GAMMA GLUTAMYLTRANSFERASE IMPACT IN THERAPEUTIC RESPONSE OF CHRONIC HEPATITIS C: a systematic review of the literature

QUEIROGA, Maria de Lourdes Albuquerque de; PARANÁ, Raymundo; MEDEIROS FILHO, José Eymard Moraes de; FIGUEIREDO, Giovannini Cesar A; ARAÚJO, Ananda Peixoto de; LEITE, Hagley Walson Soares; AQUINO, Itiel de Souza; MELO NETO, Leonardo Honório de A

doi:10.1590/S0004-28032015000300016

Brasil

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Review • Arq. Gastroenterol. 52 (3) • Jul-Sep 2015 • https://doi.org/10.1590/S0004-28032015000300016 linkcopy

GAMMA GLUTAMYLTRANSFERASE IMPACT IN THERAPEUTIC RESPONSE OF CHRONIC HEPATITIS C: a systematic review of the literature

Impacto da gama glutamiltransferase na resposta terapêutica da hepatite C crônica: revisão sistemática da literatura

Authorship SCIMAGO INSTITUTIONS RANKINGS

Background The standard treatment of chronic hepatitis C is the administration of pegylated interferon α2a or α2b in combination with ribavirin, but adverse effects can be observed, as well as the high cost of this therapy. Therefore, there is interest in understanding the predictors of sustained virologic response, as the gamma glutamyltransferase.

Objective To evaluate the serum levels of gamma glutamyltransferase as a predictor of response to treatment with pegylated interferon α and ribavirin in chronic hepatitis C.

Methods This is a systematic review of literature, conducted by consulting PUBMED, LILACS, MEDLINE, SCOPUS, Cochrane electronic databases, and active search of articles selected between January 2000 and April 2013.

Results A total of 4,785 titles were iden tified. Out of those material, following inclusion and exclusion criteria, 273 abstracts were selected, by two independent researchers. After reading those texts, the reviewers consensually included ten studies for systematization and classification, according to the criteria of the Oxford Scale. 1B studies are predominant (prospective cohort study - six studies). Rapid virologic response and early virological response were considered as estimates for the sustained virological response. The frequency of virologic response was identified in three studies and early virological response in two, with a total of 392 and 413 patients, respectively; sustained virologic response was reported in nine articles corresponding to 3,787 patients (76.5 %).

Conclusion Gamma glutamyltransferase is a predictor of sustained virologic response in the treatment of chronic hepatitis C with pegylated interferon α2a or α2b associated with ribavirin.

Gamma glutamyltransferase; Hepatitis C; Sustained virological response; Review

Nº Authors	Country/Year	Journal	Database	Study type/Oxford scale	Nº of patients	Gender
Nº Authors	Country/Year	Journal	Database	Study type/Oxford scale	(n)	M/F
^E1 Weich et al.	Germany/2011	J. Gastroenterol	MEDLINE	Retrospective Cohort (2B B*)	632	341/291
^E2 Kurosaki et al.	Japan/2010	Hepatology Research	MEDLINE	Prospective Cohort (1B A*)	400	182/218
^E3 Mauss et al.	Germany/2011	J. Viral Hepatitis	MEDLINE	Retrospective Cohort (2B B*)	2,378	1,363/1,015
^E4 Berg et al.	Germany/2003	Hepatology	MEDLINE	Prospective Cohort (1B A*)	260	167/93
^E5 Kronenberger et al.	Germany/2004	Hepatology	PUBMED	Prospective Cohort (1B A*)	39	21/18
^E6 Kurosaki et al.	Japan/2011	J. Gastroenterol	MEDLINE	Retrospective Cohort (2B B*)	801	421/380
^E7 Çoban et al.	Turkey/2011	Hepato - Gastroenterology	MEDLINE	Retrospective Cohort (2B B*)	112	55/57
^E8 Durant-Mangoni et al.	Italy/2009	Clinical Infectious Diseases	MEDLINE	Prospective Cohort (1B A*)	119	66/53
^E9 Berg et al.	Germany/2006	Gastroenterology	ACTIVE SEARCH	Prospective Cohort (1B A*)	455	250/205
^E10 Wagner et al.	Germany/2005	Gastroenterology	ACTIVE SEARCH	Prospective Cohort (1B A*)	153	97/56

Nº	Genotype	Therapeutic response (%)
Nº	Genotype	EVR	RVR	ETR	SVR
^E1	G1-G2-G3	NI	NI	18.2%	58.7%
^E2	G1	60%	RVR/ETR	NI	NI
^E3	G1-G2-G3-G4	NI	NI	NI	57.9%
^E4	G1-G2-G3-G4-G6	NI	NI	14.6%	53.8%
^E5	G1-G2-G3	NI	NI	80%	59.0%
^E6	G1	NI	NI	NI	55.5%
^E7	SI	NI	NI	NI	57.2%
^E8	G1-G2-G3	NI	NI	NI	56.3%
^E9	G1	55%	18.5%	67%	53.5%
^E10	G2-G3	NI	NI	93%	82.5%

