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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. Data on interactions with other NNRTIs are very limited.

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. Interactions between the elvitegravir/cobicistat combination (in the Stribild coformulation) and HCV PIs have not been studied but are expected to be significant; coadministration is not recommended. 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 C_max whereas telaprevir decreased EFV modestly; these interactions are not anticipated to be clinically significant. Telaprevir appears to increase RPV levels; these increases may be clinically significant in some persons. Data on interactions with other NNRTIs are very limited.

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. Interactions with the elvitegravir/cobicistat combination (in the Stribild coformulation) have not been studied but are expected to be significant; coadministration is not recommended.

Coadministration of HCV PIs with tenofovir increased tenofovir C_max; 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.

Conclusion

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 outside the setting of clinical trials. 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 code:

No significant interaction

Caution; dosage adjustment may be required

Coadministration is contraindicated

Interactions between HIV antiretrovirals and HCV protease inhibitors

	Boceprevir (BOC)	Telaprevir (TVR)
Note: Unless otherwise noted, no PK data are available. Abbreviations: Q8H = every 8 hours
HIV Protease Inhibitors (PIs)
Atazanavir (ATV) + ritonavir	ATV: AUC↓35%; Cmin ↓49% BOC: no significant change	ATV: AUC no change; Cmin ↑85% TVR: no significant change No dosage adjustment needed
Darunavir (DRV) + ritonavir	DRV: AUC ↓44%; Cmin ↓59% BOC AUC ↓32%; Cmin ↓35%	DRV:AUC ↓40%; Cmin ↓42% TVR: AUC ↓35%; Cmin ↓32%
Fosamprenavir (FPV) + ritonavir		FPV: AUC ↓47%; Cmin ↓56% TVR: AUC ↓32%; Cmin ↓30%
Indinavir (IDV)
Lopinavir (LPV)/ritonavir	LPV: AUC ↓34%; Cmin ↓43% BOC: AUC ↓ 45%; Cmin ↓57%	LPV: no significant change TVR: AUC ↓54%; Cmin ↓52%
Nelfinavir (NFV)
Ritonavir (RTV)	RTV: ↓ levels; dosage adjustment not established BOC: ↓ levels; dosage adjustment not established	TVR: ↓ AUC and Cmin; dosage adjustment not established
Saquinavir (SQV)
Tipranavir (TPV)
Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz (EFV)	EFV: AUC ↑ 20% BOC: AUC ↓ 19%; Cmin ↓44%	EFV: no significant change TVR: AUC ↓26%; Cmin ↓47%; must increase TVR dosage to 1,125 mg Q8H
Etravirine (ETR)	ETR: AUC ↓ 23%; Cmin ↓ 29% BOC: AUC and Cmax ↑ 10%; Cmin ↓ 12%	ETR: no significant change TVR: AUC ↓ 16%; Cmin ↓ 25%
Nevirapine (NVP)
Rilpivirine (RPV)		RPV: AUC ↑ 178%; Cmin ↑ 193%; Cmax ↑ 149% TVR: no significant change
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Tenofovir (TDF)	TDF: no change in AUC; Cmax ↑ 32%; monitor for toxicity BOC: no significant change	TDF: AUC and Cmax ↑30%; Cmin ↑41% (↑17% if given with EFV); monitor for toxicity TVR: no change
Other NRTIs	Not studied; no significant interactions expected	Not studied; no significant interactions expected
Integrase Inhibitors
Elvitegravir (EVG) + cobistat	Not studied; interactions expected	Not studied; interactions expected
Raltegravir (RAL)	RAL: no significant change BOC: no significant change (compared with historical controls)	RAL: AUC ↑ 31% TVR: no significant change
CCR5 Antagonist
Maraviroc (MVC)	Not studied; interactions expected	Not studied; interactions expected