Antonietta Cargnel

Introduction A panel of experts met in Paris on 18 April to present research and practice protocols, and to discuss topics of current interest related to the treatment of HIV/hepatitis C virus (HCV) co-infection. The information presented focussed on the following main aspects: The magnitude of the problem of HIV/HCV co-infection The differences and similarities between HIV and HCV disease paradigms, thereby allowing extrapolation of the lessons learned in HIV on the care of patients with HCV or HIV/HCV co-infections Strategies for managing HIV in HCV-co-infected patients using antiretroviral drugs Current standards for HCV treatment and ongoing management Strategies for treating HCV in HIV-co-infected patients using pegylated interferon (peg-IFN) plus ribavirin, and the management of possible adverse effects Special challenges in HIV/HCV co-infection, including non-responders to IFN/ribavirin, patients with cirrhosis, extrahepatic manifestations, and hepatitis B virus co-infection. The bulk of the meeting was devoted to a discussion of the specifics of HIV/HCV co-infection treatment, answering the questions: why? how? who? when? After presentations and discussions, a consensus of opinion regarding general treatment strategy was formulated. Hepatitis C virus treatment in co-infected patients: why? AIDS-related morbidity and mortality in HIV-infected patients continue to decrease as a result of effective antiretroviral therapy and prophylaxis for traditional opportunistic infections [1]. HIV-infected patients now have hope for a prolonged AIDS-free survival. Concurrently, however, the morbidity and mortality from co-morbid HCV infection within this population is on the increase. The magnitude of the co-infection problem becomes clear when its prevalence and impact on morbidity and mortality are considered [2–9]. Prevalence of hepatitis C virus–HIV co-infection In the United States, it is estimated that 30% of the 800 000 HIV-infected living individuals are co-infected with HCV [10,11]. Similar rates (33%) have been estimated for western Europe, although the number of HIV-infected individuals is less well defined [12]. However, the magnitude of the problem is alarming in countries such as Spain, where at least half of the 130 000 HIV-infected patients are estimated to be HIV/HCV co-infected [12]. In fact, among some sub-groups of HIV-infected patients, such as injection drug users, the prevalence of co-infection is as high as 70–90% [11–13]. Hepatitis C virus and clinical progression of HIV disease The Swiss Cohort Study demonstrated that HCV accelerates the progression of HIV disease [14]. This prospective study of patients starting highly active antiretroviral therapy (HAART) found that HCV was independently associated with an increased risk of progression to AIDS and death. This finding was not related to a lower usage or much poorer tolerance of antiretroviral drugs among individuals with hepatitis C, which is in agreement with findings from other European groups [15]. Therefore, hepatitis C might be considered to be a co-factor for HIV disease progression. On the other hand, the Johns Hopkins Cohort Study found that co-infected patients who had a baseline CD4 cell count of between 50 and 200 cells/mm3 progressed to death more quickly than their HIV-mono-infected counterparts [16]. This observation probably highlighted the fact that HCV-positive patients, most of whom were intravenous drug addicts, had significantly less exposure to HAART, with a delay in treatment until CD4 cell counts dropped below 50 cells/mm3. In contrast with this potential deleterious effect of hepatitis C on HIV disease progression, recent reports [17,18] have pointed out that the hepatitis G virus, an agent closely related to HCV, seem to exert a protective effect on the course of HIV disease. As treatment of HCV with IFN is equally effective against hepatitis G, its clearance might negatively influence HIV infection. Hepatitis C virus and response to highly active antiretroviral therapy The Swiss Cohort Study also demonstrated that HCV may impair immune reconstitution after effective HAART [14]. HCV-positive individuals were less likely to achieve a CD4 cell increase of at least 50 cells/mm3 at one year after the start of HAART compared with HCV-negative individuals. This observation has not, however, been confirmed by others [19], and warrants further studies. HIV and acceleration of hepatitis C virus liver disease HIV accelerates HCV-related liver disease [20–25]. Progression that typically takes up to 30 years or longer in HCV-mono-infected individuals has been shown to take less than half that time in co-infected individuals. An early study by Martin et al. [26] identified the development of cirrhosis within 3 years after HCV diagnosis in three co-infected patients. In 1993, Eyster et al. [27] found that liver failure was accelerated by HIV in HCV-infected haemophiliac individuals. The following year, Telfer et al. [28] published a retrospective study, which found that the median time from first exposure to HCV to clinical demise was only 16.5 years in co-infected haemophiliac individuals. In a large study of HCV-mono-infected and HIV/HCV co-infected individuals, Sánchez-Quijano et al. [29] found that within 15 years of initial HCV infection, 25% of those who were co-infected with HIV developed cirrhosis compared with only 6.5% of those without HIV infection. Similar data were obtained by Soto et al. [30], who followed a large group of HCV-mono-infected and co-infected patients. In the first 10 years, 14.9% of co-infected patients developed cirrhosis compared with only 2.6% of HCV-mono-infected patients. Overall, cirrhotic HIV-infected patients with HCV do very poorly. In a study conducted by Di Martino and colleagues [31], HIV/HCV-co-infected patients with cirrhosis were more likely to decompensate and die than patients who were HIV negative. Interestingly, HCV treatment with IFN plus ribavirin appeared to be protective in most instances, with protection extending to those with HIV. This suggests retrospectively that although HCV treatment is less effective in cirrhotic patients from an antiviral perspective, it may delay decompensation [32]. Hepatocellular carcinoma in co-infected patients Hepatocellular carcinoma (HCC) appears to occur at a younger age and after a shorter duration of HCV infection in co-infected individuals. This was the finding in a case–control study in which seven co-infected individuals with HCC were analysed [33]. The mean age at HCC diagnosis was 42 years in the co-infected group compared with 69 years in the control group. The estimated mean length of HCV infection before HCC diagnosis was 18 years in the co-infected group, compared with 28 years in the control group. End-stage liver disease mortality in co-infected patients A number of studies have demonstrated the association of HIV co-infection with an increased risk of morbidity and mortality caused by end-stage liver disease (ESLD) (Table 1) [2–9]. Iribarren et al. [34] reviewed the causes of death among a population of 1600 co-infected patients in a Spanish hospital over a 21 month period. Of the 44 total deaths, liver disease was responsible for up to 25%. Recent studies from Italy [3] and Spain [2,4] have compared the percentage of total in-hospital deaths caused by ESLD before 1995 with in-hospital deaths occurring within a time period after 1995. Although the total number of in-hospital deaths declined from the first time period to the later, the percentage of deaths caused by ESLD increased from 13 to 35% in the Italian study, and from 5 to 45% in the Spanish studies.Table 1: Mortality caused by end-stage liver disease among HIV-infected individuals. Similar results were seen in a US study [6]. In 1991, 11% of deaths in the studied HIV population were caused by ESLD. By 1998, ESLD was the leading cause of death, causing 50% of deaths (Table 1). Of those patients who died in 1998 of ESLD, 90% were HCV positive. In France, Cacoub et al. [8] documented a fivefold increase in deaths caused by liver disease in the time period before 1995 compared with after 1997, despite an overall declining death rate among co-infected individuals (Table 1). In 1997, Darby et al. [35] published a cohort study demonstrating the impact of co-infection among young men with haemophilia. HIV-infected patients, regardless of the severity of haemophilia, were found to be approximately sevenfold more likely to die of liver disease. Lesens et al. [36] also demonstrated a sevenfold increased risk of death in a 1999 prospective study of 147 HCV-positive haemophiliac individuals. Interestingly, co-infected patients with genotype 1 may have a more rapid progression of liver disease than individuals carrying other HCV genotypes [37]. Immune status influences hepatitis C virus liver disease Rockstroh et al. [38] looked at the association between immune function and the development of HCV liver disease. The study concluded either that immunosuppression accelerates the progression of liver disease or that once liver failure begins, deterioration with respect to AIDS also begins, progressing to death more rapidly. The finding of a greater severity of HCV liver disease as the immunodeficiency progresses has been confirmed by others [39]. Accordingly, the 1999 US Public Health Service/Infectious Diseases Society of America guidelines recognized HCV co-infection as an important opportunistic pathogen among HIV-infected patients [36,40]. Impact of highly active antiretroviral therapy on hepatitis C virus liver disease The impact of HAART on the progression of HCV liver disease is controversial. One possibility is that antiretroviral therapy could increase