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1.  Sensitive Tenofovir Resistance Screening of HIV-1 From the Genital and Blood Compartments of Women With Breakthrough Infections in the CAPRISA 004 Tenofovir Gel Trial 
The Journal of Infectious Diseases  2014;209(12):1916-1920.
The Centre for the AIDS Programme of Research in South Africa 004 (CAPRISA 004) study demonstrated that vaginally applied tenofovir gel is a promising intervention for protecting women from sexually acquiring human immunodeficiency virus (HIV). However, the potential for emergence of tenofovir resistance remains a concern in women who seroconvert while using the gel despite the lack of plasma virus resistance as assessed by population sequencing during the trial. We applied highly sensitive polymerase chain reaction–based assays to screen for tenofovir resistance in plasma and vaginal swab specimens. The absence of mutation detection suggested little immediate risk of tenofovir-resistant HIV-1 emergence and forward transmission in settings in which gel users are closely monitored for HIV seroconversion.
doi:10.1093/infdis/jiu026
PMCID: PMC4038144  PMID: 24436453
Vaginal microbicide; HIV prevention; pre-exposure prophylaxis; tenofovir gel; topical PrEP
2.  Enrolling Adolescents in Research on HIV and Other Sensitive Issues: Lessons from South Africa 
PLoS Medicine  2006;3(7):e180.
Jerome Singh and colleagues present the ethical and legal challenges surrounding the enrollment of adolescents in HIV observational studies and other types of sensitive research.
doi:10.1371/journal.pmed.0030180
PMCID: PMC1435780  PMID: 16608384
3.  Features of Recently Transmitted HIV-1 Clade C Viruses that Impact Antibody Recognition: Implications for Active and Passive Immunization 
PLoS Pathogens  2016;12(7):e1005742.
The development of biomedical interventions to reduce acquisition of HIV-1 infection remains a global priority, however their potential effectiveness is challenged by very high HIV-1 envelope diversity. Two large prophylactic trials in high incidence, clade C epidemic regions in southern Africa are imminent; passive administration of the monoclonal antibody VRC01, and active immunization with a clade C modified RV144-like vaccines. We have created a large representative panel of C clade viruses to enable assessment of antibody responses to vaccines and natural infection in Southern Africa, and we investigated the genotypic and neutralization properties of recently transmitted clade C viruses to determine how viral diversity impacted antibody recognition. We further explore the implications of these findings for the potential effectiveness of these trials. A panel of 200 HIV-1 Envelope pseudoviruses was constructed from clade C viruses collected within the first 100 days following infection. Viruses collected pre-seroconversion were significantly more resistant to serum neutralization compared to post-seroconversion viruses (p = 0.001). Over 13 years of the study as the epidemic matured, HIV-1 diversified (p = 0.0009) and became more neutralization resistant to monoclonal antibodies VRC01, PG9 and 4E10. When tested at therapeutic levels (10ug/ml), VRC01 only neutralized 80% of viruses in the panel, although it did exhibit potent neutralization activity against sensitive viruses (IC50 titres of 0.42 μg/ml). The Gp120 amino acid similarity between the clade C panel and candidate C-clade vaccine protein boosts (Ce1086 and TV1) was 77%, which is 8% more distant than between CRF01_AE viruses and the RV144 CRF01_AE immunogen. Furthermore, two vaccine signature sites, K169 in V2 and I307 in V3, associated with reduced infection risk in RV144, occurred less frequently in clade C panel viruses than in CRF01_AE viruses from Thailand. Increased resistance of pre-seroconversion viruses and evidence of antigenic drift highlights the value of using panels of very recently transmitted viruses and suggests that interventions may need to be modified over time to track the changing epidemic. Furthermore, high divergence such as that observed in the older clade C epidemic in southern Africa may impact vaccine efficacy, although the correlates of infection risk are yet to be defined in the clade C setting. Findings from this study of acute/early clade C viruses will aid vaccine development, and enable identification of new broad and potent antibodies to combat the HIV-1 C-clade epidemic in southern Africa.
