Jiménez-Luévano MA, et al., 2013; 12 (2):

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1 248 Jiménez-Luévno MA, et l., 2013; 12 (2): ORIGINAL ARTICLE Mrch-April, Vol. 12 No.2, 2013: Addition of pentoxifylline to pegylted interferon-lph-2 nd ribvirin improves sustined virologicl response to chronic heptitis C virus: rndomized clinicl tril Miguel Ángel Jiménez-Luévno,* José Mnuel Lerm-Díz,**, *** Georgin Hernández-Flores,** Miguel Ángel Jiménez-Prtid,**** Alejndro Brvo-Cuellr**, *** * Servicio de Gstroenterologí, Hospitl Vlentín Gómez Frís, Instituto de Seguridd y Seguro Socil de los Trbjdores del Estdo (ISSSTE), Zpopn, Jlisco, México. ** División de Inmunologí, Centro de Investigción Biomédic de Occidente (CIBO), Instituto Mexicno del Seguro Socil (IMSS), Gudljr, Jlisco, México. *** Centro Universitrio de los Altos (CUALTOS), Universidd de Gudljr (UdeG), Teptitlán de Morelos, Jlisco, México. **** Centro Universitrio Ciencis de l Slud (CUCS), UdeG, Jlisco, México. ABSTRACT Bckground nd im. The commonly ccepted tretment for heptitis C virus (HCV) infection, pegylted interferon lph (PEG INF-lph) nd ribvirin, leds to 50-60% of sustined virologicl response (SVR). On the other hnd, pentoxifylline (PTX) possesses ntivirl nd heptoprotector properties. Aim. To investigte whether the ddition of PTX to conventionl heptitis C tretment increses SVR. Mteril nd methods. Seventy two ptients of both genders were studied in rndomized fshion; the dignosis of chronic HCV infection ws mde ccording to clinicl nd lbortory criteri nd histopthologiclly clssified ccording to METAVIR scoring system criteri. HCV virl lod ws tested by PCR, bseline, nd fter 6 months of tretment, s well s nti-hcv, nti-heptitis B virus, nd nti-humn immunodeficiency virus ntibodies by enzyme-linked immunosorbent ssy. During 48 weeks, control group ptients were treted with PEG INFlph-2 plus ribvirin. PTX ws dministered to Experimentl Group ptients prior to the tretment. Results. Demogrphic dt were similr in both groups. Experimentl- nd control-group subjects were t F2 nd F3 sttes ccording to the METAVIR clssifiction. The most common HCV genotypes were 1 nd 1b (39% in the control group in ech cse, nd 42% in the experimentl group in ech cse). At the end of the study, heptic enzymes nd virl lod decresed in both groups to similr vlues. SVR in the experimentl group incresed significntly (p < 0.05) when compred with stndrd therpy lone. Conclusion. Addition of PTX to conventionl chronic heptitis C tretment my increse the percentge of ptients with SVR. Key words. Chronic heptitis C virus. Pentoxifylline. Pegylted interferon-lph-2. Ribvirin. Sustined virologicl response. INTRODUCTION Chronic heptitis C virus (HCV) infection is public helth problem worldwide. According to World Helth Orgniztion (WHO) dt, 3% of the world popultion (pproximtely 170 million persons) is infected with HCV. 1,2 The prevlence of Correspondence nd reprint request: Dr. Alejndro Brvo-Cuellr Centro de Investigción Biomédic de Occidente, IMSS Sierr Mojd 800, Col. Independenci, Gudljr, Jlisco, México. Ph.: (+52) (33) Fx: (+52) (33) E-mil: brvocster@gmil.com Mnuscript received: June 17, Mnuscript ccepted: September 14, HCV genotypes reported in Mexico is similr in the different regions of the country. The most frequent HCV genotype is 1 (73%) with the following distribution: 1 (28.6%); 1b (37.4%), nd 1/1b (4.1%). The minly risk fctor in Mexico continues to be blood trnsfusion. 3 At present, in 1 nd 1b virl HCV genotypes, PEG INF-lph 2 or 2b ssocited with ribvirin is considered the most effective stndrd therpy for chronic heptitis C, obtining SVR rtes between 54 nd 63%. 4,5 The mechnisms responsible for the progression of liver disese to severe liver injury remin poorly understood. However, there re reports suggesting tht oxidtive stress (OS) contributes to stetoheptitis nd tht incresed genertion of rective oxygen species (ROS) promotes the development of the heptic nd

