HIV-1 and Hepatitis C Co-Infection
Conditions
Keywords
HIV, HCV
Brief summary
Insulin resistance is common in people coinfected with HIV and Hepatitis C virus (HCV) and is associated with poor responses to treatment for HCV. Pioglitazone is an FDA-approved medication for the treatment of type 2 diabetes. It works by increasing the body's sensitivity to insulin. The purpose of this study is to determine whether treatment with pioglitazone prior to HCV treatment with peginterferon and ribavirin is safe and effective in improving the treatment outcome in insulin-resistant, HIV/HCV-coinfected people for whom previous treatment with peginterferon and ribavirin was unsuccessful.
Detailed description
New and better strategies for the treatment of HCV in HIV/HCV-coinfected people are urgently needed. Standard therapy for HCV includes treatment with peginterferon plus ribavirin. Peginterferon is a modified form of the drug interferon and is used either alone or in combination with ribavirin for the treatment of HCV. Ribavirin works by stopping HCV from multiplying inside the body. Sustained virologic response rates in past large studies of peginterferon plus ribavirin used for treating HCV types 1 or 4 ranged from 11% to 29%. Studies have shown that insulin resistance in HCV-infected people who are HIV uninfected leads to poorer HCV treatment response. Improving the body's response to insulin may also improve the outcome of treatment for HCV. Participants in this study will take pioglitazone alone for up to 28 weeks. At Entry and Weeks 2, 4, 8, 12,18, and 24 participants will receive clinical assessments. At Week 24, participants will undergo additional tests to ensure that they can enter Step 2 of the study. Participants who are able to continue will then take peginterferon and ribavirin in addition to the pioglitazone for up to 48 additional weeks. Clinical assessments will take place at the time of entry and Weeks 2, 4, 8, 12, 16, and 24 of Step 2. Participants who do not exhibit a response to the treatment at Weeks 12 or 24 will not continue Step 2, as it is unlikely that further treatment will elicit a response. Participants who continue in the study will return to the study site for clinical assessments at Weeks 32, 40, and 48 of Step 2. Follow-up visits will be held at Weeks 60 and 72. The assessments done at clinic visits may include any or all of the following tests: thyroid function, hematology and chemistry, fasting plasma glucose, liver function, gamma-glutamyl transferase, pregnancy, CD4/CD8, HIV-1 RNA, qualitative HCV RNA, and quantitative HCV RNA. On November 18, 2011 the study was closed to accrual due to not meeting targeted accrual goals.
Interventions
DRUGpioglitazone
Traditionally used in the treatment of type 2 diabetes to increase insulin sensitivity. Participants will take 30 mg daily in tablet form.
DRUGpeginterferon
Used in the treatment of HCV. Participants will receive 180 mcg subcutaneously once a week.
DRUGribavirin
Used in the treatment of HCV. Participants will receive 1000 to 1200 mg orally per day depending on weight.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
For Step 1: * HIV infected * Exhibited no response to previous treatment with PEG-IFN alfa-2a 180 mcg/week or alfa-2b 1.5 mcg/kg/week and at least 1000 mg/day ribavirin given for at least 12 consecutive weeks. More information on this criterion can be found in the protocol. * HOMA-IR valued greater than 2.5 within 42 days prior to study entry. More information on this criterion can be found in the protocol. * CD4 count of at least 200 cells/mm3 within 42 days prior to study entry * HCV RNA of at least 60 IU/ml by quantitative RT-PCR assay with or without reactive anti-HCV antibodies within 42 days prior to study entry * Documentation of infection with HCV genotype 1, within 42 days prior to study entry * On stable or no antiretroviral therapy for 12 weeks prior to study entry. Interruptions in treatment lasting 14 days or less are allowed if the participant reinitiated the same regimen prior to study entry. Dose modifications or changes in drug formulations during the 12 weeks prior to study entry are permissible. * Participants on antiretroviral therapy should plan to remain on the same therapy for at least 24 weeks after study entry. Participants not on antiretroviral therapy should have no plans to initiate therapy during the first 24 weeks following study entry. * Participants with documented or suspected hepatic cirrhosis must have a modified Child-Pugh-Turcotte (CPT) within 42 days prior to study entry. * Participants with documented or suspected hepatic cirrhosis must have either serum alpha-fetoprotein level of 50 ng/ml or less within 24 weeks prior to study entry; OR serum alpha-fetoprotein greater than 50 ng/ml but no greater than 400 ng/ml with an imaging procedure that shows no evidence of a hepatic tumor, both obtained within 24 weeks prior to study entry. * Certain laboratory values obtained within 42 days prior to study entry. More information on this criterion can be found in the protocol. * Willing to use effective forms of contraception throughout the study. More information on this criterion can be found in the protocol. * Ability and willingness of participant to give written informed consent. For Step 2: * No more than 28 days have passed since the Step 1, Week 24 visit * Participants who were treated in Step 1 who meet the following criteria: 1. Detectable HCV RNA (\> 60 IU/mL) at the Step 1, Week 24 evaluation 2. CD4 cell count of at least 200 cells/mm3 at Week 24. If the CD4 count is less than 200 cells/mm3 at Week 24, then it must not have decreased by more than 20 cells/mm3 from the Step 1 entry value. 3. Taking pioglitazone at the time of Step 2 entry * Certain laboratory values obtained within 28 days prior to Step 2 entry. More information on this criterion can be found in the protocol. * Willing to use an effective form of contraception throughout the study * Female participants of reproductive potential are required to have a negative serum or urine β-HCG pregnancy test within 14 days prior to Step 2 entry * Participants without a pregnant partner.
