reports of prior HIV testing results at the time of admission to the labor ward. Of 1,222 women, 15 were diagnosed as HIV-positive (on the basis of two rapid tests, dual ELISA and Western blot), yielding a seroprevalence of 1.23% (95% confidence interval [CI] 0.61%–1.8%). Of the 15 HIV test–positive women, four (27%) had presented with reported HIV status, and 11 (73%) new cases of HIV infection were detected due to rapid testing in the labor room. Thus, 11 HIV-positive women received PMTCT interventions on account of round-the-clock rapid HIV testing and counseling in the labor room. While both OraQuick tests (oral and finger-stick) were 100% specific, one false-negative result was documented (with both oral fluid and finger-stick specimens). Of the 15 HIV-infected women who delivered, 13 infants were HIV seronegative at birth and at 1 and 4 mo after delivery; two HIV-positive infants died within a month of delivery.
Conclusions
In a busy rural labor ward setting in India, we demonstrated that it is feasible to introduce a program of round-the-clock rapid HIV testing, including prepartum and extended postpartum counseling sessions. Our data suggest that the availability of round-the-clock rapid HIV testing resulted in successful documentation of HIV serostatus in a large proportion (82%) of rural women who were unaware of their HIV status when admitted to the labor room. In addition, 11 (73%) of a total of 15 HIV-positive women received PMTCT interventions because of round-the-clock rapid testing in the labor ward. These findings are relevant for PMTCT programs in developing countries.
Nitika Pant Pai and colleagues report the results of offering a round-the-clock rapid HIV testing program in a rural labor ward setting in India.
Editors' Summary
Background.
Since the first reported case of AIDS (acquired immunodeficiency syndrome) in 1981, the number of people infected with the human immunodeficiency virus (HIV), which causes AIDS, has risen steadily. Now, more than 33 million people are infected, almost half of them women. HIV is most often spread through unprotected sex with an infected partner, but mother-to-child transmission (MTCT) of HIV is also an important transmission route. HIV-positive women often pass the virus to their babies during pregnancy, labor and delivery, and breastfeeding, if nothing is done to prevent viral transmission. In developed countries, interventions such as voluntary testing and counseling, safe delivery practices (for example, offering cesarean delivery to HIV-positive women), and antiretroviral treatment of the mother during pregnancy and labor and of her newborn baby have minimized the risk of MTCT. In developing countries, the prevention of MTCT (PMTCT) is much less effective, in part because pregnant women often do not know their HIV status. Consequently, in 2007, nearly half a million children became infected with HIV mainly through MTCT.
Why Was This Study Done?
In many developing countries, women do not receive adequate antenatal care. In India, for example, nearly half the women living in rural areas do not receive any antenatal care until they are in labor. This gives health care providers very little time in which to counsel women about HIV infection, test them for the virus, and start interventions to prevent MTCT. Furthermore, testing pregnant women in labor for HIV and counseling them is a challenge, particularly where resources are limited. In this study, therefore, the researchers investigate the feasibility and impact of introducing round-the-clock, rapid HIV testing and counseling in a busy labor ward in a rural teaching hospital in Sevagram, India.
What Did the Researchers Do and Find?
Women admitted to the labor ward between January and September 2006 were offered two rapid HIV tests—one that used a saliva sample and the other that used blood taken from a finger prick. Blood was also taken from a vein for conventional HIV testing. All the women were given a 15-minute counseling session about how HIV is transmitted, the importance of HIV testing, and information on PMTCT before their child was born (prepartum counseling), and a longer postpartum counseling session. HIV-positive women were given a cesarean delivery where possible and antiretroviral drug treatment to reduce MTCT. 1,222 women admitted to the labor ward during the study period (1,003 of whom did not know their HIV status) accepted HIV testing. Of 15 study participants who were HIV positive, 11 learnt of their HIV status in the labor room. Two babies born to these HIV-positive women were HIV positive and died within a month of delivery; the other 13 babies were HIV negative at birth and at 1 and 4 months after delivery. Finally, the rapid HIV tests missed only one HIV-positive woman (no false-positive results were given), and the time from enrolling a woman into the study through referring her for PMTCT intervention where necessary averaged 40–60 minutes.
What Do These Findings Mean?
These findings show the feasibility and positive impact of the introduction of round-the-clock pre- and postpartum HIV counseling and rapid HIV testing into a busy rural Indian labor ward. Few of the women entering this ward knew their HIV status previously but the introduction of these facilities in this setting successfully informed these women of their HIV status. In addition, the round-the-clock counseling and testing led to 11 women and their babies receiving PMTCT interventions who would otherwise have been missed. These findings need to be confirmed in other settings and the cost-effectiveness and sustainability of this approach for the improvement of PMTCT in developing countries needs to be investigated. Nevertheless, these findings suggest that round-the-clock rapid HIV testing might be an effective and acceptable way to reduce MTCT of HIV in many developing countries.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050092.
Read a related PLoS Medicine Perspective article
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS and on HIV infection in women
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Women, Children, and HIV provides extensive information on the prevention of mother-to-child transmission of HIV in developing countries
Information is available from Avert, an international AIDS charity, on HIV and AIDS in India, on women, HIV, and AIDS, and on HIV and AIDS prevention, including the prevention of mother-to-child transmission
AIDSinfo, a service of the US Department of Health and Human Services provides health information for HIV-positive pregnant women (in English and Spanish)
doi:10.1371/journal.pmed.0050092
PMCID: PMC2365974  PMID: 18462011
3.  Efficacy of Neonatal HBV Vaccination on Liver Cancer and Other Liver Diseases over 30-Year Follow-up of the Qidong Hepatitis B Intervention Study: A Cluster Randomized Controlled Trial 
PLoS Medicine  2014;11(12):e1001774.
In a 30-year follow-up of the Qidong Hepatitis B Intervention Study, Yawei Zhang and colleagues examine the effects of neonatal vaccination on liver diseases.
Please see later in the article for the Editors' Summary
Background
Neonatal hepatitis B vaccination has been implemented worldwide to prevent hepatitis B virus (HBV) infections. Its long-term protective efficacy on primary liver cancer (PLC) and other liver diseases has not been fully examined.
Methods and Findings
The Qidong Hepatitis B Intervention Study, a population-based, cluster randomized, controlled trial between 1985 and 1990 in Qidong, China, included 39,292 newborns who were randomly assigned to the vaccination group in which 38,366 participants completed the HBV vaccination series and 34,441 newborns who were randomly assigned to the control group in which the participants received neither a vaccine nor a placebo. However, 23,368 (67.8%) participants in the control group received catch-up vaccination at age 10–14 years. By December 2013, a total of 3,895 (10.2%) in the vaccination group and 3,898 (11.3%) in the control group were lost to follow-up. Information on PLC incidence and liver disease mortality were collected through linkage of all remaining cohort members to a well-established population-based tumor registry until December 31, 2013. Two cross-sectional surveys on HBV surface antigen (HBsAg) seroprevalence were conducted in 1996–2000 and 2008–2012. The participation rates of the two surveys were 57.5% (21,770) and 50.7% (17,204) in the vaccination group and 36.3% (12,184) and 58.6% (17,395) in the control group, respectively. Using intention-to-treat analysis, we found that the incidence rate of PLC and the mortality rates of severe end-stage liver diseases and infant fulminant hepatitis were significantly lower in the vaccination group than the control group with efficacies of 84% (95% CI 23%–97%), 70% (95% CI 15%–89%), and 69% (95% CI 34%–85%), respectively. The estimated efficacy of catch-up vaccination on HBsAg seroprevalence in early adulthood was 21% (95% CI 10%–30%), substantially weaker than that of the neonatal vaccination (72%, 95% CI 68%–75%). Receiving a booster at age 10–14 years decreased HBsAg seroprevalence if participants were born to HBsAg-positive mothers (hazard ratio [HR] = 0.68, 95% CI 0.47–0.97). Limitations to consider in interpreting the study results include the small number of individuals with PLC, participants lost to follow-up, and the large proportion of participants who did not provide serum samples at follow-up.
Conclusions
Neonatal HBV vaccination was found to significantly decrease HBsAg seroprevalence in childhood through young adulthood and subsequently reduce the risk of PLC and other liver diseases in young adults in rural China. The findings underscore the importance of neonatal HBV vaccination. Our results also suggest that an adolescence booster should be considered in individuals born to HBsAg-positive mothers and who have completed the HBV neonatal vaccination series.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Hepatitis B is a life-threatening liver infection caused by the hepatitis B virus (HBV). HBV, which is transmitted through contact with the blood or other bodily fluids of an infected person, can cause both acute (short-term) and chronic (long-term) liver infections. Acute infections rarely cause any symptoms and more than 90% of adults who become infected with HBV (usually through sexual intercourse with an infected partner or through the use of contaminated needles) are virus-free within 6 months. However, in sub-Saharan Africa, East Asia, and other regions where HBV infection is common, HBV is usually transmitted from mother to child at birth or between individuals during early childhood and, unfortunately, most infants who are infected with HBV during the first year of life and many children who are infected before the age of 6 years develop a chronic HBV infection. Such infections can cause liver cancer, liver cirrhosis (scarring of the liver), and other fatal liver diseases. In addition, HBV infection around the time of birth can cause infant fulminant hepatitis, a rare but frequently fatal condition.
Why Was This Study Done?
HBV infections kill about 780,000 people worldwide annually but can be prevented by neonatal vaccination—immunization against HBV at birth. A vaccine against HBV became available in 1982 and many countries now include HBV vaccination at birth followed by additional vaccine doses during early childhood in their national vaccination programs. But, although HBV vaccination has greatly reduced the rate of chronic HBV infection, the protective efficacy of neonatal HBV vaccination against liver diseases has not been fully examined. Here, the researchers investigate how well neonatal HBV vaccination protects against primary liver cancer and other liver diseases by undertaking a 30-year follow-up of the Qidong Hepatitis B intervention Study (QHBIS). This cluster randomized controlled trial of neonatal HBV vaccination was conducted between 1983 and 1990 in Qidong County, a rural area in China with a high incidence of HBV-related primary liver cancer and other liver diseases. A cluster randomized controlled trial compares outcomes in groups of people (towns in this study) chosen at random to receive an intervention or a control treatment (here, vaccination or no vaccination; this study design was ethically acceptable during the 1980s when HBV vaccination was unavailable in rural China but would be unethical nowadays).
What Did the Researchers Do and Find?
The QHBIS assigned nearly 80,000 newborns to receive either a full course of HBV vaccinations (the vaccination group) or no vaccination (the control group); two-thirds of the control group participants received a catch-up vaccination at age 10–14 years. The researchers obtained data on how many trial participants developed primary liver cancer or died from a liver disease during the follow-up period from a population-based tumor registry. They also obtained information on HBsAg seroprevalence—the presence of HBsAg (an HBV surface protein) in the blood of the participants, an indicator of current HBV infection—from surveys undertaken in1996–2000 and 2008–2012. The researchers estimate that the protective efficacy of vaccination was 84% for primary liver cancer (vaccination reduced the incidence of liver cancer by 84%), 70% for death from liver diseases, and 69% for the incidence of infant fulminant hepatitis. Overall, the efficacy of catch-up vaccination on HBsAg seroprevalence in early adulthood was weak compared with neonatal vaccination (21% versus 72%). Notably, receiving a booster vaccination at age 10–14 years decreased HBsAg seroprevalence among participants who were born to HBsAg-positive mothers.
What Do These Findings Mean?
The small number of cases of primary liver cancer and other liver diseases observed during the 30-year follow-up, the length of follow-up, and the availability of incomplete data on seroprevalence all limit the accuracy of these findings. Nevertheless, these findings indicate that neonatal HBV vaccination greatly reduced HBsAg seroprevalence (an indicator of current HBV infection) in childhood and young adulthood and subsequently reduced the risk of liver cancer and other liver diseases in young adults. These findings therefore support the importance of neonatal HBV vaccination. In addition, they suggest that booster vaccination during adolescence might consolidate the efficacy of neonatal vaccination among individuals who were born to HBsAg-positive mothers, a suggestion that needs to be confirmed in randomized controlled trials before booster vaccines are introduced into vaccination programs.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001774.
The World Health Organization provides a fact sheet about hepatitis B (available in several languages) and information about hepatitis B vaccination
The World Hepatitis Alliance (an international not-for-profit, non-governmental organization) provides information about viral hepatitis, including some personal stories about hepatitis B from Bangladesh, Pakistan, the Philippines, and Malawi
The UK National Health Service Choices website provides information about hepatitis B
The not-for-profit British Liver Trust provides information about hepatitis B, including Hepatitis B: PATH B, an interactive educational resource designed to improve the lives of people living with chronic hepatitis B
MedlinePlus provides links to other resources about hepatitis B (in English and Spanish)
Information about the Qidong Hepatitis B intervention Study is available
Chinese Center for Disease Control and Prevention provides links about hepatitis B prevention in Chinese
doi:10.1371/journal.pmed.1001774
PMCID: PMC4280122  PMID: 25549238
4.  Enhancing Exposure of HIV-1 Neutralization Epitopes through Mutations in gp41 
PLoS Medicine  2008;5(1):e9.
Background
The generation of broadly neutralizing antibodies is a priority in the design of vaccines against HIV-1. Unfortunately, most antibodies to HIV-1 are narrow in their specificity, and a basic understanding of how to develop antibodies with broad neutralizing activity is needed. Designing methods to target antibodies to conserved HIV-1 epitopes may allow for the generation of broadly neutralizing antibodies and aid the global fight against AIDS by providing new approaches to block HIV-1 infection. Using a naturally occurring HIV-1 Envelope (Env) variant as a template, we sought to identify features of Env that would enhance exposure of conserved HIV-1 epitopes.
Methods and Findings
Within a cohort study of high-risk women in Mombasa, Kenya, we previously identified a subtype A HIV-1 Env variant in one participant that was unusually sensitive to neutralization. Using site-directed mutagenesis, the unusual neutralization sensitivity of this variant was mapped to two amino acid mutations within conserved sites in the transmembrane subunit (gp41) of the HIV-1 Env protein. These two mutations, when introduced into a neutralization-resistant variant from the same participant, resulted in 3- to >360-fold enhanced neutralization by monoclonal antibodies specific for conserved regions of both gp41 and the Env surface subunit, gp120, >780-fold enhanced neutralization by soluble CD4, and >35-fold enhanced neutralization by the antibodies found within a pool of plasmas from unrelated individuals. Enhanced neutralization sensitivity was not explained by differences in Env infectivity, Env concentration, Env shedding, or apparent differences in fusion kinetics. Furthermore, introduction of these mutations into unrelated viral Env sequences, including those from both another subtype A variant and a subtype B variant, resulted in enhanced neutralization susceptibility to gp41- and gp120-specific antibodies, and to plasma antibodies. This enhanced neutralization sensitivity exceeded 1,000-fold in several cases.
Conclusions
Two amino acid mutations within gp41 were identified that expose multiple discontinuous neutralization epitopes on diverse HIV-1 Env proteins. These exposed epitopes were shielded on the unmodified viral Env proteins, and several of the exposed epitopes encompass desired target regions for protective antibodies. Env proteins containing these modifications could act as a scaffold for presentation of such conserved domains, and may aid in developing methods to target antibodies to such regions.
Julie Overbaugh and colleagues analyze an HIV strain with high susceptibility to antibody neutralization and identify two gp41 envelope mutations that confer this sensitivity by exposing multiple neutralization epitopes.
Editors' Summary
Background.
In 1984 when scientists identified human immunodeficiency virus (HIV)—the cause of acquired immunodeficiency syndrome (AIDS)—many experts believed that a vaccine against HIV infection would soon be developed. Nearly 25 years later, there is still no such vaccine and with about 2.5 million new HIV infections in 2007, an effective vaccine is urgently needed to contain the AIDS epidemic. Vaccines provide protection against infectious diseases by priming the immune system to deal quickly and effectively with viruses and other pathogens. Vaccines do this by exposing the immune system to an immunogen—a fragment or harmless version of the pathogen. The immune system mounts a response against the immunogen and also “learns” from this experience so that if it is ever challenged with a virulent version of the same pathogen, it can quickly contain the threat. Many vaccines work by stimulating an antibody response. Antibodies are proteins made by the immune system that bind to molecules called antigens on the surface of pathogens. Antibodies that inactivate the invader upon binding to it are called “neutralizing” antibodies.
Why Was This Study Done?
Several characteristics of HIV have hampered the development of an effective vaccine. An “envelope” protein consisting of two subunits called gp120 and gp41 covers the outside of HIV. Many regions of this protein change rapidly, so the antibody response stimulated by a vaccine containing the envelope protein of one HIV variant provides little protection against other variants. However, other regions of the protein rarely change, so a vaccine that stimulates the production of antibodies to these “conserved” regions is likely to provide protection against many HIV variants. That is, it will stimulate the production of broadly neutralizing antibodies. Unfortunately, it has been difficult to find HIV vaccines that do this, because these conserved regions are often hidden from the immune system by other parts of the envelope protein. In this study, the researchers investigate the envelope protein of an HIV-1 variant they have isolated that is highly susceptible to inactivation by antibodies specific for these conserved regions. Comparing the envelope protein of this sensitive virus to closely related envelope proteins that are resistant to neutralization could identify features that might, if included in an envelope protein immunogen, produce a vaccine capable of generating broadly neutralizing antibodies.
What Did the Researchers Do and Find?
The researchers isolated a subtype A HIV-1 variant from a newly infected woman in Kenya that was efficiently neutralized by monoclonal antibodies (antibodies made by cells that have been cloned in the laboratory). These antibodies were specific for several different conserved regions of gp41 and gp120. The isolate was also neutralized by antibodies in blood from HIV-1-infected people. The envelope protein of the sensitive variant was the same as that of a resistant variant isolated at the same time from the woman, except for four amino acid changes in conserved regions of gp41 (proteins are made from long strings of amino acids). Using a technique called site-directed mutagenesis, the researchers introduced these amino acid changes into envelope proteins made in the laboratory and determined that just two of these changes were responsible for the neutralization sensitivity of the HIV-1 variant. The introduction of these two changes into the neutralization resistant variant and into the unrelated envelope sequences of another subtype A (common in Africa) HIV-1 variant and a subtype B HIV-1 (common in Europe and the Western Hemisphere) variant increased the sensitivity of all these viruses to antibody neutralization.
What Do These Findings Mean?
