HIV-1-infection
Conditions
Keywords
HIV, Dolutegravir, Treatment failure, Drug resistant mutations, Dolutegravir resistance, Re-suppression
Brief summary
This clinical trial will address the gap in published data on the effect of dolutegravir (DTG)-associated drug-resistant mutations on viral suppression among people remaining on DTG-based antiretroviral therapy. It will also address the gap in the optimal management strategy for this population.
Detailed description
BACKGROUND: The majority of people living with HIV (PLWH) on first-line antiretroviral therapy (ART) in low- and middle-income countries are on dolutegravir (DTG)-containing regimens. Different countries have adopted different approaches in the management of people on DTG-based first-line ART with repeat HIV viral load (VL) of \> 1,000 copies/mL after 3 months of enhanced adherence counselling. For example, Kenya recommends a drug resistance test (DRT) to guide on switch and the optimal second-line regimen; Mozambique and Tanzania recommend switch to 2 nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs) without drug resistance testing; South Africa does not recommend switch from DTG or DRT for those who are on first-line DTG-containing regimens within the first 2 years of treatment, after which management is guided by possible DRT and expert opinion. The World Health Organization has recognised the role of drug resistance testing (DRT) in a treatment failure algorithm for people living with HIV receiving DTG-based treatment to minimise unnecessary switches from this regimen. The switch to PI has disadvantages including higher cost, higher pill burden, less convenient administration (often should be taken with food), more potential drug-drug interactions, poorer tolerability and more long-term toxicities. GOAL: To assess the efficacy and safety of remaining on DTG compared to switching to DRV/r among people failing DTG-based ART with at least one major DTG DRM. METHODS: This is a phase 3b, multi-country, open-label, two-arm, active-controlled randomized clinical trial (RCT) over 12 months describing the efficacy and safety of switching from DTG to DRV/r among PLWH age ≥ 3 years who are failing DTG-based ART with HIV-1 RNA ≥ 200 copies/mL and ≥ 1 major DTG-associated DRM (and most recent prior HIV-1 RNA ≥ 1,000 copies/mL after at least 6 months on DTG-based ART). The primary efficacy endpoint is the proportion of participants with HIV-1 RNA \< 200 copies/mL at month 6. The study will be conducted in 9 sites in Kenya, Mozambique, Tanzania and Lesotho targeting 392 participants including 30 children aged between 3 and 14 years old. The primary efficacy analysis will assess the difference in the proportion of participants with viral suppression at month 6 using the Cochran-Mantel-Haenszel method. This RCT is nested within an observational cohort study describing HIV-1 viral suppression of people with HIV-1 RNA value of ≥ 1,000 copies/mL after at least six months on DTG-based ART.
Interventions
Dose will be based on weight; brand names will be as supplied through the respective national programs
Dose will be based on weight
Sponsors
Instituto Nacional de Saúde, Mozambique
Muhimbili University of Health and Allied Sciences
SolidarMed
London School of Hygiene and Tropical Medicine
University of Nairobi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a phase 3b, multi-country, open-label, two-arm, active-controlled randomized clinical trial over 12 months describing the efficacy and safety of switching from DTG to DRV/r among PLWH age ≥ 3 years who are failing DTG-based ART with HIV-1 RNA ≥ 200 copies/mL and ≥ 1 major DTG-associated DRM (substitution at codon 66K, 92Q, 118R, 138K/A/T, 140S/A/C, 148H/R/K, 155H or 263K ), and most recent prior HIV-1 RNA ≥1,000 copies/mL after at least 6 months on DTG-based ART.
