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1.  Impact of Antiretroviral Therapy on Incidence of Pregnancy among HIV-Infected Women in Sub-Saharan Africa: A Cohort Study 
PLoS Medicine  2010;7(2):e1000229.
A multicountry cohort study in sub-Saharan Africa by Landon Myer and colleagues reveals higher pregnancy rates in HIV-infected women on antiretroviral therapy (ART).
Background
With the rapid expansion of antiretroviral therapy (ART) services in sub-Saharan Africa there is growing recognition of the importance of fertility and childbearing among HIV-infected women. However there are few data on whether ART initiation influences pregnancy rates.
Methods and Findings
We analyzed data from the Mother-to-Child Transmission-Plus (MTCT-Plus) Initiative, a multicountry HIV care and treatment program for women, children, and families. From 11 programs in seven African countries, women were enrolled into care regardless of HIV disease stage and followed at regular intervals; ART was initiated according to national guidelines on the basis of immunological and/or clinical criteria. Standardized forms were used to collect sociodemographic and clinical data, including incident pregnancies. Overall 589 incident pregnancies were observed among the 4,531 women included in this analysis (pregnancy incidence, 7.8/100 person-years [PY]). The rate of new pregnancies was significantly higher among women receiving ART (9.0/100 PY) compared to women not on ART (6.5/100 PY) (adjusted hazard ratio, 1.74; 95% confidence interval, 1.19–2.54). Other factors independently associated with increased risk of incident pregnancy included younger age, lower educational attainment, being married or cohabiting, having a male partner enrolled into the program, failure to use nonbarrier contraception, and higher CD4 cell counts.
Conclusions
ART use is associated with significantly higher pregnancy rates among HIV-infected women in sub-Saharan Africa. While the possible behavioral or biomedical mechanisms that may underlie this association require further investigation, these data highlight the importance of pregnancy planning and management as a critical but neglected component of HIV care and treatment services.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Human immunodeficiency virus (HIV) causes Acquired Immunodeficiency Syndrome (AIDS), which is a major global cause of disease and death. More than 33 million people around the world are infected with HIV, with nearly 5,500 dying daily from HIV and AIDS-related complications. HIV/AIDS is especially problematic in sub-Saharan Africa, where it is the leading cause of death. There is no cure for HIV/AIDS, but medicines known as “antiretroviral therapy” (ART) can prolong life and reduce complications in patients infected with HIV. 97% of patients with HIV/AIDS live in low- and middle-income countries. According to the World Health Organization, nearly 10 million of these patients need ART. As patients' access to treatment is often hindered by the high cost and low availability of ART, global health efforts have focused on promoting ART use in resource-limited nations. Such efforts also increase awareness of how HIV is spread (contact with blood or semen, in sexual intercourse, sharing needles, or from mother to child during childbirth). ART reduces, but does not remove, the chance of a mother's passing HIV to her child during birth.
Why Was This Study Done?
By the end of 2007, 3 million HIV-infected patients in poor countries were receiving ART. Many of those treated with ART are young women of child-bearing age. Childbirth is an important means of spreading HIV in sub-Saharan Africa, where 60% of all HIV patients are women. This study questions whether the improved health and life expectancy that results from treatment with ART affects pregnancy rates of HIV-infected patients. The study explores this question in seven African countries, by examining the rates of pregnancy in HIV-infected women before and after they started ART.
What Did the Researchers Do and Find?
The authors looked at the records of 4,531 HIV-infected women enrolled in the Mother-to-Child-Transmission-Plus (MTCT-Plus) Initiative in seven African countries. MTCT -Plus, begun in 2002, is a family-centered treatment program that offers regular checkups, blood tests, counseling, and ART treatment (if appropriate) to women and their families. At each checkup, women's CD4+ cell counts and World Health Organization guidelines were used to determine their eligibility for starting ART. Over a 4-year period, nearly a third of the women starting ART experienced a pregnancy: 244 pregnancies occurred in the “pre-ART” group (women not receiving ART) compared to 345 pregnancies in the “on-ART” group (women receiving ART). The chance of pregnancy increased over time in the on-ART group to almost 80% greater than the pre-ART group, while remaining relatively low and constant in the pre-ART group. The authors noted that, as expected, other factors also increased the chances of pregnancy, including younger age, lower educational status, and use of nonbarrier contraception such as injectable hormones.
What Do These Findings Mean?
This study suggests that starting ART is associated with higher pregnancy rates in sub-Saharan Africa, nearly doubling the chances of a woman becoming pregnant. The reasons for this link are unclear. One possible explanation is behavioral: women receiving ART may feel more motivated to have children as their health and quality of life improve. However, the study did not examine how pregnancy desires and sexual activity of women changed while on ART, and cannot discern why ART is linked to increased pregnancy. By using pregnancy data gathered from patient questionnaires rather than laboratory tests, the study is limited by the possibility of inaccurate patient reporting. Understanding how pregnancy rates vary in HIV-infected women receiving ART helps support the formation of responsive, effective HIV programs. Female HIV patients of child-bearing age, who form the majority of patients receiving ART in sub-Saharan Africa, would benefit from programs that combine starting HIV treatment with ART with education and contraception counseling and pregnancy-related care.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000229.
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
A UNAIDS 2008 report is available on the global AIDS epidemic
The International Planned Parenthood Foundation provides information on sexual and reproductive health and HIV
The International Center for AIDS Care and Treatment Programs at the Columbia University Mailman School of Public health provides information to assist HIV care and treatment programs in resource-limited settings
doi:10.1371/journal.pmed.1000229
PMCID: PMC2817715  PMID: 20161723
2.  Initiating Antiretroviral Therapy for HIV at a Patient’s First Clinic Visit: The RapIT Randomized Controlled Trial 
PLoS Medicine  2016;13(5):e1002015.
Background
High rates of patient attrition from care between HIV testing and antiretroviral therapy (ART) initiation have been documented in sub-Saharan Africa, contributing to persistently low CD4 cell counts at treatment initiation. One reason for this is that starting ART in many countries is a lengthy and burdensome process, imposing long waits and multiple clinic visits on patients. We estimated the effect on uptake of ART and viral suppression of an accelerated initiation algorithm that allowed treatment-eligible patients to be dispensed their first supply of antiretroviral medications on the day of their first HIV-related clinic visit.
Methods and Findings
RapIT (Rapid Initiation of Treatment) was an unblinded randomized controlled trial of single-visit ART initiation in two public sector clinics in South Africa, a primary health clinic (PHC) and a hospital-based HIV clinic. Adult (≥18 y old), non-pregnant patients receiving a positive HIV test or first treatment-eligible CD4 count were randomized to standard or rapid initiation. Patients in the rapid-initiation arm of the study (“rapid arm”) received a point-of-care (POC) CD4 count if needed; those who were ART-eligible received a POC tuberculosis (TB) test if symptomatic, POC blood tests, physical exam, education, counseling, and antiretroviral (ARV) dispensing. Patients in the standard-initiation arm of the study (“standard arm”) followed standard clinic procedures (three to five additional clinic visits over 2–4 wk prior to ARV dispensing). Follow up was by record review only. The primary outcome was viral suppression, defined as initiated, retained in care, and suppressed (≤400 copies/ml) within 10 mo of study enrollment. Secondary outcomes included initiation of ART ≤90 d of study enrollment, retention in care, time to ART initiation, patient-level predictors of primary outcomes, prevalence of TB symptoms, and the feasibility and acceptability of the intervention. A survival analysis was conducted comparing attrition from care after ART initiation between the groups among those who initiated within 90 d. Three hundred and seventy-seven patients were enrolled in the study between May 8, 2013 and August 29, 2014 (median CD4 count 210 cells/mm3). In the rapid arm, 119/187 patients (64%) initiated treatment and were virally suppressed at 10 mo, compared to 96/190 (51%) in the standard arm (relative risk [RR] 1.26 [1.05–1.50]). In the rapid arm 182/187 (97%) initiated ART ≤90 d, compared to 136/190 (72%) in the standard arm (RR 1.36, 95% confidence interval [CI], 1.24–1.49). Among 318 patients who did initiate ART within 90 d, the hazard of attrition within the first 10 mo did not differ between the treatment arms (hazard ratio [HR] 1.06; 95% CI 0.61–1.84). The study was limited by the small number of sites and small sample size, and the generalizability of the results to other settings and to non-research conditions is uncertain.
Conclusions
Offering single-visit ART initiation to adult patients in South Africa increased uptake of ART by 36% and viral suppression by 26%. This intervention should be considered for adoption in the public sector in Africa.
Trial Registration
ClinicalTrials.gov NCT01710397, and South African National Clinical Trials Register DOH-27-0213-4177.
In the RapIT randomized controlled trial, Sydney Rosen and colleagues investigate whether accelerated initiation of antiretroviral therapy can improve viral suppression for HIV patients in South Africa.
Author Summary
Why Was This Study Done?
One of the most persistent operational challenges facing antiretroviral therapy (ART) programs for HIV/AIDS in sub-Saharan Africa is late presentation of patients for care and high rates of attrition from care between HIV testing and ART initiation.
One reason for this is that starting ART in many countries is a lengthy and burdensome process, imposing long waits and multiple clinic visits on patients; in South Africa, the country with the world’s largest HIV treatment program, patients must typically make five or six clinic visits, starting with an HIV test, before they receive medications.
There have not yet been any controlled evaluations of an integrated, rapid HIV treatment initiation algorithm that allows patients to initiate ART in a single clinic visit, so the RapIT trial was done to find out if “same-day initiation” of ART would increase the number of patients starting treatment and improve overall health outcomes, compared to current practices.
What Did the Researchers Do and Find?
We randomly assigned 377 adult patients at two public clinics in Johannesburg, South Africa, who had provided consent to participate in the study to one of two groups.
Patients in the group assigned to receive rapid treatment initiation were offered the chance to start treatment on the same day as their first clinic visit, using rapid, point-of-care laboratory tests and an accelerated sequence of other steps, including a physical exam, education, and counseling.
Patients in the group assigned to receive standard treatment initiation followed the standard schedule for treatment initiation used by the clinics, which usually required three to five additional clinic visits over a 2–4 wk period.
After the study enrollment visit, patients were followed up by reviewing their regular clinic medical records, to determine how many did start treatment and how many were still in care and had good outcomes, as indicated by a suppressed viral load, 10 mo later.
We found that 97% of patients in the rapid initiation group had started ART by 90 d after study enrollment—three-quarters of them on the same day—compared to 72% of patients in the standard initiation group.
By 10 mo after study enrollment, 64% of patients in the rapid group had good outcomes compared to 51% in the standard group.
Rapid initiation group patients spent roughly two and a half hours in the clinic to complete all the steps required before they got their medications.
What Do These Findings Mean?
The RapIT (Rapid Initiation of Treatment) trial showed that it is possible to initiate nearly all eligible patients on HIV therapy, and to do so in a much shorter time interval than previously required.
By showing that offering the opportunity to start treatment on the spot, without delay, overcomes many barriers patients would otherwise face, this study demonstrates that same-day ART initiation is an effective strategy for improving health outcomes.
More patients in the rapid initiation group dropped out of care after starting treatment than in the standard initiation group; although the rapid initiation group still had better health outcomes overall, adherence support after starting treatment remains essential.
The findings of this study are limited because the study took place in only two clinics in one part of South Africa and was carried out by study staff, not by regular clinic staff.
Based on this study’s results, consideration could be given to accelerating the process of ART initiation in many different settings and for different types of patients.
doi:10.1371/journal.pmed.1002015
PMCID: PMC4862681  PMID: 27163694
3.  Retained in HIV Care But Not on Antiretroviral Treatment: A Qualitative Patient-Provider Dyadic Study 
PLoS Medicine  2015;12(8):e1001863.
Background
Patients retained in HIV care but not on antiretroviral therapy (ART) represent an important part of the HIV care cascade in the United States. Even in an era of more tolerable and efficacious ART, decision making in regards to ART offer and uptake remains complex and calls for exploration of both patient and provider perspectives. We sought to understand reasons for lack of ART usage in patients meeting the Health Resources Services Administration definition of retention as well as what motivated HIV primary care appointment attendance in the absence of ART.
Methods and Findings
We conducted a qualitative study consisting of 70 in-depth interviews with ART-naïve and ART-experienced patients off ART and their primary care providers in two urban safety-net HIV clinics in San Francisco and New York. Twenty patients and their providers were interviewed separately at baseline, and 15 dyads were interviewed again after at least 3 mo and another clinic visit in order to understand any ART use in the interim. We applied dyadic analysis to our data. Nearly all patients were willing to consider ART, and 40% of the sample went on ART, citing education on newer antiretroviral drugs, acceptance of HIV diagnosis, social support, and increased confidence in their ability to adhere as facilitators. However, the strength of the provider recommendation of ART played an important role. Many patients had internalized messages from providers that their health was too good to warrant ART. In addition, providers, while demonstrating patient-centered care through sensitivity to patients experiencing psychosocial instability, frequently muted the offer of ART, at times unintentionally. In the absence of ART, lab monitoring, provider relationships, access to social services, opiate pain medications, and acute symptoms motivated care. The main limitations of this study were that treatment as prevention was not explored in depth and that participants were recruited from academic HIV clinics in the US, making the findings most generalizable to this setting.
Conclusions
Provider communication with regard to ART is a key focus for further exploration and intervention in order to increase ART uptake for those retained in HIV care.
In a qualitative study, Katerina Christopoulos examines the reasons for lack of ART usage in patients retained in HIV care.
Editors' Summary
Background
AIDS has killed about 39 million people since the first recorded case of the disease in 1981, and about 35 million people are currently infected with HIV, the virus that causes AIDS. HIV, which is usually transmitted through unprotected sex with an infected partner, destroys CD4 lymphocytes and other immune system cells, leaving infected individuals susceptible to other serious infections and to unusual cancers. Early in the epidemic, most HIV-positive individuals died from an AIDS-defining illness such as recurrent pneumonia, severe fungal infection, or Kaposi’s sarcoma (a type of cancer). Nowadays, although there is still no cure for AIDS, treatment with antiretroviral drugs (antiretroviral therapy or ART) can hold HIV in check, and, at least in affluent countries, HIV-positive individuals who are on ART now have a near-normal life expectancy.
Why Was This Study Done?
