Pharmacokinetic Interactions Between Antiretroviral Agents and the Investigational HCV Protease Inhibitor Telaprevir in Healthy Volunteers

Jules Levin reports on the DDIs between Telaprevir (TVR) and some of the current drugs to treat HIV. As you have probably read, the RVR rates for Telaprevir in co-infected patients ranged from 70 to 75% in a sample size of 60 randomized to patients not on treatment as well as patients currently on Viread or an Atazanavir regimen. No info was available on whether patients HIV was controlled during that four week period. Based on the data on DDIs between Telaprevir and ARTs presented by R van Heeswijk,et al, Telaprevir is both an inducer and inhibitor of CYP3A, which means it is likely to interact with most ARTs on the market. Indeed, they did see reduced exposure to Telaprevir and variable effects on HIV protease inhibitors and tenofovir.

Telaprevir AUC using the 750mg Q8h dose with Lopinavir, Durnavir, Atazanavir (ATV) and Fosamprenavir saw 54%, 20%, 35% and 32% reductions respectively. Looking at the HIV PI concentrations, Ritonavir boosted Lopinavir, Durnavir, Atazanavir and Fosamprenavir saw no change, 40% less, 17% increase and 47% decrease with Telaprevir 750mg q8h respectively.

These interactions prompted Vertex to choose regimens with the least effect on exposure for their co-infected trial. ATV/r 300/100mg qd + TVR 750mg q8h/P+r and Efavirenz 600mg qd + TVR 1125 q8h/P+r.

Despite the author conclusions below, there is cause for concern in regards to DDIs with common ARVs and TVR. The PK concentrations of drugs are highly variable in individuals due to a variety of reasons. Add DDIs to the mix and even the slightest change in drug concentrations can case a Cmin to dip below the IC50 of the virus, with potential to cause either HIV and/or HCVresistance. Because of this, we might see resurgence of Therapeutic Drug Monitoring (TDM)in an effort to prevent resistance - Chris

AUTHOR CONCLUSIONS

RTV-boosted HIV PIs + TVR 750 mg q8h
–(Mutual) drug interactions were observed
•Reduced exposure to TVR, variable effects on HIV PIs
–Protein displacement may play a role in reduction of total concentrations (in-vitro evaluation ongoing)
–Appropriate doses have not been established
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EFV and Tenofovir + TVR 1125 mg q8h
–Small changes in TVR, EFV and tenofovir exposure
–Higher TVR dose (1125 mg q8h) partly offset interaction with EFV
–
Based on these results, a pilot study of TVR in HIV/HCV co-infection was initiated with ATV/r 300/100 mg qd + TVR 750 mg q8h or EFV 600 mg qd + TVR 1125 mg q8h (plus Peg-IFN and ribavirin)