HIV Salvage Therapy Does Not Require Nucleoside Reverse Transcriptase Inhibitors: A Randomized, Controlled Trial
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Ann Intern Med. Dec 15 2015
Karen T. Tashima, MD; Laura M. Smeaton, MS; Carl J. Fichtenbaum, MD; Adriana Andrade, MD, MPH; Joseph J. Eron, MD; Rajesh T. Gandhi, MD; Victoria A. Johnson, MD; Karin L. Klingman, MD; Justin Ritz, MS; Sally Hodder, MD; Jorge L. Santana, MD; Timothy Wilkin, MD; Richard H. Haubrich, MD, on behalf of the A5241 Study Team
Background: Nucleoside reverse transcriptase inhibitors (NRTIs) are often included in antiretroviral regimens in treatment-experienced patients in the absence of data from randomized trials.
Objective: To compare treatment success between participants who omit versus those who add NRTIs to an optimized antiretroviral regimen of 3 or more agents.
Design: Multicenter, randomized, controlled trial. (ClinicalTrials.gov: NCT00537394)
Setting: Outpatient HIV clinics.
Participants: Treatment-experienced patients with HIV infection and viral resistance.
Intervention: Open-label optimized regimens (not including NRTIs) were selected on the basis of treatment history and susceptibility testing. Participants were randomly assigned to omit or add NRTIs.
Measurements: The primary efficacy outcome was regimen failure through 48 weeks using a noninferiority margin of 15%. The primary safety outcome was time to initial episode of a severe sign, symptom, or laboratory abnormality before discontinuation of NRTI assignment.
Results: 360 participants were randomly assigned, and 93% completed a 48-week visit. The cumulative probability of regimen failure was 29.8% in the omit-NRTIs group versus 25.9% in the add-NRTIs group (difference, 3.2 percentage points [95% CI, −6.1 to 12.5 percentage points]). No significant between-group differences were found in the primary safety end points or the proportion of participants with HIV RNA level less than 50 copies/mL. No deaths occurred in the omit-NRTIs group compared with 7 deaths in the add-NRTIs group.
Limitation: Unblinded study design, and the study may not be applicable to resource-poor settings.
Conclusion: Treatment-experienced patients with HIV infection starting a new optimized regimen can safely omit NRTIs without compromising virologic efficacy. Omitting NRTIs will reduce pill burden, cost, and toxicity in this patient population.
Primary Funding Sources: National Institute of Allergy and Infectious Diseases, Boehringer Ingelheim, Janssen, Merck, ViiV Healthcare, Roche, and Monogram Biosciences (LabCorp).
⋅ 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.
⋅ 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.
⋅ The trial was not blinded.
⋅ 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.
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 non-R5-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-1-infected 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).
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 daily-depending on other drugs in the regimen-according 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 1-log10 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 NRTIs) at 24 or 48 weeks, change in CD4+ cell count from baseline to 48 weeks, and occurrence of newly acquired HIV drug resistance between treatment dispensation and confirmed virologic failure. Secondary outcomes not reported here include the time from treatment dispensation to first antiretroviral modification, excluding NRTIs; change in cardiovascular risk score from baseline to 24 and 48 weeks; time from treatment dispensation to serious non-AIDS-defining events; change in fasting non-high-density lipoprotein cholesterol level from baseline to 24 and 48 weeks; and 96-week outcomes.
On the basis of a planned sample size of 177 participants per group, the study had 80% power to test for the noninferiority of omitting versus adding NRTIs, with a 1-sided significance level of 2.5%, assuming a failure rate of 35% in each group, and a noninferiority margin of 15%. This noninferiority margin was chosen to yield a feasible study design with a clinically significant margin. Analyses were done with SAS, version 9 (SAS Institute).
The cumulative probability of regimen failure by 48 weeks (primary outcome) was estimated using a stratified Kaplan-Meier estimator, with strata defined by the 4 unique groups of ENF or integrase strand transfer inhibitors experience with MVC or non-MVC regimens. These estimates were found by weighting the stratum-specific estimates (PROC LIFETEST), according to treatment group, using inverse variance weights. The CIs were calculated using the log(-log)-transformed Greenwood-estimated variance. Participants without regimen failure who left the study before 48 weeks were censored at the scheduled week of the last visit.
