Jonas Schreiber

Background and aim Insulin resistance plays an important role in chronic liver disease, where it has been associated with the progression of fibrosis and correlated with portal hypertension in cirrhotic patients with mixed etiology. However, the impact of insulin resistance in alcoholic liver disease remains mostly unknown. The aim of this study was to evaluate the association between insulin resistance, portal hypertension, severity of liver disease, and mortality in patients with alcoholic cirrhosis. Patients and methods A total of 106 consecutive alcoholic cirrhotic patients undergoing hepatic venous pressure gradient measurement at Erasme Hospital were included. Insulin resistance was estimated using the homeostatic model assessment-2 index. Results The median model for end-stage liver disease (MELD) score was 15 (9–21) and the mean hepatic venous pressure gradient was16.3±6 mmHg. Twenty-six percent of the patients had compensated cirrhosis. Insulin resistance was significantly associated with portal hypertension in compensated cirrhotic patients and with the presence of esophageal varices, but was not associated with the MELD score and mortality. MELD score was the only independent covariate associated with mortality at 6 (PP<0.001). Conclusion Insulin resistance is associated with the presence of esophageal varices, suggesting that the presence of insulin resistance could be harmful to alcoholic liver disease patients.

During a phase 3 study evaluating the combination of sofosbuvir‐velpatasvir for 12 weeks in patients with genotype 1, 2, 4, 5, and 6 hepatitis C virus (HCV) infection, we enrolled a patient who was subsequently found to be infected with genotype 7 HCV. This patient tolerated the study regimen well and achieved sustained virological response 12 weeks after treatment (SVR12). (Hepatology 2016;64:983‐985)

Background & Aims: The beneficial effect of nonselective beta‐blockers (NSBB) has recently been questioned in patients with end‐stage cirrhosis. We analysed the impact of NSBB on outcomes in severe alcoholic hepatitis (AH).Methods: This study was based on a prospective database of patients with severe, biopsy‐proven AH. Patients admitted from July, 2006 to July, 2014 were retrospectively studied. Patients were divided into two groups (with and without NSBB) and assessed for the occurrence of Acute Kidney Injury (AKI) and transplant‐free mortality during a 168‐day follow‐up period.Results: One hundred thirty‐nine patients were included, the mean Maddrey score was 71 ± 34 and 86 patients (61.9%) developed AKI. Forty‐eight patients (34.5%) received NSBB. The overall 168‐day transplant‐free mortality was 50.5% (95%CI, 41.3–60.0%). The overall 168‐day cumulative incidence of AKI was 61.9% (95%CI, 53.2–69.4%). When compared, patients with NSBB had a lower heart rate (65 ± 13 vs 92 ± 12, P < 0.0001) and a lower mean arterial pressure (MAP, 78 ± 3 vs 87 ± 5, P < 0.0001). Patients with NSBB had comparable MELD scores, Maddrey scores, and medical histories. The 168‐day transplant‐free mortality was 56.8% (95%CI, 41.3–69.7%) in patients with NSBB and 46.7% (95%CI, 35.0–57.6%) without NSBB (P = 0.25). The 168‐day cumulative incidence of AKI was 89.6% (95%CI, 74.9–95.9%) with NSBB compared to 50.4% (95%CI: 39.0–60.7) for no NSBB (P = 0.0001). The independent factors predicting AKI were a higher MELD score and the presence of NSBB.Conclusions: The use of NSBB in patients with severe AH is independently associated with a higher cumulative incidence of AKI.

Recent studies suggested that IL28B polymorphisms may affect rapid and sustained virological response rates in HCV patients infected with genotype 2 or 3. To assess the role of IL28B polymorphisms on the virological response in HCV‐2 and ‐3 patients. We performed meta‐analysis of studies evaluating the impact of rs12979860 and rs8099917 polymorphisms on rapid and sustained virological response in HCV‐2 or ‐3 patients. Twenty‐three studies involving 3042 patients were included. The first meta‐analysis evaluated the impact of rs12979860 polymorphism and included 1963 patients. When compared with rs12979860 CT/TT patients, CC patients had a higher rapid virological response rate (mean difference: 12.9%, 95% CI: 6.5–19.4%, P < 0.001) and a higher sustained virological response rate (mean difference: 4.9%, 95% CI: 0.1–9.8%, P = 0.046). The second meta‐analysis evaluated the impact of rs8099917 polymorphism and included 2246 patients. When compared with rs8099917 TG/GG patients, TT patients had a higher rapid virological response rate (mean difference: 14.8%, 95% CI: 7.2–22.4%, P < 0.001) and a higher sustained virological response rate (mean difference: 5.5%, 95% CI: 0.4–10.6%, P = 0.033). When considering only patients treated for 24 weeks, results were unchanged. No potential sources of between‐study heterogeneity were identified. Favourable IL28B polymorphisms are associated with higher rapid and sustained virological response rates in HCV‐2 and ‐3 patients. However, as the impact on a sustained response is very limited, it is unlikely that IL28B polymorphisms provide additional predictive value when considering other predictors of a sustained response.

