Brandon L. Guthrie

HIV-1-discordant couples in sub-Saharan Africa: explanations and implications for high rates of discordancy.

In sub-Saharan Africa, approximately 1 in 2 HIV-1-infected persons living in a couple have a serodiscordant partner. Recent data suggest a large proportion of new HIV-1 infections in mature epidemics occur within discordant couples, making discordancy a major contributor to the spread of HIV/AIDS in Africa. What accounts for high rates of HIV-1 discordance and why some individuals remain uninfected despite repeated sexual exposure to HIV-1 is unknown. Studying HIV-1-discordant couples may contribute to understanding correlates of HIV-1 immunity and acute infection. Additionally, HIV-1-discordant couples are an important population for prevention efforts. Consequently, HIV-1-discordant couples are increasingly viewed as a valuable source of participants for HIV vaccine and prevention trials. This review summarizes and critiques existing data on HIV-1-discordant couples in developing countries, including an analysis of transmission rates within discordant couples, description of biological and behavioral characteristics important in planning HIV-1 vaccine and prevention trials, and challenges faced when carrying out such studies.

Knowledge and Acceptability of Pap Smears, Self-Sampling and HPV Vaccination among Adult Women in Kenya

Objectives Our study aimed to assess adult women’s knowledge of human papillomavirus (HPV) and cervical cancer, and characterize their attitudes towards potential screening and prevention strategies. Methods Women were participants of an HIV-discordant couples cohort in Nairobi, Kenya. An interviewer-administered questionnaire was used to obtain information on sociodemographic status, and sexual and medical history at baseline and on knowledge and attitudes towards Pap smears, self-sampling, and HPV vaccination at study exit. Results Only 14% of the 409 women (67% HIV-positive; median age 29 years) had ever had a Pap smear prior to study enrollment and very few women had ever heard of HPV (18%). Although most women knew that Pap smears detect cervical cancer (69%), very few knew that routine Pap screening is the main way to prevent ICC (18%). Most women reported a high level of cultural acceptability for Pap smear screening and a low level of physical discomfort during Pap smear collection. In addition, over 80% of women reported that they would feel comfortable using a self-sampling device (82%) and would prefer at-home sample collection (84%). Nearly all women (94%) reported willingness to be vaccinated to prevent cervical cancer if offered at no or low cost. Conclusions These findings highlight the need to educate women on routine use of Pap smears in the prevention of cervical cancer and demonstrate that vaccination and self-sampling would be acceptable modalities for cervical cancer prevention and screening.

Cervicovaginal HIV-1-neutralizing immunoglobulin A detected among HIV-1-exposed seronegative female partners in HIV-1-discordant couples.

Objective:Cervicovaginal HIV-1-neutralizing immunoglobulin A (IgA) was associated with reduced HIV-1 acquisition in a cohort of commercial sex workers. We aimed to define the prevalence and correlates of HIV-1-neutralizing IgA from HIV-1-exposed seronegative (HESN) women in HIV-1-serodiscordant relationships. Methods:HIV-1-serodiscordant couples in Nairobi were enrolled and followed quarterly up to 2 years, and women in concordant HIV-1-negative relationships were enrolled as controls. Cervicovaginal, seminal, and blood samples were collected at enrollment and follow-up. Cervicovaginal IgA was assessed for HIV-1-neutralizing activity by a peripheral blood mononuclear cell-based assay using an HIV-1 clade A primary isolate. Results:HESN women in discordant relationships had significantly more HIV-1-neutralizing IgA detected in genital secretions compared with control women [36 of 155 (23%) vs. four of 70 (6%), respectively; odds ratio (OR) 5.0; 95% confidence interval (CI) 1.70–14.64; P = 0.003]. These responses persisted over time in all available follow-up cervicovaginal samples from women with detectable HIV-1-neutralizing IgA at baseline. Partner median HIV-1 plasma viral load was lower among women who had HIV-1-neutralizing IgA compared with women without detectable activity (4.3 vs. 4.8 log10 copies/ml, respectively; OR 0.70; 95% CI 0.51–0.94; P = 0.02). A similar trend was found with partner seminal viral load (OR 0.57; 95% CI 0.32–1.02; P = 0.06). Conclusion:HESN women were five times more likely to have neutralizing IgA in cervicovaginal secretions than low-risk control women, and these responses were inversely associated with partner viral load. These observations support the existence of antiviral activity in the mucosal IgA fraction following sexual HIV-1 exposure.

