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  9th Conference on Retroviruses and Opportunistic Infections
Seattle, Washington, February, 2002
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HCV Viral Kinetics
Written by Nancy Shulman, MD, Stanford University, and Jules Levin
  These small studies compare Pegasys to standard interferon in terms of effectiveness to initial response to therapy. And examine the response of HCV/HIV coinfected patients as compared to HCV monoinfected patients. The preliminary results from these studies show that Pegasys is superior to standard interferon and coinfected patients appear to not respond as well to therapy as HCV monoinfected patients.
Two studies at Retrovirus looked at how fast the viral load drops after pegylated interferon or standard interferon in HCV/HIV patients. F. Torriani (UCSD) reported the on data from the Apricot study. K. Sherman (Hepatologist at University of Cincinnati) reported the data from ACTG 5071. 10 patients, all genotype 1, from the large Roche study (Apricot) were randomized patients to full dose Pegasys + ribavirin (800mg/day), full dose Pegasys + ribavirin placebo, vs. interferon (3 MIU/3x/day) + ribavirin (800mg/day). In this subanalysis 5 patients received Pegasys+ribavirin and 5 received interferon+RBV. The analysis compared the patient responses to the Pegasys regimen and the standard interferon regimen. 10 patients, 8 who were genotype 1, in the ACTG 5071 (5 Peg and 5 interferon) were also studied and the data presented. This study examined the initial (phase 1) viral load decline for coinfected patients. Patients were randomized to receive Pegasys (full dose, 180 mcg once weekly + ribavirin 600-1000mg/day (dose escalated), or interferon (6 MIU 3x/week initially and then 3 MIU 3x/week) + ribavirin (600-1000mg, also dose escalated) All patients had frequent blood draws in the first few days to determine the rate HCV levels decline after initiating treatment.
The baseline demographics for these two studies are described at the end of this article.
The clinical results from the Apricot study have not been presented yet. The interim results from ACTG 5071 were reported at Retrovirus by Ray Chung. At the end of 24 weeks of therapy, 44% were HCV RNA <50 copies/ml in the pegylated arm vs. only 15% in the standard interferon arm by intent-to-treat analysis where dropouts are considered failures. In Genotype I patients who are generally less responsive to treatment than other genotypes, the numbers were less at 33% and 7%. Genotypes 2 and 3 combined were had much higher rates of virologic response at 80% and 40% in the Peg and non-peg arms respectively. This is less than would be expected in HCV mono-infected patients. Overall about 14% dropped out of the study due to side affects of the medications, similar to studies of HCV mono-infected patients. We await the sustained virologic response rates (HCV RNA negative 6 months after completing therapy).
Results from Viral Kinetics studies: The Roche data was difficult to interpret due to the great degree of variability in the patient responses. They did not see the characteristic biphasic reduction of viral load (a steep initial reduction, followed by a slower second phase). In the presentation on ACTG 5071, Sherman described phase 1 and 2. It is suggested that there are two phases of HCV decline. It's suggested that the initiation of HCV therapy results in inhibition of viral production and release from hepatocyte cells during phase 1, which appears to occur in the first 10 days. Phase 1 is associated with a certain level of efficiency of HCV clearance. When the efficiency is 100%, the virus will be totally cleared. If this fails to result in 100% efficiency in clearing HCV, the ultimate outcome depends on the decline of HCV in phase 2, which can extend as far out as 80 days or longer. Decline in phase 2 is presumably related to the clearance of infected hepatocyte cells and the continued inhibition of production at some level of efficiency. The estimation of the time to clearance of HCV, when phase 1 is not 100% efficient in clearing HCV, is based on how long it will take to clear HCV through phase 1 and 2. The model Sherman used to make such estimates is based on this and referred to below. Bear in mind that clearance of HCV does not necessarily result in end-of-treatment response or in sustained viral response. Non-adherence and perhaps other unidentified factors may play roles in achieving sustained responses. The results from the analysis by Torriani suggest that having HIV may impair the ability for initial HCV clearance. She reported that in the 5 subjects with HCV RNA decline, the HCV virion half-life was 8.7 hours which compares to 2.7 hours in HCV monotherapy using 5-15 MIU of daily interferon. Again, she did not detect a phase 2 decline. Is this may related to the virion half-life, I don't know the answer to that.
