IMMUNOSUPRESSION --- A LIVER TRANSPLANTATION SUCCESS STORY.Part 1

IMMUNOSUPRESSION  --- A LIVER TRANSPLANTATION SUCCESS STORY.

DR. Thomas E Starzl did first liver transplantation in 1963. Since then Liver transplantation has evolved like anything. From initial one year survival rates of 20% now we have reached up to 5 year survivals of more than 90%.

It is a fascinating story about its evolution. What is the prime reason for this Success.

Yes, techniques have improved, Yes ICU care has improved but the prime reason for this Phenomenal Success is development in IMMUNOSUPRESSION DRUGS.

As we all know whenever some foreign subject enters our body, it tries to react against it. So, whenever other person’s liver enters our body. It reacts against the foreign liver also. To stop this we need to suppress body’s immunity and here comes precisely role of immunosuppressive drugs.

So, Let us go in past and start our journey from 1963 from where liver transplantation started and see how immunosuppression and liver transplantation success have travelled hand in hand.

Precyclosporine Era :

In 1967 in the following research paper Dr.Thomas Starzl reported his first extended survival (1 year) after liver transplantation. This was before an important immunosuppression drug cyclosporine was invented.

•       Corticosteroids and azathioprine were used in combination as immunosupressants by Starzl et al. in his first 5 transplants.

•       The majority of the Colorado (place were dr.starzl was doing liver transplantation) series from 1963 to 1976 received corticosteroids, azathioprine, and antilymphocyte globulin.

•       Survival in the Early and Late Phases of the Colorado Experience (Follow-up to January 1979)

•       Primary cause of death was rejection (reaction of body against liver)in 20% of cases

•        

Time period	No of patients	One year survival
1963-1976	111	28%

As you can see one year  survival in 111 patient at that time was only 28%.

·      Cyclosporin Era:

At the end of 1970s and in the beginning of 1980s in the following research paper  Dr.R.Y.Calne first described use of cyclosporine in the kidney transplantation.

Dr.Starzl immediately used this drug in liver transplantation and published his results in 14 patients.

As you can see he showed that one year survival rate was almost 100% in patients for whom cyclosporine with steroid drug prednisolone was used.

In 1988 he published his experience with 1000 liver transplants in which cylosporin was used and showed 5 year survival of almost 70% in patients whom cyclosporine compared to around just 20% in patients using earlier immunosuppressant drugs like azathioprine.

Now something about cyclosporine:

•       Can be administered intravenously, although it is usually given orally as a tablet or an oral suspension

•       After oral administration, cyclosporine is variably absorbed in the jejunum and enters the lymphatic system.

•       Peak blood levels are achieved in two to four hours.

•       Cyclosporine levels should be monitored frequently in the peritransplant period (typically daily), with decreasing frequency as graft function stabilizes and rejection becomes less of a threat.

•       Initial dosage 10 to 15 mg/kg/day divided into 2 doses. For any immunosuppressant its blood level has to be monitored so that it gives adequate immunosuppression while avoiding its toxic effects.

•        

•       Cyclosporin level in the blood goals:

•       Week 1-2     250-350 ng (nanogram)/mL

•       Weeks 3-4   200-300

•       Weeks 5-24            150-250 ng/mL

•       Weeks 25+  100-200 ng/mL

•       Distant – can tolerate levels <100

Adverse effects:

•       Hypertension

•       Renal dysfunction

•       Hirsutism

•       Hyperkalemia

•       Gingival hyperplasia

•       Hypomagnesemia

•       Neurologic toxicity

Tacrolimus: (latest and most widely used drug):

Its success results were first published in New England Journal of medicine in 1994

As you can see there was no difference in survival between tacrolimus and cyclosporin. So absolutely you will be tempted to question then why tacrolimus is a better drug for preventing rejection?? (Damage due to reaction of body against foreign liver)

But as you can see from the above graft proportion of patients who developed rejection were much less in tacrolimus group and also proportion of patents who require another drug for rejection was also much less in the tacrolimus group.

•       Initial dose 0.1 to 0.15 mg/kg/day orally

•       Blood level Goals (variable per patient/disease)

–      Early Post-OLT – 10-15 ng/ml

–      3-6 Months – 8-10

–      >6 Months – 5-7 (variable)

•       Tacrolimus dosing should be individualized.