hepatic necroinflammatory activity and thereby accelerate the progression of HCV-related liver disease. Vento et al. [41] reported an increased mean Knodell score (from 8 to 13) in patients after starting HAART. Conversely, other studies have suggested that the use of HIV protease inhibitors (PI) may be associated with an improvement in liver histology with respect to those without PI [42,43]. This benefit may probably equally be seen with other potent antiretroviral regimens without PI. Prospective studies involving paired liver biopsies are needed to address the impact of HAART and immune reconstitution on HCV-related liver disease. Hepatotoxicity of highly active antiretroviral therapy in co-infected patients The association of chronic HCV with hepatotoxicity during HAART is well established [44,45]. Hepatitis C is an independent risk factor for hepatotoxicity with HAART (Table 2) [46–52]. Overall, significant liver enzyme elevations are seen in approximately 15% of individuals receiving antiretroviral drugs. Severe hepatotoxicity, however, leading to drug discontinuation, occurs in less than 10% of cases. Two mechanisms have been involved (Table 3), the first of which represents a hypersensitivity reaction, often affecting the skin and other organs, and occurring a few days to weeks after beginning antiretroviral therapy. A second mechanism with delayed onset (typically appearing several months after beginning therapy) is limited to the liver, and represents an intrinsic toxic effect of the drugs in use, and therefore is dose related [52]. Drugs such as nevirapine can produce liver toxicity by both mechanisms; whereas abacavir tends to involve just the first mechanism, often in the context of a multiorganic reaction. Drugs such as stavudine may cause liver toxicity through a cumulative effect.Table 2: Major studies assessing the risk of severe hepatic damage after beginning antiretroviral therapy. Table 3: Mechanisms of liver toxicity using antiretroviral drugs [32]. More rarely, in HCV chronic carriers experiencing a dramatic CD4 cell increase after beginning antiretroviral therapy, increases in transaminases can reflect an immune reconstitution syndrome [53], resembling what has been described in individuals with latent cytomegalovirus or mycobacterial infections. Further research is needed to determine the mechanism by which HCV infection or HCV-related liver disease increases the risk of HAART-associated liver injury. Hepatitis C virus-RNA dynamics in HIV infection and impact of highly active antiretroviral therapy Overall, serum HCV-RNA titres are 1.5 to twofold higher in HIV/HCV co-infected individuals with respect to individuals with single HCV infections [54–56], probably reflecting an impairment in the control of HCV replication in the setting of immunodeficiency. Whether this increase in HCV viral burden contributes to explaining the greater liver injury noticed in HIV/HCV co-infected patients is unknown, although there is no clear correlation between the extent of liver fibrosis and the level of HCV RNA. In individuals who begin potent antiretroviral therapy, serum HCV-RNA levels tend to increase during the first 3 months [57–59], decreasing slowly thereafter, first returning to baseline levels and even decreasing much later [60] (Fig. 1). Antiretroviral therapy may thus indirectly benefit the prognosis of HCV-related liver disease, reducing HCV replication on the long term. However, the relationship of HCV load and the progression of liver disease is uncertain.Fig. 1.: Dynamics of serum hepatitis C virus RNA in HIV infection and impact of antiretroviral treatment.Hepatitis C virus treatment in co-infected patients: how? The primary goal of HCV treatment is to achieve a sustained virological response that permits fibrosis regression, the disappearance of extrahepatic manifestations, and a reduction of the risk of transmission [61]. Moreover, in patients without sustained virological response, the progression of fibrosis could be ameliorated through suppressive maintenance therapy [32,62]. Until recently, IFN plus ribavirin combination therapy was the standard of care for the treatment of HCV infection [11,61]. Peg-IFN plus ribavirin combination therapy is, however, currently the preferred option, as it allows one to achieve the highest virological response rates to date: 41–42% for genotype 1 and 76–80% for genotypes 2 and 3 (Table 4) [63,64]. In addition to inducing virological response, peg-IFN/ribavirin also allows fibrosis regression in viral sustained responders [64,65]. In non-responders, in whom the first goal is not achieved, viral eradication, the second goal, slows fibrosis progression, and the prevention of clinical outcomes (ESLD, HCC, and death) [32] might be attained with maintenance therapy using peg-IFN monotherapy.Table 4: Sustained virological response to pegylated interferons in HIV-negative individuals with chronic hepatitis C. Factors associated with sustained virological response The achievement of sustained response depends on host and viral factors. Poynard et al. [65] identified five independent predictors of sustained response to IFN/ribavirin. Genotype 2 or 3 is the most important predictor. The remaining four predictors were: low viral load (< 3.5 million copies/ml), no or just portal fibrosis, female sex, and age below 40 years. Subsequent analyses demonstrated that female sex as a predictor was an issue of body mass index rather than sex. Ribavirin doses particularly need to be adequate to weight if optimal response rates are to be achieved [64]. For instance, when using adequate ribavirin doses, up to 48% of individuals with genotype 1 and up to 88% of those with genotypes 2/3 reached sustained response using peg-IFN plus ribavirin [64]. Additional predictive factors of response related to HIV include CD4 cell counts greater than 500 cells/mm3, plasma HIV-RNA levels below 10 000 copies/ml, and no alcohol consumption [23,66]. Treatment considerations related to CD4 cell counts Co-infected patients with CD4 cell counts greater than 500 cells/mm3 should be treated for HCV eradication. In individuals with CD4 cell counts of less than 500/mm3, treatment is less effective [66], but may be considered in order to reduce the risk of hepatotoxicity of antiretroviral drugs and the higher risk of progression to liver failure among patients with lower CD4 cell counts [38,39]. Overall, current HCV treatment in HIV/HCV co-infected patients can normalize alanine aminotransferase (ALT) levels and clean HCV RNA by 50%, decrease the progression of fibrosis by 60%, and decrease the risk of dying by 16% [20–25,42,43]. Weight-based dosing Dosing on the basis of the patient's body weight seems to be the key to optimized success with minimal side-effects using peg-IFN/ribavirin: peg-IFN alfa-2b (1.5 μg/kg per week) or peg-IFN alfa-2a (180 μg per week) plus ribavirin (> 10.6 mg/kg per day) represents the most effective HCV treatment option [63,64,67]. This is especially important when considering the weight variation among population groups. For example, Americans weigh an average of 10 kg more than Europeans. Weight-based dosing not only ensures that patients receive enough drug, it also ensures that they do not receive too much drug, thereby reducing the risk of adverse events that may result if a standard dose is given to a low-weight patient. An adequate ribavirin dose, particularly at the beginning of treatment, is linked to an increased likelihood of sustained virological response. In a recent multicentre trial [68], greater ribavirin use at week 4 of treatment was associated with a greater response rate at week 24. Considering these findings, an adequate dose of ribavirin, particularly at the start of therapy, should not be modified without first trying other strategies to increase tolerance, such as the use of epoetin alfa [69]. Concern about ribavirin use in co-infected patients There has been concern about the use of ribavirin in HIV/HCV co-infected patients because of dose-dependent anaemia and drug–drug interactions [23,70]. Ribavirin-induced anaemia may be more significant in co-infected patients [21,22]. This risk, however, should not preclude treatment, because it can quite often be successfully managed with erythropoietin [69] or by ribavirin dose reduction. Prospective studies examining the efficacy of this approach are ongoing. Concerns regarding interactions between ribavirin and antiretroviral drugs are more complex. Ribavirin, a guanosine nucleoside analogue, is known to inhibit the intracellular phosphorylation of zidovudine, stavudine and zalcitabine in vitro. There is concern that this may cause anti-HIV antagonism in vivo. However, to date, clinical data have not supported these in-vitro observations [70,71]. In addition, ribavirin enhances the phosphorylation of didanosine (Fig. 2), which may be of benefit in increasing the anti-HIV effect [72]. However, recent case reports have led to concern about the possible increased risk of pancreatitis and mitochondrial toxicity in patients taking ribavirin and didanosine [73–76]. Therefore, patients receiving ribavirin in combination with nucleoside analogues such as zidovudine or didanosine should be observed closely, and in some cases, consideration may be given to modyfing HAART to avoid the combination of these drugs. Another aspect that is still unclear regards the potential compromise in the effect of ribavirin on HCV as a result of the concomitant use of zidovudine or stavudine, because all these compounds share the same phosphorylation pathways. Prospective studies are underway to evaluate the clinical and pharmacological interactions of HAART and peg-IFN/ribavirin therapy.Fig. 2.: Metabolic pathways leading