Purpose

Among patients dually infected with human immunodeficiency virus (HIV) and chronic hepatitis C virus (HCV), use of antiretroviral therapy (ART) containing mitochondrial toxic nucleoside reverse transcriptase inhibitors (mtNRTIs) might induce chronic hepatic injury, which could accelerate HCV-associated liver fibrosis and increase the risk of hepatic decompensation and death.

Methods

We conducted a cohort study among 1747 HIV/HCV patients initiating NRTI-containing ART within the Veterans Aging Cohort Study (2002-2009) to determine if cumulative mtNRTI use increased the risk of hepatic decompensation and death among HIV-/HCV-coinfected patients. Separate marginal structural models were used to estimate hazard ratios (HRs) of each outcome associated with cumulative exposure to ART regimens that contain mtNRTIs versus regimens that contain other NRTIs.

Results

Over 7033 person-years, we observed 97 (5.6%) decompensation events (incidence rate, 13.8/1000 person-years) and 125 (7.2%) deaths (incidence rate, 17.8 events/1000 person-years). The risk of hepatic decompensation increased with cumulative mtNRTI use (1-11 mo: HR, 1.79 [95% confidence interval (CI), 0.74-4.31]; 12-35 mo: HR, 1.39 [95% CI, 0.68-2.87]; 36-71 mo: HR, 2.27 [95% CI, 0.92-5.60]; >71 mo: HR, 4.66 [95% CI, 1.04-20.83]; P = .045) versus nonuse. Cumulative mtNRTI use also increased risk of death (1-11 mo: HR, 2.24 [95% CI, 1.04-4.81]; 12-35 mo: HR, 2.05 [95% CI, 0.68-6.20]; 36-71 mo: HR, 3.04 [95% CI, 1.12-8.26]; >71 mo: HR, 3.93 [95% CI, 0.75-20.50]; P = .030).

Conclusions

These findings suggest that cumulative mtNRTI use may increase the risk of hepatic decompensation and death in HIV/HCV coinfection. These drugs should be avoided when alternatives exist for HIV/HCV patients.

Importance

As men age, they experience decreased serum testosterone concentrations, decreased bone mineral density (BMD), and increased risk of fracture.

Objective

To determine whether testosterone treatment of older men with low testosterone increases volumetric BMD (vBMD) and estimated bone strength.

Design, setting, and participants

Placebo-controlled, double-blind trial with treatment allocation by minimization at 9 US academic medical centers of men 65 years or older with 2 testosterone concentrations averaging less than 275 ng/L participating in the Testosterone Trials from December 2011 to June 2014. The analysis was a modified intent-to-treat comparison of treatment groups by multivariable linear regression adjusted for balancing factors as required by minimization.

Interventions

Testosterone gel, adjusted to maintain the testosterone level within the normal range for young men, or placebo gel for 1 year.

Main outcomes and measures

Spine and hip vBMD was determined by quantitative computed tomography at baseline and 12 months. Bone strength was estimated by finite element analysis of quantitative computed tomography data. Areal BMD was assessed by dual energy x-ray absorptiometry at baseline and 12 months.

Results

There were 211 participants (mean [SD] age, 72.3 [5.9] years; 86% white; mean [SD] body mass index, 31.2 [3.4]). Testosterone treatment was associated with significantly greater increases than placebo in mean spine trabecular vBMD (7.5%; 95% CI, 4.8% to 10.3% vs 0.8%; 95% CI, -1.9% to 3.4%; treatment effect, 6.8%; 95% CI, 4.8%-8.7%; P < .001), spine peripheral vBMD, hip trabecular and peripheral vBMD, and mean estimated strength of spine trabecular bone (10.8%; 95% CI, 7.4% to 14.3% vs 2.4%; 95% CI, -1.0% to 5.7%; treatment effect, 8.5%; 95% CI, 6.0%-10.9%; P < .001), spine peripheral bone, and hip trabecular and peripheral bone. The estimated strength increases were greater in trabecular than peripheral bone and greater in the spine than hip. Testosterone treatment increased spine areal BMD but less than vBMD.

Conclusions and relevance

Testosterone treatment for 1 year of older men with low testosterone significantly increased vBMD and estimated bone strength, more in trabecular than peripheral bone and more in the spine than hip. A larger, longer trial could determine whether this treatment also reduces fracture risk.

Trial registration

clinicaltrials.gov Identifier: NCT00799617.