- Category: Approved HCV Drugs
- Published on Tuesday, 22 March 2011 00:00
- Written by Liz Highleyman
New HCV antiviral drugs can interact with some antiretroviral drugs for HIV, but others are not affected and HIV/HCV coinfected patients can be treated successfully with minimal dose adjustments.
Direct-acting antiviral drugs that target various steps of the hepatitis C virus (HCV) lifestyle are expected to usher in a new treatment paradigm. The first such medications -- the HCV protease inhibitors boceprevir and telaprevir -- are likely to be approved this summer.
A substantial number of HIV positive people are coinfected with HCV. To date, most trials of new anti-HCV agents have looked at HCV monoinfected people, but coinfected people have a pressing need for better treatments. The first data from a trial of telaprevir in HIV/HCV coinfected patients was presented this month at the 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011) in Boston.
Researchers at the conference also presented findings from studies looking at interactions between HCV and HIV drugs.
Many antiretroviral drugs are processed by the CYP450 enzyme system in the liver. As such, they can speed up or slow down processing of other agents that use the same enzymes, potentially leading to sub-therapeutic drug levels or intensified side effects.
Edward O'Mara from Merck presented data on interactions between boceprevir and various drugs in healthy volunteers. The researchers looked at a set of "probe" drugs and medications likely to be co-administered to patients with hepatitis C.
- There were no clinically relevant changes in boceprevir exposure when co-administered with pegylated interferon alfa-2b (Pegasys), ethinyl estradiol (contraceptive), or tenofovir (Viread).
- Boceprevir had no notable effect on tenofovir overall concentration (area under the curve, or AUC) or clearance by the kidneys, but did increased tenofovir maximum concentration (Cmax) by about 30%.
- Boceprevir AUC and Cmax rose slightly and minimum concentration (Cmin) rose by about 40% when administered with efavirenz (Sustiva).
- Conversely, boceprevir slightly increased efavirenz AUC and Cmax (by about 20% and 10%, respectively).
- Ritonavir (Norvir) -- which is used to boost HIV protease inhibitors -- had a minimal effect on steady-state boceprevir exposure, and actually decreased boceprevir AUC by about 20%.
- The antifungal drug ketoconazole increased boceprevir exposure by 131%.
- Midazolam (a benzodiazepine commonly used as a test drug) Cmax rose by nearly 180% and AUC by more than 400% when taken with boceprevir.
Based on these findings, the researchers suggested that CYP3A4 and P-glycoprotein (another drug processing pathway) "do not contribute substantially" to boceprevir metabolism or elimination. Increased midazolam levels indicate that boceprevir is a strong reversible CYP3A4 inhibitor.
The investigators concluded that no boceprevir dose adjustment is needed when co-administered with pegylated interferon or tenofovir, but the clinical implications of reduced boceprevir trough concentrations when taken with efavirenz are unclear. Boceprevir is not expected to decrease the effectiveness of oral contraceptives. Studies of boceprevir interactions with ritonavir-boosted HIV protease inhibitors are forthcoming.
Rudolph van Heeswijk from Tibotec followed with data on interactions between telaprevir and antiretroviral drugs in healthy volunteers.
Lopinavir/ritonavir (Kaletra), ritonavir-boosted atazanavir (Reyataz), boosted darunavir (Prezista), and boosted fosamprenavir (Lexiva) are both substrates and inhibitors of the CYP3A enzyme, as is telaprevir, the investigators noted as background. Efavirenz is an inducer of CYP3A.
- Telaprevir AUC and Cmin decreased by only about 15% when administered 750 mg 3-times-daily with boosted atazanavir.
- Telaprevir levels fell by about 50% when administered at the same dose with lopinavir/ritonavir.
- Telaprevir levels decreased by about 30% when taken with darunavir/ritonavir or fosamprenavir/ritonavir.
- Conversely, darunavir and fosamprenavir levels fell by more than half when co-administered with telaprevir.
- Atazanavir Cmin nearly doubled when taken with 750 mg telaprevir.
- Therapeutic levels of all drugs were maintained when the telaprevir dose was upped to 1250 mg 3-times-daily in combination with efavirenz and tenofovir.
- Telaprevir AUC remained high but Cmin fell by half when using 1250 mg twice-daily.
- Ritonavir alone did not significantly boost telaprevir levels.
Based on these findings, researchers chose 750 mg 3-times-daily telaprevir plus atazanavir/ritonavir, or telaprevir 1125 mg 3-times-daily with efavirenz as regimens to evaluate in clinical trials of HIV/HCV coinfected patients.
At a CROI press conference discussing the first data from such a trial, Joseph Eron form the University of North Carolina stated that given the data so far, he would only feel comfortable giving telaprevir in combination with atazanavir or efavirenz; lead investigator Mark Sulkowski from Johns Hopkins concurred.
Abstract 118: Merck & Co, Inc, Kenilworth, NJ.
Abstract 119: Tibotec BVBA, Beerse, Belgium; Vertex Pharmaceuticals Inc, Cambridge, MA.
This article was amended on 3/25/11 to correct an inaccuracy.
C Kasserra, E Hughes, M Treitel, et al. Clinical Pharmacology of BOC: Metabolism, Excretion, and Drug-Drug Interactions. 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011). Boston. February 27-March 2, 2011. Abstract 118.
R van Heeswijk, A Vandevoorde, G Boogaerts, et al. Pharmacokinetic Interactions between ARV Agents and the Investigational HCV Protease Inhibitor TVR in Healthy Volunteers. 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011). Boston. February 27-March 2, 2011. Abstract 119.