HLA-A*23 Is Associated With Lower Odds of Acute Retroviral Syndrome in Human Immunodeficiency Virus Type 1 Infection: A Multicenter Sub-Saharan African Study.

The role of human leukocyte antigen (HLA) class I and killer immunoglobulin-like receptor molecules in mediating acute retroviral syndrome (ARS) during human immunodeficiency virus type 1 (HIV-1) infection is unclear. Among 72 sub-Saharan African adults, HLA-A*23 was associated with lower odds of ARS (adjusted odds ratio, 0.10 [95% confidence interval, .01-.48]; P = .009), which warrants further studies to explore its role on HIV-1-specific immunopathogenesis.

Temporal trends and transmission dynamics of pre-treatment HIV-1 drug resistance within and between risk groups in Kenya, 1986-2020.

BACKGROUND: Evidence on the distribution of pre-treatment HIV-1 drug resistance (HIVDR) among risk groups is limited in Africa. We assessed the prevalence, trends and transmission dynamics of pre-treatment HIVDR within and between MSM, people who inject drugs (PWID), female sex workers (FSWs), heterosexuals (HETs) and perinatally infected children in Kenya. METHODS: HIV-1 partial pol sequences from antiretroviral-naive individuals collected from multiple sources between 1986 and 2020 were used. Pre-treatment reverse transcriptase inhibitor (RTI), PI and integrase inhibitor (INSTI) mutations were assessed using the Stanford HIVDR database. Phylogenetic methods were used to determine and date transmission clusters. RESULTS: Of 3567 sequences analysed, 550 (15.4%, 95% CI: 14.2-16.6) had at least one pre-treatment HIVDR mutation, which was most prevalent amongst children (41.3%), followed by PWID (31.0%), MSM (19.9%), FSWs (15.1%) and HETs (13.9%). Overall, pre-treatment HIVDR increased consistently, from 6.9% (before 2005) to 24.2% (2016-20). Among HETs, pre-treatment HIVDR increased from 6.6% (before 2005) to 20.2% (2011-15), but dropped to 6.5% (2016-20). Additionally, 32 clusters with shared pre-treatment HIVDR mutations were identified. The majority of clusters had R0 ≥ 1.0, indicating ongoing transmissions. The largest was a K103N cluster involving 16 MSM sequences sampled between 2010 and 2017, with an estimated time to the most recent common ancestor (tMRCA) of 2005 [95% higher posterior density (HPD), 2000-08], indicating propagation over 12 years. CONCLUSIONS: Compared to HETs, children and key populations had higher levels of pre-treatment HIVDR. Introduction of INSTIs after 2017 may have abrogated the increase in pre-treatment RTI mutations, albeit in the HET population only. Taken together, our findings underscore the need for targeted efforts towards equitable access to ART for children and key populations in Kenya.

Impact of the COVID-19 pandemic on routine HIV care and antiretroviral treatment outcomes in Kenya: A nationally representative analysis.

BACKGROUND: The COVID-19 pandemic adversely disrupted global health service delivery. We aimed to assess impact of the pandemic on same-day HIV diagnosis/ART initiation, six-months non-retention and initial virologic non-suppression (VnS) among individuals starting antiretroviral therapy (ART) in Kenya. METHODS: Individual-level longitudinal service delivery data were analysed. Random sampling of individuals aged >15 years starting ART between April 2018 -March 2021 was done. Date of ART initiation was stratified into pre-COVID-19 (April 2018 -March 2019 and April 2019 -March 2020) and COVID-19 (April 2020 -March 2021) periods. Mixed effects generalised linear, survival and logistic regression models were used to determine the effect of COVID-19 pandemic on same-day HIV diagnosis/ART initiation, six-months non-retention and VnS, respectively. RESULTS: Of 7,046 individuals sampled, 35.5%, 36.0% and 28.4% started ART during April 2018 -March 2019, April 2019 -March 2020 and April 2020 -March 2021, respectively. Compared to the pre-COVID-19 period, the COVID-19 period had higher same-day HIV diagnosis/ART initiation (adjusted risk ratio [95% CI]: 1.09 [1.04-1.13], p<0.001) and lower six-months non-retention (adjusted hazard ratio [95% CI]: 0.66 [0.58-0.74], p<0.001). Of those sampled, 3,296 (46.8%) had a viral load test done at a median 6.2 (IQR, 5.3-7.3) months after ART initiation. Compared to the pre-COVID-19 period, there was no significant difference in VnS during the COVID-19 period (adjusted odds ratio [95% CI]: 0.79 [95%% CI: 0.52-1.20], p = 0.264). CONCLUSIONS: In the short term, the COVID-19 pandemic did not have an adverse impact on HIV care and treatment outcomes in Kenya. Timely, strategic and sustained COVID-19 response may have played a critical role in mitigating adverse effects of the pandemic and point towards maturity, versatility and resilience of the HIV program in Kenya. Continued monitoring to assess long-term impact of the COVID-19 pandemic on HIV care and treatment program in Kenya is warranted.