HIV-positive individuals originally only started ART when their CD4 cell count fell below 200 cells/mm3 blood. As ART became more tolerable and more efficacious and as the harmful effects of viremia (HIV in the blood) became clear, the treatment threshold shifted upwards. Nowadays, the US ART guidelines, for example, recommend treatment for all HIV-infected individuals irrespective of cell count and, because ART reduces the risk of an HIV-infected individual transmitting the virus to an uninfected sexual partner, also endorse offering ART for the prevention of HIV transmission. However, 40,000 HIV-positive individuals in the US receive regular HIV care such as virus monitoring but are not prescribed ART, and 5% of individuals starting ART discontinue treatment. It is important to understand why HIV-positive individuals do not use ART, but decision making in relation to ART is complex, involving both the HIV-positive individual and their HIV care provider. HIV-positive individuals may refuse ART if they think their care provider does not believe they really need treatment, for example, and providers may not offer ART to someone they think will not adhere to treatment. Here, the researchers undertake a qualitative patient-provider dyadic study (an analysis of contrasts and overlaps between pairs of narratives) to investigate why some HIV-positive individuals are retained in HIV care but are not on ART and what motivates these individuals to attend HIV care clinics.
What Did the Researchers Do and Find?
The researchers interviewed 20 HIV-positive patients (mainly men) attending two urban US HIV clinics who were either ART-naive or ART-experienced but off ART and their HIV care providers; 15 patient-provider dyads were re-interviewed after at least 3 months and another clinic visit. Patients were asked about their attitudes to ART, their ART usage, and their relationship with their provider. Providers were asked about their ART philosophy, how they discussed ART with their patients, and about their relationship with their paired patient. Nearly all the patients were willing to consider ART and 40% began ART during the study. Reasons given by patients for accepting ART included education about newer, more tolerable drugs but the strength of the provider recommendation of ART was particularly important in patient decisions to accept ART. Specifically, many patients had internalized messages from their providers that their health was too good to warrant ART. Providers for their part often muted the offer of ART to patients experiencing psychosocial problems who they believed would find it hard to adhere to treatment. Finally, patient interviews suggested that motivations for retention in HIV care in the absence of ART included access to viral monitoring and the patient-provider relationship.
What Do These Findings Mean?
These findings may not apply to settings such as HIV clinics in sub-Saharan Africa where patients do not always see the same care provider or to women. Nevertheless, this study identifies the patient-provider encounter as a key factor in ART usage by HIV-positive individuals and highlights the importance of the discussion about ART between patient and provider in the patient’s decision to accept an offer of ART. Given these findings, the researchers make several recommendations about the role of the provider in ART initiation. For example, they suggest that provider assessment of how patients perceive their health status and the implications of ART initiation should be formalized as part of ART counseling. Attention to this and other aspects of the patient-provider encounter, they suggest, may help to improve ART usage among HIV-positive individuals and thereby increase both the individual and public-health benefits of ART.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001863.
Information is available from the US National Institute of Allergy and infectious diseases on all aspects of HIV infection and AIDS, including the treatment of HIV/AIDS
NAM/aidsmap provides basic information about HIV/AIDS, summaries of recent research findings on HIV care and treatment, and personal stories about living with HIV/AIDS
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on HIV/AIDS treatment and care and on treatment as prevention; Avert also provides personal stories about living with HIV/AIDS
The World Health Organization provides information on all aspects of HIV/AIDS (in several languages), including its guidelines on the use of ART for treating and preventing HIV infection
The 2014 UNAIDS World AIDS Day Report provides up-to-date information about the AIDS epidemic and efforts to halt it
doi:10.1371/journal.pmed.1001863
PMCID: PMC4532493  PMID: 26263532
4.  Retention in HIV Care between Testing and Treatment in Sub-Saharan Africa: A Systematic Review 
PLoS Medicine  2011;8(7):e1001056.
In this systematic review, Sydney Rosen and Matthew Fox find that less than one-third of patients who tested positive for HIV, but were not eligible for antiretroviral therapy (ART) when diagnosed, were retained in pre-ART care continuously.
Background
Improving the outcomes of HIV/AIDS treatment programs in resource-limited settings requires successful linkage of patients testing positive for HIV to pre–antiretroviral therapy (ART) care and retention in pre-ART care until ART initiation. We conducted a systematic review of pre-ART retention in care in Africa.
Methods and Findings
We searched PubMed, ISI Web of Knowledge, conference abstracts, and reference lists for reports on the proportion of adult patients retained between any two points between testing positive for HIV and initiating ART in sub-Saharan African HIV/AIDS care programs. Results were categorized as Stage 1 (from HIV testing to receipt of CD4 count results or clinical staging), Stage 2 (from staging to ART eligibility), or Stage 3 (from ART eligibility to ART initiation). Medians (ranges) were reported for the proportions of patients retained in each stage. We identified 28 eligible studies. The median proportion retained in Stage 1 was 59% (35%–88%); Stage 2, 46% (31%–95%); and Stage 3, 68% (14%–84%). Most studies reported on only one stage; none followed a cohort of patients through all three stages. Enrollment criteria, terminology, end points, follow-up, and outcomes varied widely and were often poorly defined, making aggregation of results difficult. Synthesis of findings from multiple studies suggests that fewer than one-third of patients testing positive for HIV and not yet eligible for ART when diagnosed are retained continuously in care, though this estimate should be regarded with caution because of review limitations.
Conclusions
Studies of retention in pre-ART care report substantial loss of patients at every step, starting with patients who do not return for their initial CD4 count results and ending with those who do not initiate ART despite eligibility. Better health information systems that allow patients to be tracked between service delivery points are needed to properly evaluate pre-ART loss to care, and researchers should attempt to standardize the terminology, definitions, and time periods reported.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Since 1981, AIDS has killed more than 25 million people, and about 33 million people (mostly living in low- and middle-income countries) are now infected with HIV, the virus that causes AIDS. HIV gradually destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected people died within ten years of infection. Then, in 1996, highly active antiretroviral therapy (ART) became available, and, for people living in developed countries, HIV infection became a chronic condition. Unfortunately, ART was extremely expensive, and HIV/AIDS remained a fatal illness for people living in developing countries. In 2003, governments, international agencies, and funding bodies began to implement plans to increase ART coverage in resource-limited countries. By the end of 2009, about a third of the people in these countries who needed ART (HIV-positive people whose CD4 count had dropped so low that they could not fight other infections) were receiving treatment.
Why Was This Study Done?
Unfortunately, many HIV-positive people in resource-limited countries who receive ART still do not have a normal life expectancy, often because they start ART when they have a very low CD4 count. ART is more successful if it is started before the CD4 count falls far below 350 cells/mm3 of blood, the threshold recommended by the World Health Organization for ART initiation. Thus, if the outcomes of HIV/AIDS programs in resource-limited settings are to be improved, all individuals testing positive for HIV must receive continuous pre-ART care that includes regular CD4 counts to ensure that ART is initiated as soon as they become eligible for treatment. Before interventions can be developed to achieve this aim, it is necessary to understand where and when patients are lost to pre-ART care. In this systematic review (a study that uses predefined criteria to identify all the research on a given topic), the researchers investigate the retention of HIV-positive adults in pre-ART care in sub-Saharan Africa.
What Did the Researchers Do and Find?
The researchers identified 28 studies that included data on the proportion of adult patients retained between any two time points between testing positive for HIV and starting ART in HIV/AIDS care programs in sub-Saharan Africa. They defined three stages of pre-ART care: Stage 1, the interval between testing positive for HIV and receiving CD4 count results or being clinically assessed; Stage 2, the interval between enrollment in pre-ART care and the determination of eligibility for ART; and Stage 3, the interval between being deemed eligible for ART and treatment initiation. A median of 59% of patients were retained in Stage 1 of pre-ART care, 46% were retained in Stage 2, and 68% were retained in Stage 3. Retention rates in each stage differed greatly between studies—between 14% and 84% for Stage 3 pre-ART care, for example. Because the enrollment criteria and other characteristics of the identified studies varied widely and were often poorly defined, it was hard to combine study results. Nevertheless, the researchers estimate that, taking all the studies together, less than one-third of patients testing positive for HIV but not eligible for ART when diagnosed were retained in pre-ART care continuously.
What Do These Findings Mean?
These findings suggest that there is a substantial loss of HIV-positive patients at every stage of pre-ART care in sub-Saharan Africa. Thus, some patients receiving a positive HIV test never return for the results of their initial CD4 count, some disappear between having an initial CD4 count and becoming eligible for ART, and others fail to initiate ART after having been found eligible for treatment. Because only a few studies were identified (half of which were undertaken in South Africa) and because the quality and design of some of these studies were suboptimal, the findings of this systematic review must be treated with caution. In particular, the estimate of the overall loss of patients during pre-ART care is likely to be imprecise. The researchers call, therefore, for the implementation of better health information systems that would allow patients to be tracked between service delivery points as a way to improve the evaluation and understanding of the loss of HIV-positive patients to pre-ART care in resource-limited countries.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001056.
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/AIDS treatment and care, on HIV and AIDS in Africa and on universal access to AIDS treatment (in English and Spanish)
The World Health Organization provides information about universal access to AIDS treatment, including the 2010 progress report (in English, French and Spanish); its 2010 ART guidelines can be downloaded (in several languages)
The International AIDS Economics Network posts information about economic, social, and behavioral aspects of HIV care and treatment
Up-to-date research findings about HIV care and treatment are summarized by NAM/aidsmap
doi:10.1371/journal.pmed.1001056
PMCID: PMC3139665  PMID: 21811403
5.  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
6.  The HIV Treatment Gap: Estimates of the Financial Resources Needed versus Available for Scale-Up of Antiretroviral Therapy in 97 Countries from 2015 to 2020 
PLoS Medicine  2015;12(11):e1001907.
Background
The World Health Organization (WHO) released revised guidelines in 2015 recommending that all people living with HIV, regardless of CD4 count, initiate antiretroviral therapy (ART) upon diagnosis. However, few studies have projected the global resources needed for rapid scale-up of ART. Under the Health Policy Project, we conducted modeling analyses for 97 countries to estimate eligibility for and numbers on ART from 2015 to 2020, along with the facility-level financial resources required. We compared the estimated financial requirements to estimated funding available.
Methods and Findings
Current coverage levels and future need for treatment were based on country-specific epidemiological and demographic data. Simulated annual numbers of individuals on treatment were derived from three scenarios: (1) continuation of countries’ current policies of eligibility for ART, (2) universal adoption of aspects of the WHO 2013 eligibility guidelines, and (3) expanded eligibility as per the WHO 2015 guidelines and meeting the Joint United Nations Programme on HIV/AIDS “90-90-90” ART targets. We modeled uncertainty in the annual resource requirements for antiretroviral drugs, laboratory tests, and facility-level personnel and overhead.
We estimate that 25.7 (95% CI 25.5, 26.0) million adults and 1.57 (95% CI 1.55, 1.60) million children could receive ART by 2020 if countries maintain current eligibility plans and increase coverage based on historical rates, which may be ambitious. If countries uniformly adopt aspects of the WHO 2013 guidelines, 26.5 (95% CI 26.0 27.0) million adults and 1.53 (95% CI 1.52, 1.55) million children could be on ART by 2020. Under the 90-90-90 scenario, 30.4 (95% CI 30.1, 30.7) million adults and 1.68 (95% CI 1.63, 1.73) million children could receive treatment by 2020. The facility-level financial resources needed for scaling up ART in these countries from 2015 to 2020 are estimated to be US$45.8 (95% CI 45.4, 46.2) billion under the current scenario, US$48.7 (95% CI 47.8, 49.6) billion under the WHO 2013 scenario, and US$52.5 (95% CI 51.4, 53.6) billion under the 90-90-90 scenario. After projecting recent external and domestic funding trends, the estimated 6-y financing gap ranges from US$19.8 billion to US$25.0 billion, depending on the costing scenario and the U.S. President’s Emergency Plan for AIDS Relief contribution level, with the gap for ART commodities alone ranging from US$14.0 to US$16.8 billion.
The study is limited by excluding above-facility and other costs essential to ART service delivery and by the availability and quality of country- and region-specific data.
Conclusions
The projected number of people receiving ART across three scenarios suggests that countries are unlikely to meet the 90-90-90 treatment target (81% of people living with HIV on ART by 2020) unless they adopt a test-and-offer approach and increase ART coverage. Our results suggest that future resource needs for ART scale-up are smaller than stated elsewhere but still significantly threaten the sustainability of the global HIV response without additional resource mobilization from domestic or innovative financing sources or efficiency gains. As the world moves towards adopting the WHO 2015 guidelines, advances in technology, including the introduction of lower-cost, highly effective antiretroviral regimens, whose value are assessed here, may prove to be “game changers” that allow more people to be on ART with the resources available.
Arin Dutta and colleagues project global ART-related funding, global ART-related need under established targets, and the gap between the two.
Editors' Summary
Background
AIDS has killed 39 million people since 1981, and over 36 million people (mostly living in resource-limited countries) are currently living with HIV, the virus that causes AIDS. HIV destroys immune system cells (including CD4 lymphocytes), leaving HIV-infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected individuals died within ten years of infection. Then, in 1996, effective antiretroviral therapy (ART) became available. For people living in affluent countries, HIV/AIDS became a chronic condition, but it remained fatal for people living in resource-limited countries. In 2003, the international community began to work towards universal access to ART. Now, more than a third of people living with HIV are receiving ART, and the global death rate from HIV/AIDS is falling. The “90-90-90” targets recently set by UNAIDS—90% of all people living with HIV knowing their status, 90% of all people diagnosed with HIV infection receiving ART, and 90% of all people receiving ART having robust viral suppression by 2020—aim to end the AIDS epidemic by 2030.
Why Was This Study Done?
Because early ART initiation both improves the health of HIV-positive individuals and reduces HIV transmission, the latest WHO guidelines (September 2015) recommend that people living with HIV should initiate ART upon diagnosis, regardless of their CD4 count. Previous WHO guidelines recommended initiating ART in certain populations based on CD4 count; for instance, the 2013 guidelines recommended adults living with HIV start ART only when their CD4 count fell below 500 cells/mm3 blood. Following the latest guidelines and meeting the UNAIDS targets will involve a rapid scale-up of ART, but are the financial resources available for this scale-up? Here, the researchers use mathematical modeling to estimate the numbers of people eligible for and receiving ART in 97 countries from 2015 to 2020 and the facility-level financial resources needed under three ART scale-up scenarios. Facility-level financial resources cover the costs of antiretroviral drugs, laboratory testing, and facility-level personnel and overhead (e.g., utilities, support staff, transportation, and other supplies), but not costs above the facility level or the costs of other services that are often integrated into ART provision. The facility-level ART costs are compared to the estimated financial resources available from domestic and external sources to assess the ART funding gap in the 97 countries.
What Did the Researchers Do and Find?
