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Background: A significant minority of people living with HIV (PLWH) achieve viral suppression (VS) on antiretroviral therapy (ART) but do not regain healthy CD4 counts. Clinical factors affecting this immune non-response (INR) and its effect on incident serious non-AIDS events (SNAEs) have been challenging to understand due to confounders that are difficult to control in many study settings. Setting: The U.S. Military HIV Natural History Study (NHS) and African Cohort Study (AFRICOS). Methods: PLWH with sustained VS (Results: INR prevalence was 10.8% and 25.8% in NHS and AFRICOS, respectively. Higher CD4 nadir was associated with decreased odds of INR (aOR=0.31 [95% CI: 0.26, 0.37] and aOR=0.50 [95% CI: 0.43, 0.58] per 100 cells/µl in NHS and AFRICOS, respectively). After adjustment, INR was associated with a 61% increase in relative risk of SNAE [95% CI: 1.12, 2.33]. Probability of "SNAE-free" survival at 15 years since sustained VS was approximately 20% lower comparing those with and without INR; nearly equal to the differences observed by 15-year age groups. Conclusion: CD4 monitoring before and after VS is achieved can help identify PLWH at risk for INR. INR may be a useful clinical indicator of future risk for SNAEs.

Introduction:sub-Saharan Africa bears a high prevalence for hepatitis B virus (HBV) infection. This analysis aims at elucidating the exposure to HBV across different age groups in Mbeya Region in Tanzania and determines prevalences of hepatitis C (HCV) and hepatitis delta antigen (HDV) infections. Methods:plasma samples from children and adults with defined HIV status were analysed for HBV, HCV and HDV markers. Results:hepatitis B (HBs)-antigen positivity was 8.3% (3/36) in the 0 to 5 years age group, 13.3% (8/60) in the 6 to 7 years, 17.2% (10/58) in the 8 to 14 years and 13.3% (8/60) in the 15 to 18 years age groups. In adults 5.0% of samples were HBs-antigen positive. Overall, 17.1% were HIV-1 positive. Adults infected with HIV-1 were significantly more often HBs-antigen positive (7.5%) than HIV-1 negative adults (4.5%; p

Introduction With increased use of antiretroviral therapy (ART), HIV mortality rates are declining and people living with HIV (PLWH) are surviving longer. We characterized CD4 recovery and viral suppression among adults aged Methods Beginning in January 2013, PLWH at twelve clinics in Kenya, Uganda, Tanzania and Nigeria underwent medical history review, CD4 and viral load testing as part of the ongoing African Cohort Study (AFRICOS). ART-naïve PLWH who initiated ART within 30 days of enrollment and had at least one year of follow-up were included in these analyses. To compare ART response in participants Results Between January 2013 and September 2019, 2918 PLHV were enrolled in the cohort. Of these, 443 were ART naïve and initiated on ART within 30 days of enrollment, with 90% (n = 399) aged 3, IQR:130–547 vs. 277cells/mm3, IQR: 132–437). In adjusted models examining CD4 recovery and viral suppression there were no significant differences by age group over time. By the end of follow-up viral suppression was high among both groups of adults (96% of adults ≥ 50 years old and 92% of adults Conclusion This study found no difference in long-term CD4 recovery or viral suppression by age at ART initiation. We found that particularly among younger adults participants had lower median CD4 counts at ART initiation, suggesting the importance of identifying and putting this population on treatment earlier in the disease course.

Washington, DC, and sub-Saharan Africa are both affected by generalized HIV epidemics. However, care for persons living with HIV (PLWH) and clinical outcomes may differ in these geographically and culturally diverse areas. We compared patient and clinical site characteristics among adult persons living with HIV (PLWH) enrolled in two longitudinal HIV cohort studies-the African Cohort Study (AFRICOS) and the DC Cohort.The DC Cohort is a clinic-based city-wide longitudinal cohort comprised of PLWH attending 15 HIV clinics in Washington, DC. Patients' socio-demographic characteristics, clinical evaluations, and laboratory data are retrospectively collected from electronic medical records and limited manual chart abstraction. AFRICOS is a prospective observational cohort of PLWH and uninfected volunteers attending 12 select HIV care and treatment facilities in Nigeria, Kenya, Uganda and Tanzania. AFRICOS study participants are a subset of clinic patients who complete protocol-specific visits every 6 months with history and physical examination, questionnaire administration, and blood/sputum collection for ascertainment of HIV outcomes and comorbidities, and neurocognitive and functional assessments. Among participants aged ≥ 18 years, we generated descriptive statistics for demographic and clinical characteristics at enrollment and follow up and compared them using bivariable analyses.The study sample included 2,774 AFRICOS and 8,420 DC Cohort participants who enrolled from January 2013 (AFRICOS)/January 2011 (DC Cohort) through March 2018. AFRICOS participants were significantly more likely to be women (58.8% vs 27.1%) and younger (83.3% vs 61.1% aged50 years old) and significantly less likely to be MSM (only 0.1% of AFRICOS population reported MSM risk factor) than DC Cohort. Similar rates of current viral suppression (about 75% of both samples), hypertension, hepatitis B coinfection and alcohol use were observed. However, AFRICOS participants had significantly higher rates of CD4200 and tuberculosis and significantly lower rates of obesity, DM, hepatitis C coinfection and syphilis.With similar viral suppression outcomes, but many differences between our cohorts noted, the combined sample provides unique opportunities to assess and compare HIV care and treatment outcomes in the U.S. and sub-Saharan Africa. Comparing these two cohorts may inform care and treatment practices and may pave the way for future pathophysiologic analyses.

