Transitioning women to first-line preferred TLD regimen is lagging in Sub-Saharan Africa.

INTRODUCTION: In 2019, the World Health Organization (WHO) recommended tenofovir disoproxil fumarate-lamivudine-dolutegravir (TLD) as the preferred first line regimen for adults and adolescents regardless of childbearing status. Nevertheless, final eligibility is determined by local policies which may vary from WHO recommendations. We examined TLD transition by gender across five PEPFAR-supported HIV care programs in sub-Saharan Africa. METHODS: The African Cohort Study (AFRICOS) enrolls people living with HIV (PLWH) engaged in care in Uganda, Kenya (South Rift Valley and Kisumu West), Tanzania and Nigeria. PLWH with at least one study visit after the country introduced TLD were included. We generated Kaplan-Meier (KM) curves to compare TLD transition by gender from 1) time countries' introduction of TLD and 2) time of TLD eligibility according to local policies. RESULTS: Among 2.476 participants enrolled through September 2021 at 4 sites in sub-Saharan Africa and eligible to transition to TLD, fewer women (68%) compared to men (80%, p < 0.001) were taking TLD. Kaplan-Meier analysis showed time to transition varied by site, with women in Tanzania transitioning at the same rate as men. In Nigeria, women initially had a slower transition but caught up to men. After adjusting for local policies, women[1] in Kisumu West transitioned at the same rate as men. In South Rift Valley and Uganda, women were less likely to be transitioned. CONCLUSIONS: Despite TLD being the WHO's preferred regimen since 2019, transition of women to potentially lifesaving TLD has been slower than men at certain clinical sites even after accounting for local eligibility criteria.

Epidemiological and clinical implications of asymptomatic malaria and schistosomiasis co-infections in a rural community in western Kenya.

BACKGROUND: Malaria and schistosomiasis present considerable disease burden in tropical and sub-tropical areas and severity is worsened by co-infections in areas where both diseases are endemic. Although pathogenesis of these infections separately is well studied, there is limited information on the pathogenic disease mechanisms and clinical disease outcomes in co-infections. In this study, we investigated the prevalence of malaria and schistosomiasis co-infections, and the hematologic and blood chemistry abnormalities in asymptomatic adults in a rural fishing community in western Kenya. METHODS: This sub-study used samples and data collected at enrollment from a prospective observational cohort study (RV393) conducted in Kisumu County, Kenya. The presence of malaria parasites was determined using microscopy and real-time-PCR, and schistosomiasis infection by urine antigen analysis (CCA). Hematological analysis and blood chemistries were performed using standard methods. Statistical analyses were performed to compare demographic and infection data distribution, and hematologic and blood chemistry parameters based on different groups of infection categories. Clinically relevant hematologic conditions were analyzed using general linear and multivariable Poisson regression models. RESULTS: From February 2017 to May 2018, we enrolled 671 participants. The prevalence of asymptomatic Plasmodium falciparum was 28.2% (157/556) and schistosomiasis 41.2% (229/562), with 18.0% (100/556) of participants co-infected. When we analyzed hematological parameters using Wilcoxon rank sum test to evaluate median (IQR) distribution based on malarial parasites and/or schistosomiasis infection status, there were significant differences in platelet counts (p = 0.0002), percent neutrophils, monocytes, eosinophils, and basophils (p < 0.0001 each). Amongst clinically relevant hematological abnormalities, eosinophilia was the most prevalent at 20.6% (116/562), whereas thrombocytopenia was the least prevalent at 4.3% (24/562). In univariate model, Chi-Square test performed for independence between participant distribution in different malaria parasitemia/schistosomiasis infection categories within each clinical hematological condition revealed significant differences for thrombocytopenia and eosinophilia (p = 0.006 and p < 0.0001, respectively), which was confirmed in multivariable models. Analysis of the pairwise mean differences of liver enzyme (ALT) and kidney function (Creatinine Clearance) indicated the presence of significant differences in ALT across the infection groups (parasite + /CCA + vs all other groups p < .003), but no differences in mean Creatinine Clearance across the infection groups. CONCLUSIONS: Our study demonstrates the high burden of asymptomatic malaria parasitemia and schistosomiasis infection in this rural population in Western Kenya. Asymptomatic infection with malaria or schistosomiasis was associated with laboratory abnormalities including neutropenia, leukopenia and thrombocytopenia. These abnormalities could be erroneously attributed to other diseases processes during evaluation of diseases processes. Therefore, evaluating for co-infections is key when assessing individuals with laboratory abnormalities. Additionally, asymptomatic infection needs to be considered in control and elimination programs given high prevalence documented here.