Barriers to antiretroviral initiation in HIV-1-discordant couples.

BackgroundIn Kenya and much of sub-Saharan Africa, nearly half of all couples affected by HIV are discordant. Antiretroviral therapy (ART) slows disease progression in HIV-1–infected individuals and reduces transmission to uninfected partners. We examined time to ART initiation and factors associated with delayed initiation in HIV-1–discordant couples in Nairobi. MethodsHIV-1–discordant couples were enrolled and followed quarterly for up to 2 years. Clinical staff administered questionnaires and conducted viral loads and CD4 counts. Participants with a CD4 count meeting ART criteria were referred to a nearby US Presidents Emergency Plan for AIDS Relief–funded treatment center. Barriers to ART initiation among participants with a CD4 count eligible for ART were assessed by Cox regression. ResultsOf 439 HIV-1–infected participants (63.6% females and 36.4% males), 146 met CD4 count criteria for ART during follow-up. Median time from meeting CD4 criteria until ART initiation was 8.9 months, with 42.0% of eligible participants on ART by 6 months and 63.4% on ART by 1 year. The CD4 count at the time of eligibility was inversely associated with time to ART initiation (hazard ratio = 0.49, P < 0.001). Compared with homeowners, those paying higher rents started ART 48% more slowly (P = 0.062) and those paying lower rents started 71% more slowly (P = 0.002). ConclusionsDespite access to regular health care, referrals to treatment centers, and free access to ART, over one-third of participants with an eligible CD4 count had not started ART within 1 year. Factors of lower socioeconomic status may slow ART initiation, and targeted approaches are needed to avoid delays in treatment initiation.

HIV-neutralizing activity of cationic polypeptides in cervicovaginal secretions of women in HIV-serodiscordant relationships.

Background HIV exposed seronegative (HESN) women represent the population most in need of a prophylactic antiviral strategy. Mucosal cationic polypeptides can potentially be regulated for this purpose and we here aimed to determine their endogenous expression and HIV neutralizing activity in genital secretions of women at risk of HIV infection. Methodology/Principal Findings Cervicovaginal secretions (CVS) of Kenyan women in HIV-serodiscordant relationships (HESN, n = 164; HIV seropositive, n = 60) and low-risk controls (n = 72) were assessed for the cationic polypeptides HNP1–3, LL-37 and SLPI by ELISA and for HIV neutralizing activity by a PBMC-based assay using an HIV primary isolate. Median levels of HNP1–3 and LL-37 in CVS were similar across study groups. Neither HSV-2 serostatus, nor presence of bacterial vaginosis, correlated with levels of HNP1–3 or LL-37 in the HESN women. However, an association with their partners viral load was observed. High viral load (>10,000 HIV RNA copies/ml plasma) correlated with higher levels of HNP1–3 and LL-37 (p = 0.04 and 0.03, respectively). SLPI was most abundant in the low-risk group and did not correlate with male partners viral load in the HESN women. HIV neutralizing activity was found in CVS of all study groups. In experimental studies, selective depletion of cationic polypeptides from CVS rendered the remaining CVS fraction non-neutralizing, whereas the cationic polypeptide fraction retained the activity. Furthermore, recombinant HNP1–3 and LL-37 could induce neutralizing activity when added to CVS lacking intrinsic activity. Conclusions/Significance These findings show that CVS from HESN, low-risk, and HIV seropositive women contain HIV neutralizing activity. Although several innate immune proteins, including HNP1–3 and LL-37, contribute to this activity these molecules can also have inflammatory properties. This balance is influenced by hormonal and environmental factors and in the present HIV serodiscordant couple cohort study we show that a partners viral load is associated with levels of such molecules.