Schistosomiasis is a leading cause of morbidity in Africa. Understanding the disease ecology and environmental factors that influence its distribution is important to guide control efforts. Geographic information systems have increasingly been used in the field of schistosomiasis environmental epidemiology. This study reports prevalences of Schistosoma haematobium infection and uses remotely sensed and questionnaire data from over 17000 participants to identify environmental and socio-demographic factors that are associated with this parasitic infection. Data regarding socio-demographic status and S. haematobium infection were obtained between May 2006 and May 2007 from 17280 participants (53% females, median age = 17 years) in the Mbeya Region, Tanzania. Combined with remotely sensed environmental data (vegetation cover, altitude, rainfall etc.) this data was analyzed to identify environmental and socio-demographic factors associated with S. haematobium infection, using mixed effects logistic regression and geostatistical modelling. The overall prevalence of S. haematobium infection was 5.3% (95% confidence interval (CI): 5.0–5.6%). Multivariable analysis revealed increased odds of infection for school-aged children (5–15 years, odds ratio (OR) = 7.8, CI: 5.9–10.4) and the age groups 15–25 and 25–35 years (15–25 years: OR = 5.8, CI: 4.3–8.0, 25–35 years: OR = 1.6, CI: 1.1–2.4) compared to persons above 35 years of age, for increasing distance to water courses (OR = 1.4, CI: 1.2–1.6 per km) and for proximity to Lake Nyasa (4 km. Odds of infection decreased with higher altitude (OR = 0.7, CI: 0.6–0.8 per 100 m increase) and with increasing enhanced vegetation index EVI (OR = 0.2, CI: 0.1–0.4 per 0.1 units). When additionally adjusting for spatial correlation population density became a significant predictor of schistosomiasis infection (OR = 1.3, CI: 1.1–1.5 per 1000 persons/km2) and altitude turned non-significant. We found highly focal geographical patterns of S. haematobium infection in Mbeya Region in Southwestern Tanzania. Despite low overall prevalence our spatially heterogeneous results show that some of the study sites suffer from a considerable burden of S. haematobium infection, which is related to various socio-demographic and environmental factors. Our results could help to design more effective control strategies in the future, especially targeting school-aged children living in low altitude sites and/or crowded areas as the persons at highest need for preventive chemotherapy., Author summary Urinary schistosomiasis caused by the parasitic blood fluke Schistosoma haematobium is an important public health concern in the tropics and subtropics. Freshwater snails of the genus Bulinus are the intermediate hosts and infection is acquired by contact with fresh water inhabited by infected snails. This means that transmission of the parasite strongly depends on environmental factors, which we wanted to explore in this study. Individually assessed questionnaire and laboratory data from a study in Mbeya Region in Southwestern Tanzania were combined with remotely sensed and other environmental data that were publicly available. We found that the odds of urinary schistosomiasis were higher in school-aged children and young adults than in older age groups and in children below 5 years. Odds of infection were also higher at lower altitudes, in areas with less vegetation and in the vicinity of Lake Nyasa. These results add to the general knowledge regarding S. haematobium infection and could help to design more effective control strategies in the future, both locally and on larger scales.

Consistent condom use is an inexpensive and efficacious HIV prevention strategy. Understanding factors associated with condom use and barriers to use can inform strategies to increase condom uptake. The ongoing African Cohort Study prospectively enrolls adults at 12 clinical sites in Uganda, Kenya, Tanzania, and Nigeria. At enrollment, participants are asked about condom use at last sex with a regular partner. Robust Poisson regression models were used to evaluate predictors of self-reported condom use. Participants who reported not using condoms were asked to provide reasons. From January 2013 to September 2019, 2482 participants reported having at least one regular sexual partner in the preceding 6 months. Of those, 1577 (63.5%) reported using a condom at last sex. Condom use was more common among older participants, males, HIV-infected participants, and those with an HIV-infected partner. Married participants, those with a partner of unknown HIV status, and those reporting alcohol use were less likely to report condom use at last sex. Condom use at last sex also varied significantly by clinical site. Partner disapproval or refusal to use a condom was a consistent driver of disparities in condom use among participants who were HIV infected, female, and aged 18-24 years. Effective HIV prevention programs should integrate condom education with the tools necessary to negotiate condom use with regular partners.

Most HIV-1 infected individuals do not know their infection dates. Precise infection timing is crucial information for studies that document transmission networks or drug levels at infection. To improve infection timing, we used the prospective RV217 cohort where the window when plasma viremia becomes detectable is narrow: the last negative visit occurred a median of four days before the first detectable HIV-1 viremia with an RNA test, referred below as diagnosis. We sequenced 1,280 HIV-1 genomes from 39 participants at a median of 4, 32 and 170 days post-diagnosis. HIV-1 infections were dated by using sequence-based methods and a viral load regression method. Bayesian coalescent and viral load regression estimated that infections occurred a median of 6 days prior to diagnosis (IQR: 9–3 and 11–4 days prior, respectively). Poisson-Fitter, which analyzes the distribution of hamming distances among sequences, estimated a median of 7 days prior to diagnosis (IQR: 15–4 days) based on sequences sampled 4 days post-diagnosis, but it did not yield plausible results using sequences sampled at 32 days. Fourteen participants reported a high-risk exposure event at a median of 8 days prior to diagnosis (IQR: 12 to 6 days prior). These different methods concurred that HIV-1 infection occurred about a week before detectable viremia, corresponding to 20 days (IQR: 34–15 days) before peak viral load. Together, our methods comparison helps define a framework for future dating studies in early HIV-1 infection., Author summary HIV-1 infected individuals rarely know when they became infected but knowing when an infection occurred provides critical information regarding HIV-1 pathogenesis and epidemiology. Using a unique cohort in which infection was known to have occurred in a narrow interval, we investigated methods to estimate the timing of infections. Several methods suggested that HIV-1 infection typically occurs a median of one week before the infection can be detected by HIV-1 RNA testing. Going forward, we provide a strategy that can be used to elucidate the origin of an acute/early infection.

