The Liver Meeting
54th Annual Meeting of The American Association for the Study of Liver Diseases
October 24 - 28
Boston, Massachusetts
John B. Hynes Convention Center

HIV-HBV Coinfected Patients Show Sustained Suppression of Epivir-HBV-resistant HBV Through 3 Years of Treatment with Hepsera 10/29/03

Report Confirms Safety of Liver Transplantation in HIV-HCV Co-infected Patients 10/29/03

GB Virus C (GBV-C) Clearance Is Frequent in HIV-HCV Coinfected Patients Receiving Interferon and Ribavirin and Does Not Elevate HIV RNA Levels 10/29/03

HIV-HCV Coinfection Status Does Not Affect HCV Viral Kinetic Response to Interferon 11/10/03

HCV co-infection is common among patients with HIV disease. It has been documented that HIV co-infection accelerates the course of liver disease in patients with HCV, and that liver failure is higher in co-infected patients.

At this moment, there is no effective treatment for HCV non-responders to interferon therapy. Interferon monotherapy and interferon-ribavirin combination is only effective in 2-3% and 5-10% interferon-resistant patients respectively. Treatment strategies to slow the progression to cirrhosis and to prevent liver failure in this population are needed.
 

This report examines the efficacy of Peg IFN alfa 2-a (Pegasys) vs Pegasys/RBV 800mg in co-infected HCV/HIV patients that have not responded to a previous 6-12 months course IFN-alfa. The study also examines the histological benefit of treatment in this population.

76 patients were randomized 1:1 to receive either Pegasys 180mcg weekly x 24 weeks (group 1) or Pegasys 180mcg weekly plus 800mg RBV for 24 weeks (group 2). Patients that have HCV non-detectable or 2-log decrease from baseline at week 24 (group1) were added RBV 800mg.

All similar responders (group 2) continue treatment for a total of 48 weeks. Baseline demographics were similar between both groups. More than 70% of patients were nonresponders to IFN monotherapy. Most patients in both groups (80%) were genotype 1. The mean HIV baseline log was 2.92 (SD .64) group 1, vs 2.85 (SD .57) group 2 and most patients had baseline CD4 levels >400 cells, and were in stable antiretroviral therapy. The majority of patients (81%) are non cirrhotic, with mean grading group 1 6.63 (SD 3.24), group 2 7 (SD 3.64), and mean staging, group 1 3.51 (SD 2.2), and group 2 3.48 (SD 1.70).

Results

Efficacy
Group 1 Group 2 Total
(N=33) (N=43) (N=76)
Baseline HCV RNA Log 5.67 Log 5.94
(SD .86) (SD .83)
12 Weeks
HCV RNA N/D 8 (24%) 17 (39%) 25 (32%)
HCV RNA > 2log 9 (27%) 21 (48%) 30 (39%)
24 Weeks
HCV RNA N/D 8 (24%) 17 (39%) 25 (32%)
HCV RNA 2log 13 (39%) 19 (44%) 32 (42%)
48 Weeks *
HCV RNA N/D 6 (18% )* 10 (23%)* 16 (21%)*
HCV RNA > 2log 6 (18%)* 11 (25%)* 17 (22%)*
72 Weeks *
HCV RNA N/D 1 (3%)* 3(6%)* 4 (5%)* ITTHCVRNA N/D Patients with Tx.>24weeks-4(7%)
Histology Mean * Group 1 Group 2
Grading Bl 3.63 SD 3.24 7.0 SD 3.64
Grading 72th 4.00 SD 2.13 4.18 SD 2.52
Staging Bl 3.51 SD 2.20 3.48 SD 1.70
Staging 72th 2.5 SD 2.0 2.90 SD 1.50
FPR Bl .37 SD .36 .44 SD .45
FPR 72th .41 SD 1.2 .62 SD 1.76
Histology by virological response (mean)
Non Responders FPR¹ (N=57) .42 SD .41 (.08 - 2.4)
FPR² (N=8) 1.48 SD 1.15 (-.62 - 3.12)
Relapsers FPR¹ (N=4) .52 SD .58 (.16 - 1.4)
FPR² (N=3) 0.0 SD 1.0 (-.62 - 1.25)
Responders FPR¹ (N=3) .20 SD .209 (.11 - .29)
FPR² (N=2) -1.87 SD .888 (-2.5 - -1.25)

