Effect of the relationship between anaemia and systemic inflammation on the risk of incident tuberculosis and death in people with advanced HIV: a sub-analysis of the REMEMBER trial.

Background: Tuberculosis (TB) is an infectious morbidity that commonly occurs in people living with HIV (PWH) and increases the progression of HIV disease, as well as the risk of death. Simple markers of progression are much needed to identify those at highest risk for poor outcome. This study aimed to assess how baseline severity of anaemia and associated inflammatory profiles impact death and the incidence of TB in a cohort of PWH who received TB preventive therapy (TPT). Methods: This study is a secondary posthoc analysis of the AIDS Clinical Trials Group A5274 REMEMBER clinical trial (NCT0138008), an open-label randomised clinical trial of antiretroviral-naïve PWH with CD4 <50 cells/µL, performed from October 31, 2011 to June 9, 2014, from 18 outpatient research clinics in 10 low- and middle-income countries (Malawi, South Africa, Haiti, Kenya, Zambia, India, Brazil, Zimbabwe, Peru, and Uganda) who initiated antiretroviral therapy and either isoniazid TPT or 4-drug empiric TB therapy. Plasma concentrations of several soluble inflammatory biomarkers were measured prior to the commencement of antiretroviral and anti-TB therapies, and participants were followed up for at least 48 weeks. Incident TB or death during this period were primary outcomes. We performed multidimensional analyses, logistic regression analyses, survival curves, and Bayesian network analyses to delineate associations between anaemia, laboratory parameters, and clinical outcomes. Findings: Of all 269 participants, 76.2% (n = 205) were anaemic, and 31.2% (n = 84) had severe anaemia. PWH with moderate/severe anaemia exhibited a pronounced systemic pro-inflammatory profile compared to those with mild or without anaemia, hallmarked by a substantial increase in IL-6 plasma concentrations. Moderate/severe anaemia was also associated with incident TB incidence (aOR: 3.59, 95% CI: 1.32-9.76, p = 0.012) and death (aOR: 3.63, 95% CI: 1.07-12.33, p = 0.039). Interpretation: Our findings suggest that PWH with moderate/severe anaemia display a distinct pro-inflammatory profile. The presence of moderate/severe anaemia pre-ART was independently associated with the development of TB and death. PWH with anaemia should be monitored closely to minimise the occurrence of unfavourable outcomes. Funding: National Institutes of Health.

Isoniazid Adherence Reduces Mortality and Incident Tuberculosis at 96 Weeks Among Adults Initiating Antiretroviral Therapy With Advanced Human Immunodeficiency Virus in Multiple High-Burden Settings.

Background: People with human immunodeficiency virus (HIV) and advanced immunosuppression initiating antiretroviral therapy (ART) remain vulnerable to tuberculosis (TB) and early mortality. To improve early survival, isoniazid preventive therapy (IPT) or empiric TB treatment have been evaluated; however, their benefit on longer-term outcomes warrants investigation. Methods: We present a 96-week preplanned secondary analysis among 850 ART-naive outpatients (≥13 years) enrolled in a multicountry, randomized trial of efavirenz-containing ART plus either 6-month IPT (n = 426) or empiric 4-drug TB treatment (n = 424). Inclusion criteria were CD4 count <50 cells/mm3 and no confirmed or probable TB. Death and incident TB were compared by strategy arm using the Kaplan-Meier method. The impact of self-reported adherence (calculated as the proportion of 100% adherence) was assessed using Cox-proportional hazards models. Results: By 96 weeks, 85 deaths and 63 TB events occurred. Kaplan-Meier estimated mortality (10.1% vs 10.5%; P = .86) and time-to-death (P = .77) did not differ by arm. Empiric had higher TB risk (6.1% vs 2.7%; risk difference, -3.4% [95% confidence interval, -6.2% to -0.6%]; P = .02) and shorter time to TB (P = .02) than IPT. Tuberculosis medication adherence lowered the hazards of death by ≥23% (P < .0001) in empiric and ≥20% (P < .035) in IPT and incident TB by ≥17% (P ≤ .0324) only in IPT. Conclusions: Empiric TB treatment offered no longer-term advantage over IPT in our population with advanced immunosuppression initiating ART. High IPT adherence significantly lowered death and TB incidence through 96 weeks, emphasizing the benefit of ART plus IPT initiation and completion, in persons with advanced HIV living in high TB-burden, resource-limited settings.

