Aa
Nivolumab lowers hbsag and cures chronic hepatitis b
In this document: https://www.ilc-congress.eu/wp-content/uploads/2017/04/ebooks/2017EASL_WEB_FullEmbargo.pdf
It says:
Background and Aims: Insufficient T-cell responses may underlie HBV persistence in chronically infected patients. Strategies to increase HBV-specific T-cell frequency and activity may result in durable control of HBV. To evaluate this hypothesis, treatment with nivolumab, an inhibitor of the immune checkpoint receptor PD-1, was evaluated with or without the therapeutic vaccine,
GS-4774 in virally-suppressed HBeAg negative chronic HBV (CHB) patients.
Methods: In this Phase 1 exploratory study (GS-US-330-1938), virally suppressed HBeAg negative patients without advanced fibrosis were enrolled. Patients received either single dose of nivolumab at 0.1 mg/kg (Sentinel A; n = 2), at 0.3 mg.kg (Cohort A; n = 12) or received 40 Yeast Units GS-4774 at baseline and at Week 4 prior to single dose of nivolumab of 0.3 mg/kg at Week 4 (Cohort B; n = 10). The primary endpoint was change in HBsAg 12 weeks after nivolumab dosing using a mixed effect model for repeated measures. Patients were assessed for safety and immunologic changes, including receptor occupancy, flow cytometry, and in vitro responses by ELISpot.
Results: There were no grade 3 or 4 treatment emergent adverse events (TEAE) or serious AEs. Grade 1 nivolumab-related TEAEs were observed in 3 patients (25%) of Cohort A only. Least squares mean (95% CI) changes in HBsAg 12 weeks after nivolumab dosing ( primary endpoint) were −0.30 (−0.58, −0.02) IU/ml for Cohort A and −0.16 (−0.47, 0.15) IU/ml for Cohort B. While Cohort A showed significant decline in HBsAg levels compared to baseline ( p = 0.035), no statistical difference was observed between Cohort A or B (p= 0.48). One patient in Cohort A experienced a decline of HBsAg from baseline of 1173 IU/ml to undetectable levels at Week 20 with an anti-HBs response that developed after the completion of the study. This subject experienced at ALT flare (grade 3) at week 4 that resolved by week 8 accompanied by an improvement in T-cell ELISpot response, most prominently at Week 24. The patient remains HBV DNA and HBsAg negative and anti-HBs positive with normal liver tests 24 weeks off nucleoside analog therapy. Final receptor occupancy, flow cytometry, and ELISpot will be presented.
Conclusions: Single dose nivolumab up to 0.3 mg/kg was well- tolerated in virally suppressed HBeAg negative CHB infected patients. There was a significant decline in HBsAg in patients receiving nivolumab, with no added benefit of GS-4774. Checkpoint blockade or similar approaches may lead to functional control of HBV in certain HBeAg negative patients.
This makes perfect sense because as this document: https://www.ncbi.nlm.nih.gov/pubmed/27156385
says:
"This impairment of CD8(+) T cell responses was mediated by hepatic macrophages, which were predisposed by maternal HBV e antigen (HBeAg) to support HBV persistence by upregulation of inhibitory ligand PD-L1 and altered polarization upon restimulation with HBeAg. Depletion of hepatic macrophages led to CD8(+) T cell activation and HBV clearance in the offspring, raising the possibility of targeting macrophages to treat chronic HBV patients."
So, the hepatic macrophages put out a signal to weaken the immune response (this immune response is meant to be used by cells to communicate that the threat has passed, and that the immune response can soften up now). Nivolumab is a drug which will bind to that signal that weakens the immune response, and disables it. So then what happens is that the patients body has the correct response to the chronic hepatitis b infection.
Even though only one person cleared it in the above study, it seems fair to assume that it's an incredible result because they only had 1 single dose. I would imagine that with multiple doses many more people would have seroconverted and become hbsag negative.
The downside would be that this is a serious drug that does have serious side effects on some people. That's why so far it's mostly been limited to usage in victims of severe cancer.
Thoughts?
It says:
Background and Aims: Insufficient T-cell responses may underlie HBV persistence in chronically infected patients. Strategies to increase HBV-specific T-cell frequency and activity may result in durable control of HBV. To evaluate this hypothesis, treatment with nivolumab, an inhibitor of the immune checkpoint receptor PD-1, was evaluated with or without the therapeutic vaccine,
GS-4774 in virally-suppressed HBeAg negative chronic HBV (CHB) patients.
