Elizabeth Anne Bukusi

Daily aciclovir for HIV-1 disease progression in people dually infected with HIV-1 and herpes simplex virus type 2: a randomised placebo-controlled trial

Background Well-tolerated medications that slow HIV-1 disease progression and delay initiation of antiretroviral therapy (ART) are needed. Most HIV-1-infected persons are dually-infected with herpes simplex virus type 2 (HSV-2). Daily HSV-2 suppression reduces plasma HIV-1 levels, but whether HSV-2 suppression delays HIV-1 disease progression is unknown.BACKGROUND Most people infected with HIV-1 are dually infected with herpes simplex virus type 2. Daily suppression of this herpes virus reduces plasma HIV-1 concentrations, but whether it delays HIV-1 disease progression is unknown. We investigated the effect of acyclovir on HIV-1 progression. METHODS In a trial with 14 sites in southern Africa and east Africa, 3381 heterosexual people who were dually infected with herpes simplex virus type 2 and HIV-1 were randomly assigned in a 1:1 ratio to acyclovir 400 mg orally twice daily or placebo, and were followed up for up to 24 months. Eligible participants had CD4 cell counts of 250 cells per mL or higher and were not taking antiretroviral therapy. We used block randomisation, and patients and investigators were masked to treatment allocation. Effect of acyclovir on HIV-1 disease progression was defined by a primary composite endpoint of first occurrence of CD4 cell counts of fewer than 200 cells per microL, antiretroviral therapy initiation, or non-trauma related death. As an exploratory analysis, we assessed the endpoint of CD4 falling to <350 cells per microL. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00194519. FINDINGS At enrollment, the median CD4 cell count was 462 cells per microL and median HIV-1 plasma RNA was 4.1 log(10) copies per microL. Acyclovir reduced risk of HIV-1 disease progression by 16%; 284 participants assigned acyclovir versus 324 assigned placebo reached the primary endpoint (hazard ratio [HR] 0.84, 95% CI 0.71-0.98, p=0.03). In those with CD4 counts >or=350 cells per microL, aciclovir delayed risk of CD4 cell counts falling to <350 cells per microL by 19% (0.81, 0.71-0.93, p=0.002) INTERPRETATION The role of suppression of herpes simplex virus type 2 in reduction of HIV-1 disease progression before initiation of antiretroviral therapy warrants consideration. FUNDING Bill & Melinda Gates Foundation.

Multisite Laboratory Evaluation of a Dual Human Immunodeficiency Virus (HIV)/Syphilis Point-of-Care Rapid Test for Simultaneous Detection of HIV and Syphilis Infection

Background.  Recently, test developers have created rapid point-of-care tests that can simultaneously detect multiple infections within the same specimen using a single device. The SD BIOLINE Duo HIV/Syphilis rapid point-of-care test uses a solid-phase immunochromatographic assay to detect immunoglobulin (Ig)G, IgM, and IgA antibodies to human immunodeficiency virus (HIV)-specific antigens (HIV-1 gp41, sub O, HIV-2 gp36) and recombinant Treponema pallidum antigen (17 kDa) in human serum. This study was a multisite laboratory-based evaluation of the performance of SD BIOLINE HIV/Syphilis Duo test using previously characterized sera in 6 countries. Methods.  Laboratories in Ghana, Mexico, Laos, Togo, Kenya, and Myanmar participated in the evaluation during 2012–2013. Each site characterized sera using T pallidum particle agglutination assay or T pallidum hemagglutination assay and HIV enzyme immunoassay, Western blot, and/or HIV antibody rapid tests. Those gold standard test results were compared with SD BIOLINE Duo test results. We calculated the sensitivity and specificity of test performance and used the exact binomial method to calculate 95% confidence intervals (CIs). Results.  The sensitivity and specificity for the HIV antibody test component (n = 2336) were estimated at 99.91% (95% CI, 99.51% and 100%) and 99.67% (95% CI, 99.16% and 99.91%), respectively. For the T pallidum test component (n = 2059), the sensitivity and specificity were estimated at 99.67% (95% CI, 98.82% and 99.96%) and 99.72% (95% CI, 99.29% and 99.92%), respectively. Conclusions.  The sensitivity and specificity of the SD BIOLINE HIV/Syphilis Duo test were consistently high across sera specimens from 6 countries around the world. Dual rapid tests should be considered for improved HIV and syphilis screening coverage.

