HIV/HCV drug interaction updates from CROI
by Larry Buhl

Several panels from CROI 2012 showed drug-drug interactions between new direct-acting antiviral agents for hepatitis C (HCV) and antiretroviral HIV drugs.

Approximately one-third of HIV-positive people are coinfected with HCV, but new direct-acting antivirals for HCV are not yet approved for coinfected patients. The concern is that some drug interactions can cause side effects or reduce the effectiveness of one or all of the drugs.

Research involved small samples of healthy volunteers with neither HIV nor HCV. Right now no pharmaceutical company is planning clinical trials of PIs on coinfected patients.

Boceprevir (Victrelis) was tested with the ritonavir-boosted HIV protease inhibitors (PIs) atazanavir (Reyataz), darunavir (Prezista) and lopinavir/ritonavir (Kaletra). Thirty-nine volunteers first received 800 mg three-times-daily boceprevir for six days. They then took 300/100 mg once-daily atazanavir/ritonavir, 600/100 mg twice-daily darunavir/ritonavir, or 400/100 mg twice-daily lopinavir/ritonavir for about two weeks, adding boceprevir during the last five days.

Co-administration of boceprevir with all three boosted HIV PIs was generally well-tolerated, with no serious side effects. It did lead to some significant decreases in blood levels of HIV PIs. Boceprevir decreased ritonavir exposure in all three combinations. Co-administration with atazanavir/ritonavir did not significantly alter total boceprevir levels. Lopinavir/ritonavir, however, decreased boceprevir total concentration by forty-five percent and darunavir/ritonavir did so by thirty-two percent.

These drug-drug interactions were already known, and Merck does not recommend co-administration of boceprevir with ritonavir-boosted HIV PIs.
Another CROI presentation showed that boceprevir combined with older HCV meds, pegylated interferon and ribavirin, appeared safe and effective for HIV/HCV coinfected individuals taking boosted HIV PIs.

Researchers investigated interactions between TMC435 and the antiretrovirals rilpivirine (Edurant), tenofovir (Viread), efavirenz (Sustiva),
and raltegravir.

Forty-eight volunteers were randomly assigned to receive 150 mg TMC435 once-daily, followed by an antiretroviral alone (25 mg rilpivirine once-daily, 300 mg tenofovir once-daily, 600 mg efavirenz once-daily, or 400 mg raltegravir twice-daily), followed by TMC435 combined with an antiretroviral.

All drug combinations were well-tolerated, with no serious adverse events or discontinuations for this reason. Plasma concentrations of rilpivirine, tenofovir, efavirenz, and raltegravir did not change significantly when co-administered with TMC435. TMC435 levels did not change appreciably when combined with rilpivirine, tenofovir, or raltegravir. Co-administration with efavirenz, however, reduced total TMC435 concentration by about seventy percent.

Researchers concluded that no dose adjustments are required when combining TMC435 with rilpivirine, raltegravir, or tenofovir, but co-administration of TMC435 and efavirenz is not recommended.

In two studies, a total of twenty-nine participants first received 60 mg daclatasvir once-daily for four days, then added either 300/100 mg atazanavir/ritonavir once-daily or 600 mg efavirenz once-daily for up to eighteen days. In the third study, twenty participants took the same dose of daclatasvir or 300 mg tenofovir once-daily or both for seven days.

All drug combinations were well-tolerated. Atazanavir/ritonavir and efavirenz plasma concentrations did not change significantly when co-administered with daclatasvir. Daclatasvir total exposure (AUC) was 110 percent higher and peak concentration (Cmax) was thirty-five percent higher when given with atazanavir/ritonavir. Total and peak daclatasvir levels were reduced by thirty-two percent and sixty-seven percent, respectively, when co-administered with efavirenz. Levels of both daclatasvir and tenofovir remained within expected ranges when administered together.

Researchers said lowering the daclatasvir dose when given with atazanavir/ritonavir, or raising it when used with efavirenz, may provide optimal daclatasvir exposure.

HIV/HCV drug-drug interactions, when they occur, could be managed by adjusting the dosages. Although some interactions decreased the effectiveness of some drugs, researchers say the growing diversity of antiretrovirals for treating HCV means that HIV/HCV coinfected people should be able to find a safe and effective antiretroviral regimen, as long as doctors are aware of the drug-drug interactions and frequently monitor both HIV and HCV viral load.

Larry Buhl is a freelance journalist and screenwriter living in Los Angeles.

May 2012