Author Summary
Vaccine and passive immunization prophylactic trials that rely on antibody-mediated protection are planned for HIV-1 clade C epidemic regions of southern Africa, which have amongst the highest HIV-1 incidences globally. This includes a phase 2b trial of passively administered monoclonal antibody, VRC01; as well as a phase 3 trial using the clade C modified version of the partially efficacious RV144 vaccine. The extraordinary diversity of HIV-1 poses a major obstacle to these interventions, and our study aimed to determine the implications of viral diversity on antibody recognition. Investigations using our panel of very early viruses augment current knowledge of vulnerable targets on transmitted viruses for vaccine design and passive immunization studies. Evidence of antigenic drift with viruses becoming more resistant over time suggests that these prevention modalities will need to be updated over time and that combinations of antibodies will be necessary to achieve coverage in passive immunization studies. We further show that it may be more difficult to obtain protection in the genetically diverse clade C epidemic compared to RV144 where the epidemic is less diverse, although it should be noted that the correlates of infection risk are yet to be defined in the clade C setting.
doi:10.1371/journal.ppat.1005742
PMCID: PMC4951126  PMID: 27434311
4.  Genital Inflammation and the Risk of HIV Acquisition in Women 
In a these South African women, the risk of human immunodeficiency virus (HIV) acquisition was higher in those with persistently raised genital inflammatory cytokine concentrations (including HIV target cell–recruiting chemokines macrophage inflammatory protein (MIP)-1α, MIP-1β, and interferon-γ inducible protein-10).
Background. Women in Africa, especially young women, have very high human immunodeficiency virus (HIV) incidence rates that cannot be fully explained by behavioral risks. We investigated whether genital inflammation influenced HIV acquisition in this group.
Methods. Twelve selected cytokines, including 9 inflammatory cytokines and chemokines (interleukin [IL]-1α, IL-1β, IL-6, tumor necrosis factor-α, IL-8, interferon-γ inducible protein-10 [IP-10], monocyte chemoattractant protein-1, macrophage inflammatory protein [MIP]-1α, MIP-1β), hematopoietic IL-7, and granulocyte macrophage colony-stimulating factor, and regulatory IL-10 were measured prior to HIV infection in cervicovaginal lavages from 58 HIV seroconverters and 58 matched uninfected controls and in plasma from a subset of 107 of these women from the Centre for the AIDS Programme of Research in South Africa 004 tenofovir gel trial.
Results. HIV seroconversion was associated with raised genital inflammatory cytokines (including chemokines MIP-1α, MIP-1β, and IP-10). The risk of HIV acquisition was significantly higher in women with evidence of genital inflammation, defined by at least 5 of 9 inflammatory cytokines being raised (odds ratio, 3.2; 95% confidence interval, 1.3–7.9; P = .014). Genital cytokine concentrations were persistently raised (for about 1 year before infection), with no readily identifiable cause despite extensive investigation of several potential factors, including sexually transmitted infections and systemic cytokines.
Conclusions. Elevated genital concentrations of HIV target cell–recruiting chemokines and a genital inflammatory profile contributes to the high risk of HIV acquisition in these African women.
doi:10.1093/cid/civ298
PMCID: PMC4565995  PMID: 25900168
HIV transmission; female genital tract; inflammation; cytokine
5.  HIV-Positive Status Disclosure in Patients in Care in Rural South Africa: Implications for Scaling up Treatment and Prevention Interventions 
AIDS and behavior  2015;19(2):322-329.
A nuanced understanding of HIV-positive status disclosure is urgently needed to inform the implementation of prevention interventions, including TasP and PrEP. To provide such understanding for the high HIV-burden setting of rural KwaZulu-Natal, we conducted a prospective cohort study to characterize determinants and trends in HIV-positive status disclosure. 687 consenting HIV-positive individuals (73.2% female; 60.3% ART initiated) were enrolled. Reports of any incidence of disclosure to either a family member or sexual partner at enrollment and follow-up visits (median 4.4 months post-enrolment) were common (91.0%); however, reports of disclosure specifically to sexual partners were relatively rare (34.1%), especially in women (29.8%). Participants not engaged in a stable partnerships, not ART-imitated, and/or who had disclosed to their family were at risk of non-disclosure to sexual partners. These data highlight both an urgent need to empower HIV-positive individuals, and the significant barriers to targeting sero-discordant couples for HIV prevention in this setting.
doi:10.1007/s10461-014-0951-4
PMCID: PMC4345171  PMID: 25677128
Status disclosure; rural South Africa; HIV prevention; treatment; anti-retroviral therapy
6.  Strengthening HIV surveillance in the antiretroviral therapy era: rationale and design of a longitudinal study to monitor HIV prevalence and incidence in the uMgungundlovu District, KwaZulu-Natal, South Africa 
BMC Public Health  2015;15:1149.
Background
South Africa has over 6,000,000 HIV infected individuals and the province of KwaZulu-Natal (KZN) is the most severely affected. As public health initiatives to better control the HIV epidemic are implemented, timely, detailed and robust surveillance data are needed to monitor, evaluate and inform the programmatic interventions and policies over time. We describe the rationale and design of the HIV Incidence Provincial Surveillance System (HIPSS) to monitor HIV prevalence and incidence.
