Immune response to ART initiation in advanced HIV infection.

OBJECTIVES: Our objective was to compare the immunological responses to commonly used antiretroviral therapy (ART) regimens among people with advanced HIV in the USA and to assess virological outcomes and regimen persistence. METHODS: This study included ART-naïve adults with advanced HIV infection (CD4 cell count <200 cells/µL) initiating ART with bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF), boosted darunavir (bDRV), dolutegravir (DTG), or elvitegravir (EVG/c)-containing regimens between 1 January 2018 and 31 December 2020 in the Observational Pharmaco-Epidemiology Research and Analysis (OPERA) cohort. Cox proportional hazards models and linear mixed models with random intercept were fit with inverse probability of treatment weighting. RESULTS: Overall, 1349 people with advanced HIV (816 B/F/TAF, 253 DTG, 146 EVG/c, 134 bDRV) were followed for a median of 22 months. Compared with B/F/TAF, a lower likelihood of achieving a CD4 cell count ≥200 cells/µL was observed with bDRV (hazard ratio [HR] 0.76; 95% confidence interval [CI] 0.60-0.96), DTG (HR 0.82; 95% CI 0.69-0.98), and EVG/c (HR 0.73; 95% CI 0.57-0.93). All groups had a similar pattern of CD4:CD8 ratio changes: a rapid increase in the first 6 months (ranging from +0.15 to +0.16 units), followed by a slower increase thereafter. Only 40 individuals (4%) achieved CD4:CD8 ratio normalization (≥1). B/F/TAF was associated with a faster time to virological suppression (viral load <200 copies/mL) and a slower time to discontinuation compared with other regimens. CONCLUSIONS: Among people with advanced HIV infection, B/F/TAF initiation was associated with faster CD4 cell count recovery and favourable virological outcomes compared with bDRV-, DTG-, and EVG/c-based regimens, although no difference was observed in CD4:CD8 ratio changes over time across regimens.

Efficiency in PrEP Delivery: Estimating the Annual Costs of Oral PrEP in Zimbabwe.

Although oral PrEP is highly effective at preventing HIV acquisition, optimizing continuation among beneficiaries is challenging in many settings. We estimated the costs of delivering oral PrEP to populations at risk of HIV in seven clinics in Zimbabwe. Full annual economic costs of oral PrEP initiations and continuation visits were estimated from the providers' perspective for a six-clinic NGO network and one government SGBV clinic in Zimbabwe (January-December 2018). Disaggregating costs of full initiation and incremental follow-up visits enabled modeling of the impact of duration of continuation on the cost per person-year ($pPY) on PrEP. 4677 people initiated oral PrEP, averaging 2.7 follow-up visits per person. Average cost per person initiated was $238 ($183-$302 across the NGO clinics; $86 in the government facility). The full cost per initiation visit, including central and direct costs, was $178, and the incremental cost per follow-up visit, capturing only additional resources used directly in the follow up visits, was $22. The average duration of continuation was 3.0 months, generating an average $pPY of $943, ranging from $839 among adolescent girls and young women to $1219 in men. Oral PrEP delivery costs varied substantially by scale of initiations and by duration of continuation and type of clinic. Extending the average oral PrEP continuation from 2.7 to 5 visits (about 6 months) would greatly improve service efficiency, cutting the $pPY by more than half.

Reducing undiagnosed HIV infection among adolescents in sub-Saharan Africa: Provider-initiated and opt-out testing are not enough.

Community efforts and peer support programs are needed in addition to provider-initiated and opt-out HIV testing in adolescents, Sheri Weiser and colleagues discuss.

"I am still human and worth a life:" a qualitative study of the impacts of a community based, peer-led, treatment support model for young adults living with HIV in Zimbabwe.

