Phase 2 Open-Label Study of Long-Term Safety, Tolerability, and Antiviral Activity of Rilpivirine in Antiretroviral-Naive Adolescents Living with HIV-1.

This phase 2 study investigated long-term safety and efficacy of rilpivirine (RPV) plus two investigator-selected nucleos(t)ide reverse transcriptase inhibitors (NRTIs) in HIV-1-infected antiviral therapy-naive adolescents. Participants (≥12 to <18 years of age) were treated with RPV at 25 mg once daily (q.d.

Brief Report: No Differences Between Lopinavir/Ritonavir and Nonnucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy on Clearance of Plasmodium falciparum Subclinical Parasitemia in Adults Living With HIV Starting Treatment (A5297).

Background: HIV protease inhibitors anti-Plasmodium falciparum activity in adults remains uncertain.

Methods: Adults with HIV CD4+ counts >200 cells/mm3 starting antiretroviral therapy (ART) with P. falciparum subclinical parasitemia (Pf SCP) were randomized 1:1 to (step 1) protease inhibitor lopinavir/ritonavir (LPV/r)-based (arm A) or nonnucleoside reverse transcriptase inhibitor (nNRTI)-based ART (arm B) for 15 days.

Towards access for all: 1st Working Group Report for the Global Gene Therapy Initiative (GGTI).

The gene and cell therapy field saw its first approved treatments in Europe in 2012 and the United States in 2017 and is projected to be at least a $10B USD industry by 2025. Despite this success, a massive gap exists between the companies, clinics, and researchers developing these therapeutic approaches, and their availability to the patients who need them. The unacceptable reality is a geographic exclusion of low-and middle-income countries (LMIC) in gene therapy development and ultimately the provision of gene therapies to patients in LMIC.

Efficacy of convalescent plasma for treatment of COVID-19 in Uganda.

Rationale: Convalescent plasma (CCP) has been studied as a potential therapy for COVID-19, but data on its efficacy in Africa are limited.

Objective: In this trial we set out to determine the efficacy of CCP for treatment of COVID-19 in Uganda.

Measurements: Patients with a positive SARS-CoV-2 reverse transcriptase (RT)-PCR test irrespective of disease severity were hospitalised and randomised to receive either COVID-19 CCP plus standard of care (SOC) or SOC alone.

Translocated microbiome composition determines immunological outcome in treated HIV infection.

The impact of the microbiome on HIV disease is widely acknowledged although the mechanisms downstream of fluctuations in microbial composition remain speculative. We detected rapid, dynamic changes in translocated microbial constituents during two years after cART initiation. An unbiased systems biology approach revealed two distinct pathways driven by changes in the abundance ratio of Serratia to other bacterial genera.

Feasibility of collecting and processing of COVID-19 convalescent plasma for treatment of COVID-19 in Uganda.

Introduction: Evidence that supports the use of COVID-19 convalescent plasma (CCP) for treatment of COVID-19 is increasingly emerging. However, very few African countries have undertaken the collection and processing of CCP. The aim of this study was to assess the feasibility of collecting and processing of CCP, in preparation for a randomized clinical trial of CCP for treatment of COVID-19 in Uganda.

Predictors of failure on second-line antiretroviral therapy with protease inhibitor mutations in Uganda.

Introduction: Failure on second-line antiretroviral therapy (ART) with protease inhibitor (PI) mutations (VF-M) is on the rise. However, there is a paucity of information on the factors associated with this observation in low-income countries. Knowledge of underlying factors is critical if we are to minimize the number of PLHIV switched to costly third-line ART.

Impact of Integrase Inhibition Compared With Nonnucleoside Inhibition on HIV Reservoirs in Lymphoid Tissues.

Background: HIV is produced in lymphoid tissues (LT) and stored on the follicular dendritic cell network in LT. When antiretroviral therapy is started, plasma viremia decays in 2 phases; the first within days of starting therapy and the second over weeks. Raltegravir (RAL), an integrase inhibitor, has been associated with only a single rapid phase of decay, and we speculated this may be due to higher intracellular concentration (IC) of RAL in LT.

Lymphoid tissue fibrosis is associated with impaired vaccine responses.

Vaccine responses vary by geographic location. We have previously described how HIV-associated inflammation leads to fibrosis of secondary lymph nodes (LNs) and T cell depletion. We hypothesized that other infections may cause LN inflammation and fibrosis, in a process similar to that seen in HIV infection, which may lead to T cell depletion and affect vaccine responses.

