Between August 1, 1996, and September 30, 1999, a total of 1,312 antiretroviral-naïve participants aged 18 y and over initiated triple combination therapy consisting of two nucleosides plus a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor. Of these, 121 (9.2%) were excluded from this analysis for not having both baseline CD4 and plasma HIV-1 RNA level measures available within 6 mo prior to the start of antiretroviral therapy or for having initiated therapy as part of a clinical trial. Among the remaining 1,191 study participants, there were 679 patients with HIV-drug-resistance genotyping done on samples of plasma HIV-1 RNA before initiating HAART at the time of this analysis. HIV-drug resistance to any class was observed in 53 (7.8%) of the patients. Among these patients, 39 (73.6%) exhibited resistance to one class, ten (18.9%) to two classes, and four (7.6%) to three classes. A total of 14 (26.4%) exhibited mutations conferring resistance to lamivudine, 29 (54.7%) to other nucleoside reverse transcriptase inhibitors, eight (15.1%) to non-nucleoside reverse transcriptase inhibitors, and 19 (35.8%) to protease inhibitors. These patients exhibiting baseline resistance were excluded from the analysis, and the total study sample was based on the remaining 1,138 (86.7%) participants. Study participants had HIV-1 RNA levels higher than those of individuals excluded from the analysis (median viral load 87 versus 120 copies/ml; p < 0.001). No other significant associations were noted between the two groups.
Among the remaining HOMER participants (n = 1,138), a total of 229 (20.1%) patients achieved durable viral suppression (HIV-1 RNA levels < 1,000 copies/ml) during the entire follow-up period. There were 776 (68.2%) patients with at least one HIV-1 RNA level measurement at 1,000 copies/ml or above that showed no detectable resistance during the follow-up period, and we assumed these individuals had no drug resistance. Although we systematically genotyped all samples with HIV-1 RNA levels of 1,000 copies/ml or more during follow-up, there were three (0.3%) patients for whom the resistance test failed at least once for technical reasons, and for these particular tests we assumed that no mutation was detected.
Study participants were first prescribed 26 different triple combination antiretroviral regimens. shows that over half of these participants (848; 74.5%) initiated therapy with a protease inhibitor, while the rest of the study participants (290; 25.5%) had a regimen that included a non-nucleoside reverse transcriptase inhibitor. A total of 123 (10.8%) commenced therapy in 1996, 402 (35.3%) in 1997, 340 (29.9%) in 1998, and 273 (24.0%) in 1999. The median age was 37 y (inter-quartile range: 32, 44 y), CD4 cell count was 280 cells/mm3 (inter-quartile range: 130, 430 cells/mm3), plasma HIV-1 RNA level was 120,000 copies/ml (inter-quartile range: 43,000, 310,500 copies/ml), physician experience was 44 patients per physician (inter-quartile range: 5, 131 patients per physician). There were 317 (27.9%) participants who had a history of injection drug use and 149 (13.1%) study participants with a prior diagnosis of AIDS. Among all participants, 956 were males (84.0%).
Baseline Characteristics of Patients Initiating Any Triple Combination Antiretroviral Therapy
The overall median time of follow-up was 56.4 mo (inter-quartile range: 45.8, 69.2 mo). The median number of CD4 count measurements was 3.59 per year (inter-quartile range: 2.24, 4.59 per year), and the median number of plasma HIV-1 RNA measurements was 3.44 per year (inter-quartile range: 2.56, 4.25 per year). A total of 17,632 CD4 cell counts and 17,358 HIV-1 RNA determinations were collected for participants over the study period. The median numbers of CD4 cell counts and HIV-1 RNA determinations per participant were 15 (inter-quartile range: 7, 23) and 15 (inter-quartile range: 9, 21), respectively. In this study, a switch in drug regimen was recorded when any modification (addition or removal) in the original drug regimen occurred. Men and women switched one or more drugs in their regimen a median three times (inter-quartile range: 1, 5 times) over the follow-up period. Protease inhibitors were added to or removed from a regimen a median of one time (inter-quartile range: 1, 3 times), non-nucleoside reverse transcriptase inhibitors one time (inter-quartile range: 0, 2 times), and nucleoside reverse transcriptase inhibitors three times (inter-quartile range: 1, 5 times). The median time to first switch was 7.8 mo (inter-quartile range: 2.1, 23.6 mo) in this study population.
Drug-resistance testing was completed on a total 3,099 samples over the first 30 mo of follow-up. A median of three (inter-quartile range: 1, 5) samples were tested per participant. HIV-drug resistance to any class was observed in 302 (28.5%) participants. Of these, 19 (6.3%) exhibited resistance to all three classes, 137 (45.4%) to two classes, and 146 (48.3%) to one class. A total of 221 (73.2%) exhibited mutations conferring resistance to lamivudine, 98 (32.5%) to other nucleoside reverse transcriptase inhibitors, 157 (52.0%) to non-nucleoside reverse transcriptase inhibitors, and 66 (21.9%) to protease inhibitors. The median time to first emergence of resistance to any class of drug under study was 16.5 mo (inter-quartile range: 8, 27 mo).
presents the association between baseline characteristics, adherence during first yea,r and emergence of resistance. Persons who developed any mutations were more likely to be injection drug users (p = 0.007), to have lower CD4 counts (p < 0.001), and to have higher plasma viral load (p < 0.001) than persons who did not develop any resistance over the first 30 mo.
