ARV Interactions with HCV Serine Protease Inhibitors
April 17, 2012
Boceprevir and telaprevir, the hepatitis C virus (HCV) serine protease inhibitors, are likely to play important roles in the treatment of individuals with HIV/HCV coinfection, as well as in persons with HCV monoinfection. However, both boceprevir and telaprevir are inhibitors and substrates of cytochrome P450 3A4 (CYP3A4); thus, interactions with antiretroviral (ARV) medications used for treatment of HIV are expected, particularly HIV protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). Few studies have examined drug-drug interactions between HCV protease inhibitors and ARVs, but the available data do make it clear that the HCV PIs have significant interactions with certain ARVs. Interactions, especially those involving HIV PIs and NNRTIs, may substantially affect the efficacy or toxicity of either HCV therapy or HIV therapy (though in many cases the clinical impact of these interactions has not been studied). The table below presents a summary of known interactions between ARVs and HCV PIs, along with recommendations for coadministration.
ARV Effects on HCV Protease Inhibitors
Pharmacokinetic (PK) studies have shown that coadministration of efavirenz with either of the HCV PIs lowers levels of the HCV PI. The dosage of telaprevir should be increased when given with efavirenz (see table below). There are no data to guide dosage adjustment of boceprevir when given with efavirenz, and coadministration of those two drugs is not recommended. Interactions with other NNRTIs have not been studied.
Coadministration of ritonavir-boosted HIV PIs with HCV PIs has produced more heterogeneous results. Atazanavir-ritonavir appears to have modest impact on HCV PI levels but other studied HIV PIs reduce telaprevir and boceprevir levels substantially; the clinical significance of these effects is not known (see table).
The integrase inhibitor raltegravir does not appear to affect telaprevir levels significantly and is not anticipated to affect boceprevir. Studies of interactions with NRTIs (apart from tenofovir; see table) and coreceptor antagonists are lacking.
HCV Protease Inhibitor Effects on ARVs
In PK studies, boceprevir increased EFV Cmax whereas telaprevir decreased EFV modestly; these interactions are not anticipated to be clinically significant. Interactions of other NNRTIs with HCV PIs have not been studied.
The effect of HCV PIs on serum levels of HIV PIs is more noteworthy. Boceprevir substantially reduced the trough levels of the studied ritonavir-boosted HIV PIs (atazanavir, lopinavir, and darunavir), though the clinical significance of those effects is not clear. Telaprevir has a more heterogeneous effect on ritonavir-boosted HIV PIs, raising the trough levels of atazanavir but substantially decreasing levels of darunavir and having little effect on lopinavir.
Boceprevir does not appear to have significant impact on serum levels of the integrase inhibitor raltegravir, whereas telaprevir increases raltegravir exposure. These interactions are not expected to be clinically significant.
Coadministration of HCV PIs with tenofovir increased tenofovir Cmax; it is not known whether that effect will have clinical significance. Interactions with other NRTIs have not been studied, but adverse PK effects are not expected. Coadministration with CCR5 antagonists has not been studied.
It is extremely important to consider known and potential PK interactions when selecting an ARV regimen for patients for whom initiation of boceprevir or telaprevir is being considered. Based on available data, coadministration of boceprevir with HIV PIs, NNRTIs, or CCR5 antagonists is not recommended. Coadministration with raltegravir or NRTIs appears to be safe, although clinical data are lacking. Coadministration of telaprevir with efavirenz or ritonavir-boosted atazanavir appears to be feasible (though dosage adjustment of efavirenz is required; see table below); coadministration with raltegravir is anticipated to be safe; however, data are lacking. Use of telaprevir with other NNRTIs, PIs, or CCR5 antagonists is not recommended.
For recommendations on administration of boceprevir or telaprevir with antiretrovirals, see the table below, and the HIV InSite Database of Antiretroviral Drug Interactions. Note that boceprevir and telaprevir also interact with many non-ARV medications; consult product labels.