Defining total-body AIDS-virus burden with implications for curative strategies.

In the quest for a functional cure or the eradication of HIV infection, it is necessary to know the sizes of the reservoirs from which infection rebounds after treatment interruption. Thus, we quantified SIV and HIV tissue burdens in tissues of infected nonhuman primates and lymphoid tissue (LT) biopsies from infected humans. Before antiretroviral therapy (ART), LTs contained >98% of the SIV RNA and DNA cells.

Genome-wide association study of nevirapine hypersensitivity in a sub-Saharan African HIV-infected population.

Background: The antiretroviral nevirapine is associated with hypersensitivity reactions in 6%-10% of patients, including hepatotoxicity, maculopapular exanthema, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).

Objectives: To undertake a genome-wide association study (GWAS) to identify genetic predisposing factors for the different clinical phenotypes associated with nevirapine hypersensitivity.

Methods: A GWAS was undertaken in a discovery cohort of 151 nevirapine-hypersensitive and 182 tolerant, HIV-infected Malawian adults.

Rilpivirine as a Treatment for HIV-infected Antiretroviral-naïve Adolescents: Week 48 Safety, Efficacy, Virology and Pharmacokinetics.

Background: Rilpivirine 25 mg qd yields similar exposure in adolescents and adults (Pediatric study in Adolescents Investigating a New NNRTI TMC278 [PAINT] Cohort 1, Part 1). We report rilpivirine safety, efficacy, virology and pharmacokinetics in adolescents during 48 weeks of treatment (Cohort 1, Part 2).

Methods: PAINT (NCT00799864) is a phase II, ongoing, open-label, single-arm trial of rilpivirine plus 2 investigator-selected nucleoside/nucleotide reverse-transcriptase inhibitors.

Partner-based adherence intervention for second-line antiretroviral therapy (ACTG A5234): a multinational randomised trial.

Background: Adherence is key to the success of antiretroviral therapy. Enhanced partner support might benefit patients with previous treatment failure. We aimed to assess whether an enhanced partner-based support intervention with modified directly observed therapy would improve outcomes with second-line therapy in HIV-infected patients for whom first-line therapy had failed.

CYP2B6 c.983T>C polymorphism is associated with nevirapine hypersensitivity in Malawian and Ugandan HIV populations.

Background: Nevirapine, an NNRTI used in HIV treatment, can cause hypersensitivity reactions in 6%-10% of patients. In the most serious cases (1.3%) this can manifest as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN).

HIV-associated anemia after 96 weeks on therapy: determinants across age ranges in Uganda and Zimbabwe.

Given the detrimental effects of HIV-associated anemia on morbidity, we determined factors associated with anemia after 96 weeks of antiretroviral therapy (ART) across age groups. An HIV-positive cohort (n=3,580) of children age 5-14, reproductive age adults 18-49, and older adults ≥50 from two randomized trials in Uganda and Zimbabwe were evaluated from initiation of therapy through 96 weeks. We conducted logistic and multinomial regression to evaluate common and differential determinants for anemia at 96 weeks on therapy.

Antiretroviral drug resistance profiles and response to second-line therapy among HIV type 1-infected Ugandan children.

We sought to determine the pattern of resistance-associated mutations (RAMs) among HIV-1-infected children failing first-line antiretroviral therapy (ART) and ascertain their response to second-line regimens in 48 weeks of follow-up. The design involved a cohort study within an HIV care program. We studied records of 142 children on ART with virological failure to first-line ART and switched to second-line ART with prior genotypic resistance testing.

Lopinavir/ritonavir monotherapy after 24 weeks of second-line antiretroviral therapy in Africa: a randomized controlled trial (SARA).

Background: Boosted protease inhibitor (bPI) monotherapy (bPImono) potentially has substantial cost, safety and operational benefits. It has never been evaluated as second-line antiretroviral therapy (ART) in Africa.

Methods: After 24 weeks of lopinavir/ritonavir-containing second-line therapy, DART participants were randomized to remain on combination therapy (CT), or change to bPImono maintenance (SARA trial; ISRCTN53817258).

Adherence to antiretroviral therapy in HIV-positive adolescents in Uganda assessed by multiple methods: a prospective cohort study.