Exclusion criteria
* Presence of known causes of significant liver disease. More information on this criterion can be found in the protocol. * Evidence of decompensated liver disease manifested by presence or history of ascites, variceal bleeding, or hepatic encephalopathy * History of HCV treatment within 28 days prior to study entry * Evidence that nonresponse to prior HCV treatment may have been due to nonadherence or certain dose reductions. More information on this criterion can be found in the protocol. * Use of interferon gamma, TNF-alpha inhibitors, rifampin, rifabutin, pyrazinamide, isoniazid, ganciclovir, or hydroxyurea within 14 days prior to study entry * Current use of didanosine or zidovudine or plans to initiate use of either during the study * Active drug or alcohol abuse or dependence that, in the opinion of the study investigator, could interfere with adherence to study requirements * History of uncontrolled seizure disorder * Uncontrolled depression or other psychiatric disorder, such as untreated Grade 3 psychiatric disorder, Grade 3 disorder not amenable to medical intervention, or any hospitalization within the past 52 weeks that may affect tolerability of study requirements * History of autoimmune disorders, including but not limited to Crohn's disease, ulcerative colitis, severe psoriasis, and rheumatoid arthritis, that have been exacerbated by previous interferon use * Any systematic antineoplastic or immunomodulatory treatment or radiation within 24 weeks prior to study entry * Serious illness including malignancy, active symptomatic coronary artery disease within 24 weeks prior to study entry, or other chronic medical condition that could interfere with safe study completion * Presence of AIDS-defining opportunistic infections within 12 weeks prior to study entry * Hemoglobinopathy (e.g., thalassemia major) or any other cause of or tendency to hemolysis. Subjects with thalassemia minor may be enrolled at the discretion of the investigator. * History of major organ transplantation with an existing functional graft * Use of antidiabetic medications for any reason within 12 weeks prior to study entry * Fasting plasma glucose level of at least 126 mg/dl within 42 days prior to study entry or current or previous treatment at any time for diabetes with measures other than diet. Women with a history of gestational diabetes, patients with diabetes or hyperglycemia occurring in the context of short term use of corticosteroids, growth hormone, or other diabetogenic medication, and patients with diabetes or hyperglycemia following an episode of pancreatitis who no longer require treatment for diabetes are not excluded. * Known osteoporosis or receipt of treatment of osteopenia or osteoporosis within 12 weeks prior to study entry with the following medications: risedronate (Actonel®), ibandronate (Boniva®), etidronate (Didronel®), raloxifene (Evista®), teriparatide (Forteo®), aledronate (Fosamax®), calcitonin (Miacalcin®). * Known initiation or change in dose of any statins, fibrates, omega-3 fatty acids, bile acid sequestrants, ezetimibe, and niacin derivatives within 12 weeks prior to study entry * Known allergy, sensitivity, or hypersensitivity to components of the study drugs or their formulation * Regular and excessive use of alcohol within the 12 weeks prior to study entry. More information on this criterion can be found in the protocol. * Unwilling to restrict alcohol use during the study to 120 g of alcohol per week or less for men and 60 g of alcohol per week or less for women * Known glucocorticoid use in supraphysiologic doses (e.g., more than 10 mg per day of prednisone or equivalent doses of other glucocorticoids) within 12 weeks prior to study entry * Known glucocorticoid use in physiologic replacement doses (e.g., 10 mg or less per day of prednisone or equivalent doses of other glucocorticoids) initiated within 28 days prior to study entry * History of congestive heart failure corresponding to New York Heart Association Class II or greater * Current use of prohibited concomitant medications. More information on this criterion is available in the protocol. * Current participation in experimental studies that include treatments not approved by the FDA or any blinded treatments, with the exception of investigational antiretrovirals available through expanded access programs * Body mass index (BMI) greater than 35 kg/m2 * Participant or participant's partner is pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The Proportion of All Subjects With HCV Viral Load < 60 IU/mL at Week 24 of Step 2. | Week 24 of Step 2 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability | Step 1 (Up to 24 to 28 weeks) | Summary of the number of subjects with at least one grade 3 or higher sign/symptom or laboratory abnormality. |
