Karine Dubé

How does the timing of antiretroviral therapy initiation in acute infection affect HIV reservoirs

Purpose of reviewThe long-lived viral reservoir is a major obstacle to achieving a cure for HIV. Therapeutic strategies, such as early antiretroviral therapy (ART), may be a prerequisite to achieving long-term control of viral replication upon ART withdrawal. Recent findingsHIV persistence is established early in acute HIV infection (AHI) with infection in long-lived memory CD4+ T cells. Studies conducted in nonhuman primates have suggested that this could occur as early as 3 days postinfection; however, the timing in humans is uncertain. ART during AHI significantly restricts the HIV reservoirs as compared with later treatment. Early ART, particularly prior to the detection of HIV immunoglobulin M, may also reduce the contribution of the long-lived central memory CD4+ T cells to the total HIV reservoir, a profile observed in individuals who naturally control HIV without ART. SummaryIt is clear that early ART has a greater impact in limiting the HIV reservoirs than later treatment. However, latently infected long-lived memory CD4+ T cells persist in most early treated individuals. Therefore, additional interventions will likely be required to eliminate all cells capable of producing replication-competent virus but treatment in AHI may be the critical first step in containing the HIV reservoirs.

Determinants of prevalent HIV infection and late HIV diagnosis among young women with two or more sexual partners in Beira, Mozambique.

Background The prevalence and determinants of HIV and late diagnosis of HIV in young women in Beira, Mozambique, were estimated in preparation for HIV prevention trials. Methods An HIV prevalence survey was conducted between December 2009 and October 2012 among 1,018 women aged 18–35 with two or more sexual partners in the last month. Participants were recruited in places thought by recruitment officers to be frequented by women at higher-risk, such as kiosks, markets, night schools, and bars. Women attended the research center and underwent a face-to-face interview, HIV counseling and testing, pregnancy testing, and blood sample collection. Results HIV prevalence was 32.6% (95% confidence interval (CI) 29.7%–35.5%). Factors associated with being HIV infected in the multivariable analysis were older age (p<0.001), lower educational level (p<0.001), self-reported genital symptoms in the last 3 months (adjusted odds ratio (aOR) = 1.4; CI 1.1–2.0), more than one lifetime HIV test (aOR = 0.4; CI 0.3–0.6), and not knowing whether the primary partner has ever been tested for HIV (aOR = 1.7; CI 1.1–2.5). About a third (32.3%) of participants who tested HIV-positive had a CD4 lymphocyte count of <350 cells/µl at diagnosis. Factors associated with late diagnosis in multivariable analyses were: not knowing whether the primary partner has ever been tested for HIV (aOR = 2.2; CI 1.1–4.2) and having had a gynecological pathology in the last year (aOR = 3.7; CI 1.2–12.0). Conclusions HIV prevalence and late diagnosis of HIV infection were high in our study population of young women with sexual risk behavior in Beira, Mozambique. HIV prevention programs should be strengthened, health care providers should be sensitized, and regular HIV testing should be encouraged to enroll people living with HIV into care and treatment programs sooner.

Towards Multidisciplinary HIV-Cure Research: Integrating Social Science with Biomedical Research.

The quest for a cure for HIV remains a timely and key challenge for the HIV research community. Despite significant scientific advances, current HIV therapy regimens do not completely eliminate the negative impact of HIV on the immune system; and the economic impact of treating all people infected with HIV globally, for the duration of their lifetimes, presents significant challenges. This article discusses, from a multidisciplinary approach, critical social, behavioral, ethical, and economic issues permeating the HIV-cure research agenda. As part of a search for an HIV cure, both the perspective of patients/participants and clinical researchers should be taken into account. In addition, continued efforts should be made to involve and educate the broader community.

HIV Prevalence and Incidence in a Cohort of Women at Higher Risk for HIV Acquisition in Chókwè, Southern Mozambique

Background Reliable HIV incidence estimates for Mozambique are limited. We conducted a prospective HIV incidence study as part of a clinical research site development initiative in Chókwè district, Gaza Province, southern Mozambique. Methods Between June 2010 and October 2012, we recruited women at sites where women at higher risk of HIV infection would likely be found. We enrolled and tested 1,429 sexually active women in the screening phase and 479 uninfected women in the prospective phase. Participants were scheduled for 12+ months follow-up, when they underwent face-to-face interviews, HIV counseling and testing, and pregnancy testing. We observed a total of 373.1 woman-years (WY) of follow-up, with mean (median) of 9.4 (9.7) women-months per participant. Results The prevalence of HIV was 29.4% (95% confidence interval [CI]: 27.0–31.8%). In multivariable logistic regression analysis, factors that remained significantly associated with prevalent HIV were: older age (OR: 0.6; 95% CI: 0.4–0.7), lower educational level (OR: 0.4; 95% CI: 0.3–0.7), and using hormonal contraception (OR: 0.6; 95% CI: 0.4–0.7) or condoms (OR: 0.5; 95% CI: 0.3–0.7). We observed an HIV incidence rate of 4.6 per 100 WY (95% CI: 2.7, 7.3). The HIV incidence was 4.8 per 100 WY (95% CI: 2.5, 8.3) in women aged 18–24 years, 4.5 per 100 WY (95% CI: 1.2, 11.4) in women aged 25–29 years and 3.2 per 100 WY (95% CI: 0.1, 18.0) in the 30–35 years stratum. None of the demographic factors or time-varying behavioral factors examined was significantly associated with incident HIV infection in bivariable analysis at p≤0.10. Conclusions We found a high HIV incidence among sexually active young women in Chókwè, Mozambique. HIV prevention programs should be strengthened in the area, with more comprehensive reproductive health services, regular HIV testing, condom promotion, and messaging about multiple sexual partners.

