2008 Wolters Kluwer Health I

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1 Lippincott LIT Nturl history of heptitis C virus infection in H IV -infected individuls nd the impct of HIV in the er of highly ctive ntiretrovirl therpy: met-nlysis Hl-Hi Thein,b, Qilong Vie, Gregory j. Dored nd Murry D. Krhn,b,e Objectives: To estimte stge-specific trnsition probbilities in individuls coinfected with HIV nd heptitis C virus (HCV), to exmine the effect of covrites on these rtes, nd to investigte the effect of HIV on HCV-relted cirrhosis in the er of highly ctive ntiretrovirl therpy (HAART). Design: Systemtic review of nturl history studies mong HCV-infected individuls. Methods: Mrkov mximum likelihood estimtion method ws used to estimte stgespecific trnsition probbilities. A met-nlysis ws performed to obtin pooled trnsition probbilities, nd met-regression to investigte the impct of covrites on these rtes. Risk of cirrhosis between individuls monoinfected with HCV nd coinfected with HIV/HCV were compred by HAART sttus. Results: The estimted men (95% confidence intervls) nnul trnsition probbilities of 3567 individuls coinfected with HIV/HCV (n = 17 studies) were s follows: fibrosis stge (F) FO, F1.122 ( ); F1, F2.115 ( ); F2, F3.124 ( ); nd F3, F4.115 ( ) units/yer. The prevlence of cirrhosis fter 2 nd 3 yers of HCV infection ws 21% (16-28%) nd 49% (4-59%), respectively. Longer durtion of HCV infection ws significntly ssocited with slower rte of fibrosis progression. The overll rte rtio of cirrhosis between individuls coinfected with HIV/HCV nd mono infected with HCV (n = 27 studies) ws 2.1 (1.5-3.), 2.5 ( ) in the non-haart group, nd 1.7 ( ) in the HAART group. Conclusion: The rte of fibrosis progression mong individuls coinfected with HIV/ HCV ppers constnt. Our results confirm tht chronic heptitis C outcomes re worse mong coinfected individuls. Over the period studied, HAART did not pper to fully correct the dverse effect of HIV infection on HCV prognosis. 28 Wolters Kluwer Helth I AIDS 28, 22: Willims & Wilkins Keywords: cirrhosis, fibrosis, heptitis C virus, HIV/heptitis C virus coinfection, met-regression, risk fctors, systemtic review University Helth Network, Division of Clinicl Decision-Mking nd Helthcre Reserch, Toronto, btoronto Helth Economics nd Technology Assessment Collbortive (THETA), University of Toronto, Toronto, cntionl Epidemiology nd Surveillnce, Cndin Blood Service, Ottw, Ontrio, Cnd, dntionl Centre in HIV Epidemiology nd Clinicl Reserch, The University of New South Wles, Sydney, NSW, Austrli nd euniversity of Toronto, Deprtments of Medicine nd Helth Policy, Mngement nd Evlution nd Fculty of Phrmcy, Toronto, Ontrio, Cnd. Correspondence to Hl-Hi Thein, MD, MPH, PhD, Division of Clinicl Decision-Mking & Helthcre Reserch, Toronto Generl Hospitl, 2 Elizbeth Street EN13-222A, Toronto, Ontrio M5G 2C4, Cnd. Tel: x 3687; fx: ; e-mil: rthein uhnres.utoronto.c Received: 16 Jnury 28; revised: 2 June 28; ccepted: 26 June 28. DOI:1.1 97/QAD.Ob13e3283e6d51 ISSN Wolters Kluwer Helth I Lippincott Willims & Wilkins 1979

2 LIT AIDS 28, Vol 22 No 15 Introduction Coinfection with HIV nd heptitis C virus (HCV) is common mong injecting drug users nd ptients with hemophili who received contminted blood or blood products prior to serologic screening of donted blood for HCV [1-3]. Low rtes of liver fibrosis progression hve been reported in medium-term to long-term follow-up of HCV-infected injecting drug users. The prevlence of cirrhosis hs been reported to be less thn 5% fter 1-25 yers of infection [4-6]. On the contrry, severl nturl history studies mong individuls infected with HCV nd hemophili nd mixed popultions hve demonstrted tht HIV ccelertes the progression of liver disese [7-18], with incresed risk of cirrhosis nd heptocellulr crcinom, nd shorter survivl following heptic decompenstion [19-21 J. The underlying mechnism of this ccelerted rte of liver fibrosis progression is uncler, but my be linked to immunosuppression [ 12, 16,22]. As highly ctive ntiretrovirl therpy (HAART) becme widely ccessible in developed countries fter 1996 [23], the survivl of individuls with HIV /HCV coinfection hs considerbly improved nd HCV-relted end-stge liver disese hs emerged s significnt burden of disese in this popultion [24-27]. In both HCV-monoinfected nd individuls coinfected with HIV /HCV, the rte of liver fibrosis progression vries [12,19,28-32] due to fctors tht re not well understood. Previous estimtes hve been undermined by the ssumption of liner progression of liver fibrosis over time nd indequte djustment for potentil covrites, including study design fctors, clinicl fctors, nd the effect of HAART A systemtic review [33] of eight studies in the pre HAART er