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.

Schistosoma mansoni infection alters the host pre-vaccination environment resulting in blunted Hepatitis B vaccination immune responses.

Schistosomiasis is a disease caused by parasitic flatworms of the Schistosoma spp., and is increasingly recognized to alter the immune system, and the potential to respond to vaccines. The impact of endemic infections on protective immunity is critical to inform vaccination strategies globally. We assessed the influence of Schistosoma mansoni worm burden on multiple host vaccine-related immune parameters in a Ugandan fishing cohort (n = 75) given three doses of a Hepatitis B (HepB) vaccine at baseline and multiple timepoints post-vaccination. We observed distinct differences in immune responses in instances of higher worm burden, compared to low worm burden or non-infected. Concentrations of pre-vaccination serum schistosome-specific circulating anodic antigen (CAA), linked to worm burden, showed a significant bimodal distribution associated with HepB titers, which was lower in individuals with higher CAA values at month 7 post-vaccination (M7). Comparative chemokine/cytokine responses revealed significant upregulation of CCL19, CXCL9 and CCL17 known to be involved in T cell activation and recruitment, in higher CAA individuals, and CCL17 correlated negatively with HepB titers at month 12 post-vaccination. We show that HepB-specific CD4+ T cell memory responses correlated positively with HepB titers at M7. We further established that those participants with high CAA had significantly lower frequencies of circulating T follicular helper (cTfh) subpopulations pre- and post-vaccination, but higher regulatory T cells (Tregs) post-vaccination, suggesting changes in the immune microenvironment in high CAA could favor Treg recruitment and activation. Additionally, we found that changes in the levels of innate-related cytokines/chemokines CXCL10, IL-1ß, and CCL26, involved in driving T helper responses, were associated with increasing CAA concentration. This study provides further insight on pre-vaccination host responses to Schistosoma worm burden which will support our understanding of vaccine responses altered by pathogenic host immune mechanisms and memory function and explain abrogated vaccine responses in communities with endemic infections.

Schistosoma mansoni infection alters the host pre-vaccination environment resulting in blunted Hepatitis B vaccination immune responses.

The impact of endemic infections on protective immunity is critical to inform vaccination strategies. In this study, we assessed the influence of Schistosoma mansoni infection on host responses in a Ugandan fishing cohort given a Hepatitis B (HepB) vaccine. Concentrations of schistosome-specific circulating anodic antigen (CAA) pre-vaccination showed a significant bimodal distribution associated with HepB titers, which were lower in individuals with high CAA. We established that participants with high CAA had significantly lower frequencies of circulating T follicular helper (cTfh) subpopulations pre- and post-vaccination and higher regulatory T cells (Tregs) post-vaccination. Polarization towards higher frequencies of Tregs: cTfh cells can be mediated by changes in the cytokine environment favoring Treg differentiation. In fact, we observed higher levels of CCL17 and soluble IL-2R pre-vaccination (important for Treg recruitment and development), in individuals with high CAA that negatively associated with HepB titers. Additionally, alterations in pre-vaccination monocyte function correlated with HepB titers, and changes in innate-related cytokines/chemokine production were associated with increasing CAA concentration. We report, that by influencing the immune landscape, schistosomiasis has the potential to modulate immune responses to HepB vaccination. These findings highlight multiple Schistosoma -related immune associations that could explain abrogated vaccine responses in communities with endemic infections. Author Summary: Schistosomiasis drives host immune responses for optimal pathogen survival, potentially altering host responses to vaccine-related antigen. Chronic schistosomiasis and co-infection with hepatotropic viruses are common in countries where schistosomiasis is endemic. We explored the impact of Schistosoma mansoni ( S. mansoni ) infection on Hepatitis B (HepB) vaccination of individuals from a fishing community in Uganda. We demonstrate that high schistosome-specific antigen (circulating anodic antigen, CAA) concentration pre-vaccination, is associated with lower HepB antibody titers post-vaccination. We show higher pre-vaccination levels of cellular and soluble factors in instances of high CAA that are negatively associated with HepB antibody titers post-vaccination, which coincided with lower frequencies of circulating T follicular helper cell populations (cTfh), proliferating antibody secreting cells (ASCs), and higher frequencies of regulatory T cells (Tregs). We also show that monocyte function is important in HepB vaccine responses, and that high CAA is associated with alterations in the early innate cytokine/chemokine microenvironment. Our findings suggest that in individuals with high CAA and likely high worm burden, schistosomiasis creates and sustains an environment that is polarized against optimal host immune responses to the vaccine, which puts many endemic communities at risk for infection against HepB and other diseases that are preventable by vaccines.

