LETTER TO THE EDITOR Spontaneous clearance of hepatitis C virus after long-term opiate dependence therapy with buprenorphine E. Brunelle, 1 S. Ledru, 2 M. Rotily, 3 C. Becker, 4 T. Davion, 4 V. Vosgien, 1 M. Martinot 5 and P. Halfon 6 1 Centre de Traitement des De ´pendances Le Square, Lens; 2 Bacteriology and Virology Unit, Hospital Center of Lens, Lens; 3 ClinSearch, Bagneux; 4 Hepato-Gastroenterology Unit, Hospital Center of Lens, Lens; 5 INSERM U 481, Beaujon Hospital, Clichy; and 6 Alphabio Laboratory, Marseille, France Abbreviations: HCV, hepatitis C virus; IDU, injecting drug user; PCR, polymerase chain reaction; TMA, transcription- mediated amplification assay. Correspondence: Emmanuel Brunelle, Centre de Traitement des De ´pendances Le Square, 31 rue Souvraz, 62307 LENS cedex, France. E-mail: emmanuel.brunelle@wanadoo.fr Dear Sir, Spontaneous hepatitis C virus (HCV) clearance is known to occur in at least 15% of the cases within the first months after infection [1,2]. Although the reasons are unclear, several have been proposed: younger age, female sex, source of infection, size of inoculum, a number of co-factors (hepatitis B virus infection, alcohol abuse and immune status), and certain major histocompatibility complex genes. The virus is known to clear within the first months after infection [1,2]. To our knowledge, no reports exist of virus clearance in patients with chronic infection. We document here a case of spontaneous HCV clearance several years after infection. A 28-year-old male injecting drug user (IDU) was under follow-up in our drug agency since 1995 (Table 1). HCV enzyme immunoassay became positive in November 1995. Viral genotype 1a was confirmed twice. There was no co-infection with human immunodeficiency virus, and he was vaccinated against hepatitis B. The patient stopped psychoactive drug and alcohol abuse, and started opiate addiction therapy with sublingual buprenorphine in March 1996. Liver biopsy and/or antiviral therapy were never required since no signs or clinical symptoms developed and liver echography and serum alanine transaminase levels remained normal (<30 IU/mL). HCV RNA levels were 97 077 copies per millilitre when first measured in March 1999 by quantitative polymerase chain reaction (PCR; Amplicor, Roche, Meylan, France). The patient started misusing buprenorphine intravenously during the first half of the year 2000. RNA levels were still elevated (98 200 IU/mL) in April 2001, then dropped to 1200 IU/mL in May 2002. There was little liver fibrosis and no liver activity, as measured retrospectively by the surro- gate biochemical markers FibroTestÒ and ActiTestÒ [3,4]. In August 2002, PCR was negative (threshold 50 IU/mL) and retrospective transcription-mediated amplification assay (TMA; Bayer, Paris, France) [5] evidenced a viral load of 20 IU HCV RNA per millilitre. In September 2002, whilst the patient declared that he did not abuse opiates anymore, the viral load as assessed by PCR rose to 307 IU/mL (significant 1 ) log 10 increase). Six weeks after sublingual buprenorphine reintroduction at his request (December 2002), HCV RNA became again unde- tectable by PCR, and also by TMA (threshold 5–10 IU/mL). Viral clearance was confirmed by PCR in February 2003. FibroTestÒ and ActiTestÒ scores showed no liver fibrosis or activity. Our previous and present findings suggest that drug maintenance with high-dose buprenorphine in opiate- dependent patients could help to clear HCV spontaneously. Obviously a coincident factor cannot be ruled out. Never- theless, during chronic infection RNA levels are known to be stable [1] or with low (<0.5 log 10 ) fluctuations [6]. This individual may still have an ongoing infection undetectable in serum that may still be detectable in liver. The serum PCR status has however, been shown to reflect truly a cleared past infection as assessed by the liver biopsy PCR status [7]. Furthermore, a HCV prevalence lower than that usually observed in IDUs was recently reported in 460 opiate- dependent persons in our drug agency [8]. Interestingly HCV RNA levels were undetectable (<50 IU/mL) in 75% of the seropositive patients, who were all naive to any treatment. Our experience may provide further accumulating evi- dence that HCV is cleared through mechanisms involving the immune system. In the present case, repeated exposure to genotype 1a through the needle and syringe during buprenorphine misuse might have led to immune system stimulation. An important role of immune host factors has been demonstrated in an Irish cohort of women with chronic HCV, in whom acute icteric hepatitis and the HLA DRB1*01 allele were associated with viral clearance [7,9]. Vertically infected HCV infants also had the ability to spontaneously clear the virus [10]. Moreover, when chimpanzees had been previously infected or vaccinated, viral persistence and severity of subsequent HCV infection were diminished [11]. IDUs previously infected with HCV were half as likely to develop new viraemia than those with previous infection, and the authors suggested that human beings can also acquire immunity, which protects against HCV persistence [12]. A transient loss of T-cell reactivity was reported in a Journal of Viral Hepatitis, 2004, 11, 571–573 Ó 2004 Blackwell Publishing Ltd