reported three-fold increse in the risk of cirrhosis in individuls coinfected with HIV /HCV compred with HCV-monoinfected individuls. Although recent dt suggest tht HAART is ssocited with reduction in liver-relted mortlity [34,35], its effects on liver fibrosis progression remin uncler. Crosssectionl or retrospective studies hve shown tht n effective HAART cn ttenute the rte of liver fibrosis progression in individuls coinfected with HIV /HCV [14,31,36-39]. Other studies [12,16,22,4], however, hve not demonstrted beneficil effect of HAART The objectives of our systemtic review nd met-nlysis were: to obtin more precise rtes of fibrosis progression by estimting stge-specific trnsition probbilities in individuls coinfected with HIV /HCV; to exmine the effect of covrites on these rtes; nd to investigte the effect of HIV on HCV disese progression by compring the rte of progression to cirrhosis between individuls with HCV monoinfection nd HIV /HCV coinfection in the er of HAART Methods Serch strtegy nd selection criteri Humn studies tht exmined liver fibrosis progression in individuls with HCV monoinfection nd HIV /HCV coinfection were serched by the MED LINE, EMBASE, nd PubMed dtbses of publictions in ny lnguge covering the period from Jnury 199 to September 27 (up to December 26 for non-english rticles), with combintions of 'HCV', 'heptitis non-a', 'HIV', 'AIDS', 'fibrosis', 'cirrhosis', 'cohort studies', 'csecontrol studies', 'prognosis', 'disese-free survivl', 'medicl: futil', 'tretment outcome', 'tretment filure', 'disese progression', 'morbidity', 'mortlity', 'ftl outcome', 'hospitl mortlity', 'survivl nlysis', nd 'nturl history'. Cittions were crosschecked through review of bibliogrphies of relevnt published ppers (Fig. 1). For the estimtion of stge-specific trnsition probbilities, studies were included if they stisfied the following criteri: full-length nd peer-reviewed originl rticles; chronic HCV infection defined s the presence of nti HCV ntibody detected by second or third genertion enzyme-linked immunosorbent ssy nd t lest one of HCV RNA s detected by polymerse chin rection, recombinnt immunoblot ssy positivity, n elevted lnine minotrnsferse (ALT) level without n lterntive cuse of chronic liver disese, or liver biopsy consistent with chronic heptitis C; HIV infection determined by the positivity of both enzyme-linked immunosorbent ssy nd western blot ssys; nd no HCV tretment prior to the first liver biopsy or between subsequent biopsies. To compre the rte of progression to cirrhosis between individuls monoinfected with HCV nd coinfected with HIV /HCV, studies were included if they stisfied the bove criteri, nd wherever the infected groups were directly compred. Studies were excluded if they included fewer thn 2 ptients or if fibrosis progression rtes could not be clculted (e.g. durtion ofhcv infection not reported). If duplicte publictions presented severl updtes of the dt, the most recent dt or studies with more complete informtion were included. Dt bstrction Dt were collected using dt bstrction forms tht included relevnt items identified in previous studies such s study-relted fctors; host-relted fctors - ge, sex, estimted durtion of HIV nd HCV infection, mode of HCV cquisition, lcohol consumption, heptitis B virus infection, nd presence of heptic stetosis; virus-relted fctors - HCV genotype, HCV RNA positivity, HIV nd HCV virl lod, nd history of ntiretrovirl therpy; immunologic fctors - CD4+ T-cell count nd CDC clinicl ctegory [41]; nd liver-relted fctors - ALT

3 LIT Liver fibrosis in HIV/HCV coinfection Thein et l I Potentilly relevnt cittions identified N = 4182 Cittions excluded: N After review of title After review of bstrct 1262 I Retrievl of potentilly relevnt ppers N = 263 Excluded fter ssessment of full text: N No fibrosis stge dt 17 1 r--- I Studies included in the systemtic review N = 93 Excluded from met-nlysis: N Excluded from met- Incomplete fibrosis stge dt 63 nlysis: N Less thn 2 cses 4- f-. HIV/HCV group only 65 Duplicte publiction 9 Less thn 2 cses 1 I Studies included in the met- Studies included in the met-nlysis of fibrosis progression rtes nlysis of risk of cirrhosis N = 17 N = 27 Fig. 1. Identifiction of relevnt literture of the nturl history of heptitis C. HCV, heptitis C virus. level, fibrosis stge on the bsis of estblished histopthologic criteri [ 42-46], clinicl or histologicl dignosis of cirrhosis, nd histologicl ctivity index. Cirrhosis ws defined on the bsis of well estblished histopthologic criteri [42-46]. In those studies tht lso used nonhistopthologic criteri, cirrhosis ws defined on the bsis of clinicl or ultrsound evidence consistent with cirrhosis [ 47, 48]. The men ge t HCV cquisition ws clculted by tking