Ozonoterapia in tratamentul Hepatitei C


OZONE THERAPY IN PATIENTS WITH
VIRAL HEPATITIS "C"

TEN YEARS EXPERIENCE

 

By

 M. N. Mawsouf * and T. T. Tanbouli **

* Cancer Institute, Cairo University

** Cairo Medical Clinics


Abstract
Hepatitis "C" is a medical problem in Egypt. The usual line of treatment is very expensive with major side effects and low efficacy especially in genotype 4, which is common in Egypt. In the past ten years several studies were done to evaluate the role of ozone therapy in HCV. The first study included 60 genotype 4 hepatitis "C" patients who received combined ozone treatment of Major AutoHaemotherapy in a dose range from 4mg to 9 mg and rectal insufflation in a dose range from 6mg to 14 mg per visit. The numbers of visits were three times per week for eight weeks followed by twice per week for sixteen weeks. It was found that following eight weeks of ozone therapy, the viral load decreased in 91.67% of cases that reached -ve PCR in 20 % 0f cases. Following 24 weeks of ozone therapy, there was further decrease of the viral load that reached 95 % of cases with a -ve PCR level in 36.67 % 0f cases.  After eight weeks of ozone therapy, the abnormal enzyme levels were back to normal in 20 % of cases for the SGPT enzyme, and were back to normal in 23.33 % of cases for the SGOT enzyme.

A second study included 50 genotype 4 hepatitis "C" patients who received ozone therapy for 24 weeks. Patients received combined treatment of Major AutoHaemotherapy in a dose range from 2.8 mg to 8.4 mg and rectal insufflation in a dose range from 6mg to 12 mg per visit. The number of visits were three times per week for 12 weeks followed by twice per week for 12 weeks. The general condition in 94 % of cases improved. There was a decrease in the quantitative P.C.R. in 71.8 % of cases that reached -ve P.C.R. in 24 % of cases after 8 weeks treatment. The number of -ve P.C.R. cases for HCV virus increased to reach 36 % of cases after 24 weeks treatment. There was a statistically significant improvement as regards the parameters of SGOT, SGPT, albumin, bilirubin and prothrombin after 8 weeks from the start of the study. A third study was carried on 30 HCV patients gave similar results to the previous two. Ozone therapy was found to be effective even in cases of liver cirrhosis and impending liver cell failure where there is no place for drug therapy.

Several researches are going on and from the preliminary data of those we noticed that the use of combined ozone and interferon therapy gave better results than either of them. Ozone enhanced the effect of interferon and decreased its side effects. One year follow-up of HCV cases treated with ozone therapy had a 40% relapse. However the liver function tests were not affected denoting that the virus had little effect on the liver.

A histo-pathological study on 98 HCV patients denoted that ozone has an anti-inflammatory and anti-fibrotic effect.

Ozone therapy was found to be an effective, safe and less expensive method in Hepatitis "C" patients weather used alone or in combination with drug therapy and weather the condition is early or late.

Key Wards

Hepatitis, Ozone, HCV

Aim of the Studies

These studies were made to evaluate the effectiveness and safety of ozone therapy in hepatitis C genotype 4 infections and to evaluate a proposed ozone therapy protocol in HCV genotype 4 treatment. Several studies and clinical observations were done within ten years from year 1999 to the year 2008.
Introduction
Hepatitis C (HCV) is a worldwide medical problem. It is estimated that more than 300 millions on earth are suffering from HCV. Hepatitis C is a major medical problem in Egypt. It is postulated that more than 15% i.e. more than 10 millions of the population in Egypt are suffering from HCV. This disease is slowly progressing, detected mainly accidentally, devitalizing and difficult to treat. The usual line of treatment is very expensive with major side effects and low efficacy.
Hepatitis C in most cases leads to complications e.g. liver cirrhosis, ascitis, liver carcinoma and ultimately liver cell failure. Liver Cirrhosis is estimated to develop in 20 -25 % of patients with HCV within 20 years. Hepato-cellular carcinoma was found to develop in 5% of HCV cases..
It is not only a medical problem, but also an economic problem (less work, less production and very high costs of usual treatment).
So far there are six genotypes of HCV with worldwide prevalence of genotypes 1, 2 &3.  In Africa genotype 4 and 5 are more dominant. In Asia genotype 6 is more dominant. Genotype differences have shown varying susceptibility to antiviral therapy. In Egypt genotype 4 is prevalent and it is known that is relatively resistant to antiviral treatment.
The main line of treatment nowadays for hepatitis C includes interferon and ribavirin. Ribavirin and interferon have significant medical and psychiatric side effects.
Antiviral effect of ozone
Ozone is a powerful oxidizing agent. It disrupts viral envelope proteins, lipoproteins, lipids, and glycoproteins. The presence of numerous double bonds in these unsaturated molecules makes them vulnerable to the oxidizing effects of ozone. Molecular architecture is disrupted and widespread breakage of the envelope ensues. Deprived of an envelope, virions cannot sustain nor replicate themselves. Ozone proper, and the peroxide compounds it creates, may directly alter structures on the viral envelope, which are necessary for attachment to host cells. Peplomers, the viral glycoproteins protuberances that connect to host cell receptors are likely sites of ozone action. Alteration in peplomer integrity impairs attachment to host cellular membranes foiling viral attachment and penetration.
Ozone stimulate leucocytes function and cytokine production
Ozone is a powerful oxidant by itself and leads to production of peroxides with an oxidative power. Hydrogen peroxide crosses the cell membrane and activates the cytoplasmic gene-regulatory nuclear factor kappa B, ultimately causing the transcription of mRNAs of several cytokines, namely interleukin (IL-1,2,4,6,8,10), tumor necrosis factor (TNF-µ) and interferon (IFN b and g).
 In HCV, viral load appears to be a major factor in the invasiveness and virulence of the disease process. Ozone induces the release of cytokines by leucocytes. Stimulation of the immune mechanisms will lead to significant reduction of circulating virions.

