Combination Therapy Arrives for Hepatitis C

Combination Therapy Arrives for Hepatitis C

by David W. Sharp

WHAT'S HOT IN MEDICINE...

Rank	Paper	Citations This Period Mar- Apr 00	Rank Last Period Jan- Feb 00
1	B. Fisher, et al., "Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 study," J. Natl. Cancer Inst., 90(18):1371-88, 16 September 1998. [10 U.S. and Canadian institutions] *120NT	48	4
2	L. Hansson, et al., "Effects of intensive blood-pressure- lowering and low-dose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatment (HOT) randomised trial," The Lancet, 351(9118):1755-62, 13 June 1998. [10 institutions worldwide] *ZU444	46	2
3	F.O. Nestle, et al., "Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells," Nature Medicine, 4(3):328-32, March 1998. [U. Zurich Med. Sch., Switzerland; U. Heidelberg, Germany; U. Munstervon, Munster, Germany] *ZN163	43	5
4	S. Hulley, et al., "Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women," JAMA-J. Amer. Med. Assoc., 280(7):605-13, 19 August 1998. [U. Calif., San Francisco; Johns Hopkins U., Baltimore, MD; Wake Forest U. Sch. Med., Winston-Salem, NC; Wyeth-Ayerst Res., Radnor, PA] *110ME	42	1
5	J.G. McHutchinson, et al., "Interferon alpha-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C," New Engl. J. Med., 339(21):1485-92, 19 November 1998. [8 U.S. institutions] *139VT	41	8
6	F.J. Palella, et al., "Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection," New Engl. J. Med., 338(13):853-60, 26 March 1998. [5 U.S. institutions] *ZD284	39	3
7	J.R. Downs, et al., "Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. Results of AFCAPS/TexCAPS," JAMA-J. Amer. Med. Assoc., 279(20):1615-22, 27 May 1998. [7 U.S. institutions] *ZP489	39	6
8	S.A. Rosenberg, et al., "Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma," Nature Medicine, 4(3):321-7, March 1998. [NCI, NIH, Bethesda, MD] *ZN163	37	9
9	T. Poynard, et al., "Randomised trial of interferon a2b ribavirin for 48 weeks or for 24 weeks versus interferon a2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus," The Lancet, 352(9138):1426-32, 31 October 1998. [11 institutions worldwide] *134AJ	34	†
10	G.L. Davis, et al., "Interferon a2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis c," New Engl. J. Med., 339(21):1493-9, 19 November 1998. [10 institutions worldwide] *139VT	29	†

SOURCE: ISI's Hot Papers Database NB. Read the full legend.

epatitis C virus used to be referred to as non-A, non-B; everyone knew there was at least one other major hepatitis virus out there but for a long time all that could be said for sure about it was that it was not type A or type B. For both these long-recognized causes of viral hepatitis vaccines are available, but there is nothing yet for hepatitis C. It is possible to be infected with hepatitis C virus (HCV) yet have no symptoms, but with long-term infection the risk is progression to chronic liver disease, including severe liver damage (cirrhosis) and even liver cancer. Anyone tempted to underplay the importance of this virus in the western world will be brought up short by a recent estimate that, with improvements in the treatment of AIDS, HCV may soon be killing more people in the United States than HIV does. The burden worldwide is significant, with estimates of 100-170 million people infected with HCV.

In the early 1990s a treatment emerged–namely, the cytokine interferon. Helpful but not perfect. Ribavirin is an antiviral agent but when it was tried in hepatitis C it had no effect on circulating levels of HCV but it was associated with a fall in the serum activity of transaminase, a marker for liver damage. Trying a combination of the two agents was the next step, and in a paper published in October, 1998 (paper #9), and another published in the following month (#10) came the first strong evidence from clinical trials that combining interferon alfa-2b with ribavirin was a useful advance.

The two trials differed in that one was done in patients who had not had either drug before (#9) while in the other (#10) the patients had relapsed after interferon therapy.

Science Watch contacted Thierry Poynard, from Paris, France, the lead author on paper #9, not so much to find out why these papers should be "hot"–obvious, perhaps, since the combination "was able to double the percentage of sustained response among HCV-infected patients (from 20% to 40%)"–but to ask what has happened since.

There is good news from the follow-up, says Poynard. "Less than 2% of patients have a late relapse, and we can speak now [with caution, he adds] of cure." Back in 1998 one pilot study had already pointed the way and all studies since the two seminal trials have confirmed the results. There is a problem with tolerance of therapy since one-fifth of patients stop or reduce the treatment, Poynard admits, but therapy can be tailored to the individual.

Where next? We still do not know how this combination of drugs works but a new form of interferon that has been "pegylated" (PEG = polyethyleneglycol) shows promise, and Poynard reckons that combining this with ribavirin might yield a further10% improvement. No major clinical trials have yet been completed with the emerging specific anti-HCV drugs. However, if the fibrotic process that hits the liver so hard can be slowed–and maybe that is how the interferon makes its contribution or how interleukin-10, another cytokine, might in future–perhaps patients currently labelled non-responders at a virological level can buy time to wait for specific agents.

The solid confirmation of these papers already means that in Dr. Poynard's liver clinic the "atmosphere of our consultations has changed a lot in these last years."

Mr. David W. Sharp, MA (Cambridge) is Deputy Editor of The Lancet, London, U.K.