Tenofovir Gel for the Prevention of Herpes Simplex Virus Type 2 Infection.

BACKGROUND: Globally, herpes simplex virus type 2 (HSV-2) infection is the most common cause of genital ulcer disease. Effective prevention strategies for HSV-2 infection are needed to achieve the goals of the World Health Organization global strategy for the prevention and control of sexually transmitted infections. METHODS: We assessed the effectiveness of pericoital tenofovir gel, an antiviral microbicide, in preventing HSV-2 acquisition in a subgroup of 422 HSV-2-negative women enrolled in the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 study, a double-blind, randomized, placebo-controlled trial. Incident HSV-2 cases were identified by evidence of seroconversion on an HSV-2 IgG enzyme-linked immunosorbent assay between study enrollment and exit. A confirmatory analysis was performed by Western blot testing. RESULTS: The HSV-2 incidence rate was 10.2 cases per 100 person-years (95% confidence interval [CI], 6.8 to 14.7) among 202 women assigned to tenofovir gel, as compared with 21.0 cases per 100 person-years (95% CI, 16.0 to 27.2) among 222 women assigned to placebo gel (incidence rate ratio, 0.49; 95% CI, 0.30 to 0.77; P=0.003). The HSV-2 incidence rate among the 25 women with vaginal tenofovir concentrations of 10,000 ng per milliliter or more was 5.7 cases per 100 person-years, as compared with 15.5 cases per 100 person-years among the 103 women with no detectable vaginal tenofovir (incidence rate ratio, 0.37; 95% CI, 0.04 to 1.51; P=0.14). As confirmed by Western blot testing, there were 16 HSV-2 seroconversions among women assigned to tenofovir gel as compared with 36 among those assigned to the placebo gel (incidence rate ratio, 0.45; 95% CI, 0.23 to 0.82; P=0.005). CONCLUSIONS: In this study in South Africa, pericoital application of tenofovir gel reduced HSV-2 acquisition in women. (Funded by the U.S. Agency for International Development and others; ClinicalTrials.gov number, NCT00441298.).

Restoration of CD4+ Responses to Copathogens in HIV-Infected Individuals on Antiretroviral Therapy Is Dependent on T Cell Memory Phenotype.

Antiretroviral therapy (ART) induces rapid suppression of viral replication and a progressive replenishment of CD4(+) T cells in HIV-infected individuals. However, the effect of ART on restoring pre-existing memory CD4(+) T cells specific for common copathogens is still unclear. To better understand the dynamics of Ag-specific CD4(+) T cells during ART, we assessed the frequency, functional capacity, and memory profile of CD4(+) T cells specific for Mycobacterium tuberculosis and CMV in 15 HIV-infected individuals before and 1 y after ART initiation. After ART initiation, the frequency of M. tuberculosis-specific CD4(+) T cells showed little change, whereas CMV-specific CD4(+) T cells were significantly lower (p = 0.003). There was no difference in the polyfunctional or memory profile of Ag-specific CD4(+) T cells before and after ART. The replenishment of Ag-specific CD4(+) T cells correlated with the memory differentiation profile of these cells prior to ART. Pathogen-specific CD4(+) T cells exhibiting a late differentiated profile (CD45RO(+)CD27(-)) had a lower capacity to replenish (p = 0.019; r = -0.5) compared with cells with an early differentiated profile (CD45RO(+)CD27(+); p = 0.04; r = 0.45). In conclusion, restoration of copathogen-specific memory CD4(+) T cells during treated HIV infection is related to their memory phenotype, in which early differentiated cells (such as most M. tuberculosis-specific cells) have a higher replenishment capacity compared with late differentiated cells (such as most CMV-specific cells). These data identify an important, hitherto unrecognized, factor that may limit restoration of copathogen immunity in HIV-infected individuals on ART.

Differences in HIV type 1 neutralization breadth in 2 geographically distinct cohorts in Africa.

