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.

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.

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.

The African Genome Variation Project shapes medical genetics in Africa.

Given the importance of Africa to studies of human origins and disease susceptibility, detailed characterization of African genetic diversity is needed. The African Genome Variation Project provides a resource with which to design, implement and interpret genomic studies in sub-Saharan Africa and worldwide. The African Genome Variation Project represents dense genotypes from 1,481 individuals and whole-genome sequences from 320 individuals across sub-Saharan Africa. Using this resource, we find novel evidence of complex, regionally distinct hunter-gatherer and Eurasian admixture across sub-Saharan Africa. We identify new loci under selection, including loci related to malaria susceptibility and hypertension. We show that modern imputation panels (sets of reference genotypes from which unobserved or missing genotypes in study sets can be inferred) can identify association signals at highly differentiated loci across populations in sub-Saharan Africa. Using whole-genome sequencing, we demonstrate further improvements in imputation accuracy, strengthening the case for large-scale sequencing efforts of diverse African haplotypes. Finally, we present an efficient genotype array design capturing common genetic variation in Africa.

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.

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.

Safety and Efficacy of a Dapivirine Vaginal Ring for HIV Prevention in Women.

BACKGROUND: The incidence of human immunodeficiency virus (HIV) infection remains high among women in sub-Saharan Africa. We evaluated the safety and efficacy of extended use of a vaginal ring containing dapivirine for the prevention of HIV infection in 1959 healthy, sexually active women, 18 to 45 years of age, from seven communities in South Africa and Uganda. METHODS: In this randomized, double-blind, placebo-controlled, phase 3 trial, we randomly assigned participants in a 2:1 ratio to receive vaginal rings containing either 25 mg of dapivirine or placebo. Participants inserted the rings themselves every 4 weeks for up to 24 months. The primary efficacy end point was the rate of HIV type 1 (HIV-1) seroconversion. RESULTS: A total of 77 participants in the dapivirine group underwent HIV-1 seroconversion during 1888 person-years of follow-up (4.1 seroconversions per 100 person-years), as compared with 56 in the placebo group who underwent HIV-1 seroconversion during 917 person-years of follow-up (6.1 seroconversions per 100 person-years). The incidence of HIV-1 infection was 31% lower in the dapivirine group than in the placebo group (hazard ratio, 0.69; 95% confidence interval [CI], 0.49 to 0.99; P=0.04). There was no significant difference in efficacy of the dapivirine ring among women older than 21 years of age (hazard ratio for infection, 0.63; 95% CI, 0.41 to 0.97) and those 21 years of age or younger (hazard ratio, 0.85; 95% CI, 0.45 to 1.60; P=0.43 for treatment-by-age interaction). Among participants with HIV-1 infection, nonnucleoside reverse-transcriptase inhibitor resistance mutations were detected in 14 of 77 participants in the dapivirine group (18.2%) and in 9 of 56 (16.1%) in the placebo group. Serious adverse events occurred more often in the dapivirine group (in 38 participants [2.9%]) than in the placebo group (in 6 [0.9%]). However, no clear pattern was identified. CONCLUSIONS: Among women in sub-Saharan Africa, the dapivirine ring was not associated with any safety concerns and was associated with a rate of acquisition of HIV-1 infection that was lower than the rate with placebo. (Funded by the International Partnership for Microbicides; ClinicalTrials.gov number, NCT01539226 .).

Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis.