Background: A persistent treatment gap remains between children and adults living with HIV. The Zvandiri program, developed by Africaid, is one of the few models of differentiated service delivery for children, adolescents, and youth that has been shown to improve outcomes along the HIV care continuum, employing Community Adolescent Treatment Supporters (CATS) to offer peer counseling and patient navigation. Our qualitative study provides an in-depth analysis of the feelings and experiences Zimbabwean youth had following an HIV diagnosis, and the ways that CATS facilitated linkage and retention in care. Methods: We conducted in-depth interviews in Shona with adolescents and young adults who were recently diagnosed with HIV in Zimbabwe. Interviews were audio-recorded, transcribed, and then translated to English. Interviews were coded in Dedoose using a structured a priori codebook. We wrote semi-structured summary memos for each interview. We co-conducted thematic analysis, guided by interpretive phenomenology with a team of Zimbabwean and American experienced qualitative researchers and community partners. We co-developed memos to elaborate and understand key themes across interviews. Results: Most of our interview participants recounted an immediate sense of loss upon testing HIV positive and a fear that "there was no hope for the future." CATS played a pivotal role for youth, providing emotional, educational, and logistical support to facilitate treatment initiation, adherence, and persistence in care. The CATS program supported youth through multiple approaches: group sessions, individual meetings, and via text or phone. While CATS offered counseling and comfort to participants, they emphasized the long-term importance of identifying at least one other person in participants' lives who could know their status and support them around HIV. Conclusion: Our findings delineate some of the key concerns that face youth after receiving an HIV diagnosis and the ways that a community-based adherence peer navigation program supported participants to navigate both their feelings and the health care system. Results can inform practice at community-based agencies that are implementing or considering peer youth navigation programs and garner support for policy to fund interventions for youth.

If, when and how to tell: a qualitative study of HIV disclosure among young women in Zimbabwe.

In the Shona culture of Zimbabwe, a high regard for childbearing contributes to strong pressures on women to have children. For young women living with HIV, consequently, disclosure of HIV status can be a central strategy to garner support for controlling fertility. This paper reports findings from qualitative interviews with 28 young women aged 16-20 living with HIV in urban Zimbabwe and discusses how these findings can contribute to better policies and programs for this population. Regardless of their current relationship status, interview participants described disclosure as a turning point in romantic partnerships, recounting stressful experiences with major ramifications such as abuse and abandonment on the one hand, and support and love on the other. All but one participant had been in a committed relationship, and most had disclosed to a previous or current partner, with about half of disclosure experiences resulting in adverse reactions. Findings suggest that sexual and reproductive health services must do more to help young women living with HIV negotiate the complexities of disclosure in the context of achieving desired fertility.

Casting a Wide Net: HIV Drug Resistance Monitoring in Pre-Exposure Prophylaxis Seroconverters in the Global Evaluation of Microbicide Sensitivity Project.

BACKGROUND: Evidence of HIV drug resistance (HIVDR) in individuals using oral pre-exposure prophylaxis (PrEP) who acquire HIV is limited to clinical trials and case studies. More data are needed to understand the risk of HIVDR with oral PrEP during PrEP rollout. Mechanisms to collect these data vary, and are dependent on cost, scale of PrEP distribution, and in-country infrastructure for the identification, collection, and testing of samples from PrEP seroconverters. METHODS: The Global Evaluation of Microbicide Sensitivity (GEMS) project, in collaboration with country stakeholders, initiated HIVDR monitoring among new HIV seroconverters with prior PrEP use in Eswatini, Kenya, South Africa, and Zimbabwe. Standalone protocols were developed to assess HIVDR among a national sample of PrEP users. In addition, HIVDR testing was incorporated into existing demonstration projects for key populations. LESSONS LEARNED: Countries are supportive of conducting a time-limited evaluation of HIVDR during the early stages of PrEP rollout. As PrEP rollout expands, the need for long-term HIVDR monitoring with PrEP will need to be balanced with maintaining national HIV drug resistance surveillance for pretreatment and acquired drug resistance. Laboratory capacity is a common obstacle to setting up a monitoring system. CONCLUSIONS: Establishing HIV resistance monitoring within PrEP programs is feasible. Approaches to drug resistance monitoring may evolve as the PrEP programs mature and expand. The methods and implementation support offered by GEMS assisted countries in developing methods to monitor for drug resistance that best fit their PrEP program needs and resources.

Uncovering tensions and capitalizing on synergies in HIV/AIDS and antiviolence programs.

Research frequently points to the need to empower women to effectively combat the twin epidemics of HIV/AIDS and gender-based violence. Simultaneously, there has been increased attention given to working with men in gender equality efforts. The latter approach intervenes on masculinities as part of the fight against HIV/AIDS and violence. No research has considered these 2 lines of work side by side to address several important questions: What are the points of overlap, and the tensions and contradictions between these 2 approaches? What are the limitations and unintended consequences of each? We analyzed these 2 parallel research trends and made suggestions for how to capitalize on the synergies that come from bolstering each position with the strengths of the other.

