Killer-cell Immunoglobulin-like Receptor (KIR) gene profiles modify HIV disease course, not HIV acquisition in South African women.

BACKGROUND: Killer-cell Immunoglobulin-like Receptors (KIR) interact with Human Leukocyte Antigen (HLA) to modify natural killer- and T-cell function. KIR are implicated in HIV acquisition by small studies that have not been widely replicated. A role for KIR in HIV disease progression is more widely replicated and supported by functional studies. METHODS: To assess the role of KIR and KIR ligands in HIV acquisition and disease course, we studied at-risk women in South Africa between 2004-2010. Logistic regression was used for nested case-control analysis of 154 women who acquired vs. 155 who did not acquire HIV, despite high exposure. Linear mixed-effects models were used for cohort analysis of 139 women followed prospectively for a median of 54 months (IQR 31-69) until 2014. RESULTS: Neither KIR repertoires nor HLA alleles were associated with HIV acquisition. However, KIR haplotype BB was associated with lower viral loads (-0.44 log10 copies/ml; SE = 0.18; p = 0.03) and higher CD4+ T-cell counts (+80 cells/µl; SE = 42; p = 0.04). This was largely explained by the protective effect of KIR2DL2/KIR2DS2 on the B haplotype and reciprocal detrimental effect of KIR2DL3 on the A haplotype. CONCLUSIONS: Although neither KIR nor HLA appear to have a role in HIV acquisition, our data are consistent with involvement of KIR2DL2 in HIV control. Additional studies to replicate these findings are indicated.

Improved survival in multidrug-resistant tuberculosis patients receiving integrated tuberculosis and antiretroviral treatment in the SAPiT Trial.

BACKGROUND: The therapeutic effects of antiretroviral treatment (ART) in patients with multidrug-resistant tuberculosis (MDR-TB) and human immunodeficiency virus (HIV) infection have not been established. OBJECTIVE: To assess therapeutic outcomes of integrating ART with treatment for MDR-TB. DESIGN: A subgroup of MDR-TB patients from a randomised controlled trial, the SAPiT (Starting Antiretroviral Therapy at Three Points in Tuberculosis) study, conducted in an out-patient clinic in Durban, South Africa, from 2008 to 2012. METHODS: Clinical outcomes at 18 months were compared in patients randomised to receive ART within 12 weeks of initiating standard first-line anti-tuberculosis treatment with those who commenced ART after completing anti-tuberculosis treatment. RESULTS: Mycobacterium tuberculosis drug susceptibility results were available in 489 (76%) of 642 SAPiT patients: 23 had MDR-TB, 14 in the integrated treatment arm and 9 in the sequential treatment arm. At 18 months, the mortality rate was 11.9/100 person-years (py; 95%CI 1.4-42.8) in the combined integrated treatment arm and 56.0/100 py (95%CI 18.2-130.8) in the sequential treatment arm (hazard ratio adjusted for baseline CD4 count and whether MDR-TB treatment was initiated: 0.14; 95%CI 0.02-0.94, P = 0.04). CONCLUSION: Despite the small sample size, the 86% reduction in mortality due to early initiation of ART in MDR-TB patients was statistically significant.

Phase I safety and immunogenicity evaluations of an alphavirus replicon HIV-1 subtype C gag vaccine in healthy HIV-1-uninfected adults.

