| |
Progression of liver fibrosis in patients coinfected with HCV and HIV undergoing antiretroviral therapy
|
| |
| |
Journal of Antimicrobial Chemotherapy April 2005 55(4):417-419
Juan A. Pineda* and Juan Macias
Service of Internal Medicine, Unit of Infectious Diseases, Hospital Universitario de Valme, Seville, Spain
......The impact of antiretroviral drugs on the progression of HCV-related liver fibrosis is far from clear..... HAART may have a dual effect on the progression of CHC-associated liver fibrosis....by reducing immunosuppression but also association with hepatotoxicity. .....although HIV/HCV coinfection is associated with a 2-10-fold chance of showing aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) values above the upper level of normality (ULN) after starting HAART, compared with HIV infection alone.....sequential liver biopsies are required to assess changes in liver fibrosis accurately. This practise is poorly tolerated by patients..... Long-term prospective studies are necessary to establish definitely the impact of antiretroviral drugs on the progression of HCV-related liver disease. The end points of these studies should be clinical, such as the emergence of liver failure or liver-related death.....
Abstract
As the immunosuppression caused by human immunodeficiency virus (HIV) accelerates the progression of hepatitis C virus (HCV)-related liver fibrosis, the immune reconstitution associated with highly active antiretroviral therapy (HAART) may have the opposite effect. However, hepatotoxicity related to HAART could enhance the progression of liver fibrosis. Some retrospective studies have shown that therapy with the protease inhibitors may be associated with less severe liver fibrosis, whereas nevirapine use seems to correlate with faster progression. Low-grade liver toxicity associated with nevirapine could account for this effect. However, other studies have not confirmed these findings. Long-term prospective studies are needed to analyse the impact of antiretroviral drugs on the progression of HCV-related liver disease. Meanwhile, no specific recommendations can be made on the use of individual drugs or drug classes in HIV/HCV-coinfected patients. Most importantly however, the inherent benefits of HAART largely outweigh the risk of enhancing fibrosis progression. Additionally, in coinfected patients, other factors that promote fibrogenesis, such as alcohol consumption, should be avoided. Antiviral treatment of chronic hepatitis C could also reduce the risk of liver damage associated with HAART.
Introduction
In areas where highly active antiretroviral therapy (HAART) is easily accessible, hepatitis C virus (HCV) infection has become an important cause of morbidity and mortality in human immunodeficiency virus (HIV)-infected patients. HIV/HCV coinfection is a common problem. On average, 33% of HIV-infected patients in the United States are coinfected with HCV.1 As many as 66% of HIV carriers are infected with HCV in some areas from southern Europe.2
Chronic hepatitis C (CHC) induces necrosis and inflammation of the liver, which appear to be responsible for the associated fibrogenesis. Mortality caused by this disease results predominantly from the development of progressive liver fibrosis, which ultimately leads to decompensated liver cirrhosis.
Patient management
Currently, we lack sufficient information to make specific recommendations about antiretroviral therapy in HIV/HCV-coinfected patients. Indeed, the benefits provided by HAART outweigh the risk of severe liver damage. Because of this, CHC should not be a limitation to initiation of therapy. It is reasonable to use drugs that are less hepatotoxic or seemingly protective against liver fibrosis progression, such as protease inhibitors, as first-line therapy. Nonetheless, no drug should be excluded if no alternative is available. Moreover, the potential for liver toxicity or fibrosis enhancement has to be balanced with the risk for other unwanted effects, such as metabolic or cardiovascular toxicity. On the other hand, it should be taken into account that HAART prevents the development of profound immune suppression, a factor associated with severe liver fibrosis in coinfected patients.
HCV infection should be treated with pegylated interferon plus ribavirin, if there is no contraindication. Although the hypothesis is untested, it seems plausible that a sustained virological response leads to a reduction in the risk for liver injury due to HAART.
Other factors that are associated with advanced liver fibrosis independently of HAART should be eliminated. Hence, alcohol consumption must be avoided. HBV infection, if present, should be treated.