Modelling the impact of combining HIV prevention interventions on HIV dynamics in fishing communities in Uganda.

BACKGROUND: In countries with mature generalized HIV epidemics such as Uganda, there are still groups of individuals that are disproportionately affected. Among the key populations in Uganda are fishing communities, which make up about 10% of the population. Compared to the general population, HIV prevalence and incidence among individuals living in these communities is high. This high HIV burden has been attributed to several factors including limited access to prevention and treatment services as well as ongoing high-risk sexual behaviour. METHODS: We investigated the impact of combined HIV prevention interventions on HIV transmission dynamics in high-risk fishing communities in Uganda using a deterministic compartmental model. The model was calibrated to seroprevalence data from a census performed in 2014. To account for remaining uncertainty in the calibrated model parameters, 50 000 simulated scenarios were modelled to investigate the impact of combined prevention interventions. RESULTS: The projected HIV incidence decreased from 1.87 per 100 PY without intervention scale-up to 0.25 per 100 PY after 15 years (2014-2029) of intervention scale-up. A potential combination achieving this 87% reduction in incidence over 15 years in Ugandan FCs included condom use in about 60% of sexual acts, 23% of susceptible men circumcised, 87% of people living with HIV aware of their status, 75% of those on ART, and about 3% of susceptible individuals on oral PrEP. Uncertainty analysis revealed relative reductions in incidence ranging from 30.9 to 86.8%. Sensitivity analyses suggested that condom use and early ART were the most important interventions. CONCLUSION: Reducing HIV incidence, as well as prevalence and AIDS-related mortality, in these high-risk fishing communities in Uganda is attainable over 15 years with a combination prevention package. Our projected intervention coverage levels are well within the national targets set by the Uganda government and enable coming close to reaching the UNAIDS 95-95-95 targets to end AIDS as a public health threat by 2030.

Infection with HIV-1 subtype D among acutely infected Ugandans is associated with higher median concentration of cytokines compared to subtype A.

Objective: The observation that HIV-1 subtype D progresses faster to disease than subtype A prompted us to examine cytokine levels early after infection within the predominant viral subtypes that circulate in Uganda and address the following research questions: (1) Do cytokine levels vary between subtypes A1 and D? (2) Do cytokine profiles correlate with disease outcomes? Methods: To address these questions, HIV-1 subtypes were determined by population sequencing of the HIV-1 pol gene and 37 plasma cytokine concentrations were evaluated using V-Plex kits on Meso Scale Discovery platform in 65 recent sero-converters. Results: HIV-1 subtype D (pol) infections exhibited significantly higher median plasma concentrations of IL-5, IL-16, IL-1α, IL-7, IL-17A, CCL11 (Eotaxin-1), CXCL10 (IP-10), CCL13 (MCP-4) and VEGF-D compared to subtype A1 (pol) infections. We also found that IL-12/23p40 and IL-1α were associated with faster CD4+T cell count decline, while bFGF was associated with maintenance of CD4+ counts above 350 cells/microliter. Conclusion: Our results suggest that increased production of cytokines in early HIV infection may trigger a disruption of the immune environment and contribute to pathogenic mechanisms underlying the accelerated disease progression seen in individuals infected with HIV-1 subtype D in Uganda.

Characterization of Near Full-Length Transmitted/Founder HIV-1 Subtype D and A/D Recombinant Genomes in a Heterosexual Ugandan Population (2006-2011).

