Henning Drechsler

Osteoporotic fracture risk associated with cumulative exposure to tenofovir and other antiretroviral agents.

Background:Whereas tenofovir (TDF) exposure has been associated with decreased bone density, it remains unclear whether it is associated with increased risk of osteoporotic fractures. Methods:Patients with any osteoporotic fracture (defined as wrist, vertebral or hip fracture) occurring after HIV diagnosis were identified by International Classification of Diseases – 9th Revision (ICD-9) code in the Veterans Affairs’ Clinical Case Registry from 1988 to 2009. Osteoporotic fracture risk associated with cumulative exposure to TDF and other antiretrovirals was examined in univariate analysis and multivariate model 1 (MV1 – controlling for race, age, tobacco use, diabetes, body mass index, and hepatitis C status) and model 2 (MV2 – controlling for MV1 variables + concomitant antiretroviral exposures). Results:Among 56 660 patients evaluated, TDF exposure (total 46 062 person-years) was associated with an osteoporotic fracture hazard ratio of 1.080 [95% confidence interval (CI) 1.02–1.15, P < 0.001] in univariate analysis, 1.06 (0.99–1.12) in MV1 and 1.06 (0.99–1.14) in MV2. Among patients entering the cohort in the highly active antiretroviral therapy (HAART) era (n = 32 439), TDF exposure was associated with a yearly hazard ratio for osteoporotic fracture of 1.16 (95% CI 1.08–1.24, P < 0.001) in univariate model, 1.13 (1.05–1.21, P = 0.001) in MV1 and 1.12 (1.03–1.21, P = 0.011) in MV2. Boosted protease inhibitor exposure was associated with hazard ratio of 1.11 (1.05–1.18, P = 0.001) in univariate model, 1.08 (1.01–1.15, P = 0.026) in MV1 and 1.05 (0.97–1.13, P = 0.237) in MV2. Among protease inhibitors, lopinavir/ritonavir (LPV/RTV) had an osteoporotic fracture hazard ratio of 1.09 (CI 1.00–1.20, P = 0.051) in MV2. Conclusion:Cumulative exposure to TDF and, among protease inhibitors, LPV/RTV was independently predictive of increased risk of osteoporotic fracture in the HAART era.

Gilbert Syndrome and the Development of Antiretroviral Therapy–Associated Hyperbilirubinemia

BACKGROUND Unconjugated hyperbilirubinemia results from Gilbert syndrome and from antiretroviral therapy (ART) containing protease inhibitors. An understanding of the interaction between genetic predisposition and ART may help to identify individuals at highest risk for developing jaundice. METHODS We quantified the contribution of UGT1A1*28 and ART to hyperbilirubinemia by longitudinally modeling 1386 total bilirubin levels in 96 human immunodeficiency virus (HIV)-infected individuals during a median of 6 years. RESULTS The estimated average bilirubin level was 8.8 micromol/L (0.51 mg/dL). Atazanavir increased bilirubin levels by 15 mu mol/L (0.87 mg/dL), and indinavir increased bilirubin levels by 8 micromol/L (0.46 mg/dL). Ritonavir, lopinavir, saquinavir, and nelfinavir had no or minimal effect on bilirubin levels. Homozygous UGT1A1*28 increased bilirubin levels by 5.2 micromol/L (0.3 mg/dL). As a consequence, 67% of individuals homozygous for UGT1A1*28 and receiving atazanavir or indinavir had > or =2 episodes of hyperbilirubinemia in the jaundice range (>43 micromol/L [>2.5 mg/dL]), versus 7% of those with the common allele and not receiving either of those protease inhibitors (P<.001). Efavirenz resulted in decreased bilirubin levels, which is consistent with the induction of UDP-glucuronosyltransferase 1A1. CONCLUSIONS Genotyping for UGT1A1*28 before initiation of ART would identify HIV-infected individuals at risk for hyperbilirubinemia and decrease episodes of jaundice.

Abacavir Use and Risk of Acute Myocardial Infarction and Cerebrovascular Events in the Highly Active Antiretroviral Therapy Era

