The Effect of Interrupted/Deferred Antiretroviral Therapy on Disease Risk: A SMART and START Combined Analysis

Abstract

Background: Pooled data from the SMART and START trials were used to compare deferred/intermittent versus immediate/continuous antiretroviral therapy (ART) on disease risk.

Methods: Endpoints assessed were AIDS, serious non-AIDS (SNA), cardiovascular disease (CVD), cancer, and death. Pooled (stratified by study) hazard ratios (HRs) from Cox models were obtained for deferred/intermittent ART versus immediate/continuous ART; analyses were conducted to assess consistency of HRs across baseline-defined subgroups.

Results: Among 10156 participants, there were 124 AIDS, 247 SNA, 117 cancers, 103 CVD, and 120 deaths. Interventions in each trial led to similar differences in CD4 count and viral suppression. Pooled HRs (95% confidence interval) of deferred/intermittent ART versus immediate/continuous ART were for AIDS 3.63 (2.37-5.56); SNA 1.62 (1.25-2.09); CVD 1.59 (1.07-2.37); cancer 1.93 (1.32-2.83); and death 1.80 (1.24-2.61). Underlying risk was greater in SMART than START. Given the similar HRs for each trial, absolute risk differences between treatment groups were greater in SMART than START. Pooled HRs were similar across subgroups.

Conclusions: Treatment group differences in CD4 count and viral suppression were similar in SMART and START. Likely as a consequence, relative differences in risk of AIDS and SNA between immediate/continuous ART and deferred/intermittent ART were similar.

Clinical trials registration: NCT00027352 and NCT00867048.

Figure 1.

Study design. Abbreviations: ART, antiretroviral therapy; DC, drug conservation; DEF, deferred ART; HIV, human immunodeficiency virus; IMM, immediate; ART; SMART, Strategies for Management of Antiretroviral Therapy; START, Strategic Timing of Antiretroviral Treatment; VS, viral suppression.

Figure 2.

Mean CD4 cell counts over follow-up by treatment group for START, SMART, and the pooled deferred/intermittent and immediate/continuous ART groups. The vertical lines around the data points represent the 95% confidence interval (CI). Graph is truncated at 48 months. The table within the figure presents the mean CD4 cell count difference (with 95% CI) over follow-up between the immediate and deferred groups in START, the viral suppression and drug conservation groups in SMART, and the pooled immediate/continuous and deferred/intermittent ART groups. Abbreviations: ART, antiretroviral therapy; DC, drug conservation; DEF, deferred ART; IMM, immediate ART; SMART, Strategies for Management of Antiretroviral Therapy; START, Strategic Timing of Antiretroviral Treatment; VS, viral suppression.

Figure 3.

Percent of participants with human immunodeficiency virus (HIV) RNA ≤400 copies/mL over follow-up, by treatment group for START, SMART, and the pooled deferred/intermittent and immediate/continuous ART groups. Graph is truncated at 48 months. Abbreviations: ART, antiretroviral therapy; DC, drug conservation; DEF, deferred ART; IMM, immediate ART; SMART, Strategies for Management of Antiretroviral Therapy; START, Strategic Timing of Antiretroviral Treatment; VS, viral suppression.

Figure 4.

Hazard ratios (HRs) with 95% confidence intervals (95% CI) comparing event risk by treatment group within START and SMART separately, and between the pooled deferred/intermittent and immediate/continuous ART groups. The P value for interaction is comparing the HR for each event between the deferred versus immediate group within START to the HR for the same event between the viral suppression versus drug conservation group within SMART. Abbreviations: CVD, cardiovascular disease; SMART, Strategies for Management of Antiretroviral Therapy; SNA, serious non-AIDS; START, Strategic Timing of Antiretroviral Treatment.

Figure 5.

Subgroup analyses for the composite endpoint of AIDS, SNA, or death events; hazard ratios (HRs) with 95% confidence intervals (95% CI) comparing the deferred/intermittent ART group versus immediate/continuous ART group within the pooled cohort. For subgroups of age, CD4 cell count, CD4:CD8 ratio, body mass index, d-dimer, and IL-6, the continuous variables were used for the interaction tests. Baseline CD4:CD8 ratio, hepatitis B/C coinfection, d-dimer, and IL-6 were not available for all participants; HRs within subgroups for these measures were computed using participants with available baseline data. Abbreviations: ART, antiretroviral therapy; IL-6, interleukin-6; SNA, serious non-AIDS.