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1.  Cautious Optimism for HIV Vaccine Science 
Current opinion in HIV and AIDS  2013;8(5):367-368.
PMCID: PMC4089146  PMID: 23924996
2.  Morbidity and Mortality among Infants Born to HIV-Infected Women in South Africa: Implications for Child Health in Resource-Limited Settings 
Journal of Tropical Pediatrics  2010;57(2):109-119.
Background: We examined correlates of infant morbidity and mortality within the first 3 months of life among HIV-exposed infants receiving post-exposure antiretroviral prophylaxis in South Africa. Methods: We conducted a prospective cohort study of 848 mother–child dyads. Multivariable Cox proportional hazards models were used. Results: The main causes of infant morbidity were gastrointestinal and respiratory infections. Morbidity was higher with infant HIV infection (HR: 2.61; 95% CI: 1.40–4.85; p = 0.002) and maternal plasma viral load (PVL) >100 000 copies ml−1 (HR: 1.87; 95% CI: 1.01–3.48; p = 0.048), and lower with maternal age <20 years (HR: 0.25; 95% CI: 0.07–0.88; p = 0.031). Mortality was higher with infant HIV infection (HR: 4.10; 95% CI: 1.18–14.31; p = 0.027) and maternal PVL >100 000 copies ml−1 (HR: 6.93; 95% CI: 1.64–29.26; p = 0.008). Infant feeding status did not influence the risk of morbidity nor mortality. Conclusions: Future interventions that minimize pediatric HIV infection and reduce maternal viremia, which are the main predictors of child health soon after birth, will impact positively on infant health outcomes.
PMCID: PMC3107462  PMID: 20601692
South Africa; mother-to-child transmission; breast-feeding; infant HIV-1 infection; mortality; morbidity
3.  Adolescent HIV—Cause for Concern in Southern Africa 
PLoS Medicine  2010;7(2):e1000227.
Glenda Gray discusses the implications of a new study that found that almost half of all adolescents hospitalized in Zimbabwe were HIV-infected.
PMCID: PMC2820351  PMID: 20161804
4.  International Seroepidemiology of Adenovirus Serotypes 5, 26, 35, and 48 in Pediatric and Adult Populations 
Vaccine  2011;29(32):5203-5209.
Recombinant adenovirus serotype 5 (rAd5) vaccine vectors for HIV-1 and other pathogens have been shown to be limited by high titers of Ad5 neutralizing antibodies (NAbs) in the developing world. Alternative serotype rAd vectors have therefore been constructed. Here we report Ad5, Ad26, Ad35, and Ad48 NAb titers in 4,381 individuals from North America, South America, sub-Saharan Africa, and Southeast Asia. As expected, Ad5 NAb titers were both frequent and high magnitude in sub-Saharan Africa and Southeast Asia. In contrast, Ad35 NAb titers proved infrequent and low in all regions studied, and Ad48 NAbs were rare in all regions except East Africa. Ad26 NAbs were moderately common in adults in sub-Saharan Africa and Southeast Asia, but Ad26 NAb titers proved markedly lower than Ad5 NAb titers in all regions, and these relatively low Ad26 NAb titers did not detectably suppress the immunogenicity of 4×1010 vp of a rAd26-Gag/Pol/Env/Nef vaccine in rhesus monkeys. These data inform the clinical development of alternative serotype rAd vaccine vectors in the developing world.
PMCID: PMC3138857  PMID: 21619905
6.  The HVTN503/Phambili HIV vaccine trial: a comparison of younger and older participants 
By comparing younger to older participants enrolled in a HIV vaccine efficacy trial, we aimed to gain insights into the inclusion of adolescents in future trials. This was a sub-analysis of a multisite HIV vaccine randomized clinical trial in South Africa, conducted January-September, 2007. Motivations for trial enrollment, social harms, adverse events, and loss to follow-up were compared between younger (18-20 years old) and older participants (21-35 years old). Both younger (n=238) and older participants (n=563) were equally likely to report enrolling for altruistic reasons. Younger females were less likely than older participants to join for trial reimbursement (p=0.005), while younger males were more likely to enroll because the vaccine may provide protection from HIV-acquisition (p<0.001). There were no significant differences in the number of social harms reported. Compared to males over 20 years-old, 18-20-year-old females were less likely to experience adverse events (OR=0.1, CI 0.01-0.80) and no more likely to be lost to follow up (OR=0.7, CI 0.39-1.25), while 18-20-year-old males were no more likely to experience adverse events (OR=1.3, CI 0.58-2.83) or loss to follow-up (OR=0.8, CI 0.51-1.41). Our data support the inclusion of younger participants who are at risk for HIV in future HIV vaccine efficacy trials.