 
Patients and methods
One of the studies included 60 hepatitis "C" genotype 4 patients, 45 males and 15 females. Their age ranged between 34 and 65 years. Another study included 50 hepatitis "C" genotype 4 patients, 44 males and 6 females. Their age ranged between 23 and 58 years.
Investigations including C.B.C., liver function tests, A.F.P., serological tests for Bilharziasis, P.C.R. quantitative for H.C.V., prothrombin time and concentration and abdominal ultrasonography were done before and 8 weeks, 24 weeks after starting treatment with ozone.
In the first study patients received combined treatment of Major AutoHaemotherapy in a dose range from 4mg to 9 mg and rectal insufflation in a dose range from 6mg to 14 mg per visit. The numbers of visits were three times per week for eight weeks followed by twice per week for sixteen weeks. In the second study; patients received combined treatment of Major AutoHaemotherapy in a dose range from 2.8 mg to 8.4 mg and rectal insufflation in a dose range from 6 mg to 12 mg per visit. The numbers of visits were three times per week for twelve weeks followed by twice per week for another twelve weeks.   
Investigations were repeated after 8 and 24 weeks of treatment. General health and daily activity were observed.
Ozone Treatment Protocol
In the first study, the first session of major AutoHaemotherapy was given in a concentration of 25µ/ml ozone in oxygen for two successive times, then increased to 30µ/ml ozone in oxygen for another two successive times and so on, increasing the concentration by 5µ/ml every two sessions till reaching a maximum of 60µ/ml were this concentration was fixed till the end of treatment course. The rationale of start low and go slow was respected. The ozone in oxygen volume was fixed in all sessions at 150 ml. The blood weight was constant in each session at 150 gm. First session of rectal insufflation was given in a concentration of 20µ/ml ozone in oxygen with a volume of 300 ml for two successive times, then increased to 25µ/ml ozone in oxygen with the same volume for another two successive times, then 30µ/ml x 300 ml twice, then 35µ/ml x 300 ml twice followed by 35µ/ml x 350 ml twice till we reach a maximum of 40µ/ml x 350 ml were this concentration and volume was fixed till the end of treatment.
In the second study, the first session of major AutoHaemotherapy was given in a concentration of 20 µ/ml ozone in oxygen for two successive times, then increased to 25 µ/ml ozone in oxygen for another two successive times and so on, increasing the concentration by 5µ/ml every two sessions till reaching a maximum of 60µ/ml were this concentration was fixed till the end of treatment course. The rationale of start low and go slow was respected. The ozone in oxygen volume was fixed in all sessions at 140 ml. The blood weight was constant in each session at 140 gm. First session of rectal insufflation  was given in a concentration of 15 µ/ml ozone in oxygen with a volume of 250 ml for two successive times, then increased to 20 µ/ml ozone in oxygen with the same volume for another two successive times, then 25 µ/ml x 250 ml twice, then 30 µ/ml x 250 ml twice followed by 30 µ/ml x 300 ml, then 35µ/ml x 300 ml twice till we reach a maximum of 40µ/ml x 300 ml were this concentration and volume was fixed till the end of treatment.
Results

In the first study it was found that following eight weeks of ozone therapy, the viral load decreased in 91.67% of cases (P value < 0.001) that reached PCR -ve level in 20 % 0f cases. Following 24 weeks of ozone therapy, there was further decrease of the viral load that reached 95 % of cases (P value < 0.001) with a PCR -ve level in 36.67 % 0f cases figure 1, 2, 3.  After eight weeks of ozone therapy, the abnormal enzyme levels were back to normal in 23.33 % of cases (P value <0.0.13) for the SGOT enzyme, and were back to normal in 20 % of cases (P value < 0.001) for the SGPT enzyme (normal levels are < 45 U/L for the SGOT enzyme, and < 42 U/L   for the SGPT enzyme) figure 4, 5.