To investigate whether distinct populations have differing human immunodeficiency virus type 1 (HIV) neutralizing antibody responses, we compared 20 women from Tanzania's HIV Superinfection Study (HISIS) cohort, who were infected multiple HIV subtypes, and 22 women from the Centre for the AIDS Programme of Research in South Africa (CAPRISA) cohort, who were infected exclusively with HIV subtype C. By 2 years after infection, 35% of HISIS subjects developed neutralization breadth, compared with 9% of CAPRISA subjects (P = .0131). Cumulative viral loads between 3 and 12 months were higher in the HISIS group (P = .046) and strongly associated with breadth (P < .0001). While viral load was the strongest predictor, other factors may play a role, as the odds of developing breadth remained higher in HISIS even after correction for viral load.

Genital inflammation and the risk of HIV acquisition in women.

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-1ß, 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-1ß), 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-1ß, 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.

South African HIV-1 subtype C transmitted variants with a specific V2 motif show higher dependence on α4ß7 for replication.

BACKGROUND: The integrin α4ß7 mediates the trafficking of immune cells to the gut associated lymphoid tissue (GALT) and is an attachment factor for the HIV gp120 envelope glycoprotein. We developed a viral replication inhibition assay to more clearly evaluate the role of α4ß7 in HIV infection and the contribution of viral and host factors. RESULTS: Replication of 60 HIV-1 subtype C viruses collected over time from 11 individuals in the CAPRISA cohort were partially inhibited by antibodies targeting α4ß7. However, dependence on α4ß7 for replication varied substantially among viral isolates from different individuals as well as over time in some individuals. Among 8 transmitted/founder (T/F) viruses, α4ß7 reactivity was highest for viruses having P/SDI/V tri-peptide binding motifs. Mutation of T/F viruses that had LDI/L motifs to P/SDI/V resulted in greater α4ß7 reactivity, whereas mutating P/SDI/V to LDI/L motifs was associated with reduced α4ß7 binding. P/SDI/V motifs were more common among South African HIV subtype C viruses (35%) compared to subtype C viruses from other regions of Africa (<8%) and to other subtypes, due in part to a founder effect. In addition, individuals with bacterial vaginosis (BV) and who had higher concentrations of IL-7, IL-8 and IL-1α in the genital tract had T/F viruses with higher α4ß7 dependence for replication, suggesting that viruses with P/SDI/V motifs may be preferentially transmitted in the presence of BV in this population. CONCLUSIONS: Collectively, these data suggest a role for α4ß7 in HIV infection that is influenced by both viral and host factors including the sequence of the α4ß7 binding motif, the cytokine milieu and BV in the genital tract. The higher frequency of P/SDI/V sequences among South African HIV-1 subtype C viruses may have particular significance for the role of α4ß7 in this geographical region.

TRIM5α and TRIM22 are differentially regulated according to HIV-1 infection phase and compartment.

UNLABELLED: The antiviral role of TRIM E3 ligases in vivo is not fully understood. To test the hypothesis that TRIM5α and TRIM22 have differential transcriptional regulation and distinct anti-HIV roles according to infection phase and compartment, we measured TRIM5α, TRIM22, and type I interferon (IFN-I)-inducible myxovirus resistance protein A (MxA) levels in peripheral blood mononuclear cells (PBMCs) during primary and chronic HIV-1 infection, with chronic infection samples being matched PBMCs and central nervous system (CNS)-derived cells. Associations with biomarkers of disease progression were explored. The impact of IFN-I, select proinflammatory cytokines, and HIV on TRIM E3 ligase-specific expression was investigated. PBMCs from individuals with primary and chronic HIV-1 infection had significantly higher levels of MxA and TRIM22 than did PBMCs from HIV-1-negative individuals (P < 0.05 for all comparisons). PBMCs from chronic infection had lower levels of TRIM5α than did PBMCs from primary infection or HIV-1-uninfected PBMCs (P = 0.0001 for both). In matched CNS-derived samples and PBMCs, higher levels of MxA (P = 0.001) and TRIM5α (P = 0.0001) in the CNS were noted. There was a negative correlation between TRIM22 levels in PBMCs and plasma viral load (r = -0.40; P = 0.04). In vitro, IFN-I and, rarely, proinflammatory cytokines induced TRIM5α and TRIM22 in a cell type-dependent manner, and the knockdown of either protein in CD4(+) lymphocytes resulted in increased HIV-1 infection. These data suggest that there are infection-phase-specific and anatomically compartmentalized differences in TRIM5α and TRIM22 regulation involving primarily IFN-I and specific cell types and indicate subtle differences in the antiviral roles and transcriptional regulation of TRIM E3 ligases in vivo. IMPORTANCE: Type I interferon-inducible TRIM E3 ligases are a family of intracellular proteins with potent antiviral activities mediated through diverse mechanisms. However, little is known about the contribution of these proteins to antiviral immunity in vivo and how their expression is regulated. We show here that TRIM5α and TRIM22, two prominent members of the family, have different expression patterns in vivo and that the expression pattern depends on HIV-1 infection status and phase. Furthermore, expression differs in peripheral blood versus central nervous system anatomical sites of infection. Only TRIM22 expression correlated negatively with HIV-1 viral load, but gene silencing of both proteins enhances HIV-1 infection of target cells. We report subtle differences in TRIM5α and TRIM22 gene induction by IFN-I and proinflammatory cytokines in CD4(+) lymphocytes, monocytes, and neuronal cells. This study enhances our understanding of antiviral immunity by intrinsic antiviral factors and how their expression is determined.