Conclusions

Sustained virological response (SVR) (Intention to treat), will be of the order of 5-20%. (11 group 2 results are pending). In this study, 10 patients were discontinued because of adverse events and 10 were lost to follow up, before week 24.

SVR in patients that completed at least 24 weeks of therapy will be of the order of 7-26%. A significant number of end of treatment responders have relapsed at week 72. Histology analysis shows improvement in both groups of the mean grading and staging after treatment.

In responders and relapsers the FPR becomes static or regressive. These results show that Pegasys /RBV therapy is effective in this population. The study also suggests that longer duration of therapy and higher doses of RBV should be studied in coinfected nonresponders

10/27/03

Reference
M Rodriguez-Torres and others. EFFICACY OF PEG-IFN-ALFA 2A(PEGASYS) VSPEGASYS AND RBV FOR HIV/HCV COINFECTED PATIENTS THAT ARE NONRESPONDERS TO PREVIOUS IFN THERAPY. Abstract 343 (poster). Program and Abstracts of the 54^th AASLD. October 24-28, 2003. Boston, MA.

Host Factors Responsible for a Viral Response May Be Different in Responders Compared with Nonresponders and Independent of Serum PEG-Intron Concentrations
 

Approximately one half of hepatitis C virus (HCV) infected patients will fail to respond to current treatment regimens, pegylated interferon alfa and ribavirin. Modeling of HCV RNA decay in response to antiviral therapy can provide insight into viral and host determinants of viral response.

Pharmacokinetic, pharmacodynamic, and immunologic outcomes were evaluated on 24 co-infected patients in order to: 1) evaluate the relationship between HCV RNA decay and PEG-IFN alfa2b serum concentrations in HIV/HCV co-infected patients and 2) Evaluate association between HCV-specific immune responses and virologic outcome.

24 co-infected, therapy-naïve patients were treated with PEG-IFN alfa2b 1.5μg/kg/wk and RBV 13 ± 2 mg/kg/day. Serum was obtained for HCV RNA, HIV-1 RNA and serum PEG-IFN alfa2b levels at baseline, after the first dose (6, 12, 24 hours) and on days 2, 3, 5, 6; after the second dose (6, 12, 24 hours) and on days 8, 9; and after the third dose on days 14, 15, and 16. Peripheral blood mononuclear cells were obtained at baseline, weekly for the first month, and monthly thereafter.

HCV and HIV-1 RNA levels were determined by reverse-transcriptase polymerase chain reaction and PEG-IFN alfa2b levels were measured by ELISA. CD4⁺ cell proliferative responses to HCV antigens (core, NS3, NS4, NS5) and HIV-1 gag were performed at baseline, day 7 and 14, and weeks 4, 8, 12, and 24. Among 24 co-infected patients, 21 are males, the mean age was 46 ± 5.8 years, 8 are Caucasian, 12 are African-American and 4 are Hispanic. 20/24 patients were infected with genotype 1, 3/24 patients with genotype 2, and 1/24 with genotype 3a.

Study Results

Pharmacokinetics: To date, 21 patients have been evaluated. 10/21 patients were end of treatment responders, but 2 of these were “late responders” (i.e. HCV RNA declines after week 8 and is undetectable by week 24). Data fitting during the first seven days revealed a free virion clearance rate c of 13.3 (day^-1) and an infected cell clearance rate δ of 0.21 (day^-1). The half-lives were 2.7 hours and 4.0 days, respectively.

