Care of patients with hepatitis C and HIV co-infection

Abstract

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