Prevalence and patterns of victimization and polyvictimization among female sex workers in Soweto, a South African township: a cross-sectional, respondent-driven sampling study.

BACKGROUND: Female sex workers (FSWs) are disproportionately affected by violence from multiple partner categories. This increases their vulnerability to HIV. OBJECTIVES: To describe patterns of violence and polyvictimization among female SWs in Soweto. METHODS: A respondent-driven sampling (RDS) recruitment methodology was used to enrol 508 Soweto-based FSWs using a survey instrument. Raw and RDS adjusted data were descriptively analysed, Spearman's correlation and chi2 test of association were used to show associations. Polyvictimization patterns are shown within a modified Venn diagram. RESULTS: The median age of FSWs in Soweto was 31 years, and most had an incomplete education (74.2%). The prevalence of exposure to physical/sexual intimate partner violence (IPV) in the past year was 53.8%, 46.8% by clients, and 18.5% by police. Past year prevalence of sexual/physical violence by any perpetrator category was 70.8% and lifetime exposure was 76.0%. Childhood sexual violence was reported by 44.3%. Lifetime non-partner rape was 55.5% and all rape exposure was 62.4%. As a result of engaging in sex work in the past year, 65.2% women had been discriminated against. Client, police, IPV, and childhood trauma were all significantly associated with one another, with IPV being the most common co-occurrence. Polyvictimization was seen in almost two-thirds of FSWs, and increased with exposure to discrimination. CONCLUSION: In Soweto, FSWs are exposed to high rates of violence in multiple forms across their lifetime. Our findings show that violence continues unabated into adulthood at levels far higher than in the general population and overall at higher levels than previously recorded among SWs in South Africa. We argue that violence against FSWs is rooted in discrimination. The disparate burden of violence on FSWs requires urgent interventions to proactively address and reframe the normalisation of violence against all women.

A double-blind, randomised, placebo-controlled, dose-finding trial of the novel tuberculosis vaccine AERAS-402, an adenovirus-vectored fusion protein, in healthy, BCG-vaccinated infants.

BACKGROUND: Several novel tuberculosis vaccines are currently in clinical trials, including AERAS-402, an adenovector encoding a fusion protein of Mycobacterium tuberculosis antigens 85A, 85B, and TB10.4. A multicentred trial of AERAS-402 safety and immunogenicity in healthy infants was conducted in three countries in sub-Saharan Africa, using an adaptive design. METHODS: In a double-blind, randomised, placebo-controlled, dose-finding trial, we enrolled BCG-vaccinated, HIV-uninfected infants aged 16-26 weeks. Infants in the safety/dose-finding phase received two doses of AERAS-402 across three dose levels, or placebo, intramuscularly on days 0 and 28. Infants in the expanded safety phase received three doses of the highest dose level, with the 3rd dose at day 280. Follow up for safety and immunogenicity was for up to two years. RESULTS: We enrolled 206 infants (52 placebo and 154 AERAS-402 recipients) into the dose-finding phase and 281 (141 placebo and 140 AERAS-402 recipients) into the expanded safety phase. Safety data were acceptable across all dose levels. No vaccine-related deaths were recorded. A single serious adverse event of tachypnoea was deemed related to study vaccine. Antibodies directed largely against Ag85A and Ag85B were detected. Low magnitude CD4+ and CD8+ polyfunctional T cell responses were observed at all dose levels. The addition of a third dose of AERAS-402 at the highest dose level did not increase frequency or magnitude of antibody or CD8+ T cell responses. CONCLUSIONS: AERAS-402 has an acceptable safety profile in infants and was well tolerated at all dose levels. Response rate was lower than previously seen in BCG vaccinated adults, and frequency and magnitude of antigen-specific T cells were not increased by a third dose of vaccine.

Does participation in an HIV vaccine efficacy trial affect risk behaviour in South Africa?

