Hepatitis C virus (HCV) coinfection of individuals positive for human immunodeficiency virus (HIV) was once seen as unimportant in the setting of HIV infection. However, this view changed sharply after the introduction of highly active antiretroviral therapy (HAART) a decade ago. The life expectancy of HIV-infected persons has dramatically improved, so that chronic hepatitis C now has the opportunity to evolve to end-stage liver disease (ESLD). Recognition of HCV as an important co-pathogen in HIV-infected persons is strengthened by at least three facts. First, HIV-associated immunodeficiency accelerates progression of HCV-related hepatic damage [1,2]. Second, individuals with underlying chronic hepatitis C are at higher risk of developing a hepatotoxic response to antiretroviral drugs [3]. Third, the number of coinfected individuals is enormous—approximately 9 million of the 36 million HIV-positive persons worldwide are coinfected with HCV [4]. Thus, HCV coinfection currently represents one of the leading causes of morbidity and mortality in HIV-positive individuals, at least in developed countries where HAART is widely used [5,6]. A better understanding of the interactions between HIV and HCV may permit the design of strategies to minimize the deleterious impact of HIV/HCV coinfection.
EPIDEMIOLOGY OF HIV/HCV COINFECTION
As HCV and HIV share similar routes of transmission, coinfection with both agents is relatively frequent in populations at risk for exposure to contaminated blood or blood products, such as intravenous drug users (IDUs) or hemophiliacs [7]. In contrast, whereas sexual and vertical transmission of HIV is relatively frequent, HCV transmission is rare through these routes [8-10]. This fact accounts for significant differences in rates of HIV/HCV coinfection in distinct geographical regions and at-risk populations. For example, in places where IDUs are the principal at-risk demographic for HIV infection—currently Eastern European countries [11] and Southeast China—HCV coinfection may be recognized in up to three quarters of all HIV-positive persons. In contrast, in most African countries and India, where heterosexual contact is the main route of HIV transmission, the prevalence of HIV/HCV coinfection is below 5% [10]. Finally, in regions where HIV is found mainly in men who have sex with men (MSM), such as in North America and Central and Northern Europe, low to intermediate rates (~10%) of HCV coinfection are seen in HIV-infected persons. Increased opportunities for HCV exposure due to promiscuity and more traumatic sexual practices account for the higher risk of HCV infection among MSM compared to heterosexual populations, and recent outbreaks of acute hepatitis C among MSM underscores the need for continuing preventive measures in this population [12-14].
In the United States the overall prevalence of HCV infection in the whole HIV population is around 18%, but rises to 60% in HIV-positive inmates, most of whom had been IDUs [15,16]. In Europe, the best data on HCV prevalence and distribution among HIV-infected persons are from EuroSIDA. A recent virological study showed that HCV genotype distribution significantly differs according to risk group and geographical region. Although HCV genotype 1 predominates in all regions (overall 40-60%), the rate of HCV genotype 3 (overall 20-40%) is significantly higher in Eastern Europe, whereas HCV genotype 2 (overall prevalence 1-5%) is mainly seen in Northern and Central Europe; the North African HCV genotype 4 (overall prevalence 5-15%) is less frequent in Northern Europe but represents up to 20% of HCV infections in Southern Europe (Figure 1) [11].
 | Figure 1. Distribution of HCV genotypes in EuroSIDA. |
Although HCV is not efficiently transmitted by perinatal exposure (generally in fewer than 5% of HCV-RNA positive women), HIV coinfection clearly increases the rate of vertical transmission of HCV (to 8-20%) [17]. Nevertheless, HIV/HCV-coinfected pregnant women under effective HAART do not show an increased risk of HCV transmission to their newborns [18]. Maternal serum HCV-RNA titers appear to be an important determinant of perinatal HCV transmission. The practice of cesarean section may further reduce perinatal HCV transmission in coinfected mothers, but only marginally [19,20]. As breastfeeding may be a risk factor for both HIV and HCV perinatal transmission, the use of safe infant formula for infants of HIV/HCV-coinfected mothers is advised [21].
