Considerations for Antiretroviral Use in Patients with Coinfections
Hepatitis C (HCV)/HIV Coinfection
(Last updated:3/27/2012; last reviewed:3/27/2012)
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Updates to this section focus on the newly approved HCV NS3/4A protease inhibitors (PIs) boceprevir and telaprevir, the known interactions between these drugs and ART, and interim results from current ongoing research in HIV/HCV coinfected patients. The updated section includes preliminary recommendations on coadministration of the HCV NS3/4A drugs and ART.
A combination regimen of peginterferon and ribavirin (PegIFN/RBV) has been the mainstay of treatment for HCV infection. In HCV genotype 1-infected patients without HIV, addition of a HCV NS3/4A protease inhibitor (PI) boceprevir or telaprevir to PegIFN/RBV significantly improves the rate of sustained virologic response (SVR) [14, 15]. Clinical trials of these HCV PIs in combination with PegIFN/RBV for the treatment of HCV genotype 1 infection in HIV-infected patients are currently under way. Both boceprevir and telaprevir are substrates and inhibitors of CYP3A4/5 and p-glycoprotein (p-gp); boceprevir is also metabolized by aldo-ketoreductase. These drugs have significant interactions with certain ARV drugs that are metabolized by the same pathways. As such, the presence of HCV infection and the treatment of HCV may influence HIV treatment as discussed below.
Concurrent treatment of HIV and HCV is feasible but may be complicated by high pill burden, drug interactions, and overlapping drug toxicities. In this context, the decision to treat chronic HCV should also include consideration of the medical need for such treatment on the basis of an assessment of HCV disease stage. Some clinicians may choose to defer HCV therapy in HIV/HCV-coinfected patients with no or minimal liver fibrosis. If treatment with PegIFN/RBV alone or in combination with one of the HCV NS3/4A PIs (boceprevir or telaprevir) is initiated, the ART regimen may need to be modified to reduce the potential for drug interactions and/or toxicities that may develop during the period of concurrent HIV and HCV treatment.
Considerations for the use of HCV NS3/4A protease inhibitors (boceptrevir and telapracir) and antiretroviral therapy:
The science of HCV drug development is evolving rapidly. As new clinical trial data on the management of HIV/HCV-coinfected patients with newer HCV drugs become available, the Panel will modify its recommendations accordingly.
Boceprevir is approved for the treatment of HCV genotype 1 infection in patients without HIV infection. After 4 weeks of PegIFN/RBV therapy, boceprevir is added to the regimen for 24, 32, or 44 additional weeks of HCV therapy. Data on the use of an HCV regimen containing boceprevir together with ART in HIV/HCV-coinfected individuals are limited. In 1 small study of coinfected patients, higher HCV response was observed with boceprevir plus PegIFN/RBV (64 patients) than with PegIFN/RBV alone (34 patients). In this study, patients received ART that included HIV-1 ritonavir-boosted atazanavir (ATV/r), darunavir (DRV/r), or lopinavir (LPV/r) or raltegravir (RAL) plus dual NRTIs [40].
Boceprevir is primarily metabolized by aldo-keto reductase, but because the drug is also a substrate and inhibitor of CYP3A4/5 and p-gp enzymes, it may interact with ARVs metabolized by these pathways. Based on drug interaction studies in healthy volunteers, boceprevir can be coadministered with RAL [41]. However, coadministration of boceprevir with ATV/r, DRV/r, LPV/r, or efavirenz (EFV) is not recommended because of bidirectional drug interactions [42, 43] (see Table 15a and 15b). Importantly, the pharmacokinetic (PK) interactions of HIV PIs with boceprevir were not identified before the approval of boceprevir and before participant enrollment in the HIV/HCV-coinfection trial; consequently, some coinfected patients have received HIV PIs and boceprevir during HCV treatment. Patients who are currently receiving these drug combinations should be advised not to stop any medication until contacting their health care providers. If therapy with HIV PIs and boceprevir is continued, patients should be closely monitored for HIV and HCV responses and consideration should be given to switching the HIV PI or EFV to RAL during boceprevir therapy. Additional clinical trial data are needed to determine if other ARVs may be coadministered with boceprevir.
Telaprevir is approved for the treatment of HCV genotype 1 infection in patients without HIV infection. Telaprevir is administered in combination with PegIFN/RBV for the initial 12 weeks of HCV therapy followed by 12 or 36 weeks of additional treatment with PegIFN/RBV. Data on the use of this regimen in HIV/HCV-coinfected individuals are limited. In 1 small study of coinfected patients, higher HCV response was observed with telaprevir plus PegIFN/RBV (38 patients) than with PegIFN/RBV alone (22 patients). In this study, patients received ART containing EFV or ATV/r plus tenofovir/emtricitabine (TDF/FTC) or no ART during the HCV therapy [44].
Because telaprevir is a substrate and an inhibitor of CYP3A4 and p-gp enzymes, the drug may interact with ARVs metabolized by these pathways. On the basis of drug interaction studies in healthy volunteers and data on responses in coinfected patients enrolled in the small clinical trial noted above, telaprevir can be coadministered with ATV/r [45] and RAL [46] at the standard recommended dose of telaprevir (750 mg every 7Ð9 hours) and with EFV at an increased dose of telaprevir (1125 mg every 7Ð9 hours) (see Table 15b); however, coadministration of telaprevir with DRV/r, fosamprenavir/ritonavir (FPV/r), or LPV/r is not recommended because of bidirectional drug interactions [45]. Data on PK interactions of telaprevir with other ARVs including non-nucleoside reverse transcriptase inhibitors (NNRTIs) other than EFV and with maraviroc (MVC) are not available; therefore, coadministration of telaprevir with other ARVs cannot be recommended.
Following are preliminary recommendations for the use of boceprevir or telaprevir in HIV patients coinfected with HCV genotype 1 based on current ART use. These recommendations may be modified as new drug interaction and clinical trial information become available.
Patients receiving other ARV regimens:
· If HCV disease is minimal (no or mild portal fibrosis), consider deferring HCV treatment given rapidly evolving HCV drug development.
· If good prognostic factors for HCV treatment response are presentÑIL28B CC genotype or low HCV RNA level (<400,000 International Unit [IU]/mL)Ñconsider use of PegIFN/RBV without HCV NS3/4A PI.
· On the basis of ART history and HIV genotype testing results, if possible, consider switching to the ART regimens listed above to permit the use of boceprevir or telaprevir.
· For patients with complex ART history or resistance to multiple classes of ART, consultation with experts regarding the optimal strategy to minimize the risk of HIV breakthrough may be needed. In such patients, telaprevir may be the preferred HCV NS3/4A PI because its duration of use (12 weeks) is shorter than that of boceprevir (24 to 44 weeks).
In summary, HCV coinfection and use of PegIFN/RBV with or without HCV NS3/4A PIs (telaprevir or boceprevir) to treat HCV may impact the treatment of HIV because of increased pill burden, toxicities, and drug-drug interactions. Because ART may slow the progression of HCV-related liver disease, ART should be considered for most HIV/HCV-coinfected patients, regardless of CD4 count. If treatment with PegIFN/RBV alone or in combination with one of the HCV NS3/4A PIs (telaprevir or boceprevir) is initiated, the ART regimen may need to be modified to reduce the potential for drug-drug interactions and/or drug toxicities that may develop during the period of concurrent HIV and HCV treatment. The science of HCV drug development is evolving rapidly. As new clinical trial data on the management of HIV/HCV-coinfected patients with newer HCV drugs become available, the Panel will modify its recommendations accordingly.
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