Treating HCV/HIV Coinfection: adherence, tolerability & response

In the two last years we have seen or heard of results from several small & ongoing studies of HCV therapy showing HCV/HIV coinfected respond about the same to HCV therapy as persons infected only with HCV. In the December Journal of AIDS, these 3 Italian investigators submitted a letter reporting on a study 50 coinfected persons, half with genotype 1 and half with genotype 2 or 3. Coinfected patients had mean CD4s of 515 and HIV-RNA <50 copies/ml. The authors reported that at 48 weeks 20% (n=10) had biochemical (ALT) & virologic (< 100 copies/ml), but they did not say if this was end-of-treatment (ETR) or sustained virologic response (6 months after treatment stopped, which is the accepted measure of success). I assume they gave 48 weeks therapy so 20% is ETR, which if this is the case is a poor response as usually ETR is higher than sustained response.

Relapse rate after end of treatment usually reduces sustained response. Its also important to bear in mind when looking at these low response rates that IFN alone is no longer the standard of care. Ribivarin + interferon yields a 38-43% sustained virologic response after 12 months treatment, and Pegasys interferon alone yielded 39% in chronic HCV when HIV was not present. And recent data showed an overall 60% sustained response from PegIntron+ribivarin in HCV alone infected, where dose was adjusted for weight, but the rate was 64% without adjusting dose by weight. Of course response rates for genotype 1 individuals is less and most HIV coinfected persons are genotype 1.

It's also important to bear in mind that HIV accelerates HCV progression. It appears interferon improves inflammation & fibrosis even for virologic non-responders in many cases. This is important to individuals who are unable to get a virologic response & for persons with advanced liver disease who can't get a virologic response. This may help slow or stop HCV progression until there are new drugs. One small French study suggests that HAART with a PI slowed fibrosis progression. This suggests HAART could stop or slow progression but many doctors I've spoken with are skeptical of these information. Further studies are needed to confirm this. But there are 2 interesting points worth mentioning from this study and the Soriano study below:

1. 24 patients (48%) dropped out of the study, "mainly because of side-effects related to overlapping toxicity of INF and antiretroviral therapy". In general, some coinfected individuals will likely have difficulty in coping with the adherence & tolerability aspects of taking IFN/RBV with HAART or without HAART.
   

2. In Soriano study, persons with CD4 count over 500 before starting therapy responded better. Currently, researchers are suggesting that if a person has >200 CD4s they should respond as well to therapy as persons with HCV alone: Two variables were independently associated with a response in HIV-infected patients: a CD4+ T lymphocyte count of > 500 x 10(6)/L and a baseline HCV viremia level of < 10(7) copies/mL

Aggressive Daily Interferon Therapy in HIV-HCV Coinfected Patients
    Raffaele Bruno; Paolo Sacchi; Carlo Filice; Gaetano Filice
    JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Dec 1 2000;25:372-373

To the Editor: HIV-hepatitis C virus (HCV) coinfection is common and affects more than one third of all HIV-infected persons worldwide. HIV-HCVñcoinfected patients have higher HCV RNA levels and a more rapid risk of progression of HCV-related liver disease with increased risk of cirrhosis. Chronic HCV infection mimics opportunistic diseases because the natural history of HCV infection is accelerated in HIV patients (1) Since the natural prognosis of HIV disease has been changed by highly active antiretroviral therapy (HAART), the need to treat HCV coinfection has become a significant issue.

However, few studies have described the use of interferon- (IFN-) for treatment of chronic HCV infection in HIV-infected patients. The reports of Boyer et al. (2) and Marriot (3) showed a poor sustained response. In the largest published study, Soriano et al. (4) described how 20% of patients achieved a sustained virologic response; in this study, IFN- appeared to be well tolerated. These results were obtained with a three-times-weekly interferon schedule. Strategies to improve the response to therapy are needed to modify the progression of HCV-related liver diseases.

In our previous study performed in immunocompetent patients (5), we demonstrated that daily IFN administration is more effective than three-times-weekly dosage. The need for a more aggressive therapy in HIV-HCV patients is justified by the worst clinical course. The aim of this study is to evaluate after 48 weeks the efficacy and safety of daily-dose IFN administration in HIV-HCV coinfected patients.

We evaluated 50 coinfected patients (42 men and 8 women) being treated with HAART (two nucleoside reverse transcriptase inhibitors and one protease inhibitor). All patients had persistently elevated alanine transaminase levels and underwent liver biopsy. Of these, 26 patients had HCV genotype 1b, and 24 patients had genotypes 2 and 3. INF- was administered at a dose of 3 million units daily.

The mean baseline values were as follows:

• CD4+ count, 515 cells/mm3;

• HIV RNA level, <50 copies/ml in all patients; and

• HCV RNA level, 2485 x 10-6th.

• Thirty-four patients had a high Histologic Activity Index score (>10), and 18 patients had severe hepatic disease with high fibrosis stage.

At 48 weeks,

• 10 patients (20%) achieved biochemical and virologic response (HCV RNA <100 copies/ml);

• 16 patients (32%) did not respond to treatment, with persistently elevated ALT and detectable viremia; and

• 24 patients (48%) dropped out of the study, mainly because of side-effects related to overlapping toxicity of INF and antiretroviral therapy.

These preliminary results indicate the difficulty in treating HIV-HCVñcoinfected patients with IFN, because side-effects restrict the compliance to IFN therapy and could affect the adherence to HAART. IFN therapy probably adversely influenced the tolerability of HAART, but this was justified by the advanced stage of liver diseases. The high dropout rate reduces the percentage of responders, which could be improved by using a better-tolerated schedule such as that for pegylated interferon.

Division of Infection and Tropical Diseases
IRCCS S. Matteo Hospital, University of Pavia, Pavia, Italy

REFERENCES

1. Sulkowski MS, Mast EE, Seeff LB, et al. Hepatitis C virus infection as an opportunistic disease in persons infected with human immunodeficiency virus. Clin Infect Dis 2000;30:S77ñ84. 

2. Boyer N, Marcellin P, Degott C. Recombinant interferon  for chronic hepatitis C in patients positive for antibodies to human immunodeficiency virus. J Infect Dis 1992;165:723ñ6. 

3. Marriot E, Navas S, del Romero J. Treatment recombinant interferon  for chronic hepatitis C in anti-HIV positive patients. J Med Virol 1993;40:107ñ11. 

4. Soriano V, Garcia-Samaniego J, Bravo R. Interferon  for the treatment of chronic hepatitis C in patients infected with human immunodeficiency virus. Clin Infect Dis 1996;23:585ñ91. 

5. Bruno R, Debiaggi M, Sacchi P. Daily Interferon regimen for chronic hepatitis C. A prospective randomized study. Clin Drug Invest 1999;18:11ñ16.

Interferon alpha for the treatment of chronic hepatitis C in patients infected with human immunodeficiency virus. Hepatitis-HIV Spanish Study Group.
     Clin Infect Dis 1996 Sep;23(3):585-91
     Soriano V, Garcia-Samaniego J, Bravo R, Gonzalez J, Castro A, Castilla J, Martinez-Odriozola P, Colmenero M, Carballo E, Suarez D, Rodriguez-Pinero FJ, Moreno A, del Romero J, Pedreira J, Gonzalez-Lahoz J Centro de Investigacion Clinica, Instituto de Salud Carlos III, Madrid, Spain.