Postepy Hig Med Dosw. (online), 2012; 66: 339-347
Original Article
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Results of antiviral treatment of patients with chronic hepatitis C: experience of Poznan centre
Wyniki leczenia przeciwwirusowego pacjentów z przewlekłym zapaleniem wątroby typu C- doświadczenia ośrodka poznańskiego
Maciej BuraABCDEF, Arleta Kowala-PiaskowskaBEF, Agnieszka AdamekABCDEF, Aleksandra BuraBCDE, Arkadiusz CzajkaBD, Katarzyna HryckiewiczABD, Iwona BereszyńskaAB, Iwona Mozer-LisewskaABCDEFG
Department of Infectious Diseases, Poznan University of Medical Sciences, Poland
Corresponding author
Maciej Bura MD, PhD, Department of Infectious Diseases, Poznan University of Medical Sciences, ul. Szwajcarska 3, 61-288 Poznan, Poland

Authors' Contribution:
A - Study Design, B - Data Collection, C - Statistical Analysis, D - Data Interpretation, E - Manuscript Preparation, F - Literature Search, G - Funds Collection

Received:  2012.02.15
Accepted:  2012.05.25
Published:  2012.06.12

Streszczenie
Wstęp: W Polsce zakażenie HCV dotyczy około 750 tys. osób. Zapobieganie marskości wątroby oraz ra­kowi wątrobowokomórkowemu, którymi zagrożonych jest prawie 20% pacjentów z przewlekłym zapaleniem wątroby (pzw C) polega na dążeniu do eradykacji wirusa poprzez stosowanie lecze­nia przeciwwirusowego preparatami pegylowanego interferonu alfa z rybawiryną.
Materiał/Metody:
W pracy przeanalizowano wyniki standardowego leczenia pzw C w grupie 169 dorosłych pa­cjentów, które rozpoczęto w okresie 01.01.2007-30.06.2008 r.; ponadto zbadano wpływ różnych czynników klinicznych, biochemicznych i wirusologicznych na uzyskanie sukcesu terapeutycz­nego pod postacią utrwalonej odpowiedzi wirusologicznej (SVR).
Wyniki:
W grupie 128 pacjentów, którzy otrzymali pełen kurs leczenia przeciwwirusowego, SVR osią­gnęło 67,2% chorych (86 osób), natomiast biorąc pod uwagę wszystkich 169 pacjentów, którzy rozpoczęli terapię - utrwalony zanik wiremii stwierdzono u 53,2% chorych (90 osób). W odnie­sieniu do 155 osób, u których nie przerywano leczenia z przyczyn innych niż wirusologiczne, wartość ta wyniosła 55,5%.
Utrwalonemu zanikowi wiremii sprzyjały: genotyp 3 wirusa, wiek poniżej 40 rż., masa ciała do 75kg, prawidłowa wartość wskaźnika masy ciała (BMI), niska aktywność gamma-glutamylo­transpeptydazy (GGTP) przed leczeniem, minimalne zaawansowanie włóknienia wątrobowego w bioptacie wątroby (S1), całkowita wczesna odpowiedź biochemiczna (cEBR), ponadto - uzy­skanie negatywizacji wiremii po 12 tygodniach leczenia w grupie chorych zakażonych genoty­pem 1 (całkowita wczesna odpowiedź wirusologiczna, cEVR). Czynniki te były silnie skorelo­wane ze sobą, dlatego niemożliwa była analiza metodą logistycznej regresji wielokrotnej.
Działania niepożądane leczenia oraz inne problemy zdrowotne były przyczyną wcześniejszego zaprzestania stosowania standardowego schematu terapeutycznego u 14 chorych, przy czym brak SVR wystąpił u 10 z nich (71,5%, co stanowi 5,9% populacji badanej).
Słowa kluczowe: hepatitis C • treatment • interferon • ribavirin