PATHOGENESIS OF HIV/HCV COINFECTION
There is a worsening of the natural course of chronic HCV infection in HIV-infected individuals [1,2]. Coinfected subjects progress faster to a cirrhotic stage and are at increased risk of death from ESLD or hepatocarcinoma [22]. HIV infection modifies the natural history of chronic hepatitis C in several ways (Figure 2). First, HCV clearance in the acute phase is less likely to occur in HIV-infected persons [23]. This might be due to an impaired immune response associated with HIV infection and/or to the fact that HCV reinfection seems to be more common among IDUs, increasing the chances of chronicity after multiple independent episodes of HCV exposure [11,24]. In contrast, sexual HCV transmission is mainly determined by higher HCV-RNA levels but without increasing chronicity rates, due to smaller and less frequent HCV challenges [25].
 | Figure 2. Influence of HIV on the natural history of hepatitis C virus (HCV) infection. |
Because HIV/HCV-coinfected individuals tend to show higher serum HCV-RNA levels than their HIV-negative counterparts (~1 log on average) [26,27], an increased risk of HCV transmission and a reduced response to anti-HCV therapy is expected in this population. Disruption of the immune response toward HCV may, in part, explain this finding: HCV-specific CD4+ T cells are drastically diminished in coinfected individuals [28,29]. However, it is unclear why HCV-specific immune responses vanish so early in HIV-infected persons, whereas immune responses to other infectious agents disappear only at late stages of HIV disease. In contrast, HCV-specific CD8+ interferon gamma responses decline only in HIV/HCV-coinfected patients with low CD4+ T-cell counts [30,31].
HIV also accelerates the histological impact of HCV on the liver, leading to advanced degrees of hepatic fibrosis in shorter periods of time [2]. A reduction of intrahepatic CD4+ T lymphocytes secreting antiinflammatory and antifibrotic cytokines (such as interleukin 10), together with higher levels of HCV RNA might explain these findings [32]. More recently, it has been postulated that hepatic stellate cells, which produce collagen and drive the fibrotic process in the liver, could be infected and activated by HIV itself [33].
OUTCOME OF ACUTE HEPATITIS C IN HIV-INFECTED PERSONS
The overall incidence of acute hepatitis C has fallen in recent years, mainly due to effective blood donor screening, needle exchange programs, and increased education among IDUs. The current estimated annual incidence of new cases of HCV in the United States is around 38,000 infections, with only 16% presenting with symptomatic acute hepatitis C. Acute HCV infection rose from a low rate (<44 per 100,000 persons) before 1965 to its peak in the 1980s (100-200 per 100,000 persons), declining since 1990 to its current incidence in the United States and Western Europe (10-17 per 100,000 persons) [34].
HCV is less likely to be transmitted by sexual exposure in comparison to HIV or hepatitis B virus (HBV). Recent studies have reported a very low rate of transmission among monogamous couples [35]. However, since 2000, a rise in the diagnosis of acute HCV infection has been reported among HIV-infected MSM in Europe, the United States, and Australia [36-41]. In most cases, unprotected anal intercourse and concomitant ulcerative sexually transmitted diseases (mainly syphilis) could be found. In France, an incidence of acute HCV infection of 3.5 per 1000 patient-years among HIV-positive MSM was reported in one study [37]. In another study, Ghosn et al [42] included 379 HIV-infected subjects from the French PRIMO Cohort who were HCV-negative at baseline and were followed for at least 18 months; the incidence of HCV infection was found to be 4.3 per 1000 patient-years. In the United Kingdom, in a case–control study of 111 HIV-positive MSM with acute hepatitis C diagnosed between 1999 and 2005, a high number of sexual partners, high-risk sexual behaviors (fisting, use of sexual toys, group sex, etc), and sexual activity under the influence of drugs were identified as independent risk factors for acquiring HCV infection [13]. Altogether, these data support the conclusion that sexual transmission of HCV should no longer be considered an insignificant route of transmission, particularly among MSM with HIV infection. Several factors could explain this observation. First, serum HCV-RNA levels are higher in HIV-positive subjects, so that greater levels of HCV-RNA are also seen in semen [43]. In this context, unprotected traumatic anal sex, associated in some cases with ulcerative lesions, may facilitate the chance of semen-to-blood or blood-to-blood contact required for efficient HCV transmission.
Up to a third of HIV-negative patients with acute HCV infection may be able to clear the virus spontaneously. Younger age, female gender, genotype 3, low-peak HCV-RNA titers, Caucasian race, symptomatic acute infection, and rapid decline in serum HCV-RNA levels within the first 4 weeks of diagnosis have all been associated with a higher chance of spontaneous cure of HCV infection [44-47]. Cellular immune responses appear to play an important role in determining the outcome of acute HCV infection. Strong T-cell responses, both CD4+ and CD8+, are associated with viral clearance and protection from disease progression [48,49]. HIV-mediated effects on the immune system (mainly loss of CD4+ and CD8+ T-cell antiviral responses) reduce the rate of HCV clearance, leading to chronic HCV infection in around 80% of cases [50,51].