Background: The effectiveness of traditional adherence measurements used in adolescent populations is difficult to assess. Antiretroviral (ARV) adherence research among adolescents living with HIV in resource-constrained countries is particularly challenging and little evidence is available.

Objectives: The primary objective of this study was to determine the feasibility of a large-scale, long-term study using electronic adherence monitoring in Uganda.

Nevirapine- versus lopinavir/ritonavir-based initial therapy for HIV-1 infection among women in Africa: a randomized trial.

Background: Nevirapine (NVP) is widely used in antiretroviral treatment (ART) of HIV-1 globally. The primary objective of the AA5208/OCTANE trial was to compare the efficacy of NVP-based versus lopinavir/ritonavir (LPV/r)-based initial ART.

Methods And Findings: In seven African countries (Botswana, Kenya, Malawi, South Africa, Uganda, Zambia, and Zimbabwe), 500 antiretroviral-naïve HIV-infected women with CD4<200 cells/mm(3) were enrolled into a two-arm randomized trial to initiate open-label ART with tenofovir (TDF)/emtricitabine (FTC) once/day plus either NVP (n = 249) or LPV/r (n = 251) twice/day, and followed for ≥48 weeks.

Response to antiretroviral therapy of HIV type 1-infected children in urban and rural settings of Uganda.

From 2006 to 2011, a cohort study was conducted among 1000 children resident in urban and rural settings of Uganda to ascertain and compare the response to antiretroviral therapy (ART) among urban versus rural children and the factors associated with this response. Clinical, immunological, and virological parameters were ascertained at baseline and weeks 24, 48, 96, and 144 after ART initiation. Adherence to ART was assessed at enrollment by self-report (SR) and pill counts (PC).

Cost effectiveness analysis of clinically driven versus routine laboratory monitoring of antiretroviral therapy in Uganda and Zimbabwe.

Background: Despite funding constraints for treatment programmes in Africa, the costs and economic consequences of routine laboratory monitoring for efficacy and toxicity of antiretroviral therapy (ART) have rarely been evaluated.

Methods: Cost-effectiveness analysis was conducted in the DART trial (ISRCTN13968779). Adults in Uganda/Zimbabwe starting ART were randomised to clinically-driven monitoring (CDM) or laboratory and clinical monitoring (LCM); individual patient data on healthcare resource utilisation and outcomes were valued with primary economic costs and utilities.

Glomerular dysfunction and associated risk factors over 4-5 years following antiretroviral therapy initiation in Africa.

Background: The aim of this study was to investigate long-term renal function in HIV-infected adults initiating antiretroviral therapy (ART) with a CD4(+) T-cell count < 200 cells/mm³ in Africa.

Methods: This was an observational analysis within the DART trial randomizing 3,316 adults to routine laboratory and clinical monitoring (LCM) or clinically driven monitoring (CDM). Serum creatinine was measured pre-ART (all ≤ 360 μmol/l), at weeks 4 and 12, then every 12 weeks for 4-5 years; estimated glomerular filtration rate (eGFR) was determined using the Cockcroft-Gault formula.

Uptake of family planning methods and unplanned pregnancies among HIV-infected individuals: a cross-sectional survey among clients at HIV clinics in Uganda.

Background: Prevention of unplanned pregnancies among HIV-infected individuals is critical to the prevention of mother to child HIV transmission (PMTCT), but its potential has not been fully utilized by PMTCT programmes. The uptake of family planning methods among women in Uganda is low, with current use of family planning methods estimated at 24%, but available data has not been disaggregated by HIV status. The aim of this study was to assess the utilization of family planning and unintended pregnancies among HIV-infected people in Uganda.

Validation of World Health Organisation HIV/AIDS clinical staging in predicting initiation of antiretroviral therapy and clinical predictors of low CD4 cell count in Uganda.

Introduction: The WHO clinical guidelines for HIV/AIDS are widely used in resource limited settings to represent the gold standard of CD4 counts for antiviral therapy initiation. The utility of the WHO-defined stage 1 and 2 clinical factors used in WHO HIV/AIDS clinical staging in predicting low CD4 cell count has not been established in Uganda. Although the WHO staging has shown low sensitivity for predicting CD4<200 cells/mm(3), it has not been evaluated at for CD4 cut-offs of <250 cells/mm(3) or <350 cells/mm(3).