Methods/Design
The household-based survey will include a sample of men and women from two sub-districts of the uMgungundlovu municipality (Vulindlela and the Greater Edendale) of KZN, South Africa. The study is designed as two sequential cross-sectional surveys of 10,000 randomly selected individuals aged 15–49 years to be conducted one year apart. From the cross sectional surveys, two sequential cohorts of HIV negative individuals aged 15–35 years will be followed-up one year later to measure the primary outcome of HIV incidence. Secondary outcomes include the laboratory measurements for pulmonary tuberculosis, sexually transmitted infections and evaluating tests for estimating population-level HIV incidence.
Antiretroviral therapy (ART) access, HIV-1 RNA viral load, and CD4 cell counts in HIV positive individuals will assess the effectiveness of the HIV treatment cascade. Household and individual-level socio-demographic characteristics, exposure to HIV programmatic interventions and risk behaviours will be assessed as predictors of HIV incidence. The incidence rate ratio of the two cohorts will be calculated to quantify the change in HIV incidence between consecutive samples. In anticipation of better availability of population-level HIV prevention and treatment programmes leading to decreases in HIV incidence, the sample size provides 84 % power to detect a reduction of 30 % in the HIV incidence rate between surveys.
Discussion
The results from HIPSS will provide critical data regarding HIV prevalence and incidence in this community and will establish whether HIV prevention and treatment efforts in a “real world”, non-trial setting have an impact on HIV incidence at a population level. Importantly, the study design and methods will inform future methods for HIV surveillance.
doi:10.1186/s12889-015-2179-2
PMCID: PMC4654918  PMID: 26588902
7.  The need for multipurpose prevention technologies in sub-Saharan Africa 
Women bear a disproportionate burden of the HIV epidemic in sub-Saharan Africa and account for about 60% of all adults living with HIV in that region. Young women, including adolescent girls, unable to negotiate mutual faithfulness and/or condom use with their male partners are particularly vulnerable. In addition to the high HIV burden, women in Africa also experience high rates of other sexually transmitted infections and unwanted pregnancies. The development of technologies that can simultaneously meet these multiple sexual reproductive health needs would therefore be extremely beneficial in the African setting.
doi:10.1111/1471-0528.12842
PMCID: PMC4206830  PMID: 25335838
8.  Assessing the implementation effectiveness and safety of 1% tenofovir gel provision through family planning services in KwaZulu-Natal, South Africa: study protocol for an open-label randomized controlled trial 
Trials  2014;15:496.
Background
The Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial demonstrated a 39% reduction in HIV infection, with a 54% HIV reduction in women who used tenofovir gel consistently. A confirmatory trial is expected to report results in early 2015. In the interim, we have a unique window of opportunity to prepare for and devise effective strategies for the future policy and programmatic scale-up of tenofovir gel provision. One approach is to integrate tenofovir gel provision into family planning (FP) services. The CAPRISA 008 implementation trial provides an opportunity to provide post-trial access to tenofovir gel while generating empiric evidence to assess whether integrating tenofovir gel provision into routine FP services can achieve similar levels of adherence as the CAPRISA 004 trial.
Methods/design
This is a two-arm, open-label, randomized controlled non-inferiority trial. A maximum of 700 sexually active, HIV-uninfected women aged 18 years and older who previously participated in an antiretroviral prevention study will be enrolled from an urban and rural site in KwaZulu-Natal, South Africa. The anticipated study duration is 30 months, with active accrual requiring approximately 12 months (following which an open cohort will be maintained) and follow-up continuing for approximately 18 months. At each of the two sites, eligible participants will be randomly assigned to receive tenofovir gel through either FP services (intervention arm) or through the CAPRISA research clinics (control arm). As part of the study intervention, a quality improvement approach will be used to assist the FP services to expand their current services to include tenofovir gel provision.
Discussion
This protocol aims to address an important implementation question on whether FP services are able to effectively incorporate tenofovir gel provision for this at-risk group of women in South Africa. Provision of tenofovir gel to the women from the CAPRISA 004 trial meets the ethical obligation for post-trial access, and helps identify a potential avenue for future scale-up of microbicides within the public health system of South Africa.
