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Three Year Treatment with Adefovir in Chronic Hepatitis B Patients with Lamivudine (3TC) Resistant HBV and HIV Coinfection Results in Significant and Sustained Clinical Improvement
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Yves Benhamou (GH Pitie-Salpetriere, Paris, France) and colleagues from Gilead Sciences reported on the results of using adefovir to treat HBV in HBV/HIC coinfected patients (poster 835) at the 11th Annual Retrovirus Conference (Feb 8-11, 2004, San Francisco). They reported results after 3 years of adefovir treatment.
SUMMARY: This is a study of HBV/HIV coinfected patients who were receiving HAART with 3TC and who added adefovir 10 mg tablet taken once daily for treatment of chronic hepatitis B. Median HBV DNA (HBV viral load) progressively decreased to a decrease of --5.25 log copies/ml from baseline at week 144, 3 years. At baseline o% of patients had <1,000 copies/ml HBV DNA viral load, and at week 144 64% of patients had HBV DNA <1000 copies/ml. When the study started 3% of patients had normal ALT and at week 144 64% had normalized ALT. No adefivir HBV or HIV (K65R, K70E) genotypic mutations were observed through 144 weeks therapy. The authors reported adefovir was well tolerated. There was no evidence of nephrotoxicity. HIV viral load and Cd4 count remained stable throughout the 3 years. There was no evidence of ALT falres, there were transient elevations reported in first 12 weeks which the authors reported were followed by sustained ALT reduction and normalization. Stopping of 3TC did not result in increases of HBV DNA viral load. These results suggest that adefovir can be considered for treating chronic HBV in HIV coinfected patients on HAART.
BACKGROUND
Adefovir (ADV) is a nucleotide analalogue of adenosine monophosphate, and is a chain terminator of HBV DNA. ADV has activity against wild-type (non-resistant) HBV and 3TC (lamivudine) resistanr HBV(1). The dosing is one tablet of once daily orally, but the dose interval is modified for creatinine clearance <50 mL/min. ADV has shown HBV DNA (HBV viral load) suppression with a high threshold for the development of drug resistance, it is difficult to develop resistance to ADV. The safety profile for 48 weeks in study (1, 2) has been presented and it was similar to placebo, and the safety profile over 96 weeks was similar.
The objective of this study was to evaluate the safety and efficacy of ADV once daily for the treatment of 3TC-resistant HBV in patients with HIV coinfection up to 144 weeks, 3 years.
Patients had HBV/HIV coinfection; positive serum HBV DNA by hybridization assays or >=6 log10 copies/ml by Roche Amplicor Monitor PCR assay; had ongoing 3TC therapy, ALT levels >=1.2 x ULN; 3TC-resistant with HBV ploymerase gene mutations (M204V or M204!) confirmed at baseline; HIV RNA <=2.3 log copies/ml (c/ml); adequate renal function (serum creatinine <1.5 mg/dL).
ADV once daily was added to existing antiretroviral therapy (ART) including ongoing 3TC 150 mg twice daily (bid) for 144 weeks; changes to ART were permitted; patients were seen monthly in the first 48 weeks, then every 12 weeks from week 48 to week 144. They were assessed for adverse events, HBV & HIV markers, and laboratory values (hematology, chemistry, urinalysis).
Lab measurements used: Serum HBV DNA—Roche Amplicor COBAS PCR (LLQ 2.3 log10 c/ml); plasma HIV RNA—Roche Amplicor PCR HIV Monitor 1.5 (LLQ 2.3 log c/ml). Sequencing of the HIV RT and HBV DNA polymerase was done at weeks 48, 96, and 144; serum ALT; CD4 cell count.
BASELINE CHARACTERISTICS: 35 patients; median age 39 yrs; 34 men; median prior 3TC use: 42 months.
BASELINE HBV DISEASE CHARACTERISTICS: 35 patients; median HBV DNA; 8.75 log c/ml; median ALT: 81 IU/L; HBeAg positive 94%.
LIVER HISTOLOGY (Metavir):
Mean activity: 1.52±0.15
Mean fibrosis: 2.04±
Cirrhosis: 22%
BASELINE HIV CHARACTERISTICS:
Mean HIV RNA: 2.88 log10 c/ml
Mean CD4 cell count: 422
RESULTS
MEDIAN CHANGE IN SERUM HBV DNA
At weeks 48, 96, and 144 the log reduction in HBV DNA was --3.88 (n=31), -4.81 (n=30), and --5.45 (n=28), respectively.
MEDIAN SERUM ALT
Median ALT was 81 IU/L at baseline, and was at weeks 48, 96, and 144 --53 IU/L, 45 IU/L, and 31 IU/L, respectively.
SERUM HBV DNA & ALT
PERCENT OF PATIENTS WITH HBV <=1,000 c/ml
Baseline: 0%
Week 48: 6%
Week 96: 27%
Week 144: 46%
PERCENT WITH ALT NORMALIZATION
Baseline: 3%
Week 48: 19%
Week 96: 37%
Week 144: 64%
OTHER CLINICAL OBSERVATIONS
HBeAg loss and HbeAb serocenversion was observed in 3 and 2 patients, respectively.
Cessation of 3TC in 3 patients had no impact on serum HBV DNA levels.
There were no significant changes in serum HIV RNA levels and CD4 counts over 144 weeks:Mean HIV RNA was 2.66, 2.92, and 2.85 log copies/ml at weeks 48, 96, and 144, respectively.
Mean CD4 count at weeks 48, 96, and 144 was 469, 487, and 492, respectively.
RESISTANCE
No adefovir-associated resistance mutations (rtN236T) in the HBV DNA polymerase or (K65, K70E) in the HIV RT were identified at weeks 48, 96, and 144.
SAFETY
No evidence of nephrotoxicity up to week 144:
--no ADV-related serum creatinine elevations (>=0.5 mg/dL increase from baseline)
--no serum phosphorous <1.5 mg/dL
No evidence of ALT flares on treatment up to 144 weeks:
--transient ALT increase in the first 12 weeks followed by sustained ALT reduction & normalization
Three serious adverse events reported, all unrelated to ADV:
--two patients developed hepatocellular carcinoma and one of these died due to disease progression
AUTHOR CONCLUSIONS
Three year treatment with AFV 10 mg once daily in patients with 3TC resistance and HIC coinfection demonstrated:
--Significant and sustained reductions in serum HBV DNA and ALT levels
--increased magnitude of reduction in serum HBV DNA with treatment duration and no loss of suppression
No adefovir-associated resistance mutations were identified in up to 144 weeks for HBV DNA polymerase and HIV reverse transcriptase
ADV was well tolerated
Patients continue in long-term followup.
REFERENCES
1. Hadziyannis SJ et al. NEJM 2003; 348: 800-807, Feb 27, 2003
2. Marcellin P, et al. NEJM 2003; 348: 808-816; Feb 27, 2003
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