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Rate and Timing of Hepatitis C Virus Relapse after a Successful Course of Pegylated Interferon plus Ribavirin

  1. José Medrano1,
  2. Pablo Barreiro1,
  3. Salvador Resino4,
  4. Paula Tuma1,
  5. Violeta Rodríguez1,
  6. Eugenia Vispo1,
  7. Pablo Labarga1,
  8. Antonio Madejón1,2,
  9. Javier García-Samaniego2,
  10. Inmaculada Jiménez-Nácher3,
  11. Luz Martín-Carbonero1, and
  12. Vincent Soriano1
  1. 1Department of Infectious Diseases, Madrid, Spain
  2. 2Service of Hepatology and CIBERehd, Madrid, Spain
  3. 3Service of Pharmacy, Hospital Carlos III, Madrid, Spain
  4. 4Laboratory of Molecular Epidemiology of Infectious Diseases, National Centre for Microbiology, Instituto de Salud Carlos III, Madrid, Spain
  1. Reprints or correspondence: Dr Vincent Soriano, Dept of Infectious Diseases, Hospital Carlos III, Calle Sinesio Delgado 10, 28029 Madrid, Spain (vsoriano{at}dragonet.es).
 
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Abstract

Information on the rate and timing of hepatitis C virus (HCV) relapse after treatment with pegylated interferon plus ribavirin is scarce. Among 604 patients treated for chronic hepatitis C, the 386 who were human immunodeficiency virus (HIV) positive attained an end-of-treatment response less frequently and experienced relapse more often than did the 218 who were HIV negative. However, episodes of HCV relapse occurred before week 12 in most cases, regardless of HIV status.

Treatment with pegylated interferon (peginterferon) plus ribavirin attains a sustained virological response (SVR) in nearly half of patients with chronic hepatitis C virus (HCV) infection. Viral genotype and comorbidities, such as human immunodeficiency virus (HIV) coinfection, are important determinants of response [1-5]. HCV eradication is presumed to occur in most patients attaining undetectable serum HCV RNA at the end of treatment (EOT) and remain negative for 24 weeks thereafter [6]. Patients with a sustained virological response normalize liver enzyme levels, improve liver histology [7, 8], and show minimal liver-related morbidity and mortality [9, 10]. The odds of HCV reappearance once a sustained virological response has been attained are very low [11, 12].

In HCV-monoinfected patients, relapses generally occur soon after discontinuation of successful therapy—within the first 12 weeks in 98% of cases in one study that used standard interferon [13]. Given that HIV coinfection is frequent in patients with chronic hepatitis C and that hypothetically HIV-associated immune abnormalities might impair definitive HCV clearance after hepatitis C therapy, we examined the rate and timing of HCV relapse in coinfected patients treated with peginterferon plus ribavirin. This information is particularly relevant now that clinical trials testing the efficacy of new hepatitis C drugs have begun, and there is pressure for changing definitions of treatment success to earlier time points after completion of therapy [14, 15].

Methods. We conducted a retrospective analysis of all patients with chronic hepatitis C who were interferon naive and who initiated treatment with peginterferon (alfa-2a or alfa-2b) plus oral ribavirin from 2001 through 2008 at a reference hospital in Madrid. Patients who were positive for hepatitis B surface antigen (HBsAg) were excluded. Criteria for indication of hepatitis C therapy were in accordance with international guidelines, both in HCV-monoinfected and HIV/HCV-coinfected patients [16, 17].

Only patients who attained a serum HCV RNA level <10 IU/mL at the planned EOT were analyzed. Standard doses of both peginterferon modalities were given. Oral ribavirin dosage was adjusted to weight (1000 mg/day if <75 kg and 1200 mg/day if ⩾75 kg). Treatment was administered for 48 weeks except in patients infected with HCV genotypes 2 or 3 experiencing rapid virological response (week 4 serum HCV RNA level, <10 IU/mL) since 2006, who were given treatment for only 24 weeks.