In the second study it was found that following eight weeks of ozone therapy, the viral load decreased in 63.85% of cases (P value < 0.004) that reached PCR -ve value reading in 24 % 0f cases (P value <0.001). Following 24 weeks of ozone therapy, there was further decrease of the viral load that reached 71.84% of cases (P value < 0.005) with a PCR -ve reading in 36 % 0f cases (P value <0.001) figure 6,7.  After eight weeks of ozone therapy, the abnormal enzyme levels were back to normal in 52 % of cases ( P value <0.001 ) for the SGOT enzyme, and were back to normal in 58 % of cases (P value <0.001) for the SGPT enzyme (normal levels are ≤ 40 U/L) figure 8,9. After eight weeks of ozone therapy, the abnormal bilirubin levels (normal value ≤ 1 mg%) were back to normal in 28% of cases (P value < 0.001) figure 10. Following also the same period of therapy, the abnormal albumin parameters (normal value ≥ 3.5 mg %) were back to normal in 18% of cases (P value < 0.032) figure 11. The prothrombin concentration improved towards the normal level (P value < 0.001) figure 12.




 

 

Figure 1

 


 

PCR average number before, during and after ozone therapy

 

 

 

 

 

Figure 2

 

 

Number of PCR negative cases during and after ozone therapy

 

 

 

Figure 3

 

 

Number of cases with a decrease in PCR viral load during and after ozone therapy

 

 

 

 

 

 

Figure 4

 

 

Normal and abnormal SGOT enzyme levels before and after ozone therapy

 

 

 

 

Figure 5

 

 

Normal and abnormal SGPT enzyme levels before and after ozone therapy

 

 

 

 

 

 

Figure 6

 

 

 

PCR average number before, during and after ozone therapy

 

 

 

 

 

Figure 7

 

 

 

Number of PCR negative cases during and after ozone therapy

 

 

 

 

 

 

 

 

 

Figure 8

 

 

 

Normal and abnormal SGOT enzyme levels before and after ozone therapy

 

 

 

 

 

Figure 9

 

 

 

Normal and abnormal SGPT enzyme levels before and after ozone therapy

 

 

 

 

 

 

Figure 10

 

 

 

Normal and abnormal bilirubin levels before and after ozone therapy

 

 

 

 

Figure 11

 

 

 

Normal and abnormal albumin levels before and after ozone therapy

 

 

 

 

 

Figure 12

 

 

 

Normal and abnormal prothrombin levels before and after ozone therapy

 

 

 

 

Other Researches

Several other researches by the authors are being carried on revealed the following as a preliminary data:

  • A third research on 30 HCV genotype 4 patients performed in a different center gave almost the same results like the first two researches.
  • From the previous researches we found that ozone therapy has a positive effect on the liver function tests even in late stages with liver cirrhosis where interferon is contraindicated.
  • Combination of interferon administration and ozone therapy in four HCV type 4 patients gave better results than either one of them alone with less side effects of interferon
  • One year follow-up of HCV cases treated with ozone therapy for 6 months revealed that there was a relapse rate of approximately 40%. However the liver function tests were not affected denoting that the relapsed virus had little effect on the liver.
  • The effect of ozone on the HCV infected blood units was studied. Medical ozone was bubbled through the infected blood units with different concentrations ranging from 20 to 50 µ/ml for 5 successive days. There was no statistically significant decrease in the HCV viral load.

One histo-pathological study was done by Elbasha H. et al. in the year 2006. It was performed on 98 HCV patients to evaluate the effect of ozone therapy on the liver tissue in 12 weeks therapy period. They came to the conclusion that ozone therapy induces downgrading in necro-inflammatory changes in liver biopsy by 2-8 points. Also they found that ozone therapy induced down staging in fibrosis by 1-2 points in 65 - 82.5 % of cases picture 1.


 

Picture 1 - Effect of ozone therapy on the liver tissue

    

  Before treatment 8/18 grade of inflammation,             
   After treatment 4/18 grade of inflammation, 0/6   
      3/6 Stage of fibrosis H&E, X200                                               stage of fibrosis H&E, X200
Discussion

The significant decrease in viral load is an important factor - among other factors - for judging the improvement of a case of hepatitis C virus. In these studies, it was found that following ozone therapy; there was a significant reduction of viral load. This decrease was evident after 8 weeks and further decline following another 16 weeks of ozone therapy.

