Entecavir Intensification for Persistent HBV Viremia in HIV-HBV Infection

Design: This is a randomized, controlled pilot study of open-label entecavir for the treatment of persistent HBV viremia in HIV-HBV coinfected individuals who have failed to suppress HBV replication after 48 weeks on tenofovir containing therapy.

Primary Objective: To evaluate the mean log reduction of HBV DNA with entecavir(ETV) intensification in comparison to continued standard therapy with tenofovir and lamivudine/emtricitabine at 24 weeks of therapy

Study Population: HIV-HBV co-infected individuals with detectable HBV DNA after 48 weeks of therapy with tenofovir and lamivudine/emtricitabine whose HIV viremia is well controlled ( < 75 copies at time of enrollment)

Treatment: Subjects will be randomized to continue with standard therapy or to receive intensification with 1 mg daily of open label entecavir for the 24 week duration of the study.

Sample Size: 24 subjects will be enrolled.

Duration 24 weeks of treatment

Primary Endpoint: Mean log10 reduction of HBV DNA at 24 weeks of standard therapy vs. entecavir intensification.

Inclusion criteria

• Ability and willingness to provide written informed consent
• HIV infection, documented in patient medical record. Acceptable forms of documentation include positive HIV antibody or detectable HIV RNA.
• Chronic HBV infection, defined as HBsAg positivity. Both hepatitis B "e" antigen (HBeAg) positive and negative subjects will be eligible.
• Detectable HBV DNA ( > 160 copies/ml) after 48 weeks of therapy with TDF in conjunction with either 3TC or FTC
• Compensated liver disease, defined as a Child-Pugh-Turcot(CPT) Score <7 at the time of enrollment.

Note: If Bilirubin in elevated, direct and indirect bilirubin levels will be evaluated. If only indirect bilirubin elevated, direct bilirubin will be used for CPT score. If BOTH direct and indirect bilirubin are elevated, total bilirubin will be used for the CPT score.

• Stable antiretroviral therapy with no changes in the prior 8 weeks due to antiretroviral failure. HIV therapy modification for reasons other than virologic failure and without change in the tenofovir(TDF), lamivudine(3TC) or emtricitabine(FTC) moiety of the antiretroviral therapy will be permitted. HIV therapy must include TDF in conjunction with 3TC or FTC, and at least one other anti-HIV agent.
• HIV RNA of <75 copies/ml within 8 weeks of study enrollment.
• Estimated creatinine clearance by Cockcroft-Gault of ≥ 50 ml/min
• Serum alpha-fetoprotein (AFP) of ≤50 ng/ml within 8 weeks of study entry, or if elevated > 50 ng/ml, an imaging study demonstrating no evidence of hepatic tumor within 8 weeks of enrollment.
• Female study volunteers must not participate in a conception process (e.g., active attempt to become pregnant). If participating in sexual activity that could lead to pregnancy, the female study volunteer must use the following forms of contraception while receiving study-specific medication(s) and for 30 days after stopping the medication. One of the following methods MUST be used appropriately:

• Condoms1 (male or female) with or without a spermicidal agent
• Diaphragm or cervical cap with spermicide
• intrauterine device(IUD)
• Hormonal-based method

• Condoms are recommended because their appropriate use is the only contraception method effective for preventing HIV transmission.

Note: Subjects with concomitant Hepatitis C infection will be permitted to enroll.

Exclusion criteria

• Allergy or sensitivity to study drug
• Pregnancy, breastfeeding or unwillingness/inability to adhere to contraceptive methods for the duration of the study
• Prisoners or subjects who are incarcerated.
• Evidence of malignancy that would make the subject, in the opinion of the investigator, unsuitable for the study. This includes any systemic antineoplastic or immunomodulatory treatment or radiation within 24 weeks prior to study entry or the expectation that such treatment will be needed at any time during the study.
• Receipt of systemic corticosteroids within 90 days prior to study entry (as this medication may increase HBV replication).
• Investigational anti-HIV agents will be allowed on a case-by-case basis with the approval of the protocol team.
• Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements.
• Any active medical, psychiatric or social circumstance that in the opinion of the investigator puts the subject at potential risk from study participation or makes adherence to the study protocol unlikely.
• Receipt of the following drugs with anti-HBV activity within 90 days prior to study entry or anticipated receipt during the course of the study including: adefovir(ADV), telbivudine, alpha interferon, penciclovir (Denavir) (except if given for < 4 weeks), famciclovir (Famvir), diaminopurine dioxolane (DAPD), clevudine (L-FMAU), thymosin alpha 1, ganciclovir (treatment limited to < 7 days is acceptable) (Cytovene), L-deoxythymidine, and L-deoxythymidine compounds and other investigational agents with anti-HBV activity.
• Receipt of nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, vancomycin, cidofovir [Vistide], foscarnet [Foscavir], cisplatin, intravenous pentamidine [Pentam], oral tacrolimus [Prograf], cyclosporine [Sandimmune]) or the competitor of renal excretion, probenecid (Benemid), within 8 weeks prior to study entry or expected use of these agents during the course of the study. (Topical tacrolimus is allowed.)