The researchers estimated current ART coverage levels and future treatment needs using country-specific epidemiological and demographic data for 97 countries. They estimated annual numbers of people eligible for and receiving treatment assuming that countries continued to follow their current criteria for treatment (scenario 1), universally adopted aspects of the WHO 2013 eligibility criteria (scenario 2), or expanded eligibility to meet the WHO 2015 guidelines and the 90-90-90 targets (scenario 3) while increasing the percentage of persons reached based on historical rates. Under scenario 1, 25.7 million adults and 1.57 million children living with HIV could receive ART by 2020. Under scenarios 2 and 3, 26.5 million and 30.4 million adults, respectively, and 1.53 million and 1.68 million children, respectively, could receive ART by 2020. The estimated facility-level financial resources needed for ART scale-up from 2015 to 2020 were US$45.8 billion, US$48.7 billion, and US$52.5 billion under scenarios 1, 2, and 3, respectively. Finally, the estimated gap over six years between the resources needed for ART scale-up and the domestic and external financial resources available ranged from US$19.8 billion to US$25.0 billion depending on the eligibility scenario and the level of ART support provided by PEPFAR (the U.S. President’s Emergency Plan for AIDS Relief) and the Global Fund to Fight AIDS, Tuberculosis and Malaria, two major external ART funding sources.
What Do These Findings Mean?
The accuracy of this study’s findings may be limited by the quality of country- and region-specific data, assumptions made about the funding available for ART, and the fact that only the facility-level costs of ART provision were considered. However, the estimates of the number of people receiving ART by 2020 suggest that countries are unlikely to meet the 90-90-90 treatment target (81% of people living with HIV on ART by 2020; that is, 90% of people living with HIV diagnosed and 90% of diagnosed patients receiving ART) unless countries expand ART access to all people living with HIV and rapidly increase coverage. Moreover, the estimated future resource needs for ART scale-up are large enough to threaten the sustainability of the global response to AIDS unless additional resources are made available through domestic or external financing sources or through efficiency gains. Thus, the researchers conclude, advances in technology and the introduction of new lower-cost antiretroviral regimens could be essential to allow more people to receive ART with the resources available.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001907.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap also provides basic information about HIV/AIDS, summaries of recent research findings on HIV care and treatment, and personal stories about living with HIV/AIDS
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on universal access to ART, the 90-90-90 targets, and starting, monitoring, and switching ART; Avert also provides personal stories about living with HIV/AIDS
WHO provides information on all aspects of HIV/AIDS, including its 2013 ART guidelines and its early-released 2015 ART guidelines
The UNAIDS Fast-Track Strategy to End the AIDS Epidemic by 2030 provides up-to-date information about the AIDS epidemic, including progress towards universal access to ART; UNAIDS also provides detailed information about its 90-90-90 treatment targets
The Health Policy Project examines ways to make existing funds for ART go further and to maximize the effectiveness and efficiency of ART programs; information on PEPFAR and on the Global Fund to Fight AIDS, Tuberculosis and Malaria is available
doi:10.1371/journal.pmed.1001907
PMCID: PMC4658189  PMID: 26599990
7.  Lessons learned from the PMTCT program in Swaziland: challenges with accepting lifelong ART for pregnant and lactating women – a qualitative study 
BMC Public Health  2016;16:1119.
Background
Swaziland has one of the highest HIV prevalence rates in sub-Saharan Africa, 26 % of the adult population is infected with HIV. The prevalence is highest among pregnant women, at 41.1 %. According to Swaziland’s prevention of mother-to-child transmission (PMTCT) guidelines, approximately 50 % of pregnant women are eligible for antiretroviral therapy (ART) by CD4 criteria (<350 cells/ml). Studies have shown that most mother-to-child transmission and postnatal deaths occur among women who are eligible for ART. Therefore, ensuring that ART eligible women are initiated on ART is critical for PMTCT and for mother and baby survival. This study provides insight into the challenges of lifelong ART initiation among pregnant women under Option A in Swaziland. We believe that these challenges and lessons learned from initiating women on lifelong ART under Option A are relevant and important to consider during implementation of Option B+.
Methods
HIV-positive, treatment-eligible, postpartum women and nurses were recruited within maternal and child health (MCH) units using convenience and purposive sampling. Participants came from both urban and rural areas. Focus group discussions (FGDs) and structured interviews using a short answer questionnaire were conducted to gain an understanding of the challenges experienced when initiating lifelong ART. Seven FGDs (of 5–11 participants) were conducted, four FGDs with nurses, two FGDs with women who initiated ART, and one FGD with women who did not initiate ART. A total of 83 interviews were conducted; 50 with women who initiated ART and 33 with women who did not initiate. Data collection with the women was conducted in the local language of SiSwati and data collection with the nurses was done in English. FGDs were audio-recorded and simultaneously transcribed and translated into English. Analysis was conducted using thematic analysis. Transcripts were coded by two researchers in the qualitative software program MAXqda v.10. Thematic findings were illustrated using verbatim quotes which were selected on the basis of being representative of a specific theme. The short-answer interview questionnaire included specific questions about the different steps in the woman’s experience initiating ART; therefore the responses for each question were analyzed separately.
Results
Findings from the study highlight women feeling overwhelmed by the lifetime commitment of ART, feeling “healthy” when asked to initiate ART, preference for short-course prophylaxis and fear of side effects (body changes). Also, the preference for nurses to determine on an individual basis the number of counseling appointments a woman needs before initiating ART, more information about HIV and ART needed at the community level, and the need to educate men about HIV and ART.
Conclusion
Women face a myriad of challenges initiating lifelong ART. Understanding women’s concerns will aid in developing effective counseling messages, designing appropriate counseling structures, understanding where additional support is needed in the process of initiating ART, and knowing who to target for community level messages.
doi:10.1186/s12889-016-3767-5
PMCID: PMC5078916  PMID: 27776495
8.  Evolution of antiretroviral therapy services for HIV-infected pregnant women in Cape Town, South Africa 
Journal of acquired immune deficiency syndromes (1999)  2015;10.1097/QAI.0000000000000584.
Background
Approaches to antiretroviral therapy (ART) in HIV-infected pregnant women have changed considerably in recent years, but there are few comparative data on the implementation of different models of service delivery.
Methods
Using routine clinic records we examined ART initiation in pregnant women attending a large antenatal care (ANC) facility between January 2010 and December 2013 in Cape Town, South Africa. Over this time six different service delivery models were implemented sequentially to provide ART in pregnancy, including the integration of ART into ANC, use of point-of-care CD4 cell count testing, and universal ART initiation for all HIV-infected pregnant women.
Results
During the study period 19,432 women sought ANC, levels of HIV testing were high (98%) and 30% of pregnant women tested HIV-positive. Integration of ART into ANC was associated with significant increases in the proportion of eligible women initiating treatment before delivery compared to referral to a separate ART clinic (p<0.001). When CD4 cell counts were used to determine ART eligibility, point-of-care testing was associated with decreased delays to ART initiation compared to laboratory-based testing (p<0.001). The strategy of universal ART led to the highest levels of ART initiation (with 92% of women starting before delivery) and the shortest delays, with 82% of women starting ART on the day of the first ANC visit.
Conclusion
Developments in service delivery models, most notably service integration and universal ART for pregnant women, have improved antenatal ART initiation dramatically in this setting. Further research is needed into how strategies for antenatal ART initiation impact maternal and child health over the long-term.
doi:10.1097/QAI.0000000000000584
PMCID: PMC4550573  PMID: 25723138
antiretroviral therapy; mother-to-child transmission; pregnancy; antenatal care; service integration; point-of-care CD4; South Africa
9.  Predicting Patterns of Long-Term CD4 Reconstitution in HIV-Infected Children Starting Antiretroviral Therapy in Sub-Saharan Africa: A Cohort-Based Modelling Study 
PLoS Medicine  2013;10(10):e1001542.
Using data from the ARROW trial, Joanna Lewis and colleagues investigate the CD4 cell count recovery profiles of children infected with HIV starting antiretroviral therapy in Sub-Saharan Africa.
Please see later in the article for the Editors' Summary
Background
Long-term immune reconstitution on antiretroviral therapy (ART) has important implications for HIV-infected children, who increasingly survive into adulthood. Children's response to ART differs from adults', and better descriptive and predictive models of reconstitution are needed to guide policy and direct research. We present statistical models characterising, qualitatively and quantitatively, patterns of long-term CD4 recovery.
Methods and Findings
CD4 counts every 12 wk over a median (interquartile range) of 4.0 (3.7, 4.4) y in 1,206 HIV-infected children, aged 0.4–17.6 y, starting ART in the Antiretroviral Research for Watoto trial (ISRCTN 24791884) were analysed in an exploratory analysis supplementary to the trial's pre-specified outcomes. Most (n = 914; 76%) children's CD4 counts rose quickly on ART to a constant age-corrected level. Using nonlinear mixed-effects models, higher long-term CD4 counts were predicted for children starting ART younger, and with higher CD4 counts (p<0.001). These results suggest that current World Health Organization–recommended CD4 thresholds for starting ART in children ≥5 y will result in lower CD4 counts in older children when they become adults, such that vertically infected children who remain ART-naïve beyond 10 y of age are unlikely ever to normalise CD4 count, regardless of CD4 count at ART initiation. CD4 profiles with four qualitatively distinct reconstitution patterns were seen in the remaining 292 (24%) children. Study limitations included incomplete viral load data, and that the uncertainty in allocating children to distinct reconstitution groups was not modelled.
Conclusions
Although younger ART-naïve children are at high risk of disease progression, they have good potential for achieving high CD4 counts on ART in later life provided ART is initiated following current World Health Organization (WHO), Paediatric European Network for Treatment of AIDS, or US Centers for Disease Control and Prevention guidelines. In contrast, to maximise CD4 reconstitution in treatment-naïve children >10 y, ART should ideally be considered even if there is a low risk of immediate disease progression. Further exploration of the immunological mechanisms for these CD4 recovery profiles should help guide management of paediatric HIV infection and optimise children's immunological development.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, about 3.3 million children under 15 years old are infected with HIV, the virus that causes AIDS. More than 90% of these children live in sub-Saharan Africa, where nearly 600 children become infected with HIV every day, usually acquiring the virus from their mother during pregnancy, birth, or breastfeeding. HIV gradually reduces the numbers of CD4 lymphocytes in the immune system, leaving infected individuals susceptible to other infections. HIV infection can be kept in check but not cured with antiretroviral therapy (ART)—cocktails of drugs that have to be taken every day throughout life. ART reduces the amount of virus in the blood (viral load), which allows the immune system to recover (long-term immune reconstitution). Unfortunately, ART is very expensive, but concerted international efforts over the past decade mean that about a third of children who need ART are now receiving it, including half a million children in sub-Saharan Africa.
Why Was This Study Done?
World Health Organization (WHO) guidelines recommend initiation of ART at age-related CD4 cell count thresholds based on the risk of short-term disease progression. The guidelines recommend that all HIV-positive children under two years old begin ART as soon they receive a diagnosis of HIV infection. For children aged 2–5 years, ART initiation is recommended once the CD4 count drops below 750 cells/µl blood, whereas for older children the threshold for ART initiation is 350 CD4 cells/µl. Because of improved ART coverage, many more HIV-infected children now survive into adulthood than in the past. It is therefore important to know how the timing of ART initiation in childhood affects long-term immune reconstitution. Unfortunately, although several studies have examined the effect of ART on immune reconstitution in adults, the results of these studies cannot be extrapolated to children because of age-related differences in immune reconstitution. In this cohort-based modelling study, the researchers investigate long-term CD4 recovery in a cohort (group) of HIV-infected children initiating ART in Uganda and Zimbabwe, and present statistical models that predict patterns of long-term CD4 status based on age and CD4 count at ART initiation.
What Did the Researchers Do and Find?
To investigate long-term CD4 reconstitution in children, the researchers used CD4 counts collected during the ARROW trial, a study designed to investigate monitoring strategies during first-line ART in 1,206 HIV-positive children. In three-quarters of the children, CD4 reconstitution following ART initiation was asymptotic—CD4 counts increased rapidly immediately after ART initiation, then slowed before eventually reaching a constant level of about 80% of the CD4 count expected in an uninfected child of the same age. Using a nonlinear mixed-effects statistical model that fitted this pattern of immune reconstitution, the researchers predicted CD4 trajectories for children starting ART at different ages and with different CD4 counts. Higher long-term counts were predicted for children starting ART earlier and with higher CD4 counts. Thus, to achieve a CD4 count greater than 700 cells/µl at age 20 years, CD4 counts of at least 96 cells/µl, 130 cells/µl, and 557 cells/µl are needed for children aged two, five, and 12 years, respectively, when they initiate ART. Qualitatively distinct reconstitution patterns were seen in the remaining children in the study.
What Do These Findings Mean?
These findings suggest that young HIV-positive, ART-naïve children can achieve high CD4 counts in later life, provided ART is initiated as recommended in the current WHO guidelines. However, the recommended CD4 count thresholds for ART initiation are unlikely to maximize immune reconstitution in treatment-naïve children over ten years old. Rather, these findings suggest that ART initiation should be considered in these older children when their CD4 count is still high—even though they have a low risk of immediate disease progression—in order to achieve higher long-term CD4 levels. The omission of viral load measurements in the researchers' model may limit the accuracy of these findings. Moreover, although the predictions made by the model apply to children who will go on to experience asymptotic recovery, they are less relevant to those with different recovery profiles, who cannot currently be accurately identified. Further exploration of the immunological mechanisms underlying the CD4 recovery profiles described here should improve our understanding of the factors that determine the response of HIV-positive children to ART and provide information to guide the management of HIV infections in children.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001542.
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
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 HIV infection in children (in English and Spanish)
The UNAIDS World AIDS Day Report 2012 provides up-to-date information about the AIDS epidemic and efforts to halt it; the UNAIDS's 2013 Progress Report on the Global Plan provides information on progress towards eliminating new HIV infections among children by 2015
The World Health Organization provides information about universal access to AIDS treatment (in several languages); its 2010 guidelines for ART in infants and children can be downloaded
Information about the ARROW trial is available
Personal stories about living with HIV/AIDS, including stories from young people infected with HIV, are available through Avert, through Nam/aidsmap, and through the charity website Healthtalkonline
doi:10.1371/journal.pmed.1001542
PMCID: PMC3812080  PMID: 24204216
10.  Early and Late Direct Costs in a Southern African Antiretroviral Treatment Programme: A Retrospective Cohort Analysis 
PLoS Medicine  2009;6(12):e1000189.
Gary Maartens and colleagues describe the direct heath care costs and identify the drivers of cost over time in an HIV managed care program in Southern Africa.
Background
There is a paucity of data on the health care costs of antiretroviral therapy (ART) programmes in Africa. Our objectives were to describe the direct heath care costs and establish the cost drivers over time in an HIV managed care programme in Southern Africa.
