Pharmacy and Poisons Board: Applications

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Protocol No:

ECCT/14/08/02

Date of Protocol:

16-09-2011

Study Title:	Management Using the Latest Technologies in Resource-limited Settings to Optimize Combination Therapy After Viral Failure (MULTI-OCTAVE)
Study Objectives:
Laymans Summary:	Title of the study was “Management Using the Latest Technologies in Resource-Limited Settings to Optimize Combination Therapy After Viral Failure (MULTI-OCTAVE).” The main purpose of this study was to see whether using new anti-HIV drugs along with laboratory and clinical management tools could lead to suppression of HIV at about 1 year in more than 65% of people with HIV presenting with second-line anti-HIV treatment failure. The new anti-HIV drugs were: etravirine (ETR), raltegravir (RAL), and ritonavir-boosted darunavir (DRV). The contemporary management tools included the following: resistance testing to choose anti-HIV drugs. Resistance tests look at the HIV in your blood to see which drugs might work best to lower your HIV infection interventions to improve adherence regular testing of the amount of HIV in your blood. From Jan 10, 2013, to Sept 10, 2015, 545 people joined this study. The results of the study showed that for people who had resistance to a standard second-line anti-HIV drug (lopinavir, boosted with ritonavir), who took a regimen containing DRV/r and RAL with or without ETR, the study was a success (more than 65% achieved suppression). For people who did not have resistance to lopinavir, who continued to take their second-line anti-HIV drugs; the study was not a success (less than 65% achieved suppression). We believe that the study results support the use of resistance testing to select appropriate drugs for people with second-line treatment failure. People without resistance to second-line anti-HIV drugs may need additional help and resources to control HIV. This paper was published in the Lancet journal with the following details; Beatriz Grinsztejn, Michael D Hughes, Justin Ritz et al. Third-line antiretroviral therapy in low-income and middle-income countries (ACTG A5288): a prospective strategy study. Lancet HIV, July 29, 2019 http://dx.doi.org/10.1016/S2352-3018(19)30146-8
Abstract of Study:	DESIGN A5288 is an open-label phase IV, prospective interventional, strategy study in resource-limited settings (RLS) for HIV-infected participants with triple-class experience or resistance to [nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs (NNRTIs), and protease inhibitors (PIs)] and who are failing their current regimen. The use of novel agents and contemporary management tools that include standard genotyping, plasma viral load (VL) monitoring will be evaluated. The screening genotype results and antiretroviral (ARV) history will be used to allocate potential participants to one of the four cohorts and for selection of ARV regimen for each potential participant. Refer to the flow chart, At sites where feasible and relevant, the study will also conduct an adherence study. This will be a randomized comparison of cell phone-based adherence intervention plus local standard-of-care adherence procedures (CPI+SOC) versus the SOC adherence procedures. Genotyping and Identification of Cohort and ARV Regimen A standard viral population-based genotype assay determining resistance in protease and partial reverse transcriptase (RT) will be performed in real time at screening. Following receipt of the genotype resistance report, the site investigator will make the initial recommendation for each potential participant (ie, candidate) with regard to the following: 1) Selection of the appropriate cohort AND 2) Planned ARV regimen if the potential participant will be placed in Cohort A (switch of NRTIs to study-provided NRTIs is allowed but not required) OR Choice of at least two NRTIs if the potential participant is to be placed into Cohort B or Cohort C OR The proposed ARV regimen if the potential participant is to be placed into Cohort D. The Clinical Management Committee (CMC) of the A5288 protocol team will review and confirm the site’s recommendation via the CoSPAR System (ACS). After CMC approval of the site-selected cohort and site-recommended regimen options, candidates will be assigned to one of the cohorts, as outlined above. In the event of a confirmed VF on study, participants agreeing to continue in the study will have another genotype resistance test and will be assigned to a Step 2 cohort/ARV treatment