If the upper 95% confidence bound of the stratified difference in cumulative probability of regimen failure between groups at 48 weeks was less than 15%, then noninferiority would be concluded. Tests for statistical interactions between baseline characteristics and treatment effect used a stratified logistic regression model (PROC LOGISTIC).
Safety analyses used superiority hypotheses and stratified log-rank tests (PROC LIFETEST). Because of the similarity in results regardless of stratification, we did not adjust cumulative incidence (Kaplan-Meier) plots of time to the various safety outcomes and estimated cumulative probabilities of events by 48 weeks for strata.
Between-group comparisons of changes in CD4+ cell count by 48 weeks used a stratified extension to the Wilcoxon rank-sum test called the van Elteren test (PROC FREQ). The secondary outcome of an HIV-1 RNA level less than 50 copies/mL was compared between groups at 48 weeks with the use of an exact Cochran-Mantel-Haenszel test (PROC MULTTEST). All participants with outcomes at 48 weeks (or baseline and 48-week outcomes for CD4+ cell count) were included in these secondary analyses. Those in 24- or 48-week follow-up who were missing adherence data (and did not report a reason for missed data) were counted as having missed 1 or more doses of the chosen antiretroviral regimen.
Reported P values are 2-sided. Secondary outcomes evaluated between 48 and 96 weeks are not presented. Results from 53 participants who were not randomly assigned and whose available regimens had a cPSS of 2.0 or less are not presented.
Study conduct, safety, and efficacy data were reviewed yearly by an independent National Institute of Allergy and Infectious Diseases Data and Safety Monitoring Board.
Role of the Funding Source
The study was supported by the National Institute of Allergy and Infectious Diseases. Study medications were provided by Roche (ENF), ViiV Healthcare (MVC), AbbVie (RTV), Janssen (darunavir and ETR), Merck (RAL), and Boehringer Ingelheim (tipranavir). Monogram Biosciences performed the viral resistance and tropism testing. The funding sources did not have a role in the design, conduct, and analysis of the study or in the decision to submit the manuscript for publication.
Participants were enrolled between March 2008 and May 2011 at 62 centers in the United States, with follow-up through 48 weeks completed by 31 May 2012. Of 720 potential participants screened for resistance testing, 516 were available for eligibility screening (Figure 1); 360 were randomly assigned. Fifty-three participants could not be randomly assigned because only regimens with a cPSS of 2.0 or less could be constructed for them; they were assigned treatment with an optimized regimen and NRTIs (data not presented).
Baseline characteristics were similar among the randomized groups (Table).The median cPSS of chosen regimens (excluding NRTIs) was 3.0. The median number of active NRTIs was 1.0. The most common antiretroviral regimen was RAL plus RTV-boosted darunavir with ETR (56%); in the add-NRTIs group, 81% of participants used tenofovir plus emtricitabine (or lamivudine) (Appendix Table 3). Note that randomization to the add-NRTIs group occurred after selection of the optimized regimen and NRTIs. Three participants did not start the study treatment. A total of 337 (94%) participants completed follow-up, and at each of the 8 visits over 48 weeks, at least 95% of participants completed a study visit. In the add-NRTIs group, 90% of participants reported receiving NRTIs for at least 42 weeks. In the omit-NRTIs group, 26 (15%) participants reported missing 1 or more doses of their chosen antiretroviral regimen by 4-day recall versus 25 (15%) from the add-NRTIs group at 24 weeks. Results were similar at 48 weeks (26 participants [16%] in the omit-NRTIs group and 30 [18%] in add-NRTIs group).