•       start with a low dose (0.5 to 1 mg every

•       12 hours) on postoperative day one, and aim for a level of 7 to 10 ng/mL by the end of the first week.

•       Often with the addition of an auxiliary agent like mycophenolate mofetil or a monoclonal antibody

Adverse effects:

•       Posttransplant diabetes mellitus

•       Nausea, vomiting, diarrhea

•       Hyperkalemia

•       Tremor

•       Hypertension

•       Hypomagnesemia

•       Headache

•       Renal dysfunction

Tripple Therapy ;

Now a days triple therapy is used for any liver transplantation, that is adding of mycophenolate to tacrolimus and steroid (prednisolone). Why it is effective??

Add caption

AS you can see from this research patient survival and graft survival was  higher when another drug mycophenolate was added to the tacrolimus and steroids.

Freedom from rejection is also much higher with triple drug therapy.

As you can see from each and every graft here that as we progressed from precyclosporinera to cyclosproin aera and to tacrolimus and to the present triple drug therapy how liver transplantation survival rates have improved and rejection rate have decreased.

Liver transplant success story is a truly success story of imuunosupressants.

Will post in another post about other drugs like sirolimus, monoclonal antibodies how to use various immunosuppressant in different situations.

New Treatment of Hepatitis C available at lower cost in India - Why it is considered as Wonder Drug and How useful it is in India ??

New Hepaptis C drug Sofosbuvir—A wonder drug for hepatitis c treatment.

Just few days before there was news in medias that new hepatitis c drug sofosbuvir will cost around 1 lakh of Indian rupees for its 12 week of treatment instead of its cost in us 84000 us$ (around 50 lakh Indian rupees) and liver specialists all over India are very happy. Reason for this low cost is Gillard pharmaceuticals, which holds patent for this drug has given licenses to a few Indian companies at very low rate. 

Now let us see why Sofosbuvir is considered a wonder drug in Hepatitis C treatment.

The basic difference between Hepatitis C and Hepatitis B is Hepatitis C is a RNA virus while Hepatitis B is a DNA virus. Due to this nature as science students will understand that though majority of hepatitis c virus reside in liver but it can enter any cells rapidly while hepatitis B cannot.

Thus in hepatitis B cirrhosis if transplanted hepatitis b can be controlled with medications and its recurrence chances are less with latest treatment while in case of hepatitis C recurrence rates are 100%. Thus Transplant can prolong the life in hepatitis c but cannot treat it. However it can prolong the life for more than 10 year or so and that is also significant achievement.

Now let us see about hepatitis c treatment and how Sofusbuvir has changed the equations.

First I would like you to understand following term.

Sustained Viral Response : Sustained Viral response (SVR) is defined as aviremia (absence of detectable virus in the blood) 24 weeks after completion of antiviral therapy for chronic hepatitis C virus (HCV) infection.

Hepatitis C has mainly 6 types of 6 genotypes 1 to 6.

In india most commonly type 3 (65%) genotype is seen, In eastern countries like Taiwan and korea type 2 genotype is seen, where as un USA type 1 genotype is seen.

Out of those type 1 is most dangerous.

The goal of treatment in all infected individuals, regardless of which of the six major genotypes (G1–6) are present, has been and continues to be the achievement of a sustained virological response (SVR) in which circulating HCV RNA is undetectable with the use of a highly sensitive assay following treatment. Initially, SVR was measured at 24 weeks (SVR24) after the end of treatment. In 2013, sufficient data from clinical trials were available to demonstrate that SVR measured at 12 weeks post-treatment (SVR12) showed a high concordance with SVR24.

In the United States, the Food and Drug Administration (FDA) has indicated that SVR12 is an appropriate primary end-point for registration trials seeking FDA approval.

Long-term follow-up studies indicate that disease progression is interrupted, histological, clinical and laboratory features of advanced disease may be reversed, and life-expectancy may return towards normal. Nevertheless, it is now clear that among patients with advanced hepatic fibrosis (biopsy Finding, a risk of hepatocellular carcinoma remains for several years after achievement of a SVR.

In the early years of chronic hepatitis C management, treatment with nonpegylated interferons without and later with ribavirin resulted in low efficacy and was poorly tolerated. Between 2001 and 2011, the standard of care became a combination of pegylated interferon (peginterferon) plus ribavirin, and treatment duration was determined by genotype. In general, with 48 weeks of combination therapy in genotype 1 (G1), SVR rates varied from 40 to 50%.