Pharmacodynamics: Viron production was blocked after the first dose of PEG-IFN alfa with an average maximum effectiveness (ε_max ) of 89%. We estimated that the fifty percent effective concentration (EC₅₀) of PEG-IFN alfa2b_, the theoretical in vivo drug concentration at which the drug efficacy is 50%, was five-fold lower in responders compared with non-responders while the maximum (C_max) and minimum (C_min) concentrations did not differ significantly (Table I). The calculated minimum (ε_min) and maximum (ε_max) efficacy were also significantly increased in responders.

Immunologic: The mean number of CD4⁺, CD8⁺ and CD56⁺ cells did not differ significantly at baseline or during treatment between responders and nonresponders. Peripheral blood CD4⁺ HCV-specific proliferative responses did not differ significantly between responders and nonresponders except that the response to core antigen was increased in non-responders compared with responders at weeks 4 and 12. HIV gag CD4⁺ proliferative responses were stronger than HCV-specific responses at all time points evaluated.

Conclusions

The serum PEG-IFN alfa2b concentration necessary for an end of treatment response is five-fold lower in responders compared with non-responders while there are no significant differences in the maximum and minimum PEG-IFN alfa-2b concentrations in responders and nonresponders.

These data suggest that host factors responsible for a viral response may be different in responders compared with nonresponders, independent of serum PEG-IFN alfa2b concentrations.

Supported by the NIH and conducted at Weill Medical College of Cornell, NY, Los Alamos National Laboratory and New York Blood Center.

10/27/03

Reference
P Golia and others. PHARMACODYNAMICS AND PHARMACOKINETICS OF HEPATITIS C VIRUS (HCV) AND PEGYLATED INTERFERON-ALFA-2B IN HUMAN IMMUNODEFICIENCY VIRUS (HIV)/HCV CO-INFECTED PATIENTS. Abstract 385 (poster). Program and Abstracts of the 54^th AASLD. October 24-28, 2003. Boston, MA.

HIV-HBV Coinfected Patients Show Sustained Suppression of Epivir-HBV-resistant HBV Through 3 Years of Treatment with Hepsera

Gilead Sciences today (10/28/03) announced that treatment with its once daily, oral antiviral agent Hepsera (adefovir dipivoxil 10 mg) was associated with sustained reductions in levels of hepatitis B virus (HBV) DNA through 144 weeks (approximately three years) among patients chronically infected with Epivir-HBV (lamivudine)-resistant HBV and co-infected with HIV. 

Data from the single-center, open-label clinical trial (Study 460i) were presented today at the 54^th AASLD by Yves Benhamou, MD, Service d’Hépato-Gastroentérologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.  This presentation is one of eight Hepsera-related abstracts featured at the conference.

“Patients co-infected with HIV and HBV can be difficult to treat.  The development of resistance – which emerges in up to 90 percent of immunocompromised HBV-infected patients after four years of therapy with lamivudine – can lead to progression of chronic hepatitis B,” said Dr. Benhamou.  “In this study, co-infected patients who received Hepsera showed sustained suppression of HBV through nearly three years of therapy.”

About Study 460i

Gilead released the following information about study 460i:

“Study 460i is a single-center, open-label study of Hepsera in chronic hepatitis B patients with lamivudine-resistant HBV and co-infected with HIV.  The study enrolled 35 patients with controlled HIV infection (mean baseline HIV RNA serum level of 2.88 log₁₀ copies/mL by Roche Amplicor Monitor PCR) who were receiving lamivudine 150 mg twice daily as part of their combination anti-HIV treatment regimen for a median of 42.3 months prior to enrollment. 

“Lamivudine-resistant HBV (confirmed “YMDD” mutation) was detected in patients a median of 21.3 months prior to initiating treatment with Hepsera.  The median baseline serum HBV DNA level in these patients was 8.75 log₁₀ copies/mL (Roche Amplicor™ Monitor PCR).