Treatment of acute hepatitis C in an HIV-positive setting has a lower rate of cure than in HIV-negative counterparts, in whom it is seen in 91% of cases after 24 weeks of pegylated (PEG) interferon alfa [52]. Since the antiviral activity of interferon may be mediated through the cytokine network, immunologic abnormalities in the HIV setting could determine the lower response rate seen in these patients. Some recent studies of HIV-positive patients with acute HCV infection have reported very disappointing results [39]. However, other larger studies have reported rates of sustained virological response (SVR) of 60-75% [53-55]. Interestingly, no significant differences between PEG-interferon alfa alone, standard interferon alfa and ribavirin or PEG-interferon alfa plus ribavirin could be demonstrated.
Patients with acute hepatitis C due to genotypes 2 or 3 respond better than those infected by genotypes 1 or 4, both in HIV-negative and HIV-positive individuals [56]. More elevated alanine aminotransferase (ALT) levels during the acute episode and rapid viral clearance on therapy predict better chances of SVR, regardless of HIV status. In contrast, patient’s age, CD4 count, plasma HIV-RNA and HCV-RNA levels, and having a symptomatic infection do not seem to influence the response of acute hepatitis C to treatment [57].
At this time it is unclear whether adding ribavirin to PEG-interferon alfa would offer any advantage in treating acute hepatitis C in an HIV setting. However, given the worse prognosis of HCV infection in HIV-positive subjects, it seems worthwhile to provide ribavirin to maximally ensure the attainment of HCV clearance. Following what is advised for HIV-negative persons, 24 weeks of therapy is the recommended duration of treatment for acute hepatitis C in HIV-infected subjects, regardless of HCV genotype [4].
HCV-RELATED PROGRESSION OF LIVER FIBROSIS IN HIV INFECTION
Hepatic fibrosis is a nonspecific consequence of chronic liver damage, which follows the accumulation of extracellular matrix proteins (ECMs). Consequently, accumulated ECMs distort the hepatic architecture by forming a fibrous scar; subsequent development of nodules of regenerating hepatocytes defines liver cirrhosis. The cirrhotic state leads to hepatocellular dysfunction and increased intrahepatic resistance to blood flow, which results in hepatic insufficiency and portal hypertension, causing the main complications of ESLD. The pathogenesis of HCV-induced liver fibrosis is poorly understood. HCV escapes the immune response, infects hepatocytes, produces oxidative stress, and induces the recruitment of inflammatory cells. These events lead to activation of hepatic stellate cells and deposition of collagen. The HCV core, NS5 and NS3 proteins have been shown to interact with different host proteins resulting in several events that finally lead to liver fibrosis progression [58].
An estimate of fibrosis progression represents an important surrogate marker for the susceptibility of a given individual to cirrhosis. The distribution of the rates of fibrosis progression suggests the existence of at least three populations: ‘rapid fibrosers’, ‘intermediate fibrosers’, and ‘slow fibrosers’. Identification of risk factors related to an accelerated course of liver fibrosis progression is essential to extend the survival time of HCV-infected patients.
HCV-dependent factors
Data that correlate viral features with progression of established chronic hepatitis C are controversial. Serum HCV-RNA level, HCV genotype, and HCV quasispecies do not seem to influence to a large extent the rate of progression of liver fibrosis [59,60]. However, HCV genotype 3 tends to be associated with more elevated liver enzymes and hepatic steatosis, both of which, at least in some studies, have been associated with faster liver fibrosis progression [61,62]. On the other hand, HCV genotype 1 infections have been shown to result in higher HCV-RNA levels [11,63,64], and indirect evidence has correlated greater HCV load with enhanced liver damage and more rapid progression to ESLD. Whereas HCV load may not have a direct effect on progression of liver fibrosis, higher levels of HCV RNA might reflect a more severe immune dysregulation, which may finally account for faster liver disease progression [65].
