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Treatment of Hepatitis C in HIV/Hepatitis C Co-Infected Patients: What is the Evidence?

Posted on: Friday, 11 February 2005, 03:00 CST

Summary: Before the advent of highly active antiretroviral therapy (HAART), the vast majority of HIV-infected patients died from AIDS-related diseases. But, amongst those with access to HAART, AIDS is no longer the leading cause of death. Instead, liver disease is fast becoming the commonest cause of death in HIV-infected patients, particularly in those who have a co-infection with hepatitis C (HCV).

The four recent comparative trials of peginterferon and ribavirin in HIV/HCV co-infected patients have provided valuable new information about the most appropriate treatment of this difficult group of patients. As with HIV-negative patients, it is clear that peginterferon alpha has advantages over non-pegylated treatment, with superior efficacy, in the form of higher sustained virological responders and comparable safety. Discontinuation rates were higher than reported in HCV mono-infected patients but comparable for most treatment arms. Furthermore, in about half the patients, treatments were not stopped during the first months of treatment because of side effects, but due to non-early virological response.

Keywords: hepatitis C virus, human immunodeficiency virus, treatment, liver disease

Introduction

Before the advent of highly active antiretroviral therapy (HAART), the vast majority of HIV-infected patients died from AIDS- related diseases. However, among those with access to HAART, AIDS is no longer the leading cause of death.1-3 Instead, liver disease is fast becoming the commonest cause of death in HIV-infected patients, due to the growing prevalence of co-infection with hepatitis C (HCV).4

Combination treatment with peginterferon alpha and ribavirin is the treatment of choice for HCV, but the treatment of patients co- infected with HIV and HCV represents a particular challenge for physicians, both in achieving satisfactory viral response rates and in delaying the progression of liver disease.

Three recent clinical trials have endeavoured to establish the most effective treatment regimen for HIV/HCV co-infection. Their results, presented at the 11th Conference on Retroviruses and Opportunistic Infections (CROI) in San Francisco in February 2004 and at the 39th Annual Meeting of the European Association for the Study of the Liver (EASL) in Berlin in April 2004, have provided important new information and raised further issues for consideration.

Epidemiology

The global prevalence of HCV in HIV-infected people is about 30%, although this may rise to as high as 90% in people with haemophilia and in areas where HIV is spread mainly by intravenous drug use.

In the non-HIV population, 75-80% of those with acute HCV become chronically infected, with 20% developing cirrhosis during the subsequent 20 years.5,6 Decompensation is seen in 6-10% and hepatocellular carcinoma (HCC) develops in a further 5-10%; overall mortality is about 5-10%.5,6 However, there is evidence that HIV speeds up the progression from chronic hepatitis to cirrhosis and end-stage liver disease.4

Recent studies in France and the USA have demonstrated end-stage liver disease as a growing cause of mortality in HIV/HCV co- infected patients.1-3 In 2001, in 65 French internal medicine and infectious disease units caring for over 25,000 HIV-infected patients, 14.2% of deaths were due to end-stage liver disease. This compared with 6.6% in 1997 and 1.4% in 1995.1,2 Between 1995 and 2001, the prevalence of HCC as a cause of death rose from 4.7% to 25%. A further follow-up of mortality in this French population for 2003 is in progress.

A similar trend has been reported in the USA.3 A retrospective analysis of mortality data from a Boston health-care facility showed end-stage liver disease to be responsible for 11.5% of deaths in HIV- infected patients in 1991, rising to 13.9% in 1996 and 50% in 2000.

Developments in hepatitis C treatment

Interferon alpha-2b (Intron A) first became available for the treatment of HCV in 1991. In the early studies, when patients were treated for 24 weeks, sustained viral responses (SVRs) were seen in just 6% of HCV patients. Prolonging the course of treatment to 48 weeks led to an increase in SVR to 16%. But it was not until 1998 that large, multicentre trials confirmed the advantages of combination treatment with Intron A and the synthetic guanosine analogue ribavirin, with SVRs of around 40%.7-9

Interferon alpha-2a (Roferon-A) was introduced in 1996 and, like Intron A, was initially recommended for six months, and later changed to 12 months therapy. Subsequent research showed that an efficacy comparable with that of Intron A could be achieved and, again, combination treatment with ribavirin produced superior results.