the difference between the men ge t ssessment for liver disese nd the men durtion ofhcv infection when this informtion ws not directly vilble. Studies reporting Ishk [44] fibrosis stges (SO-S6) were converted to the well vlidted METAVIR scoring system [ 42], in which the stge of fibrosis is ssessed on five-point scle: FO =no fibrosis, Fl =portl fibrosis without sept, F2 =portl fibrosis with rre sept, F3 =numerous sept without cirrhosis, F4 =cirrhosis (i.e. SO= FO; Sl = Fl; S2 = F2; S3-S4 = F3; S5- S6 = F4). For the Knodell scoring system (FO-F4 without F2 stge), F3 ws distributed 5: 5 to F2 nd F3. Stge distribution ws not performed if three or more stges were reported collectively (e.g. FO-F2, F2-F4). Sttisticl nlysis Estimtion of fibrosis progression rtes We used two methods to estimte fibrosis progression rtes: the Mrkov mximum likelihood estimtion (MMLE) method developed nd vlidted by Yi et l. [49] to estimte nnul stge-specific trnsition probbilities (e.g. FO ---J- Fl,..., F3 ---J- F4); nd the indirect (stge-constnt) method tht ssumes tht fibrosis progression rtes re constnt [5]. For ech study, the men observtion time nd distribution of fibrosis stges t the ltest follow-up point in longitudinl studies (if vilble) nd t time of recruitment in cross-sectionl/ retrospective studies were used to clculte the most likely set of trnsition probbilities chrcterizing the rte of movement between stges. In the stge-constnt method [5], the METAVIR stge ws divided by the estimted durtion of HCV infection (person-yers). A met-nlysis ws performed to estimte the pooled trnsition probbilities derived using the MMLE nd the stge-constnt methods. Both fixed nd rndom effects model estimtes were obtined from the individul study trnsition probbilities nd their stndrd errors (SEs); inverse vrince weighting w = 1 /SE 2 ws used for pooling of trnsition probbilities [51 J, which gives men estimte nd 95% confidence intervls (Cis). The effect of individul studies on the pooled trnsition probbilities ws ssessed by re-estimting the overll effect fter omitting ech study. We exmined studyspecific dt grphiclly with funnel plots for pprent heterogeneity cross studies nd potentil publiction bis, nd tested for significnce with Egger's test for symmetry [52]. The cumultive probbility of cirrhosis (men, 95% Cis) up to 3 yers fter HCV exposure ws estimted using the estimted progression rtes nd their lower nd upper bounds. The impct of potentilly importnt covrites on stgespecific trnsition probbilities ws exmined by univrite regression nlysis nd met-regression. For the met-regression, we used liner mixed model-

4 LIT AIDS 28, Vol 22 No 15 mximum likelihood method, djusting for covrites. Missing dt were replced using the multiple imputtion method [53]. The met-regression models included sex, ge t HCV infection, durtion of infection, injecting drug use, HCV cquisition vi blood trnsfusion, excess lcohol consumption, genotype, CD4+ T-cell count t liver disese ssessment, nd HAART s explntory fctors nd nturl log of stge-specific trnsition probbilities nd single pooled trnsition probbilities s dependent vribles. The regression ws weighted by multiplictive vrince djustment fctor, tking into ccount both within-study vrinces of trnsition probbilities nd the residul between-study heterogeneity [54]. Risk rtios of cirrhosis We extrcted djusted reltive risks or risk rtios (RRs) nd 95% Cls of cirrhosis mong individuls monoinfected with HCV nd coinfected with HIV /HCV from studies when vilble [7-11,18,21,33,55]. For other studies, RRs nd 95% Cls were estimted using the number of individuls with cirrhosis in ech infection group nd the corresponding estimted durtion of HCV infection. RRs were reported s djusted vlues in which HCV groups were mtched for specific covrites. For two studies in which there were no reports of cirrhosis in the group monoinfected with HCV [1] or the group coinfected with HIV /HCV [56], n event in ech group ws ttributed to fcilitte the clcultion of RRs. A met-nlysis nd met-regression ofrrs for cirrhosis ws performed using the method described bove. The met-regression model included CD4+ T-cell count nd proportion receiving HAART s explntory fctors nd nturl log of the RR s dependent vrible. A two-sided significnce level of.5 ws used in ll sttisticl procedures. Sttisticl nlysis ws performed with SAS Inc. (Cry, North Crolin, USA) version 9.1 nd Proc Mixed ML [57] ws used for met-regression. Results Estimted fibrosis progression rtes in studies of HIV/heptitis C virus coinfection Seventeen reports of nturl history studies, involving 3567 individuls coinfected with HIV /HCV were included in the met-nlysis (Tbles 1 nd 2 [12-14, 16,22,29,3,32,38-4,58-72]). All studies hd crosssectionl/retrospective