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Efficacy of early treatment of acute hepatitis C infection with pegylated interferon and ribavirin in HIV-infected patients
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"....In the intent-to-treat analysis, 10/14 patients (71%) had sustained virological responses (at week 48).... we opted to begin treatment no earlier than 12 weeks after diagnosis in order to avoid treating patients who might spontaneously clear the virus..."
AIDS: Volume 20(8) 12 May 2006 p 1157-1161
Dominguez, Stephaniea; Ghosn, Jadea; Valantin, Marc-Antoinea; Schruniger, Aureliec; Simon, Anned; Bonnard, Philippee; Caumes, Erica; Pialoux, Gillese; Benhamou, Yvesb; Thibault, Vincentc; Katlama, Christinea
From the aDepartment of Infectious and Tropical Diseases/INSERM U 720, France.
bHepatogastroenterology Service, France.
cVirology Laboratory, France.
dDepartment of Internal Medicine, CHU Pitie-Salpetriere, France.
eDepartment of Infectious and Tropical Diseases, CHU Tenon, Paris, France.
Introduction
The incidence of syphilis and gonorrhoea is increasing in Europe [1], reflecting a decline in safer sexual practices. Likewise, the incidence of infection with hepatitis C virus (HCV) among HIV-infected homosexual men is increasing in France [2,3], Germany, the UK and the Netherlands [4-6]. Recent data suggest that sustained virological responses are more frequent when treatment is started in the acute phase of HCV infection [7-9], but it is not known whether this also applies to patients who are coinfected by HIV.
Progression of HCV infection towards fibrosis and cirrhosis is less rapid in patients infected by HCV alone than in HIV-coinfected patients, about 80% of whom develop chronic HCV infection [10-15]. Moreover, the response to combined anti-HCV treatment with pegylated interferon (PegIFN) and ribavirin is less favourable in HIV-coinfected patients [16-18]. Recent European guidelines recommend that acute HCV infection in HIV-seronegative patients should be treated with PegIFN monotherapy, starting less than 6 months after HCV seroconversion [19].
Given the poorer outcome of untreated HCV infection in HIV-infected patients, together with their lower frequency of spontaneous HCV RNA clearance [11] and poorer virological response to anti-HCV combination therapy [16,17], the prospective pilot study described here examined early treatment of HCV infection based on pegylated interferon alfa 2a (PegIFNa2a) and ribavirin in HIV-infected patients. Results are available for sustained treatment response (after 48 weeks) for 14 patients who have completed the programme; five patients are still within the programme.
Abstract
Background: Treatment of acute hepatitis C (HCV) in HIV-infected patients has been poorly addressed.
Objective: To evaluate the efficacy and tolerability of a 24 week course of pegylated interferon alfa 2a (PegIFNa2a) and ribavirin for the treatment of acute HCV infection in HIV-infected patients.
Methods: This was a prospective pilot study of 25 consecutive HIV-infected men with acute HCV infection defined by documented HCV seroconversion to anti-HCV positive antibody and positive qualitative HCV RNA measurement. Patients with detectable HCV RNA (> 50 IU/ml) 12 weeks after diagnosis were offered treatment with PegIFNa2a (180 mg/week) and ribavirin (800 mg/day) for 24 weeks. Sustained virological response was defined by a negative qualitative HCV RNA measurement 24 weeks after the end of treatment.
Results: At baseline, 23 patients were taking HAART, 23 patients had HIV RNA < 200 copies/ml and a median CD4 count of 345 cells/ml. Only one patient, with genotype 3 HCV, had a spontaneous clearance of HCV RNA. Of the remaining 24 patients, four refused anti-HCV therapy, ribavirin was contraindicated in one and 19 initiated anti-HCV therapy. Median time between acute HCV diagnosis and initiation of study treatment was 14 weeks. Of the 14 patients who have achieved the post-treatment follow-up at 24 weeks, 10 had a sustained virological response (71%). Study treatment was well tolerated, with no change in CD4 cell count.
The study reported genotype on 14 patients: 3 had 1a; 1 patient had 1a+4; 4 had 3a; 1 had 3; 3 had genotype 4; 2 patients had 4d.
Conclusion: Early treatment of acute HCV infection with PegIFNa2a and ribavirin for 24 weeks yields a high sustained virological response rate in HIV-infected patients.