BACKGROUND: Cryptococcal meningitis associated with human immunodeficiency virus (HIV) infection causes more than 600,000 deaths each year worldwide. Treatment has changed little in 20 years, and there are no imminent new anticryptococcal agents. The use of adjuvant glucocorticoids reduces mortality among patients with other forms of meningitis in some populations, but their use is untested in patients with cryptococcal meningitis. METHODS: In this double-blind, randomized, placebo-controlled trial, we recruited adult patients with HIV-associated cryptococcal meningitis in Vietnam, Thailand, Indonesia, Laos, Uganda, and Malawi. All the patients received either dexamethasone or placebo for 6 weeks, along with combination antifungal therapy with amphotericin B and fluconazole. RESULTS: The trial was stopped for safety reasons after the enrollment of 451 patients. Mortality was 47% in the dexamethasone group and 41% in the placebo group by 10 weeks (hazard ratio in the dexamethasone group, 1.11; 95% confidence interval [CI], 0.84 to 1.47; P=0.45) and 57% and 49%, respectively, by 6 months (hazard ratio, 1.18; 95% CI, 0.91 to 1.53; P=0.20). The percentage of patients with disability at 10 weeks was higher in the dexamethasone group than in the placebo group, with 13% versus 25% having a prespecified good outcome (odds ratio, 0.42; 95% CI, 0.25 to 0.69; P<0.001). Clinical adverse events were more common in the dexamethasone group than in the placebo group (667 vs. 494 events, P=0.01), with more patients in the dexamethasone group having grade 3 or 4 infection (48 vs. 25 patients, P=0.003), renal events (22 vs. 7, P=0.004), and cardiac events (8 vs. 0, P=0.004). Fungal clearance in cerebrospinal fluid was slower in the dexamethasone group. Results were consistent across Asian and African sites. CONCLUSIONS: Dexamethasone did not reduce mortality among patients with HIV-associated cryptococcal meningitis and was associated with more adverse events and disability than was placebo. (Funded by the United Kingdom Department for International Development and others through the Joint Global Health Trials program; Current Controlled Trials number, ISRCTN59144167.).

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.

Acceptability and Predictors of Uptake of Anti-retroviral Pre-exposure Prophylaxis (PrEP) Among Fishing Communities in Uganda: A Cross-Sectional Discrete Choice Experiment Survey.

We used a discrete choice experiment to assess the acceptability and potential uptake of HIV pre-exposure prophylaxis (PrEP) among 713 HIV-negative members of fishing communities in Uganda. Participants were asked to choose between oral pill, injection, implant, condoms, vaginal ring (women), and men circumcision. Product attributes were HIV prevention effectiveness, sexually transmitted infection (STI) prevention, contraception, waiting time, and secrecy of use. Data were analysed using mixed multinomial logit and latent class models. HIV prevention effectiveness was viewed as the most important attribute. Both genders preferred oral PrEP. Women least preferred the vaginal ring and men the implant. Condom use was predicted to decrease by one third among men, and not to change amongst women. Oral PrEP and other new prevention technologies are acceptable among fishing communities and may have substantial demand. Future work should explore utility of multiple product technologies that combine contraception with HIV and other STI prevention.

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.

Linear mixed model for heritability estimation that explicitly addresses environmental variation.

The linear mixed model (LMM) is now routinely used to estimate heritability. Unfortunately, as we demonstrate, LMM estimates of heritability can be inflated when using a standard model. To help reduce this inflation, we used a more general LMM with two random effects-one based on genomic variants and one based on easily measured spatial location as a proxy for environmental effects. We investigated this approach with simulated data and with data from a Uganda cohort of 4,778 individuals for 34 phenotypes including anthropometric indices, blood factors, glycemic control, blood pressure, lipid tests, and liver function tests. For the genomic random effect, we used identity-by-descent estimates from accurately phased genome-wide data. For the environmental random effect, we constructed a covariance matrix based on a Gaussian radial basis function. Across the simulated and Ugandan data, narrow-sense heritability estimates were lower using the more general model. Thus, our approach addresses, in part, the issue of "missing heritability" in the sense that much of the heritability previously thought to be missing was fictional. Software is available at https://github.com/MicrosoftGenomics/FaST-LMM.

Characterization of the Neutralizing Antibody Response in a Case of Genetically Linked HIV Superinfection.

This report describes the identification of a genetically confirmed linked heterosexual human immunodeficiency virus (HIV) superinfection (HIV-SI) in a woman with chronic HIV infection who acquired a second strain of the virus from her husband. Serum neutralizing antibody (NAb) responses against their homologous and heterologous viruses, including the superinfecting strain, in the woman and her husband were examined before and after onset of HIV-SI. The woman displayed a moderately potent and broad anti-HIV NAb response prior to superinfection but did not possess NAb activity against the superinfecting strain. This case highlights the unique potential of linked HIV-SI studies to examine natural protection from HIV infection.

Broadly Neutralizing Antibody Responses in a Large Longitudinal Sub-Saharan HIV Primary Infection Cohort.

