Entecavir Intensification for Persistent HBV Viremia in HIV-HBV Infection

HIV Infections Clinical Trial

Official title:

Entecavir Intensification for Persistent Hepatitis B Virus (HBV) Viremia in HIV-HBV Infection

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00662545
• Other study ID #: A109324
• Secondary ID: AI463-162
• Status: Completed
• Phase: Phase 4
• First received: April 16, 2008
• Last updated: May 17, 2013
• Start date: April 2008
• Est. completion date: May 2010

Study information

• Verified date: May 2013
• Source: University of California, San Francisco
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

This study will evaluate HIV-HBV infected individuals who have evidence of HBV replication in the blood after taking 48 weeks of more of the HBV active medication tenofovir in combination with emtricitabine or lamivudine. Eligible participants will be randomized to receive 24 weeks of entecavir (ETV) 1 mg versus continued standard of care antiretroviral therapy. After 24 weeks, individuals on entecavir or who remain HBV viremic on standard of care will receive ETV o for an additional 24 weeks. The hypothesis is that intensification with entecavir will reduce HBV DNA at 24 weeks more than continued antiretroviral therapy without entecavir.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: May 2010
• Est. primary completion date: February 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

1. 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.)

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis B
• HIV Infections
• Infection

Intervention

Drug:
• Entecavir with continued standard of care antiretroviral therapy
1 mg by mouth daily
• continued standard of care with tenofovir in addition to emtricitabine or lamivudine
continued standard of care with tenofovir in addition to emtricitabine or lamivudine

Locations

Country	Name	City	State
United States	San Francisco General HIV Clinical Trials Group	San Francisco	California

Sponsors (2)

Lead Sponsor	Collaborator
University of California, San Francisco	Bristol-Myers Squibb

Country where clinical trial is conducted

United States, 

References & Publications (18)

Benhamou Y, Fleury H, Trimoulet P, Pellegrin I, Urbinelli R, Katlama C, Rozenbaum W, Le Teuff G, Trylesinski A, Piketty C; TECOVIR Study Group. Anti-hepatitis B virus efficacy of tenofovir disoproxil fumarate in HIV-infected patients. Hepatology. 2006 Mar;43(3):548-55. — View Citation

Benhamou Y, Tubiana R, Thibault V. Tenofovir disoproxil fumarate in patients with HIV and lamivudine-resistant hepatitis B virus. N Engl J Med. 2003 Jan 9;348(2):177-8. — View Citation

Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, Lok AS, Han KH, Goodman Z, Zhu J, Cross A, DeHertogh D, Wilber R, Colonno R, Apelian D; BEHoLD AI463022 Study Group. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006 Mar 9;354(10):1001-10. — View Citation

Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, Huang GT, Iloeje UH; REVEAL-HBV Study Group. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006 Jan 4;295(1):65-73. — View Citation

Chen G, Lin W, Shen F, Iloeje UH, London WT, Evans AA. Past HBV viral load as predictor of mortality and morbidity from HCC and chronic liver disease in a prospective study. Am J Gastroenterol. 2006 Aug;101(8):1797-803. Epub 2006 Jun 30. — View Citation

Colin JF, Cazals-Hatem D, Loriot MA, Martinot-Peignoux M, Pham BN, Auperin A, Degott C, Benhamou JP, Erlinger S, Valla D, Marcellin P. Influence of human immunodeficiency virus infection on chronic hepatitis B in homosexual men. Hepatology. 1999 Apr;29(4):1306-10. — View Citation

Fattovich G, Rugge M, Brollo L, Pontisso P, Noventa F, Guido M, Alberti A, Realdi G. Clinical, virologic and histologic outcome following seroconversion from HBeAg to anti-HBe in chronic hepatitis type B. Hepatology. 1986 Mar-Apr;6(2):167-72. — View Citation

Hoofnagle JH, Shafritz DA, Popper H. Chronic type B hepatitis and the "healthy" HBsAg carrier state. Hepatology. 1987 Jul-Aug;7(4):758-63. Review. — View Citation