design, nd were performed in tertiry cre settings such s HIV, infectious diseses, or liver clinics. The studies primrily included men (75%), individuls reporting injecting drug use s the mode of HCV cquisition (82%), HCV RNA positive individuls (98%), those with elevted ALT levels (83%), nd those receiving ntiretrovirl therpy (79%). Two-thirds (67%) of the ptients were receiving HAART, including 41% of individuls who were on protese inhibitor-bsed regimen. The proportion of ptients with genotype 1 ws 5%. The men (rnge) ge t liver disese ssessment ws 4 (34-5) yers. The estimted durtion of HCV infection ws 17 (1-24) yers. The men (rnge) CD4+ T-cell count t liver disese ssessment ws 46 (32-629) cells/ fll Seven studies included individuls with CD4+ T-cell count less thn 2 cells/ fll (men, 14%) nd five studies included individuls with Centres for Disese Control nd Prevention (CDC) ctegory C or AIDS (men, 25%). Most ptients hd liver biopsy (99%). There were 515 ptients offo, 15 F1, 863 F2, 683 F3, nd 51 ptients of cirrhosis with person-yers of follow-up. Excess lcohol consumption ws defined s more thn 2 g/ dy in one, more thn 4 g/ dy in two nd more thn 5 g/ dy in eight studies. The pooled nnul stge-specific trnsition probbilities re reported in Tble 3. Due to the presence of significnt heterogeneity in the trnsition probbilities between most studies (Supplementry Tble 1), the results for the fixed effects model should be interpreted with cution, though they re not substntilly different from the rndom effects model estimtes. Bsed on the rndom effects model, the estimted weighted men (95% Cl) stgespecific trnsition probbilities were: FO ---J- F1.122 ( ); F1 ---J- F2.115 ( ); F2 ---J- F3.124 ( ); nd F3 ---J- F4.115 ( ) units/yer. The estimted weighted proportions of individuls with cirrhosis t 2 nd 3 yers fter HCV infection were 21% (95% Cl, 16-28%) nd 49% (4-59%), respectively (Tble 3). The djusted trnsition probbilities did not pper to be different from the undjusted estimtes. The corresponding medin (IQR) estimtes were.124 ( );.123 ( );.147 ( ); nd.119 ( ). The 2-yer nd 3-yer cirrhosis rtes using the medin progression rtes were 25% (15-31%) nd 54% (38-63%), respectively. Visul exmintion of the funnel plots of the log stgespecific trnsition probbilities ginst the study size of ll studies included in the met-nlysis reveled symmetry of the individul studies to the pooled men estimtes. Sensitivity nlyses showed tht the pooled estimtes were in generl robust to the exclusion of ny one study. Bsed on the rndom effects model, the estimted weighted men (95% Cl) fibrosis progression rtes using the stge-constnt method were.115 ( ) units/yer. This corresponds to cirrhosis prevlence of 19% (16-22%) t 2 yers nd 46% (4-51 %) t 3 yers. In the univrite regression nlysis, genotype 1 ws significntly ssocited with fibrosis progression from FO ---J- F1 (coefficient= -1.28, SE=.46, P=.44) nd durtion of HCV infection ws significntly ssocited

5 () ::::J. cc ::::r r -o "' 5" iii" 3 en $2 2S: ::::J c :::J m c g ::::J. N CD. m "'. c :::J -::::r c;; m ;:::. er CD c;; "' ::::r c= p.. Tble 1. Study nd clinicl chrcteristics of individuls with HIV/heptitis C virus coinfection. Men Men Liver Men ge t HCV durtion of Histologicl Reference Study period Country Smple biopsy, N ge (yers) (yers) HCV (yers) clssifiction FO, n F1, n F2, n F3, n F4, n Person-yersb [13, 14,58,59] Frnce MET A VIR [6] USA Scheuer [61] 2-22 USA Schcucr [29,3,32,3 9,62-64] Spin Scheuer [22] Europe MET A VIR [16] Spin Scheuer/Desmet [4] USA MET AVI R!lshk [12] UK MET AVI R!lshk [65] USA Btts-Ludwig [66] Spin Knodell [67] Frnce METAVIR!Knodell [68] 2-25 Spin Btts-Ludwig [69] NA Frnce MET A VIR [38] NA Spin Knodell [7] Itly lshk [71] Spin Scheuer [72] Frnce METAVIR!Knodell HCV, heptitis C virus infection. Heptic fibrosis stge bsed on MET A VIR fibrosis scoring system: FO =no fibrosis, F1 =portl fibrosis without sept, F2 =portl fibrosis with few sept, F3 =portl fibrosis with numerous sept without cirrhosis, F4 =cirrhosis. bperson-yers were clculted by multiplying the men durtion of infection by the met-nlysis smple size. For exmple, in study reporting stge distribution of 15 FO, 62 F1, 45 F2, 34 F3, nd 26 F4 with n estimted men durtion of infection of 15 yers, the fibrosis progression is clculted s follows: [(15 x ) + (62 x 1) + (45 x 2) + (34 x 3) + (26 x 4)]/[( ) x 15] =.131 fibrosis units per yer. r- :;;: ID... :n "... (J) ;;; :; ::c ::c (") < 1"1 :; it 1"1 -o :l, ::::r- Ill ::J I'll :-- r... <. QO... w