Sexual risk-taking behavior amongst emerging adults in a tertiary institution of learning in Coastal Kenya: A qualitative study of stakeholders' perspectives using causal loop mapping.

BACKGROUND: It is known from previous studies that university students in sub-Saharan Africa (sSA) engage in sexual risk-taking behaviour (SRTB). However, there is paucity of data on factors contributing to SRTB among university students (emerging adults) at the Kenyan Coast thus hindering intervention planning. This study seeks to provide an in-depth qualitative understanding of the factors contributing to SRTB and their interconnectedness among university students at the Kenyan Coast combining qualitative research with a systems thinking approach. METHODS: Using the ecological model, and employing in-depth interviews, we explored the perceptions of twenty-six key informants (twenty-one emerging adults and five other stakeholders) on what constitutes and influences SRTB among emerging adults at a tertiary institution of learning in Coastal Kenya. Data were analysed using a thematic framework approach. A causal loop diagram (CLD) was developed to map the interconnectedness of the correlates of SRTB. RESULTS: Our findings show that unprotected sex, transactional sex, cross-generational sex, multiple sex partnerships, gender-based violence, sex under influence of alcohol/drugs, early sex debut, and sharing sex toys were common SRTBs. Based on the ecological model and CLD, most of the reported risk factors were interconnected and operated at the individual level. CONCLUSION: Our study shows that emerging adults are frequently engaging in unprotected sex. Enhancing sexuality education programs for students in Kenyan universities and strengthening support systems including counselling for those using alcohol/drugs may help reduce SRTB among emerging adults in Kenyan universities.

Leveraging electronic medical records for HIV testing, care, and treatment programming in Kenya-the national data warehouse project.

BACKGROUND: Aggregate electronic data repositories and population-level cross-sectional surveys play a critical role in HIV programme monitoring and surveillance for data-driven decision-making. However, these data sources have inherent limitations including inability to respond to public health priorities in real-time and to longitudinally follow up clients for ascertainment of long-term outcomes. Electronic medical records (EMRs) have tremendous potential to bridge these gaps when harnessed into a centralised data repository. We describe the evolution of EMRs and the development of a centralised national data warehouse (NDW) repository. Further, we describe the distribution and representativeness of data from the NDW and explore its potential for population-level surveillance of HIV testing, care and treatment in Kenya. MAIN BODY: Health information systems in Kenya have evolved from simple paper records to web-based EMRs with features that support data transmission to the NDW. The NDW design includes four layers: data warehouse application programming interface (DWAPI), central staging, integration service, and data visualization application. The number of health facilities uploading individual-level data to the NDW increased from 666 in 2016 to 1,516 in 2020, covering 41 of 47 counties in Kenya. By the end of 2020, the NDW hosted longitudinal data from 1,928,458 individuals ever started on antiretroviral therapy (ART). In 2020, there were 936,869 individuals who were active on ART in the NDW, compared to 1,219,276 individuals on ART reported in the aggregate-level Kenya Health Information System (KHIS), suggesting 77% coverage. The proportional distribution of individuals on ART by counties in the NDW was consistent with that from KHIS, suggesting representativeness and generalizability at the population level. CONCLUSION: The NDW presents opportunities for individual-level HIV programme monitoring and surveillance because of its longitudinal design and its ability to respond to public health priorities in real-time. A comparison with estimates from KHIS demonstrates that the NDW has high coverage and that the data maybe representative and generalizable at the population-level. The NDW is therefore a unique and complementary resource for HIV programme monitoring and surveillance with potential to strengthen timely data driven decision-making towards HIV epidemic control in Kenya. DATABASE LINK: ( https://dwh.nascop.org/ ).

Exposure to common infections may shape basal immunity and potentially HIV-1 acquisition amongst a high-risk population in Coastal Kenya.

