Antiretroviral therapy and liver fibrosis in HIV-infected patients with chronic hepatitis C

CORRESPONDENCE

Grading Alcoholic Hepatitis

To the Editor:

The paper by Dunn et al. sought to establish the Model for End-Stage Liver Disease (MELD) as an accurate predictor of mortality inalcoholic hepatitis.1 However, this study has retrospectively assessed aheterogeneous population. Of the 73 patients studied, a large propor-tion (21.9%) had gastrointestinal bleeding. The prognosis of patientswith a clinical diagnosis of alcoholic hepatitis with gastrointestinalbleeding is not necessarily the same as that of those without bleeding.The patients with gastrointestinal bleeding will also benefit fromMELD’s predictive potential, because MELD was conceived to assessprognosis in variceal hemorrhage.2 Dunn et al. have also included 11patients with either chronic viral hepatitis or possible acetaminophentoxicity, and also 12 patients who had received either corticosteroids oretanercept. It is difficult to draw conclusions regarding a prognosticscore when patients with co-existent diseases and patients given dis-ease-modifying drugs are studied. Despite having the advantage ofusing patients with gastrointestinal bleeding, the MELD score wasonly equivalent to the modified discriminant function (mDF). This issimilar to another study of 34 patients with alcoholic hepatitis.3 An-other analysis of 98 patients determined that MELD was equivalent tothe Child-Turcotte-Pugh score, but no comparison with the mDF wasmade.4

In our study of prognostic factors in alcoholic hepatitis we analyzed241 patients and have described the Glasgow Alcoholic Hepatitis Score(GAHS) (Table 1). This has been validated in an additional 195 pa-tients.5 No patient had co-existent liver disease. None had receivedcorticosteroids, pentoxifylline, or anti–tumor necrosis factor (TNF)treatment. GAHS was significantly more accurate than the mDF inpatients with either a clinical diagnosis or histological confirmation ofalcoholic hepatitis. GAHS appears to be accurate regardless of whetherthe International Normalized Ratio (INR) or the prothrombin timeratio is used, and it is easy to calculate without a handheld computer orwebsite calculator. In contrast to MELD, GAHS does not use serumcreatinine, as some laboratories still use the Jaffe reaction for this mea-surement, which will underestimate serum creatinine in the context ofhyperbilirubinaemia.

Another difficulty with the MELD assessment of alcoholic hepati-tis is in finding the optimal cut point. Dunn et al. identify two cutpoints: 22 for 30-day mortality and 21 for 90-day mortality. Sheth etal. identified the optimal cut point to be 11. In our validation study weassessed the MELD in 46 patients for whom the optimal cut point was15. GAHS has a constant cut point of 9 for scores calculated on day 1or on day 7 for both 28- and 84-day mortality. Using this cut point,GAHS appears to identify those patients who may benefit from corti-costeroid treatment.6

In conclusion, we agree with Dunn et al. that the identification ofsubsets of patients with significant disease is vital for the management

of alcoholic hepatitis. The published studies of MELD in alcoholichepatitis all have demonstrated that MELD is not superior to mDF.GAHS is more accurate than mDF and is an easy-to-calculate scoringsystem that can guide treatment decisions.

EWAN FORREST1

SAKET SINGHAL2

GEOFFREY HAYDON3

CHRISTOPHER DAY4

NEIL FISHER5

ALISON BRIND6

PETER HAYES7

1Glasgow Royal InfirmaryGlasgow, United Kingdom2Sandwell General HospitalWest Bromwich, United Kingdom3University HospitalBirmingham, United Kingdom4University of NewcastleNewcastle-upon-Tyne, United Kingdom5Dudley HospitalsWest Midlands, United Kingdom6University HospitalNorth Staffordshire, United Kingdom7Royal Infirmary of EdinburghEdinburgh, United Kingdom

References1. Dunn W, Jamil LH, Brown LS, Wiesner RH, Kim WR, Menon KVN, et

al. MELD accurately predicts mortality in patients with alcoholic hepatitis.HEPATOLOGY 2005;41:353-358.

2. Malinchoc M, Kamath P, Gordon F, Peine C, Rank J, ter Borg P. A modelto predict poor survival in patients undergoing transjugular portosystemicshunts. HEPATOLOGY 2000;31:864-871.