These findings show that two amino acid changes in gp41 of a neutralization-sensitive HIV-1 variant are responsible for the sensitivity of this variant to several neutralizing antibodies. The finding that the inclusion of these changes in the envelope protein of neutralization-resistant HIV-1 variants greatly increases their sensitivity to neutralizing antibodies indicates that the normally shielded regions of the protein are somehow made accessible to antibody by these changes. One possibility is that the amino acid changes might modify the overall shape of the envelope protein, thus exposing multiple, normally hidden regions in the HIV-1 envelope protein to antibodies. Importantly, these findings open up the possibility that the inclusion of these modifications in envelope-based immunogens might improve the ability of vaccines to generate broadly neutralizing antibodies against HIV-1.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050009.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIVInSite has comprehensive information on all aspects of HIV/AIDS, including links to resources dealing with HIV vaccine development
Information is available from Avert, an international AIDS charity, on all aspects of HIV and AIDS, including HIV vaccines
The US Centers for Disease Control and prevention provides information on HIV/AIDS including information on its HIV vaccine unit (in English and some information in Spanish)
The AIDS Vaccine Clearinghouse provides clear information about HIV vaccine science, research and product development
The International AIDS Vaccine Initiative also provides straightforward information about the development of HIV vaccines
doi:10.1371/journal.pmed.0050009
PMCID: PMC2174964  PMID: 18177204
5.  Adherence to Antiretroviral Prophylaxis for HIV Prevention: A Substudy Cohort within a Clinical Trial of Serodiscordant Couples in East Africa 
PLoS Medicine  2013;10(9):e1001511.
Jessica Haberer and colleagues investigate the association between high adherence to antiretroviral pre-exposure prophylaxis and HIV transmission in a substudy of serodiscordant couples participating in a clinical trial.
Please see later in the article for the Editors' Summary
Background
Randomized clinical trials of oral antiretroviral pre-exposure prophylaxis (PrEP) for HIV prevention have widely divergent efficacy estimates, ranging from 0% to 75%. These discrepancies are likely due to differences in adherence. To our knowledge, no studies to date have examined the impact of improving adherence through monitoring and/or intervention, which may increase PrEP efficacy, or reported on objective behavioral measures of adherence, which can inform PrEP effectiveness and implementation.
Methods and Findings
Within the Partners PrEP Study (a randomized placebo-controlled trial of oral tenofovir and emtricitabine/tenofovir among HIV-uninfected members of serodiscordant couples in Kenya and Uganda), we collected objective measures of PrEP adherence using unannounced home-based pill counts and electronic pill bottle monitoring. Participants received individual and couples-based adherence counseling at PrEP initiation and throughout the study; counseling was intensified if unannounced pill count adherence fell to <80%. Participants were followed monthly to provide study medication, adherence counseling, and HIV testing. A total of 1,147 HIV-uninfected participants were enrolled: 53% were male, median age was 34 years, and median partnership duration was 8.5 years. Fourteen HIV infections occurred among adherence study participants—all of whom were assigned to placebo (PrEP efficacy = 100%, 95% confidence interval 83.7%–100%, p<0.001). Median adherence was 99.1% (interquartile range [IQR] 96.9%–100%) by unannounced pill counts and 97.2% (90.6%–100%) by electronic monitoring over 807 person-years. Report of no sex or sex with another person besides the study partner, younger age, and heavy alcohol use were associated with <80% adherence; the first 6 months of PrEP use and polygamous marriage were associated with >80% adherence. Study limitations include potential shortcomings of the adherence measures and use of a convenience sample within the substudy cohort.
Conclusions
The high PrEP adherence achieved in the setting of active adherence monitoring and counseling support was associated with a high degree of protection from HIV acquisition by the HIV-uninfected partner in heterosexual serodiscordant couples. Low PrEP adherence was associated with sexual behavior, alcohol use, younger age, and length of PrEP use.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, about 2.5 million people (mostly living in sub-Saharan Africa) become infected with HIV, the virus that causes AIDS. HIV, which is usually transmitted through unprotected sex with an HIV-infected partner, destroys immune system cells, leaving infected individuals susceptible to other infections. There is no cure for AIDS, although antiretroviral drugs can hold HIV in check, and there is no vaccine against HIV infection. Individuals can reduce their risk of HIV infection by abstaining from sex, by having only one or a few low risk sexual partners, and by always using a condom. In addition, antiretroviral drugs can potentially be used in two ways to reduce HIV transmission. First, these drugs could be given to HIV-positive individuals to reduce their infectiousness. Second, antiretroviral drugs could be given to HIV-uninfected people to reduce acquisition of the virus. This approach—pre-exposure prophylaxis (PrEP)—has provided varying levels of protection against HIV infection in randomized controlled trials (RCT; studies that monitor the outcomes of groups of patients randomly assigned to receive different test drugs or a placebo/dummy drug).
Why Was This Study Done?
One hypothesis for the varying efficacy of PrEP in RCTs is differential adherence—differences in whether trial participants took the antiretroviral drugs correctly. Antiretroviral drugs only control HIV infections effectively when they are taken regularly and adherence to antiretroviral PrEP is probably also important for HIV prevention. Here, the researchers investigate adherence to antiretroviral prophylaxis in a substudy within the Partners PrEP Study, a placebo-controlled RCT of oral antiretroviral drugs among nearly 5,000 HIV-uninfected members of serodiscordant couples in East Africa. In serodiscordant couples, only one partner is HIV-positive; 20% of couples in Africa who know their HIV status are serodiscordant. In the Partner PrEP Study, the efficacy of HIV protection with oral antiretroviral drugs was 67%–75%.
What Did the Researchers Do and Find?
The researchers selected a “convenience” sample—a sample is taken non-randomly from a population that is close at hand—of 1,147 HIV-uninfected partners enrolled in Uganda. They used unannounced home-based pill counts (an approach that reduced the chance of participants dumping unused pills to appear more adherent than they actually were) and electronic pill bottle monitoring (a microchip in the medication bottle cap recorded whenever the bottle was opened) to measure PrEP adherence in this cohort. All the participants received adherence counseling at PrEP initiation and throughout the study; counseling was intensified if unannounced pill count adherence fell below 80%. Fourteen participants, all of whom had been assigned to placebo, became HIV-positive during the adherence substudy. The average adherence to PrEP was 99.1% and 97.2% as measured by unannounced pill counts and by electronic monitoring, respectively. About 7% and 26% of participants had less than 80% adherence as measured by unannounced pill count and electronic monitoring, respectively, during at least one 3-month period of the substudy. Greater than 80% adherence was associated with the first 6 months of PrEP use and polygamous marriage. Adherence less than 80% was associated with report of no sex or sex with another person besides the study partner, younger age, and heavy alcohol use. Finally, the adherence intervention (intensified counseling) was well received and in the first unannounced pill count after the intervention, adherence increased to above 80% in 92% of participants.
What Do These Findings Mean?
These findings indicate that the high level of PrEP adherence achieved in the setting of active adherence monitoring and counseling support was associated with a high level of protection from HIV acquisition by the HIV-uninfected partner in heterosexual serodiscordant couples. The findings also suggest that low PrEP adherence is associated with sexual behavior, alcohol use, younger age, and length of PrEP use. Several aspects of the study design may limit the accuracy of these findings. For example, although the adherence measures used here are probably more accurate than participant reports of missed doses and clinic-based pill counts (adherence measures that are often used in RCTs), they are not perfect. Nevertheless, these findings provide further support for the ability of PrEP to prevent HIV acquisition when taken regularly; they suggest that adherence interventions in the implementation setting should address sexual behavior, risk perception, and heavy alcohol use; and they provide data to guide ethical decisions about resource allocation for prevention and treatment of HIV infection.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001511.
The 2012 UNAIDS World AIDS Day Report provides up-to-date information about the AIDS epidemic and efforts to halt it
Information is available from the US National Institute of Allergy and infectious diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, summaries of recent research findings on HIV care and treatment, and information on HIV transmission and prevention and on PrEP
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on HIV and AIDS in Uganda, on HIV prevention, and on PrEP (in English and Spanish)
PrEP Watch provides detailed information about PrEP and links to other resources; it includes personal stories from people who have chosen to use PrEP
More information about the Partners PrEP Study is available
Personal stories about living with HIV/AIDS are available through Avert, through Nam/aidsmap, and through the charity website Healthtalkonline
doi:10.1371/journal.pmed.1001511
PMCID: PMC3769210  PMID: 24058300
6.  Pregnancy and Infant Outcomes among HIV-Infected Women Taking Long-Term ART with and without Tenofovir in the DART Trial 
PLoS Medicine  2012;9(5):e1001217.
Diana Gibb and colleagues investigate the effect of in utero tenofovir exposure by analyzing the pregnancy and infant outcomes of HIV-infected women enrolled in the DART trial.
Background
Few data have described long-term outcomes for infants born to HIV-infected African women taking antiretroviral therapy (ART) in pregnancy. This is particularly true for World Health Organization (WHO)–recommended tenofovir-containing first-line regimens, which are increasingly used and known to cause renal and bone toxicities; concerns have been raised about potential toxicity in babies due to in utero tenofovir exposure.
Methods and Findings
Pregnancy outcome and maternal/infant ART were collected in Ugandan/Zimbabwean HIV-infected women initiating ART during The Development of AntiRetroviral Therapy in Africa (DART) trial, which compared routine laboratory monitoring (CD4; toxicity) versus clinically driven monitoring. Women were followed 15 January 2003 to 28 September 2009. Infant feeding, clinical status, and biochemistry/haematology results were collected in a separate infant study. Effect of in utero ART exposure on infant growth was analysed using random effects models.
382 pregnancies occurred in 302/1,867 (16%) women (4.4/100 woman-years [95% CI 4.0–4.9]). 226/390 (58%) outcomes were live-births, 27 (7%) stillbirths (≥22 wk), and 137 (35%) terminations/miscarriages (<22 wk). Of 226 live-births, seven (3%) infants died <2 wk from perinatal causes and there were seven (3%) congenital abnormalities, with no effect of in utero tenofovir exposure (p>0.4). Of 219 surviving infants, 182 (83%) enrolled in the follow-up study; median (interquartile range [IQR]) age at last visit was 25 (12–38) months. From mothers' ART, 62/9/111 infants had no/20%–89%/≥90% in utero tenofovir exposure; most were also zidovudine/lamivudine exposed. All 172 infants tested were HIV-negative (ten untested). Only 73/182(40%) infants were breast-fed for median 94 (IQR 75–212) days. Overall, 14 infants died at median (IQR) age 9 (3–23) months, giving 5% 12-month mortality; six of 14 were HIV-uninfected; eight untested infants died of respiratory infection (three), sepsis (two), burns (one), measles (one), unknown (one). During follow-up, no bone fractures were reported to have occurred; 12/368 creatinines and seven out of 305 phosphates were grade one (16) or two (three) in 14 children with no effect of in utero tenofovir (p>0.1). There was no evidence that in utero tenofovir affected growth after 2 years (p = 0.38). Attained height- and weight for age were similar to general (HIV-uninfected) Ugandan populations. Study limitations included relatively small size and lack of randomisation to maternal ART regimens.
Conclusions
Overall 1-year 5% infant mortality was similar to the 2%–4% post-neonatal mortality observed in this region. No increase in congenital, renal, or growth abnormalities was observed with in utero tenofovir exposure. Although some infants died untested, absence of recorded HIV infection with combination ART in pregnancy is encouraging. Detailed safety of tenofovir for pre-exposure prophylaxis will need confirmation from longer term follow-up of larger numbers of exposed children.
Trial registration
www.controlled-trials.com ISRCTN13968779
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Currently, about 34 million people (mostly in low- and middle-income countries) are infected with HIV, the virus that causes AIDS. At the beginning of the epidemic, more men than women were infected with HIV but now about half of all people living with HIV/AIDS are women, most of who became infected through unprotected sex with an infected partner. In sub-Saharan Africa alone, 12 million women are HIV-positive. Worldwide, HIV/AIDS is the leading cause of death among women of child-bearing age. Moreover, most of the 400,000 children who become infected with HIV every year acquire the virus from their mother during pregnancy or birth, or through breastfeeding, so-called mother-to-child transmission (MTCT). Combination antiretroviral therapy (ART)—treatment with cocktails of powerful antiretroviral drugs—reduces HIV-related illness and death among women, and ART given to HIV-positive mothers during pregnancy and delivery and to their newborn babies greatly reduces MTCT.
Why Was This Study Done?
Because of ongoing international efforts to increase ART coverage, more HIV-positive women in Africa have access to ART now than ever before. However, little is known about pregnancy outcomes among HIV-infected African women taking ART throughout pregnancy for their own health or about the long-term outcomes of their offspring. In particular, few studies have examined the effect of taking tenofovir (an antiretroviral drug that is now recommended as part of first-line ART) throughout pregnancy. Tenofovir readily crosses from mother to child during pregnancy and, in animal experiments, high doses of tenofovir given during pregnancy caused bone demineralization (which weakens bones), kidney problems, and impaired growth among offspring. In this study, the researchers analyze data collected on pregnancy and infant outcomes among Ugandan and Zimbabwean HIV-positive women who took ART throughout pregnancy in the Development of AntiRetroviral Therapy in Africa (DART) trial. This trial was designed to test whether ART could be safely and effectively delivered in Africa without access to the expensive laboratory tests that are routinely used to monitor ART toxicity and efficacy in developed countries.
What Did the Researchers Do and Find?
The pregnancy outcomes of 302 women who became pregnant during the DART trial and information on birth defects among their babies were collected as part of the DART protocol; information on the survival, growth, and development of the infants born to these women was collected in a separate infant study. Most of the women who became pregnant were taking tenofovir-containing ART before and throughout their pregnancies. 58% of the pregnancies resulted in a live birth, 7% resulted in a stillbirth (birth of a dead baby at any time from 22 weeks gestation to the end of pregnancy), and 35% resulted in a termination or miscarriage (before 22 weeks gestation). Of the 226 live births, seven infants died within 2 weeks and seven had birth defects. Similar proportions of the infants exposed and not exposed to tenofovir during pregnancy died soon after birth or had birth defects. Of the 182 surviving infants who were enrolled in the infant study, 14 subsequently died at an average age of 9 months, giving a 1-year mortality of 5%. None of the surviving children who were tested (172 infants) were HIV infected. No bone fractures or major kidney problems occurred during follow-up and prebirth exposure to tenofovir in utero had no effect on growth or weight gain at 2 years (in contrast to a previous US study).
What Do These Findings Mean?
By showing that prebirth tenofovir exposure does not affect pregnancy outcomes or increase birth defects, growth abnormalities, or kidney problems, these findings support the use of tenofovir-containing ART during pregnancy among HIV-positive African women, and suggest that it could also be used to prevent women of child-bearing age acquiring HIV-infection heterosexually. Notably, the observed 5% 1-year infant mortality is similar to the 2%–4% infant mortality normally seen in the region. The absence of HIV infection among the infants born to the DART participants is also encouraging. However, this is a small study (only 111 infants were exposed to tenofovir throughout pregnancy) and women were not randomly assigned to receive tenofovir-containing ART. Consequently, more studies are needed to confirm that tenofovir exposure during pregnancy does not affect pregnancy outcomes or have any long-term effects on infants. Such studies are essential because the use of tenofovir as a treatment for women who are HIV-positive is likely to increase and tenofovir may also be used in the future to prevent HIV acquisition in HIV-uninfected women.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001217.
Information is available from the US National Institute of Allergy and infectious diseases on all aspects of HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment (in several languages)
Information is available from Avert, an international AIDS nonprofit on many aspects of HIV/AIDS, including detailed information on HIV/AIDS treatment and care, women, HIV and AIDS, children, HIV and AIDS, and on HIV/AIDS and pregnancy (some information in English and Spanish); personal stories of women living with HIV are available
More information about the DART trial is available
Additional patient stories about living with HIV/AIDS are available through the nonprofit website Healthtalkonline
doi:10.1371/journal.pmed.1001217
PMCID: PMC3352861  PMID: 22615543
7.  Feasibility and Safety of ALVAC-HIV vCP1521 Vaccine in HIV- exposed Infants in Uganda: Results from the First HIV Vaccine Trial in Infants in Africa 
Background
The development of a safe and effective vaccine against human immunodeficiency virus type 1 (HIV-1) for prevention mother-to-child transmission of HIV would significantly advance the goal of eliminating HIV infection in children. Safety and feasibility results from Phase I, randomized, double blind, placebo-controlled trial of ALVAC-HIV vCP1521 in infants born to HIV-1-infected women in Uganda are reported.
Methods
HIV exposed infants were enrolled at birth and randomized (4:1) to receive vaccine or saline placebo intramuscular injections at birth, 4, 8 and 12 weeks of age. Vaccine reactogenicity was assessed at vaccination, and days 1 and 2 post-vaccination. Infants were followed until 24 months of age. HIV infection status was determined by HIV DNA PCR.
Findings
From October 2006 to May 2007, 60 infants (48 vaccine, 12 placebo) were enrolled with 98% retention at 24 months. One infant was withdrawn, but there were no missed visits or vaccinations among the 59 infants retained. Immune responses elicited by Diptheria, Polio, Hepatitis B and Heamophilus influenzae type B and measles vaccination were similar in the two arms. The vaccine was well tolerated with no severe or life-threatening reactogenicity events. Adverse events were equally distributed across both study arms. Four infants were diagnosed as HIV infected [3 at birth (2 vaccine, 1 placebo) and one in vaccine arm at 2 weeks of age].
Interpretation
The ALVAC-HIV vCP1521 vaccination was feasible and safe in infants born to HIV-infected women in Uganda. The conduct of high quality infant HIV vaccine trials is achievable in Africa.
doi:10.1097/QAI.0b013e31827f1c2d
PMCID: PMC3625520  PMID: 23221981
HIV vaccine; ALVAC; infants; Africa; breast milk transmission
8.  Triple-Antiretroviral Prophylaxis to Prevent Mother-To-Child HIV Transmission through Breastfeeding—The Kisumu Breastfeeding Study, Kenya: A Clinical Trial 
PLoS Medicine  2011;8(3):e1001015.
Timothy Thomas and colleagues report the results of the Kisumu breastfeeding study (Kenya), a single-arm trial that assessed the feasibility and safety of a triple-antiretroviral regimen to suppress maternal HIV load in late pregnancy.
Background
Effective strategies are needed for the prevention of mother-to-child HIV transmission (PMTCT) in resource-limited settings. The Kisumu Breastfeeding Study was a single-arm open label trial conducted between July 2003 and February 2009. The overall aim was to investigate whether a maternal triple-antiretroviral regimen that was designed to maximally suppress viral load in late pregnancy and the first 6 mo of lactation was a safe, well-tolerated, and effective PMTCT intervention.
Methods and Findings
HIV-infected pregnant women took zidovudine, lamivudine, and either nevirapine or nelfinavir from 34–36 weeks' gestation to 6 mo post partum. Infants received single-dose nevirapine at birth. Women were advised to breastfeed exclusively and wean rapidly just before 6 mo. Using Kaplan-Meier methods we estimated HIV-transmission and death rates from delivery to 24 mo. We compared HIV-transmission rates among subgroups defined by maternal risk factors, including baseline CD4 cell count and viral load.
