May 13, 2013

Toward Improved Outcomes in HCV Mono- and Coinfection

Valerie Martel-Laferriere, MD, Douglas Dieterich, MD

May 13, 2013

The International Conference on Viral Hepatitis (ICVH), organized in collaboration with the International Association of Providers of AIDS Care and the Icahn School of Medicine at Mount Sinai in New York and held March 25-26, 2013, focused on the use of new agents in the treatment of hepatitis C (HCV), and particularly on the rapid progress made in the treatment of HIV/HCV-coinfected patients.

Management of HCV Monoinfection: The Promise of Novel Agents

New data on 2 novel agents in development were presented during ICVH. SOUND-C2 is a phase 2b open-label randomized trial in treatment-naive patients with HCV genotype 1; it is evaluating the combination of faldaprevir, a NS3/4A protease inhibitor, and BI 207127, a nonnucleoside NS5B inhibitor.[1] This was a 5-arm study: faldaprevir 120 mg daily, BI 207127 600 mg 3 times daily, and ribavirin for 16 weeks, 28 weeks, or 40 weeks; faldaprevir 120 mg daily, BI 207127 600 mg twice daily, and ribavirin for 28 weeks; or faldaprevir 120 mg daily and BI 207127 600 mg 3 times daily, without ribavirin, for 28 weeks. A total of 362 patients were enrolled, approximately two thirds of whom were HCV genotype 1b. Around 25% were IL28B CC, and 10% were cirrhotic. The primary endpoint was achievement of sustained virologic response 12 weeks after treatment (SVR12).

The arm in which BI 207127 was administered twice daily had the best response, with an SVR12 of 69%. The arm without ribavirin did the worst, with an SVR12 of only 39%. Subgroup analysis showed that genotype had a very important effect on results: SVR12 ranged from 11% to 47% for patients with genotype 1a to 56% to 85% for patients with genotype 1b. IL28B had less of an effect, with a difference of 10%-25% between IL28B non-CC vs CC. In multivariate analysis, sex, HCV subtype, IL28B genotype, and baseline gamma-glutamyltransferase level significantly affectedSVR12.

No patients had relapse between week 12 and 24 post-treatment, but not all patients reached this time point. There was 1 late relapse that occurred between 24 and 48 weeks post-treatment.

Side effects were tolerable: Grade 3 hemoglobin levels were reported in 8 patients, 1 patient had a grade 4 anemia, and 7 patients developed severe rashes. As expected, depending on study arm, 13%-46% of patients developed grade 3/4 elevated total bilirubin levels. Phase 3 studies combining faldaprevir 120 mg daily, BI 207127 600 mg twice daily, and ribavirin are under way.

Finally, 2 presentations discussed the resistance profile of the novel protease inhibitor MK-5172.[2,3] In vitro studies identified mutations associated with resistance in genotype 1a (Q41R, D168A/E/G/V), genotype 1b (F43S, A156S/T, D168A/G/V), genotype 2a (Y56H, V71A, A156T, D168E), and genotype 3a (Q168R).[2] After treatment with MK-5172 monotherapy for 14 days, D168A/E/V was found in genotype 1a, A156S/T and D168A/V were found in genotype 1b, and Q168R was found in genotype 3a.

Of note, MK-5172 maintained good antiviral activity when tested against virus with mutations associated with failure of first-generation protease inhibitor treatment.[3] MK-8742, an NS5A inhibitor, demonstrated fewer resistant replicons than did daclatasvir or ledipasvir (GS-5885) when tested alone or in combination with MK-5172.[3] The barrier to resistance of the combination of MK-5172 and MK-8742 is thought to be high because combined mutations conferring resistance to NS3 and NS5A were rare in the replicons.

HIV/HCV Coinfected Patients: Focus on Acute Infections and Reinfections

HCV is now recognized as a sexually transmitted disease in HIV-infected men who have sex with men (MSM). Over the 5-year period from 2008 to 2012, Sanchez and colleagues[4] recorded an increase in the rate of syphilis in Madrid, Spain, from 3.1% to 10.4%, whereas the rate of HCV increased from 0.05% to 0.3%. These results are concordant with those seen in the CASCADE Collaboration study,[5] which showed a slowly but steadily increase of HCV in HIV-infected MSM between 1990 and 2007, increasing from 0.09-0.22 per 100 person-years in 1990 to 2.34-5.11 per 100 person-years in 2007.

The close relationship with viruses seen in intravenous drug users in Spain and the concomitant diagnosis of syphilis and HCV seen in 7 patients underscores the importance of preventive measures and periodic HCV screening among MSM to maximize treatment benefit during the acute phase of HCV infection.

Treatment of acute HCV infection in HIV infected patients is associated with significantly better outcomes than is treatment of chronic infection: SVR rates range from 53% to 82% for acute HCV infection vs 14% to 38% for chronic HCV genotype 1 and 44% to 72% for HCV genotype 2 or 3.[6-17] Dr. Daniel Fierer of Mount Sinai Hospital[18] presented results of a study of 20 consecutive HIV-infected MSM with newly diagnosed HCV treated with 12 weeks of telaprevir, pegylated interferon, and ribavirin. The study is still ongoing, but preliminary data show SVR at 4 weeks of 85% (17 of 20 patients). A limitation of the study is that the favorable IL28B polymorphism CC was overrepresented (65%) compared with what is usually seen in the US population, and this may partially account for the high response rate.