PMCID: PMC3968181  PMID: 24104693
HIV; vaccine trials; clinical trials; youth; South Africa
7.  Isoniazid preventive therapy, HAART and tuberculosis risk in HIV-infected adults in South Africa: a prospective cohort 
AIDS (London, England)  2009;23(5):631-636.
The World Health Organization recommends isoniazid preventive therapy (IPT) for preventing tuberculosis in HIV-infected adults, although few countries have instituted this policy. Both IPT and highly active antiretroviral therapy (HAART) used separately result in reductions in tuberculosis risk. There is less information on the combined effect of IPT and HAART. We assessed the effect of IPT, HAART or both IPT and HAART on tuberculosis incidence in HIV-infected adults in South Africa.
Two clinical cohorts of HIV-infected patients were studied. Primary exposures were receipt of IPT and/or HAART and the primary outcome was incident tuberculosis. Crude incident rates and incident rate ratios were calculated and Cox proportional hazards models investigated associations with tuberculosis risk.
Among 2778 HIV-infected patients followed for 4287 person-years, 267 incident tuberculosis cases were diagnosed [incidence rate ratio (IRR) = 6.2/100 person-years; 95% CI 5.5–7.0]. For person-time without IPT or HAART, the IRR was 7.1/100 person-years (95% CI 6.2–8.2); for person-time receiving HAART but without IPT, the IRR was 4.6/100 person-years (95% CI 3.4–6.2); for person-time after IPT but prior to HAART, the IRR was 5.2/100 person-years (95% CI 3.4–7.8); during follow-up in patients treated with HAART after receiving IPT the IRR was 1.1/100 person-years (95% CI 0.02–7.6). Compared to treatment-naive patients, HAART-only patients had a 64% decreased hazard for tuberculosis [adjusted hazard ratio (aHR) = 0.36; 95% CI 0.25–0.51], and patients receiving HAART after IPT had a 89% reduced hazard (aHR = 0.11; 95% CI 0.02–0.78).
Tuberculosis risk is significantly reduced by IPT in HAART-treated adults in a high-incidence operational setting in South Africa. IPT is an inexpensive and cost-effective strategy and our data strengthen calls for the implementation of IPT in conjunction with the roll-out of HAART.
PMCID: PMC3063949  PMID: 19525621
HAART; isoniazid; preventive treatment; sub-Saharan Africa; tuberculosis
8.  A Viable and Simple Self-Sampling Method for Human Papillomavirus Detection among South African Adolescents 
Journal of immunological techniques in infectious diseases  2013;2(3):10.4172/2329-9541.1000113.
Self-sampling for Human Papillomavirus (HPV) testing may offer improved patient acceptability, decreased cost, and greater practicality than clinician collection of specimens. HPV testing among adolescents is necessary to conduct vaccine surveillance and may play a role in cervical cancer screening among some populations.
A cross-sectional prevalence study was conducted to compare the results of self-collected and clinician-collected specimens for Human papillomavirus (HPV) testing among South African adolescent females. All participants provided self-sampled vaginal swabs and underwent clinician-collection of cervical swabs for HPV DNA analysis. The level of agreement between HPV DNA results from the two specimen collection methods was measured.
The level of agreement between HPV DNA results from self-collected and clinician-collected specimens was high (κ=86.7; p<0.001). A high prevalence of HPV overall was found by both specimen collection methods (57%; 95% CI 0.37–0.75). Low-risk HPV (LR-HPV) types were found slightly more frequently in self-collected specimens.
There is a high level of agreement between the HPV DNA results from self-collected and clinician-collected specimens. Self-collection of specimens for HPV testing is a viable alternative among adolescents.
PMCID: PMC3855317  PMID: 24324979
Self-sampling; Human papillomavirus; Adolescent; Cervical cancer prevention; South Africa
9.  African infants’ CCL3 gene copies influence perinatal HIV transmission in the absence of maternal nevirapine 
AIDS (London, England)  2007;21(13):1753-1761.