BACKGROUND: Increased sexual risk behaviour in participants enrolled in HIV prevention trials has been a concern. The HVTN 503/Phambili study, a phase 2B study of the Merck Ad-5 multiclade HIV vaccine in South Africa, suspended enrollment and vaccinations following the results of the Step study. Participants were notified of their treatment allocation and continue to be followed. We investigated changes in risk behaviour over time and assessed the impact of study unblinding. METHODS: 801 participants were enrolled. Risk behaviours were assessed with an interviewer-administered questionnaire at 6-month intervals. We assessed change from enrolment to the first 6-month assessment pre-unblinding and between enrolment and at least 6 months post-unblinding on all participants with comparable data. A one-time unblinding risk perception questionnaire was administered post-unblinding. RESULTS: A decrease in participants reporting unprotected sex was observed in both measured time periods for men and women, with no differences by treatment arm. At 6 months (pre-unblinding), 29.6% of men and 35.8% of women reported changing from unprotected to protected sex (p<0.0001 for each). Men (22%) were more likely than women (14%) to report behaviour change after unblinding (p=0.009). Post-enrolment, 142 (45%) of 313 previously uncircumcised men underwent medical circumcision. 663 participants completed the unblinding questionnaire. More vaccine (24.6%) as compared to placebo recipients (12.0%) agreed that they were more likely to get HIV than most people (p<0.0001), and attributed this to receiving the vaccine. CONCLUSION: We did not find evidence of risk compensation during this clinical trial. Some risk behaviour reductions including male circumcision were noted irrespective of treatment allocation.

Influence of intragenic CCL3 haplotypes and CCL3L copy number in HIV-1 infection in a sub-Saharan African population.

Two CCL3 haplotypes (HapA1 and Hap-A3) and two polymorphic positions shared by the haplotypes (Hap-2SNP (single nucleotide polymorphism)) were investigated together with CCL3L copy number (CN), for their role in HIV-1 disease. Hap-A1 was associated with protection from in utero HIV-1 infection: exposed uninfected (EU) infants had higher representation of wild type (WT)/Hap-A1 than infected infants (excluding intrapartum (IP)-infected infants), which maintained significance post maternal Nevirapine (mNVP) and viral load (MVL) correction (P=0.04; odds ratio (OR)=0.33). Mother-infant pair analyses showed the protective effect of Hap-A1 is dependent on its presence in the infant. Hap-A3 was associated with increased IP transmission: WT/Hap-A3 was increased in IP-transmitting vs non-transmitting (NT) mothers, and remained significant post mNVP and MVL correction (P=0.02; OR=3.50). This deleterious effect of Hap-A3 seemed dependent on its presence in the mother. Hap-2SNP was associated with lower CD4 count in the NT mothers (P=0.03). CCL3 Hap-A1 was associated with high CCL3L CN in total (P=0.001) and EU infants (P=0.006); the effect was not additive, however, having either Hap-A1 or high CCL3L CN was more significantly (P=0.0008) associated with protection from in utero infection than Hap-A1 (P=0.028) or high CCL3L CN (P=0.002) alone. Linkage disequilibrium between Hap-A1 and high CCL3L CN appears unlikely given that a Nigerian population showed an opposite relationship.

Anticipated changes in sexual risk behaviour following vaccination with a low-efficacy HIV vaccine: survey results from a South African township.

We assessed the potential for anticipated changes in sexual risk-taking behaviour following hypothetical administration of a low-efficacy preventive HIV vaccine. We developed a survey and collected self-reported data from 158 HIV-negative volunteers in a cohort undergoing prescreening for Phase I/II HIV vaccine trials in Soweto. Overall, 22% reported they might use condoms less frequently; 9% reported that they might increase their frequency of sex with casual/anonymous partners; and 55% reported their sexual partners might want to use condoms less frequently knowing they were vaccinated. Multivariate analyses revealed that anticipated decrease in condom use was predicted by poor comprehension and by young age. Individuals may increase their risk-taking behaviour knowing that a vaccine would provide only incomplete protection against HIV transmission. In HIV vaccine trials and future vaccination programmes, education and risk-reduction counselling will be needed for vaccinated individuals and their partners, and mass media education campaigns may be necessary.

Prevalence and associations with hepatitis B and hepatitis C infection among HIV-infected adults in South Africa.

We assessed prevalence and factors associated with hepatitis B in a cross section of HIV-infected primary care and antinatal clinic patients in South Africa and evaluated a rapid hepatitis B surface antigen (HBsAg) assay. We enrolled 998 patients; 88% were women, median age was 29 years and median CD4 count was 354 cells/mm(3). HBsAg enzyme-linked immunosorbent assay (ELISA), anti-hepatitis B core (HBc) antibodies and hepatitis C virus antibody were positive among 4.2%, 37% and 0.1% of subjects, respectively. Univariate and multivariate associations were assessed using logistic regression. Anti-HBc antibodies were associated with alcohol use, traditional medicines and higher CD4 counts; HBsAg positivity was associated with lower CD4. Compared with the HBsAg ELISA, a rapid HBsAg test had a sensitivity of 75.0% and specificity of 99.6%. In conclusion, we identified a moderate prevalence of both HBsAg and anti-HBc. Importantly, we found that subjects with HBsAg positivity had lower CD4 counts.

Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2.

BACKGROUND: Most persons who are infected with human immunodeficiency virus type 1 (HIV-1) are also infected with herpes simplex virus type 2 (HSV-2), which is frequently reactivated and is associated with increased plasma and genital levels of HIV-1. Therapy to suppress HSV-2 reduces the frequency of reactivation of HSV-2 as well as HIV-1 levels, suggesting that suppression of HSV-2 may reduce the risk of transmission of HIV-1. METHODS: We conducted a randomized, placebo-controlled trial of suppressive therapy for HSV-2 (acyclovir at a dose of 400 mg orally twice daily) in couples in which only one of the partners was seropositive for HIV-1 (CD4 count, > or = 250 cells per cubic millimeter) and that partner was also infected with HSV-2 and was not taking antiretroviral therapy at the time of enrollment. The primary end point was transmission of HIV-1 to the partner who was not initially infected with HIV-1; linkage of transmissions was assessed by means of genetic sequencing of viruses. RESULTS: A total of 3408 couples were enrolled at 14 sites in Africa. Of the partners who were infected with HIV-1, 68% were women, and the baseline median CD4 count was 462 cells per cubic millimeter. Of 132 HIV-1 seroconversions that occurred after randomization (an incidence of 2.7 per 100 person-years), 84 were linked within couples by viral sequencing: 41 in the acyclovir group and 43 in the placebo group (hazard ratio with acyclovir, 0.92, 95% confidence interval [CI], 0.60 to 1.41; P=0.69). Suppression with acyclovir reduced the mean plasma concentration of HIV-1 by 0.25 log(10) copies per milliliter (95% CI, 0.22 to 0.29; P<0.001) and the occurrence of HSV-2-positive genital ulcers by 73% (risk ratio, 0.27; 95% CI, 0.20 to 0.36; P<0.001). A total of 92% of the partners infected with HIV-1 and 84% of the partners not infected with HIV-1 remained in the study for 24 months. The level of adherence to the dispensed study drug was 96%. No serious adverse events related to acyclovir were observed. CONCLUSIONS: Daily acyclovir therapy did not reduce the risk of transmission of HIV-1, despite a reduction in plasma HIV-1 RNA of 0.25 log(10) copies per milliliter and a 73% reduction in the occurrence of genital ulcers due to HSV-2. (ClinicalTrials.gov number, NCT00194519.)

HAART and risk of tuberculosis in HIV-infected South African children: a multi-site retrospective cohort.

SETTING: Four human immunodeficiency virus (HIV) clinics located at South African tertiary hospitals. OBJECTIVE: To assess the effectiveness of highly active antiretroviral therapy (HAART) in reducing incident tuberculosis (TB) in HIV-infected children. DESIGN: Retrospective cohort. RESULTS: A total of 1132 children's records were included in the study. At entry to the cohort, the median (interquartile range [IQR]) age, CD4%, CD4 count and viral load of all children was respectively 6.3 years (4.1-8.8), 15% (9.0-22.2), 576 cells/mm(3) (287-960) and 160 000 copies/ml (54 941.5-449 683); 75.9% were started on HAART. The male:female ratio was 1:1, and median follow-up time was 1.7 years. In children whose follow-up included both pre-HAART and on-HAART periods, the incidence of clinically diagnosed TB was respectively 21.1 per 100 person-years (py; 95%CI 18.2-24.4) and 6.4/100 py (95%CI 4.8-8.1), and when restricted to confirmed cases, respectively 3.1/100 py (95%CI 2.2-4.2) and 0.8/100 py (95%CI 0.5-1.4). Only 23% of all cases of TB were microbiologically confirmed. Multivariate analyses showed that HAART reduced incident TB by approximately 70%, both for confirmed and all TB cases. CONCLUSIONS: In this high TB burden country, the incidence of diagnosis of TB in HIV-infected children is at least as high as that of adults. HAART reduces incident TB, but further prospective TB preventive and diagnostic studies are urgently needed in children.

Sexual risk behaviour of the first cohort undergoing screening for enrollment into Phase I/II HIV vaccine trials in South Africa.