6 () ::::J. cc ::::r r -o "' 5" iii" 3 en $2 2S: ::::J c :::J m c g ::::J. N CD. m "'. c :::J -::::r c;; m ;:::. er CD c;; "' ::::r c= p.. Tble 2. Clinicl chrcteristics of individuls with HIV/HCV coinfection. Excess lcohol HCV HCV Genotype HIV CD4 CD4 Totl Men ALT >2g/dy IDU BT Spordic RNA+ lod Genotype 1 non1 lod cellsfr-d <2 cellsfr-d AIDS ART HAART Men log 1 log 1 Reference % IU/1 % % % % % copies/m I % % copies/m I Men % % % % [13, 14,58,59] 63 ND ND ND ND [6] ND ND [61] ND ND ND ND [2 9,3,32,3 9,62-64] ND ND 54 ND ND [22] 75 ND ND ND 48 9 ND [16] ND ND 1 1 [4] ND ND ND ND ND [12] ND ND 32 ND ND [65] 92 ND ND ND ND ND [66] ND ND [67] 71 ND ND ND ND [68] 76 ND ND 58 4 ND 484 ND 1 1 [69] ND ND ND 629 ND [38] ND [7] 72 ND ND 5 ND ND [71] ND ND [72] 65 ND ND 8 ND ND ND ND ND HAART is defined s three-drug regimen tht included one or two nucleoside nlogues nd protese inhibitor or nonnucleoside reverse trnscriptse inhibitor; ptients who received ART consisting of protese inhibitor or non nucleoside reverse-trnscriptse inhibitor. ALT, lnine minotrnsferse; ART, ntiretrovirl therpy; BT, blood/blood product trnsfusion; HAART, highly ctive ntiretrovirl therpy; HCV, heptitis C virus; HIV, humn immunodeficiency virus; I DU, injecting drug use; IU/1, interntionl units per I iter; ND, no dt; RNA, ribonucleic cid.... <. QO """ V'l N,OCJ < 2._ N N z ln r =i \)

7 LIT Liver fibrosis in HIV/HCV coinfection Thein et l Tble 3. Annul stge-specific trnsition probbilities nd predicted cumultive probbility of cirrhosis in individuls with HIV/HCV coinfection - Mrkov mximum likelihood estimtion. Fixed effects model undjusted probbility Men (95% Cl) Fibrosis stge FO--> F1.119 ( F1 --> F2.114 ( F2--> F3.139 ( F3 --> F4.115 ( Predicted cumultive probbility of cirrhosis fter HCV infection 5 yers.1 (.8-.11) 1 yers 2.5 ( ) 15 yers 9.9 ( ) 2 yers 21.8 ( ) 25 yers 35.9 ( ) 3 yers 5. ( ) Rndom effects model undjusted probbility Men (95% Cl).122 ( ).115 ( ).124 ( ).115 ( ).1 (.6-.15) 2.3 ( ) 9.3 ( ) 2.8 (16., 27.6) 34.6 ( ) 48.5 ( ) Rndom effects model djusted probbility Men (95% Cl).123 ( ).113 ( ).124 ( ).116 ( ).9 (.6-.13) 2.3 ( ) 9.3 ( ) 2.8 ( ) 34.6 ( ) 48.5 ( ) Cl, confidence intervls; HCV, heptitis C virus. Heptic fibrosis stge bsed on MET A VIR fibrosis scoring system: FO =no fibrosis, F1 =portl fibrosis without sept, F2 =portl fibrosis with few sept, F3 =portl fibrosis with numerous sept without cirrhosis, F4 =cirrhosis. Adjusted for men proportions/vlues of covrites: mle gender (74.8%), ge t HCV infection (22.4 yers), durtion of HCV infection (16.9 yers), injecting drug use (81.8%), blood/blood product trnsfusion (4.8%), excess lcohol consumption (22.6%), CD4 cell count (46/r.d), HAART (67.1 %) (Tbles 2 nd 4). with fibrosis progression from Fl ---J> F2 (coefficient= -.57, SE=.24, P=.33). In the met-regression nlysis (stge-specific models), durtion of HCV infection ws the only fctor significntly ssocited with progression from Fl---J> F2 (coefficient= -.68, SE=.24, P=.4) (Tble 4). Similrly, in the single pooled model, durtion of HCV infection ws significntly ssocited with fibrosis progression (coefficient= -.82, SE=.23, P=.27. The effects of other covrites, including CD4+ T-cell count nd HAARTon trnsition rtes, did not rech sttisticl significnce. Risk rtios of cirrhosis A totl of 27 reports of nturl history studies, involving 7666 individuls with HCV monoinfection (n = 497) nd HIV /HCV coinfection (n = 2636) were included in the met-nlysis (Supplementry Tbles 2 nd 3). There were 74 nd 8% men (P=.1), 54 nd 72% of individuls reporting injecting drug use s mode of HCV cquisition (P=.7), 36 nd 2% reporting receipt of blood or blood product (P=.3), 2 nd 22% reporting excess lcohol consumption (P=.77), 89 nd 83% with HCV RNA positivity (P=.76), nd 51 nd 45% with genotype 1 (P=.42), respectively, in ech group. The men ge of individuls monoinfected with HCV ws 39.5 yers compred with 36.9 yers in the individuls coinfected with HIV /HCV (P=.25), nd the durtion of HCV infection ws 16.5 yers nd 15.5 yers (P=.52), respectively. Among individuls coinfected with HIV /HCV, CD4+ T-cell count t liver disese ssessment ws reported in 17 studies. The men CD4+ T-cell count ws 429 cells/ fll There were no reports of HAART in 13 studies. In studies reporting HAART (n = 13), 74% of the individuls were receiving Tble 4. Met-regression" of covrites ssocited with heptic fibrosis progression in individuls with HIV/HCV coinfection. FO --> F1 b F1 --> F2b F2 --> F3b Covrites i3 SE p i3 SE p i3 SE p i3 F3 --> F4b SE p Intercept Mend Age t HCV infection Durtion of infection Injecting drug use Blood trnsfusiond Excess lcohol used Genotype 1d CD4 cell counf HAARTd [3, coefficient; HAART, highly ctive ntiretrovirl therpy; HCV, heptitis C virus; RR, reltive risk; SE, stndrd error. liner mixed model - mximum likelihood method. blog stge-specific trnsition probbilities. ccd4 cell count expressed s per 1 per fli. dproportion.