Normal enzyme levels are a very important indicator denoting the sound integrity of liver cells. In these studies, it was found that following ozone therapy; there was a significant change of abnormal enzyme levels towards normal values. Some patients received DDB pills that are a Chinese herbal medicine capable of lowering the enzyme level, but without any anti-viral action. Stoppage of DDB is followed by increase in enzyme level to the previous level. This can explain why some of the patients had a normal enzyme level before starting ozone therapy.

One of the major important parameters that signify liver function are the bilirubin and albumin levels. In the second study it was found that both parameters were improved and back to normal with a statistically significant readings denoting liver function improvement.

One histo-pathological study proved that ozone therapy has an anti-inflammatory and anti-fibrotic effect on the liver of HCV patients. This proves the beneficial effect of ozone therapy on the integrity of liver tissue.

Clinical observations and questioning of the patients revealed that in more than 90 % of cases the general condition improved and some of patients returned to work after they were staying at home. Moreover in most cases there were improvement of the quality of life and they had the sense of well-being. All the previous data; points to the important role of ozone a safe, effective method of therapy.

Not only ozone was effective in managing HCV cases, but also it had a therapeutic effect on some associated conditions e.g. diabetes, hypertension and prostatic enlargement.

It is understandable that the response to treatment will be less in complicated cases with e.g. liver cirrhosis and ascitis or cases associated with chronic diseases e.g. diabetes and bilharziasis, but these were not considered as factors in ineffectiveness. However; even in those cases the beneficial effect of ozone therapy was evident.

These researches signifies that ozone therapy has a positive effect on the liver function tests even in late stages with liver cirrhosis where interferon is contraindicated

In spite of the high percentage of relapse (+ve PCR) observed following ozone therapy, it had little effect on the liver function tests. This means that quantitative PCR is not a major factor for evaluation of liver performance; but only one factor among others.

It was found by a preliminary research that there was no significant decrease in the HCV viral load following exposing the HCV infected blood units to medical ozone. This suggests that the main effect of ozone therapy on the virus is due to its immune-stimulating effect rather than a direct antiviral effect.

In some cases there was no response to ozone therapy on the viral load. Observation of those patients and by clinical analysis reveled that there were three major factors for irresponsiveness: 1- improper diet with lots of fats and proteins that is capable of lying great stress on the liver as an organ for metabolism and exhausting this organ. 2- physical exhaustion with lots of effort and long hours in work. This will through a great burden on the body as a whole and the liver as a part of the body. 3- hepatotoxic drugs that might be taken by the patient for treatment of another disease.

In these studies there was no control group and the patient was considered to be a control to himself. The main issue, as a clinical study was to compare the clinical and laboratory findings before and after ozone therapy for each patient. In order to reach a proper protocol for ozone therapy, several pilot studies had to be accomplished. Trial MAH twice/week for 2 months, MAH three times/week for 2 months, RI twice/week for 2 months, RI three times /week for 2 months following rationale of start low and go slow. Good results were obtained but not as good as the protocol of these studies. Combination of MAH and RI was important to deliver ozone therapy to both systemic and portal circulation. Ozone therapy was found to induce hyper-oxygenation of portal circulation.

Conclusion

Ozone therapy was found to be an effective, safe and less expensive method in Hepatitis "C" genotype 4 patients. It can be used safely even if there is a complication or associated disease. Further studies are important. The protocol of ozone therapy in this study was found to be the best of many other protocols dealing with hepatitis C genotype 4.

Recommendations

It is recommended to start a double blind randomized placebo controlled study. The patients must be selected with no complications (cirrhosis, ascitis, liver cell failure, etc..) and no associated chronic disease (Diabetes, Bilharziasis, etc..) Considering the high relapse rate following ozone therapy; it is recommended that this study should be a long-term study for one year and the follow-up by observation and investigations for another year. Evaluation should be based on many parameters i.e. general condition, liver Function tests (synthesis, excretions, integrity), quantitative PCR, abdominal ultrasonograpohy and liver biopsy. As there will be a long term oxidative therapy by ozone; there should be monitoring of the total anti-oxidant status and reduced glutathione levels of the patients.

It is also recommended to make a study with large number of patients to evaluate the efficacy of combination of interferon administration and ozone therapy in HCV genotype 4 patients. Also to evaluate the possible role of ozone in increasing the efficacy, and diminishing both the side effects and course duration of interferon therapy.

An extensive study on the effect of frequent exposure of HCV infected blood units to medical ozone is recommended.

Quantitative PCR can be considered as a guide for evaluation but is not conclusive because of the sharp fluctuations of viral load and so far there is no precise and accurate method for quantitative estimation of viral load. Different methods, different units and wide variation from one laboratory to another must be put in consideration

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