Drug interactions may compromise response to boceprevir and telaprevir

Concurrent use of drugs that alter concentrations of boceprevir (Victrelis) or telaprevir (Incivek or Incivo) in the body may contribute to poor response to interferon-based triple therapy for chronic hepatitis C virus (HCV), according to study findings presented at the Digestive Disease Week meeting (DDW 2013) last month in Orlando.

Boceprevir and telaprevir are both HCV protease inhibitors metabolised by the cytochrome P450 enzyme system in the liver. Many different types of medication – ranging from statins to antiretroviral drugs for HIV – are processed by the CYP3A4 enzyme. Agents that inhibit or slow down processing can raise levels of other drugs, while agents that induce or speed up processing can lower drug levels.

Manie Juneja from Georgetown University Hospital and colleagues evaluated the effects of "polypharmacy", or use of multiple drugs, on outcomes of hepatitis C treatment using boceprevir or telaprevir in combination with pegylated interferon and ribavirin.

As described in the study abstract, this retrospective analysis included 74 people (46 men and 28 women) treated at a hepatitis clinic. Most (85%) used telaprevir, the rest boceprevir; nearly 60% had previously been treated with interferon-based therapy. The abstract reported rates of rapid virological response (RVR), or undetectable HCV RNA at week 4 of treatment, according to use of concurrent drugs.

About one-third of participants were classified as having "minor polypharmacy", defined as concurrent use of three to five medications, while 70% had "major polypharmacy", defined as six or more medications. The average number of drugs used by people on hepatitis C triple therapy was 7.35.

Nearly half of participants were taking CYP3A4 inhibitors – most commonly statins for elevated blood lipids and SSRIs for depression – and 3 people were on CYP3A4 inducers. Eight per cent were taking drugs considered contraindicated with hepatitis C triple therapy and therefore discontinued. In addition, six people were using milk thistle or silymarin, an over-the-counter supplement.

• Overall, 44% of study participants achieved RVR, including 47% of treatment-naive patients and 43% of prior non-responders.
• People who achieved RVR were taking 5.00 medications on average, compared with 9.24 for those who did not have RVR.
• 86% of participants classified as having minor polypharmacy achieved RVR, compared with just 27% of those with major polypharmacy, a statistically significant difference.
• 22% of patients using CYP3A4 inhibitors reached RVR, compared with 66% who were not on CYP3A4 inhibitors, again a significant difference.

"A large number of patients on [triple therapy] are taking medications that can interfere with the CYP3A4 enzyme", the researchers concluded. "Polypharmacy appears to plays an important role in treatment outcomes based on RVR responses. Further studies are warranted to fully define the effects of polypharmacy on HCV therapies."

Drugs that interfere with cytochrome P450 enzymes can have contradictory effects. While CYP3A4 inhibitors might be expected to increase effectiveness by raising boceprevir or telaprevir levels, they may also lead to intensified side-effects that cause more people to stop treatment. Fortunately, many of the new direct-acting antiviral agents (DAAs) now in development – including next-generation HCV protease inhibitors – have fewer drug-drug interactions and side-effects than the first two approved DAAs.