Broadly neutralizing antibodies (bnAbs) are thought to be a critical component of a protective HIV vaccine. However, designing vaccines immunogens able to elicit bnAbs has proven unsuccessful to date. Understanding the correlates and immunological mechanisms leading to the development of bnAb responses during natural HIV infection is thus critical to the design of a protective vaccine. The IAVI Protocol C program investigates a large longitudinal cohort of primary HIV-1 infection in Eastern and South Africa. Development of neutralization was evaluated in 439 donors using a 6 cross-clade pseudo-virus panel predictive of neutralization breadth on larger panels. About 15% of individuals developed bnAb responses, essentially between year 2 and year 4 of infection. Statistical analyses revealed no influence of gender, age or geographical origin on the development of neutralization breadth. However, cross-clade neutralization strongly correlated with high viral load as well as with low CD4 T cell counts, subtype-C infection and HLA-A*03(-) genotype. A correlation with high overall plasma IgG levels and anti-Env IgG binding titers was also found. The latter appeared not associated with higher affinity, suggesting a greater diversity of the anti-Env responses in broad neutralizers. Broadly neutralizing activity targeting glycan-dependent epitopes, largely the N332-glycan epitope region, was detected in nearly half of the broad neutralizers while CD4bs and gp41-MPER bnAb responses were only detected in very few individuals. Together the findings suggest that both viral and host factors are critical for the development of bnAbs and that the HIV Env N332-glycan supersite may be a favorable target for vaccine design.

Utility of Different Adherence Measures for PrEP: Patterns and Incremental Value.

Measuring PrEP adherence remains challenging. In 2009-2010, the International AIDS Vaccine Initiative randomized phase II trial participants to daily tenofovir disoproxil fumarate/emtricitabine or placebo in Uganda and Kenya. Adherence was measured by electronic monitoring (EM), self-report (SR), and drug concentrations in plasma and hair. Each adherence measure was categorised as low, moderate, or high and also considered continuously; the incremental value of combining measures was determined. Forty-five participants were followed over 4 months. Discrimination for EM adherence by area under receiver operating curves (AROC) was poor for SR (0.53) and best for hair (AROC 0.85). When combining hair with plasma or hair with self-report, discrimination was improved (AROC > 0.9). Self-reported adherence was of low utility by itself. Hair level was the single best PK measure to predict EM-assessed adherence; the other measurements had lower discrimination values. Combining short-term (plasma) and long-term (hair) metrics could be useful to assess patterns of drug-taking in the context of PrEP.

Factors associated with uptake of home-based HIV counselling and testing and HIV care services among identified HIV-positive persons in Masaka, Uganda.

We investigated uptake of home-based HIV counselling and testing (HBHCT) and HIV care services post-HBHCT in order to inform the design of future HBHCT programmes. We used data from an open-label cluster-randomised controlled trial which had demonstrated the effectiveness of a post-HBHCT counselling intervention in increasing linkage to HIV care. HBHCT was offered to adults (≥18 years) from 28 rural communities in Masaka, Uganda; consenting HIV-positive care naïve individuals were enrolled and referred for care. The trial's primary outcome was linkage to HIV care (clinic-verified registration for care) six months post-HBHCT. Random effects logistic regression was used to investigate factors associated with HBHCT uptake, linkage to care, CD4 count receipt, and antiretroviral therapy (ART) initiation; all analyses of uptake of post-HBHCT services were adjusted for trial arm allocation. Of 13,455 adults offered HBHCT, 12,100 (89.9%) accepted. HBHCT uptake was higher among men [adjusted odds ratio (aOR) 1.20, 95% confidence interval (CI) = 1.07-1.36] than women, and decreased with increasing age. Of 551 (4.6%) persons who tested HIV-positive, 205 (37.2%) were in care. Of those not in care, 302 (87.3%) were enrolled in the trial and of these, 42.1% linked to care, 35.4% received CD4 counts, and 29.8% initiated ART at 6 months post-HBHCT. None of the investigated factors was associated with linkage to care. CD4 count receipt was lower in individuals who lived ≥30 min from an HIV clinic (aOR 0.60, 95%CI = 0.34-1.06) versus those who lived closer. ART initiation was higher in older individuals (≥45 years versus <25 years, aOR 2.14, 95% CI = 0.98-4.65), and lower in single (aOR 0.60, 95% CI = 0.28-1.31) or divorced/separated/widowed (aOR 0.47, 95% CI = 0.23-0.93) individuals versus those married/cohabiting. HBHCT was highly acceptable but uptake of post-HBHCT care was low. Other than post-HBHCT counselling, this study did not identify specific issues that require addressing to further improve linkage to care.