3. Sheth M. Riggs M. Patel T. Utility of the Mayo End-Stage Liver Disease(MELD) score in assessing prognosis of patients with alcoholic hepatitis.BMC Gastroenterol 2002;2:2.

4. Said A, Williams J, Holden J, Remington P, Gangnon R, Musat A, et al.Model for end stage liver disease score predicts mortality across a broadspectrum of liver disease. J Hepatol 2004;40:897-903.

5. Forrest EH, Evans CDJ, Stewart S, Phillips M, Oo YH, McAvoy N, et al.Analysis of factors related to mortality in alcoholic hepatitis and the deri-vation and validation of the Glasgow Alcoholic Hepatitis Score. Gut 2005,in press.

6. Forrest EH, Stewart S, Phillips M, Oo YH, Fisher NC, Singhal S, et al.Validation of the Glasgow Alcoholic Hepatitis Score: relevance to progno-sis and corticosteroid response. HEPATOLOGY 2004;40(Suppl 1):624A.

Copyright © 2005 by the American Association for the Study of Liver Diseases.Published online in Wiley InterScience (www.interscience.wiley.com).DOI 10.1002/hep.20771Potential conflict of interest: Nothing to report.

Reply:

We thank Forrest and colleagues for their interest in our study. Theycomment on the limitations of our study1 and three independently con-ducted studies that corroborate with our results.2-4 They also highlight theuse of their prognostic model in alcoholic hepatitis (AH). These criticismsof the Model for End-Stage Liver Disease (MELD) scoring suggest amisunderstanding of MELD. MELD is effective in ranking severity ofillness in patients with liver disease both with and without gastrointestinalbleeding.5 This is a positive feature of MELD in AH, not a detractor assuggested by Forrest and coworkers.

Table 1. The Glasgow Alcoholic Hepatitis Score

Score Given

1 2 3

Age �50 �50 —WCC (109/L) �15 �15 —Urea (mmol/L) �5 �5 —PT ratio/INR �1.5 1.5-2.0 �2.0Bilirubin (�mol/L) �125 125-250 �250

NOTE. A value between 5 and 12 is obtained. A score �9 is associated withpoor prognosis.

Abbreviations: WCC, white blood cell count; PT, prothrombin; INR, InternationalNormalized Ratio.

495

The relationship between cut-point and treatment also requires clari-fication. The cut-point reflects the point of highest sensitivity and speci-ficity on the ROC curve and does not dictate the point at which a therapymust be instituted. For AH, a benign therapy may be initiated at a lowerMELD score, while a higher MELD score might be used for a more riskyintervention. Our website calculator at http://www.mayoclinic.org/gi-rst/mayomodel7.html provides convenient calculation of MELD and trans-lation to 90-day mortality in AH, thereby allowing clinicians to make theirown treatment decision. The variations in cut-point between studies re-lating to MELD and AH largely reflect the different MELD formulationsthat were used. We used the United Network for Organ Sharing (UNOS)MELD, whereas Sheth et al.3 used the original MELD because the UNOSmodification had not yet been conceived at that time. A constant of 6.4points accounts for the majority of the difference of optimal MELD cut-point between these two studies.

With regard to Forrest et al.’s scoring system, only independentvalidation that comes with the “test of time” will support or refute theirmodel. MELD has begun to pass this test, having been validated for avariety of liver conditions. In the meantime, it is important to pointout some limitations of Forrest et al.’s model. First, the model is notcontinuous and therefore suffers from the same limitations as all mod-els that employ categorical discrimination. Second, the model seems tobe compared with historical optimal cut-point of MELD rather thanoptimal cut-points from their own data set. This would be necessaryfor a head-to-head comparison within their data set. Even more wor-risome is that Forrest et al. apparently have made an error in theirMELD calculations. Table 1 in their “in press” manuscript that wasprovided for us depicts a MELD calculation with an InternationalNormalized Ratio constant of 1.2—this should be 11.2! Hopefully,this error will be rectified in their published manuscript. Third, themodel is not weighted, thus allocating equal footing to each criterion.Actually, most of the criteria that constitute Forrest et al.’s model arevariables that constitute MELD; thus, it would be interesting to seehow much age and white blood cell count add to Forrest et al.’s modelbeyond bilirubin, international normalized ratio, and renal function.Last, individuals with gastrointestinal bleeding—a sizeable percentageof patients with AH—were excluded in Forrest et al.’s analysis. In thepresence of gastrointestinal bleeding, we wonder whether Forrest et

al.’s model will be valid, because BUN is confounded by gastrointes-tinal bleeding.