to the potentiation of didanosine by ribavirin. Ribavirin inhibits inosine monophosphate (IMP) dehydrogenase. This leads to an increase of the IMP pool, which acts as a phosphate donor for the conversion of didanosine (ddI) into dideoxy-IMP (ddIMP). This compound is then metabolized into the triphosphorylated metabolites dideoxy-adenosine monophosphate (ddAMP), dideoxy-adenosine 5'-diphosphate (ddADP) and dideoxy-adenosine triphosphate (ddATP). The increased concentrations of ddATP inhibits both HIV reverse transcriptase and mitochondrial DNA polymerase γ.Warning on the risk of lactic acidosis acidosis is of the of associated with mitochondrial toxicity of mitochondrial toxicity may not be and include and lactic analogues not only in the of more but in their potential for causing disease there is no of mitochondrial toxicity of lactic acidosis with the use of ribavirin without other nucleoside A 1995 study observed patients over 5 years with anti-HIV and found a rate of lactic acidosis of per A more recent study found per among patients observed over 18 with nucleoside only patients taking stavudine and didanosine were the increased to per The and has reports of of lactic acidosis associated with nucleoside Of were associated with a single nucleoside and with [69]. Overall, stavudine and didanosine were the most associated with lactic and of the cases, A mortality rate of among these reported to the US and the severity of the Ribavirin is a potent of inosine monophosphate (IMP) which leads to levels of the active of a key involved in mitochondrial toxicity (Fig. of the of ribavirin as a for has not been as the development of ribavirin that of lactic acidosis with ribavirin have been described in individuals with HCV of lactic acidosis or mitochondrial toxicity associated with ribavirin have been identified up to however, in HIV/HCV-co-infected individuals of had data reported that the specifics of what drugs the patients were were on a fact that suggests the possibility that was the One was not receiving nucleoside and that was with and was to continue with of the were also on stavudine, and of the were on abacavir is a analogue, it is involved in the same as didanosine (Fig. it could with ribavirin. However, current data that abacavir has a very low potential for mitochondrial toxicity treating HIV/HCV co-infected patients need to be of the potential risk of lactic acidosis associated with the concomitant use of ribavirin and nucleoside Although this has been seen only in combination with the risk may also in combination with other nucleoside into these the use of ribavirin with particularly with clinical and should of serum and levels in HIV/HCV co-infected patients to didanosine and ribavirin. in co-infected patients Until 2 years IFN was the only drug for the treatment of chronic hepatitis C. Overall, response rates to IFN observed in co-infected patients were to those observed in HIV-negative patients (Table However, response rates were significantly lower among HIV/HCV co-infected patients with low CD4 cell counts In combination therapy the standard of care for the treatment of chronic hepatitis C [61]. on the and efficacy of combination therapy in co-infected individuals is (Table and Table co-infected patients treated with standard were followed by et al. at 18 months had a sustained virological response. et al. noticed a sustained response rate of taking in 18 HIV/HCV to a course of IFN studies and others were a of to determine with adequate CD4 HCV could be in a co-infected patient. in a prospective study, et al. followed co-infected patients who were non-responders to IFN at 3 After months on combination therapy, one achieved and HCV-RNA Treatment response to interferon in HIV/hepatitis C virus co-infected patients. Table Treatment response to interferon plus ribavirin in HIV/hepatitis C virus co-infected patients. Table to interferon plus ribavirin in HIV/hepatitis C virus co-infected patients who or to after a course of interferon data that patients receiving achieve a higher sustained response rate than patients receiving IFN/ribavirin, especially in those with HCV genotype 1 In an ongoing study from the Hepatitis HCV-RNA after weeks of therapy in 35% of patients receiving IFN plus ribavirin compared with only of those receiving standard IFN three plus ribavirin. This the that exposure to rather than three is more effective for viral eradication. findings that an with IFN are by an ongoing large Spanish trial In patients who after a course of IFN with an overall rate of response of one (Table in co-infected patients The first of the and efficacy of combination therapy with peg-IFN plus ribavirin in individuals has shown that the overall rate of response was The trial is conducted in Spain, and individuals have The rate of for these patients should be at the of the The study is a prospective multicentre trial currently in date, patients have been to receive either IFN 3 three a week plus ribavirin 800 or peg-IFN 1.5 μg/kg per week plus ribavirin 800 for to weeks after the onset of treatment, the HIV viral load has in both treatment groups. CD4 cell total and counts all declined after the onset of HCV treatment, with no between the groups. of severe adverse events have been in the peg-IFN/ribavirin group, in the group, and one before events and for drug The of in 13 in the peg-IFN/ribavirin group and in the group. Of these cases, were by the as a result of and a not to start the trial studies with peg-IFN/ribavirin in co-infected patients are ongoing. The trial to include and an study include patients. The first results of these studies are to be in of therapy The duration of therapy should be to the patient's virological response at weeks of treatment and the number of predictors of response HCV RNA is by polymerase treatment should be and other strategies is and the has than four predictors of response, treatment should continue the has four or more treatment may be at Moreover, results from a recent trial suggested that the of HCV RNA after weeks on peg-IFN plus ribavirin is highly predictive of a of further sustained response. Therefore, treatment might be at this early drug exposure and This observation is of in patients, most of whom are other drugs. Further studies are needed to this of anaemia with erythropoietin The of ribavirin is levels below in to 35% of patients receiving therapy Although this is managed by ribavirin dose reduction or discontinuation, erythropoietin therapy has to be an effective treatment In addition, the ribavirin dose is more likely to in patients with anaemia treated with what is known about the of adequate and

Introduction Chronic hepatitis C (HCV) infection is currently one of the most clinically relevant comorbidities in the HIV population; overall, it affects one third of HIV-positive individuals [1]. Progression to end-stage liver disease occurs faster in coinfected patients [2–4] and decompensated cirrhosis is one of the main causes of hospitalization and death in this population [5–8]. However, the risk of hepatotoxicity using antiretroviral drugs is increased in subjects with underlying HCV infection [9,10]. Therefore, the optimal management of chronic HCV in HIV-positive patients is currently a priority. Several guidelines for caring for HCV infection in HIV-positive individuals have been released [11–15]. Because new and relevant information has recently appeared, it is convenient to update them. Eleven areas have been identified in which new recommendations are particularly needed: management of patients with persistently normal aminotransferases liver fibrosis assessment: when and how predictors of response to anti-HCV therapy in coinfected patients optimal dosages of pegylated interferon (pegIFN) and ribavirin (RBV) optimal duration of anti-HCV therapy treatment of non-responders and/or relapsers care of patients with end-stage liver disease treatment of acute HCV infection in HIV-infected individuals management of patients with multiple hepatitis viruses interactions between HCV medications and antiretroviral drugs hepatotoxicity of antiretroviral drugs. Patients with persistently normal aminotransferases The exact definition of persistently normal aminotransferases is not well established in patients with chronic HCV infection. Fluctuations in aspartate/alanine aminotransferases (AST/ALT) are frequent in HCV-related liver disease and differences in the prevalence of persistently normal ALT may reflect the length of follow-up and/or the number of biochemical determinations made [16–18]. We propose a definition requiring the demonstration of normal ALT in at least three consecutive tests made at least 2 months apart each, over a period of 12 months. One third of individuals who initially meet these criteria, however, may show ALT elevations as the period of observation extends [19–22]. Therefore, the characterization of patients with normal ALT should not be based on sporadic determinations of liver enzymes, and the term ‘asymptomatic’ or ‘healthy’ HCV carrier is inappropriate [22]. A further consideration is that the so-called ‘normal’ limit of aminotransferases has to be revisited, since recent studies have shown that aminotransferase levels in subjects without any liver injury [23] or in persons free of liver-related death on follow-up [24] are definitely lower than those accepted as normal in the past. The degree of aminotransferase elevation generally reflects the extent of liver inflammation. Around 25% of HCV-monoinfected patients show persistently normal ALT [19–22,25] and liver disease is generally less severe in this group [25–28]. Women tend to show more frequently persistently normal ALT than men [28], as well as subjects infected