HIV-uninfected Female Sex Workers Research Articles

Feasibility of Identifying a Female Sex Worker Cohort at High Risk of HIV Infection in the Caribbean for HIV Vaccine Efficacy Trials: Longitudinal Results of HVTN 907.

Identifying cohorts of Caribbean women with HIV infection rates sufficient for inclusion in HIV vaccine efficacy trials has been challenging. HVTN 907 determined the feasibility of identifying and retaining a cohort of women at high risk for HIV acquisition by focusing recruitment on female sex workers (FSWs). HIV uninfected FSWs, residing in Haiti, Dominican Republic, and Puerto Rico, who reported unprotected sex and met previously described more stringent site-specific eligibility criteria, were eligible. Behavioral risk assessment, HIV counseling and testing, and pregnancy testing were performed at baseline, 6, 12, and 18 months. Among 799 FSWs (264 from Dominican Republic, 334 from Haiti, and 201 from Puerto Rico), the median age was 26 years, with 54% having less than a high school education and 45% having a monthly household income of less than $US 100. Median number of male partners 6 months before screening was 200. Retention at 18 months was 93%. Twelve women became HIV infected, 9 from Haiti. The annualized HIV incidence was 1.07% (95% confidence interval: 0.55% to 1.87%). Pregnancy incidence was 22.5% (95% confidence interval: 21.9% to 29.5%). Statistically significant declines in risk behaviors occurred between screening and the 18-month visit assessment. The HVTN 907 study identified a high-risk cohort of women with excellent retention for all 3 sites, despite major challenges especially in Haiti. These results show that a bridging study of a vaccine shown to be efficacious in other clade settings would be possible among FSWs in the region, particularly in Haiti.

Risk Factors for HIV Acquisition in a Prospective Nairobi-Based Female Sex Worker Cohort.

With two million new HIV infections annually, ongoing investigations of risk factors for HIV acquisition is critical to guide ongoing HIV prevention efforts. We conducted a prospective cohort analysis of HIV uninfected female sex workers enrolled at an HIV prevention clinic in Nairobi (n=1640). In the initially HIV uninfected cohort (70%), we observed 34 HIV infections during 1514 person-years of follow-up, i.e. an annual incidence of 2.2% (95% CI 1.6-3.1%). In multivariable Cox Proportional Hazard analysis, HIV acquisition was associated with a shorter baseline duration of sex work (aHR 0.76, 95% CI 0.63-0.91), minimum charge/sex act (aHR 2.74, 0.82-9.15, for low vs. intermediate; aHR 5.70, 1.96-16.59, for high vs. intermediate), N.gonorrhoeae infection (aAHR 5.89, 95% CI 2.03-17.08), sex with casual clients during menses (aHR 6.19, 95% CI 2.58-14.84), Depo Provera use (aHR 5.12, 95% CI 1.98-13.22), and estimated number of annual unprotected regular partner contacts (aHR 1.004, 95% CI 1.001-1.006). Risk profiling based on baseline predictors suggested that substantial heterogeneity in HIV risk is evident, even within a key population. These data highlight several risk factors for HIV acquisition that could help to re-focus HIV prevention messages.

HIV Postexposure Prophylaxis in an Urban Population of Female Sex Workers in Nairobi, Kenya