Dynamics and Correlates of CD8 T-Cell Counts in Africans with Primary Human Immunodeficiency Virus Type 1 Infection.

In individuals with HIV-1 infection, depletion of CD4+ T cells is often accompanied by a malfunction of CD8+ T cells that are persistently activated and/or exhausted. While the dynamics and correlates of CD4 counts have been well documented, the same does not apply to CD8 counts. Here, we examined the CD8 counts in a cohort of 497 Africans with primary HIV-1 infection evaluated in monthly to quarterly follow-up visits for up to 3 years in the absence of antiretroviral therapy. Statistical models revealed that (i) CD8 counts were relatively steady in the 3- to 36-month period of infection and similar between men and women; (ii) neither geography nor heterogeneity in the HIV-1 set-point viral load could account for the roughly 10-fold range of CD8 counts in the cohort (P > 0.25 in all tests); and (iii) factors independently associated with relatively high CD8 counts included demographics (age ≤ 40 years, adjusted P = 0.010) and several human leukocyte antigen class I (HLA-I) alleles, including HLA-A*03:01 (P = 0.013), B*15:10 (P = 0.007), and B*58:02 (P < 0.001). Multiple sensitivity analyses provided supporting evidence for these novel relationships. Overall, these findings suggest that factors associated with the CD8 count have little overlap with those previously reported for other HIV-1-related outcome measures, including viral load, CD4 count, and CD4/CD8 ratio. IMPORTANCE: Longitudinal data from 497 HIV-1 seroconverters allowed us to systematically evaluate the dynamics and correlates of CD8+ T-cell counts during untreated primary HIV-1 infection in eastern and southern Africans. Our findings suggest that individuals with certain HLA-I alleles, including A*03 (exclusively A*03:01), persistently maintain relatively high CD8 counts following HIV-1 infection, a finding which may offer an intriguing explanation for the recently reported, negative association of A*03 with HIV-1-specific, broadly neutralizing antibody responses. In future studies, attention to HLA-I genotyping data may benefit in-depth understanding of both cellular and humoral immunity, as well as the intrinsic balances of these types of immunity, especially in settings where there is emerging evidence of antagonism between the two arms of adaptive immunity.

Pregnancy and HIV Disease Progression in an Early Infection Cohort from Five African Countries.

BACKGROUND: Understanding associations between pregnancy and HIV disease progression is critical to provide appropriate counseling and care to HIV-positive women. METHODS: From 2006 to 2011, women less than age 40 with incident HIV infection were enrolled in an early HIV infection cohort in Kenya, Rwanda, South Africa, Uganda, and Zambia. Time-dependent Cox models evaluated associations between pregnancy and HIV disease progression. Clinical progression was defined as a single CD4 measurement <200 cells/µl, percent CD4 <14%, or category C event, with censoring at antiretroviral (ART) initiation for reasons other than prevention of mother-to-child transmission (PMTCT). Immunologic progression was defined as two consecutive CD4s ≤350 cells/µl or a single CD4 ≤350 cells/µl followed by non-PMTCT ART initiation. Generalized estimating equations assessed changes in CD4 before and after pregnancy. RESULTS: Among 222 women, 63 experienced clinical progression during 783.5 person-years at risk (8.0/100). Among 205 women, 87 experienced immunologic progression during 680.1 person-years at risk (12.8/100). The association between pregnancy and clinical progression was adjusted hazard ratio [aHR] = 0.7; 95% confidence interval (CI): 0.2, 1.8. The association between pregnancy and immunologic progression was aHR = 1.7; 95% CI: 0.9, 3.3. Models controlled for age; human leukocyte antigen alleles A*03:01, B*45, B*57; CD4 set point; and HIV-1 subtype. CD4 measurements before versus after pregnancies were not different. CONCLUSIONS: In this cohort, pregnancy was not associated with increased clinical or immunologic HIV progression. Similarly, we did not observe meaningful deleterious associations of pregnancy with CD4s. Our findings suggest that HIV-positive women may become pregnant without harmful health effects occurring during the pregnancy. Evaluation of longer-term impact of pregnancy on progression is warranted.

Linkage to HIV care after home-based HIV counselling and testing in sub-Saharan Africa: a systematic review.

