Research Article: Rifaximin Reduces Markers of Inflammation and Bacterial 16S rRNA in Zambian Adults with Hepatosplenic Schistosomiasis: A Randomized Control Trial

Date Published: April 12, 2018

Publisher: The American Society of Tropical Medicine and Hygiene

Author(s): Edford Sinkala, Kanekwa Zyambo, Ellen Besa, Patrick Kaonga, Bright Nsokolo, Violet Kayamba, Michael Vinikoor, Rabison Zulu, Martin Bwalya, Graham R. Foster, Paul Kelly.


Cirrhosis is the dominant cause of portal hypertension globally but may be overshadowed by hepatosplenic schistosomiasis (HSS) in the tropics. In Zambia, schistosomiasis seroprevalence can reach 88% in endemic areas. Bacterial translocation (BT) drives portal hypertension in cirrhosis contributing to mortality but remains unexplored in HSS. Rifaximin, a non-absorbable antibiotic may reduce BT. We aimed to explore the influence of rifaximin on BT, inflammation, and fibrosis in HSS. In this phase II open-label trial (ISRCTN67590499), 186 patients with HSS in Zambia were evaluated and 85 were randomized to standard care with or without rifaximin for 42 days. Changes in markers of inflammation, BT, and fibrosis were the primary outcomes. BT was measured using plasma 16S rRNA, lipopolysaccharide-binding protein, and lipopolysaccharide, whereas hyaluronan was used to measure fibrosis. Tumor necrosis factor receptor 1 (TNFR1) and soluble cluster of differentiation 14 (sCD14) assessed inflammation. 16S rRNA reduced from baseline (median 146 copies/µL, interquartile range [IQR] 9, 537) to day 42 in the rifaximin group (median 63 copies/µL, IQR 12, 196), P < 0.01. The rise in sCD14 was lower (P < 0.01) in the rifaximin group (median rise 122 ng/mL, IQR-184, 783) than in the non-rifaximin group (median rise 832 ng/mL, IQR 530, 967). TNFR1 decreased (P < 0.01) in the rifaximin group (median -39 ng/mL IQR-306, 563) but increased in the non-rifaximin group (median 166 ng/mL, IQR 3, 337). Other markers remained unaffected. Rifaximin led to a reduction of inflammatory markers and bacterial 16S rRNA which may implicate BT in the inflammation in HSS.

Partial Text

The most significant cause of mortality and morbidity in patients with hepatosplenic schistosomiasis (HSS) is variceal bleeding as a result of portal hypertension.1–3 The commonest cause of portal hypertension globally is cirrhosis but in the tropics, HSS dominates.4,5 In Zambia, the prevalence of schistosomiasis can reach 77% in endemic parts of the country,6 whereas in the western part of the country, Mutengo et al. found active infection of 42% of adults screened and Payne et al. found seroprevalence to be 88% in the same district.7,8

One hundred and eighty-six patients were evaluated and of the 101 ineligible patients, most of them were seronegative for schistosomiasis (Figure 1); although many of these may have had schistosomiasis in the past, we required seropositivity to ensure homogeneity of the trial population. The rifaximin and non-rifaximin groups were similar with respect to demographic and most laboratory data (Table 1). The commonest cause of referral to the hospital was hematemesis (Table 1). At baseline, most of the patients had pancytopenia, but there was an increase in hemoglobin in both groups after 42 days of follow-up; other full blood count indices remained the same (Tables 1 and 2). There were apparent good responses to beta blockade in both rifaximin and non-rifaximin groups after the 42-day follow-up (Table 2). Ten (23%) patients in rifaximin group and seven (24%) patients in the non-rifaximin group had ascites at baseline. Even after 42 days of follow-up, eight patients had ascites on physical examination, five (12%) patients in the rifaximin group, and three (8%) patients in the non-rifaximin group. All patients had normal body temperature at baseline and after 42 days in both groups.

The reduction in inflammatory markers and 16S rRNA copies after 42 days of intestinal decontamination with rifaximin provide evidence that BT may have a clinical association with inflammatory processes in HSS-related portal hypertension. We know that BT is associated with cirrhosis, and this drives the disease process by increasing portal hypertension.10,11 Our results suggest that similar mechanisms may also be driving portal hypertension in HSS.

We showed that rifaximin led to the reduction of systemic inflammatory cytokines and bacterial 16S rRNA, a direct marker of BT. This suggests that BT may be involved in the pathophysiology of HSS and warrants the further study to demonstrate if rifaximin gives clinical benefit. It would be of interest to study patients recruited immediately after acute variceal bleeds, with clinical endpoints, perhaps as a multicenter placebo-controlled trial on a larger scale.




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