Detailed characterization of transmitted HIV-1 variants in Uganda is fundamentally important to inform vaccine design, yet studies on the transmitted full-length strains of subtype D viruses are limited. Here, we amplified single genomes and characterized viruses, some of which were previously classified as subtype D by sub-genomic pol sequencing that were transmitted in Uganda between December 2006 to June 2011. Analysis of 5' and 3' half genome sequences showed 73% (19/26) of infections involved single virus transmissions, whereas 27% (7/26) of infections involved multiple variant transmissions based on predictions of a model of random virus evolution. Subtype analysis of inferred transmitted/founder viruses showed a high transmission rate of inter-subtype recombinants (69%, 20/29) involving mainly A1/D, while pure subtype D variants accounted for one-third of infections (31%, 9/29). Recombination patterns included a predominance of subtype D in the gag/pol region and a highly recombinogenic envelope gene. The signal peptide-C1 region and gp41 transmembrane domain (Tat2/Rev2 flanking region) were hotspots for A1/D recombination events. Analysis of a panel of 14 transmitted/founder molecular clones showed no difference in replication capacity between subtype D viruses (n = 3) and inter-subtype mosaic recombinants (n = 11). However, individuals infected with high replication capacity viruses had a faster CD4 T cell loss. The high transmission rate of unique inter-subtype recombinants is striking and emphasizes the extraordinary challenge for vaccine design and, in particular, for the highly variable and recombinogenic envelope gene, which is targeted by rational designs aimed to elicit broadly neutralizing antibodies.

Visual inspection with acetic acid (VIA) positivity among female sex workers: a cross-sectional study highlighting one-year experiences in early detection of pre-cancerous and cancerous cervical lesions in Kampala, Uganda.

BACKGROUND: Although cervical cancer is preventable, most women in sub-Saharan Africa (SSA) do not receive routine screening and few treatment options exist. Female Sex Workers (FSWs) are among the Ugandan female population at highest risk of acquiring sexually transmitted infections (STIs) including HIV and human papilloma viruses (HPV), the cause of cervical cancer. We report one-year experiences of visual inspection with acetic acid (VIA) positivity among FSWs in the early detection of pre-cancerous and cancerous cervical lesions in Kampala, Uganda. METHODS: Between June 2014 and July 2015, we enrolled FSWs into a cross-sectional study at a research clinic. The women were screened using the VIA method (application of 3-5 % acetic acid to the cervix). All VIA positive women were referred to a tertiary hospital for colposcopy, biopsy, and immediate treatment (if indicated) at the same visit according to national guidelines. Data on socio-demographic, sexual behaviour, sexual reproductive health and clinical characteristics were collected. We used logistic regression to identify factors associated with VIA positivity. RESULTS: Of 842 women assessed for eligibility, 719 (85 %) of median age 30 (IQR 26, 35) were screened, and 40 (6 %) women were VIA positive. Of the 24 histology specimens analysed, 6 showed inflammation, only 1 showed cervical intraepithelial neoplasia (CIN) 1, 13 women showed CIN2/3, while 4 women already had invasive cervical cancer. The overall prevalence of HIV was 43 %, of whom only 35 % were receiving ART. In the age-adjusted analysis, VIA positivity was more likely among women who reported having > 100 life-time partners (aOR = 3.34, 95 %CI: 1.38-8.12), and HIV positive women (aOR = 4.55; 95 %CI: 2.12-9.84). CONCLUSIONS: We found a relatively low proportion of VIA positivity in this population. The experience from our program implies that the VIA results are poorly reproducible even among a category of trained professional health workers. VIA positivity was more likely among women with a high number of sexual partners and HIV infection. Interventions for improving cervical cancer screening should be recommended as part of HIV care for FSWs to reduce the disease burden in this population.

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.

HIV-1 Gag-Pol Sequences from Ugandan Early Infections Reveal Sequence Variants Associated with Elevated Replication Capacity.

The ability to efficiently establish a new infection is a critical property for human immunodeficiency virus type 1 (HIV-1). Although the envelope protein of the virus plays an essential role in receptor binding and internalization of the infecting virus, the structural proteins, the polymerase and the assembly of new virions may also play a role in establishing and spreading viral infection in a new host. We examined Ugandan viruses from newly infected patients and focused on the contribution of the Gag-Pol genes to replication capacity. A panel of Gag-Pol sequences generated using single genome amplification from incident HIV-1 infections were cloned into a common HIV-1 NL4.3 pol/env backbone and the influence of Gag-Pol changes on replication capacity was monitored. Using a novel protein domain approach, we then documented diversity in the functional protein domains across the Gag-Pol region and identified differences in the Gag-p6 domain that were frequently associated with higher in vitro replication.

Willingness of female sex workers in Kampala, Uganda to participate in future HIV vaccine trials: a case control study.

