"Entecavir in HIV/HBV Co-Infected Patients: Safety and Efficacy in a Phase II Study (ETV-038)"
Reported by Jules Levin
MG Pessoa reported week 24 results from the study of entecavir, a new drug for hepatitis B, in co-infected patients. In study 038 51 HIV+ patients added entecavir to a 3TC containing HAART regimen and 17 patients received placebo. HBV DNA (viral load was reduced by -3.66 log at week 24. There were no safety issues. CD4 & HIV RNA remained the same through the 24 week study.
The FDA is reviewing entecavir for approval now. At the annual liver meeting (AASLD, Nov 2004), three key phase III studies were reported:
Entecavir: new hepatitis B drug-phase III study results of 48-weeks therapy in HBeAg+ nucleoside-naïve patients
Entecavir: new HBV drug, phase III study in nucleoside-naïve HBeAg-negative patients
Entecavir in Lamivduine Experienced Patients
Pessoa reported this background:
--Worldwide HBV infection- 350-370 million
--Worldwide HIV infection- 40 million
--Co-infection with HBV occurs in 10% of HIV (+) population worldwide
--Increased liver mortality with co-infection
--90% of HBV (+)/ HIV (+) patients developed 3TC resistance after 4 years of therapy
--Potent and selective inhibitor of HBV DNA polymerase
--No anti-HIV activity
--No inhibition of human mitochondrial (gamma) polymerase
--No interaction with CYP450 system or P-GP
--Lack of PK interaction with 3TC, adefovir, or tenofovir
--Superior to 3TC in Phase III studies in the following HBV-infected patients:
HBeAg (+) and HBeAg (-), 3TC-refractory
--Well-tolerated with safety profile comparable to 3TC
51 patients were randomized to entecavir 1,0 mg once daily plus continued 3TC (150mg bid or 300mg QD), or entecavir placebo plus continued 3TC (n=17). HBV DNA levels were evaluated by PCR assay at weeks 2, 12, & 24. After week 24 open-label entecavir was offered until the end of the study at week 48.
Age >=16 years
HIV/HBV co-infection; no evidence of HCV or HDV infection
3TC-containing HAART for >=24 weeks prior to enrollment or presence of YMDD mutation
HIV RNA <400 copies/mL >=12 weeks prior to screening
HBV DNA >=105 log10 copies/mL (by PCR) >=4 weeks prior to screening
HBeAg-positive or HBeAg-negative/HBeAb-positive
HBsAg-positive for >=24 weeks prior to screening
Compensated liver disease
Screening serum ALT <=10 x ULN
No concomitant medications with activity against HBV (except for 3TC)The
Primary Study Endpoints
EFFICACY: mean HBV DNA reduction by PCR (Roche Amplicor) Assay) assay at week 24
SAFETY: proportion of patients who discontinue study due to AEs.
41 yrs old
51 patients in the Entecavir group: 80% Caucasian 20% black/African American
17 patients in the placebo group: 100% Caucasian.
About 50% of the patients were from South America, 35% from Europe, 12-16% from North America.
--HBV DNA by PCR was 9.13 log in entecavir arm & 9.12 in the placebo arm.
46/48 in the entecavir arm & 14/15 in the placebo arm had HBV 3TC mutations.
--99% of patients were HBV eAg positive.
--Mean ALT was 75 in entecavir arm & 61 IU/L in placebo group.
--mean HIV RNA was 2.15 log in entecavir arm & 2.03 in placebo group.
--mean CD4 count was 508 in entecavir arm & 520 in placebo group
Proportion of patients with HBV DNA <400 copies/ml or >=2 log reduction from baseline:
Entecavir- 76% at week 12 & 84% at week 24 (on-treatment analysis); 0 for placebo.
Proportion of Patients with ALT Normalization at week 24:
| ||<1.25 x ULN ||<1 x ULN |
|entecavir ||46% ||34%* |
|Placebo ||17% ||8% |
*entecavir vs placebon at week 24 (p=0.08)
HIV RNA & CD4 count remained unchanged during 24 week study
MEAN CHANGE IN HBV DNA from baseline to week 24 by PCR
-3.66 log for entecavir group vs no change for the placebo group.
The profile was similar for both groups. 83% had any AE. 15% in the ETV arm had grade 3-4 ALT flares & 6% had this in placebo. ALT 3 x baseline: 14% ETV, 12% placebo.
No patients discontinued in either group due to AE.
SERIOUS AE: 1 patient on ETV had encephalopathy on day 5 of therapy & esophageal varoces reported on day 44 of therapy. These events were considered not to be drug related. There were no deaths in the study.
CLINICAL ADVERSE EVENTS REPORTED
Profile was similar for both treatment groups:
Diarrhea: 6% ETV, 12% placebo
Vomiting: 6% ETV, 12% placebo
Depression: 0% ETV, 12% placebo
HIV viral load & CD4 counts did not change during the 24 weeks on entecavir.