2 Addition of pentoxifylline to pegylted interferon-lph-2., 2013; 12 (2): extrheptic complictions of HCV infection. 6 It hs lso been reported tht Tumor necrosis fctor-lph (TNF-lph) is required for grnulom formtion nd is one of the most importnt cytokines involved in liver injury. These dt suggest tht TNF-lph inhibitors my represent new therpeutic strtegy to tret immune-medited inflmmtory liver diseses. 7 The methylxnthine drug pentoxifylline (PTX) hs shown ntioxidnt properties nd is considered to be potent inhibitor of nucler trnscription fctor-kpp B (NF-κB), 8 which is key regultor of genes relted to the immune response including regultion of proinflmmtory cytokines such s TNF-lph. Moreover, PTX my reverse humn immunodeficiency virus-relted endothelil dysfunction by directly inhibiting the endothelil leukocyte dhesion pthwy 9 nd in combintion with vitmin E cn meliorte ribvirin-ssocited hemolysis. 10 PTX hs been proven experimentlly to inhibit HIV- 1 repliction. PTX is lso ble to protect liver nd kidney from the side effects of chemotherpy nd rdiotherpy. 11 The effectiveness of the ddition of PTX to conventionl tretment with PEG INF-lph-2 nd ribvirin ws tested in prospective controlled blind rndomized ssigned prllel-group pilot study in ptients with HCV chronic infection. MATERIAL AND METHODS Study universe Of 136 ptients, we studied 72 ptients from the Vlentín Gómez Frís Stte Workers Sfety nd Socil Security Institution (ISSSTE) Hospitl in Gudljr, Jlisco Stte, Mexico, from Jnury 2009 through September These ptients were selected rndomly by men of rndom numbers tble. 12 Forty eight were not included due to other virl genotypes nd 16 were eliminted due to brech-of-tretment (Figure 1). Inclusion criteri Ptients included in the study hd chronic heptitis C virus (HCV) infection dignosed ccording to clinicl nd lbortory criteri 13 (with genotypes 1, 1b, nd mixed 1/1b), of both genders, between 18 nd 70 yers of ge, nd with dignosis of HCV confirmed by heptic enzymes, by determintion of nti-hcv ntibodies, virl lod 600 Interntionl units (IU)/mL, nd histologicl studies ccording to the METAVIR clssifiction. Non-inclusion criteri We did not include pregnnt or nursing women, ptients with degenertive chronic or hemtologicl disese, decompensted heptopthy, nd ptients with terminl-phse ischemic disese. Exclusion criteri Ptients excluded from the study were those with tretment intolernce, severe heptic decompenstion, pltelets < 50,000/mL, nd ptients who did not comply with 80% of the tretment. Ptients with HCV n = 136 Genotypes 1, 1b or 1/1b Other genotypes n = 88 n = 48 Group1 (n = 36) Group 2 (n = 36) Left the study 1 (n = 14) 1 (n = 15) n = 16 1b (n = 14) 1b (n = 15) 1/1b (n = 8) 1/1b (n = 6) Responders Non-responders Responders Non-responders Not dhering to Non-responders 22/61.1% 14/38.8% 31/86.1% 5/13.8% tretment (week 12) Group 1, n = 8 Group 1, n = 4 Group 2, n = 3 Group 2, n = 1 Figure 1. Chrcteristics of ptients with heptitis virus C (HVC).