| The Proportion of All Subjects With HCV Viral Load < 60 IU/mL at Week 72of Step 2. | Week 72 of Step 2 | — |
| Absolute Change From Entry to Week 24 of Step 1 in AST and ALT. | From Entry to Week 24 of Step 1 | — |
| Absolute Change From Entry to Week 24 of Step 1 in Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR) | From Entry to Week 24 of Step 1 | — |
| Absolute Change From Entry to Week 24 of Step 1 in Fasting Total Cholesterol and Triglycerides. | From Entry to Week 24 of Step 1 | — |
Countries
United States
Participant flow
Recruitment details
Subjects were enrolled at 8 ACTG sites. The dates of first and last study enrollments were March 31, 2009 and May 26, 2010, respectively.
Pre-assignment details
A5239 was a single-arm study which enrolled prior nonresponders to peginterferon (PEG-IFN) and ribavirin (RBV)\> therapy with documented insulin resistance. 31 potential subjects failed to meet all inclusion/exclusion criteria. 22 of these potential subjects did not meet the HOMA-IR criterion (\> 2.5 within 42 days prior to study entry).
Participants by arm
| Arm | Count |
|---|---|
| PIO (Step 1) Then PIO+PEG-INF+RBV (Step 2) All participants in Step 1 received pioglitazone therapy for 24 to 28 weeks. Participants continued pioglitazone and add peginterferon and ribavirin to their treatment regimen for up to 48 additional weeks in Step 2. | 19 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Study Step 1 | Adverse Event | 1 |
| Study Step 1 | Withdrawal by Subject | 2 |
| Study Step 2 | Lack of Efficacy | 12 |
| Study Step 2 | Lost to Follow-up | 2 |
Baseline characteristics
| Characteristic | PIO (Step 1) Then PIO+PEG-INF+RBV (Step 2) |
|---|---|
| Absolute neutrophil count | 2501 cells/mm^3 STANDARD_DEVIATION 1031 |
| Age categorical 30 - 39 years | 1 participants |
| Age categorical 40 - 49 years | 9 participants |
| Age categorical 50 - 59 years | 8 participants |
| Age categorical 60 - 69 years | 1 participants |
| Age, Continuous | 49 years STANDARD_DEVIATION 7 |
| Alanine Aminotransferase (ALT) | 1.4 * ULN STANDARD_DEVIATION 1.2 |
| Aspartate Aminotransferase (AST) | 1.5 * ULN STANDARD_DEVIATION 0.9 |
| Body Mass Index (BMI) | 27.7 kg/m^2 STANDARD_DEVIATION 4.1 |
| CD4 count | 567 cells/mm^3 STANDARD_DEVIATION 192 |
| Direct bilirubin | 1.0 * ULN STANDARD_DEVIATION 0.6 |
| Fasting glucose | 100 mg/dL STANDARD_DEVIATION 12 |
| Fasting insulin | 25 mIU/L STANDARD_DEVIATION 13 |
| Gamma-glutamyl transferase | 154 U/L STANDARD_DEVIATION 127 |
| Hemoglobin | 14.4 g/dL STANDARD_DEVIATION 1.5 |
| HIV-1 RNA 100 - 499 copies/mL | 2 participants |
| HIV-1 RNA 50 - 99 copies/mL | 2 participants |
| HIV-1 RNA < 50 copies/mL | 15 participants |
| Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR) | 6.3 mg/dL x mIU/L / 405 STANDARD_DEVIATION 3.5 |
| IV drug history Never | 7 participants |
| IV drug history Previously | 12 participants |
| Nadir CD4 count 101 - 200 cells/mm^3 | 4 participants |
| Nadir CD4 count 201 - 500 cells/mm^3 | 6 participants |
| Nadir CD4 count > 500 cells/mm^3 | 1 participants |
| Nadir CD4 count <= 50 cells/mm^3 | 4 participants |
| Nadir CD4 count 51 - 100 cells/mm^3 | 4 participants |
| Platelets | 185842 cells/mm^3 STANDARD_DEVIATION 67375 |
| Prior hepatitis C virus (HCV) non-response type < 2 log10 drop AND detectable >= 10 and < 22 weeks | 13 participants |
| Prior hepatitis C virus (HCV) non-response type Detectable after >= 22 and < 30 weeks | 6 participants |
| Race/Ethnicity, Customized Black non-Hispanic | 9 participants |
| Race/Ethnicity, Customized Hispanic (regardless of race) | 2 participants |
| Race/Ethnicity, Customized White non-Hispanic | 8 participants |
| Region of Enrollment United States | 19 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 16 Participants |
| Thyrotropin | 1.49 mIU/L STANDARD_DEVIATION 0.67 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 18 / 19 |
| serious Total, serious adverse events | 2 / 19 |
Outcome results
Primary
The Proportion of All Subjects With HCV Viral Load < 60 IU/mL at Week 24 of Step 2.