The main end points were the prevalence and timing of HCV RNA rebound in patients with an EOT response, determined on the basis of longitudinal assessments of serum HCV RNA level at weeks 12, 24, 36, and 48 after completion of hepatitis C therapy. Three types of HCV relapse were considered: (1) early, defined as an HCV RNA rebound occurring between the EOT and week 12; (2) late, defined an HCV RNA rebound occurring between weeks 12 and 24; and (3) very late, defined an HCV RNA rebound occurring beyond week 24.

To investigate the source of HCV RNA rebounds beyond week 24 after completion of therapy and to try to elucidate whether HCV recurrences or reinfections had occurred, phylogenetic trees were constructed in which viral sequences obtained at the time of last detectable viremia before or during therapy and at the time of first HCV RNA rebound after completion of therapy were compared. A fragment of the viral E1/E2 coding region was analyzed.

Results. A total of 616 patients with chronic hepatitis C had initiated treatment with peginterferon plus ribavirin during the 7-year study period. Twelve patients were excluded from further analyses because not enough follow-up had been completed. Of the remaining 604 patients, 386 (64%) were HIV positive, and 218 (36%) were HIV negative. Of this initial treated population, 329 patients (54.5%) experienced early virological failure or viral breakthrough during treatment, discontinued prematurely because of adverse effects, or were lost to follow-up before reaching the planned EOT. Overall, only 275 (45.5%) of the original treated population completed the planned duration of hepatitis C therapy and had undetectable serum HCV RNA, and these patients comprised the final population for our analysis. Of the patients, 76 (27.6%) experienced an HCV RNA rebound. The main characteristics of the patients who attained an EOT response are summarized in Table 1. The population was segregated into 132 HCV-monoinfected patients and 145 HIV/HCV-coinfected patients.

Figure 1
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Figure 1

Distribution of episodes of hepatitis C virus (HCV) relapse by HCV genotype (A ) and timing after end of treatment (B ), according to human immunodeficiency virus (HIV) status. Note that 9 patients were excluded from the analyses because of lack of information on HCV genotype or missed HCV RNA measurements between the end of treatment and week 24.

Table 1
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Table 1

Main Characteristics of the Study Population

The rate of EOT response was statistically significantly lower (37% vs 60.5%) and relapses more frequent (32.9% vs 22%) in coinfected than in HCV-monoinfected patients (Table 1). When the analysis of HCV relapses was stratified according to HCV genotype (Figure 1A), it becomes clear that HCV genotypes 1–4 relapsed more frequently overall than did HCV genotypes 2–3, particularly in HIV/HCV-coinfected patients (41.2% vs 12.5%; P=.001). On the other hand, HCV relapses in patients infected with HCV genotypes 1–4 occurred more often in HIV/HCV-coinfected patients than in HCV-monoinfected patients (41.2% vs 24.7%; P=.02). This difference was not observed for HCV genotypes 2–3.

The time of HCV RNA rebound could be examined in detail in 71 of 76 patients who experienced relapse (for 5 patients there was no result from week 12 after EOT, nor were there stored specimens for retrospective testing). In these patients, HCV relapse could be either early or late. For the rest, Table 2. Two occurred in HIV/HCV-coinfected patients, one carrying HCV-1b and another HCV-3a. The HCV-monoinfected individual was infected with HCV-1b. All 3 patients experienced relapsed beyond 24 weeks but before 1 year of completion of HCV therapy, and the same initial HCV genotype was found at the time of HCV RNA rebound. Significant genetic distances in the phylogenetic analysis were found for the 2 patients infected with HCV-1b (data not shown). In contrast, the HIV/HCV-coinfected patient with HCV-3a at both baseline and rebound showed closely related viral sequences.

