Multicenter, Open-Label Study of Telaprevir in Combination With Peginterferon Alfa and Ribavirin in Human Immunodeficiency Virus/Genotype 1 Chronic Hepatitis C Coinfected Subjects With Severe Fibrosis or Compensated Cirrhosis.

Study Objective
 

The objective of this open-label safety study is to collect safety and tolerability data on telaprevir treatment in combination with Peg-IFN-alfa and RBV in subjects with HIV/genotype 1 chronic HCV coinfection with severe fibrosis or compensated cirrhosis who are not eligible for enrollment into an ongoing clinical study of telaprevir.

Participation conditions

Inclusion criteria

• Be a man or woman, between 18 and 70 years of age, inclusive.
• Have diagnosis of HIV-1 or HIV-2 infection, or HIV-1 and HIV-2 coinfection for more than 6 months before the screening visit. For HIV-1, infection must be documented by any licensed enzyme-linked immunosorbent assay (ELISA) test kit and confirmed by Western blot, HIV-1 culture, HIV-1 antigen, plasma HIV-1 RNA,  immunofluorescent  antibody test  (IFA),  or  a  second  antibody test  by a method other than ELISA at any time before Day 1. For HIV-2, infection must be documented and confirmed using respective available laboratory methods at any time before Day 1.
• Should have been on a stable permissible HAART regimen for more than 8 weeks before Day 1 without switches. Investigators should prescribe HAART regimens according to local guidelines, indications, and/or clinical practice. Permissible HAART regimens include the combinations of:

1. efavirenz, TDF, plus either emtricitabine or lamivudine
2. efavirenz, abacavir, plus either emtricitabine or lamivudine
3. ritonavir-boosted atazanavir, TDF, plus either emtricitabine or lamivudine
4. ritonavir-boosted atazanavir, abacavir, plus either emtricitabine or lamivudine
5. raltegravir, TDF, plus either emtricitabine or lamivudine
6. raltegravir, abacavir, plus either emtricitabine or lamivudine
7. etravirine, TDF, plus either emtricitabine or lamivudine
8. etravirine, abacavir, plus either emtricitabine or lamivudine
9. rilpivirine, TDF, plus either emtricitabine or lamivudine
10. rilpivirine, abacavir, plus either emtricitabine or lamivudine

Note:  Additional antiretroviral therapies for which favorable pharmacokinetic interaction or  in  vitro  experiments support coadministration with telaprevir may be allowed after the sponsor has notified the investigators, applicable IECs and Health Authorities.

OR
Not on a HAART regimen and not expected to start HIV treatment during the study, ie, have CD4 count of ≥ 500 cells/mm3 and a HIV-1 and/or HIV-2 viral load ≤ 50,000 copies/mL at screening.
• If  on  stable  permissible  HAART  regimen,  have  CD4  count  ≥ 200  cells/mm3 or ≥ 15% and HIV-1 and/or HIV-2  viral  load  <50 copies/mL for at least 6 months before starting treatment is recommended.
• Have evidence of HCV infection genotype 1 (molecular assay).
• Have a quantifiable plasma HCV RNA.
• Have  documentation  of  severe fibrosis (Metavir F3 or Ishak 3-4) or cirrhosis (Metavir F4 or Ishak 5-6) assessed by liver  biopsy or  non-invasive  test (eg, fibrotest, fibroscan [eg, fibroscan ≥ 9.5 pKa for severe fibrosis, ≥ 12.5 pKa for cirrhosis;  or  assignment  to  severe  fibrosis  or cirrhosis based on pKa levels according to local practice]) within 18 months before screening.
• Have compensated liver disease (Child-Pugh Grade A clinical classification).
• Have access to the hepatitis C treatments Peg-IFN-alfa and RBV.
• Have laboratory values (assessed at local laboratory) that meet the following or adhere to local prescribing information or standard of care:
• Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3
• Platelet count ≥ 90,000 cells/mm3
• Hemoglobin concentration ≥ 12 g/dL in females or ≥ 13 g/dL in males
• Calculated creatinine clearance ≥ 70 mL/min
• Potassium ≥ 3.5 mmol/L
• If  a  women  of  childbearing  potential,  must  have  a  negative  serum  b-human chorionic gonadotropin (b-hCG)  or  urine  pregnancy test  documented at the screening visit and a negative serum or urine pregnancy test before the first dose of  study drug  to  ensure  that  they are not pregnant at the time of starting treatment.
• If heterosexually active, a  female  subject  of  childbearing  potential  and  a nonvasectomized male subject who has a female partner of childbearing potential must agree to use 2 effective contraceptives from screening onwards until 4 months (female subject) or 7 months (male subject) after  RBV therapy has ended.
Note: Hormonal contraceptives may be continued but may not be reliable during telaprevir  dosing and  for  up  to  2  months  following  cessation  of  telaprevir. Therefore, to be eligible for this study, subjects should  agree to use 2 effective non-hormonal  methods  of contraception  during  combination therapy and for 2 months after the last intake of telaprevir.
• Sign the informed consent document indicating that they understand the purpose of  and  procedures  required  for  the  study and  are  willing  to  participate  in  the study.
• Sign the informed consent form for pharmacogenomic research in order to participate in the optional pharmacogenomic component of this study (where local regulations permit).  Refusal to  give  consent  for  this  component  does  not exclude a subject from participation in the study.

