Third-line antiretroviral therapy in low-income and middle-income countries (ACTG A5288): a prospective strategy study

Abstract

Background: Antiretroviral therapy (ART) management is challenging for individuals in resource-limited settings presenting for third-line treatment because of complex resistance patterns, partly due to reduced access to viral load monitoring. We aimed to evaluate use of newer antiretroviral drugs and contemporary management approaches, including population-based sequencing, to select appropriate antiretrovirals, plasma viral load monitoring, and interventions to improve adherence in individuals presenting with second-line viral failure.

Methods: A5288 was a phase 4, third-line ART strategy study done at 19 urban sites in ten countries that enrolled adult participants with confirmed plasma HIV-1 RNA (viral load) of 1000 copies per mL or more after more than 24 weeks of protease inhibitor-based second-line ART. The primary objective was to use antiretrovirals (raltegravir, etravirine, and ritonavir-boosted darunavir) and diagnostic monitoring technologies, including viral load, genotyping, and adherence support to achieve viral load suppression (defined as ≤200 copies per mL) in 65% or more of participants. ART history and real-time drug resistance genotypes were used to assign participants to one of four cohorts: cohort A (no lopinavir resistance) stayed on second-line ART and cohorts B (B1, best available nucleoside reverse transcriptase inhibitors [NRTIs] plus ritonavir-boosted darunavir plus raltegravir; B2, ritonavir-boosted darunavir plus raltegravir plus etravirine; B3, ritonavir-boosted darunavir, raltegravir, and either tenofovir plus emtricitabine or tenofovir plus lamivudine), C (ritonavir-boosted darunavir plus raltegravir plus tenofovir-emtricitabine or tenofovir plus lamivudine), and D (best available NRTIs plus ritonavir-boosted darunavir plus raltegravir) were defined by increasing levels of resistance and received appropriate regimens, including new antiretrovirals. Participants in Cohort B without detectable hepatitis B surface antigen were assigned by blocked randomisation to cohorts B1 and B2, and those with detectable hepatitis B surface antigen were assigned to cohort B3. The trial is registered with ClinicalTrials.gov, number NCT01641367.

Findings: From Jan 10, 2013, to Sept 10, 2015, 545 participants were enrolled. 287 (53%) were assigned to cohort A, 74 (14%) to B1, 72 (13%) to B2, eight (1%) to B3, 70 (13%) to C, and 34 (6%) to D. Overall, 349 (64%, 95% CI 60-68) participants achieved viral suppression at week 48, with proportions varying from 125 (44%) of 287 in cohort A to 65 (88%) of 74 in cohort B1, 63 (88%) of 72 in B2, eight (100%) of eight in B3, 63 (90%) of 70 in C, and 25 (74%) of 34 in D. Participants in cohort A remained on their second-line protease inhibitor, and had the most participants with grade 3 or higher adverse events (147 [51%]).

Interpretation: Targeted real-time genotyping to select third-line ART can appropriately allocate more costly antiretrovirals to those with greater levels of HIV drug resistance.

Funding: National Institutes of Health.

Figure 1:. Cohort Definitions, Assignment and Antiretroviral Regimens

Figure showing criterion by which participants were assigned to the respective cohorts and the regimen for each. Figure 1 definitions: ARV = antiretroviral; CPI = cell-phone intervention; SOC = standard of care; NRTI = nucleoside reverse transcriptase inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; HepB = hepatitis B; 3TC = lamivudine; DRV = darunavir; ETR = etravirine; FTC = emtricitabine; LPV = lopinavir; RAL = raltegravir; RTV = ritonavir; TDF = tenofovir

Figure 2:. Trial Profile

The progress of all participants from screening through assignment/randomization and analysis are displayed. Key outcomes are identified within each block. Populations for analyses are also summarized.

Figure 3:. Baseline Resistance by Cohort and Drug Class

Showing the percentage of participants in each cohort with resistance to at least one drug in the class. Drug resistance interpretation for the study used the Stanford HIVDB 6.2 algorithm, but with rules for etravirine (ETR) and darunavir (DRV) resistance modified for this study. Drugs included in the interpretation of nucleoside reverse transcriptase inhibitor (NRTI) class resistance were lamivudine (3TC), emtricitabine (FTC), abacavir (ABC), zidovudine (ZDV), stavudine (D4T), didanosine (DDI) and tenofovir (TDF); drugs included for non-nucleoside reverse transcriptase inhibitor class resistance were efavirenz (EFV), nevirapine (NVP) and etravirine (ETR); and drugs included for protease inhibitor (PI) class resistance were atazanavir (ATV), darunavir (DRV), indinavir (IDV), lopinavir (LPV), nelfinavir (NFV), saquinavir (SQV), tipranavir (TPV) and fosamprenavir (FPV).

FIGURE 4:. PANEL ‘A’ – HIV-1 RNA ≤ 200 copies/mL at week 48 with accompanying table:

Showing the percentage of participants in each cohort with HIV-1 RNA ≤ 200 copies/mL at week 48, irrespective of the antiretroviral regimen being taken at the time. The black dashed line at 65% represents the pre-defined suppression rate evaluated on the study. The week 48 measurement was the measurement closest to exactly 48 weeks (i.e. 7×48=336 days) after the date of study entry within a window of 295 to 378 days after study entry, inclusive. Participants who died or were lost to follow-up before week 48 are considered as not having HIV-1 RNA ≤200 copies/mL at week 48. Participants with a missing HIV-1 RNA measurement at week 48 were considered as not having HIV-1 RNA ≤200 copies/mL at week 48 unless the immediately preceding and immediately succeeding HIV-1 RNA measurements were both ≤200 copies/mL.

FIGURE 4-. PANEL ‘B’– Cumulative incidence of virologic failure and accompanying table displaying development of resistance associated mutations

Shown are the cumulative percentage of participants who experienced confirmed virologic failure over time. At-risk numbers for each cohort and time point are displayed. For participants who did not experience confirmed virologic failure (including those who died), censoring was at the last HIV-1 RNA measurement on or before the end of follow up. Virologic failure was defined as two consecutive HIV-1 RNA values greater than or equal to 1000 copies/mL at or after 24 weeks on study. Evaluations for virologic failure included in the analysis occurred on or after 22 weeks (specifically, on or after 154 days from study entry) to allow for the scheduled visit window for the week 24 visit. The identification of new resistance-associated mutations was defined as the development of a mutation, not present at screening, identified and scored by the Stanford HIVDB 6.2 algorithm. Changes in mixture mutations were not counted as new mutations. Participants indicated as having developed new mutations may have lost mutations present at screening.