Methods: In this Phase 1 exploratory study (GS-US-330-1938), virally suppressed HBeAg negative patients without advanced fibrosis were enrolled. Patients received either single dose of nivolumab at 0.1 mg/kg (Sentinel A; n = 2), at 0.3 mg.kg (Cohort A; n = 12) or received 40 Yeast Units GS-4774 at baseline and at Week 4 prior to single dose of nivolumab of 0.3 mg/kg at Week 4 (Cohort B; n = 10). The primary endpoint was change in HBsAg 12 weeks after nivolumab dosing using a mixed effect model for repeated measures. Patients were assessed for safety and immunologic changes, including receptor occupancy, flow cytometry, and in vitro responses by ELISpot.
Results: There were no grade 3 or 4 treatment emergent adverse events (TEAE) or serious AEs. Grade 1 nivolumab-related TEAEs were observed in 3 patients (25%) of Cohort A only. Least squares mean (95% CI) changes in HBsAg 12 weeks after nivolumab dosing ( primary endpoint) were −0.30 (−0.58, −0.02) IU/ml for Cohort A and −0.16 (−0.47, 0.15) IU/ml for Cohort B. While Cohort A showed significant decline in HBsAg levels compared to baseline ( p = 0.035), no statistical difference was observed between Cohort A or B (p= 0.48). One patient in Cohort A experienced a decline of HBsAg from baseline of 1173 IU/ml to undetectable levels at Week 20 with an anti-HBs response that developed after the completion of the study. This subject experienced at ALT flare (grade 3) at week 4 that resolved by week 8 accompanied by an improvement in T-cell ELISpot response, most prominently at Week 24. The patient remains HBV DNA and HBsAg negative and anti-HBs positive with normal liver tests 24 weeks off nucleoside analog therapy. Final receptor occupancy, flow cytometry, and ELISpot will be presented.
Conclusions: Single dose nivolumab up to 0.3 mg/kg was well- tolerated in virally suppressed HBeAg negative CHB infected patients. There was a significant decline in HBsAg in patients receiving nivolumab, with no added benefit of GS-4774. Checkpoint blockade or similar approaches may lead to functional control of HBV in certain HBeAg negative patients.
This makes perfect sense because as this document: https://www.ncbi.nlm.nih.gov/pubmed/27156385
says:
"This impairment of CD8(+) T cell responses was mediated by hepatic macrophages, which were predisposed by maternal HBV e antigen (HBeAg) to support HBV persistence by upregulation of inhibitory ligand PD-L1 and altered polarization upon restimulation with HBeAg. Depletion of hepatic macrophages led to CD8(+) T cell activation and HBV clearance in the offspring, raising the possibility of targeting macrophages to treat chronic HBV patients."
So, the hepatic macrophages put out a signal to weaken the immune response (this immune response is meant to be used by cells to communicate that the threat has passed, and that the immune response can soften up now). Nivolumab is a drug which will bind to that signal that weakens the immune response, and disables it. So then what happens is that the patients body has the correct response to the chronic hepatitis b infection.
Even though only one person cleared it in the above study, it seems fair to assume that it's an incredible result because they only had 1 single dose. I would imagine that with multiple doses many more people would have seroconverted and become hbsag negative.
The downside would be that this is a serious drug that does have serious side effects on some people. That's why so far it's mostly been limited to usage in victims of severe cancer.
Thoughts?
This is a highly interesting study of potential importance in improving the tcell response in chronic hbv.
The questions on hand are the severity of the side effects and the likelihood of a more permanent positive effect on patients liver status.
If the intensity of tcell attack does not lead to a stable improved control, then the increased inflammatory state of the liver will be rather profibrogenic and could lead to more immune resistance buildup by adaptive hbv mutations surviving and contributing a larger percentage of the infected liver cell population, reducing future chances of stable seroconversion.
This is similar to the effects of interferon pretreatment for patients on the naps therapy : the incidence of subsequent clearing flares is substantially reduced.
The future role of this type of therapy seems open at this time. Repeated injections might improve conversion rates but also side effects incidents.
The questions on hand are the severity of the side effects and the likelihood of a more permanent positive effect on patients liver status.
If the intensity of tcell attack does not lead to a stable improved control, then the increased inflammatory state of the liver will be rather profibrogenic and could lead to more immune resistance buildup by adaptive hbv mutations surviving and contributing a larger percentage of the infected liver cell population, reducing future chances of stable seroconversion.
This is similar to the effects of interferon pretreatment for patients on the naps therapy : the incidence of subsequent clearing flares is substantially reduced.
The future role of this type of therapy seems open at this time. Repeated injections might improve conversion rates but also side effects incidents.
12 Comments
One thing I'm not sure about is that it says 0.3MG/KG was used in this test, but the standard dose of nivolumab is 3.0mg/kg. Do you think they used 1/10th of the dose, or was it a misprint?
I'm not sure that hbv mutations would be such a concern with this, since any mutation would presumably be met with an immune response as well if the immune system were functioning like it should.
