Pegylated interferon α2b plus ribavirin for the treatment of chronic hepatitis C in HIV-infected patients
Moreno, Leonor; Quereda, Carmen; Moreno, Ana; Perez-Elías, María J; Antela, Antonio; Casado, José L; Dronda, Fernando; Mateos, Maria La; Bárcena, Rafaelb; Moreno, Santiago
From the Department of Infectious Diseases, the aDepartment of Microbiology and the bDepartment of Hepatology-Gastroenterology, Hospital Ramón y Cajal, Madrid, Spain.
See also pp. 1, 59, 75, 121, 131
Correspondence to L. Moreno, Servicio de Enfermedades Infecciosas, Hospital Ramón y Cajal, Carretera de Colmenar Km 9,100, 28034 Madrid, Spain.
Note: Presented in part at the 41th Interscience on Antimicrobial Agents and Chemotherapy, Chicago, December 2001.
Received: 13 May 2003; revised: 30 July 2003; accepted: 11 August 2003.
Background: Hepatitis C virus (HCV) and HIV coinfection constitutes an important epidemiological and clinical problem. We evaluated the safety and efficacy of Pegylated interferon α2b (Peg-IFN) and a fixed dose of ribavirin in the treatment of chronic hepatitis C in HIV coinfection.
Methods: Open, prospective study in HCV–HIV coinfected patients with persistently elevated alanine aminotransferase (ALT) levels and a liver biopsy showing either portal or bridging fibrosis. Therapy included Peg-IFN (50 μg weekly) with ribavirin 800 mg for 48 weeks. The primary end point was sustained virological response (SVR). Univariate and multivariate analyses were performed to determine factors associated with response.
Results: By intent-to-treat analysis, 11 of 35 patients (31%) reached SVR. SVR was significantly better for genotypes 2/3 than for genotype 1 (54% versus 21%; P < 0.05). By multivariate logistic regression analysis, only a non-1 genotype was an independent factor for SVR [odds ratio (OR), 6; 95% confidence interval (CI), 1.1–31.7; P < 0.005]. A decrease of at least 1.5 log10 HCV RNA at week 12 of therapy was highly predictive of SVR (OR, 49.9; 95% CI, 4.9–508.2; P < 0.001). Most patients developed adverse events, although only six patients (17%) discontinued treatment due to toxicity.
Conclusions: The combination of low doses of Peg-IFN plus a fixed dose of ribavirin resulted in a rate of SVR similar to that obtained with higher doses of the drugs in HIV-infected patients and lower than those obtained in non-HIV patients. Response at week 12 may be useful to help guide therapy in HCV–HIV co-infected patients.
The availability of highly active antiretroviral therapy (HAART) has reduced morbidity and mortality related to HIV infection, producing a significant increase in life expectancy . In this setting, co-infection with the hepatitis C virus (HCV), highly prevalent among HIV infected patients, has become a leading cause of death and hospital admission . Chronic hepatitis C has been shown to exhibit an accelerated progression to liver fibrosis in HIV infected patients as compared with HIV-seronegative immunocompetent individuals . HCV co-infection may limit the adequate treatment of HIV and is associated with an increased toxicity of antiretroviral drugs [4,5]. Thus, the adequate management of HCV-related chronic liver disease in HIV infected patients arises as a major concern in this population.
Recent published data  favour treatment of HCV in HIV co-infected patients, although emphasize the need for further studies able to determine the safety of HCV treatment in this population. Prior studies using monotherapy with interferon α (IFN) showed similar rates of response between HIV negative and HIV infected patients, despite a trend to poorer outcomes in HIV co-infected patients with low CD4 cell counts . Combined treatment with IFN plus ribavirin (RBV) has become the gold standard for HCV treatment since 1998 [8,9]. However, there is a lack of randomized, comparative data on combined therapy for HCV in HIV co-infected patients. Most published studies are observational and yield rates of sustained virological response (SVR) ranging from 20% [10,11] to 40% .
New formulations of IFN have been developed to improve the outcome of HCV treatment, and now Pegylated-interferon (Peg-IFN) plus RBV constitutes the cornerstone of therapy for chronic hepatitis C [13,14]. Peg-IFN – with a molecule of polyethylene glycol – improves the pharmacokinetic and pharmacodinamic profile of the active IFN protein, producing a significant increase in its plasmatic half-life, thus optimizing its activity and allowing once weekly administration. To date, there is little information about the safety and efficacy of combined treatment with Peg-IFN plus RBV in HIV co-infected patients. Preliminary results of clinical trials and some observational studies have shown a lower efficacy of the combination in this population, and a higher rate of adverse events, some of them related to the interaction between anti-hepatitis and antiretroviral drugs [15–18].