Introduction: The impact of exposure to endemic infections on basal immunity and susceptibility to HIV-1 acquisition remains uncertain. We hypothesized that exposure to infections such as cytomegalovirus (CMV), malaria and sexually transmitted infections (STIs) in high-risk individuals may modulate immunity and subsequently increase susceptibility to HIV-1 acquisition. Methods: A case-control study nested in an HIV-1 negative high-risk cohort from Coastal Kenya was used. Cases were defined as volunteers who tested HIV-1 positive during follow-up and had a plasma sample collected 3 ± 2 months prior to the estimated date of HIV-1 infection. Controls were individuals who remained HIV-1 negative during the follow-up and were matched 2:1 to cases by sex, age, risk group and follow-up time. STI screening was performed using microscopic and serologic tests. HIV-1 pre-infection plasma samples were used to determined exposure to CMV and malaria using enzyme-linked immunosorbent assays and to quantify forty-one cytokines and soluble factors using multiplexing assays. Multiplexing data were analyzed using principal component analysis. Associations between cytokines and soluble factors with subsequent HIV-1 acquisition were determined using conditional logistic regression models. Results and discussion: Overall, samples from 47 cases and 94 controls were analyzed. While exposure to malaria (p=0.675) and CMV (p=0.470) were not associated with HIV-1 acquisition, exposure to STIs was (48% [95% CI, 33.3 - 63] vs. 26% [95% CI, 17.3 - 35.9]. Ten analytes were significantly altered in cases compared to controls and were clustered into four principal components: PC1 (VEGF, MIP-1ß, VEGF-C and IL-4), PC2 (MCP-1, IL-2 and IL-12p70), PC3 (VEGF-D) and PC4 (Eotaxin-3). PC1, which is suggestive of a Th2-modulatory pathway, was significantly associated with HIV-1 acquisition after controlling for STIs (adjusted odds ratio, (95% CI), p-value: 1.51 [1.14 - 2.00], p=0.004). Elevation of Th2-associated pathways may dampen responses involved in viral immunity, leading to enhanced susceptibility to HIV-1 acquisition. Immunomodulatory interventions aimed at inhibiting activation of Th2-associated pathways may be an additional strategy to STI control for HIV-1 prevention and may reduce dampening of immune responses to vaccination.

Uptake and effect of universal test-and-treat on twelve months retention and initial virologic suppression in routine HIV program in Kenya.

Early combination antiretroviral therapy (cART), as recommended in WHO's universal test-and-treat (UTT) policy, is associated with improved linkage to care, retention, and virologic suppression in controlled studies. We aimed to describe UTT uptake and effect on twelve-month non-retention and initial virologic non-suppression (VnS) among HIV infected adults starting cART in routine HIV program in Kenya. Individual-level HIV service delivery data from 38 health facilities, each representing 38 of the 47 counties in Kenya were analysed. Adults (>15 years) initiating cART between the second-half of 2015 (2015HY2) and the first-half of 2018 (2018HY1) were followed up for twelve months. UTT was defined based on time from an HIV diagnosis to cART initiation and was categorized as same-day, 1-14 days, 15-90 days, and 91+ days. Non-retention was defined as individuals lost-to-follow-up or reported dead by the end of the follow up period. Initial VnS was defined based on the first available viral load test with >400 copies/ml. Hierarchical mixed-effects survival and generalised linear regression models were used to assess the effect of UTT on non-retention and VnS, respectively. Of 8592 individuals analysed, majority (n = 5864 [68.2%]) were female. Same-day HIV diagnosis and cART initiation increased from 15.3% (2015HY2) to 52.2% (2018HY1). The overall non-retention rate was 2.8 (95% CI: 2.6-2.9) per 100 person-months. When compared to individuals initiated cART 91+ days after a HIV diagnosis, those initiated cART on the same day of a HIV diagnosis had the highest rate of non-retention (same-day vs. 91+ days; aHR, 1.7 [95% CI: 1.5-2.0], p<0.001). Of those included in the analysis, 5986 (69.6%) had a first viral load test done at a median of 6.3 (IQR, 5.6-7.6) months after cART initiation. Of these, 835 (13.9%) had VnS. There was no association between UTT and VnS (same-day vs. 91+ days; aRR, 1.0 [95% CI: 0.9-1.2], p = 0.664). Our findings demonstrate substantial uptake of the UTT policy but poor twelve-month retention and lack of an association with initial VnS from routine HIV settings in Kenya. These findings warrant consideration for multi-pronged program interventions alongside UTT policy for maximum intended benefits in Kenya.

Phylogeographic Assessment Reveals Geographic Sources of HIV-1 Dissemination Among Men Who Have Sex With Men in Kenya.

HIV-1 transmission dynamics involving men who have sex with men (MSM) in Africa are not well understood. We investigated the rates of HIV-1 transmission between MSM across three regions in Kenya: Coast, Nairobi, and Nyanza. We analyzed 372 HIV-1 partial pol sequences sampled during 2006-2019 from MSM in Coast (N = 178, 47.9%), Nairobi (N = 137, 36.8%), and Nyanza (N = 57, 15.3%) provinces in Kenya. Maximum-likelihood (ML) phylogenetics and Bayesian inference were used to determine HIV-1 clusters, evolutionary dynamics, and virus migration rates between geographic regions. HIV-1 sub-subtype A1 (72.0%) was most common followed by subtype D (11.0%), unique recombinant forms (8.9%), subtype C (5.9%), CRF 21A2D (0.8%), subtype G (0.8%), CRF 16A2D (0.3%), and subtype B (0.3%). Forty-six clusters (size range 2-20 sequences) were found-half (50.0%) of which had evidence of extensive HIV-1 mixing among different provinces. Data revealed an exponential increase in infections among MSM during the early-to-mid 2000s and stable or decreasing transmission dynamics in recent years (2017-2019). Phylogeographic inference showed significant (Bayes factor, BF > 3) HIV-1 dissemination from Coast to Nairobi and Nyanza provinces, and from Nairobi to Nyanza province. Strengthening HIV-1 prevention programs to MSM in geographic locations with higher HIV-1 prevalence among MSM (such as Coast and Nairobi) may reduce HIV-1 incidence among MSM in Kenya.