Incidence of liver fibrosis in HIV/HCV-coinfected patients
The progression of liver fibrosis is accelerated in HIV-coinfected patients with CHC.3 Although the underlying mechanism of this faster progression remains obscure, it seems to be related to immunosuppression, since the severity of fibrosis is inversely associated with CD4 cell counts.3-5 Thus, HIV-coinfected patients harbouring CHC show advanced liver fibrosis more commonly than HIV-uninfected individuals.3,4 In 172 consecutive coinfected patients who underwent a liver biopsy in our unit, 69 (40%) patients showed liver cirrhosis or pre-cirrhotic fibrosis (F4 or F3 stages, respectively). This incidence of severe liver fibrosis is similar to that found by other investigators in coinfected patients.3,5 In addition, the liver fibrosis progression rate (FPR), calculated as the quotient of the numeric fibrosis stage divided by the estimated or known duration of HCV infection in years, is faster in coinfected patients.3,4 In the population undergoing liver biopsy in our unit, 34% had an FPR equal to or greater than 0.2 fibrosis units per year.6 If we assume that liver fibrosis progression is linear over time, these patients would develop cirrhosis in less than 20 years. However, more probably, fibrosis by itself enhances the fibrogenesis process,7 so that the progression may be even faster.
Effects of HAART on HCV-related disease
Since the acceleration of liver fibrosis progression in HIV/HCV-coinfected patients seems to be related to immunosuppression, one could expect the FPR to be slowed down as a consequence of the HAART-induced immune reconstitution. In agreement with this, HAART has been shown to reduce liver-related mortality in these patients.1,8 However, in coinfected patients, all classes of antiretroviral drugs have been associated with some degree of hepatotoxicity. The episodes of drug-induced liver toxicity cause necrosis and inflammation which may lead to an enhancement of fibrogenesis.6 Consequently, HAART may have a dual effect on the progression of CHC-associated liver fibrosis.
Liver toxicity associated with antiretroviral drugs
HIV/HCV-coinfected patients are more prone to develop hepatotoxicity caused by HAART than HIV-monoinfected individuals. HIV/HCV coinfection is associated with a 2-10-fold chance of showing aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) values above the upper level of normality (ULN) after starting HAART, compared with HIV infection alone.1 The reasons for this increased susceptibility to drug-induced liver damage are not well understood.
It has been proposed that immune reconstitution may lead to an enhancement of liver injury caused by HAART in coinfected patients, due to a more vigorous immune response. However, a number of prospective studies have questioned this hypothesis.1 Antiretroviral drug-related hepatotoxicity has been found to be associated with the degree of CD4 cell recovery in some studies.9 However, a greater CD4 cell gain may be a marker of better adherence to HAART, which also increases the risk of liver toxicity appearing. Other factors that increase the risk of HAART-related hepatotoxicity in coinfected patients are alcohol consumption, infection with hepatitis B virus and higher baseline aminotransferase levels.1,9-12
Nucleoside reverse transcriptase inhibitors, such as zidovudine, didanosine or stavudine, may cause mitochondrial dysfunction, leading to lactic acidosis and steatohepatitis, which may result in liver failure.
In addition to the unconjugated hyperbilirubinaemia associated with indinavir and atazanavir therapy (note from Jules Levin: in studies so far conducted, atazanavir is approved about 2 yrs, the unconjugated hyperbilirubinemia associated with atazanavir use has not been shown to be associated with elevations in liver enzyme), protease inhibitors also cause elevations in hepatic aminotransferases. As many as 30% of patients prescribed full-dose ritonavir show a grade 3 or 4 change in levels of AST and/or ALT, i.e. an increase > 5 times the upper ULN or > 3.5 times the baseline level, if they were abnormal.13 Reduced doses of ritonavir cause increases in the aminotransferase levels less frequently. This incidence is also lower for the remaining protease inhibitors, with frequencies ranging from 1% to 9.5%.13
A grade 3 or 4 change in the values of AST and/or ALT occurs in 10-15% of patients after starting nevirapine. This incidence ranges from 4% to 8% in individuals prescribed efavirenz.9,10,12 Although the evidence is conflicting, symptomatic liver disease seems to be more frequently associated with nevirapine than with efavirenz or the protease inhibitors. Thus, about 5% of patients undergoing nevirapine therapy develop symptomatic hepatic events. Cases of fulminant liver failure have been reported in HIV-infected patients on nevirapine therapy, including pregnant women receiving multiple doses for the prevention of mother-to-child HIV transmission.10 Likewise, health-care workers taking nevirapine for post-exposure prophylaxis after occupational HIV exposures have developed life-threatening hepatotoxicity.14 Nevertheless, fulminant hepatic failure or severe decompensations of chronic liver disease are uncommon.