with HCV genotype 4 [29–31]. In contrast, patients with HCV genotype 3 show normal ALT less frequently [31]. As expected considering the immune-mediated nature of HCV-related liver disease, there is little correlation between serum HCV RNA and aminotransferases [32]. Few studies have been conducted so far in coinfected patients with normal ALT. Only 7–9% of this population show persistently normal liver enzymes [31,33]. Exposure to antiretroviral drugs, alcohol abuse and other conditions explain, on the one hand, the lower rate of normal ALT in HIV-positive patients with chronic HCV infection. On the other hand, significant liver fibrosis has been reported in up to 25–40% of coinfected patients with normal ALT [31,33], a prevalence higher than the 10–30% reported in HCV-monoinfected individuals [28,34]. In two recent studies, 12–14% of coinfected patients with normal ALT had cirrhosis on liver biopsy [33,35]. Since less than 15% of HCV-monoinfected individuals with minimal or absent liver fibrosis progress to cirrhosis within 15 years [36], and most patients with normal ALT have mild liver disease [37], these individuals have formerly not been considered for HCV therapy. Moreover, flares in ALT activity and lower treatment responses were reported in the past in patients with normal ALT exposed to IFN, which further discouraged their treatment. However, recent studies in HCV-monoinfected patients have alerted clinicians to the higher liver fibrosis progression in initially mild chronic HCV infection [38] and similar responses to pegIFN plus ribavirin RBV have been obtained in patients with normal than with elevated aminotransferases [39]. Recommendation Given that the prevalence of and progression to advanced liver fibrosis in patients with normal ALT is higher in HIV-positive patients [31,33], these patients should be considered for anti-HCV therapy. Treatment should be recommended based on patient's motivation, disease duration, fibrosis stage and virological profile regardless ALT levels [40]. Liver fibrosis assessment: when and how? The extent of hepatic fibrosis is the best prognostic factor of disease progression in patients with chronic HCV infection, and therefore it is worth considering this before initiating HCV therapy. Liver biopsy has been for many years the only tool to assess hepatic fibrosis. It has the advantage of providing additional information on other relevant histological findings, such as necroinflammation and steatosis. However, the development of non-invasive tools for staging hepatic fibrosis has been prompted by the several limitations of liver biopsy, such as its invasive nature, with occasional serious and even life-threatening complications [41]; sampling error owing to relatively small size and/or fragmentation of examined tissue [42] and/or to the inherent heterogeneity of hepatic fibrosis [43]; low acceptance by most patients; and relatively elevated cost [44]. Non-invasive procedures to assess liver fibrosis are currently divided into two major categories: imaging techniques, such as elastometry (FibroScan) [45–48] and serum biochemical markers (i.e., Fibrotest, APRI, SHASTA, FIB-4, Forn's index, etc.) [49–53]. These tools are generally accurate in discriminating between lack of fibrosis and advanced fibrosis but are less precise in distinguishing between intermediate fibrosis stages. Their predictive value is particularly good for advanced hepatic fibrosis and cirrhosis [54]. However, serum fibrosis markers are generally less reliable in coinfected patients, given the inflammatory nature of HIV disease and/or the frequent prescription of drugs in this population that may interfere with some fibrosis markers in the blood [55,56], as with bilirubin elevations in atazanavir therapy, gamma-glutamate transaminase abnormalities with non-nucleoside reverse transcriptase inhibitors, or cholesterol elevations associated with some protease inhibitors. In contrast, fibrosis staging using elastometry seems to be more reliable in this setting, avoiding such interference [48,57]. Elastometric measurements can be made in 10 min, be repeated periodically, are inexpensive and have more than 90% positive predictive value for advanced fibrosis [45–47]. When the diagnosis of a hepatic disease is clear by other means, as occurs with chronic HCV infection using virological markers (serum HCV RNA), the need for a liver biopsy to stage hepatic fibrosis and guide treatment decisions is currently no longer justified in most instances [58,59]. The higher response to pegIFN–RBV compared with that to standard IFN, the faster progression of HCV-related liver disease in the HIV setting and the chance to assess the virological response at earlier time-points to identify who will and who will not respond to therapy are all factors that allow the opportunity to prescribe HCV therapy to most patients while avoiding a liver biopsy [59]. The availability of easier means to assess liver fibrosis accurately has permitted this invasive procedure to be abandoned in most cases in routine clinical practice outside academic purposes. Moreover, these new tools have opened further opportunities to improve our knowledge of the natural history of HCV-related liver damage. Large cross-sectional and longitudinal studies have allowed recognition of (1) HCV genotype 3 as an independent predictor of accelerated liver fibrosis [60]; (2) different fibrosis thresholds in cirrhotic patients for developing distinct complications (e.g., esophageal varices, ascites or bleeding) [61]; and (3) of the possibility that severe liver fibrosis, including cirrhosis, can partially revert in at least a subset of patients who clear HCV after IFN therapy [62–64]. The information needed about hepatic fibrosis in chronic HCV infection is limited to that required to divide patients into those with and those without fibrosis (the latter group has not immediate need to be treated) and to recognize liver cirrhosis. Treatment is particularly needed for those with compensated cirrhotic disease; moreover, they should undergo periodic screening for esophageal varices and hepatocarcinoma, and overall are more prone to experience liver toxicity under antiretroviral therapy [65]. With this view, the distinction of histopathological stages of hepatic fibrosis based on a liver biopsy is currently unnecessary, avoiding the inherent problems derived from intra- and interobserver variations [66] and the other limitations mentioned above. Figure 1 summarizes the main variables that should be assessed before prescribing HCV therapy.Fig. 1: Main variables to assess in patients considered as candidates for hepatitis C (HCV) therapy. *Low viral load defined as HCV RNA < 500 000–800 000 IU/ml. Ab, antibody.Recommendation Information on liver fibrosis staging is important for therapeutic decisions in coinfected patients. However, a liver biopsy is not mandatory for considering the treatment of chronic HCV infection. A combination of non-invasive methods to assess liver fibrosis accurately predicts hepatic fibrosis in most cases. Predictors of response to hepatitis C therapy Baseline serum HCV RNA and HCV genotype are the main predictors of sustained virological response (SVR) to pegIFN–RBV in coinfected [11,14,67,68] as in HCV-monoinfected patients. Several other variables, however, may influence treatment responses, although generally to a lesser extent (Table 1). They can be grouped in three categories, determining a better outcome as follows: (1) host (younger age, non-black ethnicity, lower body mass index, lack of insulin resistance), (2) HCV status (elevated ALT, less advanced hepatic fibrosis), and (3) treatment schedule (optimal doses of pegIFN and/or RBV, enough length of therapy, good adherence). In addition, treatment outcomes could be better depending on some HIV variables, such as higher CD4 cell counts [69] or low HIV load, although it may just reflect a better tolerance of the anti-HCV medication in this subset of patients [70].Table 1: Factors associated with sustained virological response to HCV therapy.Particular attention has recently been paid to the negative impact of insulin resistance on HCV treatment response [71]. Insulin resistance is quite prevalent in coinfected patients at least in part because of the use of certain antiretroviral drugs [72,73]. Therefore, prevention of insulin resistance and/or its adequate management (even considering treatment with insulin-sensitizer agents when indicated) might improve HCV treatment outcomes in coinfected patients [74]. As in HCV-monoinfected patients, treatment adherence should be encouraged as much as possible. The ‘80/80/80’ rule is equally valid in coinfected patients, meaning that subjects who take more than 80% of pegIFN and of RBV doses during at least 80% of planned period of therapy respond significantly better than the rest [75]. Therefore, adequate selection of treatment candidates [76], psychological and/or psychiatric support [77] and use of growth factors to avoid dose reductions of either pegIFN and/or RBV [78,79] must all be encouraged in order to maintain adequate doses of anti-HCV medications in the majority of patients. The kinetics of HCV load in response to pegIFN–RBV is a reliable indicator of treatment efficacy. The availability of sensitive quantitative tools to closely monitor HCV decays under treatment has permitted the recognition of early time-points with high predictive value of SVR. Overall, the early virological response to HCV therapy divides patients into those sensitive and those refractory to therapy. Nearly 20% of HCV-monoinfected subjects do not show a significant reduction in HCV viremia (defined as a decline > 1 log IU/ml) during the first month of pegIFN–RBV [80], and this figure increases up to 30% in coinfected patients [81]. In virological responders, the best positive predictive value for SVR is achieved when a negative serum HCV RNA is attained at week 4 of therapy (rapid virological response, RVR), while the best negative predictive value for SVR is seen when HCV RNA falls < 2 log IU/ml at week 12 [67,68,82–86]. Higher baseline HCV RNA levels in coinfected patients compared with HCV-monoinfected individuals may explain why they achieve undetectable HCV viremia at week 4 less frequently and, therefore, achieve SVR less often [87]. Coinfected patients may show slower HCV decays on HCV therapy [88]. Interestingly, this could be overcome at least partially using higher RBV doses [81]. The so-called ‘2-log stopping rule’ refers to the strong predictive value of non-response at the week 12 assessment of virological response [80]. The failure to achieve HCV RNA declines > 2 log IU/ml (early virological response) at this time point permits the premature discontinuation of anti-HCV therapy, avoiding side effects and costs, when there is no chance of attaining the main goal of anti-HCV therapy, which is eradication of HCV infection. Fortunately, this rule works as well in coinfected as in HCV-monoinfected patients [67,68,82–86]. By comparison, a negative serum HCV RNA 6 months after completing anti-HCV therapy, which defines SVR, correlates with the long-term clearance of serum HCV as well as with histological and clinical improvements in most patients [89–91]. Therefore, ‘occult’ HCV infections with the potential worry of late HCV relapses are very rare. Recommendation The achievement of SVR can be predicted on the basis of negative serum HCV RNA at week 4 of therapy. On the other hand, a reduction < 2 log IU/ml in HCV RNA at week 12 and/or the presence of detectable viremia at week 24 both predict lack of SVR; accordingly these patients should be advised to stop prematurely anti-HCV therapy. Optimal dosages of pegylated interferon and ribavirin Adequate exposure to RBV is crucial to maximize responses to anti-HCV therapy [92–94]. Weight-based dosing seems well able to balance the highest efficacy and the lowest limiting toxicities of the drug, namely anemia. Pharmacokinetic studies have shown a good correlation between RBV plasma levels and HCV RNA responses [95,96]. Therefore, the use of fixed low doses of RBV (800 mg/day) in most trials conducted so far in coinfected patients could explain lower SVR [67,68,82–85,97–100]. The use of higher RBV doses (1000–1200 mg/day) in the PRESCO trial has confirmed this assumption, since the overall SVR in this trial (50%) is the highest reported so far in coinfected patients [101]. Figure 2 shows the proportion of patients achieving SVR in pivotal trials as a function of distinct doses of RBV and HIV status. Clearly, while HCV/HIV-coinfected patients may respond less, low RBV exposure may further impair treatment outcomes.Fig. 2: Proportion of patients with sustained virological response (SVR) in three different large trials in HIV-positive (pos) and HIV-negative (neg) patients using low or weight-based ribavirin (RBV) doses (intent-to-treat analysis).Optimal exposure to RBV could be particularly important in coinfected patients if the main mechanism of RBV action is hypermutagenesis [93,94,102,103]. Causing errors in the virus replication cycle, RBV activity should be maximized in HIV-positive individuals, in whom the immune-mediated effects of IFN are compromised. Moreover, the benefit of adequate RBV exposure might not be limited to patients infected with HCV genotypes 1–4 and may expand to genotype 3 [81]. In HCV-monoinfected individuals, a flat RBV dose of 800 mg/day is enough for genotype 3 [104], as long as therapy is provided for at least 24 weeks. However, shorter periods of therapy seem to require greater RBV doses in order to minimize relapses [105,106]. Anemia is the main drawback of increasing RBV dosing and may force a reduction in RBV dosage. When dose adjustments are made within the first weeks of therapy, reduced SVR may be expected [107], especially in patients with HCV genotypes 1–4. The use of zidovudine with pegIFN–RBV significantly increases the risk of developing severe anemia [108]. Therefore, when possible, zidovudine should be avoided and the use of erythropoetin should be encouraged in patients developing anemia under pegIFN–RBV in order to avoid the need for RBV dose reductions [78,79]. The efficacy of higher doses of pegIFN in coinfected patients has been explored in a few studies. In the CORAL-1 trial, the administration of 270 μg/week of pegIFN alpha-2a for the first 4 weeks did not improve the early virological response, whether measured as the proportion of patients with undetectable HCV load at week 4 or as reductions of > 2 log IU/ml HCV RNA at week 12, when compared with the administration of standard doses (180 μg/week) [109]. However, the size of the study population in that study was relatively small and nearly half the patients carried non-1 HCV genotypes. In contrast, data from studies conducted in HCV-monoinfected individuals suggest that there is a subset of patients who may benefit from exposure to higher doses of pegIFN [110] and this issue still warrants further investigation. Recommendation The current treatment of chronic HCV infection in HIV-positive persons should be pegIFN at standard doses plus weight-based RBV (1000 mg/day if < 75 kg and 1200 mg/day if > 5 kg). Optimal duration of therapy Studies conducted in HCV-monoinfected patients have shown that RVR, defined as undetectable HCV load at week 4, in patients treated with pegIFN–RBV may allow therapy to be shortened safely. Accordingly, treatment for only 12–16 weeks in patients with HCV genotype 3 [105,106] or for only 24 weeks in HCV genotype 1 [111,112] have been proposed for patients with RVR. The picture seems to be slightly different in coinfected patients. First, HCV load is generally higher in this population, which could explain why a smaller proportion reaches undetectable viremia at week 4 despite showing good early virological response [87]. Second, HCV clearance driven by IFN could be delayed in the HIV setting [86,88]. Third, the relapse rate upon completion of treatment might be increased in coinfected patients. This was shown to be the case for 24 weeks of therapy in HCV genotypes 2–3 in earlier trials [98,113]. For all these reasons, prior guidelines have recommended that duration of treatment in coinfected patients should be 48 weeks regardless HCV genotype [12,15]. It is important to note that the 2 log IU/ml rule at week 12 is also highly predictive of non-SVR in coinfected patients [12,15], which permits premature cessation of anti-HCV therapy when there is no chance of achieving a cure. Recent studies, however, have questioned these simple views to some extent. In a retrospective study conducted in coinfected patients with HCV genotypes 2–3, the subset who reached undetectable HCV RNA at week 4 could safely stop therapy at week 24, with minimal risk of relapse [114]. Similar findings have been reported in another recent Irish study [115]. However, a retrospective substudy of the APRICOT trial has shown that patients with HCV genotype 1 with low baseline HCV RNA and RVR obtained high rates of SVR (61%) and did not relapse [116], suggesting that shorten periods of therapy could have been enough in those patients. Overall, all these preliminary data encourage the provision of shorten periods of therapy on the basis of viral response at week 4, and clearly studies specifically designed to confirm this hypothesis in coinfected patients are needed. It might be the case that relapses could be limited to the subset of patients with high baseline HCV load and/or advanced fibrosis despite experiencing RVR, in whom 48 weeks of therapy would still be advisable [117]. In some patients with slow virological response, extended periods of treatment may permit SVR to be achieved [118]. Detectable viremia at week 4 seems to identify a subset of patients with genotypes 1–4 who may benefit from longer duration of therapy provided that it proves to be effective (> 2 log IU/ml fall in HCV RNA at week 12 by undetectable viremia at week However, the main with extended periods of therapy is This may be particularly in coinfected individuals, given that a tolerance of the medication has on outcomes in many trials trials designed to the efficacy of extended periods of therapy in coinfected patients without RVR therefore, this the information the that shorter periods of therapy could be advised in patients with HCV genotypes 2–3 with RVR, as long as HCV load is there is good there is not advanced hepatic fibrosis and weight-based RBV dosing is For the rest of the patients with HCV genotypes 2–3, 48 weeks of therapy could still be In patients with HCV genotypes of treatment 48 weeks could be recommended in the of RVR if the medication is well However, as high rates might limit the benefit of this optimal duration of hepatitis C (HCV) therapy in HCV/HIV-coinfected patients. patients with baseline low viral load and minimal liver fibrosis. The current treatment of chronic HCV infection in HIV-positive persons should be pegIFN plus weight-based RBV for 48 weeks. Patients infected with HCV genotype 2–3 and RVR could benefit from shorter of therapy. In contrast, of HCV genotypes 1 and 4 with early virological response but not RVR might benefit from extended of therapy. Treatment of non-responders and/or relapsers A number of coinfected patients have been exposed to without achieving SVR. These patients to be at risk for progression to end-stage liver disease, including the development of 2 summarizes the distinct these of