HIV risk perception and sexual behavior among HIV-uninfected men and transgender women who have sex with men in sub-Saharan Africa: Findings from the HPTN 075 qualitative sub-study.

There remains a limited understanding of how men who have sex with men (MSM) and transgender women (TGW) in sub-Saharan Africa (SSA) perceive their risk for HIV and how risk influences behavior during sexual interactions. We performed thematic analysis on in-depth interviews from the qualitative sub-study of HPTN 075 in Kenya, Malawi, and South Africa. Using the Integrated Behavioral Model (IBM) constructs, we found that most MSM and TGW perceived themselves to be at risk for HIV, leading them to regularly engage in safer sexual behaviors. Notably, even though these MSM and TGW perceived themselves to be at risk for HIV, some of them reported engaging in transactional sex, sex under the influence of alcohol, and intentional non-use of condoms. This indicates that HIV risk perception was not always associated with safer sexual behaviors or a reduction in risk behaviors. Attitudes (negative attitudes toward condom use), perceived norms (social pressures), and environment constraints (contextual barriers) were related to MSM and TGW not engaging in safe sexual behavior. Hearing the perspectives of MSM and TGW on their sexual behavior continues to be important for the development and implementation of effective prevention policies and interventions. Eliminating structural barriers such as stigma, discrimination, and criminalization of same-sex sexuality is a crucial prerequisite for the success of interventions to promote sexual health among MSM and TGW in SSA.

Correlates of Adherence to the Dapivirine Vaginal Ring for HIV-1 Prevention.

Understanding characteristics associated with adherence to pre-exposure prophylaxis (PrEP) methods for HIV-1 prevention may assist with optimizing implementation efforts. The dapivirine vaginal ring is a novel topical PrEP delivery method. Using data from a randomized, double-blind, placebo-controlled, phase III trial of the dapivirine vaginal ring conducted in four African countries, generalized estimating equation models were used to evaluate correlates of ring adherence. Two levels of quarterly dapivirine blood plasma, and dapivirine released from returned rings defined measures of adherence for recent and cumulative use, respectively. Time on study, calendar time, primary partner knowledge that the participant was taking part in the study, and use of long-acting contraceptive methods were associated with ring adherence whereas younger age, ring worries, condom use, episodes of menstrual bleeding and vaginal washing were associated with non-adherence. These findings may be useful for recruitment into future clinical studies and dapivirine ring implementation efforts.

Factors Associated with Uptake of HIV Test Results in a Nationally Representative Population-Based AIDS Indicator Survey.

Population-based surveys with HIV testing in settings with low testing coverage provide opportunities for participants to learn their HIV status. Survey participants (15-64 years) in a 2007 nationally representative population-based HIV serologic survey in Kenya received a voucher to collect HIV test results at health facilities 6 weeks after blood draw. Logistic regression models were fitted to identify predictors of individual and couple collection of results. Of 15,853 adults consenting to blood draw, 7,222 (46.7%) collected HIV test results (46.5% men, 46.8% women). A third (39.5%) of HIV-infected adults who were unaware of their infection and 48.2% of those who had never been tested learned their HIV status during KAIS. Individual collection of HIV results was associated with older age, with the highest odds among adults aged 60-64 years (adjusted odds ratio [AOR], 1.6, 95% confidence interval [CI] 1.2-2.1); rural residence (AOR 1.8, 95%CI 1.2-2.6); and residence outside Nairobi, with the highest odds in the sparsely populated North Eastern province (AOR 8.0, 95%CI 2.9-21.8). Of 2,685 married/cohabiting couples, 18.5% collected results as a couple. Couples in Eastern province and in the second and middle wealth quintiles were more likely to collect results than those in Nairobi (AOR 3.2, 95%CI 1.1-9.4) and the lowest wealth quintile (second AOR 1.5, 95%CI 1.1-2.3; middle AOR 1.6, 95% CI 1.2-2.3, respectively. Many participants including those living with HIV learned their HIV status in KAIS. Future surveys need to address low uptake of results among youth, urban residents, couples and those with undiagnosed HIV infection.

Child mortality levels and trends by HIV status in Blantyre, Malawi: 1989-2009.

