Hepatitis C: Viral kinetics

HEPATOLOGY Vol. 26, No. 6, 1997 CORRESPONDENCE 1691 BURCKHARDT RINGE, M.D. Georg-August-Universität Göttingen Klinik für Transplantationschirurgie Göttingen, Germany clude a given patient from the only life-saving therapy if there is a chance of cure from a lethal disease? I do not believe that the answer to this question is an anonymous and imperfect statistical model. Hepatitis C: Viral Kinetics To the Editor: Lam et al. reported an exponential decline in viral load after one injection of interferon in hepatitis C, genotype 1 positive patients who were naive for interferon.1 A dosedependent relation was found with the maximal drop in viral load after one injection of 10 MU interferon. An exponential decline in viral load was described in the first 2 days after injection, followed by a decrease in the slope of viral decline after day 2. Based on these results, it was suggested that prolonged therapy with 10 MU would continue this rapid viral decline. We conducted a study in which we re-treated nonresponders with a previous standard dose of interferon. Patients received 10 MU of interferon daily for one week, followed by 10 MU thrice weekly, thereafter, until week 4. We collected the same early plasma samples as Lam et al., pre-treatment and after 24, 48, and 72 hours, as well as later samples after 2 and 4 weeks of treatment. Samples were tested with a sensitive, validated, quantitative polymerase chain reaction assay for hepatitis C virus RNA, detection limit between 102 to 103 copies/mL (Superquant, National Genetics Institute, Los Angeles, CA). We calculated the half-life and the production rate of the hepatitis C virus from the results of exponential decline, which was observed within the first days of treatment. To compare our data with those of Lam et al., we restricted our analysis to the six patients with genotype 1. During the first two days, a steep decline in viral load was observed similar to that reported by Lam et al.; however, the slope change after 2 days, which was attributed by Lam et al. to a weaning of the effect of the single dose of interferon, was also observed in 5 of 6 patients who were continued on treatment with daily high doses of interferon. The drop in viral load proved to have 2 phases: first an exponential rapid decline from day 1 to day 3 followed by a much slower second phase of viral decline from day 3 onward. The slope (a) of the viral decline can be used to calculate the half-life (T1/2 ) according to the equation: T1/2 Å a/log2. The mean half-life for these 6, genotype 1 patients was 6.7 hours for the initial phase (Fig. 1, T1/2 alpha), with a range between 2 and 13 hours. This was followed by a much slower elimination in 4 of 6 patients with a half-life of approximately 400 hours (Fig. 1, T1/2 beta) and a range between 244 and 573 hours. In 2 patients no half-life of the second phase (T1/2 beta) could be calculated; one patient had a very fast drop in viral load and became HCV RNA negative after 24 hours and had a sustained response, and one patient showed a very slight rise in viral load between day 2 and day 28. If we examine the observed drop in viral load, the decline cannot be described by a simple exponential model but fits into a second-order kinetic model, as for substances that are dissolved in 2 compartments with 2 different elimination rates. Based on the initial half-life of about 6.7 hours FIG. 1. Mean drop in hepatitis C viral load observed between day 0 and week 4 in 6 chronic hepatitis C patients, infected with genotype 1. Alpha slope: viral decline observed between days 0-2; and beta slope: viral decline observed between days 2 to 28. AID Hepa 0029 / 5p2a$$1081 11-21-97 11:20:20 (1) hepas WBS: Hepatology 1692 CORRESPONDENCE HEPATOLOGY December 1997 and on the average pre-treatment viral load of about 3.107 copies/mL, it can be calculated that if a viral load of õ1 copy/mL is to be reached, a high-dose induction treatment would be needed for at least 7 days. This means that we need at least 20 1 T1/2 alpha before we would reach hepatitis C virus RNA negativity based on the initial fastest decline. However, the prolongation of high dose interferon for up to 1 to 2 weeks is probably not the simple solution for patients who fail to reach very low viral levels (below 100-1,000 copies/mL) after the first 2 days of high-dose treatment because of the appreciable change in elimination rate. If we consider the much longer half-life of the hepatitis C virus observed after day 2, much longer treatment is needed to reach hepatitis C virus RNA–negativity. Based on the T1/2 beta of around 400 hours and on an average viral load of 20,000 copies/mL after the first 2 days of treatment, about 250 days of treatment are needed, equaling 15 1 T1/2 beta. Long-term treatment in combination with high-dose induction seems to be the best solution until the biology of viral clearance is better understood. FRANK C. BEKKERING, M.D. JOHANNES T. BROUWER, M.D. SOLKO W. SCHALM, M.D. Department of