aDivision of Infectious Diseases, Department of Medicine, Sweden
bDivision of Clinical Virology, Department of Laboratory Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Correspondence to Olle Karlström, MD, Division of Infectious Diseases, Department of Medicine, Karolinska University Hospital Huddinge, S 141 86 Stockholm, Sweden. Tel: +46 8 585 800 00; fax: +46 8 585 819 16; e-mail: firstname.lastname@example.org
We prospectively studied early hepatitis C virus kinetics and sustained virological response rates in HIV/HCV coinfected (n = 13) and HCV monoinfected matched controls (n = 26) with HCV genotype 2/3 treated with pegylated interferon (peg-IFN) alpha-2a 135 μg/week plus ribavirin 11 mg/kg daily during 24 weeks. No significant difference in HCV-RNA decay was seen at any time point during the intial 12 weeks of therapy. Sustained virological response was achieved in 9/13 (69%) versus 20/26 (77%) patients (intent-to-treat), respectively. The lower-than-standard peg-IFN dose offered high compliance and reasonable sustained virological response rates.
Pegylated interferon (peg-IFN) and ribavirin (RBV) combination therapy in HIV/HCV coinfected patients generates lower sustained virological response (SVR) rates than in HCV monoinfected patients regardless of genotype [1–4]. More frequent adverse events, dose reductions and treatment withdrawals in HIV/HCV coinfected offers some explanation.
A slower HCV RNA decay in HIV/HCV coinfected than in HCV monoinfected patients during treatment has been reported by some groups whereas others have failed to see such a difference [5,6]. Studies on HCV RNA kinetics have mainly been performed in patients with genotype 1. HCV RNA kinetics in HIV/HCV coinfected patients versus in matched HCV monoinfected controls during combination therapy for genotype 2/3 infections has not been studied.
Monotherapy with lower-than-standard dose of peg-IFN in patients with HCV infection caused by genotype 2/3 who are not infected with HIV yielded the same SVR rates as a higher standard dose (180 μg peg-IFN alfa-2a or 1.5 μg/kg bw peg-IFN alfa-2b) used in the pivotal combination trials [7,8]. In a study of 100 HCV monoinfected patients with genotype 2/3, from which our controls were chosen, a lower than standard dose of peg-IFN alfa-2a (135 μg q.w.) in combination with RBV (11 mg/kg/day) yielded a low drop-out rate and an SVR rate of 86% .
In this pilot study, the early HCV RNA kinetics, rapid virological response (RVR), end of-treatment response (ETR), and SVR rates were prospectively studied in HIV/HCV coinfected patients with genotype 2/3 infection and compared with that in HCV monoinfected controls matched for baseline viral load, genotype, and age during therapy with a lower-than-standard dose of peg-IFN alfa-2a plus weight-based RBV. The controls were chosen from a parallel study including 100 consecutive HCV monoinfected patients with genotype 2 or 3 run in the same university clinic (11). Main exclusion criteria were chronic hepatitis B, decompensated liver disease, ongoing substance abuse, and severe psychiatric illness. HIV/HCV coinfected patients were on successful antiretroviral therapy (ART) (minimum 6 months), or had not initiated ART (3/13). Patients on didanosine or zidovudine were switched to other drugs prior to inclusion.
Matching was done for HCV genotype, baseline HCV-RNA, and age (±5 years) in that order. Matching was undertaken with the investigator being blinded for all parameters except HIV-status and the three chosen baseline-matching criteria. Liver biopsies were not performed in any patient according to Swedish consensus, which concludes that genotypes 2 and 3 can be treated without a prior biopsy .
All patients received peg-IFN alpha-2a 135 μg weekly (Pegasys; Roche) in combination with RBV (Copegus, Roche) dosed according to weight (11 mg/kg) in two daily divided doses during 24 weeks. Dose reductions were undertaken following clinical practice, growth factors were not used.
HCV-RNA was assessed by theTaqman RT-PCR test (detection limit of 15 IU/ml) at days 0, 2, 7, 14, at week 4, 12, 24 and during follow-up 1, 3 and 6 months after treatment stop. HCV genotyping was performed with a line probe assay (Inno-LiPA HCV II, Innogenetics NV, Gent, Belgium)  or an inhouse method . The chi-square test or Fisher's exact two-tailed test was used to test categorical variables, and the Wilcoxon rank sum test for continuous variables. A P-value less than 0.05 was considered statistically significant.
Except for male gender being more frequent in HIV/HCV coinfected patients, all other baseline factors were well matched. In cases (HIV+) and controls (HIV-), the baseline resulting matching parameters were: numbers with genotype 2: 4/13 versus 8/26 patients; baseline HCV-RNA 6.49 (5.95–7.36) versus 6.41 (5.64–7.47), log10 IU/ml and age 51 (38–62) versus 50 (30–61) years.
Baseline alanine aminotransferase levels were slightly lower in HIV/HCV coinfected patients, 1.3 (0.5–4.3) versus 2.0 (0.5–5.9) μkat/l. Caucasian race was predominant and seen in 11/13 cases versus in 25/26 matched controls.