3 250 Jiménez-Luévno MA, et l., 2013; 12 (2): Heptic enzymes Alnine minotrnsferse (ALT) nd sprtte minotrnsferse (AST) were determined in the serum of ptients by the spectrophotometriclly enzymtic utomtized Beckmn Coulter Synchron method 14 employing kits nd , respectively. Determintion of nti-hcv, nti-heptitis B virus, nd nti-hiv ntibodies HCV ws determined utilizing the nti-hcv kit (Abbott 6C37), which detects HCV HCr43, nd c100-3 ntigens. Anti-heptitis B virus (HBV) ntibodies were detected with the HBsAg kit (Abbott 6C36), while HIV ws detected with the HIV Ag/Ab Combo Kit, which detects HIV-1/HIV-2 ntibodies nd the HIV p24 ntigen (Abbott /R4). The detection system ws bsed on chemiluminescent microprticle two-step immunossy employing the ARCHITECT system (Abbott) ccording to the mnufcturer s instructions. Virl lod Heptitis C virl lod ws mesured by polymerse chin rection (PCR) (Cobs Amplicor HCV Monitor v2.0; Roche Dignostics, Somerville, NJ, USA) following the mnufcturer s instructions. Briefly, 100 µl of serum ws subjected to chotropic lysis in the presence of known mounts of n internl Quntittion stndrd (QS). The QS comprises synthetic RNA trnscript with primer binding regions identicl to those of the HCV trget sequence, rndomized internl sequence similr in length nd bse composition to the HCV trget sequence, nd unique probe-binding region tht differentites QS from the trget mplicon. After isopropnol precipittion nd n ethnol wsh, trget virl RNA nd QS were resuspended in Specimen Diluent (Roche) nd this mixture ws mixed with n equl volume of the mplifiction-redy solution (Mster Mix; Roche) contining primers KY78 (biotinylted) nd KY80 (non-biotinylted), deoxynucleoside triphosphtes, AmpErse, nd rtth DNA polymerse. Amplifiction, mplicon dilution, detection, nd quntittion were utomticlly performed by the COBAS AMPLICOR nlyzer. 15 Histology The ptients hd n heptic biopsy by ultrsound or lproscopy with Tru-Cut needles. The biopsy slices were stined with hemtoxylin nd eosin nd observed under light microscopy. Degree of fibrosis nd histologic ctivity were scored ccording to the METAVIR clssifiction. Protocol Non previously treted ptients were divided into two groups of 36 ptients ech. Control group (group 1) ptients were treted with PEG INFlph-2 (180 µg/week, subcutneous [s.c.]; Roche Lbortories), plus ribvirin (Virzide Grossmn Lbortories) with weight-dependnt doses (800-1,200 mg per dy, dministered in two or three doses per os (p.o.). In the experimentl group (group 2), pentoxifylline (PTX) (Tentrl Aventis Phrm Lbortories) ws dded t dose of 400 mg/12 h p.o. to the previously described schedule of PEG INF-lph-2 plus ribvirin. Both groups were treted during 48 weeks. If ptient did not respond to tretment within week period, he/she ws excluded from the study. All tests were crried out t the beginning of tretment nd 6 months lter t the end of tretment. Sustined virologicl response This is defined s the bsence of detectble HVC 24 weeks fter the end of the tretment. Sttisticl nlysis Results represent the men ± stndrd error (SE) between groups; the Mnn-Whitney U test ws utilized for quntittive vribles nd the χ 2 test, for qulittive vribles; p 0.05 ws considered significnt. In some cses, Δ%, which represents the percentge of increse or decrese reltive to the vlue found t the beginning of the study, ws clculted s follows: First determintion x 100 Δ% = -100 Lst determintion Ethicl considertions The protocol ws uthorized by the Institutionl Scientific nd Ethics Committees nd registered with the number ISSSTE/CEI/019/08. All procedures were those strictly used in the mngement of this pthology nd ll ptients signed n informed consent form.

