Boceprevir Drug Combination for Hepatitis C Treatment in People With and Without HIV

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.