During the first few weeks of therapy including non-nucleoside reverse transcriptase inhibitors (NNRTIs), liver injury may appear in the setting of a hypersensitivity reaction to these drugs, along with rash and fever. However, from half to two-thirds of liver toxicity cases emerge after 3 months on treatment.9,11,12 Moreover, the risk of NNRTI-related hepatotoxicity increases steadily over time during the first year of therapy.9,11,12
The pathogenic mechanism for liver toxicity associated with NNRTIs is not known. At least with nevirapine, it is unlikely that the same mechanism underlies all cases. Hepatitis cases appearing along with rash and hypereosinophilia are due to a hypersensitivity reaction. The remaining cases, specifically those occurring later in the course of the therapy, are more probably due to a cumulative effect of nevirapine.12 In HIV/HCV-coinfected patients, plasma nevirapine levels have been reported to be associated with the risk of hepatotoxicity.10 Whether high plasma nevirapine levels are the cause of liver toxicity or a mere consequence of liver dysfunction remains to be elucidated.
Effects of antiretroviral drugs on liver fibrosis progression
The impact of antiretroviral drugs on the progression of HCV-related liver fibrosis is far from clear. Prospective studies aimed at assessing this topic face two major obstacles. Firstly, sequential liver biopsies are required to assess changes in liver fibrosis accurately. This practise is poorly tolerated by patients. The second drawback is that antiretroviral drugs are prescribed as combinations. This makes it difficult to ascertain to what extent each drug contributes to liver damage.
A number of retrospective studies have been carried out to explore ways to overcome these problems. The FPR has been used to assess the speed of fibrosis development. However, this parameter might be fallacious, due to a lack of linear progression of fibrosis and to mistakes in the estimation of HCV infection date. Associations between individual drugs, drug classes or combinations and the FPR or the fibrosis stage have been analysed in these studies.
In a study of 152 HIV/HCV-coinfected patients in our unit, 31% of patients who had been treated with protease inhibitors had fibrosis F3 or F4, while this degree of fibrosis was seen in 49% of patients who were protease inhibitor naive. In addition, therapy with the protease inhibitors was associated with a lower FPR than therapy with nevirapine or efavirenz. Conversely, a history of nevirapine therapy was associated with higher FPR. Moreover, more patients among nevirapine recipients than among nevirapine-naive individuals showed advanced liver fibrosis (56% versus 36%, P=0.04). The prevalence of advanced fibrosis was greater in patients exposed to this drug for longer than 1 year. The levels of ALT had increased 2.5-fold from baseline in 27% of patients on protease inhibitors and in 76% of individuals who had received nevirapine. Efavirenz tended to be associated with a low FPR, but this association did not reach statistical significance. No other association with individual drugs or drug classes was detected in this study. According to these results, protease inhibitor-based combinations seem to protect against the progression of fibrosis, whereas nevirapine as the backbone of HAART is associated with faster liver fibrosis development. This effect of nevirapine seems to be cumulative and parallels ALT increases during therapy, which suggests that it is a consequence of the toxic effect of this drug on the liver. The different impact on the progression of liver fibrosis observed with these drugs is striking, given that they cause similar rates of liver toxicity. However, the reported frequencies of hepatotoxicity were estimated on the basis of the development of grade 3 or 4 changes in aminotransferases. It should be pointed out that AST and ALT remain less than 1.25 times the ULN or the baseline level in only 20% of nevirapine recipients. This rate is higher than that observed in patients on efavirenz9 or protease inhibitors.13 It is conceivable that this low-grade liver injury may lead to an enhancement of fibrosis progression.
Other studies addressing the impact of antiviral therapy on the progression of liver fibrosis have yielded conflicting results. Antiretroviral therapy, considered as a whole, was not associated with the severity of liver fibrosis in two studies.4,5 A longer time on antiretroviral therapy correlated with lower degrees of liver fibrosis in another Spanish study.15 Benhamou et al.16 also found protease inhibitors to be a protective factor against the progression of liver fibrosis. No relationship between NNRTI therapy and the severity of liver fibrosis was found in a European collaborative study.5 However, the effect of nevirapine could have been underestimated as nevirapine was grouped with efavirenz in the latter study. These conflicting results may reflect differences in analytic approach, patient populations and in the rate of use of specific antiretroviral drugs and combinations. In addition, a low statistical power may have accounted for the failure to detect some associations.