Trial registration
This trial was registered with the South Africa Department of Health (reference: DOH-27-0812-4129) and ClinicalTrials.gov (reference: NCT01691768) on 05 July 2012.
doi:10.1186/1745-6215-15-496
PMCID: PMC4300828  PMID: 25527071
South Africa; HIV prevention; Microbicide; Tenofovir gel; Health systems strengthening; Implementation
9.  Low adverse event rates following voluntary medical male circumcision in a high HIV disease burden public sector prevention programme in South Africa 
Introduction
The provision of voluntary medical male circumcision (VMMC) services was piloted in three public sector facilities in a high HIV disease burden, low circumcision rate province in South Africa to inform policy and operational guidance for scale-up of the service for HIV prevention. We report on adverse events (AEs) experienced by clients following the circumcision procedure.
Methods
Prospective recruitment of HIV-negative males aged 12 and older volunteering to be circumcised at three select public health facilities in KwaZulu-Natal between November 2010 and May 2011. Volunteers underwent standardized medical screening including a physical assessment prior to the surgical procedure being performed. AEs were monitored at three time intervals over a 21-day period post-operatively to determine safety outcomes in this pilot demonstration programme.
Results
A total of 602 volunteers participated in this study. The median age of the volunteers was 22 years (range 12–56). Most participants (75.6%) returned for the 48-hour post-operative visit; 51.0% for day seven visit and 26.1% for the 21st day visit. Participants aged 20–24 were most likely to return. The AE rate was 0.2% intra-operatively. The frequency of moderate AEs was 0.7, 0.3 and 0.6% at 2-, 7- and 21-day visits, respectively. The frequency of severe AEs was 0.4, 0.3 and 0.6% at 2-, 7- and 21-day visits, respectively. Swelling and wound infection were the most common AEs with mean appearance duration of seven days. Clients aged between 35 and 56 years presented with most AEs (3.0%).
Conclusions
VMMC can be delivered safely at resource-limited settings. The intensive three-visit post-operative review practice may be unfeasible due to high attrition rates over time, particularly amongst older men.
doi:10.7448/IAS.17.1.19275
PMCID: PMC4236629  PMID: 25406951
medical male circumcision; HIV prevention; adverse events; follow-up visit
10.  ARV-based HIV prevention for women – where we are in 2014 
Journal of the International AIDS Society  2014;17(3Suppl 2):19154.
Women continue to be at special risk for HIV acquisition due to a complex mix of biological, behavioural, structural, cultural and social factors, with unacceptable rates of new infection. Scientific advances over the past decade have highlighted the use of antiretroviral (ARV) drugs as pre-exposure prophylaxis (PrEP) to prevent HIV acquisition (sexually, parenterally and vertically) and ARV treatment (ART) for HIV-positive patients to prevent onward transmission (treatment as prevention – TasP). This paper reviews the evidence base for PrEP and TasP, describes new products in development and the need to translate research findings into programmes with impact at the population level.
doi:10.7448/IAS.17.3.19154
PMCID: PMC4164013  PMID: 25224614
HIV; AIDS; antiretroviral agents; women; HIV prevention; HIV treatment; PrEP
11.  Limited HIV-1 Superinfection in Seroconverters from the CAPRISA 004 Microbicide Trial 
Journal of Clinical Microbiology  2014;52(3):844-848.
HIV-1 superinfection (SI) occurs when an infected individual acquires a distinct new viral strain. The rate of superinfection may be reflective of the underlying HIV risk in a population. The Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 clinical trial demonstrated that women who used a tenofovir-containing microbicide gel had lower rates of HIV infection than women using a placebo gel. Women who contracted HIV-1 during the trial were screened for the occurrence of superinfection by next-generation sequencing of the viral gag and env genes. There were two cases (one in each trial arm) of subtype C superinfection identified from the 76 women with primary infection screened at two time points (rate of superinfection, 1.5/100 person-years). Both women experienced a >0.5-log increase in viral load during the window when superinfection occurred. The rate of superinfection was significantly lower than the overall primary HIV incidence in the microbicide trial (incidence rate ratio [IRR], 0.20; P = 0.003). The women who seroconverted during the trial reported a significant increase in sexual contact with their stable partner 4 months after seroconversion (P < 0.001), which may have lowered the risk of superinfection in this population. The lower frequency of SI compared to the primary incidence is in contrast to a report from a general heterosexual African population but agrees with a study of high-risk women in Kenya. A better understanding of the rate of HIV superinfection could have important implications for ongoing HIV vaccine research.
doi:10.1128/JCM.03143-13
PMCID: PMC3957790  PMID: 24371237
12.  Honing in on enteric fever 
eLife  2014;3:e03545.