BACKGROUND: Home-based HIV counselling and testing (HBHCT) has the potential to increase HIV testing uptake in sub-Saharan Africa (SSA), but data on linkage to HIV care after HBHCT are scarce. We conducted a systematic review of linkage to care after HBHCT in SSA. METHODS: Five databases were searched for studies published between 1st January 2000 and 19th August 2016 that reported on linkage to care among adults newly identified with HIV infection through HBHCT. Eligible studies were reviewed, assessed for risk of bias and findings summarised using the PRISMA guidelines. RESULTS: A total of 14 studies from six countries met the eligibility criteria; nine used specific strategies (point-of-care CD4 count testing, follow-up counselling, provision of transport funds to clinic and counsellor facilitation of HIV clinic visit) in addition to routine referral to facilitate linkage to care. Time intervals for ascertaining linkage ranged from 1 week to 12 months post-HBHCT. Linkage ranged from 8.2% [95% confidence interval (CI), 6.8-9.8%] to 99.1% (95% CI, 96.9-99.9%). Linkage was generally lower (<33%) if HBHCT was followed by referral only, and higher (>80%) if additional strategies were used. Only one study assessed linkage by means of a randomised trial. Five studies had data on cotrimoxazole (CTX) prophylaxis and 12 on ART eligibility and initiation. CTX uptake among those eligible ranged from 0% to 100%. The proportion of persons eligible for ART ranged from 16.5% (95% CI, 12.1-21.8) to 77.8% (95% CI, 40.0-97.2). ART initiation among those eligible ranged from 14.3% (95% CI, 0.36-57.9%) to 94.9% (95% CI, 91.3-97.4%). Additional linkage strategies, whilst seeming to increase linkage, were not associated with higher uptake of CTX and/or ART. Most of the studies were susceptible to risk of outcome ascertainment bias. A pooled analysis was not performed because of heterogeneity across studies with regard to design, setting and the key variable definitions. CONCLUSION: Only few studies from SSA investigated linkage to care among adults newly diagnosed with HIV through HBHCT. Linkage was often low after routine referral but higher if additional interventions were used to facilitate it. The effectiveness of linkage strategies should be confirmed through randomised controlled trials.

Uptake of hormonal contraceptives and correlates of uptake in a phase III clinical trial in rural South Western Uganda.

BACKGROUND: Use of a reliable contraception method has become an inclusion criterion in prevention trials to minimize time off product. We report on hormonal contraceptive prevalence, uptake, sustained use and correlates of use in the Microbicides Development Programme (MDP 301) trial at the Masaka Centre in Uganda. METHODS: HIV negative women in sero-discordant relationships were enrolled and followed-up for 52 to 104 weeks from 2005 to 2009. Contraceptive use data was collected through self-report at baseline and dispensing records during follow-up. Hormonal contraceptives were promoted and provided to women that were not using a reliable method at enrolment. Baseline contraceptive prevalence, uptake and sustained use were calculated. Uptake was defined as a participant who reported not using a reliable method at enrolment and started using a hormonal method at any time after. Logistic regression models were fitted to investigate predictors of hormonal contraceptive uptake. RESULTS: A total of 840 women were enrolled of whom 21 aged ≥50 years and 12 without follow-up data were excluded; leaving 807 (median age 31 IQR 26-38) in this analysis. At baseline, 228 (28%) reported using a reliable contraceptive; 197 hormonal, 28 female-sterilisation, two IUCD and one hysterectomy. As such 579 were not using a reliable contraceptive at enrolment, of whom 296 (51%) subsequently started using a hormonal contraceptive method; 253 DMPA, four oral pills, and two norplant. Overall 193 (98%) existing users and 262 (88%) new users sustained use throughout follow-up. Independent correlates of hormonal contraceptive uptake were: younger women ≤30 years, aOR = 2.5, 95% CI: 1.7-3.6 and reporting not using contraceptives at baseline due to lack of access or money, breastfeeding or other reasons, in comparison to women who reported using unreliable method. CONCLUSION: Promotion and provision of hormonal contraception doubled the proportion of women using a reliable method of contraception. Uptake was pronounced among younger women and those not previously using a reliable method because of lack of access or money, and breastfeeding. Promotion and provision of hormonal contraceptives in trials that require the interruption or discontinuation of investigational products during pregnancy is important to reduce the time off product. TRIAL REGISTRATION: Protocol Number ISRCTN64716212 .