On the basis of positive preclinical data, we evaluated the safety and immunogenicity of an alphavirus replicon HIV-1 subtype C gag vaccine (AVX101), expressing a nonmyristoylated form of Gag, in two double-blind, randomized, placebo-controlled clinical trials in healthy HIV-1-uninfected adults. Escalating doses of AVX101 or placebo were administered subcutaneously to participants in the United States and Southern Africa. Because of vaccine stability issues, the first trial was halted prior to completion of all dose levels and a second trial was implemented. The second trial was also stopped prematurely due to documentation issues with the contract manufacturer. Safety and immunogenicity were evaluated through assessments of reactogenicity, reports of adverse events, and assessment of replication-competent and Venezuelan equine encephalitis (VEE) viremia. Immunogenicity was measured using the following assays: enzyme-linked immunosorbent assay (ELISA), chromium 51 ((51)Cr)-release cytotoxic T lymphocyte (CTL), gamma interferon (IFN-γ) ELISpot, intracellular cytokine staining (ICS), and lymphoproliferation assay (LPA). Anti-vector antibodies were also measured. AVX101 was well tolerated and exhibited only modest local reactogenicity. There were 5 serious adverse events reported during the trials; none were considered related to the study vaccine. In contrast to the preclinical data, immune responses in humans were limited. Only low levels of binding antibodies and T-cell responses were seen at the highest doses. This trial also highlighted the difficulties in developing a novel vector for HIV.

Screening for 'window-period' acute HIV infection among pregnant women in rural South Africa.

OBJECTIVES: The aim of this study was to evaluate the HIV-1 RNA pooled nucleic acid amplification testing (NAAT) strategy to screen pregnant women in the 'window period' of acute HIV infection (AHI) in rural South Africa. METHODS: In 2007 and 2008, 750 consecutive pregnant women on their first antenatal care visit to a primary health care clinic were tested anonymously for HIV infection. HIV-1 RNA pooled NAAT was performed on HIV antibody-negative samples. All positive pools were tested individually and positive samples were classified as incident cases to calculate HIV incidence. RESULTS: The overall HIV prevalence was 37.3% [95% confidence interval (CI) 34.3­41.3]. Of the 467 HIV antibody-negative samples, four (0.9%) were HIV-1 RNA-positive. The mean viral load in the four samples was 386 260 HIV-1 RNA copies/mL (range 64 200­1 228130). The HIV incidence was 11.2%per year (95% CI 0.3­22.1) and all women with AHI were 21 years of age. CONCLUSIONS: Identifying AHI in pregnancy is important for health interventions to reduce perinatal and heterosexual transmission of HIV, and to estimate HIV incidence for epidemiological surveillance.

Opportunities for treating sexually transmitted infections and reducing HIV risk in rural South Africa.

AIM: This paper is a report of a study to determine the aetiological distribution of sexually transmitted infections and prevalence of human immunodeficiency virus infection in selected primary health care clinic attendees. BACKGROUND: South Africa has a high prevalence of human immunodeficiency virus and other sexually transmitted infections. Sexually transmitted infections are managed syndromically in the public sector as part of the essential nurse-driven primary care services provided at no cost to the client. METHOD: This cross-sectional study was conducted in a rural community in South Africa between September and November 2002. A total of 277 consenting women were recruited. Vulvo-vaginal swabs were collected for screening for Neisseriae gonorrheae, Chlamydia trachomatis and Trichomonas vaginalis using DNA amplification methods and Gram stain with Nugent's score for the diagnosis of bacterial vaginosis. Seroprevalence of syphilis and human immunodeficiency virus infection were determined. FINDINGS: The overall prevalence of human immunodeficiency virus in the study was 43.7% (95% confidence interval 37.6-50.0) with the prevalence in family planning clinic attendees 45.5% (95% confidence interval 38.9-52.3) and antenatal clinic attendees 33.3% (95% confidence interval 19.6-50.3). The prevalence of sexually transmitted infections amongst both the antenatal clinic and family planning attendees accounted for at least 70% of cases. Fifty per cent of women had one recognized sexually transmitted infection with 17.9% of the family planning and 14.5% of the antenatal clinic attendees having infections from two recognized pathogens. All infections were asymptomatic. CONCLUSION: Nurse-driven antenatal and family planning services provide a useful opportunity for integrating reproductive health services, human immunodeficiency virus voluntary counselling and testing and treatment of sexually transmitted infections.

TB treatment outcomes following directly-observed treatment at an urban outpatient specialist TB facility in South Africa.