Early identification of confirmed virological failure is paramount to avoid accumulation of drug resistance in patients on antiretroviral therapy (ART). Scale-up of HIV-RNA monitoring in Africa and timely switch to second-line regimens are challenged.A WHO adapted confirmed virological treatment screening algorithm (HIV-RNA screening, enhanced adherence counselling, confirmatory HIV-RNA testing) was evaluated in HIV-infected patients on first-line ART from Tanzania. The main endpoints included viral resuppression and virological failure rates, retention and turnaround time of the screening algorithm until second-line ART initiation. Secondary endpoints included risk factors for virological treatment failure and patterns of genotypic drug resistance.HIV-RNA1000 copies/ml at first screening was detected in 58/356 (16.3%) patients (median time-on-treatment 6.3 years, 25% immunological treatment failure). Adjusted risk factors for virological failure were age30 years (RR 5.2 [95% CI: 2.5-10.8]), years on ART ≥3 years (RR 3.0 [1.0-8.9]), CD4-counts200 cells/µl (RR 9.3 [4.0-21.8]) and poor self-reported treatment adherence (RR 2.0 [1.2-3.4]). Resuppression of HIV-RNA1000 copies/ml was observed in 5/50 (10%) cases after enhanced adherence counselling. Confirmatory testing within 3 months was performed in only 46.6% and switch to second-line ART within 6 months in 60.4% of patients. Major NNRTI-mutation were detected in all of 30 patients, NRTI mutations in 96.7% and ≥3 thymidine-analogue mutations in 40%. No remaining NRTI options were predicted in 57% and limited susceptibility in 23% of patients.We observed low levels of viral resuppression following adherence counselling, associated with high levels of accumulated drug resistance. High visit burden and turnaround times for confirmed virological failure diagnosis further delayed switching to second-line treatment which could be improved using novel point-of-care viral load monitoring systems.L'identification précoce de l'échec virologique confirmé est primordiale pour éviter l'accumulation de résistance aux médicaments chez les patients sous traitement antirétroviral (ART). L'intensification du suivi de l'ARN du VIH en Afrique et le passage en temps opportun aux schémas thérapeutiques de deuxième intention sont adressés. MÉTHODES: Nous avons évalué un algorithme adapté de l’OMS confirmé pour le dépistage du traitement virologique (dépistage de l'ARN du VIH, adhésion renforcée du conseil, test de confirmation de l'ARN du VIH) chez des patients infectés par le VIH sous ART de première intention en Tanzanie. Les critères principaux comprenaient la répression virale et les taux d’échec virologique, la rétention et et la durée de rotation de l'algorithme de dépistage jusqu'à l'initiation de l’ART de deuxième ligne. Les critères d'évaluation secondaires comprenaient les facteurs de risque d'échec du traitement virologique et les profils de résistance génotypique aux médicaments. RÉSULTATS: Un ARN-VIH1000 copies/ml au premier dépistage a été détecté chez 58/356 (16,3%) patients (durée médiane de traitement de 6,3 ans, 25% d'échec immunologique du traitement). Les facteurs de risque ajustés pour l'échec virologique étaient l'âge30 ans (RR: 5,2 [IC95%: 2,5-10,8]), les années sous ART ≥3 ans (RR: 3,0 [1,0-8,9]), la numération des CD4200 cellules/µL (RR: 9,3 [4,0-21,8]) et une mauvaise compliance au traitement autodéclarée (RR: 2,0 [1,2-3,4]). Une re-suppression du VIH-ARN1000 copies/mL a été observée chez 5/50 (10%) des cas après renforcement du conseil pour la compliance. Un test de confirmation dans les 3 mois n'a été réalisé que dans 46,6% des cas et le passage à l’ART de deuxième ligne dans les 6 mois chez 60,4% des patients. Des mutations NNRTI majeures ont été détectées chez tous les 30 patients, des mutations NRTI chez 96,7% et ≥3 mutations analogues à la thymidine chez 40%. Aucune option NRTI restante n'a été prévue chez 57% des cas et une sensibilité limitée chez 23% des patients.Nous avons observé de faibles taux de re-suppression virale après des conseils d'adhésion, associés à des taux élevés de résistance accumulée aux médicaments. La charge élevée des visites et les délais de rotation pour le diagnostic confirmé d'échec virologique ont retardé le passage au traitement de deuxième intention, ce qui pourrait être amélioré à l'aide de nouveaux systèmes de surveillance de la charge virale au point des soins.

