Great expectation for a great need https://www.natap.org/2020/HIV/hep.31177.pdf
This article among others by Dr. Giada Sebastiani from 2020 is discussing the need for developing a drug for NASH among PLWH, one important factor which is discussed is drug-drug interaction between the drugs in development for general population and their potential interactions with ARTs, The only drug which showed definitely no interaction is Tesamorelin which has been used of over a decade by HIV patients on ARTs therefore the study suggests instead of excluding PLWH these NASH trials should include a subgroup of cohorts with HIV which we know THTX’s current NASH protocol has. There is a reference to Tesamorelin’s trial. It appears the relative difference of the fibrosis progression between two arms was 27% in other words Tesamorelin stopped the progression of fibrosis in PLWH and NAFLD who are prone to higher rates of fibrosis and faster rates of the progression of NAFLD to NASH. The article also discusses the significant positive correlation between metabolic syndrome and NAFLD/NASH in both HIV and general population. The prevalence of NASH/significant liver fibrosis in PLWH is 48% and 23% respectively as per the result of 43 studies to date (8230 patients in total).
Prevalence and Characteristics of Nonalcoholic Fatty Liver Disease and Fibrosis in People Living With HIV Monoinfection: A Systematic Review and Meta-analysis - Clinical Gastroenterology and Hepatology
Point is the current NASH trials exclude HIV when and if approved with unknown drug-drug interactions with antiviral drugs. The HIV NASH is more progressive with higher mortality and currently in the US about one million people are confirmed HIV positive thus a large group of cohorts which need desperately a drug for the condition are left out from the current NASH trials.
Reference to Tesamorelin:
“A particular case is represented by tesamorelin, a synthetic form of growth hormone–releasing hormone, which is Food and Drug Administration– approved for the treatment of excess abdominal fat in HIV-associated lipodystrophy. In a randomized, double-blind, multicenter trial including 61 PLWH with NAFLD, Stanley et al. assessed its effect on liver fat and histology. At baseline, liver biopsies revealed that 43% of patients had liver fibrosis and 33% had NASH. After 12 months of treatment, liver fat in patients on tesamorelin had decreased by 32% from baseline, while it had increased by 5% in placebo patients (P = 0.02), amounting to a 37% relative reduction in liver fat. Furthermore, 35% of patients in the tesamorelin group returned to liver fat values below 5% in comparison to only 4% of patients on placebo (P = 0.007).(39) The study also concluded that 10.5% of patients in the tesamorelin group experienced progression of liver fibrosis compared with 37.5% in patients receiving a placebo (P = 0.04) (Table 3).(39) The DDI potential of tesamorelin has been evaluated with simvastatin, a cytochrome P4503A4 (CYP3A4) sensitive substrate, and the HIV protease inhibitor ritonavir. Tesamorelin (2 mg, multiple doses) was shown to have a minimal effect on simvastatin (80 mg) and ritonavir (100 mg) pharmacokinetics in healthy volunteers,(40) suggesting that tesamorelin is unlikely to alter the exposure of antiretroviral drugs (Table 2). Because tesamorelin induces the secretion of growth hormone, concerns have been raised that CYP expression and/or activity may be modulated by growth hormone. However, growth hormone was shown to have no significant effect on CYP2D6 and CYP3A4 activity (CYPs contributing the metabolism of several antiretroviral drugs) in a randomized, double-blind, placebo-controlled clinical study in which individuals received injections of growth hormone or placebo.
NASH is a common problem in aging populations of PLWH treated with antiretroviral. The predominating pathophysiological mechanisms are likely to be similar to the general population and closely related to the metabolic complications of obesity. PLWH are likely to benefit from the therapeutic targets investigated in current trials, and where there is adequate knowledge of DDIs, they should be included as a prespecified subpopulation to improve the generalizability of the results and expedite the introduction of therapies in this population.”