Lessons from an international trial evaluating vaccination strategies for recovered inpatients with COVID-19 (VATICO)

The protection provided by natural versus hybrid immunity from COVID-19 is unclear. We reflect on the challenges from trying to conduct a randomized post-SARS-CoV-2 infection vaccination trial study with rapidly evolving scientific data, vaccination guidelines, varying international policies, difficulties with vaccine availability, vaccine hesitancy, and a constantly evolving virus

Cardiometabolic risk among HIV-POSITIVE Ugandan adults: prevalence, predictors and effect of long-term antiretroviral therapy.

INTRODUCTION: We investigated the prevalence, predictors of and effect of Antiretroviral Therapy (ART) regimen on cardiometabolic risk among HIV-positive Ugandan adults at enrolment into a prospective cohort to study the Complications of Long-Term ART (CoLTART). METHODS: We collected data on cardiometabolic risk factors including dyslipidemia, hypertension, hyperglycemia, obesity and calculated the mean atherogenic index for Plasma (AIP) and 10 year Framingham risk score (FHS). Exposures were: ART regimen, duration on ART, demographic, socio-economic, behavioral, and life-style factors including smoking, physical activity and diet (including fruit and vegetables consumption). RESULTS: We enrolled 1024 participants, 65% female, mean age was 44.8 years (SD 8.0) and median duration on ART was 9.4 years (IQR 6.1-9.8). The prevalence of abdominal obesity was 52.6%, BMI?25 kg/m2 -26.1%, hypertension-22.6%, high AIP-31.3% and FHS above 10% was 16.6%. The prevalence of low High Density Lipoprotein (HDL) was 37.5%, high Total cholesterol (Tc)-30.2%, high Low Density Lipoprotein (LDL) -23.6%, high Triglycerides (TG)-21.2%, low physical activity-46.4% and alcohol consumption-26.4%. In multivariate linear regression analyses, increasing age was associated with higher mean Tc, HDL, LDL, FHS (P10% compared to the non PI regimen. CONCLUSION: ART increases cardiometabolic risk. Integration of routine assessment for cardiometabolic risk factors and preventive interventions into HIV care programs in resource-limited settings is recommended

Prevalence and factors associated with hypertension among people living with HIV/AIDS on antiretroviral therapy in Uganda.

INTRODUCTION: antiretroviral therapy (ART) has improved survival of People Living with HIV (PLWH); however, this has resulted in an increasingly high prevalence of non-communicable diseases (NCD) like hypertension. Hypertension is a major risk factor for cardiovascular and cerebral vascular disease, which are both associated with high morbidity and mortality rates. We studied the prevalence and factors associated with hypertension among PLWH on ART. METHODS: we conducted a retrospective data analysis of PLWH on ART enrolled between 2011 and 2014 into a randomized double-blinded placebo-controlled trial investigating the safety of discontinuing cotrimoxazole prophylaxis (COSTOP) among PLWH in Central Uganda. We used the mean blood pressure (BP) measurements of the first four monthly clinic visits to define hypertension. Patients were categorised as: having normal BP (?120/80mmHg), elevated BP (systolic >120-129, and diastolic ?80), Stage 1 hypertension (systolic 130-139, or diastolic >80-89) and Stage 2 hypertension (systolic ?140 or diastolic ?90). Multiple logistic regression was used to evaluate factors associated with hypertension. RESULTS: data from 2026 COSTOP trial study participants were analysed, 74.1% were women and 77.2% were aged 35 years and above. The overall prevalence of hypertension was 29%, of whom 19.5% had Stage 1 hypertension and 9.5% had Stage 2 hypertension. About 21.4% were overweight or obese. Factors independently associated with hypertension among PLWH on ART included increasing age (p?0.001) and high body mass index (p?0.001). Efavirenz (p?0.001) and lopinavir/ritonavir (p=0.036) based regimen had lower odds of hypertension than Nevirapine based regimens. CONCLUSION: PLWH on ART have a high prevalence of hypertension, which rises with increasing age and body mass index (BMI) and among those on nevirapine-based ART. Implementation of hypertension prevention measures among PLWH on ART and integration of NCD and HIV care to improve patients' management outcomes are required

Discontinuing cotrimoxazole preventive therapy in HIV-infected adults who are stable on antiretroviral treatment in Uganda (COSTOP): A randomised placebo controlled trial.

BACKGROUND: Cotrimoxazole (CTX) preventive therapy (CPT) reduces opportunistic infections and malaria in HIV-infected patients. In Africa, policies on sustained CPT during antiretroviral therapy (ART) differ between countries. We assessed the safety of discontinuing CPT in stable patients on ART in Uganda. METHODS: COSTOP was a double-blind placebo-controlled trial. Patients aged ≥18 years, on CPT, and stable on ART (CD4 counts ≥250 cells/μL); were randomised to daily oral placebo (PLC group) or cotrimoxazole 960 mg/tablet (CTX group). Co-primary outcomes were: (i) time to first cotrimoxazole-preventable infection, with non- inferiority of PLC defined as the upper one-sided 95% confidence limit of the adjusted hazard ratio(aHR) ≤1.25; and (ii) time to first grade 3/4 haematological adverse event. FINDINGS: 2180 subjects (1091 PLC; 1089 CTX) were enrolled. 932 PLC and 943 CTX completed the trial after 12 months minimum follow up. Ninety-eight participants (59 PLC; 39 CTX) experienced 120 cotrimoxazole- preventable events, mainly bacterial pneumonia (72 events, 4 deaths PLC); (48 events, 2 deaths CTX). The aHR for time to first event was 1.57 (upper one-sided 95% confidence limit 2.21) in per protocol population (similar results in ITT population). 551 participants (318 CTX; 233 PLC) experienced 1043 haematological adverse events (616 CTX; 427 PLC). Time to the first adverse event, mainly neutropenia, was shorter in the CTX group (aHR 0.70 95%CI 0.59-0.82; log-rank χ2 = 18.08; P<0.0001). 362 (276 PLC, 86 CTX) participants experienced at least one episode of confirmed clinical malaria (P<0.0001). INTERPRETATION: In ART stable patients with CD4 counts ≥250 cells/μL, continued CPT significantly reduces risk of severe bacterial infections and protects against malaria, while discontinuing CPT reduces haematological adverse events

Antiretroviral initiation at ≥800 CD4+ cells/ mm 3 associated with lower HIV reservoir size.

