HIV Salvage Therapy Does Not Require Nucleoside Reverse Transcriptase Inhibitors: A Randomized, Controlled Trial.

Context Nucleoside reverse transcriptase inhibitors (NRTIs) are often included in antiretroviral regimens for treatment-experienced patients with HIV infection, but no randomized, controlled trials have evaluated this approach. Contribution This large randomized, controlled trial in treatment-experienced patients with HIV infection found no difference in either efficacy or safety when NRTIs were included or excluded in initial optimized antiretroviral regimens. More deaths occurred in the group that added NRTIs to the regimen, but these were not believed to be related to treatment. Caution The trial was not blinded. Implication Regimens for treatment-experienced patients with HIV infection may not need NRTIs, which could have benefit in terms of cost, toxicity, and pill burden. Guidelines for the treatment of HIV-infected patients in whom antiretroviral therapy has failed recommend using a new regimen that combines at least 2, and preferably 3, fully active medications to suppress viral replication (1, 2). Recommendations about which agents to use are lacking, and fully active medications may not be available because of drug resistance. When starting a new regimen in treatment-experienced patients (that is, those who have used antiretroviral drugs before), the standard of care includes nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs); however, treatment-experienced patients have HIV isolates with mutations that significantly compromise NRTI activity. If NRTIs do not contribute to virologic suppression in a well-constructed regimen, their inclusion will only add to the pill burden, cost, and potential toxicity. The availability of several newer antiretroviral agents, which act on targets distinct from the NRTIs, has enabled clinicians to construct regimens using drug resistance assays that include more than 2 active drugs without using NRTIs. These newer non-NRTIs (NNRTIs), protease inhibitors (PIs), integrase strand transfer inhibitors, and entry inhibitors can be combined to construct optimized regimens. We hypothesized that, in the setting of a continuous phenotypic susceptibility score (cPSS) greater than 2 (a research measure of antiretroviral activity), a new regimen that omitted NRTIs would not be inferior to one that added NRTIs. We designed the OPTIONS (Optimized Treatment That Includes or Omits NRTIs) trial to evaluate treatment success and safety in participants receiving a new antiretroviral regimen that omitted or added NRTIs. Supplement. Study protocol. Methods Design Overview The OPTIONS trial is a multicenter, open-label, prospective, randomized, controlled study evaluating the benefits and risks of omitting versus adding NRTIs to a new optimized antiretroviral regimen (3). The study population consists of HIV-infected patients for whom a PI-based regimen has failed and who have triple-class experience (NNRTIs, NRTIs, and PIs) and viral resistance. Participants were randomly assigned to receive an optimized regimen (the omit-NRTIs group) or to add NRTIs to the optimized regimen (the add-NRTIs group). Optimized and NRTI regimens were constructed on the basis of treatment history, viral resistance, and coreceptor tropism tests (performed by Monogram Biosciences using PhenoSense GT and Trofile). The planned primary outcome was regimen failure, defined as virologic failure or change in NRTI group assignment, evaluated through 48 weeks. The study design had 2 important changes. On 13 June 2008, the enhanced Trofile assay (Monogram Biosciences) was introduced and increased the sensitivity in detecting nonR5-using virus by using the complete gp160 coding region of the HIV-1 envelope protein, with clinical laboratory improvement amendment validation experiments showing success at detecting 0.3% CXCR4-using minor variants. On 8 April 2009, follow-up was extended through 96 weeks to evaluate treatment durability (data not presented). The institutional review board at each participating site approved the study protocol. Written informed consent was obtained from all participants in compliance with human experimentation guidelines (U.S. Department of Health and Human Services). Study Participants and Eligibility Criteria Study participants were recruited from 62 outpatient medical clinics into the trial centers across the United States from March 2008 through May 2011, with follow-up through 48 weeks (31 May 2012). The study population included HIV-1infected persons who were at least 16 years of age; had a plasma HIV RNA level of 1000 copies/mL or more; had received a PI-based antiretroviral regimen; had previously used or had evidence of resistance to NRTIs and NNRTIs; and had acceptable laboratory values, including a calculated creatinine clearance of 50 mL/min/1.73 m2. Persons were ineligible if they had active hepatitis B infection, were pregnant or breastfeeding, or were using prohibited medications. A key criterion for randomization