BACKGROUND: We anticipate large efficacy trials of novel HIV vaccines that have shown acceptable safety profiles. We determined willingness to participate (WTP) in future HIV vaccine efficacy trials among HIV negative female sex workers (FSWs) in Kampala Uganda. METHODS: We conducted a case control study in the Good Health for Women Project cohort. Cases received HIV prevention services and, enrolled in a 12-month simulated vaccine efficacy trial (SiVET) that used Hepatitis B vaccine; they underwent vaccine trial procedures as would be in an actual trial. Controls received similar health services but did not enroll in SiVET. We matched cases and controls (ratio 2:1) for age and duration in the cohort. We described a hypothetical HIV vaccine trial to cases (after 9 months in SiVET) and controls including trial attributes: randomization, delaying pregnancy, frequent blood draws (80-100mls) and study visits for 3 years. We compared WTP and willingness for vaccine trial attributes by case/control using chi-squared or Fisher's exact tests and fitted conditional logistic regression models to determine independent predictors of WTP. RESULTS: We analyzed data for 311 volunteers (219 cases, 92 controls); median age 27 years (IQR: 23-32), 39.9% had ≥secondary education, 57.9% had sex work as their main job and 81.9% used illicit drugs. Compared to controls, more cases had lived in the community for > 1 year, (85.4% vs 64.1%; p < 0.001) and fewer cases reported illicit drug use in the past 3 months, (79.0% vs 89.1%; p = 0.03). Overall, 278 (89.4%) volunteers expressed WTP in an HIV vaccine trial, the most common reason being hope of protection against HIV. More cases than controls (58.2% vs 44.7%) did not need to consult anyone before trial participation (p = 0.03); cases were more willing to delay pregnancy (99.0% vs 94.0%; p = 0.03). Combining vaccine trial attributes, 249 (89.6%) of the 278 accepted all attributes. After controlling for case/ control status women with secondary education or higher expressed less WTP (aOR 0.17; 95% CI 0.04-0.80). CONCLUSION: FSWs in Kampala demonstrated high WTP. Prior experience with trial requirements like contraception may improve their uptake during actual trials. Family involvement is important for those without prior trial experience.

Feasibility of establishing an HIV vaccine preparedness cohort in a population of the Uganda Police Force: Lessons learnt from a prospective study.

BACKGROUND: Members of uniformed armed forces are considered to be at high risk for HIV infection and have been proposed as suitable candidates for participation in HIV intervention studies. We report on the feasibility of recruitment and follow up of individuals from the community of the Uganda Police Force (UPF) for an HIV vaccine preparedness study. METHODS: HIV-negative volunteers aged 18-49 years, were identified from UPF facilities situated in Kampala and Wakiso districts through community HIV counselling and testing. Potential volunteers were referred to the study clinic for screening, enrolment and quarterly visits for one year. HIV incidence, retention rates were estimated and expressed as cases per 100 person years of observation (PYO). Rate ratios were used to determine factors associated with retention using Poisson regression models. RESULTS: We screened 560 to enroll 500 volunteers between November 2015 and May 2016. One HIV seroconversion occurred among 431 PYO, for an incidence rate of 0.23/100 PYO (95% confidence interval [CI]: 0.03-1.64). Overall, retention rate was 87% at one year, and this was independently associated with residence duration (compared to <1 year, 1 to 5 years adjusted rate ratio (aRR) = 1.19, 95%CI: 1.00-1.44); and >5 years aRR = 1.34, 95%CI: 0.95-1.37); absence of genital discharge in the last 3 months (aRR = 1.97, 95% CI: 1.38-2.83, absence of genital ulcers (aRR = 1.90, 95%CI: 1.26-2.87, reporting of new sexual partner in the last month (aRR = 0.57, 95%CI: 0.45-0.71, being away from home for more than two nights (aRR = 1.27, 95%CI: 1.04-1.56, compared to those who had not travelled) and absence of knowledge on HIV prevention (aRR = 2.67, 95%CI: 1.62-4.39). CONCLUSIONS: While our study demonstrates the feasibility of recruiting and retaining individuals from the UPF for HIV research, we did observe lower than anticipated HIV incidence, perhaps because individuals at lower risk of HIV infection may have been the first to come forward to participate or participants followed HIV risk reduction measures. Our findings suggest lessons for recruitment of populations at high risk of HIV infection.

Comparing Alcohol Use Disorders Identification Test (AUDIT) with Timeline Follow Back (TLFB), DSM-5 and Phosphatidylethanol (PEth) for the assessment of alcohol misuse among young people in Ugandan fishing communities.