Konopnicki D, Mocroft A, de Wit S, Antunes F, Ledergerber B, Katlama C, Zilmer K, Vella S, Kirk O, Lundgren JD; EuroSIDA Group. Hepatitis B and HIV: prevalence, AIDS progression, response to highly active antiretroviral therapy and increased mortality in the EuroSIDA cohort. AIDS. 2005 Mar 24;19(6):593-601. — View Citation

Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, DeHertogh D, Wilber R, Zink RC, Cross A, Colonno R, Fernandes L; BEHoLD AI463027 Study Group. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2006 Mar 9;354(10):1011-20. Erratum in: N Engl J Med. 2006 Apr 27;354(17):1863. — View Citation

Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, Tanwandee T, Tao QM, Shue K, Keene ON, Dixon JS, Gray DF, Sabbat J; Cirrhosis Asian Lamivudine Multicentre Study Group. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004 Oct 7;351(15):1521-31. — View Citation

McMahon MA, Jilek BL, Brennan TP, Shen L, Zhou Y, Wind-Rotolo M, Xing S, Bhat S, Hale B, Hegarty R, Chong CR, Liu JO, Siliciano RF, Thio CL. The HBV drug entecavir - effects on HIV-1 replication and resistance. N Engl J Med. 2007 Jun 21;356(25):2614-21. — View Citation

Schmutz G, Nelson M, Lutz T, Sheldon J, Bruno R, von Boemmel F, Hoffmann C, Rockstroh J, Stoehr A, Wolf E, Soriano V, Berger F, Berg T, Carlebach A, Schwarze-Zander C, Schürmann D, Jaeger H, Mauss S. Combination of tenofovir and lamivudine versus tenofovir after lamivudine failure for therapy of hepatitis B in HIV-coinfection. AIDS. 2006 Oct 3;20(15):1951-4. — View Citation

Sheldon J, Camino N, Rodés B, Bartholomeusz A, Kuiper M, Tacke F, Núñez M, Mauss S, Lutz T, Klausen G, Locarnini S, Soriano V. Selection of hepatitis B virus polymerase mutations in HIV-coinfected patients treated with tenofovir. Antivir Ther. 2005;10(6):727-34. — View Citation

Sherman M, Yurdaydin C, Sollano J, Silva M, Liaw YF, Cianciara J, Boron-Kaczmarska A, Martin P, Goodman Z, Colonno R, Cross A, Denisky G, Kreter B, Hindes R; AI463026 BEHoLD Study Group. Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B. Gastroenterology. 2006 Jun;130(7):2039-49. — View Citation

Stephan C, Berger A, Carlebach A, Lutz T, Bickel M, Klauke S, Staszewski S, Stuermer M. Impact of tenofovir-containing antiretroviral therapy on chronic hepatitis B in a cohort co-infected with human immunodeficiency virus. J Antimicrob Chemother. 2005 Dec;56(6):1087-93. Epub 2005 Nov 3. — View Citation

Thio CL, Seaberg EC, Skolasky R Jr, Phair J, Visscher B, Muñoz A, Thomas DL; Multicenter AIDS Cohort Study. HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS). Lancet. 2002 Dec 14;360(9349):1921-6. — View Citation

Yu MW, Yeh SH, Chen PJ, Liaw YF, Lin CL, Liu CJ, Shih WL, Kao JH, Chen DS, Chen CJ. Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men. J Natl Cancer Inst. 2005 Feb 16;97(4):265-72. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Hepatitis B Virus (HBV) DNA	HBV DNA carries the genetic blueprint of the virus. How many HBV DNA "particles" or "copies" are found in the blood indicates how rapidly the virus is reproducing in the liver.	week 24	No
Secondary	Incidence of Permanent Discontinuation Due to Toxicity		24 weeks	Yes
Secondary	Incidence of New Hepatic Decompensation( Ascites, Variceal Hemorrhage, Encephalopathy)		every 4 weeks for 24 weeks	Yes
Secondary	Incidence of ALT Flares	ALT flare: sudden increase in blood level of alanine transaminase (ALT)	every 4 weeks for 24 weeks	Yes
Secondary	HIV RNA < 75 Copies/ml		entry, week 12, and week 24	No