The treatment of 450 consecutive new patients with pulmonary TB was evaluated to determine outcome following directly-observed treatment. In all, 176 (39.1%) patients were cured, 23 (5.1%) completed treatment, 80 (17.8%) defaulted treatment, 24 (5.3%) died, 54 (12.0%) were lost to follow-up and 93 (20.7%) were transferred out. Increasing age was significant for death. Males were more likely to default and those with negative pretreatment sputum smears and those who were unemployed were more likely to be lost to follow-up. The overall treatment success rate remains low. Our data suggests that greater emphasis is needed to improve TB treatment success.

High HIV incidence and prevalence among young women in rural South Africa: developing a cohort for intervention trials.

OBJECTIVE: To measure prevalence and model incidence of HIV infection. SETTING: 2013 consecutive pregnant women attending public sector antenatal clinics in 1997 in Hlabisa health district, South Africa. Historical seroprevalence data, 1992-1995. METHODS: Serum remaining from syphilis testing was tested anonymously for antibodies to HIV to determine seroprevalence. Two models, allowing for differential mortality between HIV-positive and HIV-negative people, were used. The first used serial seroprevalence data to estimate trends in annual incidence. The second, a maximum likelihood model, took account of changing force of infection and age-dependent risk of infection, to estimate age-specific HIV incidence in 1997. Multiple logistic regression provided adjusted odds ratios (OR) for risk factors for prevalent HIV infection. RESULTS: Estimated annual HIV incidence increased from 4% in 1992/1993 to 10% in 1996/1997. In 1997, highest age-specific incidence was 16% among women aged between 20 and 24 years. In 1997, overall prevalence was 26% (95% confidence interval [CI], 24%-28%) and at 34% was highest among women aged between 20 and 24 years. Young age (<30 years; odds ratio [OR], 2.1; p = .001), unmarried status (OR 2.2; p = .001) and living in less remote parts of the district (OR 1.5; p = .002) were associated with HIV prevalence in univariate analysis. Associations were less strong in multivariate analysis. Partner's migration status was not associated with HIV infection. Substantial heterogeneity of HIV prevalence by clinic was observed (range 17%-31%; test for trend, p = .001). CONCLUSIONS: This community is experiencing an explosive HIV epidemic. Young, single women in the more developed parts of the district would form an appropriate cohort to test, and benefit from, interventions such as vaginal microbicides and HIV vaccines.

Phase 1 trial of nonoxynol-9 film among sex workers in South Africa.

OBJECTIVES: To assess the acceptability and safety of a vaginal nonoxynol-9 film in a group of sex workers at a truck stop in South Africa. DESIGN: A randomized double-blinded crossover trial was conducted between April 1995 and July 1995. INTERVENTION: Seventy-two mg nonoxynol-9 film and an identical glycerine placebo film. METHODS: Following informed consent, each study participant was randomly assigned the designated pre-coded film for 1 month. The second month was a film-free washout period and the participants used the alternate film in the third month. Besides measuring behavioural and clinical outcomes, colposcopy examination for genital lesions, serology and microbiology investigations for sexually transmitted diseases and semi-quantitative PCR for vaginal HIV load estimates were performed. RESULTS: Twenty women participated in the study. The women reported, on average, 19 sexual encounters per week. Vaginal intercourse was protected 25% of the time by condoms. On average, 11 vaginal films, either nonoxynol-9 or placebos were inserted per week. There were no statistically significant differences between the two treatment groups for genital lesions (P = 0.29), reported side effects (P = 0.73), and viral load (P = 0.9). However, the proportions of clinically detected genital lesions (six out of eight versus two out of eight) and self-reported side-effects (five out of eight versus three out of eight) were higher in the nonoxynol-9 group when compared with the placebo group. Incident sexually transmitted diseases occurred more frequently in the placebo group. An increased viral load was associated with the development of a genital lesion (relative risk, 6.0; 95% confidence interval, 0.81-44.4). CONCLUSIONS: The 72 mg film formulation of nonoxynol-9 was an acceptable product for use in this population of sex workers. Although no statistically significant differences in adverse outcomes were detected, clinically there appeared to be an increase in minor lesions and self-reported side-effects with nonoxynol-9 and less protection against sexually transmitted diseases with the placebo. Furthermore, HIV shedding was correlated with the presence of incident vaginal or cervical lesions. This brings into question the potential narrow margin of safety for this product; additional Phase 2 studies are therefore required.