Time frame: Week 24 of Step 2
Population: All enrolled subjects.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PIO (Step 1) Then PIO+PEG-INF+RBV (Step 2) | The Proportion of All Subjects With HCV Viral Load < 60 IU/mL at Week 24 of Step 2. | 0.158 proportion of participants |
Comparison: The proportion of subjects responding was compared to a historical null rate of 0.10. The hypothesized response rate was 0.30.p-value: 0.29Exact test of proportions
Secondary
Absolute Change From Entry to Week 24 of Step 1 in AST and ALT.
Time frame: From Entry to Week 24 of Step 1
Population: Subjects with both Entry and Week 24 LFT results.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| PIO (Step 1) Then PIO+PEG-INF+RBV (Step 2) | Absolute Change From Entry to Week 24 of Step 1 in AST and ALT. | 24 week change in ALT (n=17) | -0.14 x ULN |
| PIO (Step 1) Then PIO+PEG-INF+RBV (Step 2) | Absolute Change From Entry to Week 24 of Step 1 in AST and ALT. | 24 week change in AST (n=17) | -0.20 x ULN |
Secondary
Absolute Change From Entry to Week 24 of Step 1 in Fasting Total Cholesterol and Triglycerides.
Time frame: From Entry to Week 24 of Step 1
Population: Subjects with both Entry and Week 24 fasting lipid results.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| PIO (Step 1) Then PIO+PEG-INF+RBV (Step 2) | Absolute Change From Entry to Week 24 of Step 1 in Fasting Total Cholesterol and Triglycerides. | 24 week change in total cholesterol (n=16) | 5.5 mg/dL |
| PIO (Step 1) Then PIO+PEG-INF+RBV (Step 2) | Absolute Change From Entry to Week 24 of Step 1 in Fasting Total Cholesterol and Triglycerides. | 24 week change in triglycerides (n=16) | 28.5 mg/dL |
Secondary
Absolute Change From Entry to Week 24 of Step 1 in Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR)
Time frame: From Entry to Week 24 of Step 1
Population: Subjects with both Entry and Week 24 HOMA-IR results.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PIO (Step 1) Then PIO+PEG-INF+RBV (Step 2) | Absolute Change From Entry to Week 24 of Step 1 in Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR) | -1.2 mg/dL x uIU/mL / 405 |
Secondary
Safety and Tolerability
Summary of the number of subjects with at least one grade 3 or higher sign/symptom or laboratory abnormality.
Time frame: Step 1 (Up to 24 to 28 weeks)
Population: All enrolled subjects.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PIO (Step 1) Then PIO+PEG-INF+RBV (Step 2) | Safety and Tolerability | 7 participants |
Secondary
Safety and Tolerability
Summary of the number of subjects with at least one grade 3 or higher sign/symptom or laboratory abnormality.
Time frame: Step 2 (Up to 72 weeks)
Population: All subject enrolled in Step 2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PIO (Step 1) Then PIO+PEG-INF+RBV (Step 2) | Safety and Tolerability | 13 participants |
Secondary
The Proportion of All Subjects With HCV Viral Load < 60 IU/mL at Week 72of Step 2.
Time frame: Week 72 of Step 2
Population: All enrolled subjects.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PIO (Step 1) Then PIO+PEG-INF+RBV (Step 2) | The Proportion of All Subjects With HCV Viral Load < 60 IU/mL at Week 72of Step 2. | 0.053 proportion of participants |
Comparison: The proportion of subjects responding was compared to a historical null rate of 0.02. The hypothesized response rate was 0.15.p-value: 0.42Exact test of proportions