The use of metabolomics could lead to improved diagnostics for enteric fever.
doi:10.7554/eLife.03545
PMCID: PMC4077202  PMID: 24986861
metabolites; mass spectrometry; enteric fever; typhoid; Salmonella Typhi; Salmonella Paratyphi A; human
13.  Neither microbial translocation nor TLR responsiveness are likely explanations for pre-existing immune activation in women who subsequently acquired HIV in CAPRISA004 
Journal of acquired immune deficiency syndromes (1999)  2013;63(3):10.1097/QAI.0b013e31828e604b.
Innate immune activation was a strong predictor of HIV acquisition in women at risk for HIV in CAPRISA004. Identifying the cause/s of activation could enable targeted prevention interventions. In this study, plasma concentrations of lipopolysaccharide, soluble CD14 and intestinal fatty-acid binding protein did not differ between subjects who did or did not subsequently acquire HIV, nor were these levels correlated with plasma cytokines or natural killer cell activation. There was no difference between HIV-acquirers and non-acquirers in the chemokine and cytokine responses of peripheral blood mononuclear cells stimulated with TLR2, 4 or 7/8 agonists. Further studies are required.
doi:10.1097/QAI.0b013e31828e604b
PMCID: PMC3683111  PMID: 23481666
HIV; microbial translocation; LPS; sCD14; I-FABP; TLR2; TLR4; TLR7/8; immune activation
14.  Antiretroviral prophylaxis: a defining moment for HIV prevention 
Lancet  2011;378(9809):e23-e25.
doi:10.1016/S0140-6736(11)61136-7
PMCID: PMC3253379  PMID: 21771566
15.  Sustainability of task-shifting for antiretroviral treatment 
Lancet  2012;380(9857):1907-1908.
doi:10.1016/S0140-6736(12)62110-2
PMCID: PMC3616248  PMID: 23200500
16.  Innate Immune Activation Enhances HIV Acquisition in Women, Diminishing the Effectiveness of Tenofovir Microbicide Gel 
The Journal of Infectious Diseases  2012;206(7):993-1001.
The antiretroviral agent, tenofovir, formulated as a vaginal microbicide gel, reduces human immunodeficiency virus (HIV) acquisition by 39% in women. This study assessed the role of preexisting immune activation in HIV acquisition in women from the CAPRISA 004 trial, to identify potential strategies to increase the effectiveness of tenofovir gel. Systemic cytokine and cellular immune mediators (platelets and natural killer [NK] cells) were assessed in women at high risk for HIV assigned to either tenofovir or placebo gel in the CAPRISA 004 trial. Notwithstanding tenofovir gel use, women who acquired HIV had significantly higher systemic innate immune activation prior to infection than women who remained uninfected. Activation of both soluble (cytokine) and cellular (NK cells) immune mediators were associated with HIV acquisition, individually or in combination. Hence, an innate immune activation suppressant could be added to tenofovir gel as a potential combination gel strategy in developing the next generation of higher efficacy antiretroviral microbicides.
doi:10.1093/infdis/jis465
PMCID: PMC3501691  PMID: 22829639
17.  Ratio of Monocytes to Lymphocytes in Peripheral Blood Identifies Adults at Risk of Incident Tuberculosis Among HIV-Infected Adults Initiating Antiretroviral Therapy 
The Journal of Infectious Diseases  2013;209(4):500-509.
Background. Eight decades ago, the ratio of monocytes to lymphocytes (hereafter, the “ML ratio”) was noted to affect outcomes of mycobacterial infection in rabbits. Recent transcriptomic studies support a role for relative proportions of myeloid and lymphoid transcripts in tuberculosis outcomes. The ML ratio in peripheral blood is known to be governed by hematopoietic stem cells with distinct biases.
Methods. The predictive value of the baseline ML ratio was modeled in 2 prospective cohorts of HIV-infected adults starting cART in South Africa (primary cohort, 1862 participants; replication cohort, 345 participants). Incident tuberculosis was diagnosed with clinical, radiographic, and microbiologic methods per contemporary guidelines. Kaplan-Meier survival analyses and Cox proportional hazards modeling were conducted.
Results. The incidence rate of tuberculosis differed significantly by baseline ML ratio: 32.61 (95% confidence interval [CI], 15.38–61.54), 16.36 (95% CI, 12.39–21.23), and 51.80 (95% CI, 23.10–101.71) per 1000 patient-years for ML ratios of less than the 5th percentile, between the 5th and 95th percentiles, and greater than the 95th percentile, respectively (P = .007). Neither monocyte counts nor lymphocyte counts alone were associated with tuberculosis. After adjustment for sex, World Health Organization human immunodeficiency virus disease stage, CD4+ T-cell counts, and previous history of tuberculosis, hazards of disease were significantly higher for patients with ML ratios of less than the 5th percentile or greater than the 95th percentile (adjusted hazard ratio, 2.47; 95% CI, 1.39–4.40; P = .002).