HIV incidence in a cohort of women at higher risk in Beira, Mozambique: prospective study 2009-2012

Background HIV is prevalent in Sofala Province, Mozambique. To inform future prevention research, we undertook a study in the provincial capital (Beira) to measure HIV incidence in women at higher risk of HIV and assess the feasibility of recruiting and retaining them as research participants. Methods Women age 18–35 were recruited from schools and places where women typically meet potential sexual partners. Eligibility criteria included HIV-seronegative status and self-report of at least 2 sexual partners in the last month. History of injection drug use was an exclusion criterion, but pregnancy was not. Participants were scheduled for monthly follow-up for 12 months, when they underwent face-to-face interviews, HIV counseling and testing, and pregnancy testing. Results 387 women were eligible and contributed follow-up data. Most were from 18–24 years old (median 21). Around one-third of participants (33.8%) reported at least one new sexual partner in the last month. Most women (65.5%) reported not using a modern method of contraception at baseline. Twenty-two women seroconverted for a prospective HIV incidence of 6.5 per 100 woman-years (WY; 95% confidence interval (CI): 4.1–9.9). Factors associated with HIV seroconversion in the multivariable analysis were: number of vaginal sex acts without using condoms with partners besides primary partner in the last 7 days (hazard ratio (HR) 1.7; 95% CI: 1.2–2.5) and using a form of contraception at baseline other than hormonal or condoms (vs. no method; HR 25.3; 95% CI: 2.5–253.5). The overall retention rate was 80.0% for the entire follow-up period. Conclusions We found a high HIV incidence in a cohort of young women reporting risky sexual behavior in Beira, Mozambique. HIV prevention programs should be strengthened. Regular HIV testing and condom use should be encouraged, particularly among younger women with multiple sexual partners.

Nevirapine-based antiretroviral therapy does not reduce oral contraceptive effectiveness.

Objective:To evaluate the effect of nevirapine-containing antiretroviral therapy (ART) on combined oral contraceptive (COC) effectiveness. Design:Nonrandomized prospective clinical trial. Methods:We enrolled HIV-infected women aged 18–35 years in South Africa and Uganda who had regular menses, were sexually active, and had no medical contraindications to COC use. We enrolled 196 women taking nevirapine-containing ART and 206 women not yet eligible for ART as a control group. We treated all participants with low-dose COCs. Our main outcomes were ovulation and pregnancy rates. We estimated ovulation in the first two cycles using weekly serum progesterone and tested for pregnancy monthly for 24 weeks. Results:The median age of participants was 29 and their median CD4+ cell count was 486. In the ART group, 43 of 168 (26%) ovulated in cycle 1, 30 of 163 (18%) in cycle 2, and 18 of 163 (11%) in both cycles. In the non-ART group, 26 of 168 (16%) ovulated in cycle 1, 31 of 165 (19%) in cycle 2, and 20 of 165 (12%) in both cycles. We found no significant difference in ovulation rates between groups: unadjusted odds ratio 1.36 (95% confidence interval 0.85–2.18). Pregnancy rates also did not differ: 10.0 per 100-women-years in the ART group and 10.1 per 100-women-years in the non-ART group. Self-reported COC adherence, condom use, vaginal bleeding, and adverse events were similar. Five serious adverse events were reported, all in the non-ART group. Conclusion:ART use did not affect risk of ovulation or pregnancy in women taking COCs, suggesting that nevirapine-containing ART does not interfere with COC contraceptive effectiveness.

Prevalence, incidence and determinants of herpes simplex virus type 2 infection among HIV-seronegative women at high-risk of HIV infection: a prospective study in Beira, Mozambique.