We agree with Forrest and colleagues that development and vali-dation of new models of prognostication in AH is important. Hope-fully, advances will facilitate and translate into better treatment of thisdifficult condition.

WINSTON DUNN

PATRICK S. KAMATH

RUSSELL H. WIESNER

W. RAY KIM

VIJAY SHAH

Advanced Liver Disease Study GroupMayo ClinicRochester, MN

References1. Dunn W, Jamil LH, Brown LS, Wiesner RH, Kim WR, Menon KV, et al.

MELD accurately predicts mortality in patients with alcoholic hepatitis.HEPATOLOGY 2005;41:353-358.

2. Said A, Williams J, Holden J, Remington P, Gangnon R, Musat A, et al.Model for end stage liver disease score predicts mortality across a broadspectrum of liver disease. J Hepatol 2004;40:897-903.

3. Sheth M, Riggs M, Patel T. Utility of the Mayo End-Stage Liver Disease(MELD) score in assessing prognosis of patients with alcoholic hepatitis.BMC Gastroenterol 2002;2:2.

4. Srikureja W, Kyulo NL, Runyon BA, Hu KQ. MELD score is a betterprognostic model than Child-Turcotte-Pugh score or discriminant func-tion score in patients with alcoholic hepatitis. J Hepatol 2005;42:700-706.

5. Kamath PS, Wiesner RH, Malinchoc M, Kremers W, Therneau TM,Kosberg CL, et al. A model to predict survival in patients with end-stageliver disease. HEPATOLOGY 2001;33:464-470.


HIV Coinfection Shortens the Survival of Patients With Hepatitis C Virus–RelatedDecompensated Cirrhosis

To the Editor:

We read with interest the article by Pineda et al. in which HIVcoinfection as an independent risk factor for decreased survival inpatients with hepatitis C virus (HCV)-related cirrhosis was identified.1

The authors estimated that the 1-year and 5-year survival rates were74% and 44%, respectively, for HCV-monoinfected patients and 54%and 25%, respectively, for HIV/HCV-coinfected patients. Interest-ingly, liver-related deaths occurred with similar frequency in HCV-monoinfected patients (86%) and in HIV/HCV-coinfected patients(81%). Why HIV coinfection reduces survival in HCV patients whohave cirrhosis remains a critical question.

The authors note that 43% of HIV-coinfected patients were onhighly active antiretroviral therapy (HAART), but they do not indicatehow many of the HIV/HCV-coinfected patients who died were onHAART. HCV coinfection increases the chance of HAART-associ-ated hepatotoxicity by 2- to 10-fold compared with HIV-monoin-fected patients.2 It is not fully clear why HCV coinfection contributesto hepatotoxicity in HIV patients on HAART, but the HCV coreprotein may play a role. Glutathione has mitochondrial and cytoplas-mic antioxidant properties that may offer protection against drug-

induced liver injury, and the HCV core protein decreases intracellularglutathione stores.3 HIV infection is also associated with depletion ofglutathione, and HIV and HCV may synergistically increase suscepti-bility to drug-induced hepatotoxicity.4 Furthermore, HAART and theHCV core protein have been implicated in causing mitochondrialtoxicity, which can lead to dyspnea, abdominal pain, weight loss, vom-iting, cardiomyopathy, pancreatitis, and lactic acidosis.5 Such sequelaeof HAART may have a more deleterious effect in patients who haveadvanced liver disease. Identifying how many deceased patients tookHAART and whether they took HAART when they had more histo-logically advanced liver disease could determine the contribution ofHAART to the increased risk of death.