Quantifying rates of HIV-1 flow between risk groups and geographic locations in Kenya: A country-wide phylogenetic study.

In Kenya, HIV-1 key populations including men having sex with men (MSM), people who inject drugs (PWID) and female sex workers (FSW) are thought to significantly contribute to HIV-1 transmission in the wider, mostly heterosexual (HET) HIV-1 transmission network. However, clear data on HIV-1 transmission dynamics within and between these groups are limited. We aimed to empirically quantify rates of HIV-1 flow between key populations and the HET population, as well as between different geographic regions to determine HIV-1 'hotspots' and their contribution to HIV-1 transmission in Kenya. We used maximum-likelihood phylogenetic and Bayesian inference to analyse 4058 HIV-1 pol sequences (representing 0.3 per cent of the epidemic in Kenya) sampled 1986-2019 from individuals of different risk groups and regions in Kenya. We found 89 per cent within-risk group transmission and 11 per cent mixing between risk groups, cyclic HIV-1 exchange between adjoining geographic provinces and strong evidence of HIV-1 dissemination from (i) West-to-East (i.e. higher-to-lower HIV-1 prevalence regions), and (ii) heterosexual-to-key populations. Low HIV-1 prevalence regions and key populations are sinks rather than major sources of HIV-1 transmission in Kenya. Targeting key populations in Kenya needs to occur concurrently with strengthening interventions in the general epidemic.

Predictors of testing history and new HIV diagnosis among adult outpatients seeking care for symptoms of acute HIV infection in coastal Kenya: a cross-sectional analysis of intervention participants in a stepped-wedge HIV testing trial.

BACKGROUND: HIV testing is the first step to stop transmission. We aimed to evaluate HIV testing history and new diagnoses among adult outpatients in Kenya aged 18-39 years seeking care for symptoms of acute HIV infection (AHI). METHODS: The Tambua Mapema Plus study, a stepped-wedge trial, enrolled patients presenting to care at six primary care facilities with symptoms of AHI for a targeted HIV-1 nucleic acid (NA) testing intervention compared with standard provider-initiated testing using rapid antibody tests. Intervention participants underwent a questionnaire and NA testing, followed by rapid tests if NA-positive. Multinomial logistic regression was used to analyse factors associated with never testing or testing > 1 year ago ("late retesting") relative to testing ≤ 1 year ago ("on-time testers"). Logistic regression was used to analyse factors associated with new diagnosis. All analyses were stratified by sex. RESULTS: Of 1,500 intervention participants, 613 (40.9%) were men. Overall, 250 (40.8%) men vs. 364 (41.0%) women were late retesters, and 103 (16.8%) men vs. 50 (5.6%) women had never tested prior to enrolment. Younger age, single status, lower education level, no formal employment, childlessness, sexual activity in the past 6 weeks, and > 1 sexual partner were associated with testing history among both men and women. Intimate partner violence > 1 month ago, a regular sexual partner, and concurrency were associated with testing history among women only. New diagnoses were made in 37 (2.5%) participants (17 men and 20 women), of whom 8 (21.6%) had never tested and 16 (43.2%) were late retesters. Newly-diagnosed men were more likely to have symptoms for > 14 days, lower education level and no religious affiliation and less likely to be young, single, and childless than HIV-negative men; newly-diagnosed women were more likely to report fever than HIV-negative women. Among men, never testing was associated with fivefold increased odds (95% confidence interval 1.4-20.9) of new diagnosis relative to on-time testers in adjusted analyses. CONCLUSION: Most new HIV diagnoses were among participants who had never tested or tested > 1 year ago. Strengthening provider-initiated testing targeting never testers and late retesters could decrease time to diagnosis among symptomatic adults in coastal Kenya. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03508908 registered on 26/04/2018.

Alcohol and illicit drug use among young people living with HIV compared to their uninfected peers from the Kenyan coast: prevalence and risk indicators.

