What's New?
ENTECAVIR (Baraclude)- Newest drug for hepatitis-B viral infection:
A London New drugs group publication- February-2007
  • Entecavir is a guanosine analogue with marked activity against HBV DNA polymerase.
  • The European Medicines Evaluation Agency (EMEA) has granted marketing authorisation for Entecavir (Baraclude) for the treatment of chronic hepatitis B virus (HBV) infection in adults with compensated liver disease and evidence of active viral replication, persistently elevated serum ALT levels and histological evidence of active inflammation and/or fibrosis.
  • The Scottish Medicines Consortium approved the use of Entecavir for the treatment of chronic hepatitis B virus infection, in adults with liver disease and evidence of active viral replication, persistently elevated alanine aminotransferase levels and evidence of active inflammation and or fibrosis.
  • Phase III trials in nucleoside-naive patients with both HBeAg-positive and -negative chronic hepatitis B have been carried out.
  • In nucleoside-naive patients with HBeAg-positive and HBeAg-negative chronic hepatitis B, the use of entecavir was associated with significantly higher rates of histologic, virologic and biochemical improvements compared with lamivudine. This appears to be due to its potent suppression of HBV replication, as seen by the higher number of patients with undetectable levels of HBV DNA (less than 300 copies/ml) after 48 weeks.
  • The higher rates of histologic improvement seen with Entecavir suggest that long-term use could result in a reduced risk of end-stage liver disease and heptatocellular carcinoma. Entecavir was tolerated as well as lamivudine, though long-term safety needs to be determined. ALT flares were less frequent in the entecavir group, and those that did occur where associated with lowered HBV DNA levels.
  • A phase III trial of Entecavir in lamivudine-refractory patients with HBeAg-positive chronic hepatitis B showed that Entecavir treatment was associated with superior responses across histologic, virologic, serologic and biochemical endpoints. Entecavir strongly suppressed HBV DNA levels compared with lamivudine. The higher seroconversion rates in the Entecavir group suggests that longer term treatment will result in a higher proportion of patients achieving HBeAg seroconversion and resolution of chronic hepatitis.
  • Resistance to Entecavir was not seen in any trial of nucleoside naive patients after 96 weeks of treatment. In lamivudine refractory patients, resistance to Entecavir occurred in 15% of patients after 3 years of follow up.
  • In all trials ALT flares were seen in both Entecavir- and lamivudine treated patients, though more were linked with lamivudine use. The majority of the flares seen with entecavir were not associated with hepatic decompensation or rising HBV DNA levels.
  • Other adverse events did not differ significantly between the groups.
Instructions to patients on Baraclude (Entacavir):
  • The dosage should be advised by a qualified liver specialist (usually 0.5 to 1 mg/ day).
  • The drug should be taken on empty stomach- either 2 hours before or after a meal with plenty of water.
  • The drug can cause side effects such as- weakness, nausea, jaundice, loose bowel motions, lactic acidocis (build up of acid in the blood), liver enlargement and change in heart rhythms.
  • The dosage of drug needs modification in patients who are on other drugs that interfere with the kidney function (eg; Cyclosporine, Tacrolimus), in presence of kidney dysfunction.
Treatment of Hypersplenism:
Hyperactivity of the spleen, an organ that usually bears the brunt of high pressure in the portal vein, is relatively common among patients with liver cirrhosis. This hyperactivity results in drop in the red blood cell, white blood cell and the platelet counts along with enlargement of the organ. Some times the organ is so large that it can be easily felt in the abdomen and it may also cause pain in the left loin. This condition assumes greater importance in the cirrhotics since they have a tendency to bleed and some cannot undertake anti-viral treatment for hepatitis-B or C, a sthe cell count is dangerously low.

The conditions that cause hypersplenism are:
  • Liver cirrhosis
  • Malarial spleen
  • Haemolytic anaemia
  • Extrahepatic portal vein occlusion
Surgical removal of the spleen, by open or laparoscopic surgery used to be the core treatment for this condition. However with advancement in interventional radiology, it is now possible to cut off part of the blood supply to the spleen by a process called partial splenic artery embolization. This involves puncturing the artery to the leg and introducing a guide wire into the artery going to the spleen. Subsequently a sheath is placed and a micro-catheter is introduced. With this system various branches of the artery within the spleen are occluded with Gelfoam particles. This results in death of the area of spleen that is deprived of blood flow. The usual target area for embolization is 60 -65 % of the volume of the spleen. This procedure can be done at select centers with expertise in interventional radiology.

