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Adefovir for HBV/HIV Coinfection with 3TC Resistance: 4 years followup
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Reported by Jules Levin
"Long-Term Treatment with Adefovir 10 mg (ADV) in Patients with Lamivudine-resistant (LAM-R) HBV and HIV Co-infection Results in Significant and Sustained Clinical Improvement"
Yves Benhamou and colleagues reported results after 192 weeks of treatment in this study at XV International AIDS Conference, July 11-16, in Bangkok, Thailand.
The objective of this study is to evaluate the safety & efficacy of ADV treatment of chronic hepatitis B in 35 patients with lamivudine (3TC) resistant HBV and HIV co-infection up to 192 weeks (year 4).
Benahmou provided this background. 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) demonstrated similar HBV DNA reduction in HIV negative CHB patients and those with HIV co-infection. LAM is, however, associated with the rapid development of HBV resistance in HIV co-infection in 47% of patients by 2 years and 90% by 4 years. Adefovir (ADV) is a nucleotide analogue of adenosine monophosphate; a chain terminator of HBV DNA; has activity against wild-type and LAM --R HBV. ADV dose is one 10 mg tablet once daily (dose interval modified for creatinine clearance <50 mL/min). ADV has demonstrated efficacy & safety in CHB patients for treatment periods up to 144 weeks with a similar safety profile to placebo in 48 week controlled trials. ADV has shown HBV DNA suppression with a high threshold for the development of resistance.
BRIEF SUMMARY: at week 192
--HBV DNA declined -6.2 log c/ml (n=27)
--58% HBV DNA <1000 c/ml; 70% ALT normalized
--improvement in METAVIR Score (fibrosis) at week 48: 33% improved; 20% worsened (n=15); at week 192: 50% improved; 8% worsened (n=12)
--No ADV related nephrotoxicity up to 192 weeks (see details below)
--No evidence of ALT flares on treatment up to 192 weeks
--transient ALT increase in the first 12 weeks followed by sustained ALT reduction and normalization
--HIV remained stable (HIV RNA & CD4)
--HBeAg loss and HBeAb serocenversion was observed in 3 and 2 patients, respectively
--no HBV or HIV resistance seen
COMPARATIVE INCIDENCE OF HBV RESISTANCE IN PATIENTS TREATED WITH ADV OR LAM
| ADV | LAM (YMDD) | LAM (YMDD in HIV/HBV) | | 1 year: | 0% | 24% | | | 2 yrs | 2% | 42% | 47% | | 3 yrs | 3.9% | 53% | | | 4 yrs | Na-yet | 70% | 90% |
KEY SELECTION CRITERIA FOR STUDY SUBJECTS
Serum HBV DNA positive by hybridization assays with 6 log or greater copies/ml by PCR.
Ongoing LAM (150 mg bid) therapy.
LAM-R confirmed at baseline.
HIV RNA 2.6 log or less copies/ml.
ALT levels of 1.2 or more times the upper limit of normal.
STUDY DESIGN
ADV 10 mg once daily was added to existing ART including 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 weeks.
Assessments made at each visit include:
--adverse events
--HBV & HIV markers
--lab tests: chemistry, hematology, urinalysis
LAB MEASURES
--serum HBV DNA: Roche Amplcor COBAS PCR (LLQ 2.3 log c/ml)
--Plasma HIV RNA: Roche Amplicor PCR, HIV Monitor 1.5 (LLQ 2.3 log c/ml)
--Gene sequencing: HBV reverse transcriptase (RT) domain sequencing for all patients with detectable HBV DNA
--Serum ALT
--CD4 cell count
BASELINE DEMOGRAPHICS & HIV DISEASE MARKERS
N=35
39 yrs median age
34 males
42.3 median prior months LAM
2.88 log mean HIV RNA
422 mean CD4 count
PRIOR HBV DNA RESPONSE TO LAM
At initiation of LAM mean HBV DNA was 2000 pg/mL. Viral load was reduced to low level and then breakthrough occurred to between 500-1000 pg/mL. 6 months prior to starting ADV mean viral load increased to about 1800 pg/mL where it remained until ADV was started in this study.
BASELINE HBV DISEASE CHARACTERISTICS
Median HBV DNA: 9.76 log c/ml
Median ALT: 81 IU/L
HBeAg positive: 94%
Liver Histology:
--mean Activity: 1.52
--mean Fibrosis: 2.04
--cirrhosis: 22%
RESULTS
MEDIAN CHANGE FROM BASELINE IN SERUM HBV DNA
--week 48: -4.7 log c/ml (n=31)
--week 96: -5.5 log c/ml (n=30)
--week 144: -5.9 log c/ml (n=29)
--week 192: -6.2 log c/ml (n=27)
MEDIAN SERUM ALT was 81 at baseline, increased to 110 at week 12, and steadily declined after this to 30 at week 192.
SERUM HBV DNA & ALT RESPONSE
Baseline: 0% HBV DNA <1000 c/ml; 6% ALT normal
Week 48: 6% HBV DNA <1000 c/ml; 35% ALT normalization
Week 96: 27% HBV DNA <1000 c/ml; 47% ALT normalized
Week 144: 46% HBV DNA <1000 c/ml; 66% ALT normalized
Week 192: 58% HBV DNA <1000 c/ml; 70% ALT normalized
HBeAg loss and HBeAb serocenversion was observed in 3 and 2 patients, respectively.
Cessation of LAM in 3 patients had no impact on serum HBV DNA or ALT levels.
Median HIV RNA remained the same, 2.3 log. Median CD4 count remained about the same.
IMPROVEMENT IN FIBROSIS -- METAVIR SCORE
Improvement defined as 1point or more reduction.
Worsening defined as 1 point or more increase.
WEEK 48: 33% improved; 20% worsened (n=15)
WEEK 192: 50% improved; 8% worsened (n=12)
Median METAVIR Fibrosis Score at baseline was=2.
SAFETY
No ADV related nephrotoxicity up to 192 weeks
--two serum creatinine elevations (>=0.5 mg/dL increase from baseline) in year 1: both resolved with discontinuation of ADV and other medications; ADV re-instituted and continued for >3 yrs 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 followed by sustained ALT reduction and normalization
Three serious advsere events reported, all unrelated to ADV.
Two patients developed hepatocellular carcinoma and one died due to disease progression.
HBV & HIV RESISTANCE
No ADV associated HBV polymerase resistance mutations (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 CONCLUSION
ADV 10 mg daily in patients with CHB, LAM-R HBV, and HIV co-infection demonstrated:
--significant and sustained reductions in serum HBV DNA and ALT
--increased proportion of patients with undetectable serum HBV DNA (<1000 copies/ml) and ALT normalization
HIV disease (CD4 & HIV RNA) remains stable.
No ADV associated resistance mutations up to 144 weeks.
Long-term safety profile of ADV was similar to that seen in year one of the placebo controlled studies: no ADV associated nephrotoxicity up to 192 weeks.
Study is ongoing for up to 5 yrs.
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