INTRODUCTION: Continuous evaluation of child survival is needed in sub-Saharan Africa where HIV prevalence among women of reproductive age continues to be high. We examined mortality levels and trends over a period of ∼20 years among HIV-unexposed and -exposed children in Blantyre, Malawi. METHODS: Data from 5 prospective cohort studies conducted at a single research site from 1989 to 2009 were analyzed. In these studies, children born to HIV-infected and -uninfected mothers were enrolled at birth and followed longitudinally for at least 2 years. Information on sociodemographic, HIV infection status, survival, and associated risk factors was collected in all studies. Mortality rates were estimated using birth-cohort analyses stratified by maternal and infant HIV status. Multivariate Cox regression models were used to determine risk factors associated with mortality. RESULTS: The analysis included 8286 children. From 1989 to 1995, overall mortality rates (per 100 person-years) in these clinic-based cohorts remained comparable among HIV-uninfected children born to HIV-uninfected mothers (range 3.3-6.9) or to HIV-infected mothers (range 2.5-7.5). From 1989 to 2009, overall mortality remained high among all children born to HIV-infected mothers (range 6.3-19.3) and among children who themselves became infected (range 15.6-57.4, 1994-2009). Only lower birth weight was consistently and significantly (P < 0.05) associated with higher child mortality. CONCLUSIONS: HIV infection among mothers and children contributed to high levels of child mortality in the African setting in the pretreatment era. In addition to services that prevent mother-to-child transmission of HIV, other programs are needed to improve child survival by lowering HIV-unrelated mortality through innovative interventions that strengthen health infrastructure.

Trends in birth weight and gestational age for infants born to HIV-infected, antiretroviral treatment-naive women in Malawi.

BACKGROUND: We analyzed birth outcomes among infants of treatment-naive, HIV-infected women from a series of mother-to-child transmission of HIV studies in Blantyre, Malawi. METHODS: Data from 6 prospective studies at 1 research site were analyzed. Mean birth weight (BW) and gestational age (GA), and frequency of low birth weight (LBW; <2500 g) and preterm (PT) birth (GA < 37 weeks) were estimated. We assessed risk factors for LBW and PT birth using mixed-effects logistic regression. Adjusted odds ratios (AOR) and 95% confidence intervals from earlier studies (1989-1994) and later studies (2000-2007) are presented separately. RESULTS: The analysis included 8874 HIV-exposed infants. Mean BW and GA ranged from 2793 to 3079 g, and from 37.8 to 39.0 weeks. Greater maternal age was consistently (during both the early and late periods) associated with lower odds of LBW and PT birth; AOR (95% confidence intervals) for both outcomes in the early and late periods, respectively, were 0.98 (0.96-1.00) and 0.97 (0.95-0.99). Female infant gender was consistently associated with higher odds of PT birth during both periods and with higher odds of LBW during the later period. During the early period, higher maternal education was associated with lower odds of LBW (AOR 0.67 [0.48-0.95]) and PT birth (AOR 0.70 [0.51-0.95]), and later birth year was associated with lower odds of PT birth (AOR 0.35 [0.19-0.70]). CONCLUSIONS: BW and GA remained stable within each time period. This analysis provides important baseline information for monitoring HIV treatment effects on birth outcomes. Modifiable factors affecting BW and GA should continue to be explored.

Prevalence of herpes simplex virus type 2 infection, human immunodeficiency virus/herpes simplex virus type 2 coinfection, and associated risk factors in a national, population-based survey in Kenya.

BACKGROUND: Herpes simplex virus type 2 (HSV-2) is a known biologic cofactor for human immunodeficiency virus (HIV) transmission and acquisition. The Kenya AIDS Indicator Survey 2007 provided Kenya's first nationally representative estimate of HSV-2 prevalence and risk factors. METHODS: KAIS was a household serosurvey among women and men aged 15 to 64 years. The survey included a behavioral interview and serum testing for HSV-2, HIV, and syphilis infections. Results were weighted for sampling design and nonresponse. RESULTS: Of 19,840 eligible individuals, 90% completed an interview and 80% consented to testing. In all, 35% were infected with HSV-2, of which 42% were women and 26% were men. Between 15 and 24 years of age, HSV-2 prevalence increased from 7% to 34% in women and 3% to 14% in men. Among couples, 30% were HSV-2 concordant-positive, 21% were discordant, and 49% were concordant-negative. In all, 81% of HIV-infected persons were coinfected with HSV-2. HIV prevalence was 16% among those with HSV-2 and 2% among those without HSV-2. Women with circumcised partners had an HSV-2 prevalence of 39% compared to 77% of women with uncircumcised partners. CONCLUSIONS: One-third of Kenyans were HSV-2 infected. HIV-1 infection, age, female sex, and lack of male circumcision were population-level predictors for HSV-2 infection. Targeted prevention interventions are needed, including an effective vaccine.