Among 487 live-born, singleton, or first-born infants, cumulative HIV-transmission rates at birth, 6 weeks, and 6, 12, and 24 mo were 2.5%, 4.2%, 5.0%, 5.7%, and 7.0%, respectively. The 24-mo HIV-transmission rates stratified by baseline maternal CD4 cell count <500 and ≥500 cells/mm3 were 8.4% (95% confidence interval [CI] 5.8%–12.0%) and 4.1% (1.8%–8.8%), respectively (p = 0.06); the corresponding rates stratified by baseline maternal viral load <10,000 and ≥10,000 copies/ml were 3.0% (1.1%–7.8%) and 8.7% (6.1%–12.3%), respectively (p = 0.01). None of the 12 maternal and 51 infant deaths (including two second-born infants) were attributed to antiretrovirals. The cumulative HIV-transmission or death rate at 24 mo was 15.7% (95% CI 12.7%–19.4%).
Conclusions
This trial shows that a maternal triple-antiretroviral regimen from late pregnancy through 6 months of breastfeeding for PMTCT is safe and feasible in a resource-limited setting. These findings are consistent with those from other trials using maternal triple-antiretroviral regimens during breastfeeding in comparable settings.
Trial registration
ClinicalTrials.gov NCT00146380
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, about half a million children become infected with human immunodeficiency virus (HIV), which causes acquired immunodeficiency syndrome (AIDS). Nearly all these newly infected children live in resource-limited countries and most acquire HIV from their mother, so-called mother-to-child transmission (MTCT). Without intervention, 25%–50% of babies born to HIV-positive mothers become infected with HIV during pregnancy, delivery, or breastfeeding. This infection rate can be reduced by treating mother and child with antiretroviral (ARV) drugs. A single dose of nevirapine (a “non-nucleoside reverse transcriptase inhibitor” or NNRTI) given to the mother at the start of labor and to her baby soon after birth nearly halves the risk of MTCT. Further reductions in risk can be achieved by giving mother and baby three ARVs—an NNRTI and two nucleoside reverse transcriptase inhibitors (NRTIs such as zidovudine and lamivudine)—during pregnancy and perinatally (around the time of birth).
Why Was This Study Done?
Breastfeeding is crucial for child survival in poor countries but it is also responsible for up to half of MTCT. Consequently, many researchers are investigating how various ARV regimens given to mothers and/or their infants during the first few months of life as well as during pregnancy and perinatally affect MTCT. In this single-arm trial, the researchers assess the feasibility and safety of using a triple-ARV regimen to suppress the maternal HIV load (amount of virus in the blood) from late pregnancy though 6 months of breastfeeding among HIV-positive women in Kisumu, Kenya, and ask whether this approach achieves a lower HIV transmission rate than other ARV regimens that have been tested in resource-limited settings. In a single-arm trial, all the participants are given the same treatment. By contrast, in a “randomized controlled” trial, half the participants chosen at random are given the treatment under investigation and the rest are given a control treatment. A randomized controlled trial provides a better comparison of treatments than a single-arm trial but is more costly.
What Did the Researchers Do and Find?
In the Kisumu Breastfeeding Study (KiBS), HIV-infected pregnant women took a triple-ARV regimen containing zidovudine and lamivudine and either nevirapine or the protease inhibitor nelfinavir from 34–36 weeks of pregnancy to 6 months after delivery. They were advised to breastfeed their babies (who received single-dose nevirapine at birth), and to wean them rapidly just before 6 months. The researchers then used Kaplan-Meier statistical methods to estimate HIV transmission and death rates among 487 live-born infants from delivery to 24 months. The cumulative HIV transmission rate rose from 2.5% at birth to 7.0% at 24 months. The cumulative HIV transmission or death rate at 24 months was 15.7%; no infant deaths were attributed to ARVs. At 24 months, 3.0% of babies born to mothers with a low viral load were HIV positive compared to 8.7% of babies born to mothers with a high viral load, a statistically significant difference. Similarly, at 24 months, 8.4% of babies born to mothers with low baseline CD4 cell counts (CD4 cells are immune system cells that are killed by HIV; CD4 cell counts indicate the level of HIV-inflicted immune system damage) were HIV positive compared to 4.1% of babies born to mothers with high baseline CD4 cell counts, although this difference did not achieve statistical significance.
What Do These Findings Mean?
Although these findings are limited by the single-arm design, they support the idea that giving breastfeeding women a triple-ARV regimen from late pregnancy to 6 months is a safe, feasible way to reduce MTCT in resource-limited settings. The HIV transmission rates in this study are comparable to those recorded in similar trials in other resource-limited settings and are lower than MTCT rates observed previously in Kisumu in a study in which no ARVs were used. Importantly, the KiBS mothers took most of the ARVs they were prescribed and most stopped breastfeeding by 6 months as advised. The intense follow-up employed in KiBS may be partly responsible for this good adherence to the trial protocol and thus this study's findings may not be generalizable to all resource-limited settings. Nevertheless, they suggest that a simple triple-ARV regimen given to HIV-positive pregnant women regardless of their baseline CD4 cell count can reduce MTCT during pregnancy and breastfeeding in resource-limited setting.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001015.
The accompanying PLoS Medicine Research article by Zeh and colleagues describes the emergence of resistance to ARVs in KiBS
Information on HIV and AIDS is available from the US National Institute of Allergy and Infectious Diseases
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on children, HIV, and AIDS and on preventing mother-to-child transmission of HIV (in English and Spanish)
UNICEF also has information about children and HIV and AIDS (in several languages)
The World Health organization has information on mother-to-child transmission of HIV http://www.who.int/hiv/topics/mtct/en/index.html (in several languages)
doi:10.1371/journal.pmed.1001015
PMCID: PMC3066129  PMID: 21468300
9.  Two-Year Morbidity–Mortality and Alternatives to Prolonged Breast-Feeding among Children Born to HIV-Infected Mothers in Côte d'Ivoire 
PLoS Medicine  2007;4(1):e17.
Background
Little is known about the long-term safety of infant feeding interventions aimed at reducing breast milk HIV transmission in Africa.
Methods and Findings
In 2001–2005, HIV-infected pregnant women having received in Abidjan, Côte d'Ivoire, a peripartum antiretroviral prophylaxis were presented antenatally with infant feeding interventions: either artificial feeding, or exclusive breast-feeding and then early cessation from 4 mo of age. Nutritional counseling and clinical management were provided for 2 y. Breast-milk substitutes were provided for free. The primary outcome was the occurrence of adverse health outcomes in children, defined as validated morbid events (diarrhea, acute respiratory infections, or malnutrition) or severe events (hospitalization or death). Hazards ratios to compare formula-fed versus short-term breast-fed (reference) children were adjusted for confounders (baseline covariates and pediatric HIV status as a time-dependant covariate). The 18-mo mortality rates were also compared to those observed in the Ditrame historical trial, which was conducted at the same sites in 1995–1998, and in which long-term breast-feeding was practiced in the absence of any specific infant feeding intervention. Of the 557 live-born children, 262 (47%) were breast-fed for a median of 4 mo, whereas 295 were formula-fed. Over the 2-y follow-up period, 37% of the formula-fed and 34% of the short-term breast-fed children remained free from any adverse health outcome (adjusted hazard ratio [HR]: 1.10; 95% confidence interval [CI], 0.87–1.38; p = 0.43). The 2-y probability of presenting with a severe event was the same among formula-fed (14%) and short-term breast-fed children (15%) (adjusted HR, 1.19; 95% CI, 0.75–1.91; p = 0.44). An overall 18-mo probability of survival of 96% was observed among both HIV-uninfected short-term and formula-fed children, which was similar to the 95% probability observed in the long-term breast-fed ones of the Ditrame trial.
Conclusions
The 2-y rates of adverse health outcomes were similar among short-term breast-fed and formula-fed children. Mortality rates did not differ significantly between these two groups and, after adjustment for pediatric HIV status, were similar to those observed among long-term breast-fed children. Given appropriate nutritional counseling and care, access to clean water, and a supply of breast-milk substitutes, these alternatives to prolonged breast-feeding can be safe interventions to prevent mother-to-child transmission of HIV in urban African settings.
Given appropriate nutritional counseling and care, access to clean water, and supply of breast milk substitutes, replacing prolonged breast-feeding with formula-feeding appears to be a safe intervention to prevent mother-to-child transmission of HIV in this setting.
Editors' Summary
Background.
The HIV virus can be transmitted from infected mothers to their babies during pregnancy and birth as well as after birth through breast milk. Mother-to-child transmission in developed countries has been all but eliminated by treatment of mothers with the best available combination of antiretroviral drugs and by asking them to avoid breast-feeding. However, in many developing countries, the best drug treatments are not available to mothers. Moreover, breast-feeding is generally the best nutritional choice for infants, especially in areas where resources such as clean water, formula feed, and provision of healthcare are scarce. And even if formula feed is available, formula-fed babies might be at higher risk of dying from diarrhea and chest infections, which are more common in infants who are not breast-fed. International guidelines say that HIV-positive mothers should avoid all breast-feeding and adopt formula feeding instead if this option is practical and safe for them, which would require that they can afford formula feed and have easy access to clean water. If formula-feeding is not feasible, guidelines recommend that mothers should breast-feed only for the first few months and then stop and switch the baby to solid food. One of these two alternative options should be feasible in most African cities if mothers are given the right support.
Why Was This Study Done?
Several completed and ongoing studies are assessing the relative risks and benefits of the two recommended strategies for different developing country locations, and this is one of them. The study, the “Ditrame Plus” trial by researchers from France and Côte d'Ivoire, was conducted in Abidjan, an urban West African setting. The goal was to compare death rates and rates of certain diseases (such as diarrhea and chest infections) between babies born to HIV-positive mothers that were formula-fed and those that were breast-fed for a short time after birth.
What Did the Researchers Do and Find?
HIV-positive pregnant women were invited to enter the study, and they received short-term drug treatments intended to reduce the risk of HIV transmission to their babies. Women in the trial were then asked to choose one of the two feeding options and offered support and counseling for either one. This support included free formula, transport, and healthcare provision. Babies were followed up to their second birthday, and data were collected on death rates and any serious illnesses. A total of 643 women were enrolled into the study, and safety data were collected for 557 babies, of whom 295 were in the formula group and 262 were in the short-term breast-feeding group. The researchers corrected for HIV infection in the babies and found no evidence that the risk of other negative health outcomes and death rates was any different between the formula-fed babies and short-term breast-fed babies. Looking specifically at individual diseases, the researchers found that the risks for diarrhea and chest infections were slightly higher among formula-fed babies, but this did not translate into a greater risk of death or worse overall health. They also compared the death rates in this study with some historical data from a previous research project done in the same area on children born to HIV-positive mothers who had practiced long-term breast-feeding. The mother-to-child transmission rate of HIV had been much higher in that earlier trial, but looking only at the HIV-negative children, the researchers found no difference in risk for death or serious disease between the formula-fed or short-term breast-fed babies from the Ditrame Plus trial and the long-term breast-fed babies from the earlier trial.
What Do These Findings Mean?
This study shows that if HIV-positive mothers are well supported, either of the two feeding options currently recommended (formula-only feed, or short-term breast-feeding) are likely to be equivalent in terms of the baby's chances for survival and health. However, women in this study were offered a great deal of support and the findings may not necessarily apply to real-life situations in other settings in Africa, or outside the context of a research project. In addition to routine care after birth, access to better drugs to prevent mother-to-child transmission in developing countries remains an important goal.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/doi:10.1371/journal.pmed.0040017.
Resources from Avert (an AIDS charity) on HIV and infant feeding.
Information from the US Centers for Disease Control on mother-to-child transmission of HIV
Guidelines from the World Health Organization on mother-to-child transmission of HIV
AIDSMap pages on breast-feeding and HIV
HIV Care and PMTCT in Resource-Limited Setting contains monthly bulletins and a database devoted to HIV/AIDS infections and prevention of the mother-to-child transmission of HIV
The Ghent group is a network of researchers and policymakers in the area of prevention of mother-to-child transmission of HIV
doi:10.1371/journal.pmed.0040017
PMCID: PMC1769413  PMID: 17227132
10.  Hormonal Contraception and the Risk of HIV Acquisition: An Individual Participant Data Meta-analysis 
PLoS Medicine  2015;12(1):e1001778.
In a meta-analysis of individual participant data, Charles Morrison and colleagues explore the association between hormonal contraception use and risk of HIV infection in sub-Saharan Africa.
Background
Observational studies of a putative association between hormonal contraception (HC) and HIV acquisition have produced conflicting results. We conducted an individual participant data (IPD) meta-analysis of studies from sub-Saharan Africa to compare the incidence of HIV infection in women using combined oral contraceptives (COCs) or the injectable progestins depot-medroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) with women not using HC.
Methods and Findings
Eligible studies measured HC exposure and incident HIV infection prospectively using standardized measures, enrolled women aged 15–49 y, recorded ≥15 incident HIV infections, and measured prespecified covariates. Our primary analysis estimated the adjusted hazard ratio (aHR) using two-stage random effects meta-analysis, controlling for region, marital status, age, number of sex partners, and condom use. We included 18 studies, including 37,124 women (43,613 woman-years) and 1,830 incident HIV infections. Relative to no HC use, the aHR for HIV acquisition was 1.50 (95% CI 1.24–1.83) for DMPA use, 1.24 (95% CI 0.84–1.82) for NET-EN use, and 1.03 (95% CI 0.88–1.20) for COC use. Between-study heterogeneity was mild (I2 < 50%). DMPA use was associated with increased HIV acquisition compared with COC use (aHR 1.43, 95% CI 1.23–1.67) and NET-EN use (aHR 1.32, 95% CI 1.08–1.61). Effect estimates were attenuated for studies at lower risk of methodological bias (compared with no HC use, aHR for DMPA use 1.22, 95% CI 0.99–1.50; for NET-EN use 0.67, 95% CI 0.47–0.96; and for COC use 0.91, 95% CI 0.73–1.41) compared to those at higher risk of bias (pinteraction = 0.003). Neither age nor herpes simplex virus type 2 infection status modified the HC–HIV relationship.
Conclusions
This IPD meta-analysis found no evidence that COC or NET-EN use increases women’s risk of HIV but adds to the evidence that DMPA may increase HIV risk, underscoring the need for additional safe and effective contraceptive options for women at high HIV risk. A randomized controlled trial would provide more definitive evidence about the effects of hormonal contraception, particularly DMPA, on HIV risk.
Editors’ Summary
Background
AIDS has killed about 36 million people since the first recorded case of the disease in 1981. About 35 million people (including 25 million living in sub-Saharan Africa) are currently infected with HIV, the virus that causes AIDS, and every year, another 2.3 million people become newly infected with HIV. At the beginning of the epidemic, more men than women were infected with HIV. Now, about half of all adults infected with HIV are women. In 2013, almost 60% of all new HIV infections among young people aged 15–24 years occurred among women, and it is estimated that, worldwide, 50 young women are newly infected with HIV every hour. Most women become infected with HIV through unprotected intercourse with an infected male partner—biologically, women are twice as likely to become infected through unprotected intercourse as men. A woman’s risk of becoming infected with HIV can be reduced by abstaining from sex, by having one or a few partners, and by always using condoms.
Why Was This Study Done?
Women and societies both benefit from effective contraception. When contraception is available, women can avoid unintended pregnancies, fewer women and babies die during pregnancy and childbirth, and maternal and infant health improves. However, some (but not all) observational studies (investigations that measure associations between the characteristics of participants and their subsequent development of specific diseases) have reported an association between hormonal contraceptive use and an increased risk of HIV acquisition by women. So, does hormonal contraception increase the risk of HIV acquisition among women or not? Here, to investigate this question, the researchers undertake an individual participant data meta-analysis of studies conducted in sub-Saharan Africa (a region where both HIV infection and unintended pregnancies are common) to compare the incidence of HIV infection (the number of new cases in a population during a given time period) among women using and not using hormonal contraception. Meta-analysis is a statistical method that combines the results of several studies; an individual participant data meta-analysis combines the data recorded for each individual involved in the studies rather than the aggregated results from each study.
What Did the Researchers Do and Find?
The researchers included 18 studies that measured hormonal contraceptive use and incident HIV infection among women aged 15–49 years living in sub-Saharan Africa in their meta-analysis. More than 37,000 women took part in these studies, and 1,830 became newly infected with HIV. Half of the women were not using hormonal contraception, a quarter were using depot-medroxyprogesterone acetate (DMPA; an injectable hormonal contraceptive), and the remainder were using combined oral contraceptives (COCs) or norethisterone enanthate (NET-EN, another injectable contraceptive). After adjustment for other factors likely to influence HIV acquisition (for example, condom use), women using DMPA had a 1.5-fold increased risk of HIV acquisition compared to women not using hormonal contraception. There was a slightly increased risk of HIV acquisition among women using NET-EN compared to women not using hormonal contraception, but this increase was not statistically significant (it may have happened by chance alone). There was no increased risk of HIV acquisition associated with COC use. DMPA use was associated with a 1.43-fold and 1.32-fold increased risk of HIV acquisition compared with COC and NET-EN use, respectively. Finally, neither age nor herpes simplex virus 2 infection status modified the effect of hormonal contraceptive use on HIV acquisition.
What Do These Findings Mean?
The findings of this individual patient data meta-analysis provide no evidence that COC or NET-EN use increases a woman’s risk of acquiring HIV, but add to the evidence suggesting that DMPA use increases the risk of HIV acquisition. These findings are likely to be more accurate than those of previous meta-analyses that used aggregated data but are likely to be limited by the quality, design, and representativeness of the studies included in the analysis. These findings nevertheless highlight the need to develop additional safe and effective contraceptive options for women at risk of HIV, particularly those living in sub-Saharan Africa, where although contraceptive use is generally low, DMPA is the most widely used hormonal contraceptive. In addition, these findings highlight the need to initiate randomized controlled trials to provide more definitive evidence of the effects of hormonal contraception, particularly DMPA, on HIV risk.
Additional Information.
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001778.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment, including personal stories about living with HIV/AIDS and a news report on this meta-analysis
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including detailed information on women, HIV, and AIDS, and on HIV and AIDS in South Africa (in English and Spanish); personal stories of women living with HIV are available
The World Health Organization provides information on all aspects of HIV/AIDS (in several languages); information about a 2012 WHO technical consultation about hormonal contraception and HIV
The 2013 UNAIDS World AIDS Day report provides up-to-date information about the AIDS epidemic and efforts to halt it; UNAIDS also provides information about HIV and hormonal contraception
doi:10.1371/journal.pmed.1001778
PMCID: PMC4303292  PMID: 25612136
11.  A Model for the Roll-Out of Comprehensive Adult Male Circumcision Services in African Low-Income Settings of High HIV Incidence: The ANRS 12126 Bophelo Pele Project 
PLoS Medicine  2010;7(7):e1000309.