Methods/Findings
We analysed the direct costs of treating HIV-infected adults enrolled in the managed care programme from 3 years before starting non-nucleoside reverse transcriptase inhibitor-based ART up to 5 years afterwards. The CD4 cell count criterion for starting ART was <350 cells/µl. We explored associations between variables and mean total costs over time using a generalised linear model with a log-link function and a gamma distribution. Our cohort consisted of 10,735 patients (59.4% women) with 594,497 mo of follow up data (50.9% of months on ART). Median baseline CD4+ cell count and viral load were 125 cells/µl and 5.16 log10 copies/ml respectively. There was a peak in costs in the period around ART initiation (from 4 mo before until 4 mo after starting ART) driven largely by hospitalisation, following which costs plateaued for 5 years. The variables associated with changes in mean total costs varied with time. Key early associations with higher costs were low baseline CD4+ cell count, high baseline HIV viral load, and shorter duration in HIV care prior to starting ART; whilst later associations with higher costs were lower ART adherence, switching to protease inhibitor-based ART, and starting ART at an older age.
Conclusions
Drivers of mean total costs changed considerably over time. Starting ART at higher CD4 counts or longer pre-ART care should reduce early costs. Monitoring ART adherence and interventions to improve it should reduce later costs. Cost models of ART should take into account these time-dependent cost drivers, and include costs before starting ART.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 30 million people (22 million people in sub-Saharan Africa alone) are infected with the human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS). HIV destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, on average HIV-positive people died within 10 years of infection. Then, in 1996, highly active antiretroviral therapy (ART; combinations of powerful antiretroviral drugs) was developed. For people living in affluent, developed countries HIV/AIDS became a chronic, treatable condition, but for the millions of HIV-infected people living in low- and middle-income countries, effective treatment was unavailable and HIV/AIDS remained a fatal illness. In 2003, this situation was declared a global health emergency and governments, international agencies, and funding bodies began to implement plans to increase ART coverage in developing countries. By the end of 2008, of the 9.5 million people in need of ART in low- and middle-income countries, more than 4 million people were receiving treatment.
Why Was This Study Done?
Good progress is being made towards achieving universal access to ART, partly because the cost of antiretroviral drugs has plummeted in developing countries. But the provision of antiretroviral drugs is not the only direct cost associated with ART. General practitioner, specialist, and maternity-related care for patients receiving ART, hospital accommodation when necessary, and the investigations that are needed to monitor the progress of HIV infection such as CD4 cell counts and viral load measurements all incur considerable costs. To use their limited resources effectively, public-health officials in developing countries need to know as much as possible about the direct costs of HIV health care but few studies have investigated these costs, particularly those incurred before an individual starts taking ART. In this study, the researchers explore health care costs in a South African private-sector HIV/AIDS program and examine the variables that drive the costs of HIV health care around the time of ART initiation and during later phases of ART.
What Did the Researchers Do and Find?
The researchers analyzed the direct costs of treating more than 100,000 HIV-infected adults enrolled in a private HIV care program in South Africa from 3 years before they started ART until up to 5 years after ART initiation; within this program, individuals began to receive ART when their CD4 cell count fell below 350 cells/µl of blood. The researchers found a peak in direct health costs from 4 months before to 4 months after starting ART (the “peri-ART” period), which was driven mainly by hospital costs. After the peri-ART period, costs dropped (although not to the levels seen before this period) and stabilized at an intermediate level for the next 5 years. Detailed statistical analyses suggest that the key variables associated with higher costs in the peri-ART period were a low baseline CD4 cell count, a high baseline HIV viral load, and a shorter time in HIV care before ART initiation. The key variable associated with higher costs later in ART was lower adherence to the drug therapy. That is, costs were higher among patients who did not take their antiretroviral drugs regularly.
What Do These Findings Mean?
This study involved patients enrolled in a private health care program in which the criteria for initiating ART differed somewhat from those recommended by the World Health Organization for ART initiation in resource-limited settings. Thus, the absolute mean total costs calculated by the researchers are unlikely to be generalizable to public HIV care systems in South Africa and in other resource-poor settings. However, the finding that the drivers of mean total costs change considerably over time may be generalizable and provides some useful information for public-health planners that can now be tested in other, more resource-limited patient populations. In particular, the findings of this study suggest that the high early costs of ART programs could be reduced by starting ART at higher CD4 cell counts or by providing longer pre-ART care. In addition, the findings suggest that monitoring ART adherence and introducing interventions to improve ART adherence could reduce the later direct costs of ART programs.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000189.
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 the HIV and AIDS in Africa, and on universal access to AIDS treatment (in English and Spanish)
The World Health Organization provides information about universal access to AIDS treatment, including the September 2009 progress report (in English and French)
The US Centers for Disease Control and Prevention also provides information on global efforts to deal with the HIV/AIDS epidemic
doi:10.1371/journal.pmed.1000189
PMCID: PMC2777319  PMID: 19956658
11.  HIV Shedding from Male Circumcision Wounds in HIV-Infected Men: A Prospective Cohort Study 
PLoS Medicine  2015;12(4):e1001820.
Background
A randomized trial of voluntary medical male circumcision (MC) of HIV—infected men reported increased HIV transmission to female partners among men who resumed sexual intercourse prior to wound healing. We conducted a prospective observational study to assess penile HIV shedding after MC.
Methods and Findings
HIV shedding was evaluated among 223 HIV—infected men (183 self—reported not receiving antiretroviral therapy [ART], 11 self—reported receiving ART and had a detectable plasma viral load [VL], and 29 self—reported receiving ART and had an undetectable plasma VL [<400 copies/ml]) in Rakai, Uganda, between June 2009 and April 2012. Preoperative and weekly penile lavages collected for 6 wk and then at 12 wk were tested for HIV shedding and VL using a real—time quantitative PCR assay. Unadjusted prevalence risk ratios (PRRs) and adjusted PRRs (adjPRRs) of HIV shedding were estimated using modified Poisson regression with robust variance. HIV shedding was detected in 9.3% (17/183) of men not on ART prior to surgery and 39.3% (72/183) of these men during the entire study. Relative to baseline, the proportion shedding was significantly increased after MC at 1 wk (PRR = 1.87, 95% CI = 1.12–3.14, p = 0.012), 2 wk (PRR = 3.16, 95% CI = 1.94–5.13, p < 0.001), and 3 wk (PRR = 1.98, 95% CI = 1.19–3.28, p = 0.008) after MC. However, compared to baseline, HIV shedding was decreased by 6 wk after MC (PRR = 0.27, 95% CI = 0.09–0.83, p = 0.023) and remained suppressed at 12 wk after MC (PRR = 0.19, 95% CI = 0.06–0.64, p = 0.008). Detectable HIV shedding from MC wounds occurred in more study visits among men with an HIV plasma VL > 50,000 copies/ml than among those with an HIV plasma VL < 400 copies/ml (adjPRR = 10.3, 95% CI = 4.25–24.90, p < 0.001). Detectable HIV shedding was less common in visits from men with healed MC wounds compared to visits from men without healed wounds (adjPRR = 0.12, 95% CI = 0.07–0.23, p < 0.001) and in visits from men on ART with undetectable plasma VL compared to men not on ART (PRR = 0.15, 95% CI = 0.05–0.43, p = 0.001). Among men with detectable penile HIV shedding, the median log10 HIV copies/milliliter of lavage fluid was significantly lower in men with ART—induced undetectable plasma VL (1.93, interquartile range [IQR] = 1.83–2.14) than in men not on ART (2.63, IQR = 2.28–3.22, p < 0.001). Limitations of this observational study include significant differences in baseline covariates, lack of confirmed receipt of ART for individuals who reported ART use, and lack of information on potential ART initiation during follow—up for those who were not on ART at enrollment.
Conclusion
Penile HIV shedding is significantly reduced after healing of MC wounds. Lower plasma VL is associated with decreased frequency and quantity of HIV shedding from MC wounds. Starting ART prior to MC should be considered to reduce male-to-female HIV transmission risk. Research is needed to assess the time on ART required to decrease shedding, and the acceptability and feasibility of initiating ART at the time of MC.
In this prospective cohort study, Aaron Tobian and colleagues examine the associations between male circumcision wound healing, as well as plasma viral load, and HIV shedding from male circumcision wounds.
Editors' Summary
Background
About 35 million people are currently infected with HIV, the virus that causes AIDS by destroying immune system cells, and every year, 2 million more people become HIV-positive. Antiretroviral therapy (ART) can keep HIV in check, but there is no cure for AIDS. Consequently, prevention of HIV acquisition and transmission is an important component of efforts to control the AIDS epidemic. Because HIV is most often spread through unprotected sex with an infected partner, individuals can reduce their risk of becoming HIV-positive by abstaining from sex, by having only one or a few partners, and by using male or female condoms. In addition, three trials undertaken in sub-Saharan Africa a decade ago showed that male circumcision—the surgical removal of the foreskin, a loose fold of skin that covers the head of the penis—can halve the HIV acquisition rate in men. Thus, since 2007, the World Health Organization (WHO) has recommended voluntary medical male circumcision for individuals living in countries with high HIV prevalence as part of its HIV prevention strategy.
Why Was This Study Done?
With the rollout of voluntary medical male circumcision programs, circumcision has become more normative (regarded as acceptable), and HIV-positive men are increasingly requesting circumcision because they want to avoid any stigma associated with being uncircumcised and because circumcision provides health benefits. WHO recommends that, although circumcision should not be promoted for HIV-positive men, voluntary circumcision programs should operate on HIV-positive men if they request circumcision. However, in a trial of circumcision of HIV-infected men, HIV transmission to their female partners increased if the couples had sexual intercourse before the circumcision wound had healed. Moreover, in studies of current male circumcision programs, two-thirds of married men and a third of all men reported that they resumed sexual intercourse before their circumcision wounds had healed. Thus, better understanding of how male circumcision increases HIV transmission to female partners is essential, and improved ways to prevent transmission in the post-surgical period are needed. Here, in a prospective observational study (an investigation that collects data over time from people undergoing a specific procedure), the researchers assess HIV shedding from the penis after circumcision.
What Did the Researchers Do and Find?
The researchers evaluated penile HIV shedding among 223 HIV-infected men (183 men who self-reported not being on ART and 40 men who self-reported being on ART, 29 of whom had no detectable virus in their blood) living in Rakai, Uganda, by examining preoperative and postoperative penile lavage (wash) samples. Viral shedding was detected in 9.3% of the men not on ART before surgery and in 39.3% of these men during the entire study. Relative to baseline, a greater proportion of men shed virus at one, two, and three weeks after circumcision, but a lower proportion shed virus at six and twelve weeks after circumcision. HIV shedding was more frequent among men with a high amount of virus in their blood (a high viral load) than among men with a low viral load. Moreover, the frequency of HIV shedding was lower in visits from men with healed circumcision wounds than in visits from men with unhealed wounds, and in visits from men on ART with no detectable virus in their blood than in visits from men not on ART men. Finally, among men with detectable penile HIV shedding, men on ART with no detectable virus in their blood shed fewer copies of virus than men not on ART.
What Do These Findings Mean?
The findings suggest that healed circumcision wounds are associated with reduced penile HIV shedding in HIV-positive men compared to unhealed circumcision wounds and HIV shedding prior to circumcision In addition, they suggest that a lower HIV viral load in the blood is associated with a decreased frequency and quantity of HIV shedding from circumcision wounds. Because this was an observational study, these findings cannot prove that healed wounds or reduced blood viral load actually caused reduced penile HIV shedding. Moreover, the accuracy of these findings may be affected by the lack of information on ART initiation during follow-up among men not initially on ART and by reliance on ART self-report. Nevertheless, these findings highlight the importance of counseling HIV-positive men undergoing circumcision to avoid sexual intercourse until their circumcision wound heals. In addition, these findings suggest that it might be possible to reduce HIV transmission among HIV-positive men immediately after circumcision by starting these individuals on ART before circumcision. Further research is needed to assess how long before circumcision ART should be initiated and to assess the acceptability and feasibility of initiating ART concurrent with circumcision.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001820.
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, information on male circumcision for the prevention of HIV transmission, and personal stories about living with HIV/AIDS
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on HIV prevention, on voluntary medical male circumcision for HIV prevention, and on HIV/AIDS in sub-Saharan Africa; Avert also provides personal stories about living with HIV/AIDS
The World Health Organization provides information on all aspects of HIV/AIDS (in several languages), including on voluntary medical male circumcision for HIV prevention
The UNAIDS Fast-Track Strategy to End the AIDS Epidemic by 2030 provides up-to-date information about the AIDS epidemic and efforts to halt it
The Clearinghouse on Male Circumcision for HIV Prevention provides up-to-date information and resources on male circumcision for HIV prevention
doi:10.1371/journal.pmed.1001820
PMCID: PMC4412625  PMID: 25919012
12.  Gender Differences in Survival among Adult Patients Starting Antiretroviral Therapy in South Africa: A Multicentre Cohort Study 
PLoS Medicine  2012;9(9):e1001304.
Morna Cornell and colleagues investigate differences in mortality for HIV-positive men and women on antiretroviral therapy in South Africa.
Background
Increased mortality among men on antiretroviral therapy (ART) has been documented but remains poorly understood. We examined the magnitude of and risk factors for gender differences in mortality on ART.
Methods and Findings
Analyses included 46,201 ART-naïve adults starting ART between January 2002 and December 2009 in eight ART programmes across South Africa (SA). Patients were followed from initiation of ART to outcome or analysis closure. The primary outcome was mortality; secondary outcomes were loss to follow-up (LTF), virologic suppression, and CD4+ cell count responses. Survival analyses were used to examine the hazard of death on ART by gender. Sensitivity analyses were limited to patients who were virologically suppressed and patients whose CD4+ cell count reached >200 cells/µl. We compared gender differences in mortality among HIV+ patients on ART with mortality in an age-standardised HIV-negative population.
Among 46,201 adults (65% female, median age 35 years), during 77,578 person-years of follow-up, men had lower median CD4+ cell counts than women (85 versus 110 cells/µl, p<0.001), were more likely to be classified WHO stage III/IV (86 versus 77%, p<0.001), and had higher mortality in crude (8.5 versus 5.7 deaths/100 person-years, p<0.001) and adjusted analyses (adjusted hazard ratio [AHR] 1.31, 95% CI 1.22–1.41). After 36 months on ART, men were more likely than women to be truly LTF (AHR 1.20, 95% CI 1.12–1.28) but not to die after LTF (AHR 1.04, 95% CI 0.86–1.25). Findings were consistent across all eight programmes. Virologic suppression was similar by gender; women had slightly better immunologic responses than men. Notably, the observed gender differences in mortality on ART were smaller than gender differences in age-standardised death rates in the HIV-negative South African population. Over time, non-HIV mortality appeared to account for an increasing proportion of observed mortality. The analysis was limited by missing data on baseline HIV disease characteristics, and we did not observe directly mortality in HIV-negative populations where the participating cohorts were located.