8 LIT AIDS 28, Vol 22 No 15 Study Risk Lower Upper Z-vlue P-vlue Risk rtio (95% Cl) Smple Covrites djusted rtio limit limit Allory, t 16 Age t HCV, gender, durtion of HCV. mode of HCV. lcohol Benhmou, Age t HCV. gender, durtion of HCV, mode of HCV, lcohol Bierhoff, Bru, Age, gender, durtion of HCV, mode of HCV Di Mrtino, Age Eyster, Age, gender, current lcohol use, genotype Gslightwl & Bini, Gonzlez, Grbczewsk, Age Lesens, Mcis, Age t HCV. severity of hemophili Mkris, Age t HCV, gender, durtion of HCV Mrine'-Brjon, Age, gender, durtion of HCV, lcohol Mrtinez-Sierr, Age, gender, durtion of HCV, mode of HCV, AL T Mohsen, Age t HCV, gender Monto, Age t HCV, durtion of HCV, lcohol, immune sttus Pol, 199B Alcohol Pol, 1998b Age t HCV, durtion of HCV, lcohol, HBsAg positivity Rgni, Age t HCV, gender, lcohol, ALT, genotype Rodriguez-Torres, Gender, durtion of HCV, lcohol Romeo, Srmento-Cstro, Age, ge t HCV, gender, durtion of HCV, mode of HCV, lcohol Age, gender, durtion of HCV. mode of HCV Sertty, Durtion of HIV infection Soto, Telfer, Vlle Tovo, Verm, Fixed effects model Rndom effects model HCV mono infection Lower risk of cirrhosis HIV/HCV coinfection Higher risk of cirrhosis Fig. 2. Risk rtios of cirrhosis between individuls monoinfected with heptitis C virus nd individuls coinfected with HIV/ HCV - met-nlysis. Risk rtios were clculted from vilble dt. Adjusted reltive risks were obtined directly from [7-11,18,21,55]. AL T, lnine minotrnsferse; HBsAg, heptitis B surfce ntigen; HCV, heptitis C virus. HAART for t lest 1 yer t the time of liver disese ssessment. The estimted weighted pooled RRs of cirrhosis for the 27 studies re shown in Figs 2 nd 3 ([73-77]). There ws significnt heterogeneity in the RRs between studies (P<.1). On the bsis of the rndom effects model, the overll RR of cirrhosis mong ptients coinfected with HIV /HCV, reltive to HCV monoinfected ptients ws 2.11 (95% Cl, ); 1.4 ( ) for studies undjusted for covrites (n = 8); nd 2.61 ( ) for studies djusted for covrites ( n = 19). For the non-haart group, the RR ws 2.49 (95% Cl, ). The RR of cirrhosis in the HAART group ws 1.72 (95% Cl, ) (Fig. 3). In the met-regression nlysis, there ws no significnt ssocition between HAARTnd risk of cirrhosis (n = 26 studies; P=.25). Similrly, there ws no significnt ssocition between CD4+ T-cell count nd risk of cirrhosis (n = 17 studies, P=.59). The ssocitions between HAART nd CD4+ T-cell count nd risk of cirrhosis remined insignificnt when djusted for both HAART (P=.26) nd CD4+ T-cell count (P=.43). Discussion Our systemtic review of the nturl history of heptitis C, involving 3567 individuls coinfected with HIV I HCV, hs demonstrted tht liver fibrosis progression in this group ppers to be constnt cross ll stges of fibrosis, nd tht disese progression is significntly influenced by durtion ofhcv infection. The predicted cumultive probbility of cirrhosis t 2 yers fter HCV infection ws 21% (95% Cl, 17-26%) nd 49% (4-59%) t 3 yers. The cumultive cirrhosis rte ws modestly lower in the stge-constnt method compred with the MMLE method. Our 2-yer-predicted estimte of 21% cirrhosis differs from estimtes mong ptients with hemophili: 11% in study by Telfer et l. [11 J; nd 42% in study by Eyster et l. [1]. Our smple consists minly of injecting drug users. Our 2-yer-predicted cirrhosis rtes mong individuls coinfected with HIV /HCV re comprble to published estimtes mong ptients monoinfected with HCV in liver clinic series (22%, 95% Cl, 18-26%) nd posttrnsfusion cohorts (24%, 11-37%), but much higher thn those of blood donor series (4%, 1-7%) or community-bsed cohorts (7%, 4-1%) [78]. Severl fctors such s mle gender, older ge t HCV infection, longer durtion of HCV infection, excess lcohol consumption, nd immunosuppression hve been ssocited with incresed risk of fibrosis progression in individuls coinfected with HIV/HCV [9,12,14,16, 18,22,79]. Our results found tht longer durtion of HCV infection ws significntly ssocited with slower rte of fibrosis progression. The resons re uncler, but my include diminishing trnsition rtes over time; recll