Daily Acyclovir to Decrease Herpes Simplex Virus Type 2 (HSV-2) Transmission from HSV-2/HIV-1 Coinfected Persons: A Randomized Controlled Trial

BACKGROUND Daily suppressive therapy with valacyclovir reduces risk of sexual transmission of herpes simplex virus type 2 (HSV-2) in HSV-2-serodiscordant heterosexual couples by 48%. Whether suppressive therapy reduces HSV-2 transmission from persons coinfected with HSV-2 and human immunodeficiency virus type 1 (HIV-1) is unknown. METHODS Within a randomized trial of daily acyclovir 400 mg twice daily in African HIV-1 serodiscordant couples, in which the HIV-1-infected partner was HSV-2 seropositive, we identified partnerships in which HIV-1-susceptible partners were HSV-2 seronegative to estimate the effect of acyclovir on risk of HSV-2 transmission. RESULTS We randomly assigned 911 HSV-2/HIV-1-serodiscordant couples to daily receipt of acyclovir or placebo. We observed 68 HSV-2 seroconversions, 40 and 28 in acyclovir and placebo groups, respectively (HSV-2 incidence, 5.1 cases per 100 person-years; hazard ratio [HR], 1.35 [95% confidence interval, .83-2.20]; P = .22). Among HSV-2-susceptible women, vaginal drying practices (adjusted HR, 44.35; P = .004) and unprotected sex (adjusted HR, 9.91; P = .002) were significant risk factors for HSV-2 acquisition; having more children was protective (adjusted HR, 0.47 per additional child; P = .012). Among HSV-2-susceptible men, only age ≤30 years was associated with increased risk of HSV-2 acquisition (P = .016). CONCLUSIONS Treatment of African HSV-2/HIV-1-infected persons with daily suppressive acyclovir did not decrease risk of HSV-2 transmission to susceptible partners. More-effective prevention strategies to reduce HSV-2 transmission from HIV-1-infected persons are needed.

Seroprevalence, predictors and estimated incidence of maternal and neonatal Herpes Simplex Virus Type 2 infection in semi-urban women in Kilifi, Kenya

BackgroundHerpes Simplex Virus type 2 (HSV-2) has public health importance as a leading cause of genital ulcers, a co-factor in HIV-1 acquisition and transmission and as a cause of neonatal herpes infections. Little is known of its epidemiology and burden in Coastal Kenya.MethodsWe screened plasma samples for HSV-2 infection from 826 women aged 15-34 years who participated in an HIV-1 survey in Kilifi in 2004. The sample comprised 563 women selected randomly from a demographic surveillance system (DSS) and 263 women who presented for voluntary counseling and testing (VCT). Predictors for HSV-2 seropositivity were determined using multivariate logistic regression. The incidence of HSV-2 infection and risk of neonatal herpes were estimated by a simple catalytic model fitted to age-seroprevalence data.ResultsHSV-2 prevalence was 32% in the DSS recruits vs. 44% in the VCT recruits (P < 0.001), while, HIV-1 prevalence was 8% in the DSS recruits vs. 12% in the VCT recruits (P = 0.12). Independent risk factors for HSV-2 infection in all women were: older age (30-34 years; odds ratio (OR) 10.5, 95% confidence interval (CI): 5.2 - 21.0), recruitment from VCT (OR 1.5, 95% CI: 1.1 - 2.1), history of genital ulcers (OR 1.7, 95% CI: 1.2 - 2.3) and HIV infection (OR 2.7, 95% CI: 1.6-4.6). Education beyond primary (OR 0.7, 95% CI: 0.5 - 0.9) was inversely associated with HSV-2 infection. In the DSS sample, HSV-2 incidence was estimated at 4 cases (95% CI: 3.3 - 4.4) per 100 women per year, 17 cases (95% CI: 16-18) per 1,000 pregnancies per year and 33 neonatal cases (95% CI: 31-36) per 100,000 births per year.ConclusionsHSV-2 transmission is rapid following the onset of sexual activity and likely to result in a significant burden of genital ulcer disease. Nevertheless, the burden of neonatal HSV-2 can be predicted to be low. Educating young women about HSV-2 infection may help in reducing its burden in this semi-urban population.