The objective of this study was to assess the outcome, in terms of SVR and adverse events, of a 48-week cycle of Peg-IFN-α-2b plus RBV in previously untreated HCV patients co-infected with HIV-1.
Pilot, prospective, uncontrolled, open trial, performed at the specialized HIV Unit of the Ramón y Cajal Hospital, a tertiary centre in Madrid, Spain, from June 2000 to July 2002. Our ERC approved the protocol, and all patients gave signed informed consent. The enrolment period was from June to December 2000. Thirty-five HIV infected patients co-infected with HCV were included in a study of the efficacy and tolerance of a 48-week cycle of subcutaneous Peg-IFN-α-2b at a dose of 50 μg once weekly (Peg-Intron, Schering-Plough. Kenilworth. New Jersey, USA) plus oral RBV (Rebetol, Schering-Plough) 800 mg/day divided into two doses. Follow-up was planned until week 72, in order to assess the rate of SVR.
Eligible patients were previously untreated HCV infected adults with serum detectable HCV RNA as determined by PCR, serum alanine aminotransferase (ALT) levels above the upper limit of normal within 6 months before study entry, and liver biopsy findings consistent with the diagnosis of chronic hepatitis C. Haemoglobin values ≥ 12 g/dl, a leukocyte count ≥ 3 × 106 cells/l (with neutrophils ≥ 1.5 × 106 cells/l), platelets ≥ 1 × 108cells/l, and prothrombin activity, bilirubin, albumin, and creatinine within normal ranges were also required.
Regarding HIV infection, we included clinically stable patients with CD4 cell counts of at least 300 × 106 cells/l and HIV-1 viral load (VL) < 10 000 copies/ml, whether or not they were on current antiretroviral therapy. Liver biopsy was performed in all patients before study entry, using a Tru-cut needle. All histological examinations were assessed by a single experienced pathologist and graded according to the Knodell Activity Index.
Exclusion criteria were as follows: cirrhosis, other causes of liver disease, prior psychiatric or cardiovascular diseases, history of seizures, haemoglobinopathies, uncontrolled diabetes, severe retinopathies, treatment with steroids, chronic bronchitis, pregnancy or breast-feeding. Patients with alcohol/drug dependence within 6 months, or enrolled in another drug investigating trial before 30 days of study entry were also excluded.
Assessment of efficacy
The primary end-point of the study was to determine the rate of SVR, defined as undetectable HCV RNA in serum at the end of follow-up according to a fully automated system PCR assay (COBAS AmpliPrep Specimen Preparation, COBAS HCV Amplification and Detection version 2.0, Roche Diagnostic Systems, Nutley, New Jersey, USA). The sensitivity of this test is 60 IU/ml of HCV RNA.
Early virologic response (EVR) was evaluated at week 12 of therapy by measuring the decrease from baseline HCV RNA. Biochemical response was defined as the presence of normal AST and ALT values 6 months after the end of treatment. Hepatitis C virus genotypes were determined by reverse hybridization using the Inno-Lipa HCV (Innogenetics, Ghent, Belgium). Serum HCV RNA levels were measured by a quantitative PCR assay (COBAS AMPLICOR MONITOR test rit, Roche Diagnostic Systems) with a sensitivity of 600 IU/ml, at entry and then at weeks 4, 12, 24 and 48 while on treatment, and at weeks 12 and 24 once therapy was discontinued.
Assessment of safety
Safety was the secondary end-point of the study. Adverse events were graded following the World Health Organisation scale as mild, moderate or life-threatening, and were periodically assessed, at weeks 2, 4, 8 12, 16, 20, 24 and each 3 months thereafter until the end of follow-up. The percentage of early discontinuations was also recorded. Subjective adverse events, including psychiatric abnormalities, were assessed and graded according to the patients’ spontaneous report. Haematology and analyses of biochemical parameters were performed at baseline and at each visit until week 72. CD4 cell counts (by flow cytometry) and HIV RNA plasma levels (by branched DNA; Chiron, Emeryville, California, USA; threshold 50 copies/ml) were determined at baseline, at weeks 4, 12, 24 and then every 3 months.