Bertrand Auvert and colleagues describe the large-scale roll-out of adult male circumcision through a program in South Africa.
Background
World Health Organization (WHO)/Joint United Nations Programme on AIDS (UNAIDS) has recommended adult male circumcision (AMC) for the prevention of heterosexually acquired HIV infection in men from communities where HIV is hyperendemic and AMC prevalence is low. The objective of this study was to investigate the feasibility of the roll-out of medicalized AMC according to UNAIDS/WHO operational guidelines in a targeted African setting.
Methods and Findings
The ANRS 12126 “Bophelo Pele” project was implemented in 2008 in the township of Orange Farm (South Africa). It became functional in 5 mo once local and ethical authorizations were obtained. Project activities involved community mobilization and outreach, as well as communication approaches aimed at both men and women incorporating broader HIV prevention strategies and promoting sexual health. Free medicalized AMC was offered to male residents aged 15 y and over at the project's main center, which had been designed for low-income settings. Through the establishment of an innovative surgical organization, up to 150 AMCs under local anesthesia, with sterilized circumcision disposable kits and electrocautery, could be performed per day by three task-sharing teams of one medical circumciser and five nurses. Community support for the project was high. As of November 2009, 14,011 men had been circumcised, averaging 740 per month in the past 12 mo, and 27.5% of project participants agreed to be tested for HIV. The rate of adverse events, none of which resulted in permanent damage or death, was 1.8%. Most of the men surveyed (92%) rated the services provided positively. An estimated 39.1% of adult uncircumcised male residents have undergone surgery and uptake is steadily increasing.
Conclusion
This study demonstrates that a quality AMC roll-out adapted to African low-income settings is feasible and can be implemented quickly and safely according to international guidelines. The project can be a model for the scale-up of comprehensive AMC services, which could be tailored for other rural and urban communities of high HIV prevalence and low AMC rates in Eastern and Southern Africa.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Acquired immunodeficiency syndrome (AIDS) has killed about 25 million people since 1981, and more than 30 million people (22 million in sub-Saharan Africa alone) are now infected with the human immunodeficiency virus (HIV), which causes AIDS. There is no cure for HIV/AIDS. Consequently, prevention of HIV infection is extremely important. Because HIV is most often spread through unprotected sex with an infected partner, individuals can reduce their risk of HIV infection by abstaining from sex, by having one or a few partners, and by always using a male or female condom. In addition, three trials in sub-Saharan Africa recently reported that medicalized adult male circumcision (AMC)—the surgical removal of the foreskin, a loose fold of skin that covers the head of the penis—can reduce HIV transmission rates in men by more than a half. Thus, AMC delivered as a catch-up campaign—in the long-term, circumcision of male infants is likely to be a more sustainable strategy—has the potential to reduce the prevalence of HIV (the proportion of the population infected with HIV) in sub-Saharan Africa.
Why Was This Study Done?
The World Health Organization (WHO) and the Joint United Nations Programme on AIDS (UNAIDS) now recommend that AMC programs should be rolled-out wherever there is a generalized HIV epidemic and few men are circumcised. Accordingly, these organizations have defined a minimum package of AMC services and have issued guidelines and tools designed to engage communities in the roll-out and to ensure that appropriate AMC counseling and surgical facilities are available. But is rapid AMC roll-out feasible in real-life settings? Here, the researchers try to find out by studying the “Bophelo Pele” (Health First) project. This project, which follows the WHO/UNAIDS guidelines for AMC, aims to offer free, safe AMC services to all men aged 15 years or more living in the Orange Farm township in South Africa as part of a community-based intervention against HIV. Orange Farm is in a low-income region of South Africa where HIV prevalence is 15.2% and AMC prevalence is about 25%.
What Did the Researchers Do and Find?
Before the Bophelo Pele project started in January 2008, the researchers consulted the community about the implementation of AMC, helped to create a community advisory board, organized community workshops to discuss the project, and surveyed people's knowledge about AMC and willingness to undergo AMC. These activities indicated a high level of community support for the project and a high level of willingness among men to undergo AMC. Once the project started, the researchers used multiple communication channels to tell the Orange Farm residents about AMC and broader HIV prevention strategies and provided eligible men with counseling about AMC and with voluntary HIV counseling and testing during the recruitment process. Three days after recruitment, eligible men were circumcised free-of-charge at the project's main center, where three teams of one medical circumciser and five nurses were able to complete up to 150 AMCs per day. By November 2009, 14,011 men had been circumcised (more than a third of the eligible men in the township), and AMC uptake was still increasing steadily. Nearly all the men circumcised over one 2-month period rated the AMC services positively in a survey and adverse effects (all mild) occurred after fewer than 1 in 50 circumcisions.
What Do These Findings Mean?
These findings suggest that the rapid roll-out of high-quality, free AMC as an intervention against HIV has been successful in the Orange Farm township. However, other findings highlight some of the challenges that face AMC roll-out. For example, only a quarter of the participants agreed to voluntary HIV counseling and testing, which is worrying because newly circumcised HIV-positive men have an increased risk of transmitting HIV if they resume sexual activity too soon after the operation. Similarly, only two-thirds of the participants returned for a check-up after circumcision; this proportion needs to be increased to ensure the safety and efficacy of AMC programs. Nevertheless, these findings and those from similar intervention programs in Kenya and Uganda indicate that AMC scale-up should be feasible, at least in the short term, as an HIV prevention strategy in low-income communities where there is a high HIV prevalence and a low AMC rate.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000309.
Information is available from the US National Institute of Allergy and infectious diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on HIV and AIDS in South Africa, and on circumcision and HIV (in English and Spanish)
More information about male circumcision is available from WHO and from the Clearinghouse on Male Circumcision, including a June 2010 report from WHO/UNAIDS entitled Progress in male circumcision scale-up: country implementation and research update
More information about the Bophelo Pele project is available
doi:10.1371/journal.pmed.1000309
PMCID: PMC2907271  PMID: 20652013
12.  Measuring Coverage in MNCH: Population HIV-Free Survival among Children under Two Years of Age in Four African Countries 
PLoS Medicine  2013;10(5):e1001424.
Background
Population-based evaluations of programs for prevention of mother-to-child HIV transmission (PMTCT) are scarce. We measured PMTCT service coverage, regimen use, and HIV-free survival among children ≤24 mo of age in Cameroon, Côte D'Ivoire, South Africa, and Zambia.
Methods and Findings
We randomly sampled households in 26 communities and offered participation if a child had been born to a woman living there during the prior 24 mo. We tested consenting mothers with rapid HIV antibody tests and tested the children of seropositive mothers with HIV DNA PCR or rapid antibody tests. Our primary outcome was 24-mo HIV-free survival, estimated with survival analysis. In an individual-level analysis, we evaluated the effectiveness of various PMTCT regimens. In a community-level analysis, we evaluated the relationship between HIV-free survival and community PMTCT coverage (the proportion of HIV-exposed infants in each community that received any PMTCT intervention during gestation or breastfeeding). We also compared our community coverage results to those of a contemporaneous study conducted in the facilities serving each sampled community. Of 7,985 surveyed children under 2 y of age, 1,014 (12.7%) were HIV-exposed. Of these, 110 (10.9%) were HIV-infected, 851 (83.9%) were HIV-uninfected, and 53 (5.2%) were dead. HIV-free survival at 24 mo of age among all HIV-exposed children was 79.7% (95% CI: 76.4, 82.6) overall, with the following country-level estimates: Cameroon (72.6%; 95% CI: 62.3, 80.5), South Africa (77.7%; 95% CI: 72.5, 82.1), Zambia (83.1%; 95% CI: 78.4, 86.8), and Côte D'Ivoire (84.4%; 95% CI: 70.0, 92.2). In adjusted analyses, the risk of death or HIV infection was non-significantly lower in children whose mothers received a more complex regimen of either two or three antiretroviral drugs compared to those receiving no prophylaxis (adjusted hazard ratio: 0.60; 95% CI: 0.34, 1.06). Risk of death was not different for children whose mothers received a more complex regimen compared to those given single-dose nevirapine (adjusted hazard ratio: 0.88; 95% CI: 0.45, 1.72). Community PMTCT coverage was highest in Cameroon, where 75 of 114 HIV-exposed infants met criteria for coverage (66%; 95% CI: 56, 74), followed by Zambia (219 of 444, 49%; 95% CI: 45, 54), then South Africa (152 of 365, 42%; 95% CI: 37, 47), and then Côte D'Ivoire (3 of 53, 5.7%; 95% CI: 1.2, 16). In a cluster-level analysis, community PMTCT coverage was highly correlated with facility PMTCT coverage (Pearson's r = 0.85), and moderately correlated with 24-mo HIV-free survival (Pearson's r = 0.29). In 14 of 16 instances where both the facility and community samples were large enough for comparison, the facility-based coverage measure exceeded that observed in the community.
Conclusions
HIV-free survival can be estimated with community surveys and should be incorporated into ongoing country monitoring. Facility-based coverage measures correlate with those derived from community sampling, but may overestimate population coverage. The more complex regimens recommended by the World Health Organization seem to have measurable public health benefit at the population level, but power was limited and additional field validation is needed.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
For a pregnant woman who is HIV-positive, the discrepancy across the world in outlook for mother and child is stark. Mother-to-child transmission of HIV during pregnancy is now less than 1% in many high-income settings, but occurs much more often in low-income countries. Three interventions have a major impact on transmission of HIV to the baby: antiretroviral drugs, mode of delivery, and type of infant feeding. The latter two are complex, as the interventions commonly used in high-income countries (cesarean section if the maternal viral load is high; exclusive formula feeding) have their own risks in low-income settings. Minimizing the risks of transmitting HIV through effective drug regimes therefore becomes particularly important. Monitoring progress on reducing the incidence of mother-to-child HIV transmission is essential, but not always easy to achieve.
Why Was This Study Done?
A research group led by Stringer and colleagues recently reported a study from four countries in Africa: Cameroon, Côte D'Ivoire, South Africa, and Zambia. The study showed that even in the health facility setting (e.g., hospitals and clinics), only half of infants whose mothers were HIV-positive received the minimum recommended drug treatment (one dose of nevirapine during labor) to prevent HIV transmission. Across the population of these countries, it is possible that fewer receive antiretroviral drugs, as the study did not include women who did not access health facilities. Therefore, the next stage of the study by this research group, reported here, involved going into the communities around these health facilities to find out how many infants under two years old had been exposed to HIV, whether they had received drugs to prevent transmission, and what proportion were alive and not infected with HIV at two years old.
What Did the Researchers Do and Find?
The researchers tested all consenting women who had delivered a baby in the last two years in the surrounding communities. If the mother was found to be HIV-positive, then the infant was also tested for HIV. The researchers then calculated how many of the infants would be alive at two years and free of HIV infection.
Most mothers (78%) agreed to testing for themselves and their infants. There were 7,985 children under two years of age in this study, of whom 13% had been born to an HIV-positive mother. Less than half (46%) of the HIV-positive mothers had received any drugs to prevent HIV transmission. Of the children with HIV-positive mothers, 11% were HIV-infected, 84% were not infected with HIV, and 5% had died. Overall, the researchers estimated that around 80% of these children would be alive at two years without HIV infection. This proportion differed non-significantly between the four countries (ranging from 73% to 84%). The researchers found higher rates of infant survival than they had expected and knew that they might have missed some infant deaths (e.g., if households with infant deaths were less likely to take part in the study).
The researchers found that their estimates of the proportion of HIV-positive mothers who received drugs to prevent transmission were fairly similar between their previous study, looking at health facilities, and this study of the surrounding communities. However, in 14 out of 16 comparisons, the estimate from the community was lower than that from the facility.
What Do These Findings Mean?
This study shows that it would be possible to estimate how many infants are surviving free of HIV infection using a study based in the community, and that these estimates may be more accurate than those for studies based in health facilities. There are still a large proportion of HIV-positive mothers who are not receiving drugs to prevent transmission to the baby. The authors suggest that using two or three drugs to prevent HIV may help to reduce transmission.
There are already community surveys conducted in many low-income countries, but they have not included routine infant testing for HIV. It is now essential that organizations providing drugs, money, and infrastructure in this field consider more accurate means of monitoring incidence of HIV transmission from mother to infant, particularly at the community level.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001424.
The World Health Organization has more information on mother-to-child transmission of HIV
The United Nations Children's Fund has more information on the status of national PMTCT responses in the most affected countries
doi:10.1371/journal.pmed.1001424
PMCID: PMC3646218  PMID: 23667341
13.  Antiretroviral Pre-exposure Prophylaxis Prevents Vaginal Transmission of HIV-1 in Humanized BLT Mice 
PLoS Medicine  2008;5(1):e16.
Background
Worldwide, vaginal transmission now accounts for more than half of newly acquired HIV-1 infections. Despite the urgency to develop and implement novel approaches capable of preventing HIV transmission, this process has been hindered by the lack of adequate small animal models for preclinical efficacy and safety testing. Given the importance of this route of transmission, we investigated the susceptibility of humanized mice to intravaginal HIV-1 infection.
Methods and Findings
We show that the female reproductive tract of humanized bone marrow–liver–thymus (BLT) mice is reconstituted with human CD4+ T and other relevant human cells, rendering these humanized mice susceptible to intravaginal infection by HIV-1. Effects of HIV-1 infection include CD4+ T cell depletion in gut-associated lymphoid tissue (GALT) that closely mimics what is observed in HIV-1–infected humans. We also show that pre-exposure prophylaxis with antiretroviral drugs is a highly effective method for preventing vaginal HIV-1 transmission. Whereas 88% (7/8) of BLT mice inoculated vaginally with HIV-1 became infected, none of the animals (0/5) given pre-exposure prophylaxis of emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) showed evidence of infection (Chi square = 7.5, df = 1, p = 0.006).
Conclusions
The fact that humanized BLT mice are susceptible to intravaginal infection makes this system an excellent candidate for preclinical evaluation of both microbicides and pre-exposure prophylactic regimens. The utility of humanized mice to study intravaginal HIV-1 transmission is particularly highlighted by the demonstration that pre-exposure prophylaxis can prevent intravaginal HIV-1 transmission in the BLT mouse model.
J. Victor Garcia and colleagues show that mice with immune systems reconstituted from human bone marrow, liver, and thymus transplants provide a model for prevention of intravaginal HIV infection.
Editors' Summary
Background.
Since the first cases of acquired immunodeficiency syndrome (AIDS) in 1981, the AIDS epidemic has spread rapidly. About 33 million people are now infected with the human immunodeficiency virus (HIV), the cause of AIDS. More than half of newly acquired infections now occur in women, mostly through unprotected vaginal sex with an infected male partner. Women are biologically more susceptible than men to HIV infection during vaginal intercourse and often cannot persuade their partner to use a condom. Consequently, alternative strategies that prevent intravaginal transmission of HIV (infection through the vagina) are urgently needed, particularly strategies that women can use without their partner's agreement. A vaccine would be ideal but it could be many years before an effective HIV vaccine is available so researchers are investigating other preventative strategies such as the use of microbicides—compounds that protect against HIV when applied inside the vagina—and pre-exposure treatment (prophylaxis) with antiretroviral drugs.
Why Was This Study Done?
Before any new strategy to prevent intravaginal HIV transmission is tried by women, it has to be tested in animals. Currently, this can only be done in macaques, an expensive option. In this study, the researchers have investigated whether “humanized BLT” mice could be used instead. When HIV enters the human body during vaginal intercourse, it sticks to dendritic cells (a type of immune system cell) in the vaginal lining. These cells carry the virus to the body's lymphoid tissues (collections of immune cells), where it infects and kills CD4+ T cells (another type of immune cell). Dendritic cells and CD4+ T cells have molecules on their surface that HIV recognizes. Mice are not normally susceptible to infection with HIV because their immune system cells lack these molecules. Humanized BLT mice have a nearly human immune system—BLT stands for bone marrow, liver, thymus. They are produced by implanting pieces of human fetal liver and thymus (the organ where T cells learn to recognize foreign invaders) under the kidney capsule of immunodeficient mice (animals born without an immune system) and then transplanting human hematopoietic stem cells (the source of the major immune system cells) into the mice.
What Did the Researchers Do and Find?
When the researchers examined the female reproductive tract of humanized BLT mice for human immune system cells, they found CD4+ T cells, dendritic cells and macrophages, all of which are involved in HIV infection. Furthermore, half of the blood cells of the BLT mice were human. Most of the BLT mice, the researchers report, were susceptible to intravaginal HIV infection as shown, for example, by a rapid loss of human CD4+ T cells from their blood. However, BLT mice pretreated with antiretroviral drugs (a mixture of emtricitabine and tenofovir disoproxil fumarate) were resistant to intravaginal HIV infection. As in human HIV infections, CD4+ T cells were also depleted in several other organs of the BLT mice after intravaginal HIV infection. Again, this depletion was prevented by antiretroviral pre-exposure prophylaxis. Finally, human CD4+ T cells also disappeared from the gut-associated lymphoid tissue (an important site for HIV replication and CD4+ T cell depletion during human HIV disease) of the BLT mice after infection with HIV.
What Do These Findings Mean?
These findings show that humanized BLT mice are susceptible to intravaginal infection with HIV and that many aspects of HIV infection in these mice closely mimic infection in people. In addition, by showing that pre-exposure prophylaxis with antiretroviral drugs prevents HIV infection, these results suggest that humanized BLT mice could be used to test new strategies designed to prevent intravaginal infection. As with all animal models, any approach that works in humanized BLT mice will still have to be tested in people. Nevertheless, these findings provide preclinical evidence that pre-exposure prophylaxis with antiretroviral drugs may be an effective way to prevent intravaginal transmission of HIV and, therefore, provide valuable support for clinical trials of this approach.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050016.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS and on HIV infection in women
HIVInSite has comprehensive information on all aspects of HIV/AIDS, including articles on women and HIV and on safer sex, which includes information on pre-exposure prophylaxis and microbicides
Information is available from Avert, an international AIDS charity, on HIV prevention, on women, HIV, and AIDS, and on microbicides
The US Centers for Disease Control and Prevention provides information on HIV/AIDS, including information on HIV/AIDS among women and on CDC trials of pre-exposure prophylaxis for HIV prevention (in English and some information in Spanish)
PrEP Watch is a comprehensive information source on pre-exposure prophylaxis for HIV prevention
doi:10.1371/journal.pmed.0050016
PMCID: PMC2194746  PMID: 18198941
14.  Causes of Acute Hospitalization in Adolescence: Burden and Spectrum of HIV-Related Morbidity in a Country with an Early-Onset and Severe HIV Epidemic: A Prospective Survey 
PLoS Medicine  2010;7(2):e1000178.
Rashida Ferrand and colleagues show that HIV infection is the commonest cause of hospitalization among adolescents in a high HIV prevalence setting.