Sexually transmitted infections among HIV-1-discordant couples.

Introduction More new HIV-1 infections occur within stable HIV-1-discordant couples than in any other group in Africa, and sexually transmitted infections (STIs) may increase transmission risk among discordant couples, accounting for a large proportion of new HIV-1 infections. Understanding correlates of STIs among discordant couples will aid in optimizing interventions to prevent HIV-1 transmission in these couples. Methods HIV-1-discordant couples in which HIV-1-infected partners were HSV-2-seropositive were tested for syphilis, chlamydia, gonorrhea, and trichomoniasis, and HIV-1-uninfected partners were tested for HSV-2. We assessed sociodemographic, behavioral, and biological correlates of a current STI. Results Of 416 couples enrolled, 16% were affected by a treatable STI, and among these both partners were infected in 17% of couples. A treatable STI was found in 46 (11%) females and 30 (7%) males. The most prevalent infections were trichomoniasis (5.9%) and syphilis (2.6%). Participants were 5.9-fold more likely to have an STI if their partner had an STI (P<0.01), and STIs were more common among those reporting any unprotected sex (OR = 2.43; P<0.01) and those with low education (OR = 3.00; P<0.01). Among HIV-1-uninfected participants with an HSV-2-seropositive partner, females were significantly more likely to be HSV-2-seropositive than males (78% versus 50%, P<0.01). Conclusions Treatable STIs were common among HIV-1-discordant couples and the majority of couples affected by an STI were discordant for the STI, with relatively high HSV-2 discordance. Awareness of STI correlates and treatment of both partners may reduce HIV-1 transmission. Trial Registration ClinicalTrials.gov NCT00194519

Depot medroxyprogesterone acetate use is associated with elevated innate immune effector molecules in cervicovaginal secretions of HIV-1-uninfected women

Objective:The effects of sex hormones on the immune defenses of the female genital mucosa and its susceptibility to infections are poorly understood. The injectable hormonal contraceptive depot medroxyprogesterone acetate (DMPA) may increase the risk for HIV-1 acquisition. We assessed the local concentration in the female genital mucosa of cationic polypeptides with reported antiviral activity in relation to DMPA use. Methods:HIV-1–uninfected women were recruited from among couples testing for HIV in Nairobi, Kenya. Cervicovaginal secretion samples were collected, and the concentrations of HNP1–3, LL-37, lactoferrin, HBD-2, and SLPI were measured by enzyme-linked immunosorbent assays. Levels of cationic polypeptides in cervicovaginal secretions were compared between women who were not using hormonal contraception and those using DMPA, oral, or implantable contraception. Results:Among 228 women, 165 (72%) reported not using hormonal contraception at enrollment, 41 (18%) used DMPA, 16 (7%) used an oral contraceptive, and 6 (3%) used a contraceptive implant. Compared with nonusers of hormonal contraception, DMPA users had significantly higher mean levels of HNP1–3 (2.38 vs. 2.04 log10 ng/mL; P = 0.024), LL-37 (0.81 vs. 0.40 log10 ng/mL; P = 0.027), and lactoferrin (3.03 vs. 2.60 log10 ng/mL; P = 0.002), whereas SLPI and HBD-2 were similar. Conclusions:Although all analyzed cationic polypeptides have intrinsic antiviral capacity, their interaction and cumulative effect on female genital mucosa susceptibility to infections in vivo has yet to be unraveled. This study suggests a potential mechanism underlying the effect of DMPA on the innate immune defenses, providing a rationale to investigate its effect on HIV-1 acquisition risk.

Genital Injury Signatures and Microbiome Alterations Associated With Depot Medroxyprogesterone Acetate Usage and Intravaginal Drying Practices.