HIV-associated immunodeficiency
It is well established that patients coinfected with HCV and HIV show faster liver fibrosis progression than controls [61,66,67], even before the occurrence of a marked decline in CD4+ T-cell counts [68]. This is true even after adjusting for other variables such as age, gender, alcohol consumption, etc. The loss of antiviral CD4+ T-cell responses in HIV-positive patients has not been closely linked to crude CD4+ T-cell counts, and most likely occurs earlier. It is unclear why HCV-specific responses are so sensitive to the effects of HIV, whereas immune responses to other infectious agents are only reduced at later stages of HIV infection. Altered cellular immune responses associated with HIV infection can lead to greater HCV replication, more severe liver-cell injury and, finally, to more progressive liver disease. HIV infection has been associated with increased production of proinflammatory and profibrogenic cytokines [32]. Other cofactors that frequently complicate HIV infection are male gender, older age, alcohol abuse, drug-related hepatotoxicity, HAART-related metabolic syndrome, and high necroinflammatory activity and steatosis in the liver [69-72].
Other viral hepatitides
Overlapping routes of transmission for HIV, HCV, HBV, and hepatitis D virus (HDV) account for the relatively high prevalence of multiple viral hepatitides in HIV-infected subjects. This subset of patients shows an even further accelerated course of liver fibrosis [73]. They are more prone to develop hepatocellular carcinoma [22] and to die from ESLD compared to subjects with HBV or HCV monoinfections [73]. In Europe there is a north-to-south gradient in the proportion of HIV patients with multiple hepatitides [74-76], mainly driven by the proportion of IDUs in the whole HIV population. IDUs are more often coinfected with HCV and either HBV and/or HDV than are MSM.
The predominance of one virus over another may fluctuate over time [77,78], and viral interference phenomena explain why replication of either HCV or HBV is suppressed in the presence of the other replicating virus. However, in patients with severe immunosuppression, replication of all these viruses (B, C, and D) may occur simultaneously [79]. In contrast, in most HIV patients with relatively good immune status, viral interference seems to favor HCV over HBV replication [78]. Despite this fact, it is noteworthy that the proportion of subjects with HCV antibodies showing negative serum HCV RNA is much higher in patients carrying serum HBV surface antigen (HBsAg). In patients with chronic hepatitis due to HDV, this virus dominates, suppressing the replication of other viral hepatitis agents. HDV is the causative agent of the most aggressive viral hepatitis, with an average time to cirrhosis of <20 years [80].
THE DOUBLE EFFECT OF ANTIRETROVIRAL THERAPY ON CHRONIC HEPATITIS C
The more rapid liver fibrosis progression seen in HIV/HCV-coinfected patients may result from immune deterioration and/or greater viral replication. Thus, the risk of liver disease would be expected to decrease after the availability of HAART. However, the opposite has been observed in some series, and HCV-related liver disease has emerged as a leading cause of morbidity and mortality in this population [81]. Even if it were simply the ‘unmasking’ of liver disease because of the longer survival of HIV patients on HAART, other factors such as irreversibility of HCV-related liver damage and chronic hepatotoxicity of antiretrovirals must be taken into account.
Several studies have suggested that HAART may be associated with an amelioration of HCV-associated liver-related mortality, though effects on hepatic fibrosis remain controversial [71,82,83]. Longitudinal examination of liver fibrosis progression has been difficult because paired liver biopsies cannot be easily obtained. Only recently have noninvasive tools to estimate and measure hepatic fibrosis become available to facilitate this task [84]. One of the potential protective effects of HAART might be the immune restoration that is induced after suppressing HIV replication. Some studies have claimed improvements in liver damage using HAART in direct association with CD4+ recovery [85]. However, it is unclear to what extent treatment of HIV infection may restore specific CD4+ T-cell responses against HCV. On the other hand, it is also unclear what effect, if any, HAART has on serum HCV-RNA levels. In fact, paradoxical increases in plasma HCV RNA following HAART initiation have been reported [86]. If liver disease progression is slowed without improvement in anti-HCV responses, it may be that abnormal HIV-related immune dysregulation is halted with HAART. Other potential protective effects of HAART might be related to specific drug classes, as has been claimed for protease inhibitors [82,87,88] or occasionally for nevirapine [89]. In this regard, further studies are required to clarify whether differences exist between distinct antiretroviral agents.