which may require a distinct 2: of and for patients coinfected with hepatitis C and HIV who are to prior prior (i.e., shorter duration, low RBV with standard who prematurely therapy owing to side or who were to the medication are not treatment and could be better considered as patients. This group should be to current in The data that subjects who a prior of therapy may achieve but lower SVR rates than patients Overall, the for treatment response in patients are higher as the efficacy of the was lower the efficacy of pegIFN–RBV also on whether it was virological non-response or relapse to the prior and overall responses tend to be better in the should be defined as patients who an optimal of therapy with pegIFN–RBV at doses and to achieve early virological response (> 2 log IU/ml decline in HCV RNA at week or undetectable HCV load at week are patients who HCV after stopping a of therapy. of any of these patients permits SVR to be although relapsers might benefit more than virological of treatment and/or use of higher than recommended doses of HCV medications may slightly improve response rates although SVR will When the achievement of SVR is not the goal of therapy may be to or progression of liver Interestingly, hepatic fibrosis in of coinfected patients despite not attaining SVR Since liver in these studies were at baseline and after completion of it should be that this benefit most will as time as in studies conducted both in HCV-monoinfected and in coinfected patients for longer periods of However, these that histological improvements while on HCV therapy or reflect the effects of IFN and the for whether therapy with pegIFN could liver disease when HCV eradication is not Large trials in HCV-monoinfected and coinfected virological non-responders are currently under to this hypothesis Several should be in with to these trials in coinfected patients. First, it is not whether CD4 cell and effects of IFN may be in these patients when the is provided for long Second, side effects and of will limit the administration of pegIFN in a proportion of these patients. drugs HCV are particularly for the large and of coinfected patients who to clear HCV with the current progression of liver disease will shorten their in the of to those 3 summarizes the main anti-HCV drugs in the the efficacy and of these drugs in coinfected patients should be without for the of trials conducted in HCV-monoinfected With the of should encourage these anti-HCV in and relapsers to prior of HCV therapy are a population and therapeutic in should be of end-stage liver disease The management of coinfected persons with advanced liver cirrhosis is They should be for staging of liver disease and management of liver-related complications such as ascites and Because of an increased risk of life-threatening complications during pegIFN–RBV therapy, persons with hepatic are not candidates for therapy to liver is therapy may significantly improve and outcomes in HIV-positive patients with hepatic and, therefore, should not be However, the effective treatment of HIV in persons with advanced cirrhosis may be owing to in hepatic of antiretroviral drugs and risk of liver injury this liver is the treatment for coinfected patients with stage or C cirrhosis (Table In a recent study 24 HIV-positive was similar to that and HIV-negative 12, 24 and months after liver rates were and HIV-positive patients and and HIV-negative patients. However, when only patients were there was an significant in coinfected compared with HCV-monoinfected The rates at 2 and 3 years were and in HCV-monoinfected subjects and and in coinfected patients. Factors associated with were to CD4 cell counts < detectable plasma HIV RNA and HCV infection for liver in HIV-infected patients with end-stage liver HIV infection should no longer be considered a to liver However, coinfected patients and highly problems including HCV infection and interactions between agents and protease Accordingly, liver in

Introduction Liver disease caused by chronic hepatitis C virus (HCV) infection is now a leading cause of morbidity and mortality among HIV-infected patients in the developed world, where classic opportunistic complications of severe immunodeficiency have declined dramatically as a result of the widespread use of potent antiretroviral therapies [1]. Over the past few years, several consensus reports have addressed the issue of viral hepatitis and HIV infection [2,3]. In 2000, a group of experts in the field were invited to join the HCV–HIV International Panel. The first consensus conference took place in Paris [4]. Two years later, the large amount of new information on HCV and HIV, as well as important changes made in the guidelines for using antiretroviral drugs [5], prompted us to organize another consensus conference, which was held in Barcelona in the summer of 2002. Following international recommendations for the development of clinical guidelines [6], the meeting was planned as a full one-day workshop in which nine experts in the field of HIV and viral hepatitis discussed a total of nine questions, which were selected in advance as the most relevant and currently conflicting topics in the management of chronic viral hepatitis in the setting of HIV infection. A draft was written and circulated among panel members during the following months. Finally, in a second meeting that took place in February 2003, a final consensus was reached, and is presented here. The statements are graded according to the Infectious Diseases Society of America scoring system [6], with minor changes (see Table 1).Table 1: Modified Infectious Diseases Society of America scoring system for consensus recommendations.Influence of hepatitis C virus infection on HIV disease progression and response to antiretroviral therapy Background The state of permanent immune activation provided by chronic HCV infection might act deleteriously in HIV-positive individuals, favouring HIV transcription within infected cells and the more rapid destruction of CD4 T lymphocytes [7]. On the other hand, the immune recovery seen after beginning effective antiretroviral therapy could be partly blunted in individuals with HCV infection as a result of similar mechanisms, or through the infection of immune cells by HCV itself [8,9]. Clinical studies that have examined whether there is an influence of HCV on HIV disease progression show conflicting results. Whereas some have demonstrated an association between HCV infection and faster HIV disease progression, others have not [10–30]. In the Swiss cohort [20], HIV-positive individuals with HCV infection progressed faster to AIDS and death than those who were HCV negative. Some of the available data support a direct negative impact of HCV on HIV disease progression, although to a slight extent. In addition, HCV may negatively influence HIV disease in indirect ways, such as making the discontinuation of antiretroviral treatment more frequent because of an increased risk of liver toxicity [4,31]. Panel recommendation HCV might act as a co-factor for HIV disease progression by several mechanisms. First, unspecific immune stimulation driven by chronic HCV infection might enhance HIV replication. Second, the infection of immune cells by HCV could favour CD4 T-cell depletion and partly blunt the immune recovery that follows successful antiretroviral therapy. Third, HCV could compromise the benefit of antiretroviral drugs as a result of a higher incidence of liver toxicity and treatment discontinuation. However, a negative impact of HCV on HIV disease progression has not been recognized in some large clinical-epidemiological studies. SCORE: C.II Candidates for anti-hepatitis C virus treatment Background All HIV-infected individuals should be screened for HCV antibodies in the serum or plasma. HCV-antibody-negative but HCV-RNA-positive cases may exist, mainly in patients with severe cellular immune suppression as a result of HIV [32–34]. Those with repeatedly elevated aminotransferase levels should be tested for HCV load and HCV genotype, in order to assess anti-HCV therapy. All HIV-positive individuals with chronic HCV infection should be considered as candidates for anti-HCV therapy, given their higher risk of progression to end-stage liver disease and their higher risk of liver toxicity after beginning antiretroviral therapy, compared with HIV-negative individuals [4]. As the response to anti-HCV therapy is dependent on the CD4 cell count [35,36], ideally it should be prescribed only when the CD4 cell count is above 350 cells/μl, a threshold that is relatively easy to obtain in most instances when antiretroviral therapy is used properly. Besides, this is currently the immunological cut-off to begin antiretroviral therapy in drug-naive patients [5]. In individuals with CD4 cell counts between 200 and 350 cells/μl, and already under long-term antiretroviral therapy, the decision to treat HCV might be considered taking into account other factors, such as the estimated length of HCV infection, the severity of liver disease, the extent of suppression of HIV replication, and classic predictors of response to anti-HCV therapy, such as HCV genotype and HCV load. Finally, anti-HCV therapy should be deferred in individuals with CD4 cell counts of less than 200 cells/μl, because the response rate is very low in this subgroup of patients [35,36]. Moreover, the risk of opportunistic infections in the short term may be high, and may worsen with anti-HCV therapy [37,38]. Therefore, they should be treated with antiretroviral therapy and receive prophylaxis for opportunistic infections as a priority. Later on, when their CD4 cell counts have risen and their plasma HIV-RNA level is under control, the prescription of