Both use of sulphadoxine-pyrimethamine (SP) and SP-resistance of Plasmodium falciparum are increasing in sub-Saharan Africa. Mutations in the P. falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes can predict treatment failure of SP, however, the degree of this relationship varies regionally. In northern Ghana, pre-treatment dhfr/dhps genotypes were examined in 126 children and associations with PCR-corrected SP treatment outcome and gametocyte carriage were analysed. SP treatment failure within 4 weeks of follow-up occurred in 28%. Among all pre-treatment isolates, the dhfr triple mutation (Ile-51 + Arg-59 + Asn-108) was detected in 47%. Compared with dhfr wildtype parasites, the presence of the dhfr triple mutation increased the risk of treatment failure tenfold. Likewise, parasite clearance was delayed in the presence of dhfr variants. Dhfr mutants and dhps Gly-437 were selected in treatment failure isolates. Gametocytaemia 1 week following treatment was strongly associated with dhfr mutations. Remarkably, this was also true for the prevalence of gametocytes at recruitment. Dhps alleles did neither influence treatment outcome nor gametocyte carriage. In northern Ghana, the prevalence of the dhfr triple mutation can be used as a tool to screen for and to monitor SP resistance. The lack of association between dhps alleles and SP treatment outcome suggests a minor role of these molecular markers in this region at present.

Summary: The therapeutic efficacy of sulfadoxine–pyrimethamine (SP) alone, SP plus amodiaquine (AQ), and SP plus artesunate (AS) was assessed in a randomized, placebo‐controlled, and double‐blind trial among 438 children with uncomplicated Plasmodium falciparum malaria in northern Ghana. Clinical and parasitological responses were monitored for 28 days following treatment; 86%, 98% and 97% of SP‐, SP + AQ‐, and SP + AS‐treated patients achieved adequate clinical and parasitological response (ACPR) within 2 weeks, respectively. Parasite clearance was better with SP + AS than with SP or SP + AQ treatment but re‐infections were more common. Polymerase chain reaction (PCR)‐corrected rates of ACPR at day 28 were 72.2% for SP, 94.1% for SP + AQ (P < 0.0001), and 94.5% for SP + AS (P < 0.0001). Gametocyte prevalence and density 1 week after treatment were highest in children treated with SP, and lowest in patients receiving SP + AS. No severe adverse events attributable to study medication were observed. In northern Ghana, more than one of four children suffered SP treatment failure within 4 weeks. Both SP + AQ and SP + AS are efficacious alternative therapeutic options in this region. Although SP + AS and SP + AQ treatments have virtually identical cure rates, rapid parasite clearance and pronounced gametocidal effects are the advantages of the former, whereas cost and a lower rate of late re‐infections are those of the latter.

Summary: Atovaquone‐proguanil has recently been introduced for the treatment and prophylaxis of malaria. However, resistance of Plasmodium falciparum is increasingly reported. We assessed P. falciparum polymorphisms associated with resistance to atovaquone (cytochrome b, cytb) and to cycloguanil, the active compound of proguanil (dihydrofolate reductase, dhfr) in 100 isolates from northern Ghana. None of these exhibited cytb codon 268 mutations. Moreover, no dhfr V16A, S108T or I164L mutations linked with cycloguanil resistance were detected. However, dhfr triple mutants (S108N‐I51L‐C59R) conferring resistance to proguanil and sulphadoxine‐pyrimethamine were seen in 51% of the isolates. In northern Ghana, P. falciparum cytb codon 268 mutations associated with atovaquone resistance are absent. Although proguanil appears to act synergistically with atovaquone in a way different from its antifolate property, the abundance of dhfr polymorphisms will likely compromise the prevention of dissemination of atovaquone‐resistant parasites once emerged.