The next step towards a more effective treatment of HCV came with the introduction of the first pegylated formulation of interferon alpha-2b (Peglntron) in 2000. Pegylation involves the conjugation of a polyethylene glycol (PEG) molecule to the interferon alpha protein in order to enhance its pharmacological activity and extend its half- life.

There are currently two formulations of pegylated interferon that are used in combination therapy with ribavirin. PegIntron is administered according to a patient's weight, at a dose of 1.5 g/ kg/ week, while Pegasys (peginterferon alpha-2a) is administered in a flat dose of 180 g, once a week, to all patients regardless of weight.

In a series of major treatment trials, both formulations have been associated with further improvements in SVR to levels of about 80% in HCV patients with the easier-to-treat genotypes 2 and 3(10,11) and 40-50% with the more-difficult-to-treat genotype 1.10,12

A new clinical trial, called the IDEAL Study, is for the first time directly comparing the Peglntron and Pegasys treatment regimens. The aim of the study is to find out which is safer and more effective in treating genotype 1 patients.

Additional refinements to treatment schedules are focusing on tailoring treatment to particular types of patient; for example, there is early evidence that it may be possible to reduce the duration of combination treatment to 12 weeks in patients with genotype 2/3 disease, with the potential for reduced side-effects and improved adherence to treatment.13

While significant progress has thus been made in improving HCV treatment in mono-infected patients, less is known about the efficacy of the latest peginterferon alpha/ribavirin combinations in HIV/HCV-infected individuals. Three large prospective, randomized clinical trials were set up to address this question, and all have recently reported preliminary results at international meetings.14- 16

Trials summary

AIDS Clinical Trials Group (ACTC) A5071(14)

In this 21-centre study, 133 patients with HIV/HCV were randomized to peginterferon alpha-2a (PEG-23) 180 g weekly or to interferon alpha-2a (IFN-2a) 6MIU TIW for 12 weeks, and then 3MIU TIW for 36 weeks. Both groups received ribavirin in a dose- escalation schedule from 600 to 1000 mg/day. Follow-up continued for 24 weeks after the end of treatment. Baseline characteristics of the two groups are summarized in Table 1.

At week 24, patients who had failed to achieve HCV clearance underwent liver biopsy, and medications were continued for virological or histological response. At week 24, a viral response was seen in 44% of patients in the PEG-2a/ribavirin group, compared with 15% of those in the IFN-2a/ ribavirin group (P < 0.001).

At 72 weeks (24 weeks after stopping anti-HCV treatment), an SVR was seen in 27% of those in the PEG-2a/ribavirin group, compared with 12% of those taking IFN-2a/ribavirin (P < 0.03). In the genotype 1 patients, SVRs were 14% and 6%, respectively (P < 0.001), and in the non-genotype 1 patients, SVRs were 73% and 33%, respectively (P <0.07).

Early virological response (defined by a negative HCV PCR or a 2- log drop of HCV viral load at week 12) was predictive of SVR. In all, 41% of study patients had an early response, of whom 51% had an SVR. In contrast, of the 59% of study patients who did not have an early response, none achieved an SVR.

Table 1 ACTG A5071: baseline characteristics (data from Chung et al.14)

Adverse events were more common in the PEG-2a/ribavirin group (17% versus 4%), although the proportion having to stop treatment because of adverse events was the same in both groups (12%).

AIDS Pegasys Ribavirin International Co-infection Trial (APRICOT)15

This much larger, multicentre study randomized 868 patients in 19 countries to

(1) IFN-2a 3 MIU TIW +ribavirin 800 mg/day;

(2) PEG-2a 180 g weekly + placebo of ribavirin;

(3) PEG-2a 180 g weekly + ribavirin 800 mg/day.