9 LIT Liver fibrosis in HIV/HCV coinfection Thein et l () Risk Lower Upper Risk rtio (95% Cl) rtio limit limit Z-vlue P-vlue Allory, Bierhoff, Di Mrtino, Eyster, Grbczewsk, Lesens, Mkris, Pl, Pl, 1998b Romeo, Serfty, Solo, Teller, Fixed effects Rndom effects (b) Benhmou, Bru, Gslightwl & Bini, Gonzlez, Mcis, Mrine'-Brjon, Mrtinez-Sierr, Mohsen, Monto, Rodriguez-Torres, Srmento-Cstro, Vlle Tovo, Verm, Fixed effects Rndom effects HCV monoinfection HIV/HCV eo infection Fig. 3. Risk rtios of cirrhosis between individuls monoinfected with heptitis C virus monoinfected nd individuls coinfected with HIV!HCV. () Non-HAART group; nd (b)* HAART group. *74% of individuls were receiving HAART. HAART, highly ctive ntiretrovirl therpy; HCV, heptitis C virus. bis for those with remote dte of infection; nd referrl or survivl bis, such tht individuls surviving longer nd who were infected erlier my hve n overll lower risk of progression. Progression of fibrosis ws not relted to other fctors, including the proportion of ptients on HAART or the men CD4+ T-cell count. We found tht liver fibrosis progression ppers constnt cross ll stges of fibrosis. We did not hve prticulr hypotheses bout how trnsition probbilities vry cross stges s function of study popultion. We believe tht referrl bis is potentil problem in cohort studies, nd tht, when present, my ffect the pttern of trnsition probbilities cross stges. The methodology of our nlysis hs some potentil limittions. First, the concept of dynmic fibrosis progression restricts the nlyses to individuls with known or estimted durtion ofhcv infection nd studies tht reported intermedite stges of fibrosis FO-F4.

10 LIT AIDS 28, Vol 22 No 15 Exclusion of studies tht do not report durtion ofinfection mens tht our estimtes my not be generlizble to the pproximtely 14% of the whole popultion without known risk fctors. Second, though the MMLE method hs the dvntge of estimting stge-specific trnsition rtes from single biopsy, these estimtes re sensitive to the completeness of fibrosis stge dt nd the ccurcy of stge clssifiction [ 49]. In ddition, the requirement of individul ptient dt from the primry ppers my introduce bis, s some covrites were not vilble for number of studies. Nevertheless, in the bsence of individul ptient dt, met-regression offers the best method to explin heterogeneity mong study results [8]. Third, exclusion of the 'gry literture' nd smll studies ( <2 cses) my msk potentil publiction bis. However, publiction bis is more of concern in experimentl studies, in which negtive trils re more likely to be suppressed. Here, we reviewed prognostic studies. We could not identify prticulr incentive for fvorble or unfvorble prognostic studies to be selectively suppressed. Thus, though we cnnot exclude the possibility tht exclusion of the 'gry literture' my be source of bis, we think it unlikely. Fourth, the prevlence of cirrhosis in our study my be underestimted due to selection bis. Ptients who ttended clinicl visits were dherent to ntiretrovirl therpy, were bstinent from lcohol, hd stble HIV infection, nd my hve been more likely to undergo liver biopsy. Thus, there is possible bis towrds ptients with less dvnced HIV infection. Finlly, our met-regression model my be underpowered nd my miss some predictors of fibrosis progression. Our results in reltively homogeneous popultion suggest tht chronic heptitis C outcomes re significntly worse in individuls coinfected with HIV /HCV thn in individuls monoinfected with HCV The estimted risk of cirrhosis for the 27 studies ws two-fold higher in individuls with HIV /HCV coinfection compred with those with HCV monoinfection: 2.5 (95% Cl, ) in the non-haart group; nd 1.7 ( ) in the HAART group. Overll, the risk of cirrhosis in our study in the HAART er is slightly lower compred with the pre-haart met-nlysis [33] (RR: 2.11, 95% Cl, vs. 2.92, ). Over the period studied, HAART did not pper to fully correct the dverse effect of HIV infection on HCV prognosis. This my be explined by number of fctors. Approximtely three-qurters (74%) of coinfected ptients were receiving HAART in the HAART group. HAART ptients hd short durtion of exposure nd some hd suboptiml response. In ddition, HAART my hve dul effects [81,82], producing slower fibrosis progression s result of immune reconstitution, but lso inducing liver toxicity [83], which my led to n enhncement of fibrogenesis. Finlly, there my be some other fctors