A Phase 2 interventional study of Nitazoxanide (NTZ) and Pegylated interferon alfa-2a (PEG) in HIV Infection and Hepatitis C Infection, sponsored by National Institute of Allergy and Infectious Diseases (NIAID). Completed at 18 sites in 2 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2021-11-04.
Sponsored by National Institute of Allergy and Infectious Diseases (NIAID) · Phase 2, Interventional, and Treatment
Infection with hepatitis C virus (HCV) can cause liver scarring, or cirrhosis, and this usually occurs more rapidly among people infected with both HCV and human immunodeficiency virus (HIV). People infected with both HCV and HIV have poor response to the current HCV treatments. This phase II pilot study evaluated whether adding a new HCV medication improves response to the current standard HCV treatment with pegylated interferon and ribavirin in people with both HCV and HIV.
Chronic hepatitis C virus (HCV) is a significant cause of liver scarring, or cirrhosis, and accounts for up to 30% of all liver transplants in the United States. People infected with HIV are at a high risk of coinfection with HCV, and the combination of these two infections appears to accelerate progression to cirrhosis. Current treatment for HCV infection includes a 48-week course of two medications taken together, peginterferon alfa-2a (PEG) and ribavirin (RBV). This combination is only effective in 14% to 29% of people infected with both HIV and HCV genotype 1 (the genotype most common in the United States). Further complicating treatment, antiretrovirals (which are used to treat HIV) and HCV medications can often have high toxicity when taken together, limiting dosing.
Nitazoxanide (NTZ) is a medication currently approved to treat intestinal infections that is being investigated for use in treating HCV. NTZ has few side effects and has been shown to increase effectiveness of HCV treatment when combined with PEG and RBV among HCV monoinfected people. This study will test whether adding NTZ to PEG+RBV regimen for people coinfected with HCV and HIV improves HCV treatment outcomes.
Participation in this study will last up to 76 weeks. At study entry, participants completed a brief physical exam, provided a urine sample for a routine safety test, provided a blood sample, and completed a pregnancy test. Participants then initiated NTZ, which they took twice a day with food for up to a year. After 4 weeks on NTZ, participants completed the second study visit, at which they completed the same assessments as at study entry and were asked about the medications they were taking. At this visit, participants initiated the other two study drugs, PEG and RBV. PEG was delivered via injection weekly and RBV was taken orally twice a day with dose dependent on participant's weight at entry.
Participants took NTZ, PEG and RBV together for up to 48 weeks. During this time, participants completed study visits every 4 weeks until Week 52 and then completed follow-up visits at Weeks 64 and 76. At these visits, participants completed the same assessments as at previous visits, and, at certain weeks, also fasted for 8 hours before blood draw. Additional blood samples were collected and stored at Weeks 4, 8, 16, 52 and 76 in order to do future testing.
Participants who did not achieve an early virologic response to the study treatment (at least a 2-log10 decrease in HCV viral load or undetectable HCV viral load at Week 16), or had detectable HCV viral load at Week 28), stopped study treatment and discontinued study early, at about 20 or 32 weeks, respectively.
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This study's enrollment of 68 is below the median of 120 across 4,200 interventional studies indexed under Infections.
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Exclusion Criteria:
Participants received nitazoxanide (NTZ) alone for 4 weeks followed by 48 weeks of NTZ with pegylated interferon (PEG) and ribavirin (RBV). Participants who did not achieve early virologic response (EVR) at Week 16 or had detectable hepatitis C virus (HCV) viral load at Week 28 discontinued treatment.
Drug: Nitazoxanide (NTZ) · Drug: Pegylated interferon alfa-2a (PEG) · Drug: Ribavirin (RBV)
500 mg twice daily, taken orally with food
Also known as: Alinia
180 micrograms via subcutaneous injection once weekly
Also known as: Pegasys
Weight-based dosing; 1,000 mg daily, taken orally, for people weighing less than 75 kg or 1,200 mg for people weighing at least 75 kg.
Also known as: Copegus
Percentage of Participants With Complete Early Virologic Response (cEVR)
Complete early virologic response (cEVR) was defined as undetectable HCV viral load (\<43 IU/ml) at week 16, where 43 is the lower limit of quantification of the assay (Cobas AmpliPrep/Taqman HCV Test).
Time frame: Week 16
Percentage of Participants With Early Virologic Response (EVR)
Early virologic response (EVR) was defined as undetectable HCV viral load (\<43 IU/ml) at Week 16 or at least a 2-log10 decrease in HCV viral load from study entry at Week 16, where 43 is the lower limit of quantification of the assay (Cobas AmpliPrep/Taqman HCV Test).
