Written by Jules Levin

Entecavir vs 3TC Resistance

A more detailed report is forthcoming but here are a few highlights from this meeting. several apparently promisingly drugs for treating HBV are in human development and moving along and had data presented on them here at AASLD: LDT, FTC (not good for 3TC resistance), adefovir, and entecavir. This morning data was presented on entecavir in 3TC resistant patients. Previous study data showed 0.5 mg (highest of 3 doses) dose of ETV reduced viral load by over 4 log in treatment-naive at week 20. The data this morning was presented in oral session. 85% reportedly had YMDD mutation. Three ETV doses were used: 0.1mg, 0.5mg and 1.0mg. Mean HBV DNA was about 9 log. About 40 patients in each arm. 79% in the high dose arm (1.0 mg) had undetectable HBV-DNA at week 24 by bDNA, and a 4.4 log reduction in HBV-DNA. By PCR 17% had undetectable HBV-DNA. 93% had 2 or more log reduction. There was a dose response. The group receiving 3TC 100mg had little HBV-DNA response. 11% in the high dose group (n=27) had loss of HBeAg compared to 6% in the 3TC continuation arm. There were 67 adverse events in the ETV 1.0 mg arm: headache (19), fatigue (5), abdominal pain (10), rhinitis (7). 5 discontinued and 5 had serious AE. The incidence of AEs was not different than in the 3TC arm. Although there were 2 serious AEs in the 3Tc arm. Several patients had elevated ALT.

Adefovir

This morning an oral talk was presented on a study for adefovir (ADV) for patients with HBeAg+ chronic HBV. This study looked at changes in liver histology. This 48+ week study looks at fibrosis, Knodell score, and necroinflammation. HBV-DNA was 8.4 log at baseline ALT 95. About 20% were nonresponders to IFN and <1%-3% had prior 3TC. Median Knodell scores were about the same in placebo 10mg and 30mg ADV arms: 9.5-10.0, necroinflammation 7.0-8.0, fibrosis 1.0. Cirrhosis: 4% in 30mg arm, 7% in 10mg arm, 8% in placebo. The 10 and 30 mg arms had about the same response measured by Knoedell (Histology): 53-59% showed improvement compared to 25% in placebo arm. 28%-36% showed no improvement in ADV arms compared to 65% in placebo arm. 10-12% of patients across the 3 arms had missing data. The difference between ADV 10 mg and placebo was significant (p<0.001). Necroinflammation: similar results--71-77% showed improvement in ADV arms vs 41% in placebo; 12-15% in ADV arms showed no imprivement compared to 26% in placebo. 34% in placebo showed worsening compared to 10-13% in ADV arms. Fibrosis: 41% showed improvement in 10mg ADV arm, 54% in ADV 30mg arm, and 26% in placebo. 26% worsened in placebo while 14% worsened in 10mg arm and 19% in 30mg arm. 50% remained the same in placebo vs 45% in 10mg and 37% in 30 mg arm. HBV-DNA: reduced by median 3.52 log in 10 mg arm (n=172) (21% <400 copies/ml HBV-DNA), 4.76 in 30 mg arm (n=173) (39% <400 HBV-DNA) and .55 in placebo (0%). 14% HBeAg seroconverted in 30mg arm, 12% in 10mg arm, and 6% in placebo. 33% exp erienced HBeAg loss in 30mg arm, 23% in 10mg arm, 17% in placebo. Serious AEs, AEs, and discontinuations were about the same in all 3 arms (5% serious AE, 87-95% AE, 7-8% disct. Dose reduction was 25% in 30mg ADV arm vs 3% in 10mg arm. 8% in 30 mg arm had confirmed increase 0.5 or more serum creatinine increase from baseline. No serum phosphorous confirmed decreases <1.5 mg/dL in any arm. Resistance reported later in conference. ADV 10 mg selected for development due to renal lab abnormalities with 30mg dose.

Data on FTC is also being presented showing viral load reductions. Maureen Myers reported median HBV-DNA reduction of 3.63 log at week 4 using highest dose og 400mg per day. In lower doses 2-3 log reductions seen. She reported no serious adverse events, toxicities.