To assess biological and behavioral factors in HIV-uninfected female sex workers (FSWs) accessing postexposure prophylaxis (PEP) and to characterize the circumstances preceding PEP, time to access, and adherence. Participants were HIV-uninfected FSWs enrolled in an HIV care and prevention program in Nairobi, Kenya. Those accessing PEP between 2009 and 2010 were enrolled and compared with controls. Multiple logistic regression models were used to compare PEP-related biological and behavioral parameters. PEP users (n = 326) had been involved in sex work for a shorter duration than nonusers [n = 2570; 3.3 vs. 5.1 yrs, AOR: 0.92, 95% confidence interval (CI): 0.89 to 0.95] and were less likely to report a regular partner (54.9% vs. 72.5%, AOR: 0.52, 0.39 to 0.68). PEP use was associated with gonorrhea infection (6.9% vs. 2.6%, AOR: 2.37, 95% CI: 1.34 to 4.21) and alcohol use (84.3% vs. 76.1%, AOR: 1.58, 95% CI: 1.09 to 2.31), but with increased condom use (85.1% vs. 68.2%, AOR 1.80, 95% CI: 1.38-2.35) and a history of prior HIV testing (89.2 vs. 76.2%, AOR: 2.22, 95% CI: 1.45 to 3.40). Reasons for PEP access centered on issues of client mistrust. The median time from exposure to PEP was 18 hours, with an estimated adherence of 49%. Precise PEP efficacy could not be calculated, but HIV incidence was 0.6% in users (2/326) compared with 2.1% (30/1417) in nonusers (Cox regression P = 0.35). "PEP services were accessed by 10% of FSWs during the study period and were not implicated in any incident HIV cases." Users had indicators of increased sexual risk and higher health care literacy. Increasing PEP access and compliance in FSWs may be an important HIV prevention strategy.

Relative HIV Resistance in Kenyan Sex Workers is Not Due to an Altered Prevalence or Mucosal Immune Impact of Herpes Simplex Virus Type 2 Infection

Chronic infection by herpes simplex virus type 2 (HSV-2) increases HIV susceptibility, perhaps due to HSV-2-associated increases in activated mucosal immune cells. A small number of Kenyan female sex workers (FSWs) exhibit relative HIV resistance. We examined whether relative HIV resistance was related to differences in the prevalence or mucosal immune impact of HSV-2. Participants were recruited from an open cohort of HIV-uninfected FSWs in Nairobi, Kenya. Women who had been practicing sex work in the cohort for >or=3 years without acquiring HIV were defined as relatively HIV resistant. HSV-2 diagnostics were performed, and cervical immune cell subsets were examined by flow cytometry in a subset of participants. The study population comprised 139 HIV-uninfected FSWs. HSV-2 seroprevalence was actually higher in FSWs meeting criteria for relative HIV resistance than in non-resistant FSWs (75/80, 94% vs 46/59, 78%; LR = 7.5; P = 0.006), likely due to the increased age and longer duration of sex work in the resistant subgroup. Late HIV acquisition was not associated with recent HSV-2 infection, and HSV-2 associated increases in HIV-susceptible cervical immune cell populations were similar in both groups. Relative HIV resistance in Kenyan FSWs was not due to a reduced prevalence or mucosal immune impact of HSV-2 infection.

Genital immunoglobulin A and HIV-1 protection: virus neutralization versus specificity

