Research Focus: Hepatitis C Update

Liver disease, particularly hepatitis C, has emerged as a major cause of morbidity and mortality for people with HIV/AIDS in the era of potent antiretroviral therapy. Mortality is increased in patients with HIV–hepatitis C virus (HCV) coinfection compared with that in patients with HIV alone.^1,2

CLINICAL TRIALS
While effective treatments are available for patients with HIV-HCV coinfection,^3-5 coinfected patients show a poorer response to pegylated interferon (PEG-IFN) plus ribavirin (RBV) than do HCV-monoinfected persons.6 Three pivotal clinical trials for treatment of HIV-HCV coinfection have been published and are summarized below and in Table 1.

• Adult AIDS Clinical Trials Group (ACTG) Study A5071 was a randomized controlled 48-week study of PEG-IFN (Pegasys) with RBV versus standard IFN/RBV for the treatment of chronic HCV infection in HIV-coinfected persons. One hundred thirty-three coinfected patients were randomized in this open-label study. Sixty-six patients randomized to the PEG-IFN arm received 180 mg/wk with escalating doses of RBV that started at 600 mg/d and subsequently increased by 200 mg/d every 4 weeks to a maximum of 1000 mg/d. (Most patients were maintained with 800 mg/d.) Patients randomized to receive standard IFN began therapy with 6 million units 3 times weekly, with a dose reduction to 3 million units 3 times weekly after 12 weeks, along with dose-escalating RBV.

• AIDS Pegasys Ribavirin International Coinfection Trial (APRICOT) was the largest HIV-HCVÐcoinfection treatment trial conducted to date. This trial randomized 868 patients through clinical sites in 19 countries. Two hundred eighty-five patients were selected to receive standard IFN/RBV (3 million units 3 times a week plus 800 mg RBV); 286 were randomized to receive PEG-IFN (Pegasys 180 mg/wk)/placebo; and 289 were randomized to receive PEG-IFN/RBV. Eight patients did not receive the drug. Approximately 60% of patients in all 3 groups had HCV genotype 1.

• Agence Nationale de Recherches sur le SIDA HC02 (RIBAVIC) study, a French study, was an open-label, randomized, controlled comparison of standard IFN/RBV and PEG-IFN/RBV. In this study, PEG-IFN (PEG-Intron) was used at a dosage of 1.5 mg/kg/wk, along with a fixed dosage of RBV (800 mg/d).

While these 3 studies are not directly comparable, the overall response rates in the RIBAVIC study are similar to the response rates in the other 2. On the other hand, sustained virologic responses (SVRs) in the RIBAVIC study with PEG-IFN/RBV for nonÐgenotype 1 appear to be lower than those in the other 2 trials. Possible explanations include protocol differences in each: In APRICOT, for example, dose adjustments and treatment discontinuations were protocol-defined; in the RIBAVIC study, they were investigator-defined. The RIBAVIC study enrolled patients with more advanced liver disease who were excluded from the other trials.

Each of the 3 trials compared PEG-IFN/RBV with standard IFN/RBV. In addition, APRICOT randomized patients to a third treatment group: PEG-IFN/placebo. This third arm helped demonstrate the contribution of RBV to the improvement of overall SVR (20% vs 40% in the PEG-IFN/placebo arm vs PEG-IFN/RBV arm, respectively), highlighting its importance in HCV treatment (see Table 1).

Response in all trials was determined by a greater than 2-log10 decrease in or undetectable HCV RNA. Each of these studies was slightly different in terms of protocol for dosage adjustments and discontinuation of therapy. In the end, however, each shows that PEG-IFN/RBV results in higher rates of SVR than either PEG-IFN alone or standard IFN/RBV. The general conclusions from these studies are that response rates were higher with PEG-IFN/RBV treatment and that patients with non-genotype-1 had higher response rates than did genotype-1 patients.

• In the pivotal trials in monoinfected and coinfected patients treated with PEG-IFN/RBV, overall SVRs (undetectable HCV RNA 24 weeks after the end of treatment) were 66% and 40%, respectively.4,6 The reasons for the differences in SVR in coinfection patients are unclear. However, 2 variables currently under investigation are the role of a fixed low dosage of RBV (800 mg/d) in most trials and the shorter treatment duration of generally 48 weeks total in all coinfected patients regardless of genotype.
  