The Transformative Impact of the African Cohort Study (AFRICOS) Toward Reaching HIV 95-95-95 Goals in Sub-Saharan Africa.

Over the last 20 years, the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) has rapidly expanded and made remarkable progress toward the UNAIDS 95-95-95 targets to end the HIV epidemic. Nevertheless, HIV continues to pose a significant health challenge globally, with a particular impact on the African continent. Funded by PEPFAR, the African Cohort Study (AFRICOS) has served as a monitoring and evaluation tool for PEPFAR to help guide HIV policy and PEPFAR programming for the last 10 years since its inception and offers a compelling example of how PEPFAR's investment in science continues to reap dividends. This paper details and critically reviews the transformative research AFRICOS has had on helping to end the HIV epidemic as a public health threat by 2030.

Epidemiology of Tuberculosis Among People Living With HIV in the African Cohort Study From 2013 to 2021.

BACKGROUND: The prevalence and incidence of tuberculosis (TB) is high among people living with HIV (PLWH) but is often underdiagnosed in HIV programmatic settings. SETTING: President's Emergency Plan for AIDS Relief (PEPFAR)-supported research sites in Uganda, Kenya, Tanzania, and Nigeria. METHODS: All patients underwent molecular testing at entry into a longitudinal cohort of PLWH and annually thereafter. We assessed the prevalence and incidence of TB and identified clinical and demographic factors associated with prevalent and incident TB using logistic regression and Cox proportional hazard models. RESULTS: From 21 January, 2013, to 1 December 2021, 3171 PLWH were enrolled with a TB prevalence of 3% (n = 93). Of the cases with prevalent TB, 66% (n = 61) were bacteriologically confirmed. The adjusted odds of prevalent TB were significantly higher among those with higher educational attainment, PLWH for 1-5 years since their HIV diagnosis, those who were underweight, and those with CD4 counts <200 cells/mm 3 . The overall TB incidence rate was 600 per 100,000 person-years (95% CI: 481-748). We found that shorter time since HIV diagnosis, being underweight, taking antiretroviral therapy <6 months, and having a CD4 count <200 cells/mm 3 were significantly associated with incident TB. PLWH on dolutegravir/lamivudine/tenofovir had a 78% lower risk of incident TB compared with those on tenofovir/lamivudine/efavirenz (hazard ratio: 0.22; 95% CI: 0.08-0.63). CONCLUSION: The prevalence and incidence of TB was notably high in this cohort sourced from PEPFAR clinics. Aggressive efforts to enhance HIV diagnosis and optimize treatment in programmatic settings are warranted to reduce the risk of HIV-TB co-occurrence in this cohort.

High-risk human papillomavirus genotype distribution among women living with and at risk for HIV in Africa.

OBJECTIVE: Cervical cancer is a common preventable cancer among African women living with HIV (WLWH). Molecular diagnostics for high-risk human papillomavirus (HR-HPV) genotypes are standard components of cervical cancer screening in resource-rich countries but not in resource-limited settings. We evaluated HR-HPV genotypes among women with and without HIV in four African countries to inform cervical cancer preventive strategies. METHODS: The African Cohort Study (AFRICOS) enrolled participants with and without HIV at 12 clinics in Tanzania, Kenya, Uganda, and Nigeria. Cervical cytobrush specimens from women were genotyped for 14 HR-HPV types using the multiplex Seegene Anyplex real-time PCR assay. Robust Poisson regression was used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for factors associated with HR-HPV in WLWH. RESULTS: From January 2015 to March 2020, 868 WLWH and 134 women living without HIV (WLWoH) were tested for HR-HPV with prevalence of 50.9 and 38.1%, respectively ( P  = 0.007). Among WLWH, 844 (97.4%) were antiretroviral therapy (ART)-experienced and 772 (89.7%) virally suppressed 1000 copies/ml or less. The most frequent HR-HPV types among WLWH were HPV-16 (13.5%), HPV-52 (9.5%), and HPV-35 (9.3%). HR-HPV infection was more common among Tanzanian WLWH (adjusted RR: 1.23, 95% CI 1.05-1.44, P  = 0.012). Also, WLWH with CD4 + T cells of less than 200 cell/µl had 1.51-fold increased risk of having HR-HPV (95% CI 1.23-1.86, P  < 0.001). CONCLUSION: HR-HPV was common in WLWH in four African countries, particularly among women with low CD4 + cell count. Scale up of HPV vaccines and development of vaccines with broader activity against less common HR-HPV types may improve cervical cancer prevention in Africa.