anti-HCV therapy should be assessed again. Patients with previous liver decompensation (ascites, gastrointestinal bleeding, hepatic encephalopathy, etc.) should not be treated, given the higher risk of serious side-effects using the current drugs, pegylated interferon (peg-IFN) and ribavirin. These patients should be assessed for liver transplantation. However, patients with compensated cirrhosis (Child–Pugh class A) must be treated. Individuals with a previous history of severe neuropsychiatric disorders should not be treated, because IFN can exacerbate these conditions. Individuals currently engaged in a heavy alcohol intake or illegal drug addiction practices should delay treatment, whereas all efforts should be devoted to put them into detoxification programmes. Patients on methadone are acceptable candidates for anti-HCV therapy. Up to one third of patients may need adjustments in methadone dosage [39]. Ideally, a multidisciplinary team, including experts in addiction medicine, psychologists/psychiatrists and infectologists should take care of these patients [40,41]. Following recent National Institutes of Health Consensus Conference Recommendations [3], individuals with repeated normal liver enzymes might benefit from current anti-HCV therapy, particularly those infected with HCV genotypes 2 or 3. However, more data on liver damage in this subgroup of HCV–HIV- co-infected patients are needed to balance the cost–benefit of anti-HCV therapy in them. In drug-naive individuals with HCV–HIV-co-infection, chronic hepatitis C should be treated first if the CD4 cell count does not require the initiation of antiretroviral therapy. However, in patients with CD4 cell counts greater than 350 cells/μl but high plasma HIV-RNA levels (i.e. above 50 000 copies/ml), it is not clear whether the suppression of HIV replication should be done at first, deferring anti-HCV therapy to the moment when undetectable HIV viraemia is attained. In these patients, a possible greater efficacy of anti-HCV therapy then should be balanced with a higher risk of interactions between antiretroviral agents and anti-HCV drugs. Panel recommendation All HIV-infected individuals should be screened for HCV antibodies. Those with positive HCV serology should be tested for HCV-RNA. Individuals with positive HCV-RNA should be considered as candidates for anti-HCV treatment. A plasma HCV load and genotyping should be requested before initiating therapy. Treatment should be provided to patients with repeated elevated alanine aminotransferase levels, CD4 cell counts greater than 350 cells/μl, relatively low plasma HIV-RNA levels (i.e. less than 50 000 copies/ml), no active consumption of illegal drugs or high alcohol intake, and no previous severe neuropsychiatric conditions. Treatment in patients with normal alanine aminotransferase levels should be carried out in the context of study protocols or when a liver biopsy has proved the presence of clinically significant fibrosis, i.e. F2 or above. Treatment in patients with CD4 cell counts below 350 cells/μl should be prescribed cautiously. The treatment of choice is the combination of peg-IFN plus ribavirin. SCORE: A.II Liver biopsy before recommending treatment Background Liver histology allows the staging of HCV hepatic damage and predicts in the short–mid term who will develop cirrhosis. At the same time, it may rule out other causes of liver damage, such as haemochromatosis, alcohol-related steatosis, Wilson disease, autoimmune hepatitis, etc., although these conditions may also be recognized by other non-invasive means [42–45]. The value of liver biopsy before prescribing anti-HCV therapy is under debate [42–45]. This controversy may be less justified in HCV–HIV-co-infected patients, in whom the rate of significant liver fibrosis is much higher than in HCV-monoinfected individuals (see Table 2) [46–49]. A priori, anti-HCV therapy will be almost always justified considering the extent of histological damage in HIV–HCV-co-infected patients [50]. Moreover, nearly half of HCV–HIV-co-infected patients may show unexpected cirrhosis or pre-cirrhosis [46–48]. The main predictor of advanced fibrosis stages seems to be the estimated duration of HCV infection [48]. On average, nearly half of patients will have cirrhosis 25 years after the first HCV exposure. If we consider that the mean age of HCV–HIV-co-infected patients is currently 40 years, and that most are former intravenous drug users who began to exchange needles when they were on average 20 years old, it should be expected that many of them will currently show significant liver fibrosis. Therefore, if not treated, a rapid increase in liver complications among HIV-infected individuals should occur over the next decade [51,52].Table 2: Stage of liver fibrosis in patients with chronic hepatitis C according to HIV status.Those who defend performing a liver biopsy before treating chronic hepatitis C in HIV-co-infected patients argue that the side-effects, the risk of interactions with antiretroviral drugs and the relatively low efficacy of current anti-HCV therapy in this population are major limitations that only justify prescribing the medication for those who really need it histologically. However, given that liver damage is a dynamic process and fibrosis progression rate is accelerated in HCV–HIV-co-infected patients [53,54], supporters of this point of view should be reminded that if treatment is not offered to patients with a lack of or only minimal fibrosis, liver biopsy should be repeated at 2–3 year intervals. However, this option will face opposition from many patients and may increase the costs significantly. Accordingly, a recent analysis has pointed out the cost-effectiveness of therapy in co-infected individuals [55]. Panel recommendation The role of liver biopsy for treatment decision purposes is controversial in HIV–HCV-co-infected patients. The patients’ reluctance to accept it or other difficulties should not defer the prescription of anti-HCV therapy once it is considered appropriate, given the faster progression to end-stage liver disease in co-infected patients. When the histological information is available for patients with HCV genotypes 1 or 4, treatment could be deferred if there is no fibrosis (F0), or in patients with F1 willing to accept a second follow-up liver biopsy. In patients with normal transaminase levels, liver biopsy should be performed before prescribing therapy. SCORE: C.III Treatment of chronic hepatitis C in HIV-positive patients Background Available data from interim analysis of large ongoing clinical trials and from a few studies already completed show that response rates to anti-HCV therapy are lower in HIV-co-infected patients, using the new peg-IFN with response rates are in the of which is half the seen in HIV-negative individuals should be that and are much lower in HIV–HCV-co-infected patients. Moreover, also to be more frequent to peg-IFN plus in HCV–HIV-co-infected anti-HCV therapy a response in the setting of HIV infection may be As peg-IFN and at as immune from HIV infection might negatively impact on the of these drugs, in patients with high CD4 cell counts and undetectable plasma HIV-RNA levels under antiretroviral to low response rates to anti-hepatitis C virus therapy in C addition, there is a high rate of anti-HCV treatment discontinuation in some of the trials in HIV-co-infected patients, of individuals it may a higher rate of serious in this population compared with HIV-negative individuals, in whom it is less than it might also that some HIV are not with the management of side-effects of anti-HCV therapy. to side-effects with and the management of complications are to the of anti-HCV therapy in most patients. Panel recommendation The response to anti-HCV therapy is lower in patients co-infected with response rates of are seen in patients with HCV genotypes 2 or but lower than in those with HCV genotypes 1 or and are less and more in co-infected patients compared with HCV-monoinfected The benefit of therapy than for HCV genotypes 2 or and more than for HCV genotypes 1 or in should be examined in clinical Moreover, treatment should be considered a for the of response and must be over the treatment SCORE: A.II the response to anti-hepatitis C virus therapy in HIV-positive patients Background all patients who will clear HCV with anti-HCV treatment show an response after beginning therapy Therefore, an of serum or plasma HCV-RNA after treatment may the of those who benefit from therapy and those who In HIV-negative patients, those who show a in HCV-RNA levels greater than 2 or undetectable levels at of therapy are those who will a response In almost of those who show HCV-RNA of less than 2 at that Therefore, anti-HCV therapy may be at considering these in This to HCV therapy might side-effects and costs in individuals with no of In HIV–HCV-co-infected patients these should be as more because interactions between antiretroviral drugs and anti-HCV therapy are and to in individuals under are of much studies that HCV after beginning therapy with IFN may be in the setting of HIV infection (see Therefore, the of the of a in HCV-RNA at it might not in HCV–HIV-co-infected patients. However, data that a in HCV-RNA in HIV-co-infected patients after beginning anti-HCV therapy, all patients who will a response show a greater than 2 at on therapy Therefore, the anti-HCV therapy in HIV-negative individuals may also to HIV-co-infected patients (see However, patients with high HCV may show an but may not undetectable viraemia at but will clear HCV much This subgroup of patients less than of HCV-monoinfected individuals, but may be among HIV-co-infected patients, in whom higher HCV-RNA are frequent and HCV-RNA