It seems apparent that combination therapy for HBV should be the approach.
 

Reported by Jules Levin

There were a few studies reported today in posters on response to HCV therapy by HCV/HIV coinfected patients. The data is preliminary as I'll explain below but suggest that coinfected patients may not respond as well to therapy as patients with HCV alone. Is this a reason to not treat your HCV? I don't think so. A study was reported by Thierry Poynard showing that interferon+ribavirin appears to improve, slow, or stop liver damage even if there is no viral response (non-responders). And yesterday the Japanese research group reported from a large analysis that interferon improves disease progression. Other studies have suggested that interferon can slow disease progression even if there is little viral load response. In speaking with French researchers here their experience is that coinfected patients respond less by about 5-10% in terms of percent achieving a sustained virologic response. It's my understanding that genotype 1 is less prevalent in Europe (50%) while here in the USA genotype 1 prevalence is 70%. Among IVDUs genotype 1 is reportedly found 80% of the time. While several studies report over 90% of African-Americans have genotype 1. So, one reason coinfected patients don't respond as well is because they have a higher percentage of genotype 1. However, there may be other factors. HIV may impair the immune response. Evaluating a person's immunity by their CD4 count is a crude way to assess the capacity of their immune system. Inside liver cells there are CD4 cells. Researchers have yet to examine inside liver cells in coinfected patients to see if their immune response is impaired. Additionally, the overall immune response in HIV is not well understood. More research is needed to understand the role of HIV in perhaps limiting the response to HCV therapy. Other factors may also be involved such-is the HIV viral load undetectable which may improve response to HCV therapy; alcohol intake; is HAART playing a role; do individual drugs play a role; the length of time a person has had HCV.

PEGASYS

Roche reported very preliminary data on their study of coinfected patients in the USA. 150 coinfected patients are being enrolled in this study to receive Pegasys (pegylated interferon alfa-2a) 180 ug by subcutaneous injection for 48 weeks. Patients receive Pegasys momotherapy for 12 weeks and can add ribavirin if they have detectable viral load at 12 weeks or do not achieve 2 or more log reduction in HCV viral load. Patients could have CD4s as low as 100 for this study and detectable HIV-RNA. 106 patients enrolled; age 44; 82% male (women respond better); ALT 101; 59% had high viral load (6 million); average HCV-RNA 6.3 log IU/mL; 80% genotype 1 (this is a high percentage of genotype 1); average HIV-RNA 2.3 log; 11% cirrhotic.

Cd4 at baseline was 513 and 436 at week 12. 63% had <50 copies/ml HIV-RNA at baseline and 72% at week 12. 19.1% (17/89) had negative HCV-RNA at week 12 (on Pegasys monotherapy). 33.7% (30/89) had a reduction in HCV-RNA of 2 or more log. 9 patients (8.5%) have discontinued therapy: 5 patients (4.7%) because of expected adverse events and 4 because of refusal of treatment or failure to return. The authors reported that no unexpected adverse effects of the study meds were seen. The lowest post-baseline neutrophil count of grade 4 neutropenia (<500/mm3) occurred in 9 patients (8.5%); the lowest post-baseline hemoglobin level grade 1 (8.0-9.4) occurred in 2 patients; and thrombocytopenia (platelet count <20,000 mm3) occurred in 1 patient.

82% of patients experienced at least 1 AE: fatigue 35%; myalgia (muscle aches) 27%; headache 22%; nausea 20%; pyrexia 19%; rigors 18%; arthralgia 12%; injection site inflammation 12%; depression 12%.

These results are obviously preliminary, at week 12. And we look forward to further analysis.

Edmund Bini, from New York City, reported on a small study of coinfected patients receiving standard interferon + ribavirin. Consecutive HIV and HCV coinfected patients were treated with IFN alfa-2b 3 million units three times per week with 800-1200mg/day of RBV. The results in these patients were compared to a matched group (similar characteristics) of patients with HCV alone. The duration of therapy was 24 weeks if genotype 2/3 or up to 48 weeks in those with genotype 1. Sustained virologic response was defined as <100 copies/ml 24 weeks after stopping therapy. In patients with genotype 1, treatment was discontinued if HCV was still detectable at week 24. All data was analyzed by an intent-to-treat analysis. 96 patients were included in the study- 32 with coinfection and 64 with HCV alone.