We considered the following criteria for treatment withdrawal: the development of life-threatening adverse events, progression to an AIDS-defining illness, pregnancy, and an adverse event-related treatment discontinuation for more than 4 weeks. Serious adverse events were managed by decreasing the doses of Peg-IFN and RBV to 25 μg/week and 600 mg/day, respectively, and restarting full doses once complete recovery was achieved. In case of anaemia, RBV dose was adjusted to 600 mg/day if haemoglobin fell ≤ 10 g/dl, or to complete withdrawal if ≤ 8.5 g/dl. The adjusted dose of RBV was maintained for at least 4 weeks. In patients with cardiovascular risk and persistent haemoglobin values ≤ 12 g/dl despite dose reduction for at least 4 weeks RBV was withdrawn. A polymorphonuclear lymphocyte count < 750 × 103 cells/l led to a half reduction in Peg-IFN dose. Treatment was discontinued when platelet counts fell to < 50 × 106cells/l, or if a two-fold increase from baseline, or 10-fold increase over the upper limits of normal were observed in the transaminase levels.
Analysis of the patients’ characteristics was performed by considering two subgroups of patients (SVR versus non-SVR). Comparisons were performed using Student's t test. The χ2 test was used to compare proportions. All P values were two-tailed, and differences were considered significant when P < 0.05. Different variables were used in a stepwise logistic multivariate regression analysis to identify variables independently associated with SVR. Receiver operating characteristics (ROC) curves were used to assess the cut-off of HCV RNA decrease with the best sensitivity and specificity to discriminate between patients with or without EVR. All data analysis was conducted using the SPSS for Windows, version 10.0 (SPSS Inc., Chicago, Illinois, USA).
The baseline demographics of the 35 patients are given in Table 1. Most patients, 83% (n = 29) were prior injecting drug users, with a mean duration of drug use of 18 years. Twenty-eight patients (80%) were receiving HAART during the study period and the median HIV RNA plasma levels and CD4 cell count were < 1.7 log10 copies/ml and 544 × 106 cells/l respectively. Most patients (89%) received RBV at a dose > 10.6 mg/kg and Peg-IFN dose ranged between 0.5 and 1 μg/kg.
Efficacy of therapy
In an intent-to-treat analysis, 11 patients (31%) reached SVR after 48 weeks of combined Peg-IFN at 50 μg/week plus RBV at a fixed dose of 800 mg/day. The rate of SVR was significantly higher for genotypes 2/3 than for genotype 1 (54% versus 21%; P < 0.05) (Table 2). The overall percentage of biochemical response was 46% (16 patients), and again it was significantly better for genotypes 2/3 than for genotype 1 (69% versus 36%; P < 0.05). After a multivariate logistic regression analysis including age, sex, baseline HCV RNA load, genotype, pretreatment histologic findings and baseline CD4 cell counts, only a non-1 genotype was an independent factor for SVR [odds ratio (OR), 6; 95 confidence interval (CI), 1.1–31.7; P < 0.05].
We evaluated the virological response in 25 patients who had plasma samples available for analysis at week 12. Median decrease was 1.3 log10 HCV RNA IU/ml, including seven patients (20%) who reached undetectable HCV RNA load. Among those who did not reach undetectability at week 12, seven (20%) showed a decrease of at least 1.5 log10 HCV RNA IU/ml from baseline, eight (23%) showed a decrease of at least 1 log10 HCV RNA IU/ml, and 3 (9%) did not show any decrease. ROC curves showed that a decrease of at least 1.5 log10 HCV RNA IU/ml at week 12 (EVR) was the best cut-off to discriminate between patients with or without SVR. Among 14 patients who obtained an EVR, 10 (71%) reached SVR, compared with only one of 21 (5%) of those without EVR (OR, 49.9; 95% CI, 4.9–508.2; P < 0.001).
Seven out of 35 patients included in the study discontinued treatment (20%), mostly due to adverse events (n = 6, 86%): weight loss > 10 kg, lactic acidosis, depression, severe flu-like syndrome, anaemia requiring hospitalization and blood transfusion, in one patient each, or both depression and influenza like syndrome in the remaining. One patient decided to withdraw therapy after 24 weeks. Table 3 shows the most frequently reported clinical adverse events.
Laboratory adverse events included haematologic or metabolic changes and lactic acidosis (Table 4). Neutropenia was the most frequent haematologic adverse events, present in 21 patients (60%), mild or moderate in most cases. Granulocyte-stimulating factor was successfully used in four patients with severe neutropenia, without relevant adverse events. Seven patients (20%) developed anaemia, which was severe in only one. Among patients with anaemia, concomitant zidovudine use as a part of antiretroviral therapy was significantly more frequent than stavudine use (71% versus 28%; P = 0.021). Moreover, all patients with moderate or severe anaemia were on zidovudine.
During the study period there were two cases (6%) of symptomatic hyperlactataemia, defined as lactate levels > 2.5 mmol/l plus weight loss, abdominal pain, nausea or vomiting. Concomitant stavudine was used in both cases, with didanosine and nelfinavir in one case, and lamivudine and ritonavir/indinavir in the other patient. One patient discontinued HAART and the other discontinued both HAART and HCV therapy, leading to complete recovery.