BACKGROUND Some studies have suggested that exposure to antiretroviral therapy (ART) with abacavir is associated with an increased risk of acute myocardial infarction (AMI). METHODS Using the Veterans Health Administrations Clinical Case Registry we calculated the risk of AMI and cerebrovascular events (CVA) associated with the cumulative use of abacavir and other nucleoside combinations. We also evaluated the impact of pre-existing chronic kidney disease on the selection of abacavir versus tenofovir in the last recorded ART regimen, and on highly active antiretroviral therapy-associated AMI and CVA risks. RESULTS A total of 19,424 human immunodeficiency virus-infected patients contributed 76,376 patient-years of follow. After adjusting for age, hypercholesterolemia, hypertension, type 2 diabetes, and smoking, the hazard ratio (HR) for each year of abacavir use was 1.18 (95% confidence interval [CI], .92-1.50; P=.191) for AMI and 1.16 (95% CI, .98-1.37; P=.096) for CVA. Abacavir use was more common among patients with prior chronic kidney disease than was tenofovir use (12.46% versus 7.15%; P=.0001), and chronic kidney disease was associated with a significantly higher risk of AMI (HR, 2.41; 95% CI, 1.73-3.36), and CVA (HR, 1.80; 95% CI, 1.44-2.24). Compared with patients who received neither tenofovir nor abacavir, patients who received tenofovir had lower risk of AMI (HR, 0.16; 95% CI, .08-.33; P=.0001) and CVA (HR, 0.22; 95% CI, .15-.32; P=.001). Use of abacavir was associated with lower risk of CVA (HR, 0.60; 95% CI, .45-.79). CONCLUSIONS We observed no association between cumulative or current abacavir use and AMI or CVA. Abacavir use was more common than was tenofovir use among patients with prior chronic kidney disease, and chronic kidney disease independently predicted higher rates of AMI and CVA.

Switching effective antiretroviral therapy: A review

One approach to target the long-term metabolic toxicity and disfiguring body-shape changes associated with antiretroviral therapy is to switch one component of a regimen to an alternative drug, usually from a different class of antiretrovirals. Most commonly, substitutions have involved protease inhibitors, but the thymidine analogue nucleosides, especially stavudine, have been investigated more recently. Certain trends from these studies have emerged. First, if the patient has had sustained viral suppression, switching therapy is generally virologically safe. Second, metabolic disturbances, such as insulin resistance and dyslipidemia, appear to be at least partially reversible. Substitution of other agents for protease inhibitors has not been associated with reversal or improvement in fat redistribution. Studies in which thymidine analogue reverse-transcriptase inhibitors have been switched have reported modest improvements in peripheral lipoatrophy. Larger, controlled, long-term studies and a more standardized approach to definition of metabolic and morphological abnormalities are needed.

Hepatitis C virus coinfection and the risk of cardiovascular disease among HIV-infected patients

Among HIV‐infected patients, hepatitis C virus (HCV) coinfection is associated with lower cholesterol levels, but it remains unclear how it affects cardiovascular outcomes.

APOBEC3F and APOBEC3G mRNA Levels Do Not Correlate with Human Immunodeficiency Virus Type 1 Plasma Viremia or CD4+ T-Cell Count

ABSTRACT APOBEC3F and APOBEC3G (hA3F and hA3G) are part of an innate mechanism of antiretroviral defense. The human immunodeficiency virus type 1 (HIV-1) accessory protein Vif targets both proteins for proteasomal degradation. Using mRNA from peripheral blood mononuclear cells of 92 HIV-infected subjects not taking antiretroviral therapy and 19 HIV-uninfected controls, we found that hA3F (P < 0.001) and hA3G (P = 0.016) mRNA levels were lower in HIV-infected subjects and were positively correlated with one another (P = 0.003). However, we found no correlation in the abundance of either hA3F or hA3G mRNA with either viral load or CD4 counts in HIV-infected subjects.

Niacin in HIV-infected individuals with hyperlipidemia receiving potent antiretroviral therapy

BACKGROUND Extended release (ER)-niacin therapy, which has been associated with reduced glucose tolerance in human immunodeficiency virus (HIV)-seronegative individuals, has not been evaluated in the HIV-infected population. METHODS This open, prospective trial evaluated the safety and efficacy of ER-niacin therapy for antiretroviral therapy-associated dyslipidemia. Fourteen individuals received ER-niacin at maximum doses of 2000 mg per day for 14 weeks. RESULTS Significant reductions in serum levels of triglycerides (P=.02), total cholesterol (P=.005), and non-HDL cholesterol (P=.04) were seen after ER-niacin therapy. Seven of 11 subjects were glucose intolerant after ER-niacin therapy; for 3 of these subjects, this was a new finding. Beta-cell sensitivity to basal glucose levels increased significantly without concomitant increase in overall glucose disposition indices. The values for the homeostasis model of insulin resistance index increased significantly (P=.005). CONCLUSION ER-niacins role in the treatment of antiretroviral therapy-associated dyslipidemia requires further evaluation, but the results of this pilot study indicate that it is safe and tolerated and provides a valuable treatment option.

The RADAR study: week 48 safety and efficacy of RAltegravir combined with boosted DARunavir compared to tenofovir/emtricitabine combined with boosted darunavir in antiretroviral-naive patients. Impact on bone health.