4 Addition of pentoxifylline to pegylted interferon-lph-2., 2013; 12 (2): Tble 1. Generl chrcteristics of ptients with heptitis virus C (HVC). Group Age (yers) Gender (n / %) Mode of infection Virl genotype Histology Virl lod (IU/mL) Tretment response Rnge / X ± SD Femle/Mle (n / %) (n / %) (METAVIR) X ± SD (n / %) (n / %) All cses / 28 / 78.0 Blood trnsfusion 1 14 / 39 F1A1 1 / 30 (B) 492,000 ± Responders (n = 36) 52.1 ± / / 72.2 (ETR) 97,002 ± 4, / 61.1 Drug buse 1b 14 / 39 F2A2 1 / 30 Responder No responders 5 / 13.8 (B) 208,000 ± 27, / 38.8 (ETR) 600 Others 1/1b 8 / 22 F3A3 14 / 40 Non responder 5 / 13.8 (B) 284,000 ± 31,016 (ETR) 354,000 ± 42,372 All cses / 29 / 80.5 Blood trnsfusion 1 15 / 42 F1A1 7 / 20 (B) 519,000 ± 10,381 Responders (n = 36) 48.2 ± / / 80.5 (ETR) 49,000 ± 4, / 86.1 Drug buse 1b 15 / 42 F2A2 18 / 50 Responder No responders 3 / 8.3 (B) 167,000 ± 16,440 5 / 13.8 (ETR) 600 Others 1/1b 6 / 16 F3A3 11 / 30 Non responder 4 / 11.3 (B) 354,000 ± 42,372 (ETR) 389,000 ± 49,830 P vlue NS NS NS NS NS (B) vs. (ETR) p = χ 2 = P < 0.01 All cses (ETR) group 1 vs. group 2 p < 0.05 IU: interntionl units. SD: stndrd devition. SE: stndrd error. vs: versus. B: Bseline. ETR: end of tretment response. NS: not significnt. METAVIR clssifiction, F1: portl fibrosis; F2: few sept; F3: numerous sept; F4: cirrhosis. A0: without histologicl ctivity; A1: minimum ctivity; A2: moderte ctivity; A3: severe. Group 1: pegylted interferon (PEG INF)-lph-2 [180 μg/week, subcutneously (s.c.) plus ribvirin (800 mg t 1,200 mg/kg/dy, divided into two or three doses, per os [p.o.])]. Group 2 = pentoxifylline (PTX) (400 mg/12 h, p.o.) plus PEG INF lph-2 plus ribvirin.

5 252 Jiménez-Luévno MA, et l., 2013; 12 (2): RESULTS Control group 1, treted with PEG INF-lph-2 plus ribvirin, ws composed of 28 femles (78%) nd eight mles (22%) (men ge, 52.1 ± 8.2 yers; rnge, yers), while experimentl group 2, treted with PTX plus PEG INF-lph-2, ws composed of 29 femles (80.5%) nd seven mles (19.5%) (men ge, of 48.2 ± 12.5 yers; rnge, yers). There were no sttisticl differences in demogrphic dt (Tble 1). Histologicl study Seventy percent of control group 1 ptients were clssified in sttes F2 nd F3 ccording to the METAVIR clssifiction, while 80% of experimentl group 2 ptients were clssified in these sme sttes (Tble 1). Lesions were evident in both groups. Virl genotype Virl genotypes (Tble 1) were similr in both groups. Control group 1 hd 14 cses with genotype 1 nd 14 cses with genotype 1b (39% in ech cse). Experimentl group 2 hd 15 cses of genotype 1 nd 15 cses of genotype 1b (42% in ech cse). Finlly, there were eight cses in control group 1 nd six cses in experimentl group 2 of 1/1b genotype (22 nd 16%, respectively). Heptic enzymes The heptic enzymes studied were the following: lnine minotrnsferse (ALT) nd sprtte minotrnsferse (AST), nd these were determined before nd fter tretment. At the beginning of tretment, control group 1 hd