BACKGROUND: In sub-Saharan Africa, there is paucity of research on substance use patterns among young people living with HIV (YLWH). To address the gap, we sought to: i) determine the prevalence of substance use, specifically alcohol and illicit drug use, among YLWH compared to their HIV-uninfected peers; ii) investigate the independent association between young people's HIV infection status and substance use; iii) investigate the risk indicators for substance use among these young people. METHODS: Between November 2018 and September 2019, a cross-sectional study was conducted at the Kenyan coast recruiting 819 young people aged 18-24 years (407 HIV-positive). Alcohol and drug use disorders identification tests (AUDIT and DUDIT) were administered via audio computer-assisted self-interview alongside other measures. Logistic regression was used to determine substance use risk indicators. RESULTS: The point prevalence of current substance use was significantly lower among YLWH than HIV-uninfected youths: current alcohol use, 13% vs. 24%, p <  0.01; current illicit drug use, 7% vs. 15%, p <  0.01; current alcohol and illicit drug use comorbidity, 4 vs. 11%, p <  0.01. Past-year prevalence estimates for hazardous substance use were generally low among young people in this setting (< 10%) with no significant group differences observed. Being HIV-positive independently predicted lower odds of current substance use, but not hazardous substance use. There was overlap of some risk indicators for current substance use between young people with and without HIV including male sex, khat use and an experience of multiple negative life events, but risk indicators unique to either group were also identified. Among YLWH, none of the HIV-related factors was significantly associated with current substance use. CONCLUSIONS: At the Kenyan coast, substance use is a reality among young people. The frequency of use generally appears to be low among YLWH compared to the HIV-uninfected peers. Substance use prevention initiatives targeting young people, regardless of HIV infection status, are warranted in this setting to avert their potential risk for developing substance use disorders, including dependence. The multifaceted intrapersonal and interpersonal factors that place young people at risk of substance use need to be addressed as part of the substance use awareness and prevention initiatives.

The Role of Phylogenetics in Discerning HIV-1 Mixing among Vulnerable Populations and Geographic Regions in Sub-Saharan Africa: A Systematic Review.

To reduce global HIV-1 incidence, there is a need to understand and disentangle HIV-1 transmission dynamics and to determine the geographic areas and populations that act as hubs or drivers of HIV-1 spread. In Sub-Saharan Africa (sSA), the region with the highest HIV-1 burden, information about such transmission dynamics is sparse. Phylogenetic inference is a powerful method for the study of HIV-1 transmission networks and source attribution. In this review, we assessed available phylogenetic data on mixing between HIV-1 hotspots (geographic areas and populations with high HIV-1 incidence and prevalence) and areas or populations with lower HIV-1 burden in sSA. We searched PubMed and identified and reviewed 64 studies on HIV-1 transmission dynamics within and between risk groups and geographic locations in sSA (published 1995-2021). We describe HIV-1 transmission from both a geographic and a risk group perspective in sSA. Finally, we discuss the challenges facing phylogenetic inference in mixed epidemics in sSA and offer our perspectives and potential solutions to the identified challenges.

Prevalence, risk and protective indicators of common mental disorders among young people living with HIV compared to their uninfected peers from the Kenyan coast: a cross-sectional study.

BACKGROUND: In sub-Saharan Africa, common mental disorders (CMDs) like depression and anxiety are under-investigated amongst young people living with HIV (YLWH). To address the gap, in Kenya we: a) determined the prevalence of CMDs among YLWH compared to their uninfected peers; b) investigated HIV status as an independent predictor of CMDs in young people; c) investigated CMDs risk and protective indicators with more focus on YLWH. METHODS: Between November 2018 and September 2019, 819 young people aged 18-24 years (407 HIV-infected) were recruited from two Counties on the Kenyan coast. Locally adapted pre-existing mental health measures, Patient Health Questionnaire (9-item) and Generalized Anxiety Disorder scale (7-item), were administered among other questionnaires via audio computer-assisted self-interview. Logistic regression was used to determine the correlates of CMDs. RESULTS: Prevalence of CMDs was significantly elevated among YLWH compared to their uninfected peers i.e. 29% vs. 12%; p < 0.001 for depressive symptoms, 19% vs. 8%; p < 0.001 for anxiety symptoms, and 16% vs. 5%; p < 0.001 for comorbid depressive and anxiety symptoms. HIV status independently predicted depressive symptoms and its co-occurrence with anxiety symptoms. Among YLWH, negative life events, higher perceived HIV-related stigma and low adherence to antiretroviral therapy were the risk indicators for elevated CMDs. Among HIV-uninfected youths, death of both parents was a risk indicator for elevated depressive symptoms. Protective indicators against CMDs among youths with and without HIV included higher social support and health-related quality of life. CONCLUSION: At the Kenyan coast, YLWH have significantly higher burden of CMDs compared to their uninfected peers. Being HIV-positive as a youth in this setting is predictive of more depressive symptoms and its comorbidity with anxiety symptoms. YLWH at high risk of CMDs in coastal Kenya can benefit from early detection, referral and treatment if routine screening for CMDs is integrated in their care package. The mental wellbeing of bereaving HIV-unaffected youths could be improved through continued support to help them come to terms with their loss. At the community level, programmes strengthening the social capital or improving the overall quality of life of youths with or without HIV may be beneficial to their mental health.

