The subgroup of patients who were taking antiretroviral therapy at baseline discontinued therapy if randomized to the episodic therapy arm and remained on therapy if randomized to the continuous therapy arm. Current health scores by visual analog scale seemed to decline among those who discontinued therapy and to improve among those who remained on therapy (see Fig. 3A). The treatment difference in change in current health in this subgroup was estimated at −1.45 (P = 0.08). The subgroup of patients who were not on antiretroviral therapy at baseline were to start therapy if randomized to the continuous therapy arm and to remain off therapy until the CD4 count was <250 cells/mm3 in the episodic therapy arm. Current health status seemed to improve for both groups (see Fig. 3B). The treatment difference was not significant (−1.31; P = 0.37).
Subgroup analyses by HIV RNA level were restricted to patients who were on antiretroviral therapy at study entry. In the subgroup of patients with HIV RNA ≤400 copies/mL at study entry, current health outcomes were inferior in the episodic treatment group (treatment difference for change in current health of −2.63; P = 0.01). In contrast, changes in current health were similar among patients entering the study with higher viral loads. Therefore, the treatment difference (between continuous therapy and episodic therapy) in current health was larger for patients entering the study with HIV RNA ≤400 copies/mL compared with those with baseline HIV RNA >400 copies/mL (P = 0.03 for interaction, last column in Fig. 3).
Among the 1225 participants, 52 in the episodic therapy group (3.6 per 100 person-years) and 24 in the continuous therapy group (1.6 per 100 person-years) experienced a new opportunistic disease or death. The HR in this substudy (HR = 2.3, 95% CI: 1.4 to 3.7; P < 0.001) is similar to that in the entire SMART study (HR = 2.6, 95% CI: 1.9 to 3.7).14
There were marked declines in all QOL measures from baseline to visits preceding an opportunistic disease or death (decreases of 2.5 to 14.1 units; P < 0.005 for all QOL measures). To evaluate whether the inferior QOL outcomes of the episodic therapy strategy can be explained by the higher incidence of opportunistic disease or death, the treatment difference in QOL was estimated with and without patients who experienced an opportunistic disease or died. For all QOL measures, excluding patients with opportunistic disease or death had little effect on the treatment difference estimate (data not shown).
The composite endpoint of serious non-AIDS events (major cardiovascular events, liver failure, renal failure, cancers not associated with HIV infection, or death not attributed to AIDS) was somewhat more common among patients in this substudy who were randomized to episodic therapy (HR = 1.3; P = 0.25). Excluding patients who had a serious non-AIDS event had little effect on the treatment difference in QOL between the 2 randomized arms, however.
At baseline, 9.6% of patients in the episodic therapy group and 7.6% in the continuous therapy group had grade 3 symptoms, and none had grade 4 symptoms. During follow-up, 112 patients in the episodic therapy arm reported grade 3 or 4 symptoms versus 102 in the continuous therapy group (HR = 1.15, 95% CI: 0.88 to 1.51; P = 0.30). Peripheral neuropathy (grade 3) was reported for 18 and 19 patients in the episodic and continuous therapy groups, respectively.
The SMART study demonstrated that episodic antiretroviral therapy guided by CD4 lymphocyte counts has an increased risk of opportunistic illnesses, death, and serious cardiovascular and metabolic events compared with continuous antiretroviral therapy.14 The present analysis shows that the QOL outcomes of the SMART study also favor continuous therapy, and thus mirror the clinical outcomes. Overall summary measures of QOL (current health by visual analog scale, PCS) and specific domains of the SF-12 instrument (general health perception, physical functioning, and energy) were inferior among patients randomized to CD4 count-guided episodic therapy. The treatment differences in QOL were apparent in the first year, often by the first follow-up visit at 4 months. Whenever the treatment difference in QOL outcomes was significant, the episodic therapy strategy was inferior to continuous therapy, and this finding was consistent across all investigated subgroups of patients. Finally, the episodic therapy strategy was not associated with decreased symptom burden.
