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1.  The Mpumalanga Men's Study (MPMS): Results of a Baseline Biological and Behavioral HIV Surveillance Survey in Two MSM Communities in South Africa 
PLoS ONE  2014;9(11):e111063.
The Mpumalanga Men's Study (MPMS) is the assessment of the Project Boithato HIV prevention intervention for South African MSM. Boithato aims to increase consistent condom use, regular testing for HIV-negative MSM, and linkage to care for HIV-positive MSM. The MPMS baseline examined HIV prevalence and associated risk behaviors, and testing, care, and treatment behaviors among MSM in Gert Sibande and Ehlanzeni districts in Mpumalanga province, South Africa in order to effectively target intervention activities. We recruited 307 MSM in Gert Sibande and 298 in Ehlanzeni through respondent-driven sampling (RDS) between September 2012-March 2013. RDS-adjusted HIV prevalence estimates are 28.3% (95% CI 21.1%–35.3%) in Gert Sibande, and 13.7% (95% CI 9.1%–19.6%) in Ehlanzeni. Prevalence is significantly higher among MSM over age 25 [57.8% (95% CI 43.1%–72.9%) vs. 17.9% (95% CI 10.6%–23.9%), P<0.001 in Gert Sibande; 34.5% (95%CI 20.5%–56.0%) vs. 9.1% (95% CI 4.6%–13.9%), P<0.001 in Ehlanzeni]. In Gert Sibande, prevalence is higher among self-identified gay and transgender MSM vs. other MSM [39.3% (95%CI, 28.3%–47.9%), P<0.01], inconsistent condom users [38.1% (18.1%–64.2%), P<0.05], those with a current regular male partner [35.0% (27.1%–46.4%), P<0.05], and those with lifetime experience of intimate partner violence with men [40.4%, (95%CI 28.9%–50.9%), P<0.05]. Prevalence of previous HIV testing was 65.8% (95%CI 58.8%–74.0%) in Gert Sibande, and 69.3% (95%CI 61.9%–76.8%) in Ehlanzeni. Regular HIV testing was uncommon [(34.6%, (95%CI 27.9%–41.4%) in Gert Sibande; 31.0% (95%CI 24.9%–37.8%) in Ehlanzeni]. Among HIV-positive participants, few knew their status (28.1% in Gert Sibande and 14.5% in Ehlanzeni), or were appropriately linked to care (18.2% and 11.3%, respectively), or taking antiretroviral therapy (13.6% and 9.6% respectively). MPMS results demonstrate the importance of implementing interventions for MSM to increase consistent condom use, regular HIV testing, and linkage and engagement in care for HIV-infected MSM.
doi:10.1371/journal.pone.0111063
PMCID: PMC4234301  PMID: 25401785
2.  Contextual Correlates of Per Partner Unprotected Anal Intercourse Rates Among MSM in Soweto, South Africa 
AIDS and behavior  2013;17(0 1):S4-11.
Men who have sex with men (MSM) throughout the world are at high-risk of HIV acquisition and transmission. Although individual behavior remains a central feature of HIV prevention efforts in sub-Saharan Africa and beyond, contextual factors likely influence behavioral risk. We identify contextual factors at the individual, dyadic (within the partnership), and extra-dyadic (relationships external to the focal dyad) levels that are associated with increased rates of unprotected anal intercourse with a given male partner among MSM in Soweto, South Africa. Drawing on data from The Soweto Men’s Study, multilevel models were applied to 758 partnerships nested within 377 MSM respondents. Independent of overall sexual engagement, dyadic (e.g. description of partner as ‘regular’), psychosocial (e.g. experiences of homonegativity), and sociocultural (e.g. income) contextual factors were significant predictors of differential 6-month rates of UAI with a given partner. By contrast, sexual partnerships outside of the focal sexual pair were not significantly related to UAI rates within the focal pair. Our findings support the need for continuing to understand and intervene on partner-level, psychosocial, and sociocultural dimensions of sexual behavior and sexual risk among MSM in Soweto.
doi:10.1007/s10461-012-0324-9
PMCID: PMC4227910  PMID: 23054039
HIV; MSM; South Africa; Risk behavior
3.  Early limited antiretroviral therapy is superior to deferred therapy in HIV-infected South African infants: results from the CHER (Children with HIV Early antiRetroviral) Randomized Trial 
Lancet  2013;382(9904):1555-1563.
Background
Interim results from the CHER trial showed that early antiretroviral therapy (ART) was life-saving for HIV-infected infants. Given limited options and potential for toxicity with life-long ART, CHER compared early limited ART with deferred ART.
Methods
CHER was an open 3-arm trial in HIV-infected asymptomatic infants aged <12 weeks with CD4% ≥25%. Infants were randomized to deferred (ART-Def) or immediate ART for 40weeks (ART-40W) or 96weeks (ART-96W), followed by interruption. Criteria for ART initiation in ART-Def and re-initiation after interruption were CD4% <25% in infancy; otherwise <20% or CDC severe stage B or stage C disease. Lopinavir-ritonavir, zidovudine, lamivudine was the first-line regimen at ART initiation and re-initiation. The primary endpoint was time-to-failure of first-line ART (immunological/clinical/virological) or death. Comparisons were by intent-to-treat, using time-to-event methods.
