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New HCV drugs, new ultrasensitive HCV viral load test, preliminary data on pegylated interferon in HCV/HIV coinfected patients, response to pegylated interferon in previous non-responders to Rebetron
Written by Jules Levin
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I just arrived in Dallas yesterday for this annual leading conference which runs from Nov through Nov 13. This is a preliminary report prior to the start of the conference. Last night I went out for ribs at Bone Daddies. Which I was told is one of the best rib joints in Dallas. The ribs were very good. My goal is to try a different rib place each night so I can become a rib expert and know where the best ribs in Dallas can be found. I may not die of HIV or HCV but after eating all these ribs I'll get heart disease.
Non-Responders to Rebetron
There are several study reports here following up on initial data reported at DDW in the Spring on patients who previously failed Rebetron (IFN+RBV) but are responding to pegylated interferon+ribavirin. The data is preliminary but it appears as though a 25% (SVR) to 40% response rate (negative PCR) is being seen so far. This is based on a small percentage of individuals in the studies.
Pegasys in HCV/HIV Coinfection
Roche will present the first data on pegylated interferon+ribavirin in HCV/HIV coinfected patients. The study results being presented are preliminary but will give the first glimpse at treating HCV/HIV coinfected patients. Up until now we have only seen small studies. These recently conducted studies suggest coinfected patients can respond similarly as patients with HCV alone to HCV therapy. In HIV, the results of studies are not always duplicated in clinical practice. Adherence and other factors become more relevant. In coinfection, the prevalence of genotype 1and HCV viral load may be factors, as well as simultaneous treatment with HAART.
New HCV Drugs
There are several presentations here on early studies for new treatments for HCV. An intro study of a helicase inhibitor appears interesting. ISIS 14803 is an antisense inhibitor of HCV. Preliminary data in a small study of HCV-infected patients shows decreases in HCV-RNA of greater than 1 log. Transient ALT flares (>10x ULN)occurred for some patients although the presenters said biopsies did not show druginduced hepatotoxicity. The flares were reported in the abstract book not to be associated with changes in albumin, bilirubin, nor prothrombin time values. Unfortunat;y, this dru is administered by subcutaneous injection twice weekly. A study in HCV-infected patients is starting up now. In NYC, Ira Jacobson, MD, Cornell, is a site.
Heptazyme is a ribozyme designed to attach itself to a conserved portion of the HCV genome. It issupposed to be able to prevent HCV reproduction. An early study on safety and tolerability presented here encouraging. Heptazyme is also administered by a weekly subcutaneous injection. A small study of Heptazyme + Infergen interferon in treatment-naive patients is starting now. In NYC, Ira Jacobson, MD, Cornell is a site.
EPO for Low Hemoglobin
EPO can be used by patients who experience anemia (low hemoglobin) during HCV therapy. A study was presented by Doug Dieterich at DDW 2001 showing EPO can raise hemoglobin in patients who had 11.7 hemoglobin during HCV therapy. A concern that has been raised is that some doctors have reservations about using EPO unless hemoglobin reaches 10. Why? The long-term effect of EPO on bone marrow is not known. It is possible that undesirable effects could occur. Thus, they feel that unless hemoglobin is low (10) they have reservations about using it. It is my understanding that some patients are using EPO before starting HCV therapy or before hemoglobin reaches low levels. EPO has not been studied as far as I know in such a preventative fashion such as before HCV therapy has started or shortly thereafter. As well, there have not been long-term safety data on use of EPO in this way.
New Ultrasensitive HCV Viral Load Test
Previously, it's been reported that using a new ultrasensitive HCV viral load test (TMA) may identify which patients may relapse following HCV therapy. Bear in mind this new test is not FDA approved yet. Preliminary research suggests that some patients who may have undetectable HCV viral load using the standard ultrasensitive HCV viral load test (NGI, <100 IU or copies) may not have undetectable HCV viral load if using the TMA test which measures to as low as 5 IU/mL (50 copies/mL). It was previously reported (Sarrazin, Hepatology 2000; 32:818-823) at a prior conference that 50% of patients who were undetectable at the end-of-treatment using PCR (amplicor 2.0) had detectable virus at the end-of-treatment using the more sensitive TMA test from Bayer (measures to 5 IU/mL). The important clinical implication is that if you finish 12 months therapy with interferon+ribavirin and have undetectable HCV by the standard test currently used (<100 IU or copies), you may still have detectable HCV using the potentially more sensitive test. If you still have virus present you may be more likely to relapse. If a patient has detectable HCV using the TMA 5 copy test they may want to continue treatment for a total of 18 months. Patients who failed prior therapy with Rebetron and are now responding well with undetectable viral load due to treatment with pegylated interferon+ribavirin may be more likely to relapse. Testing viral load with the TMA test after 12 months treatment may suggest they should consider extending therapy to 18 months, if TMA is positive although the NGI test is negative. Bear in mind, the TMA test is not FDA approved yet. Phase 3 study is ongoing and FDA review is expected during 2nd half of 2002. TMA is a new technology and different than PCR. It is my understanding that some commercial labs, such as Quest and Speciality are making this test available. I hear that reimbursement may be possible varying depending on the insurer. If your state Medicaid is reimbursing for HCV-RNA they may reimburse for the TMA test.