Conclusions. The ML ratio may be a useful, readily available tool to stratify the risk of tuberculosis and suggests involvement of hematopoietic stem cell bias in tuberculosis pathogenesis.
doi:10.1093/infdis/jit494
PMCID: PMC3903371  PMID: 24041796
tuberculosis; HIV; combination antiretroviral therapy; monocytes; lymphocytes; ML ratio
18.  Genital Tract Inflammation During Early HIV-1 Infection Predicts Higher Plasma Viral Load Set Point in Women 
The Journal of Infectious Diseases  2012;205(2):194-203.
Background. The biggest challenge in human immunodeficiency virus type 1 (HIV-1) prevention in Africa is the high HIV-1 burden in young women. In macaques, proinflammatory cytokine production in the genital tract is necessary for target cell recruitment and establishment of simian immunodeficiency virus (SIV) infection following vaginal inoculation. The purpose of this study was to assess if genital inflammation during early HIV-1 infection predisposes women to rapid disease progression.
Methods. Inflammatory cytokine concentrations were measured in cervicovaginal lavage (CVL) from 49 women 6, 17, 30, and 55 weeks after HIV-1 infection and from 22 of these women before infection. Associations between genital inflammation and viral load set point and blood CD4 cell counts 12 months after infection were investigated.
Results. Elevated genital cytokine concentrations 6 and 17 weeks after HIV-1 infection were associated with higher viral load set points and, to a lesser extent, with CD4 depletion. CVL cytokine concentrations during early infection did not differ relative to preinfection but were elevated in women who had vaginal discharge, detectable HIV-1 RNA in their genital tracts, and lower blood CD4 counts.
Conclusion. Genital inflammation during early HIV-1 infection was associated with higher viral load set point and CD4 depletion, which are markers of rapid disease progression. Strategies aimed at reducing genital inflammation during early HIV-1 infection may slow disease progression.
doi:10.1093/infdis/jir715
PMCID: PMC3244362  PMID: 22190580
19.  Integration of Antiretroviral Therapy with Tuberculosis Treatment 
The New England journal of medicine  2011;365(16):1492-1501.
Background
We previously reported that integrating antiretroviral therapy (ART) with tuberculosis treatment reduces mortality. However, optimal time to initiate ART during tuberculosis treatment remains contentious.
Methods
To address this, we conducted a 3-arm, open-label randomized controlled trial in South Africa in acid-fast bacilli smear positive patients (n=642) with HIV and CD4+ counts <500 cells/mm3. Findings on the early therapy group (ART initiated within 4 weeks of tuberculosis treatment initiation, n=214) and late therapy group (ART initiated within the first 4 weeks of the continuation phase of tuberculosis treatment, n=215) are presented here.
Results
Median CD4+ count and viral load at baseline was 150 cells/mm3 and 161000 copies/ml, being similar in both groups. Incidence rate of AIDS or death was 6.9 (18/259.4) and 7.8 (19/244.2) per 100 person-years in the early and late therapy groups respectively (Incidence Rate Ratio (IRR)=0.89; 95%Confidence Interval (95%CI): 0.44,1.79; P=0.73). However, in patients with CD4+ counts <50 cells/mm3, the incidence rates of AIDS or death were 8.5 (early) and 26.3 (late) per 100 person-years (IRR=0.32; 95%CI: 0.07,1.13; P=0.06). Immune reconstitution inflammatory syndrome (IRIS) incidence rates were 20.2 (early) and 7.7 (late) per 100 person-years (IRR=2.62; 95%CI: 1.48,4.82; P<0.001). Adverse events requiring antiretroviral drug switches occurred in 10 (early) and 1 (late) patients (P=0.006).
Conclusions
The benefits of AIDS-free survival balanced against the risks of IRIS and ART-related adverse events, support early ART initiation in patients with CD4+ counts <50 cells/mm3 and deferred ART initiation to the continuation phase of tuberculosis treatment when CD4+ counts are higher.
doi:10.1056/NEJMoa1014181
PMCID: PMC3233684  PMID: 22010915
20.  HIV prevalence among high school learners - opportunities for schools-based HIV testing programmes and sexual reproductive health services 
BMC Public Health  2012;12:231.