“Hepsera was associated with a significant and progressive change from baseline in median serum HBV DNA levels after 144 weeks of treatment: -5.45 log₁₀ copies/mL (n=29; p<0.001) at week 144, compared with -4.0 log₁₀ copies/mL at week 48 and -4.8 log₁₀ copies/mL at week 96. 

“Approximately 46 percent of patients had undetectable HBV DNA levels (<3.0 log₁₀ copies/mL) after nearly three years of therapy.  By week 144, two patients had experienced HBeAg seroconversion.

“Levels of serum alanine aminotransferase (ALT) – a measure of liver damage – also continued to decrease toward normal values throughout the study.  At 144 weeks, 61 percent of patients had normal ALT levels.  The median ALT was 31 IU/L, a further improvement from 96 weeks (46 IU/L), 48 weeks (53 IU/L) and a significant decline from the pre-study value (81 IU/L; p<0.001).

“There were a total of three serious adverse events reported, all of which were determined to be unrelated to study drug. Two patients with transient changes in serum creatinine (³0.5 mg/dL increases from baseline) were reported, both events resolved on continued treatment, and no patients had serum phosphorus levels less than 1.5 mg/dL, both laboratory markers of renal function.  No adefovir-associated HBV resistance mutations (rtN236T) related to Hepsera treatment were identified through week 144.”

About Hepsera

Hepsera, the first nucleotide analogue for chronic hepatitis B, is administered as a once-daily 10 mg tablet and works by blocking HBV DNA polymerase, an enzyme involved in the replication of the virus in the body.

In clinical trials and expanded access programs, approximately 7,000 patients have been treated with Hepsera for periods of up to three years. Hepsera is now available in the United States, the United Kingdom, France, Germany, Portugal, Ireland, Greece, Spain, Norway, Austria and Sweden.  In April 2002, Gilead signed a licensing agreement with GlaxoSmithKline (GSK), granting GSK rights to commercialize Hepsera in Asia, Latin America and other territories.

In the United States, Hepsera is indicated for the treatment of chronic hepatitis B in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. 

10/29/03

Reference
Y Benhamou and others. LONG TERM TREATMENT WITH ADEFOVIR DIPIVOXIL (ADV) FOR THREE YEARS IN PATIENTS WITH LAMIVUDINE-RESISTANT (LAM-R) HBV AND HIV CO-INFECTION RESULTS IN SIGNIFICANT AND SUSTAINED CLINICAL IMPROVEMENT. Abstract 1158 (poster). 54^th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, October 24-28, 2003.

Report Confirms Safety of Liver Transplantation in HIV-HCV Co-infected Patients

Although liver transplantation in patients with HIV infection in the era of highly active antiretroviral therapy (HAART) has been successful, some have reported significant graft loss in patients with hepatitis C due to its aggressive recurrence post transplant.

In a report presented at the 54^th AASLD, authors reported the clinical outcomes of hepatitis C recurrence and treatment in 15 patients who underwent liver transplantation between March, 1997 and the present.

Of the 15 patients, 3 were excluded because of early deaths (<30 days) due to sepsis (2 patients) or primary non-function. The 12 remaining patients had a mean follow-up of 22.1 months (1.4 - 57.3 months).

Four patients have died, with 1 each succumbing to hepatocellular carcinoma, chronic rejection, overwhelming fungal sepsis, and bacterial pneumonia. Two of these patients had biopsy-proven hepatitis C including 1 who developed cirrhosis despite interferon-α and ribavirin.

Of the 8 patients who are alive – 4 of whom are currently on treatment, three with Pegylated-interferon/ribavirin – 7 have biopsy-proven recurrent hepatitis C diagnosed at a mean time of 6.7 ± 2.4 months after their transplant.

Histologically, the only patient who cleared HCV still progressed to cirrhosis. All of the patients currently alive have CD4 counts greater than 200 and undetectable HIV viral loads.

The authors conclude: “Liver transplantation in patients co-infected with HIV and HCV is a successful therapeutic option. We have not had any rapid or aggressive courses of recurrent hepatitis C leading to allograft failure.

