Virological Response Can Help Determine Optimal Duration of Pegylated interferon/ribavirin Treatment for HIV-HCV Coinfected Patients

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The standard of care for treatment of chronic hepatitis C virus (HCV) infection in HCV monoinfected patients and in HIV-HCV coinfected patients is pegylated interferon plus ribavirin. For monoinfected individuals, the recommended length of treatment is 24 weeks for patients with HCV genotypes 2 or 3 and 48 weeks for those with genotypes 1 or 4.

The most useful predictor of treatment outcome is virological response. Both HCV monoinfected and HIV-HCV coinfected patients who do not experience an early virological response (EVR) after 12 weeks of therapy (defined as > 2 log reduction in HCV RNA) are unlikely to achieve eventual eradication of HCV, known as sustained virological response (SVR), or continued undetectable HCV RNA 24 weeks after completion of treatment.

Detection of virological failure at 12 weeks is considered a useful indicator for stopping treatment, thereby avoiding the adverse effects of further therapy with pegylated interferon plus ribavirin and reducing the high cost of treatment.

The time to achievement of undetectable HCV viral load is the best predictor of sustained response in HCV-monoinfected individuals. This allows physicians to individualize the duration of treatment in these patients. For example, it has been shown that most HCV monoinfected people who experience rapid virological response (RVR), or undetectable HCV RNA at week 4, may shorten the duration of treatment to 12-16 weeks for genotypes 2 or 3 or to 24 weeks for genotypes 1 or 4. Conversely, clinicians may recommend treatment for 48-72 weeks for patients who achieve HCV RNA suppression later than 12 weeks.

Treatment Duration for HIV-HCV Coinfected Patients

Updated guidelines in 2007 from an international panel of experts recommended 48 weeks of treatment, regardless of genotype, for HIV-HCV patients who achieve EVR.

However, the optimal treatment duration across different genotypes in this population is not yet known, and individual outcomes could be improved by tailoring treatment duration according to the time to undetectable HCV viral load. Several reports have demonstrated high SVR rates in HIV-HCV coinfected patients who achieve EVR, and a randomized trial showed that the risk of viral relapse was low in coinfected genotype 3 patients who achieve RVR at 4 weeks.

Researchers at the Autonomous University of Barcelona, Spain, conducted a pilot study to further explore the utility of a response-guided therapy for HIV-HCV coinfected patients by offering individualized treatment duration based on the virological response after 4, 12, and 24 weeks of treatment. Results of the study were published in the April 15, 2009 issue of Clinical Infectious Diseases.

The study included 60 HIV-HCV coinfected patients recruited from January 2005 through December 2006. Most were men (78.3%), former injection drug users (86.7%), and recipients of HAART according to current antiretroviral treatment guidelines.

All participants received 1.5 microgram/kg per week pegylated interferon alfa-2b (PegIntron) plus 800-1400 mg/day weight-based ribavirin. Treatment duration was individualized on the basis of week 4 and week 12 virological response:

Patients who achieved RVR, defined as viral load < 50 IU/mL at treatment week 4, completed 24 weeks of therapy.

Patients who did not achieve RVR were reassessed at week 12. Those with a complete EVR, defined as HCV RNA < 600 IU/mL, were treated for 48 weeks.

Patients with a partial EVR at week 12, defined as an HCV RNA decrease of ? 2 log10 and an HCV RNA level ? 600 IU/mL, who attained undetectable viral load at week 24 were treated for 60 weeks.

The primary efficacy endpoint was SVR, defined as HCV RNA < 50 IU/mL 24 weeks after the end of treatment.

Results

Overall, 33 of 60 patients (55%) achieved a sustained virological response:

11 of 25 patients (44%) with HCV genotype 1;
3 of 11 patients (27%) with genotype 4;
19 of 24 patients (79%) with genotype 3.

One-third of patients demonstrated a rapid virological response:

4 of 25 (16%) with genotype 1,
1 of 11 (9%) with genotype 4;
14 of 24 (58%) with genotype 3.

Of the 19 patients with a RVR, 17 (89.5%) eradicated the virus after 24 weeks of therapy.

The SVR rate was significantly higher among patients with genotype 3 and low pretreatment HCV RNA levels.

A high relapse rate (46%) after 48 weeks of therapy occurred among patients with genotypes 1 or 4 who first achieved undetectable HCV RNA at treatment week 12.

"The results of this exploratory study suggest that a response-guided therapy may be very useful to optimize HCV treatment in patients coinfected with HIV," concluded the study authors. "The SVR rates for each genotype are among the highest reported to date for patients coinfected with HIV," they wrote.

They observed that shortening treatment duration to 24 weeks "may be sufficient in patients with genotype 3 who achieve an RVR and could be considered in patients with genotypes 1 or 4 and low pretreatment viral load who achieve a rapid response."

However, they added, "More than 48 weeks of therapy may be necessary to reduce the high risk of relapse observed among slow responders with residual viremia at week 12 of treatment."

Finally, they recommended, "Prospective randomized trials should be undertaken to evaluate this response-guided strategy in a large number of patients coinfected with HCV and HIV."

Infectious Diseases Department, Liver Unit, Department of Medicine, and Department of Biochemistry, Vall d'Hebron Hospital, Autonomous University of Barcelona, Spain.

3/20/09

Reference

E van den Eynde, M Crespo, JI Esteban, and others. Response-Guided Therapy for Chronic Hepatitis C Virus Infection in Patients Coinfected with HIV: A Pilot Trial. Clinical Infectious Diseases 48(8): 1152-1159. April 15, 2009.

Selected Articles Cited by the Study Authors

1. Soriano V, Puoti M, Sulkowski M, et al. Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV-HIV International Panel. AIDS 2007; 21: 1073-1089.

2. Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology 2003; 38:645-52.

3. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. New England Journal of Medicine 2004; 351:438-50.

4. Jensen DM, Morgan TR, Marcellin P, et al. Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40 kd)/ribavirin therapy. Hepatology 2006; 43:954-60.

5. Shiffman ML, Suter F, Bacon BR, et al. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. New England Journal of Medicine 2007; 357:124-34.

6. Zeuzem S, Buti M, Ferenci P, et al. Efficacy of 24 weeks treatment with peginterferon alfa?2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia. Journal of Hepatology 2006; 44:97-103.

7. Ferenci P, Laferl H, Scherzer TM, et al. Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1 and 4 patients with rapid virological response. Gastroenterology 2008; 135:451-458.

8. Mangia A, Minerva N, Bacca D, et al. Individualized treatment duration for hepatitis C genotype 1 patients: a randomized controlled trial. Hepatology 2008; 47:43-50.

9. Nunez M, Marino A, Miralles C, et al. Baseline serum hepatitis C virus (HCV) RNA level and response at week 4 are the best predictors of relapse after treatment with pegylated interferon plus ribavirin in HIV/HCV-coinfected patients. Journal of Acquired Immune Deficiency Syndromes 2007; 45:439-44.

10. Nunez M, Miralles C, Berdun MA, et al. Role of weight?based ribavirin dosing and extended duration of therapy in chronic hepatitis C in HIV-infected patients: the PRESCO trial. AIDS Research and Human Retroviruses 2007; 23:972-82.