Background DNA plasmids promise a pragmatic alternative to viral vectors for prime-boost HIV-1 vaccines. We evaluated DNA plasmid versus canarypox virus (ALVAC) primes in 2 randomized, double-blind, placebo-controlled trials in southern Africa with harmonized trial designs. HIV Vaccine Trials Network (HVTN) 111 tested DNA plasmid prime by needle or needleless injection device (Biojector) and DNA plasmid plus gp120 protein plus MF59 adjuvant boost. HVTN 100 tested ALVAC prime and ALVAC plus gp120 protein plus MF59 adjuvant boost (same protein/adjuvant as HVTN 111) by needle. Methods and findings The primary endpoints for this analysis were binding antibody (bAb) responses to HIV antigens (gp120 from strains ZM96, 1086, and TV1; variable 1 and 2 [V1V2] regions of gp120 from strains TV1, 1086, and B.CaseA, as 1086 V1V2 and B.CaseA were correlates of risk in the RV144 efficacy trial), neutralizing antibody (nAb) responses to pseudoviruses TV1c8.2 and MW925.26, and cellular responses to vaccine-matched antigens (envelope [Env] from strains ZM96, 1086, and TV1; and Gag from strains LAI and ZM96) at month 6.5, two weeks after the fourth vaccination. Per-protocol cohorts included vaccine recipients from HVTN 100 (n = 186, 60% male, median age 23 years) enrolled between February 9, 2015, and May 26, 2015 and from HVTN 111 (n = 56, 48% male, median age 24 years) enrolled between June 21, 2016, and July 13, 2017. IgG bAb response rates were 100% to 3 Env gp120 antigens in both trials. Response rates to V1V2 were lower and similar in both trials except to vaccine-matched 1086 V1V2, with rates significantly higher for the DNA-primed regimen than the ALVAC-primed regimen: 96.6% versus 72.7% (difference = 23.9%, 95% CI 15.6%–32.2%, p < 0.001). Among positive responders, bAb net mean fluorescence intensity (MFI) was significantly higher with the DNA-primed regimen than ALVAC-primed for 1086 V1V2 (geometric mean [GM] 2,833.3 versus 1,200.9; ratio = 2.36, 95% CI 1.42–3.92, p < 0.001) and B.CaseA V1V2 (GM 2314.0 versus 744.6, ratio = 3.11, 95% CI 1.51–6.38, p = 0.002). nAb response rates were >98% in both trials, with significantly higher 50% inhibitory dilution (ID50) among DNA-primed positive responders (n = 53) versus ALVAC-primed (n = 182) to tier 1A MW965.26 (GM 577.7 versus 265.7, ratio = 2.17, 95% CI 1.67–2.83, p < 0.001) and to TV1c8.2 (GM 187.3 versus 100.4, ratio = 1.87, 95% CI 1.48–2.35, p < 0.001). CD4+ T-cell response rates were significantly higher with DNA plasmid prime via Biojector than ALVAC prime (91.4% versus 52.8%, difference = 38.6%, 95% CI 20.5%–56.6%, p < 0.001 for ZM96.C; 88.0% versus 43.1%, difference = 44.9%, 95% CI 26.7%–63.1%, p < 0.001 for 1086.C; 55.5% versus 2.2%, difference = 53.3%, 95% CI 23.9%–82.7%, p < 0.001 for Gag LAI/ZM96). The study’s main limitations include the nonrandomized comparison of vaccines from 2 different trials, the lack of data on immune responses to other non–vaccine-matched antigens, and the uncertain clinical significance of the observed immunological effects. Conclusions In this study, we found that further investigation of DNA/protein regimens is warranted given enhanced immunogenicity to the V1V2 correlates of decreased HIV-1 acquisition risk identified in RV144, the only HIV vaccine trial to date to show any efficacy., Zoe Moodie and co-workers study immunological responses with DNA priming in trials of a candidate HIV vaccine., Author summary Why was this study done? HIV remains a major global health problem, especially in sub-Saharan Africa. Developing an efficacious HIV vaccine for subtype C infections, which predominate in southern Africa, is a high priority. Comparing immune responses after DNA plasmid versus viral vector priming in 2 similar subtype C HIV vaccine regimens could help inform the choice of priming strategy to use moving forward. DNA plasmid vaccines are cost-effective, easy to manufacture, and tolerable. What did the researchers do and find? We compared antibody and cellular immune responses to two phase I/II HIV-1 vaccines that differed in their priming mechanism (canarypox virus [ALVAC] vector versus DNA) but were matched in their protein boost and adjuvant. Specifically, we measured T-cell and binding and neutralizing antibody (nAb) responses to the vaccine-matched antigens from the HIV Vaccine Trials Network (HVTN) 100 and HVTN 111 trials. The vaccine regimens with DNA plasmid priming in general stimulated higher binding antibody (bAb) response magnitudes to the variable 1 and 2 (V1V2) correlates of decreased risk in RV144 and higher neutralizing responses to tier 1 viruses than the vaccine regimen with ALVAC priming. Both regimens stimulated high binding and neutralizing response rates, while DNA plasmid priming with MF59 adjuvanted protein boost induced significantly higher CD4+ T-cell response rates than ALVAC priming with MF59 adjuvanted protein boost. What do these findings mean? Our results suggest that DNA plasmid is a superior priming method for stimulating vaccine-matched humoral and cellular responses for HIV vaccine trials using this prime/boost approach. Additional investigations are warranted to optimize DNA plasmid delivery methods, such as electroporation for priming of DNA–protein combinations.

