In FIRST, 933 participants were randomized to the PI (n = 470) or NNRTI (n = 463) strategies. Thirty participants (3%) were excluded from these analyses (13 in the PI strategy; 17 in the NNRTI strategy) due to no adherence measurement, no HIV RNA measurement at or after the 4-month visit, or no resistance test results available at initial virological failure. There were no significant differences in baseline characteristics between included participants randomized to the PI versus NNRTI strategies (data not shown). Detailed characteristics of the FIRST population have been published previously [8
]. In brief, the population averaged 38 years of age, were racially diverse (54% Black, 26% White, 17% Latino/a, and 3% other), and 22% were female. The antiretroviral naive population assessed in these analyses had advanced HIV disease with a mean CD4 lymphocyte count of 212 cells/ul and 39% had a prior AIDS diagnosis.
Specific antiretroviral medications used in FIRST have been previously reported [8
]. In summary, in the PI strategy the most common PIs used were nelfinavir (61%), indinavir/ritonavir (13%), indinavir (11%), and lopinavir/ritonavir (8%). In the NNRTI strategy the most common NNRTIs used were efavirenz (63%) and nevirapine (37%). In both strategies the most common NRTI combinations used were zidovudine/lamivudine (56%), stavudine/lamivudine (20%), abacavir/lamivudine (9%), and didanosine/stavudine (9%).
Among participants in the PI strategy, 326 (71%) of 457 developed initial virological failure a median of 1.2 years after initiating therapy (). At the time of virological failure, antiretroviral medication resistance within at least one class was present in 135 (30%); 37 (8%) had PI resistance and 121 (26%) had NRTI resistance. Among participants in the NNRTI strategy, 262 (59%) of 446 developed virological failure a median of 3.0 years after initiating therapy. Antiretroviral medication resistance was present in 127 (28%); 112 (25%) had NNRTI resistance and 63 (14%) had NRTI resistance. Two- or three-class antiretroviral medication resistance at initial virological failure developed in 39 (9%) participants randomized to PI and 50 (11%) participants randomized to NNRTI. The most common resistance mutations were for PIs the D30N (n = 26), for NNRTIs the K103N (n = 81), and for NRTIs the M184I/V (n = 171). A comprehensive list of specific resistance mutations in FIRST has been reported [12
Antiretroviral medication resistance at initial virological failure by randomized strategy in the CPCRA FIRST Study
Cumulative self-reported adherence at the time of initial virological failure or censoring was excellent in both the PI (median 91.6%, interquartile range [IQR] 77.1 – 100%) and NNRTI (median 93.3%, IQR 76.4 – 100%) strategies (p = 0.96). Within the PI strategy, median cumulative adherence levels at the time of initial virological failure were 89.8% (IQR 66.7 – 100) and 93.1% (IQR 79.1 – 100) for the boosted and nonboosted PI recipients respectively. When assessing cumulative adherence prior to initial virological failure or censoring as a categorical variable in the PI strategy, 148 participants had 100% cumulative adherence, 187 had 80 –99% adherence, and 120 had 0 – 79% adherence. In the NNRTI strategy 120 participants had 100% cumulative adherence, 204 had 80 –99% adherence, and 125 had 0 – 79% adherence.
The results of multivariate Cox regression analyses of time to initial virological failure with class-specific antiretroviral medication resistance are presented in . In the PI strategy no association was found between cumulative adherence (continuous variable) and PI resistance at initial virological failure (HR 1.1, 95% CI 0.9 – 1.4, per 10% lower cumulative adherence). In the NNRTI strategy, lower cumulative adherence increased the risk of NNRTI resistance at initial virological failure (HR 1.2, 95% CI 1.1 – 1.3 per 10% lower cumulative adherence). In both strategies lower cumulative adherence was associated with an increased risk of NRTI resistance (). The results from on-treatment analyses, with censoring at first switch from randomized strategy, were similar in direction, magnitude, and significance (data not shown).
Hazard ratios (95% CI) from multivariate Cox regression analyses of time to initial virological failure* with antiretroviral resistance in the CPCRA FIRST Study, adherence is presented as a continuous variable
Results from multivariate Cox proportional hazards regression analyses assessing cumulative adherence as a time-updated categorical value (0–79%, 80–99%, and 100%) are presented in . In the PI strategy, once again, there was no association between cumulative adherence and PI resistance, while in the NNRTI strategy there was an increased risk of NNRTI resistance in the 80–99% (HR 2.3, 95% CI 1.4 – 3.7) and the 0–79% (HR 6.5, 95% CI 3.9 – 10.7) cumulative adherence groups compared to individuals with 100% cumulative adherence. In both strategies there was in increased risk of NRTI resistance in individuals with cumulative adherence levels less than 100% (). The greatest risk of NNRTI resistance was in individuals with the lowest adherence (0 – 79%).
Risk (hazard ratio) of initial virological failure with resistance by randomized strategy and cumulative adherence categories in the CPCRA FIRST Study.
Among participants randomized to the PI strategy, 116 (25%) were prescribed a ritonavir boosted PI at study entry, 338 (74%) were prescribed a nonboosted PI, and 3 (1%) did not initiate therapy with a PI (). Of those on a boosted PI regimen 52% were on indinavir/ritonavir, 31% were on lopinavir/ritonavir, and 10% were on saquinavir/ritonavir. Nonboosted versus boosted PI use was associated with a significantly higher risk of PI resistance (10% compared to 2%; p<0.01) and NRTI resistance (29% compared to 19%; p=0.03) at initial virological failure. In multivariate Cox regression analysis there was no relationship between cumulative adherence and PI resistance for participants initiating therapy with a nonboosted PI. Similar analyses were not possible for those who initiated with a boosted-PI due to the rarity of events in this group. The two individuals failing boosted PI based therapy with PI resistance were no longer receiving boosted PI based therapy at the time of initial virological failure.
Antiretroviral medication resistance at initial virological failure by PI type (non-randomized comparison) in the CPCRA FIRST Study
In a final analysis, participants experiencing virological failure prior to strategy switch were categorized by their cumulative adherence at initial virological failure: 0–79%, 80–99%, and 100%. Within each cumulative adherence category the proportion of participants with class-specific antiretroviral medication resistance at the time of virological failure are presented in . The percentage of individuals failing nonboosted PI based therapy with PI resistance (5 – 30%, depending on cumulative adherence category, ) was lower than the percentage of individuals failing NNRTI based therapy with NNRTI resistance (37 – 75%). The percentage of individuals with NRTI resistance at the time of virological failure was higher in participants failing nonboosted PI based therapy (38 – 64%) compared to participants failing NNRTI based therapy (7 – 39%) or boosted PI based therapy (0 – 41%). At the time of virological failure, NRTI resistance was highest among participants with 80–99% cumulative adherence on all three classes of therapy ().
Figure 2 Class-specific resistance at initial virological failure by cumulative adherence category in the CPCRA FIRST Study, assessed in individuals experiencing virological failure during follow-up on NNRTIs (n = 136), Nonboosted PI (n = 164), and Ritonavir Boosted (more ...)