HIV-positive status disclosure in patients in care in rural South Africa: implications for scaling up treatment and prevention interventions.

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.

Risk Factors for HIV Acquisition in High Risk Women in a Generalised Epidemic Setting.

In South Africa young women bear a disproportionate burden of HIV infection however, risk factors for HIV acquisition are not fully understood in this setting. In a cohort of 245 women, we used proportional hazard regression analysis to examine the association of demographic, clinical and behavioural characteristics with HIV acquisition. The overall HIV incidence rate (IR) was 7.20 per 100 women years (wy), 95 % confidence interval (CI) 4.50-9.80. Women 18-24 years had the highest HIV incidence (IR 13.20 per 100 wy, 95 % CI 6.59-23.62) and were almost three times more likely to acquire HIV compared to women 25 years and older [adjusted Hazard Ratio (aHR) 2.61, 95 % CI 1.05-6.47]. Similarly, women in relationships with multiple sex partners had more than twice the risk of acquiring HIV when compared to women who had no partner or who had a husband or stable partner (aHR 2.47, 95 % CI 0.98-6.26). HIV prevention programmes must address young women's vulnerability and sex partner reduction in this setting.

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 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.

Rapid disease progression in HIV-1 subtype C-infected South African women.

BACKGROUND: Whereas human immunodeficiency virus (HIV) subtype B-infected individuals generally progress to AIDS within 8-10 years, limited data exist for other clades, especially from Africa. We investigated rates of HIV disease progression of clade C-infected South African women. METHODS: Prospective seroincidence cohorts in KwaZulu-Natal were assessed for acute HIV infection monthly (n = 245) or every 3 months (n = 594) for up to 4 years. Rapid disease progression was defined as CD4 decline to <350 cells/µL by 2 years postinfection. Serial clinical and laboratory assessments were compared using survival analysis and logistic regression models. RESULTS: Sixty-two women were identified at a median of 42 days postinfection (interquartile range, 34-59), contributing 282 person-years of follow-up. Mean CD4 count dropped by 39.6% at 3 months and 46.7% at 6 months postinfection in women with preinfection measurements. CD4 decline to <350 cells/µL occurred in 31%, 44%, and 55% of women at 1, 2, and 3 years postinfection, respectively, and to <500 cells/µL in 69%, 79%, and 81% at equivalent timepoints. Predictors of rapid progression were CD4 count at 3 months postinfection (hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.31-3.28; P = .002), setpoint viral load (HR, 3.82; 95% CI, 1.51-9.67; P = .005), and hepatitis B coinfection (HR, 4.54; 95% CI, 1.31-15.69; P = .017). Conversely, presence of any of HLAB*1302, B*27, B*57, B*5801, or B*8101 alleles predicted non-rapid progression (HR, 0.19; 95% CI, .05-.74; P = .016). CONCLUSIONS: Nearly half of subtype C-infected women progressed to a CD4 count <350 cells/µL within 2 years of infection. Implementing 2013 World Health Organization treatment guidelines (CD4 count <500 cells/µL) would require most individuals to start antiretroviral therapy within 1 year of HIV infection.