Individuals with more copies of CCL3L1 (CCR5 ligand) than their population median have been found to be less susceptible to HIV infection. We investigated whether maternal or infant CCL3L1 gene copy numbers are associated with perinatal HIV transmission when single-dose nevirapine is given for prevention.
A nested case–control study was undertaken combining data from four cohorts including 849 HIV-infected mothers and their infants followed prospectively in Johannesburg, South Africa. Access to antiretroviral drugs for the prevention of perinatal transmission differed across the cohorts. Maternal and infant CCL3L1 gene copy numbers per diploid genome (pdg) were determined by real-time polymerase chain reaction for 79 out of 83 transmitting pairs (~10% transmission rate) and 235 randomly selected non-transmitting pairs.
Higher numbers of infant, but not maternal, CCL3L1 gene copies were associated with reduced HIV transmission (P=0.004) overall, but the association was attenuated if mothers took single-dose nevirapine or if the maternal viral load was low. Maternal nevirapine was also associated with reduced spontaneously released CCL3 (P=0.007) and phytohemagglutinin-stimulated CCL3 (P=0.005) production in cord blood mononuclear cells from uninfected infants.
We observed a strong association between higher infant CCL3L1 gene copies and reduced susceptibility to HIV in the absence of maternal nevirapine. We also observed a reduction in newborn CCL3 production with nevirapine exposure. Taken together, we hypothesize that nevirapine may have direct or indirect effects that partly modify the role of the CCR5 ligand CCL3 in HIV transmission, obscuring the relationship between this genetic marker and perinatal HIV transmission.
PMCID: PMC2386991  PMID: 17690574
CCL3/MIP1alpha; chemokines; mother-to-child HIV transmission ; nevirapine
10.  Pilot study on the immunogenicity of paired Env immunogens from mother-to-child transmitted HIV-1 isolates 
Human Vaccines & Immunotherapeutics  2012;8(11):1638-1647.
Recent studies have reported that founder viruses play unique roles in establishing HIV-1 infection. Understanding the biological and immunological features of envelope glycoproteins (Env) from such viruses may facilitate the development of effective vaccines against HIV-1. In this report, we evaluated the immunogenicity of gp120 immunogens from two pairs of clade B and two pairs of clade C mother-to-child transmitted (MTCT) HIV-1 variants that had various levels of sensitivity to broadly neutralizing monoclonal antibodies. Individual gp120 DNA and protein vaccines were produced from each of the eight MTCT Env antigens included in the current study. Rabbits were immunized with these gp120 immunogens by the DNA prime-protein boost approach. High level Env-specific antibody responses were elicited by all MTCT gp120 immunogens. However, their abilities to elicit neutralizing antibody (NAb) responses differed and those from relatively neutralization-resistant variants tended to be more effective in eliciting broader NAb. Results of this pilot study indicated that not all MTCT Env proteins have the same potential to elicit NAb. Understanding the mechanism(s) behind such variation may provide useful information in formulating the next generation of HIV vaccines.
PMCID: PMC3601138  PMID: 23151449
HIV-1; mother-to-child transmission; immunogenicity; antibody; DNA-protein boost vaccination
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.
PMCID: PMC3724418  PMID: 23104758
HIV/AIDS; HBV; HBsAg; HCV; rapid test; Africa
12.  A Qualitative Analysis of Factors Influencing HPV Vaccine Uptake in Soweto, South Africa among Adolescents and Their Caregivers 
PLoS ONE  2013;8(8):e72094.
In South Africa, the prevalence of oncogenic Human Papillomavirus (HPV) may be as high as 64%, and cervical cancer is the leading cause of cancer-related death among women. The development of efficacious prophylactic vaccines has provided an opportunity for primary prevention. Given the importance of psycho-social forces in vaccine uptake, we sought to elucidate factors influencing HPV vaccination among a sample of low-income South African adolescents receiving the vaccine for the first time in Soweto.
The HPV vaccine was introduced to adolescents in low-income townships throughout South Africa as part of a nationwide trial to understand adolescent involvement in future vaccine research targeting human immunodeficiency virus (HIV). We performed in-depth semi-structured interviews with purposively-sampled adolescents and their care providers to understand what forces shaped HPV vaccine uptake. Interviews were recorded, transcribed, translated, and examined using thematic analysis.