Time frame: Weeks 0, 16
Percentage of Participants With Sustained Virologic Response (SVR)
Sustained virologic response (SVR) was defined as undetectable HCV viral load (\<43 IU/ml) at 24 weeks after treatment discontinuation, where 43 is the lower limit of quantification of the assay (Cobas AmpliPrep/Taqman HCV Test). Participants who failed to achieve EVR or had detectable HCV RNA at Week 28 and per protocol discontinued study, and participants without HCV RNA from 24 weeks after treatment discontinuation, were considered non-responders.
Time frame: 24 weeks after treatment discontinuation
Percentage of Participants With Rapid Virologic Response (RVR)
Rapid virologic response (RVR) was defined as undetectable HCV viral load (\<43 IU/ml) at Week 8 where 43 is the lower limit of quantification of the assay (Cobas AmpliPrep/Taqman HCV Test).
Time frame: Week 8
Number of Participants With Adverse Events of Grade 2 or Higher
Number of participants who experienced an adverse event of Grade 2 or higher at any time after study entry. Grading of adverse events (signs and symptoms and laboratory toxicities) was according to Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, December 2004.
Time frame: From study entry to up to week 76
Change in Hemoglobin Level From Study Entry
Change in hemoglobin (HGB) was calculated as HGB at later time point (Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76) minus HGB at study entry.
Time frame: Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76.
Percent Change in Fasting Insulin Level From Study Entry
Percent Change in fasting insulin (FINS) was calculated as FINS at later time point (16, 28, 52, 76) minus FINS at study entry, divided by FINS at study entry x 100%. Study protocol required fasting for at least 8 hours (nothing by mouth except medications and water) prior to specimen collection for fasting insulin testing.
Time frame: Weeks 0, 16, 28, 52, and 76
Percent Change in Fasting Glucose Level From Study Entry
Percent Change in fasting glucose (FGLUC) was calculated as FGLUC at later time point (16, 28, 52, 76) minus FGLUC at study entry, divided by FGLUC at study entry x 100%. Study protocol required fasting for at least 8 hours (nothing by mouth except medications and water) prior to specimen collection for fasting glucose testing.
Time frame: Weeks 0, 16, 28, 52, and 76
Percent Change in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) From Study Entry
HOMA-IR was calculated as \[fasting glucose (mg/dL) x fasting insulin (uIU/mL)\]/405. Percent Change in HOMA-IR was calculated as HOMA-IR at later time point (16, 28, 52, 76) minus HOMA-IR at study entry, divided by HOMA-IR at study entry x 100%. Study protocol required fasting for at least 8 hours (nothing by mouth except medications and water) prior to specimen collection for fasting insulin and fasting glucose testing.
Time frame: Weeks 0, 16, 28, 52, and 76
Change in log10 HCV Viral Load After 4 Weeks of Nitazoxanide (NTZ) Monotherapy.
Change in log10 HCV viral load was calculated as log10-transformed HCV viral load at Week 4 minus log10-transformed HCV viral load at study entry. HCV viral load testing was done using Cobas AmpliPrep/Taqman HCV Test.
Time frame: Weeks 0, 4
Number of Participants With HCV Genotype 1
Confirmatory HCV genotyping was performed on stored plasma from entry using VERSANT HCV Genotype assay v2.0 (LiPA, RUO, Siemens Healthcare Diagnostics Inc., Tarrytown, NY).
Time frame: Week 0
Men and women at least 18 years of age with genotype 1 hepatitis C virus (HCV) and human immunodeficiency virus (HIV) coinfection and naive to previous HCV treatment were recruited for participation in this study.
| Milestone | NTZ/PEG/RBV |
|---|---|
| Started | 67 |
| Completed week 16 | 61 |
| Completed | 55 |
| Not completed | 12 |
| Withdrew: Adverse event | 1 |
| Withdrew: Physician decision | 2 |
| Withdrew: Withdrawal by subject | 3 |
| Withdrew: Lost to follow-up | 4 |
| Withdrew: Protocol violation | 2 |
Complete early virologic response (cEVR) was defined as undetectable HCV viral load (\<43 IU/ml) at week 16, where 43 is the lower limit of quantification of the assay (Cobas AmpliPrep/Taqman HCV Test).
| percentage of participants | NTZ/PEG/RBV |
|---|---|
| Percentage of Participants With Complete Early Virologic Response (cEVR) | 38.8 (28.8 to 49.6) |
Early virologic response (EVR) was defined as undetectable HCV viral load (\<43 IU/ml) at Week 16 or at least a 2-log10 decrease in HCV viral load from study entry at Week 16, where 43 is the lower limit of quantification of the assay (Cobas AmpliPrep/Taqman HCV Test).