ttributing to worse HCV prognosis thn the coinfection per se. In our nlysis of risk of cirrhosis, exclusion of ptients with decompensted liver disese in some studies my underestimte the difference in the rtes of cirrhosis between individuls coinfected with HIV /HCV nd monoinfected with HCV Complete cse nlysis for the effect of CD4+ T-cell count nd HAART on the risk of cirrhosis my lso reduce precision of the results [84]. However, the lck of n effect of HAART on the risk of cirrhosis persisted even without complete cse nlysis. Our study lso hs significnt strengths, thereby improving on previous studies such s it is more comprehensive, including non-english lnguge studies; it uses MMLE method to estimte prognosis, which does not require the ssumption of constnt progression rtes for ech stge; it llows estimtion of the effects of clinicl fctors nd HAART on liver fibrosis progression; nd it compres the risk of cirrhosis between individuls receiving HAART nd those not receiving HAART Our estimtes re generlizble to the injecting drug user popultion with HIV /HCV coinfection. These estimtes should provide more ccurte informtion for the prediction of HCV disese burden, economic evlution of ntivirl therpies nd preventive strtegies, nd helthcre policy decision-mking mong the injecting drug user popultion. Our findings hve implictions for the erly evlution of HCV tretment in individuls coinfected with HIV /HCV Acknowledgements The uthors thnk Ms Kren Liu for her ssistnce m retrieving ppers, nd Ms Kren Bremner for her editoril ssistnce to the finl drft of the mnuscript. H.-H.T is supported by the Ntionl Cndin Reserch Trining Progrm in Heptitis C postdoctorl fellowship. H.-H.T designed the study, conducted the sttisticl nlyses, drfted the originl mnuscript, nd ddressed the reviewers' comments. Q.Y contributed to the sttisticl nlyses, interprettion of the results, nd response to the reviewers' comments. G.D. nd M.K. contributed to the interprettion of the results, revision of the mnuscript, nd response to the reviewers' comments. There re no conflicts of interest. Dt presented in prt t the 4th!AS Conference 22-25th July, 27, Sydney; 58th Annul Meeting of the Americn Assocition for the Study of Liver Diseses

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13 LIT Liver fibrosis in HIV/HCV coinfection Thein et l Srmento-Cstro R, Hort A, Vsconcelos, Coelho H, Mendez J, Tvres AP, et l. Impct of peginterferon lph-2b nd ribvirin tretment on liver tissue in ptients with HCV or HCV-HIV eo-infection. j Infect 27; 54: Serfty L, Costgliol D, Wendum D, Picrd, Meyohs MC, Girrd PM, et l. Impct of erly-untreted HIV infection on chronic heptitis C in intrvenous drug users: cse-control study. AIDS 21; 15: Vlle Tovo C, Alves de Mttos A, Ribeiro de Souz A, Ferrri de Oliveir Rigo J, Leris de Almeid PR, Glperim B, et l. Impct of humn immunodeficiency virus infection in ptients infected with the heptitis C virus. Liver lnt 27; 27: Freemn AJ, Dore GJ, Lw MG, Thorpe M, Von Overbeck J, Lloyd AR, et l. Estimting progression to cirrhosis in chronic heptitis C virus infection. Heptology 21; 34: Cnchis PW, Yee HT, Fiel Ml, Dieterich DT, Liu R-C, Chiribog L, et l. Intrheptic CD4+ cell depletion in heptitis C virus/ HIV-coinfected ptients. j Acquir Immune Defic Syndr 24; 37: Schmid CH, Strk PC, Berlin JA, Lndis P, Lu j. Met-regression detected ssocitions between heterogeneous tretment effects nd study-level, but not ptient-level, fctors. j Cfin Epidemiol24; 57: Sulkowski MS, Mst EE, Seeff LB, Thoms DL. He;>titis C virus infection s n opportunistic disese in persons mfected with humn immunodeficiency virus. Cfin Infect Dis 2; 3 (Suppl 1):S77-S Thoms DL. Heptitis C nd humn immunodeficiency virus infection. Heptology 22; 36:S21-S Sulkowski MS, Thoms DL, Meht SH, Chisson RE, Moore RD. Heptotoxicity ssocited with nevirpine or efvirenz-contining ntiretrovirl therpy: role of heptitis C nd B infections. Heptology 22; 35: Koopmn L, vn der Heijden GJ, Grobbee DE, Rovers MM. Comprison of methods of hndling missing dt in individul ptient dt met-nlyses: n empiricl exmple on ntibiotics in children with cute otitis medi. Am j Epidemiol 28; 167: Copyright Lippincott Willims & Wilkins_ Unuthorized reproduction of this rticle is prohibited.