| BackgroundChronic hepatitis B (CHB) remains a serious global health concern, which is the main cause of cirrhosis and hepatocellular carcinoma. Antiviral therapy was the effective method of preventing the progression of chronic hepatitis B to cirrhosis and liver failure. Interferon-αand nucleoside analogues (NAs)are currently available for the treatment of chronic hepatitis B.Interferon-a including conventional IFN-a and Peg-IFN-α,3times per week (IFN-a) or once a week (Peg-IFN) subcutaneous injection for at least6-12months, achieves combination response rate from30%to40%. There are factors which determine the antiviral efficacy. The patients with higher ALT level, lower HBV DNA load, HBV genotype A and female achieved better efficacy, but it is still difficult to predict the outcome at the beginning of treatment. Moreover, adverse events and costs associated with higher doses and prolonged treatment warrant caution in recommending it in practice. The most frequently reported adverse effects of IFN-a are flu-like symptoms, headache, fatigue, myalgia, alopecia, mental disorder such as depression, loss of peripheral blood cells and autoimmune diseases such as hyperthyroidism.The oral tablet of nucleoside analogues (NAs), including lamivudine (LAM), adefovir (ADV), entecavir (ETV), telbivudine (LDT) and tenofovir (TDF), can reduce serum HBV DNA levels safely and conveniently. These advantages gradually made the nucleoside analogues a major therapy in anti-HBV therapy. But the treatment duration needs for several years, even more than ten years or decades due to the lower serological response rate and higher rebound rate after withdraws. Another problem of NAs is higher rate of drug resistance.Both nucleotides analogues and interferon possess inherent characteristics, but their drawbacks limit their clinical applications. We need to explore the new therapy. In the passed decade ozone therapy has been applied in a variety of diseases, including skin trauma such as bedsore and burn or skin ulcer, pain cure, intervertebral disc herniation, rheumatoid arthritis, diabetic foot, etc. As a suitable medical technology, medical ozone has been known, recognized and accepted gradually in different medical disciplines. Ozone-therapy of herniated intervertebral disc is regarded as classical minimally invasive treatments by China’s ministry of health this year. Ozone (blue gas, irritating odor) with its strong oxidizability has been widely used in our daily life. Under normal temperature and atmospheric pressure, the half-life of ozone is45minutes when ozone converts into oxygen. Medical ozone called ozone-therapy was firstly used in emphysematous gangrene in Germany during the World War I. With the emerging of ozone generator design to produce accurate ozone concentration and the progress of basic pharmacodynamics research, ozone-therapy had being fashionable in Europe from the1970s. Ozone is clinical using via several routes, including local injection, major autohaemotherapy (MAH), rectal perfusion, gas bath etc. In our department we have tried to apply medical ozone to the treatment of chronic hepatitis B (CHB) from the end of2004.ObjectiveTo study the efficacy and safety of medical ozone in patients with chronic hepatitis B.Methods1.1PatientsThe enrolled patients were inpatients or outpatients from Nanfang hospital from July2004to January2012.They were assigned according to patient’s intention to receive medical ozone therapy or conventional interferon-a treatment. Inclusion criteria:Patients were eligible if they had been positive for hepatitis B surface antigen (HBsAg) for at least6months with abnormal serum ALT level and signed informed consent. Patients were excluded if they had decompensated liver disease, thyroid dysfunction, uncontrolled diabetes and hypertension, significant renal, cardiovascular, respiratory comorbidity, hemorrhagic disease, coexisting psychiatric illness, autoimmune disorder disease or long-term immunosuppressive therapy including organ transplant patients, neutrophil count less than1500per cubic millimeter or a platelet count of less than90,000per cubic millimeter, coexisting hepatitis A or C or D virus or human immunodeficiency virus (HIV)infection, history of alcohol or drug abuse within one year before enrollment and pregnant.1.2Therapeutic regimenThe Ozone group was treated by medical ozone with major autohaemotherapy,3times per week for at least12weeks. Major autohaemotherapy (MAH):100ml venous blood was treated with100ml medical ozone of the concentration from20μg/ml to40μg/ml and then the ozonated blood was intravenously infused back to the patients. The medical ozone was made by the ozone generator which was made by Germany.Patients in the IFN treatment group received subcutaneouslly injection of5million units of conventional interferon-ain three times per week for at least24weeks to48weeks. Patients in both groups were followed-up for24weeks.1.3Outcome measuresThe outcome measure indexes were HBeAg seroconversion, loss of HBeAg and HBsAg, HBV DNA below detectable level, normalization of ALT at the time of baseline,12weeks after the treatment, at the end of treatment and after24weeks of follow-up. Accordingly, the safety analysis were recorded at the same time. HBeAg (titer≥1S/CO is difined positive), anti-HBe (titer≤1S/CO is defined positive),HBsAg (titer≥0.05IU/mL is defined positive) and serum HBV DNA (undetectable HBV DNA is defined as less than1000copies/ml) were measured by using of the Architect i2000and the Cobas Amplicor HBV Monitor Test (Roche Diagnostics), respectively. ALT was tested in the Medical Testing Center of the hospital.1.4Definition of the efficacy measures indexCombined response(CR):fulfill all following items.HBeAg loss and/or HBeAg seroconversion, Serum HBV DNA below detection limit of a PCR-based assay, and normalization of serum ALT level.Partial response (PR):at least fulfill one of item of combined response.Biochemical response (BR):normalization of serum ALT level.Viral response (VR):Serum HBV DNA below detection limit of a PCR-based assay, or HBV DNA<103copies/ml.Serological response (SR):HBe antigen loss and/or companied with e antibody positive or HBsAg