A Stronger Innate Immune Response During Hyperacute Human Immunodeficiency Virus Type 1 (HIV-1) Infection Is Associated With Acute Retroviral Syndrome.

BACKGROUND: Acute retroviral syndrome (ARS) is associated with human immunodeficiency virus type 1 (HIV-1) subtype and disease progression, but the underlying immunopathological pathways are poorly understood. We aimed to elucidate associations between innate immune responses during hyperacute HIV-1 infection (hAHI) and ARS. METHODS: Plasma samples obtained from volunteers (≥18.0 years) before and during hAHI, defined as HIV-1 antibody negative and RNA or p24 antigen positive, from Kenya, Rwanda, Uganda, Zambia, and Sweden were analyzed. Forty soluble innate immune markers were measured using multiplexed assays. Immune responses were differentiated into volunteers with stronger and comparatively weaker responses using principal component analysis. Presence or absence of ARS was defined based on 11 symptoms using latent class analysis. Logistic regression was used to determine associations between immune responses and ARS. RESULTS: Of 55 volunteers, 31 (56%) had ARS. Volunteers with stronger immune responses (n = 36 [65%]) had increased odds of ARS which was independent of HIV-1 subtype, age, and risk group (adjusted odds ratio, 7.1 [95% confidence interval {CI}: 1.7-28.8], P = .003). Interferon gamma-induced protein (IP)-10 was 14-fold higher during hAHI, elevated in 7 of the 11 symptoms and independently associated with ARS. IP-10 threshold >466.0 pg/mL differentiated stronger immune responses with a sensitivity of 84.2% (95% CI: 60.4-96.6) and specificity of 100.0% (95% CI]: 90.3-100.0). CONCLUSIONS: A stronger innate immune response during hAHI was associated with ARS. Plasma IP-10 may be a candidate biomarker of stronger innate immunity. Our findings provide further insights on innate immune responses in regulating ARS and may inform the design of vaccine candidates harnessing innate immunity.

Benefits of enhanced infection prophylaxis at antiretroviral therapy initiation by cryptococcal antigen status.

OBJECTIVES: To assess baseline prevalence of cryptococcal antigen (CrAg) positivity; and its contribution to reductions in all-cause mortality, deaths from cryptococcus and unknown causes, and new cryptococcal disease in the REALITY trial. DESIGN: Retrospective CrAg testing of baseline and week-4 plasma samples in all 1805 African adults/children with CD4+ cell count less than 100 cells/µl starting antiretroviral therapy who were randomized to receive 12-week enhanced-prophylaxis (fluconazole 100 mg/day, azithromycin, isoniazid, cotrimoxazole) vs. standard-prophylaxis (cotrimoxazole). METHODS: Proportional hazards models were used to estimate the relative impact of enhanced-prophylaxis vs. standard-cotrimoxazole on all, cryptococcal and unknown deaths, and new cryptococcal disease, through 24 weeks, by baseline CrAg positivity. RESULTS: Excluding 24 (1.4%) participants with active/prior cryptococcal disease at enrolment (all treated for cryptococcal disease), 133/1781 (7.5%) participants were CrAg-positive. By 24 weeks, 105 standard-cotrimoxazole vs. 78 enhanced-prophylaxis participants died. Of nine standard-cotrimoxazole and three enhanced-prophylaxis cryptococcal deaths, seven and two, respectively, were CrAg-positive at baseline. Among deaths of unknown cause, only 1/46 standard-cotrimoxazole and 1/28 enhanced-prophylaxis were CrAg-positive at baseline. There was no evidence that relative reductions in new cryptococcal disease associated with enhanced-prophylaxis varied between baseline CrAg-positives [hazard-ratio = 0.36 (95% confidence interval 0.13-0.98), incidence 19.5 vs. 56.5/100 person-years] and CrAg-negatives [hazard-ratio = 0.33 (0.03-3.14), incidence 0.3 vs. 0.9/100 person-years; Pheterogeneity = 0.95]; nor for all deaths, cryptococcal deaths or unknown deaths (Pheterogeneity > 0.3). CONCLUSION: Relative reductions in cryptococcal disease/death did not depend on CrAg status. Deaths of unknown cause were unlikely to be cryptococcus-related; plausibly azithromycin contributed to their reduction. Findings support including 100 mg fluconazole in an enhanced-prophylaxis package at antiretroviral therapy initiation where CrAg screening is unavailable/impractical.