All patients except one control completed the 24-week regimen. The control not completing therapy stopped at week 12 due to side effects and did not achieve ETR.
The decline in HCV-RNA levels in HIV/HCV coinfected versus HCV monoinfected controls during the first 4 weeks of treatment is given as box plots in Fig. 1. No significant difference in HCV RNA decline at any time point (d2, w1, w2, and w4) was seen between HIV/HCV coinfected and mono-infected controls. The median CD4 count in the coinfected patients was 430 (range 250–800) 109/l. No difference in HCV RNA decline at any time point between HIV/HCV coinfected patients with baseline CD4 count above and below 400 cells/ul was seen (data not shown).
RVR (<15 IU/ml at week 4) was achieved in 6/13 coinfected versus in 16/26 monoinfected patients (P = 0.34). ETR was seen in 13/13 and 25/26 patients respectively, while SVR was achieved in 9/13 (69%) and 20/26 (77%) patients (intent-to-treat), respectively. One HIV/HCV coinfected patient (counted as failure) was HCV RNA negative week 24, but continued treatment for 48 week due to protocol violation – and achieved SVR.
Among patients with relapse after having had ETR 3/3 HIV/HCV coinfected and 3/5 HCV monoinfected controls had failed to achieve RVR treatment week 4.
The given RBV dosage at baseline was similar in HIV/HCV coinfected patients and controls, median 11.1 (9.6–14) versus 11.4 (10.0–14.5) mg/kg. In practice, the vast majority of patients were given 800 mg daily. Hence, a lower RBV dose than presently recommended (1000 mg if <75 kg, 1200 mg if > 75 kg regardless of genotype) for HIV/HCV coinfected patients was given .
Dose reduction of peg-IFN to 90 μg per week (neutropenia) was done in four HIV/HCV coinfected patients starting from week 4–18 and onwards, yet all four achieved SVR, whereas two out of four who had their RBV dose reduced (anemia) experienced relapse. Among HCV monoinfected controls who had peg-IFN or RBV dose reductions, all achieved SVR.
In summary the HCV-RNA decay during the initial 12 weeks of antiviral therapy in HIV/HCV co-infected patients infected with genotype 2/3 was similar to that in HCV monoinfected controls matched for genotype, baseline HCV-RNA levels and age. Despite the usage of what is now considered a suboptimal RBV dose, the outcome in this pilot study indicates that a lower-than-standard dose of peg-IFN used merits further studies in HCV/HIV coinfected patients infected with genotype 2/3 infection.
1. Carrat F, Bani-Sadr F, Pol S, Rosenthal E, Lunel-Fabiani F, Benzekri A, et al
. Pegylated 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.
2. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr, et al
. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347:975–982.
3. Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P, et al
. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140:346–355.
4. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, Lissen E, Gonzalez-Garcia J, Lazzarin A, et al
. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004; 351:438–450.
5. Sherman KE, Shire NJ, Rouster SD, Peters MG, James Koziel M, Chung RT, et al
. Viral kinetics in hepatitis C or hepatitis C/human immunodeficiency virus-infected patients. Gastroenterology 2005; 128:313–327.
6. Torriani FJ, Ribeiro RM, Gilbert TL, Schrenk UM, Clauson M, Pacheco DM, et al
. Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) dynamics during HCV treatment in HCV/HIV coinfection. J Infect Dis 2003; 188:1498–1507.
7. Lindsay KL, Trepo C, Heintges T, Shiffman ML, Gordon SC, Hoefs JC, et al
. A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C. Hepatology 2001; 34:395–403.
8. Pockros PJ, Carithers R, Desmond P, Dhumeaux D, Fried MW, Marcellin P, et al
. Efficacy and safety of two-dose regimens of peginterferon alpha-2a compared with interferon alpha-2a in chronic hepatitis C: a multicenter, randomized controlled trial. Am J Gastroenterol 2004; 99:1298–1305.
9. Weiland O, Schvarcz R, Mattsson L, Glaumann H, Hollander A, Enquist R, et al
. 135 μg peg-IFN alpha 2A in combination with weight-based ribavirin for genotype 2 and 3 is highly efficacious. J Hepatology 2006; 44(Suppl 2):619.
10. Wejstal R, Alaeus A, Fischler B, Reichard O, Uhnoo I, Weiland O. Chronic hepatitis C: updated Swedish consensus. Scand J Infect Dis 2003; 35:445–451.
11. Stuyver L, Wyseur A, van Arnhem W, Hernandez F, Maertens G. Second-generation line probe assay for hepatitis C virus genotyping. J Clin Microbiol 1996; 34:2259–2266.
12. Yun Z, Lara C, Johansson B, Lorenzana de Rivera I, Sonnerborg A. Discrepancy of hepatitis C virus genotypes as determined by phylogenetic analysis of partial NS5 and core sequences. J Med Virol 1996; 49:155–160.
13. Soriano V, Puoti M, Sulkowski M, Cargnel A, Benhamou Y, Peters M, et al
. Care of coinfected patients with HIV and hepatitis C virus: 2007 updated recommendations from the HCV-HIV international panel. AIDS 2007; 21:1073–1089.
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