Two studies published earlier this year in the journal AIDS added to the accumulating data on the complex relationship between bone health, HIV and antiretroviral treatment (ART).
In the first, Roger Bedimo and colleagues reported on the relationship between osteoporotic fracture risk and cumulative exposure to ARVs. They reported that cumulative exposure to tenofovir was independently predictive of increased risk of osteoporotic fracture (12% higher risk per year of exposure) after controlling for traditional osteoporotic risk factors and concomitant ART.1
This was a retrospective analysis from patients treated from 1988 to 2009 in the U.S. Veterans Health Administration clinical case registry. ICD-9 diagnostic codes were used to identify osteoporotic fractures (defined as wrist, vertebral or hip fracture) after patients had been diagnosed with HIV. Cumulative ART exposure (drug or class) was defined from initial prescription to the first recorded fracture.
Multivariate analyses used two models: model 1 (MV1), controlled for age, race, tobacco use, diabetes, chronic kidney disease (CKD), hepatitis C virus (HCV) and BMI; model 2 (MV2), controlled MV1 variables and concomitant exposure to other antiretroviral drugs.
From over 56,600 patients indentified in this predominently male (98%) cohort, 39,277 (69.4%) had at least 1 month of antiretroviral therapy (ART) exposure with the total ART exposure in the cohort being 164,414 person-years (PY). A total of 951 individual patients sustained osteoporotic fractures. Multiple fractures were censored after the first event.
Patients with osteoporotic fracture had a slightly higher median age than those without (46 vs. 44 years), were more likely to be white (57% vs. 45% of those without fracture), a BMI below 20 (49% vs. 33%) and have HCV co-infection (51% vs. 31% (p<0.0001 for all comparisons).
Tenofovir exposure (46,062 PY) was associated with a yearly hazard ratio for osteoporotic fracture of 1.08 (95% CI 1.02-1.15, p<0.001). Exposure to abacavir, AZT or d4T or NNRTIs were not significantly associated with increased risk of osteoporotic fracture in univariate or multivariate models.
For the 32,439 patients who entered the cohort in the HAART era, tenofovir exposure (38,009 PY) was associated with a yearly hazard ratio (HR: 95%CI) for osteoporotic fracture of HR 1.13 (1.05-1.21, p=0.001) in MV1 and HR 1.12 (1.03-1.21, p=0.011) in MV2. Boosted protease inhibitor exposure PI/r (32,109 PY) was associated with HR 1.08 (1.01-1.15, p=0.026) in MV1 but was not significant at HR 1.05 (0.97-1.13, p= 0.237) in MV2. Exposure to abacavir, AZT, d4T or NNRTI was again not significantly associated with increased risk of osteoporotic fracture in either model.
Concomitant exposure to both tenofovir and PI/r was associated with a greater osteoporotic fracture risk (HR 1.16; 95%CI 1.04-1.30) than exposure to either tenofovir without PI/r (HR 1.11, 95%CI 1.01-1.21) or PI/r without tenofovir (HR 1.10; 95%CI 1.01-1.22).
Of the protease inhibitors, only lopinavir/ritonavir (15,319 PY) was associated with significantly increased osteoporotic fracture risk in MV1 (HR 1.13; 95%CI 1.04-1.22, p=0.005) and barely in MV2 (HR 1.09; 95%CI 1.00-1.20, p=0.051).
The second study was a nested case-control study by Linda Mundy and colleagues and reported a reduced risk of fracture in HIV positive people on ART (including tenofovir).2
This was a nested case-control design in a cohort of almost 60,000 HIV positive people (approximately 25% women) enrolled from 1997 to 2008 in a U.S. medical insurance database. ART was prescribed to 51% of patients at some point and was more common from 2003-2008 (72%) than 1998-2003 (29%). Cumulative ART exposure was again derived from prescription history. During this period, 2,411 individuals were identified with closed non-traumatic fractures according to ICD-9 codes and were matched by age and sex to 9144 HIV positive controls without fractures.
Variables included in the analysis included excess alcohol use, low physical activity, low body weight, hepatitis C virus (HCV) infection, excess steroid use and treatment for osteoporosis with bisphosphonates.
In this study, fracture risk was significantly reduced in people exposed to ART (OR 0.64, 95% CI 0.58-0.71; p<0.0001). Furthermore, reduced risk for fracture was associated with exposures to both NRTI and NNRTI drug classes, with a pattern of incremental reduction of risk with increased duration of exposure. A null effect was associated with those exposed to protease inhibitors (PI), but this effect was reduced after extended exposure of 18 months or more in a subset of patients.
Fracture risks were also reported for individual drug exposure. Reduced risk was reported for efavirenz, FTC, 3TC, tenofovir and AZT. Increased risk was reported for darunavir, delavirdine and saquinavir. After an initial increase in risk, nevirapine, ddI, nelfinavir, ritonavir and d4T were associated with a reduced risk after increasing the duration of exposure. Null or uncertain risk for fracture was associated with amprenavir, atazanavir, enfuvirtide, fosamprenavir, indinavir, lopinavir, tipranavir, and T-20 (although limited data was available for some of these drugs).
A sub-analysis of 8,879 cases enrolled in care after 2001, assessed the exposure-response relationship to abacavir and tenofovir, two drugs that have previously been associated with altering BMD levels. No statistically significant association was reported even after 12 months of cumulative exposure to either drug. Fracture risk after 12 months of exposure to tenofovir was not significant (aOR 1.08 95% CI 0.83-1.40).
In the discussion the authors note the complexity of estimating time-dependent drug-specific risks over different time periods, especially given the dynamics of bone metabolism with age. However, ART exposure, including by class and drug was generally protective of fracture risk suggesting an overall benefit of treatment. Although the number of fractures with darunavir was low, the associated was notable (aOR = 1.93, 95% CI = 1.05-3.56; global P-value = 0.043) and may warrant further study.
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