Summary
Introduction: Hepatitis C virus (HCV) infection in Poland affects approximately 750 thousand persons. The prevention of cirrhosis and hepatocellular carcinoma, of which approximately 20% of patients with chronic hepatitis C virus are at risk, aims at eradication of the virus by applying antiviral treatment with pegylated interferon alpha with ribavirin.
Material/Methods:
In this paper the results of the standard treatment of chronic hepatitis C in a population of 169 adult patients in whom it was started in the period of 01.01.2007-30.06.2008 are analyzed. Moreover, the influence of various clinical, biochemical and viral factors on achieving therapeutic success in the form of the sustained virological response (SVR) was studied.
Results:
In the group of 128 patients who received the full course of antiviral treatment, the SVR was achieved by 67.2% of patients (86 persons), whereas regarding all 169 patients who started the therapy, the sustained disappearance of viremia was found in 53.2% of patients (90 persons).
Regarding 155 persons in whom the treatment was not interrupted for reasons others than viro­logy, this value was 55.5%.
For the sustained disappearance of viremia the following was favorable: genotype 3 virus, age un­der 40 years, body mass up to 75 kg, correct value of body mass index (BMI), low gamma-glutamyl transpeptidase (GGTP) activity before the treatment, minimum advancement of liver fibrosis in a liver biopsy (S1), complete early biochemical response (cEBR), and moreover, the achievement of negation of viremia after 12 weeks of the treatment in a group of patients infected with genotype 1 (complete early virological response, cEVR). These factors were strongly correlated with each other and that is why an analysis by the method of logistic multiple regression was impossible.
Adverse reactions to the treatment and other health problems were the reasons for earlier discon­tinuation of the standard therapeutic scheme in 14 patients, whereby the lack of an SVR occur­red in 10 of them (71.5% which is 5.9% of the studied population).
Key words: hepatitis C • treatment • interferon • ribavirin




