Boceprevir Drug Combination for Hepatitis C Treatment in People With and Without HIV
Condition: Hepatitis; HIV/AIDS
MeSH terms: Hepatitis A; Hepatitis
Intervention: Boceprevir; Peg-Interferon-alfa 2B; Ribavirin
Intervention MeSH terms: Interferons; Ribavirin; Interferon-alpha; Interferon alpha-2; Peginterferon alfa-2b
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 4.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Hepatitis; Immunological Response; Virological Response; Resistance Mutations; Viral Kinetics; Hepatitis C; HCV

Summary:

      Background:

      - Standard treatment for the hepatitis C virus (HCV) is a combination of the drugs peg-IFN
      and ribavirin. However, this treatment is not very effective in people with a serious type of
      HCV (HCV genotype 1) and also in people who have human immunodeficiency virus (HIV)
      coinfection. Researchers want to add a new drug, boceprevir to see if it can improve
      treatment results in people with both HCV genotype 1 and HIV. Boceprevir used in combination
      with peg-IFN and ribavirin has been recently approved for the treatment of people with HCV
      genotype 1 infection only, and is currently being studied in those with HIV and HCV.

      Objectives:

      - To test boceprevir, peg-IFN, and ribavirin as a treatment for HCV genotype 1 in people with
      HCV monoinfection compared to those with both HIV and HCV infections.

      Eligibility:

        -  Individuals at least 18 years of age who have HCV genotype 1 infection, and have not
           received interferon treatment for HCV

        -  Half of the study participants will also have HIV infection.

      Design:

        -  Participants will be screened with a medical history and physical exam. They will also
           have blood and urine tests.

        -  Participants will also have heart and liver function tests, and answer questions about
           mood and depression.

        -  Those in the study will receive ribavirin tablets to take twice a day, and peg-IFN to
           inject under the skin weekly.

        -  Two weeks after starting treatment, participants will have blood tests to study the
           treatment.

        -  Four weeks after starting treatment, participants will start taking boceprevir three
           times a day.

        -  Participants will have regular study visits with blood samples and other tests. The
           length of therapy will depend on the level of virus detected in the blood at several
           clinic visits. Those who do not respond well to the medicines at 12 weeks will stop
           treatment. The full length of treatment is 48 weeks.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        To be eligible for participation on this protocol, a participant must satisfy all of the
        following conditions:

          1. Be greater than or equal to18 years old and have an identifiable primary care
             provider.

          2. Have documented chronic HCV infection by demonstration of a positive test for
             hepatitis C antibody and HCV RNA of 2,000 IU/mL or greater.

          3. Infected with HCV GT-1 virus.

          4. If coinfected, have either documentation of HIV-1 infection by licensed enzyme-linked
             immunosorbent assay (ELISA) confirmed by a Western Blot or history of HIV RNA of 1,000
             copies/mL or greater.

          5. If coinfected, must meet one of the following prior to enrollment:

               1. If on a stable non-NNRTI or non-PI antiretroviral regimen that HAS NOT changed
                  within the past 6 months, must have an HIV-1 VL of less than 400 copies/mL for at
                  least 3 months; or

               2. If on a current antiretroviral regimen that HAS changed within the past 6 months,
                  have an HIV-1 VL of less than 50 copies/mL for at least 3 months; or

               3. Be a long-term nonprogressor as documented in the medica record.

          6. Have histopathologic features consistent with chronic HCV infection at the time of
             enrollment. A liver biopsy within 3 years (36 calendar months) prior to screening may
             be used as the baseline biopsy. Participants can opt out of a liver biopsy if they had
             one more than 3 years prior and have a contraindication, such as receipt of chronic
             anticoagulation therapy. Participants with decompensated liver disease are excluded
             from the study.

          7. Are na(SqrRoot) ve to prior IFN-based treatment for HCV.

          8. Have CD4 cell counts greater than or equal to 100 cells/mm(3).

          9. Willing to have genetic testing.

         10. Not pregnant or breastfeeding. Serum pregnancy test must be negative at screening for
             female participants.