Findings
377 infants were enrolled: median age 7.4weeks; CD4% 35% and HIV RNA log 5.7copies/ml. Median follow-up was 4.8 years; 34 (9%) were lost-to-follow-up. Median time to ART initiation in ART-Def was 20 (IQR 16–25) weeks. Time to restarting ART after interruption was 33 (26–45) weeks in ART-40W and 70 (35–109) weeks in ART-96W; at trial end 19% and 32% respectively, remained off ART. Proportions of follow-up time spent on ART were 81%, 70% and 69% in ART-Def, ART-40W and ART-96W arms. 48/125(38%), 32/126(25%) and 26/126(21%) children reached the primary endpoint; hazard ratio (95%CI), relative to ART-Def, was 0.59(0.38-0.93, p=0.02) for ART-40W and 0.47(0.27-0.76, p=0.002) for ART-96W. Seven children (3 ART-Def, 3 ART-40W, 1 ART-96W) switched to second-line ART.
Interpretation
Early limited ART had superior clinical/immunological outcome with no evidence of excess disease progression during subsequent interruption and less overall ART exposure than deferred ART.
Longer time on primary ART permits longer subsequent interruption with marginally better outcomes.
doi:10.1016/S0140-6736(13)61409-9
PMCID: PMC4104982  PMID: 24209829
4.  Daily Acyclovir to Decrease Herpes Simplex Virus Type 2 (HSV-2) Transmission from HSV-2/HIV-1 Coinfected Persons: A Randomized Controlled Trial 
The Journal of Infectious Diseases  2013;208(9):1366-1374.
Background. Daily suppressive therapy with valacyclovir reduces risk of sexual transmission of herpes simplex virus type 2 (HSV-2) in HSV-2–serodiscordant heterosexual couples by 48%. Whether suppressive therapy reduces HSV-2 transmission from persons coinfected with HSV-2 and human immunodeficiency virus type 1 (HIV-1) is unknown.
Methods. Within a randomized trial of daily acyclovir 400 mg twice daily in African HIV-1 serodiscordant couples, in which the HIV-1–infected partner was HSV-2 seropositive, we identified partnerships in which HIV-1–susceptible partners were HSV-2 seronegative to estimate the effect of acyclovir on risk of HSV-2 transmission.
Results. We randomly assigned 911 HSV-2/HIV-1–serodiscordant couples to daily receipt of acyclovir or placebo. We observed 68 HSV-2 seroconversions, 40 and 28 in acyclovir and placebo groups, respectively (HSV-2 incidence, 5.1 cases per 100 person-years; hazard ratio [HR], 1.35 [95% confidence interval, .83–2.20]; P = .22). Among HSV-2–susceptible women, vaginal drying practices (adjusted HR, 44.35; P = .004) and unprotected sex (adjusted HR, 9.91; P = .002) were significant risk factors for HSV-2 acquisition; having more children was protective (adjusted HR, 0.47 per additional child; P = .012). Among HSV-2–susceptible men, only age ≤30 years was associated with increased risk of HSV-2 acquisition (P = .016).
Conclusions. Treatment of African HSV-2/HIV-1–infected persons with daily suppressive acyclovir did not decrease risk of HSV-2 transmission to susceptible partners. More-effective prevention strategies to reduce HSV-2 transmission from HIV-1–infected persons are needed.
doi:10.1093/infdis/jit333
PMCID: PMC3789565  PMID: 23901094
HSV-2; HIV-1; acyclovir; transmission; serodiscordant couples; Africa
5.  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
6.  High Seroprevalence of Human Herpesviruses in HIV-Infected Individuals Attending Primary Healthcare Facilities in Rural South Africa 
PLoS ONE  2014;9(6):e99243.
Seroprevalence data of human herpesviruses (HHVs) are limited for sub-Saharan Africa. These are important to provide an indication of potential burden of HHV-related disease, in particular in human immunodeficiency virus (HIV)-infected individuals who are known to be at increased risk of these conditions in the Western world. In this cross-sectional study among 405 HIV-infected and antiretroviral therapy naïve individuals in rural South Africa the seroprevalence of HHVs was: herpes simplex virus type 1 (HSV-1) (98%), herpes simplex virus type 2 (HSV-2) (87%), varicella zoster virus (VZV) (89%), and 100% for both Epstein-Barr virus (EBV) and cytomegalovirus (CMV). Independent factors associated with VZV seropositivity were low educational status and having children. Lack of in-house access to drinking water was independently associated with positive HSV-1 serostatus, whereas Shangaan ethnicity was associated with HSV-2 seropositivity. Increasing age was associated with higher IgG titres to both EBV and CMV, whereas CD4 cell count was negatively associated with EBV and CMV IgG titres. Moreover, IgG titres of HSV-1 and 2, VZV and CMV, and CMV and EBV were positively correlated. The high HHV seroprevalence emphasises the importance of awareness of these viral infections in HIV-infected individuals in South Africa.