The design of the SMART study allowed analyses of the effects on QOL of stopping and starting contemporary antiretroviral therapy, largely among antiretroviral-experienced patients. For most patients (76%) who enrolled while on antiretroviral therapy, the episodic versus continuous treatment group comparison describes the effects of stopping versus continuing combination antiretroviral therapy. Stopping antiretroviral therapy was associated with a relative decline in QOL among those who enrolled with an HIV RNA level ≤400 copies/mL on antiretroviral therapy. The inferior QOL outcomes in patients who interrupted virologically successful antiretroviral therapy (ie, HIV RNA ≤400 copies/mL) mirror the clinical outcomes of the SMART study; among patients who entered the study on antiretroviral therapy, the relative risk of opportunistic disease or death in the episodic therapy arm versus the continuous therapy arm was substantially higher among patients with baseline HIV RNA ≤400 copies/mL than among those with higher viral loads.14
For patients who enrolled while off antiretroviral therapy (24%), the episodic versus continuous therapy group comparison evaluates the effects of (re)starting antiretroviral therapy at a CD4 lymphocyte count >350 cells/mm3. Unlike earlier studies of high-dose zidovudine monotherapy or combination therapy with a ritonavir-based regimen among patients with relatively high CD4 lymphocyte counts,20,21 starting contemporary combination antiretroviral therapy in this subgroup of participants was not associated with a decline in QOL.
The large sample size of this QOL study allowed analyses of the associations between QOL and the occurrence of HIV disease progression events. In all QOL measures, there was a marked decline in QOL preceding an opportunistic disease or death, providing clinical validation of the QOL instruments used. Because there was a higher rate of opportunistic disease and death in the episodic therapy arm, we explored whether the inferior QOL outcomes in the episodic therapy arm were attributable to the higher rate of opportunistic disease and death. Excluding patients with these clinical events from the analysis resulted in only small changes in the treatment difference estimates, and episodic therapy resulted in inferior QOL outcomes even among persons who did not have HIV disease progression events.
Two prior studies assessed QOL outcomes associated with fixed-duration antiretroviral treatment interruptions. In a nonrandomized study of 12 patients interrupting therapy for 30 days (or until the viral load had increased to >3000 copies/mL), there was no improvement in overall QOL during treatment interruptions, although self-perceived health status did improve.11 In a randomized trial (n = 46) comparing continuous antiretroviral therapy with a fixed-duration cycle (4 weeks on antiretroviral therapy and 8 weeks off), there were no significant differences in QOL outcomes between the 2 arms.22 Our study used a different form of episodic therapy, CD4 count-guided interruptions, and had much greater statistical power to detect differences in QOL outcomes.
This study has several limitations. First, we evaluated only 1 type of antiretroviral treatment interruption, a specific CD4 count-guided episodic therapy strategy. In our study, this strategy resulted in long initial treatment interruptions for most patients (median time to (re)initiation of therapy of 16 months). The effects of other treatment interruption strategies on QOL may be different from those seen in our study. Second, patients in this QOL study were drawn only from study sites in the United States. Although these patients had demographic and clinical characteristics similar to those of patients in HIV care in the United States,23 QOL outcomes of treatment interruption may differ in other settings. Finally, we compared the 2 treatment strategies for each of the 11 QOL outcome measures separately, without adjustment for multiple comparisons. For each outcome measure, however, whenever the treatment difference was statistically significant, it favored the continuous therapy. The consistency of these findings across the QOL measures argues that episodic therapy is associated with inferior QOL outcomes.
The results of this randomized comparison of episodic versus continuous therapy are contrary to the hypothesized benefits of antiretroviral treatment interruption on QOL and symptom burden. The impact of antiretroviral therapy on QOL is complex and may depend on the medications used, duration of therapy, and stage of HIV disease at which therapy is started.21,24-26 Although antiretroviral medications have appreciable rates of adverse effects, HIV infection has adverse effects as well, in addition to its major complications of opportunistic disease and death. The results of this study demonstrate that the balance of these opposing effects on QOL favors continuous antiretroviral therapy among patients with the characteristics of those in the SMART study. This finding was consistent across demographic and clinically defined subgroups and was not solely attributable to the increased risk of clinical events in the episodic therapy group.
