- Post by: Allan Atukunda
- October 26, 2021
JCRC participated in the DART trial as well as several other successfully concluded studies, as outlined below.
Currently, the ongoing adult studies include: PASER, START. WAVES, GILEAD protocol 0117 and SALIF studies.
Development of AntiRetroviral Therapy in Africa (DART) (ISRCTN13968779)
Study period: 2003 to 2009
Source of funding: MRC, DFID, Rockefeller Foundation
DART, the largest ART clinical trial in Africa was an open randomized trial evaluating strategic approaches for the management of ART in previously untreated symptomatic HIV infected adults with CD4 cell counts <200 cells/mm3 initiating ART in Africa. A total of 3316 HIV infected symptomatic ART naïve adults took part across three centres in Uganda, and one in Zimbabwe. The main question was whether clinical monitoring only would be as safe and effective as clinical and laboratory monitoring for toxicity (haematology and biochemistry) and efficacy (CD4 counts); no virological monitoring was performed. A second part, comparing structured treatment interruptions (STIs: 12 weeks on, 12 weeks off ART) with continuous ART in patients who achieve CD4 cell counts ≥300 cells/mm3 after 48 or 72 weeks of ART was discontinued in March 2006 following DSMC review, and all patients were switched to continuous ART. The majority of patients were started on triple NRTI: 2469 patients initiated CBV/TDF, 300 CBV/ABC and 547 CBV/NVP. Minimum follow up of each patient was be 6 years.
It demonstrated that first-line ART can be delivered safely without routine biochemistry and haematology monitoring for toxic effects.
Participants from DART form a cohort for long term follow and a resource for answering pertinent questions to issues like long term efficacy, toxicities, resistance profiles and adherence issues.
Second-line Anti-Retroviral Therapy in Africa (SARA) Study (a sub study of DART)
This SARA protocol separately explored issues of the best specific regimens for second-line combination ART following first-line 2NRTI/NNRTI or triple NRTI regimens, specifically, which ARV combinations could best provide an optimised background regimen to support Aluvia. It was a three centre open-label randomised trial in HIV infected adults receiving Aluvia containing second-line ART in Africa to evaluate the efficacy of maintenance monotherapy with ritonavir-boosted lopinavir (Aluvia tablets) following initiation with 24 weeks of combination therapy in second-line ART in Africa. The main objective was to compare two strategies for second-line ART after 24 weeks of combination Aluvia (or Kaletra) containing ART: Arm 1: continued combination Aluvia-containing ART; Arm 2: maintenance with Aluvia monotherapy. Patients were randomized in a 1:1 ratio and followed up to 96 weeks. The initial data were encouraging and this was the basis for a larger clinical end-point trial called EARNEST (described below).
Short Cycle Treatment Interruption (STI) Study (NCT00339456)
Study period: 2002 to 2008
Source of funding: NIH/NIAID
This study involved 146 HIV-positive individuals recruited at JCRC. This randomized trial evaluated the effects of continuous vs 2 approaches to short cycle intermittent ART on viral load. We evaluated both the 7 days on-HAART/ 7 days off-HAART as well as a 2 days off HAART/ 5 days on-HAART approach. Secondary study objectives included changes in CD4 T-cell count, virus resistance patterns, toxicity and side effects, quality of life and adherence. Interrupted therapy was expected to minimize toxicity/ side effects and reduce costs.
In the study, structured treatment interruptions of 5 days on and 2 days off treatment were found to be equivalent in outcomes to continuous treatment. The results of this study inspired the development of the PENTA 16 (BREATHER) trial in adolescents, where JCRC is the only African centre, as described below.
The project also has stored samples that may be used to answer additional questions. Scholars may benefit from these ready to use samples.
RAND study (2007HE007)
Study period: Phase I – 2007 to 2009
Phase II – 2009 to 2012
Grant amount: Phase I –
Phase II- US $45,864
Source of funding: RAND Corporation
The JCRC and the RAND Corporation jointly conducted a study which combined qualitative formative research with prospective longitudinal cohort assessments to examine impact of ART on multiple dimensions of health, including economic (work status; utilization of assets), social (household remaining intact, children attending school), mental (depression), and sexual (risk behavior, disclosure of HIV status). The project drew from the Social Cognitive Theory, to examine patient characteristics, including physical and mental health, and characteristics of the household and clinic to develop a multi-level model that explains the pathways that link ART to these specific health domains and how these outcomes may be related to each other.
JPF PEPFAR study
Study period: 2008 to 2011
Grant amount: US $206, 699
Source of funding: NIH
The study evaluated the role of routine lab monitoring in improving the outcomes of antiretroviral therapy among 600 HIV infected Ugandan patients above 18 yrs of age receiving treatment under the umbrella of the PEPFAR supported programs. Other outcomes included durability of antiretroviral regimens and requirements for regimen change. The study also assessed the role of genotypic HIV resistance testing by performing resistance assays on a subset of these patients. The results of the analyses helped health providers in better management of HIV, as well as regulatory and government agencies in formulating policies and recommendations in HIV treatment programs.