BACKGROUND: Identifying factors that determine the frequency of latently infected CD4+ T-cells on antiretroviral therapy (ART) may inform strategies for HIV cure. We investigated the role of CD4 count at ART initiation for HIV persistence on ART. METHODS: Among participants of the Strategic Timing of Antiretroviral Treatment (START) Study, we enrolled people with HIV (PWH) who initiated ART with CD4+ T-cell counts of 500-599, 600-799 or ≥800 cells/mm 3. After 36-44 months on ART, we quantified levels of total HIV-DNA, cell-associated unspliced HIV-RNA (CA-US HIV-RNA) and 2-long terminal repeat HIV-DNA in CD4+ T-cells and measured plasma HIV-RNA by single-copy assay. We measured T-cell expression of HLA-DR, programmed death-1, phosphorylated signal transducer and activator of transcription-5 (pSTAT5). Virological and immunological measures were compared across CD4+ strata. RESULTS: We enrolled 146 PWH, 36 in the 500-599, 60 in the 600-799 and 50 in the ≥800 CD4 strata. After 36-44 months of ART, total HIV-DNA, plasma HIV-RNA and HLA-DR expression were significantly lower in PWH with CD4+ T-cell count ≥800 cells/mm 3 at ART initiation compared to 600-799 or 500-599 cells/mm 3. The median level of HIV-DNA after 36-44 months of ART was lower by 75% in participants initiating ART with ≥800 vs. 500-599 cells/mm 3 [median (IQR): 16.3 (7.0-117.6) vs. 68.4 (13.7-213.1) copies/million cells, respectively). Higher pSTAT5 expression significantly correlated with lower levels of HIV-DNA and CA-US HIV-RNA. Virological measures were significantly lower in females.. CONCLUSION: Initiating ART with a CD4+ count ≥800 cells/mm 3 compared to 600-799 or 500-599 cells/mm 3 was associated with achieving a substantially smaller HIV reservoir on ART

Long-Term Benefits from Early Antiretroviral Therapy Initiation in HIV Infection

BACKGROUND: For people with HIV and CD4+ counts >500 cells/mm3, early initiation of antiretroviral therapy (ART) reduces serious AIDS and serious non-AIDS (SNA) risk compared with deferral of treatment until CD4+ counts are 500 cells/mm3, excess risk of AIDS and SNA associated with delaying treatment initiation was diminished after ART initiation, but persistent excess risk remained. (Funded by the National Institute of Allergy and Infectious Diseases and others.)

Reduced bacterial skin infections in HIV-infected African children randomized to long-term cotrimoxazole prophylaxis

Objective To evaluate whether cotrimoxazole prophylaxis prevents common skin conditions in HIV-infected children. Design Open-label randomized controlled trial of continuing versus stopping daily cotrimoxazole (post-hoc analysis). Setting Three sites in Uganda, one in Zimbabwe. Participants 758 children aged >3 years receiving antiretroviral therapy (ART) for >96 weeks in the ARROW trial were randomized to stop (n=382) or continue (n=376) cotrimoxazole after median(IQR) 2.1(1.8,2.2) years on ART. Intervention Continuing versus stopping daily cotrimoxazole. Main Outcome Measures Nurses screened for signs/symptoms at 6-weekly visits. This was a secondary analysis of ARROW trial data, with skin complaints categorized blind to randomization as bacterial, fungal, or viral infections; dermatitis; pruritic papular eruptions (PPE); or other (blisters, desquamation, ulcers, urticaria). Proportions ever reporting each skin complaint were compared across randomized groups using logistic regression. Results At randomization, median(IQR) age was 7(4,11) years and CD4 was 33%(26,39); 73% had WHO stage 3/4 disease. Fewer children continuing cotrimoxazole reported bacterial skin infections over median 2 years follow-up (15% versus 33%, respectively; P<0.001), with similar trends for PPE (P=0.06) and other skin complaints (p=0.11), but not for fungal (P=0.45) or viral (P=0.23) infections or dermatitis (P=1.0). Bacterial skin infections were also reported at significantly fewer clinic visits (1.2% vs 3.0%, P<0.001). Independent of cotrimoxazole, bacterial skin infections were more common in children aged 6-8 years, with current CD4<500 cells/mm3, WHO stage 3/4, less time on ART and lower socioeconomic status. Conclusions Long-term cotrimoxazole prophylaxis reduces common skin complaints, highlighting an additional benefit for long-term prophylaxis in sub-Saharan Africa

Lessons from an international trial evaluating vaccination strategies for recovered inpatients with COVID-19 (VATICO).

The protection provided by natural versus hybrid immunity from COVID-19 is unclear. We reflect on the challenges from trying to conduct a randomized post-SARS-CoV-2 infection vaccination trial study with rapidly evolving scientific data, vaccination guidelines, varying international policies, difficulties with vaccine availability, vaccine hesitancy, and a constantly evolving virus