doi:10.1371/journal.pone.0099243
PMCID: PMC4051661  PMID: 24914671
7.  Patient factors to target for elimination of mother-to-child transmission of HIV 
Background
There is great impetus to achieve elimination of mother-to-child transmission of HIV (eMTCT) by 2015, and part of this is to identify factors to target to achieve the goal. This study thus identified key patient factors for MTCT in a high HIV prevalence setting in Johannesburg, South Africa. Between November 2010 and May 2012, we conducted a case–control study among HIV-infected women with HIV-infected (cases) and uninfected (controls) infants diagnosed around six weeks of age as part of routine, early infant diagnosis. Mothers and infants were identified through registers in six healthcare facilities that provide antenatal, postpartum and HIV care. Structured interviews were conducted with a focus on history of HIV infection, antenatal, intrapartum and immediate postpartum management of the mother-infant pair. Patient-related risk factors for MTCT were identified.
Results
A total of 77 women with HIV-infected infants and 154 with –uninfected infants were interviewed. Among HIV-infected cases, 13.0% of the women knew their HIV status prior to conception, and 83.1% reported their pregnancies as unplanned. Antenatal antiretroviral coverage was high in the control group – only 1/154 (0.7%) reported receiving no prophylaxis or treatment compared with 17/74 (22.9%) of cases. In multivariate analysis, key patient-related risks for HIV transmission were: unknown HIV status prior to conception (adjusted odds ratio [AOR] = 6.6; 95% CI = 2.4 – 18.4; p < 0.001); accessing antenatal care after 20 weeks gestation (AOR = 4.3; 95% CI = 2.0 – 9.3; p < 0.001); less than 12 years of formal education (AOR = 3.4; 95% CI = 1.6 – 7.5; p = 0.002); and unplanned pregnancy (AOR = 2.7; 95% CI = 1.2 to 6.3; p = 0.022). Mean age at first HIV test was 6.6 weeks (SD = 3.5) for infants who were diagnosed as HIV-infected, and the mean age at antiretroviral treatment initiation was 10.8 weeks (SD = 4.4). HIV-uninfected infants were diagnosed at a mean age of 6.0 weeks (SD = 0.2).
Conclusions
Undiagnosed maternal HIV infection prior to conception, unplanned pregnancies, delays in accessing antenatal care, and low levels of education were the most significant patient risk factors associated with MTCT. While the emphasis has been on increasing availability and coverage of efficacious antiretroviral regimens, and strengthening health systems within eMTCT initiatives, there is a need to also address patient-related factors if we are to achieve eMTCT goals.
doi:10.1186/1744-8603-10-36
PMCID: PMC4026120  PMID: 24886029
Elimination of mother-to-child transmission; HIV and pregnancy; Patient factors
8.  Attitudes toward couples-based HIV counseling and testing among MSM in Cape Town, South Africa 
AIDS and behavior  2013;17(0 1):43-50.
Couples-based voluntary HIV counseling and testing (CVCT) allows couples to receive their HIV test results together and has been demonstrated to be effective in reducing HIV transmission, increasing and sustaining condom use, and reducing sexual risk-taking among at-risk heterosexual couples. However, the acceptability of CVCT among MSM has yet to be evaluated in an African setting. The results from seven focus group discussions and twenty-nine in-depth interviews conducted in Cape Town, South Africa exhibit overwhelmingly high acceptance of CVCT. Participants were attracted to the counseling components of the service, stating that these would allow for the couple to increase their commitment and to explore methods of how to effectively reduce their risk of acquiring or transmitting HIV in the presence of a trained counselor. These results suggest CVCT would be highly welcomed and could work to fill the significant lack of services available and accessible to MSM couples in Cape Town.
doi:10.1007/s10461-012-0293-z
PMCID: PMC3529975  PMID: 22961498
CVCT; MSM; HIV testing; Couples
9.  Plasma Viral Loads During Early HIV-1 Infection Are Similar in Subtype C– and Non-Subtype C–Infected African Seroconverters 
The Journal of Infectious Diseases  2013;207(7):1166-1170.
Recent data suggest that infection with human immunodeficiency virus type 1 (HIV-1) subtype C results in prolonged high-level viremia (>5 log10 copies/mL) during early infection. We examined the relationship between HIV-1 subtype and plasma viremia among 153 African seroconverters. Mean setpoint viral loads were similar for C and non-C subtypes: 4.36 vs 4.42 log10 copies/mL (P = .61). The proportion of subtype C–infected participants with viral loads >5 log10 copies/mL was not greater than the proportion for those with non-C infection. Our data do not support the hypothesis that higher early viral load accounts for the rapid spread of HIV-1 subtype C in southern Africa.
doi:10.1093/infdis/jit015
PMCID: PMC3583276  PMID: 23315322
HIV-1; group M subtype; plasma viral load; early infection; Africa
10.  Sexual Behavior and Reproductive Health Among HIV-Infected Patients in Urban and Rural South Africa 
Journal of acquired immune deficiency syndromes (1999)  2008;47(4):10.1097/QAI.0b013e3181648de8.