Of 224 adolescents recruited, 201 initiated the vaccine; 192 (95.5%) received a second immunization; and 164 (81.6%) completed three doses. In our qualitative study of 39 adolescent-caregiver dyads, we found that factors driving vaccine uptake reflected a socio-cultural backdrop of high HIV endemnicity, sexual violence, poverty, and an abundance of female-headed households. Adolescents exercised a high level of autonomy and often initiated decision-making. Healthcare providers and peers provided support and guidance that was absent at home. The impact of the HIV epidemic on decision-making was substantial, leading participants to mistakenly conflate HPV and HIV.
In a setting of perceived rampant sexual violence and epidemic levels of HIV, adolescents and caregivers sought to decrease harm by seeking a vaccine targeting a sexually transmitted infection (STI). Despite careful consenting, there was confusion regarding the vaccine’s target. Future interventions promoting STI vaccines will need to provide substantial information for participants, particularly adolescents who may exercise a significant level of autonomy in decision-making.
PMCID: PMC3758285  PMID: 24023613
13.  Influence of intragenic CCL3 haplotypes and CCL3L copy number in HIV-1 infection in a sub-Saharan African population 
Genes and immunity  2012;14(1):42-51.
Two CCL3 haplotypes (HapA1 and Hap-A3) and two polymorphic positions shared by the haplotypes (Hap-2SNP) were investigated together with CCL3L copy number (CN), for their role in HIV-1 disease. Hap-A1 was associated with protection from in utero HIV-1 infection: exposed-uninfected infants had higher representation of WT/Hap-A1 than infected infants (excluding intrapartum-infected infants), which maintained significance post maternal Nevirapine (mNVP) and viral load (MVL) correction (P=0.04; OR=0.33). Mother-infant pair analyses showed the protective effect of Hap-A1 is dependent on its presence in the infant. Hap-A3 was associated with increased intrapartum transmission: WT/Hap-A3 was increased in intrapartum vs. non-transmitting mothers, and remained significant post mNVP and MVL correction (P=0.02; OR=3.50). This deleterious effect of Hap-A3 seemed dependent on its presence in the mother. Hap-2SNP was associated with lower CD4 count in the non-transmitting mothers (P=0.03). CCL3 Hap-A1 was associated with high CCL3L CN in total (P=0.001) and exposed-uninfected infants (P=0.006); the effect was not additive, however having either Hap-A1 or high CCL3L CN was more significantly (P=0.0008) associated with protection from in utero infection than Hap-A1 (P=0.028) or high CCL3L CN (P=0.002) alone. Linkage disequilibrium between Hap-A1 and high CCL3L CN appears unlikely given that a Nigerian population showed an opposite relationship.
PMCID: PMC3554858  PMID: 23151487
CCL3; CCL3L; HIV-1; Haplotypes; SNPs; Mother-to-child-transmission
14.  Influence of intragenic CCL3 haplotypes and CCL3L copy number in HIV-1 infection in a sub-Saharan African population 
Genes and immunity  2012;14(1):42-51.
Two CCL3 haplotypes (HapA1 and Hap-A3) and two polymorphic positions shared by the haplotypes (Hap-2SNP) were investigated together with CCL3L copy number (CN), for their role in HIV-1 disease. Hap-A1 was associated with protection from in utero HIV-1 infection: exposed-uninfected infants had higher representation of WT/Hap-A1 than infected infants (excluding intrapartum-infected infants), which maintained significance post maternal Nevirapine (mNVP) and viral load (MVL) correction (P=0.04; OR=0.33). Mother-infant pair analyses showed the protective effect of Hap-A1 is dependent on its presence in the infant. Hap-A3 was associated with increased intrapartum transmission: WT/Hap-A3 was increased in intrapartum vs. non-transmitting mothers, and remained significant post mNVP and MVL correction (P=0.02; OR=3.50). This deleterious effect of Hap-A3 seemed dependent on its presence in the mother. Hap-2SNP was associated with lower CD4 count in the non-transmitting mothers (P=0.03). CCL3 Hap-A1 was associated with high CCL3L CN in total (P=0.001) and exposed-uninfected infants (P=0.006); the effect was not additive, however having either Hap-A1 or high CCL3L CN was more significantly (P=0.0008) associated with protection from in utero infection than Hap-A1 (P=0.028) or high CCL3L CN (P=0.002) alone. Linkage disequilibrium between Hap-A1 and high CCL3L CN appears unlikely given that a Nigerian population showed an opposite relationship.