Weight gain during the dolutegravir transition in the African Cohort Study.

INTRODUCTION: Dolutegravir (DTG) has become a preferred component of first-line antiretroviral therapy (ART) in many settings but may be associated with excess weight gain. We evaluated changes in weight and body mass index (BMI) after switch to single-tablet tenofovir/lamivudine/dolutegravir (TLD) by people living with HIV (PLWH) in four African countries. METHODS: The African Cohort Study (AFRICOS) prospectively follows adults with and without HIV in Kenya, Uganda, Tanzania and Nigeria. Demographics, ART regimen, weight, BMI and waist-to-hip ratio were collected every 6 months. Multivariable Cox proportional hazards modelling was used to estimate hazard ratios and 95% confidence intervals (CIs) for factors associated with developing a BMI ≥25 kg/m2 . Linear mixed effects models with random effects were used to examine the average change in BMI, weight and waist-to-hip ratio. RESULTS: From 23 January 2013 to 1 December 2020, 2950 PLWH were enrolled in AFRICOS and 1474 transitioned to TLD. In adjusted models, PLWH on TLD had 1.77 times the hazard of developing a high BMI (95% CI: 1.22-2.55) compared to PLWH on non-TLD ART. Examining change in weight among all PLWH on ART, participants on TLD gained an average of 0.68 kg (95% CI: 0.32-1.04) more than PLWH on other regimens after adjusting for duration on ART, sex, age, study site and CD4 nadir. Among participants who switched to TLD, the average change in weight prior to TLD switch was 0.35 kg/year (95% CI: 0.25-0.46) and average change in weight was 1.46 kg/year (95% CI: 1.18-1.75) in the year following transition to TLD after adjustment for confounders. CONCLUSIONS: Elevated BMI and weight gain among PLWH on TLD are concerning safety signals. Implications for the development of metabolic comorbidities should be monitored, particularly if annual weight gain persists during continued follow-up after transitioning to TLD.

Clinical laboratory hematology reference values among infants aged 1month to 17 months in Kombewa Sub-County, Kisumu: A cross sectional study of rural population in Western Kenya.

There is an urgent need for reliable region-specific hematological reference values for clinical monitoring. Laboratory reference ranges are important for assessing study participant eligibility, toxicity grading and management of adverse events in clinical trials and clinical diagnosis. Most clinical laboratories in Kenya rely on hematological reference values provided by instrument manufacturers and/or textbooks, which are based on population from Europe or North America. The use of such values in medical practice could result in improper patient management, selection bias in selection of appropriate participants for clinical trials and flawed classification of the clinical adverse events when applied to African populations. The aim of this study was to establish local laboratory hematological reference values in infants aged 1 month to 17 months from Kombewa Sub-county that could be true representative of the existing rural population. The study participants in the current study were those who had previously been recruited from GSK-sponsored study. This study was a phase III, Double Blind, Randomized, GSK-sponsored, Malaria Vaccine Clinical Trial that was conducted in infants aged 1month to 17months. 1,509 participants were included in the study analysis. Data were partitioned into 3 different age groups (1-6 months[m], 6-12 m and 12-17 m) and differences between gender were compared within each group. Data were analyzed using Graphpad prism V5 to generate 95% reference ranges (2.5th-97.5th percentile). There was evidence of gender differences in hemoglobin values (p = 0.0189) and platelet counts (p = 0.0005) in the 1 to 6m group. For the 12-17m group, there were differences in MCV (p<0.0001) and MCH (p = 0.0003). Comparing gender differences for all age groups, differences were noted in percent lymphocytes (p = 0.0396), percent monocytes (p = 0.0479), percent granulocytes (p = 0.0044), hemoglobin (p = 0.0204), hematocrit (p = 0.0448), MCV (p = 0.0092), MCH (p = 0.0089), MCHC (p = 0.0336) and absolute granulocytes (p = 0.0237). In 1 to 6m age group and all age groups assessed, for WBCs, hemoglobin, hematocrit, MCV and lymphocytes absolute counts, both 2.5th and 97.5th percentiles for Kisumu infants were higher than those from Kilifi. Platelet ranges for Kisumu children were narrower compared to Kilifi ranges. Kisumu hematology reference ranges were observed to be higher than the ranges of Tanzanian children for the WBCs, absolute lymphocyte and monocyte counts, hemoglobin, hematocrit and MCV. Higher ranges of WBCs, absolute lymphocyte and monocyte counts were observed compared to the values in US/Europe. Wider ranges were observed in hemoglobin, hematocrit, and MCV. Wider ranges were observed in platelet counts in Kisumu infants compared to the US/Europe ranges. Compared to Harriet Lane Handbook reference values that are used in the area, higher counts were observed in WBC counts, both absolute and percent lymphocyte counts, as well as monocyte counts for current study. Wider ranges were observed in RBC, platelets and RDW, while lower ranges noted in the current study for hemoglobin, hematocrit and granulocyte counts. This study underscores the importance of using locally established hematology reference ranges of different age groups in support of proper patient management and for clinical trials.