Patients continued treatment for 48 weeks, with a further 24- week follow-up. Again, patients were well matched, with baseline characteristics summarized in Table 2.

In all, 40% of patients in the PEG-2a/ribavirin group achieved an SVR, compared with 20% of the PEG-2a/placebo group and 12% of the IFN-2a/ ribavirin group. SVRs in genotype 1 patients were 29%, 14% and 7%, respectively, and in the genotype 2/3 patients 62%, 36% and 20%, respectively.

Overall, 27% of patients taking PEG-2a/ribavirin stopped treatment because of adverse events, compared with 36% of those taking PEG-2a/ placebo and 39% of those taking IFN-2a/ribavirin.

RIBAVIC ANRS HCO2(16)

In this third study, 398 HIV/HCV patients were randomized to peginterferon alpha-2b (PEG-2b) 1.5 g/kg weekl\y + ribavirin 800 mg/ d or interferon alpha-2b (IFN-2b) 3 MIU TIW+ribavirin 800 mg/day. The baseline characteristics are summarized in Table 3.

At 72 weeks, the SVR in the PEG-2b/ribavirin group was 27%, compared with 19% in the IFN-2b/ ribavirin-treated patients (P < 0.03). Among the genotype 1 patients, SVRs were 15% and 5%, respectively (P < 0.03), while in the genotype 2/3 group they were 43% and 47%.

Table 2 AIDS Pegasys Ribavirin International Co-infection Trial (APRICOT): baseline characteristics (data from Torriani et al.15)

Table 3 RIBAVIC-ANRS HCO^sub 2^: baseline characteristics (data from Perrone et al.16)

For each treatment group, 31% of patients had group 4 adverse events, with 36% and 35%, respectively, having to discontinue treatment.

A further analysis of efficacy was carried out on the basis of patients who completed treatment (per protocol analysis). This showed SVRs of 36% for the PEG-2b/ribavirin group, compared with 28% in the IFN-2b/ribavirin group (P < 0.03).

How do the results compare?

The superiority of peginterferon over non-pegylated interferon in HIV/HCV co-infected patients was consistent. SVR rates across the three studies ranged from 27% to 40% for PEG/ribavirin, compared with 12-19% for IFN/ribavirin. In the most-difficult-to-treat genotype 1 patients, SVRs ranged from 14% to 29% for PEG/ribavirin, compared with 5-7% for IFN/ribavirin.

Despite using different types of peginterferon, ACTG and RIBAVIC showed identical overall SVR rates of 27% in the PEG-treated patients. In APRICOT, the SVR achieved with PEG-2a was somewhat higher, at 40%.

Valid comparisons of data from the three trials are complicated by significant differences in the baseline characteristics of the patients included in the studies.

While age, sex ratio, mean CD4 levels, and levels of HAART and HIV control were similar across the three studies, those in RIBAVIC tended to have the most severe disease, e.g.:

(1) IVDU: 78-80% in RTBAVIC, compared with only 62-71% in APRICOT. No figure has been provided in presentations of ACTG data.

(2) ALT elevated: 82-85% in RIBAVlC and APRICOT, but only 66-68% in ACTG.

(3) Genotype 1: 77-78% in ACTG, 64-69% in RIBAVIC, but only 60- 61% in APRICOT.

(4) Severe liver histological lesions: 39-40% in RIBAVIC, but only 9-11% in ACTG and 15-16% in APRICOT.

Genotype and liver histology, in particular, have well- documented prognostic implications. Better results might therefore be expected in studies such as APRICOT, with smaller numbers of genotype 1 patients and where patients have less advanced liver disease. In addition, RIBAVIC had considerably more intravenous drug users than APRICOT - a factor that might be expected to influence response and discontinuation rates.

Discontinuation rates in RIBAVIC and APRICOT were high and comparable for most treatment arms (35-39%), although the rates were surprisingly low for the PEG-2a/ribavirin group in APRICOT (27%). Other surprise findings included a low discontinuation rate of just 12% in the ACTG study at week 24, which did not increase over the subsequent 24 weeks.

