Pharmacokinetics and hepatotoxicity of lopinavir/ritonavir in non-cirrhotic HIV and hepatitis C virus (HCV) co-infected patients

Canta, Francesca; Marrone, Rosalia; Bonora, Stefano; D’Avolio, Antonio; Sciandra, Mauro; Sinicco, Alessandro; Rosa, Francesco Giuseppe De; Perri, Giovanni Di

doi:10.1093/jac/dkh516

Cited by 37 publications

(22 citation statements)

References 4 publications

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“…Our results show that patients co-infected with hepatitis viruses (CHP) achieve therapeutic drug concentrations more frequently than CHN patients. Importantly, high lopinavir C trough was not correlated with occurrence of hepatotoxicity, confirming previous observations [34].…”

Section: Discussionsupporting

confidence: 88%

Influence of viral chronic hepatitis co-infection on plasma drug concentrations and liver transaminase elevations upon therapy switch in HIV-positive patients

Torti

Lapadula

Uccelli

et al. 2007

International Journal of Antimicrobial Agents

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Section: Discussionsupporting

confidence: 88%

Influence of viral chronic hepatitis co-infection on plasma drug concentrations and liver transaminase elevations upon therapy switch in HIV-positive patients

Torti

Lapadula

Uccelli

et al. 2007

International Journal of Antimicrobial Agents

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“…Ritonavir (RTV), initially used simply as an active drug, is now used at low dosages (100 mg once [QD] or twice daily [BID]) as a booster in PI-based regimens; this is due to the drug's inhibitory activity on various cytochrome P450 isoenzymes (5). However, the toxicity of this drug (6), which led to its transition from an antiviral drug (high dosage, 600 mg twice daily) to a pharmacoenhancer (low dosage), has led to the introduction of alternative booster molecules, e.g., cobicistat (COBI) (7)(8)(9).…”

mentioning

confidence: 99%

Intracellular Antiviral Activity of Low-Dose Ritonavir in Boosted Protease Inhibitor Regimens

Nicolò

Simiele

Calcagno

et al. 2014

Antimicrob Agents Chemother

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Protease inhibitors are largely used for the treatment of HIV infection in combination with other antiretroviral drugs. Their improved pharmacokinetic profiles can be achieved through the concomitant administration of low doses of ritonavir (RTV), a protease inhibitor currently used as a booster, increasing the exposure of companion drugs. Since ritonavir-boosted regimens are associated with long-term adverse events, cobicistat, a CYP3A4 inhibitor without antiviral activity, has been developed. Recently, high intracellular concentrations of ritonavir in lymphocytes and monocytes were reported even when ritonavir was administered at low doses, so we aimed to compare its theoretical antiviral activity with those of the associated protease inhibitors. Intracellular concentrations of ritonavir and different protease inhibitors were determined through the same method. Inhibitory constants were obtained from the literature. The study enrolled 103 patients receiving different boosted protease inhibitors, darunavir-ritonavir 600 and 100 mg twice daily and 800 and 100 mg once daily (n ‫؍‬ 22 and 4, respectively), atazanavir-ritonavir 300 and 100 mg once daily (n ‫؍‬ 40), lopinavir-ritonavir 400 and 100 mg twice daily (n ‫؍‬ 21), or tipranavir-ritonavir 500 and 200 mg twice daily (n ‫؍‬ 16). According to the observed concentrations, we calculated the ratios between the intracellular concentrations of ritonavir and those of the companion protease inhibitor and between the theoretical viral protease reaction speeds with each drug, with and without ritonavir. The median ratios were 4.04 and 0.63 for darunavir-ritonavir twice daily, 2.49 and 0.74 for darunavir-ritonavir once daily, 0.42 and 0.74 for atazanavir-ritonavir, 0.57 and 0.95 for lopinavir-ritonavir, and 0.19 and 0.84 for tipranavir-ritonavir, respectively. Therefore, the antiviral effect of ritonavir was less than that of the concomitant protease inhibitors but, importantly, mostly with darunavir. Thus, further in vitro and in vivo studies of the RTV antiviral effect are warranted. Infection with HIV is a worldwide health problem, with an estimated burden of 34 million infected patients. With the introduction of highly active antiretroviral therapy (HAART), it has been possible to manage infections and prevent the occurrence of AIDS and HIV-related complications (1, 2). HAART is based on the coadministration of drugs that target several important HIV enzymes or cell coreceptors, including reverse transcriptase, integrase, protease, and CCR5. Currently, protease inhibitor (PI)-based regimens are often adopted for HIV treatment (3, 4). Ritonavir (RTV), initially used simply as an active drug, is now used at low dosages (100 mg once [QD] or twice daily [BID]) as a booster in PI-based regimens; this is due to the drug's inhibitory activity on various cytochrome P450 isoenzymes (5). However, the toxicity of this drug (6), which led to its transition from an antiviral drug (high dosage, 600 mg twice daily) to a pharmacoenhancer (low dosage), has led to the introduction o...

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“…In an observational, prospective study involving 78 HIV-monoinfected and 71 HIV/HCV-coinfected non-cirrhotic patients, liver function tests and steady-state lopinavir C trough values were obtained at 1, 3, 6 and 12 months. Incidence of moderate to severe increase in transaminases was significantly higher in HCV-coinfected subjects, but the pharmacokinetics of lopinavir-ritonavir, as assessed by serial measurements of C trough , showed no differences in the two groups, and no association was found between the serum concentration of lopinavir and the development of hepatotoxicity [18].…”

Section: It Is Not Clear Whether Enzyme Induction or Inhibition Is LImentioning

confidence: 84%

Assessing the impact of hepatitis C virus coinfection on lopinavir/ritonavir trough concentrations in HIV-infected patients

Calza

Mosca

Pocaterra

et al. 2010

Eur J Clin Pharmacol

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Pharmacokinetics and hepatotoxicity of lopinavir/ritonavir in non-cirrhotic HIV and hepatitis C virus (HCV) co-infected patients

Cited by 37 publications

References 4 publications

Influence of viral chronic hepatitis co-infection on plasma drug concentrations and liver transaminase elevations upon therapy switch in HIV-positive patients

Influence of viral chronic hepatitis co-infection on plasma drug concentrations and liver transaminase elevations upon therapy switch in HIV-positive patients

Intracellular Antiviral Activity of Low-Dose Ritonavir in Boosted Protease Inhibitor Regimens

Assessing the impact of hepatitis C virus coinfection on lopinavir/ritonavir trough concentrations in HIV-infected patients

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