STD syndrome packets: improving syndromic management of sexually transmitted diseases in developing countries.

OBJECTIVE: To design, introduce, and evaluate "STD syndrome packets" containing recommended drugs for each syndrome, four condoms, a partner treatment card, and a patient information leaflet, with the goal of improving sexually transmitted disease (STD) case management. METHODS: Packet design evolved around available packaging technology, informed by pilot testing with nurses working in primary care clinics, doctors in private medical practices, and patients with an STD, in Hlabisa, South Africa. Evaluation 1 year later included analysis of distribution records and interviews with 16 nurses and 64 patients. RESULTS: A cheap packet (2 U. S. cents each, excluding contents) compatible with current legislation was designed and introduced to six public sector clinics and as a short pilot to five private medical practices. Four thousand eighty-five packets were distributed to the clinics, equivalent to approximately 115% of the STDs reported over that period. All 16 nurses reported using the packets, but only 63% did so all the time because of occasional supply problems. All believed the packets improved treatment by saving time (75%), improving supply of condoms and partner cards (44%), and making treatment easier (56%). Patients also responded positively, and most said they would buy a packet (up to $5) at a pharmacy (84%) or store (63%) if available. CONCLUSIONS: The STD syndrome packets have the potential to improve STD syndromic management by standardizing therapy and improving the supply of condoms, partner cards, and information leaflets. Packets are popular with practitioners and patients, but consistent supply is essential for maximal impact. There may be scope for social marketing of the packets, which could further increase use.

PIP: As part of an intervention to improve the syndromic management of sexually transmitted diseases (STDs), the acceptability of STD syndrome packets was tested in Hlabisa, South Africa. The packets contained drugs recommended for each syndrome, four condoms, a partner treatment card, and a patient information sheet. 4085 such packets were distributed, at a cost of US$0.02 each, to six public sector clinics during the 1-year study period. These clinics treated a total of 3535 STD patients in that time period. Interviews conducted with 16 clinic nurses 1 year after project implementation indicated that they thought the packets made treatment easier and saved staff time. 10 nurses indicated they used the packets all the time; the remaining 6 used them most of the time, with gaps attributed to supply shortages. Also interviewed were 64 STD patients who received the packets. 84% indicated they would be willing to buy the packet from a pharmacy and 63% would buy it from a general store. 67% of STD patients were prepared to spend up to US$5 on the packet. These findings suggest that STD packets have an important role to play in increasing access to STD treatment in developing countries. Use could be increased even further by social marketing of the packets.

Unrecognized sexually transmitted infections in rural South African women: a hidden epidemic.

Sexually transmitted infections (STIs) are of major public health concern in developing countries, not least because they facilitate transmission of human immunodeficiency virus (HIV). The present article presents estimates of the prevalence, on any given day, of STIs among women in rural South Africa and the proportion who are asymptomatic, symptomatic but not seeking care, and symptomatic and seeking care. The following data sources from Hlabisa district were used: clinical surveillance for STI syndromes treated in health facilities, microbiological studies among women attending antenatal and family planning clinics, and a community survey. Population census provided denominator data. Adequacy of drug treatment was determined through quality of care surveys. Of 55,974 women aged 15-49 years, a total of 13,943 (24.9%) were infected on any given day with at least one of Trichomonas vaginalis, Neisseria gonorrhoeae, Chlamydia trachomatis, or Treponema pallidum. Of the women investigated, 6697 (48%) were asymptomatic, 6994 (50%) were symptomatic but not seeking care, 238 (1.7%) were symptomatic and would seek care, and 14 (0.3%) were seeking care on that day. Only 9 of the 14 women (65%) were adequately treated. STIs remained untreated because either women were asymptomatic or the symptoms were not recognized and acted upon. Improved case management alone is therefore unlikely to have a major public health impact. Improving partner treatment and women's awareness of symptoms is essential, while the potential of mass STI treatment needs to be explored.