Background
With the rollout of antiretroviral therapy in South Africa and its potential to prolong the lives of HIV-infected individuals, understanding the sexual behavior of HIV-positive people is essential to curbing secondary HIV transmission.
Methods
We surveyed 3819 HIV-positive patients during their first visit to an urban wellness clinic and a rural wellness clinic.
Results
Urban residents were more likely than rural residents to have current regular sex partners (75.1% vs. 46.0%; χ2 odds ratio [OR] = 3.531; P < 0.001), to have any current sexual partners (75.3% vs. 51.2%; χ2 OR = 2.908; P < 0.001), and to report consistent condom use with regular partners (78.4% vs. 48.3%; χ2 OR = 3.886; P < 0.001) and with casual partners (68.6% vs. 48.3%; χ2 OR = 2.337; P < 0.001). In multivariate analysis, independent predictors of consistent condom use with regular partners included across gender, urban residence, and higher education levels; for women, disclosure and younger age; and for men only, no history of alcohol consumption. Male and female participants with a casual sexual partner were less likely to use a condom consistently with regular partners. Additionally, urban residence and a CD4 count greater than 200 cells/mm3 as well as (for women only) a higher household income and a history of alcohol consumption were predictors of having a regular sexual partner.
Conclusions
HIV prevention programs in South Africa that emphasize the importance of condom use and disclosure and are tailored to the needs of their attending populations are critical given the potential for HIV-infected individuals to resume risky sexual behavior with improving health.
doi:10.1097/QAI.0b013e3181648de8
PMCID: PMC3811008  PMID: 18209685
condom use; HIV prevention; positive prevention; sexual behavior; South Africa; urban-rural
11.  Prevalence and Associations with Hepatitis B and Hepatitis C infection Amongst HIV-infected Adults in South Africa 
International journal of STD & AIDS  2012;23(10):e10-e13.
We assessed prevalence and factors associated with hepatitis B in a cross-section of HIV-infected primary care and anti-natal clinic patients in South Africa and evaluated a rapid hepatitis B surface antigen (HBsAg) assay. We enrolled 998 patients; 88% were women, median age was 29 years, and median CD4 count was 354 cells/mm3. HBsAg ELISA, anti-hepatitis B core (HBc) antibodies, and hepatitis C virus antibody were positive among 4.2%, 37%, and 0.1% of subjects, respectively. Univariate and multivariate associations were assessed using logistic regression. Anti-HBc antibodies were associated with alcohol use, traditional medicines, and higher CD4. HBsAg positivity was associated with lower CD4. Compared to the HBsAg ELISA, a rapid HBsAg test had a sensitivity of 75.0% and specificity of 99.6%. In conclusion, we identified a moderate prevalence of both HBsAg and anti-HBc. Importantly, we found subjects with HBsAg positivity had lower CD4 counts.
doi:10.1258/ijsa.2009.009340
PMCID: PMC3724418  PMID: 23104758
HIV/AIDS; HBV; HBsAg; HCV; rapid test; Africa
12.  Comparison of point-of-care versus laboratory-based CD4 cell enumeration in HIV-positive pregnant women 
Introduction
Early initiation of antiretroviral therapy (ART) in eligible pregnant women is a key intervention for prevention of mother-to-child transmission (PMTCT) of HIV. However, in many settings in sub-Saharan Africa where ART-eligibility is determined by CD4 cell counts, limited access to laboratories presents a significant barrier to rapid ART initiation. Point-of-care (POC) CD4 cell count testing has been suggested as one approach to overcome this challenge, but there are few data on the agreement between POC CD4 cell enumeration and standard laboratory-based testing.
Methods
Working in a large antenatal clinic in Cape Town, South Africa, we compared POC CD4 cell enumeration (using the Alere PimaTM Analyzer) to laboratory-based flow cytometry in consecutive HIV-positive pregnant women. Bland–Altman methods were used to compare the two methods, including analyses by subgroups of participant gestational age.
Results
Among the 521 women participating, the median gestational age was 23 weeks, and the median CD4 cell count according to POC and laboratory-based methods was 388 and 402 cells/µL, respectively. On average, the Pima POC test underestimated CD4 cell count relative to flow cytometry: the mean difference (laboratory test minus Pima POC) was 22.7 cells/µL (95% CI, 16.1 to 29.2), and the limits of agreement were −129.2 to 174.6 cells/µL. When analysed by gestational age categories, there was a trend towards increasing differences between laboratory and POC testing with increasing gestational age; in women more than 36 weeks’ gestation, the mean difference was 45.0 cells/µL (p=0.04).