The complications are usually- pain and fever. Rarely serious infection of the dead area of the spleen has been reported. In author's personal experience there was no incidence of serious infection or abscess as adequate precautions and use of antibiotics can prevent this potentially serious complication.

Liver transplantation for Cholangiocarcinoma:
Until recent times hilar cholangiocarcinoma or cancer of the bile duct bifurcation was considered a sinister disease with very poor outcome (< 20% 3 year survival after transplant). The results following liver transplantation has generally been poor, with rapid recurrence of disease. However the clinical research published from Mayo clinic college, Rochester, MN, USA, by Rea DJ et.al, in Annals of surgery-2005-September has given a ray of hope for the patients who suffer from early cholangiocarcinoma (ie; stage-I and II). In the published data on liver transplantation in 38 of the 71 patients enrolled for the study, the one, three and five year survival of patients after neoadjuvant chemoradiation (treatment protocol in a nut shell- External beam radiation of 4500 cGy in 30 fractions with 5FU 500mg/Sq m daily bolus for first 3 days of radiation. Two to three weeks after external beam radiation, transcatheter iridium-192 brachytherapy was given with a target of 2000 - 3000 cGy. Oral Capecitabine (2000mg/ Sq m/Day) was continued until transplant. Survival after staging laparotomy and liver transplant was 92%, 82% and 82% respectively as compared to that after resection, namely 82%, 48% and 21% respectively. The post transplant disease recurrence was 13% vs recurrence after surgical resection - 27%. In essence for the first time long term results after transplantation was far superior to that of surgical resection according to the conclusions of the study. This is certainly a major advancement in treatment of this disease which caries a very poor prognosis.

TheraSphere treatment for liver cancer: Radioembolzation with Yitrium90 microsperes is the newest state of the art radiation treatment for primary and secondary liver cancer. The versatility of this modality to treat early and advanced cancers of the liver is truly amazing. Cost apart, it is the best form of treatment for very large or deep seated, inoperable liver cancers.

Y-90 Therasphere is an insoluble, biocompatible glass matrix with radioactive Yitrium-90 isotope as an integral constituent. The size of the spheres is around 0.4 microns, little bigger than a red blood cell. The Beta radiation emitted per sphere is around 2500 Bq. These spheres are provided in a liquid suspension that is ready for injection in unit doses ranging from 3 to 20 GBq. The required dose of radiation for a given is calculated by complex dosimetry involving calculations based on the target vascular bed in the liver in which the tumour lies. The microspheres are injected selectively through micro catheters under X-ray imaging into the vessels that supply the tumour in the liver. These spheres then get entrapped in the tumour microvasculature and emit radiation to the surrounding tumour until the radiation decays. Since the tumours are more vascular than the surrounding liver, they tend to trap most of the radioactive spheres in the tumour bed. The effect of radiation is limited to approximately 2 cm surrounding the bead. This natural selection is the greatest advantage of this technique. The tumour radiation is maximized without much radiation injury to the normal liver and the concentrated dose of radiation received by the tumour is several fold higher than what can normally be given by conventional external radiation techniques. 50% of the tumours treated show significant response as shown by volume reduction on CT scan and 80% show response when pre and post treatment PET scans are compared. These results are irrespective of the tumour size and numbers.

Liver tumour before and after treatment. Microscopic tissue section showing theraspheres trapped in the tumour bed. Even tumours in cirrhotic livers, vascular metastatic tumours and tumours invading the portal vein with portal vein thrombosis have been treated with varying degrees of success. The adverse reactions are tolerable and include fatigue, mild abdominal pain or discomfort, nausea and rarely stomach ulceration(related to faulty technique). It is conceivable that in the near future this treatment platform will be made suitable to treat various tumours of other solid organs (like brain tumours) as well. This technique could also become a bridge to those patients waiting for a liver transplant, who also develop cancers before or after getting on to the waiting list, by keeping the cancer in check until a cadaver liver becomes available. The only downside seems to be the cost of therapy (around 15000 USD/ treatment). The contraindications include evidence of advanced liver failure and presence of high lung shunting as shown by Tcm-MAA scans. The TheraSphere treatment is now available at selected centers in India.