men ALT level of 76.7 ± 7.1 Interntionl units (IU)/L, nd 6 months lter t the end of the tretment, this vlue down to 42.4 ± 5.4 IU/L (p < 0.001). Experimentl group 2 hd serum level vlues of 67.8 ± 7.3 IU/L, nd 6 months lter t the end of the tretment, 37.3 ± 3.5 IU/L (p < 0.01). There ws no difference between both groups either t the beginning or t the end of tretment. The whole popultion ws lso divides between no responder nd responder ptients to the tretment. At the beginning of tretment the ALT level of no responder ptients to the tretment ws 54.1 ± 7.3 IU/L nd for responder ptients ws 28.1 ± 8.5 IU/L, Δ% = 48.0 nd t the end of tretment the vlues diminished in no responder subpopultion to 36.3 ± 12.4 IU/L nd for responder subgroup the ALT concentrtion ws not modified 23.5 ± 2.4 IU/L. In contrst in experimentl group for the first ALT vlues similr vlues were observed in no responder nd responder ptients (31.6 ± 2.9 IU/L nd 26.8 ± 2.3 IU, nd t the end of study the vlues for both subpopultions prcticlly were not modified (32.5 ± 3.1 IU/L nd 37.3 ± 3.6 IU/L repectively). For the AST enzyme t the beginning of tretment, control group 1 hd serum level of 69.4 ± 5.3 IU/L, nd t the end of the study 29.9 ± 3.6 IU/L (p < 0.01). At the beginning of the tretment, experimentl group shown AST serum vlues of 67.2 ± 6.3 IU/L, which decreses t the end of tretment 32.5 ± 3.1 IU/L (p < 0.01). The vlues of AST ccording to no responder nd responder ptients to the tretment. In reltion to control group t the beginning of study similr AST levels were found between no responder 30.8 ± 1.7 IU/L nd responder ptients 31.6 ± 2.3 IU/L, for the lst determintion tendency to increment ws observed in no responder ptients 51.6 ± 6.4 IU/L nd in responder group prcticlly the AST level ws not modified 26.9 ± 3.3 IU/L. In the cses of experimentl group t the beginning of the study the AST level for no responder group ws slightly higher 62.4 ± 7.3 IU/L nd in responder subpopultion 41.5 ± 5.4 IU/L, in contrst t the end of the tretment we did not observe differences in both subpopultions group 1: 43.6 ± 5.4 IU/L nd group 2: 47.7 ± 5.5 IU/L. Virl lod Virl lod is one of the most importnt lbortory tests for monitoring HCV. Vlues t the beginning nd the end of the ssy 6 months fter the tretment re reported in tble 1. Initil virl lod counts were comprble: control group 1 viremi ws 492,000 ± 26,721 IU/mL, nd tht of experimentl group 2 519,001 ± 10,381 IU/mL (p < 0.05). At the end of the ssy, control group 1 viremi ws 97,002 ± 4,792 IU/mL nd experimentl group 2 viremi ws 49,000 ± 4,244 IU/mL, vlues significntly different from their respective bseline vlues (p = 0.006), Δ% ws clculted; the decrese in virl lod between bseline nd finl vlues ws Δ%= -407 for control group 1 nd Δ% = -1,028 for experimentl group 2, n indiction of better behvior of the group of ptients who received PTX. In reltion to tretment of responders ptients from groups 1 nd 2 showed virl lod of 208,000 ± 27,966 IU/mL nd 167,000 ± 16,440 IU/mL, respectively, nd for both groups t the end of the study, the virl lod ws 600 IU/mL. In contrst, virl

