High acceptability and viral suppression of patients on Dolutegravir-based first-line regimens in pilot sites in Uganda: A mixed-methods prospective cohort study.

Uganda adopted the integrase inhibitor dolutegravir (DTG) as part its preferred first-line HIV treatment regimen in 2018. Prior to the national rollout, the Uganda Ministry of Health and Clinton Health Access Initiative (CHAI) launched a pilot study in July 2017 aimed at better understanding patients' and prescribers' experience and acceptability of DTG. Patients were enrolled in the study if they were newly initiating treatment or switched from an NNRTI regimen due to intolerance. Patients were followed up for 6 months after initiation onto DTG and acceptability and experiences were assessed through questionnaires at one-month and six-month follow-up visits. In addition to acceptability side effects of patients on DTG regimens were assessed. Analysis was conducted using MS Excel and SAS 9.4 and confidence intervals were adjusted for facility level clustering. A total of 365 patients from 6 study sites were enrolled in the study, of whom 50% were treatment-experienced and 50% treatment naïve. 325 patients completed the 6 months of follow-up. Survey results showed a high level of acceptability (more than 90%) of DTG-containing regimens for both categories of patients during the from one-month and six-months interviews. The rate of self-reported side effects amongst patients was 33% overall and higher for experienced (37%) than naïve (29%) patients at 6 months. Although frequencies declined between month-1 and month-6, the changes were not statistically significant. Almost all patients (94%) were virally suppressed at 6 months. Overall, the study findings showed a very high level of acceptability of Dolutegravir-based regimens across both experienced and naïve patients. The overall viral suppression rate in this cohort was 94% at six months of taking DTG-based regimen

Effects of Prednisolone on Disease Progression in Antiretroviral-Untreated HIV Infection: A 2-Year Randomized, Double-Blind Placebo-Controlled Clinical Trial

Background HIV-disease progression correlates with immune activation. Here we investigated whether corticosteroid treatment can attenuate HIV disease progression in antiretroviral-untreated patients. Methods Double-blind, placebo-controlled randomized clinical trial including 326 HIV-patients in a resource-limited setting in Tanzania (clinicaltrials.gov NCT01299948). Inclusion criteria were a CD4 count above 300 cells/μl, the absence of AIDS-defining symptoms and an ART-naïve therapy status. Study participants received 5 mg prednisolone per day or placebo for 2 years. Primary endpoint was time to progression to an AIDS-defining condition or to a CD4-count below 200 cells/μl. Results No significant change in progression towards the primary endpoint was observed in the intent-to-treat (ITT) analysis (19 cases with prednisolone versus 28 cases with placebo, p = 0.1407). In a per-protocol (PP)-analysis, 13 versus 24 study participants progressed to the primary study endpoint (p = 0.0741). Secondary endpoints: Prednisolone-treatment decreased immune activation (sCD14, suPAR, CD38/HLA-DR/CD8+) and increased CD4-counts (+77.42 ± 5.70 cells/μl compared to -37.42 ± 10.77 cells/μl under placebo, p < 0.0001). Treatment with prednisolone was associated with a 3.2-fold increase in HIV viral load (p < 0.0001). In a post-hoc analysis stratifying for sex, females treated with prednisolone progressed significantly slower to the primary study endpoint than females treated with placebo (ITT-analysis: 11 versus 21 cases, p = 0.0567; PP-analysis: 5 versus 18 cases, p = 0.0051): No changes in disease progression were observed in men. Conclusions This study could not detect any significant effects of prednisolone on disease progression in antiretroviral-untreated HIV infection within the intent-to-treat population. However, significant effects were observed on CD4 counts, immune activation and HIV viral load. This study contributes to a better understanding of the role of immune activation in the pathogenesis of HIV infection

Study drug adherence and loss to follow-up.

<p><b>A, B</b>: Study drug adherence calculated from pill counts of returned, unused study medication in female (A) and male (B) study participants. P-values were calculated by 2way ANOVA <b>C</b>: Loss to follow-up during the two-year study. P value was calculated by log-rank (Mantel-Cox) analysis.</p

Effects of prednisolone on CD4 counts and CD4/CD8 ratio.

<p><b>A</b>: Mean CD4 ± S.D. P-values were determined by 2way ANOVA. <b>B</b>: Mean CD4 changes ± S.D. relative to baseline and linear regression of the data. 2-year gains/losses were calculated from slope of linear regression. <b>C</b>: Mean ± S.D. CD4/CD8-ratio and linear regression. B, C: P values on the right indicate non-zero hypotheses for the slope. P-value on the left for difference between the two data sets was calculated by 2way ANOVA. <b>D-F</b> and <b>G-I</b>: Post-hoc analyses for female study participants (D-F) and for male study participants (H-I) for absolute CD4 counts (D, G), CD4 relative CD4 changes (E, H), and CD4/CD8 ratio (F, I).</p

Study participants at risk.

<p>Number of study participants at risk within the intent-to-treat (ITT) population (<b>A</b>) or the per protocol (PP) population (<b>B</b>). Separate analyses for female study participants (C, D) and for male study participants (E, F).</p

CONSORT statement 2010 flow diagram.

<p>The number of participants enrolled, randomized, allocated to study medication, followed-up and analyzed is shown. Study participants who progressed to the endpoint of the study (CD4 < 200 or CDC stage-C disease) received HAART. In some cases, study participants also received HAART when they progressed to CD4 < 350 in combination with WHO stage 3-disease. This was in accordance to the National Tanzanian treatment recommendations Update in 2008 (1 case in the placebo arm and 3 cases in the prednisolone arm). In addition, one patient in the placebo arm and 2 study participants in the prednisolone arm received HAART without fulfilling either the study endpoint or the criteria listed in the National Treatment recommendation update.</p

Effects of prednisolone on HIV disease progression: Primary Study Endpoint.

<p>Kaplan-Meyer estimate of progression to combined study endpoint (onset of CDC stage-C-condition or drop of CD4 counts below 200) within the intent-to-treat (ITT) population (<b>A</b>) or the per protocol (PP) population (<b>B</b>). <b>C</b>: Progression to AIDS-defining condition. All study participants who received HAART, but did not reach the study endpoint were censored for the KM analysis. <b>D-F</b> and <b>G-I</b>: Post-hoc analyses for female study participants (D-F) and for male study participants (H-I) for progression to combined endpoint within the ITT population (D, G), progression to combined endpoint within the PP population (E, H), and progression to AIDS-defining condition (F, I). A-I: P values were calculated by log-rank (Mantel-Cox) analysis.</p

Progression to HAART as treated.

<p>Kaplan-Meyer estimate of progression to HAART as treated within the intent-to-treat (ITT) population (<b>A</b>) or the per protocol (PP) population (<b>B</b>). Separate analyses for female study participants (B, E) and for male study participants (C, F) for progression to HART as treated. P values were calculated by log-rank (Mantel-Cox) analysis.</p