Entecavir Intensification for Persistent HBV Viremia in HIV-HBV Infection

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Completed
• CT.gov ID: NCT00662545
• Collaborator: Bristol-Myers Squibb (Industry)
• Enrollment: 10
• Location: 1
• Arms: 2
• Duration (Months): 25
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
HIV Infections; Hepatitis B	Drug: Entecavir with continued standard of care antiretroviral therapy; Drug: continued standard of care with tenofovir in addition to emtricitabine or lamivudine	Phase 4

Detailed 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Entecavir Intensification for Persistent Hepatitis B Virus (HBV) Viremia in HIV-HBV Infection
• Study Start Date: Apr 1, 2008
• Actual Primary Completion Date: Feb 1, 2010
• Actual Study Completion Date: May 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A 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; 1 mg by mouth daily; Other Names: Baraclude, Tenofovir, Truvada, Viread, 3TC, FTC, Epivir, Emtriva
Active Comparator: B 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; continued standard of care with tenofovir in addition to emtricitabine or lamivudine; Other Names: Tenofovir, Truvada, Viread, 3TC, FTC, Epivir, Emtriva

Outcome Measures

Primary Outcome Measures

1. Hepatitis B Virus (HBV) DNA [week 24]

   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.

Secondary Outcome Measures

1. Incidence of Permanent Discontinuation Due to Toxicity [24 weeks]

2. Incidence of New Hepatic Decompensation( Ascites, Variceal Hemorrhage, Encephalopathy) [every 4 weeks for 24 weeks]

3. Incidence of ALT Flares [every 4 weeks for 24 weeks]

   ALT flare: sudden increase in blood level of alanine transaminase (ALT)

4. HIV RNA < 75 Copies/ml [entry, week 12, and week 24]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	San Francisco General HIV Clinical Trials Group	San Francisco	California	United States	94110

Sponsors and Collaborators

• University of California, San Francisco
• Bristol-Myers Squibb

Investigators

• Principal Investigator: Anne F Luetkemeyer, MD, HIV/AIDS Division, San Francisco General Hospital, University of California, San Francisco

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT00662545
• Other Study ID Numbers: A109324; AI463-162
• First Posted: Apr 21, 2008
• Last Update Posted: May 27, 2013
• Last Verified: May 1, 2013

• Keywords provided by University of California, San Francisco: HIV; Hepatitis B; treatment experienced
• Additional relevant MeSH terms: Infections; Communicable Diseases; Hepatitis A; Hepatitis B; Viremia; Hepatitis; Tenofovir; Lamivudine; Emtricitabine; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Entecavir; Anti-Retroviral Agents

Study Results

Participant Flow

Recruitment Details	participants recruited from medical clinic, between 7/2008 and 6/2009and 20011
Pre-assignment Detail	Overall sample size was reduced to 10 due to difficulty in recruitment

Arm/Group Title	Entecavir Intensification	Standard of Care
Arm/Group Description	Entecavir 1 mg for 24 weeks in addition to continued standard of care antiretroviral therapy containing tenofovir in addition to emtricitabine or lamivudine	continued standard of care antiretroviral therapy which will include tenofovir in addition to emtricitabine or lamivudine
Period Title: Overall Study
STARTED	5	5
COMPLETED	5	5
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Entecavir Intensification	Standard of Care	Total
Arm/Group Description	Entecavir 1 mg for 24 weeks in addition to continued standard of care antiretroviral therapy containing tenofovir in addition to emtricitabine or lamivudine	continued standard of care antiretroviral therapy which will include tenofovir in addition to emtricitabine or lamivudine	Total of all reporting groups
Overall Participants	5	5	10
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	5 100%	5 100%	10 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	5 100%	5 100%	10 100%
Region of Enrollment (participants) [Number]
United States	5 100%	5 100%	10 100%
HBV DNA at enrollment (log10 IU/ML) [Median (Full Range) ]
Median (Full Range) [log10 IU/ML]	3.2	3.8	3.2

Outcome Measures

1. Primary Outcome

Title	Hepatitis B Virus (HBV) DNA
Description	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.
Time Frame	week 24

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Entecavir Intensification	Standard of Care
Arm/Group Description	Entecavir 1 mg for 24 weeks in addition to continued standard of care antiretroviral therapy containing tenofovir in addition to emtricitabine or lamivudine	continued standard of care antiretroviral therapy which will include tenofovir in addition to emtricitabine or lamivudine
Measure Participants	5	5
Median (Full Range) [log 10 IU/ml]	2.4	0.8

2. Secondary Outcome

Title	Incidence of Permanent Discontinuation Due to Toxicity
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Entecavir Intensification	Standard of Care
Arm/Group Description	Entecavir 1 mg for 24 weeks in addition to continued standard of care antiretroviral therapy containing tenofovir in addition to emtricitabine or lamivudine	continued standard of care antiretroviral therapy which will include tenofovir in addition to emtricitabine or lamivudine
Measure Participants	5	5
Number [participants]	0 0%	0 0%

3. Secondary Outcome

Title	Incidence of New Hepatic Decompensation( Ascites, Variceal Hemorrhage, Encephalopathy)
Time Frame	every 4 weeks for 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Entecavir Intensification	Standard of Care
Arm/Group Description	Entecavir 1 mg for 24 weeks in addition to continued standard of care antiretroviral therapy containing tenofovir in addition to emtricitabine or lamivudine	continued standard of care antiretroviral therapy which will include tenofovir in addition to emtricitabine or lamivudine
Measure Participants	5	5
Number [participants]	0 0%	0 0%

4. Secondary Outcome

Title	Incidence of ALT Flares
Description	ALT flare: sudden increase in blood level of alanine transaminase (ALT)
Time Frame	every 4 weeks for 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Entecavir Intensification	Standard of Care
Arm/Group Description	Entecavir 1 mg for 24 weeks in addition to continued standard of care antiretroviral therapy containing tenofovir in addition to emtricitabine or lamivudine	continued standard of care antiretroviral therapy which will include tenofovir in addition to emtricitabine or lamivudine
Measure Participants	5	5
Number [participants]	0 0%	0 0%

5. Secondary Outcome

Title	HIV RNA < 75 Copies/ml
Time Frame	entry, week 12, and week 24

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Entecavir Intensification	Standard of Care
Arm/Group Description	Entecavir 1 mg for 24 weeks in addition to continued standard of care antiretroviral therapy containing tenofovir in addition to emtricitabine or lamivudine	continued standard of care antiretroviral therapy which will include tenofovir in addition to emtricitabine or lamivudine
Measure Participants	5	5
Number [participants]	5 100%	5 100%

Adverse Events

Arm/Group Title	Entecavir Intensification		Standard of Care
Arm/Group Description	Entecavir 1 mg for 24 weeks in addition to continued standard of care antiretroviral therapy containing tenofovir in addition to emtricitabine or lamivudine		continued standard of care antiretroviral therapy which will include tenofovir in addition to emtricitabine or lamivudine
All Cause Mortality
	Entecavir Intensification		Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Entecavir Intensification		Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	Entecavir Intensification		Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/5 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.