Background
Survival to older childhood with untreated, vertically acquired HIV infection, which was previously considered extremely unusual, is increasingly well described. However, the overall impact on adolescent health in settings with high HIV seroprevalence has not previously been investigated.
Methods and Findings
Adolescents (aged 10–18 y) systematically recruited from acute admissions to the two public hospitals in Harare, Zimbabwe, answered a questionnaire and underwent standard investigations including HIV testing, with consent. Pre-set case-definitions defined cause of admission and underlying chronic conditions. Participation was 94%. 139 (46%) of 301 participants were HIV-positive (median age of diagnosis 12 y: interquartile range [IQR] 11–14 y), median CD4 count = 151; IQR 57–328 cells/µl), but only four (1.3%) were herpes simplex virus-2 (HSV-2) positive. Age (median 13 y: IQR 11–16 y) and sex (57% male) did not differ by HIV status, but HIV-infected participants were significantly more likely to be stunted (z-score<−2: 52% versus 23%, p<0.001), have pubertal delay (15% versus 2%, p<0.001), and be maternal orphans or have an HIV-infected mother (73% versus 17%, p<0.001). 69% of HIV-positive and 19% of HIV-negative admissions were for infections, most commonly tuberculosis and pneumonia. 84 (28%) participants had underlying heart, lung, or other chronic diseases. Case fatality rates were significantly higher for HIV-related admissions (22% versus 7%, p<0.001), and significantly associated with advanced HIV, pubertal immaturity, and chronic conditions.
Conclusion
HIV is the commonest cause of adolescent hospitalisation in Harare, mainly due to adult-spectrum opportunistic infections plus a high burden of chronic complications of paediatric HIV/AIDS. Low HSV-2 prevalence and high maternal orphanhood rates provide further evidence of long-term survival following mother-to-child transmission. Better recognition of this growing phenomenon is needed to promote earlier HIV diagnosis and care.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Acquired immunodeficiency syndrome (AIDS) has killed more than 25 million people since 1981, and more than 30 million people are now infected with the human immunodeficiency virus (HIV) that causes AIDS. HIV destroys the cells in the immune system that normally provide protection against disease-causing organisms. Consequently, people infected with HIV are susceptible to so-called opportunistic infections, including tuberculosis and pneumonia. HIV is most commonly spread through unprotected sex with an infected partner but another major route of transmission is mother-to-child (vertical transmission) during pregnancy or delivery or during breast feeding. Mother-to-child transmission can be prevented by giving antiviral drugs to HIV-positive mothers during their pregnancy and to their newborn children. But, although most mothers in developed countries have access to this intervention, fewer than half of HIV-positive mothers in low- and middle-income countries receive this treatment and, every year, nearly half a million children become infected with HIV.
Why Was This Study Done?
It is generally thought that HIV infections in infants progress rapidly and that half of the children who acquire HIV from their mothers will die before their second birthday if not treated with antiretroviral drugs. However, as the AIDS epidemic matures, more children are surviving to adolescence with untreated, vertically acquired HIV infection in sub-Saharan Africa, the region where most children with HIV/AIDS live. Little is known about the burden of HIV infection and its contribution to illness and death in adolescents in sub-Saharan Africa but this information is needed to help health care providers prepare for this new aspect of the AIDS epidemic. In this study, the researchers examine the causes of acute hospital admissions (admissions for conditions with a sudden onset and usually a short course) among adolescents in Zimbabwe, a country where the HIV epidemic started early and where one in seven adults is HIV-positive and more than 17,000 children are infected with HIV every year, mainly through vertical transmission.
What Did the Researchers Do and Find?
The researchers recruited 301 10–18-year olds who were admitted to each of the two public hospitals in Harare (Zimbabwe) for acute illnesses between September 2007 and April 2008. Each patient completed a questionnaire about themselves and their health and underwent standard investigations, including HIV testing. Nearly half the participants were HIV positive; about a quarter of these HIV-positive individuals only found out about their status during the study. HIV-positive participants were more likely to be stunted, to have pubertal delay, and to be maternal orphans or have an HIV-infected mother than HIV-negative participants. 69% of HIV-positive participants were admitted to hospital because of infections, often tuberculosis or pneumonia whereas only 19% of the HIV-negative participants were admitted for infections. More than a quarter of all the participants had underlying heart, lung, or other chronic conditions. Finally, 22% of the HIV-positive participants died while in hospital compared to only 7% of the HIV-negative participants. Factors that increased the risk of death among all the participants were advanced HIV infection, pubertal immaturity, and chronic conditions.
What Do These Findings Mean?
These findings indicate that HIV infection is the commonest cause of acute adolescent admission to hospital in Harare (and probably elsewhere in Zimbabwe). Most of these admissions are due to opportunistic infections similar to those seen in HIV-positive adults and to long-term complications of having HIV/AIDS as an infant such as delayed puberty. Other findings indicate that most of the HIV-positive adolescents who participated in this study were infected via vertical transmission, which supports the idea that long-term survival after vertical infection is possible. Because the AIDS epidemic started early in Zimbabwe, there is likely to be a lag before adolescent survivors of vertical HIV transmission become common elsewhere. Nevertheless, all African countries and other places where HIV infection in adults is common need to recognize that the burden of HIV in their acutely unwell adolescents is likely to increase over the next few years. To deal with this emerging aspect of the AIDS epidemic, measures must be introduced to ensure early diagnosis of HIV in this previously neglected age group so that treatment can be started before HIV-positive adolescents become critically ill.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000178.
This study is further discussed in a PLoS Medicine Perspective by Glenda Gray
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS, including a list of articles and other sources of information about the primary care of adolescents with HIV
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on the HIV and AIDS in Zimbabwe, and on children, HIV, and AIDS (in English and Spanish)
UNICEF also has information about children and HIV and AIDS (in several languages)
doi:10.1371/journal.pmed.1000178
PMCID: PMC2814826  PMID: 20126383
15.  Bacterial Vaginosis Associated with Increased Risk of Female-to-Male HIV-1 Transmission: A Prospective Cohort Analysis among African Couples 
PLoS Medicine  2012;9(6):e1001251.
In a prospective study, Craig Cohen and colleagues investigate the association between bacterial vaginosis and the risk of female-to-male HIV-1 transmission.
Background
Bacterial vaginosis (BV), a disruption of the normal vaginal flora, has been associated with a 60% increased risk of HIV-1 acquisition in women and higher concentration of HIV-1 RNA in the genital tract of HIV-1–infected women. However, whether BV, which is present in up to half of African HIV-1–infected women, is associated with an increase in HIV-1 transmission to male partners has not been assessed in previous studies.
Methods and Findings
We assessed the association between BV on female-to-male HIV-1 transmission risk in a prospective study of 2,236 HIV-1–seropositive women and their HIV-1 uninfected male partners from seven African countries from a randomized placebo-controlled trial that enrolled heterosexual African adults who were seropositive for both HIV-1 and herpes simplex virus (HSV)-2, and their HIV-1–seronegative partners. Participants were followed for up to 24 months; every three months, vaginal swabs were obtained from female partners for Gram stain and male partners were tested for HIV-1. BV and normal vaginal flora were defined as a Nugent score of 7–10 and 0–3, respectively. To reduce misclassification, HIV-1 sequence analysis of viruses from seroconverters and their partners was performed to determine linkage of HIV-1 transmissions. Overall, 50 incident HIV-1 infections occurred in men in which the HIV-1–infected female partner had an evaluable vaginal Gram stain. HIV-1 incidence in men whose HIV-1–infected female partners had BV was 2.91 versus 0.76 per 100 person-years in men whose female partners had normal vaginal flora (hazard ratio 3.62, 95% CI 1.74–7.52). After controlling for sociodemographic factors, sexual behavior, male circumcision, sexually transmitted infections, pregnancy, and plasma HIV-1 RNA levels in female partners, BV was associated with a greater than 3-fold increased risk of female-to-male HIV-1 transmission (adjusted hazard ratio 3.17, 95% CI 1.37–7.33).
Conclusions
This study identified an association between BV and increased risk of HIV-1 transmission to male partners. Several limitations may affect the generalizability of our results including: all participants underwent couples HIV counseling and testing and enrolled in an HIV-1 prevention trial, and index participants had a baseline CD4 count ≥250 cells/mm3 and were HSV-2 seropositive. Given the high prevalence of BV and the association of BV with increased risk of both female HIV-1 acquisition and transmission found in our study, if this association proves to be causal, BV could be responsible for a substantial proportion of new HIV-1 infections in Africa. Normalization of vaginal flora in HIV-1–infected women could mitigate female-to-male HIV-1 transmission.
Trial Registration: ClinicalTrials.com NCT00194519
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Since the first reported case of AIDS in 1981, the number of people infected with HIV, the virus that causes AIDS, has risen steadily. By the end of 2010, 34 million people were living with HIV/AIDS. At the beginning of the epidemic more men than women were infected with HIV. Now, however, 50% of all adults infected with HIV are women and in sub-Saharan Africa, where two-thirds of HIV-positive people live, women account for 59% of people living with HIV. Moreover, among 15–24 year-olds, women are eight times more likely than men to be HIV-positive. This pattern of infection has developed because most people in sub-Saharan Africa contract HIV through unprotected heterosexual sex. The risk of HIV transmission for both men and women in Africa and elsewhere can be reduced by abstaining from sex, by only having one or a few partners, by always using condoms, and by male circumcision. In addition, several studies suggest that antiretroviral therapy (ART) greatly reduces HIV transmission.
Why Was This Study Done?
Unfortunately, in sub-Saharan Africa, only about a fifth of HIV-positive people are currently receiving ART, which means that there is an urgent need to find other effective ways to reduce HIV transmission in this region. In this prospective cohort study (a type of study that follows a group of people for some time to see which personal characteristics are associated with disease development), the researchers investigate whether bacterial vaginosis—a condition in which harmful bacteria disrupt the normal vaginal flora—increases the risk of female-to-male HIV transmission among African couples. Bacterial vaginosis, which is extremely common in sub-Saharan Africa, has been associated with an increased risk of HIV acquisition in women and induces viral replication and shedding in the vagina in HIV-positive women, which may mean that HIV-positive women with bacterial vaginosis are more likely to transmit HIV to their male partners than women without this condition. If this is the case, then interventions that reduce the incidence of bacterial vaginosis might be valuable HIV prevention strategies.
What Did the Researchers Do and Find?
The researchers analyzed data collected from 2,236 heterosexual African couples enrolled in a clinical trial (the Partners in Prevention HSV/HIV Transmission Study) whose primary aim was to investigate whether suppression of herpes simplex virus infection could prevent HIV transmission. In all the couples, the woman was HIV-positive and the man was initially HIV-negative. The female partners were examined every three months for the presence of bacterial vaginosis and the male partners were tested regularly for HIV infection. The researchers also determined whether the men who became HIV-positive were infected with the same HIV strain as their partner to check that their infection had been acquired from this partner. The HIV incidence in men whose partners had bacterial vaginosis was 2.9 per 100 person-years (that is, 2.9 out of every 100 men became HIV-positive per year) whereas the HIV incidence in men whose partners had a normal vaginal flora was 0.76 per 100 person-years. After controlling for factors that might affect the risk of HIV transmission such as male circumcision and viral levels in female partner's blood, the researchers estimated that bacterial vaginosis was associated with a 3.17-fold increased risk of female-to-male HIV transmission in their study population.
What Do These Findings Mean?
These findings suggest that HIV-positive African women with bacterial vaginosis are more than three times as likely to transmit HIV to their male partners as those with a normal vaginal flora. It is possible that some unknown characteristic of the men in this study might have increased both their own risk of HIV infection and their partner's risk of bacterial vaginosis. Nevertheless, because bacterial vaginosis is so common in Africa (half of the women in this study had bacterial vaginosis at least once during follow-up) and because this condition is associated with both female HIV acquisition and transmission, these findings suggest that bacterial vaginosis could be responsible for a substantial proportion of new HIV infections in Africa. Normalization of vaginal flora in HIV-infected women by frequent presumptive treatment with antimicrobials (treatment with a curative dose of antibiotics without testing for bacterial vaginosis) or possibly by treatment with probiotics (live “good” bacteria) might, therefore, reduce female-to-male HIV transmission in sub-Saharan Africa.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001251.
Information is available from the US National Institute of Allergy and infectious diseases on all aspects of HIV infection and AIDS and on bacterial vaginosis
The US Centers for Disease Control and Prevention has information on all aspects of HIV/AIDS, including specific information about HIV/AIDS and women; it also has information on bacterial vaginosis (in English and Spanish)
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment, and information on bacterial vaginosis and HIV transmission (in several languages)
Information is available from Avert, an international AIDS nonprofit group on many aspects of HIV/AIDS, including detailed information on HIV and AIDS prevention, on women, HIV and AIDS and on HIV/AIDS in Africa (in English and Spanish); personal stories of women living with HIV are available; the website Healthtalkonline also provides personal stories about living with HIV
More information about the Partners in Prevention HSV/HIV Transmission Study is available
doi:10.1371/journal.pmed.1001251
PMCID: PMC3383741  PMID: 22745608
16.  Efficacy of Short-Course AZT Plus 3TC to Reduce Nevirapine Resistance in the Prevention of Mother-to-Child HIV Transmission: A Randomized Clinical Trial 
PLoS Medicine  2009;6(10):e1000172.
Neil Martinson and colleagues report a randomized trial of adding short-course zidovudine+lamivudine to reduce drug resistance from single-dose nevirapine used to prevent mother-to-child transmission of HIV.
Background
Single-dose nevirapine (sdNVP)—which prevents mother-to-child transmission of HIV—selects non-nucleoside reverse-transcriptase inhibitor (NNRTI) resistance mutations in the majority of women and HIV-infected infants receiving it. This open-label, randomised trial examined the efficacy of short-course zidovudine (AZT) and lamivudine (3TC) with sdNVP in reducing NNRTI resistance in mothers, and as a secondary objective, in infants, in a setting where sdNVP was standard-of-care.
Methods and Findings
sdNVP alone, administered at the onset of labour and to the infant, was compared to sdNVP with AZT plus 3TC, given as combivir (CBV) for 4 (NVP/CBV4) or 7 (NVP/CBV7) days, initiated simultaneously with sdNVP in labour; their newborns received the same regimens. Women were randomised 1∶1∶1. HIV-1 resistance was assessed by population sequencing at: baseline, 2, and 6 wk after birth. An unplanned interim analysis resulted in early stopping of the sdNVP arm. 406 pregnant women were randomised and took study medication (sdNVP 74, NVP/CBV4 164, and NVP/CBV7 168). HIV-1 resistance mutations emerged in 59.2%, 11.7%, and 7.3% of women in the sdNVP, NVP/CBV4, and NVP/CBV7 arms by 6 wk postpartum; differences between NVP-only and both NVP/CBV arms were significant (p<0.0001), but the difference between NVP/CBV4 and NVP/CBV7 was not (p = 0.27). Estimated efficacy comparing combined CBV arms with sdNVP was 85.6%. Similar resistance reductions were seen in infants who were HIV-infected by their 6-wk visit.
Conclusions
A short course of AZT plus 3TC, supplementing maternal and infant sdNVP, reduces emergent NNRTI resistance mutations in both mothers and their infants. However, this trial was not powered to detect small differences between the CBV arms.
Trial registration
www.ClinicalTrials.gov NCT 00144183
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Currently, about 33 million people are infected with the human immunodeficiency virus (HIV), which causes AIDS. HIV can be treated with combination antiretroviral therapy (ART), commonly three individual antiretroviral drugs that together efficiently suppress the replication of the virus. HIV infection of a child by an HIV-positive mother during pregnancy, labor, delivery, or breastfeeding is called mother-to-child transmission (MTCT). In 2007, an estimated 420,000 children were newly infected with HIV, the majority through MTCT. Most of these mothers and children live in sub-Saharan Africa where child and maternal mortality rates are high and mortality in HIV-infected children is extremely high. MTCT is preventable and there is a global commitment, agreed at the UN General Assembly Session on HIV/AIDS in 2001, to reduce the proportion of infants infected with HIV by 50% by 2010.
Why Was This Study Done?
In many resource-limited settings, MTCT is prevented by giving a single dose of nevirapine (an antiretroviral drug which has a long duration in the body and protects the fetus during labor and delivery only) to HIV-infected women in labor and also to a baby within 72 hours of birth. However, nevirapine, a non-nucleoside reverse-transcriptase inhibitor (NNRTI), which suppresses the replication of the virus, is associated with increased resistance of HIV, in mother and child, to NNRTI. This resistance reduces the effectiveness of future treatments of both mother and child with combination ART that includes an NNRTI; such regimens are the mainstay for long-term treatment of HIV in developing countries. The researchers investigated whether giving other antiretroviral drugs with nevirapine, during labor and delivery, to both mother and her newborn reduced the chances of them developing resistance to NNRTIs.
What Did the Researchers Do and Find?
The researchers selected 406 HIV-positive pregnant women for study across five sites in South Africa between February 2003 and May 2007. The women and their newborn babies were randomly assigned to receive, either (i) a single dose of nevirapine, (ii) a single dose of nevirapine plus combivir (zidovudine combined with lamivudine) for four days, or (iii) a single dose of nevirapine plus combivir for seven days. At two days, two weeks, and six weeks after delivery blood was collected from mothers and babies. HIV virus from blood samples was analyzed for resistance mutations, and mothers and children with resistance mutations were monitored for a further 96 weeks until no resistance was detected or combination ART (also called “HAART”) was started. Enrollment into the single-dose nevirapine arm was stopped early because a very high rate of NNRTI resistance mutations was found and other investigators reported long-term bad consequences of NNRTI-resistance on subsequent ART. The two nevirapine plus combivir arms were continued. The researchers found that selection of resistance mutations by single-dose nevirapine was reduced in mother and child by the addition of zidovudine and lamivudine for a short period; resistance mutations were found in 59.2% of women who got nevirapine only but only 11.7%, and 7.3% of women treated nevirapine plus four days combivir, and nevirapine plus seven days combivir respectively. A reduction was also seen in new NNRTI resistant mutations in the HIV-infected infants that received combivir. The study did not have enough women to show that there was a real difference between the resistance in the four-day and seven-day combivir regimens.
What Do These Findings Mean?
These findings show that a short-course treatment of zidovudine and lamivudine in addition to a single dose of nevirapine during labor and birth reduces the selection of NNRTI resistance mutations in both mother and child. The drug regimens appeared safe, and easy to provide and adhere to. Preliminary results from this study contributed to a change in clinical practice for the care of pregnant women with HIV; in 2004 the World Health Organisation guidelines introduced a short course of combivir with nevirapine for the management of pregnant HIV-infected women. However, the study had some limitations. It used HIV-positive women who were mainly infected with a subtype of HIV called HIV-1 clade C and who had a lot of virus in their blood. NNRTI resistance after treatment with nevirapine is more common in clade C than in others and this study does not address the effect of these combinations for preventing NNRTI resistance in other HIV subtypes. Also, World Health Organization, national, and international guidelines recommend combination ART during pregnancy, as it decreases HIV transmission from mother to child in the uterus to <2% in resource-limited settings. Although long-term combination treatment may not be available in all locations, this study does not tell us how the short-term combinations during and after delivery tested would compare to longer-term combinations given to pregnant women in reducing both HIV transmission and HIV drug resistance.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000172.