BACKGROUND: Validated tools for assessing alcohol use among young people in low-income countries are needed to estimate prevalence and evaluate alcohol-reduction interventions. We validated Alcohol Use Disorders Identification Test (AUDIT) against Timeline Follow Back (TLFB), Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and phosphatidylethanol (PEth); and the 30-day-AUDIT against the 12-months-AUDIT among young Ugandans. METHODS: In 2018, we collected retrospective data on 30-day and 12-month AUDIT, TLFB and DSM-5 in a cross-sectional study of 15-24 year old residents of Ugandan fishing communities. AUDIT was administered by Audio Computer Assisted Self-Interviewing (ACASI) and DSM-5 and TLFB by psychiatric nurses. We determined PEth16:0/18:1 levels from dried blood spots using liquid chromatography tandem-mass spectrometry (heavy usage, ≥210 ng/mL) and calculated sensitivity and specificity of AUDIT against the other measures. RESULTS: Among 1281 participants (52.7% male, mean age 20 years), half (n = 659; 51.4%) reported ever drinking alcohol, 19.4% had 12-month-AUDIT ≥ 8 (21.5% men; 17.0% women), and 24.2% had 30-day-AUDIT ≥ 8 (29.0% men; 18.9% women). Twenty percent of participants had detectable PEth with 55 (4.3%) classified as heavy drinkers; 50.7% reported ≥ 2 symptoms on DSM-5 and 6.3% reported binge drinking in the previous month based on TLFB (8.9% men, 3.5% women). The 30-day-AUDIT ≥ 8 had sensitivity 86.7%, 95%CI: 81.8%-90.7% and specificity 90.9%, 95%CI:89.0%-92.6% versus 12-month-AUDIT ≥ 8. Both 30-day and 12-month-AUDIT ≥ 8 were sensitive and specific markers of heavy drinking by PEth (12-month-AUDIT sensitivity = 80.0%; 95%CI:67.0%-89.6%; specificity = 83.3%; 95%CI:81.1%-85.3%). The 30-day-AUDIT was a sensitive and specific marker of binge drinking based on TLFB (sensitivity = 82.7%; 95%CI:72.7%-90.2%, specificity = 79.8%; 95%CI:77.4%-82.1%); 12-month-AUDIT had lower sensitivity. Both 30-day and 12-month AUDIT ≥ 8 were highly specific but insensitive markers of having DSM-5 ≥ 2 symptoms. CONCLUSION: Among young people in Uganda, ACASI-administered 30-day and 12-month-AUDIT have good diagnostic properties compared to PEth, DSM-5 and TLFB. Self-reported AUDIT provides a quick and valid means of assessing alcohol misuse in these communities.

Uganda Genome Resource Enables Insights into Population History and Genomic Discovery in Africa.

Genomic studies in African populations provide unique opportunities to understand disease etiology, human diversity, and population history. In the largest study of its kind, comprising genome-wide data from 6,400 individuals and whole-genome sequences from 1,978 individuals from rural Uganda, we find evidence of geographically correlated fine-scale population substructure. Historically, the ancestry of modern Ugandans was best represented by a mixture of ancient East African pastoralists. We demonstrate the value of the largest sequence panel from Africa to date as an imputation resource. Examining 34 cardiometabolic traits, we show systematic differences in trait heritability between European and African populations, probably reflecting the differential impact of genes and environment. In a multi-trait pan-African GWAS of up to 14,126 individuals, we identify novel loci associated with anthropometric, hematological, lipid, and glycemic traits. We find that several functionally important signals are driven by Africa-specific variants, highlighting the value of studying diverse populations across the region.

The transferability of lipid loci across African, Asian and European cohorts.

Most genome-wide association studies are based on samples of European descent. We assess whether the genetic determinants of blood lipids, a major cardiovascular risk factor, are shared across populations. Genetic correlations for lipids between European-ancestry and Asian cohorts are not significantly different from 1. A genetic risk score based on LDL-cholesterol-associated loci has consistent effects on serum levels in samples from the UK, Uganda and Greece (r = 0.23-0.28, p < 1.9 × 10-14). Overall, there is evidence of reproducibility for ~75% of the major lipid loci from European discovery studies, except triglyceride loci in the Ugandan samples (10% of loci). Individual transferable loci are identified using trans-ethnic colocalization. Ten of fourteen loci not transferable to the Ugandan population have pleiotropic associations with BMI in Europeans; none of the transferable loci do. The non-transferable loci might affect lipids by modifying food intake in environments rich in certain nutrients, which suggests a potential role for gene-environment interactions.