Introduction
The hepatitis C virus (HCV) infection is currently a leading issue of infectious hepatology in industrialized countries, on a world scale as well as in Poland. Its significance - as a problem important from the point of view of public he­alth - results from several premises, namely:
- the occurrence frequency (notably it is a consequence of exposure of a significant percentage of the popula­tion in the past in relation to among other things trans­fusion of infected blood or blood products and proce­dures connected with the break in continuity of tissue),
• possible clinical consequences of chronic hepatitis C,
• the occurrence of extrahepatic manifestations of HCV infection which can decrease the quality of life of the patients,
• economic consequences for the health care systems (di­rect liability, i.e. costs of hospitalization and treatment of the patients, including liver transplantations and in­direct, i.e. the loss of productivity, rehabilitation and an­nuity benefits),
• patients infected with HCV are a reservoir of the virus and in certain situations a potential epidemiological dan­ger for the community.
According to the assessments of numerous experts, the in­tensity of essential health problems connected with HCV infection (cirrhosis together with its complications, hepa­tocellular carcinoma) will increase in the world at least for the next two or three decades [5,14,17].
In diagnosing HCV infection a crucial role is played by spe­cific tests, i.e. serological and molecular tests. The biochemi­cal significance of non-specific tests, i.e. activity of amino­transferases (mainly alanine transaminase, ALT), is smaller. Moreover, the knowledge of HCV genotype has an influence on the length of therapy and is significant for predicting the chances of an infected patient receiving the sustained viro­logical response (SVR) after antiviral treatment with pegy­lated interferon alpha (PEG-IFN-α) with ribavirin (RBV).
For many years various factors having significance for pro­gnosing hepatitis C therapy (among other things genotype, viremia, the length of infection duration, coexisting dise­ases, coinfections, sex, age, race, body mass, ALT activi­ty and others) have been searched for.
The aim of this paper was:
• characterization of the course of a standard antiviral the­rapy in patients with chronic hepatitis C,
• analysis of the results of antiviral therapy (virological and biochemical response) of chronic hepatitis C with PEG-IFN-α with RBV in patients not treated earlier,
• an attempt to determine factors conditioning the achie­vement of SVR in adult patients infected with HCV, un­dergoing antiviral treatment.
Material and Methods
The study comprised 169 patients who were not treated earlier, including 70 women and 99 men infected with HCV, aged 18 to 73 (mean: 41.3±12.8 years, median: 42 years) in whom the therapy of chronic hepatitis C with PEG-IFN-α with RBV in doses adjusted to their body mass was started in the period from 01.01.2007 to 30.06.2008. The body mass of the pa­tients ranged from 44 kg to 120 kg (mean: 76.5±15.2 kg, me­dian: 76.7 kg), and the body mass index (BMI) ranged from 18 to 41 kg/m2 (mean: 25.9±4.5 kg/m2, median: 25.5 kg/m2).
Chronic hepatitis C was diagnosed according to general­ly accepted criteria.
In the studied group of patients 87 (51.5%) received PEG-IFN-α-2b and the remaining 82 patients (48.5%) received PEG-IFN-α-2a, in both cases with RBV.
Definitions useful for the assessment of virological respon­se depending on the time of its execution:
EVR - early virological response: at least 100-fold (2 log10) decrease of concentration of HCV-RNA after 12 weeks of the treatment compared to pre-therapeutic value; two kinds of EVR were distinguished:
a) cEVR - complete early virological response: non-de­tectability of HCV-RNA by the qualitative test,
b) pEVR - partial early virological response: HCV-RNA detectable by the qualitative test.
EVR was not assessed in patients infected with genotype 3.
EOTVR - end of treatment virological response: non-de­tectability of HCV-RNA directly after completion of the antiviral therapy, verified by the qualitative test.
SVR - sustained virological response: non-detectability of HCV-RNA directly after completion of the antiviral the­rapy and 24 weeks after completion of the antiviral thera­py, verified by the qualitative test.
cEBR - complete early biochemical response: normaliza­tion of ALT activity after 12 weeks of the treatment com­pared to pre-therapeutic value.
In patients infected with the virus of genotype 3 the treat­ment was 24 weeks; in patients infected with other geno­types of HCV the time of treatment was 48 weeks, on the condition of receiving EVR in the 12th week of the treatment and of the lack of occurrence of serious adverse reactions.
In the studied group of patients the genotype distribution was as follows: 1a -->n=5 (3.0%), 1b --> n=131 (77.5%), 1a + 1b --> n= 3 (1.8%), 3a --> n=29 (17.1%), 1b+3a --> n=1 (0.6%).
At the moment of initiation of the antiviral therapy the initial viremia HCV-RNA fluctuated from 50-599 IU/ml (the positive result of qualitative determination of HCV-RNA, the quantitative test of sensitivity 600 IU/ml showed viremia below this threshold) to 1.36×108 IU/ml (Fig. 1).
Figure 1. HCV RNA viremia in the blood serum of patients before implementing the antiviral treatment (n=169)

The activity of alanine transaminase (ALT), gamma-glu­tamyl transpeptidase (GGTP) and the selected parameters of complete blood count in the analyzed population at the moment of initiation of the antiviral treatment is presen­ted in Table 1. The normal initial GGTP activity was fo­und in 52 women and 74 men, which was 74.6% of per­sons in the studied group of patients.
Table 1. ALT activity and the value of selected parameters of complete blood count at the beginning of the treatment

The results of liver biopsy obtained from 154 patients con­cerning the inflammation activity (G, grading) and the sta­ge of fibrosis (S, staging) are presented in Figures 2 and 3.
Figure 2. Inflammatory activity in the studied group of patients (n=154)

Figure 3. The advancement of fibrosis in the studied group of patients (n=154)