In the Apricot/Torriani study, four patients responded by 24 weeks, 2 of whom became undetectable within 5 days and one who became undetectable at 9 days, and the 4th reached undetectable at week 21. These 4 patients received Pegasys+ribavirin. The 5th patient received interferon+ribavirin and reached undetectable at 28 days but relapsed. The virologic responders had a lower pre-treatment HCV RNA, they appeared to be below 1 million. The remaining 5 patients had transient or minimal reduction in HCV RNA; 4/5 received interferon+ribavirin while 1 patient received Pegasys+ribavirin. Torriani speculated that the reason she did not observe a phase 2 may be due to the presence of a second phase below the detection of the limit of the assay. Or, the interaction with HIV, which might require a modification of the current model for HCV dynamics. She said the first hypothesis regarding the limits of the assay makes more sense to her. Her explanation about this did not make sense to me. In all 4 subjects below the detection limit by 12 weeks, decline in ALT closely paralled HCV RNA decline, leading her to suggest that frequent ALT measures may prove useful in monitoring treatment response. She suggested, and this makes sense to me, that perhaps coinfected patients may require higher interferon dosing or longer treatment to achieve sustained viral suppression. Based on statistical modeling, Torriani estimated the efficacy of the initial viral response was 60% for patients receiving the standard interferon regimen vs. 99% for patients receiving the Pegasys regimen. But this efficacy data is based on preliminary initial response data; final study results on patient response to therapy is not available yet. Clearly, HCV in HIV-infected patients needs more in-depth study as it appears there may be important and identifiable differences in response to therapy from HCV monoinfected patients.
The ACTG data was more interpretable. They saw first and second phase HCV declines, unlike in the Apricot study. The slope of the first phase slope and the second phase of the Pegasys vs. the interferon were both much steeper (which generally is accepted to correlate to potency). The lag time to response (first few hours before viral load starts to decline) was about the same for Pegasys vs IFN (7.7-9 hours). The overall efficacy of phase 1 response was 90% in the Pegasys patients vs 65% in the interferon patients (p<0.02). Based on these data and Sherman's modeling technique, the estimated time to clear the virus from the body in the Pegasys group was a mere 194 days, where the estimated time clearance for the interferon group was calculated to be 2400 days, because some did not reduce viral load at all making the number very high. Sherman said that if the model is correct you ought to be able to predict response to therapy, based on the initial response in the early days after starting therapy. In applying the model, they were able to predict response (n=4) and non-response (n=6) at week 24, with 100% accuracy, suggesting the validity of their model although the number of patients is small.
Sherman summarized the following from ACTG 5071. Pegasys appears to be superior to standard IFN alfa-2a in terms of phase 1 efficacy in coinfected patients, and in phase 2 decline in viral load. Using this combination of measures and the model to evaluate the initial response (phase 1 and 2 responses) appears to help estimate initial response, and initial response appears to correlate with week 24 response and to be superior for Pegasys.
Take home message on HCV treatment: Pegylated interferons are superior to interferon in HIV+ as it is in HIV- and are the current standard of care. We don't have any data to suggest that one Pegylated product is superior to another in HIV+ patients. HCV+/HIV+ have lower response rates than HCV monoinfected patients.
1. Abstract LB-15. Chung, et al.
2. Abstract 651. Sulkowski, et al.
3. Abstract 652. Perez-Olmeda, et al.
4. Abstract 121. Torriani, et al.
5. Abstract 122. Sherman, et al.
Additional baseline demographics information from the two viral kinetics studies.
Apricot/Torriani Study. 80% (8/10) had <50 copies/ml HIV RNA. CD4 counts were 600. CD4 % was 28.6%. HIV RNA was 2.1 log. 90% were on HAART. Average time on HAART was 3.1 years. 90% had IVDU as risk factor for HIV. Middle aged men 44 years of age. 5 whites, 3 African-American, and 2 Hispanics. Average HCV RNA was 5.5 log IU/mL. 100% genotype 1. Average ALT was 122. Average (Ishak modified HAI score) necroinflammatory score (0-18) 5.8 (3-10). Fibrosis stage (0-6) was 1.9. 1 person had cirrhosis.
Sherman/ACTG 5071 Study. 9/10 men. 45 years of age. CD4s 550 (175-1000). 1 cirrhotic. HCV RNA 9.8 million in IFN/RBV arm vs 3.97 million in Pegasys/RBV arm, no statistical difference between the 2 arms. 8/10 genotype 1.