This study is further discussed in a PLoS Medicine Perspective by Lehman et al.
The US Centers for Disease Control and Prevention provide information for HIV treatment and prevention
MedlinePlus provides extensive information on symptoms and treatment for HIV/AIDS as well as access to related clinical trials and medical literature
aidsmap, a nonprofit, nongovernmental organization provides information on HIV and supporting those living with HIV
The World Health Organization gives information on the prevention of mother-to-child transmission of HIV
doi:10.1371/journal.pmed.1000172
PMCID: PMC2760761  PMID: 19859531
17.  When Do HIV-Infected Women Disclose Their HIV Status to Their Male Partner and Why? A Study in a PMTCT Programme, Abidjan 
PLoS Medicine  2007;4(12):e342.
Background
In Africa, women tested for HIV during antenatal care are counselled to share with their partner their HIV test result and to encourage partners to undertake HIV testing. We investigate, among women tested for HIV within a prevention of mother-to-child transmission of HIV (PMTCT) programme, the key moments for disclosure of their own HIV status to their partner and the impact on partner HIV testing.
Methods and Findings
Within the Ditrame Plus PMTCT project in Abidjan, 546 HIV-positive and 393 HIV-negative women were tested during pregnancy and followed-up for two years after delivery. Circumstances, frequency, and determinants of disclosure to the male partner were estimated according to HIV status. The determinants of partner HIV testing were identified according to women's HIV status. During the two-year follow-up, disclosure to the partner was reported by 96.7% of the HIV-negative women, compared to 46.2% of HIV-positive women (χ2 = 265.2, degrees of freedom [df] = 1, p < 0.001). Among HIV-infected women, privileged circumstances for disclosure were just before delivery, during early weaning (at 4 mo to prevent HIV postnatal transmission), or upon resumption of sexual activity. Formula feeding by HIV-infected women increased the probability of disclosure (adjusted odds ratio 1.54, 95% confidence interval 1.04–2.27, Wald test = 4.649, df = 1, p = 0.031), whereas household factors such as having a co-spouse or living with family reduced the probability of disclosure. The proportion of male partners tested for HIV was 23.1% among HIV-positive women and 14.8% among HIV-negative women (χ2 = 10.04, df = 1, p = 0.002). Partners of HIV-positive women who were informed of their wife's HIV status were more likely to undertake HIV testing than those not informed (37.7% versus 10.5%, χ2 = 56.36, df = 1, p < 0.001).
Conclusions
In PMTCT programmes, specific psychosocial counselling and support should be provided to women during the key moments of disclosure of HIV status to their partners (end of pregnancy, weaning, and resumption of sexual activity). This support could contribute to improving women's adherence to the advice given to prevent postnatal and sexual HIV transmission.
In a mother-to-child HIV prevention program in Côte d'Ivoire, Annabel Desgrées-du-Loû and colleagues identify three junctures at which women tend to disclose their HIV status to partners.
Editors' Summary
Background.
Since the first reported case of AIDS (acquired immunodeficiency syndrome) in 1981, the number of people infected with the human immunodeficiency virus (HIV), which causes AIDS, has risen steadily. By the end of 2006, nearly 40 million people were infected, 25 million of them in sub-Saharan Africa. HIV is most often spread by having unprotected sex with an infected partner. In Africa, most sexual transmission of HIV is between partners in stable relationships—many such couples do not adopt measures that prevent viral transmission, such as knowing the HIV status of both partners and using condoms if one partner is HIV-positive. HIV can also pass from a mother to her baby during pregnancy, labor, or delivery, or through breastfeeding. Mother-to-child transmission (MTCT) of HIV can be reduced by giving anti-HIV drugs to the mother during pregnancy and labor and to her newborn baby, and by avoiding breastfeeding or weaning the baby early.
Why Was This Study Done?
Many African countries have programs for prevention of MTCT (PMTCT) that offer pregnant women prenatal HIV counseling and testing. As a result, women are often the first member of a stable relationship to know their HIV status. PMTCT programs advise women to disclose their HIV test result to their partner and to encourage him to have an HIV test. But for many women, particularly those who are HIV-positive, talking to their partner about HIV/AIDS is hard because of fears of rejection (which could mean loss of housing and food) or accusations of infidelity. Knowing more about when women disclose their HIV status and what makes them decide to do so would help the people running PMTCT programs to support women during the difficult process of disclosure. In this study, the researchers have investigated when and why women participating in a PMTCT research project in Abidjan (Côte d'Ivoire) told their partner about their HIV status and the impact this disclosure had on their partner's uptake of HIV testing.
What Did the Researchers Do and Find?
At regular follow-up visits, the researchers asked women in the Abidjan PMTCT project whether they had told their partners their HIV status and whether they were breast-feeding or had resumed sexual activity. Nearly all the women who tested negative for HIV, but slightly fewer than half of the HIV-positive (infected) women had told their partner about their HIV status by two years after childbirth. Two-thirds of the HIV-positive women who disclosed their status did so before delivery. Other key times for disclosure were at early weaning (4 months after birth) for women who breast-fed their babies, and when sexual activity resumed. HIV-positive women who bottle fed their babies from birth were more likely to tell their partners of their status than women who breast-fed. Factors that prevented women disclosing their HIV status included living in a polygamous relationship or living separately from their partners. Finally, the researchers report that the partners of HIV-positive women who disclosed their HIV status were about three times more likely to take an HIV test than the partners of HIV-positive women who did not disclose.
What Do These Findings Mean?
These findings identify three key times when women who have had an HIV test during pregnancy are likely to disclose their HIV status to their partner. The main one is before delivery and relates, in part, to how the mother plans to feed her baby. To bottle feed in Abidjan, women need considerable support from their partners and this may be the impetus for disclosing their HIV status. Disclosure at early weaning may reflect the woman's need to enlist her partner's support for this unusual decision—the normal time for weaning in Abidjan is 17 months. Finally, disclosure when sexual activity resumes may be necessary so that the woman can explain why she wants to use condoms. Although these findings need confirmation in other settings, targeting counseling and support within PMTCT programs to these key moments might help HIV-positive women to tell their partners about their status. This, hopefully, would help to reduce sexual transmission of HIV within stable relationships in sub-Saharan Africa.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040342.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS and on HIV infection in women
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Women Children and HIV provides extensive information on prevention of mother-to-child transmission of HIV in developing countries
Information is available from Avert, an international AIDS charity, on HIV and AIDS in Africa and on HIV and AIDS prevention
AIDSinfo, a service of the US Department of Health and Human Services provideshealth information for HIV-positive pregnant women (in English and Spanish)
doi:10.1371/journal.pmed.0040342
PMCID: PMC2100145  PMID: 18052603
18.  Immunotherapy with Canarypox Vaccine and Interleukin-2 for HIV-1 Infection: Termination of a Randomized Trial 
PLoS Clinical Trials  2007;2(1):e5.
Objectives:
To determine whether immunotherapy of chronic HIV-1 infection can prevent or attenuate viremia upon antiviral discontinuation.
Design:
This was a Phase II randomized, partially double blinded, 2×2 factorial study of three steps of 12 wk/step. Step I involved four groups: (1) vaccine placebo, (2) vaccine (ALVAC, vCP1452), (3) placebo + interleukin 2 (IL-2), and (4) vaccine + IL-2. Step II involved a 12-wk diagnostic treatment interruption (DTI). Step III involved an extension of the DTI for an additional 12 wk.
Setting:
The Weill-Cornell General Clinical Research Center.
Participants:
Chronically infected HIV-1 positive adults with undetectable HIV-1 levels and > 400 CD4+ T cells/μl.
Interventions
An HIV canarypox vaccine (vCP1452) and vaccine placebo, administered every 4 wk for four doses, and low-dose IL-2 administered daily for 12–24 wk.
Outcome measures:
Primary endpoints: (1) Proportion of participants with undetectable plasma HIV RNA during trial Step II, (2) mean log10 HIV RNA copies/ml ([HIV]) from weeks 21–25, and (3) proportion of individuals eligible for trial Step III.
Results:
44 participants were randomized, but 16 withdrew or were withdrawn before completing Step II. As all participants underwent viral relapse in Step II, the study was terminated after 28 participants completed Step II. Among the four groups, there was no difference in mean [HIV] or the proportion of individuals with < log10 4.48 HIV; no difference between the mean [HIV] of the two groups that received ALVAC (n = 17) versus placebo (n = 11); and no significant difference between the mean [HIV] of the two groups that received IL-2 (n = 11) versus placebo (n = 17).
Conclusions:
Neither ALVAC (vCP1452) nor low-dose daily IL-2 nor their combination prevented the relapse of viremia upon discontinuation of antiviral therapy.
Editorial Commentary
Background: Currently, providing that an individual infected with HIV can get access to highly active antiretroviral therapy (HAART), prognosis can be very good. However, although these treatments suppress replication of HIV, they do not eliminate HIV entirely. One current area of HIV research focuses on whether and how it is possible to take a break from antiretroviral therapy—which is very toxic—and at the same time achieve very low levels of HIV. Some research groups are also interested in whether and how it might be possible to eliminate the virus completely from the bloodstream and immune system of infected people, and therefore achieve a long-term cure. One such approach involves administration of interleukin-2 (IL-2, a hormone involved in the immune response), in the hope that IL-2 will boost the ability of the body's own immune system to eliminate HIV. Various candidate HIV vaccines have also been designed that, it is hoped, will prime the immune system to make it more receptive to IL-2. In the trial reported here, the researchers wanted to test whether IL-2 administration either alone or in combination with an HIV vaccine, ALVAC vCP1452, would maintain low levels of HIV in the blood of people who had stopped taking antiretroviral drugs. Therefore, participants in the trial were assigned to one of four arms: a placebo version of the vaccine only; vaccine only; placebo version of vaccine plus IL-2; or vaccine plus IL-2. The investigators planned to recruit 92 people into the trial who would be given the various interventions tested here for 12 weeks, while also receiving HAART (step 1). Then, HAART was stopped for 12 weeks (step 2), or, in some people, for 24 weeks if HIV levels remained below a certain threshold (step 3).
What the trial shows: 44 people were recruited into the study, but it was terminated once results were analysed from those individuals who had completed 12 weeks without HAART. The researchers did not see any significant differences between the treatment groups in any of the three primary outcome measures, which were the proportion of people with undetectable HIV levels during step 2; the average HIV levels during the last four weeks of step 2; and the proportion of people eligible to continue to step 3. Therefore, the investigators concluded that neither the ALVAC vaccine nor IL-2 alone or in combination with each other, prevented HIV from replicating when HAART was stopped.
Strengths and limitations: In the trial, randomized assignment to the different treatments was performed by the dispensing pharmacist, so study investigators were not able to predict which treatments the next participant would receive. A further strength in the design of this trial is the use of a placebo vaccine to control for ALVAC vCP1452, which enabled participants and investigators to be blinded to whether a patient received vaccine or placebo. However, a placebo was not used as a control for IL-2 because patients often experience characteristic side effects to this treatment. Limitations in the design of this study include the small numbers of participants, which means that the trial did not have enough power to exclude the possibility of a small effect of IL-2 or vaccine on HIV levels in blood. The follow-up in the trial was also short, and efficacy outcomes did not include measures that patients might consider important, such as survival.
Contribution to the evidence: Currently, large-scale trials are evaluating the clinical effectiveness and safety of IL-2 at higher doses than those tested here, together with antiretroviral drugs as treatment for HIV. This study adds data suggesting that IL-2 at a lower dose either with or without the ALVAC vCP1452 vaccine does not prevent HIV replication once antiretroviral drug treatment is stopped.
doi:10.1371/journal.pctr.0020005
PMCID: PMC1783674  PMID: 17260026
19.  Male Circumcision at Different Ages in Rwanda: A Cost-Effectiveness Study 
PLoS Medicine  2010;7(1):e1000211.
Agnes Binagwaho and colleagues predict that circumcision of newborn boys would be effective and cost-saving as a long-term strategy to prevent HIV in Rwanda.
Background
There is strong evidence showing that male circumcision (MC) reduces HIV infection and other sexually transmitted infections (STIs). In Rwanda, where adult HIV prevalence is 3%, MC is not a traditional practice. The Rwanda National AIDS Commission modelled cost and effects of MC at different ages to inform policy and programmatic decisions in relation to introducing MC. This study was necessary because the MC debate in Southern Africa has focused primarily on MC for adults. Further, this is the first time, to our knowledge, that a cost-effectiveness study on MC has been carried out in a country where HIV prevalence is below 5%.
Methods and Findings
A cost-effectiveness model was developed and applied to three hypothetical cohorts in Rwanda: newborns, adolescents, and adult men. Effectiveness was defined as the number of HIV infections averted, and was calculated as the product of the number of people susceptible to HIV infection in the cohort, the HIV incidence rate at different ages, and the protective effect of MC; discounted back to the year of circumcision and summed over the life expectancy of the circumcised person. Direct costs were based on interviews with experienced health care providers to determine inputs involved in the procedure (from consumables to staff time) and related prices. Other costs included training, patient counselling, treatment of adverse events, and promotion campaigns, and they were adjusted for the averted lifetime cost of health care (antiretroviral therapy [ART], opportunistic infection [OI], laboratory tests). One-way sensitivity analysis was performed by varying the main inputs of the model, and thresholds were calculated at which each intervention is no longer cost-saving and at which an intervention costs more than one gross domestic product (GDP) per capita per life-year gained. Results: Neonatal MC is less expensive than adolescent and adult MC (US$15 instead of US$59 per procedure) and is cost-saving (the cost-effectiveness ratio is negative), even though savings from infant circumcision will be realized later in time. The cost per infection averted is US$3,932 for adolescent MC and US$4,949 for adult MC. Results for infant MC appear robust. Infant MC remains highly cost-effective across a reasonable range of variation in the base case scenario. Adolescent MC is highly cost-effective for the base case scenario but this high cost-effectiveness is not robust to small changes in the input variables. Adult MC is neither cost-saving nor highly cost-effective when considering only the direct benefit for the circumcised man.
Conclusions
The study suggests that Rwanda should be simultaneously scaling up circumcision across a broad range of age groups, with high priority to the very young. Infant MC can be integrated into existing health services (i.e., neonatal visits and vaccination sessions) and over time has better potential than adolescent and adult circumcision to achieve the very high coverage of the population required for maximal reduction of HIV incidence. In the presence of infant MC, adolescent and adult MC would evolve into a “catch-up” campaign that would be needed at the start of the program but would eventually become superfluous.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Acquired immunodeficiency syndrome (AIDS) has killed more than 25 million people since 1981 and more than 31 million people (22 million in sub-Saharan Africa alone) are now infected with the human immunodeficiency virus (HIV), which causes AIDS. There is no cure for HIV/AIDS and no vaccine against HIV infection. Consequently, prevention of HIV transmission is extremely important. HIV is most often spread through unprotected sex with an infected partner. Individuals can reduce their risk of HIV infection, therefore, by abstaining from sex, by having one or a few sexual partners, and by always using a male or female condom. In addition, male circumcision—the removal of the foreskin, the loose fold of skin that covers the head of penis—can halve HIV transmission rates to men resulting from sex with women. Thus, as part of its HIV prevention strategy, the World Health Organization (WHO) recommends that male circumcision programs be scaled up in countries where there is a generalized HIV epidemic and where few men are circumcised.
Why Was This Study Done?
One such country is Rwanda. Here, 3% of the adult population is infected with HIV but only 15% of men are circumcised—worldwide, about 30% of men are circumcised. Demand for circumcision is increasing in Rwanda but, before policy makers introduce a country-wide male circumcision program, they need to identify the most cost-effective way to increase circumcision rates. In particular, they need to decide the age at which circumcision should be offered. Circumcision soon after birth (neonatal circumcision) is quick and simple and rarely causes any complications. Circumcision of adolescents and adults is more complex and has a higher complication rate. Although several studies have investigated the cost-effectiveness (the balance between the clinical and financial costs of a medical intervention and its benefits) of circumcision in adult men, little is known about its cost-effectiveness in newborn boys. In this study, which is one of several studies on male circumcision being organized by the National AIDS Control Commission in Rwanda, the researchers model the cost-effectiveness of circumcision at different ages.
What Did the Researchers Do and Find?
The researchers developed a simple cost-effectiveness model and applied it to three hypothetical groups of Rwandans: newborn boys, adolescent boys, and adult men. For their model, the researchers calculated the effectiveness of male circumcision (the number of HIV infections averted) by estimating the reduction in the annual number of new HIV infections over time. They obtained estimates of the costs of circumcision (including the costs of consumables, staff time, and treatment of complications) from health care providers and adjusted these costs for the money saved through not needing to treat HIV in males in whom circumcision prevented infection. Using their model, the researchers estimate that each neonatal male circumcision would cost US$15 whereas each adolescent or adult male circumcision would cost US$59. Neonatal male circumcision, they report, would be cost-saving. That is, over a lifetime, neonatal male circumcision would save more money than it costs. Finally, using the WHO definition of cost-effectiveness (for a cost-effective intervention, the additional cost incurred to gain one year of life must be less than a country's per capita gross domestic product), the researchers estimate that, although adolescent circumcision would be highly cost-effective, circumcision of adult men would only be potentially cost-effective (but would likely prove cost-effective if the additional infections that would occur from men to their partners without a circumcision program were also taken into account).
What Do These Findings Mean?
As with all modeling studies, the accuracy of these findings depends on the many assumptions included in the model. However, the findings suggest that male circumcision for infants for the prevention of HIV infection later in life is highly cost-effective and likely to be cost-saving and that circumcision for adolescents is cost-effective. The researchers suggest, therefore, that policy makers in Rwanda and in countries with similar HIV infection and circumcision rates should scale up male circumcision programs across all age groups, with high priority being given to the very young. If infants are routinely circumcised, they suggest, circumcision of adolescent and adult males would become a “catch-up” campaign that would be needed at the start of the program but that would become superfluous over time. Such an approach would represent a switch from managing the HIV epidemic as an emergency towards focusing on sustainable, long-term solutions to this major public-health problem.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000211.