| percentage of participants | NTZ/PEG/RBV |
|---|---|
| Percentage of Participants With Early Virologic Response (EVR) | 65.7 (55.0 to 75.3) |
Sustained virologic response (SVR) was defined as undetectable HCV viral load (\<43 IU/ml) at 24 weeks after treatment discontinuation, where 43 is the lower limit of quantification of the assay (Cobas AmpliPrep/Taqman HCV Test). Participants who failed to achieve EVR or had detectable HCV RNA at Week 28 and per protocol discontinued study, and participants without HCV RNA from 24 weeks after treatment discontinuation, were considered non-responders.
| percentage of participants | NTZ/PEG/RBV |
|---|---|
| Percentage of Participants With Sustained Virologic Response (SVR) | 32.8 (23.4 to 43.5) |
Rapid virologic response (RVR) was defined as undetectable HCV viral load (\<43 IU/ml) at Week 8 where 43 is the lower limit of quantification of the assay (Cobas AmpliPrep/Taqman HCV Test).
| percentage of participants | NTZ/PEG/RBV |
|---|---|
| Percentage of Participants With Rapid Virologic Response (RVR) | 10.4 (5.0 to 18.7) |
Number of participants who experienced an adverse event of Grade 2 or higher at any time after study entry. Grading of adverse events (signs and symptoms and laboratory toxicities) was according to Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, December 2004.
| participants | NTZ/PEG/RBV |
|---|---|
| Number of Participants With Adverse Events of Grade 2 or Higher | 65 |
Change in hemoglobin (HGB) was calculated as HGB at later time point (Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76) minus HGB at study entry.
| g/dL | NTZ/PEG/RBV |
|---|---|
| Change in HGB at Week 4 | -0.1 (-0.6 to 0.4) |
| Change in HGB at Week 8 | -2.1 (-3.0 to -1.1) |
| Change in HGB at Week 12 | -2.5 (-3.5 to -1.8) |
| Change in HGB at Week 16 | -2.5 (-3.5 to -1.4) |
| Change in HGB at Week 20 | -2.5 (-3.8 to -1.3) |
| Change in HGB at Week 24 | -2.4 (-3.2 to -1.3) |
| Change in HGB at Week 28 | -2.5 (-3.4 to -1.6) |
| Change in HGB at Week 32 | -2.7 (-3.4 to -1.7) |
| Change in HGB at Week 36 | -2.5 (-3.9 to -1.7) |
| Change in HGB at Week 40 | -2.6 (-3.4 to -2.1) |
| Change in HGB at Week 44 | -2.6 (-3.9 to -1.6) |
| Change in HGB at Week 48 | -2.7 (-3.4 to -1.9) |
| Change in HGB at Week 52 | -2.9 (-3.8 to -1.6) |
| Change in HGB at Week 76 | -0.9 (-1.3 to -0.5) |
Percent Change in fasting insulin (FINS) was calculated as FINS at later time point (16, 28, 52, 76) minus FINS at study entry, divided by FINS at study entry x 100%. Study protocol required fasting for at least 8 hours (nothing by mouth except medications and water) prior to specimen collection for fasting insulin testing.
| percentage of FINS at study entry | NTZ/PEG/RBV |
|---|---|
| Percent change in FINS at Week 16 | 0 (-30.8 to 64.7) |
| Percent change in FINS at Week 28 | 8.8 (-33.2 to 67.9) |
| Percent change in FINS at Week 52 | 28.2 (-15.0 to 87.5) |
| Percent change in FINS at Week 76 | 8.3 (-48.0 to 56.3) |
Percent Change in fasting glucose (FGLUC) was calculated as FGLUC at later time point (16, 28, 52, 76) minus FGLUC at study entry, divided by FGLUC at study entry x 100%. Study protocol required fasting for at least 8 hours (nothing by mouth except medications and water) prior to specimen collection for fasting glucose testing.
| percentage of FGLUC at study entry | NTZ/PEG/RBV |
|---|---|
| Percent change in FGLUC at Week 16 | -3.2 (-12.6 to 7.0) |
| Percent change in FGLUC at Week 28 | -5.3 (-9.9 to 4.9) |
| Percent change in FGLUC at Week 52 | 1.1 (-11.8 to 8.0) |
| Percent change in FGLUC at Week 76 | 0 (-7.4 to 8.4) |
HOMA-IR was calculated as \[fasting glucose (mg/dL) x fasting insulin (uIU/mL)\]/405. Percent Change in HOMA-IR was calculated as HOMA-IR at later time point (16, 28, 52, 76) minus HOMA-IR at study entry, divided by HOMA-IR at study entry x 100%. Study protocol required fasting for at least 8 hours (nothing by mouth except medications and water) prior to specimen collection for fasting insulin and fasting glucose testing.