group following receipt of the genotype resistance report. The Step 2 cohort selection and confirmation process will be the same as for Step 1 except that for the Step 2 cohort and regimen selection, both genotype resistance reports from screening and Step 1 will be considered. At the completion of Steps 1 and 2 (see Duration below), participants taking RAL, DRV, or ETR may remain on study by entering Step 3. In Step 3, RAL, DRV, and ETR will be provided through the study for up to 96 additional weeks. Participants will have twice yearly clinic visits and sites will be asked to provide information about the local standard of care follow-up that is being provided outside of the study. DURATION 48 weeks after registration/randomization of the last participant (Steps 1 and 2); study completion is defined as remaining in study follow up for this period of time. Step 3, an optional step for participants taking RAL, DRV, or ETR at the study completion, is an additional 96 weeks beginning at study completion. SAMPLE SIZE 500 participants. POPULATION HIV-1-infected males and females at non-US sites, aged ≥18 years, who have experience with or resistance to NRTIs, NNRTIs, and PIs, and are currently failing a PI-containing regimen. RANDOMIZATION Following cohort registration (Cohort A, sub-cohort B3, or Cohorts C or and D) or randomization (to sub-cohorts B1 or B2; see below), participants at sites that are participating in the adherence study will be randomized 1:1 to either CPI+SOC or to SOC adherence procedures. Candidates assigned to Cohort B will be randomized 1:1 at study entry to sub-cohort B1 or B2 if they do not have active hepatitis B infection. Candidates assigned to Cohort B who have active hepatitis B infection will be placed into sub-cohort B3 at study entry. Active hepatitis B infection is defined as HBsAg+ at screening or having a history of HBsAg+ in the past with no subsequent documented positive anti-HBsAb and currently on therapy with drugs active against hepatitis B. REGIMEN Cohort Profiles and Proposed ARV Regimens (Steps 1 and 2) Cohort A: No resistance to NRTIs, PIs, or NNRTI Continue current second-line regimen; NRTIs can be modified Cohort B: Susceptible to DRV/RTV and ETR with or without resistance to NRTIs (and may have resistance to other PIs) Participants without active hepatitis B infection at screening will be randomized 1:1 to sub-cohort B1 or B2 Sub-cohort B1: Best available NRTIs, RAL, and DRV/RTV Sub-cohort B2: ETR, RAL, and DRV/RTV Participants with active hepatitis B infection at screening will be assigned to: Sub-cohort B3: RAL, DRV/RTV, and FTC/TDF or TDF plus 3TC Cohort C: Resistance to NRTIs and ETR or resistance to ETR alone (and may have resistance to PIs other than DRV) Best available NRTIs, RAL, and DRV/RTV Cohort D: Multiple NRTI resistance and/or DRV/RTV resistance or prior RAL exposure Best available regimen, including study-provided and any locally available drugs DRV, ETR, RAL, FTC/TDF, and RTV will be provided by the study for use in study regimens. All other study-required regimen drugs must be obtained locally by the participants from their providers before registration/randomization. Support for the provision of rifabutin (RBT) will be provided through the study. Screening Procedures for Cohort Identification and ARV Regimen Selection Confirmation of Virologic Failure Viral load/s performed (need two HIV-1 RNA results that are ≥1000 copies/mL) Sample collected for Real-Time Genotype assay (protease and partial RT). Resistance Testing and Cohort Identification Screening genotype sample shipped to regional testing laboratory Resistance results sent back to site in real time Based on genotyping results and ARV history, site identifies appropriate cohort, NRTI options (for Cohorts A, B, and C), and proposed ARV regimen for Cohort D Site completes and enters data in the Cohort Selection/Proposed ARV Regimen (CoSPAR) and the Screening HIV-1 RNA and Genotype Tracking forms, uses file exchange utility to attach the genotype resistance report to the A5288 CoSpar System (ACS) and enters the screening tracking form The ACS sends notification via email to CMC that these are ready for review CMC reviews/confirms site selection of cohort and ARV regimen; sends communication to site using the ACS Cohort A Continue 2nd line regimen; NRTIs can be modified Randomized 1:1 to CPI+SOC or SOC Cohort B Randomized 1:1 to sub-cohort B1 or B2 or assigned to B3 Cohort C Best available NRTIs, RAL and DRV/RTV Randomized 1:1 to CPI+SOC or