The authors also note that hepatic encephalopathy more frequentlycaused first hepatic decompensation and liver-related death in HIV/HCV-coinfected patients than in HCV-monoinfected patients. Al-though the authors suggest that HIV patients may have been morelikely to take central nervous system depressants through substanceabuse, one cannot overlook the effect of HIV infection itself on cog-nition. HIV neuropathology includes cerebral atrophy and diffusewhite matter damage with myelin loss.6 Clinical manifestations in-clude difficulties with concentration and memory loss.7 Furthermore,other neurological sequelae of HIV/AIDS—including primary central

496 CORRESPONDENCE HEPATOLOGY, August 2005

nervous system lymphoma, progressive multifocal leukoencepalopa-thy, and opportunistic infections—remain important causes of HIV-related neurological deficits.6,8 Pineda et al. defined hepaticencephalopathy as patient confusion or disorientation “in the absenceof any other likely nonhepatic causes.”1 Greater detail of the criteriaused to distinguish hepatic encephalopathy from HIV-related neuro-psychiatric deficits would perhaps clarify if encephalopathy in thesepatients was due solely to underlying end-stage liver disease.

The study by Pineda et al. represents an important contribution tothe body of existing data on HIV/HCV coinfection. Despite its retro-spective study design, it raises important questions about why HIVincreases mortality in HIV/HCV coinfected patients, thus providing afoundation for much-needed prospective studies on the interplay ofHIV and HCV infection in liver disease.

CARLA W. BRADY, M.D.1

ANDREW J. MUIR, M.D., M.H.S.21Division of GastroenterologyDurham VA Medical CenterDurham, NC2Division of GastroenterologyDuke Clinical Research InstituteDuke University Medical CenterDurham, NC

References1. Pineda JA, Romero-Gomez M, Dıaz-Garcıa F, Giron-Gonzalez JA,

Montero JL, Torre-Cisneros J, et al. HIV coinfection shortens the survivalof patients with hepatitis C virus-related decompensated cirrhosis. HEPA-TOLOGY 2005;41:779-789.

2. Bonacini M. Liver injury during highly active antiretroviral therapy: theeffect of hepatitis C coinfection. Clin Infect Dis 2004;38(Suppl):S104–S108.

3. Moriya K, Nakagawa K, Santa T, Shintani Y, Fujie H, Miyoshi H, et al.Oxidative stress in the absence of inflammation in a mouse model forhepatitis C virus-associated hepatocarcinogenesis. Cancer Res 2001;61:4365-4370.

4. Barbaro G, Di Lorenzo G, Soldini M, Parrotto S, Bellomo G, Belloni G, etal. Hepatic glutathione deficiency in chronic hepatitis C: quantitative eval-uation in patients who are HIV positive and HIV negative and correlationswith plasmatic and lymphocytic concentrations and with the activity of theliver disease. Am J Gastroenterol 1996;91:2569-2573.

5. Montaner JSG, Cote HCF, Harris M, Hogg RS, Yip B, Harrigan PR, et al.Nucleoside-related mitochondrial toxicity among HIV-infected patientsreceiving antiretroviral therapy: insights from the evaluation of venouslactic acid and peripheral blood mitochondrial DNA. Clin Infect Dis2004;38(Suppl):S73–S79.

6. Neuenburg JK, Brodt HR, Herndier BG, Bickel M, Bacchetti P, PriceRW, et al. HIV-related neuropathology, 1985 to 1999: rising prevalence ofHIV encephalopathy in the era of highly active antiretroviral therapy. JAcquir Immune Defic Syndr 2002;31:171-177.

7. Chang L, Speck O, Miller EN, Braun J, Jovicich J, Koch C, et al. Neuralcorrelates of attention and working memory deficits in HIV patients. Neu-rology 2001;57:1001-1007.

8. Ammassari A, Cingolani A, Pezzotti P, De Luca A, Murri R, Giancola ML,et al. AIDS-related focal brain lesions in the era of highly active antiretro-viral therapy. Neurology 2000;55:1194-1200.


Reply:

We appreciate the comments of Brady et al. related to our recentstudy in which we analyzed the survival of hepatitis C virus (HCV)-

infected patients with decompensated cirrhosis.1 They raise two veryinteresting issues.