This study is further discussed in a PLoS Medicine Perspective by Seth Kalichman
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
Information is available from the Joint United Nations Programme on HIV/AIDS (UNAIDS) on HIV infection and AIDS and on male circumcision in relation to HIV and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on HIV and AIDS in Africa, and on circumcision and HIV (some information in English and Spanish)
More information about male circumcision is available from the Clearinghouse on Male Circumcision
The National AIDS Control Commission of Rwanda provides detailed information about HIV/AIDS in Rwanda (in English and French)
doi:10.1371/journal.pmed.1000211
PMCID: PMC2808207  PMID: 20098721
20.  Nevirapine- Versus Lopinavir/Ritonavir-Based Initial Therapy for HIV-1 Infection among Women in Africa: A Randomized Trial 
PLoS Medicine  2012;9(6):e1001236.
In a randomized control trial, Shahin Lockman and colleagues compare nevirapine-based therapy with lopinavir/ritonavir-based therapy for HIV-infected women without previous exposure to antiretroviral treatment.
Background
Nevirapine (NVP) is widely used in antiretroviral treatment (ART) of HIV-1 globally. The primary objective of the AA5208/OCTANE trial was to compare the efficacy of NVP-based versus lopinavir/ritonavir (LPV/r)-based initial ART.
Methods and Findings
In seven African countries (Botswana, Kenya, Malawi, South Africa, Uganda, Zambia, and Zimbabwe), 500 antiretroviral-naïve HIV-infected women with CD4<200 cells/mm3 were enrolled into a two-arm randomized trial to initiate open-label ART with tenofovir (TDF)/emtricitabine (FTC) once/day plus either NVP (n = 249) or LPV/r (n = 251) twice/day, and followed for ≥48 weeks. The primary endpoint was time from randomization to death or confirmed virologic failure ([VF]) (plasma HIV RNA<1 log10 below baseline 12 weeks after treatment initiation, or ≥400 copies/ml at or after 24 weeks), with comparison between treatments based on hazard ratios (HRs) in intention-to-treat analysis. Equivalence of randomized treatments was defined as finding the 95% CI for HR for virological failure or death in the range 0.5 to 2.0. Baseline characteristics were (median): age = 34 years, CD4 = 121 cells/mm3, HIV RNA = 5.2 log10copies/ml. Median follow-up = 118 weeks; 29 (6%) women were lost to follow-up. 42 women (37 VFs, five deaths; 17%) in the NVP and 50 (43 VFs, seven deaths; 20%) in the LPV/r arm reached the primary endpoint (HR 0.85, 95% CI 0.56–1.29). During initial assigned treatment, 14% and 16% of women receiving NVP and LPV/r experienced grade 3/4 signs/symptoms and 26% and 22% experienced grade 3/4 laboratory abnormalities. However, 35 (14%) women discontinued NVP because of adverse events, most in the first 8 weeks, versus none for LPV/r (p<0.001). VF, death, or permanent treatment discontinuation occurred in 80 (32%) of NVP and 54 (22%) of LPV/r arms (HR = 1.7, 95% CI 1.2–2.4), with the difference primarily due to more treatment discontinuation in the NVP arm. 13 (45%) of 29 women tested in the NVP versus six (15%) of 40 in the LPV/r arm had any drug resistance mutation at time of VF.
Conclusions
Initial ART with NVP+TDF/FTC demonstrated equivalent virologic efficacy but higher rates of treatment discontinuation and new drug resistance compared with LPV/r+TDF/FTC in antiretroviral-naïve women with CD4<200 cells/mm3.
Trial registration
ClinicalTrials.gov NCT00089505
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 34 million people (mostly living in low- or middle-income countries) are currently infected with HIV, the virus that causes AIDS. HIV destroys CD4 lymphocytes and other immune cells, leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected people died within 10 years of infection. Then, in 1996, antiretroviral therapy (ART)—cocktails of drugs that attack different parts of HIV—became available. For people living in affluent countries, HIV/AIDS became a chronic condition. But, because ART was expensive, for people living in developing countries, HIV/AIDS remained a fatal illness. In 2006, the international community set a target of achieving universal access to ART by 2010 and, although this target has not been reached, by the end of 2010, 6.6 million of the estimated 15 million people in need of ART in developing countries were receiving one of the ART regimens recommended by the World Health Organization (WHO) in its 2010 guidelines.
Why Was This Study Done?
A widely used combination for the initial treatment of HIV-infected people (particularly women) in resource-limited settings is tenofovir and emtricitabine (both nucleotide reverse transcriptase inhibitors; reverse transcriptase is essential for HIV replication) and nevirapine (NVP, a non-nucleoside reverse transcriptase inhibitor). However, little is known about the efficacy of this NVP-based ART combination. Moreover, its efficacy and toxicity has not been compared with regimens containing lopinavir/ritonavir (LPV/r). LPV/r, which inhibits the viral protease that is essential for HIV replication, is available in resource-limited settings but is usually reserved for second-line treatment. LPV/r-based ART is more expensive than NVP-based ART but if it were more effective or better tolerated than NVP-based ART, then first-line treatment with LPV/r-based ART might be cost-effective in resource-limited settings. Conversely, evidence of the clinical equivalence of NVP-based and LPV/r-based ART would provide support for NVP-based ART as an initial therapy. In this randomized equivalence trial, the researchers compare the efficacy and toxicity of NVP-based and LVP/r-based initial therapy for HIV infection among antiretroviral-naïve African women. In a randomized trial, patients are assigned different treatments by the play of chance and followed to compare the effects of these treatments; an equivalence trial asks whether the effects of two treatments are statistically equivalent.
What Did the Researchers Do and Find?
The researchers followed 500 antiretroviral-naïve HIV-infected women with a low CD4 cell count living in seven African countries, half of whom received NVP-based ART and half of whom received LPV/r-based ART, for an average of 118 weeks and recorded the time to virologic failure (the presence of virus in the blood above pre-specified levels) or death among the participants. Forty-two women in the NVP arm reached this primary endpoint (37 virologic failures and five deaths) compared to 50 women in the LPV/r arm (43 virologic failures and seven deaths), a result that indicates equivalent virologic efficacy according to preset statistical criteria. During the initial assigned treatment, similar proportions of women in both treatment arms developed serious drug-related signs and symptoms and laboratory abnormalities. However, whereas 14% of the women in the NVP arm discontinued treatment because of adverse effects, none of the women in the LPV/r arm discontinued treatment. Finally, nearly half of the women tested in the NVP arm but only 15% of the women tested in the LVP/r arm had developed any drug resistance at the time of virologic failure.
What Do These Findings Mean?
These findings indicate that, among HIV-infected, treatment-naïve African women, initial NVP-based ART is as effective as LPV/r-based ART in terms of virologic failure and death although more women in the NVP arm discontinued treatment or developed new drug resistance than in the LPV/r arm. Several limitations of this study may affect the accuracy of these findings. In particular, some of the study participants may have been exposed to single-dose NVP during childbirth to prevent mother-to-child transmission of HIV; in a parallel randomized trial, the researchers found that LPV/r-based ART was superior to NVP-based ART among women with prior exposure to single-dose NVP. Moreover, the duration of the current study means the long-term effects of the two treatments cannot be compared. Nevertheless, these findings support the WHO recommendation of NVP-based ART with careful early toxicity monitoring as an initial affordable and effective HIV treatment regiment in resource-limited settings, until access to better-tolerated and more potent regimens is possible.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001236.
Information is available from the US National Institute of Allergy and Infectious Diseases on all aspects of HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment (in several languages)
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including detailed information on HIV treatment and care (in English and Spanish)
WHO provides information about universal access to AIDS treatment (in English, French and Spanish); its 2010 ART guidelines can be downloaded
More information about this trial, the OCTANE trial, is available
MedlinePlus provides detailed information about nevirapine and lopinavir/ritinovir (in English and Spanish)
Patient stories about living with HIV/AIDS are available through Avert; the nonprofit website Healthtalkonline also provides personal stories about living with HIV, including stories about taking anti-HIV drugs and the challenges of anti-HIV drugs
doi:10.1371/journal.pmed.1001236
PMCID: PMC3373629  PMID: 22719231
21.  Insensitivity of Paediatric HIV-1 Subtype C Viruses to Broadly Neutralising Monoclonal Antibodies Raised against Subtype B 
PLoS Medicine  2006;3(7):e255.
Background
A Phase I clinical trial has been proposed that uses neutralising monoclonal antibodies (MAbs) as passive immunoprophylaxis to prevent mother-to-child transmission of HIV-1 in South Africa. To assess the suitability of such an approach, we determined the sensitivity of paediatric HIV-1 subtype C viruses to the broadly neutralising MAbs IgG1b12, 2G12, 2F5, and 4E10.
Methods and Findings
The gp160 envelope genes from seven children with HIV-1 subtype C infection were cloned and used to construct Env-pseudotyped viruses that were tested in a single-cycle neutralisation assay. The epitopes defining three of these MAbs were determined from sequence analysis of the envelope genes. None of the seven HIV-1 subtype C pseudovirions was sensitive to 2G12 or 2F5, which correlated with the absence of crucial N-linked glycans that define the 2G12 epitope and substitutions of residues integral to the 2F5 epitope. Four viruses were sensitive to IgG1b12, and all seven viruses were sensitive to 4E10.
Conclusions
Only 4E10 showed significant activity against HIV-1 subtype C isolates, while 2G12 and 2F5 MAbs were ineffective and IgG1b12 was partly effective. It is therefore recommended that 2G12 and 2F5 MAbs not be used for passive immunization experiments in southern Africa and other regions where HIV-1 subtype C viruses predominate.
Editors' Summary
Background.
AIDS is caused by HIV. By killing the cells of the body's immune system, HIV infection makes people vulnerable to many potentially fatal bacterial and viral diseases. HIV is most commonly spread through unprotected sex with an infected partner but it can also pass from mother to child during late pregnancy or birth, or through breast milk. At least one in four infected women will transmit HIV to their babies if left untreated. But if infected women are treated with drugs that fight HIV—so-called antiretrovirals—during late pregnancy and if breastfeeding does not occur, only one to two babies in 100 will become infected with HIV. In addition, elective Caesarian section has been found to be protective against HIV infection. Implementation of this approach has greatly reduced mother-to-child transmission in developed countries, but most HIV-infected women live in developing countries where access to antiretrovirals is limited. In these cases, treatment of pregnant women (during pregnancy and delivery) and their newborn babies with a single dose of one antiretroviral drug, which can halve HIV transmission, is used, even though WHO/UNAIDS recommends simple antenatal, intrapartum, and postnatal antiretroviral regimens to achieve levels of less than 5% transmission in resource poor settings. These strategies will not have an impact on breastmilk transmission, which accounts for half the transmissions in these settings.
Why Was This Study Done?
One way to reduce breastmilk transmission of HIV might be by “passive immunization.” In this, newborn babies would be injected with HIV-specific antibodies—proteins that stick to molecules on the surface of HIV. Because the virus uses these molecules to invade the baby's immune cells, injected antibodies might stop HIV from the mother becoming established in her offspring. Four antibodies have been made in the laboratory—so-called human monoclonal antibodies—that bind to the surface of HIV subtype B, which is found mainly in Europe and North America, and stop HIV from killing human cells. However, most HIV isolated in Africa is subtype C, so in this study researchers have tested whether these antibodies prevent HIV subtype C killing cells grown in the laboratory. It is important, they argue, that antibodies should be shown to work outside the body before testing passive immunization in babies.
What Did the Researchers Do and Find?
The researchers isolated several subtype C viruses from babies born in Johannesburg, South Africa, and made artificial viruses (known as “pseudotyped” viruses) from them. These artificial viruses could then be used in tests to see whether the human monoclonal antibodies could prevent the viruses infecting human cells in a laboratory test, that is, whether the viruses were “sensitive” to the antibodies. All the viruses were insensitive to two of the antibodies (2G12 and 2F5), and the researchers show that this was because the viruses lacked the specific parts of the HIV surface molecules recognized by these antibodies. Four of the viruses were sensitive to an antibody called IgG1b12, and all were sensitive to antibody 4E10, albeit at high concentrations that might be difficult to achieve in people. Finally, the researchers report that the sensitivity of the viruses was not enhanced by using all four antibodies at the same time.
What Do These Findings Mean?
Given these results, the researchers warn against using 2G12 and 2F5 antibodies for passive immunization to prevent mother-to-child transmission, in particular postnatal transmission, in areas where most people are infected with HIV subtype C viruses. Furthermore, because animal studies have indicated that only combinations of at least three monoclonal antibodies with activity against HIV in laboratory tests provide complete protection against HIV infection, the researchers question whether any clinical trials on passive immunization should be started with currently available antibodies. Their doubts about such trials are heightened by observations that 4E10 and 2F5 react against antigens present on human cells, which might make them unsafe for use in people, although so far no adverse effects have been seen in adults treated with these antibodies. However, these experiments used an artificial laboratory-based assay and it's possible that these antibodies might kill HIV subtype C more effectively in people; other components of the immune system might help them deal with the virus. If clinical studies of these antibodies do go ahead, it is essential that the babies in these trials must be carefully monitored to ensure that the antibodies are safe, and they and their mothers should also be given access to optimal antiretroviral prophylaxis according to WHO/UNAIDS guidelines. In a related PLoS Medicine Perspective paper (http://dx.doi.org/10.1371/journal.pmed.0030259), Miroslaw Gorny1 and Susan Zolla-Pazner discuss the study further and stress the critical need to determine if passive immunization with such antibodies could decrease mother-to-child transmission of HIV, and if so what the best antibodies would be.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030255.
•  National Institute of Allergy and Infectious Diseases fact sheets on HIV infection and AIDS
•  US Department of Health and Human Services information on HIV/AIDS, including clinical guidelines and fact sheets on preventing transmission from mother to child
•  US Centers for Disease Control and Prevention information on HIV/AIDS, including pages on the prevention of mother-to-child transmission
•  MedlinePlus encyclopedia entry on HIV/AIDS
•  Preventing mother-to-child transmission of HIV Web page
Assessment of viruses from seven children with HIV-1 subtype C infection showed generally poor sensitivity to four monoclonal antibodies proposed for a trial of passive immunoprophylaxis to prevent mother-to-child transmission.
doi:10.1371/journal.pmed.0030255
PMCID: PMC1502151  PMID: 16834457
22.  HIV-1 Drug Resistance Emergence among Breastfeeding Infants Born to HIV-Infected Mothers during a Single-Arm Trial of Triple-Antiretroviral Prophylaxis for Prevention of Mother-To-Child Transmission: A Secondary Analysis 
PLoS Medicine  2011;8(3):e1000430.
Analysis of a substudy of the Kisumu breastfeeding trial by Clement Zeh and colleagues reveals the emergence of HIV drug resistance in HIV-positive infants born to HIV-infected mothers treated with antiretroviral drugs.
Background
Nevirapine and lamivudine given to mothers are transmitted to infants via breastfeeding in quantities sufficient to have biologic effects on the virus; this may lead to an increased risk of a breastfed infant's development of resistance to maternal antiretrovirals. The Kisumu Breastfeeding Study (KiBS), a single-arm open-label prevention of mother-to-child HIV transmission (PMTCT) trial, assessed the safety and efficacy of zidovudine, lamivudine, and either nevirapine or nelfinavir given to HIV-infected women from 34 wk gestation through 6 mo of breastfeeding. Here, we present findings from a KiBS trial secondary analysis that evaluated the emergence of maternal ARV-associated resistance among 32 HIV-infected breastfed infants.
Methods and Findings
All infants in the cohort were tested for HIV infection using DNA PCR at multiple study visits during the 24 mo of the study, and plasma RNA viral load for all HIV-PCR–positive infants was evaluated retrospectively. Specimens from mothers and infants with viral load >1,000 copies/ml were tested for HIV drug resistance mutations. Overall, 32 infants were HIV infected by 24 mo of age, and of this group, 24 (75%) infants were HIV infected by 6 mo of age. Of the 24 infants infected by 6 mo, nine were born to mothers on a nelfinavir-based regimen, whereas the remaining 15 were born to mothers on a nevirapine-based regimen. All infants were also given single-dose nevirapine within 48 hours of birth. We detected genotypic resistance mutations in none of eight infants who were HIV-PCR positive by 2 wk of age (specimens from six infants were not amplifiable), for 30% (6/20) at 6 wk, 63% (14/22) positive at 14 wk, and 67% (16/24) at 6 mo post partum. Among the 16 infants with resistance mutations by 6 mo post partum, the common mutations were M184V and K103N, conferring resistance to lamivudine and nevirapine, respectively. Genotypic resistance was detected among 9/9 (100%) and 7/15 (47%) infected infants whose mothers were on nelfinavir and nevirapine, respectively. No mutations were detected among the eight infants infected after the breastfeeding period (age 6 mo).
Conclusions
Emergence of HIV drug resistance mutations in HIV-infected infants occurred between 2 wk and 6 mo post partum, most likely because of exposure to maternal ARV drugs through breast milk. Our findings may impact the choice of regimen for ARV treatment of HIV-infected breastfeeding mothers and their infected infants.
Trial Registration
ClinicalTrials.gov NCT00146380
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Globally, more than 2 million children are infected with the human immunodeficiency virus (HIV) that causes acquired immunodeficiency syndrome (AIDS), and half a million children are newly infected every year. These infections are mainly the result of mother-to-child transmission (MTCT) of HIV during pregnancy, labor and delivery, or through breastfeeding. MTCT can be greatly reduced by treating HIV-positive mothers and their babies with antiretroviral drugs (ARVs). Without ARVs, up to half of babies born to HIV-positive mothers become infected with HIV. This rate of transmission falls to below 5% if a combination of three ARVs is given to the mother throughout pregnancy. Unfortunately, this triple-ARV therapy is too expensive for use in the resource-limited countries where most MTCT occurs. Instead, many such countries have introduced simpler, shorter ARV regimens such as a daily dose of zidovudine (a nucleoside reverse transcriptase inhibitor or NRTI) given to HIV-positive women during late pregnancy coupled with single-dose nevirapine (a non-nucleoside reverse transcriptase inhibitor or NNRTI) at the onset of labor, zidovudine and lamivudine (another NRTI) during labor and delivery, and single-dose nevirapine given to the baby at birth.
Why Was This Study Done?
More than 95% of HIV-exposed children are born in resource-limited settings where breastfeeding is the norm and is crucial for child survival even though it poses a risk of HIV transmission. Consequently, several recent studies have investigated whether MTCT can be further reduced by giving the mother ARVs while she is breastfeeding. In the Kisumu Breastfeeding Study (KiBS), for example, researchers assessed the effects of giving zidovudine, lamivudine, and either nevirapine or nelfinavir (a protease inhibitor) to HIV-infected women from 34 weeks of pregnancy through 6 months of breastfeeding. The results of KiBS indicate that this approach might be a safe, feasible way to reduce MTCT (see the accompanying paper by Thomas and colleagues). However, low amounts of nevirapine and lamivudine are transferred from mother to infant in breast milk and this exposure to ARVs could induce the development of resistance to ARVs among HIV-infected infants. In this KiBS substudy, the researchers investigate whether HIV drug resistance emerged in any of the HIV-positive infants in the parent study.