Hepatogastroenterology and Internal Medicine University Hospital Rotterdam, Dijkzigt Rotterdam, The Netherlands ANDRE ELEWAUT, M.D., PH.D. Department of Gastroenterology, University Hospital Gent, Belgium REFERENCES 1. Lam NP, Neumann AU, Gretch DR, Wiley TE, Perelson AS, Layden TJ. Dose-dependent acute clearance of hepatitis C genotype 1 virus with interferon alfa. HEPATOLOGY 1997;26:226-231. followed by lower dose (5 mU daily) of IFN for 6 months, we also observed biphasic HCV viral clearance kinetics similar to that shown by Bekkering et al. A full report of these results will be published elsewhere. We would also like to point out that some of the observations made by Bekkering et al. should be interpreted with some caution. Bekkering et al. did not measure the HCV RNA level at the end of the one week daily induction treatment; this may affect the calculated estimate of the half-life in the second phase of viral decline. As in recent work on HIV kinetics,4 Bekkering et al. attempted to estimate, based on the half-lives of the two phases, T1/2 alpha and T1/2 beta, respectively the duration of induction treatment and as well as the length of treatment to be continued after induction to lead to eradication of HCV. Although this could be an interesting and clinically relevant approach, the eradication of HCV is not a simple issue that is solely based on viral kinetics. Until the biological bases for the two phase decline in serum HCV concentrations are understood, it is difficult to deduce the treatment duration and doses needed for both induction and maintenance therapy. In our unpublished study of genotype 1 patients using high dose induction IFN treatment followed by prolonged lower dose maintenance IFN treatment,2,3 we found that despite significant pronounced reductions in serum viral loads during the initial rapid decline, in some patients there was no further significant viral clearance with continuation of treatment (¢6 months). The study of viral kinetics allows us to assess the interaction between IFN and HCV and to design more rational approaches to therapy. However, it must be appreciated that such interaction is complex and most likely involves multiple mechanisms including antiviral, as well as immunologic activities. More studies are needed to assess the implications of viral kinetics in the optimization of drug therapies in chronic hepatitis C. NANCY P. LAM, PHARM.D. University of Illinois at Chicago Chicago, IL Reply: Bekkering et al. confirm some of our previous findings on hepatitis C virus (HCV) kinetics during interferon (IFN) treatment.1 As we reported, HCV follows an exponential decline during the first 24 hours after IFN injection; the rate of decline is rapid for 24 hours after a dose of 10 mU of IFN; and the half-life of HCV estimated from the slope of viral decline in the initial phase of viral clearance is approximately 7 hours (6.7 hours in the study of Bekkering et al. and 7.2 hours in our study). In addition to the evaluation of viral decline within 24 hours after the first dose of 10 mU of IFN, Bekkering et al. continued the administration of daily IFN for 1 week followed by administration thrice weekly until week 4. They noted that the viral decline was much slower after the first two days and suggested that there were two phases of HCV clearance: a first phase characterized by a rapid exponential decline followed by a much slower second phase. The mathematical model that we presented in Lam et al.1 predicts that two-phase decline. Further, in our recent study2,3 using various two-week high induction doses (5-15 mU daily) of IFN AID Hepa 0029 / 5p2a$$1021 11-21-97 11:20:20 AVIDAN U. NEUMANN, PH.D. Bar-Ilan University Israel ALAN S. PERELSON, PH.D. Los Alamos National Laboratory Los Alamos, NM THOMAS J. LAYDEN, M.D. University of Illinois at Chicago Chicago, IL REFERENCES 1. Lam NP, Neumann AU, Gretch DR, Wiley TE, Perelson AS, Layden TJ. Dose-dependent acute clearance of hepatitis C genotype 1 virus with interferon alfa. HEPATOLOGY 1997;26:226-231. 2. Lam NP, Neumann AU, Gretch DR, Wiley TE, Falkenholm J, Perelson AS, Layden TJ. Genotype 1A and 1B infected patients (pt) require high initial daily interferon (IFN) doses [Abstract]. Gastroenterology 1997; 112(suppl 4):1312A. 3. Lam NP, Neumann AU, Gretch DR, Wiley TE, Perelson AS, Layden hepas WBS: Hepatology HEPATOLOGY Vol. 26, No. 6, 1997 CORRESPONDENCE TJ. Rapid HCV clearance with high induction interferon (IFN) doses is important for sustained response [Abstract]. Gastroenterology 1997; 112(suppl 4):1312A. 1693 4. Perelson AS, Essunger P, Cao Y, Vesanen M, Hurley A, Saksela K, Markowitz M, et al. Decay characteristics of HIV-1 infected compartments during combination therapy. Nature 1997;387:188-191. Prevention of Variceal Bleeding With Band Ligation To the Editor: We read with interest the recent paper by Lay et al.1 The authors should be congratulated for having been able to select a group of patients with an extremely high risk of first bleeding by means of Beppu’s2 