“Thus far, these patients have been able to tolerate treatment and they appear to have a similar short-term response as compared to HCV patients without HIV. It remains to be seen whether HIV and immunosuppression will significantly hasten HCV recurrence with longer follow-ups.”

10/29/03

Reference
ME de Vera and others. PROGRESSION AND TREATMENT OF RECURRENT HEPATITIS C AFTER LIVER TRANSPLANTATION IN PATIENTS CO-INFECTED WITH HIV. Abstract 12 (plenary). Program and Abstracts of the 54^th Annual Meeting of the American Association for the Study of Liver Diseases. October 24-28, 2003. Boston, MA.

GB Virus C (GBV-C) Clearance Is Frequent in HIV-HCV Coinfected Patients Receiving Interferon and Ribavirin and Does Not Elevate HIV RNA Levels

Co-infection with the flavivirus GB virus C (GBV-C) has recently been shown to have a beneficial effect on the course of HIV disease progression. While previous studies have demonstrated an inverse relationship between levels of HIV-1 RNA and GBV-C RNA, it is not known what effect clearance of GBV-C has on HIV-1 RNA levels and disease control.

Researchers in the Adult ACTG A5071 Study Group investigated the prevalence of GBV-C infection in a large cohort of HIV-HCV co-infected subjects and the effect of interferon (IFN) + ribavirin (RBV) combination treatment on GBV-C replication. We also evaluated the effect of GBV-C clearance on HIV-1 RNA levels.
 

The investigators retrospectively studied 131 HIV-HCV co-infected subjects who were enrolled in the AIDS Clinical Trials Group (ACTG) A5071 trial, a multicenter randomized trial evaluating the efficacy of IFN α-2a + RBV or PEG-IFNα-2a + RBV treatment for HCV infection in individuals co-infected with HIV.

GBV-C viremia was detected by nested RT-PCR and quantified by real-time PCR from stored sera at baseline and treatment week 24. In some patients who continued treatment beyond week 24 for a total of 48 weeks (HCV virologic responders and histologic responders among HCV virologic nonresponders), additional sera from weeks 48 and 72 were available for analysis. HIV-1 RNA levels were recorded at corresponding time points.

As markers of prior GBV-C clearance, serum samples were also tested for GBV-C anti-E2 antibodies.
 

Study Results

At baseline, 85% of patients had signs of GBV-C infection: 22% were GBV-C RNA+, 55% were anti-E2+ and 8% were both GBV-C RNA and anti-E2+. There were no differences in HIV-1 RNA or CD4 count between GBV-C RNA+ and RNA- subjects.

Of the 40 GBV-C RNA+ subjects, HIV-1 RNA levels were undetectable (<50 copies/mL) in 23 (58%) at entry. 37 (93%) were on active antiretroviral therapy.

No subject acquired GBV-C RNA during the study observation period (mean 63 wks). Among the 38 GBV-C RNA+ subjects who completed 24 weeks of IFN + RBV or PEG-IFN + RBV therapy, GBV-C RNA clearance was observed in 17 (45%), without development of anti-E2 antibodies.

Among the 21 subjects who were followed up to 72 weeks, sustained clearance of GBV-C RNA was observed in 7 (33%; 18% by intent-to-treat). Entry GBV-C RNA levels were not significantly associated with clearance of GBV-C viremia (p=0.1).

At week 24, no correlation was observed between GBV-C RNA clearance and rise in HIV-1 RNA levels.
 

Conclusions

In a US ACTG clinical trial cohort,

(1)     remote or active GBV-C infection is extremely common among HIV-HCV co-infected patients;

(2)     GBV-C viremia was present in 30% of HIV-HCV coinfected patients;

(3)     GBV-C viremia is cleared in 45% of HIV-HCV/GBV-C triply infected patients after 24 weeks of combination antiviral therapy for HCV;

(4)     GBV-C sustained virologic response occurs in at least 18% of treated patients with combination antiviral therapy;

(5)     The clearance of GBV-C RNA is not associated with elevations in HIV-1 RNA. The long-term outcome of this clearance is not known.