Primary Outcome of Regimen Failure
We noted 53 regimen failures in the omit-NRTIs group and 48 in the add-NRTIs group (Figure 2). Only 5 participants left the study before 48 weeks and were not adjudicated as regimen failures. The estimated cumulative probabilities of regimen failure by 48 weeks were 29.8% and 25.9% in the omit- and add-NRTIs groups, respectively (estimated difference, 3.2 percentage points [95% CI, −6.1 to 12.5 percentage points]), which allowed for the conclusion of noninferiority between the groups. The time to regimen failure did not differ between the groups (stratified log-rank P = 0.50) (Figure 3, A). Of the 101 regimen failures, 83 were triggered by virologic failure (41 and 42 in the omit- and add-NRTIs groups, respectively), 16 were triggered by NRTI strategy discontinuation (10 and 6, respectively) (Appendix Table 4), and 2 had both concurrently (omit-NRTIs group). The separate end points of confirmed virologic failure and NRTI strategy discontinuation showed noninferiority of the omit-NRTIs group (Figure 2).
When we examined the primary end point of regimen failure by sex, race, number of active NRTIs, viral tropism, stratification factors, cPSS of the regimen, or the use of ENF, we found no evidence of significant differences in treatment effect (Appendix Figure).
HIV-1 RNA Level and CD4+ Cell Count Changes Over Time
In the omit-NRTIs group, 64% (CI, 56% to 72%) of participants with available HIV-1 RNA results had less than 50 copies/mL at 48 weeks compared with 66% (CI, 59% to 73%) in the add-NRTIs group (P = 0.73) (Figure 4, top). Among participants with baseline and 48-week values, the median increase in CD4+ count from baseline to 48 weeks (Figure 4, bottom) was 0.090 x 109 cells/L (interquartile range, 0.033 to 0.167 x 109 cells/L) in the omit-NRTIs group and 0.106 x 109 cells/L (interquartile range, 0.046 to 0.214 x 109 cells/L) in the add-NRTIs group (P = 0.112).
Adverse Events and Changes in Creatinine Clearance and Lipid Levels
The estimated probability of a primary safety event was 38% (CI, 32% to 46%) (Figure 3, B) in the omit-NRTIs group versus 35% (CI, 28% to 43%) in the add-NRTIs group (P = 0.93). Time to first severe or worse sign or symptom did not significantly differ between groups (P = 0.149) (Figure 3, C) (Appendix Table 5). The omit-NRTIs group had a nonsignificantly shorter time to first severe or worse laboratory abnormality than the add-NRTIs group (P = 0.093) (Figure 3, D); this was primarily due to lipid elevations. Grade 3 or higher hepatic abnormalities were rare (4% and 2% in the omit- and add-NRTIs groups, respectively) as were elevations in creatinine clearance (2% in each group). The omit-NRTIs group had larger increases in lipid values than the add-NRTIs group, although changes in creatinine clearance did not significantly differ between groups (Appendix Table 6).
Serious Adverse Events and Deaths
Thirty-seven (21%) and 44 (24%) participants in the omit- and add-NRTIs groups, respectively, had a serious adverse event. Three serious adverse events in the omit-NRTIs group and 13 in the add-NRTIs group were thought to be at least possibly related to antiretroviral therapy.
After treatment initiation, there were no deaths in the omit-NRTIs group and 6 deaths in the add-NRTIs group (3.3 deaths per 100 person-years [CI, 1.5 to 7.4 deaths per 100 person-years]). The causes of death were as follows: heart failure in a participant with lymphoma (9 weeks on study treatment), Listeria meningitis (17 weeks), renal failure (21 weeks), sepsis with liver failure (25 weeks), progressive multifocal leukoencephalopathy (30 weeks), and abdominal bleeding in a participant with hepatitis C virus and cirrhosis (52 weeks). Three deaths occurred during the prerandomization screening period (median follow-up, 63 days), when all participants (n = 516) continued an NRTI-based regimen, yielding an incidence of death before randomization of 4.2 deaths per 100 person-years (CI, 1.3 to 12.9 deaths per 100 person-years).
Emergence of HIV-1 Drug Resistance Among Participants With Virologic Failure
In the omit-NRTIs group, resistance to ETR developed in 9 of 43 (21.0%) participants who had resistance testing after virologic failure. In the add-NRTIs group, 13 of 45 (29.0%) participants with virologic failure developed ETR resistance and 5 of 45 (11.0%) had decreased susceptibility to tenofovir. Emergence of resistance to other study antiretroviral drugs was rare.