6 Addition of pentoxifylline to pegylted interferon-lph-2., 2013; 12 (2): lod vlues for no responder ptients of control group 1 were 284,000 ± 31,016 IU/mL t the beginning nd these were prcticlly ws not modified t the end of the study, 354,000 ± 42,372 IU/mL. In reltion to no responder ptients from group 2, virl lod vlues were 352,000 ± 41,525 IU/mL t the beginning nd t the end of the study, 389,000 ± 49,830 IU/mL. Sustined virologicl response Sustined virologicl response (SVR) in chronic heptitis C is considered the gold stndrd for ssessment of tretment response. SVR is obtined when viremi is mintined t vlue < 600 IU/ ml t 24 weeks fter the end of tretment. In control group 1, 22 of 36 ptients (61%) chieved SVR vs. 31 of 36 ptients (86%) in experimentl group 2. χ 2 test nlysis (p < 0.01) between the two groups (Figure 2). SVR (%) P < Groups Figure 2. Six months fter tretment percentge of sustined virologicl response (SVR) in ptiens with chronic heptitis C. Group 1: PEG-INF-lph 2 (180 µg/week, s.c.) plus ribvirin (800 t 1,200 mg kg/dy, divided in 2 or 3 doses, p.o.). Group 2: pentoxifylline (400 mg/12 h p.o.) plus PEG- INF-lph 2 plus ribvirin. N = 36 ptients/group. Tretments during 48 weeks. χ 2, group 1 vs. group 2 P < Side effects Experimentl group 2 presented the sme side effects s control group 1, lthough the following were present more frequently: nuse; vomiting; dyspepsi; norexi, nd nemi. However, in every cse, the ptients did not stop tretment nd their side effects were esily controlled (Tble 2). DISCUSSION In this study, when PTX ws dded to the conventionl PEG INF-lph-2 plus ribvirin tretment of chronic heptitis C virus, higher percentge of SVR ws obtined. Both groups hd similr demogrphic nd histopthologic chrcteristics nd ptients were infected with the sme virus types, with predominnce of genotypes 1 nd 1b. Tble 2. Side effects of ptients treted with either pegylted Interferon (PEG INF)-lph-2 plus ribvirin (control group 1) or pentoxifylline (PTX) plus PEG INF-lph-2 plus ribvirin (experimentl group 2). Group 1 Group 2 Symptoms (n/%) (n/%) P vlue Flu 5/14 4/11 NS Astheni 24/67 22/61 NS Mylgi 16/44 20/55 NS Fever 16/44 16/44 NS Nuse 5/14 24/66 < Vomiting 1/3 5/14 < Dyspepsi 2/5 15/41 < Anorexi 2/5 7/19 < Anemi 8/22 16/44 < Weight loss 10/28 1/39 NS Thrombocytopeni 3/8 2/4 NS Hypothyroidism 1/3 - NS Depression 4/11 3/8 NS Sleep ltertions 2/5 4/11 NS During 48 weeks, control group 1 (n = 36) ws treted with pegylted interferon (PEG INF)-lph-2 (180 μg/week, subcutneously [s.c.]) plus ribvirin (800-1,200 mg/kg/dy) nd experimentl group 2, pentoxifylline (PTX) (400 mg/12 h, per os (p.o.) plus PEG INF-lph-2 (180 μg /week, s.c.) plus ribvirin (800-1,200 mg/kg/dy, p.o.). The dt were nlyzed by chi-squre test. NS: not significnt.