Factors associated with vaccination completion and retention among HIV negative female sex workers enrolled in a simulated vaccine efficacy trial in Kampala, Uganda.

BACKGROUND: Female sex workers (FSWs) at substantial risk of HIV are potentially a suitable group for HIV prevention trials including vaccine trials. Few HIV vaccine preparatory studies have been conducted among FSWs in Sub-Saharan Africa (SSA); data are therefore limited on acceptability of vaccine trial procedures. We determined vaccination completion and one-year retention among FSWs in Kampala, Uganda. METHODS: We conducted a prospective study that simulated a vaccine efficacy trial among HIV negative FSWs (18-49 years). Hepatitis B vaccine (Engerix B) was used to mimic an HIV vaccine product. Volunteers received 1 ml intramuscular injection at 0, 1 and 6 months, and made additional visits (3 days post-vaccination and months 3, 9 and 12). They were censored at that visit if diagnosed as HIV positive or pregnant. We collected socio-demographic, behavioral and clinical data at baseline, 6 and 12 months and fitted Poisson regression models with robust standard error to find factors associated with vaccination completion and retention. RESULTS: We enrolled 290 volunteers (median age 27 years) of whom 230 reached a study end-point as follows: 7 became HIV infected, 11 became pregnant and 212 completed both the vaccination schedule and 12-month visit giving a retention of 77.9% (212/272). Vaccination completion was 82.4%. Non-retention at 1 year was more likely among those reporting symptoms of genital ulcer disease (GUD) in the past 3 months (IRR 1.90; 95% CI 1.09-3.32) and those < 35 years; (IRR 6.59; 95% CI 2.11-20.57). Non-completion of the vaccination schedule was associated with being < 35 years (IRR 13.10; 95% CI 1.89-90.92, reporting GUD symptoms (IRR 3.02; 95% CI 1.71-5.33) and reporting consistent condom use with new sexual partners (IRR 2.57; 95% CI 1.10-6.07). CONCLUSIONS: FSWs are at substantial risk of HIV infection and yet willing to participate in HIV vaccine and prevention research; young FSWs should be empowered, and those reporting GUD symptoms need close follow up to improve participation in future HIV vaccine trials.

The effect of childhood stunting and wasting on adolescent cardiovascular diseases risk and educational achievement in rural Uganda: a retrospective cohort study.

Background: Little is known about the long-term effects of early childhood undernutrition on adolescent cardiovascular disease risk and educational performance in low-income countries. We examined this in a rural Ugandan population. Objective: To investigate if stunting or wasting among children aged 2-5 years is associated with cardiovascular disease risk or educational achievement during adolescence. Methods: We conducted analyses using data from a cohort of children followed from early childhood to adolescence. Weight and height were measured in 1999-2000 when the children were 2-5 years of age and repeated in 2004/2005 and 2011. We compared cardiovascular disease risk parameters (mean blood pressure, lipids, HbA1c) and schooling years achieved in 2011 among 1054 adolescents categorised into four groups: those who experienced stunting or wasting throughout follow-up; those who recovered from stunting or wasting; those who were normal but later became stunted or wasted; and those who never experienced stunting or wasting from childhood up to adolescence. We controlled for possible confounding using multiple generalised linear regression models along with Generalised Estimating Equations to account for clustering of children within households. Results: Wasting was negatively associated with systolic blood pressure (-7.90 95%CI [-14.52,-1.28], p = 0.02) and diastolic blood pressure (-3.92, 95%CI [-7.42, -0.38], p = 0.03). Stunting had borderline negative association with systolic blood pressure (-2.90, 95%CI [-6.41, 0.61] p = 0.10). Recovery from wasting was positively associated with diastolic blood pressure (1.93, 95%CI [0.11, 3.74] p = 0.04). Stunting or wasting was associated with fewer schooling years. Conclusion: Recovery from wasting rather than just an episode in early childhood is associated with a rise in blood pressure while educational achievement is compromised regardless of whether recovery from undernutrition happens. These findings are relevant to children exposed to undernutrition in low-income settings.

Control of the HIV-1 Load Varies by Viral Subtype in a Large Cohort of African Adults With Incident HIV-1 Infection.