on treatment have been C virus under interferon therapy. of HIV infection. C virus treatment patients with high hepatitis C virus (HCV) treatment might be the of viraemia at that if a greater than 2 was at of therapy. the of higher rates in the setting of HCV–HIV patients at and to anti-HCV therapy might consider therapy genotypes or genotypes pegylated is a second of of HCV-RNA in individuals on anti-HCV therapy, which for the destruction of infected cells A in the setting of HIV infection (see could the discontinuation of therapy might result in higher rates in data support this and it to anti-HCV therapy should be in This seems to particularly to HCV genotype because are in HIV-negative individuals infected with this genotype, whereas it in to a third of HIV–HCV-co-infected patients who receive anti-HCV therapy for only following is in HIV-negative individuals studies of anti-HCV therapy (i.e. in HCV genotypes 2 and and to in HCV genotypes 1 and should be in to whether this may their of reports have that HCV-monoinfected patients who not clear HCV-RNA on anti-HCV treatment, might benefit from long-term therapy with IFN therapy with IFN may histological and the risk of and is currently as an in large trials in HCV-monoinfected patients and this may be considered in some HIV–HCV-co-infected individuals with advanced fibrosis who not to anti-HCV therapy should be The use of lower of peg-IFN those as first may and long-term of the Panel recommendation response to anti-HCV therapy predicts the of response in HIV-co-infected patients as it does in HCV-monoinfected Moreover, the use of an for treatment seems to be in co-infected patients. patients a in serum HCV-RNA levels greater than 2 at on therapy will have of a Therefore, treatment might be in the This is of given the the risk of toxicity from interactions between anti-HCV therapy and antiretroviral drugs. SCORE: C.II of of anti-hepatitis C virus therapy in HIV-positive patients Background The side-effects of anti-HCV are and may be into main neuropsychiatric disorders gastrointestinal and at In addition, other may develop more such as and they to treatment discontinuation in of HCV-monoinfected patients, and to of peg-IFN or in another treatment discontinuation rates have been in some studies in HIV-co-infected individuals The lack of in the management of HCV side-effects by the in as well as information given to patients may have to the high These should be addressed in the The may be caused by peg-IFN or ribavirin. caused by is and caused by and is by an increase in may the incidence of to be the of has been in these patients of are the of should be to half when the level below and it should be if it below However, seems for a higher response particularly in patients HCV genotype 1 to patients on of the drug (i.e. using should be and less may develop with In patients should be in advance of the risk of in their CD4 cell counts In most instances they the CD4 cell but not the of these Moreover, it after IFN therapy to the use of factors, such as may be considered and over peg-IFN particularly in patients with HCV genotype Panel recommendation therapy causes in the of Patients should be in advance these side-effects and to and them for The treatment of should be considered as as begin to may significant CD4 T-cell and which are after may cause within the first of therapy. should their in the management of these side-effects, to patients on therapy as as no serious SCORE: caused by interactions between antiretroviral drugs and anti-hepatitis C virus therapy. to Background As is a frequent of should be to those patients who are taking also to In patients with this drug should be before prescribing ribavirin. of over the first of therapy is damage from the of by can enhance the of and result in a higher risk of toxicity cases of or have been and a from the and has been on the risk of and Therefore, patients who begin treatment with should the use of the of serum and levels are and patients should be in advance of with The role of in the development of in these patients has also been in the although to a extent cases of hepatic some of them have been in individuals with All were individuals with and and leading to liver Therefore, the of and should be in patients with advanced liver fibrosis. Finally, several have the that could when used with some mainly In this severe the progression of could be another from the of and antiretroviral drugs. Patients should be in advance the risk of this when drugs with a lower should be Panel recommendation between antiretroviral drugs and may be the higher risk of and in all treated patients as well as of liver decompensation in individuals, should be when taking ribavirin. On the other hand, should be used with when is because may Patients should be of the of severe a rapid progression of as a result of a of damage in the taking and some SCORE: A.II of antiretroviral drugs Background or liver occur on average in of patients who antiretroviral therapy The rate is higher in patients with chronic hepatitis C Moreover, some drugs (i.e. at full cause more than others Therefore, liver should be in individuals who antiretroviral treatment, particularly when some of the drugs above are to patients with chronic hepatitis toxicity may the liver when using some drugs. If not after beginning therapy, it may later, after on therapy. This has been seen with drugs such as Liver after antiretroviral treatment may occur by other than the direct of the and may account for some cases In patients with low CD4 cell counts or high HIV-RNA successful therapy may enhance immune to a that hepatic cells HCV may be recognized and As as the and transaminase levels not above the of normal treatment could be with the of because a of liver enzymes to in most cases These of hepatitis, are On the other hand, that may develop after to or may be by liver in the context of a more The presence of chronic hepatitis C does not to a role in the of this Liver toxicity may also occur as a of damage in patients particularly and of hepatic are frequent in this setting and are more in and individuals Panel recommendation Liver after beginning antiretroviral therapy are more frequent in patients with chronic hepatitis and Therefore, drugs with more (i.e. should be used in co-infected patients. Treatment should be in patients with or in aminotransferase In immune may to in transaminase levels after potent therapy. The of these patients during the first may them to on therapy, because they a of liver treatment. SCORE: A.II Liver in HIV-co-infected patients Background HIV-infected patients with end-stage liver disease develop classic complications of including gastrointestinal bleeding, and The only treatment available at this is liver before the of active antiretroviral therapy provided very Those reports that only a of HIV-positive whereas most an accelerated to the of HIV-infected liver have their short and the of is no as as HIV infection is with in the Table the with in HIV-infected patients during the cases from the used for liver were In candidates not have history of opportunistic CD4 cell counts greater than cells/μl and undetectable plasma HIV-RNA on in with they available drugs for successful treatment in the were at patients with end-stage liver disease to chronic hepatitis C who and some of them to 2 In one of the in cases of in has a rate at 1 year similar to that at the for rates were seen for These have been at years in a more recent Liver in C patients during the of active antiretroviral information available may be in the following The risk of opportunistic infections in the is very low when HIV replication is well with most cases with undetectable viral CD4 cell counts or increase with Therefore, the use of therapy in patients with HIV infection does not increase their to opportunistic infections or conditions. and can HIV replication in and may the efficacy of The benefit of these interactions is currently are important interactions between some antiretroviral drugs, and and mainly and may increase the levels of and whereas may their levels, because of their over the These interactions have caused some of in patients who taking drug of agents is when taking antiretroviral drugs. with a can also be in liver and liver should be HCV is very frequent after and to cirrhosis in nearly of cases within The rapid progression of liver disease in HIV-infected a major and the main for a of these patients. anti-HCV therapy must be prescribed as as possible after following the recommendations in point 3. In addition, other such as therapy (i.e. using IFN before in the of should be and As in the seems to be much in HIV-co-infected patients, to available liver after a to this should be Panel recommendation All HIV-infected patients with end-stage liver disease as a result of HCV should be considered as candidates for liver as as they not have advanced HIV In those with severe immunodeficiency CD4 the of HIV replication and immune should be The and the and management of HIV-positive candidates for must an of a and members of and detoxification programmes. HIV-positive candidates should have CD4 cell counts greater than cells/μl and plasma HIV-RNA levels below 200 or the of undetectable using drugs for successful treatment after transplantation. Moreover, they should have from the consumption of alcohol and illegal drugs for at months. Patients with a immunological response to but a previous history of opportunistic infections or and given the higher risk of of those conditions using SCORE: This was in by and

The authors would like to apologise for the following error. In the Key Words section, the word “amtricitabine” is misspelt. It should read “emtricitabine”