PMCID: PMC3554858  PMID: 23151487
CCL3; CCL3L; HIV-1; Haplotypes; SNPs; Mother-to-child-transmission
15.  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 
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.
PMCID: PMC3570247  PMID: 17589368
AIDS vaccines; mathematical models; sexual behavior; heterosexual transmission; Africa; condoms; models/projections
16.  Identification and characterisation of vaginal lactobacilli from South African women 
Bacterial vaginosis (BV), which is highly prevalent in the African population, is one of the most common vaginal syndromes affecting women in their reproductive age placing them at increased risk for sexually transmitted diseases including infection by human immunodeficiency virus-1. The vaginal microbiota of a healthy woman is often dominated by the species belonging to the genus Lactobacillus namely L. crispatus, L. gasseri, L. jensenii and L. iners, which have been extensively studied in European populations, albeit less so in South African women. In this study, we have therefore identified the vaginal Lactobacillus species in a group of 40 African women from Soweto, a township on the outskirts of Johannesburg, South Africa.
Identification was done by cultivating the lactobacilli on Rogosa agar, de Man-Rogosa-Sharpe (MRS) and Blood agar plates with 5% horse blood followed by sequencing of the 16S ribosomal DNA. BV was diagnosed on the basis of Nugent scores. Since some of the previous studies have shown that the lack of vaginal hydrogen peroxide (H2O2) producing lactobacilli is associated with bacterial vaginosis, the Lactobacillus isolates were also characterised for their production of H2O2.
Cultivable Lactobacillus species were identified in 19 out of 21 women without BV, in three out of five women with intermediate microbiota and in eight out of 14 women with BV. We observed that L. crispatus, L. iners, L. jensenii, L. gasseri and L. vaginalis were the predominant species. The presence of L. crispatus was associated with normal vaginal microbiota (P = 0.024). High level of H2O2 producing lactobacilli were more often isolated from women with normal microbiota than from the women with BV, although not to a statistically significant degree (P = 0.064).
The vaginal Lactobacillus species isolated from the cohort of South African women are similar to those identified in European populations. In accordance with the other published studies, L. crispatus is related to a normal vaginal microbiota. Hydrogen peroxide production was not significantly associated to the BV status which could be attributed to the limited number of samples or to other antimicrobial factors that might be involved.
PMCID: PMC3600991  PMID: 23351177
Bacterial vaginosis; Lactobacillus; South Africa; Hydrogen peroxide
17.  Sexual Risk Behaviors Among HIV-Infected South African Men and Women with Their Partners in a Primary Care Program: Implications for Couples-Based Prevention 
AIDS and Behavior  2012;16(1):139-150.
We studied 1163 sexually-active HIV-infected South African men and women in an urban primary care program to understand patterns of sexual behaviors and whether these behaviors differed by partner HIV status. Overall, 40% reported a HIV-positive partner and 60% a HIV-negative or status unknown partner; and 17.5% reported >2 sex acts in the last 2 weeks, 16.4% unprotected sex in the last 6 months, and 3.7% >1 sex partner in the last 6 months. Antiretroviral therapy (ART) was consistently associated with decreased sexual risk behaviors, as well as with reporting a HIV-negative or status unknown partner. The odds of sexual risk behaviors differed by sex; and were generally higher among participants reporting a HIV-positive partner, but continued among those with a HIV-negative or status unknown partner. These data support ART as a means of HIV prevention. Engaging in sexual risk behaviors primarily with HIV-positive partners was not widely practiced in this setting, emphasizing the need for couples-based prevention.
PMCID: PMC3184366  PMID: 21476005
HIV; AIDS; South Africa; Sexual risk behavior; ART
18.  Willingness to participate in biomedical HIV prevention studies after the HVTN 503/Phambili trial: A survey conducted amongst adolescents in Soweto, South Africa 
Adolescents may be appropriate for inclusion in biomedical HIV prevention trials. Adolescents’ overall willingness to participate (WTP) in biomedical HIV preventive trials was examined, including after the prematurely discontinued phase IIB HVTN 503/Phambili HIV vaccine trial, in Soweto, South Africa.