         11. Agree not to become pregnant if a female of childbearing potential while on the study
             and for at least 6 months after stopping RBV. Because of the potential teratogenic
             effects of RBV treatment, subjects and their partners must remain abstinent or use two
             methods of birth control, which may be selected from the following list (oral
             contraceptive concentrations are decreased, and may not be effective when used during
             BOC treatment and, therefore, are not included in this list):

             Surgical sterilization of either partner

             Intrauterine device

             Male or female condoms with or without a spermicide

             Diaphragm, cervical cap, or sponge

         12. Male participants who are not documented to be sterile must agree to either abstain
             from intercourse or consistently use a condom while their female partner (if
             applicable) agrees to use one of the appropriate medically accepted methods of birth
             control listed above from the date of screening until 6 months after the last dose of
             RBV.

         13. Be able and willing to either learn to safely inject medication or find another person
             to inject the medication for him/her.

         14. Be willing to allow storage of blood or tissue samples for future research.

        Co-enrollment Guidelines:

        Participants may be enrolled in other NIH protocols as long as the amount of research blood
        drawn does not exceed the acceptable NIH guidelines and the protocol does not include other
        experimental therapies (including expanded access/compassionate use of HIV
        antiretrovirals).

        EXCLUSION CRITERIA:

        A participant will be ineligible to participate on this study if any of the following
        criteria are met:

          1. Use of other experimental therapies (including expanded access/compassionate use of
             HIV antiretrovirals) within 30 days or 5 half-lives (whichever is longer), prior to
             enrollment.

          2. Current use of an efavirenz-based (or other NNRTI) or protease inhibitor HIV
             antiretroviral regimen.

          3. Use of any of the following medications within 6 weeks prior to enrollment.

             Alfuzosin (Uroxatral )

             Alprazolam (Xanax )

             Atorvastatin (Lipitor )

             AZT or zidovudine (Retrovir )

             Carbamazepine (Tegretol )

             Cisapride (Propulsid )

             Colchicine (Colcrys ) - If patient has renal or hepatic impairment.

             DDI or didanosine (Videx )

             d4T or stavudine (Zerit )

             Delaviridine (Rescriptor )

             Digoxin (Lanoxin )

             Dihydroergotamine

             Drosperinone (Yaz )

             Efavirenz (Sustiva )

             Ergonovine (Ergotrate )

             Ergotamine (Cafergot )

             Etravirine (Intelence )

             Ganciclovir (Cytovene )

             Immunosuppressive therapy (including oral steroids)

             ---Use of any use of any immunosuppressive therapy, including systemic steroids
             (prednisone equivalent of greater than 10 mg/day) for a duration of 6 weeks or more
             within 6 months prior to enrollment. Use of inhaled/nasal steroids should be avoided.

             Isoniazid or INH (Ingredient in Rifater )

             Ketoconazole (Nizoral )

             Lovastatin (Mevacor )

             Methylergonovine (Methergine )

             Midazolam given orally (Versed )

             Nevirapine (Viramune )

             Phenobarbital (Luminal )

             Phenytoin (Dilantin )

             Pimozide (Orap )

             Pyrazinamide (Ingredient in Rifater )

             Rifabutin (Mycobutin )

             Rifampin/rifampicin

             Rilpivirine (Edurant )

             Sildenafil (Viagra ) - Phosphodiesterase type 5 inhibitors are prohibited when used
             for pulmonary hypertension

             Simvistatin (Zocor )

             St. Johns s Wort

             Tadalafil (Cialis ) - Phosphodiesterase type 5 inhibitors are prohibited when used for
             pulmonary hypertension

             Thalidomide (Thalomid )

             Theophylline (Slo-Phylllin )

             Triazolam (Halcion )

             Vardenafil (Levitra ) - Phosphodiesterase type 5 inhibitors are prohibited when used
             for pulmonary hypertension

             Warfarin (Coumadin )

             Zalcitabine (Hivid )

             There may be other brand names for these products listed above.

