Early guidance on use of hepatitis C protease inhibitors in HIV-co-infected patients

Doctors in the US state of Maryland have issued preliminary guidance for the use of hepatitis C protease inhibitors by patients co-infected with HIV. Published in the online edition of Clinical Infectious Diseases, the provisional recommendations support use of the protease inhibitors in selected groups of co-infected patients.

“The benefits of including these medications will outweigh the risks for some individuals,” comment the authors.

In May 2011 the protease inhibitors boceprevir and telaprevir were approved in the US for the treatment of chronic hepatitis C genotype 1 infection. In clinical trials, involving hepatitis C-mono-infected individuals, the use of these drugs in combination with pegylated interferon and ribavirin improved rates of sustained virological response by between 25% and 31%.

Clinical trials into the safety and efficacy of these hepatitis C protease inhibitors are currently underway involving patients co-infected with HIV.

Hepatitis C is a leading cause of serious illness and death in co-infected patients. There is therefore considerable interest in the potential role of boceprevir and telaprevir in the hepatitis C therapy of co-infected individuals.

An opinion was therefore provided to the Maryland AIDS Assistance Program on what is known about the safety and efficacy of these drugs in co-infected patients, and which patients could be considered candidates for their off-label use.

The authors believe the opinion “may be useful to others.”

Published data on the safety and efficacy of these drugs in co-infected patients are scarce.

However, results of a phase 2 study evaluating telaprevir are available. The study involved 59 individuals. These included 13 patients not currently taking HIV therapy because their HIV infection was well controlled. A further 13 patients treated with efavirenz (Sustiva) and FTC/tenofovir (Truvada) and 24 individuals taking ritonavir-boosted atazanavir (Reyataz) and Truvada were also recruited to the study.

All received standard hepatitis C therapy consisting of pegylated interferon and ribavirin lasting 48 weeks. However, for the first twelve weeks of therapy, the patients were randomised to receive either telaprevir or a placebo. The dose of telaprevir was 750 mg, taken at intervals of approximately eight hours. The drug was taken with food with a high fat content. After four weeks of treatment, 70% of patients in the telaprevir arm had an undetectable hepatitis C viral load compared to 5% of individuals taking the placebo. Twelve-week outcomes also favoured telaprevir.

The treatment appeared safe and there were no unexpected side-effects. HIV remained well controlled. However, two patients experienced an increase in their hepatitis C viral load probably due to resistance. Complete safety and efficacy results are expected in 2013.

Results of a phase 2 study evaluating boceprevir are also available. The research involved 99 co-infected patients and lasted 48 weeks. It had two stages. For the first four weeks, all the patients were treated with pegylated interferon and ribavirin. They were then randomised on a 2:1 basis to take either a thrice-daily 800 mg dose of boceprevir or a placebo.

Patients were ineligible for the study if they were taking AZT, ddI (Videx), d4T (stavudine, Zerit), efavirenz (Sustiva), etravirine (Intelence), or nevirapine (Viramune). Ritonavir-boosted protease inhibitors and raltegravir (Isentress) were permitted.

Four weeks after randomisation, 38% of patients in the boceprevir arm had an undetectable hepatitis C viral load compared to 15% of those taking a placebo. Similarly, at week 24, some 71% of patients taking the protease inhibitor still had suppressed hepatitis C viral load compared to 34% of individuals taking the placebo. Rates of treatment discontinuation were broadly similar between the two study arms. Complete results of the study are expected in 2013.

Recommendations

The authors recommend that pegylated interferon and ribavirin should remain the standard of care for patients co-infected with hepatitis C genotype 2, 3, or 4. Likewise, this treatment should remain standard for individuals who need to take other essential medications - including HIV therapy -  when interactions with the hepatitis C protease inhibitors cannot be confidently ruled out or managed.

However, boceprevir and telaprevir may be suitable for some patients with genotype-1 infection. These protease inhibitors must always be used in combination with pegylated interferon and ribavirin. They must never be used as monotherapy. This could lead to the emergence of drug-resistant strains of hepatitis C.

The benefits of therapy with these new drugs are likely to be greatest for individuals with significant liver fibrosis (METAVIR fibrosis stage 0-1). For patients with less advanced liver disease, the risks of using these drugs may outweigh the benefits.

Patients should have well-controlled HIV infection. For individuals not taking antiretroviral therapy this is defined as a CD4 cell count above 500 cells/mm³ and a viral load below 20,000 copies/ml. Individuals receiving HIV treatment are expected to have an undetectable viral load.

Before any patient takes the drug, potential interactions with other drugs must be considered.

Other factors known to affect the outcome of hepatitis C therapy should also be taken into consideration. These include stage of liver disease, IL28B status and race.

The authors make specific recommendations about the use of both drugs.

Recommendations - telaprevir

• Telaprevir with pegylated interferon and ribavirin for twelve weeks followed by 36 weeks of pegylated interferon and ribavirin alone.
• Well-controlled HIV disease without the need for antiretroviral therapy.
• Ritonavir-boosted atazanavir 300/100mg plus once-daily Truvada. Telaprevir 750mg every seven to nine hours with food with over 20g of fat.
• Raltegravir 400mg twice daily with once-daily Truvada. Telaprevir 750mg every seven to nine hours with food with over 20g of fat.
• Efavirenz 600mg daily at bedtime with once-daily Truvada. If this antiretroviral combination is used, the dose of telaprevir should be increased to 1125mg, taken every seven to nine hours with food with over 20g of fat.
• Telaprevir therapy should be stopped if viral load increases by one log. All hepatitis C therapy should be discontinued if hepatitis C viral load is not suppressed below 1000 iu/ml at weeks 4 and 12. Patients who meet these milestones but who have a detectable hepatitis C viral load at week 24 should also stop treatment.

Recommendations - boceprevir

• Pegylated interferon and ribavirin for four weeks, with boceprevir added to the combination for a further 44 weeks of therapy.
• Well-controlled HIV disease without the need for antiretroviral therapy.
• A ritonavir-boosted protease inhibitor or raltegravir with Truvada.
• Do not take the NNRTIs efavirenz, etravirine or nevirapine.
• Boceprevir 800 mg every seven to nine hours.
• Boceprevir therapy should be stopped if viral load increases by one log. All hepatitis C therapy should be discontinued if hepatitis C viral load is not suppressed below 1000 iu/ml at weeks 4 and 12. Patients who meet these milestones but who have a detectable hepatitis C viral load at week 24 should also stop treatment.

“Approvals of boceprevir and telaprevir for treatment of  hepatitis C virus infection are major advances in the care of persons with chronic genotype 1 hepatitis C virus infection,” conclude the investigators. “HIV/hepatitis C virus-co-infected persons should be included at earlier stages in drug development so that practical guidance can be based more on data and less on expert opinion.”