Bini said there were no significant differences between the coinfected patients and those with HCV alone. Treatment was completed in 75% of the coinfected patients and 83% of those with HCV alone (p=0.37). The coinfected patients had HIV for 7.5 years, on average. CD4 count was 433. Average HIV viral load was <50 copies/ml (range <50 to 83,000). Average number of ART medications was 3. Bini reported 84% had genotype 1in both groups. In both groups, 40% had >2 million viral load. Average HCV-RNA was 1.5 million copies/ml. Histologic Activity Index (0-18) was 6.7 in HIV group and 6.1 in HCV group (NS). Cirrhosis was 22% in each group. Duration of HCV was 16.8 years in HIV group and 19 years in the HCV group. So, these patients had HCV for much longer than they had HIV. 68-73% had IVDU as the risk factor for HCV. 56-65% were African-American. 18-25% were Hispanic. 90% male. Age was 49 on average.

The end-of-treatment viral response was 39% in the HCV alone group and 34% in the coinfected group (p=0.66, NS). So, the 2 groups responded the same. At the end of followup (sustained response) 26.6% in the HCV alone group and 21.9% in the coinfected group (p=0.62, no difference) had a viral response. Response according to genotype: genotype 1: 22% in HCV alone and 18.5% in coinfected; genotype 2/3 Ð 50% in HCV group and 40% in the coinfected patients. No coinfected patient with undetectable HIV viral load developed HIV viremia during treatment or follow-up. Treatment with IFN+RBV did not result in a significant CD4 count decrease. There were no serious adverse events. Bini reported there was no difference between the 2 groups in terms of dose reductions and other adverse events. This is unusual. In real life, you would expect coinfected patients to discontinue more often and have higher incidence of reduced hemoglobin. Bini concluded that the response was the same between coinfected patients and those with HCV alone.

The AmFar study in coinfected patients was reported but there are some problems with this study. It was conducted at 21 sites including Puerto Rico. 110 patients received either standard interferon monotherapy 3 million units 3 times per week or IFN+RBV. But, patients in the IFN/RBV arm received IFN monotherapy for 12 weeks and if detectable they could replace RBV placebo with RBV at week 16 (in a blinded fashion). Although it wasn't stated in the poster, I was told that patients who added RBV were still considered non-responders. Patients were somewhat evenly divided between being white, black, or hispanic. 85% were men. 75% had genotype 1 and baseline HCV-RNA was 4.4 million copies/ml. Fibrosis was present in 84% of participants. 15% had cirrhosis. Hepatic necrosis was present in 59%. Median HIV-RNA was 400 copies/ml and mean viral load was 37,000 in the IFN/RBV group. Average CD4 was 500. 56% had undetectable HIV-RNA. 57% were on a PI regimen. 15% were not on any ART. 26% were taking AZT and 54% were taking d4T. ALT was about 100. RESULTS: at week 72, 8% receiving IFN/RBV had undetectable HCV-RNA. But remember patients were initially randomized to 16 weeks of IFN monotherapy. Although it wasn't mentioned in the poster and may not be true, I was told that those who added RBV because they weren't undetectable were considered failures (nonresponders). 0% (0/40) with genotype 1 had a sustained response while 25% with other genotypes had a sustained response. These results are strange. A response rate of 0% in genotype 1 is unexpectly low. 28% were African-American in the study and 36% were white. 21 patients (19%) experienced an undetectable viral load during at least one evaluation during the study. 3 of these patients were taking IFN monotherapy at the time of being undetectable. The authors reported that 50% of patients discontinued study drugs before prematurely. And 20% reported premature discontinuation was due to an adverse event. This is a high discontinuation rate. The most commonly reported adverse events were Ð elevated ALT 32% (???); leukopenia 28%; elevated triglycerides 25%; anemia 24%; asthenia (fatigue 24%. It sounds to me as if patient management was not handled well. 24 patients were reported to have bilirubinemia, 18 with depression. 15 with elevated amylase, 13 elevated lipase, 12 hypoglycemia. The response rate at week 12 was 23% for those receiving IFN/RBV.