The pathomorphological assessment of preparations was performed according to the criteria established in "Podsumowanie wstępne dotyczące wypracowania stan­dardu oceny histopatologicznej bioptatów w przebiegu przewlekłych zapaleń wątroby - Katowice 15.04.1999" [Preliminary summary concerning the standard of histo­pathological assessment of bioptates in the course of the chronic hepatitis] in the scale 0-4 points [9].
The initial doses of PEG-IFN-α drugs per kilogram of body mass of the patient were: for PEG-IFN-α-2a, 1.57-3.74 µg (mean: 2.40±0.47 µg, median: 2.27 µg); and for PEG-IFN-α-2b, 1.25-1.68 µg (mean: 1.48±0.08 µg, median: 1.48 µg).
The initial dose of RBV was 6.31-20.79 mg/kg (mean: 14.15±1.97 mg/kg, median: 13.9 mg/kg).
The statistical assessment was performed in the Poznan Medical University Department of Computer Science and Statistics.
Results
Early virological response (EVR)
Out of the group of 169 patients, 161 patients received the 12-week course of treatment (in 8 patients the therapy was stopped before this time). EVR was assessed in 132 pa­tients infected with a virus of non-3 genotype. This para­meter was not analyzed in 29 patients infected with a vi­rus of genotype 3. EVR was achieved by 105 among 132 patients (79.5%) infected with a virus of genotype non-3. In 85 cases the disappearance of HCV-RNA (cEVR) was found, and in another 20 patients it came to at least 100-time reduction of viremia, but it was possible to detect HCV-RNA in the blood serum (pEVR), and 27 patients did not fulfill the criteria of EVR, so the therapy was in­terrupted at this stage.
End of treatment virological response (EOTVR)
128 patients received the complete course of antiviral tre­atment depending on the HCV genotype, including 99 in­dividuals infected with a virus of genotype "non-3" and 29 infected with a virus of genotype 3. In total EOTVR was obtained by 114 patients (89.1%), remaining 14 patients (10.9%) did not reach non-detectability of HCV-RNA at this point. 100% of patients (n=29) with genotype 3 ob­tained EOTVR, while in patients with genotype "non-3" 85 among 99 assessed (85.8%) received a negative result of HCV-RNA determined by the qualitative method. In patients with "non-3" genotype who reached cEVR, the EOTVR was found in 91.4% (74 among 81 patients who completed therapy), while in patients with pEVR, the EOTVR reached 61.1% (11 among 18 patients who com­pleted therapy).
Sustained virological response (SVR)
Among 114 patients without detectable viremia within the time of the assessment of the EOTVR, 6 months la­ter this state was confirmed in 75.4% of this population, which means that the SVR was reached in 86 out of a gro­up of 128 patients (67.2%) who received the complete, de­pendent on the genotype, course of standard treatment. Therapeutic success was achieved by 61.6% of persons (61 patients) with "non-3" genotype and 86.2% (25 patients) infected with genotype 3. In patients with "non-3" geno­type who received cEVR, SVR was found in 70.4% (57 among 81 patients who completed therapy), while in pa­tients with pEVR, SVR was observed in 22.2% from this group (4 among 18 patients who completed therapy). In to­tal, among 169 patients who started the therapy, SVR was achieved by 90 patients (53.2%), while among patients with "non-3" genotype this value was 46.4% (65/140 pa­tients of initial population).
For the purposes of the analysis of the treatment results, out of the population of 169 patients a group of 155 persons in whom the treatment was not interrupted for reasons other than virological (called the comprehensive group) was di­stinguished. It comprised 128 patients who completed the full course of antiviral therapy and a group of 27 patients who did not reach EVR and did not continue the treatment.
A comparison of the assessment of the SVR assessed in various groups of patients is presented in Table 2.
Table 2. Summary of the SVR assessment in various groups of patients

ALT activity
The ALT activity analysis was performed at the moment of implementation of treatment (T0), in the 12th week of therapy (T12), at the end of the therapy (TEOTVR) and 24 we­eks after the therapy completion (TSVR) during the SVR assessment. This parameter was analyzed only in patients who received the complete course of the antiviral therapy (n=128) and is presented in Table 3.
Table 3. ALT activity in patients who received the complete course of antiviral treatment with PEG-IFN-α with RBV (n=128)

The influence of various clinical, virological and bioche­mical factors for reaching SVR was assessed in 155 pa­tients in whom the treatment was not interrupted for re­asons other than virological (the comprehensive group). The results of this analysis are presented in Table 4.
Table 4. Influence of clinical, virological and biochemical factors on achieving the SVR in the population of patients from the comprehensive group (n=155)