Background
Young girls in sub Saharan Africa are reported to have higher rates of human immunodeficiency virus (HIV) infection compared to boys in the same age group. Knowledge of HIV status amongst high schools learners provides an important gateway to prevention and treatment services. This study aimed at determining the HIV prevalence and explored the feasibility of HIV testing among high school learners.
Methods
Between September 2010 and February 2011, a linked, anonymous cross-sectional survey was conducted in two public sector high schools in the rural KwaZulu-Natal midlands. Following written informed consent, dried blood spot samples (DBS) were collected and tested for HIV. The overall and age-specific HIV prevalence were compared with select demographic variables.
Results
The HIV prevalence in learners aged 12 to 25 in school A was 4.7% (95% CI 2.8-6.5) compared to 2.5% (95% CI 1.6-3.5) in school B, (p = 0.04). Whilst the HIV prevalence was similar for boys at 1.3% (95% CI 0-2.8) in school A and 1.7% (95% CI 0.5-2.8) in school B, the prevalence in girls was consistently higher and was 7.7% (95% CI 4.5-10.9) in school A and 3.2% (95% CI 1.8-4.6) in school B. The age-specific HIV prevalence in girls increased 1.5 to 2 fold for each two year age category, while for boys the prevalence was stable across all age groups.
Conclusions
The high HIV prevalence in female learners underscores the importance of sexual reproductive health and schools-based HIV testing programs as an important gateway to prevention and treatment services.
doi:10.1186/1471-2458-12-231
PMCID: PMC3359203  PMID: 22439635
Young girls; HIV prevalence; surveillance
21.  Gender-sensitive reporting in medical research 
Sex and gender differences influence the health and wellbeing of men and women. Although studies have drawn attention to observed differences between women and men across diseases, remarkably little research has been pursued to systematically investigate these underlying sex differences. Women continue to be underrepresented in clinical trials, and even in studies in which both men and women participate, systematic analysis of data to identify potential sex-based differences is lacking. Standards for reporting of clinical trials have been established to ensure provision of complete, transparent and critical information. An important step in addressing the gender imbalance would be inclusion of a gender perspective in the next Consolidated Standards of Reporting Trials (CONSORT) guideline revision. Uniform Requirements for Manuscripts Submitted to Biomedical Journals, as a set of well-recognized and widely used guidelines for authors and biomedical journals, should similarly emphasize the ethical obligation of authors to present data analyzed by gender as a matter of routine. Journal editors are also promoters of ethical research and adequate standards of reporting, and requirements for inclusion of gender analyses should be integrated into editorial policies as a matter of urgency.
doi:10.1186/1758-2652-15-11
PMCID: PMC3313880  PMID: 22400977
22.  Experience in international clinical research: the HIV Prevention Trials Network 
Clinical investigation  2011;1(12):1609-1618.
The HIV Prevention Trials Network (HPTN) is supported by the NIH to conduct randomized clinical trials to assess the efficacy of HIV prevention strategies and technologies to reduce HIV transmission between adults. A special focus of attention is on the use of antiretroviral drugs to prevent HIV transmission, both by reducing infectiousness among HIV-infected persons taking combination antiretroviral therapy (cART) and also by reducing susceptibility among HIV-uninfected persons taking antiretrovirals for pre-exposure prophylaxis. Studies may be developmental in nature to assess novel ideas for interventions or for assessing trial feasibility. However, pivotal efficacy trials to test HIV-specific prevention strategies and technologies are the main HPTN priority. Examples include a major protocol investigating the impact of expanded testing and linkage to care on HIV surveillance indicators in the USA (HPTN 065). Another protocol is addressing similar issues while also investigating how combinations of prevention approaches are best deployed to make a community-level impact in southern Africa (HPTN 071). HPTN 068 is evaluating a novel conditional cash transfer structural intervention to increase school completion rates in young girls and thereby reduce their HIV risk. Studies outside the US address the epidemic in most at-risk populations and include an assessment of opiate agonist therapy to reduce risk of HIV seroconversion among injection drug users (HTPN 058), methods to increase HIV testing rates (HTPN 043), as well as methods for reducing high-risk behaviors, and increasing adherence to cART in HIV-infected individuals (HPTN 062 and HPTN 063, respectively). The recent HPTN 052 study demonstrated that a 96% reduction in HIV transmission could be achieved between serodiscordant sexual partners by providing the infected partners with cART at a CD4+ cell count (350–550/µl) above the level that would usually qualify them for therapy in low- and middle-income countries. The immediate relevance to public health policy showcased in these trials is a paradigm for the HPTN: design and conduct of clinical trials using available licensed tools that can be rapidly translated for implementation (‘Prevention NOW!’).
doi:10.4155/cli.11.156
PMCID: PMC3281583  PMID: 22348195
developing country; HIV/AIDS; prevention; randomized clinical trial; research collaboration; research infrastructure
23.  Understanding Methods for Estimating HIV-Associated Maternal Mortality 
Journal of Pregnancy  2011;2012:958262.