Some negative effects of HAART on liver fibrosis are also well characterized. Liver enzyme elevations and metabolic abnormalities associated with steatosis have all been described with antiretroviral therapy [3]. At least five different mechanisms of hepatotoxicity of antiretroviral agents have been described: i) direct injury (e.g., tipranavir); ii) mitochondrial toxicity (e.g., didanosine or stavudine); iii) immune reconstitution phenomena (mainly in patients with underlying HBV infection); iv) hypersensitivity reactions (e.g., nevirapine or abacavir); and v) hepatic steatosis [3]. Nonalcoholic hepatic steatosis is often associated with the metabolic syndrome, with dyslipidemias and insulin resistance being the result of some antiretroviral regimens (Figure 3). It is highly possible that fatty liver through a process of oxidative stress leads to mitochondrial DNA damage and liver inflammation (steato-hepatitis). In this way it is not surprising that patients carrying HCV genotype 3, which typically induces more hepatic steatosis, are most prone to develop hepatotoxic events with HAART [90].
Altogether, current knowledge suggests that HAART may lead to an initial improvement of liver damage in HIV/HCV-coinfected patients, mainly through an immunological and anti-HIV effect. However, subsequently the chronic hepatotoxicity of some antiretroviral agents, directly or indirectly, might favor progression of liver fibrosis (Figure 4). This is the ‘double-edged sword’ effect of HAART in HIV/HCV coinfection (Figure 5).
 | Figure 3. Metabolic syndrome and progression of liver fibrosis in HIV/HCV-coinfected patients.
|
 | Figure 4. Time-dependent effect of HAART on liver fibrosis in HIV/HCV-coinfected patients. |
 | Figure 5. Impact of HAART on liver fibrosis in HCV-HIV coinfected patients: the "double-edged sword" effect. |
IMPACT OF ANTI-HCV THERAPY
Treatment with the combination of PEG-interferon alfa plus ribavirin may provide permanent clearance of HCV infection in 30-45% of HIV/HCV-coinfected patients [4]. Patients with undetectable serum HCV-RNA levels after 24 weeks after the end of therapy are designated as having achieved SVR, and are considered as having permanently eliminated the virus [91]. Improvement in the degree of liver fibrosis after successful interferon-based therapies has been investigated in HCV-monoinfected patients. Most studies have demonstrated lower inflammatory activity and less fibrosis in patients attaining SVR compared to nonresponders [92]. Although results in HIV/HCV-coinfected patients are still scarce, a recent study found that achievement of SVR is associated with steady reversion of hepatic fibrosis in this population [93]. The main difference between that report and previous studies was the longer interval between the end of interferon-based therapy and the second measurement of liver fibrosis (40 and 12 months on average, respectively). Accordingly, even if achievement of SVR may be limited to only a subset of patients, the benefits of long-term viral clearance on liver fibrosis progression make it worth the effort to treat all HIV/HCV-coinfected patients having no contraindication for interferon-based therapy.
A further benefit of treating chronic hepatitis C in HIV-infected patients derives from the improved tolerance of antiretroviral drugs following achievement of SVR [94]. Finally, following what was recently reported for HCV-monoinfected patients in the HALT-C (HCV Antiviral Long-term Treatment against Cirrhosis) study [95], administration of PEG-interferon alfa as a maintenance therapy in HIV/HCV-coinfected individuals was not found to be efficacious in the SLAM-C (Sustained Long-term Antiviral Maintenance) study [96].
OUTCOME OF HIV/HCV-COINFECTED PATIENTS WITH ADVANCED LIVER CIRRHOSIS
The prevalence of cirrhosis in HIV-infected patients depends on the characteristics of the population examined. Using noninvasive measures, one study found cirrhosis in up to 8% of all HIV-positive individuals [75]. Chronic hepatitis C is the main predisposing condition in places where IDUs largely contribute to the HIV population [75,97]. Other factors that may cause severe liver disease, such as alcohol consumption, drug-related hepatotoxicity, or liver steatosis, are also more prevalent in the HIV population [61,75]. Patients coinfected with multiple viral hepatitides are particularly at risk for developing ESLD.
Once liver cirrhosis has developed, the survival of HIV/HCV-coinfected patients is significantly reduced. The course to symptomatic liver disease is faster in the HIV setting than in immunocompetent persons. After a first episode of liver decompensation, HIV/HCV-coinfected patients show a 30% probability of survival at 3 years [98] compared to 60% in HCV-monoinfected ones [99]. In another study, in which 92 HIV/HCV-coinfected subjects with asymptomatic liver cirrhosis were followed, the risk of developing a first liver decompensation event at 2 years was 14% [100]. As in HCV-monoinfected persons [99], complications derived from portal hypertension and its main clinical consequences (ascites, bleeding due to esophageal varices, encephalopathy) are the most frequent causes of liver decompensation [75,100]. However, the proportion of cirrhosis with Child-Pugh classes B and C is higher in HIV/HCV-coinfected patients than in HCV-monoinfected individuals, which is in agreement with the shorter survival of the former group [98]. Even if hepatocellular carcinoma in the HIV setting does not show a higher incidence compared to HCV-monoinfected patients, it more often presents with more advanced disease stages, multifocal nodules, and at a younger age [22].