An interview-administered cross-sectional survey was conducted among 506 adolescents (16–18 yo) between October 2008 and March 2009. The assessment included WTP in HIV prevention trials, sexual and substance use behavior, and related psychosocial constructs. Multivariate logistic regression analyses examined predictors of WTP in biomedical prevention trials.
The sample was primarily female (n=298, 59%) and 50% of all participants were sexually active. WTP in general was high (93%), with 75% WTP in a vaccine trial after being informed about the HVTN 503/Phambili trial. Less exposure to stressors (OR 2.8, CI: 1.3–6.3) was associated with adolescents’ WTP in HIV biomedical prevention trials overall. Those with less exposure to stressors (OR 1.7, CI: 1.1–2.8) and not sexually active (OR 2.1, CI: 1.4–3.3) were predictive of WTP after the HVTN 503/Phambili trial. A higher number of sexual partners was associated with unwillingness to participate more generally (p=0.039) and specifically after the HIV vaccine trial (p=0.0004).
The high level of adolescents’ WTP in biomedical prevention trials is encouraging, especially after the prematurely discontinued HVTN 503/Phambili HIV vaccine trial. High risk youth were less likely to be WTP, although those not yet sexually active were more WTP. Future biomedical HIV preventive trials should address challenges to enrollment of high-risk adolescents who may show less WTP.
PMCID: PMC3175322  PMID: 21765362
willingness to participate; HVTN 503/Phambili trial; Biomedical; HIV prevention
19.  New Regimens to Prevent Tuberculosis in Adults with HIV Infection 
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.
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.
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.
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.
PMCID: PMC3407678  PMID: 21732833
20.  Pregnancy Incidence and Correlates during the HVTN 503 Phambili HIV Vaccine Trial Conducted among South African Women 
PLoS ONE  2012;7(4):e31387.
HIV prevention trials are increasingly being conducted in sub-Saharan Africa. Women at risk for HIV are also at risk of pregnancy. To maximize safety, women agree to avoid pregnancy during trials, yet pregnancies occur. Using data from the HVTN 503/“Phambili” vaccine trial, we report pregnancy incidence during and after the vaccination period and identify factors, measured at screening, associated with incident pregnancy.
To enrol in the trial, women agreed and were supported to avoid pregnancy until 1 month after their third and final vaccination (“vaccination period”), corresponding to the first 7 months of follow-up. Unsterilized women, pooled across study arms, were analyzed. Poisson regression compared pregnancy rates during and after the vaccination period. Cox proportional hazards regression identified associations with first pregnancy.
Among 352 women (median age 23 yrs; median follow-up 1.5 yrs), pregnancy incidence was 9.6/100 women-years overall and 6.8/100 w-yrs and 11.3/100 w-yrs during and after the vaccination period, respectively [Rate Ratio = 0.60 (0.32–1.14), p = 0.10]. In multivariable analysis, pregnancy was reduced among women who: enrolled at sites providing contraception on-site [HR = 0.43, 95% CI (0.22–0.86)]; entered the trial as injectable contraceptive users [HR = 0.37 (0.21–0.67)] or as consistent condom users (trend) [HR = 0.54 (0.28–1.04)]. Compared with women with a single partner of HIV-unknown status, pregnancy rates were increased among women with: a single partner whose status was HIV-negative [HR = 2.34(1.16–4.73)] and; 2 partners both of HIV-unknown status [HR = 4.42(1.59–12.29)]. Women with 2 more of these risk factors: marijuana use, heavy drinking, or use of either during sex, had increased pregnancy incidence [HR = 2.66 (1.24–5.72)].
It is possible to screen South African women for pregnancy risk at trial entry. Providing injectable contraception for free on-site and supporting consistent condom use may reduce incident pregnancy. Screening should determine the substance use, partnering, and HIV status of both members of the couple for both pregnancy and HIV prevention.
Trial Registration
SA National Health Research Database DOH-27-0207-1539; NCT00413725
PMCID: PMC3331975  PMID: 22532824
21.  Natural Killer Cell Responses to HIV-1 Peptides are Associated With More Activating KIR Genes and HLA-C Genes of the C1 Allotype 
What characterizes individuals whose natural killer (NK) cells are able to respond to HIV-1 peptides is not known.