Eligibility
Sex/Gender
ALL
Age
3 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Enrolled in the Ndovu cohort study * Able and willing to understand and comply with the protocol requirements, instructions and restrictions * Able and willing to provide informed consent for the nested clinical trial (assent as appropriate and legal guardian consent if \< 18 years) * Age ≥ 3 years * Most recent HIV-1 RNA ≥ 200 copies/mL * At least one major DTG-associated DRM (substitution at codon 66K, 92Q, 118R, 138K/A/T, 140S/A/C, 148H/R/K, 155H or 263K)
Exclusion criteria
* Pregnant or breastfeeding * Using any concomitant therapy disallowed as per the reference safety information and product labelling for the study drugs * WHO stage 3 or 4 opportunistic infection which would prevent randomisation to either arm (e.g. due to drug interactions or significant liver or renal injury) within 4 weeks prior to RCT screening * Investigator opinion that the potential participant should discontinue DTG immediately for clinical reasons * Investigator opinion that the potential participant should not switch to DRV/r for clinical reasons
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of participants with HIV-1 RNA of <200 copies/mL at 6 months | 6 months | The comparative efficacy of switching to a DRV/r-based regimen after confirmed virologic failure and of remaining on DTG-based ART in achieving viral suppression of \<200 copies/mL at 6 months from randomization among participants with ≥1 major DTG-associated DRM |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Superiority of switch to DRV/r | 6 months | Evaluate if switching to DRV/r-based ART after virologic failure is superior to remaining on DTG-based ART in achieving viral suppression to \<200 copies/mL at 6 months from randomization |
| Viral suppression with cut-off of 50 copies/mL | 6 and 12 months | Evaluate the difference in viral suppression using HIV-RNA cut-off of \<50 copies/mL at 6 and 12 months from randomization |
| Viral suppression with cut-off of 1,000 copies/mL | 6 and 12 months | Evaluate the difference in viral suppression using HIV-RNA cut-off of \<1,000 copies/mL at 6 and 12 months from randomization |
| Viral suppression by age strata | 6 and 12 months | Viral load suppression rate by age strata: 3-9, 10-19, ≥20, 20-24, 25-34, 35-44, and ≥45 years old |
| Viral suppression by sex at birth | 6 and 12 months | Viral load suppression based on participant's sex |
| Incidence of adverse events by study arm | 6 and 12 months | Incidence and severity of adverse events and laboratory abnormalities |
| Association between adherence and suppression | 6 months | Adherence levels, based on DBS TFV-DP levels, associated with suppression and selection of treatment-emergent DRMs |
| Incidence of drug resistant mutations (DRMs) | 6 and 12 months | Incidence of treatment-emergent DRMs over 12 months of follow-up |
| Proportion of participants with HIV-1 RNA of <200 copies/mL at 12 months | 12 months | Viral suppression to HIV-RNA of \<200 copies/mL at 12 months from randomization |
| Drug resistant mutations (DRM) patterns associated with non-suppression | 6 and 12 months | Evaluate drug resistant mutation patterns that are associated with sustained non-suppression |
| Predictors of DTG-associated drug resistant mutations (DRMs) | 6 and 12 months | Investigate the predictors of selection of DTG-associated drug resistant mutations |
| Viral suppression by pre-enrolment nucleoside reverse transcriptase inhibitor (NRTI) | 6 and 12 months | Assess viral suppression based on pre-enrolment NRTI |
| Viral suppression by tenofovir disoproxil fumarate versus tenofovir alafenamide | 6 and 12 months | Assess viral suppression based on tenofovir disoproxil fumarate (TDF) versus tenofovir alafenamide (TAF) as the study nucleoside reverse transcriptase inhibitor |
| Change in cluster of differentiation 4 (CD4) Count | 6 and 12 months | The impact of regimen on change in cluster of differentiation 4 (CD4) count |
| Patient satisfaction as measured using the HIV Treatment Satisfaction Questionnaire - Status version (HIVTSQs) which scores 10 variables on a 7-point likert score ranging from 0 to 6 with a higher score representing a better outcome | 6 months | Patient satisfaction (HIVTSQs) at baseline |
| Change in patient satisfaction as measured using the HIV Treatment Satisfaction Questionnaire - Change version (HIVTSQc) which scores 10 variables on a 7-point likert score ranging from -3 to +3 with a higher score representing a better outcome | Month 6 | Patient satisfaction (HIVTSQc) at month 6 |
| Patterns of accumulated drug resistant mutations (DRMs) | 6 and 12 months | Describe the patterns of accumulated drug resistant mutations over 12 months of follow-up |
Countries
Kenya, Lesotho, Mozambique, Tanzania
Contacts
Primary ContactJoseph Nkuranga, MBChB, MSc
Outcome results
None listed