          4. Has ingested silymarin (milk thistle), s-adenosylmethionine (SAM-e), glycyrrhizin,
             Sho-saiko-to (SST), or other herbal supplements that may be either liver beneficial or
             toxic, within 28 days prior to enrollment.

          5. Mixed HCV genotypes (e.g., 1 & 2, 1 & 3, 1 & 4) (mixed genotype 1a/1b can be
             included).

          6. Has any other known, or clinically suspected, cause of liver disease, including active
             hepatitis B.

          7. For participants with cirrhosis, a Child Turcotte Pugh score greater than 7, or Child
             s B or C cirrhosis.

          8. Certain abnormal hematological and biochemical parameters, including:

               1. Neutrophil count less than1000 cells/mm3

               2. Hemoglobin less than10g/dL

               3. Platelet count less than or equal to 50,000 cells/mm3

               4. Estimated glomerular filtration rate less than50 mL/min/1.73 m(2), calculated
                  automatically by the NIH lab using the original MDRD (modification of diet in
                  renal disease) study equation

               5. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) greater
                  than or equal to10 time ULN

               6. Prothrombin time International Normalized Ratio (PT-INR) less than2 and/or on
                  chronic anticoagulation medications

               7. If total bilirubin is greater than 1.5 mg/dL, then direct bilirubin can be no
                  more than 70% of the total, up to a direct bilirubin of 2.0 mg/dL.

          9. Alpha-fetoprotein less than20 ng/mL, unless an ultrasound, computerized tomography
             scan (CT), or magnetic resonance imaging (MRI) has been performed to rule out
             hepatoma.

         10. Hepatic mass suggestive of hepatocellular carcinoma as detected by ultrasound scan,
             dual-phase CT, or MRI.

         11. History of esophageal or gastric varices.

         12. Any neoplastic disease or any nonmetastatic skin, cervical, or anal cancer that has
             been resected in the past 5 years EXCEPT Kaposi s sarcoma not requiring systemic
             chemotherapy.

         13. Prior organ transplantation other than cornea or hair.

         14. Evidence of severe cardiac disease (greater than or equal to Grade 3 congestive
             cardiac failure, symptomatic coronary artery disease, significant arrhythmias, or
             uncontrolled hypertension) despite intervention or medical therapy.

         15. Evidence of severe chronic pulmonary disease with functional impairment.

         16. Severe psychiatric disorder that would interfere with adherence to protocol
             requirements, and that is not stably treated.

         17. Evidence of autoimmune disorders including inflammatory bowel diseases, psoriasis, and
             optic neuritis.

         18. Evidence of an uncontrolled seizure disorder defined as more than 1 episode of
             generalized seizure within the past year.

         19. Chronic pancreatitis based on clinical history.

         20. History of severe retinopathy.

         21. History of hemophilia.

         22. Any hemoglobinopathy (e.g., Thalassemia, sickle cell disease).

         23. Active systemic infections other than HCV and HIV-1.

         24. Evidence of gastrointestinal malabsorption, chronic nausea, or vomiting.

         25. Has any systemic illness that will make it unlikely that the participant will be able
             to return for the required study visits.

         26. Any condition that, in the opinion of the investigator, contraindicates participation
             in this protocol.

        Exclusion of Children:

        Because there are insufficient data regarding the safety and efficacy of BOC, PEG, or RBV
        in the pediatric population, children are excluded from this study.

        Exclusion of Women:

        Pregnancy: Pregnant women are excluded from this study because the effects of BOC, PEG, and
        RBV on the developing human fetus are unknown. Preclinical animal data indicate that the
        use of RBV treatment during pregnancy is potentially teratogenic.

        Breastfeeding: Because there is an unknown but potential risk for adverse effects in
        nursing infants secondary to treatment of the mother with BOC, PEG, or RBV, breastfeeding
        women are excluded from this study.