score. This, however, contrasts with the prospective validation of Beppu’s score that we made in the North-Italian Endoscopic Club study,3 because in that study patients with a Beppu’s score of 00.38 or lower had a 2-year incidence of bleeding of 41%, which is much lower than the figure of 60% reported by Lay et al. Moreover, in our series, patients with such values of Beppu’s score represented only 15% of the whole series, as compared with 30% in the series presented by Lay et al. As it has been shown that the higher the bleeding rate in the control group, the higher will be the efficacy of prophylactic treatment,4 it is not surprising that variceal band ligation was also very effective in preventing first bleeding in the study by Lay et al. In such conditions, endoscopic sclerotherapy was also very effective.5 However, the possibility exists for banding, as it does for sclerotherapy, that further studies might be less fortunate in selecting very-high-risk patients. Under such circumstances, the value of band ligation remains to be established. Another important point concerns the handling of patients in the control group. In the study by Lay et al., such patients ‘were randomly allocated . . . to the control group’. The only other information that we have about the follow-up of these patients is in the Results section, where the authors state, ‘‘the follow-up was indeed different in the two groups’’ and then continue, ‘‘the follow-up, including endoscopic treatment (?) had been the same . . .’’. It is not clear how many endoscopies were carried out in the control patients and in patients in the active treatment group. Even more importantly, it has now been confirmed that medical therapy with non-selective beta-blockers is very effective in preventing the first variceal bleed in cirrhotics.4 In one meta-analysis6 beta-blockers were also shown to reduce bleeding-related mortality. Accordingly, three International Consensus Conferences,7-8 including the recent AASLD Single Topic Symposium on Portal Hypertension and Variceal Bleeding (Reston, VA, June 23-24,1996) concluded that beta-blockers are the first choice treatment in the prevention of first bleeding in cirrhosis. In view of this, the ethical appropriateness of comparing a new treatment, such as banding, with ‘no treatment’ is highly AID Hepa 0029 / 5p2a$$1041 11-21-97 11:20:20 questionable. A comparison between banding and beta-blockers would have been mandatory. The authors do state in the discussion that, although they had considered using betablockers in the control patients, ‘‘they did not have enough patients to proceed with such a study’’. This is hardly a justification. The authors do not indicate how they calculated the sample size of the study, and, therefore, we do not know the ‘a priori’ hypothesis they made about the rate of bleeding in the control group and the expected therapeutic gain in the banding group. Even if they had admitted that such calculation had been made and if they had shown that a number of patients larger than that available to the authors was needed to appropriately compare banding with beta-blockers, this would not constitute an ethical justification for the authors to perform a study comparing banding to nothing. Instead, a multicenter design should have been considered to collect enough patients to perform the appropriate study, i.e., a comparison between banding and beta-blockers. ROBERTO DE FRANCHIS, M.D. MASSIMO PRIMIGNANI, M.D. Gastroenterology and Gastrointestinal Endoscopy Service Institute of Internal Medicine University of Milan Milan, Italy REFERENCES 1. Lay CS, Tsai YT, Teg CY, et al. Endoscopic variceal ligation in prophylaxis of first variceal bleeding in cirrhotic patients with high-risk esophageal patients. HEPATOLOGY 1997;25:1346-1350. 2. Beppu K, Inokuch K, Koyanagi N, et al. Prediction of variceal hemorrhage by esophageal endoscopy. Gastro Endoscopy 1981;27:213-218. 3. North Italian Endoscopic Club for the study and treatment of esophageal varices. Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. N Engl J Med 1988;319:983-989. 4. Pagliaro L, D’Amico G, Soerensen TIA, et al. Prevention of first bleeding in cirrhosis. A meta-analysis of randomized clinical trials of nonsurgical treatment. Ann Intern Med 1992;117:59-70. 5. Paquet KJ. Prophylactic endoscopic sclerosing treatment of the esophageal wall in varices: a prospective controlled randomized trial. Endoscopy 1982;14:4-5. 6. Poynard T, Calès P, Pasta L, et al. b-adrenergic-antagonists in the prevention of first gastrointestinal bleeding in patients with cirrhosis and esophageal varices. An analysis of data and prognostic factors in 589 patients from four randomized clinical trials. N Eng J Med 1991;324:1532-1538. 7. de Franchis R, Pascal JP, Ancona E, et al. Definitions, methodology and therapeutic strategies in Portal Hypertension. A consensus development workshop. J Hepatol 1992;15:256-261. 8. de Franchis R. Developing consensus in Portal Hypertension. J Hepatol 1996;25:390-394 hepas WBS: Hepatology