7 254 Jiménez-Luévno MA, et l., 2013; 12 (2): ALT nd AST serum levels decresed fter the conventionl nd the experimentl tretments. Becuse the experimentl tretment introduced n dditionl drug, greter toxicity ws expected; however, heptic enzyme vlues were identicl, very likely due to the fct tht PTX possesses heptoprotector effects 11,16,17 nd exhibits nti-inflmmtory nd ntioxidnt properties; in irrdited nimls, PTX rised glutthione peroxidse levels, preserving the smll intestine mucos nd decresing cid mlondildehyde, prostglndin E2 (PGE2), nd thromboxne B2, s did the ssocited PTX tretment, with n importnt diminution in Nucler fctor-kpp B (NF-κB) nd TNF-lph expression. 17 Trcing chnges in virl lod provides the clerest ide of how quickly the infection is progressing. Both tretment schedules were effective in reducing the virl lod, this more intensively in the experimentl group. However, Δ% clcultions clerly showed tht the decrese ws more importnt in experimentl group 2 becuse Δ% ws then 2.5 times lower thn control group 1 vlues. PTX does not impir the ctivity of PEG IFN-lph-2 nd ribvirin. Our results clerly indicte tht the ddition of PTX to conventionl tretment with PEG INFlph-2 plus Ribvirin increses SVR by 26% in ptients when compred with the conventionl tretment (p < 0.01), ssuming tht this difference ws due to PTX. In greement with our results, PTX hs lso been used with encourging results in non-lcoholic stetoheptitis, lcoholic heptitis, nd hepto-renl syndrome. 18,19 On the other hnd, every tretment exhibits side effects. In this regrd, it is importnt to consider the following two points: the first is tht with the experimentl tretment, certin side effects, such s nuse, vomiting, dyspepsi, norexi, nd nemi, were observed more frequently thn in ptients with the conventionl tretment schedule with PEG INFlph-2 plus ribvirin. However, these sideeffects were esily controlled nd tretment ws not discontinued in ny group. Thus, it is possible tht when the drugs re combined, some properties my be mintined while others my pper. With these results, it is possible to stte tht the ddition of PTX is sfe. Recently, we published encourging results utilizing PTX in the tretment of fulminting C heptitis. 20 It is lso note worthy tht other experimentl protocols, such s those conducted with protese inhibitors (Telprevir), reched 70% of SVR, but its side effects re considerble, suchs virl resistnce nd llergic rections in 51% of ptients in whom 5% were of severe nture, contrry to PTX, which is described s nephroprotector. 21 Study of the PTX ction mechnism lies outside of the scope of the present work; however, it is possible tht our observtions my be due to the ntioxidnt, ntivirl, nd nti-inflmmtory properties described for this methylxnthine. Finlly, it is importnt to stress tht the n of the ptients ws not extensive nd tht this work ws not blinded. However, despite these fcts, we think tht these did not ply n importnt role in our observtions becuse despite the n of cses between both groups, we re ble to observe, clerly nd without mbiguity, sttisticl differences relted with SVR. The second reson is due to tht determintion of SVR is bsed on lbortory results, minimizing the reserch effect. In conclusion, the tretment schedule of HCV with PTX plus PEG INF-lph-2 plus ribvirin incresed the number of ptients with SVR by 26% vs. the response observed with conventionl tretment with PEG INF-lph-2 plus ribvirin. However, despite the encourging results described in previous publictions, 20 it is necessry to confirm these observtions with other d hoc protocols. ABBREVIATIONS HCV: heptitis C virus. HBV: heptitis B virus. PEG INF-lph: pegylted interferon-lph. SVR: sustined virologicl response. PTX: pentoxifylline. ALT: lnine minotrnsferse. AST: sprtte minotrnsferse. IU: interntionl units. TNF-lph: tumor necrosis fctor-lph. SD: stndrd devition. SE: stndrd error. ACKNOWLEDGMENTS We re indebted to Din Mldondo-Sánchez, B.Sc., for proof reding the mnuscript. We lso thnk our technicins Letici Rmos-Zvl, Mrí de Jesús Delgdo-Ávil, nd Mrlin Coron-Pdill. REFERENCES 1. Lvnchy D. Chronic virl heptitis s public helth issue in the world. Best Prct Res Clin Gstroenterol 2008; 22: Czepiel J, Biesid G, Mch T. Virl heptitis C. Pol Arch Med Wewn 2008; 118:

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