What Did the Researchers Do and Find?
In KiBS, 32 infants were HIV-positive at 24 months old; 24 were HIV-positive at 6 months old when their mothers stopped taking ARVs and when breastfeeding was supposed to stop. The researchers analyzed blood samples taken from these infants at various ages and from their mothers for the presence of HIV drug resistance mutations (DNA changes that make HIV resistant to killing by ARVs). They detected no resistance mutations in samples taken from 2-week old HIV-positive infants or from the infants who became infected after the age of 6 months. However, they found resistance mutations in a third and two-thirds of samples taken from 6-week and 6-month old HIV-positive infants, respectively. The commonest mutations conferred resistance to lamivudine and nevirapine. Moreover, resistance mutations were present in samples taken from all the HIV-positive infants whose mothers who had received nelfinavir but in only half those taken from infants whose mothers who had received nevirapine. Finally, most of the mothers of HIV-positive infants had no HIV drug resistance mutations, and only one mother-infant pair had an overlapping pattern of HIV drug resistance mutations.
What Do These Findings Mean?
These findings indicate that, in this KiBS substudy, the emergence of HIV drug resistance mutations in HIV-infected infants whose mothers were receiving ARVs occurred between 2 weeks and 6 months after birth. The pattern of mutations suggests that drug resistance most likely arose through exposure of the infants to low levels of ARVs in breast milk rather than through MTCT of drug-resistant virus. These findings need confirming but suggest that infants exposed to ARVs through breast milk—a situation that may become increasingly common given the reduction in MTCT seen in KiBS and other similar trials—should be carefully monitored for HIV infection. Providers should consider the mothers' regimen when choosing treatment for infants who are found to be HIV-infected despite maternal triple drug prophylaxis. Infants exposed to a maternal regimen with NNRTI drugs should receive first-line therapy with lopinavir/ritonavir, a protease inhibitor. The significance of the NRTI mutations such as M184V with regard to response to therapy needs further evaluation. The M184V mutation may result in hypersensitization to other NRTI drugs and delay or reverse zidovudine resistance. Given the limited availability of alternative drugs for infants in resource-limited settings, provision of the standard WHO-recommended first-line NRTI backbone, which includes 3TC, with enhanced monitoring of the infant to ensure virologic suppression, could be considered. Such an approach should reduce both illness and morbidity among infants who become HIV positive through breastfeeding.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/ 10.1371/journal.pmed.1000430.
The accompanying PLoS Medicine Research article by Thomas and colleagues describes the primary findings of the Kisumu Breastfeeding Study
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on HIV/AIDS
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on children, HIV, and AIDS and on preventing mother-to-child transmission of HIV (in English and Spanish)
UNICEF also has information about children and HIV and AIDS (in several languages)
The World Health organization has information on mother-to-child transmission of HIV (in several languages), and guidance on the use of ARVs for preventing MTCT
doi:10.1371/journal.pmed.1000430
PMCID: PMC3066134  PMID: 21468304
23.  Antiretroviral Treatment and Prevention of Peripartum and Postnatal HIV Transmission in West Africa: Evaluation of a Two-Tiered Approach 
PLoS Medicine  2007;4(8):e257.
Background
Highly active antiretroviral treatment (HAART) has only been recently recommended for HIV-infected pregnant women requiring treatment for their own health in resource-limited settings. However, there are few documented experiences from African countries. We evaluated the short-term (4 wk) and long-term (12 mo) effectiveness of a two-tiered strategy of prevention of mother-to-child transmission of HIV (PMTCT) in Africa: women meeting the eligibility criteria of the World Health Organization (WHO) received HAART, and women with less advanced HIV disease received short-course antiretroviral (scARV) PMTCT regimens.
Methods and Findings
The MTCT-Plus Initiative is a multi-country, family-centred HIV care and treatment program for pregnant and postpartum women and their families. Pregnant women enrolled in Abidjan, Côte d'Ivoire received either HAART for their own health or short-course antiretroviral (scARV) PMTCT regimens according to their clinical and immunological status. Plasma HIV-RNA viral load (VL) was measured to diagnose peripartum infection when infants were 4 wk of age, and HIV final status was documented either by rapid antibody testing when infants were aged ≥ 12 mo or by plasma VL earlier. The Kaplan-Meier method was used to estimate the rate of HIV transmission and HIV-free survival. Between August 2003 and June 2005, 107 women began HAART at a median of 30 wk of gestation, 102 of them with zidovudine (ZDV), lamivudine (3TC), and nevirapine (NVP) and they continued treatment postpartum; 143 other women received scARV for PMTCT, 103 of them with sc(ZDV+3TC) with single-dose NVP during labour. Most (75%) of the infants were breast-fed for a median of 5 mo. Overall, the rate of peripartum HIV transmission was 2.2% (95% confidence interval [CI] 0.3%–4.2%) and the cumulative rate at 12 mo was 5.7% (95% CI 2.5%–9.0%). The overall probability of infant death or infection with HIV was 4.3% (95% CI 1.7%–7.0%) at age week 4 wk and 11.7% (95% CI 7.5%–15.9%) at 12 mo.
Conclusions
This two-tiered strategy appears to be safe and highly effective for short- and long-term PMTCT in resource-constrained settings. These results indicate a further benefit of access to HAART for pregnant women who need treatment for their own health.
In an observational cohort study from Côte d'Ivoire, François Dabis and colleagues report on prevention of mother-to-child HIV transmission among women receiving antiretroviral therapy according to World Health Organization recommendations.
Editors' Summary
Background
Effective treatments are available to prevent AIDS in people who are infected with HIV, but not everyone with HIV needs to take medication. Usually, anti-HIV medication is recommended only for those whose immune systems have been significantly affected by the virus, as evidenced by symptoms or by the results of a blood test, the CD4 lymphocyte (“T cell”) count. Treating HIV usually requires a combination of three or more medications. These combinations (called HAART) must be taken every day, can cause complications, and can be expensive.
Worldwide, more than half a million children became infected with HIV each year. Most of these children acquire HIV from their mothers during pregnancy or around the time of birth. If a pregnant woman with HIV takes HAART, her chances of passing HIV to the baby are greatly reduced, but the possible side effects of HAART on the baby are not known. Also, most transmission of HIV from mothers to babies occurs in poor countries where supplies of HAART are limited. For these reasons, World Health Organization (WHO) does not recommend that every pregnant woman receive HAART to prevent HIV transmission to the baby, unless the woman needs HAART for her own health (for example if her T cells are low or she has severe symptoms of HIV infection). For pregnant women with HIV who do not need to take HAART for their own health, less complicated treatments, involving a short course of one or two HIV drugs, can be used to reduce the risk of passing HIV to the baby.
Why Was This Study Done?
The WHO recommendations for HAART in pregnancy are based on the best available evidence, but it is important to know how well they work in actual practice. The authors of this study were providing HIV treatment to pregnant women with HIV in West Africa through an established clinic program in Abidjan, Côte d'Ivoire, and wanted to see how well the WHO recommendations for HAART or short-course treatments, depending on the mother's condition, were working to protect babies from HIV infection.
What Did the Researchers Do and Find?
The researchers studied 250 HIV-infected pregnant women who received HIV medications in the Abidjan program between mid-2003 and mid-2005. In accordance with WHO guidelines, 107 women began HAART for their own health during pregnancy, and 143 women did not qualify for HAART but received other short course treatments (scARV) to prevent HIV transmission to their babies. The authors monitored mothers and babies for treatment side effects and tested the babies for HIV infection up to age 1 y.
They found that HAART was relatively safe during pregnancy, although babies born to women on HAART were more likely (26.3%) to have low birth weight than babies born to women who received scARV (12.4%). Also, 7.5% of women on HAART developed side effects requiring a change in their medications. Combining the results from HAART and scART groups, the chance of HIV transmission around the time of birth was 2.2%, increasing to 5.7% at age 1 y. (Three-quarters of the infants were breast-fed; safe water for mixing formula was not reliably available.) The study found no difference in risk of HIV infection between babies whose mothers received HAART and those whose mothers received scARV according to guidelines.
What Do These Findings Mean?
These results support the safety and effectiveness of the WHO two-tiered approach for preventing mother-to-child transmission. This study was not designed to compare HAART to scART directly, because the women who received HAART were the ones with more advanced HIV infection, which might have affected their babies in many ways.
Compared to earlier pregnancy studies of HAART in rich countries, this study of the WHO approach in West Africa showed similar success in protecting infants from HIV infection around the time of birth. Unfortunately, because formula feeding was not generally available in resource-limited settings, protection declined over the first year of life with breast-feeding, but some protection remained.
This study confirms that close monitoring of pregnant women on HAART is necessary, so that drugs can be changed if side effects develop. The study does not tell us whether using scARV in pregnancy might change the virus in ways that would make it more difficult to treat the same women with HAART later if they needed it. The reason for low birth weight in some babies born to mothers on HAART is unclear. It may be because the women who needed HAART had more severe health problems from their HIV, or it may be a result of the HAART itself.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040257.
World Health Organization has a page on prevention of mother-to-child transmission of HIV
“Women, Children, and HIV” is a resource site from the François Xavier Bagnoud Center and UCSF
The MTCT-Plus initiative at Columbia University supports the programs in Abidjan
doi:10.1371/journal.pmed.0040257
PMCID: PMC1949842  PMID: 17713983
24.  Differences in HIV vaccine acceptability between genders 
AIDS care  2008;20(5):542-546.
The development of safe and efficacious preventive HIV vaccines offers the best long-term hope of controlling the AIDS pandemic. Nevertheless, suboptimal uptake of safe and efficacious vaccines that already exist suggest that HIV vaccine acceptability cannot be assumed, particularly among communities most vulnerable to HIV. The present study aimed to identify barriers and motivators to future HIV vaccine acceptability among low socioeconomic, ethnically diverse men and women in Los Angeles County. Participants completed a cross-sectional survey assessing their attitudes and beliefs regarding future HIV vaccines. Hypothetical HIV vaccine scenarios were administered to determine HIV vaccine acceptability. Two-sided t-tests were performed, stratified by gender, to examine the association between vaccine acceptability and potential barriers and motivators. Barriers to HIV vaccine acceptability differed between men and women. For women, barriers to HIV vaccine acceptability were related to their intimate relationships (p <0.05), negative experiences with health care providers (p <0.05) and anticipated difficulties procuring insurance (p <0.01). Men were concerned that the vaccine would weaken the immune system (p <0.005) or would affect their HIV test results (p <0.05). Motivators for women included the ability to conceive a child without worrying about contracting HIV (p <0.10) and support from their spouse/significant other for being vaccinated (p <0.10). Motivators for men included feeling safer with sex partners (p <0.05) and social influence from friends to get vaccinated (p <0.005). Family support for HIV immunization was a motivator for both men and women (p <0.10). Gender-specific interventions may increase vaccine acceptability among men and women at elevated risk for HIV infection. Among women, interventions need to focus on addressing barriers due to gendered power dynamics in relationships and discrimination in health care. Among men, education that addresses fears and misconceptions about adverse effects of HIV vaccination on health and the importance of vaccination as one component of integrated HIV prevention may increase vaccine acceptability.
doi:10.1080/09540120701867180
PMCID: PMC2836013  PMID: 18484322
HIV vaccine; barriers; gender; motivators; acceptability
25.  Efficacy and Safety of the RTS,S/AS01 Malaria Vaccine during 18 Months after Vaccination: A Phase 3 Randomized, Controlled Trial in Children and Young Infants at 11 African Sites 
PLoS Medicine  2014;11(7):e1001685.
Mary Hamel and colleagues in the RTS,S Clinical Trials Partnership report updated safety and efficacy results from an ongoing Phase 3 trial, including calculations of vaccine impact (malaria cases prevented).
Please see later in the article for the Editors' Summary
Background
A malaria vaccine could be an important addition to current control strategies. We report the safety and vaccine efficacy (VE) of the RTS,S/AS01 vaccine during 18 mo following vaccination at 11 African sites with varying malaria transmission.
Methods and Findings
6,537 infants aged 6–12 wk and 8,923 children aged 5–17 mo were randomized to receive three doses of RTS,S/AS01 or comparator vaccine.
VE against clinical malaria in children during the 18 mo after vaccine dose 3 (per protocol) was 46% (95% CI 42% to 50%) (range 40% to 77%; VE, p<0.01 across all sites). VE during the 20 mo after vaccine dose 1 (intention to treat [ITT]) was 45% (95% CI 41% to 49%). VE against severe malaria, malaria hospitalization, and all-cause hospitalization was 34% (95% CI 15% to 48%), 41% (95% CI 30% to 50%), and 19% (95% CI 11% to 27%), respectively (ITT).
VE against clinical malaria in infants was 27% (95% CI 20% to 32%, per protocol; 27% [95% CI 21% to 33%], ITT), with no significant protection against severe malaria, malaria hospitalization, or all-cause hospitalization.
Post-vaccination anti-circumsporozoite antibody geometric mean titer varied from 348 to 787 EU/ml across sites in children and from 117 to 335 EU/ml in infants (per protocol).
VE waned over time in both age categories (Schoenfeld residuals p<0.001). The number of clinical and severe malaria cases averted per 1,000 children vaccinated ranged across sites from 37 to 2,365 and from −1 to 49, respectively; corresponding ranges among infants were −10 to 1,402 and −13 to 37, respectively (ITT). Meningitis was reported as a serious adverse event in 16/5,949 and 1/2,974 children and in 9/4,358 and 3/2,179 infants in the RTS,S/AS01 and control groups, respectively.
Conclusions
RTS,S/AS01 prevented many cases of clinical and severe malaria over the 18 mo after vaccine dose 3, with the highest impact in areas with the greatest malaria incidence. VE was higher in children than in infants, but even at modest levels of VE, the number of malaria cases averted was substantial. RTS,S/AS01 could be an important addition to current malaria control in Africa.
Trial registration
www.ClinicalTrials.gov NCT00866619
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, more than 200 million cases of malaria occur worldwide, and more than 600,000 people, mainly children living in sub-Saharan Africa, die from this parasitic disease. Malaria parasites are transmitted to people through the bites of infected night-flying mosquitoes and cause fever that needs to be treated promptly with anti-malarial drugs to prevent anemia (a reduction in red blood cell numbers) and life-threatening organ damage. Malaria transmission can be prevented by using long-lasting insecticides sprayed on the indoor walls of homes to kill the mosquitoes that spread the malaria parasite or by sleeping under insecticide-treated nets to avoid mosquito bites and further reduce mosquito numbers. Widespread use of these preventative measures, together with the introduction of artemisinin combination therapy (an effective anti-malarial treatment), has reduced the global burden of malaria by 45% in all age groups, and by 51% among young children, since 2000.
Why Was This Study Done?
Unfortunately, the emergence of insecticide and drug resistance is threatening this advance in malaria control. Moreover, additional interventions—specifically, effective malaria vaccines—will be needed to eliminate malaria in the large areas of Africa where malaria transmission remains high. Currently, there is no licensed malaria vaccine, but RTS,S/AS01, the most advanced malaria vaccine candidate, is undergoing phase 3 clinical trials (the last stage of testing before licensing) in infants and children in seven African countries. The RTS,S Clinical Trials Partnership reported encouraging results on the efficacy and safety of RTS,S/AS01 during 12 months of follow-up in 2011 and 2012. Here, researchers report on the 18-month efficacy and safety of RTS,S/AS01. Vaccine efficacy (VE) is the reduction in the incidence of a disease (the number of new cases that occur in a population in a given period) among trial participants who receive the vaccine compared to the incidence among participants who do not receive the vaccine.
What Did the Researchers Do and Find?
The researchers randomly assigned 6,537 infants aged 6–12 weeks and 8,923 children aged 5–17 months to receive three doses of RTS,S/AS01 or a control vaccine. During 18 months of follow-up, there were 0.69 episodes of clinical malaria (a high temperature and parasites in the blood) per person-year among the children who received all the planned doses of RTS,S/AS01 (the “per protocol” population) and 1.17 episodes per person-year among the control children—a VE against clinical malaria in the per-protocol population of 46%. A similar VE was seen in an intention-to-treat analysis that included all the enrolled children, regardless of whether they received all of the planned vaccine doses; intention-to-treat analyses reflect the real-life situation—in which children sometimes miss vaccine doses—better than per-protocol analyses. In intention-to-treat analyses, the VE among children against severe malaria (fever, parasites in the blood, and symptoms such as anemia) and hospitalization for malaria was 34% and 41%, respectively. Among infants, the VE against clinical malaria was 27% in both per-protocol and intention-to-treat analyses; the vaccine showed no protection against severe malaria or hospitalization. In both infants and children, VE waned with time since vaccination. Across all the study sites, RTS,S/AS01 averted an average of 829 and 449 cases of clinical malaria per 1,000 children and infants vaccinated, respectively. Finally, the serious adverse event meningitis (inflammation of the tissues lining the brain and spinal cord) occurred more frequently in trial participants given RTS,S/AS01 than in those given the control vaccine, but the incidence of other serious adverse events was similar in both groups of participants.
What Do These Findings Mean?
These and other findings show that, during 18 months of follow-up, vaccination of children and young infants with RTS,S/AS01 prevented many cases of clinical and severe malaria and that the impact of vaccination was highest in regions with the highest incidence of malaria. They indicate, as in the earlier analysis, that the VE against clinical and severe malaria is higher in children than in young infants and suggest that protection wanes over time. Whether or not the vaccine played a causal role in the observed cases of meningitis cannot be determined from these results, and the occurrence of meningitis will be followed closely during the remainder of the trial. Other study limitations (for example, variations in the clinical characteristics of participants from one center to another) may also affect the accuracy of these findings and their interpretation. However, by showing that even a modest VE can avert a substantial number of malaria cases, these findings suggest that vaccination with RTS,S/AS01 could have a major public health impact in sub-Saharan Africa.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001685.
Information is available from the World Health Organization on all aspects of malaria (in several languages), including malaria immunization; the World Malaria Report 2013 provides details of the current global malaria situation; the World Health Organization also provides information on its Global Immunization Vision and Strategy (in English and French)
The US Centers for Disease Control and Prevention provides information on malaria, including a selection of personal stories about malaria
Information is available from the Roll Back Malaria Partnership on the global control of malaria and on the Global Malaria Action Plan (in English and French); its website includes a fact sheet about malaria in Africa
The latest results from the phase 3 trial of RTS,S are available on the website of the PATH Malaria Vaccine Initiative, a global program of the international nonprofit organization PATH that aims to accelerate the development of malaria vaccines and ensure their availability and accessibility in the developing world
MedlinePlus provides links to additional information on malaria and on immunization (in English and Spanish)
doi:10.1371/journal.pmed.1001685
PMCID: PMC4114488  PMID: 25072396

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