Despite the effectiveness of treatment for acute HCV infection, reinfection remains a concern. In 2011, Lambers and colleagues[19] showed that among 51 HIV-infected MSM treated successfully for an acute HCV infection at 2 clinics in Amsterdam, The Netherlands, 11 became reinfected shortly after, resulting in a reinfection rate of 15.2 over 100 person-years. At ICVH, Dr. Emma Page of the Chelsea and Westminster Hospital in the United Kingdom[20] reported data from a similar evaluation conducted at her hospital, where the incidence rate of reinfection was 8.1 per 100 person-years among a cohort of 145 MSM followed from January 2004 to April 2012. Of note, reinfection occurred within 4 years of documented negative HCV antibody testing.

Treating Chronic HCV Infection: Real-Life Experiences

The addition of telaprevir and boceprevir to treatment regimens for HCV genotype 1 has greatly changed the outcome of chronic HCV treatment. However, these drugs have significant side effects and drug interactions, little is known so far about their effectiveness in real life, and their use in HCV/HIV-coinfected patients is off-label.

Ahmed and colleagues[21] presented the experience at Chelsea and Westminster Hospital with using boceprevir and telaprevir in 5 coinfected patients with previous treatment failure and who had bridging fibrosis or cirrhosis on liver biopsy. All patients achieved early virologic response, and 4 patients achieved SVR at 24 weeks. The remaining patient had an undetectable viral load at the end of treatment but died during follow-up.

Adverse events, including anemia, were common, and 80% of patients received erythropoietin. No patient had a detectable HIV load during treatment. Evaluation of 7 coinfected patients who started a telaprevir-based regimen is ongoing.

The use of telaprevir at the Icahn School of Medicine at Mount Sinai and John Hopkins University[22] in 33 coinfected and 117 monoinfected patients also showed good results and no statistically significant difference between groups in the SVR12 rate (61% vs 43%; P = .07), even though the coinfected group consisted of a more difficult-to-treat population (more African Americans and more prior nonresponders or patients who were intolerant of therapy). Discontinuation because of adverse events and severe anemia was common, but the proportions did not differ between the groups.

Drug/Drug Interactions

A recurrent theme during ICVH was the issue of drug/drug interactions with the use of the new direct-acting antivirals, especially in coinfected patients.[23] Boceprevir and telaprevir are both CYP3A inhibitors, although telaprevir is a little more permissive than boceprevir when it comes to drug/drug interactions. For example, efavirenz can be used at an increased dose (1125 mg 3 times daily) with telaprevir, but cannot be used with boceprevir.[24,25] Atazanavir boosted with ritonavir is also an acceptable option in patients taking telaprevir, but the US Food and Drug Administration does not recommend its use with boceprevir because of the potential for HIV escape.[25,26] Because data on drug/drug interactions in clinical settings are not always available, clinicians should be cautious when they select a treatment regimen for coinfected patients.

Liver Transplantation in Coinfected Patients: Facing the Challenges

For many years, HIV-infected patients were not considered potential liver transplant candidates. Now, well-selected HIV-positive patients can benefit from liver transplant, but the outcomes vary widely. Thus, given the shortage of available donor livers, the debate is still open about whether HIV-positive patients should undergo transplant.

In a series of 22 patients with hepatitis B coinfection, the difference in the 5-year survival rate did not statistically differ between coinfected and monoinfected patients (86% vs 100%; P = .09).[27] No patients died of HIV or hepatitis B virus infection during follow-up. Of note, around one half of the patients had low viremia, which may support the long-term use of hepatitis B immunoglobulins plus antivirals.

The benefits of transplantation in HIV/HCV coinfection are more difficult to assess: Studies have shown higher rates of wait-list mortality, higher rates of post-transplant mortality, and more severe recurrent HCV disease.[28] Indeed, data from a prospective multicenter trial showed significantly higher 3-year survival and graft survival in HCV-monoinfected transplant recipients vs coinfected transplant recipients (overall survival, 60% vs 79% [P < .001]; graft survival, 53% vs 74% [P < .001]).[29] However, contrary to what was expected, acute rejection was more common in coinfected patients than it was in monoinfected patients (35% vs 18%). The challenges of managing immunosuppressive drugs in already immunosuppressed patients, as well as a potential drug/drug interactions, may explain this phenomenon. As a precaution, some have advised that HIV protease inhibitors be avoided in this population to reduce the risk for interactions.[28]

Conclusions

Hepatitis C research is a rapidly moving field. Over the past year, the epidemiology of the disease has started to change with the appearance of more sexually transmitted cases among HIV-infected patients. Understanding of the timing of treatment in acute infection has been refined, and new treatments are available and in development for chronic infection. Although HIV is still a barrier to liver transplantation in coinfected patients, it is no longer an absolute contraindication.

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