Color and symbol code:
No significant interaction Caution; dosage adjustment may be required Coadministration is contraindicated
|Boceprevir (BOC)||Telaprevir (TVR)|
|HIV Protease Inhibitors (PIs)|
|Atazanavir (ATV) + ritonavir|
ATV: AUC↓35%; Cmin ↓49%
ATV: AUC no change; Cmin ↑85%
|Darunavir (DRV) + ritonavir|
DRV: AUC ↓44%; Cmin ↓59%
DRV:AUC ↓40%; Cmin ↓42%
|Fosamprenavir (FPV) + ritonavir|
FPV: AUC ↓47%; Cmin ↓56%
LPV: AUC ↓34%; Cmin ↓43%
LPV: no significant change
RTV: ↓ levels; dosage adjustment not established
TVR: ↓ AUC and Cmin; dosage adjustment not established
|Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)|
EFV: AUC ↑ 20%
EFV: no significant change
|Nucleoside Reverse Transcriptase Inhibitors (NRTIs)|
TDF: no change in AUC; Cmax ↑ 32%; monitor for toxicity
TDF: AUC and Cmax ↑30%; Cmin ↑41% (↑17% if given with EFV); monitor for toxicity
Not studied; no significant
Not studied; no significant
RAL: no significant change
RAL: AUC ↑ 31%
Not studied; interactions expected
Not studied; interactions expected
Note: Unless otherwise noted, no PK data are available.
Abbreviations: Q8H = every 8 hours
- De Kanter C, Blonk M, Colbers A, et al. The influence of the HCV protease inhibitor boceprevir on the pharmacokinetics of the HIV integrase inhibitor raltegravir. In: Program and abstracts of the 19th Conference on Retroviruses and Opportunistic Infections; March 5-8, 2012; Seattle. Abstract 772LB.
- Hulskotte E, Feng HP, Xuan F, et al. Pharmacokinetic interaction between the HCV protease inhibitor boceprevir and ritonavir-boosted HIV-1 protease inhibitors atazanavir, lopinavir, and darunavir. In: Program and abstracts of the 19th Conference on Retroviruses and Opportunistic Infections; March 5-8, 2012; Seattle. Abstract 771LB.
- Incivek [package insert]. Vertex Pharmaceuticals: Cambridge, MA; 2011.
- McNicholl I. Database of ARV Drug Interactions. HIV InSite. San Francisco: UCSF Center for HIV Information.
- Merck & Co. Dear Health Care Professional. Results of Pharmacokinetic Study in Healthy Volunteers Given Victrelis (boceprevir) and Ritonavir-Boosted HIV Protease Inhibitors May Indicate Clinically Significant Drug Interactions for Patients Coinfected with Chronic Hepatitis C and HIV. West Point, PA; February 6, 2012.
- O'Mara E. Clinical pharmacology of BOC: metabolism, excretion, and drug-drug interactions. In: Program and abstracts of the 18th Conference on Retroviruses and Opportunistic Infections; February 27-March 2, 2011; Boston. Oral abstract.
- Van Heeswijk R, Garg V, Boogaerts G, et al. The pharmacokinetic Interaction between telaprevir and raltegravir in healthy volunteers. In: Program and abstracts of the 51st Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2011; Chicago. Abstract A1-1738a.
- Van Heewsijk R, Vandevoorde A, Boogaerts G, et al. Pharmacokinetic interactions between ARV agents and the investigational HCV protease inhibitor TVR in healthy volunteers. In: Program and abstracts of the 18th Conference on Retroviruses and Opportunistic Infections; February 27-March 2, 2011; Boston. Oral abstract.
- Victrelis [package insert]. Schering Corporation: Whitehouse Station, NJ; 2011.
Susa Coffey is medical editor of the NCRC. She is a Professor of Medicine at UCSF in the Division of HIV, Infectious Diseases and Global Medicine and a longtime clinician and educator in the HIV at San Francisco General Hospital clinic (“Ward 86”). She also is medical editor of HIV InSite.
Dr. Leutkemeyer is in practice at the UCSF HIV/AIDS Division at San Francisco General Hospital