Clinical evidence for repurposing chloroquine and hydroxychloroquine as antiviral agents: a systematic review

BackgroundRepurposing hydroxychloroquine (HCQ) and chloroquine (CQ) as antiviral agents is a re-emerging topic with the advent of new viral epidemics.AimsTo summarize evidence from human clinical studies for using HCQ or CQ as antiviral agents for any viral infection.SourcesPubMed, EMBASE, Scopus, Web of Science for published studies without time or language restrictions; Cochrane Clinical Trial Registry and Chinese Clinical Trials Registry for trials registered after 2015; MedRxiv for preprints within the last 12 months.ContentStudy eligibility criteria were interventional and prospective observational studies (with or without a control group). Participants were adults and children with a confirmed viral infection. Interventions included the use of CQ or HCQ as antiviral agent in one or more groups of the study. Two authors independently screened abstracts, and all authors agreed on eligible studies. A meta-analysis was planned if studies were available which were similar in terms of participants, intervention, comparator and outcomes. Nineteen studies (including two preprints) were eligible (HIV 8, HCV 2, dengue 2, chikungunya 1, COVID-19 6). Nine and ten studies assessed CQ and HCQ respectively. Benefits of either drug for viral load suppression in HIV are inconsistent. CQ is ineffective in curing dengue (high-certainty evidence) and may have little or no benefit in curing chikungunya (low-certainty evidence). The evidence for COVID-19 infection is rapidly evolving but at this stage we are unsure whether either CQ or HCQ has any benefit in clearing viraemia (very-low-certainty evidence).ImplicationsUsing HCQ or CQ for HIV/HCV infections is now clinically irrelevant as other effective antivirals are available for viral load suppression (HIV) and cure (HCV). There is no benefit of CQ in dengue, and the same conclusion is likely for chikungunya. More evidence is needed to confirm whether either HCQ or CQ is beneficial in COVID-19 infection.     

Chronic hepatitis B in pregnancy: unique challenges and opportunities

Chronic hepatitis B (CHB) affects 350 million individuals worldwide. Perinatal transmission leads to high rates of chronic infection and complications, including cirrhosis and hepatocellular carcinoma. It is important to recognize and appropriately treat CHB in pregnancy, thereby reducing the risk of neonatal transmission and HBV-associated morbidity and mortality. Screening for CHB is recommended in all pregnant mothers as is universal vaccination of infants with hepatitis B virus (HBV) vaccine with or without hepatitis B immunoglobulin (HBIG). This has resulted in a lower incidence of HBsAg seropositivity and HCC in regions where universal infant vaccination has been endorsed. Mode of delivery and breastfeeding do not appear to affect HBV transmission rates based on available data. Overall, CHB does not increase perinatal maternal-fetal mortality. Administration of oral antiviral therapy during the third trimester to HBsAg-positive mothers with HBV DNA≥7 log IU/mL may be useful in preventing breakthrough infection. Treatment may be considered earlier in pregnancy for persistently active liver disease shown by high ALT, HBV DNA levels and/or significant hepatic fibrosis. Lamivudine, tenofovir and telbivudine are safe and effective and are the agents of choice in pregnancy. However, further clinical studies are necessary to elucidate the role of antiviral therapy in the pregnant HBV carrier.     

Nipah virus entry can occur by macropinocytosis

Nipah virus (NiV) is a zoonotic biosafety level 4 paramyxovirus that emerged recently in Asia with high mortality in man. NiV is a member, with Hendra virus (HeV), of the Henipavirus genus in the Paramyxoviridae family. Although NiV entry, like that of other paramyxoviruses, is believed to occur via pH-independent fusion with the host cell's plasma membrane we present evidence that entry can occur by an endocytic pathway. The NiV receptor ephrinB2 has receptor kinase activity and we find that ephrinB2's cytoplasmic domain is required for entry but is dispensable for post-entry viral spread. The mutation of a single tyrosine residue (Y304F) in ephrinB2's cytoplasmic tail abrogates NiV entry. Moreover, our results show that NiV entry is inhibited by constructions and drugs specific for the endocytic pathway of macropinocytosis. Our findings could potentially permit the rapid development of novel low-cost antiviral treatments not only for NiV but also HeV.     

Predictive factors for survival and score application in liver retransplantation for hepatitis C recurrence