Identifying the correlates of immune protection against HIV-1 acquisition may be an important step in the development of an HIV vaccine, as discussed in a timely commentary by Dr Moog [1]. We were honored to see our work [2] cited in this commentary, but hope to clarify one issue that may cause confusion. Specifically, we did not identify ‘HIV-specific immunoglobulin A (IgA)’ – at least as defined by binding assays such as enzyme-linked immunosorbent assay (ELISA) or western blot – to be a correlate of protection in our prospective study examining the immune correlates of HIV protection. Previous studies of highly exposed, persistently HIV-1 seronegative (HEPS) individuals have described a number of genetic and immune correlates of protection, including innate and adaptive immunity in both the systemic and genital tract compartments. IgA is the predominant antibody isotype at most mucosal surfaces, albeit not that of the lower genital tract [3]. This antibody isotype has been associated with the HEPS phenotype in two distinct capacities. First, ‘HIV-specific IgA’, with HIV specificity defined by binding to various viral antigens in an ELISA or western blot system, has been found in the blood and genital secretions of individuals from some HEPS cohorts [4–10] but not others [11,12]; the latter discrepancies may relate to inter-cohort differences in HIV exposure levels [13] or to variability between different laboratories and different ELISA systems in the detection of low-concentration IgA antibodies [14]. Second, IgA antibodies with HIV inhibitory capacity (most commonly the ability to neutralize HIV replication in peripheral blood mononuclear cells (PBMCs), or to inhibit epithelial transcytosis) have been described in similar HEPS cohorts [4,15,16]. The distinction between ‘HIV-specific IgA’ and IgA antibodies with HIV inhibitory capacity may be an important one to make. Even well defined HIV-binding monoclonal antibodies may lack some HIV inhibitory functions, including the ability to block transcytosis [17]. On the contrary, antibody-mediated inhibition of HIV replication may not require specificity for HIV antigens, as it can be achieved through alternate mechanisms such as the downregulation or blocking of the chemokine (C-C motif) receptor 5 coreceptor on target cells [18], blocking of Dendritic Cell-Specific ICAM-3 Grabbing Nonintegrin [19], or alloimmune responses directed against human leukocyte antigens [20,21]. Although some HEPS studies have described IgA that is both HIV-specific and has anti-HIV functional capacity [4,9], most have focused on either one aspect or the other. In our recent prospective study [2], we purified IgA from the genital secretions of high-risk, HIV-uninfected female sex workers at a single time point, and then followed participants for an average of just over 2 years. IgA neutralization of primary HIV isolates was tested in an operator-blinded fashion, using previously described methods and an assay cut-off that had been validated in HIV low-risk individuals from the region [16]. A PBMC-based assay was used to ensure the detection of IgA reactivity to both HIV protein structures and other possible epitopes involved in HIV fusion and entry. The ability of genital IgA to neutralize HIV was independently correlated with subsequent protection against HIV acquisition (as was HIV-specific proliferation of blood CD8+ T lymphocytes). We did not screen for HIV-specific IgA by ELISA or western blot in a comprehensive fashion, nor did we detect such antibodies in the subset in which these assays were performed (Hirbod T and Broliden K; unpublished data). The mechanism of HIV neutralization was not defined and will be an important area for future research; if HIV-specific IgA was involved, then such work should include mapping the epitope specificity of these antibodies. An additional caveat should be highlighted. Although our prospective study was rigorously performed, with operator-blinded performance of predefined IgA neutralization assays, this was an observational study and shares the limitations of all such studies. Specifically, the direction of causality in the observed association between immune parameters and reduced HIV acquisition cannot be proven. It remains possible that HIV protection was mediated through another mechanism – be that genetic, immune, behavioral or other – and that the immune responses we measured were induced as a result of HIV exposure without infection, rather than mediating the phenomenon. In summary, our recent data demonstrates that IgA antibodies with HIV-neutralizing capacity were present in the lower genital tract of some HEPS female sex workers, and were associated with reduced rates of HIV acquisition. It may be important to make the distinction between IgA antibodies with functional activity against HIV, and ‘HIV-specific’ IgA antibodies (as defined by ELISA). It was the former that we observed to be associated with HIV protection in our prospective study.

Negative mucosal synergy between Herpes simplex type 2 and HIV in the female genital tract

There is substantial epidemiological evidence that infection by Herpes simplex virus type 2 (HSV2) enhances both HIV susceptibility and subsequent sexual transmission. Both infections are extremely common in female sex workers (FSWs) in sub-Saharan Africa, and up to 80% of new HIV infections in urban men in the region are acquired via transactional sex. The present study aimed to elucidate the mucosal immune interactions between HIV and HSV2 in the genital tract. Endocervical immune cell populations, cytokine/chemokine protein levels in cervico-vaginal secretions and cervical immune gene expression profiles were measured in a well-defined cohort of HIV-infected and uninfected Kenyan FSWs. Associations between the genital immune milieu and infection by and/or shedding of common genital co-pathogens were examined. HIV-infected FSWs were much more likely to be infected by HSV2, and to shed HSV2 DNA in the genital tract. There was also a profound negative 'mucosal synergy' between these viruses. In HIV uninfected FSWs, HSV2 infection was associated with a ten-fold increase in cervical immature dendritic cells (iDC) expressing DC-SIGN, and a three-fold increase in cervical CD4+ T cells expressing CCR5. HIV infection was associated with iDC depletion in the cervix, and with increased HSV2 genital reactivation, which in turn was associated with HIV shedding levels. The findings suggest a mucosal vicious circle in which HSV2 infection increases HIV target cells in the genital mucosa, subsequent HIV infection impairs HSV2 mucosal immune control, and local HSV2 reactivation enhances both HSV2 and HIV transmission.