A comparison of three highly active antiretroviral treatment strategies consisting of non-nucleoside reverse transcriptase inhibitors, protease inhibitors, or both in the presence of nucleoside reverse trancriptase inhibitors as initial therapy (CPCRA 058 FIRST Study): a long-term randomized trial

Background: A long term trial compare the clinical outcomes of different antiretroviral regimens as initial treatment has never been investigated.

 

Objective: This study compared the clinical efficacy and safety of three different antiretroviral regimens for a median time span of 5 years.

 

Methods: The study was prospective, randomized, and parallel. Patients were enrolled between 1999 and 2002 at 18 different clinical trial units in the United States. Subjects were eligible if they were 13 years of age or older, diagnosed with HIV, had never taken a PI or an NNRTI, had never taken lamivudine greater than one week, or a nucleoside reverse transcriptase inhibitor (NRTI) greater than four weeks. Eligible patients either had their medication chosen by a clinician or consented to take a randomized medication from each class. Patients were randomized according clinical unit and CD4 count. One thousand, three hundred and ninety-seven patients were randomized to receive a PI strategy (PI + 2 NRTIs), NNRTI strategy (NNRTI + 2 NRTIs), or a three-class strategy (PI + NNRT + 1 or 2 NRTIs). The first primary outcome measured a composite score or an AIDS-related event, death, or CD4 count less than 200/mm³ between the PI and NNRTI groups. For a power of 80%, 292 subjects were needed for comparison of the PI and NNRTI groups to find a 0.67 difference in the hazard ratio for the first primary outcome. The second primary outcome measured the difference between mean changes in CD4 cell count for the three-class group and the two class groups combined. One-thousand,one-hundred and seventy-six patients were needed for the entire patient population to give a power of 80% to find a 40-cell difference in the second primary outcome. Secondary outcomes included change in initial treatment strategy, virological suppression, and adverse events. The subjects had study visits at month 1 and 4, then returned every 4 months. Intent to treat analysis was used to evaluate the first primary outcome and the secondary outcomes.

 

Results: The median follow up duration was five years. The hazard ratio for the composite endpoint was 1.02 (95% CI 0.79-1.31) for NNRTI versus PI and 1.15 (0.94-1.42) for the three-class versus two-class.  The difference between the three-class and the combined two-class groups’ mean CD4 counts was 6.7 (-20-33). The hazard ratio for death was 0.95(0.66-1.37) and 0.87 (0.75-1.00) for NNRTI vs. PI and the three-class group vs. the combined two-class group, respectively. Time for first switch in treatment strategy was significant for NNRTI vs. PI at 0.65 (0.53-0.81). Time to decrease in HIV RNA concentration to less than 50 copies/mL was significantly greater in the NNRTI vs. PI measurement at 1.42 (1.23-1.64), but no difference was found between three-class group vs. two-class group (HR 1.31, 1.00-1.28). Virological failure due to drug resistance happened less frequently in the NNRTI group compared to the PI group (HR 0.78, 0.61-0.99). The only grade 4 adverse events that differed between groups was increased liver function tests which were more frequent in the NNRTI group compared to the PI and 3 class groups (p=0.03).

 

Strengths: This study was one of the first long-term clinical trials to examine the difference between three antiretroviral strategies in treatment naïve patients. Also, this study was one of the first controlled studies to measure clinical efficacy among the different groups.

 

Weaknesses: Many of the patients switched treatment strategies during the study (PI 43%, NNRTI 32%, Three-class strategy 80%), which may have affected the study’s results. Also, the study was not blinded which could potentially lead to bias. Different drugs within each class were used, however some specific drugs were used more frequently than others. Therefore, the results do not accurately reflect the entire drug class’s clinical effect.

 

Conclusion: The authors conclude that either an NNRTI or PI strategy should be used instead of the three-class strategy due to its increased toxic effects and lack of benefit in CD4 counts and composite endpoints. The authors interpret the three strategies to be equally effective, however some of the outcomes were statistically significant for differences between the NNRTI and PI treatment strategies. A more controlled trial with pre-selected medications for each drug class may provide a more accurate interpretation of the different treatment strategy’s clinical efficacy.

 

MacArthur RD, Novak M, Peng G, Chen L, Xiang Y, Huppler Hullsiek K, Kozal MJ, van der Ber-Wolf M, Henely C, Schmetter B, Dehlinger M. A comparison of three highly active retroviral treatment strategies consisting of non-nucleoside reverse transcriptase inhibitors, protease inhibitors, or both in the presence of nucleoside reverse transcriptase inhibitors as initial therapy (CPCRA 058 FIRST Study): a long term randomised trial. Lancet 2006;368: 2125-2135.

 

Sarah Workman, Pharm.D. Candidate