ATRIPLA Food study (PACTR 2009120001702102)
Study period: 2009 – 2010
Source of funding: Health Research Board, Ireland
This pharmacokinetic study investigated the effect of food on the bioavailability of the active components of the fixed drug combination of tenofovir/emtricitabine/efavirenz.
Study period: 2008 to 2010
Source of funding: MERCK Sharpe and Dome (MSD)
The study was carried out in collaboration with MERCK and was for salvage therapy among patients that have demonstrated triple class ART resistance. Participants received raltegravir and optimised background ART, which often included darunavir, etravirine and other ARVs based on the viral resistance genotype. Their short and long term outcomes were evaluated. Participation in this study allowed JCRC to be the first institution in Uganda to use Raltegravir.
Source of funding:
This was a four-week randomized clinical trial conducted among HIV positive patients with grade 1 to 2 anaemia to determine the effect of low dose erythropoietin on the patients’ hemoglobin and their quality of life.
The EARNEST Trial (ISRCTN: 37737787)
Study period: 2009 to 2013
Grant amount: Euros 1, 837,496
Source of funding: EDCTP, MRC UK
The Europe and Africa Research Network for Evaluation of Second Line Therapy in HIV infection (EARNEST) trial is investigating the optimal second line regimens for individuals that have failed firstline ART. It is the biggest trial worldwide investigating second-line ART among 1277 participants in 14 clinical sites in 9 African countries. 6 of the trial sites are JCRC clinics.
The trial aims to compare several boosted protease inhibitor-containing second line regimens in patients failing first line therapy. It is a 3-arm, open label randomized trial of HIV infected adults failing first line therapy. They are randomised to either ART regimens of boosted PI (bPI) plus 2 new NRTI as per WHO and national guidelines of standard of care, bPI + Integrase Inhibitor, or bPI monotherapy (preceded by a 4 week induction period with NRTIs). Follow up will be for a minimum of 144 weeks. The primary outcome parameter for the trial is “good clinical and immunological outcome” (defined as being alive with no new or recurrent WHO stage 4 clinical events since the time of switch to second-line and having a CD4 count >250 cells at 144 weeks). This outcome parameter is highly relevant to ART rollout programs in Africa.
PharmAccess African Studies to Evaluate Resistance (PASER) Program
Study period: Phase I – 2006 to 2010
Phase II – 2011 – 2015
Grant amount: Phase I – Euros 77,600
Phase II – Co-funded with MARCH II and ARTA II
Source of funding: Phase I – Pharmaccess, Netherlands Ministry of Foreign affairs
Phase II – AIGHD
The PASER program is a multi site project in collaboration with PharmAccess Foundation, a Dutch multi-service, not-for-profit organization. The target geographic settings are areas where ART programs are being rapidly scaled up and where transmitted HIVDR is likely to appear first. A total of 12 clinical sites in 6 African countries with 3 of the sites in the JCRC national network of clinics recruited over 3000 participants, 720 of them from JCRC sites. The JCRC laboratory is one of the 2 quality assured regional reference laboratories in the program for resistance testing. Phase I of the program run for a period of 5 years (2006-2010), while phase II will involve an additional follow up for 5 years.
The objectives are to evaluate the success of ART programs to prevent and minimize the emergence of HIVDR, to measure the emergence of HIVDR over time, the durability of the standard first-line regimens in use, the specific HIVDR mutations and mutational patterns, the associated programmatic and patient (adherence) factors, and to disseminate the results to support policy makers, and to support optimal ART program practices.
The project consists of integral components namely a) HIV Drug Resistance Monitoring Protocol (PASER-M); involves the monitoring of HIVDR emerging during ART. Prospective cohorts of consecutively enrolled HIV infected patients who either start first-line ART or who switch to second-line ART, are followed for a period of maximum five years. Genotypic testing is performed on an annual basis and in case of stopping or switching treatment. b) HIV Drug Resistance Surveillance Protocol (PASER-S) involves cross-sectional surveillance threshold surveys in recently infected, treatment naïve patients, in geographic settings where transmitted HIVDR is likely to appear first. One-time genotypic testing is performed in each patient. c) Clinical Observational Database and Quality Assurance constitute an integral part of the monitoring and surveillance components.
Grant amount: US $72, 219
Source of funding: European Union
The overall aim of this study is to understand the pathogenesis of TB-IRIS, and to define its determinants by conducting a comprehensive investigation of clinical, virological, immunological and molecular parameters in a cohort of HIV-infected patients with different levels of exposure to TB.