The impact of HIV on maternal mortality and more broadly on the health of women, remains poorly documented and understood. Two recent reports attempt to address the conceptual and methodological challenges that arise in estimating HIV-related maternal mortality and trends. This paper presents and compares the methods and discusses how they affect estimates at global and regional levels. Country examples of likely patterns of mortality among women of reproductive age are provided to illustrate the critical interactions between HIV and complications of pregnancy in high-HIV-burden countries. The implications for collaboration between HIV and reproductive health programmes are discussed, in support of accelerated action to reach the Millennium Development Goals and improve the health of women.
doi:10.1155/2012/958262
PMCID: PMC3182332  PMID: 21966594
24.  Effectiveness and Safety of Tenofovir Gel, an Antiretroviral Microbicide, for the Prevention of HIV Infection in Women 
Science (New York, N.Y.)  2010;329(5996):1168-1174.
The CAPRISA 004 trial assessed effectiveness and safety of a 1% vaginal gel formulation of tenofovir, a nucleotide reverse transcriptase inhibitor, for the prevention of HIV acquisition in women. A double-blind, randomized controlled trial was conducted comparing tenofovir gel (n=445) with placebo gel (n=444) in sexually active, HIV-uninfected 18-40 year-old women in urban and rural KwaZulu-Natal, South Africa HIV serostatus, safety, sexual behavior and gel and condom use were assessed at monthly follow-up visits for 30 months. HIV incidence in the tenofovir gel arm was 5.6 per 100 women-years (wy), i.e. person time of study observation, (38/680.6wy) compared to 9.1 per 100 wy (60/660.7wy) in the placebo gel arm (Incidence Rate Ratio (IRR)=0.61; p=0.017).In high adherers (gel adherence >80%), HIV incidence was 54% lower (p=0.025) in the tenofovir gel arm. In intermediate adherers (gel adherence 50-80%) and low adherers (gel adherence < 50%) the HIV incidence reduction was 38% and 28% respectively. Tenofovir gel reduced HIV acquisition by an estimated 39% overall, and by 54% in women with high gel adherence. No increase in the overall adverse event rates was observed. There were no changes in viral load and no tenofovir resistance in HIV seroconvertors. Tenofovir gel could potentially fill an important HIV prevention gap, especially for women unable to successfully negotiate mutual monogamy or condom use.
doi:10.1126/science.1193748
PMCID: PMC3001187  PMID: 20643915
25.  Plasma cytokine levels during acute HIV-1 infection predict HIV disease progression 
AIDS (London, England)  2010;24(6):819-831.
Background
Both T cell activation during early HIV-1 infection and soluble markers of immune activation during chronic infection are predictive of HIV disease progression. Although the acute phase of HIV infection is associated with increased pro-inflammatory cytokine production, the relationship between cytokine concentrations and HIV pathogenesis is unknown.
Objectives
To identify cytokine biomarkers measurable in plasma during acute HIV-1 infection that predict HIV disease progression.
Design
Study including 40 South African women who became infected with HIV-1 and were followed longitudinally from the time of infection.
Methods
The concentrations of 30 cytokines in plasma from women with acute HIV-1 infection were measured and associations between cytokine levels and both viral load set-point 12 months post-infection and time taken for CD4 counts to fall below 350 cells/μl were determined using multivariate and Cox proportional-hazards regression.
Results
We found that the concentrations of 5 plasma cytokines, IL-12p40, IL-12p70, IFN-γ, IL-7 and IL-15, in women with acute infection predicted 66% of the variation in viral load set-point 12 months post infection. IL-12p40, IL-12p70 and IFN-γ were significantly associated with lower viral load whereas IL-7 and IL-15 were associated with higher viral load. Plasma concentrations of IL-12p40 and GM-CSF during acute infection were associated with maintenance of CD4 counts above 350 cells/μl while IL-1α, eotaxin and IL-7 were associated with more rapid CD4 loss.
Conclusions
A small panel of plasma cytokines during acute HIV-1 infection was predictive of long-term HIV disease prognosis in this group of South African women.
doi:10.1097/QAD.0b013e3283367836
PMCID: PMC3001189  PMID: 20224308
HIV-1; cytokines; acute infection; viral load; disease progression

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