In Table 5 the adverse reactions are specified as well as other essential health events that were the reason for mo­difying doses of antiviral drugs or stopping therapy. As can be seen from the data presented in Table 5, among 169 patients who started the antiviral therapy, in 94 pa­tients doses of antiviral drugs were modified or the stan­dard treatment was abandoned before completing a 12-week therapeutic course. Among patients treated over 12 weeks similar interventions were necessary in 95 cases. Moreover, in 56 patients thyroid function disorders ma­nifesting as incorrect TSH (thyroid stimulating hormone) values were found.
Table 5. Significant events (including adverse reactions) which are the reason for modifying the doses of the antiviral drugs or interrupting PEG-IFN-α and RBV therapy

Discussion
Despite numerous studies on drugs which could be used in the antiviral therapy of chronic hepatitis C the standard still remains combination therapy using IFN-α (the pre­ferred option is due to comfortable dosing and better tre­atment results PEG-IFN-α) and RBV.
Among the studied patients the permanent disappearance of viremia was achieved by 86 among 128 persons who received the complete course of the standard PEG-IFN-α with RBV therapy (66.2%). However, it seems that the more realistic value for effectiveness of the applied treat­ment is the result achieved in the group of 155 patients (the comprehensive group), considering also 27 persons witho­ut EVR. In the mentioned population the estimated SVR was 55.5%. The reason for such an attitude is the results of the studies in which the patients without the early virologi­cal response were treated to the end of the 48 week treat­ment period. The sustained disappearance of viremia was reached in such cases only by 0-3% among them. Based on the above data, in the group of patients in whom it did not result in at least 100-fold decrease in concentration of HCV-RNA after 12 weeks of the therapy, at most one person would have the chance to obtain final success of the treatment (27×0.03=0.81), which would increase the SVR value in the group of assessed patients by only 0.6%.
In summary, the results of antiviral treatment in this gro­up of patients compared with the SVR values obtained by other researchers both domestic [12,13] and foreign [1,4,7,10,15,18] are similar.
It should be stressed that among the 169 patients who star­ted the PEG-IFN-α with RBV therapy, a low percentage of patients was burdened with serious coexisting diseases that could influence the course and results of the antiviral therapy of chronic hepatitis C, and in almost 60% of them no additional pathology was found. Also the fact of a low percentage of patients participating in the study with ad­vanced liver disease (18/154, i.e. 11.7% persons who had biopsy of this organ) is significant.
The standard antiviral therapy was abandoned in 14 among 169 patients who started it (8.3%). This is a relatively low value compared to the frequency of this kind of event pro­vided by authors of the main studies registering the descri­bed treatment in the United States, i.e. 10-16% [8,10,15].
The most common adverse reactions requiring changes to the initially set treatment scheme (dose, preparation) were: hemolytic anemia induced by RBV and the results of my­elosuppressive activity of interferon, which corresponds well with the data from the literature [8,15]. Serious he­alth events both connected with and those most probably independent of therapy (intracerebral hematoma after fall from height) were rare.
In reference to the patients infected with non-3 HCV ge­notype (in this analysis these were practically patients in­fected with genotype 1 of the virus) the carried out study only confirms the relative significance of EVR for pre­dicting chances for the achievement of final therapeutic success. The higher value of the discussed parameter wi­thin this range after considering the variety of the kind of the early virological response (complete vs. partial EVR, respectively in 64.3% and 22.2%) remains in ac­cordance with the data presented among other people by Berg et al. [3] and Fried et al. [7]. It should be stressed here that a significantly better prediction indicator of re­aching SVR is confirmation of the so-called rapid viral response (RVR), defined as non-detectability of viremia 4 weeks after the moment of giving the first PEG-IFN-α injection [6].
Data concerning the significance of gender as a predicti­ve factor for success of the antiviral therapy of chronic he­patitis C are ambiguous. The studies by Manns et al. [15] and Fried et al. [8] in which PEG-IFN-α drugs were used did not confirm the beneficial influence of the female gen­der in this aspect. Similar conclusions result from the as­sessment carried out in the current paper.
Younger patients (<40 years) have a greater chance for suc­cessful completion of the therapy, which is a commonly recognized fact. This also concerned patients assessed in this analysis. The negative influence of a more advanced age on achieving the SVR can be explained by among other things alleged longer mean duration of HCV infection and the greater average number of health burdens among older people. This may be the reason for more advanced liver da­mage compared to the children's population.