JBS – Damaged Niche Hypothesis study (JCRC 12401)
Study period: 2010 – 2012
Grant amount: 117, 749
Source of funding: University of Minnesota
This study was done in collaboration with Prof. Timothy Schacker from the University of Minnesota. It investigated the extent of fibrosis in the lymph nodes and the gut, among HIV positive individuals prior to ART and after one year of ART. The study had a baseline comparator group of HIV-negative individuals.
START Trial (NCT00867048)
Study period: 2009 to 2016
Grant amount: Reimbursement per patient
Source of funding: NIH, MRC UK
A randomized study to determine whether immediate initiation of antiretroviral treatment (ART) is superior to deferral of ART until the CD4+ declines to < 350cell/ul.
- To find out if the chance of developing a serious illness or of getting AIDS is less if patients start taking HIV medicines at a time when their cluster-of-differentiation-4 (CD4)+ cell count is still fairly high, instead of waiting until the CD4+ count is at the level where there is good evidence for starting medicines.
- To learn more about how a strategy of starting HIV medicines early might affect other aspects of care, such as the chances of developing other illnesses or resistance to HIV medicines, the frequency of doctor visits, the cost of medical care, and general health and satisfaction.
The START Study recruited in 232 sites in 35 countries on six continents. JCRC is one of the 2 Ugandan/ African sites. START recruited 4,600 participants and JCRC, is the 4th top recruiting site with 159 participants across the START network of 232 sites
SALIF Trial (NCT01709084)
Study period: 2013 – 2015
Funding: US $56, 250 (at JCRC Kampala); Note: It is US $3750 per patient recruited and US $250 per screen failure. JCRC recruited 25 patient.
Source of Funds: Janssen-Cilag International NV
The purpose of this study is to demonstrate noninferiority (a new treatment is equivalent to standard treatment) in terms of the percentage of patients who have plasma human immunodeficiency virus-type 1 (HIV-1) ribonucleic acid (RNA) levels less than 400 copies per mL after 48 weeks of randomized treatment with tenofovir disoproxil fumarate/emtricitabine/rilpivirine (TDF/FTC/RPV) versus TDF/FTC/efavirenz (TDF/FTC/EFV).
SALIF (Switching at Low HIV-1 RNA to Fixed Dose Combinations) is a 48-week, multicenter, multinational, open-label, randomized study to assess whether tenofovir disoproxil fumarate/emtricitabine/rilpivirine (TDF/FTC/RPV) shows non-inferior response rates of HIV-1 RNA suppression less than 400 copies per mL, compared with TDF/FTC/efavirenz (TDF/FTC/EFV). The study consists of 3 phases including, the screening phase (of 6 weeks), treatment phase (of 48 weeks), and follow up phase (of 30 to 35 days after the last dose of study medication). During the 48 weeks treatment phase, patients with HIV-1 RNA suppression less than 50 copies per mL on their first-line antiretroviral regimen, were randomized in a 1:1 ratio, in 2 groups, ie, Group 1 (treatment group) and Group 2 (control group). Both these groups received a fixed dose combination (FDC) regimen (ie, FDC tablet: one tablet per day) of either TDF/FTC/RPV in Group 1 or TDF/FTC/EFV in Group 2. Patients will return for study visits at Week 4, 12, 24, 36, and 48 during the treatment period, and then every 24 weeks thereafter during the extended treatment period until the last patient has his or her Week 48 (or treatment discontinuation) visit. Safety evaluations for adverse events, clinical laboratory (central and local) tests, electrocardiogram, vital signs, and physical examination are performed throughout the study. The treatment duration for each patient is expected to be between 48 and 108 weeks.
WAVES Study (NCT01705574)
Study period: 2012 – 2016
Grant amount: US $100, 695. Note: It is US $10,070 per recruited patient. The budget allows for 10 patients, but it is expected that 150 patients will be recruited.
Source of Funding: Gilead Sciences
This study is to evaluate the safety, efficacy, and tolerability of a regimen containing elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF) single-tablet regiment (STR) versus ritonavir (RTV)-boosted atazanavir (ATV) plus emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) in HIV-1 infected, antiretroviral treatment-naive adult women. This study consists of two phases: Double-Blinded Treatment Phase (60 weeks) and Open Label Extension (OLE) Phase (48 weeks). Participants who are virologically suppressed at Week 48 during the Double-Blinded Treatment Phase will have the option to enter the OLE Phase. Participants randomized to the EVG/COBI/FTC/TDF arm in the Double-Blinded Treatment Phase will continue on open-label EVG/COBI/FTC/TDF STR while participants randomized to the RTV+ATV+FTC/TDF arm will be rerandomized in a 3:1 ratio to receive either open label elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (EVG/COBI/FTC/TAF) STR or RTV+ATV+FTC/TDF.
Study period: 2013 – 2015
Grant amount: US $ 46,000
Source of funding: University of Minnesota
This study will be carried out in collaboration with Prof Timothy Schacker of the Uinversity of Minnesota. It will investigate the role of the integrase inhibitor Raltegravir in HIV kinetics among infected individuals.