Effect of Condom Use on Per-act HSV-2 Transmission Risk in HIV-1, HSV-2-discordant Couples

BACKGROUND The efficacy of condoms for protection against transmission of herpes simplex virus type 2 (HSV-2) has been examined in a variety of populations with different effect measures. Often the efficacy has been assessed as change in hazard of transmission with consistent vs inconsistent use, independent of the number of acts. Condom efficacy has not previously measured on a per-act basis. METHODS We examined the per-act HSV-2 transmission rates with and without condom use among 911 African HSV-2 and human immunodeficiency virus type 1 (HIV-1) serodiscordant couples followed for an average of 18 months in an HIV prevention study. Infectivity models were used to associate the log10 probability of HSV-2 transmission over monthly risk periods with reported numbers of protected and unprotected sex acts. Condom efficacy was computed as the proportionate reduction in transmission risk for protected relative to unprotected sex acts. RESULTS Transmission of HSV-2 occurred in 68 couples, including 17 with susceptible women and 51 with susceptible men. The highest rate of transmission was from men to women: 28.5 transmissions per 1000 unprotected sex acts. We found that condoms were differentially protective against HSV-2 transmission by sex; condom use reduced per-act risk of transmission from men to women by 96% (P < .001) and marginally from women to men by 65% (P = .060). CONCLUSIONS Condoms are recommended as an effective preventive method for heterosexual transmission of HSV-2.

Impact of loop electrosurgical excision procedure for cervical intraepithelial neoplasia on HIV-1 genital shedding: a prospective cohort study

We sought to examine the impact of the loop electrosurgical excision procedure (LEEP) on the rate and magnitude of HIV‐1 genital shedding among women undergoing treatment for cervical intraepithelial neoplasia 2/3 (CIN2/3).

P1-S5.25 Acyclovir and transmission of HSV-2 from HSV-2/HIV-1 dually infected persons

Background Daily suppressive therapy with valacyclovir reduces the risk of sexual transmission of HSV-2 in healthy HSV-2 serodiscordant heterosexual couples by 48%. Whether suppressive therapy reduces HSV-2 transmission from persons who have both HIV-1 and HSV-2 is unknown. Methods Within a randomised trial of daily acyclovir 400 mg bid in African HIV-1 serodiscordant couples, in which the HIV-1 infected partner was HSV-2 seropositive, we identified partnerships in which the HIV-1 susceptible partners were HSV-2 seronegative. Cox proportional hazards analysis was used. Results We followed 911 HIV-1 and HSV-2 serodiscordant couples for a median of 18 months (IQR 3, 24). For 112 couples (12%), the HIV-1/HSV-2 infected partner was male, of whom 37% (34/91) were circumcised. 68 HSV-2 seroconversions were observed (an incidence of 5.1 per 100 person-years): 40 in the acyclovir group and 28 in the placebo group (HR 1.4, 95% CI 0.8 to 2.2; p=0.2). In a multivariate analysis of HSV-2 susceptible women, hormonal contraception (HR 3.84, 95% CI 1.32 to 11.14, p=0.013) and having an uncircumcised male partner (HR 8.91, 95% CI 1.17 to 67.85, p=0.035) were significant risk factors for HSV-2 acquisition. Among HSV-2 susceptible men, younger age was the only significant HSV-2 risk factor (p=0.014). Conclusions Suppressive acyclovir therapy did not decrease the risk of HSV-2 transmission within HSV-2-serodiscordant couples in which the HSV-2-seropositive partner also had HIV-1 infection. Hormonal contraceptive use and lack of male circumcision in the HIV-1/HSV-2 dually infected male partners increased the risk of HSV-2 acquisition among initially HSV-2 seronegative women.