Antiretroviral therapy may significantly improve short-and mid-term outcomes in HIV-positive patients with liver cirrhosis. Therefore, HAART should not be denied for the sake of reducing the risk of liver toxicity in this population. However, effective treatment of HIV in persons with advanced liver cirrhosis may be challenging, owing to alterations in hepatic metabolism of antiretroviral drugs and risk of drug-induced liver injury [101]. Any compromise in liver function in patients with chronic viral hepatitides is mainly due to the loss of a substantial proportion of hepatocytes, which are replaced by fibrotic tissue. As a consequence, the ability of the liver to clear drugs from the blood may be significantly compromised. Depending on the metabolic pathways used for distinct drugs (either cytochrome P450 or glucuronization), altered pharmacokinetics could be more or less frequent. Other important variables which may affect distinct drug exposure in cirrhotics are the protein binding of any given drug and the presence of vascular hepatic shunts. Overall, HIV-infected patients with HCV-related compensated liver cirrhosis are more prone to show greater plasma levels of non-nucleoside reverse transcriptase inhibitors (NNRTIs), especially for efavirenz. In contrast, less clear is the evidence showing increased levels of protease inhibitors in subjects with advanced liver fibrosis [102]. Since there is an association between the extent of liver fibrosis and the risk of liver toxicity using NNRTIs [103], it is suspected that high drug exposure might play a role. Therefore, NNRTIs may well be considered for therapeutic drug monitoring in HIV/HCV-coinfected patients with liver cirrhosis.
OUTCOME OF HIV/HCV-COINFECTED PATIENTS FOLLOWING LIVER TRANSPLANTATION
In the setting of ESLD, patients with chronic hepatitis C are generally no longer qualified for antiviral therapy, and thus are at high risk of liver-related death. Although liver transplantation remains a challenging option in HIV/HCV-coinfected patients, the short-term survival of transplanted patients has significantly improved after the advent of HAART [104-106]. Inclusion and exclusion criteria have been recently reviewed [107]. Ideally, patients should not have suffered previously from AIDS-defining illnesses (with the possible exception of tuberculosis, candidiasis, or Pneumocystis jirovecii pneumonia). Patients must show a well-controlled HIV infection, with a CD4 count >100 cells/mm3 and low or preferably undetectable plasma HIV RNA [108]. Because liver cirrhosis progresses faster in the HIV setting than in HIV-negative persons as the number of decompensation events increases, coinfected patients should be evaluated for orthotopic liver transplantation (OLT) after the first liver decompensation event [109].
In the post-transplant period, special attention needs to be paid to the interactions between antiretrovirals and immune suppressive agents. Plasma concentrations of both drug classes should be monitored and doses adjusted accordingly. Failure to do so is often associated with liver graft rejection. Current data are encouraging since they show that HIV-infected patients do not have an increased risk of post-operative complications or a higher incidence of opportunistic infections or tumors compared to their HIV-negative counterparts [110]. Therefore, OLT should be considered for all HIV/HCV-coinfected patients with ESLD.
CONCLUSION
At least one quarter of all HIV patients in Europe and the United States have concomitant HCV infection. The epidemiology of HCV in the HIV setting may show particular characteristics, with a greater tendency to chronicity and more efficient transmission among MSM. HIV accelerates the course of HCV-associated liver disease and the influence of HAART may be a double-edged sword. Early benefits can be seen, such as the amelioration of the hepatic fibrosis process due to immune restoration, but also late worsening of liver damage due to metabolic abnormalities secondary to antiretroviral therapy or long-term side effects of the medication. With the advent of new antiretroviral drugs with a better hepatotoxicity profile, it is currently advisable to provide HAART to all HIV/HCV-coinfected patients regardless of CD4 count. Of course, anti-HCV therapy should be considered up front and be given to all subjects with no contraindications. HCV eradication following treatment may improve the tolerance of antiretroviral drugs and is associated with regression of liver fibrosis over time. Finally, HIV-positive patients with ESLD should not be withheld from treatment options such as OLT, as they show similar outcomes to HIV-negative individuals.
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