First, they suggest that highly active antiretroviral therapy(HAART) could be associated with an increased risk of death in HIV/HCV-coinfected patients with advanced liver disease. They supportsuch a hypothesis based on the fact that antiretroviral therapy–inducedhepatotoxicity may lead to an enhancement of liver damage. However,an acceleration of liver fibrosis progression in HIV/HCV-coinfectedpatients has been associated with immunosupression.2 Consequently,immune restoration is expected to influence positively the evolution ofliver disease after starting HAART. In our study, 34 (34%) of the 100HIV-infected deceased patients took HAART, whereas 43 (54%) of80 coinfected survivors were under HAART (P � .008). This seem-ingly protective factor is in agreement with other studies in which anassociation between HAART and a lower liver-related mortality hasbeen observed.3,4

Second, Brady et al. state that HIV-related central nervous systemdamage might have been misinterpreted as hepatic encephalopathy(HE) because of the diagnosis criteria we used. However, we think thisis very unlikely. In fact, in our hospitals, cerebral computed tomogra-phy, brain magnetic resonance imaging, and, in most cases, studies ofcerebrospinal fluid are included in routine diagnostic examinations ofHIV-infected patients with neurological symptoms. Moreover, mea-surement of plasma ammonia levels and electroencephalography helpus to support the diagnosis of HE. Finally, although there are nospecific clinical manifestations of this disorder, symptoms and signsincluded in a commonly used grading system of HE are required toestablish such a diagnosis.5 Thus it is unlikely that a false diagnosis ofHE in this population would have occurred.

We agree with Brady and colleagues that prospective studies on theinterplay of HIV/HCV infection on liver disease are needed. We arepleased that our study stimulates such questions.

JUAN A. PINEDA, PH.D.JOSE A. GARCıA-GARCıA, M.D.Unidad de Enfermedades InfecciosasServicio de Medicina InternaHospital Universitario de ValmeSeville, Spain

References1. Pineda JA, Romero-Gomez M, Dıaz-Garcıa F, Giron-Gonzalez JA,

Montero JL, Torre-Cisneros J, et al. HIV coinfection shortens the survivalof patients with hepatitis C virus-related decompensated cirrhosis. HEPA-TOLOGY 2005;41:779-789.

2. Macıas J, Castellano V, Merchante N, Palacios RB, Mira JA, Saez C, et al.Effect of antiretroviral drugs on liver fibrosis in HIV-infected patients withchronic hepatitis C: harmful impact of nevirapine. AIDS 2004;18:767-774.

3. Bonacini M, Louie S, Bzowej N, Wohl AR. Survival in patients with HIVinfection and viral hepatitis B or C: a cohort study. AIDS 2004;18:2039-2045.

4. Qurishi N, Kreuzberg C, Luchters G, Effenberger W, Kupfer B, Sauer-bruch T, et al. Effect of antiretroviral therapy on liver-related mortality inpatients with HIV and hepatitis C virus coinfection. Lancet 2003;362:1708-1713.

5. Riordan SM, Williams R. Treatment of hepatic encephalopathy. N EnglJ Med 1997;337:473-479.


HEPATOLOGY, Vol. 42, No. 2, 2005 CORRESPONDENCE 497

Antiretroviral Therapy and Liver Fibrosis in HIV-Infected Patients With Chronic Hepatitis C

To the Editor:

Mehta el al.1 assessed, in a cross-sectional retrospective study, theprevalence and factors associated with liver fibrosis among patientswith human immunodeficiency virus and hepatitis C virus (HCV)coinfection. The authors found no evidence that antiretroviral therapy(ART) caused serious histological liver disease. However, we believethe design of the study allows only statistical associations to be inferred.Further criteria are needed to infer causality.2,3

Our study is referenced as an example of different results.4 How-ever, there are a number of agreements between both studies. First,Mehta et al. found that ART was associated with less liver inflamma-tion. It is plausible, as the authors discuss, that this reduced inflamma-tion could ultimately slow the progression of liver fibrosis. In thisregard, we found that patients who used protease inhibitors showedslower progression of fibrosis. To the contrary, previous use of nevi-rapine was associated with bridging fibrosis or cirrhosis (�F3).4 Sec-ond, Mehta et al. reported that persistently high alanineaminotransferase (ALT) levels seen in more than 33% of prebiopsydeterminations that are more than 2.5 times the upper limit of normalwere associated with �F3. The odds of �F3 were similar for patientswith persistently high ALT levels with or without a history of ART-related liver enzyme elevations. We performed a less-detailed assess-ment of prebiopsy ALT levels. We found that patients with elevationsmore than 2.5 times the ALT levels before starting ART were morelikely to show �F3.