Conclusions

The three recent comparative trials of peginterferon and ribavirin in HIV/HCV co-infected patients have provided valuable new information about the most appropriate treatment of this difficult group of patients. As with HIV-negative patients, it is clear that peginterferon. alpha has advantages over non-pegylated treatment, with superior efficacy, in the form of higher SVRs and comparable safety.

However, it remains unclear as to whether fixed dose treatment with PEG-2a and ribavirin has any advantages over a weight-based treatment with PEG-2b and ribavirin, or vice versa. This is because significant differences in the baseline characteristics of patients in the three studies, notably in the proportion of patients with genotype I and/or severe liver disease, may have important prognostic implications.

Further studies are therefore likely to be needed in order to compare the efficacy and safety of these two treatments in HIV/HCV co-infected patients.

References

1 Cacoub P, Geffray L, Rosenthal E, et al. Mortality among human immunodeficiency virus-infected patients with cirrhosis or hepatocellular carcinoma due to hepatitis C virus in French departments of internal medicine/infectious diseases, in 1995 and 1997. Clin Infect Dis 2001;32:1207-14

2 Rosenthal E, Poiree M, Pradier C, et al. Mortality due to hepatitis C-related liver disease in HIV-infected patients in France (Mortavic 2001 study). AIDS 2003;17:1803-9

3 Bica I, McGovern B, Dhar R, et al. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis 2001; 32:492-7

4 Sherman KE, Rouster SD, Chung RT. Hepatitis C virus prevalence among patients infected with human immunodeficiency virus: a cross- sectional analysis of the US Adult AIDS Clinical Trials Group. Clin Infect Dis 2002;34:831-7

5 Hoofnagle JH. Hepatitis C: the clinical spectrum of disease. Hepatology 1997;26(Suppl 1):15-20S

6 Di Bisceglie AM. Natural history of hepatitis C: its impact on clinical management. Hepatology 2000;31:1014-88

7 McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alpha- 2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 1998;339:1485-92

8 Poynard T, Marcellin P, Lee SS, et al. Randomised trial of interferon alpha 2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha 2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet 1998;352:1426-32

9 Davis GL, Esteban-Mur R, Rustgi V, et al. Interferon alpha-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. N Engl J Med 1998; 339:1493-9

10 Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alpha-2b plus ribavirin compared with interferon alpha-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958-65

11 Fried MW. Peginterferon alpha-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347: 975-982

12 Hadziyannis SJ, Sette Jr H, Morgan TR, et al. Peginterferon- alpha-2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140:346-55

13 Mangia A, Minerva N, Ricci GL, et al. HCV genotype 2 and 3 can be cured by PEG-IFN-ALF-2B and RBV for 12 wks: a randomized controlled study. J Hepatol 2004;40(Suppl 1):34 (abstract 93)

14 Chung R, Andersen J, Volberding P, et al. PEG-interferon- alpha-2a plus ribavirin versus interferon-alpha-2a plus ribavirin for chronic hepatitis C virus infection in HIV-co-infected persons. N Engl J Med 2004;351:451-9

15 Torriani FJ, Rodriguez-Torres M, Rockstroh J, et al. Peginterferon-alpha-2a+ribavirin vs interferon-alpha-2a+ ribavirin in HIV-infected patients. N Engl J Med 2004;351: 438-50

16 Carrat F, Bani-Sadr F, Pol S, et al. A randomized controlled trial of pegylated-interferon-alpha-2b plus ribavirin vs interferon- alpha-2b plus ribavirin for initial treatment of chronic hepatitis C in HIV-infected patients. (RIBAVIC-ANRS HCO2). JAMA (in press)

(Accepted 1 August 2004)

Patrice Cacoub MD

Department of Internal Medicine, Hpital La Piti Salptrire, 41 Boulevard de l'hpital, 75013 Paris, France

Email: patrice.cacoub@psl.ap-hop-paris.fr

Copyright Royal Society of Medicine Press Ltd. Jan 2005

Source: International Journal of STD & AIDS

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