loss. Clinical relapse:HBV DNA>1,000copies/mL or ALT>1xULN or HBeAg positive after stopping treatment in patients with combined response.Sustained response (SR):No clinical relapse during follow-up after stopping therapy.1.5Statistical analysisMeasurement data were expressed as mean±SD. Student’s t-test was used to compare means, and the chi-square test was used to compare frequencies.Both Student’s t-test and chi-square test were used in analysis of baseline clinical characteristics. Data were analyzed using the SPSS software package (version13; SPSS Inc., Chicago, IL, USA). All probability (P) values were two-tailed with significant set at<0.05.Results1.1Patients enrolledOne hundred and seventy-three patients were enrolled in ozone-therapy group. The mean age was(30.41±7.08)years,122(77.7%) were male and122(77.7%) were HBeAg positive. Sixteen cases were lost and157(90.7%) cases were followed-up to24weeks.The IFN treatment group enrolled266cases of CHB. The mean age was (29.66±8.48) years,195(82.3%) patients were male and187(78.9%) cases of HBeAg positive. Twenty-nine cases withdrew during the study and237(89.1%) patients fulfilled the study.1.2Efficacy of the two treatment groupsSerological Response:Comparing with the IFN treatment group at the end of treatment(EOT), ozone therapy group achieved HBeAg seroconversion at18%. There was no significant difference (18.0%vs24.0%, P=0.209) between the two groups. At the end of24weeks of follow-up, serological response of both groups increased and also showed no significant difference (24.6%vs.32.1%, P=0.156)HBsAg loss:At the end of treatment and follow-up, it did not differ significantly between two groups on HBsAg negative rate (0.6%vs.1.7%, P=0.362;0.6%vs.1.3%, P=0.542).Biological Response:At the end of course, normalization of ALT was associated with a lower rate compared with the IFN group (19.1%vs.34.2%, P<0.01),but the end of follow-up, there was no significant difference (23.6%vs.32.1%, P=0.068)HBV DNA level:The mean viral load continued fell throughout the course of the study for both of groups. At the end of follow-up, the mean value of HBV DNA did not differ significantly (4.59±1.63vs.4.18±1.71log10copies/ml, P=0.244)Virological Response:At the end of treatment and follow-up,Ozone group were significantly lower than the control group7.1%vs.41.4%(P<0.01) and8.4%vs.26.6%(P<0.01)Combined response:Ozone group were significantly lower than the control group (5.7%vs.30.8%, P<0.01;7.6%vs.16%, P=0.014)Sustaining Response:At the end of follow up, ozone group(6/9,66.7%),the IFN group (37/73,49.4%),there was no difference(P=0.365).1.3Comparison of efficacy between E antigen positive and negative with medical ozone or IFN-aFor patients treated with medical ozone:Virological Response:the virological response to medical ozone in this study in HBeAg positive patients appeared inferior to that observed in HBeAg negative patients, but there were no significant difference (4.9%vs.14.3%, P=0.056;8.2%vs.8.6%, P=0.943). Biological Response:At the end of treatment, HBeAg positive patients still achieved bad efficacy, but still did not differ significantly (18.3%vs.28.6%, P=0.106).At the end of follow-up, however, HBeAg positive patients had good efficacy, but no significant difference(27.5%vs.17.6%, P=0.356). Combined response:At the end of treatment and follow-up, HBeAg positive patients achieved lower rates of combined response in comparison with HBeAg negative patients, but there were both no significant differences (4.1%vs.11.4%, P=0.1;5.7%vs.14.3%, P=0.093). Rates of sustaining Response and relapse did not differ significantly (P=0.508and P=0.078respectively).For the group with IFN-a:Virological Response:At the end of treatment and follow-up, rates of HBV DNA suppression both appeared significantly lower in HBeAg positive patients in comparison with HBeAg negative patients (33.7%vs.68%, P<0.01;18.7%vs.58%, P<0.01). Biological Response:At the end of treatment, the rate of ALT normalization in HBeAg positive patients got lower than HBeAg negative patients, but no significant difference(49.2%vs.58%, P=0.269).At the end of follow-up, HBeAg positive patients also achieved lower rate of biological response, but there was significant difference (20.3%vs.40%, P=0.004). Combined response:At the end of treatment and follow-up, HBeAg positive patients got diminished efficacy in comparison with HBeAg negative patients and there were significant differences (27.3%vs.44%, P=0.023;12.8%vs.28%, P=0.009).Rate of clinical relapse did not differ significantly (P=0.533)1.4SafetyFive patients receiving medical ozone (2.9%) were censored due to rashes.Four other patients were reported of fatigue coexisting slight headache and two patients had elevated ALT but less than five times the normal which could not affect the continued medical ozone therapy.Ninteen patients (7.1%) with IFN-a treatment did not finish the treatment. Depression, which is a potential concern with interferon-based therapy, was reported by12patients. The most common adverse events receiving interferon alfa included pyrexia, fatigue, headache and myalgia.And5of interferon antibody,2of hyperthyreosis.1.5Summary of the results1. Medical ozone within a median duration of14weeks appeared diminished efficacy in comparison with convention interferon-a with a median course of40weeks regardless of antiviral or combined response.However,at the end of24weeks follow-up,there were no significant differences between two groups on HbeAg seroconversion(24.6%),ALT normalization(23.6%) and HBV DNA level (4.59±1.631g10copies/ml)2. CHB patients receiving medical ozone with HbeAg positive got the similar efficacy to the HBeAg negative.3. The patients receiving medical ozone with MAH for three months were safe and well tolerated.Conclusions1. Short duration of medical ozone therapy via MAH in patients with CHB retained certain activity against HBV, although it was inferior to the conventional interferon-a. However, the efficacy of ozone therapy at the end of follow-up was close to the conventional interferon-a.2. There were no serious adverse events for patients receiving medical ozone therapy. |
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