Discussion
These data suggest reasonable overall agreement between Pima POC CD4 testing and laboratory-based flow cytometry among HIV-positive pregnant women. The finding for decreasing agreement with increasing gestational age requires further investigation, as does the operational role of POC CD4 testing to increase access to ART within PMTCT programmes.
doi:10.7448/IAS.16.1.18649
PMCID: PMC3776301  PMID: 24044627
point-of-care test; CD4 cell count; reliability; pregnancy; HIV; antiretroviral therapy; South Africa
13.  Frequent Emergence of N348I in HIV-1 Subtype C Reverse Transcriptase with Failure of Initial Therapy Reduces Susceptibility to Reverse-Transcriptase Inhibitors 
N348I emerges frequently with failure of first-line antiretroviral therapy (ART) in subtype C human immunodeficiency virus type 1 infection and affects susceptibility to nevirapine, efavirenz, etravirine, and zidovudine. This finding has implications for cross-resistance to subsequent ART regimens in resource-limited settings.
Background. It is not known how often mutations in the connection and ribonuclease H domains of reverse transcriptase (RT) emerge with failure of first-line antiretroviral therapy (ART) in subtype C human immunodeficiency virus type 1 (HIV-1) infection and how these mutations affect susceptibility to other antiretrovirals.
Methods. We compared full-length RT sequences in plasma obtained before therapy and at virologic failure of initial ART among 63 participants with subtype C HIV-1 infection enrolled in the Comprehensive International Program of Research on AIDS in South Africa (CIPRA-SA) study. Recombinant viruses containing full-length plasma-derived RT sequences from participants with N348I at virologic failure were assayed for drug susceptibility.
Results. Y181C and M184V mutations in the RT polymerase domain were associated with failure of stavudine-lamivudine-nevirapine (d4T/3TC/NVP; P < .01), and K103N, V106M, and M184V with failure of d4T/3TC/efavirenz (EFV; P < .01). N348I in the RT connection domain emerged in 45% (P = .002) and 12% (P = .06) of participants receiving failing regimens containing NVP or EFV, respectively. Longitudinal analyses revealed that nonnucleoside RT inhibitor resistance mutations in the polymerase domain generally appeared first. N348I emerged at the same time, or after, M184V. N348I in the context of polymerase domain mutations reduced susceptibility to NVP (8.9–13-fold), EFV (4–56-fold), etravirine (ETV; 1.9–4.7-fold) and decreased hypersusceptibility to zidovudine (AZT; 1.4–2.2-fold).
Conclusions. N348I emerges frequently with virologic failure of first-line ART in subtype C HIV-1 infection and reduces susceptibility to NVP, EFV, ETV, and AZT. Additional studies are warranted to characterize the effects of N348I on virologic response to second- and third-line regimens in resource-limited settings where subtype C predominates.
doi:10.1093/cid/cis501
PMCID: PMC3491849  PMID: 22618567
14.  Viewpoint Men and antiretroviral therapy in Africa: our blindspot 
doi:10.1111/j.1365-3156.2011.02767.x
PMCID: PMC3749374  PMID: 21418449
15.  Efavirenz-induced gynecomastia in a prepubertal girl with human immunodeficiency virus infection: a case report 
BMC Pediatrics  2013;13:120.
Background
Prepubertal gynecomastia is a rare condition and most frequently classified as idiopathic. In HIV-infected adults gynecomastia is a recognised but infrequent side-effect of antiretroviral treatment (ART) and mostly attributed to efavirenz use. Gynecomastia should be distinguished from pseudogynecomastia as part of the lipodystrophy syndrome caused by Nucleoside Reverse Transcriptase Inhibitors (NRTIs) to avoid incorrect substitution of drugs. In the medical literature only five cases of prepubertal gynecomastia in children taking ART are described and underlying pathogenesis was unknown. The occurrence of adverse effects of ART may interfere with therapy adherence and long-term prognosis and for that reason requires attention. We report the first case of prepubertal gynecomastia in a young girl attributed to efavirenz use.
Case presentation
A seven-year-old African girl presented with true gynecomastia four months after initiation on ART (abacavir, lamivudine, efavirenz). History, physical examination and laboratory tests excluded known causes of gynecomastia and efavirenz was considered as the most likely cause. Six weeks after withdrawal of efavirenz the breast enlargement had completely resolved.
Conclusions
Efavirenz-induced gynecomastia may occur in children as well as in adults. With the increasing access to ART, the possibility of efavirenz-exposure and the potential occurrence of its associated side-effects may be high. In resource-poor settings, empirical change from efavirenz to nevirapine may be considered, providing no other known or alarming cause is identified, as efavirenz-induced gynecomastia can resolve quickly after withdrawal of the drug. Timely recognition of gynecomastia as a side-effect of efavirenz is important in order to intervene while the condition may still be reversible, to sustain adherence to ART and to maintain the sociopsychological health of the child.
doi:10.1186/1471-2431-13-120
PMCID: PMC3751361  PMID: 23941256
Gynecomastia; HIV; Efavirenz; Child; Prepubertal
16.  Low rates of nucleoside reverse transcriptase inhibitor (NRTI) resistance detected in a well monitored cohort in South Africa accessing antiretroviral therapy 
Antiviral therapy  2011;17(2):313-320.
