Background: Long-term data from randomised trials on the consequences of treatment with a protease inhibitor (PI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or both are lacking. Here, we report results from the FIRST trial, which compared initial treatment strategies for clinical, immunological, and virological outcomes. Methods: Between 1999 and 2002, 1397 antiretroviral-treatment-naive patients, presenting at 18 clinical trial units with 80 research sites in the USA, were randomly assigned in a ratio of 1:1:1 to a protease inhibitor (PI) strategy (PI plus nucleoside reverse transcriptase inhibitor [NRTI]; n=470), a non-nucleoside reverse transcriptase inhibitor (NNRTI) strategy (NNRTI plus NRTI; n=463), or a three-class strategy (PI plus NNRTI plus NRTI; n=464). Primary endpoints were a composite of an AIDS-defining event, death, or CD4 cell count decline to less than 200 cells per mm3 for the PI versus NNRTI comparison, and average change in CD4 cell count at or after 32 months for the three-class versus combined two-class comparison. Analyses were by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT00000922. Findings: 1397 patients were assessed for the composite endpoint. A total of 388 participants developed the composite endpoint, 302 developed AIDS or died, and 188 died. NNRTI versus PI hazard ratios (HRs) for the composite endpoint, for AIDS or death, for death, and for virological failure were 1·02 (95% CI 0·79-1·31), 1·07 (0·80-1·41), 0·95 (0·66-1·37), and 0·66 (0·56-0·78), respectively. 1196 patients were assessed for the three-class versus combined two-class primary endpoint. Mean change in CD4 cell count at or after 32 months was +234 cells per mm3 and +227 cells per mm3 for the three-class and the combined two-class strategies (p=0·62), respectively. HRs (three-class vs combined two-class) for AIDS or death and virological failure were 1·15 (0·91-1·45) and 0·87 (0·75-1·00), respectively. HRs (three-class vs combined two-class) for AIDS or death were similar for participants with baseline CD4 cell counts of 200 cells per mm3 or less and of more than 200 cells per mm3 (p=0·38 for interaction), and for participants with baseline HIV RNA concentrations less than 100 000 copies per mL and 100 000 copies per mL or more (p=0·26 for interaction). Participants assigned the three-class strategy were significantly more likely to discontinue treatment because of toxic effects than were those assigned to the two-class strategies (HR 1·58; p<0·0001). Interpretation: Initial treatment with either an NNRTI-based regimen or a PI-based regimen, but not both together, is a good strategy for long-term antiretroviral management in treatment-naive patients with HIV.
Bibliographical noteFunding Information:
We thank the people who participated in the study; the staff at participating CPCRA units; Lynn Besch for her many years of involvement on the protocol team; Doug Mayers as former protocol co-chair; David Cohn, Wafaa El-Sadr, Fred Gordin, and Jim Neaton for their thoughtful comments and manuscript review; and Bristol-Myers Squibb and GlaxoSmithKline for provision of some study medication. This study was supported by grants (5U01AI042170-10 and 5U01AI046362-03) from the National Institute of Allergy and Infectious Diseases, National Institutes of Health.
RDM has received speaking honoraria and consulting fees from Bristol-Myers Squibb, GlaxoSmithKline, Abbott, Pfizer, Gilead Sciences, Boehringer-Ingelheim, and Roche and has received speaking honoraria from Merck. RDM has also received grant support from GlaxoSmithKline, Pfizer, and Abbott. RMN has consulting agreements with Abbott, Pfizer, Gilead Sciences, Tibotec, and Boehringer-Ingelheim and also has research contracts with Bristol-Myers Squibb, Abbott, GlaxoSmithKline, and Merck. MJK has received royalties from a patent owned by Stanford University for some HIV genotype resistance tests. MJK is the local primary investigator on two Merck HIV-1 integrase inhibitor studies. In the past, MJK has received honoraria and speakers fees, including reimbursement of travel and accommodation expenses from Abbott, Agouron, Bristol-Myers Squibb, GlaxoSmithKline, and Gilead Sciences. MBW has received speaking honoraria from GlaxoSmithKline, Gilead Sciences, and Roche and has received grant support from Abbott. CH has received honoraria from the CPCRA and has represented the consumer's interests as a member of the FIRST protocol team since its early development. All other authors declare no conflict of interest.