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Objective: To determine rates and predictors of treatment refusal in newly identified HIV-infected individuals in Soweto, South Africa., Design: It is designed as a cross-sectional study., Methods: 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(+) cell count < 200 cells/μl or WHO stage 4). Multiple logistic regression models were used to investigate factors associated with refusal., Results: From December 2008 to December 2009, 7287 adult clients were HIV tested after counseling. Two thousand, five hundred and sixty-two (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/μl and triple the rate of active tuberculosis as seen in nonrefusers. In adjusted models, single clients [adjusted odds ratio (AOR) 1.80, 95% confidence interval (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., Conclusion: 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 comorbidities such as tuberculosis. These findings highlight the urgent need for research to inform interventions targeting ART refusers.

Objective: To ascertain progression and regression of cervical dysplasia in HIV-infected women in Soweto., Design: Prospective cohort., Methods: 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 at least 5.5 months apart. Hazard ratios were used to ascertain predictors of progression., Results: Two thousand, three hundred and twenty-five women had a baseline smear; their median age and CD4 cell count was 32 years 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, 1074 had another smear; progression from normal to LSIL was 9.6/100 person-years (95% CI 8.3-11.1) and progression from normal or LSIL to HSIL was 4.6/100 person-years (95% CI 3.9-5.5). Of 225 women with LSIL at baseline and at least one subsequent smear at least 11.5 months later, 44.0% regressed to normal (21.2/100 person-years (95% CI 17.5-25.7)). Multivariate models suggested increasing risk for progression in women with CD4 cell count below 500 cells/μl and HAART may reduce the risk of progression [adjusted hazard ratio (aHR) 0.72 (0.52-0.99)]., Conclusion: 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 cell counts below 500 cells/μl.

Objective: In light of increasing access to 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., Design: Prospective observational cohort., Methods: 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 to 2010, representing 19703 clinic visits. The primary outcomes were being sexually active, unprotected sex, and more than one sex partner and were evaluated at 6 monthly intervals. Generalized estimated equations assessed the impact of HAART on sexual risk behaviors., Results: 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 [adjusted odds ratio: 0.86 (95% confidence interval: 0.78-0.95)]. Unprotected sex and having more than one sex partner were reduced at visits following HAART initiation compared to pre-HAART visits [adjusted odds ratio: 0.40 (95% confidence interval: 0.34-0.46) and adjusted odds ratio: 0.20 (95% confidence interval: 0.14-0.29), respectively]., Conclusion: 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.

Background: High BMI has been shown to be protective against tuberculosis (TB) among HIV-uninfected individuals, as well as against disease progression and mortality among those with HIV. We examined the effect of BMI on all-cause mortality and TB incidence among a cohort of HIV-infected adults in Soweto, South Africa., Methods: A clinical cohort of 3456 HIV-infected adults from South Africa was prospectively followed from 2003 to 2008 with regular monitoring. The primary exposure was BMI and the outcomes of interest were all-cause mortality and a newly diagnosed episode of TB. Cox proportional hazard models assessed associations with risk of mortality or incident TB., Results: Incidence rates of mortality were 10.4/100 person-years for baseline BMI of 18.5 or less, 3.6/100 person-years for baseline BMI 18.6-25, 1.7/100 person-years for baseline BMI 25.1-30, and 1.6/100 person-years for baseline BMI more than 30. Compared to those with normal BMI, overweight and obese participants had a significantly reduced risk of mortality [adjusted hazard ratio 0.59 (95% confidence interval, CI 0.40-0.87) and 0.48 (95% CI 0.29-0.80), respectively]. Incidence rates of TB by baseline BMI were 7.3/100 person-years for underweight, 6.0/100 person-years for normal, 3.2/100 person-years for overweight, and 1.9/100 person-years for obese. Compared to those with normal BMI, those with overweight and obese BMI were at a significantly reduced risk of developing TB [adjusted hazard ratio 0.56 (95% CI 0.38-0.83) and 0.33 (95% CI 0.19-0.55), respectively]., Conclusion: HIV-infected individuals with obese and overweight BMI have a significantly reduced risk of both mortality and TB, after adjusting for HAART use and CD4 cell count.