Long-term prospective studies are necessary to establish definitely the impact of antiretroviral drugs on the progression of HCV-related liver disease. The end points of these studies should be clinical, such as the emergence of liver failure or liver-related death.
REFERENCES
1. Bonacini, M. (2004). Liver injury during highly active antiretroviral therapy: the effect of hepatitis C coinfection. Clinical Infectious Diseases 38, Suppl. 2, S104-8
2. Macias, J., Melguizo, I., Fernandez-Rivera, F. J. et al. (2002). Mortality due to liver failure and impact on survival of hepatitis virus infections in HIV-infected patients on potent antiretroviral therapy. European Journal of Clinical Microbiology and Infectious Diseases 21, 775-81
3. Martinez-Sierra, C., Arizcorreta, A., Diaz, F. et al. (2003). Progression of chronic hepatitis C to liver fibrosis and cirrhosis in patients coinfected with hepatitis C virus and human immunodeficiency virus. Clinical Infectious Diseases 36, 491-8.
4. Mohsen, A. H., Easterbrook, P. J., Taylor, C. et al. (2003). Impact of human immunodeficiency virus (HIV) infection on the progression of liver fibrosis in hepatitis C virus infected patients. Gut 52, 1035-40.
5. Martin-Carbonero, L., Benhamou, Y., Puoti, M. et al. (2004). Incidence and predictors of severe liver fibrosis in human immunodeficiency virus-infected patients with chronic hepatitis C: a European collaborative study. Clinical Infectious Diseases 38, 128-33.
6. Macias, J., Castellano, V., Merchante, N. et al. (2004). Effect of antiretroviral drugs on liver fibrosis in HIV-infected patients with chronic hepatitis C: harmful impact of nevirapine. AIDS 18, 767-74
7. Marcellin, P., Asselah, T. & Boyer, N. (2002). Fibrosis and disease progression in hepatitis C. Hepatology 36, Suppl. 1, S47-S56.
8. Qurishi, N., Kreuzberg, C., Luchters, G. et al. (2003). Effect of antiretroviral therapy on liver-related mortality in patients with HIV and hepatitis C virus coinfection. Lancet 362, 1708-13.
9. Sulkowski, M. S., Thomas, D. L., Mehta, S. H. et al. (2002). Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections. Hepatology 35, 182-9.
10. Dieterich, D. T., Robinson, P. A., Love, J. et al. (2004). Drug-induced liver injury associated with the use of nonnucleoside reverse-transcriptase inhibitors. Clinical Infectious Diseases 38, Suppl. 2, S80-9.
11. Martinez, E., Blanco, J. L., Arnaiz, J. A. et al. (2001). Hepatotoxicity in HIV-1-infected patients receiving nevirapine-containing antiretroviral therapy. AIDS 15, 1261-8.
12. Martin-Carbonero, L., Nunez, M., Gonzalez-Lahoz, J. et al. (2003). Incidence of liver injury after beginning antiretroviral therapy with efavirenz or nevirapine. HIV Clinical Trials 4, 115-20.
13. Sulkowski, M. S. (2004). Drug-induced liver injury associated with antiretroviral therapy that includes HIV-1 protease inhibitors. Clinical Infectious Diseases 38, Suppl. 2, S90-7.
14. Anon. (2001). Serious adverse events attributed to nevirapine regimens for postexposure prophylaxis after HIV exposures—worldwide, 1997-2002. Morbidity and Mortality Weekly Report 49, 1153-6.
15. Tural, C., Fuster, D., Tor, J. et al. (2003). Time on antiretroviral therapy is a protective factor for liver fibrosis in HIV and hepatitis C virus (HCV) co-infected patients. Journal of Viral Hepatitis 10, 118-25.
16. Benhamou, Y., Martino, V., Bochet, M. et al. (2001). Factors affecting liver fibrosis in human immunodeficiency virus- and hepatitis C virus-coinfected patients: impact of protease inhibitor therapy. Hepatology 34, 283-7.
|
|
| |
| |
|
|
|