Abstract Background. Increasing evidence suggests depot medroxyprogesterone acetate (DMPA) and intravaginal practices may be associated with human immunodeficiency virus (HIV-1) infection risk; however, the mechanisms are not fully understood. This study evaluated the effect of DMPA and intravaginal practices on the genital proteome and microbiome to gain mechanistic insights. Methods. Cervicovaginal secretions from 86 Kenyan women, including self-reported DMPA users (n = 23), nonhormonal contraceptive users (n = 63), and women who practice vaginal drying (n = 46), were analyzed using tandem-mass spectrometry. Results. We identified 473 human and 486 bacterial proteins from 18 different genera. Depot medroxyprogesterone acetate use associated with increased hemoglobin and immune activation (HBD, HBB, IL36G), and decreased epithelial repair proteins (TFF3, F11R). Vaginal drying associated with increased hemoglobin and decreased phagocytosis factors (AZU1, MYH9, PLAUR). Injury signatures were exacerbated in DMPA users who also practiced vaginal drying. More diverse (H index: 0.71 vs 0.45; P = .009) bacterial communities containing Gardnerella vaginalis associated with vaginal drying, whereas DMPA showed no significant association with community composition or diversity. Conclusions. These findings provide new insights into the impact of DMPA and vaginal drying on mucosal barriers. Future investigations are needed to confirm their relationship with HIV risk in women.

Delayed initiation of antiretroviral therapy among HIV-discordant couples in Kenya

Abstract Timely initiation of antiretroviral therapy (ART) is particularly important for HIV-discordant couples because viral suppression greatly reduces the risk of transmission to the uninfected partner. To identify issues and concerns related to ART initiation among HIV-discordant couples, we recruited a subset of discordant couples participating in a longitudinal study in Nairobi to participate in in-depth interviews and focus group discussions about ART. Our results suggest that partners in HIV-discordant relationships discuss starting ART, yet most are not aware that ART can decrease the risk of HIV transmission. In addition, their concerns about ART initiation include side effects, sustaining an appropriate level of drug treatment, HIV/AIDS-related stigma, medical/biological issues, psychological barriers, misconceptions about the medications, the inconvenience of being on therapy, and lack of social support. Understanding and addressing these barriers to ART initiation among discordant couples is critical to advancing the HIV “treatment as prevention” agenda.

Incident HSV-2 Infections Are Common Among HIV-1-discordant Couples

BACKGROUND The synergy between herpes simplex virus type 2 (HSV-2) and human immunodeficiency virus type 1 (HIV-1) is well known, but lack of knowledge about the epidemiology of HSV-2 acquisition in HIV-1-discordant couples hampers development of HSV-2 prevention interventions that could reduce HIV-1 transmission. METHODS HIV-1-discordant couples were enrolled in Nairobi, Kenya, and followed for up to 2 years. HSV-2 status was determined using HerpeSelect HSV-2 ELISA. Correlates of prevalence and incidence were assessed. RESULTS.: Of 469 HIV-1-discordant couples, at baseline, 353 (75.3%) were affected by HSV-2, of which 189 (53.5%) were concordantly HSV-2 seropositive and 164 (46.5%) were HSV-2-discordant. Prevalence was lowest among HIV-1-uninfected men (39.9%) compared to HIV-1-infected women (64.8%), HIV-1-infected men (66.7%), and HIV-1-uninfected women (68.5%). During follow-up, HSV-2 seroincidence was 14.9 per 100 person-years. Incidence was 1.6-fold higher among females compared to males (95% confidence interval [CI], 1.00-2.48) and 2.5-fold higher in HIV-1-infected compared to uninfected women (95% CI, 1.12-5.74). At least 30% of incident HSV-2 infections originated from an outside partner. CONCLUSIONS The high HSV-2 prevalence and incidence in HIV-1-discordant couples in sub-Saharan Africa suggest HSV-2 treatment and prevention could be an effective targeted strategy to reduce HSV-2 and HIV-1 transmission in this high-risk population.