Background The Pox-Protein Public-Private Partnership is performing a suite of trials to evaluate the bivalent subtype C envelope protein (TV1.C and 1086.C glycoprotein 120) vaccine in the context of different adjuvants and priming agents for human immunodeficiency virus (HIV) type 1 (HIV-1) prevention. Methods In the HIV Vaccine Trials Network 111 trial, we compared the safety and immunogenicity of DNA prime followed by DNA/protein boost with DNA/protein coadministration injected intramuscularly via either needle/syringe or a needle-free injection device (Biojector). One hundred thirty-two healthy, HIV-1–uninfected adults were enrolled from Zambia, South Africa, and Tanzania and were randomized to 1 of 6 arms: DNA prime, protein boost by needle/syringe; DNA and protein coadministration by needle/syringe; placebo by needle/syringe; DNA prime, protein boost with DNA given by Biojector; DNA and protein coadministration with DNA given by Biojector; and placebo by Biojector. Results All vaccinations were safe and well tolerated. DNA and protein coadministration was associated with increased HIV-1 V1/V2 antibody response rate, a known correlate of decreased HIV-1 infection risk. DNA administration by Biojector elicited significantly higher CD4+ T-cell response rates to HIV envelope protein than administration by needle/syringe in the prime/boost regimen (85.7% vs 55.6%; P = .02), but not in the coadministration regimen (43.3% vs 48.3%; P = .61). Conclusions Both the prime/boost and coadministration regimens are safe and may be promising for advancement into efficacy trials depending on whether cellular or humoral responses are desired. Clinical Trials Registration South African National Clinical Trials Registry (application 3947; Department of Health [DoH] no. DOH-27–0715–4917) and ClinicalTrials.gov (NCT02997969)., DNA and protein coadministration was associated with increased human immunodeficiency virus (HIV) type 1 V1/V2 antibody response. Biojector DNA administration elicited significantly greater CD4+ T-cell responses to HIV envelope protein than needle/syringe in the prime/boost but not the coadministration regimen.

Background Susceptibility to HIV has been linked to systemic CD4+ T cell activation in cohorts of seronegative individuals with high HIV-exposure risk. We recently described an increased risk of HIV transmission in individuals infected with Wuchereria bancrofti, the causative agent for lymphatic filariasis, in a prospective cohort study. However, the reason for this phenomenon needs further investigation. Methodology/Principal findings Two-hundred and thirty-five HIV negative adults were tested using Trop Bio ELISA for detection of W. bancrofti infection and Kato Katz urine filtration and stool based RT-PCR for detection of soil transmitted helminths and schistosomiasis. FACS analysis of the fresh peripheral whole blood was used to measure T cell activation markers (HLA-DR, CD38), differentiation markers (CD45, CD27), markers for regulatory T cells (FoxP3, CD25) and the HIV entry receptor CCR5. Frequencies of activated HLA-DRpos CD4 T cells were significantly increased in subjects with W. bancrofti infection (n = 33 median: 10.71%) compared to subjects without any helminth infection (n = 42, median 6.97%, p = 0.011) or those with other helminths (Schistosoma haematobium, S. mansoni, Trichuris trichiura, Ascaris lumbricoides, hookworm) (n = 151, median 7.38%, p = 0.009). Similarly, a significant increase in HLA-DRposCD38pos CD4 T cells and effector memory cells CD4 T cells (CD45ROposCD27neg) was observed in filarial infected participants. Multivariable analyses further confirmed a link between W. bancrofti infection and systemic activation of CD4 T cells independent of age, fever, gender or other helminth infections. Conclusions/Significance W. bancrofti infection is linked to systemic CD4 T cell activation, which may contribute to the increased susceptibility of W. bancrofti infected individuals to HIV infection., Author summary The importance of CD4 T cell activation for HIV susceptibility has been emphasized in several studies focusing on HIV transmission and prevention. Particularly, activated HLA-DR+ CD4 T cells may play a major role in HIV susceptibility. In this analysis we describe systemic activation of CD4 T cells in individuals infected with W. bancrofti the causative agent of lymphatic filariasis. This helminth disease leads to debilitating pathology in some of the individuals; however, the majority of infected persons remain asymptomatic. We recently described an increased HIV incidence in subjects infected with W. bancrofti compared to uninfected individuals from the same area. To decipher underlying reasons for this phenomenon, we measured immune activation parameters in CD4 and CD8 T cells. The increased percentage of HLADR positive and HLADR/CD38 positive CD4 T cells and also effector memory CD4 T cells that we describe here could be a possible mechanism to explain our previous findings of increased HIV incidence in individuals infected with this filarial nematode.

BackgroundNoninfectious comorbid diseases (NCDs) contribute to morbidity and mortality in human immunodeficiency virus (HIV)–infected populations in resource-rich countries. With antiretroviral therapy (ART) scale-up in Africa, understanding burden NCD informs public health strategy.MethodsAt enrollment, participants at 11 HIV clinics in Kenya, Uganda, Tanzania, and Nigeria underwent medical history, physical, laboratory, and neuropsychological assessments to identify elevated blood pressure, hypercholesterolemia, dysglycemia, renal insufficiency, and cognitive impairment. Poisson regression models estimated adjusted relative risks (ARRs) and 95% confidence intervals (CIs) for the number of NCDs associated with factors of interest. Logistic regression was used to evaluate each NCD separately among HIV-infected participants.ResultsAmong 2720 participants with complete NCD data, 2159 (79.4%) were HIV-infected. Of those, 1426 (66.0%) were taking ART and 813 (37.7%) had at least 1 NCD. HIV infection was associated with more NCDs, especially with ART (ARR, 1.42; 95% CI, 1.22–1.66). In addition to age, body mass index, and program site, ART usage was associated with more NCDs (ARR, 1.50; 95% CI, 1.27–1.78 for virologically suppressed and ARR, 1.38; 95% CI, 1.13–1.68 for viremic) among HIV-infected participants. In participants taking ART, CD4 nadir below 200 cells/mm3 was associated with more NCDs (ARR, 1.43; 95% CI, 1.06–1.93). ART use was independently associated with hypercholesterolemia and dysglycemia. Program site was significantly associated with all comorbidities except renal insufficiency.ConclusionsHIV infection was a risk for NCDs, which were common in HIV-infected participants, geographically variable, and largely consistent with metabolic complications of first-line ART.