The Peginterferon Ribavirina Espa–a Coinfecci-n (PRESCO) trial is one such trial evaluating the role of extended therapy and/or higher doses of RBV in the treatment of HIV-HCVÐcoinfected patients.7 The PRESCO study is a multicenter, prospective, open, comparative trial being conducted in Spain and is designed to evaluate the efficacy and safety of PEGÐIFN a-2a (Pegasys) 180 µg/wk plus RBV 1000 to 1200 mg/d for treatment of chronic hepatitis C in HIV-infected persons. Only patients who achieved an early virologic response (greater than a 2-log¹⁰ decrease in HCV RNA level at week 12) were allowed to continue receiving therapy.

The results of the PRESCO trial have been presented most recently at the 2006 meeting of the American Association for the Study of Liver Diseases. Nunez and colleagues7 presented data from 389 IFN-naive, coinfected participants who were treated with PEG-IFN 180 µg/wk and weight-based dosages of RBV (1000 mg/d for patients weighing less than 75 kg; 1200 mg/d for patients weighing 75 kg or more). Those with HCV genotypes 1 and 4 (61%) were treated for 48 or 72 weeks, while those with genotypes 2 and 3 (39%) were treated for 24 or 48 weeks. SVR was measured in all patients using the standard metric of 24 weeks after the end of treatment, with the primary end point defined as an HCV RNA level of less than 50 IU/mL. The results are shown in Table 2.

Overall, 50% of PRESCO participants achieved an SVR, slightly higher than the 40% of APRICOT participants who achieved an SVR.4,6 In a multivariate analysis, prolonged treatment did not independently predict SVR.

However, this analysis identified several independent predictors of achieving SVR:

• Infection with genotype 2/3 (P = .001).
• Baseline HCV RNA level of less than 500,000 IU/mL (P < .0001).
• Undetectable HCV RNA at week 12 (P < .0001).

Although the results of the PRESCO study and those of trials such as APRICOT are not directly comparable, extended treatment beyond 48 weeks for genotype 1 or 4 and beyond 24 weeks in genotype 2 or 3 does not seem to affect outcome. On the other hand, the PRESCO trial does link improved outcomes using weight-based RBV, and this deserves further study.

OPTIMAL TREATMENT DURATION: RATE OF VIRAL DECAY TELLS THE STORY
Another important focus of recent HCV research involves optimizing treatment duration in an effort to better manage adverse events and drug costs. Investigations to answer this question have been conducted primarily in HCV monoinfection, but answers for optimal treatment duration in HIV-HCV coinfection are likely to follow.

The predictive role of early virologic response at 12 weeks (ie, greater than a 2-log¹⁰ decrease or undetectable HCV RNA) has been shown for both monoinfection and coinfection.^4,6 More recently, a number of trials have looked at rapid virologic response (RVR) at 4 weeks of treatment as a predictor of SVR.

For some patients with hepatitis HCV genotypes 2 and 3, 12 weeks of therapy is as good as 24 weeks, according to the results of a recent randomized trial from Italy. Mangia and colleagues8 reported that data on viral kinetics suggest that in patients with HCV genotype 2 or 3 in whom HCV RNA is not detectable after 4 weeks of therapy, 12 weeks of treatment may be as effective as the recommended course of 24 weeks.

A total of 283 patients began treatment with a standard 24-week regimen of 1.0 µg/kg of PEG-IFN a-2b weekly plus 1000 or 1200 mg of RBV daily, based on body weight. Of these, 70 patients were randomized to the 24-week regimen (standard-duration group) and 213 patients to a variable regimen (variable-duration group) of 12 or 24 weeks, on the basis of whether HCV RNA was undetectable or detectable at week 4. The primary outcome was the standard SVR (by polymerase chain reaction assay) 24 weeks after the end of treatment.