Associations between Baseline Variables and Emergence of Any Resistance in 1,138 Participants First Prescribed Any Triple Combination Antiretroviral Therapy
As of June 30, 2003, a total of 207 deaths were identified in the study population over the follow-up period, with an overall crude mortality rate of 18.2%. The product limit estimate of the cumulative mortality rate at 12 and 24 mo was 4.4% (±0.6%) and 8.7% (±0.8%), respectively. Of these deaths, 30 (14.5%) were to patients who exhibited resistance to one class, 26 (12.6%) to two classes, and one (0.5%) to three classes. A total of 41 (19.8%) deaths were to patients who exhibited resistance to lamivudine, 15 (7.3%) to other nucleosides, 32 (15.5%) to non-nucleoside reverse transcriptase inhibitors, and six (2.9%) to protease inhibitors. Nearly, three-quarters of the deaths involved no resistance to any class of drug (150; 72.5%).
The univariable and multivariable analyses of the baseline and time-dependent factors associated with all cause mortality are presented in through four different models. In the univariable analysis for baseline characteristics (Model 1), only age, a prior AIDS diagnosis, protease inhibitor use, physician experience, CD4 count, and HIV-1 RNA level were associated with mortality. When we considered time-dependent factors, the univariable analysis (Model 2) showed us that age, baseline drug combination, physician experience, a prior AIDS diagnosis, protease inhibitor use, adherence, CD4 cell count, HIV-1 RNA level, and resistance to any antiretroviral were associated with mortality. We also observed that resistance to some classes of drug, more specifically to lamivudine and non-nucleoside reverse transcriptase inhibitors, were also associated with mortality. After controlling for other prognostic explanatory variables, Model 3 shows that there is a strong association between emergence of any resistance and risk of death (hazard ratio: 1.58 [95% confidence interval (CI): 1.14, 2.20]). The heterogeneity in the association between resistance and mortality also depends on the type of resistance that was acquired (Model 4), with persons who exhibited resistance to non-nucleoside reverse transcriptase inhibitors being 2.57 times (95% CI: 1.74, 3.78) more likely to die.
Univariable and Multivariable Analyses of the Baseline and Time-Dependent Factors Associated with Survival among 1,138 Persons First Prescribed Any Triple Combination Antiretroviral Therapy
The same analyses were repeated with non-accidental deaths as the outcome of interest (n = 160; 77.3%). Individuals dying from non-accidental deaths in the study had less experienced physicians (median: 16 patients per physician [inter-quartile range: 2, 81 patients per physician]), worse CD4 cell counts (median: 150 cells/mm3 [inter-quartile range: 45, 310 cells/mm3]), and higher viral load levels (median: 175,000 copies/ml [inter-quartile range: 88,000, 405,000 copies/ml]) than the individuals included in the all cause mortality (see ). When we assessed the association between survival and resistance in this population we observed that persons who exhibited reduced sensitivity to any antiretroviral had death rates that were 1.51 times (95% CI: 1.04, 2.20) higher than those who did not exhibit resistance. We also looked at the individuals dying via accidental death (n = 47; 22.7%). These individuals had more experienced physicians (median: 53 patients per physician [inter-quartile range: 12, 131 patients per physician]), better CD4 cell counts (median: 300 cells/mm3 [inter-quartile range: 210, 470 cells/mm3]), and lower viral load levels (median: 129,000 copies/ml [inter-quartile range: 39,000, 210,000 copies/ml]) than the individuals included in the all cause mortality (see ). When we assessed the association between survival and emergence of resistance in this population we observed that the hazard ratio was 1.83 (95% CI: 0.92, 3.63).
presents the final marginal structural models of the causal effect of drug resistance on mortality. In all models, the time-dependent confounders were protease inhibitor/non-nucleoside experience, AIDS diagnosis, CD4 cell count, viral load, and HAART regimen. The exposures of main interest were emergence of any resistance, and emergence of resistance to each separate class of mutation (lamivudine, other nucleosides, non-nucleosides, and protease inhibitors). Model 1 considers the emergence of any resistance as the exposure of main interest. The results show that persons who developed any resistance had death rates that were 1.75 times (95% CI: 1.27, 2.43) higher than those who did not exhibit any resistance. When we considered each separate class of mutation as the exposure of interest (Models 2–5), while controlling for the presence/absence of other mutations, we observed that those persons who exhibited reduced sensitivity to non-nucleoside reverse transcriptase inhibitors had the highest risk: they were 3.02 times (95% CI: 1.99, 4.57) more likely to die than those who did not exhibit this type of resistance.
Hazard Ratio Estimates from the Marginal Structural Model of the Causal Effect of Drug Resistance on Mortality