Background World Health Organization (WHO) guidelines identify human immunodeficiency virus (HIV) viral load Methods The African Cohort Study enrolled HIV-infected adults at clinics in Uganda, Kenya, Tanzania, and Nigeria, with assessments every 6 months. We evaluated participants prescribed ART for at least 6 months without virologic failure for pLLV. We used multinomial logistic regression to evaluate associations between prespecified factors of interest and 3 levels of pLLV ( Results We included 1511 participants with 4382 person-years of follow-up. PLLV Conclusions Participants with pLLV ≥200 copies/mL were at increased risk of subsequent virologic failure. Optimized HIV care in this setting should target viral suppression

In order to inform the rational design of HIV-1 preventive and cure interventions it is critical to understand the events occurring during acute HIV-1 infection (AHI). Using viral deep sequencing on six participants from the early capture acute infection RV217 cohort, we have studied HIV-1 evolution in plasma collected twice weekly during the first weeks following the advent of viremia. The analysis of infections established by multiple transmitted/founder (T/F) viruses revealed novel viral profiles that included: a) the low-level persistence of minor T/F variants, b) the rapid replacement of the major T/F by a minor T/F, and c) an initial expansion of the minor T/F followed by a quick collapse of the same minor T/F to low frequency. In most participants, cytotoxic T-lymphocyte (CTL) escape was first detected at the end of peak viremia downslope, proceeded at higher rates than previously measured in HIV-1 infection, and usually occurred through the exploration of multiple mutational pathways within an epitope. The rapid emergence of CTL escape variants suggests a strong and early CTL response. Minor T/F viral strains can contribute to rapid and varied profiles of HIV-1 quasispecies evolution during AHI. Overall, our results demonstrate that early, deep, and frequent sampling is needed to investigate viral/host interaction during AHI, which could help identify prerequisites for prevention and cure of HIV-1 infection., Author summary The development of safe, effective, and scalable vaccines and cure strategies to control the HIV-1 pandemic is a major public health concern. The rational design of these preventive and treatment measures requires a profound knowledge of the interaction between HIV-1 and its host during the first weeks that follow viral infection (i.e., acute infection). Here we performed a systematic and in-depth study of individuals whose infection was detected before peak viremia and before the emergence of the first antibody responses. Plasma samples were collected twice weekly during acute infection and we performed next-generation sequencing of the viral swarms. In most participants, we first detected viral escape from the initial adaptive cellular immune responses at the end of peak viremia downslope. Viral escape proceeded at higher rates than previously measured in HIV-1 infection and usually through the exploration of multiple mutational pathways. The analysis of sequences from infections established by multiple viral lineages revealed dramatic shifts in the frequencies of the viruses that composed the HIV-1 population within each host. These results, using early, deep, and frequent sampling, support rapidly changing viral lineages likely in response to both adaptive cellular immunity and possibly other host responses during acute HIV-1 infection.

Supplemental Digital Content is available in the text, Objective: Use of zidovudine (ZDV) in antiretroviral therapy is limited by toxicity and twice daily (b.i.d.) dosing. Fozivudine (FZD) is a ZDV prodrug, which is activated intracellularly to ZDV-monophosphate especially in mononuclear cells but not in bone marrow cells. FZD promises improved myelotoxicity and once daily (o.d.) dosing. Design: Randomized clinical trial. Methods: We conducted an open-label, phase II, proof-of-concept trial investigating three different FZD doses (800 mg o.d., 600 mg b.i.d., 1200 mg o.d.) versus ZDV (300 mg b.i.d.) in combination with lamivudine and efavirenz in HIV-infected, ART-naive patients from Tanzania and Côte d’Ivoire. The primary objective was to demonstrate virological efficacy after 24 weeks in intent-to treat and per-protocol analysis. Secondary endpoints included safety and pharmacokinetic outcomes. Results: Of 119 participants included in the intent-to treat analysis, HIV RNA less than 50 copies/ml at 24 weeks was observed in 64 of 88 (73%) patients in the combined FZD arms versus 24 of 31 (77%) in the ZDV arm (RR 0.94, 95% confidence interval 0.75–1.18). In the per-protocol analysis, responses were 64 of 77 (87%) versus 23 of 29 (79%), respectively (RR 1.09, 95% confidence interval 0.89–1.34). Outcomes were similar between FZD arms. Overall, treatments were well tolerated. Severe or worse anaemia occurred in two cases (one related to FZD, one to ZDV), grade III/IV neutropenia was less frequent in FZD compared with ZDV arms (22 versus 42%, P = 0.035). Pharmacokinetic analysis supported o.d. administration of FZD. Conclusion: Virological 24-week efficacy was demonstrated in b.i.d. and o.d. administered FZD-based regimens. Reduced myelotoxicity of FZD needs to be confirmed in a larger trial.