Authors (year)	Genotype	Protocol of treatment (PEG-IFN/RBV3)	Therapy response
^E1 - The determination of GGT is the most reliable predictor of non responsiveness to interferon-alpha based therapy in HCV type-1 infection
Weich et al. (2011)	G1 (n=561) G2/3 (n=71)	PEG IFN α2a 180 μg/week and α2b 1.5 μg/kg/week + RBV 800 at 1200 mg/day/24 to 48 weeks.	Predictive power of the GGT level to SVR - correlation with several isolated variables, age and virological load; association of the binary variables, age (≤40 vs >40 years), presence or absence of severe fibrosis or cirrhosis; association among GGT low levels and ALT high base levels. GGT < ULN: associated with best virologic response (SVR and EVR) at G1 (P<0.0001); predictive GGT regardless SVR: Multivariate logistic regression identified low GGT (P<0.0001), high ALT (P<0.0006), low viremia (P<0.0014), RVS independent predictors. This predictive factor may improve infection individualized theraphy; HCV G1; SVR n=371; 58.7%; ETR n= 115; 18.2%; NR n=146; 23.1%.
^E2 - A predictive model of response to peginterferon Ribavirin in chronic hepatitis C using classification and regression tree analysis
Kurosaki et al. (2010)	G1 (n=400)	PEG-IFN α2b 1.5 μg/kg/week + RBV 60 mg <60 Kg; 800 mg 60-80 Kg; 1000 mg >80 Kg/day/24 toa 48 weeks CART; The Classification and Regression Tree used to evaluate baseline predictors of response to treatment PEG-IFN/RBV among the clinic, biochemical, virologic and histological to define the pre treatment algorithm and discriminate patients who are likely responders. Model n=269; Validation n=131	Low GGT-RVR/EVR predictor. Performed univariate logistic regression analysis (P<0.004) and multivariate logistic regression (P<0.005) showed significance for GGT <40 vs ≥40; low GGT predictor of the likelihood of RVR/RVPc (60% vs 35%), with 46% ratio for RVR/EVR. Estimates for SVR.
^E3 - Estimating the likelihood of sustained virological response in chronic hepatitis C therapy
Mauss et al. (2011)	G1 G2 G3 G4 (n=2,378)	PEG-IFN α2a ande α2b Associated with RBV PRACTICE: Pegylated interferon and Ribavirin: analysis of chronic hepatitis C treatment in centres of excellence.	GGT normal vs >ULN (>66 U/L/Male; >35U/L/female). GGT normal (n=1094; 62%) significantly higher SVR compared GGT>ULN (n=822; 41.2%) in univariate logistic regression (P<0.001). SVR significantly associated with GGT. In univariate analysis n=1377 (57.9%) achieved an SVR (P<0.001). Review of G1 / 4 (n=1496) SVR rate 46.5%; G2 / 3 (n=882) rate was 77.3% (P<0.001). GGT>ULN, age >40 years - negative predictors of SVR in multivariate analysis. Positive predictors SVR - multivariate analysis G2, G3 and low viral load; PEG-IFN α2a treatment is a positive predictor of SVR compared with PEG-IFN α2b.
^E4 - Prediction of treatment outcome in patients with chronic hepatitis C: significance of baseline parameters and viral dynamics during therapy
Berg et al. (2003)	G1 G2 G3 G4 G6 (n=260)	PEG-IFN α2a 180 μg/week and α2b 1.0-1.5 μg/kg/week + RBV 800 toa 1200 mg/day/24 to 48 weeks. IFN α2a and α2b; PEG-IFN α2a.	Low levels of GGT significantly associated with SVR by univariate analysis (P<0.0001). For multivariate analysis G2 n=21; 8.1% and G3 n=58, 22.2% (P<0.0001), low levels of GGT (P<0.0001) and levels of ALT (P=0.0002), were considered independent predictors of SVR. SVR n=140/260, 53.8% ETR n=38; NR 14.6% n=82, 31.5%.
^E5 - Viral kinetics during antiviral therapy in patients with chronic hepatitis C and persistently normal ALT levels
Kronenberger et al. (2004)	G1 G2 G3 (n=39)	PEG-IFN α2a 180 μg/1x/week + RBV 800-1200 mg/24 to 48 weeks	Normal GGT levels: associated with greater loss of infected cells before treatment (P=0.005). GGT high: association with reduced efficacy of blocking virus production and less loss of the infected cell. ULN/GGT: 52UI/L/masc; 33UI/L/fem. Normal basal levels of GGT greater loss of infected cells during treatment compared with baseline levels of GGT levels (P=0.02). GGT levels were significantly lower in SVR compared to NR 24 weeks after completion of therapy (P=0.002)
