I had UND HBDNA at start of viread 1 year ago. Not been able to havd HBSAG quantitative test yet, but planning to start Interferon soon. My question is, can preuse of Aldara before tdf+intf be of good benefit, and if yes,can alsara be kept on during intf? Many thanks
The use of TLR7 stimulation by imiquimod in HBV patients would be totally experimental at this point in time, possibly used off label by some brave hepatologists. Gileads drug. which is NOT imiquimod, but also a TLR7 agonist and possibly chemically quite similar ( they are totally secretive about this!) to imiquimod given orally has shown dramatic results in woodchucks only, patient trials will hopefully start soon.
Abstract
Title GS-9620 INDUCES A PRESYSTEMIC INNATE IMMUNE RESPONSE IN THE ABSENCE OF SERUM INTERFERON OR ADVERSE EFFECTS IN BOTH NON-CLINICAL SPECIES AND HUMANS
Speaker: Abigail Fosdick
Author: D. Tumas1, A. Fosdick 1 *, X. Zheng1, R. Lanford2, J. Hesselgesser1, C. Frey1, W. Grushenka1, R. Halcomb1, U. Lopatin1
Affiliation: 1Gilead Sciences, Inc., Foster City, CA, 2Department of Virology and Immunology, Texas Biomedical, Research Institute, San Antonio, TX, USA. * abigail.fosdick _AT_ gilead.com
Background: The side effects associated with interferon-α (IFN-α) make it a challenging therapeutic option for many patients with chronic HBV or HCV infection. Therefore, we are a developing a potent Toll-like receptor 7 (TLR-7) agonist , GS-9620, as an oral immunomodulatory agent capable of inducing an antiviral immune response at the level of the liver and gut associated lymphoid tissue (GALT) without induction of systemic IFN-α or its side effects. (ie a "pre-systemic the response).
Aim: To demonstrate that low oral doses of the TLR-7 agonist GS-9620 can induce a pre-systemic innate immune response in the liver in the absence of induction of systemic IFN-α.
Methods: Single and / or multiple doses of GS-9620 were evaluated in mice, cynomolgus monkeys, chimpanzees (uninfected and HBV infected) and human healthy volunteers (0.3 to 12 mg doses). Pharmacokinetics, pharmacodynamic responses (serum IFN-α, cytokines and interferon stimulated genes (ISGs) in blood and / or liver), and safety parameters were evaluated.
Results: At a similar serum Cmax exposure level, oral administration of GS-9620 provides a markedly greater serum IFN-a response than does intravenous administration. In cynomolgus monkeys and normal and HBV-infected chimpanzees, low oral doses of GS-9620 induced ISGs in the liver and / or in circulating blood cells with no increase in serum levels of IFN-α and caused a reduction of viral load in infected animals. In healthy humans, low oral doses of GS-9620 (<8 mg) induced a similar pre-systemic ISG response with neither detectable serum IFN-α nor adverse effects including signs or symptoms associated with systemic IFN-α.
[Figure 1]
Conclusions: In preclinical species, oral administration of GS-9620 induced more IFN-α than intravenous administration relative to GS-9620 exposure. This suggests that cells in the GALT and / or liver can be stimulated to induce a locally restricted TLR7 response following oral administration of GS-9620. In support of this hypothesis, following low oral doses of GS-9620 ISG induction was found in blood cells in the absence of either detectable serum IFN-α or adverse effects associated with systemic levels of IFN-α in normal and chronically HBV-infected non-human primates as well as in healthy human volunteers.
This is good news, if the response without IFNalpha induction is sufficient to induce an antiviral effect in the liver.
They had a second abstract re TLR7agonist, that concluded that even once weekly administration was sufficient to induce a consistent systemic stimulation.
No doubt the effects in question have many levels of intensity. At the highest level of dosing, the woodchuck group had a phantastically rapid clearance of surface antigen in 4 weeks.But they also had substantial side effects. Here it is shown that a dosing level might be possible that has no or very low side effects, and it might still systematically reduce cccDNA containing cells, only at a slower pace.
Also the lower systemic dosing that can be achieved by imiquimod cream might therefore still have a realistic effect in the desired direction, with minimum side effects. Since the exposure to the gut mucosa seems to be important as shown in this abstract, one wonders if an application of imiquimod to the oral mucosa might be advantageous. Imiquimod is inactivated at the oral route, possibly in the stomach.
actually i was thinking how to apply the cream to reach gut mucosa after i read this
just eat it?charge it to liposomes?
i have seen liposomes machines online available to make lipo vitamin c and other compounds
also increasing dose to 3 or 4 sachests per day is possible, there are no sides at all on my healthy skin at 2 sachets per day.
i wonder: is liver skin the best way for imiquimod to reach inside liver or maybe genital mucosas+liver skin surface may allow higher absorption?
off labels therapies are common in italy and i have found clinics using off label interferon+imiquimod for hpv and they say with increadible high success
they also say that imiquimod is good used on mucosa because absorption is more, just needed close doctors monitroing in case of inflammation
Applying it over the liver on the local skin will have no advantage whatsoever over applying it somewhere else. Thin, sensitive skin should give the best systemic absorption. It seems scary to apply it at nasal or oral mucosa, the idea to use liposomes as protectors to pass the stomach acid is interesting.