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09/16/2013

Osteoporosis in HIV: The Effects of Antiretroviral Agents are Further Defined at ICAAC 2013


Osteoporosis is increased in HIV-infected individuals. Traditional risk factors, HIV-infection itself and antiretroviral therapy (ART) all may contribute to the pathogenesis of this condition. Most previous studies have shown that bone mineral density (BMD) declines during the first 6-18 months on ART, then stabilizes. The magnitude of decline may be affected by the specific components of the regimen. With use of tenofovir DF (TDF) or protease inhibitors, BMD declines are usually greater. Two studies presented at ICAAC 2013 compared the bone effects of TDF/emtricitabine (FTC) with abacavir/lamivudine (ABC/3TC) using serum markers of bone turnover rather than direct measurement of bone mineral density (BMD). The SINGLE trial was a large, randomized, double blind comparison of the regimen ABC/3TC plus the integrase inhibitor dolutegravir and coformulated TDF/FTC/efavirenz (EFV). Analysis of the primary safety and efficacy endpoints have been presented elsewhere. At 48 weeks, the bone resorption marker C-telopeptide (CTx) and the markers of new bone formation osteocalcin (OC), bone-specific alkaline phosphatase (BSAP) and procollagen type 1 N-terminal propeptide (P1NP) all increased, but the increases were significantly greater in the TDF/FTC/EFV arm [1]. Vitamin D levels also were measured and did not differ between arms. The ASSURE study [2] enrolled patients stably suppressed on a first or second ART regimen consisting of TDF/FTC plus ritonavir-boosted atazanavir and no history of virologic failure. Participants were randomized 2:1 to switch to open-label ABC/3TC/atazanavir without boosting or to continue the baseline regimen. At 48 weeks, 77% and 81% of subjects in the switch and control groups, respectively, maintained an HIV RNA <50 copies/mL, a statistically non-significant difference (FDA snapshot analysis). Three bone turnover markers, BSAP, CTx, OC declined at weeks 24 and 48 in the switch group, while all remained stable in the control group. PTH also declined in the switch arm, although serum calcium was unchanged. The differences in marker levels between arms at week 48 were statistically significant. Other study findings included no clinically significant differences in lipid profile, no differences in estimated GFR and no differences in the inflammatory markers hsCRP, IL-6 or d-dimer. There were also no differences in adverse events or laboratory toxicities, except for the expected higher rate of hyperbilirubinemia in the control arm that used ritonavir boosted atazanavir.

These findings are consistent with previous studies that used DEXA to demonstrate a greater loss of BMD with TDF/FTC containing ART. The SINGLE study findings suggest the inclusion of the new integrase inhibitor dolutegravir does not alter the effect on bone. However, unlike BMD measurement, the clinical significance of changes in bone turnover markers and their ability to predict risk for clinical events such as fracture has not been established. In the absence of correlation between bone turnover markers and fractures, studies directly measuring BMD will have greater clinical relevance.

References:
1. Tebas P, Kumar P, Hicks PC, et al. 48 Week Bone Marker Changes with Dolutegravir (DTG; GSK1349572) plus Abacavir/Lamivudine (ABC/3TC) vs. Tenofovir/Emtricitabine/Efavirenz (EFV/TDF/FTC): the SINGLE Trial. 53rd ICAAC, Denver CO, Sept 10-13, 2013, Abstract H-1461.
2. Wohl D, Bhatti L, Small CB et al. Simplification to Abacavir/Lamivudine (ABC/3TC) + Atazanavir (ATV) from Tenofovir/Emtricitabine (TDF/FTC) + ATV/Ritonavir (r) Maintains Viral Suppression and Improves Bone Biomarkers: 48 Week ASSURE Study Results. 53rd ICAAC, Denver CO, Sept 10-13, 2013, Abstract H-665.


Source: Reporting from Denver for the PRN News: David H Shepp, MD