Cause-specific mortality in the Kombewa health and demographic surveillance systems site, rural Western Kenya from 2011-2015.

BACKGROUND: The vast majority of deaths in the health and Kombewa demographic surveillance system (HDSS) study area are not registered and reported through official systems of vital registration. As a result, few data are available regarding causes of death in this population. OBJECTIVES: To describe causes of death among residents of all ages in the Kombewa HDSS, located in rural Western Kenya. METHODS: Verbal autopsy (VA) interviews at the site were conducted using the modified 2007 and later 2012 standardized WHO questionnaires. Assignment of causes of death was made using the InterVA-4 model version 4.02. Cox regression model, adjusted for sex, was built to evaluate the influence of age on mortality. RESULTS: There were a total of 5196 deaths recorded between 2011 and 2015 at the site. VA interviews were successfully completed for 3903 of these deaths (75.1%). Mortality rates were highest among neonates HR = 38.54 (<0.001) and among Infants HR = 2.07 (<0.006) in the Kombewa HDSS. Among those deaths in which VA was performed, the top causes of death were HIV/AIDS (12.6%), Malaria (10.3%), Pneumonia (10.1%), Acute abdomen (7.0%), Stroke (5.2%) and TB (4.9%) for the whole population in general. Stroke, acute abdomen heart diseases and Pneumonia were common causes of death (CODs) among the elderly over the age of 65. CONCLUSIONS: The analysis established the main CODs among people of all ages within the area served by the Kombewa HDSS. We hope that information generated from this study will help better address preventable deaths in the surveyed community as well as help mitigate negative health impacts in other rural communities throughout the Western Kenya region.

A Spatiotemporal Analysis of HIV-Associated Mortality in Rural Western Kenya 2011-2015.

BACKGROUND: Reliable data on the HIV epidemic is critical for the measurement of the impact of HIV response and for the implementation of further interventions. METHODS: We used mortality data from the Kombewa health and demographic surveillance systems (HDSS) from January 1, 2011 to December 31, 2015 to examine the space-time pattern of HIV-associated mortality. HIV mortality rate was calculated per 1000 persons living with HIV (for comparison with regional and national averages) and per 1000 person-years (p-y) for comparison with data from other HDSS sites. We used the Optimized Hot Spot Analysis to examine whether HIV-associated deaths would form statistically significant local aggregation in the 5-year period. P-value of <0.05 and <0.01 was considered significant. RESULTS: The HIV-associated mortality rate over the 5-year period was 9.8 per 1000 persons living with HIV (PLHIV). Mortality declined from 11.6 per 1000 PLHIV in 2011 to 7.3 per 1000 PLHIV by the end of 2015. The rates of HIV were highest among infants [hazard ratio (HR) = 2.39 (<0.001)]. Tuberculosis mortality rates were highest in the age group 5-14 years [HR = 2.29 (0.002)] and the age group 50-64 years [HR = 1.18 (0.531)]. The overall trend in HIV-associated mortality showed a decline from 1.8 per 1000 p-y in 2011 to 1.3 per 1000 p-y by the end of 2015. The hotspot analysis showed that 20.0% of the study area (72 km) was detected as hotspots (Z = 2.382-3.143, P ≤ 0.001) and 4.2% of the study area as cold spots (15 km). CONCLUSIONS: HIV attributable death in the HDSS population is substantial, although it is lower than both the national and the regional estimates.