Significant and Sustained Efficacy of Adefovir After 4 Years of Treatment in Chronic HBV Patients with Lamivudine-Resistant HBV and HIV Coinfection
Reported by Jules Levin
Yves Benhamou and colleagues including Gilead Sciences reported this information & study results at Digestive Disease Week annual conference May 2004 in New Orleans, LA in the opening hepatitis oral session.
10% of HIV-infected patients are HBsAg carriers. HIV/HBV co-infection is associated with a higher prevalence of cirrhosis than HIV-negative chronic Hepatitis B (CHB). HBV co-infection decreases survival in HIV-infection. Lamivudine (LAM) is effective in reducing HBV DNA however is associated with the rapid development of resistance in HIV coinfection in 47% of patients by 2 years and 90% by 4 years.
Adefovir has activity against wild-type and LAM-resistant (LAM-R) HBV. ADV dose is one 10 mg tablet once daily. It has demonstrated efficacy & safety in CHB for treatment periods up to 144 weeks, with durable HBV DNA suppression and with a high threshold for the development of resistance.
The incidence of drug resistance has been reported out to 3 years for ADV & 4 yrs for LAM: incidence at 1, 2, and 3 years for ADV—0%, 2%, and 3.9%, respectively; for LAM—24%, 42%, 53%, and 70%--in HBV/HIV HBV YMDD resistance, LAM-R has been reported at 47% after 2 years and 90% after 4 years. Regardless, for coinfected patients the development of 3TC resistance is an issue.
BRIEF SUMMARY OF STUDY RESULTS REPORTED BY INVESTIGATORS: 35 patients in this study. HBV DNA (viral load) decreased at increasing proportions over 192 weeks to --6.0 log at week 192 (n=24). Baseline HBV DNA 9.76 log copies/ml. At week 192, 59% of patients had undetectable (<1000 copies/ml) HBV DNA. Mean ALT was 81 IU/L at baseline and 32 Iu/L at week 192 with 70% achieving normalization. Fibrosis (METAVIR Score) improved in 50% and worsened in 8% at week 192 (1 pt reduction or increase defined improvement or worsening). No evidence of ALT flares. See safety report below as author's report no ADV nephrotoxicity, two mild transient serum creatinine elevations. No ADV resistance, no changes in HIV disease (CD4, viral load). HBeAg loss and HBeAb seroconversion was observed in 3 and 2 patients.
KEY SELECTION CRITERIA
Serum HBV DNA positive by hybridization assays or >=6 log10 copies/ml by PCR.
Ongoing LAM (150 mg bid) therapy.
LAM-R confirmed by genotyping at baseline.
HIV RNA <=2.6 log10 copies/ml.
ALT levels of >=1.2 x ULN.
Adequate renal function.
ADV 10 mg once daily was added to existing anti-retroviral therapy (ART) including ongoing LAM 150 mg bid for 192 weeks. Changes to ART were permitted. Patients were seen monthly in the first 48 weeks, then every 12 weeks from week 48 to 192. Assessments at each visit included: adverse events, HBV & HIV markers, laboratory (chemistry, hematology, urinalysis).
LAB MEASURES: serum HBV DNA, Roche Amplicor COBAS PCR (LLQ 2.3 log10 c/ml). Plasma HIV RNA: Roche Amplicor PCR, HIV Monitor 1.5 (LLQ2.3 log10 copies/ml). Serum ALT. CD4 cell count. Gene sequencing: HBV reverse transcriptase (RT) domain sequenced for all patients with detectable HBV DNA annually. HIV RT domain sequenced for all patients with detectable HIV RNA.
BASELINE DEMOGRAPHICS & HIV DISEASE CHARACTERTISTICS
N=35. Median age 39 yrs; 34 men/1 female; median prior LAM: 42 months; HIV RNA (log10 copies/ml) mean 2.88; CD4 count mean 422 cells.
History of HBV DNA for the patients in the study: Over the course of about 4 years prior to starting HBV, HBV DNA was detectable prior to LAM, undetectable during LAM, then broke through and detectable for about 2 years before starting ADV.
History of Mean HBV DNA (pg/mL): over 21 month period-- pre-LAM 2,200, initial LAM undetectable, breakthrough about 800; during 23 month period following breakthrough—HBV DNA about 1,500 6 months prior to ADV & 3 months prior a little higher, and a bit higher at baseline.
BASELINE HBV DISEASE CHARACTERISTICS
Median HBV DNA (log10 copies/ml) 9.76
Median ALT (IU/L) 81
HBeAg positive 33 (94%)
Liver Histology (METAVIR) n=23
Mean activity (±SEM) 1.52 ± 0.15
Mean fibrosis (±SEM) 2.04 ± 0.24
Cirrhosis 5 (22%)
MEDIAN CHANGE from BASELINE in SERUM HBV DNA
-4.7 log* c/ml at week 48 (n=31)
-5.5 log* c/ml at week 96 (n=30)
-5.9 log* c/ml at week 144 (n=29)
-6.0 log* c/ml at week 192 (n=24)
Median serum ALT (IU/L): 53, 46, 31, 32 at weeks 48, 96, 144, 192, respectively*
ALT NORMALIZATION: 35%, 47%, 66%, 70% at weeks 48, 96, 144, 192, respectively.
HBV DNA <1000 copies/ml: 0% at baseline; 6%, 27%, 46%, 59% at weeks 48, 96, 144, 192, respectively.
Improvement in Fibrosis -- METAVIR Score
Week 48 n=15: 33% improved; 20% worsened
Week 192 n=12: 50% improved, 8% worsened
Definitions: worsened 1 pt or greater increase; improved 1 pt or greater reduction.
HBeAg loss and HBeAb seroconversion was observed in 3 and 2 patients, respectively. Cessation of LAM in 3 pts had no impact on serum HBV DNA or ALT levels. No significant changes in plasma HIV RNA levels and CD4 counts over 192 weeks.
no ADV-related nephrotoxicity up to 192 weeks: two mild transient serum creatinine elevations (>=0.5 mg/dL increase from baseline) in year one—both resolved with discontinuation of ADV and other medications; ADV re-instituted and continued for >3 years with no recurrence. No serum phosphorous <1.5 mg/dL.
No evidence of ALT flares on treatment up to 192 weeks: transient ALT increase in the first 12 weeks in the first 12 weeks followed by sustained ALT reduction and normalization.
3 serious adverse events reported, all unrelated to ADV: 2 pts developed hepatocellular carcinoma and died from disease progression.
HBV & HIV RESISRANCE SURVEILLANCE
Benhamou reported no ADV associated HBV polymerase resistance (rtN236T, rtA181V) identified at weeks 48, 96, and 144. Week 192 HBV pol genotyping in progress. No ADV associated HIV RT mutations (K65R, K70E) identified at weeks 48, 96 and 144. Week 192 HIV RT genotyping in progress.
AUTHOR CONCLUSIONS AT 4 YEARS
Long term administration of ADV 10 mg in HIV+ patients with LAM-R HBV demonstrated:
--significant and sustained reductions in serum HBV DNA & ALT
--increasing proportions of patients with undetectable serum HBV DNA and ALT normalization
--safety profile similar to that seen in 1 year of placebo-controlled studies
--no influence on HIV disease
--no adefovir associated HBV or HIV resistance up to 144 weeks
--study is ongoing for up to 5 years