Integration of HIV prevention and sexual and reproductive health in the era of anti-retroviral-based prevention: findings from assessments in Kenya, Malawi and Zimbabwe.

Background: Though substantial progress has helped curb the HIV epidemic, high rates of new HIV infections persist among adolescent girls and young women (AGYW) in sub-Saharan Africa, reflecting critical gaps in reaching them with integrated HIV prevention and sexual and reproductive health (SRH) services. The scale-up of oral pre-exposure prophylaxis (PrEP) and multiple novel HIV prevention products on the horizon offer countries a unique opportunity to expand innovative approaches to deliver comprehensive, integrated HIV prevention/SRH services. Methods: This article comparatively analyzes findings from rapid assessments in Kenya, Malawi and Zimbabwe across key themes to highlight cross-country trends and contextual realities around HIV prevention/SRH integration, with a focus on oral PrEP and contraception. In Kenya and Zimbabwe, assessments were completed by Ministries of Health (MOH) and the HIV Prevention Market Manager and include 20 health facility assessments, 73 key informant interviews (KIIs) and six community dialogues. In Malawi, the assessment was completed by the MOH and Georgetown University Center for Innovation in Global Health and includes 70 KIIs and a review of national policies and program implementation in Blantyre. Findings were contextualized through a review of literature and policies in each country. Results: Across countries, the policy environment is conducive to HIV prevention/SRH integration, though operationalization presents ongoing challenges, with most policies preceding and not accounting for oral PrEP rollout. National coordination mechanisms, youth-friendly health services and prevention of mother-to-child transmission programs are promising practices, while siloed and resource-constrained health systems, limited provider capacity, underfunded demand generation and structural factors exacerbate barriers to achieving integration. Conclusions: As new HIV prevention products are introduced, demand for integrated HIV prevention/SRH services is likely to grow. Investing in HIV prevention/SRH integration can help to ensure a sustainable response to the HIV epidemic, streamline service delivery and improve the health outcomes and lives of AGYW.

Poverty, gender inequities, and women's risk of human immunodeficiency virus/AIDS.

Entrenched economic and gender inequities together are driving a globally expanding, increasingly female, human immunodeficiency virus (HIV)/AIDS epidemic. To date, significant population-level declines in HIV transmission have not been observed, at least in part because most approaches to prevention have presumed a degree of individual control in decision making that does not speak to the reality of women's and girls' circumstances in many parts of the world. Such efforts have paid insufficient attention to critical characteristics of the risk environment, most notably poverty and gender power inequities. Even fewer interventions have addressed specific mechanisms through which these inequities engender risky sexual practices that result in women's disproportionately increased vulnerabilities to HIV infection. This article focuses on identifying those mechanisms, or structural pathways, that stem from the interactions between poverty and entrenched gender inequities and recommending strategies to address and potentially modify those pathways. We highlight four such structural pathways to HIV risk, all of which could be transformed: (1) lack of access to critical information and health services for HIV/sexually transmitted infection (STI) prevention, (2) limited access to formal education and skill development, (3) intimate partner violence, and (4) the negative consequences of migration prompted by insufficient economic resources. We argue for interventions that enhance women's access to education, training, employment, and HIV/STI prevention information and tools; minimize migration; and by working with men and communities, at the same time reduce women's poverty and promote gender-equitable norms. In conclusion, we identify challenges in developing and evaluating strategies to address these structural pathways.

Understanding and measuring uptake and coverage of oral pre-exposure prophylaxis delivery among adolescent girls and young women in sub-Saharan Africa.