A Novel HIV-1 RNA Testing Intervention to Detect Acute and Prevalent HIV Infection in Young Adults and Reduce HIV Transmission in Kenya: Protocol for a Randomized Controlled Trial.

BACKGROUND: Detection and management of acute HIV infection (AHI) is a clinical and public health priority, and HIV infections diagnosed among young adults aged 18 to 39 years are usually recent. Young adults with recent HIV acquisition frequently seek care for symptoms and could potentially be diagnosed through the health care system. Early recognition of HIV infection provides considerable individual and public health benefits, including linkage to treatment as prevention, access to risk reduction counseling and treatment, and notification of partners in need of HIV testing. OBJECTIVE: The Tambua Mapema Plus study aims to (1) test 1500 young adults (aged 18-39 years) identified by an AHI screening algorithm for acute and prevalent (ie, seropositive) HIV, linking all newly diagnosed HIV-infected patients to care and offering immediate treatment; (2) offer assisted HIV partner notification services to all patients with HIV, testing partners for acute and prevalent HIV infection and identifying local sexual networks; and (3) model the potential impact of these two interventions on the Kenyan HIV epidemic, estimating incremental costs per HIV infection averted, death averted, and disability-adjusted life year averted using data on study outcomes. METHODS: A modified stepped-wedge design is evaluating the yield of this HIV testing intervention at 4 public and 2 private health facilities in coastal Kenya before and after intervention delivery. The intervention uses point-of-care HIV-1 RNA testing combined with standard rapid antibody tests to diagnose AHI and prevalent HIV among young adults presenting for care, employs HIV partner notification services to identify linked acute and prevalent infections, and follows all newly diagnosed patients and their partners for 12 months to ascertain clinical outcomes, including linkage to care, antiretroviral therapy (ART) initiation and virologic suppression in HIV-infected patients, and pre-exposure prophylaxis uptake in uninfected individuals in discordant partnerships. RESULTS: Enrollment started in December 2017. As of April 2020, 1374 participants have been enrolled in the observation period and 1500 participants have been enrolled in the intervention period, with 13 new diagnoses (0.95%) in the observation period and 37 new diagnoses (2.47%), including 2 AHI diagnoses, in the intervention period. Analysis is ongoing and will include adjusted comparisons of the odds of the following outcomes in the observation and intervention periods: being tested for HIV infection, newly diagnosed with prevalent or acute HIV infection, linked to care, and starting ART by week 6 following HIV diagnosis. Participants newly diagnosed with acute or prevalent HIV infection in the intervention period are being followed for outcomes, including viral suppression by month 6 and month 12 following ART initiation and partner testing outcomes. CONCLUSIONS: The Tambua Mapema Plus study will provide foundational data on the potential of this novel combination HIV prevention intervention to reduce ongoing HIV transmission in Kenya and other high-prevalence African settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT03508908; https://clinicaltrials.gov/ct2/show/NCT03508908. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/16198.

HIV-1 Transmission Patterns Within and Between Risk Groups in Coastal Kenya.

HIV-1 transmission patterns within and between populations at different risk of HIV-1 acquisition in Kenya are not well understood. We investigated HIV-1 transmission networks in men who have sex with men (MSM), injecting drug users (IDU), female sex workers (FSW) and heterosexuals (HET) in coastal Kenya. We used maximum-likelihood and Bayesian phylogenetics to analyse new (N = 163) and previously published (N = 495) HIV-1 polymerase sequences collected during 2005-2019. Of the 658 sequences, 131 (20%) were from MSM, 58 (9%) IDU, 109 (17%) FSW, and 360 (55%) HET. Overall, 206 (31%) sequences formed 61 clusters. Most clusters (85%) consisted of sequences from the same risk group, suggesting frequent within-group transmission. The remaining clusters were mixed between HET/MSM (7%), HET/FSW (5%), and MSM/FSW (3%) sequences. One large IDU-exclusive cluster was found, indicating an independent sub-epidemic among this group. Phylodynamic analysis of this cluster revealed a steady increase in HIV-1 infections among IDU since the estimated origin of the cluster in 1987. Our results suggest mixing between high-risk groups and heterosexual populations and could be relevant for the development of targeted HIV-1 prevention programmes in coastal Kenya.

Beyond Their HIV Status: the Occurrence of Multiple Health Risk Behavior Among Adolescents from a Rural Setting of Sub-Saharan Africa.