We assessed risk behaviour in a heterosexual cohort undergoing prescreening for the first Phase I/II HIV vaccine trials in Soweto. We developed a survey and collected self-reported data from HIV-negative potential volunteers. Of 488 participants, most were single and approximately half were from households with incomes below the poverty level. Males reported higher rates of heavy alcohol use (P < 0.001), marijuana use (P < 0.001) and other recreational drug use (P < 0.01). Males reported more sex partners than females in the previous six months (P < 0.001), as well as more casual/anonymous partners (P < 0.001) and one-night stands (P < 0.001). Multivariate analyses revealed substance use and male gender predicted higher risk behaviours, including <100% condom use with known/suspected HIV-positive partners, having casual/anonymous partners and having more than two partners. For this population, male volunteers may need increased risk-reduction counselling during Phase I/II trials and additional recruitment methods may be necessary to identify high-risk female volunteers for Phase III efficacy trials.

Identification of new variants within the two functional genes CCL3 and CCL3L encoding the CCL3 (MIP-1alpha) chemokine: implications for HIV-1 infection.

The CC chemokine CCL3 is encoded by two functional genes, namely CCL3 and CCL3L, and has been identified as a key chemokine in HIV-1 susceptibility and disease progression. The complete CCL3 and CCL3L genes and core promoters of 43 African mother-infant pairs (86 samples) and 28 Caucasian adults in South Africa were sequenced and extensively analysed for genetic variations. Africans were found to be more polymorphic in both genes with 25 single nucleotide polymorphisms (SNPs) in the CCL3 gene and 14 gene copy number single nucleotide polymorphisms (gcnSNPs) in the CCL3L gene, compared to nine CCL3 SNPs and eight CCL3L gcnSNPs in Caucasians. A total of 14 polymorphisms across the two genes were newly identified in this study, most (12/14) of which were exclusive to the African population. In addition, two indels were identified and characterized in the CCL3 and CCL3L genes of a small number of individuals. Of the numerous unique intragenic haplotypes found in the two genes, none were shared by the two population groups. A newly identified five-SNP CCL3 haplotype (Hap-C1) found in a high frequency in Caucasians, however, seems to be evolutionarily related to the most prevalent newly identified African seven-SNP CCL3 haplotype (Hap-A1). Hap-A1 also includes an SNP in the core promoter region and previous CCL3 haplotypes that have been reported to be associated with HIV-1 infection appear to be smaller haplotypes within Hap-A1. We thus propose Hap-A1 as a likely candidate for influencing levels of CCL3 production and in turn outcomes of HIV-1 infection.

Pediatric admissions with human immunodeficiency virus infection at a regional hospital in Soweto, South Africa.

The prevalence and clinical spectrum of HIV disease in hospitalized African children has not been adequately characterized in Southern Africa. This study aimed to determine the prevalence and disease profile of HIV infected children under 5 years of age admitted to a tertiary care hospital in Soweto, South Africa and to assess the impact of pediatric HIV on health services. Over a 6-month period, serial pediatric admissions to one of the children's wards were screened for HIV. Data on demographics and disease profile were recorded for all patients. A total of 549 patients were admitted, of whom 507 were tested for HIV; 29.2 per cent were considered to be truly infected. Previous admissions to hospital were more frequent in the HIV infected group, 48 per cent compared with 20.4 per cent of HIV uninfected children (p < 0.01), with a median length of stay of 8 days compared with 6 days (p < 0.01). There were more malnourished children in the HIV infected group (65.8 per cent compared with 33.1 per cent) (p < 0.01) and more died (17 per cent compared with 4.6 per cent) (p < 0.01). The most common reasons for admission in all children were infectious diseases such as pneumonia and gastroenteritis (85 and 31.9 per cent compared with 51 and 22.5 per cent, respectively in the HIV infected and uninfected groups, p < 0.01 and p < 0.03). It was concluded that pediatric HIV infection accounts for almost a third of childhood admissions to this hospital and has become a significant burden on the health service.

A review of herbal medicines for psychiatric disorders.

OBJECTIVE: This review examines herbs commonly used for psychiatric symptoms-St. John's wort, kava, ginkgo biloba, and valerian. METHODS: MEDLINE was searched for articles related to the use of herbs in psychiatry published after 1990. A secondary search examined sources cited in articles obtained from the MEDLINE search. RESULTS: Of nine controlled and standardized trials of St. John's wort, five showed the herb's superiority to placebo, and four found no differences in effectiveness when compared with antidepressant drugs. The pharmacologically active components are not known. Several double-blind, placebo-controlled trials have demonstrated the anxiolytic efficacy of kava, but these studies had ill-defined patient populations, small sample sizes, and short treatment duration. All but one of 40 controlled trials of ginkgo extracts in the treatment of dementia found clinically significant improvement in memory loss, concentration, fatigue, anxiety, and depressed mood. Most studies of gingko had poorly defined patient populations and small sample sizes and used nonstandard measures. A recent well-designed multicenter study showed significantly less decline in cognitive function among patients with dementia receiving gingko. Valerian has been shown to decrease sleep latency and nocturnal awakenings and improve subjective sleep quality, but placebo effects were marked in some studies, and in some cases the beneficial effects were not seen until two to four weeks of therapy. CONCLUSIONS: Although evidence of the efficacy of herbal preparations in treating psychiatric conditions is growing, translating the results of efficacy studies into effective treatments for patients is hampered by the chemical complexity of the products, the lack of standardization of commonly available preparations, and the paucity of well-controlled studies.