^E6 - Pretreatment prediction of response to peginterferon plus Ribavirin therapy in genotype 1 chronic hepatitis C using data mining analysis
Kurosaki et al. (2011)	G1 (n=800)	PEG-IFN α2b 1.5 μg/kg/SC/week/RBV 600 mg-60 kg, 800 mg 60-80 kg, 1000 mg >80kg/day/24 to 48 weeks. Decision tree model: n=506; Validation n=294. Developed to predict RVS at PEG-IFN and RBV.	By multivariate analysis GGT is associated with SVR P=0.005. Factors associated with SVR, GGT <40IU/L associated with SVR. GGT independently associated with SVR. Pac. with low levels of GGT higher probability of SVR (57% vs 34%) SVR rate ranging from 22% to 77%.
^E7 - Gamma-glutamyltranspeptidase in predicting sustained virological response in individuals with chronic hepatitis C
Çoban et al. (2011)	SI (n=112)	PEG-IFN α2b 1.5 μg/kg/week RBV 800 to 1200 mg/day, (<65 kg, 800 mg/day; 65-85 kg, 1000 mg/day; >85 kg 1200 mg/day). During 12 months.	Low levels of GGT before treatment: associated with high rates of SVR Normal GGT predictor of SVR. SVR: n=64/112; 57.2% (combination therapy). Factors associated with SVR: lower in patients with elevated GGT levels than in those with normal GGT (44.8% vs 70.4%). SVR>GGT Normal Group (n=38/54, 70.4%) than in Group GGT>50IU/mL (n=26/58, 44.8%) P=0.0098 and GGT>100 (n=9/26, 34.6%) P=0.0018 - Analysis of multivariate regression.
^E8 - Correlates and prognostic value of the first-phase hepatitis C virus RNA kinetics during treatment
Durant-Mangoni et al. (2009)	G1n=61 G2n=44 G3n=14 (n=119)	PEG-IFN α2a 180 μg/week or PEG-IFN alfa-2b 1.5 μg/kg/week. Combined RBV 800 mg/day (400 mg twice /day) for G2 or G3; 1000 or 1200 mg/day for G1<75 ou ≥75 kg, respectively. G1 48 week. and G2/G3 24 weeks	GGT levels (P<0.001) and RVR (P<0.001) are among the factors significantly associated with SVR by univariate analysis. GGT: an independent predictor of SVR in the first phase of viral response through multivariate regression analysis SVR: n=67/119; 56.3% NR: n=29/119; Relapse 24.4%: n=23; 19.3%.
^E9 - Extended tratment duration for hepatitis C virus type 1: comparing 48 versus 72 weeks of peginterferon - alfa -2a plus Ribavirin
Berg et al. (2006)	G1 (n=455)	PEG-IFN α2a 180 μg/1x/week+RBV 800 mg VO/day Group A (n=230): 48 week; Group B (n=225): 72 weeks.	Groups A and B: GGT levels identified as independent predictors through multivariate regression analysis (P<0.001) and associates through univariate regression analysis (P<0.001) with SVR. ETF and SVR in group A and group B were 71% vs 63% and 53% vs 54% respectively, without significant difference. Extend the duration of treatment is not recommended in HCV G1 infection and should be reserved only for patients with slow virologic response, defined as HCV-RNA positive at week 12 but negative at week 24.
^E10 - Peginterferon-alfa-2a (40KD) and Ribavirin for 16 or 24 Weeks in patients with genotype 2 or 3 chronic hepatitis C
Wagner et al. (2005)	G2 (n=39; 26%) G3 (n=113; 74%) G2/3 (n=1; <1%) (n=153)	PEG-IFN α2a 180 μg/1x/week / SC + RBV 800-1200 mg/day/VO. RBV: (≤65 kg: 800mg; 65-85 kg: 1000mg; >85 kg: 1200 mg).	RVR (HCV RNA <600IU/mL at week 4): Group A: n=71; 16 weeks; ETR: 94%; SVR: 82%. Group B: n=71; 24 weeks; ETR: 85%; SVR: 80%. HCV RNA ≥600 IU/mL at week 4: Group C: n=11/153; 7%; 24% weeks; ETR: 73%; SVR: 36%. Low GGT level: independent predictor of SVR by multivariate regression analysis. G2/G3 (low viral load): RVR - Treatment / 16 weeks; G3 (high viral load): Treatment. longer may be required.

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