I'm not sure that hbv mutations would be such a concern with this, since any mutation would presumably be met with an immune response as well if the immune system were functioning like it should.
It looks like they used a reduced dose to test this indication with lesser side effect risk.
Immune adaptive mutations occur typically in epitopes, both class I as well as class II. A viral protein is only visible to the t cell system through a very small number of short peptides, which have specific requirements in terms of first and last amino acid. .the anchors and also the inside must have amino acids with a long enough and grippy side chain to allow decent strength bonding to the tcell receptor.
If the virus mutates one of these sites, then this particular immune response is lost and not replaceable.
This way the virus develops less and less immune visible quasi species and it is properly called an immune escape mutation.
Immune adaptive mutations occur typically in epitopes, both class I as well as class II. A viral protein is only visible to the t cell system through a very small number of short peptides, which have specific requirements in terms of first and last amino acid. .the anchors and also the inside must have amino acids with a long enough and grippy side chain to allow decent strength bonding to the tcell receptor.
If the virus mutates one of these sites, then this particular immune response is lost and not replaceable.
This way the virus develops less and less immune visible quasi species and it is properly called an immune escape mutation.
ah right, I get you on immune escape now thanks.
10% of the normal dose seems so small that i find that idea truly delightful.
10% of the normal dose seems so small that i find that idea truly delightful.
studyforhope will patients on nucs many years with hbvdna und and hbsag less than 1000iu/ml safe from immune escape mutations?can we already guess they will clear hbsag easier with low dose and few doses?
@stef2011. A patient on nucs should have a much much slower development of further immune escape mutations. But it will be of greatest importance how many of these nasty mutations are present already at the time nucs treatment started.
The hbsag clearance under naps treatment will at first work regardless of existing immune escape mutations, but the the degree of the effect and most importantly it's long term stability will likely depend on the remaining availability of effective , non mutated tcell epitopes.
The epitopes of the surface antigen itself will typically be free of mutations, since the hbsag excess shielded it from tcell selective mutational pressure.
If the hbsag level is on the low side, like below 1000iu, then the degree of integration is likely also low and a better starting position for treatment should exist.
The hbsag clearance under naps treatment will at first work regardless of existing immune escape mutations, but the the degree of the effect and most importantly it's long term stability will likely depend on the remaining availability of effective , non mutated tcell epitopes.
The epitopes of the surface antigen itself will typically be free of mutations, since the hbsag excess shielded it from tcell selective mutational pressure.
If the hbsag level is on the low side, like below 1000iu, then the degree of integration is likely also low and a better starting position for treatment should exist.
@studyforhop: how hopeful are you for the use of Crispr to achieve HBV cure? There are two preclinical companies using Crispr to target HBV and one of them is set to begin human trials in 2019. Crispr was recently shown to inactivate cccdna as well as cleave the entire length of integrated HBV DNA sequences from host DNA. Here's a link to the study;
://www.ncbi.nlm.nih.gov/pubmed/28382278
I believe there isn't a better candidate than crispr to realise our hope for a "sterisation cure". However, it will only be a "true" sterilisation cure if it places us in the same risk profile as a matched uninfected individual. Do you think getting rid of the integrated HBV DNA through crispr could block the process of HBV associated hepatocarcinogenesis? Do the cells have the capacity to repair the DNA after a thorough cleavage is realised? Or elimination of such cells is the only answer to achieve a "true" sterlisation cure?
://www.ncbi.nlm.nih.gov/pubmed/28382278
I believe there isn't a better candidate than crispr to realise our hope for a "sterisation cure". However, it will only be a "true" sterilisation cure if it places us in the same risk profile as a matched uninfected individual. Do you think getting rid of the integrated HBV DNA through crispr could block the process of HBV associated hepatocarcinogenesis? Do the cells have the capacity to repair the DNA after a thorough cleavage is realised? Or elimination of such cells is the only answer to achieve a "true" sterlisation cure?
price maybe the main problem here for any self trial when hbsag is very low
The crispr technology is certainly a fascinating tool. To achieve the "sterilizing cure" the elimination of cccDNA would have to be 100% complete, however. I have seen a paper where hbv sequence removal was substantial, but still a far cry from complete. In vivo, the introduction of the crispr machinery will be difficult and unlikely 100% complete, nor will the cutting efficiency be perfect.
Nevertheless, if removal of integrated hbv sequences is possible (remember, the actual integrated hbv segment will be very variable) it should lead to a reduction in cancer risk, provided that the excision of integration in a critical component of oncogene control leaves the excision borders sufficiently intact for normal function.
Nevertheless, if removal of integrated hbv sequences is possible (remember, the actual integrated hbv segment will be very variable) it should lead to a reduction in cancer risk, provided that the excision of integration in a critical component of oncogene control leaves the excision borders sufficiently intact for normal function.