A family of proteins implicated in axon guidance and outgrowth.

Rapid progress in the identification and characterization of axon guidance molecules and their receptors has left the field poised to explore the intracellular mechanisms by which signals are transduced into growth cone responses. The TUC (TOAD/Ulip/CRMP) family of proteins has emerged as a strong candidate for a role in growth cone signaling. The TUC family members reach their highest expression levels in all neurons during their peak periods of axonal growth and are strongly down-regulated afterward. When axonal regrowth in the adult is triggered by axotomy, TUC-4 is reexpressed during the period of regrowth. Mutations in unc-33, a homologous nematode gene, lead to severe axon guidance errors in all neurons. Furthermore, the TUC family is required for the growth cone-collapsing activity of collapsin-1. An important role for the TUC family is also suggested by its high degree of interspecies amino acid sequence identity, with the rat TUC-2 protein showing 98% identity with its chick ortholog and 89% identity with its Xenopus ortholog. Information gained from the study of the TUC family will be of key importance in understanding how growth cones find their targets.

Correlation between CD4+ lymphocyte counts, concurrent antigen skin test and tuberculin skin test reactivity in human immunodeficiency virus type 1-infected and -uninfected children with tuberculosis.

BACKGROUND: HIV-infected children are at high risk of developing tuberculosis after infection by Mycobacterium tuberculosis. Emphasis is placed on tuberculin skin testing (TST) for diagnosing tuberculosis in children; however, its value in HIV-infected children is controversial. OBJECTIVES: To determine whether concurrent antigen testing and/or CD4+ lymphocyte counts help in the interpretation of the TST in children with tuberculosis. METHODS: Children eligible for the study were diagnosed as having tuberculosis on clinical criteria. CD4+ lymphocyte counts and delayed-type hypersensitivity (DTH) test, using the CMI Multitest were performed when tuberculosis was diagnosed. RESULTS: One hundred thirty children were enrolled. Tuberculin reactivity was lower in HIV-infected children at all cutoff levels than in HIV-uninfected children (P < 0.0001). The positive predictive value of normal CD4+ lymphocyte counts in predicting tuberculin reactions of > or =5 mm (in HIV-1-infected) and > or =10 mm (in HIV-uninfected patients) were 50 and 80.3%, respectively (P < 0.0001). An intact DTH reaction to the CMI Multitest in predicting reactions of > or =5 mm and > or =10 mm to tuberculin in HIV-infected and -uninfected children were 55 and 76%, respectively (P < 0.001). Kwashiorkor was responsible for 53.3% of false-negative TST in HIV-uninfected children with normal CD4+ lymphocyte counts. CONCLUSION: TST is of limited value as an adjunct in diagnosing tuberculosis in HIV-infected children. CD4+ lymphocyte counts and concurrent DTH testing are not useful for predicting tuberculin reactivity in HIV-infected patients with tuberculosis.

Human ligands of the Notch receptor.

During development, the Notch signaling pathway is essential for the appropriate differentiation of many cell types in organisms across the phylogenetic scale, including humans. Notch signaling is also implicated in human diseases, including a leukemia and two hereditary syndromes known as Alagille and CADASIL. To generate tools for pursuing the role of the Notch pathway in human disease and development, we have cloned and analyzed the expression of three human homologues of the Notch ligands Delta and Serrate, human Jagged1 (HJ1), human Jagged2 (HJ2), and human Delta1 (H-Delta-1), and determined their chromosomal localizations. We have also raised antibodies to HJ1, and used these antibodies in conjunction with in situ hybridization to examine the expression of these ligands in normal and cancerous cervical tissue. We find that, as reported previously for Notch, the ligands are up-regulated in certain neoplastic tissues. This observation is consistent with the notion that Notch signaling is an important element in these pathogenic conditions, raising the possibility that modulation of Notch activity could be used to influence the fate of the cells and offering a conceivable therapeutic avenue.