Background: There are few data describing the specificity, breadth and magnitude of T cell responses to HIV-1 in infancy., Methods: HIV-specific CD8+ and CD4+ T cell responses to peptide pools representing Gag, Env, Pol, Nef and the regulatory regions (Reg) were simultaneously measured in 18 perinatally-infected infants and 14 of their chronically-infected mothers, using a whole blood interleukin-2 and interferon-gamma flow cytometric intracellular cytokine staining assay., Results: HIV-specific CD8+ T cell responses were detected in all the infants aged 6 weeks and older (range 0.1-6.62%) and their mothers (range 0.1-4.89%). HIV-specific CD4+ T cell responses were detected in 33% of the infants (range 0.11-0.54%) and 73% of the mothers (range 0.16-0.84). CD8+ T cell responses in the mothers were almost equally spread between the variable (Nef, Reg and Env) and conserved proteins (Gag and Pol). Conversely, CD8+ T cell responses to the more variable proteins dominated in the perinatally-infected infants comprising 74% of the total response. Interestingly, mothers and infants shared responses to at least one peptide pool, whereas only one mother-infant pair shared a peptide pool targeted by CD4+ T cells. Two in-utero-infected infants tested at birth had CD8+ T cell responses, and one of them had an Env-specific CD4 T cell response., Conclusion: Our observations that HIV-specific CD8+ and CD4+ T cell responses can be detected in perinatally-infected infants from 6 weeks of age and that CD8+ T cell responses predominantly target the variable proteins have important implications for HIV vaccine design.

Objective: To assess the impact of prior exposure to single-dose nevirapine (sdNVP) on mother-to-child transmission and genotypic resistance in HIV-infected women., Design: Prospective study of 120 women exposed to the HIVNET 012 sdNVP regimen in two successive pregnancies and 240 antiretroviral (ARV)-naïve, multiparous women who received sdNVP for the first time., Results: One hundred and eight of 120 and 193 of 240 women returned for a postpartum visit by 6 weeks. HIV-1 was detected in 11.1% (95% confidence interval = 5.9-18.6) of the infants of women previously exposed to sdNVP and 4.2% (95% confidence interval = 1.3-7.0) of those exposed for the first time (P = 0.028). Rates of maternal HIV-1 genotypic resistance at 6 weeks postdelivery were 37.5% and 46.4%, respectively (P = 0.119). Sensitive mutation-specific real-time PCR testing found three of 12 previously exposed women who transmitted HIV-1 to their infants had either K103N or Y181C at baseline compared with one of eight ARV-naïve, transmitting women who had Y181C. None of 40 randomly selected nontransmitting women from either group had detectable NVP resistance mutations prior to sdNVP exposure., Conclusion: This study shows that effectiveness of sdNVP may be compromised by prior exposure to sdNVP, although the increase in transmission rate after prior exposure could not be explained by the detection of NVP resistance mutations prior to re-exposure as measured both by standard genotyping and highly sensitive allele-specific PCR assays. Furthermore, transmission rates of women with prior exposure were not higher than those reported elsewhere.

Background: 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., Methods: 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., Results: 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)., Conclusion: 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.

Background: 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., Method: 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 ( approximately 10% transmission rate) and 235 randomly selected non-transmitting pairs., Results: 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., Conclusion: 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.

Background: Single-dose nevirapine (NVP) prophylaxis to mother and infant is widely used in resource-constrained settings for preventing mother-to-child transmission (MTCT) of HIV-1. Where women do not access antenatal care or HIV testing, postexposure prophylaxis to the infant may be an important preventative strategy., Methods: This multicentre, randomized, open-label clinical trial (October 2000 to September 2002) in South Africa compared single-dose NVP with 6 weeks of zidovudine (ZDV), commenced within 24 h of delivery among 1051 infants whose mothers had no prior antiretroviral therapy. HIV-1 infection rates were ascertained at birth, and at 6 and 12 weeks of age. Kaplan-Meier survival methods were used to estimate HIV-1 infection rates in an intention-to-treat analysis., Results: Overall, 6 week and 12 week MTCT probability was 12.8% [95% confidence interval (CI),10.5-15.0] and 16.3% (95% CI,13.4-19.2), respectively. At 12 weeks, among infants who were not infected at birth, 24 (7.9%) infections occurred in the NVP arm and 41 (13.1%) in the ZDV arm (log rank P = 0.06). Using multivariate analysis, factors associated with infection following birth were ZDV use [odds ratio (OR), 1.8; 95% CI,1.1-3.2; P = 0.032), maternal CD4 cell count < 500 x 10(6) cells/l (OR, 2.5; 95% CI,1.3-5.0; P = 0.007), maternal viral load > 50 000 copies/ml (OR, 3.6; 95% CI,2.0-6.2; P < 0.0001) and breastfeeding (OR, 2.2; 95% CI,1.3-3.8; P = 0.006)., Conclusion: A single-dose of NVP given to infants offers protection against HIV-1 infection and should be a strategy used in infants of mothers with untreated HIV infection.