Limited HIV-1 superinfection in seroconverters from the CAPRISA 004 Microbicide Trial.

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.

Defining genital tract cytokine signatures of sexually transmitted infections and bacterial vaginosis in women at high risk of HIV infection: a cross-sectional study.

OBJECTIVES: Sexually transmitted infections (STI) and bacterial vaginosis (BV) cause female genital tract inflammation. This inflammation, which is often present in the absence of symptoms, is associated with increased susceptibility to HIV infection. We aimed to evaluate genital cytokine profiles and the degree of inflammation associated with common STIs and BV. METHODS: HIV-uninfected women (n=227) were screened for BV, Chlamydia trachomatis, Neisseria gonorrhoeae, Herpes simplex virus type 2 (HSV-2), and Trichomonas vaginalis. Concentrations of 42 cytokines in cervicovaginal lavages and 13 cytokines in plasma were measured using Luminex. Changes in cytokine profiles were evaluated using Mann-Whitney U test, logistic regression and factor analysis. p Values were adjusted for multiple comparisons using a false discovery rate step-down procedure. RESULTS: Women with chlamydia or gonorrhoea had the highest genital cytokine concentrations, with 17/42 and 14/42 cytokines upregulated compared with women with no infection, respectively. BV was associated with elevated proinflammatory cytokine concentrations, but lower chemokine and haematopoietic cytokine concentrations. HSV-2 reactivation was associated with lower levels of inflammation, while trichomoniasis did not cause significant differences in genital cytokine concentrations. Genital infections did not influence plasma cytokine concentrations. Although certain STIs, in particular chlamydia and gonorrhoea, were associated with high genital cytokine concentrations, only 19% of women with an STI/BV had clinical signs. CONCLUSIONS: Chlamydia was associated with the highest genital cytokine levels, followed by gonorrhoea, HSV-2, trichomoniasis, and BV. In regions where HIV is prevalent and STIs are managed syndromically, better STI/BV screening is urgently needed, as certain infections were found to be highly inflammatory.

Impact of antiretroviral therapy on health-related quality of life among South African women in the CAPRISA 002 acute infection study.

Concerns are often raised regarding potentially adverse effects of antiretroviral therapy (ART) on health-related quality of life (HRQoL), but there is limited longitudinal data to prove this. Building on our prior investigation, we examined the impact of ART on HRQoL among HIV-infected South African women with extensive follow-up in the CAPRISA 002 Acute Infection Cohort Study. Overall HRQoL and five sub-domains [physical well-being (PWB), emotional well-being (EWB), functional and global well-being (FGWB), social well-being (SWB) and cognitive functioning (CF)] were assessed using the Functional Assessment of HIV Infection (FAHI) instrument. Our analyses comparing FAHI scores between pre-ART (established infection) and ART phases using paired Wilcoxon signed-rank tests and adjusted mixed-effects regression models revealed improvements on ART in overall HRQoL, and in PWB, EWB, and SWB, but not in FGWB and CF. No long-term adverse impact of ART on HRQoL was detected, providing additional non-biomedical support to early treatment strategies.

Health-related quality of life dynamics of HIV-positive South African women up to ART initiation: evidence from the CAPRISA 002 acute infection cohort study.