MARS - THE LIVER SUPPORT SYSTEM
Liver is the storehouse of energy in the body. It is also the powerhouse for detoxification of toxins from various sources in the body and drugs, the notable among them being bile acids, bilirubin, aromatic amino acids, Indole/Phenol metabolites, toxic fatty acids, Thiols, Digoxin, Benzodiazepine agonists, Ammonia, Lactate, Diazepam, Teicoplanin, Ceftriaxone, Phenytoin, Furosemide, Ibuprofen, Glibenclamide, Naproxen, Haloperidol, Quinalapril, etc. In case of liver failure, the toxins accumulate in the body and produce widespread effects on the vital organs predominantly Kidneys and Brain. Liver has great regenerating capacity and hence as little as 30% of healthy liver may be able to support the vital functions of the body.

Patients with liver damage present in one of the following ways: -
  • Acute Liver Failure
  • Acute on Chronic Liver Failure
  • Chronic Liver disease Because of liver damage, other organs may also be affected leading to:-
  • Hepto-Renal Syndrome or
  • Hepatic Encephalopathy secondary to Cerebral edema
In acute liver failure, the patient becomes jaundiced, develops fluid retention and may develop kidney failure & ultimately coma & death. If, however, given sufficient time, on withdrawal of the offending agent, the liver may be able to regenerate and function. But while waiting for liver to function, there is an unacceptably high mortality rate (80%-90%) in the absence of transplantation, which was the only effective treatment. However, now in order to sustain life during the liver regenerative phase, a new system called MARS has been introduced which helps to do the detoxifying function of the liver and thus help to buy time. However, in cases of an acute on chronic liver failure, the chances of sufficient regeneration of liver are very less. The only option in such a situation is to provide an alternative mechanism for detoxification till a suitable organ is available for transplant.
  1. Replacement of diseased liver with another healthy liver - Liver transplant
  2. Artificial method of detoxification - Molecular Adsorbent Recirculating System (MARS), Extracorporeal Liver Assist Device (ELAD) or BioArtificial Liver (BAL)
MARS is a temporary measure, which gives immediate reduction in the levels of toxins, but the benefits can be observed only for short period. After discontinuation of the therapy, the accumulation of toxins starts again. The patient therefore has to be on a continuous / intermittent but prolonged treatment. The procedure is currently very expensive and therefore is impractical for long periods of time. The attendant risks of associated infection and thrombus formation makes it a high-risk procedure to be given for prolonged periods.

Liver transplant is a one time solution for a failing liver. It however is a major procedure and carries a moderate risk of mortality as well as significant morbidity. The patients are on life-long follow-up and immunosuppressant drugs. There is however a huge gap between the demand and availability of cadaver livers. A large number of patients therefore die while on the waiting list for liver transplant. In such cases, MARS can be used to support the patient till the cadaver / donor for liver can be found. In cases, where the general condition of the patient is not good secondary to liver disease, the surgery carries very high risk. These patients can be improved with MARS therapy so that they are able to tolerate the surgery better.

How does MARS function?
Some of the toxins mentioned above and drugs are water-soluble and others are water insoluble. The ones soluble in water can be removed by conventional dialysis used for Kidney disease but those that are albumin bound require special treatment. MARS is based on the principle of albumin dialysis. Thus, the toxins that are water insoluble and are normally degraded in the liver can be selectively removed from the blood by MARS

The patient's blood is detoxified in a filter unit (MARS FLUX). Blood and cleaning fluid (human serum albumin) flow past each other, separated by a membrane. There is never any contact between patient blood and the adsorber columns. The cleaning fluid is freed from toxins, recirculated and reused for blood detoxification. Thus, a fixed amount of albumin (dialysate) is used for a cycle (600 ml of 20 % Hyman Albumin).



The system consists of two main components:
  1. MARS Monitor, enabling the procedure via a pump and electronic control mechanisms.
  2. MARS Treatment Kit, performing the actual detoxification procedure.
MARS has been in clinical use since 1993. More than 1000 patients have been treated in this time. In addition to the improvement in clinical problems (encephalopathy, renal failure, cholestasis, ascites) and the resulting increased survival probability.
 

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