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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 transcriptase inhibitors as initial therapy ( CPCRA 058 FIRST Study ) : a long-term randomised trial . 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 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 .
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Intervention_Pharmacological
non-nucleoside reverse transcriptase inhibitors , protease inhibitors , or both in the presence of nucleoside reverse transcriptase inhibitors
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Intervention_Pharmacological
protease inhibitor ( PI ) , non-nucleoside reverse transcriptase inhibitor ( NNRTI ) , or both are lacking .
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Intervention_Pharmacological
protease inhibitor ( PI ) strategy ( PI plus nucleoside reverse transcriptase inhibitor [ NRTI ] ;
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Intervention_Pharmacological
a non-nucleoside reverse transcriptase inhibitor ( NNRTI ) strategy ( NNRTI plus NRTI ;
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Intervention_Pharmacological
or a three-class strategy ( PI plus NNRTI plus NRTI ;
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Intervention_Pharmacological
NNRTI-based regimen
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Intervention_Pharmacological
PI-based regimen
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Outcome_Physical
AIDS-defining event
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Outcome_Mortality
death
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Outcome_Physical
CD4 cell count decline
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Outcome_Physical
change in CD4 cell count
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Outcome_Other
composite endpoint
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Outcome_Mortality
AIDS or death
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Outcome_Mortality
death
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Outcome_Physical
virological failure
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Outcome_Physical
Mean change in CD4 cell count
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Outcome_Other
HRs
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Outcome_Mortality
AIDS or death
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Outcome_Physical
virological failure
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Outcome_Other
HRs
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Outcome_Mortality
AIDS or death
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Outcome_Other
discontinue treatment
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Outcome_Adverse-effects
toxic effects
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Participant_Sample-size
1397
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Participant_Condition
antiretroviral-treatment-naive
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Participant_Sample-size
1397
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Participant_Sample-size
388
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Participant_Sample-size
302
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Participant_Condition
AIDS
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Participant_Sample-size
188
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Participant_Condition
HIV