Higher CD4+ counts on antiretroviral therapy are associated with lower rates of non-AIDS diseases and AIDS. These findings expand our understanding of the implications of HIV-related immunodeficiency and motivate randomized studies to evaluate the effects of antiretroviral therapy on a broad set of clinical outcomes at CD4+ counts greater than 350 cells/microl.

Objectives To assess the effects of antiretroviral therapy (ART) on bone mineral density (BMD) Design Randomized comparison of continuous ART (viral suppression group; VS) with intermittent ART (drug conservation group; DC) Setting Outpatient clinics in the United States, Australia, and Spain. Participants Participants in the Strategies for Management of Antiretroviral Therapy Body Composition substudy. Main outcome measures Annual hip and spine BMD by dual-energy radiographic absorptiometry (DXA) and spine BMD by quantitative computed tomography (qCT). Methods Comparisons were by intention-to-treat analysis, using longitudinal models for change in BMD. Risk factors for BMD loss were evaluated. Results The 214 participants (median 44 years, 19% female participants, 73% on ART; median T-scores −0.5 total hip, −0.7 spine DXA, −0.9 spine qCT; 98 randomized to VS and 116 to DC) were followed for a mean 2.4 years. With continuous ART, BMD declined per year by 0.8% (hip), 0.4% (spine DXA), and 2.4% (spine qCT). BMD declined significantly less with intermittent ART. Estimated DC minus VS group differences in mean BMD change through follow-up were 1.4% [hip; 95% confidence interval (CI) 0.6–2.3; P=0.002], 1.3% (spine DXA; 95% CI 0.1–2.4, P=0.03), and 3.0% (spine qCT; 95% CI 0.8–5.2, P=0.007). No consistent drug-specific association with BMD decline was found. In the parent study, 10 of 2753 participants in the VS group and two of 2720 in the DC group reported serious fractures (hazard ratio 4.9; 95% CI 1.1–22.5; P=0.04). Conclusion Continuous ART is associated with decline in BMD and possibly more fractures relative to intermittent, CD4 cell count-guided ART.

Background Low CD4+ increases risk for both AIDS- and non–AIDS-related morbidity and mortality. The magnitude of CD4+ recovery early after initial antiretroviral therapy (ART) is important in the ultimate duration of immune depletion. Methods We examined CD4+ recovery among 850 participants in the Community Program for Clinical Research on AIDS Flexible Initial Retrovirus Suppressive Therapies study with virologic suppression (ie, achieved an HIV RNA level <400 copies/mL) with 8 months of initial ART and determined subsequent risk for AIDS, non-AIDS diseases (non-AIDS cancers and cardiovascular, end-stage renal, and liver diseases), or death using Cox regression during a median 5-year follow-up. Results Mean pretreatment CD4+ was 221 cells/μL; 18% (n = 149) had a poor CD4+ recovery (<50 cells/μL) after 8 months of effective ART, resulting in lower CD4+ over 5 years. Older age (hazard ratio 1.34/10 yrs, P = 0.003) and lower screening HIV RNA (hazard ratio 0.65 per log10 copies/mL higher, P = 0.001), but not screening CD4+, were associated with a poor CD4+ recovery. After 8 months of effective ART, 30 patients experienced the composite outcome of AIDS, non-AIDS, or death among participants with a poor CD4+ recovery (rate = 5.8/100 person-years) and 74 patients among those with an adequate recovery (≥50 cells/μL; rate = 2.7/100 personyears) (adjusted hazard ratio = 2.24, P < 0.001). The risk of this composite outcome associated with a poor CD4+ recovery declined when ART was initiated at higher CD4+ counts (P < 0.01). Conclusions Impaired immune recovery, despite effective ART, results in longer time spent at low CD4+, thereby increasing risk for a broad category of HIV-related morbidity and mortality conditions.

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