In response to World Health Organization (WHO) guidance recommending oral pre-exposure prophylaxis (PrEP) for all individuals at substantial risk for HIV infection, significant investments are being made to expand access to oral PrEP globally, particularly in sub-Saharan Africa. Some have interpreted early monitoring reports from new programs delivering oral PrEP to adolescent girls and young women (AGYW) as suggestive of low uptake. However, a lack of common definitions complicates interpretation of oral PrEP uptake and coverage measures, because various indicators with different meanings and uses are used interchangeably. Furthermore, operationalising these measures in real-world settings is challenged by the difficulties in defining the denominator for measuring uptake and coverage among AGYW, due to the lack of data and experience required to identify the subset of AGYW at substantial risk of HIV infection. This paper proposes an intervention-centric cascade as a framework for developing a common lexicon of metrics for uptake and coverage of oral PrEP among AGYW. In codifying these indicators, approaches to clearly define metrics for uptake and coverage are outlined, and the discussion on 'low' uptake is reframed to focus on achieving the highest possible proportion of AGYW using oral PrEP when they need and want it Recommendations are also provided for making increased investments in implementation research to better quantify the sub-group of AGYW in potential need of oral PrEP.and for improving monitoring systems to more efficiently address bottlenecks in the service delivery of oral PrEP to AGYW so that implementation can be taken to scale.

Cluster randomized trial of comprehensive gender-based violence programming delivered through the HIV/AIDS program platform in Mbeya Region, Tanzania: Tathmini GBV study.

The Tathmini GBV study was a cluster randomized trial to assess the impact of a comprehensive health facility- and community-based program delivered through the HIV/AIDS program platform on reduction in gender-based violence and improved care for survivors. Twelve health facilities and surrounding communities in the Mbeya Region of Tanzania were randomly assigned to intervention or control arms. Population-level effects were measured through two cross-sectional household surveys of women ages 15-49, at baseline (n = 1,299) and at 28 months following program scale-out (n = 1,250). Delivery of gender-based violence services was assessed through routine recording in health facility registers. Generalized linear mixed effects models and analysis of variance were used to test intervention effects on population and facility outcomes, respectively. At baseline, 52 percent of women reported experience of recent intimate partner violence. The odds of reporting experience of this violence decreased by 29 percent from baseline to follow-up in the absence of the intervention (time effect OR = 0.71, 95% CI: 0.57-0.89). While the intervention contributed an additional 15 percent reduction, the effect was not statistically significant. The program, however, was found to contribute to positive, community-wide changes including less tolerance for certain forms of violence, more gender equitable norms, better knowledge about gender-based violence, and increased community actions to address violence. The program also led to increased utilization of gender-based violence services at health facilities. Nearly three times as many client visits for gender-based violence were recorded at intervention (N = 1,427) compared to control (N = 489) facilities over a 16-month period. These visits were more likely to include provision of an HIV test (55.3% vs. 19.6%, p = .002). The study demonstrated the feasibility and impact of integrating gender-based violence and HIV programming to combat both of these major public health problems. Further opportunities to scale out GBV prevention and response strategies within HIV/AIDS service delivery platforms should be pursued. Trial Registration: Pan African Clinical Trials Registry No. PACTR201802003124149.

Acute sleep deprivation enhances avoidance learning and spatial memory and induces delayed alterations in neurochemical expression of GR, TH, DRD1, pCREB and Ki67 in rats.

The current study investigated the effects of acute versus repeated periods of sleep deprivation on avoidance learning and spatial memory and on the expression of discrete biochemical brain signals involved in stress regulation, motivation and brain plasticity. Male Long-Evans rats were sleep deprived using the platform-over-water method for a single 4 h period (ASD) or for daily 4h RSD period on five consecutive days (CSD). The Y maze passive avoidance task (YM-PAT) and the Morris water maze (MWM) were used to determine learning and memory 1h following the last SD period. Region-specific changes in glucocorticoid receptors (GR), tyrosine hydroxylase (TH), dopamine 1 receptors (DRD1), phospho-CREB (pCREB) and Ki-67 expression were assessed in the hippocampal formation, hypothalamus and mesolimbic regions 72 h following RSD. Behaviorally, our findings revealed increased latency to re-enter the aversive arm in the YM-PAT and reduced distance traveled and latency to reach the platform in the MWM in ASD rats compared to all other groups, indicative of improved avoidance learning and spatial memory, respectively. Acute SD enhanced TH expression in the ventral tegmental area, nucleus accumbens and A11 neurons of the hypothalamus and DRD1 expression in the lateral hypothalamus. Cell proliferation in the subventricular zone and pCREB expression in the dentate gyrus and CA3 regions was also enhanced following acute SD. In contrast, repeated SD significantly elevated GR-ir at the hypothalamic paraventricular nucleus and CA1 and CA3 layers of the hippocampus compared to all other groups. Our study supports that a brief 4h sleep deprivation period is sufficient to induce delayed neurochemical changes.