The association between NK cell responses and KIR gene profiles and HLA-B and HLA-C alleles was investigated among 76 HIV-1-infected women in South Africa previously categorized as responders (n = 39) or nonresponders (n = 37) to HIV-1 peptide pools in a whole blood intracellular cytokine assay. Viral load was significantly lower and CD4 T-cell counts higher among responders compared with nonresponders (P = 0.023 and P = 0.030, respectively).
Possession of one HLA-C1 allele associated with increased magnitude of NK cell responses to Env (P = 0.031) and significantly decreased viral load (P = 0.027) compared with its absence. There was a trend to increased possession of KIR2DL3+HLA-C1 in responders (71.8% vs 51.4%, P = 0.098) and decreased possession of KIR2DL3/2DL3+C2C2 (2.6% vs 16.2%, P = 0.053). A total of 64.1% of responders versus 32.4% of nonresponders had 13 or more KIR genes (P = 0.0067). Notably, the 13-KIR gene containing the Bx21 genotype (has eight inhibitory and three activating genes KIR2DS2, 2DS4, 2DS5) showed substantially higher representation among the responders (28.2% vs 2.6%, P = 0.001). A significantly higher proportion of responders had both KIR2DS2 and KIR2DS5 compared with either gene alone (72.4% vs 37%; P = 0.015). At least one HLA-C1 allele together with 13 or more KIR genes was associated with NK cell responsiveness (48.7% vs 13.5%; P = 0.001).
NK cell responses to HIV-1 peptides are more likely to occur among individuals with a genotype supporting a more activating NK cell phenotype and who possess at least one HLA-C1 allele.
PMCID: PMC3280081  PMID: 21407082
HIV-specific NK cell responses; KIR; HLA-B; HLA-C
22.  Antiretroviral Refusal among Newly Diagnosed HIV-Infected Adults in Soweto, South Africa 
AIDS (London, England)  2011;25(17):2177-2181.
To determine rates and predictors of treatment refusal in newly identified HIV-infected individuals in Soweto, South Africa
Cross-sectional Study.
We analyzed data from adult clients (> 18 years) presenting for voluntary counseling and testing (VCT) at the Zazi Testing Center, Perinatal HIV Research Unit to determine rates of antiretroviral therapy (ART) refusal among treatment-eligible, HIV-infected individuals (CD4+ <200 cells/mm3 or WHO stage 4). Multiple logistic regression models were used to investigate factors associated with refusal.
From December 2008 to December 2009, 7287 adult clients were HIV tested after counseling. 2562 (35%) were HIV-infected, of whom 743 (29%) were eligible for immediate ART. One-hundred and forty-eight (20%) refused referral to initiate ART, most of whom (92%) continued to refuse after 2 months of counseling. The leading reason for ART refusal was given as “feeling healthy” (37%), despite clients having a median CD4+ cell count of 110 cells/mm3 and triple the rate of active tuberculosis as seen in non-refusers. In adjusted models, single clients (AOR= 1.80, 95% CI: 1.06–3.06) and those with active tuberculosis (AOR = 3.50, 95% CI: 1.55–6.61) were more likely to refuse ART.
Nearly one in five treatment-eligible HIV-infected individuals in Soweto refused to initiate ART after VCT, putting them at higher risk for early mortality. “Feeling healthy” was given as the most common reason to refuse ART, despite a suppressed CD4+ count and co-morbidities, such as tuberculosis. These findings highlight the urgent need for research to inform interventions targeting ART refusers.
PMCID: PMC3272300  PMID: 21832935
africa; HIV; refusal; treatment; VCT
23.  Who gets tested for HIV in a South African urban township? Implications for test and treat and gender-based prevention interventions 
With increasing calls for linking HIV-infected individuals to treatment and care via expanded testing, we examined socio-demographic and behavioral characteristics associated with HIV testing among men and women in Soweto, South Africa.
We conducted a cross-sectional household survey involving 1539 men and 1877 women as part of the community-randomized prevention trial Project ACCEPT/HPTN043 between July 2007-October 2007. Multivariable logistic regression models, stratified by sex, assessed factors associated with HIV testing, and then repeated testing.