Few studies have investigated the long-term dynamics in health-related quality of life (HRQoL) among HIV-positive persons from acute infection. From 2004, 160 women were enrolled into the CAPRISA 002 Acute Infection study at two sites in the province of KwaZulu-Natal and underwent 3-6 monthly HRQoL assessments using the functional assessment of HIV infection (FAHI) instrument. Overall and 5 sub-scale FAHI scores [physical well-being (PWB), emotional well-being (EWB), functional and global well-being (FGWB), social well-being (SWB) and cognitive functioning (CF)] were calculated up to antiretroviral therapy (ART) initiation and scores at enrollment were compared to the acute, early and established infection phases. Mixed-effects regression models adjusting for behavioral and clinical factors were applied to assess HRQoL trends and the proportion of women meeting minimally important differences was calculated. Our analyses revealed that overall/sub-scale scores improved over time, except from PWB and CF. A higher educational status, contraceptive use and a higher BMI were the strongest predictors of higher overall/sub-scale FAHI scores. CD4 count and HIV viral load were strongly associated with PWB and CF, but not overall FAHI and other sub-scales. Women newly diagnosed with acute HIV infection face profound HRQoL challenges. While early ART delivery may be important for PWB and CF, factors such as education, contraception provision and good nutritional status should be promoted to maximize HRQoL in HIV positive individuals.

The preventive misconception: experiences from CAPRISA 004.

Overestimating personal protection afforded by participation in a preventive trial, e.g. harboring a "preventive misconception" (PM), raises theoretical ethical concerns about the adequacy of the informed consent process, behavioral disinhibition, and adherence to prevention interventions. Data from the CAPRISA 004 1 % tenofovir gel trial were utilized to empirically evaluate these concerns. We found it necessary to re-think the current definition of PM during evaluation to distinguish between true misconception and reasonable inferences of protection based on increased access to evidence-based prevention interventions and/or clinical care. There was a significant association between PM and decreased condom use (p < 0.0001) and between PM and likelihood to present with an STI symptom (p = 0.023). There was, however, limited evidence in support of PM representing a lack of meaningful informed consent, or to suggest that it impacts adherence. Moreover, considering current insufficiencies in female-initiated HIV prevention interventions, PM is perhaps of limited concern in microbicide trials.

Impact of an adherence intervention on the effectiveness of tenofovir gel in the CAPRISA 004 trial.

High adherence is important in microbicide trials, but no adherence interventions to date have demonstrated empiric improvements in microbicide adherence or effectiveness. Approximately midway during the CAPRISA 004 trial, we implemented a novel adherence intervention (Adherence Support Program-ASP), based on an Information-Motivation-Behavioral Skills model and incorporating a Motivational Interviewing approach. We assessed the impact of the ASP on adherence and tenofovir gel effectiveness using a before-and-after comparison. Of the 889 women in the trial, 774 contributed 486.1 women-years of follow-up pre-ASP and 828 contributed 845.7 women-years of follow-up post-ASP. Median adherence rose from 53.6 % pre-ASP to 66.5 % post-ASP. Detectable tenofovir levels increased from 40.6 % pre-ASP to 62.5 % post-ASP in 64 women who had paired tenofovir drug samples. Gel effectiveness improved post-ASP; HIV incidence in the tenofovir gel arm was 24 % lower pre-ASP compared to 47 % lower post-ASP. Following implementation of the ASP, microbicide adherence improved with a concomitant increase in the effectiveness of tenofovir gel.

Effects of introducing Xpert MTB/RIF test on multi-drug resistant tuberculosis diagnosis in KwaZulu-Natal South Africa.

BACKGROUND: An algorithm instituted following Xpert MTB/RIF (Xpert) introduction in South Africa advocates for treating all Xpert rifampicin resistant patients as MDR-TB cases while awaiting confirmation by phenotypic or genotypic drug susceptibility testing. This study evaluates how the Xpert has influenced the diagnosis and management of drug resistant TB in the highest burdened district of KwaZulu-Natal Province. METHODS: Data was retrospectively collected from all patients with rifampicin resistance on Xpert performed between March 2011 and April 2012. Xpert results were compared with those of phenotypic and/genotypic drug susceptibility testing. Patients' records were used to determine the time to treatment initiation. RESULTS: Out of 637 patients tested by Xpert, 50% had confirmatory results, of which a third were sent on the same day as Xpert test. The rate of rifampicin discordance and monoresistance was 8.8% and 13.4% respectively and there was no difference between phenotypic and genotypic confirmation. Among those who had been initiated on treatment, 28%, 40%, 21% and 8% of patients commenced within 2 weeks, 1 month, 2 months and 3 months of Xpert testing respectively, while the remaining 3% were observed without treatment. CONCLUSION: This study emphasizes the importance of complying with the algorithm in confirming all Xpert rif resistant cases so as to ensure proper management of these patients. Despite the rapidity of the Xpert results, only about 70% of patients had been initiated treatment at one month. Therefore there is a definite need to improve the health systems in order to improve on these delays.