There were no cases of decompensated liver disease. In fact, there was only one admission, due to severe anemia requiring blood transfusion, as reported above.
Surrogate markers of HIV disease
At entry all patients had CD4 cell counts > 300 × 106 cells/l. In the follow-up there was a decrease to < 200 × 106 cells/l in three cases (9%), despite the percentage of CD4 cells remaining stable, owing to a decrease in the absolute lymphocyte count. We did not observe any opportunistic infection. Regarding HIV viral load, it was < 50 copies/ml at baseline in 23 of 35 patients (66%), and none of them experienced viral rebound leading to changes in their HAART during follow-up. Among patients with detectable baseline viral load, a decrease was observed in 75% after the first month of Peg-IFN plus RBV (mean, 0.6 log10; range, 0.1–1.2), and sustained only until the third month (66%; mean, 0.5 log10; range, 0.1–1.1).
With the regimen used in this study, we have found a sustained virological response in 31% of HIV/HCV co-infected patients, with a significantly better response in patients infected with non-1 genotypes (54% versus 21%). Despite the lower dose used, the frequency and severity of adverse events are similar to those found in other studies. Our data suggest that the virological response at week 12 of treatment could be useful in predicting non-responders and so could help to guide therapy.
In our study the fixed dose of Peg-IFN-α-2b (50 μg/week) was below the current recommended dose of 1.5 μg/kg per week. The low dose was selected due to a lesser experience in this field at the time the study was designed, and a lack of data on the optimal dosage in this population. In addition, we tried to test the hypothesis that a lower dose of Peg-IFN could have an efficacy similar to that of higher doses with a lower impact on toxicity. Despite the scarcity of published data on the treatment of chronic HCV infection with Peg-IFN plus RBV in HIV co-infected patients, our results are similar to those reported previously in terms both of efficacy and toxicity. In the 48-week French randomized RIBAVIC trial , Peg-IFN-α-2b at a dose of 1.5 μg/kg per week was significantly better than 3 × 106 IU standard IFN three times per week, both combined with 800 mg/day RBV, with an overall end-of-treatment rate of response of 38% (25% for genotypes 1/4 versus 42% for genotypes 2/3); the rate of SVR is still pending. In another study  including 40 patients receiving Peg-IFN-α-2b (1.5 μg/kg per week) with RBV at higher doses (1000–1200 mg/day) the rate of SVR was 32% (10% for genotypes 1/4 versus 80% for genotypes 2/3). Of note, genotypes 2/3 were present in 66% of the study population. In a recently published study  including 68 co-infected patients treated during the first 3 months with high dose Peg-IFN (150 μg weekly) plus RBV 800 mg/day followed by 100 μg /week plus RBV at the same doses, the overall rate of SVR was 27.9%. In all of these studies the rates of SVR are below those observed in HIV negative HCV infected patients treated with 800 mg/day RBV plus either Peg-IFN-α-2b at 1.5 μg/kg per week (54%) or 0.5 μg/kg per week (47%)  and, more recently, Peg-IFN-α-2a (180 μg/week) plus 1000–1200 mg/day RBV (56%) .
Similarly, treatment withdrawals with low dose Peg-IFN and RBV are in the range of those reported in other studies with different doses. Discontinuation rates have ranged from 15%  to 54% , but they are around 15% in most cases. Although most adverse events in our study were similar to those already published, the high rate of neuropsychiatric disturbances was remarkable, with 49% of the patients developing depression or irritability. This rate is somehow higher than has been reported in HIV-uninfected subjects [13,14], and similar to the rate described in other reports on HIV-infected patients [15,16]. In one case suicide ideation led to definitive treatment discontinuation. Moderate or severe peripheral neuropathy appeared in three patients (9%), all receiving stavudine (combined with didanosine in two). A change in the HAART regimen led to a significant improvement in peripheral neurological symptoms in the three patients.
