Boceprevir Drug Combination for Hepatitis C Treatment in People With and Without HIV
Boceprevir Drug Combination for Hepatitis C Treatment in People With and Without HIV
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.
Chronic hepatitis C virus (HCV) infection is a major public health problem with an estimated
 180 million people infected worldwide. In the United States, an estimated 4.1 million people
 are infected and HCV is the principal cause of death from liver disease and leading
 indication for liver transplantation. A combination of ribavirin (RBV) and pegylated
 interferon (peg-IFN) is the currently recommended therapy for chronic HCV infection. However,
 this therapy achieves viral clearance in only 19% to 52% of patients infected with HCV
 genotype 1 and 76% to 80% of patients infected with genotypes 2 and 3. Current therapy is
 also associated with a high incidence of adverse events and low cure rates in several
 populations. Novel therapies that do not rely on an interferon backbone will be required to
 enhance cure rates in various populations. Recent data show that adding an HCV serine
 protease inhibitor (such as boceprevir [BOC]) to peg-IFN and RBV results in HCV eradication
 rates of 70% to 80% among HCV-monoinfected subjects. However, whether human immunodeficiency
 virus (HIV)-infected subjects will have similar rates of response to triple combination
 therapy is presently not known. Previous data have suggested that HIV-infected patients with
 chronic HCV infection have much lower eradication rates to peg-IFN and RBV than
 HCV-monoinfected subjects. This study will explore whether HIV/HCV-coinfected subjects have a
 lower response rate to a BOC/peg-IFN/RBV regimen than HCV-monoinfected subjects. Participants
 who have chronic hepatitis C genotype 1 monoinfection (N=50) or coinfection with HIV-1
 (N=50), and who are na(SqrRoot) ve to IFN-based HCV treatment, will receive combination
 therapy with BOC (800 mg three times a day, every 7 to 9 hours, with food), weekly peg-IFN
 alpha-2b (1.5 mcg/kg/week) and twice daily RBV (weight based) for a maximum of 44 weeks,
 after a 4-week lead-in of peg-IFN and RBV. BOC received recent FDA approval for treating HCV
 monoinfection in combination with peg-IFN and RBV, and the approved labeling will be followed
 in this study. The primary endpoint is comparative efficacy in HCV-monoinfected and
 HIV/HCV-coinfected subjects. Secondary endpoints include determination of host predictors for
 therapeutic response, emergence of resistance biomarkers, and early viral kinetics. The
 findings from this study will aid in the understanding of whether HIV infection affects HCV
 antiviral and host responses to combination therapy using BOC/peg-IFN alfa-2b/RBV.
-  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.