Conclusions
HIV-infected men have higher mortality on ART than women in South African programmes, but these differences are only partly explained by more advanced HIV disease at the time of ART initiation, differential LTF and subsequent mortality, and differences in responses to treatment. The observed differences in mortality on ART may be best explained by background differences in mortality between men and women in the South African population unrelated to the HIV/AIDS epidemic.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
About 34 million people (most living in low- and middle-income countries) are currently infected with HIV, the virus that causes AIDS. HIV destroys CD4 lymphocytes and other immune system cells, leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected people died within 10 years of becoming infected. Then, in 1996, antiretroviral therapy (ART)—cocktails of drugs that keep HIV in check—became available. For people living in affluent countries, HIV/AIDS became a chronic condition. However, ART was expensive and, for people living in poorer countries, HIV/AIDS remained a fatal illness. In 2003, this situation was declared a global emergency, and governments and international agencies began to implement plans to increase ART coverage in resource-limited countries. Since then, ART programs in these countries have grown rapidly. In South Africa, for example, about 52% of the 3.14 million adults in need of ART were receiving an ART regimen recommended by the World Health Organization by the end of 2010.
Why Was This Study Done?
The outcomes of ART programs in resource-limited countries need to be evaluated thoroughly so that these programs can be optimized. One area of concern to ART providers is that of gender differences in survival among patients receiving treatment. In sub-Saharan Africa, for example, men are more likely to die than women while receiving ART. This gender difference in mortality may arise because men initiating ART in many African ART programs have more advanced HIV disease than women (early ART initiation is associated with better outcomes than late initiation) or because men are more likely to be lost to follow-up than women (failure to continue treatment is associated with death). Other possible explanations for gender differentials in mortality on ART include gender differences in immunologic and virologic responses to treatment (increased numbers of immune system cells and reduced amounts of virus in the blood, respectively). In this multicenter cohort study, the researchers examine the size of, and risk factors for, gender differences in mortality on ART in South Africa by examining data collected from adults starting ART at International Epidemiologic Databases to Evaluate AIDS South Africa (IeDEA-SA) collaboration sites.
What Did the Researchers Do and Find?
The researchers analyzed data collected from 46,201 ART-naïve adults who started ART between 2002 and 2009 in eight IeDEA-SA ART programs. At ART initiation, men had a lower CD4 count on average and were more likely to have advanced HIV disease than women. During the study, after allowing for factors likely to affect mortality such as HIV disease stage at initiation, men on ART had a 31% higher risk of dying than women. Men were more likely to be lost to follow-up than women, but men and women who were lost to follow-up were equally likely to die. Women had a slightly better immunological response to ART than men but virologic suppression was similar in both genders. Importantly, in analyses of mortality limited to individuals who were virologically suppressed at 12 months and to patients who had a good immunological response to ART, men still had a higher risk of death than women. However, the gender differences in mortality on ART were smaller than the gender differences in age-standardized mortality in the HIV-negative South African population.
What Do These Findings Mean?
These analyses show that among South African patients initiating ART between 2002 and 2009, men were more likely to die than women but that this gender difference in mortality on ART cannot be completely explained by gender differences in baseline characteristics, loss to follow-up, or virologic and/or immunologic responses. Instead, the observed gender differences in mortality can best be explained by background gender differences in mortality in the whole South African population. Because substantial amounts of data were missing in this study (for example, HIV disease stage was not available for all the patients), these findings need to be interpreted cautiously. Moreover, similar studies need to be done in other settings to investigate whether they are generalizable to the South African national ART program and to other countries. If confirmed, however, these findings suggest that the root causes of gender differences in mortality on ART may be unrelated to HIV/AIDS or to the characteristics of ART programs.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001304.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
Information on the treatment of HIV/AIDS in South Africa is available from the Southern African HIV Clinicians Society
NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on HIV/AIDS treatment and care, and on HIV/AIDS in South Africa (in English and Spanish)
WHO provides information about universal access to AIDS treatment (in several languages); its 2010 ART guidelines can be downloaded
Information about the IeDEA-SA collaboration is available
The Treatment Action Campaign provides information on antiretroviral therapy and South African HIV statistics
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.1001304
PMCID: PMC3433409  PMID: 22973181
13.  HIV Treatment as Prevention: Systematic Comparison of Mathematical Models of the Potential Impact of Antiretroviral Therapy on HIV Incidence in South Africa 
PLoS Medicine  2012;9(7):e1001245.
Background
Many mathematical models have investigated the impact of expanding access to antiretroviral therapy (ART) on new HIV infections. Comparing results and conclusions across models is challenging because models have addressed slightly different questions and have reported different outcome metrics. This study compares the predictions of several mathematical models simulating the same ART intervention programmes to determine the extent to which models agree about the epidemiological impact of expanded ART.
Methods and Findings
Twelve independent mathematical models evaluated a set of standardised ART intervention scenarios in South Africa and reported a common set of outputs. Intervention scenarios systematically varied the CD4 count threshold for treatment eligibility, access to treatment, and programme retention. For a scenario in which 80% of HIV-infected individuals start treatment on average 1 y after their CD4 count drops below 350 cells/µl and 85% remain on treatment after 3 y, the models projected that HIV incidence would be 35% to 54% lower 8 y after the introduction of ART, compared to a counterfactual scenario in which there is no ART. More variation existed in the estimated long-term (38 y) reductions in incidence. The impact of optimistic interventions including immediate ART initiation varied widely across models, maintaining substantial uncertainty about the theoretical prospect for elimination of HIV from the population using ART alone over the next four decades. The number of person-years of ART per infection averted over 8 y ranged between 5.8 and 18.7. Considering the actual scale-up of ART in South Africa, seven models estimated that current HIV incidence is 17% to 32% lower than it would have been in the absence of ART. Differences between model assumptions about CD4 decline and HIV transmissibility over the course of infection explained only a modest amount of the variation in model results.
Conclusions
Mathematical models evaluating the impact of ART vary substantially in structure, complexity, and parameter choices, but all suggest that ART, at high levels of access and with high adherence, has the potential to substantially reduce new HIV infections. There was broad agreement regarding the short-term epidemiologic impact of ambitious treatment scale-up, but more variation in longer term projections and in the efficiency with which treatment can reduce new infections. Differences between model predictions could not be explained by differences in model structure or parameterization that were hypothesized to affect intervention impact.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Following the first reported case of AIDS in 1981, the number of people infected with HIV, the virus that causes AIDS, increased rapidly. In recent years, the number of people becoming newly infected has declined slightly, but the virus continues to spread at unacceptably high levels. In 2010 alone, 2.7 million people became HIV-positive. HIV, which is usually transmitted through unprotected sex, destroys CD4 lymphocytes and other immune system cells, leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, half of HIV-infected people died within eleven years of infection. Then, in 1996, antiretroviral therapy (ART) became available, and, for people living in affluent countries, HIV/AIDS gradually became considered a chronic condition. But because ART was expensive, for people living in developing countries HIV/AIDS remained a fatal condition. Roll-out of ART in developing countries first started in the early 2000s. In 2006, the international community set a target of achieving universal ART coverage by 2010. Although this target has still 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 ART.
Why Was This Study Done?
Several studies suggest that ART, in addition to reducing illness and death among HIV-positive people, reduces HIV transmission. Consequently, there is interest in expanding the provision of ART as a strategy for reducing the spread of HIV (“HIV treatment as prevention"), particularly in sub-Saharan Africa, where one in 20 adults is HIV-positive. It is important to understand exactly how ART might contribute to averting HIV transmission. Several mathematical models that simulate HIV infection and disease progression have been developed to investigate the impact of expanding access to ART on the incidence of HIV (the number of new infections occurring in a population over a year). But, although all these models predict that increased ART coverage will have epidemiologic (population) benefits, they vary widely in their estimates of the magnitude of these benefits. In this study, the researchers systematically compare the predictions of 12 mathematical models of the HIV epidemic in South Africa, simulating the same ART intervention programs to determine the extent to which different models agree about the impact of expanded ART.
What Did the Researchers Do and Find?
The researchers invited groups who had previously developed mathematical models of the epidemiological impact of expanded access to ART in South Africa to participate in a systematic comparison exercise in which their models were used to simulate ART scale-up scenarios in which the CD4 count threshold for treatment eligibility, access to treatment, and retention on treatment were systematically varied. To exclude variation resulting from different model assumptions about the past and current ART program, it was assumed that ART is introduced into the population in the year 2012, with no treatment provision prior to this, and interventions were evaluated in comparison to an artificial counterfactual scenario in which no treatment is provided. A standard scenario based on the World Health Organization's recommended threshold for initiation of ART, although unrepresentative of current provision in South Africa, was used to compare the models. In this scenario, 80% of HIV-infected individuals received treatment, they started treatment on average a year after their CD4 count dropped below 350 cells per microliter of blood, and 85% remained on treatment after three years. The models predicted that, with a start point of 2012, the HIV incidence would be 35%–54% lower in 2020 and 32%–74% lower in 2050 compared to a counterfactual scenario where there was no ART. Estimates of the number of person-years of ART needed per infection averted (the efficiency with which ART reduced new infections) ranged from 6.3–18.7 and from 4.5–20.2 over the periods 2012–2020 and 2012–2050, respectively. Finally, estimates of the impact of ambitious interventions (for example, immediate treatment of all HIV-positive individuals) varied widely across the models.
What Do These Findings Mean?
Although the mathematical models used in this study had different characteristics, all 12 predict that ART, at high levels of access and adherence, has the potential to reduce new HIV infections. However, although the models broadly agree about the short-term epidemiologic impact of treatment scale-up, their longer-term projections (including whether ART alone can eliminate HIV infection) and their estimates of the efficiency with which ART can reduce new infections vary widely. Importantly, it is possible that all these predictions will be wrong—all the models may have excluded some aspect of HIV transmission that will be found in the future to be crucial. Finally, these findings do not aim to indicate which specific ART interventions should be used to reduce the incidence of HIV. Rather, by comparing the models that are being used to investigate the feasibility of “HIV treatment as prevention," these findings should help modelers and policy-makers think critically about how the assumptions underlying these models affect the models' predictions.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001245.
This study is part of the July 2012 PLoS Medicine Collection, Investigating the Impact of Treatment on New HIV Infections
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
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on HIV/AIDS treatment and care, on HIV treatment as prevention, and on HIV/AIDS in South Africa (in English and Spanish)
The World Health Organization provides information about universal access to AIDS treatment (in English, French, and Spanish); its 2010 ART guidelines can be downloaded
The HIV Modelling Consortium aims to improve scientific support for decision-making by coordinating mathematical modeling of the HIV epidemic
Patient stories about living with HIV/AIDS are available through Avert; the charity 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.1001245
PMCID: PMC3393664  PMID: 22802730
14.  Uptake of Home-Based HIV Testing, Linkage to Care, and Community Attitudes about ART in Rural KwaZulu-Natal, South Africa: Descriptive Results from the First Phase of the ANRS 12249 TasP Cluster-Randomised Trial 
PLoS Medicine  2016;13(8):e1002107.
Background
The 2015 WHO recommendation of antiretroviral therapy (ART) for all immediately following HIV diagnosis is partially based on the anticipated impact on HIV incidence in the surrounding population. We investigated this approach in a cluster-randomised trial in a high HIV prevalence setting in rural KwaZulu-Natal. We present findings from the first phase of the trial and report on uptake of home-based HIV testing, linkage to care, uptake of ART, and community attitudes about ART.
Methods and Findings
Between 9 March 2012 and 22 May 2014, five clusters in the intervention arm (immediate ART offered to all HIV-positive adults) and five clusters in the control arm (ART offered according to national guidelines, i.e., CD4 count ≤ 350 cells/μl) contributed to the first phase of the trial. Households were visited every 6 mo. Following informed consent and administration of a study questionnaire, each resident adult (≥16 y) was asked for a finger-prick blood sample, which was used to estimate HIV prevalence, and offered a rapid HIV test using a serial HIV testing algorithm. All HIV-positive adults were referred to the trial clinic in their cluster. Those not linked to care 3 mo after identification were contacted by a linkage-to-care team. Study procedures were not blinded.
In all, 12,894 adults were registered as eligible for participation (5,790 in intervention arm; 7,104 in control arm), of whom 9,927 (77.0%) were contacted at least once during household visits. HIV status was ever ascertained for a total of 8,233/9,927 (82.9%), including 2,569 ascertained as HIV-positive (942 tested HIV-positive and 1,627 reported a known HIV-positive status). Of the 1,177 HIV-positive individuals not previously in care and followed for at least 6 mo in the trial, 559 (47.5%) visited their cluster trial clinic within 6 mo. In the intervention arm, 89% (194/218) initiated ART within 3 mo of their first clinic visit. In the control arm, 42.3% (83/196) had a CD4 count ≤ 350 cells/μl at first visit, of whom 92.8% initiated ART within 3 mo. Regarding attitudes about ART, 93% (8,802/9,460) of participants agreed with the statement that they would want to start ART as soon as possible if HIV-positive. Estimated baseline HIV prevalence was 30.5% (2,028/6,656) (95% CI 25.0%, 37.0%). HIV prevalence, uptake of home-based HIV testing, linkage to care within 6 mo, and initiation of ART within 3 mo in those with CD4 count ≤ 350 cells/μl did not differ significantly between the intervention and control clusters. Selection bias related to noncontact could not be entirely excluded.
Conclusions
Home-based HIV testing was well received in this rural population, although men were less easily contactable at home; immediate ART was acceptable, with good viral suppression and retention. However, only about half of HIV-positive people accessed care within 6 mo of being identified, with nearly two-thirds accessing care by 12 mo. The observed delay in linkage to care would limit the individual and public health ART benefits of universal testing and treatment in this population.
Trial registration
ClinicalTrials.gov NCT01509508
Collins Iwuji and colleagues report implementation indicators and early health outcomes from the first phase of a cluster-randomized trial of immediate antiretroviral therapy to all HIV-positive individuals in rural KwaZulu-Natal, South Africa.
Author Summary
Why Was This Study Done?
A study in stable sexual partners in which one partner was HIV-positive and the other partner was HIV-negative (and both partners had disclosed to each other) showed that if the HIV-positive partner was on antiretroviral therapy, there was a 96% reduction in HIV transmission from the HIV-positive partner to the HIV-negative partner.
However, we do not know if antiretroviral therapy prescribed to HIV-positive individuals in the general population—and where individuals might not disclose their HIV status to sexual partners—would have a similar impact on HIV transmission.
It is important to determine whether prescribing antiretroviral therapy to all HIV-positive individuals is more effective at decreasing HIV transmission than starting individuals on antiretroviral therapy only once their HIV has progressed to the point at which local HIV treatment guidelines currently recommend that HIV-positive individuals start treatment.
What Did the Researchers Do and Find?
We designed an experiment to investigate whether antiretroviral therapy can reduce new HIV infections in the general population, and piloted the trial in ten communities in KwaZulu-Natal, South Africa, to check whether starting HIV-positive individuals on antiretroviral therapy directly after diagnosis is feasible and acceptable.