The authors consider that the impact of ART on fibrosis is expectedto be small because the duration of ART exposure is brief comparedwith the length of HCV infection. However, previous studies havefailed to show a relationship between fibrosis and length of HCVinfection.5,6 This finding is most probably the result of a nonlinearprogression of liver fibrosis.7 In our study, liver fibrosis was not asso-ciated with the duration of exposure to protease inhibitors. Con-versely, patients with exposure to nevirapine for more than 1 year weremore likely to show �F3.4 There are two possible presentations ofnevirapine hepatotoxicity: an early idiosyncratic reaction and a lateonset cumulative toxicity. Our data support that the cumulative nevi-rapine hepatotoxicity is involved in the development of liver fibrosis inpatients coinfected with HIV and HCV.

The authors report an association between steatosis and fibrosis inthe Results, but it is not discussed. However, HCV genotypes were nottaken into account in this analysis. Because the presence of genotype 3is a strong determinant of steatosis, the correlations between steatosisand fibrosis should have been controlled for HCV genotypes.

JUAN MACıAS1

JOSE A. MIRA1

SALVADOR VERGARA1

JUAN A. PINEDA2

1Servicio de Medicina InternaHospital Universitario de Valme2Unidad de Enfermedades InfecciosasServicio de Medicina InternaHospital Universitario de ValmeSeville, Spain

References1. Mehta SH, Thomas DL, Torbenson M, Brinkley S, Mirel L, Chaisson RE,

et al. The effect of antiretroviral therapy on liver disease among adults withHIV and hepatitis C coinfection. HEPATOLOGY 2005;41:123-131.

2. Hill AB. The environment and disease: association or causation? Proc RSoc Med 1965;58:295-300.

3. Phillips CV, Goodman KJ. The missed lessons of Sir Austin Bradford Hill.Epidemiol Perspect Innov 2004;1:3.

4. Macıas J, Castellano V, Merchante N, Palacios RB, Mira JA, Saez C, et al.Effect of antiretroviral drugs on liver fibrosis in HIV-infected patients withchronic hepatitis C: harmful impact of nevirapine. AIDS 2004;18:767-774.

5. Ghany MG, Kleiner DE, Alter H, Doo E, Khokar F, Promrat K, et al.Progression of fibrosis in chronic hepatitis C. Gastroenterology 2003;124:97-104.

6. Zarski JP, Mc Hutchison J, Bronowicki JP, Sturm N, Garcia-Kennedy,Hodaj E, et al. Rate of natural disease progression in patients with chronichepatitis C. J Hepatol 38;2003:307-314.

7. Rai R, Wilson LE, Astemborski J, Anania F, Torbenson M, Spoler C, et al.Severity and correlates of liver disease in hepatitis C-virus infected injectiondrug users. HEPATOLOGY 2002;35:1247-1255.


Reply:

One of the most important questions in HIV/hepatitis C virus(HCV)–coinfected patients is the relationship between exposure toantiretroviral therapy (ART) and liver fibrosis. Individual instances ofART-related liver toxicity are well documented, and liver enzyme lev-els increase to more than 5 times the upper limit of normal in approx-imately 10% of persons starting new ART.1 However, in some studies,HIV/HCV–coinfected persons taking ART actually had less liver dis-ease.2,3

As the letter from Macias and colleagues indicates, there are simi-larities and differences between the results of our studies and others.2-4

In a cohort of 210 HIV/HCV–coinfected persons, we failed to detectless or more liver fibrosis among persons treated with effective ART.5This finding contrasts with the results of two other studies that sug-gested ART use might reduce liver fibrosis.2,3 On the other hand, wedid observe that longer and more effective ART was associated withdecreased necroinflammatory activity. Because greater necroinflam-matory activity was associated with more severe fibrosis in this study, itis possible that a link between ART and fibrosis will manifest itself asindividuals have longer exposure to ART. Another difference is thatMacias and colleagues observed more advanced fibrosis among thosereceiving nevirapine, but we failed to detect an association between anyspecific drug and fibrosis.4

Why the differences? The study populations themselves are differ-ent in ways that could affect the findings, because it is impossible tocompletely account for the multiple confounding factors such as alco-hol use, duration of HCV infection, and ART. In these relatively smallcross-sectional studies, these types of exposures are difficult to measureaccurately. In addition, studies typically only measure these factors atone point in time, which is insufficient to fully account for the vari-ability of these changing exposures.

