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  53rd ICAAC Interscience Conference on
Antimicrobial Agents and Chemotherapy
September 10-13, 2013, Denver CO
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Faster Bone Turnover With Atripla
Than With Dolutegravir/ABC/3TC in 48 Weeks

  53rd ICAAC, September 10-13, 2013, Denver
ICAAC: 48 Week Bone Marker Changes in Dolutegravir (DTG; GSK1349572) Plus Abacavir/Lamivudine (ABC/3TC) vs Tenofovir/Emtricitabine/Efavirenz (EFV/TDF/FTC): The SINGLE Trial - (09/13/13)
Mark Mascolini
Bone turnover markers rose in people randomized to dolutegravir plus abacavir/lamivudine (ABC/3TC) or to efavirenz plus tenofovir/emtricitabine (coformulated at Atripla) through 48 weeks in the SINGLE trial, but increases were significantly greater in the Atripla arm [1]. Vitamin D levels fell with both treatments.
SINGLE demonstrated the virologic superiority of dolutegravir/ABC/3TC over Atripla after 48 weeks in an FDA snapshot analysis (88% versus 81% below 50 copies, difference +7.4%, 95% confidence interval +2.5% to +12.3%, P = 0.003) [2]. Research links efavirenz to declining vitamin D and tenofovir to falling bone mineral density (BMD). BMD typically drops rapidly when antiretroviral therapy starts and then stabilizes at a level below baseline. Bone marker concentrations rise--indicating faster bone turnover--when BMD falls.
Although DEXA scans measuring BMD remain the gold standard for estimating the impact of HIV and antiretrovirals on bone health, these scans are expensive and usually available only in large medical centers in developed countries. SINGLE researchers and others are evaluating bone turnover markers as a surrogate for changing BMD and fracture risk in people with HIV. Type 1 collagen cross-linked C-telopeptide (CTx) is a marker of bone destruction. Three markers of bone formation are procollagen type 1 N-terminal propeptide (P1NP), osteocalcin (OC), and bone-specific alkaline phosphatase (BSAP).
To get a better understanding of bone turnover marker and vitamin D changes in antiretroviral-naive people starting dolutegravir plus ABC/3TC or efavirenz with TDF/FTC, researchers measured vitamin D and the four just-noted bone markers before people began treatment in SINGLE and at treatment week 48. Analyses comparing bone marker and vitamin D levels in the two treatment arms were adjusted for age, gender, viral load, CD4 count, baseline bone marker levels, body mass index, smoking status, and vitamin D supplementation. Study participants did not have DEXA scans to measure BMD.
The SINGLE team analyzed data from 414 people randomized to dolutegravir/ABC/3TC and 419 randomized to Atripla. Most study participants were men (84%) and white (68%). Pretreatment viral load averaged about 48,000 copies, and 32% of participants had a viral load above 100,000 copies. Median starting CD4 count measured 338 and median body mass index 24 kg/m(2). About half of participants in both groups smoked. These variables did not differ between treatment groups.
Normal ranges for bone markers and vitamin D are 60 to 1200 pg/mL for C-terminal telopeptide for type 1 collagen, 2.7 to 21 mcg/L for bone-specific alkaline phosphatase, 8 to 37 ng/mL for osteocalcin, 22 to 87 ng/mL for procollagen type 1 N-propeptide, and 30 to 100 ng/mL for vitamin D.
Levels of all four bone markers rose in both treatment arms, and the gain was always significantly greater in the Atripla arm:
Adjusted geometric mean change and geometric mean ratios (GMR) after 48 weeks of dolutegravir/ABC/3TC versus Atripla:
-- C-terminal telopeptide for type 1 collagen: 33% vs 68%, GMR 0.789, P < 0.001
-- Bone-specific alkaline phosphatase: 15% vs 60%, GMR 0.720, P < 0.001
-- Osteocalcin: 22% vs 48%, GMR 0.827, P < 0.001
-- Procollagen type 1 N-propeptide: 30% vs 66%, GMR 0.784, P < 0.001
Vitamin D (25OHD) fell 7% in the dolutegravir/ABC/3TC group through 48 weeks and 10% in the Atripla arm, and this difference was not statistically significant (GMR 1.036, P = 0.292).
The investigators concluded that the significantly higher bone marker levels in the Atripla group after 48 weeks indicate more active bone turnover compared with the dolutegravir group. They suggested that changes in bone turnover markers will probably correlate with bone mineral density changes. And the bone marker differences, they proposed, "may correlate with known TDF-associated changes in BMD over time."
1. Tebas P, Kumar P, Hicks C, et al. 48 week bone marker changes with dolutegravir plus abacavir/lamivudine vs. tenofovir/emtricitabine/efavirenz: the SINGLE trial. 53rd ICAAC. September 10-13, 2013. Denver. Abstract H-1461.
2. Walmsley S, Antela A, Clumeck N, et al. Dolutegravir (DTG; S/GSK1349572) + abacavir/lamivudine once daily statistically superior to tenofovir/emtricitabine/efavirenz: 48-week results--SINGLE (ING114467). 52nd Interscience Conference on Antimicrobials and Chemotherapy (ICAAC). September 9-12, 2012. San Francisco. Abstract H-556b.
http://www.natap.org/2012/ICAAC/ICAAC_29.htm and http://www.natap.org/2012/ICAAC/ICAAC_06.htm