Association between use of the progestin Depot Medroxyprogesterone Acetate and Female Cervicovaginal Lavage Proinflammatory Cytokines among HIV-1 and HSV-2 co-infected African women: a case control study

Background Use of the progestin contraceptive Depot Medroxyprogesterone Acetate (DMPA) by HIV 1 infected women is associated with increased female to male transmission of HIV. Mucosal innate immune activation has been proposed as a likely mechanism. To establish the effect of DMPA upon mucosal immune activation, this study sought to evaluate the concentrations of 5 proinflammatory and the regulatory cytokine IL 10 in cervicovaginal lavage fluid. Methods This was a case control study, 70 participants were recruited, comprising of 35 asymptomatic ART naïve HIV positive women on DMPA recruited as cases and 35 age matched asymptomatic ART naive HIV positive women not on contraceptives recruited as controls. Peripheral blood CD4 and total lymphocyte counts, High vaginal swab microscopy, endocervical smears and cervical cytology were performed for each participant. Concentrations of six proinflammatory cytokines were measured on cervicovaginal lavage by multiplex cytometric bead array. Results The mean age of cases was 26.8 years and 30 years for controls. Total lymphocyte counts and CD4 cell counts were significantly higher among cases (p=0.02 and 0.004 respectively). HSV 2 prevalence as determined by ELISA was higher (p=0.034 among cases. The concentrations of the cytokines IL 1β, IL 6, IL 8, IL 12p70 and TNF α were lower among cases, with IL 1β being statistically significant (p=0.046). Concentrations of IL 10 was higher among cases (p=0.022). On multivariate analysis, reduction in IL 1β and IL 8 were associated with the duration of DMPA use (p=0.015 and 0.041 respectively). Inclusion of HSV 2 into the multivariate models showed elevation of all cytokines measured (p=<0.001). Conclusion DMPA use is associated with reduction of proinflammatory cytokines and elevation of the regulatory cytokine IL 10. This may explain increased female to male transmission of HIV infection by modulation of male genital tract mucosa in the absence of increased HIV 1 genital shedding.

WHO stage 4 conditions among adults accessing outpatient HIV care: A retrospective cohort study in Kisumu, Kenya

Opportunistic infections (OIs) are the main cause of morbidity and mortality in patients with HIV-1 infection throughout the world, particularly among patients who have not had access to anti-retroviral therapy (ART) and other HIV care services. 1, 2, 3 Among patients taking ART, OIs can present when the immune system starts to recover aka immune reconstitution inflammatory syndrome (IRIS). 4, 5 Also, some patients do not have a sustained response to ART due to lack of adherence to medications, development of drug resistance, or suboptimal therapeutic regimens. 1 Therefore, OIs continue to cause substantial morbidity and mortality even after initiation of ART. The World Health Organization (WHO) developed HIV clinical staging criteria based on OIs to standardize disease severity classification in the absence of virologic or immunologic measurements. 6, 7 Diagnosis of WHO stage 4 conditions remains important in the ART era in order to: 1) help determine timing of ART initiation, and 2) treat OIs to reduce morbidity and mortality. There are no published data from Kenya that quantify the burden of WHO stage 4 conditions that persist in the ART era and continue to negatively impact patient survival. We therefore set out to determine the prevalence and gender distribution of WHO stage 4 conditions among patients enrolled in a large peri-urban HIV clinic in western Kenya.

P3.088 Human Immuno Deficiency Syndrome: A Global Cry

Objectives The Human Immunodeficiency Virus (HIV) is a retro-virus that attacks the immune system of the host individual, slowly invading and killing T-cells. As the disease progresses, individuals become increasingly susceptible to other illnesses. Eventually usually within 7 to 10 years the compromised immune system will lead to death through another proximate cause. An individual is said to have (AIDS) once their immune system has been severely compromised. Methods The most common channels of transmission are sexual; the other major type of transmission is vertical from mother to child either in the womb, during birth, or while breastfeeding. HIV can also be spread through sharing needles (either by intravenous drug users, or poor hygiene in hospitals) and through transfusions with infected blood. Results The efficiency of these transmission mechanisms varies. Infection rates are higher for anal than vaginal sex, higher still for mother-to-child transmission, and extremely high (close 100 percent) for transfusion with infected blood. Drugs that dramatically slow the progression of HIV have become available in recent years. Use of these regimens in the developing world is rare, due both to the cost of the drugs (even in generic form) and the difficulty of administering daily drug cocktails on a continent with few doctors. Conclusions Interventions in Africa have focused more on prevention and treatment of opportunistic infections, including prevention of mother-to-child transmission, education about changes in sexual behaviour, treatment of other sexually transmitted infections (STIs) and treatment of tuberculosis and other disease associated with HIV/AIDS.