These findings have important implications for the management of HIV-HCV co-infected persons undergoing IFN-based antiviral therapy.

10/29/03

Reference
C Zander and others. GB VIRUS-C CLEARANCE IS FREQUENT IN HIV-HCV CO-INFECTED PATIENTS RECEIVING INTERFERON AND RIBAVIRIN TREATMENT BUT DOES NOT ADVERSELY AFFECT HIV-1 VIREMIA: THE ADULT ACTG A5071 STUDY GROUP. Abstract 1066 (poster). Program and Abstracts of the 54^th Annual Meeting of the American Association for the Study of Liver Diseases. October 24-28, 2003. Boston, MA

HIV-HCV Coinfection Status Does Not Affect HCV Viral Kinetic Response to Interferon

Viral kinetic modeling of HCV response to interferon-based therapy provides important insights into factors associated with treatment outcomes. HIV-HCV coinfected patients appear to have lower overall response rates than that observed in monoinfected subjects, but the reason for this is not clear. This research group speculated that kinetic responses in key parameters would be decreased in coinfected subjects.
 

HIV-HCV coinfected patients and HCV monoinfected patients prospectively matched for treatment, genotype, age (+ 5 yrs), gender, race, and histology were evaluated.

Coinfected patients were randomized within the context of a large U.S. multicenter trial (ACTG 5071) to receive Pegasys (pegylated interferon alfa-2a) + ribavirin vs. Roferon (interferon alfa-2a) + ribavirin. Quantitative HCV RNA (Roche COBAS AMPLICOR) kinetic testing was performed at 0, 6, 12, 24, 48, and 72 hours and at days 7, 14. Non-linear regression and linear models were evaluated in an effort to best predict response and identify prognostic factors.
 

Study Results

Twenty-seven subjects underwent viral kinetic sampling and evaluation. These included twelve HIV-HCV case subjects (10 men, 2 women) and 15 matched HCV controls (some patients double-matched).

The mean age of coinfected subjects was 46.1 years (range, 38-60). Among HIV+ subjects the mean CD4+ count was 325 cells/mm³ (range, 175-855). 11/12 had baseline HIV RNA <400 copies/ml. Mean HCV viral load was 6.6 log IU/ml among coinfected vs. 6.2 log IU/ml in controls.

75% of coinfected subjects had HCV genotype 1. The remainder were genotype 2. Twenty-five (25%) of coinfected patients had no detectable virus 24 weeks after completion of 48 weeks of therapy (SVR).

Overall SVR in control subjects was 46.6%. Efficiency (ε) of Phase 1 response (λ) slope at 72 hours, lambda₂ (slope of Phase 2 decline) were calculated (see table below).

Efficiency of clearance (ε) at 72 hours was highly associated with actual viral clearance across all groups (p=0.001) but λ₂ was not. Regression analysis failed to demonstrate a relationship between ε and baseline CD4+ count, HCV viral load or genotype. In contrast, #955;₂ was significantly associated with genotype.

Viral kinetic parameters were not predictive of SVR.
 

Conclusions

• Viral kinetic modeling demonstrated that the efficiency of clearance at 72 hours was significantly associated with viral clearance during treatment;
• Coinfection status did not affect key kinetic parameters;
• PEG-IFN was superior to standard interferon in terms of viral clearance efficiency, particularly in the coinfected group; and
•  Diminished SVR in coinfected patients may be related to immune factors that are operative after reduction of viral loads to undetectable levels.

11/10/03

Reference
KE Sherman and others. MODELING HCV VIRAL KINETIC RESPONSE TO PEG-IFN/RIBAVIRIN IN HCV-HIV COINFECTED PATIENTS. Abstract 315 (poster). 54^th Annual Meeting of the American Association for the Study of Liver Diseases. October 24-28, 2003. Boston, MA.