Table 2
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Table 2

Main Characteristics of Patients with Very Late Hepatitis C Virus (HCV) RNA Rebound

Discussion. To our knowledge, this is the first study to address the rate and timing of HCV relapse in patients with chronic hepatitis C treated with peginterferon plus ribavirin by comparing HCV-monoinfected and HIV/HCV-coinfected patients. Two previous studies of HCV-monoinfected patients had examined the timing of HCV relapses and concluded that they were very rare beyond week 12 [13, 18]; however, patients in these studies had been treated with standard interferon, with or without ribavirin. The use of peginterferon has been shown to increase the chances of EOT response and to minimize HCV relapses [2]. On the other hand, prescription of weight-based ribavirin (avoiding lower ribavirin exposure) has also been associated with a lower rate of HCV relapse [19-22]. Thus, our study population is somewhat unique for exploration of the rate and timing of relapse using the currently recommended treatment for chronic hepatitis C.

In the present study, the overall rate of EOT response was significantly higher among HCV-monoinfected patients than among HIV/HCV-coinfected patients (60.5% vs 37%). On the other hand, HCV relapses occurred significantly more frequently in coinfected than in HCV-monoinfected individuals (32.9% vs 22%). All these observations occurred despite EOT responses and HCV relapses being more frequent in those infected with HCV genotypes 1–4 than with genotypes 2–3, and the later were significantly more prevalent in coinfected than in HCV-monoinfected patients.

The time of HCV relapse did not differ significantly between HCV-monoinfected and coinfected patients. Most patients who experienced relapse did so within the first 12 weeks after discontinuation of peginterferon plus ribavirin. This information is important in 2 ways. First, late HCV relapse does not seem to occur more frequently with the current therapy for hepatitis C than with standard interferon, with or without ribavirin [13, 18]. On the other hand, HIV coinfection does not seem to increase the risk of HCV relapse beyond week 12 after completion of hepatitis C therapy. In any situation, most HCV relapses occur within the first 12 weeks after discontinuation of therapy.

Recurrence of HCV replication beyond 24 weeks after treatment discontinuation was seen in 3 patients. Although there is some controversy as to the existence of HCV reservoirs, the lack of integration of HCV genetic material in any stable form within infected cells [23, 24] makes it very unlikely that such reservoirs explain late HCV relapses. Phylogenetic analyses suggested that HCV reinfection occurred in 2 patients infected with HCV-1b and that recurrence of the original HCV-3a infection might have occurred in the third subject between months 9 and 12 after treatment discontinuation. However, we cannot exclude the possibility that the latter patient could have been exposed again to the same source that caused her original infection. Several of her relatives (2 brothers and a husband) were former injection drug users. In a recent study of homosexual men infected with HIV who experienced acute hepatitis C and were successfully treated with peginterferon plus ribavirin [12], HCV recurrence beyond 24 weeks was observed in 8 subjects; in 6 of these subjects, phylogenetic analyses showed quite distant sequences and, therefore, supported the notion that HCV reinfections had occurred. However, in the remaining 2 subjects HCV sequences were closely related to the original ones, and exposure to the original source (rather than relapse) was the most likely explanation [25].

In summary, HCV relapse after successful peginterferon plus ribavirin therapy is more frequent in HIV/HCV-coinfected patients than in HCV-monoinfected patients. Regardless of HIV status, HCV relapse is more common in patients infected with HCV genotypes 1–4 than with genotypes 2–3 and almost always occurs within the first 12 weeks after discontinuation of treatment. Most HCV recurrences beyond week 24 are reinfections.

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Acknowledgments

Financial support. This work was funded in part by grants from Fundación Investigación y Educación en SIDA, Red de Investigación en SIDA (RETIC 006), and the European AIDS Treatment Network. S.R. was supported by grants from Fondo de Investigación Sanitaria (PI05/2411, PI07/90201, and PI08/0738), Instituto de Salud Carlos III (UIPY 1467/07), and Fundación Investigación y Prevención del SIDA en España (36650/07).

Potential conflicts of interest. All authors: no conflicts.

  • Received February 28, 2009.
  • Accepted May 27, 2009.
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  1. Clin Infect Dis. (2009) 49 (9): 1397-1401. doi: 10.1086/630205
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