We visited people in their homes, offered HIV rapid tests every six months to all individuals 16 years and older, and referred identified HIV-positive individuals to trial clinics, where they were offered antiretroviral therapy either regardless of their CD4 count (intervention group) or when they were treatment-eligible per current national guidelines (control group).
During the two-year study, we contacted 9,927 (77%) of 12,894 eligible individuals and ascertained the HIV status of 80% of contacted women and 75% of contacted men.
HIV-positive status was ascertained for 1,339 adults who were not previously in care; 1,177 were followed in the trial at least 6 mo after referral, of whom 559 (47.5%) engaged with care within this period.
What Do These Findings Mean?
Our findings show good acceptance of home-based HIV testing in rural South Africa but highlight the challenges in reaching adequate numbers of people to offer HIV tests to, especially among men.
We also found that linkage to care was slower than expected, but amongst those who reached the clinics, uptake of antiretroviral therapy was high, with the majority of individuals achieving good control of the virus.
Our study informs health care professionals, planners, and policy makers about the challenges that need to be addressed to achieve the UNAIDS target of 90% of people living with HIV aware of their HIV diagnosis, 90% on antiretroviral therapy, and 90% achieving good control of the virus, with testing and treatment offered to all.
doi:10.1371/journal.pmed.1002107
PMCID: PMC4978506  PMID: 27504637
15.  Effectiveness of Non-nucleoside Reverse-Transcriptase Inhibitor-Based Antiretroviral Therapy in Women Previously Exposed to a Single Intrapartum Dose of Nevirapine: A Multi-country, Prospective Cohort Study 
PLoS Medicine  2010;7(2):e1000233.
In a comparative cohort study, Jeffrey Stringer and colleagues investigate the risk of ART failure in women who received single-dose nevirapine for PMTCT, and assess the duration of increased risk.
Background
Intrapartum and neonatal single-dose nevirapine (NVP) reduces the risk of mother-to-child HIV transmission but also induces viral resistance to non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs. This drug resistance largely fades over time. We hypothesized that women with a prior single-dose NVP exposure would have no more than a 10% higher cumulative prevalence of failure of their NNRTI-containing antiretroviral therapy (ART) over the first 48 wk of therapy than would women without a prior exposure.
Methods and Findings
We enrolled 355 NVP-exposed and 523 NVP-unexposed women at two sites in Zambia, one site in Kenya, and two sites in Thailand into a prospective, non-inferiority cohort study and followed them for 48 wk on ART. Those who died, discontinued NNRTI-containing ART, or had a plasma viral load ≥400 copies/ml at either the 24 wk or 48 wk study visits and confirmed on repeat testing were characterized as having failed therapy. Overall, 114 of 355 NVP-exposed women (32.1%) and 132 of 523 NVP-unexposed women (25.2%) met criteria for treatment failure. The difference in failure rates between the exposure groups was 6.9% (95% confidence interval [CI] 0.8%–13.0%). The failure rates of women stratified by our predefined exposure interval categories were as follows: 47 of 116 women in whom less than 6 mo elapsed between exposure and starting ART failed therapy (40%; p<0.001 compared to unexposed women); 25 of 67 women in whom 7–12 mo elapsed between exposure and starting ART failed therapy (37%; p = 0.04 compared to unexposed women); and 42 of 172 women in whom more than 12 mo elapsed between exposure and starting ART failed therapy (24%; p = 0.82 compared to unexposed women). Locally weighted regression analysis also indicated a clear inverse relationship between virologic failure and the exposure interval.
Conclusions
Prior exposure to single-dose NVP was associated with an increased risk of treatment failure; however, this risk seems largely confined to women with a more recent exposure. Women requiring ART within 12 mo of NVP exposure should not be prescribed an NNRTI-containing regimen as first-line therapy.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, acquired immunodeficiency syndrome (AIDS) kills nearly 300,000 children. At the end of 2008, 2.1 million children were positive for the human immunodeficiency virus (HIV), the cause of AIDS, and in that year alone more than 400,000 children were newly infected with HIV. Most HIV-positive children acquire the virus from their mothers during pregnancy or birth or through breastfeeding, so-called mother-to-child transmission (MTCT). Without intervention, 15%–30% of babies born to HIV-positive women become infected with HIV during pregnancy and delivery, and a further 5%–20% become infected through breastfeeding. These rates of infection can be greatly reduced by treating the mother and her newborn baby with antiretroviral 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 the baby soon after birth reduces the risk of MTCT by nearly a half; a further reduction in risk can be achieved by giving the mother and her baby additional antiretroviral drugs during pregnancy, around the time of birth, and while breast-feeding.
Why Was This Study Done?
Single-dose nevirapine is the mainstay of MTCT prevention programs in many poor countries but can induce resistance to nevirapine and to other NNRTIs. The drugs used to treat HIV infections fall into several different classes defined by how they stop viral growth. HIV can become resistant to any of these drugs and a virus strain that is resistant to one member of a drug class is often also resistant to other members of the same class. Because most first-line antiretroviral therapies (ARTs; cocktails of antiretroviral drugs) used in developing countries contain an NNRTI and because HIV-positive mothers eventually need ART to safeguard their own health, the resistance to NNRTIs that is induced in women by single-dose nevirapine might decrease the chances that ART will work for them later. In this multi-country, prospective cohort study, the researchers compare the effectiveness of NNRTI-containing ART in a group (cohort) of women previously exposed to single-dose nevirapine during childbirth to its effectiveness in a group of unexposed women. They also investigate whether the length of time between nevirapine exposure and ART initiation affects ART effectiveness.
What Did the Researchers Do and Find?
The researchers enrolled 355 HIV-positive nevirapine-exposed women and 523 HIV-positive nevirapine-unexposed women in Zambia, Kenya, and Thailand who were just starting NNRTI-containing ART and followed them for 48 weeks. They defined ART failure as death, discontinuation of NNRTI-containing ART, or a high virus load in the blood (virologic failure) at 24 or 48 weeks. ART failed in nearly a third of the nevirapine-exposed women but in only a quarter of the nevirapine-unexposed women. Women who began ART within 6 months of taking single-dose nevirapine to prevent MTCT were twice as likely to experience ART failure as women not exposed to single-dose nevirapine. Women who began ART 7–12 months after single-dose nevirapine had a slightly increased risk of ART failure compared to unexposed women but this increased risk was not statistically significant; that is, it could have occurred by chance. Women who began ART more than 12 months after single-dose nevirapine did not have an increased risk of ART failure compared to unexposed women. Finally, the researchers used a statistical method called locally weighted regression analysis to confirm that an increase in the interval between single-dose nevirapine and ART initiation decreased the risk of virologic failure.
What Do These Findings Mean?
These findings, which confirm and extend the results of previous studies and which are likely to be generalizable to other resource-poor countries, indicate that single-dose nevirapine given to women to prevent MTCT increases their risk of subsequent ART failure. More positively, they also show that this increased failure risk is largely confined to women who begin ART within a year of exposure to nevirapine. Because of the study design, it is possible that the nevirapine-exposed women share some additional, undefined characteristic that makes them more likely to fail ART than unexposed women. Even so, these findings suggest that, provided NNRTI-containing ART is not given to HIV-positive women within a year of nevirapine exposure, single-dose nevirapine can be safely used to prevent MTCT without compromising the mother's future antiretroviral treatment options.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000233.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS, on treatments for HIV/AIDS, and on HIV infection in infants and children
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
doi:10.1371/journal.pmed.1000233
PMCID: PMC2821896  PMID: 20169113
16.  Pharmacy Refill Adherence Compared with CD4 Count Changes for Monitoring HIV-Infected Adults on Antiretroviral Therapy 
PLoS Medicine  2008;5(5):e109.
Background
World Health Organization (WHO) guidelines for monitoring HIV-infected individuals taking combination antiretroviral therapy (cART) in resource-limited settings recommend using CD4+ T cell (CD4) count changes to monitor treatment effectiveness. In practice, however, falling CD4 counts are a consequence, rather than a cause, of virologic failure. Adherence lapses precede virologic failure and, unlike CD4 counts, data on adherence are immediately available to all clinics dispensing cART. However, the accuracy of adherence assessments for predicting future or detecting current virologic failure has not been determined. The goal of this study therefore was to determine the accuracy of adherence assessments for predicting and detecting virologic failure and to compare the accuracy of adherence-based monitoring approaches with approaches monitoring CD4 count changes.
Methodology and Findings
We conducted an observational cohort study among 1,982 of 4,984 (40%) HIV-infected adults initiating non-nucleoside reverse transcriptase inhibitor-based cART in the Aid for AIDS Disease Management Program, which serves nine countries in southern Africa. Pharmacy refill adherence was calculated as the number of months of cART claims submitted divided by the number of complete months between cART initiation and the last refill prior to the endpoint of interest, expressed as a percentage. The main outcome measure was virologic failure defined as a viral load > 1,000 copies/ml (1) at an initial assessment either 6 or 12 mo after cART initiation and (2) after a previous undetectable (i.e., < 400 copies/ml) viral load (breakthrough viremia). Adherence levels outperformed CD4 count changes when used to detect current virologic failure in the first year after cART initiation (area under the receiver operating characteristic [ROC] curves [AUC] were 0.79 and 0.68 [difference = 0.11; 95% CI 0.06 to 0.16; χ2 = 20.1] respectively at 6 mo, and 0.85 and 0.75 [difference = 0.10; 95% CI 0.05 to 0.14; χ2 = 20.2] respectively at 12 mo; p < 0.001 for both comparisons). When used to detect current breakthrough viremia, adherence and CD4 counts were equally accurate (AUCs of 0.68 versus 0.67, respectively [difference = 0.01; 95% CI −0.06 to 0.07]; χ2 = 0.1, p > 0.5). In addition, adherence levels assessed 3 mo prior to viral load assessments were as accurate for virologic failure occurring approximately 3 mo later as were CD4 count changes calculated from cART initiation to the actual time of the viral load assessments, indicating the potential utility of adherence assessments for predicting future, rather than simply detecting current, virologic failure. Moreover, combinations of CD4 count and adherence data appeared useful in identifying patients at very low risk of virologic failure.
Conclusions
Pharmacy refill adherence assessments were as accurate as CD4 counts for detecting current virologic failure in this cohort of patients on cART and have the potential to predict virologic failure before it occurs. Approaches to cART scale-up in resource-limited settings should include an adherence-based monitoring approach.
Analyzing pharmacy and laboratory records from 1,982 patients beginning HIV therapy in southern Africa, Gregory Bisson and colleagues find medication adherence superior to CD4 count changes in identifying treatment failure.
Editors' Summary
Background.
Globally, more than 30 million people are infected with the human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS). Combinations of antiretroviral drugs that hold HIV in check (viral suppression) have been available since 1996. Unfortunately, most of the people affected by HIV/AIDS live in developing countries and cannot afford these expensive drugs. As a result, life expectancy has plummeted and economic growth has reversed in these poor countries since the beginning of the AIDS pandemic. Faced with this humanitarian crisis, the lack of access to HIV treatment was declared a global health emergency in 2003. Today, through the concerted efforts of governments, international organizations, and funding bodies, about a quarter of the HIV-positive people in developing and transitional countries who are in immediate need of life-saving, combination antiretroviral therapy (cART) receive the drugs they need.
Why Was This Study Done?
To maximize the benefits of cART, health-care workers in developing countries need simple, affordable ways to monitor viral suppression in their patients—a poor virologic response to cART can lead to the selection of drug-resistant HIV, rapid disease progression, and death. In developed countries, virologic response is monitored by measuring the number of viral particles in patients' blood (viral load) but this technically demanding assay is unavailable in most developing countries. Instead, the World Health Organization recommends that CD4+ T cell (CD4) counts be used to monitor patient responses to cART in resource-limited settings. HIV results in loss of CD4 cells (a type of immune system cell), so a drop in a patient's CD4 count often indicates virologic failure (failure of treatment to suppress the virus). However, falling CD4 counts are often a result of virologic failure and therefore monitoring CD4 counts for drops is unlikely to prevent virologic failure from occurring. Rather, falling CD4 counts are often used only to guide a change to new medicines, which may be even more expensive or difficult to take. On the other hand “adherence lapses”—the failure to take cART regularly—often precede virologic failure, so detecting them early provides an opportunity for improvement in adherence that could prevent virologic failure. Because clinics that dispense cART routinely collect data that can be used to calculate adherence, in this study the researchers investigate whether assessing adherence might provide an alternative, low-cost way to monitor and predict virologic failure among HIV-infected adults on cART.
What Did the Researchers Do and Find?
The Aid for AIDS Disease Management Program provides cART to medical insurance fund subscribers in nine countries in southern Africa. Data on claims for antiretroviral drugs made through this program, plus CD4 counts assessed at about 6 or 12 months after initiating cART, and viral load measurements taken within 45 days of a CD4 count, were available for nearly 2,000 HIV-positive adults who had been prescribed a combination of HIV drugs including either efavirenz or nevirapine. The researchers defined adherence as the number of months of cART claims submitted divided by the number of complete months between cART initiation and the last pharmacy refill before a viral load assessment was performed. Virologic failure was defined in two ways: as a viral load of more than 1,000 copies per ml of blood 6 or 12 months after cART initiation, or as a rebound of viral load to similar levels after a previously very low reading (breakthrough viremia). The researchers' statistical analysis of these data shows that at 6 and 12 months after initiation of cART, adherence levels indicated virologic failure more accurately than CD4 count changes. For breakthrough viremia, both measurements were equally accurate. Adherence levels during the first 3 months of cART predicted virologic failure at 6 months as accurately as did CD4 count changes since cART initiation. Finally, the combination of adherence levels and CD4 count changes accurately identified patients at very low risk of virologic failure.
What Do These Findings Mean?
These findings suggest that adherence assessments (based in this study on insurance claims for pharmacy refills) can identify the patients on cART who are at high and low risk of virologic failure at least as accurately as CD4 counts. In addition, they suggest that adherence assessments could be used for early identification of patients at high risk of virologic failure, averting the health impact of treatment failure and the cost of changing to second-line drug regimens. Studies need to be done in other settings (in particular, in public clinics where cART is provided without charge) to confirm the generalizability of these findings. These finding do not change that fact that monitoring CD4 counts plays an important role in deciding when to start cART or indicating when cART is no longer protecting the immune system. But, write the researchers, systematic monitoring of adherence to cART should be considered as an alternative to CD4 count monitoring in patients who are receiving cART in resource-limited settings or as a way to direct the use of viral load testing where feasible.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050109.