BACKGROUND: Health risk behaviors during adolescence may cluster into patterns that might be predicted by specific factors, among which HIV may have an important role. METHOD: In a cross-sectional study conducted between 2017 and 2018, clustering of HRB and its associated factors was investigated in rural Kenya among 588 adolescents (36% perinatally HIV infected; 28% perinatally HIV exposed but uninfected; and 36% HIV unexposed/uninfected). Latent class analysis of 22 behaviors followed by multinomial logistic regression were conducted. Four risk behavior classes were identified. RESULTS: No significant differences were found in behavioral class membership across the three HIV groups (p = 0.366). The risk of membership to the higher risk behavioral classes relative to class 1 (the substance and drug abstinent low risk takers) increased with older adolescent age (p = 0.047), increased among adolescent who experienced mental distress (p < 0.001), and those who felt unsafe in their neighborhood (p < 0.002). Better working memory (p = 0.0037) was found to be protective. CONCLUSION: The results highlight a need to include screening and interventions for internalizing mental health problems and deficits in executive functioning, as well as steps to involve family members and communities to address psychosocial risk factors in adolescents in Kenya.

Presence, persistence and effects of pre-treatment HIV-1 drug resistance variants detected using next generation sequencing: A Retrospective longitudinal study from rural coastal Kenya.

BACKGROUND: The epidemiology of HIV-1 drug resistance (HIVDR) determined by Sanger capillary sequencing, has been widely studied. However, much less is known about HIVDR detected using next generation sequencing (NGS) methods. We aimed to determine the presence, persistence and effect of pre-treatment HIVDR variants detected using NGS in HIV-1 infected antiretroviral treatment (ART) naïve participants from rural Coastal Kenya. METHODS: In a retrospective longitudinal study, samples from HIV-1 infected participants collected prior [n = 2 time-points] and after [n = 1 time-point] ART initiation were considered. An ultra-deep amplicon-based NGS assay, calling for nucleotide variants at >2.0% frequency of viral population, was used. Suspected virologic failure (sVF) was defined as a one-off HIV-1 viral load of >1000 copies/ml whilst on ART. RESULTS: Of the 50 eligible participants, 12 (24.0% [95% CI: 13.1-38.2]) had at least one detectable pre-treatment HIVDR variant against Protease Inhibitors (PIs, n = 6 [12%]), Nucleoside Reverse Transcriptase Inhibitors (NRTIs, n = 4 [8.0%]) and Non-NRTIs (n = 3 [6.0%]). Overall, 15 pre-treatment resistance variants were detected (frequency, range: 2.3-92.0%). A positive correlation was observed between mutation frequency and absolute load for NRTI and/or NNRTI variants (r = 0.761 [p = 0.028]), but not for PI variants (r = -0.117 [p = 0.803]). Participants with pre-treatment NRTI and/or NNRTI resistance had increased odds of sVF (OR = 6.0; 95% CI = 1.0-36.9; p = 0.054). CONCLUSIONS: Using NGS, pre-treatment resistance variants were common, though observed PI variants were unlikely transmitted, but rather probably generated de novo. Even when detected from a low frequency, pre-treatment NRTI and/or NNRTI resistance variants may adversely affect treatment outcomes.

Determining the Origins of Human Immunodeficiency Virus Type 1 Drug-resistant Minority Variants in People Who Are Recently Infected Using Phylogenetic Reconstruction.

BACKGROUND: Drug-resistant minority variants (DRMinVs) detected in patients who recently acquired human immunodeficiency virus type 1 (HIV-1) can be transmitted, generated de novo through virus replication, or technical errors. The first form is likely to persist and result in treatment failure, while the latter two could be stochastic and transient. METHODS: Ultradeep sequencing of plasma samples from 835 individuals with recent HIV-1 infection in the United Kingdom was performed to detect DRMinVs at a mutation frequency between 2% and 20%. Sequence alignments including >110 000 HIV-1 partial pol consensus sequences from the UK HIV Drug Resistance Database (UK-HDRD), linked to epidemiological and clinical data from the HIV and AIDS Reporting System, were used for transmission cluster analysis. Transmission clusters were identified using Cluster Picker with a clade support of >90% and maximum genetic distances of 4.5% or 1.5%, the latter to limit detection to likely direct transmission events. RESULTS: Drug-resistant majority variants (DRMajVs) were detected in 66 (7.9%) and DRMinVs in 84 (10.1%) of the recently infected individuals. High levels of clustering to sequences in UK-HDRD were observed for both DRMajV (n = 48; 72.7%) and DRMinV (n = 63; 75.0%) sequences. Of these, 43 (65.2%) with DRMajVs were in a transmission cluster with sequences that harbored the same DR mutation compared to only 3 (3.6%) sequences with DRMinVs (P < .00001, Fisher exact test). Evidence of likely direct transmission of DRMajVs was observed for 25/66 (37.9%), whereas none were observed for the DRMinVs (P < .00001). CONCLUSIONS: Using a densely sampled HIV-infected population, we show no evidence of DRMinV transmission among recently infected individuals.