Entecavir Intensification for Persistent HBV Viremia in HIV-HBV Infection

NCT00662545 | Completed Phase 4 Results DMC

• 2 other identifiers: A109324AI463-162
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

HIV Infections; Hepatitis B

Keywords

HIV; Hepatitis B; treatment experienced

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (4)

• Incidence of Permanent Discontinuation Due to Toxicity

  24 weeks

• Incidence of New Hepatic Decompensation( Ascites, Variceal Hemorrhage, Encephalopathy)

  every 4 weeks for 24 weeks

• Incidence of ALT Flares

  every 4 weeks for 24 weeks

• HIV RNA < 75 Copies/ml

  entry, week 12, and week 24

Study Arms (2)

A

EXPERIMENTAL

Entecavir 1 mg for 24 weeks in addition to continued standard of care antiretroviral therapy containing tenofovir in addition to emtricitabine or lamivudine

Drug: Entecavir with continued standard of care antiretroviral therapy

B

ACTIVE COMPARATOR

continued standard of care antiretroviral therapy which will include tenofovir in addition to emtricitabine or lamivudine

Drug: continued standard of care with tenofovir in addition to emtricitabine or lamivudine

Interventions

Entecavir with continued standard of care antiretroviral therapy DRUG

1 mg by mouth daily

Also known as: Baraclude, Tenofovir, Truvada, Viread, 3TC, FTC, Epivir, Emtriva

A

continued standard of care with tenofovir in addition to emtricitabine or lamivudine DRUG

continued standard of care with tenofovir in addition to emtricitabine or lamivudine

Also known as: Tenofovir, Truvada, Viread, 3TC, FTC, Epivir, Emtriva

B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.)

Sponsors & Collaborators

• University of California, San Francisco: lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

San Francisco General HIV Clinical Trials Group

San Francisco, California, 94110, United States

Location

Related Publications (18)

• Thio CL, Seaberg EC, Skolasky R Jr, Phair J, Visscher B, Munoz 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. doi: 10.1016/s0140-6736(02)11913-1.

  PMID: 12493258 BACKGROUND

• 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. doi: 10.1097/01.aids.0000163936.99401.fe.

  PMID: 15802978 BACKGROUND

• 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. doi: 10.1002/hep.510290447.

  PMID: 10094979 BACKGROUND

• 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. doi: 10.1002/hep.1840060203.

  PMID: 3957228 BACKGROUND

• Hoofnagle JH, Shafritz DA, Popper H. Chronic type B hepatitis and the "healthy" HBsAg carrier state. Hepatology. 1987 Jul-Aug;7(4):758-63. doi: 10.1002/hep.1840070424. No abstract available.

  PMID: 3301618 BACKGROUND

• 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. doi: 10.1093/jnci/dji043.

  PMID: 15713961 BACKGROUND

• 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. doi: 10.1111/j.1572-0241.2006.00647.x. Epub 2006 Jun 30.

  PMID: 16817842 BACKGROUND

• 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. doi: 10.1001/jama.295.1.65.

  PMID: 16391218 BACKGROUND

• 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. doi: 10.1056/NEJMoa033364.

  PMID: 15470215 BACKGROUND

• 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. doi: 10.1093/jac/dki396. Epub 2005 Nov 3.

  PMID: 16269552 BACKGROUND

• 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. doi: 10.1002/hep.21055.

  PMID: 16496322 BACKGROUND

• 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, Schurmann 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. doi: 10.1097/01.aids.0000247116.89455.5d.

  PMID: 16988516 BACKGROUND

• Sheldon J, Camino N, Rodes B, Bartholomeusz A, Kuiper M, Tacke F, Nunez 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.

  PMID: 16218172 BACKGROUND

• 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. doi: 10.1056/NEJMoa051285.

  PMID: 16525137 BACKGROUND

• 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. doi: 10.1056/NEJMoa051287.

  PMID: 16525138 BACKGROUND

• 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. doi: 10.1053/j.gastro.2006.04.007.

  PMID: 16762627 BACKGROUND

• 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. doi: 10.1056/NEJMoa067710.

  PMID: 17582071 BACKGROUND

• 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. doi: 10.1056/NEJM200301093480218. No abstract available.

  PMID: 12519935 BACKGROUND

MeSH Terms

Conditions

HIV Infections; Hepatitis B

Interventions

entecavir; Tenofovir; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Racivir; Lamivudine; Emtricitabine

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Hepadnaviridae Infections; DNA Virus Infections; Hepatitis, Viral, Human; Hepatitis; Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Drug Combinations; Pharmaceutical Preparations; Zalcitabine; Dideoxynucleosides

Results Point of Contact

• Title: Anne Luetkemeyer
• Organization: UCSF SFGH

aluetkemeyer@php.ucsf.edu

415 476 4082

Study Officials

• Anne F Luetkemeyer, MD

  HIV/AIDS Division, San Francisco General Hospital, University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 16, 2008
• First Posted: April 21, 2008
• Study Start: April 1, 2008
• Primary Completion: February 1, 2010
• Study Completion: May 1, 2010
• Last Updated: May 27, 2013
• Results First Posted: May 16, 2013

Record last verified: 2013-05

Locations

US (1)