Delivering crispr to the liver is feasible through LNP.
One last question; people who establish functional control on NAPs would have the same risk for HCC as age matched control?
One last question; people who establish functional control on NAPs would have the same risk for HCC as age matched control?
It looks very much like naps induce integrated cells into apoptosis, otherwise the longer term stability of hbsag seroconversion as seen in a substantial proportion of treated patients would be impossible. If the vast majority of cells at risk for cancer by integration is removed, the cancer risk should be dramatically reduced. A small increased risk caused by increased cell turover under conditions of high inflammatory stress from the hepatitis might remain, if we assume that not all liver cancer is caused by integrations.
@studyforhpe: what do you think of technology to regenerate lever from patients own cell, may be outside of patients body?
Maybe something like -
http://news.mit.edu/2013/a-step-closer-to-artificial-livers-0602
Maybe something like -
http://news.mit.edu/2013/a-step-closer-to-artificial-livers-0602
This technology is far in the future. A functional liver is so much more than just an accumulation of hepatocytes, there is the delicate functional microarchitecture of the lobules, the sinuses, the vasculature and the biliary tree. Even a very cirrhotic liver constantly regenerates new cells, but they arrange in local nodules without functional architecture and harmonic cooperation with the capillary structure. That's why these livers still go into failure.
Does nivolumab requires some genetic test before usage ? My doctor mentioned about some clinical trial where requirements are > 1000 IU hbv dna and some genetic test. Any ideas which drug it may concern ?
3 Comments
Are you sure your doctor wasn't asking for a genotype test of your HBV variant?
I don't think so because he told that test will be made from saliva sample, not blood.
he also said that around 30% of people may be responsive to that therapy basing on that test.
Nivolumab is the first immune checkpoint inhibitor and has been very successful in treating some type of cancer. However, as with all immune checkpoint inhibitors, it will only work with certain patients and not all. Because in chronic HBV, HBV specific Tcells are also exhausted as indicated by over-expression of immune checkpoints, so these drugs should in theory also work for HBV patients. However, in small studies, it has been reported that the side effects are quite serious, these side effects may be acceptable for late-stage cancer patients, but they are not for HBV patients. Still, this field is advancing quite quickly, so it may yet lead to a cure for HBV, we hope.
3 Comments
Thanks Bravesoul. I see your point. But as you yourself have raised nearly 50% of people who were chronically infected clear the infection at about age 50 on average. While we may not understand the mechanism behind this and can only theorize (as studyforhope has been doing), it seems that ya'll are focusing on the worst-case scenario. It's not hard to imagine several scenarios whereby the virus is suppressed to a satisfactory degree. Take a look at my previous post: http://www.medhelp.org/posts/Hepatitis-B/Nivolumab-lowers-hbsag-and-cures-chronic-hepatitis-b/show/2973527
And following up on that comment, take a look at this. Very few CHB patients have been treated with a pd-1 inhibitor. But this guy was cured from it. I don't think it was a freak occurrence: https://www.omicsonline.org/open-access/seroconversion-of-hbsag-in-melanoma-patient-with-hepatitis-b-treated-withcheckpoint-inhibitors-a-case-report-2165-7920-1000951.php?aid=88890
In my opinion this is actually fantastic news for us: http://www.infohep.org/US-FDA-approves-nivolumab-immunotherapy-for-liver-cancer/page/3175886/
Because now that people with liver cancer are going to be taking nivolumab I predict that we are going to see a lot of cases where it makes them seroconvert to being hbsag negative while on treatment. So we'll effectively see a ton of people being cured from chronic hepatitis b infection by it. Irrespective of the fact that it may not be approved for use for curing chronic hepatitis b due to its toxicity, it will certainly raise my interest level even higher in taking multiple small doses (probably 0.3mg/kg or less) to treat it. Given that the general dose is 240mg/kg I would speculate that this is likely to be very safe too.
Because now that people with liver cancer are going to be taking nivolumab I predict that we are going to see a lot of cases where it makes them seroconvert to being hbsag negative while on treatment. So we'll effectively see a ton of people being cured from chronic hepatitis b infection by it. Irrespective of the fact that it may not be approved for use for curing chronic hepatitis b due to its toxicity, it will certainly raise my interest level even higher in taking multiple small doses (probably 0.3mg/kg or less) to treat it. Given that the general dose is 240mg/kg I would speculate that this is likely to be very safe too.
Have an Answer?
You are reading content posted in the Hepatitis B Community
A list of national and international resources and hotlines to help connect you to needed health and medical services.
Herpes sores blister, then burst, scab and heal.
Herpes spreads by oral, vaginal and anal sex.
STIs are the most common cause of genital sores.
Condoms are the most effective way to prevent HIV and STDs.
PrEP is used by people with high risk to prevent HIV infection.