The loss of HIV-specific CD8+ T cell cytolytic function is a primary factor underlying progressive HIV infection, but whether HIV-specific CD8+ T cells initially possess cytolytic effector capacity, and when and why this may be lost during infection, is unclear. Here, we assessed CD8+ T cell functional evolution from primary to chronic HIV infection. We observed a profound expansion of perforin+ CD8+ T cells immediately following HIV infection that quickly waned after acute viremia resolution. Selective expression of the effector-associated transcription factors T-bet and eomesodermin in cytokine-producing HIV-specific CD8+ T cells differentiated HIV-specific from bulk memory CD8+ T cell effector expansion. As infection progressed expression of perforin was maintained in HIV-specific CD8+ T cells with high levels of T-bet, but not necessarily in the population of T-betLo HIV-specific CD8+ T cells that expand as infection progresses. Together, these data demonstrate that while HIV-specific CD8+ T cells in acute HIV infection initially possess cytolytic potential, progressive transcriptional dysregulation leads to the reduced CD8+ T cell perforin expression characteristic of chronic HIV infection., Author Summary Previous studies have demonstrated that HIV-specific CD8+ T cells are critical for the initial control of HIV infection. However, this control is typically incomplete, being able to neither clear infection nor maintain plasma viremia below undetectable levels. Mounting evidence has implicated CD8+ T cell cytotoxic capacity as a critical component of the HIV-specific response associated with spontaneous long-term control of HIV replication. CD8+ T cell cytotoxic responses are largely absent in the vast majority of HIV chronically infected individuals and it is unclear when or why this functionality is lost. In this study we show that HIV-specific CD8+ T cells readily express the cytolytic protein perforin during the acute phase of chronic progressive HIV infection but rapidly lose the ability to upregulate this molecule following resolution of peak viremia. Maintenance of perforin expression by HIV-specific CD8+ T cells appears to be associated with the expression level of the transcription factor T-bet, but not with the T-bet paralogue, Eomes. These findings further delineate qualitative attributes of CD8+ T cell-mediated immunity that may serve as targets for future HIV vaccine and therapeutic research.

Summary Background The past decades have seen an ongoing controversial debate about whether the immune activation induced by helminths has an effect on the susceptibility of individuals to HIV. In view of this, we assessed the effect of lymphatic filariasis, a chronic helminth disease elicited by Wuchereria bancrofti , on HIV incidence in southwest Tanzania. Methods In this population-based cohort study, we enrolled a geographically stratified randomly chosen sample of about 10% of the households in nine distinct sites in southwest Tanzania. All household members present were followed up and tested for HIV and circulating filarial antigen, an indicator of W bancrofti adult worm burden. Our main outcome of interest was HIV incidence in participants with or without lymphatic filariasis. Findings Between May 29, 2006, and June 16, 2011, we enrolled 4283 households with roughly 18 000 participants. Of these, 2699 individuals from Kyela district participated in at least one round of the EMINI study. In the 1055 initially HIV-negative adolescents and adults with clearly defined lymphatic filariasis status, 32 new HIV infections were observed in 2626 person-years. HIV incidence in lymphatic filariasis-positive participants (1·91 cases per 100 person-years) was significantly higher than the incidence in lymphatic filariasis-negative participants (0·80 cases per 100 person-years). The age-adjusted and sex-adjusted incidence rate ratio was 2·17 (95% CI 1·08–4·37, p=0·0300). Lymphatic filariasis status remained an independent and significantly relevant risk factor for HIV infection when controlled for other known risk factors such as sexual behaviour and socioeconomic factors. Interpretation To our knowledge, this is the first prospective study demonstrating a significantly increased risk of acquiring HIV for lymphatic filariasis-infected individuals. Immunological studies and interventional treatment studies that eliminate the adult worms and not only the microfilariae are needed to follow up on the results presented. Funding European Union as part of EuropAid; German Federal Ministry of Education and Research; German Center for Infection Research.

Introduction The 2016 WHO consolidated guidelines on the use of antiretroviral drugs defines HIV virologic failure for low and middle income countries (LMIC) as plasma HIV-RNA ≥ 1000 copies/mL. We evaluated virologic failure and predictors in four African countries. Materials and methods We included HIV-infected participants on a WHO recommended antiretroviral therapy (ART) regimen and enrolled in the African Cohort Study between January 2013 and October 2017. Studied outcomes were virologic failure (plasma HIV-RNA ≥ 1000 copies/mL at the most recent visit), viraemia (plasma HIV-RNA ≥ 50 copies/mL at the most recent visit); and persistent viraemia (plasma HIV-RNA ≥ 50 copies/mL at two consecutive visits). Generalized linear models were used to estimate relative risks with their 95% confidence intervals. Results 2054 participants were included in this analysis. Viraemia, persistent viraemia and virologic failure were observed in 396 (19.3%), 160 (7.8%) and 184 (9%) participants respectively. Of the participants with persistent viraemia, only 57.5% (92/160) had confirmed virologic failure. In the multivariate analysis, attending clinical care site other than the Uganda sitebeing on 2nd line ART (aRR 1.8, 95% CI 1·28–2·66); other ART combinations not first line and not second line (aRR 3.8, 95% CI 1.18–11.9), a history of fever in the past week (aRR 3.7, 95% CI 1.69–8.05), low CD4 count (aRR 6.9, 95% CI 4.7–10.2) and missing any day of ART (aRR 1·8, 95% CI 1·27–2.57) increased the risk of virologic failure. Being on 2nd line therapy, the site where one receives care and CD4 count < 500 predicted viraemia, persistent viraemia and virologic failure. Conclusion In conclusion, these findings demonstrate that HIV-infected patients established on ART for more than six months in the African setting frequently experienced viraemia while continuing to be on ART. The findings also show that being on second line, low CD4 count, missing any day of ART and history of fever in the past week remain important predictors of virologic failure that should trigger intensified adherence counselling especially in the absence of reliable or readily available viral load monitoring. Finally, clinical care sites are different calling for further analyses to elucidate on the unique features of these sites.