Here are 2 program abstracts on this question.
CHRONIC HCV PATIENTS WITH NORMAL ALT VALUES RESPOND WELL TO REBETRON THERAPY
Abstract 668
Ann L Silverman, David Ternes, William Beaumont Hosp, Royal Oak, MI; Lorraine Comanor, Indep Clin Researcher, Palo Alto, CA; Stuart C Gordon, William Beaumont Hosp, Royal Oak, MI
Background: Normalization of ALT was the treatment endpoint of the original hepatitis C antiviral trials. Current studies continue to exclude patients with normal baseline ALT values. Aim: To determine whether chronic HCV patients with normal ALT levels respond to combination interferon/ribavirin. Methods: 16 HCV RNA positive patients with normal ALT and one with ALT < 1.2 X ULN for at least 3 consecutive months received daily interferon alpha 5 MU for one month, plus ribavirin (1000-1200 mg/d), followed by standard Rebetron. Patients were monitored at baseline, weeks 1,2,4,8,12,16,20,24,28 by the quantitative VERSANT HCV 3.0 (bDNA) assay (cut-off 615 IU/mL) up until the time they went below the cut-off at which point they were reflexed to the Bayer HCV Qualitative Test based on transcription mediated amplification (TMA, limit of detection, 5 IU/ml). Patients whose viral loads were below the bDNA assay cut-off at week 24 were treated for an additional 24 weeks. Those who had quantifiable virus at week 24 terminated therapy. All patients were followed for 72 weeks. End of treatment (EOT) and sustained response (SR) were defined as undetectable HCV RNA by TMA at treatment week (TW) 48 and follow-up (FU) week 24, respectively. Results: 7 men and 10 women (mean age, 45.3 years) were treated; 80% were genotype 1. Two patients dropped out at treatment weeks 2 and 14. Using intent to treat analysis, 8/17 (47%) were both EOT and sustained responders; 6 of these 8 were genotype 1. Seven of 8 SR patients had HCV RNA levels below the bDNA cut-off at TW 4, but only 4 had undetectable HCV RNA by TMA at this time point. At week 12, all SR were below the bDNA cut-off, while 6 had undetectable HCV RNA. One SR did not have undetectable HCV RNA by TMA until after 16 weeks of treatment. All four patients with low baseline ALT levels (< 20 U/L) achieved SR. No ALT flares were observed in any of the patients. Conclusion: A cohort of chronic HCV patients with normal ALT values responded well to combination interferon/ribavirin therapy, with a sustained response rate of 47%.
ASSESSMENT OF VIROLOGIC RESPONSE BY TRANSCRIPTION MEDIATED AMPLIFICATION IN PATIENTS WITH CHRONIC HEPATITIS C VIRUS TREATED WITH PEGINTERFERON-a 2A
Abstract 1019
Christoph Sarrazin, J W Goethe-Universitaet Frankfurt am Main, Frankfurt Germany; David A Hendricks, Bayer Diagnostics, Berkeley, CA; Sedarati Farhad, Hoffmann-LaRoche, Nutley, NJ; Stefan Zeuzem, J W Goethe-Universitaet Frankfurt am Main, Frankfurt Germany
Background: Transcription mediated amplification (TMA) is an isothermal, autocatalytic target amplification method which has the potential to detect less than 50 HCV RNA copies/mL (10 IU/mL). TMA assay was used to assess presence of residual HCV RNA in plasma from patients treated with peginterferon a-2a who showed a virologic relapse after end of therapy. Patients and Methods: Stored end-of-treatment and end of follow-up plasma samples from 177 of 267 patients treated with peginterferon a-2a (Zeuzem et al., N Engl J Med 2000;343:1666-72) were available for retesting by TMA. Plasma samples from patients in the same study who exhibited virologic relapse after treatment with standard interferon a-2a served as controls. Virologic response during the trial was defined as undetectable HCV RNA using a PCR-based test system with a sensitivity of 50 IU/mL (Cobas AmplicorTM HCV, version 2.0) and was compared with TMA-based retesting results (VERSANTTM HCV RNA Qualitative Assay). Results: Residual HCV RNA was detected in 4 of 60 cases (7%) by the TMA technology in end-of-treatment plasma samples from patients who relapsed after receiving peginterferon a-2a and in 6 of 18 patients (33%) following therapy with standard interferon a-2a. For peginterferon a-2a-treated patients with sustained virologic response HCV RNA was detectable by TMA in end-of-treatment samples in 3 of 78 cases but in none of the end of follow-up samples. For all end-of-treatment and end of follow-up plasma samples of virologic non-responders a complete concordance between the PCR-based assay and TMA was observed. Conculsions: In patients with virologic relapse after the end of therapy according to PCR who were treated with peginterferon a-2a or standard interferon a-2a, residual HCV RNA was detectable in end-of-treatment samples by the TMA-based assay in 7% and 33% of cases, respectively. The lower rate of residual HCV RNA detection by TMA in patients treated with peginterferon a-2a compared with patients treated with standard interferon a-2a may be due to the maintained antiviral pressure of the long acting peginterferon a-2a at the end-of-treatment visit.
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