|Home | About | Journals | Submit | Contact Us | Français|
Combination of pegylated-interferon (PEG-IFN) plus ribavirin (RBV) is the standard-of-care for hepatitis C virus (HCV) treatment in HIV coinfected individuals. In 2007, abacavir (ABC)-based antiretroviral therapy was for the first time reported to be associated with early virological failure during HCV treatment. The aim of our study was to evaluate the impact of ABC on the response rate to HCV-therapy.
Retrospective analysis of HIV-HCV-coinfected patients treated with PEG-IFN and weight-adjusted RBV in four hospitals in Spain was performed. A descriptive baseline variables analysis was conducted. Logistic regression models were used to test possible associations between non-response and pre-treatment characteristics including antiretroviral drugs.
A total of 244 HIV/HCV co-infected patients treated with pegylated-interferon and ribavirin were included. Eighty-five % of patients were on HAART and of them 24% received ABC-based regimens. The most frequent genotypes were 1 and 3. RBV dosing was ≥13.2 mg/kg/day in 97% of the patients. In the global intent-to-treat analyses, 46.3% of patients reached SVR (46.2% in ABC group vs. 46.7% in non-ABC group, p=1). The only two factors in the multivariate analysis statistically associated with an increased risk of failure to achieve SVR were HCV genotype 1/4 and older age. The use of ABC was not associated with failure to achieve SVR in none of the other time points evaluated.
Our data suggest that the use of ABC-based regimens in the context of HCV therapy does not negatively affects the outcome of this treatment.
Combined treatment with pegylated-Interferon (PEG-IFN) plus ribavirin (RBV) has become the standard-of-care for hepatitis C virus (HCV) treatment in HIV co-infected patients since 2004, with a rate of sustained virological response (SVR, negative HCV RNA six months after the end of treatment) of 40-44% [1-4]. Baseline serum HCV RNA and HCV genotype are the main predictors of SVR [5,6]. However, several other factors influence the outcome of this therapy, including age, ethnicity, body mass index, insulin resistance, grade of hepatic fibrosis , CD4 cell count, and HIV viral load . Certain antiretroviral drugs may present synergistic or antagonistic effects when combined with anti-HCV therapy. RBV is a purine nucleoside analog, and extensively distributes into red blood cells after oral administration and competes in vitro for thymidine and cytosine analogs such as zidovudine and stavudine [9,10]. The concomitant use of zidovudine and ribavirin should be avoided whenever possible for the increased risk of anaemia  as well as with stavudine for the risk of lactic acidosis. The phosphorylation of didanosine is increased by ribavirin, the use of this drug in patients receiving ribavirin is contraindicated due to the risk of life-threatening complications, such as lactic acidosis, decompensated cirrhosis and pancreatitis . However, until last year, no reports of decreased rate of response to HCV-therapy have been reported due to the antiretroviral regimen prescribed. In May 2007, the French group RIBAVIC reported for the first time that abacavir (ABC)-based antiretroviral therapy was associated with an early virological failure during HCV treatment. Since then, several reports have shown discordant results; Vispo et al.  and Mira et al.  demonstrated a negative impact of ABC on SVR. On the other hand, Moreno et al.  and Pineda et al.  did no find any SRV rates differences when comparing patients receiving ABC with patients on other nucleoside/nucleotide reverse transcriptase inhibitors.
The aim of our study was to evaluate the impact of ABC on the rate of response to HCV-therapy in HIV/HCV co-infected patients.
This is a retrospective cohort study of HIV-HCV coinfected patients from four hospitals in Spain (Hospital Clinic, Barcelona; Hospital Son Llàtzer, Palma de Mallorca; Hospital Son Dureta, Palma de Mallorca; Hospital Joan XXIII; Tarragona) treated, between 2002 and 2006, with PEG-IFN and RBV. Patients were included in the analysis if they met the following inclusion criteria: previously untreated chronic hepatitis C with PEG-INF and ribavirin, positive HCV-RNA in plasma, ALAT higher than 1.5 fold upper normal limit; control of the HIV infection with CD4+ cell count above 250cells/mm3 and HIV viral load lower than 50000 copies/mL, in response to an stable antiretroviral treatment (ART) or without ART if not required. Exclusion criteria included: presence of other causes of hepatopathy, decompensated cirrhosis, pregnancy and potential contraindications for interferon or for ribavirin therapy like haemoglobinopathies, cardiopathy, autoimmune diseases, major depression or other severe psychiatric pathologies and active illicit drug consumption within the last twelve months. A total of 244 patients were included.
Treatment was planed for 48 weeks in all patients. Sixty percent of patients received PEG-INF alfa-2b (Peg-Intron-A, Schering Corp, Kenilworth, NJ, USA) subcutaneous (80mcg-150mcg, body weight-adjusted dosing) each week plus oral ribavirin (Rebetol, Schering Corp, Kenilworth, NJ, USA) every day; and 40% patients received PEG-INF alfa-2a (Pegasys, Roche Corp, Hertfordshire, UK) subcutaneous (180mcg) each week plus daily oral ribavirin (Copegus, Roche Corp, Hertfordshire, UK). RBV dosing was body weight-adjusted in all cases: 800mg when the body weight was below 60kg, 1000 mg when it was between 60-75 kg, and 1200 mg when body weight was above 75 kg. When at least a 2 log reduction in HCV RNA at week 12 was obtained, patients continued treatment and were re-evaluated at week 24; if HCV RNA was negative they continued treatment until week 48.