For genotypes 2 and 3 (G2, G3), with 24 weeks of combination treatment, SVR rates were 70–80%. Although the tolerability of peginterferon was better than that for the nonpegylated forms, many patients were peginterferon intolerant, and ribavirin regularly induced a haemolytic anaemia and other adverse events. Concerns about ribavirin's teratogenicity (adverse affect in child in pregnant ladies) also complicated patient management.

In 2011, a new standard of care for genotype 1 patients, consisting of treatment with an NS3/4A HCV serine protease inhibitor drugs (either telaprevir or boceprevir), received FDA approval for use in combination with peginterferon plus ribavirin. In many patients, treatment could be shortened, but because peginterferon and ribavirin were still required and the protease inhibitors dramatically increased the severity and rapidity of the onset of haemolysis and carried other adverse events (rash, neutropenia, etc.), tolerability (and safety) remained an issue.

Discontinuation rates due to adverse events were approximately 15%. Furthermore, both protease inhibitors had to be given with food multiple times throughout the day, drug–drug interactions complicated therapy[4] and resistant HCV variants emerged in those failing to achieve a SVR. Patients with histologically advanced disease had lower response rates. The protease inhibitors were ineffective in genotypes other than G1.

As a consequence, research efforts have sought viral and host targets other than the serine protease. These include the NS5B protein and the NS5A replication protein, both of which are essential for HCV replication (Virus growth and multiplication).

Sofosbuvir – NS5B Inhibitor ;

HCV GENOTYPE  1:

Current studies indicate That for HCV Genotype 1 if Sofusbuvir is added in the current interferon with ribavirin treatment Sustain Virological response rates were increased from 58% to 90%.

These results are much higher than expected.

However for Genotype 1 at present still interferon and ribavirin is necessary along with Sofusbuvir.

When given in mild hepatic fibrosis in hepatits c (in liver biopsy results) It maintained SVR rate of around 90%

However if given in patient with moderate to sever hepatic fibrosis it achieved viral clearance in 96% cases at 4 weeks but SVR rates of 68% better than interferon/ribavirin alone but worse than expected.

Data in established cirrhosis are still scanty to conclude. But still in Phase 3 trials it achieved SVR at 12 month in around 79% patients.

Plus it can be given as 400 mg orally once daily.

HCV GENOTYPE 2 AND HCV GENOTYPE 3:

Studies in this group that we are interested in because they are the HCV Type more common in ASIA particularly GENOTYPE 3 in India.

Major break through in this group is in this group Sofusbuvir can be given as all oral therapy that is Sofusbuvir with ribavirin without interferon so it can be given without interferon and we can avoid sever side effect of Interferons and can be given in patients who are not tolerating interferon also.

In Genotype 2 patients SVR rates were 90% with Sofusbuvir with ribavirin without interferon.

With cirrhosis also Genotype 2 patient showed SVR rates of around 70-90% in different study.

SO Is It a great boon for India??

YES AND NO

Because when we come to its result in Genotype 3 which is more common in India its response rates though better than interferon and ribavirin alone are not great.

 Here in patients without cirrhosis SVR rates in-patients without cirrhosis are 30-70% and with cirrhosis around 20-60% in different studies.

So we can cure selected affording patients with that after proper workup but it is  not the one shot answer for genotype 3 which is seen in 65% of Indian patients but for the rest of patients with HCV type 1 and 2 it is indeed a wonder drung.

CONTRAINDICATIONS:

It should not be used in patients with severe kidney failure or patients who require dialysis.

Side Effects:

Minor side effects like Fatigue, headache, nausea ,chills, insomnia and joint pains.

Dose: 400 mg per oral Once daily.

Take Home messages:

1.    It has great response in HCV Type 1 patients but interferon and ribavirin required along with it.

2.    It is really boon for HCV type 2 where it has great response plus injection interferon and so its side effects can be avoided.

3.    It has lower response rates in type 3 but still better than previous therapies.

4.    It has shown promise even in cirrhotic patients but still data are insufficient

5.    It role in preventing post transplant recurrence is still to be studied.

6.    It has to be used after proper work up for best results and should not be used in every HCV positive patients

7.    Side effects are minor.