ritonavir and Nephrolithiasis

Ritonavir-boosted atazanavir (ATV/r) is a relatively well tolerated antiretroviral drug. However, side effects including hyperbilirubinemia, dyslipidemia, nephrolithiasis and cholelithiasis have been reported in the medium and long term. Unboosted ATV may be selected for some patients because it has fewer gastrointestinal adverse effects, less hyperbilirubinemia and less impact on lipid profiles.. We investigated the distribution of ATV plasma trough concentrations according to drug dosage and the potential relationship between ATV plasma trough concentrations and drug-related adverse events in a consecutive series of 240 HIV-infected patients treated with ATV/r 300/100 mg (68%) or ATV 400 mg (32%).. 43.9% of patients treated with ATV/r 300/100 mg had ATV concentrations exceeding the upper therapeutic threshold. A significant and direct association has been observed between the severity of hyperbilirubinemia and ATV plasma trough concentrations (ATV concentrations: 271 [77-555], 548 [206-902], 793 [440-1164], 768 [494-1527] and 1491 [1122-1798] ng/mL in patients with grade 0, 1, 2, 3 and 4 hyperbilirubinemia, respectively). In an exploratory analysis we found that patients with dyslipidemia or nephrolitiasis had ATV concentrations significantly higher (582 [266-1148], and 1098 [631-1238] ng/mL, respectively) (p<0.001), as compared with patients with no ATV-related complications (218 [77-541] ng/mL).. A significant proportion of patients treated with the conventional dosage of ATV (300/100) had plasma concentrations exceeding the upper therapeutic threshold. These patients that are at high risk to experience ATV-related complications may benefit from TDM-driven adjustments in ATV dosage with potential advantages in terms of costs and toxicity.

Topics: Adult; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Drug Administration Schedule; Drug Dosage Calculations; Drug Monitoring; Dyslipidemias; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Hyperbilirubinemia; Male; Middle Aged; Nephrolithiasis; Ritonavir; Viral Load

Although ritonavir-boosted atazanavir (ATV/r) is known to be associated with nephrolithiasis, little is known about the incidence of nephrolithiasis in patients treated with ritonavir-boosted Darunavir (DRV/r), the other preferred protease inhibitor.. In a single-center cohort, the incidence of nephrolithiasis was compared between HIV-infected patients who commenced DRV/r-containing antiretroviral therapy and those on ATV/r. The effects of ATV/r use over DRV/r were estimated by univariate and multivariate Cox hazards models.. Renal stones were diagnosed in only one patient (0.86 per 1000 person-years) of the DRV/r group (n=540) and 37 (20.2 per 1000 person-years) of the ATV/r group (n=517). The median [interquartile (IQR)] observation period in the DRV/r group was 27.1 months (IQR 18.1-38.4 months), and 40.6 months (IQR 17.5-42.7) for the ATV/r group. The total observation period was 1,163.6 person-years and 1,829.6 person-years for the DRV/r group and for the ATV/r group, respectively. In the 37 patients on ATV/r who developed nephrolithiasis, the median time from commencement of ATV/r to diagnosis was 28.1 months (IQR 18.4-42.7), whereas nephrolithiasis in the single patient of the DRV/r group occurred 11.2 month after the introduction of DRV/r. ATV/r use over DRV/r was significantly associated with nephrolithiasis by uni- and multivariate analyses (HR=26.01; 95% CI, 3.541-191.0; p=0.001) (adjusted HR=21.47; 95% CI, 2.879-160.2; p=0.003).. The incidence of nephrolithiasis was substantially lower in patients on DRV/r than those on ATV/r. The results suggest that DRV/r should be selected for treatment of HIV-infected patients at risk of chronic kidney disease.

Topics: Adult; Anti-HIV Agents; Atazanavir Sulfate; Darunavir; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Nephrolithiasis; Oligopeptides; Proportional Hazards Models; Pyridines; Retrospective Studies; Ritonavir; Sulfonamides

There have been no data presented on the relative rates of the development of renal stones in those receiving ritonavir-boosted atazanavir (ATZ/r) when compared with other commonly used antiretrovirals (ARVs). We compared the rate of development of renal stones in a cohort of HIV-infected individuals attending the Chelsea and Westminster Hospital Foundation Trust exposed to ATZ/r with those exposed to efavirenz (EFV)/ritonavir-boosted lopinavir (LPV/r) and ritonavir-boosted darunavir (DRV/r) over a 45-month study period. The rate of development of renal stones in the ATZ/r group (n = 1206) compared with the EFV/LPV/r/DRV/r combined group (n = 4449) was 7.3 [95% confidence interval (CI) 4.7-10.8] per 1000 patient-years and 1.9 (95% CI 1.2-2.8) per 1000 patient-years (P < 0.001), respectively. The renal stones rate remained significantly higher in the ATZ/r group after adjusting for prior ATZ/r/indinavir (IND) exposure. When choosing a boosted protease inhibitor, ATZ/r renal stones should be considered as a potential comorbidity.

Topics: Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Bilirubin; Cohort Studies; Cyclopropanes; Darunavir; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Nephrolithiasis; Oligopeptides; Pyridines; Pyrimidinones; Retrospective Studies; Ritonavir; Sulfonamides

Topics: Adenine; Adult; Alkynes; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Hepatitis B, Chronic; Hepatitis C, Chronic; Hepatitis D, Chronic; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Lopinavir; Male; Nephrolithiasis; Oligopeptides; Organophosphonates; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine; Tenofovir

The risk of nephrolithiasis associated with atazanavir is not well characterized. The US Food and Drug Administration's Adverse Event Reporting System was searched for reports of nephrolithiasis in HIV-infected patients taking an atazanavir-based regimen. Thirty cases were identified. Many patients required hospitalization for management, including lithotripsy, ureteral stent insertion, or endoscopic stone removal. Some cases of nephrolithiasis resulted in atazanavir discontinuation. Healthcare professionals and patients should be informed that nephrolithiasis is a possible adverse event with atazanavir.

Topics: Adenine; Adult; Adverse Drug Reaction Reporting Systems; Atazanavir Sulfate; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Hospitalization; Humans; Male; Middle Aged; Nephrolithiasis; Oligopeptides; Organophosphonates; Pyridines; Reverse Transcriptase Inhibitors; Ritonavir; Tenofovir; United States