Patients were evaluated before beginning treatment, 2 weeks after starting therapy and every 4 weeks until the cessation of therapy, and also 24 weeks after the end of treatment to evaluate SVR. Blood analysis including a haemogram and a complete biochemistry with lactate was carried out at every medical visit, in addition to a medical interview to establish possible secondary effects of the treatment. At week 4 and every 12 weeks thereafter: thyroid function, HIV viral load and CD4+ cell count were determined. Serum HCV-RNA was measured by quantitative PCR assay at baseline, and 12 weeks after starting therapy (Branched DNA, Siemens, Tarrytown, NY, USA). During treatment at weeks 4, 24, 36 and 48 and at 24 weeks after cessation of therapy HCV-RNA was measured by qualitative PCR assay (TMA, Siemens -Tarrytown, NY, USA- with a sensitivity of 30 UI/mL). Genotyping was done as previously described .
A descriptive analysis of baseline variables was conducted looking at the central tendency and dispersion. These values were compared with the aim of ensuring that the demographic, epidemiological, clinical, biochemical and histopathological characteristics were similar among patients in both groups of therapy. Fisher's Exact Test was used to analyze qualitative variables and Mann-Whitney test to analyze quantitative variables. Logistic regression models were used to test possible associations between non-response (outcome variable) and pre-treatment characteristics.
Characteristics with p-value < 0.1 in univariate analysis were included in multivariate logistic model based on backward elimination procedure. All statistical tests were 2-sided, with a type I error of 5%.
Data were analysed in the Epidemiology and Statistics Unit, UASP, Hospital Clinic. Barcelona.
A total of 244 HIV/HCV coinfected patients treated with pegylated interferon and ribavirin were included in this retrospective analysis. Eighty-five % of patients were on HAART and 49 of them (24 %) received ABC-based regimens. Baseline characteristics were similar between the groups of patients on ABC-based regimens and those who did not (Table 1) and they only differed in the mean time of known chronic hepatitis C infection (15.5 vs 18 years, p 0.02). The majority of the patients were males (71%) with a mean age of 41 years and a mean weight of 67.5Kg and height 170cm. Seventy six percent of the subjects had a history of illicit intravenous drug consumption. The more frequent genotypes in our series were 1 and 3 (48% and 34% respectively). Ribavirin dose was equal or higher than 13.2 mg/kg/day in 97% of the patients. Regarding HCV RNA, 60% of the patients had a viral load higher than 600,000 UI/ML and 75% higher than 400,000 UI/ml
Response rates are summarized in figure 1. In the global intent-to-treat analysis, 46.3% of patients reached SVR (46.2% in the ABC group vs. 46.7% in the non-ABC group, p=1).
To examine the influence of potentially important prognostic factors on SVR, the following variables were assessed by univariate and multivariate analyses: HCV genotype, baseline HCV-RNA, degree of fibrosis before starting therapy, presence of steatosis, age, gender, baseline CD4+ count cell , baseline HIV-VL, years with HCV infection, use or not of HAART, baseline body weight, type of PEG-INF and the necessity or not to modify the dose of HCV therapy, baseline ALT level, therapy containing abacavir, therapy with tenofovir.
The factors included in the multivariate analysis were age, genotype, ALT level, baseline HCV-ARN and CD4+ count. The only two factors that remained statistically associated with an increased risk of failure to achieve SVR were HCV genotype 1 or 4 and older age (> 40 years-old). Specifically the use of ABC was not associated with higher rates of failure to achieve virological response in none of the other time points evaluated (rapid virological, early virological, sixth months, and end of treatment)(table 2).
Since the first report on the negative impact of ABC-based therapy in the response to HCV treatment in HIV coinfected patients, an inhibitory competition between ABC and RBV (both guanosine analogs) has been suggested [13,14]. The same authors describe that this negative impact may be overcome by high ribavirin exposure. However, a low-level of antagonism between RBV and both tenofovir and abacavir has been reported in vitro, while a much higher level of antagonism with zidovudine, stavudine, emtricitabine and lamivudine was observed .
In our study the rate of SVR was not affected by the use of ABC-based regimens, in concordance with the data presented by Moreno and Pineda et al. [15,16]. One of the main reasons might be that all patients included in this study were receiving high doses of RBV.
After multivariate analysis, only HCV genotype 1 or 4, and older age were independently associated with the failure to achieve sustained virological response, two already well known prognostic factors. Even though patients without ABC have a statistically significant longer time of known HCV infection than patients in the ABC group, no difference in the grade of fibrosis was found between the two groups. For that reason it could be assumed that the longer time of HCV infection found in the non-ABC group have not negatively impact in the outcome of HCV therapy.
Our data suggest that the use of ABC-based regimens in HIV infected patients in the context of HCV therapy does not negatively affect the outcome of this treatment.
Natalia Laufer was supported by the European AIDS Clinical Society (Medical Exchange Program for Young HIV Physicians) and by Fogarty International Center/NIH grant through the AIDS International Training and Research Program at Mount Sinai School of Medicine-Argentina Program (Grant # 5D43 TW0010137).
The authors do not have any commercial or other association that might pose a conflict of interest.