Most women (64.8%) and 28.9% of men reported ever having been tested for HIV, among whom 57.9% reported repeated HIV testing. In multivariable analyses, youth and students had a lower odds of HIV testing. Men and women who had conversations about HIV/AIDS with increasing frequency and who had heard about antiretroviral therapy were more likely to report HIV testing, as well as repeated testing. Men who had ≥12 years of education and who were of high socio-economic status; and women who were married, who were of low socio-economic status, and who had children under their care had a higher odds of HIV testing. Women, older individuals, those with higher levels of education, married individuals, and those with children under their care had a higher odds of reporting repeated HIV testing. Uptake of HIV testing was not associated with condom use, having multiple sex partners, and HIV-related stigma.
Given the low uptake of HIV testing among men and youth, further targeted interventions could facilitate a test and treat strategy among urban South Africans.
PMCID: PMC3137901  PMID: 21084993
HIV; AIDS; VCT; testing; Africa
24.  Progression and Regression of Pre-malignant Cervical Lesions in HIV-infected Women from Soweto: A Prospective Cohort 
AIDS (London, England)  2011;25(1):87-94.
To ascertain progression and regression of cervical dysplasia in HIV-infected women in Soweto.
Prospective cohort
Women attending an HIV wellness clinic were offered cervical smears as part of care; smears were assessed using the Bethesda system. Those with high grade lesions or worse were referred for colposcopy. Progression analyses included women with at least two smears ≥5.5 months apart. Hazard ratios (HR) were used to ascertain predictors of progression.
2,325 women had a baseline smear; their median age and CD4 count was 32 yrs and 312 cells/μl respectively; 17% were taking highly active antiretroviral therapy (HAART); 62%, 20% and 14% had normal, low grade squamous intraepithelial lesions (LSIL) or high grade squamous intraepithelial lesions (HSIL), respectively. Of those with baseline normal or LSIL smears, 1,074 had another smear; progression from normal to LSIL was 9.6/100py (95% CI 8.3-11.1) and progression from normal or LSIL to HSIL was 4.6/100py (95% CI 3.9-5.5). Of 225 women with LSIL at baseline and ≥1 subsequent smear ≥11.5 months later, 44.0% regressed to normal (21.2/100py (95% CI 17.5-25.7)). Multivariate models suggested risk for progression in women with CD4 count <200; HAART reduced the risk of progression (aHR 0.72 [0.52-0.99]).
HIV-infected women have high rates of prevalent and incident HSIL and LSIL with relatively low risk of regression to normal from LSIL. HAART appears to protect against progression. Our findings suggest cervical screening intervals should be less than 10 years - irrespective of age in women with CD4 counts under 500 cells/mm3.
PMCID: PMC3166782  PMID: 21076276
antiretroviral therapy; cohort; squamous intraepithelial lesion; CD4; cervical cancer; HPV
25.  Decreased sexual risk behavior in the era of HAART among HIV-infected urban and rural South Africans attending primary care clinics 
AIDS (London, England)  2010;24(17):2687-2696.
In light of increasing access to highly active antiretroviral treatment (HAART) in sub-Saharan Africa, we conducted a longitudinal study to assess the impact of HAART on sexual risk behaviors among HIV-infected South Africans in urban and rural primary care clinics.
Prospective observational cohort study.
We conducted a cohort study at rural and urban primary care HIV clinics in South Africa consisting of 1544 men and 4719 women enrolled from 2003–2010, representing 19703 clinic visits. The primary outcomes were being sexually active, unprotected sex, and >1 sex partner and were evaluated at six monthly intervals. Generalized estimated equations assessed the impact of HAART on sexual risk behaviors.
Among 6263 HIV-infected men and women, over a third (37.2%) initiated HAART during study follow-up. In comparison to pre-HAART follow-up, visits while receiving HAART were associated with a decrease in those reporting being sexually active (AOR: 0.86 [95% CI: 0.78–0.95]). Unprotected sex and having >1 sex partner were reduced at visits following HAART initiation compared to pre-HAART visits (AOR: 0.40 [95% CI: 0.34–0.46] and AOR: 0.20 [95% CI: 0.14–0.29], respectively).
Sexual risk behavior significantly decreased following HAART initiation among HIV-infected South African men and women in primary care programs. The further expansion of antiretroviral treatment programs could enhance HIV prevention efforts in Africa.
PMCID: PMC3130627  PMID: 20808202
South Africa; HAART; antiretroviral therapy; sexual behavior; HIV transmission; AIDS; HIV

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