SOC Cohort D Best available regimen, includes study-provided and any locally available drugs Randomized 1:1 to CPI+SOC or SOC Sub-cohort B1 Best available NRTIs, RAL and DRV/RTV Randomized 1:1 to CPI+SOC or SOC Sub-cohort B2 ETR, RAL, and DRV/RTV Randomized 1:1 to CPI+SOC or SOC 1st Confirmed On-Study Virologic Failure (VF) Ship samples for real-time genotyping (protease, partial RT, and integrase [for participants on a RAL-containing regimen]) as soon as VF is confirmed. Step 2 Participants may change their ARV regimen (with CMC approval) after consideration of the screening and Step 1 VF genotype resistance reports and will remain on-study on Step 2 (and, as applicable, in the same randomized adherence study arm) through study completion. If there is second or subsequent confirmed VF on study, samples will be sent for batched genotyping. Step 1 Entry Allocation to Cohort and Initiation of Study Regimen (randomization to adherence study conducted only at sites participating in the adherence study) Sub-cohort B3 RAL, DRV/RTV, and FTC/TDF or TDF plus 3TC Randomized 1:1 to CPI+SOC or SOC Step 3 (Optional) At the end of Step 1 and Step 2 follow-up, participants taking RAL, ETR, or DRV may enter Step 3 and continue to receive these drugs through the study for up to 96 additional weeks. Hypotheses The availability of novel antiretroviral (ARV) agents and use of contemporary management tools for selection and monitoring of third-line treatment will enable a ≥ 65% rate of successful virologic control at 48 weeks of follow-up. Primary Objective To use novel agents and contemporary management tools, including standard genotyping to select an appropriate third-line regimen, interventions to improve adherence and plasma viral load (VL) monitoring, in order to achieve a ≥ 65% rate of virologic control at 48 weeks of follow-up. Secondary Objectives To characterize changes in HIV-1 RNA and CD4+ T-cell counts over 48 weeks and durability of responses after 48 weeks, as well as clinical outcomes (AIDS-defining and non-AIDS-defining events, hospitalizations and deaths) in four treatment groups (Cohorts A-D). To characterize the tolerability of the regimens in four treatment groups (Cohorts A-D). To characterize changes in metabolic outcomes including fasting lipids at 48 weeks among the regimens in four treatment groups (Cohorts A-D). To assess the effect of a CPI+SOC compared to SOC adherence procedures on the rate of virologic control at 48 weeks of follow-up. To determine the safety of combinations of third-line ARV therapy in terms of rates of treatment modification or discontinuation for the treatment of HIV-1 infection and to characterize drug-associated toxicities. To compare changes in HIV-1 RNA and CD4+ T-cell counts over 48 weeks, durability of responses after 48 weeks, and clinical outcomes (AIDS-defining and non-AIDS-defining events and deaths) of CPI+SOC versus SOC adherence procedures. To compare the tolerability of third-line regimens among participants receiving CPI+SOC versus SOC adherence procedures. In Cohort B, among participants without active hepatitis B infection, to explore whether the combination of ETR+DRV/RTV+RAL (etravirine, ritonavir-boosted darunavir, raltegravir) is associated with better virologic control, CD4+ T-cell responses, and tolerability than best available NRTIs+DRV/RTV+RAL. To determine the prevalence at enrollment of resistance mutations detected on a population-based and minority-variant level in the four treatment groups (Cohorts A-D), and to explore prevalence by viral subtype. To describe the mutation patterns and accumulation of mutations over time in the participants experiencing viral failure. To evaluate the impact of predictors, including viral subtype, baseline mutations and polymorphisms occurring in gag, protease, reverse transcriptase, and integrase (IN) [detected by population-based genotyping and minority-variant analysis] on the virologic outcomes in the four treatment groups (Cohorts A-D). To evaluate the association of adherence to the study regimens with virologic outcome. To provide resource utilization and quality of life (QOL) data to support modeling of cost-effectiveness of ART selected using treatment history and standard genotyping as well as cost-effectiveness of the adherence intervention. To estimate the incidence of immune reconstitution inflammatory syndrome (IRIS) and describe the clinical presentation and associated pathogens and/or inflammatory conditions. To describe DRV excretion in breast milk.