Hepatitis B, HIV Infections
Conditions
Keywords
HIV, Hepatitis B, treatment experienced
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.
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.
Interventions
DRUGEntecavir with continued standard of care antiretroviral therapy
1 mg by mouth daily
DRUGcontinued standard of care with tenofovir in addition to emtricitabine or lamivudine
continued standard of care with tenofovir in addition to emtricitabine or lamivudine
Sponsors
Bristol-Myers Squibb
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | ALT flare: sudden increase in blood level of alanine transaminase (ALT) |
| HIV RNA < 75 Copies/ml | entry, week 12, and week 24 | — |
Countries
United States
Participant flow
Recruitment details
participants recruited from medical clinic, between 7/2008 and 6/2009and 20011
Pre-assignment details
Overall sample size was reduced to 10 due to difficulty in recruitment
Participants by arm
| Arm | Count |
|---|---|
| Entecavir Intensification Entecavir 1 mg for 24 weeks in addition to continued standard of care antiretroviral therapy containing tenofovir in addition to emtricitabine or lamivudine | 5 |
| Standard of Care continued standard of care antiretroviral therapy which will include tenofovir in addition to emtricitabine or lamivudine | 5 |
| Total | 10 |
Baseline characteristics
| Characteristic | Entecavir Intensification | Standard of Care | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 5 Participants | 10 Participants |
| HBV DNA at enrollment | 3.2 log10 IU/ML | 3.8 log10 IU/ML | 3.2 log10 IU/ML |
| Region of Enrollment United States | 5 participants | 5 participants | 10 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 5 | 0 / 5 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 |
Outcome results
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.
Time frame: week 24
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Entecavir Intensification | Hepatitis B Virus (HBV) DNA | 2.4 log 10 IU/ml |
| Standard of Care | Hepatitis B Virus (HBV) DNA | 0.8 log 10 IU/ml |
Secondary
HIV RNA < 75 Copies/ml
Time frame: entry, week 12, and week 24
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Entecavir Intensification | HIV RNA < 75 Copies/ml | 5 participants |
| Standard of Care | HIV RNA < 75 Copies/ml | 5 participants |
Secondary
Incidence of ALT Flares
ALT flare: sudden increase in blood level of alanine transaminase (ALT)
Time frame: every 4 weeks for 24 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Entecavir Intensification | Incidence of ALT Flares | 0 participants |
| Standard of Care | Incidence of ALT Flares | 0 participants |
Secondary
Incidence of New Hepatic Decompensation( Ascites, Variceal Hemorrhage, Encephalopathy)
Time frame: every 4 weeks for 24 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Entecavir Intensification | Incidence of New Hepatic Decompensation( Ascites, Variceal Hemorrhage, Encephalopathy) | 0 participants |
| Standard of Care | Incidence of New Hepatic Decompensation( Ascites, Variceal Hemorrhage, Encephalopathy) | 0 participants |
Secondary
Incidence of Permanent Discontinuation Due to Toxicity
Time frame: 24 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Entecavir Intensification | Incidence of Permanent Discontinuation Due to Toxicity | 0 participants |
| Standard of Care | Incidence of Permanent Discontinuation Due to Toxicity | 0 participants |