Exclusion criteria

The subject will be excluded if he or she:
• Is eligible for enrollment into an ongoing clinical study of telaprevir.
• Is infected or coinfected with HCV of another genotype than genotype 1.
• Has a contraindication to the administration of Peg-IFN-alfa or RBV, or medical history or laboratory values that preclude treatment with Peg-IFN-alfa or RBV according to the respective local prescribing information.
• Have any contraindication to the currently prescribed HAART regimen at screening.  Note:  Subjects who have a contraindication to a nonprescribed permissible HAART medication are not excluded.
• Positive HLA-B5701 genotyping result at screening (or documented result prior to screening) if abacavir is a component of HAART
• Has planned treatment holiday for HAART regimen during the course of the study.
• Has a history of having received investigational HCV protease or polymerase inhibitors at any previous time.
• Has signs or symptoms of HCC.  Serum  alpha-fetoprotein  (AFP)  level  and ultrasonography should  be  available  at  screening  for  all  subjects  to  screen  for HCC (both tests should have been done a maximum of 4 months before the screening visit).
• Has a history of decompensated liver disease:  history of ascites, hepatic encephalopathy, or bleeding esophageal varices, and/or any of the following screening laboratory results:
• International Normalized Ratio (INR) of ≥ 1.5
• Serum albumin <3.3 g/dL
• Serum  total  bilirubin  >1.8  times  the  upper  limit  of  the  laboratory normal range, unless isolated or in subjects with Gilbert.s  Syndrome and/or due to  clinically nonsignificant  elevations  of  indirect  bilirubin attributable to the use of  atazanavir,  without  clinically significant elevations of direct bilirubin.
• Has a coinfection with active hepatitis B.
• Has inadequately controlled thyroid function, as judged by the investigator based on the thyroid stimulating hormone (TSH) results.
• Has baseline increased risk for anemia (eg, thalassemia, sickle cell anemia, spherocytosis, history of gastrointestinal bleeding) or for whom anemia would be medically problematic.
• Has congenital QT prolongation or family history of congenital QT prolongation or sudden death.
• Has a history of severe  psychiatric disease, including psychosis  and/or depression,  characterized  by a  suicide  attempt,  hospitalization  for  psychiatric disease, or a period of disability as a result of psychiatric disease.
• Has  a  history of  immunologically mediated  disease  (eg,  inflammatory  bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia, scleroderma, severe psoriasis [defined as affecting >10% of the  body, where the palm of one hand equals 1%, or if the hands and feet are affected],  rheumatoid  arthritis  requiring  more  than  intermittent  nonsteroidal anti-inflammatory medications for management).
• Have any systemic  antineoplastic  or  immunomodulatory  (eg, systemic corticosteroids)  treatment or radiation within 24 weeks before Day 1 or the expectation  that  such  treatment  will  be  needed  at  any time  during  the  study. Topical corticosteroid use is allowed.
• Presence of acute or active conditions of HIV (clinical grades 3 or 4) within 6 months before start of treatment.
• Acute Center for Disease Control (CDC) stage C opportunistic infection occurring within the 6 months before start of treatment.
• Has clinical evidence of chronic pulmonary disease associated with functional impairment.
• Has a history of uncontrolled severe seizure disorders.
• Has a history or other evidence of a clinically relevant ophthalmologic disorder due to diabetes mellitus or hypertension or history or other evidence of severe retinopathy (eg, cytomegalovirus, macular degeneration).
• Has a history of major organ transplantation with an existing functional graft with the exception of corneal transplants and skin grafts.
• Is currently enrolled in an investigational drug study or has participated in such a study within 30 days before Day 1.
• Is a woman who is pregnant or breast-feeding.
• Any condition (including, but not limited to, alcohol and drug use), which, in the opinion of the investigator, could compromise the subject.s safety or adherence to the study.

Centre Hospitalier de Luxembourg