Background NRTI-sparing regimens may avoid long-term mitochondrial, bone and renal toxicities and maintain viral suppression. Methods In the RADAR study, 85 antiretroviral-naïve HIV-infected patients were randomized to receive either raltegravir (RAL) (n = 42) or tenofovir/emtricitabine (TDF/FTC) (n = 43), each with ritonavir-boosted darunavir (DRV/r). Virologic efficacy was assessed at weeks 24 and 48. Bone mineral density (BMD) was assessed by dual energy X-ray absorptiometry (DXA) scan at baseline and week 48, and bone turnover markers (BTM) assessed at weeks 0, 16 and 48. Results Using an intention-to-treat analysis, 62.5% of RAL subjects and 83.7% of TDF/FTC subjects were responders (VL<48 copies/mL) at week 48 (p = 0.045; chi-square test). The proportions of patients achieving VL<200 copies/mL were similar: 72.5% and 86.0% (p = 0.175). Premature treatment discontinuation was the main cause for failure. No treatment-emergent resistance was observed. Changes from baseline in RAL vs. TDF/FTC for CD4+ (+199 vs. +216 cells/µL, p = 0.63), total cholesterol/HDL (−0.25 vs. −0.71 mg/dL (p = 0.270), and eGFR (−4.4 vs. −7.9 ml/min, p = 0.44) were comparable between groups. Changes in subtotal BMD to week 48 were: +9.2 with RAL vs. −7 g/cm2 with TDF/FTC (p = 0.002). Mean CTX changes were +0.04 vs. +0.24 ng/mL (p = 0.001), and mean P1NP changes were +3.59 vs. +30.09 ng/mL (p = 0.023). BTM changes at week 16 predicted change in BMD by week 48 (R = −0.394, p = 0.003 for CTX; and R = −0.477, p<0.001 for P1NP). Conclusion The NRTI-sparing regimen RAL+DRV/r did not achieve similar week 48 virologic efficacy compared with TDF/FTC+DRV/r, but was better with regard to markers of bone health. Trial Registration ClinicalTrials.gov NCT 00677300

Mechanisms of bone disease in HIV and hepatitis C virus: impact of bone turnover, tenofovir exposure, sex steroids and severity of liver disease.

Objective:Both HIV and hepatitis C virus (HCV) infections are associated with higher osteoporotic fracture risk. Increased bone turnover, liver fibrosis, tenofovir (TDF) use or hormonal imbalances are possible underlying mechanisms. Design:This prospective, cross-sectional study assessed 298 male volunteers with either virologically suppressed HIV or untreated HCV mono-infections, HIV/HCV co-infection and noninfected controls. Methodology:Study participants underwent bone mineral density (BMD) by dual-energy x-ray absorptiometry and measurement of bone turnover markers [BTM: C-telopeptide (CTX) and osteocalcin (OC)], insulin-like growth factor-1 (IGF-1), the sex steroids testosterone (T) and estradiol (E2), and the aspartate aminotransferase-to-platelet ratio index (APRI). Impact of HIV and HCV status on BMD was evaluated in multivariate models adjusting for APRI score, BTM, TDF exposure, IGF-1, and sex steroids. Results:HIV and HCV status independently predicted lower BMD, controlling for age, race, BMI, and smoking (P = 0.017 and P = 0.010, respectively), whereas APRI did not (P = 0.84). HIV was associated with increased bone resorption (CTX: P < 0.001) and formation (OC: P = 0.014), whereas HCV infection was not associated with CTX (P = 0.30) or OC (P = 0.36). TDF exposure was associated with lower BMD (P < 0.01). IGF-1 was significantly decreased in HCV and increased in HIV. Tumor necrosis factor-&agr; (P = 0.98), IGF-1 (P = 0.80), bioavailable T (P = 0.45) and E2 (P = 0.27) were not associated with BMD and did not attenuate the impact of HIV or HCV on BMD. Conclusion:HIV and TDF exposure decrease BMD through increased bone turnover, although the lower BMD in HCV is not explained by a high turnover state. Neither virus’ effect on BMD is likely mediated through increased inflammation, liver fibrosis, IGF-1, or sex steroids.

Adaptation of antiretroviral therapy in human immunodeficiency virus infection with central nervous system involvement

The authors describe a patient with known human immunodeficiency virus (HIV)-1 infection who presented with two generalized seizures and was found to have extensive white matter disease and a left/bilateral temporo-occipital focal slowing on electroencephalography (EEG). There were no magnetic resonance imaging (MRI) or cerebrospinal fluid (CSF) indications for opportunistic infection. Plasma viremia was controlled, whereas viral replication was uncontrolled in CSF. CSF-specific genotype-guided adaptation of the antiretroviral therapy in order to optimize central nervous system (CNS) penetration resulted in clinical improvement and normalization of MRI and EEG. Our case report illustrates the importance of individualized antiretroviral therapy in HIV infected patients with neurological complications.