There was no significant difference in detectability of HCV RNA between the 2 groups at week 4 (64% in the standard-duration group vs 62% in the variable-duration group had undetectable HCV RNA). SVR occurred in 53 patients (76%) in the standard-duration group and in 164 (77%) in the variable-duration group, also not significant.

There was a difference between groups, however, in rates of adverse events requiring therapy discontinuation. In the variable-duration group, fewer patients on the 12-week regimen than patients on the 24-week regimen had adverse events and withdrew (P = .045). Relapse rate, defined as HCV not detectable at the end of treatment but detectable at the end of follow-up 24 weeks later, was 3.6% in the standard-duration group and 8.9% in the variable-duration group (P = .16). Overall, SVR rate was 80% in patients with HCV genotype 2 and 66% in patients with genotype 3 (P < .001).

The authors concluded that a shorter course of therapy over 12 weeks with PEG-IFN a-2b and RBV is as effective as a 24-week course for patients with HCV genotype 2 or 3 who have an RVR to treatment at 4 weeks. The authors highlighted the fact that patients who were treated for 12 weeks were spared the expense and inconvenience of extended treatment and the group still had a high rate of response.

More recently, HCV practice guidelines from the Department of Veterans Affairs include a recommendation to measure the 4-week RVR as a strategy for monitoring therapy in HCV-monoinfected patients.⁹

There are also data emerging on the role of RVR in HIV-HCV–coinfected patients. In a substudy of APRICOT, Dieterich and colleagues¹⁰ showed that the likelihood of SVR also differed on the basis of rapid response at 4 weeks. Treatment duration was not evaluated in this arm because all patients in APRICOT were treated for 48 weeks. Just 22 (13%) of the 176 genotype-1 patients in the PEG-IFN/RBV arm experienced RVR. Among these, 18 of 22 (82%) went on to achieve SVR. The authors concluded that RVR at week 4 indicates a high probability of SVR in genotype-1 patients (approximately 80%) regardless of baseline viral load.

QUALITY MEASUREMENT/PERFORMANCE IMPROVEMENT
Although standards of care for HCV infection are evolving, it is important to evaluate performance based on today's standard of care. Several organizations have developed and published practice guidelines for treating HCV monoinfection and coinfection.^11-15 More recently, the AMA has published "Hepatitis C Physician Performance Measurement Set" through its Physician Consortium for Performance Improvement.¹⁶

The consortium has a broad membership comprising more than 100 national medical specialty and state medical societies, including the Council of Medical Specialty Societies, the American Board of Medical Specialties and its member boards, the Agency for Healthcare Research and Quality, the Centers for Medicare & Medicaid Services, and other experts in methodology and data collection. Its mission is to enhance quality of care and patient safety by taking the lead in the development, testing, and maintenance of evidence-based clinical performance measures and measurement resources for physicians.

These HCV measures are intended for any physician managing the ongoing care of patients aged 18 years or older with chronic HCV infection. The clinical performance measures are designed for individual quality improvement. Some of the measures may also be appropriate for accountability if appropriate sample sizes and implementation rules are achieved, according to the consortium report.

The draft document is in chart format for easy reading and reference. Measures are listed in 2 categories: accountability and quality improvement (Table 3).

A unique feature of the consortium's recommendations is a step-by-step outline of how to construct performance measures and how to gather data using multiple data sources, including paper medical records and administrative (claims) data, with particular emphasis on electronic health records. The recommendations also identify codes for these measures, including ICD-9 (International Classification of Diseases and Functioning and Disability) and CPT (Current Procedural Technology) evaluation and management codes.

Overall, this draft presents a comprehensive look at HCV management and offers suggestions for getting started with performance measurement. Obviously, trying to implement all performance measures is an ambitious undertaking; programs might consider a stepwise approach by selecting several measures from the list to start. For example, a graduated approach that implements measures for which data are readily available is more practical than trying to measure performance in areas where data are incomplete or lacking.

When performance meets a target set by individual health organizations, those measures might be "retired" and replaced by other measures. This type of approach also forces us to take a closer look at our data management efforts as we move forward. While the recommendations make use of electronic health records, the old-fashioned methodology of collecting data from paper records is still a viable option.