Background
Emergence of complex HIV-1 drug resistance mutations has been linked to the duration of time on a failing antiretroviral (ARV) drug regimen. This study reports on resistance profiles in a closely monitored subtype C infected cohort.
Methods
A total of 812 participants were enrolled into the CIPRA-SA ‘safeguard the household’ study, viral loads (VLs) were performed 12 weekly for 96 weeks. Virological failure was defined as either <1.5 log drop in VL at week 12 or 2 consecutive VL measurements >1000 RNA copies/ml after week 24. Regimens prescribed were in-line with the South African roll-out program (d4T, 3TC, EFV or NVP). Viral RNA was extracted from patients with virological failure, and pol RT-PCR and sequence analysis were performed to determine drug resistance mutations.
Results
Eighty three participants experienced virological failure on the first-line regimen during the study period, of which 61 (73%) had HIV-1 drug resistance mutations. The M184V mutation was the most frequent (n=46; 65%), followed by K103N (46%) and Y181C (21%). TAMS were infrequent (1%) and Q151M was not observed.
Conclusion
Drug resistance profiles were less complex than has been previously reported in South Africa using the same ARV drug regimens. This data suggests that frequent viral load monitoring limits the level and complexity of resistance observed in HIV-1 subtype C, preserving susceptibility to second-line options.
doi:10.3851/IMP1985
PMCID: PMC3600633  PMID: 22293461
HIV-1 drug resistance; subtype C; first-line failure; South Africa
17.  Predicting the Impact of a Partially Effective HIV Vaccine and Subsequent Risk Behavior Change on the Heterosexual HIV Epidemic in Low- and Middle-Income Countries A South African Example 
Summary
We developed a mathematical model to simulate the impact of various partially effective preventive HIV vaccination scenarios in a population at high risk for heterosexually transmitted HIV. We considered an adult population defined by gender (male/female), disease stage (HIV-negative, HIV-positive, AIDS, and death), and vaccination status (unvaccinated/vaccinated) in Soweto, South Africa. Input data included initial HIV prevalence of 20% (women) and 12% (men), vaccination coverage of 75%, and exclusive male negotiation of condom use. We explored how changes in vaccine efficacy and post-vaccination condom use would affect HIV prevalence and total HIV infections prevented over a 10-year period. In the base-case scenario, a 40% effective HIV vaccine would avert 61,000 infections and reduce future HIV prevalence from 20% to 13%. A 25% increase (or decrease) in condom use among vaccinated individuals would instead avert 75,000 (or only 46,000) infections and reduce the HIV prevalence to 12% (or only 15%). Furthermore, certain combinations of increased risk behavior and vaccines with <43% efficacy could worsen the epidemic. Even modestly effective HIV vaccines can confer enormous benefits in terms of HIV infections averted and decreased HIV prevalence. However, programs to reduce risk behavior may be important components of successful vaccination campaigns.
doi:10.1097/QAI.0b013e31812506fd
PMCID: PMC3570247  PMID: 17589368
AIDS vaccines; mathematical models; sexual behavior; heterosexual transmission; Africa; condoms; models/projections
18.  Increased Microbial Translocation in ≤180 Days Old Perinatally Human Immunodeficiency Virus Positive Infants as Compared with Human Immunodeficiency Virus -Exposed/Uninfected Infants of Similar Age 
Background
We investigated the effect of early versus deferred antiretroviral treatment (ART) on plasma concentration of lipopolysaccharide (LPS) and host LPS-binding molecules in HIV-infected infants up to 1 year of age.
Methods
We evaluated 54 perinatally HIV-infected and 22 HIV-exposed/uninfected infants (controls) at the first and second semester of life. All HIV-infected infants had a baseline CD4≥25%, participated in the CIPRA-SA Children with HIV Early Antiretroviral Therapy (CHER) trial in South Africa and were randomized in: Group 1 (n=20), ART deferred until CD4<25% or severe HIV disease, and Group 2 (n=34), ART initiation within 6-12 weeks of age. LPS, endotoxin-core antibodies (EndoCAb), soluble (s)CD14, and LPS-binding protein (LBP) were measured in cryopreserved plasma. T cell activation was measured in fresh whole blood.
Results
At the first semester, LPS concentration was higher in HIV-infected infants than in controls; sCD14, LBP and T cell activation were higher in Group 1 than in Group 2 and controls. While LPS was not correlated with study variables, viral load was positively associated with sCD14, LBP or EndoCAb. At the second semester, LPS was not detectable and elevated host LPS-control molecules values were sustained, in all groups and in conjunction with ART in all HIV-infected infants.
