Introduction: Prevalence estimates of osteopenia and osteoporosis (reduced bone mineral density; BMD) in HIV-infected patients and the role of antiretroviral therapy (ART) varies in the literature. Methods: We conducted a meta-analytical review of cross-sectional studies published in English to determine the pooled odds ratios (OR) of reduced BMD and osteoporosis in the following groups: HIV-positive versus HIV-negative; ART-treated versus ART-naive; protease inhibitor (PI)-treated versus PI-untreated. We searched the MEDLINE, PubMed, and EMBASE databases for eligible references between January 1966 and November 2005. Random effects models were used to generate pooled OR estimates and confidence intervals. Results: Of 37 articles identified, 20 met the inclusion criteria. Of the 884 HIV-infected patients, 67% had reduced BMD, of whom 15% had osteoporosis, yielding a pooled OR of 6.4 and 3.7, respectively, compared with HIV-uninfected controls (n = 654) using 11 studies with available data. Compared with ART-naive patients (n = 202, 10 studies), ART-treated individuals (n = 824) had a 2.5-fold increased odds of prevalent reduced BMD. The risk of prevalent osteoporosis (seven studies) was similarly elevated in ART-treated individuals. Compared with non-PI-treated HIV patients (n = 410, 14 studies), PI-treated patients (n = 791) had increased odds of reduced BMD and osteoporosis (12 studies). Few studies adjusted for important covariates such as HIV disease severity or treatment duration. Conclusion: The prevalence of osteoporosis in HIV-infected individuals is more than three times greater compared with HIV-uninfected controls. ART-exposed and PI-exposed individuals had a higher prevalence of reduced BMD and osteoporosis compared with their respective controls. The influence of other disease and treatment variables on these estimates could not be determined.

Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review.

https://www.natap.org/2015/HIV/PIIS014067361560616X.pdf

Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials

Background The efficacy of tenofovir disoproxil fumarate (TDF) as part of combination antiretroviral treatment (ART) has been demonstrated in several randomized, controlled trials. However, an increasing number of case reports suggest that TDF use may be associated with significant nephrotoxicity. Our objective was to determine the renal safety of TDF-containing ART regimens for HIV-infected individuals. Methods MEDLINE, EMBASE, Global Health, Scopus, Biosis Previews, Cochrane Library, Web of Science, and existing systematic reviews were searched. Prospective studies comparing TDF-containing with non-TDF containing ART regimens were selected for inclusion. We extracted data on study characteristics, participant characteristics, therapeutic interventions, renal function, bone density, and fracture rates. Results A total of 17 studies (including 9 randomized, controlled trials) met the selection criteria. Median sample size was 517 participants. Constituent ART regimens were diverse. There was a significantly greater loss of kidney function among the TDF recipients, compared with control subjects (mean difference in calculated creatinine clearance, 3.92 mL/min; 95% confidence interval [CI], 2.13-5.70 mL/min), as well as a greater risk of acute renal failure (risk difference, 0.7%; 95% CI, 0.2-1.2). There was no evidence that TDF use led to increased risk of severe proteinuria, hypophosphatemia, or fractures. Conclusions Although TDF use was associated with a statistically significant loss of renal function, the clinical magnitude of this effect was modest. Our findings do not support the need to restrict TDF use in jurisdictions where regular monitoring of renal function and serum phosphate levels is impractical.

Systematic Review and Meta-analysis: Renal Safety of Tenofovir Disoproxil Fumarate in HIV-Infected Patients

Background Plasma concentrations of tenofovir increase when the drug is coadministered with some ritonavir-boosted protease inhibitors (PI/r). We hypothesized that tenofovir disoproxil fumarate (TDF)-treated patients taking PI/r-based regimens would have a greater decline in renal function than patients receiving nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based therapy. Methods We compared the estimated decline in renal function among 146 human immunodeficiency virus type 1 (HIV-1)-infected patients receiving a TDF+PI/r- (n = 51), TDF+NNRTI- (n = 29), or non-TDF-containing (n = 66) regimen. Plasma tenofovir concentrations were measured at study week 2, and rates of creatinine clearance (CrCl) were estimated using the Cockcroft-Gault (C-G) and Modification of Diet in Renal Disease (MDRD) equations. Mixed-effects models were used to analyze regimen type and tenofovir concentration as predictors of change in CrCl from baseline to weeks 24 and 48. Results Decreases in C-G estimates of CrCl were not significantly different among the 3 groups during the first 24 weeks of therapy. However, in adjusted analyses, patients receiving TDF+PI/r had a greater rate of decline in CrCl than did the TDF+NNRTI group (for C-G, -13.9 vs. -6.2 mL/min/year [P = .03]; for MDRD, -14.7 vs. -4.5 mL/min/1.73 m(2)/year [P = .02]). Among TDF-treated patients, tenofovir plasma concentration was not associated with CrCl over time. Conclusions Treatment with TDF and PI/r was associated with greater declines in renal function over 48 weeks compared with TDF+NNRTI-based regimens.