Results-Virological response to pegylated interferon and ribavirin
The baseline characteristics of the 14 patients who have completed the study are shown in Table 2, along with changes in HCV RNA levels between baseline and week 48. At the diagnosis of acute HCV infection, median plasma HCV RNA level was 6.04 log10 IU/ml (range, 4.65-6.64), and the median alanine aminotransferase was 86 IU/l (range, 21-1152). All but one of the 14 patients were receiving HAART. The median plasma HIV RNA was < 200 copies/ml (range, 200-181 000) and the median CD4 cell count was 345 cells/ml (range, 230-1071).
The median time between diagnosis of acute HCV infection and specific treatment initiation was 14 weeks (range, 3-24). Two patients started treatment before week 12 because of rapidly rising HCV RNA levels. Five patients chose to postpone anti-HCV therapy. One patient was lost to follow-up 3 weeks after treatment initiation.
In the intent-to-treat analysis, 10/14 patients (71%) had sustained virological responses (at week 48). Plasma HCV RNA was undetectable in 12 patients (85%) at week 12 and in 11 patients (79%) at week 24. All patients who were HCV RNA negative at week 12 had a sustained virological response, with the exception of patient 3, for whom HCV RNA was below the lower limit of quantification at weeks 12, 24 and 36, but not at week 48. Syphilis was also diagnosed in this patient at week 48, suggesting possible HCV reinfection; this was confirmed by phylogenetic analysis (data not shown). Two patients who did not have a sustained virological response were infected by HCV genotype 4 and one patient by genotype 1. All patients with genotype 3 HCV infection had an sustained virological response. There was no association between sustained virological response and the delay between acute HCV diagnosis and initiation of study treatment. The median alanine aminotransferase value tended towards normal at week 24 (Table 2).
Discussion
This small pilot study shows the excellent efficacy of PegIFNa2a/ribavirin combination therapy on acute HCV infection in HIV-infected patients, with a sustained virological response rate of 71% in the intent-to-treat analysis and 79% in the on-treatment analysis.
In other studies of HIV-infected patients with acute HCV infection, Serpaggi et al. [22] and Danta et al. [23] found that monotherapy with standard or PegIFN yielded a sustained virological response rate of 0-10%, while Vogel et al. [4] found no advantage of adding ribavirin to PegIFN. However, in this last study, it should be noted that most sustained virological responses (9/11) were obtained in patients who had symptomatic acute HCV infection - a proportion far higher than generally observed [24,25] - and that approximately 50% of patients with symptomatic infection spontaneously clear HCV [7]. Treatment efficacy might also have been overestimated in this last study because treatment was started very early (2.6 weeks) after diagnosis of acute HCV infection. Indeed, spontaneous clearance usually occurs within 16 weeks of diagnosis [25,27,28]. In contrast, we opted to begin treatment no earlier than 12 weeks after diagnosis in order to avoid treating patients who might spontaneously clear the virus [24,26,27]. In a recent study of Gilleece et al. [28] reported that combination therapy with pegIFN and ribavirin was not more effective when initiated 12 weeks after diagnosis of acute HCV infection than when started during the chronic phase of infection. The higher rate of sustained response obtained in our study might partly be explained by the fact that only 28% of our patients were infected by HCV genotype 1, compared with 74% of patients in the study by Gilleece et al.
The frequency of genotype 4 HCV infection was unusually high in our study population [29]. Genotype 4 viruses infecting seven of our patients clustered together and were distinct from other genotype 4 strains circulating in France (data not shown), strongly suggesting a common source of infection. Serpaggi et al. [22] have reported similar findings, pointing to sexual transmission of HCV genotype 4 in the Paris area of France. The only identified risk factor for HCV infection in our patients was at-risk sexual behaviour, tending to confirm the decline in safer sexual practices among HIV-infected homosexual men observed in other European countries [5,6] and supporting a call for targeted prevention campaigns.
In conclusion, treatment of acute HCV infection in HIV-coinfectedpatients with PegIFNa2a (180 mg/week) and ribavirin (800 mg/day) for 24 weeks yielded a high rate (71%) of sustained virological response in our 14 patients. If confirmed in a larger population, these promising results would justify early diagnosis and treatment of acute HCV infection among HIV-infected patients in order both to avoid progression to chronicity and to reduce the risk of HCV transmission.
Note: These results were presented at the 10th EACS Conference, November 2005, Dublin, Ireland.