CONCLUSION
In addition to our understanding of treatment efficacy in HIV-HCV coinfection, these newer data help answer important questions about treatment duration and proper RBV dosing to achieve the best outcomes possible with a minimum of treatment-limiting adverse events. Emerging data support an evidence-based approach to the management of both HCV monoinfection and HIV-HCV coinfection. As we take a more evidence-based approach to HCV infection care, it is a good time to incorporate HCV infection in our programs for performance measurement and quality improvement.

No potential conflict of interest was reported by Dr. Valenti.

References:

References
1. Anderson KB, Guest JL, Rimland D. Hepatitis C virus coinfection increases mortality in HIV-infected patients in the highly active antiretroviral therapy era: data from the HIV Atlanta VA Cohort Study. Clin Infect Dis. 2004;39:1507-1513. Available at: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15546088&dopt=Abstract. Accessed December 1, 2006.
2. Salmon-Ceron D, Lewden C, Morlat P, et al; The Mortality 2000 study group. Liver disease as a major cause of death among HIV infected patients: role of hepatitis C and B viruses and alcohol. J Hepatol. 2005;42:799-805.
3. Chung R, Anderson J, Volberding P, et al; AIDS Clinical Trials Group Study Team. Peg-interferon alfa-2a plus ribavirin vs interferon alfa-2a plus ribavirin for chronic HCV in HIV-coinfected persons. N Engl J Med. 2004;351:451-459.
4. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al; APRICOT Study Group. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med. 2004;351:438-450.
5. Carrat F, Bani-Sadr F, Pol S, et al; ANRS HC02 RIBAVIC Study Team. Peg-interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA. 2004;292:2839-2848.
6. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.
7. Nunez M, Garcia-Samaniego J, Romero M, et al. The PRESCO trial: impact of higher ribavirin doses and longer duration of therapy with peginterferon alfa-2a plus ribavirin in HIV-infected patients with chronic hepatitis C. 57th Annual Meeting of the American Association for the Study of Liver Diseases; October 27-31, 2006; Boston. Abstract 365.
8. Mangia A, Santoro R, Minerva N, et al. Peginterferon alfa-2b and ribavirin for 12 vs 24 weeks in HCV genotype 2 or 3. N Engl J Med. 2005;352:2609-2617.
9. Yee HS, Currie SL, Darling JM, Wright TL. Management and treatment of hepatitis C viral infection: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center program and the National Hepatitis C Program office. Am J Gastroenterol. 2006;101:2360-2378.
10. Dieterich D, Duff F, Sulkowski M, et al. Sustained virologic response in HIV/HCV co-infected patients with HCV genotype infection who have a rapid virological response at week 4 of treatment with peginterferon alfa-2a plus ribavirin. AIDS Pegasys Ribavirin International Co-infection Trial (APRICOT). 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver. Abstract 856.
11. Strader DB, Wright T, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C [published correction appears in Hepatology. 2004;40:269]. Hepatology. 2004;39:1147-1171.
12. New York State Department of Health AIDS Institute, Johns Hopkins University. HIV Clinical Resource. Hepatitis C virus. Available at: www.hivguidelines. org/GuideLine.aspx?pageID=257&guideLineID=17. Accessed December 1, 2006.
13. Soriano V, Puoti M, Sulkowski M, et al. Care of patients with hepatitis C and HIV co-infection. AIDS. 2004;18:1-12. Available at: www.medscape.com/ viewarticle/467365. Accessed December 1, 2006.
14. New York State Department of Health. Clinical guidelines for the medical management of hepatitis C. 2005. Available at: www.health.state.ny.us/diseases/ communicable/hepatitis/guidelines. Accessed December 1, 2006.
15. NIH Consensus Development Program. Management of hepatitis C: 2002. National Institutes of Health Consensus Conference Statement. June 10-12, 2002. Available at: http://consensus.nih.gov/2002/2002HepatitisC2002116html.htm. Accessed December 12, 2006.
16. Physician Consortium for Performance Improvement. American Medical Association Web site. Available at: www.ama-assn.org/ama/pub/category/2946.html. Accessed December 1, 2006.