Attrition within the CD4 + T cell compartment, high viremia, and a cytokine storm characterize the early days after HIV infection. When the first emerging HIV-specific CD8 + T cell responses gain control over viral replication it is incomplete, and clearance of HIV infection is not achieved even in the rare cases of individuals who spontaneously control viral replication to nearly immeasurably low levels. Thus, despite their partial ability to control viremia, HIV-specific CD8 + T cell responses are insufficient to clear HIV infection. Studying individuals in the first few days of acute HIV infection, we detected the emergence of a unique population of CD38 + CD27 − CD8 + T cells characterized by the low expression of the CD8 receptor (CD8 dim ). Interestingly, while high frequencies of HIV-specific CD8 + T cell responses occur within the CD38 + CD27 − CD8 dim T cell population, the minority populations of CD8 bright T cells are significantly more effective in inhibiting HIV replication. Furthermore, the frequency of CD8 dim T cells directly correlates with viral load and clinical predictors of more rapid disease progression. We found that a canonical burst of proliferative cytokines coincides with the emergence of CD8 dim T cells, and the size of this population inversely correlates with the acute loss of CD4 + T cells. These data indicate, for the first time, that early CD4 + T cell loss coincides with the expansion of a functionally impaired HIV-specific CD8 dim T cell population less efficient in controlling HIV viremia. IMPORTANCE A distinct population of activated CD8 + T cells appears during acute HIV infection with diminished capacity to inhibit HIV replication and is predictive of viral set point, offering the first immunologic evidence of CD8 + T cell dysfunction during acute infection.

Objective: To evaluate the diagnostic performance of two rapid detection tests (RDTs) for HIV 1/2 in plasma and in whole blood samples. Methods: More than 15,000 study subjects above the age of two years participated in two rounds of a cohort study to determine the prevalence of HIV. HIV testing was performed using the Determine HIV 1/2 test (Abbott) in the first (2006/2007) and the HIV 1/2 STAT-PAK Dipstick Assay (Chembio) in the second round (2007/2008) of the survey. Positive results were classified into faint and strong bands depending on the visual appearance of the test strip and confirmed by ELISA and Western blot. Results: The sensitivity and specificity of the Determine RDT were 100% (95% confidence interval = 86.8 to 100%) and 96.8% (95.9 to 97.6%) in whole blood and 100% (99.7 to 100%) and 97.9% (97.6 to 98.1%) in plasma respectively. Specificity was highly dependent on the tested sample type: when using whole blood, 67.1% of positive results were false positive, as opposed to 17.4% in plasma. Test strips with only faint positive bands were more often false positive than strips showing strong bands and were more common in whole blood than in plasma. Evaluation of the STAT-PAK RDT in plasma during the second year resulted in a sensitivity of 99.7% (99.1 to 99.9%) and a specificity of 99.3% (99.1 to 99.4%) with 6.9% of the positive results being false. Conclusions: Our study shows that the Determine HIV 1/2 strip test with its high sensitivity is an excellent tool to screen for HIV infection, but that – at least in our setting – it can not be recommended as a confirmatory test in VCT campaigns where whole blood is used.

Background: The viral load setpoint (VLS) is an important predictor of HIV disease progression, but there is a lack of information regarding the VLS and its possible determinants in African populations. Methods: Initially HIV-negative adults from 3 distinct groups (female bar workers, females, and males from the general population) were followed for up to 4 years. The VLS was calculated for 108 seroconverters and associations of the VLS with possible risk factors were analyzed using univariate and multivariate regression. Results: The median VLS for female bar workers, females, and males from the general population were 69,850, 28,600, and 158,000 RNA copies per milliliter, respectively. Significant associations with an elevated viral load were observed for male gender [risk ratio (RR) = 1.83, 95% confidence interval (95% CI) = 1.14 to 2.93], the expression of harmful HLA I alleles (RR = 1.73, 95% CI = 1.13 to 2.66) and multiple infection with different HIV-1 subtypes (RR = 1.65, 95% CI = 1.03 to 2.66). Bar workers were considerably more often infected with different HIV-1 subtypes than participants from the general population. Conclusions: Our study confirms that gender and the expression of different HLA class I alleles are important determinants of the viremia at VLS, and it also corroborates an earlier finding that multiple infection with different HIV-1 subtypes is associated with a higher VLS.

Background: HIV vaccine trials generally require that pregnant women are excluded from participation, and contraceptive methods must be used to prevent pregnancy during the trial. However, access to quality services and misconceptions associated with contraceptive methods may impact on their effective use in developing countries. We describe the pattern of contraceptive use in a multi-site phase I/IIa HIV Vaccine trial in East Africa (Uganda, Kenya and Tanzania) and factors that may have influenced their use during the trial. Methods: Pregnancy prevention counseling was provided to female participants during informed consent process and at each study visit. Participants’ methods of contraception used were documented. Methods of contraceptives were provided on site. Pregnancy testing was done at designated visits during the trial. Obstacles to contraceptive use were identified and addressed at each visit. Results: Overall, 103 (31.8%) of a total of 324 enrolled volunteers were females. Female participants were generally young with a mean age of 29(67.2), married (49.5%) and had less than high school education (62.1%). Hormonal contraceptives were the most common method of contraception (58.3%) followed by condom use (22.3%). The distribution of methods of contraception among the three sites was similar except for more condom use and less abstinence in Uganda. The majority of women (85.4%) reported to contraceptive use prior to screening. The reasons for not using contraception included access to quality services, insufficient knowledge of certain methods, and misconceptions. Conclusion: Although hormonal contraceptives were frequently used by females participating in the vaccine trial, misconceptions and their incorrect use might have led to inconsistent use resulting in undesired pregnancies. The study underscores the need for an integrated approach to pregnancy prevention counseling during HIV vaccine trials. Trial Registration: ClinicalTrials.gov NCT00123968