This study is discussed further in a PLoS Medicine Perspective by David Bangsberg
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 an article about adherence to antiretroviral therapy
Information is available from Avert, an international AIDS charity, on HIV and AIDS in Africa and on providing AIDS drug treatment for millions
The World Health Organization provides information about universal access to HIV treatment (in several languages) and on its recommendations for antiretroviral therapy for HIV infection in adults and adolescents
The US Centers for Disease Control and Prevention also provides information on global efforts to deal with the HIV/AIDS pandemic (in English and Spanish)
doi:10.1371/journal.pmed.0050109
PMCID: PMC2386831  PMID: 18494555
17.  When to Start Antiretroviral Therapy in Children Aged 2–5 Years: A Collaborative Causal Modelling Analysis of Cohort Studies from Southern Africa 
PLoS Medicine  2013;10(11):e1001555.
Michael Schomaker and colleagues estimate the mortality associated with starting ART at different CD4 thresholds among children aged 2–5 years using observational data collected in cohort studies in Southern Africa.
Please see later in the article for the Editors' Summary
Background
There is limited evidence on the optimal timing of antiretroviral therapy (ART) initiation in children 2–5 y of age. We conducted a causal modelling analysis using the International Epidemiologic Databases to Evaluate AIDS–Southern Africa (IeDEA-SA) collaborative dataset to determine the difference in mortality when starting ART in children aged 2–5 y immediately (irrespective of CD4 criteria), as recommended in the World Health Organization (WHO) 2013 guidelines, compared to deferring to lower CD4 thresholds, for example, the WHO 2010 recommended threshold of CD4 count <750 cells/mm3 or CD4 percentage (CD4%) <25%.
Methods and Findings
ART-naïve children enrolling in HIV care at IeDEA-SA sites who were between 24 and 59 mo of age at first visit and with ≥1 visit prior to ART initiation and ≥1 follow-up visit were included. We estimated mortality for ART initiation at different CD4 thresholds for up to 3 y using g-computation, adjusting for measured time-dependent confounding of CD4 percent, CD4 count, and weight-for-age z-score. Confidence intervals were constructed using bootstrapping.
The median (first; third quartile) age at first visit of 2,934 children (51% male) included in the analysis was 3.3 y (2.6; 4.1), with a median (first; third quartile) CD4 count of 592 cells/mm3 (356; 895) and median (first; third quartile) CD4% of 16% (10%; 23%). The estimated cumulative mortality after 3 y for ART initiation at different CD4 thresholds ranged from 3.4% (95% CI: 2.1–6.5) (no ART) to 2.1% (95% CI: 1.3%–3.5%) (ART irrespective of CD4 value). Estimated mortality was overall higher when initiating ART at lower CD4 values or not at all. There was no mortality difference between starting ART immediately, irrespective of CD4 value, and ART initiation at the WHO 2010 recommended threshold of CD4 count <750 cells/mm3 or CD4% <25%, with mortality estimates of 2.1% (95% CI: 1.3%–3.5%) and 2.2% (95% CI: 1.4%–3.5%) after 3 y, respectively. The analysis was limited by loss to follow-up and the unavailability of WHO staging data.
Conclusions
The results indicate no mortality difference for up to 3 y between ART initiation irrespective of CD4 value and ART initiation at a threshold of CD4 count <750 cells/mm3 or CD4% <25%, but there are overall higher point estimates for mortality when ART is initiated at lower CD4 values.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Infection with HIV, the virus that causes AIDS, contributes substantially to the burden of disease in children. Worldwide, more than 3 million children younger than 15 years old (90% of whom live in sub-Saharan Africa) are HIV-positive, and every year around 330,000 more children are infected with HIV. Children usually acquire HIV from their mother during pregnancy, birth, or breastfeeding. The virus gradually destroys CD4 lymphocytes and other immune system cells, leaving infected children susceptible to other potentially life-threatening infections. HIV infection can be kept in check, with antiretroviral therapy (ART)—cocktails of drugs that have to be taken daily throughout life. ART is very effective in children but is expensive, and despite concerted international efforts over the past decade to provide universal access to ART, in 2011, less than a third of children who needed ART were receiving it.
Why Was This Study Done?
For children diagnosed as HIV-positive between the ages of two and five years, the 2010 World Health Organization (WHO) guidelines for the treatment of HIV infection recommended that ART be initiated when the CD4 count dropped below 750 cells/mm3 blood or when CD4 cells represented less than 25% of the total lymphocyte population (CD4 percent). Since June 2013, however, WHO has recommended that all HIV-positive children in this age group begin ART immediately, irrespective of their CD4 values. Earlier ART initiation might reduce mortality (death) and morbidity (illness), but it could also increase the risk of toxicity and of earlier development of drug resistance. In this causal modeling analysis, the researchers estimate the mortality associated with starting ART at different CD4 thresholds among children aged 2–5 years using observational data collected in cohort studies of ART undertaken in southern Africa. Specifically, they compared the estimated mortality associated with the WHO 2010 and WHO 2013 guidelines. Observational studies compare the outcomes of groups (cohorts) with different interventions (here, the timing of ART initiation). Data from such studies are affected by time-dependent confounding: CD4 count, for example, varies with time and is a predictor of both ART initiation and the probability of death. Causal modeling techniques take time-dependent confounding into account and enable the estimation of the causal effect of an intervention on an outcome from observational data.
What Did the Researchers Do and Find?
The researchers used g-computation (a type of causal modeling) adjusting for time-dependent confounding of CD4 percent, CD4 count, and weight-for-age z-score (a measure of whether a child is underweight for their age that provides a proxy indicator of the clinical stage of HIV infection) to estimate mortality for ART initiation at different CD4 thresholds in 2,934 ART-naïve, HIV-positive children aged 2–5 years old at their first visit to one of eight study sites in southern Africa. The average initial CD4 values of these children were a CD4 count of 592 cells/mm3 and a CD4 percent of 16%. The estimated cumulative mortality after three years was 3.4% in all children if ART was never started. If all children had started ART immediately after diagnosis irrespective of CD4 value or if the 2010 WHO-recommended threshold of a CD4 count below 750 cells/mm3 or a CD4 percent below 25% was followed, the estimated cumulative mortalities after three years were 2.1% and 2.2%, respectively (a statistically non-significant difference).
What Do These Findings Mean?
These findings suggest that, among southern African children aged 2–5 years at HIV diagnosis, there is no difference in mortality for up to three years between children in whom ART is initiated immediately and those in whom ART initiation is deferred until their CD4 value falls below a CD4 count of 750 cells/mm3 or a CD4 percent of 25%. Although causal modeling was used in this analysis, the accuracy of these results may be affected by residual confounding. For example, the researchers were unable to adjust for the clinical stage of HIV disease at HIV diagnosis and instead had to use weight-for-age z-scores as a proxy indicator of disease severity. Other limitations of the study include the large number of children lost to follow-up and a possible lack of generalizability—most of the study participants were from urban settings in South Africa. Importantly, however, these findings suggest that the recent change in the WHO guidelines for ART initiation in young children is unlikely to increase or reduce mortality, with the proviso that the long-term effects of earlier ART initiation such as toxicity and the development of resistance to ART need to be explored further.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001555
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
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 children and HIV/AIDS (in English and Spanish)
The UNAIDS World AIDS Day Report 2012 provides up-to-date information about the AIDS epidemic and efforts to halt it; the 2013 Progress Report on the Global Plan provides information on progress towards eliminating new HIV infections among children by 2015
The World Health Organization provides information about universal access to AIDS treatment (in several languages); its 2010 guidelines for ART in infants and children and its 2013 consolidated guidelines on the use of ART can be downloaded
The researchers involved in this study are part of the International Epidemiologic Databases to Evaluate AIDSSouthern Africa collaboration, which develops and implements methodology to generate the large datasets needed to address high-priority research questions related to HIV/AIDS
Personal stories about living with HIV/AIDS, including stories from young people infected with HIV, are available through Avert, through NAM/aidsmap, and through the charity website Healthtalkonline
doi:10.1371/journal.pmed.1001555
PMCID: PMC3833834  PMID: 24260029
18.  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
19.  Effectiveness of community-based support for pregnant women living with HIV: a cohort study in South Africa  
AIDS Care  2016;28(sup1):114-118.
ABSTRACT
Antiretroviral treatment (ART) initiation in HIV-infected pregnant women in sub-Saharan Africa (SSA) remains inadequate, and there is a severe shortage of professional healthcare workers in the region. The effectiveness of community support programmes for HIV-infected pregnant women and their infants in SSA is unclear. This study compared initiation of maternal antiretrovirals and infant outcomes amongst HIV-infected pregnant women and their infants who received and did not receive community-based support (CBS) in a high HIV-prevalence setting in South Africa. A cohort study, including HIV-infected pregnant women and their infants, was conducted at three sentinel surveillance facilities between January 2009 and June 2012, utilising enhanced routine clinical data. Through home visits, CBS workers encouraged uptake of interventions in the ART cascade, provided HIV-related education, ART initiation counselling and psychosocial support. Outcomes were compared using Kaplan–Meier analyses and multivariable Cox and log-binomial regression. Amongst 1105 mother–infant pairs included, 264 (23.9%) received CBS. Amongst women eligible to start ART antenatally, women who received CBS had a reduced risk of not initiating antenatal ART, 5.4% vs. 30.3%; adjusted risk ratio (aRR) = 0.18 (95% CI: 0.08–0.44; P < .0001). Women who received CBS initiated antenatal ART with less delay after the first antenatal visit, median 26 days vs. 39 days; adjusted hazard ratio (aHR) = 1.57 (95% CI: 1.15–2.14; P = .004). Amongst women who initiated antenatal zidovudine (ZDV) to prevent vertical transmission, women who received CBS initiated ZDV with less delay, aHR = 1.52 (95% CI: 1.18–2.01; P = .001). Women who received CBS had a lower risk of stillbirth, 1.5% vs. 5.4%; aRR = 0.24 (95% CI: 0.07–1.00; P = .050). Pregnant women living with HIV who received CBS had improved antenatal triple ART initiation in eligible women, women initiated ART and ZDV with shorter delays, and had a lower risk of stillbirth. CBS is an intervention that shows promise in improving maternal and infant health in high HIV-prevalence settings.
doi:10.1080/09540121.2016.1148112
PMCID: PMC4828595  PMID: 26922939
Pregnancy; prevention of mother-to-child transmission of HIV; community-based support; lay health workers; antiretroviral treatment; South Africa
20.  Cost-Effectiveness of Preventing Loss to Follow-up in HIV Treatment Programs: A Côte d'Ivoire Appraisal 
PLoS Medicine  2009;6(10):e1000173.
Based on data from West Africa, Elena Losina and colleagues predict that interventions to reduce dropout rates from HIV treatment programs (such as eliminating copayments) will be cost-effective.
Background
Data from HIV treatment programs in resource-limited settings show extensive rates of loss to follow-up (LTFU) ranging from 5% to 40% within 6 mo of antiretroviral therapy (ART) initiation. Our objective was to project the clinical impact and cost-effectiveness of interventions to prevent LTFU from HIV care in West Africa.
Methods and Findings
We used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) International model to project the clinical benefits and cost-effectiveness of LTFU-prevention programs from a payer perspective. These programs include components such as eliminating ART co-payments, eliminating charges to patients for opportunistic infection-related drugs, improving personnel training, and providing meals and reimbursing for transportation for participants. The efficacies and costs of these interventions were extensively varied in sensitivity analyses. We used World Health Organization criteria of <3× gross domestic product per capita (3× GDP per capita = US$2,823 for Côte d'Ivoire) as a plausible threshold for “cost-effectiveness.” The main results are based on a reported 18% 1-y LTFU rate. With full retention in care, projected per-person discounted life expectancy starting from age 37 y was 144.7 mo (12.1 y). Survival losses from LTFU within 1 y of ART initiation ranged from 73.9 to 80.7 mo. The intervention costing US$22/person/year (e.g., eliminating ART co-payment) would be cost-effective with an efficacy of at least 12%. An intervention costing US$77/person/year (inclusive of all the components described above) would be cost-effective with an efficacy of at least 41%.
Conclusions
Interventions that prevent LTFU in resource-limited settings would substantially improve survival and would be cost-effective by international criteria with efficacy of at least 12%–41%, depending on the cost of intervention, based on a reported 18% cumulative incidence of LTFU at 1 y after ART initiation. The commitment to start ART and treat HIV in these settings should include interventions to prevent LTFU.
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 the first reported case in 1981. Currently, about 33 million people are infected with the human immunodeficiency virus (HIV), which causes AIDS. Two-thirds of people infected with HIV live in sub-Saharan Africa. HIV infects and destroys immune system cells, thereby weakening the immune system and rendering infected individuals susceptible to infection. There is no cure for HIV/AIDS. Combination antiretroviral therapy (ART), a mixture of antiretroviral drugs that suppress the replication of the virus in the body, is used to treat and prevent HIV infection. ART is expensive but major international efforts by governments, international organizations, and funding bodies have increased ART availability. According to World Health Organization (WHO) estimates, at least 9.7 million people in low- and middle-income countries need ART and as of 2007, 3 million of those people had reliable access to the drugs.
Why Was This Study Done?
Although ART is an effective treatment for HIV, a large number of individuals who initiate ART do not receive long-term follow-up care. These patients are generally sicker and have a worse long-term outcome than those who receive follow-up care. Loss to follow up (LTFU) is a significant problem that can undermine the benefits of expanding ART availability. Strategies to improve follow up concentrate on bringing lost patients back into the health care system, but such patients often die before they can be contacted. Prevention of LTFU might be a better strategy to improve HIV care after ART initiation, but there is little information available on which specific interventions might best accomplish this goal.
What Did the Researchers Do and Find?
Given the lack of reported data on the actual costs and effectiveness of LTFU prevention, the researchers used a model to estimate the clinical impact and cost-effectiveness of several possible strategies to prevent LTFU in HIV-infected persons receiving ART in Côte d'Ivoire, West Africa. The researchers used the previously developed Cost-Effectiveness of Preventing AIDS Complications (CEPAC) computer simulation model and combined it with data from a program of ART delivery in Abidjan, Côte d'Ivoire. They then projected the clinical benefits and the cost required to attain a given level of benefit (cost-effectiveness ratio) of different LTFU-prevention strategies from the perspective of the payer (the organization that pays all the medical costs to provide care). Several interventions were considered, including reducing costs to patients (eliminating patient co-payments and paying for transportation) and increasing services to patients at their visits (improving staff training in HIV care, and providing meals at clinic times). LTFU was predicted to cause a 54.3%–58.3% reduction in the estimated life expectancy beyond age 37; patients continuing HIV care were predicted to live a further 144.7 months whie those lost to follow up by 1 year after ART initiation were predicted to live only for a further 73.9–80.7 months. LTFU-prevention strategies in the Côte d'Ivoire were deemed to be cost-effective if they cost less than $2,823 (which is 3× gross domestic product per capita) per year of life saved. The efficacy and cost of the different LTFU-prevention strategies varied in the analyses; stopping ART co-payment alone would be cost-effective at a cost of $22/person/year if it reduced LTFU rates by 12%, while including all the LTFU-prevention strategies described would be cost-effective at $77/person/year if they reduced LTFU-rates by 41%.
