Low Efficacy of Pegylated Interferon plus Ribavirin plus Nitazoxanide for HCV Genotype 4 and HIV Coinfection

<div><p>Background</p><p>Nitazoxanide (NTZ) plus pegylated interferon and ribavirin (Peg-IFN/RBV) improved the sustained virological response (SVR) achieved with Peg-IFN/RBV in hepatitis C virus genotype 4 (HCV-4)-monoinfected patients. There are no data currently on the efficacy of Peg-IFN/RBV plus NTZ for human immunodeficiency virus (HIV)/HCV-4 coinfection. Therefore, the objectives of this clinical trial were to assess the efficacy and to evaluate the safety of Peg-IFN/RBV plus NTZ in HIV/HCV-4-coinfected patients.</p><p>Patients and Methods</p><p>This was an open-label, single arm, multicenter phase II pilot clinical trial (<a href="https://clinicaltrials.gov/ct2/show/NCT01529073?term=NCT01529073&rank=1" target="_blank">NCT01529073</a>) enrolling HIV-infected individuals with HCV-4 chronic infection, naïve to HCV therapy. Patients were treated with NTZ 500 mg bid for 4 weeks, followed by NTZ 500 mg bid plus Peg-IFN alpha-2b 1.5 μg/kg/week plus weight-adjusted RBV during 48 weeks. Analyses were done by intention-to-treat (ITT, missing = failure). A historical cohort of HIV/HCV-4-infected patients treated with Peg-IFN alpha-2b and RBV at the same area was used as control.</p><p>Results</p><p>Two (9.5%) of 21 patients included in the trial compared with 5 (21.7%) of 23 patients included in the historical cohort achieved SVR (SVR risk difference, -12.2%; 95% confidence interval, -33.2% to 8.8%; p = 0.416). Virological failure was due to lack of response in 13 (62%) individuals recruited in the trial. Two (9.5%) patients included in the trial and two (9.5%) individuals from the historical cohort discontinued permanently due to adverse events.</p><p>Conclusions</p><p>No increase in SVR was observed among HIV/HCV-4-coinfected patients receiving Peg-IFN/RBV plus NTZ compared with a historical cohort treated with Peg-IFN/RBV. Interruptions due to adverse events of Peg-IFN/RBV plus NTZ were similar to those of dual therapy.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01529073?term=NCT01529073&rank=1" target="_blank">NCT01529073</a></p></div

Adverse effects experienced by the study patients.

<p>Adverse effects experienced by the study patients.</p

CONSORT 2010 flow diagram.

<p>CONSORT 2010 flow diagram.</p

Liver stiffness progression rate according to <i>PNPLA3</i> rs738409 genotype.

<p>Liver stiffness progression rate according to <i>PNPLA3</i> rs738409 genotype.</p

Main characteristics of the study population 1 and the subpopulation where liver stiffness progression was evaluated.

<p>Main characteristics of the study population 1 and the subpopulation where liver stiffness progression was evaluated.</p

Associations with significant liver stiffness progression (Study 2).

<p>Associations with significant liver stiffness progression (Study 2).</p

Rates of SVR according to marker genotypes.

<p>A: in HCV-1 infected patients and B: in HCV-4 infected patients. n/N: number of patients who achieved SVR/total number of patients (for each genotype group). For each polymorphism, the p values depicted were obtained from the comparison of SVR rates between genotype groups.</p

Main characteristics of the study population.

<p>BMI; body mass index.</p><p>*Median (quartile 1–quartile 3).</p>1<p>Determined by liver biopsy (F≥3 according to the Scheuer Index) or a liver stiffness value ≥11 kPa.</p

Univariate and multivariate analysis (one model for each genetic marker) of factors associated with SVR.

<p>SVR, Sustained viral response; BMI, body mass index; NI, not included in the model; CI, confidence interval; AOR, adjusted odds ratio.</p><p>* p values and AOR are for a recessive model (CC vs CT+TT for rs12979860 and TT/TT vs TT/−G+−G/−G for ss469415590).</p>†<p>Count for non responders were 27, 86 and 37 for TT, CT and CC genotypes respectively.</p>‡<p>Counts for non responders were 29, 87 and 34 for –G/−G, TT/−G and TT/TT genotypes respectively.</p

Predictors of grade 4 total bilirubin elevations (TBE).

<p>Predictors of grade 4 total bilirubin elevations (TBE).</p