PIP: Estimates of the prevalence, on any given day, of sexually transmitted infections (STIs) among rural South African women and the proportion of these women who are asymptomatic, symptomatic but not seeking care, and symptomatic and seeking care were developed through reference to data from the Hlabisa health district (KwaZulu/Natal). The prevalence of HIV among women attending antenatal clinics in Hlabisa rose from 4.2% in 1992 to 22% in 1997. Data sources included clinical surveillance for STI syndromes treated in health facilities, microbiologic studies among women attending antenatal and family planning clinics, and a community survey. The 1991 population census provided denominator data. It was estimated that, on any given day, 13,943 district women 15-49 years of age were infected with at least one STI--a point prevalence of 24.9% of the resident female population in this age group. Of these women, 6697 (48%) were asymptomatic and 7246 (52%) were symptomatic. Only 252 symptomatic women (2%) sought care and, of these, just 164 (65%) received adequate treatment. The majority of women with an STI were in the 15-29 year age group. Pregnant women were significantly less likely than nonpregnant women to have an asymptomatic infection (1% vs. 59%). Among nonpregnant women, syphilis and Trichomonas vaginalis were more likely to be asymptomatic (67% and 58%, respectively) than infection with Neisseria gonorrhoeae (37%) or Chlamydia trachomatis (36%). These findings indicate that improved STI case management alone is unlikely to improve STI control. Improving women's recognition of and treatment-seeking behavior for abnormal urogenital symptoms should increase the numbers treated, but a large burden of asymptomatic infection will remain unless screening or mass treatment is considered.

HIV infection and asymptomatic sexually transmitted infections in a rural South African community.

The objective was to determine the prevalence of HIV and other sexually transmitted infections (STIs) in a rural community. A population-based survey of adults in 110 homesteads was conducted in 1995. A questionnaire on demographics, sexual practices and history of STDs was administered. Neisseria gonorrhoeae and Chlamydia trachomatis infections were detected using ligase chain reaction (LCR) assay of urine. The seroprevalence of syphilis rapid plasma reagin (RPR) and Treponema pallidum haemagglutination assay (TPHA) and HIV infection (ELISA) was determined. Among 259 subjects the prevalence of HIV was 10.5%, N. gonorrhoeae 4.5%, C. trachomatis 6.1% and active syphilis 8.8%. All infections were asymptomatic. Forty per cent of sexually active men had more than one concurrent sexual partner. Only 14% of subjects had ever used condoms. The STI epidemic is being promoted by high levels of asymptomatic infections, high partner concurrency and low condom use.

PIP: This study determined the prevalence of HIV and other sexually transmitted infections (STIs) in a rural South African community. A population-based survey of adults in 110 homesteads was conducted in 1995. A questionnaire on demographics, sexual practices and histories of STIs was administered. Neisseria gonorrhea and Chlamydia trachomatis infections were detected using ligase chain reaction assay of urine. The seroprevalence of syphilis rapid plasma reagin and Treponema pallidum hemagglutination assay and HIV infection (ELISA) was determined. Among 259 subjects, the prevalence of HIV was 10.5%; N. gonorrhea, 4.5%; C. trachomatis, 6.1%; active syphilis, 8.8%. All infections were asymptomatic. About 40% of sexually active men had more than one concurrent sexual partner. Only 14% of subjects had ever used condoms. In general, these findings indicate that high levels of asymptomatic infections, high partner concurrence, and low condom use are promoting the STI epidemic in this community.