Objectives To estimate the prevalence, incidence and determinants of herpes simplex type 2 (HSV-2) infection, and associations between HSV-2 and incident HIV infection, among women at higher risk for HIV infection in Beira, Mozambique. Methods Between 2009 and 2012, 411 women aged 18–35 years at higher risk of HIV acquisition (defined as having had two or more sexual partners in the month prior to study enrollment) were enrolled and followed monthly for one year. At each study visit, they were counseled, interviewed, and tested for HSV-2 and HIV antibodies. Results The HSV-2 prevalence at baseline was 60.6% (95% CI: 55.7% –65.4%). Increasing age (aOR = 2.94, 95% CI: 1.74–4.97, P<0.001 and aOR = 3.39, 95% CI: 1.58–7.29, P = 0.002 for age groups of 21–24 and 25–35 years old respectively), lower educational level (aOR = 1.81, 95% CI: 1.09–3.02, P = 0.022), working full time (aOR = 8.56, 95% CI: 1.01–72.53, P = 0.049) and having practiced oral sex (aOR = 3.02, 95% CI: 1.16–7.89, P = 0.024) were strongly associated with prevalent HSV-2 infection. Thirty one participants seroconverted for HSV-2 (20.5%; 95% CI: 14.4% –27.9%) and 22 for HIV during the study period. The frequency of vaginal sex with a casual partner using a condom in the last 7 days was independently associated with incident HSV-2 infection (aOR = 1.91, 95% CI: 1.05–3.47, P = 0.034). Positive HSV-2 serology at baseline was not significantly associated with risk of subsequent HIV seroconversion. Conclusions Young women engaging in risky sexual behaviors in Beira had high prevalence and incidence of HSV-2 infection. Improved primary HSV-2 control strategies are urgently needed in Beira.

'Well, it's the risk of the unknown⋯ right?': A qualitative study of perceived risks and benefits of HIV cure research in the United States

Introduction Biomedical research towards an HIV cure is advancing in the United States and elsewhere, yet little is known about perceptions of risks and benefits among potential study participants and other stakeholders. We conducted a qualitative study to explore perceived risks and benefits of investigational HIV cure research among people living with HIV (PLWHIV), biomedical HIV cure researchers, policy-makers and bioethicists. Methods We conducted a qualitative research study using in-depth interviews with a purposive sample of PLWHIV, biomedical HIV cure researchers, policy-makers and bioethicists in 2015–2016. We analysed interview transcripts using thematic analysis anchored in grounded theory. Results We conducted and analyzed 36 key informant interviews. Qualitative analysis revealed four main findings. 1) Potential HIV cure study volunteers noted needing more information and education about the potential risks of HIV cure research. 2) Biomedical HIV cure researchers, policy-makers and bioethicists showed less awareness of social and financial risks of HIV cure research than PLWHIV. 3) Most respondents across the different categories of informants identified some risks that were too great to be acceptable in HIV cure research, although a subset of PLWHIV did not place an upper limit on acceptable risk. 4) PLWHIV showed a better awareness of potential psychological benefits of participating in HIV cure research than other groups of stakeholders. Conclusion Our research suggests that PLWHIV have a variable understanding of the individual risks, sometimes substantial, associated with participating in biomedical HIV cure research studies. Community engagement and increased research literacy may help improve community understanding. Intensive informed consent procedures will be necessary for ethical study implementation. The current state of HIV cure research offers greater potential benefits to society than to participants. There is likely to be disagreement among regulators, researchers, clinicians, and potential participants about what constitutes acceptable risk for HIV cure studies.

Validation of the Cepheid GeneXpert for Detecting Ebola Virus in Semen

Background Ebola virus (EBOV) RNA persistence in semen, reported sexual transmission, and sporadic clusters at the end of the 2013-2016 epidemic have prompted recommendations that male survivors refrain from unprotected sex unless their semen is confirmed to be EBOV free. However, there is no fully validated assay for EBOV detection in fluids other than blood. Methods The Cepheid Xpert Ebola assay for EBOV RNA detection was validated for whole semen and blood using samples obtained from uninfected donors and spiked with inactivated EBOV. The validation procedure incorporated standards from Clinical and Laboratory Standards Institute and Good Clinical Laboratory Practices guidelines for evaluating molecular devices for use in infectious disease testing. Results The assay produced limits of detection of 1000 copies/mL in semen and 275 copies/mL in blood. Limits of detection for both semen and blood increased with longer intervals between collection and testing, with acceptable results obtained up to 72 hours after specimen collection. Conclusions The Cepheid Xpert Ebola assay is accurate and precise for detecting EBOV in whole semen. A validated assay for EBOV RNA detection in semen informs the care of male survivors of Ebola, as well as recommendations for public health.

Perceptions of Equipoise, Risk–Benefit Ratios, and “Otherwise Healthy Volunteers” in the Context of Early-Phase HIV Cure Research in the United States: A Qualitative Inquiry

Early-phase HIV cure research is conducted against a background of highly effective antiretroviral therapy, and involves risky interventions in individuals who enjoy an almost normal life expectancy. To explore perceptions of three ethical topics in the context of HIV cure research—(a) equipoise, (b) risk–benefit ratios, and (c) “otherwise healthy volunteers”—we conducted 36 in-depth interviews (IDIs) with three groups of purposively selected key informants: clinician-researchers (n = 11), policy-makers and bioethicists (n = 13), and people living with HIV (PLWHIV; n = 12). Our analysis revealed variability in perceptions of equipoise. Second, most key informants believed there was no clear measure of risk–benefit ratios in HIV cure research, due in part to the complexity of weighing (sometimes unknown) risks to participants and (sometimes speculative) benefits to science and society. Third, most clinician-researchers and policy-makers/bioethicists viewed potential HIV cure study participants as “otherwise healthy volunteers,” but this perception was not shared among PLWHIV in our study.