Treatment outcomes for extensively drug-resistant tuberculosis and HIV co-infection.

High mortality rates have been reported for patients co-infected with extensively drug-resistant tuberculosis (XDR-TB) and HIV, but treatment outcomes have not been reported. We report treatment outcomes for adult XDR TB patients in KwaZulu-Natal Province, South Africa. Initial data were obtained retrospectively, and outcomes were obtained prospectively during 24 months of treatment. A total of 114 XDR TB patients were treated (median 6 drugs, range 3-9 drugs); 82 (73%) were HIV positive and 50 (61%) were receiving antiretroviral therapy. After receiving treatment for 24 months, 48 (42%) of 114 patients died, 25 (22%) were cured or successfully completed treatment, 19 (17%) withdrew from the study, and 22 (19%) showed treatment failure. A higher number of deaths occurred among HIV-positive patients not receiving antiretroviral therapy and among patients who did not show sputum culture conversion. Culture conversion was a major predictor of survival but was poorly predictive (51%) of successful treatment outcome.

Symptomatic vaginal discharge is a poor predictor of sexually transmitted infections and genital tract inflammation in high-risk women in South Africa.

BACKGROUND: Diagnosis and treatment of sexually transmitted infections (STIs) is a public health priority, particularly in regions where the incidence of human immunodeficiency virus (HIV) infection is high. In most developing countries, STIs are managed syndromically. We assessed the adequacy of syndromic diagnosis of STIs, compared with laboratory diagnosis of STIs, and evaluated the association between STI diagnosis and the risk of HIV acquisition in a cohort of high-risk women. METHODS: HIV-uninfected high-risk women (n = 242) were followed for 24 months. Symptoms of STIs were recorded, and laboratory diagnosis of common STI pathogens was conducted every 6 months. Forty-two cytokines were measured by Luminex in cervicovaginal lavage specimens at enrollment. Human immunodeficiency virus type 1 (HIV-1) infection was evaluated monthly. RESULTS: Only 12.3% of women (25 of 204) who had a laboratory-diagnosed, discharge-causing STI had clinically evident discharge. Vaginal discharge was thus a poor predictor of laboratory-diagnosed STIs (sensitivity, 12.3%; specificity, 93.8%). Cervicovaginal cytokine concentrations did not differ between women with asymptomatic STIs and those with symptomatic STIs and were elevated in women with asymptomatic STIs, compared with women with no STIs or bacterial vaginosis. Although laboratory-diagnosed STIs were associated with increased risk of HIV infection (hazard ratio, 3.3 [95% confidence interval, 1.5-7.2)], clinical symptoms were not. CONCLUSIONS: Syndromic STI diagnosis dependent on vaginal discharge was poorly predictive of laboratory-diagnosed STI. Laboratory-diagnosed STIs were associated with increased susceptibility to HIV acquisition, while vaginal discharge was not.

CAPRISA 004 tenofovir microbicide trial: no impact of tenofovir gel on the HIV transmission bottleneck.

Alterations of the genital mucosal barrier may influence the number of viruses transmitted from a human immunodeficiency virus-infected source host to the newly infected individual. We used heteroduplex tracking assay and single-genome sequencing to investigate the effect of a tenofovir-based microbicide gel on the transmission bottleneck in women who seroconverted during the CAPRISA 004 microbicide trial. Seventy-seven percent (17 of 22; 95% confidence interval [CI], 56%-90%) of women in the tenofovir gel arm were infected with a single virus compared with 92% (13 of 14; 95% CI, 67%->99%) in the placebo arm (P = .37). Tenofovir gel had no discernable impact on the transmission bottleneck.