was that an individualized regimen with a cPSS greater than 2.0 could be constructed using study antiretroviral medications, excluding NRTIs. A cPSS (0 [not susceptible] to 1 [susceptible]) was calculated (Appendix Table 1) or assigned for each drug in a potential regimen based on the participant's prior drug exposure, virus susceptibility, and tropism result. The regimen cPSS was then calculated by adding together the cPSSs for each drug in the regimen (note that cPSS is largely a research tool). For complete details on inclusion and exclusion criteria, see Appendix Table 2). Appendix Table 1. PSS Assignment Appendix Table 2. Inclusion and Exclusion Criteria for OPTIONS Study Randomization and Intervention Participants were randomly assigned either to omit or to add NRTIs after choosing an optimized regimen and an NRTI regimen. The centralized, computer-based, permuted block randomization (blocks of 4) was stratified by enfuvirtide (ENF) or integrase strand transfer inhibitor use (any vs. none), choice of a maraviroc (MVC)based regimen (yes vs. no), and NRTI susceptibility (susceptible to 0 vs. 1 NRTIs). The NRTI susceptibility criterion was defined by the net assessment among the entire panel of NRTIs in the genotype and phenotype resistance test at screening. Before randomization, a cPSS was calculated for each participant for 20 different optimized regimens. One or more optimized regimens with a cPSS greater than 2.0 and NRTI regimens were recommended by the study team and sent to sites for selection before randomization. Site investigators and study participants selected both an optimized regimen and an NRTI combination. Regimen recommendations were influenced by any prior intolerance or allergy to antiretroviral drugs and the participant's willingness to use ENF. Typically, sites received recommendations for between 1 to 6 optimized regimens and 3 to 4 NRTI combinations in a prioritized order from the study team (the number of options was dependent on the cPSS of each potential regimen). Twenty possible optimized regimens (3, 4) consisting of 3 to 4 medications (excluding ritonavir [RTV]) taken orally twice daily, unless otherwise noted, were composed from the following drugs: 600 mg of darunavir with 100 mg of RTV, 90 mg of ENF by subcutaneous injection, 200 mg of etravirine (ETR), 400 mg of raltegravir (RAL), and 500 mg of tipranavir with 200 mg of RTV. Further, 150, 300, or 600 mg of MVC was administered twice dailydepending on other drugs in the regimenaccording to package insert recommendations (4). Placebos were not used, and all drugs were open-label (site investigators and participants were not blinded). Outcomes and Follow-up Study evaluations were completed before entry; at entry; at weeks 1, 4, 8, 12, 16, and 24; and every 12 weeks thereafter during study follow-up in all participants. Treatment adherence was assessed by self-report at every visit using a standardized questionnaire. Adherence counseling was recommended by the study team to include pill and vial counts from returned bottles and vials of ENF. The primary efficacy outcome was regimen failure through 48 weeks, a composite outcome of first confirmed virologic failure, or discontinuation of NRTI assignment. The latter occurred when a participant in the omit-NRTIs group started any NRTI or when a participant in the add-NRTIs group never initiated NRTIs or permanently discontinued all NRTIs (event time was the scheduled week during which the event was noted). Virologic failure (event time was the scheduled week of initial RNA measurement) was defined when 1 of the following occurred (and was confirmed with another RNA measurement): less than 1log10 copies/mL decrease from baseline at the 12-week visit, virologic rebound greater than 200 copies/mL after suppression to less than 200 copies/mL, lack of suppression to less than 200 copies/mL by the 24-week visit, or an HIV-1 RNA level of 200 copies/mL or more at the 48-week visit. All potential regimen failure outcomes were reviewed by 2 nonteam members who were blinded to treatment assignment and study site. Plasma HIV-1 RNA was measured (UltraSensitive Cobas Amplicor HIV-1 Monitor UltraSensitive assay, version 1.5, Roche Molecular Systems) at Johns Hopkins University (Baltimore, Maryland). The primary safety outcome was time from treatment dispensation to first grade 3 or 4 sign, symptom, or laboratory abnormality that was at least 1 grade higher than baseline while the participant was receiving treatment. Adverse events were graded using the Table for Grading the Severity of Adult and Pediatric Adverse Events (version 1.0, December 2004; National Institute of Allergy and Infectious Diseases Division of AIDS). Secondary outcomes reported here include the time from randomization to discontinuation of NRTI assignment, time from randomization to confirmed virologic failure, probability of a plasma HIV-1 viral load less than 50 copies/mL at 24 or 48 weeks, probability of self-reported nonadherence to antiretroviral regimen (excluding N