The authors gratefully acknowledge the commitment of all the participants in the QOL substudy of the SMART study and the many investigators and clinical staff. B. Grund had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
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Participating clinical sites (number of participants enrolled) and investigators are as follows: Harlem AIDS Treatment Group, New York, NY (194): S. Caras, RN, MS, R. Contreras, RN, J. Corser, MD, K. Hennessey, MD, E. Jenny-Avital, MD, L. Johnson, MD, C. Kelley Guity, A. Loquere, RN, S. Mannheimer, MD, C. McLean-Long, MD, and F. Siegal, MD; Houston AIDS Research Team, Houston, TX (177): R.C. Arduino, MD, B.J. Barnett, MD, R. Evans, C. Hale, M. Mall, M. Rodriguez Barradas, MD, S. Schrader, MD, and E. Villareal; North Jersey Community Research Initiative, Newark, NJ (155): C. Baroni, CMA, K. Hannah, ACRN, E. McManus, MD, R. Nahass, MD, G. Perez, MD, N. Regevik, MD, M.C. Reyelt, MD, R. Roland, DO, A. Sheridan, ACRN, and C. Tobin, ACRN; New England Program for AIDS Clinical Trials, New Haven, CT (124): M.J. Kozal, MD; AIDS Research Alliance: Chicago, Chicago, IL (110): J. Brockelman, RN, OCN, M. Diaz-Linares, PharmD, P. Ferrell-Gonzalez, BSN, RN, N. French, MD, E. Goodwin, RN, R. Luskin-Hawk, MD, K. Murphy, MD, A. Pavlatos, MD, D. Pitrak, MD, R. Slotten, MD, MPH, J. Sullivan, MD, J.P. Uy, MD, and A. Vaccaro, MD; Henry Ford Hospital, Detroit, MI (103): B.K. Braxton, RN, BSN, B. Campbell, RN, BSN, L.L. Faber, RN, BSN, P. Gulick, DO, L.H. Makohon, RN, BSN, N.P. Markowitz, MD, A. Ognjan, DO, and L.C. Williams, RN; Louisiana Community AIDS Research Program, New Orleans, LA (101): S. Adams, RN, BSC, C.L. Besch, MD, S. Boarden, RN, BSN, J.M. Carrol, MD, D. Dandridge, RN, MA, H. Henderson, MD, J. Johnson, PA, N. Kimmel, RN, J. Osterberger, MD, S. Pablovich, RN, MPH, C-FNP, C. Scott, RN, BSN, and J. Walker RN, MN, C-ANP; Community Consortium of San Francisco, San Francisco, CA (96): D.I. Abrams, MD, J. Bailowitz, MD, V. Cafaro, MD, M. Estes, MD, M. John, MD, H. Lampiris, MD, S. O'Brien, MD, W. Owen, MD, S. Paul, MD, and R. Scott, MD; Wide-Reaching AIDS Program, Washington, DC (90): S.E. Campbell, CCRC, J.L. Guest, PhD, MPH, C. Jones, RN, N.G. Klimas, MD, M. Matsumoto, BSN, ACRN, CCRC, D. Rimland, MD, C.J. Savini, MSN, FNP, M. Smith, MSN, ARNP-C, M.K. Steinhaus, MSN, CNP, K.K. Summers, PharmD, K.R. Swanson, BSN, ACRN, CCRC, and D. Thomas, BSN, Med; and Denver Community Programs for Clinical Research on AIDS, Denver, CO (75): M.T. Bessesen, MD, J.D. Blum, MD, D.E. Britt, ND, D.L. Cohn, MD, N.K. Fujita, MD, L. Melecio, M. Mogyoros, MD, F.M. Moran, BSN, H.C. Pujet, MD, J.R. Rouff, MSW, MBA, J.M. Saldanha, BSN, MA, D.M. States, BSN, J.H. Witter, MD, and T.J. Wright, BA