Regarding haematologic changes, neutropenia was more common than anaemia, but it led to dose adjustment in fewer patients (20% versus 71%). There was a statistically significant association between the development and severity of anaemia and zidovudine use. Symptomatic hyperlactataemia was observed in 6% of patients in our cohort, as reported previously . Mitochondrial toxicity is related to the long-term use of nucleoside reverse transcriptase inhibitors (NRTI), and has been most frequently associated with stavudine and didanosine. Several studies have shown a significant pharmacokinetic interaction between RBV and didanosine. RVB increases didanosine phosphorylation, which increases didanosine exposure and leads to a higher risk of didanosine-related toxicities. In addition, RBV is a guanosine nucleoside analogue that can decrease the synthesis of mitochondrial DNA. For these reasons, the combination of RBV with different NRTI used as a part of HAART could increase the risk of symptomatic hyperlactataemia. Due to the high rate of non-specific symptoms and the lack of a predictive value of periodic lactate determinations, a high index of suspicion should guide its diagnosis. Recent data, however, have shown the usefulness of mitochondrial DNA level monitoring by real-time PCR in preventing lactic acidosis in HIV infected patients as a depletion in mitochondrial DNA precedes and is significantly associated with this severe adverse event [19,20]. Of note, both patients with lactic acidosis in our study were receiving stavudine (with didanosine in one). This observation makes necessary a careful monitoring of patients receiving HAART plus RBV. Stavudine and didanosine should be avoided whenever possible, specially the concomitant use of stavudine, didanosine and RBV. Treating HCV while the patient still does not need antiretroviral therapy, changes in the NRTI before starting HCV therapy, or even a transient HAART withdrawal if allowed by the immunological status could be alternative approaches to minimize toxicity.
Our study supports the value of EVR as a reliable predictor of SVR: it could allow treatment discontinuation in non-responders, with its associated benefit in terms of toxicity and health cost. Ten of 11 responders (91%) had an EVR. Thus, EVR yielded a positive predictive value of 90% and a negative predictive value of 83%. The predictive value of an EVR has been found in other studies, both in HCV monoinfected and in HCV/HIV co-infected patients [12,13,17]. In these studies, a 2 log10 decrease in HCV RNA at week 12 was considered the best cut-off to predict SVR.
Our results and conclusions may be limited by the low number of patients included in the study. However, this pilot study suggests that low doses of Peg-IFN and RBV do not preclude the development of adverse events at a rate that seems similar to that found in larger studies. The response rate is within the range of that observed in studies in the co-infected population with higher doses, in contrast with what has been demonstrated in clinical trials in HCV mono-infected patients [15,17]. This latter point clearly needs confirmation in a large clinical trial.
In conclusion, in HIV-HCV co-infected patients, the combination of low doses of Peg-IFN-α-2b (50 μg/week) plus a fixed dose of RBV (800 mg/day) resulted in a rate of SVR similar to that obtained in studies with higher doses of these drugs. The ultimate reason for the poorer outcome of treatment in HIV co-infected patients remains undetermined: it could be due to the immunological disturbances associated with HIV infection – even in patients with a good immunological status – or to drug interactions. This makes mandatory further investigations including new therapeutic approaches in this field.
This work was partially supported by a grant from Schering–Plough.
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Management of chronic hepatitis C in HIV-co-infected patients - Results from the first International Workshop on HIV and Hepatitis Co-infection 2nd-4th December 2004, Amsterdam, Netherlands
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Digestive Diseases and SciencesConsensus interferon and ribavirin in patients with chronic hepatitis c who were nonresponders to pegylated interferon alfa-2b and ribavirinDigestive Diseases and Sciences
Lancet Infectious Diseases
HIV and hepatitis C virus co-infection
Lancet Infectious Diseases, 4(7):
Current Opinion in Infectious DiseasesAdvances in chronic viral hepatitisCurrent Opinion in Infectious Diseases
Current Opinion in Infectious DiseasesNew paradigms in the management of HIV and hepatitis C virus coinfectionCurrent Opinion in Infectious Diseases
JAIDS Journal of Acquired Immune Deficiency SyndromesBaseline CD4 Cell Count and Outcome of Pegylated Interferon Plus Ribavirin Therapy in HIV/Hepatitis C Virus-Coinfected PatientsJAIDS Journal of Acquired Immune Deficiency Syndromes
JAIDS Journal of Acquired Immune Deficiency SyndromesIncidence and Risk Factors for Weight Loss During Dual HIV/Hepatitis C Virus TherapyJAIDS Journal of Acquired Immune Deficiency Syndromes
JAIDS Journal of Acquired Immune Deficiency SyndromesEffect of Treatment With Efavirenz on Neuropsychiatric Adverse Events of Interferon in HIV/HCV-Coinfected PatientsJAIDS Journal of Acquired Immune Deficiency Syndromes
Journal of Clinical GastroenterologyHepatitis C in HIV-positive Patients—Treatment and Liver Disease OutcomesJournal of Clinical Gastroenterology
The EndocrinologistHepatitis C Infection, Treatment Regimens, and Thyroid Function AbnormalitiesThe Endocrinologist
hepatitis C virus; HIV; Pegylated interferon; ribavirin
© 2004 Lippincott Williams & Wilkins, Inc.
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