Results
Baseline characteristics of the patients
The study enrolled 25 HIV-infected men who were diagnosed consecutively with acute HCV infection between January 2002 and January 2005. None of the patients originated from Africa or the Middle East. Seven patients (28%) were tested for HCV infection because they had clinical signs, while the remaining 18 patients were tested following a rise in liver enzyme activity during routine follow-up of HIV infection.
None of the 25 patients had classical risk factors for HCV infection. The only identified risk factor was unprotected anal intercourse in 24 patients of these patients and bleeding during sex for some of these. Seven patients were diagnosed with syphilis concomitantly with acute HCV infection.
HCV infection resolved spontaneously in only one patient, 3 weeks after diagnosis. Ribavirin was contraindicated in one patient (for haemolytic anaemia) and four patients refused the study treatment. The remaining 19 patients started treatment with PegIFNa2a and ribavirin. Given the encouraging high sustained virological response rate (Table 1), the results for the first 14 patients to complete 24 weeks of post-treatment follow-up are reported here. Treatment is ongoing in the remaining five patients.
Tolerability of therapy
Overall, anti-HCV treatment was well tolerated. No dose adjustments were required. One patient was lost to follow-up after 3 weeks of treatment because of psychiatric disorders, probably caused by interferon. No cellular growth factors were required. One patient was prescribed venlafaxine for depression between week 4 and week 24 of treatment. His CD4 cell count fell slightly between baseline and week 24 (Table 2), while his HIV RNA level remained stable.
Methods
Study design
HIV-infected patients with acute HCV infection were eligible for this prospective pilot study. They were first monitored for 12 weeks after diagnosis of HCV infection; patients who did not spontaneously clear HCV were offered a 24 week course of PegIFNa2a plus ribavirin. Sustained virological response was determined 24 weeks after the end of treatment.
Consecutive HIV-infected patients managed in two clinical units were enrolled at the diagnosis of acute HCV infection. All patients who had an unexplained increase in liver enzyme activities (> 3X upper limit of normal) during routine monitoring of HIV infection, and all patients with clinical signs of acute hepatitis (arthralgia, jaundice, severe fatigue, urine and stool discolouration), were screened for HCV infection.
Acute HCV infection was diagnosed on the basis of either documented seroconversion during a period shorter than 6 months (Monolisa Anti-HCV Plus v2, Biorad, Marnes la Coquette, France) or HCV RNA positivity by polymerase chain reaction (PCR) (Cobas Amplicor HCV version 2.0, detection limit 50 IU/ml, Roche, Meylan, France) and a negative PCR result on a stored plasma sample collected less than 6 months previously.
At enrollment, patients were questioned on their sexual behaviour and other classical risk factors for HCV infection and were screened for sexually transmitted diseases.
Virological assessments
The HCV genotype was determined by direct sequencing of the NS5B coding region, followed by phylogenetic analysis based on Genbank reference sequences [20].
To estimate the date of HCV infection, stored plasma samples obtained less than 12 months before diagnosis were screened for anti-HCV antibodies and HCV RNA.
Follow-up took place in two phases. The first phase of 12 weeks consisted of monthly clinical examinations, liver function tests, CD4 cell counts and qualitative and quantitative HCV RNA assay. Patients who did not spontaneously clear HCV RNA during this observation period were offered 6 months of specific treatment with PegIFNa2a (180 mg/week) and ribavirin (800 mg/day), followed by a 24 week follow-up period. Ongoing antiretroviral therapy was maintained, but zidovudine and didanosine were replaced by other nucleoside reverse transcriptase inhibitors. The patients were seen every 4 weeks during the treatment period, and then every 3 months until week 48.
Phylogenetic analysis
The NS5b gene sequences were aligned with Clustal W 1.6 software. NS5b sequences from ten subjects from the surrounding community were also studied. Pairwise evolutionary distances were estimated with DNADist software, using Kimura's two-parameter method, then phylogenetic trees were constructed by a neighbour-joining method (implemented in the Phylip package) [21]. The reliability of each tree topology was estimated from 100 bootstrap replicates.
Study endpoints
The primary endpoint was the proportion of patients who had a sustained virological response at week 48, after 24 weeks off therapy, defined as no detection of HCV RNA in plasma by PCR (Cobas Amplicor HCV version 2.0).
Secondary endpoints were the proportion of patients with undetectable HCV RNA at week 24 (at the end of the therapy period); changes in measured liver enzyme abnormalities, CD4 cell count and HIV viral load from baseline to week 48; and treatment tolerability. Both intent-to-treat and on-treatment analyses were performed.
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