What Do These Findings Mean?
The findings suggest that moderately effective strategies for preventing LTFU in resource-limited settings would improve survival, provide good value for money, and should be used to improve HIV treatment programs. Although modeling is valuable to explore the costs and effectiveness of LTFU-prevention strategies it cannot replace the need for more reported data to shed light on problems leading to LTFU and the prevention strategies required to combat it. Also, Côte d'Ivoire might not be representative of all West African countries or resource-limited settings. A similar analysis using data from other ART programs in different countries would be useful to provide better understanding of the impact of LTFU in HIV treatment programs. Finally, the research highlights the cost of second-line ART (a new antiretroviral drug combination for patients in whom first-line treatment fails) as a crucial issue. It is estimated that 5% of all people receiving ART in low- and middle-income countries receive second-line ART and these numbers are expected to increase. Second-line ART had major effects on cost-effectiveness, and a reduction in the cost of this treatment is critical in order to guarantee continued access to HIV treatment.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000173.
This study is further discussed in a PLoS Medicine Perspective by Gregory Bisson and Jeffrey Stringer
WHO provides information on disease prevention, treatment, and HIV/AIDS programs and projects
The UN Millennium Development Goals project site contains information on worldwide efforts to halt the spread of HIV/AIDS
aidsmap, a nonprofit, nongovernmental organization, provides information on HIV and supporting those living with HIV
doi:10.1371/journal.pmed.1000173
PMCID: PMC2762030  PMID: 19859538
21.  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
22.  Task Shifting for Scale-up of HIV Care: Evaluation of Nurse-Centered Antiretroviral Treatment at Rural Health Centers in Rwanda 
PLoS Medicine  2009;6(10):e1000163.
Fabienne Shumbusho and colleagues evaluate a task-shifting model of nurse-centered antiretroviral treatment prescribing in rural primary health centers in Rwanda and find that nurses can effectively and safely prescribe ART when given adequate training, mentoring, and support.
Background
The shortage of human resources for health, and in particular physicians, is one of the major barriers to achieve universal access to HIV care and treatment. In September 2005, a pilot program of nurse-centered antiretroviral treatment (ART) prescription was launched in three rural primary health centers in Rwanda. We retrospectively evaluated the feasibility and effectiveness of this task-shifting model using descriptive data.
Methods and Findings
Medical records of 1,076 patients enrolled in HIV care and treatment services from September 2005 to March 2008 were reviewed to assess: (i) compliance with national guidelines for ART eligibility and prescription, and patient monitoring and (ii) key outcomes, such as retention, body weight, and CD4 cell count change at 6, 12, 18, and 24 mo after ART initiation. Of these, no ineligible patients were started on ART and only one patient received an inappropriate ART prescription. Of the 435 patients who initiated ART, the vast majority had adherence and side effects assessed at each clinic visit (89% and 84%, respectively). By March 2008, 390 (90%) patients were alive on ART, 29 (7%) had died, one (<1%) was lost to follow-up, and none had stopped treatment. Patient retention was about 92% by 12 mo and 91% by 24 mo. Depending on initial stage of disease, mean CD4 cell count increased between 97 and 128 cells/µl in the first 6 mo after treatment initiation and between 79 and 129 cells/µl from 6 to 24 mo of treatment. Mean weight increased significantly in the first 6 mo, between 1.8 and 4.3 kg, with no significant increases from 6 to 24 mo.
Conclusions
Patient outcomes in our pilot program compared favorably with other ART cohorts in sub-Saharan Africa and with those from a recent evaluation of the national ART program in Rwanda. These findings suggest that nurses can effectively and safely prescribe ART when given adequate training, mentoring, and support.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Infection with the human immunodeficiency virus (HIV) is a serious health problem in sub-Saharan Africa. The virus attacks white blood cells that protect against infection, most commonly a type of white blood cell called CD4. When a person has been infected with HIV for a long time, the number of CD4 cells they have goes down, resulting in acquired immune deficiency syndrome (AIDS), in which the person's immune system no longer functions effectively.
The World Health Organization (WHO) has divided the disease into four stages as it progresses, according to symptoms including weight loss and so-called opportunistic infections. These are known as clinical stage I, II, III, or IV but were revised and renamed 1, 2, 3, and 4 in September 2005. HIV infection and AIDS cannot be cured but they can be managed with antiretroviral treatment (ART). The WHO currently recommends that ART is begun when the CD4 count falls below 350.
Rwanda is a country situated in the central Africa with a population of around 9 million inhabitants; over 3% of the rural population and 7% of the urban population are infected with HIV. In 2007, the WHO estimated that 220,000 Rwandan children had lost one or both parents to AIDS.
Why Was This Study Done?
The WHO estimates that 9.7 million people with HIV in low- to middle-income countries need ART but at the end of 2007, only 30% of these, including in Rwanda, had access to treatment. In many low-income countries a major factor in this is a lack of doctors. Rwanda, for example, has one doctor per 50,000 inhabitants and one nurse per 3,900 inhabitants.
This situation has led the WHO to recommend “task shifting,” i.e., that the task of prescribing ART should be shifted from doctors to nurses so that more patients can be treated. This type of reorganization is well studied in high-income countries, but the researchers wanted to help develop a system for treating AIDS that would be effective and timely in a predominantly rural, low-income setting such as Rwanda.
What Did the Researchers Do and Find?
In conjunction with the Rwandan Ministry of Health, the researchers developed and piloted a task-shifting program, in which one nurse in each of three rural Rwandan primary health centers (PHCs) was trained to examine HIV patients and prescribe ART in simple cases. Nurses had to complete more than 50 consultations observed by the doctor before being permitted to consult patients independently. More complex cases were referred to a doctor. The authors developed standard checklists, instructions, and evaluation forms to guide nurses and the doctors who supervised them once a week.
The authors evaluated the pilot program by reviewing the records of 1,076 patients who enrolled on it between September 2005 and March 2008. They looked to see whether the nurses had followed guidelines and monitored the patients correctly. They also considered health outcomes for the patients, such as their death rate, their body weight, their CD4 cell count, and whether they maintained contact with caregivers.
They found that by March 2008, 451 patients had been eligible for ART. 435 received treatment and none of the patients were prescribed ART when they should not have been. Only one prescription did not follow national guidelines.
At every visit, nurses were supposed to assess whether patients were taking their drugs and to monitor side effects. They did this and maintained records correctly for the vast majority of the 435 patients who were prescribed ART. 390 patients (over 90%) of the 435 prescribed receiving ART continued to take it and maintain contact with the pilot PHC's program. 29 patients died. Only one was lost to follow up and the others transferred to another ART site. The majority gained weight in the first six months and their CD4 cell counts rose. Outcomes, including death rate, were similar to those treated on the (doctor-led) Rwandan national ART program and other sub-Saharan African national (doctor-led) programs.
What Do These Findings Mean?
The study suggests that nurses are able to prescribe ART safely and effectively in a rural sub-Saharan setting, given sufficient training, mentoring, and support. Nurse-led prescribing of ART could mean that timely, appropriate treatment reaches many more HIV patients. It would reduce the burden of HIV care for doctors, freeing their time for other duties, and the study is already being used by the Rwandan Ministry of Health as a basis for plans to adopt a task-shifting strategy for the national ART program.
The study does have some limitations. The pilot program was funded and designed as a health project to deliver ART in rural areas, rather than a research project to compare nurse-led and doctor-led ART programs. There was no group of equivalent patients treated by doctors rather than nurses for direct comparison, although the authors did compare outcomes with those achieved nationally for doctor-led ART. The most promising sites, nurses, and patients were selected for the pilot and careful monitoring may have been an additional motivation for the nurses and doctors taking part. Health professionals in a scaled-up program may not be as committed as those in the pilot, who were carefully monitored. In addition, the nature of the pilot, which lasted for under three years and recruited new patients throughout, meant that patients were followed up for relatively short periods.
The authors also warn that they did not consider in this study the changes task shifting will make to doctors' roles and the skills required of both doctors and nurses. They recommend that task shifting should be implemented as part of a wider investment in health systems, human resources, training, adapted medical records, tools, and protocols.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000163.
PLoS Medicine includes a page collecting together its recent articles on HIV infection and AIDS that includes research articles, perspectives, editorials, and policy forums
SciDev.net provides news, views, and information about science, technology, and the developing world, including a section specific to HIV/AIDs
The World Health Organization (WHO) has published a downloadable booklet Task Shifting to Tackle Health Worker Shortages
The WHO offers information on HIV and AIDS (in Arabic, Chinese, English, French, Russian, and Spanish) as well as health information and fact sheets on individual countries, including on Rwanda
The UNAIDS/WHO working group on HIV/AIDS and Sexually Transmitted Infections (STI) Surveillance gathers and publishes data on the prevalence of HIV and AIDS in individual countries, including on Rwanda
AIDS.ORG provides information to help prevent HIV infections and to improve the lives of those affected by HIV and AIDS. Factsheets on many aspects of HIV and AIDS are available. It is the official online publisher of AIDS Treatment News
doi:10.1371/journal.pmed.1000163
PMCID: PMC2752160  PMID: 19823569
23.  Disengagement of HIV-positive pregnant and postpartum women from antiretroviral therapy services: a cohort study 
Introduction
Recent international guidelines call for expanded access to triple-drug antiretroviral therapy (ART) in HIV-positive women during pregnancy and postpartum. However, high levels of non-adherence and/or disengagement from care may attenuate the benefits of ART for HIV transmission and maternal health. We examined the frequency and predictors of disengagement from care among women initiating ART during pregnancy in Cape Town, South Africa.
Methods
We used routine medical records to follow-up pregnant women initiating ART within prevention of mother-to-child transmission of HIV services in Cape Town, South Africa. Outcomes assessed through six months postpartum were (1) disengagement (no attendance within 56 days of a scheduled visit) and (2) missed visits (returning to care 14–56 days late for a scheduled visit).
Results
A total of 358 women (median age, 28 years; median gestational age, 26 weeks) initiated ART during pregnancy. By six months postpartum, 24% of women (n=86) had missed at least one visit and an additional 32% (n=115) had disengaged from care; together, 49% of women had either missed a visit or had disengaged by six months postpartum. Disengagement was more than twice as frequent postpartum compared to in the antenatal period (6.2 vs. 2.4 per 100 woman-months, respectively; p<0.0001). In a proportional hazards model, later gestational age at initiation (HR: 1.04; 95% CI: 1.00–1.07; p=0.030) and being newly diagnosed with HIV (HR: 1.57; 95% CI: 1.07–2.33; p=0.022) were significant predictors of disengagement after adjusting for patient age, starting CD4 cell count and site of ART initiation.
Conclusions
These results demonstrate that missed visits and disengagement from care occur frequently, particularly post-delivery, among HIV-positive women initiating ART during pregnancy. Women who are newly diagnosed with HIV may be particularly vulnerable and there is an urgent need for interventions both to promote retention overall, as well as targeting women newly diagnosed with HIV during pregnancy.
doi:10.7448/IAS.17.1.19242
PMCID: PMC4192834  PMID: 25301494
antiretroviral therapy; pregnancy; postpartum; retention; prevention of mother-to-child transmission (PMTCT); HIV/AIDS; South Africa
24.  Health system weaknesses constrain access to PMTCT and maternal HIV services in South Africa: a qualitative enquiry 
Background
HIV remains responsible for an estimated 40% of mortality in South African pregnant women and their children. To address these avoidable deaths, eligibility criteria for antiretroviral therapy (ART) in pregnant women were revised in 2010 to enhance ART coverage. With greater availability of HIV services in public health settings and increasing government attention to poor maternal-child health outcomes, this study used the patient's journey through the continuum of maternal and child care as a framework to track and document women's experiences of accessing ART and prevention of mother-to-child HIV transmission (PMTCT) programmes in the Eastern Cape (three peri-urban facilities) and Gauteng provinces (one academic hospital).
Results
In-depth interviews identified considerable weaknesses within operational HIV service delivery. These manifested as missed opportunities for HIV testing in antenatal care due to shortages of test kits; insufficient staff assigned to HIV services; late payment of lay counsellors, with consequent absenteeism; and delayed transcription of CD4 cell count results into patient files (required for ART initiation). By contrast, individual factors undermining access encompassed psychosocial concerns, such as fear of a positive test result or a partner's reaction; and stigma. Data and information systems for monitoring in the three peri-urban facilities were markedly inadequate.
Conclusions
A single system- or individual-level delay reduced the likelihood of women accessing ART or PMTCT interventions. These delays, when concurrent, often signalled wholesale denial of prevention and treatment. There is great scope for health systems' reforms to address constraints and weaknesses within PMTCT and ART services in South Africa. Recommendations from this study include: ensuring autonomy over resources at lower levels; linking performance management to facility-wide human resources interventions; developing accountability systems; improving HIV services in labour wards; ensuring quality HIV and infant feeding counselling; and improved monitoring for performance management using robust systems for data collection and utilisation.
doi:10.1186/1742-6405-8-10
PMCID: PMC3058008  PMID: 21371301
25.  Prophylactic antiretroviral regimens for prevention of mother-to-child transmission of HIV in resource-limited settings 
Current Opinion in HIV and AIDS  2008;3(2):161-165.
Purpose of review
With the large international mobilization against HIV/AIDS, more HIV-infected people in resource-limited settings have access to antiretroviral therapy (ART), including pregnant women. The relevance of simplified prophylactic antiretroviral (ARV) regimens for the prevention of mother-to-child transmission (PMTCT) of HIV may become questionable due to their lower efficacy and their higher risk of inducing viral resistance than fully suppressive ART.
Recent findings
Field implementation of current recommendations, impact of prophylactic regimens on subsequent ART response and possible new indications of ART in pregnant women will be reviewed in this paper.
Summary
Prophylactic ARV PMTCT regimens reached only 10 % of the HIV-infected pregnant women in 2006, who were usually offered single-dose nevirapine only. The operational links between antenatal care and ART programmes can now be documented and demonstrate good results in terms of safety and efficacy. The negative impact of single-dose nevirapine exposure on subsequent first-line ART appears worse for mothers with advanced HIV disease at the time of delivery and short interval before ART initiation. Strengthening the links between antenatal care and ART programmes is critical for ART-eligible HIV-infected pregnant women in terms of PMTCT and subsequent ART response. The breastfeeding period could be a new indication for ART in this population.
doi:10.1097/COH.0b013e3282f51b89
PMCID: PMC2683174  PMID: 19372960
Prevention of mother-to-child transmission of HIV-1; Resource-limited settings; Prophylactic antiretroviral regimens; Single-dose nevirapine; Breastfeeding

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