Implementing Implementation Science: An Approach for HIV Prevention, Care and Treatment Programs.

Though great progress has been realized over the last decade in extending HIV prevention, care and treatment in some of the least resourced settings of the world, a substantial gap remains between what we know works and what we are actually achieving in HIV programs. To address this, leaders have called for the adoption of an implementation science framework to improve the efficiency and effectiveness of HIV programs. Implementation science (IS) is a multidisciplinary scientific field that seeks generalizable knowledge about the magnitude of, determinants of and strategies to close the gap between evidence and routine practice for health in real-world settings. We propose an IS approach that is iterative in nature and composed of four major components: 1) Identifying Bottlenecks and Gaps, 2) Developing and Implementing Strategies, 3) Measuring Effectiveness and Efficiency, and 4) Utilizing Results. With this framework, IS initiatives draw from a variety of disciplines including qualitative and quantitative methodologies in order to develop new approaches responsive to the complexities of real world program delivery. In order to remain useful for the changing programmatic landscape, IS research should factor in relevant timeframes and engage the multi-sectoral community of stakeholders, including community members, health care teams, program managers, researchers and policy makers, to facilitate the development of programs, practices and polices that lead to a more effective and efficient global AIDS response. The approach presented here is a synthesis of approaches and is a useful model to address IS-related questions for HIV prevention, care and treatment programs. This approach, however, is not a panacea, and we will continue to learn new ways of thinking as we move forward to close the implementation gap.

Early age of first sex: a risk factor for HIV infection among women in Zimbabwe.

OBJECTIVE: To explore the relationship between early age of coital debut (15 years of age or younger) and risk for HIV infection among sexually active urbanized Zimbabwean women. DESIGN: Cross-sectional analysis of screening data from a cohort study. METHODS: Sexually active women aged 18-35 years were recruited from public sector family planning clinics in and around Harare, Zimbabwe between November 1999 and September 2002. They received a brief behavioral interview and HIV testing. Of the 4675 women screened, 4393 (94%) had complete data on sexual behaviors and HIV serostatus, and were included in this analysis. RESULTS: HIV prevalence in this sample was 40.1%. The median age of coital debut was 18 years and 11.8% of women reporting having experienced coital debut at age 15 or younger. Women with early coital debut had a significantly higher risk profile, including multiple lifetime partners and not completing high school. In binary generalized linear regression models HIV risk was increased for women reporting early age of coital debut (relative hazard, 1.30; 95% confidence interval, 1.13-1.50), controlling for duration of sexual activity and current age; this effect was attenuated somewhat after controlling for other factors such as number of sexual partners. CONCLUSIONS: Our results show that early coital debut is a significant predictor of prevalent HIV infection independent of other identified factors in this population. HIV prevention strategies should include delaying the age of first coitus and should address the barriers that may prevent young women from so doing.

The SHAZ! project: results from a pilot randomized trial of a structural intervention to prevent HIV among adolescent women in Zimbabwe.

UNLABELLED: Adolescent females in Zimbabwe are at high risk for HIV acquisition. Shaping the Health of Adolescents in Zimbabwe (SHAZ!) was a randomized controlled trial of a combined intervention package including life-skills and health education, vocational training, micro-grants and social supports compared to life-skills and health education alone. SHAZ! was originally envisioned as a larger effectiveness trial, however, the intervention was scaled back due to contextual and economic conditions in the country at the time. SHAZ! enrolled 315 participants randomly assigned to study arm within blocks of 50 participants (158 intervention and 157 control). The intervention arm participants showed statistically significant differences from the control arm participants for several outcomes during the two years of follow up including; reduced food insecurity [IOR = 0.83 vs. COR = 0.68, p-0.02], and having their own income [IOR = 2.05 vs. COR = 1.67, p = 0.02]. Additionally, within the Intervention arm there was a lower risk of transactional sex [IOR = 0.64, 95% CI (0.50, 0.83)], and a higher likelihood of using a condom with their current partner [IOR = 1.79, 95% CI (1.23, 2.62)] over time compared to baseline. There was also evidence of fewer unintended pregnancies among intervention participants [HR = 0.61, 95% CI (0.37, 1.01)], although this relationship achieved only marginal statistical significance. Several important challenges in this study included the coordination with vocational training programs, the political and economic instability of the area at the time of the study, and the difficulty in creating a true standard of care control arm. Overall the results of the SHAZ! study suggest important potential for HIV prevention intervention packages that include vocational training and micro-grants, and lessons for further economic livelihoods interventions with adolescent females. Further work is needed to refine the intervention model, and test the impact of the intervention at scale on biological outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02034214.