Greater Tenofovir-Associated Renal Function Decline with Protease Inhibitor-Based versus Nonnucleoside Reverse-Transcriptase Inhibitor-Based Therapy

The use of antiretroviral medications in HIV-negative individuals as pre-exposure prophylaxis (PrEP) is a promising approach to prevent HIV infection. Tenofovir disoproxil fumarate (TDF) and emtricitabine exhibit desirable properties for PrEP including: favourable pharmacokinetics that support infrequent dosing; few major drug-drug or drug-food interactions; an excellent clinical safety record; and pre-clinical evidence for efficacy. Several large, randomized, controlled clinical trials are evaluating the safety and efficacy of TDF and emtricitabine for this new indication. A thorough understanding of variability in drug response will help determine future investigations in the field and/or implementation into clinical care. Because tenofovir and emtricitabine are nucleos(t)ide analogues, the HIV prevention and toxicity effects depend on the triphosphate analogue formed intracellularly. This review identifies important cellular pharmacology considerations for tenofovir and emtricitabine, which include drug penetration into relevant tissues and cell types, race/ethnicity/pharmacogenetics, gender, cellular activation state and appropriate episodic or alternative dosing strategies based on pharmacokinetic principles. The current state of knowledge in these areas is summarized and the future utility of intracellular pharmacokinetics/pharmacodynamics for the PrEP field is discussed.

Pharmacological considerations for tenofovir and emtricitabine to prevent HIV infection

The reverse transcriptase inhibitor 9-[2-(phosphonomethoxy)propyl]adenine (PMPA; tenofovir) was previously found to offer strong prophylactic and therapeutic benefits in an infant macaque model of pediatric human immunodeficiency virus (HIV) infection. We now summarize the toxicity and safety of PMPA in these studies. When a range of PMPA doses (4 to 30 mg/kg of body weight administered subcutaneously once daily) was administered to 39 infant macaques for a short period of time (range, 1 day to 12 weeks), no adverse effects on their health or growth were observed; this included a subset of 12 animals which were monitored for more than 2 years. In contrast, daily administration of a high dose of PMPA (30 mg/kg subcutaneously) for prolonged periods of time (>8 to 21 months) to 13 animals resulted in a Fanconi-like syndrome (proximal renal tubular disorder) with glucosuria, aminoaciduria, hypophosphatemia, growth restriction, bone pathology (osteomalacia), and reduced clearance of PMPA. The adverse effects were reversible or were alleviated following either complete withdrawal of PMPA treatment or reduction of the daily regimen from 30 mg/kg to 2.5 to 10 mg/kg subcutaneously. Finally, to evaluate the safety of a prolonged low-dose treatment regimen, two newborn macaques were started on a 10-mg/kg/day subcutaneous regimen; these animals are healthy and have normal bone density and growth after 5 years of daily treatment. In conclusion, our findings suggest that chronic daily administration of a high dose of PMPA results in adverse effects on kidney and bone, while short-term administration of relatively high doses and prolonged low-dose administration are safe.

Biological Effects of Short-Term or Prolonged Administration of 9-[2-(Phosphonomethoxy)Propyl]Adenine (Tenofovir) to Newborn and Infant Rhesus Macaques

The reverse transcriptase (RT) inhibitor tenofovir (TFV) is highly effective in the simian immunodeficiency virus (SIV) macaque model of human immunodeficiency virus infection. The current report describes extended safety and efficacy data on 32 animals that received prolonged (≥1- to 13-year) daily subcutaneous TFV regimens. The likelihood of renal toxicity (proximal renal tubular dysfunction [PRTD]) correlated with plasma drug concentrations, which depended on the dosage regimen and age-related changes in drug clearance. Below a threshold area under the concentration-time curve for TFV in plasma of ∼10 μg·h/ml, an exposure severalfold higher than that observed in humans treated orally with 300 mg TFV disoproxil fumarate (TDF), prolonged TFV administration was not associated with PRTD based on urinalysis, serum chemistry analyses, bone mineral density, and clinical observations. At low-dose maintenance regimens, plasma TFV concentrations and intracellular TFV diphosphate concentrations were similar to or slightly higher than those observed in TDF-treated humans. No new toxicities were identified. The available evidence does not suggest teratogenic effects of prolonged low-dose TFV treatment; by the age of 10 years, one macaque, on TFV treatment since birth, had produced three offspring that were healthy by all criteria up to the age of 5 years. Despite the presence of viral variants with a lysine-to-arginine substitution at codon 65 (K65R) of RT in all 28 SIV-infected animals, 6 animals suppressed viremia to undetectable levels for as long as 12 years of TFV monotherapy. In conclusion, these findings illustrate the safety and sustained benefits of prolonged TFV-containing regimens throughout development from infancy to adulthood, including pregnancy.

Chronic administration of tenofovir to rhesus macaques from infancy through adulthood and pregnancy: summary of pharmacokinetics and biological and virological effects.

Erratum: Biological effects of short-term or prolonged administration of 9-[2-(phosphonomethoxy)propyl]adenine (tenofovir) to newborn and infant rhesus macaques (Antimicrobial Agents and Chemotherapy (2004) 48, 5 (1469-1487))

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Biological Effects of Short-Term or Prolonged Administration of 9-[2-(Phosphonomethoxy)Propyl]Adenine (Tenofovir) to Newborn and Infant Rhesus Macaques

Chronic administration of tenofovir to rhesus macaques from infancy through adulthood and pregnancy: summary of pharmacokinetics and biological and virological effects.

Erratum: Biological effects of short-term or prolonged administration of 9-[2-(phosphonomethoxy)propyl]adenine (tenofovir) to newborn and infant rhesus macaques (Antimicrobial Agents and Chemotherapy (2004) 48, 5 (1469-1487))