Whereas the differences between studies remain unresolved, theevidence collectively suggests that ART does not adversely affect liverfibrosis among most HIV/HCV–coinfected patients. Prospectivestudies with longer follow-up are needed to infer causality from thesuggested associations.

SHRUTI MEHTA

DAVID THOMAS

MARK SULKOWSKI

Johns Hopkins Schools of Public Health and MedicineBaltimore, MD

498 CORRESPONDENCE HEPATOLOGY, August 2005

References1. Sulkowski MS, Mehta SH, Chaisson RE, Thomas DL, Moore RD. Hep-

atotoxicity associated with protease inhibitor-based antiretroviral regimenswith or without concurrent ritonavir. AIDS 2004;18:2277-2284.

2. Benhamou Y, Di Martino V, Bochet M, Colombet G, Thibault V, Liou A,et al. Factors affecting liver fibrosis in human immunodeficiency virus-andhepatitis C virus-coinfected patients: impact of protease inhibitor therapy.HEPATOLOGY 2001;34:283-287.

3. Qurishi N, Kreuzberg C, Luchters G, Effenberger W, Kupfer B, Sauer-bruch T, et al. Effect of antiretroviral therapy on liver-related mortality inpatients with HIV and hepatitis C virus coinfection. Lancet 2003;362:1708-1713.

4. Macias J, Castellano V, Merchante N, Palacios RB, Mira JA, Saez C, et al.Effect of antiretroviral drugs on liver fibrosis in HIV-infected patients withchronic hepatitis C: harmful impact of nevirapine. AIDS 2004;18:767-774.

5. Mehta SH, Thomas DL, Torbenson M, Brinkley S, Mirel L, Chaisson RE,et al. The effect of antiretroviral therapy on liver disease among adults withHIV and hepatitis C coinfection. HEPATOLOGY 2005;41:123-131.


LPS-Induced Tyrosine Nitration of Hepatic Glutamine Synthetase

To the Editor:

In our previous study,1 mass spectrometry identified the peptideNH2-KGYFEDR-COOH from sheep glutamine synthetase (GS) as asite of tyrosine nitration (Fig. 7 in Gorg et al.1). The amino acidsequence was aligned around Y160 of rat GS,1 which apparently linesthe ammonium binding pocket.2 Extended alignment studies demon-strated that the peptide even better fits around Y335 of rat GS, whichis highly conserved among eukaryotic GSs.

Generalized profile searches with the pftools package (http://ww-w.isrec.isb-sib.ch/ftp-server/pftools/) allowed us to reliably align mam-malian Y335 to R355 of the structurally characterized bacterial GSfrom Salmonella (PDB entry 1F1H). The position of R355 in thestructure suggests that the mammalian Y335 residue directly stackswith the purine system of GS-bound ADP/ATP (adenosine diphos-phate/adenosine triphosphate), and in addition might contribute tothe interface with the neighboring subunit (Kay Hofmann, MemorecBiotec GmbH, Cologne, Germany; personal communication). Bothfunctions may be impaired by nitration of Y335. This additional as-pect underlines our conclusion that nitration of active site tyrosineresidues critically contributes to GS inactivation by nitrosative stress.

BORIS GORG1

MATTHIAS WETTSTEIN1

SABINE METZGER2

FREIMUT SCHLIESS1

DIETER HAUSSINGER1

1Clinic for Gastroenterology, Hepatology, and Infectiology2Biological Medical Research CenterHeinrich-Heine-UniversityDusseldorf, Germany

References1. Gorg B, Wettstein M, Metzger S, Schliess F, Haussinger D. Lipopolysac-

charide-induced tyrosine nitration and inactivation of hepatic glutaminesynthetase in the rat. HEPATOLOGY 2005;41:1065-1073.

2. Eisenberg D, Gill HS, Pfluegl GMU, Rotstein SH. Structure-functionrelationships of glutamine synthetases. Biochim Biophys Acta 2000;1477:122-145.


HEPATOLOGY, Vol. 42, No. 2, 2005 CORRESPONDENCE 499

Antiretroviral therapy and liver fibrosis in HIV-infected patients with chronic hepatitis C

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