HCV genotype is a commonly recognized, essential sin­gle prognostic factor concerning SVR. Its influence on the therapeutic success is explicitly determined, at least for the most commonly met genotypic variants of the vi­rus [8,10,11,15]. This paper confirms the significance of this parameter; patients infected with genotype 3 HCV had greater chances for achieving permanent disappearance of HCV-RNA than patients infected with genotype 1 despi­te the shorter period of treatment. The basis for variation of the virological response depending on the genotype of the virus was so far not determined.
Otherwise than it results from the current opinions abo­ut the significance of viremia before the treatment in de­termining the probability for achieving the sustained ne­gation of HCV-RNA in blood serum under the influence of antiviral therapy [2,16,19] the significant difference in achieving the mentioned aim was not found in groups of patients with low (defined as HCV-RNA to 400 000 IU/ml) or high (HCV-RNA >400 000 IU/ml) viremia. The reasons for such a juncture are not clear.
It is known that overweight and obesity contribute to the more rapid liver fibrosis progression in patients with chro­nic hepatitis C. It results from the registration trials of PEG-IFN-α drugs that the lower body mass beneficially influen­ces the chance for achieving SVR. There are also data about a similar BMI significance [3]. Based on the assessment of these two parameters in reference to our patients it should be recommended that the more credible variable in this popula­tion was the body mass index odds ratio (OR=3.43 vs. 2.15 for body mass), contrary to body mass as a feature which dif­ferentiates the chances for achieving therapeutic success in both groups of patients. So the BMI maintained its progno­stic value in the aspect of predicting the success of an anti­viral therapy also in the group of patients achieving EVR.
By judging the role of the initial values of such biochemi­cal parameters as the activity of ALT and AST as well as GGTP in prognosing the chances for achieving the SVR, divergent results were obtained. The significance of ami­notransferase in this range was not confirmed. But it was found that the normal activity of GGTP before the treat­ment occurred significantly more frequently in patients in whom the therapy was successful. These results are in ac­cordance with the data from the literature [3]. Based on our own observations a thesis can be proposed about underva­luing this simple and routine biochemical parameter in da­ily clinical practice. It is worth mentioning in this context that in the group of 155 patients, comprising all patients treated with the complete course of standard therapy and 27 persons in whom the treatment was interrupted due to the lack of EVR, the value of the (OR) for achieving the SVR with the activity of GGTP before implementation of PEG-IFN-α with RBV within the range of the reference band (vs. increased) conceded only OR for the genotype and was 5.85. The possibility of an influence of a regular alcohol intake on the value of this parameter in patients infected with HCV should be also considered.
The role of a low grade of advancement of hepatic fibrosis as a positive predictive indicator for achieving eradication of HCV infection can be confirmed by a statistically signi­ficant difference of frequency of SVR among patients with minimum increase of fibrosis (S1) compared with persons of a greater extent of this histological indicator of advance­ment in liver damage. This refers to those patients in whom the therapy was not interrupted due to other reasons than virological (n=155). Among patients without the EVR it was possible to identify 13.1% of persons from the group of minimum fibrosis in comparison with 27.9% from the group of patients with the extent of fibrosis within S2-4. This is explained by the lack of a significant difference in achieving the SVR depending on the discussed variable in patients who received the complete course of a standard treatment (n=128).
The percentage of patients who did not receive the comple­te (dependent on the HCV genotype) course of an antiviral treatment due to other reasons than virological was similar in this analysis to the values found in literature comprising big groups of studied patients with the chronic hepatitis C.
Conclusions
1. The combination standard treatment of chronic hepati­tis C leads to the sustained disappearance of viremia in two thirds of patients who completed therapy.
2. There is a correlation between the analyzed clinical, bio­chemical and virological parameters and the effective­ness of therapy.
3. The antiviral treatment of patients with chronic hepati­tis C should aim at individual determination of therapy conditions considering the changes in kinetics of vire­mia, and also aiming at comprising the treatment of the highest possible number of young people.
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The authors have no potential conflicts of interest to declare.