Few human immunodeficiency virus (HIV)-infected persons can maintain low viral levels without therapeutic intervention. We evaluate predictors of spontaneous control of the viral load (hereafter, "viral control") in a prospective cohort of African adults shortly after HIV infection. Viral control was defined as ≥2 consecutively measured viral loads (VLs) of ≤10 000 copies/mL after the estimated date of infection, followed by at least 4 subsequent measurements for which the VL in at least 75% was ≤10 000 copies/mL in the absence of ART. Multivariable logistic regression characterized predictors of viral control. Of 590 eligible volunteers, 107 (18.1%) experienced viral control, of whom 25 (4.2%) maintained a VL of 51-2000 copies/mL, and 5 (0.8%) sustained a VL of ≤50 copies/mL. The median ART-free follow-up time was 3.3 years (range, 0.3-9.7 years). Factors independently associated with control were HIV-1 subtype A (reference, subtype C; adjusted odds ratio [aOR], 2.1 [95% confidence interval {CI}, 1.3-3.5]), female sex (reference, male sex; aOR, 1.8 [95% CI, 1.1-2.8]), and having HLA class I variant allele B*57 (reference, not having this allele; aOR, 1.9 [95% CI, 1.0-3.6]) in a multivariable model that also controlled for age at the time of infection and baseline CD4+ T-cell count. We observed strong associations between infecting HIV-1 subtype, HLA type, and sex on viral control in this cohort. HIV-1 subtype is important to consider when testing and designing new therapeutic and prevention technologies, including vaccines.

Alcohol Misuse and Illicit Drug Use Among Occupational Groups at High Risk of HIV in Sub-Saharan Africa: A Systematic Review.

Key occupational groups in sub-Saharan Africa (SSA) are at increased risk of HIV, and may be at increased risk of substance use. In January 2018, we systematically searched for studies reporting prevalence of, and risk factors for alcohol misuse or illicit drug use and their association with HIV incidence or prevalence among fisherfolk, uniformed personnel, truckers, miners, motorcycle taxi riders and sex workers in SSA. Seventy-one studies published between 1983 and 2017 were included: 35 reported on alcohol misuse (19 using AUDIT, 5 using CAGE) and 44 on illicit drug use (eight reported both). Median prevalence of alcohol misuse based on AUDIT/CAGE was 32.8% (IQR 20.8-48.5%). Prevalence of illicit drug use ranged from 0.1% (95% CI: 0.0-0.2%) for injection drug use to 97.1% (95% CI: 85.1-99.9%) for khat (among uniformed personnel). Among papers examining associations between substance use and HIV incidence (n = 3) or prevalence (n = 14), nine papers (53%) reported a significant positive association (2 with incidence, 7 with prevalence). Harm reduction interventions in occupational settings are urgently required to prevent new HIV infections.

Feasibility of conducting HIV combination prevention interventions in fishing communities in Uganda: A pilot cluster randomised trial.

OBJECTIVE: We assessed feasibility of an HIV-combination-prevention trial among fishing communities in Uganda. DESIGN: Cluster randomised trial in four fishing communities on Lake Victoria, Uganda. Two intervention communities received a combination-prevention-package (behaviour change communication, condom promotion, HIV testing, voluntary male medical circumcision and referral for anti-retroviral therapy if HIV-positive). All four communities received routine government HIV care services. METHODS: Using household census data we randomly selected a cohort of consenting residents aged ≥18 years. A baseline sero-survey in July 2014 was followed by two repeat surveys in March and December 2015. We measured uptake of HIV prevention methods, loss-to-follow-up and HIV incidence, accounting for multistage survey design. RESULTS: A total of 862 participants were enrolled and followed for 15 months. Participation was 62% and 74% in the control and intervention arms respectively; Overall loss to follow up (LTFU) was 21.6% and was similar by arm. Self-reported abstinence/faithfulness increased between baseline and endline in both arms from 53% to 73% in the control arm, and 55% to 67% in the intervention arm. Reported condom use throughout the study period was 36% in the intervention arm vs 28% in the control arm; number of male participants reporting circumsicion in both arms from 58% to 79% in the intervention arm, and 39% to 46% in the control arm. Independent baseline predictors of loss-to-follow-up were: being HIV positive, residence in the community for <1 year, younger age, living in an urban area, and being away from the area for >1 month/year. CONCLUSIONS: Recruitment and retention of participants in longitudinal trials in highly mobile HIV fishing communities is challenging. Future research should investigate modes for locating and retaining participants, and delivery of HIV-combination prevention.