Conclusions
While plasma concentration of LPS is higher in perinatally HIV-infected infants 0-6 months of age than in controls independent of ART initiation strategy, LPS-control molecules concentration is higher in infants with deferred ART, suggesting the presence of increased microbial translocation in HIV-infected infants with sustained early viral replication.
doi:10.1097/INF.0b013e31821d141e
PMCID: PMC3173518  PMID: 21552185
HIV-1-infected infants; LPS; microbial translocation; LPS-binding molecules
19.  Inferior quantitative and qualitative immune responses to pneumococcal conjugate vaccine in infants with nasopharyngeal colonization by Streptococcus pneumoniae during the primary series of immunization 
Vaccine  2011;29(40):6994-7001.
Background
Heightened immunogenicity, measured one month after the primary series of pneumococcal conjugate vaccine (PCV), in African children was previously hypothesized to be due to increased rates of nasopharyngeal pneumococcal colonization during early infancy.
Methods
We analyzed the effect of selected vaccine-serotype (6B, 19F and 23F) nasopharyngeal colonization prior to the first PCV dose or when colonized for the first time prior to the second or third (2nd/3rd) PCV dose on serotype quantitative and qualitative antibody responses.
Results
Colonization prior to receiving the first PCV was associated with lower geometric mean antibody concentrations (GMCs) one month after the third dose of PCV and six months later to the colonizing-serotype. Colonized infants also had lower geometric mean titers (GMTs) on opsonophagocytosis activity assay (OPA) and a lower proportion had titers ≥8 against the colonizing serotypes (19F and 23F) post vaccination. Colonization occurring only prior to the 2nd/3rd PCV dose was also associated with lower GMCs and OPA GMTs to the colonizing-serotype. The effect of colonization with serotypes 19F and 23F prior to PCV vaccination had a greater effect on a lower proportion of colonized infants having OPA titers ≥8 than the effect of colonization on the lower proportion with antibody ≥0.35 μg/ml.
Conclusion
Infant nasopharyngeal colonization at any stage before completing the primary series of PCV vaccination was associated with inferior quantitative and qualitative antibody responses to the colonizing-serotype.
doi:10.1016/j.vaccine.2011.07.035
PMCID: PMC3167924  PMID: 21787822
Streptococcus pneumoniae; pneumococcal conjugate vaccine; HIV; immunogenicity; colonization; hypo-responsiveness
20.  Active Tuberculosis Case-Finding among Pregnant Women Presenting to Antenatal Clinics in Soweto, South Africa 
Background
Human immunodeficiency virus (HIV) and tuberculosis (TB) are among the leading causes of death among women of reproductive age worldwide. TB is a significant cause of maternal morbidity. Detection of TB during pregnancy could provide substantial benefits to women and their offspring.
Methods
This was a cross-sectional implementation research study of integrating active TB case-finding with delivery of antenatal and prevention of mother-to-child transmission (PMTCT) services in six clinics in Soweto, South Africa. All pregnant women ≥18 years of age presenting for routine care to these public clinics were screened for symptoms of active TB, cough ≥2 weeks, sputum production, fevers, night sweats or weight loss, regardless of their HIV status. Participants with any symptom of active TB were asked to provide a sputum specimen for smear microscopy, mycobacterial culture and drug-susceptibility testing.
Results
Between December 2008 and July 2009, 3,963 pregnant women were enrolled and screened for TB, of whom 1,454 (36.7%) were HIV-seropositive. Any symptom of TB was reported by 23.1% of HIV-seropositive and 13.8% of HIV-seronegative women (p<0.01). Active pulmonary TB was diagnosed in 10/1,454 HIV-seropositve women (688 per 100,000) and 5/2,483 HIV-seronegative women (201 per 100,000, p = 0.03). The median CD4+ T-cell count among HIV-seropositive women with TB was similar to that of HIV-seropositive women without TB (352 versus 333 cells/μL, p=0.85).
Conclusions
There is a high burden of active TB among HIV-seropositive pregnant women. TB screening and provision of isoniazid preventive therapy and antiretroviral therapy should be integrated with PMTCT services.
doi:10.1097/QAI.0b013e31821ac9c1
PMCID: PMC3159850  PMID: 21436710
tuberculosis; HIV; pregnancy; epidemiology; screening
21.  New Regimens to Prevent Tuberculosis in Adults with HIV Infection 
BACKGROUND
Treatment of latent tuberculosis in patients infected with the human immunodeficiency virus (HIV) is efficacious, but few patients around the world receive such treatment. We evaluated three new regimens for latent tuberculosis that may be more potent and durable than standard isoniazid treatment.
METHODS
We randomly assigned South African adults with HIV infection and a positive tuberculin skin test who were not taking antiretroviral therapy to receive rifapentine (900 mg) plus isoniazid (900 mg) weekly for 12 weeks, rifampin (600 mg) plus isoniazid (900 mg) twice weekly for 12 weeks, isoniazid (300 mg) daily for up to 6 years (continuous isoniazid), or isoniazid (300 mg) daily for 6 months (control group). The primary end point was tuberculosis-free survival.