AIM: To identify risk factors associated with survival in patients retransplanted for hepatitis C virus(HCV) recurrence and to apply a survival score to this population.METHODS: We retrospectively identified 108 patients retransplanted for HCV recurrence in eight European liver transplantation centers(seven in France, one in Spain). Data collection comprised clinical and laboratory variables, including virological and antiviral treatment data. We then analyzed the factors associated with survival in this population. A recently published score that predicts survival in retransplantation in patients with hepatitis C was applied. Because there are currently no uniform recommendations regarding selection of the best candidates for retransplantation in this setting, we also described the clinical characteristics of 164 patients not retransplanted, with F3, F4, or fibrosing cholestatic hepatitis(FCH) post-first graft presenting with hepatic decompensation. RESULTS: Overall retransplantation patient survival rates were 55%, 47%, and 43% at 3, 5, and 10 years, respectively. Patients who were retransplanted for advanced cirrhosis had survival rates of 59%, 52%, and 49% at 3, 5, and 10 years, while those retransplanted for FCH had survival rates of 34%, 29%, and 11%, respectively. Under multivariate analysis, and adjusting for the center effect and the occurrence of FCH, factors associated with better survival after retransplantation were: negative HCV viremia before retransplantation, antiviral therapy after retransplantation, non-genotype 1, a Model for End-stage Liver Disease(MELD) score 25 when replaced on the waiting list, and a retransplantation donor age 60 years. Although the numbers were small, in the context of the new antivirals era, we showed that outcomes in patientswho underwent retransplantation with undetectable HCV viremia did not depend on donor age and MELD score. The Andrés score was applied to 102 patients for whom all score variables were available, producing a mean score of 43.4(SD = 6.6). Survival rates after the date of the first decompensation post-first liver transplantation(LT1) in the liver retransplantation(re LT) group(94 patients decompensated) at 3, 5, and 10 years were 62%, 59%, and 51%, respectively, among 78 retransplanted individuals with advanced cirrhosis, and 42%, 32%, and 16% among 16 retransplanted individuals with FCH. In the non-re LT group with hepatic decompensation, survival rates were 27%, 18%, and 9% at 3, 5, and 10 years, respectively(P 0.0001). Compared with non-retransplanted patients, retransplanted patients were younger at LT1(mean age 48 ± 8 years compared to 53 ± 9 years in the no re LT group, P 0.0001), less likely to have human immunodeficiency virus(HIV) co-infection(4% vs 14% among no re LT patients, P = 0.005), more likely to have received corticosteroid bolus therapy after LT1(25% in re LT vs 12% in the no re LT group, P = 0.01), and more likely to have presented with sustained virological response(SVR) after the first transplantation(20% in the re LT group vs 7% in the no re LT group, P = 0.028).CONCLUSION: Antiviral therapy before and after retransplantation had a substantial impact on survival in the context of retransplantation for HCV recurrence, and with the new direct-acting antivirals now available, outcomes should be even better in the future.     

Use of rapid tests and antiviral medications for influenza among primary care providers in the United States

Limited data are available about how physicians diagnose and treat influenza. We conducted an internet‐based survey of primary care and emergency physicians to evaluate the use of influenza testing and antiviral medications for diagnosis and treatment of influenza. In April 2005, an electronic link to a 33‐question, web‐based survey was emailed to members of the American College of Physicians, American Academy of Pediatrics, American Academy of Family Physicians, and American College of Emergency Physicians. Of the 157 674 physician members of the four medical societies, 2649 surveys were completed (1·7%). The majority of participants were internists (59%). Sixty percent of respondents reported using rapid tests to diagnose influenza. Factors associated with using rapid influenza tests included physician specialty, type of patient insurance, and practice setting. After controlling for insurance and community setting, emergency physicians and pediatricians were more likely to use rapid influenza tests than internists [odds ratio (OR) 3·7, confidence interval (CI): 2·3–6·1; and OR 1·7, CI: 1·4–2·1, respectively]. Eighty‐six percent of respondents reported prescribing influenza antiviral medications. Reasons for not prescribing antivirals included: patients do not usually present for clinical care within 48 hours of symptom onset (53·0%), cost of antivirals (42·6%) and skepticism about antiviral drug effectiveness (21·7%). The use of rapid tests and antiviral medications for influenza varied by medical specialty. Educating physicians about the utility and limitations of rapid influenza tests and antivirals, and educating patients about seeking prompt medical care for influenza‐like illness during influenza season could lead to more rapid diagnosis and improved management of influenza.     

CIHR Canadian HIV Trials Network Co-Infection and Concurrent Diseases Core: Updated Canadian guidelines for the treatment of hepatitis C infection in HIV-hepatitis C coinfected adults

BACKGROUND:Hepatitis C virus (HCV) coinfection occurs in 20% to 30% of Canadians living with HIV and is responsible for a heavy burden of morbidity and mortality. Management of HIV-HCV coinfection is more complex due to the accelerated progression of liver disease, the timing and nature of antiretroviral and HCV therapy, mental health and addictions management, socioeconomic obstacles and drug-drug interactions between new HCV direct-acting antiviral therapies and antiretroviral regimens.OBJECTIVE:To update national standards for the management of HCV-HIV coinfected adults in the Canadian context.METHODS:A standing working group with specific clinical expertise in HIV-HCV coinfection was convened by The Canadian Institute of Health Research HIV Trials Network to review recently published data regarding HCV antiviral treatments and to update the Canadian HIV-HCV coinfection guidelines.RESULTS:Recent data suggest that the gap in sustained virological response rates between HCV monoinfection and HIV-HCV coinfection has been eliminated with newer HCV antiviral regimens. All HIV-HCV coinfected individuals should be assessed for HCV therapy. First-line treatment for genotypes 1 through 6 includes pegylated interferon and weight-based ribavirin dosing plus the nucleotide sofosbuvir for 12 weeks. Sofosbuvir in combination with the protease inhibitor simeprevir is another first-line consideration for genotype 1 infection. Sofosbuvir with ribavirin for 12 weeks (genotype 2) and 24 weeks (genotype 3) is also recommended as first-line treatment.DISCUSSION:Recommendations may not supersede individual clinical judgement.