Discussion
NAFLD, non-AIDS-defining disease, PWH, inflammation, cirrhosis, fibrosis, TG
ADVERSE REACTIONS, INFLAMMATION, CIRRHOSIS, FIBROSIS, ADVERSE REACTION
These data provide preliminary evidence that add-on maraviroc as therapy for NAFLD without cirrhosis in PWH on effective cART may be safe, acceptable and feasible. We recruited ~90% of our target of 60 individuals, and, of those referred for possible participation, 66% were randomised, including all who met eligibility criteria at screen. Participant retention until week 96 was acceptable, achieving ~80%, despite the unprecedented circumstances of the SARS-CoV-2 pandemic. Adherence to maraviroc, taken twice daily by almost all participants, was high (>90%). The adverse reaction rate of 22% was numerically greater than the 10% pre-selected target; however, this figure fell within the 95% CI around 22% of 5%-49% indicating the uncertainty as to whether or not there was an increase in AR compared to the target. Taken in conjunction with findings that all adverse reactions resolved, including in the 9% who discontinued maraviroc, and that there were no serious adverse reactions, no clear evidence of a significant safety concern was identified It was notable that blip rates were numerically greater in the MVC+OBT versus OBT arms (22% versus 10%), but if baseline visit blips were excluded, these became 13% and 7% respectively. Although this remained higher in the MVC+OBT group, both rates are comparable to that seen in the clinic population for one of the participating sites with available published data (~10%) [We observed differences in the changes of two participant characteristics during follow up between the two treatment groups. ALT and LSM scores improved in the MVC+OBT but worsened in the OBT group over 96 weeks. CAP scores declined in both groups but by a numerically greater level in the MVC+OBT group. These findings raise the possibility of an improvement in liver fat and fibrosis. However, the 95% CI for the differences contained zero so were consistent with there being no detectable differences, and the trial was not powered to evaluate for differences in these characteristics. A future RCT of add-on maraviroc with a larger sample size should assess for any differences in these outcomes.There was a high level (>80%) of completion of questionnaires to assess QoL outcomes for CLDQ-NAFLD and SF36, but <50% completion for WPAI:SHIP. This was related to lack of responses to work productivity questions only, likely due to a combination of some participants being unemployed plus missing data. CLDQ-NAFLD and SF36 would therefore be more suitable for inclusion in a larger trial. Regarding QoL outcomes, 95% CI for differences between groups contained zero which was consistent with there being no detectable difference. Few individuals undertook optional CTs, either as this was not offered by sites or participant choice. This may be because CT is less acceptable than ultrasound for NAFLD follow up due to the increased radiation exposure and should not be included in a future RCT. The alternative imaging modality of Magnetic resonance imaging (MRI)–estimated proton density fat fraction (PDFF) is expensive and not routinely available.Limited data on the potential efficacy of maraviroc as a treatment for NAFLD are available from previous studies. In a retrospective cohort in PWH, 74 individuals receiving maraviroc were compared to 312 who had never been exposed to maraviroc, matched for age, sex and CD4 count nadir. In the non-maraviroc group, a significant association was found between a marker of inflammation (hsCRP) and lipoprotein levels (LDL, TG, TC) at baseline and after 3 years. By contrast, in the maraviroc group, this relationship was observed at baseline but lost after 3 years. The incidence of non-AIDS-defining disease was lower in the maraviroc group but this was not statistically significant. The authors speculated that CCR5 inhibition may offer protection against a lipid-dependent inflammatory process [In a phase III trial, PWH -NAFLD were randomised into four groups: OBT (n = 24), ± maraviroc (n = 23), metformin (n = 21) or maraviroc with metformin (n = 22). Hepatic fat scores were measured at baseline and week 48 using MRI-PDFF. Maraviroc ± metformin was found to be safe with acceptable tolerability but did not reduce liver fat scores compared to no adjunctive treatment, and LSM scores were not presented [We instituted a number of measures in response to the COVID-19 pandemic. First, time windows for visits were lengthened from ±1 to ±8 weeks to provide flexibility for staff redeployed to COVID-19 responsive work and for participants experiencing difficulty in accessing clinical sites. Second, virtual visits were permitted for follow up visits, excluding week 48 and 96. This was to provide focus on high completeness of the final dataset whilst enabling participants to avoid travel and clinical contact while self-isolating. Third, we regularly sought feedback from sites to identify problems early and work towards finding local solutions for keeping participants engaged, for example, mailing out IMP.