RESULTS
The 1148 patients had a median age of 30 years and a median CD4 cell count of 484 per cubic millimeter. Incidence rates of active tuberculosis or death were 3.1 per 100 person-years in the rifapentine–isoniazid group, 2.9 per 100 person-years in the rifampin–isoniazid group, and 2.7 per 100 person-years in the continuous-isoniazid group, as compared with 3.6 per 100 person-years in the control group (P>0.05 for all comparisons). Serious adverse reactions were more common in the continuous-isoniazid group (18.4 per 100 person-years) than in the other treatment groups (8.7 to 15.4 per 100 person-years). Two of 58 isolates of Mycobacterium tuberculosis (3.4%) were found to have multidrug resistance.
CONCLUSIONS
On the basis of the expected rates of tuberculosis in this population of HIV-infected adults, all secondary prophylactic regimens were effective. Neither a 3-month course of intermittent rifapentine or rifampin with isoniazid nor continuous isoniazid was superior to 6 months of isoniazid.
doi:10.1056/NEJMoa1005136
PMCID: PMC3407678  PMID: 21732833
22.  Mean CD4 cell count changes in patients failing a first-line antiretroviral therapy in resource-limited settings 
BMC Infectious Diseases  2012;12:147.
Background
Changes in CD4 cell counts are poorly documented in individuals with low or moderate-level viremia while on antiretroviral treatment (ART) in resource-limited settings. We assessed the impact of on-going HIV-RNA replication on CD4 cell count slopes in patients treated with a first-line combination ART.
Method
Naïve patients on a first-line ART regimen with at least two measures of HIV-RNA available after ART initiation were included in the study. The relationships between mean CD4 cell count change and HIV-RNA at 6 and 12 months after ART initiation (M6 and M12) were assessed by linear mixed models adjusted for gender, age, clinical stage and year of starting ART.
Results
3,338 patients were included (14 cohorts, 64% female) and the group had the following characteristics: a median follow-up time of 1.6 years, a median age of 34 years, and a median CD4 cell count at ART initiation of 107 cells/μL. All patients with suppressed HIV-RNA at M12 had a continuous increase in CD4 cell count up to 18 months after treatment initiation. By contrast, any degree of HIV-RNA replication both at M6 and M12 was associated with a flat or a decreasing CD4 cell count slope. Multivariable analysis using HIV-RNA thresholds of 10,000 and 5,000 copies confirmed the significant effect of HIV-RNA on CD4 cell counts both at M6 and M12.
Conclusion
In routinely monitored patients on an NNRTI-based first-line ART, on-going low-level HIV-RNA replication was associated with a poor immune outcome in patients who had detectable levels of the virus after one year of ART.
doi:10.1186/1471-2334-12-147
PMCID: PMC3573925  PMID: 22742573
HIV-1; CD4 count; CD4 slope; HIV-RNA threshold; Resource limited settings
23.  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
24.  Tuberculosis in HIV Programmes in Lower-Income Countries: Practices and Risk Factors 
SUMMARY
Background
Tuberculosis (TB) is a common diagnosis in HIV-infected patients on antiretroviral therapy (ART).
Objective
To describe TB-related practices in ART programmes in lower-income countries and identify risk factors for TB in the first year of ART.
Methods
Programme characteristics were assessed by standardized electronic questionnaire. Patient data from 2003-2008 were analyzed and incidence rate ratios (IRRs) calculated using Poisson regression models.
Results
Fifteen ART programmes in 12 countries in Africa, South America and Asia were included. Chest X-ray, sputum microscopy and culture were available free of charge in 13 (86.7%), 14 (93.3%) and eight (53.3%) programmes, respectively. Eight sites (53.3%) used directly observed therapy and five (33.3%) routinely administered isoniazid preventive therapy (IPT). A total of 19,413 patients aged ≥16 years contributed 13,227 person-years of follow-up; 1,081 new TB events were diagnosed. Risk factors included CD4 cell count (adjusted IRR comparing >350 cells/μL with <25 cells/μL 0.46, 95% CI 0.33-0.64, P<0.0001), gender (adjusted IRR comparing women with men 0.77, 0.68-0.88, P=0.0001) and use of IPT (IRR 0.24, 95% CI 0.19-0.31, p<0.0001).
Conclusions
Diagnostic capacity and practices vary widely across ART programmes. IPT prevented TB but was used in few programmes. More efforts are needed to reduce the burden of TB in HIV co-infected patients in lower income countries.
doi:10.5588/ijtld.10.0249
PMCID: PMC3140103  PMID: 21756512
tuberculosis; HIV; prevention; access; diagnostics; treatment practices; antiretroviral therapy; lower income countries; immunodeficiency; risk factor
25.  First-line antiretroviral therapy after single-dose nevirapine exposure in South Africa: A cost-effectiveness analysis of the OCTANE trial 
AIDS (London, England)  2011;25(4):479-492.
doi:10.1097/QAD.0b013e3283428cbe
PMCID: PMC3068908  PMID: 21293199
HIV; antiretroviral therapy; single-dose nevirapine; mother-to-child transmission; cost-effectiveness

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