Of the 177 participants with R5 tropic virus found during screening, 70% (124 of 177) chose an MVC-containing regimen. Twenty-two percent (27 of 124) of participants receiving MVC had virologic failure, which was similar to the 21% (11 of 53) rate of virologic failure among participants who were eligible for but did not choose an MVC-containing regimen. Among the participants choosing MVC who had virologic failure and viral tropism results, 5 of 26 (19%) shifted to dual-mixed virus.
OPTIONS was a multicenter, randomized, controlled trial in patients for whom current PI-based therapy that included NRTIs had failed. This trial showed that the addition of NRTIs, the cornerstone of initial antiretroviral regimens (1), can be safely omitted if a new optimized regimen contains several fully or partially active antiretroviral medications and the regimen has a cPSS greater than 2.0. Most participants in this trial chose a regimen with 3 to 4 antiretroviral drugs with partial or full activity. Through 48-week follow-up, regimen failure, which combined confirmed virologic failure and discontinuation of the NRTI assignment, was not more likely if NRTIs were omitted from the new optimized regimens. The noninferiority conclusion was robust and consistent across sensitivity analyses, including analysis of the separate components of the primary endpoint for regimen failure. No significant differences in regimen failure between groups were seen in subgroups of participants defined by stratification factors, demographics, or an initial cPSS less than 3.0. Further, HIV RNA suppression to less than 50 copies/mL, increase in CD4+ cell count, and time to regimen failure were similar in the omit- and add-NRTIs groups. Therefore, among treatment-experienced patients starting an antiretroviral regimen with a cPSS greater than 2.0, there is strong and consistent evidence that adding NRTIs is not necessary to achieve optimal outcomes.
This study adds substantially to our knowledge of optimal therapy for treatment-experienced patients. In small and observational studies, NRTI-sparing regimens showed promise for treatment of patients with antiretroviral drug resistance (5-8). In 2 large randomized studies conducted in resource-limited settings for virologic failure of a first-line NNRTI regimen, RAL plus lopinavir-RTV was noninferior to 2 NRTIs plus lopinavir-RTV (9-10). Studies evaluating new regimens in treatment-experienced participants with limited options had only a few patients receiving NRTI-sparing regimens (11-14). For example, in the TRIO study (14), which evaluated darunavir-ETR-RAL in treatment-experienced patients, only 16% received a regimen without NRTIs. Thus, that trial could not answer whether NRTIs should be included in regimens for treatment-experienced patients starting several active agents.
We noticed more unexplained deaths in the add-NRTIs group than in the omit-NRTIs group. The causes of death were similar to those described in large HIV cohort studies (15-18) and could not be clearly attributed to NRTI toxicities. The small number of events limits our ability to conclude that omitting NRTIs leads to reduced mortality.
Our study has limitations. The role of adding NRTIs to a regimen when the cPSS is 2.0 or less was not analyzed. Adding NRTIs may be helpful in persons whose available regimens have with a cPSS less than 2.0. In addition, the minimum number of active antiretroviral drugs required in an optimized regimen without NRTIs is unknown. These results may not apply to resource-poor settings in which genotypic or phenotypic testing and tropism assays are not available. Finally, study treatment was not blinded to participants and investigators.
Long-term toxicities of NRTIs include decreased bone mineral density, nephrotoxicity, and potential increased risk for myocardial infarction (19-21). Over 48 weeks, however, we did not observe a significant reduction in adverse events in the omit-NRTIs group.
In patients who have previously received antiretroviral drugs, NRTIs can be safely omitted from new active regimens provided that the cumulative activity of the regimen exceeds that of 2 fully active agents as measured by current genotypic and phenotypic testing and tropism assays; prior treatment history must also be accounted for. The potential benefits of omitting NRTIs include reduced pill burden; reduced cost; and, probably, a decrease in NRTI-associated toxicity over the long term. These results have been incorporated in recent antiretroviral guideline recommendations for treatment-experienced patients (2).