A randomized double-blind placebo-controlled clinical trial of nitazoxanide for treatment of mild or moderate COVID-19.

BACKGROUND: There is an urgent need for treatments of mild or moderate COVID-19 in an outpatient setting. METHODS: A randomized double-blind placebo-controlled clinical trial in 36 centers in the U.S. between August 2020 and February 2021 investigated the safety and effectiveness of oral nitazoxanide 600 mg twice daily for five days in outpatients with symptoms of mild or moderate COVID-19 enrolled within 72 h of symptom onset (ClinicalTrials.gov NCT04486313). Efficacy endpoints were time to sustained clinical recovery (TSR, a novel primary endpoint) and proportion of participants progressing to severe illness within 28 days (key secondary). FINDINGS: 1092 participants were enrolled. 379 with laboratory-confirmed SARS-CoV-2 infection were analyzed. In the primary analysis, median (IQR) TSR were 13·3 (6·3, >21) and 12·4 (7·2, >21) days for the nitazoxanide and placebo groups, respectively (p = 0·88). 1 of 184 (0·5%) treated with nitazoxanide progressed to severe illness compared to 7 of 195 (3·6%) treated with placebo (key secondary analysis, odds ratio 5·6 [95% CI 0·7 - 46·1], relative risk reduction 85%, p = 0·07). In the pre-defined stratum with mild illness at baseline, nitazoxanide-treated participants experienced reductions in median TSR (3·1 days, p = 0·09) and usual health (5·2 days, p < 0·01) compared to placebo. Nitazoxanide was safe and well tolerated. INTERPRETATION: Further trials with larger numbers are warranted to evaluate efficacy of nitazoxanide therapy in preventing progression to severe illness in patients at high risk of severe illness and reducing TSR in patients with mild illness.

Short communication: Nitazoxanide inhibits HIV viral replication in monocyte-derived macrophages.

We document the anti-HIV activity of nitazoxanide (NTZ), the first member of the thiazolide class of antiinfective drugs, originally effective against enteritis caused by Cryptosporidium parvum and Giardia lamblia. NTZ has been administered extensively worldwide, with no severe toxicities associated with its use. Here, we show for the first time that NTZ decreases HIV-1 replication in monocyte-derived macrophages (MDM) if present before or during HIV-1 infection. This NTZ effect is associated with downregulation of HIV-1 receptors CD4 and CCR5, and increasing gene expression of host cell anti-HIV resistance factors APOBEC3A/3G and tetherin. As NTZ is already in clinical use for other conditions, this newly described anti-HIV activity in MDM may facilitate innovative intensification strategies against HIV-1 when combined with current antiretroviral drug regimens.

Addition of nitazoxanide to PEG-IFN and ribavirin to improve HCV treatment response in HIV-1 and HCV genotype 1 coinfected persons naïve to HCV therapy: results of the ACTG A5269 trial.

BACKGROUND: We hypothesized that nitazoxanide (NTZ) added to pegylated interferon alfa-2a (PEG-IFN) and weight-based ribavirin (WBR) would improve hepatitis C virus (HCV) virologic responses in HCV treatment-naïve HIV-1/HCV genotype 1 coinfected persons. METHODS: Prospective, single-arm study in which subjects received 4-week lead-in (NTZ 500 mg twice daily) followed by 48 weeks of NTZ, PEG-IFN, and WBR. We compared the HCV virologic responses of these subjects to historical controls from the completed ACTG study A5178 who received PEG-IFN and WBR and had similar subject characteristics. Primary endpoints were early virologic response and complete early virologic response (EVR and cEVR). RESULTS: Among 67 subjects (78% male; 48% Black; median age, 50 years), EVR was achieved in 65.7% (90% CI, 55.0%-75.3%), cEVR in 38.8% (28.8%-49.6%). and SVR in 32.8% (23.4%-43.5%). EVR was higher with NTZ (51.4% in A5178; P = .03), but the sustained virologic response (SVR) proportion was similar (27.3% in A5178; P = .24). In contrast to A5178, SVR was similar across IL28B genotypes. Overall, NTZ was safe and well-tolerated. CONCLUSION: Whereas EVR proportion improved significantly in this pilot study, the addition of NTZ to PEG-IFN/WBR did not significantly improve SVR compared to historical controls. NTZ may be associated with an attenuation of the effect of IL28B on HCV treatment response.

Nitazoxanide for the empiric treatment of pediatric infectious diarrhea.

We conducted a double-blind, placebo-controlled clinical trial to demonstrate the efficacy of nitazoxanide suspension for the treatment of presumed infectious diarrhea in children. Eligible patients must have had diarrheal illness lasting 3-29 days. Patients were randomized to receive either nitazoxanide or placebo twice daily for three days. The primary endpoint was time from first dose to resolution of symptoms. One hundred children mean age 3.3 years were enrolled. The median time to resolution of symptoms for nitazoxanide treated patients was 23 hours (IQR 4-48 hours) vs 103.5 hours (IQR 63->168 hours) for placebo (p<0.001). An analysis by disease subset indicated nitazoxanide treated patients had statistically shorter durations of diarrheal illness associated with Giardia lamblia (n=32, p<0.001) and those with no identified enteropathogen (n=38, p=0.008), when compared to placebo. The study medication was well tolerated. Overall, nitazoxanide was effective at reducing the duration of diarrheal illness associated with multiple etiologies, including patients with no identified enteropathogen. These results suggest nitazoxanide may be a viable therapeutic option for the empiric treatment of diarrheal illness in children where the etiology is unknown or presumed to be of infectious origin. Clinical trial registry number NCT01326338.

Nitazoxanide and probiotics for the treatment of recurrent Clostridium difficile infection in a peritoneal dialysis patient.

Nitazoxanide has been proven to be efficacious for the treatment of Clostridium difficile infection (CDI), but data is limited in peritoneal dialysis (PD) patients. This report details the successful utilization of nitazoxanide and probiotics to treat multirecurrent CDI in a PD patient. A 58-year-old woman was admitted with hypotension, nausea and vomiting attributed to metronidazole therapy for CDI, her third CDI treatment regimen in 3 months. During her admission, the patient developed CDI and was started on a 6-week regimen of nitazoxanide and probiotics to assist in re-establishing the colonic flora. The regimen was well tolerated and the patient remained disease free at follow up, four months later.