Lessons from Tanzania on the integration of HIV and tuberculosis treatments into methadone assisted treatment.

To successfully address HIV and TB in the world, we must address the healthcare needs of key populations, such as drug users, and we must do this urgently. Currently in Tanzania, as in many countries, the care for these medical disorders is separated into disease specific clinical environments. Our consortium began working to integrate HIV and TB clinical services into the methadone program in Dar es Salaam, Tanzania. We present the key lessons learned in this process of integration and the importance of integrating HIV/TB into the methadone program, which serves as a critical anchor for adherence to clinical services. Integrated healthcare for people who use drugs is clearly a long-term goal and different health systems will progress upon this continuum at different rates. What is clear is that every health system that interacts with drug users must aspire to achieve some level of integrated healthcare if the incidence rates of HIV and TB are to decline.

Developing and using a partnership covenant to guide a study of late HIV diagnosis.

BACKGROUND: Late diagnosis of HIV is an important problem in the United States, particularly in ethnically and socially diverse communities. OBJECTIVES: We created and used a partnership covenant to ensure our adherence to community-based participatory research (CBPR) principles as we began studying and addressing individual and structural barriers to timely HIV testing. METHODS: Sample CBPR principles were used to help develop a partnership covenant that in turn was used in steering committee (SC) meetings to gauge our adherence to CBPR in our work together and in the field. RESULTS: Continuing dialogue around our fidelity to the covenant resulted in concrete changes including a "crash course" on sampling for community partners and development of a community advisory board (CAB). Our ability to meet the project's specific aims was enhanced by using the covenant. CONCLUSIONS: Although time consuming, development and use of a CBPR covenant can improve high-level engagement and help to accomplish a study's specific aims.

Hormonal contraceptive use and HIV disease progression among women in Uganda and Zimbabwe.

BACKGROUND: HIV-infected women need highly effective contraception to reduce unintended pregnancies and mother-to-child HIV transmission. Previous studies report conflicting results regarding the effect of hormonal contraception on HIV disease progression. METHODS: HIV-infected women in Uganda and Zimbabwe were recruited immediately after seroconversion; CD4 testing and clinical examinations were conducted quarterly. The study end point was time to AIDS (two successive CD4 200 cells/mm or less or World Health Organization advanced Stage 3 or Stage 4 disease). We used marginal structural Cox survival models to estimate the effect of cumulative exposure to depot-medroxyprogesterone acetate and oral contraceptives on time to AIDS. RESULTS: Three hundred three HIV-infected women contributed 1408 person-years. One hundred eleven women (37%) developed AIDS. Cumulative probability of AIDS was 50% at 7 years and did not vary by country. AIDS incidence was 6.6, 9.3, and 8.8 per 100 person-years for depot-medroxyprogesterone acetate, oral contraceptive, and nonhormonal users. Neither depot-medroxyprogesterone acetate (adjusted hazard ratio, 0.90; 95% confidence interval, 0.76-1.08) nor oral contraceptives ( adjusted hazard ratio, 1.07; 95% confidence interval, 0.89-1.29) were associated with HIV disease progression. Alternative exposure definitions of hormonal contraception use during the year before AIDS or at the time of HIV infection produced similar results. Sexually transmitted infection symptoms were associated with faster progression, whereas young age at HIV infection (18-24 years) was associated with slower progression. Adding baseline CD4 level and set point viral load to models did not change the hormonal contraception results, but Subtype D infection became associated with disease progression. CONCLUSION: Hormonal contraceptive use was not associated with more rapid HIV disease progression, but older age, sexually transmitted infection symptoms, and Subtype D infection were.