Reported by Jules Levin

John G McHutchison, Paul J Pockros, Scripps Clinic, La Jolla, CA; Peter Langecker, Dennis Blanchett, William - Lang, Mark Moran, BioMedicines, Inc, Emeryville, CA

Background: Omega (w) interferon (IFN) is a type 1 IFN active in vitro against DNA, RNA and retroviruses. In man w IFN increases IFN response marker levels. Aims: To evaluate in patients who failed to clear virus with alpha IFN alone, alpha IFN with ribavirin or pegylated interferon: á hepatitis C viral dynamics á HCV RNA and ALT response to increasing doses of w á safety, tolerability, and PK characteristics of w IFN Study design: Three groups of 8 patients (pts) received 15,30 or 60 mg of w IFN sc qd for 14 days. Initially mean HCV RNA levels were >105 and ALT levels were elevated. HCV RNA levels were measured at 2,4,7,10,14,19 and 24 hours after initial dosing; 5,10 and 24 hours after dose 2; and every 1-2 days through Day 14. Omega IFN blood levels were measured at 11 time points for 24 hours following the initial dose. Results: 16 males and 8 females completed 14 days of daily therapy. Median half life of elimination of w IFN was approximately 9 hours after a single 15 mg dose. Six pts required dose reduction and one discontinuation after 14 days for neutropenia (3/8 at 30 mg, 4/8 at 60 mg). One pt each discontinued because of pyelonephritis and elevated ALT. Other side effects were mild to moderate headache (60%), fever (45%) myalgia (45%). Conclusions: Omega IFN reduces levels of HCV RNA within 48 hours in genotype 1 infected patients resistant to prior alpha IFN therapy. Further reductions occur in 2 of the 3 groups at 14 days. AE's with w IFN, even with daily dosing, are not worse than those of other IFNs. Neutropenia may be dose limiting. Prospective trials are required to further determine the role of Omega IFN for the treatment of HCV infection.

OPEN-LABEL PHASE II STUDY OF OMEGA INTERFERON IN PREVIOUSLY UNTREATED HCV INFECTED PATIENTS

Mathias Plauth, Stadisches Klinikum, Dessau Germany; Helga Meisel, Inst fur Medizinische Virologie, Berlin Germany; Peter Langecker, Mark Moran, William Lang, Dennis Blanchett, BioMedicines, Emeryville, CA; Jens-Uwe Jetschmann, Campus Charite, Humboldt Univ, Berlin Germany; Jochen Brack, Klinikum Nord, Betiebsteil Ochsenzoll, Hamburg Germany; Peter Von Wussow, Privatdozent, Facharzt fur Innere Medizin, Hannover Germany

Purpose: To measure in naive HCV infected patients - the safety and tolerability of w interferon (IFN) - the effect of different doses on ALT levels -the effect of different doses on HCV RNA levels Background: Omega (w) interferon (IFN) is a type 1 IFN active in vitro against DNA, RNA and retroviruses. Human administration of w IFN increases IFN response markers. Study design: Each of three groups of treatment naive HCV infected patients (pts) received either 15, 30 or 45 m g of w IFN sc daily TIW for 12 weeks. All pts had HCV RNA levels >105 and elevated ALT levels at study entry. Pts were evaluated clinically, with hematology, chemistries and HCV RNA assays at 6 time points between day 0 and week 16. HCV RNA assays were also performed at Days 0,1,2,3,4 and 15. Dose escalation is continuing to 60, 90 and 45 m g of w IFN sc TIW. Results: Data are presented from 32 patients who have completed 4 weeks of therapy. Results for HCV RNA and ALT testing are presented in the table. Adverse events were similar to those seen with other IFNs. Leukopenia required dose reduction in two pts at the 15 mg dose level but none at higher doses. No patients discontinued treatment. Conclusions: Omega IFN is active against type 1 HCV in IFN naive patients. It induced undetectable HCV RNA levels in 10/30 pts and normalized ALT in 12/32 pts during the first 28 days of treatment. Omega IFN shows the characteristics of a clinically useful interferon for the treatment of HCV infection and further evaluation of higher doses and prolonged treatment is warranted.