icon-folder.gif   Conference Reports for NATAP  
  AASLD (American Association for the Study of Liver Diseases)
Nov 2-5, 2002, Boston, MA
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HCV Viral Kinetics During Therapy
Reported by Jules Levin
Italian study investigators (poster abstract 159) randomized 22 previously untreated patients to receive Pegasys 180 mcg or 1.0 mcg/kg, both once weekly plus 1000/1200 mg ribavirin. Patients had chronic HCV and had persistently elevated ALT. Baseline viral load was about the same. 6/12 on PegIntron and 7/10 on Pegasys had genotype 1. 20% (2/10) of patients had cirrhosis/transition to cirrhosis in the Pegasys group vs 16% (2/12) in the PegIntron group. Investigators reported that the average reduction in VL after 1 and 4 weeks was about the same for both drugs: after 1 week Pegasys patients had 4.88 log viral load, PegIntron patients had 4.95 log viral load; Pegasys VL at baseline 5.75 log, week 4 was 3.32 log; PegIntron baseline VL 5.64, week 4 was 3.64 log. At week 12 the viral load was significantly lower in Pegasys group (2.81 log vs 3.87 log). When authors assessed viral load over time out to 12 weeks in only patients with genotype 1 there was an observed difference between the two treatment groups but the difference was not significant. By looking at the graph the difference in genotype 1 patients started to diverge after 1 week increased by 4 weeks and appeared wider by week 12.
The authors said these results could be due to different exposure of the two drugs, which may result a different sustained exposure to the two agents during the dosing interval.
Andrew Talal and colleagues reported on viral kinetics in HCV/HIV coinfected patients. Talal reported that this is the first study in HCV monoinfected or HCV/HIV coinfected with a detailed characterization of HCV dynamics of the first 3 doses of peg-IFN. 20 coinfected patients received PegIntron 1.5 ug/kg and ribavirin weight based dose at 13 mg/kg. All patientsreceived liver biopsy to assess grade and stage. All patients were hospitalized for 24 hours during the first two doses of Peg-IFN administration with outpatient visits on day 2, 3, 5, 6, 9, 14, 15 and 16. Talal is collecting data on various types of immune system related cells to assess the immune response. HCV RNA was measured regularly during day 1, at 48 and 72 hours; and days 5 and 6 after the first dose; at 0.6, 12, 24, and 48 hours after the second dose.; and on days 0, 1, 2 after the third dose. Baseline HCV viral load was 6.5 log, 14/20 patients were on HAART. Most patients had undetectable HIV. Average CD4 count among responders was 400 and nonresponders 550, but both groups had the same stage & grade of disease at baseline. Patients were excluded if they had <100 CD4 count. If they had 100-200 CD4s they were required to have undetectable HIV. There were 4 African-Americans among responders vs 6 among the nonresponders. Average 9 patients had undetectable HIV viral load, and some patients had viral load that was not low; average cd4 count was 469. All patients were genotype 1, except 1 who had indeterminate genotype.
Of 13 patients analyzed and reported early, 4 demonstrated rapid HCV RNA decline (more than 2 logs in the first week), 5 demonstrated a partial decline (1 log or less during the first 28 days), and 4 are nonresponders without a discernable decline. As of Sept 2002 8/20 individuals had a virologic response. 2 of 10 were late responders: 3-8 months on treatment; in these patients HCV RNA begins to decline after week 8 and becomes undetectable after week 24; 10 of 20 patients had no phase 1 decline in viral load. These data find the coinfected patients responding apparently less well in the first few weeks of therapy, and Avidan Neumann reports that early viral load decline (kinetics) correlate with the ability to achieve a sustained viral response. Talal finds a lower percentage of coinfected patients achieve substantial viral load reductions. In Neumannıs study of monoinfected patients the percentage of monoinfected achieving substantial viral load reductions are higher.
These study data, as well as data from other studies, suggests HIV impairs the response to therapy. Talal reports it takes longer for cells to die off for these patient: average infected cell half-life ranged from 18 hours to 5 days. Average free virus half-life is 4.6 hours. This suggests perhaps conifected patients should be treated for longer. 10/20 patients had no phase 1 decline during therapy, phase I is the first few days.
Immunologic Responses. Talal reports observing significant decreases in responses to C22.5 (NS3) and NS5 in responders compared to nonresponders. Decrease in response to HIV gag also observed at week 1.
Some researchers and doctors anecdotally report they see response to therapy is delayed for some coinfected patients, but this needs confirmation with further study. Viral load response may appear after the first 28 days or be slow in starting and gaining momentum.
Talal conclusions. We have developed a new model that includes the decline in effectiveness, due to the exponential decay in peg-IFN concentrations, and which explains the data over the first week. With subsequent administrations of the drug, the high efficacy is reestablished and the viral load once again drops sharply. Immunomodulatory effect of IFN is different in responders compared with nonresponders.
Viral Kinetics in HCV Monoinfection During Therapy
Avidan Neumann (a noted viral kineticist) presented data from his viral kinetics study in which patients received PegIntron plus ribavirin at the Viral Hepatitis Therapy Workshop just prior to AASLD. So I can report that information but his more detailed poster at AASLD is not presented yet so these details will be reported later. At the Workshop Neumann reported viral load on average declined substantially during the first few days of PegIntron plus ribavirin. However, after a few days all the patients experienced an increase in viral load. Of course at the end of the first week on therapy there was a net decline in viral load. Viral load declines again in each following week in a similar fashion: down the first few days with increase in the next few days of the week.