| percentage of HOMA-IR at study entry | NTZ/PEG/RBV |
|---|---|
| Percent change in HOMA-IR at Week 16 (n=56) | -13.0 (-31.6 to 64.2) |
| Percent change in HOMA-IR at Week 28 (n=39) | -6.3 (-42.7 to 81.1) |
| Percent change in HOMA-IR at Week 52 (n=27) | 23.2 (-24.2 to 87.1) |
| Percent change in HOMA-IR at Week 76 (n=22) | 9.5 (-48.0 to 59.5) |
Change in log10 HCV viral load was calculated as log10-transformed HCV viral load at Week 4 minus log10-transformed HCV viral load at study entry. HCV viral load testing was done using Cobas AmpliPrep/Taqman HCV Test.
| log10 IU/mL | NTZ/PEG/RBV |
|---|---|
| Change in log10 HCV Viral Load After 4 Weeks of Nitazoxanide (NTZ) Monotherapy. | -0.12 (-0.30 to 0.13) |
Confirmatory HCV genotyping was performed on stored plasma from entry using VERSANT HCV Genotype assay v2.0 (LiPA, RUO, Siemens Healthcare Diagnostics Inc., Tarrytown, NY).
| participants | NTZ/PEG/RBV |
|---|---|
| Number of Participants With HCV Genotype 1 | 67 |
Collected over From study entry to Week 76.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| NTZ/PEG/RBV | — | 13/67 (19.4%) | 67/67 (100%) |
| Event | NTZ/PEG/RBV |
|---|---|
| NeutropeniaBlood and lymphatic system disorders | 3/67 |
| PneumoniaInfections and infestations | 3/67 |
| AnaemiaBlood and lymphatic system disorders | 2/67 |
| Abdominal painGastrointestinal disorders | 2/67 |
| DiarrhoeaGastrointestinal disorders | 1/67 |
| HaematemesisGastrointestinal disorders | 1/67 |
| VomitingGastrointestinal disorders | 1/67 |
| PyrexiaGeneral disorders | 1/67 |
| CellulitisInfections and infestations | 1/67 |
| UrosepsisInfections and infestations | 1/67 |
| Event | NTZ/PEG/RBV |
|---|---|
| Neutrophil count decreasedInvestigations | 54/67 |
| Alanine aminotransferase increasedInvestigations | 36/67 |
| Platelet count decreasedInvestigations | 35/67 |
| Aspartate aminotransferase increasedInvestigations | 29/67 |
| Haemoglobin decreasedInvestigations | 24/67 |
| FatigueGeneral disorders | 23/67 |
| White blood cell count decreasedInvestigations | 23/67 |
| Weight decreasedInvestigations | 21/67 |
| DiarrhoeaGastrointestinal disorders | 18/67 |
| NeutropeniaBlood and lymphatic system disorders | 16/67 |
| Age, Continuous(years) | NTZ/PEG/RBV |
|---|---|
| Mean | 48.1 ± 8.5 |
| Age, Customized(participants) | NTZ/PEG/RBV |
|---|---|
| <25 years | 1 |
| 25 to <30 years | 1 |
| 30 to <35 years | 4 |
| 35 to <40 years | 3 |
| 40 to <45 years | 11 |
| 45 to <50 years | 13 |
| 50 to <55 years | 18 |
| 55 to 60 years | 13 |
| >=60 years | 3 |
| Sex: Female, Male(Participants) | NTZ/PEG/RBV |
|---|---|
| Female | 15 |
| Male | 52 |
| Race/Ethnicity, Customized(Participants) | NTZ/PEG/RBV |
|---|---|
| White, Non-Hispanic | 21 |
| Black, Non-Hispanic | 32 |
| Hispanic, Regardless of Race | 12 |
| Other/Unknown | 2 |
| Region of Enrollment(participants) | NTZ/PEG/RBV |
|---|---|
| United States | 67 |
| HCV viral load level(log10 IU/ml) | NTZ/PEG/RBV |
|---|---|
| Median | 6.4 (6.0 to 6.7) |
| CD4+ T cell count(cells/mm3) | NTZ/PEG/RBV |
|---|---|
| Median | 452 (323 to 738) |
| Number of participants with indicated HIV viral load(participants) | NTZ/PEG/RBV |
|---|---|
| Undetectable HIV viral load | 49 |
| Detectable HIV viral load | 16 |
| Unknown | 2 |
1 further baseline measures are reported on the registry.
This study is completed, as verified in Jan 2019. You cannot join it, but the record below documents what was studied.
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