Open-Label Pilot Study of the Safety and Efficacy of Adefovir Dipivoxil in HBV/HIV Coinfected Patients with 3TC Resistant HBV

Background on HBV:

Although the use of antiretroviral therapy for HIV has made a huge impact in improving health and lowering death rates, emergence of liver disease leading to cirrhosis and liver failure has become an increasingly important problem for people coinfected with hepatitis & HIV.  To date studies have focused on management and treatment strategies in patients with hepatitis C.  Hepatitis B management has become increasingly controversial because of drug resistance and immunologic injury associated with immune reconstitution.  A significant number of patients with hepatitis B or C have dual infection including HIV.  There is little or no research on treatment of patients with HCV/HBV/HIV coinfection. But, there are an estimated 350 million carriers of HBV in the world and the World Health Organization (WHO) estimates the number of HBV carriers will reach 400 million by the year 2000.  In the United States, infection and carrier rates are usually below 1%.  The prevalence of HBV in HIV infected patients is reported to be 6-18%.

Hepatitis B in immunocompetent patients can be treated using either interferon or lamivudine.  Response rates for interferon range from <5% to greater than 50% depending on factors including duration of infection, viral load, pretreatment ALT level and gender. Treatment for HBV in the pre-HAART era was not very successful. Response rates in most studies were less than 10% using persistent hepatitis B e antigen (HBeAg) seroconversion and HBV DNA clearance as outcome measures.  Lamivudine is more effective in treatment of hepatitis B.  Long term treatment response in immunocompetent patients was shown to be 17% by Dienstag as measured by HBV DNA clearance and HBeAg conversion.  Among HIV-infected patients similar initial viral clearance rates have been observed.  3Tc is more tolerable than interferon. However, 3TC resistance due to mutations in the YMDD motif has been described.  This is sometimes associated with development of clinically significant flares of disease.  Adefovir is a nucleotide analog that appears to suppress HBV replication even when YMDD mutations are present.

THE STUDY

This study was conducted by a French research group including Yves Benhamou, Christine Katlama and Thierry Poynard., and reported at the AASLD liver conference in Dallas in October. 35 HIV/HBV coinfected persons who were receiving 3TC (lamivudine) 150 mg twice daily as part of an antiretroviral HIV regimen. Patients had controlled HIV viral load (<400 copies/ml). But all had detectable HBV DNA and HBV mutations M550V and M550I. Adefovir 10 mg once daily was added to the regimen. This dose level is less than used in treating HIV with adefovir. In treating HIV, adefovir dosing was evaluated at 60 and 120 mg once daily This is a 28-week study and these results are preliminary. At 24 weeks, data was available on 23/35 patients, and the mean decrease in HBV DNA serum levels from baseline was -3.40 log. At week 20, data was available on 32/35 persons and HBV DNA decrease was -3.16 log. There were no significant changes in ALT (about 100 at baseline & 24 weeks). Authors reported adefovir was well tolerated. There were no significant changes reported in renal function, HIV RNA or CD4s.

The ACTG is planning a study in triple infected HCV/HIV/HBV infected persons with treatment of Pegylated Interferon (Pegasys), ribivarin (800 mg daily) and adefovir 10 mg once daily.

HBV DNA viral load was assessed by Hybrid Capture (sensitivity: 5 pg/ml= 6.15 copies/ml, HBV-DNA; Digene) at least 6 months prior to study entry.

At higher doses in HIV therapy adefovir was associated with renal problems reflected by abnormal blood tests in creatinine and phosphate.

SAFETY

Based on the renal related blood tests below there did not appear to be any affect of adefovir 10 mg once daily on the key tests creatinine, phosphate, and bicarbonate.. There were elevations in amylase & lipase in this study but they were not statistically significant.

At baseline for this study serum creatinine was required to be <133 umol/l, serum phosphate > 0.65 mmol/l; amylase <1.5 times upper limit of normal; neutrophil count >750 x 10(6); platelets >50,000 10(6)/l, hemoglobin >80 g/l. Persons with decompensated cirrhosis were not permitted study entry. Individuals were not permitted prior adefovir use, history of neuropathy, clinically significant renal dysfunction within 12 months prior to study. Use of carnitine was not permitted.

Serum Creatinine

At baseline: 80 mmol/l, Week 24: 81 mmol/l (p=0.2)

Serum Phosphate

At baseline: 0.8 mmol/l, at week 24: 0.8 mmol/l (p=0.9)

Serum bicarbonate

24.8 mmol/l 24.8 mmol/l, at week 24: 24.3 mmol/l (p=0.9)

Serum amylase (normal lab upper limits of amylase & lipase are 50 IU/l and 120 IU/l, respectively)

At baseline: 95 IU/L, at week 24:  109 IU/l (p=0.7)

Serum lipase

At baseline: 50 IU/l, at week 24: 85 IU/l (p=0.9)

CD4 count was 423 at baseline & 456 at week 24 (P=0.2)

HIV viral load was 2.9 log at baseline & 2.5 log at week 24 (p=0.3)

BASELINE CHARACTERISTICS

Liver Histology (METAVIR)

Liver histology was not required for this study, so only 23/35 persons had biopsies which were performed within 18 months before study enrollment: 5/23 (22%) had cirrhosis; mean fibrosis 2 0.2, mean activity 1.4 0.2.

--M550V + L526 M 29/35 (83%), with V519L 21/35 (60%), without V519L 8/35 (23%)

--M550I + L526M 4/35 (11%), with V519L 3 (9%), without V519L 1/35 (3%)

--M550V+M550I+M526M 1 (3%)

--M550I 1 (3%)