Human Immunodeficiency Virus and Liver Disease: Conference Proceedings

Liver disease has emerged as one of the major causes of morbidity and mortality among patients infected with the human immunodeficiency virus (HIV), particularly in regions where highly active antiretroviral therapy (HAART) is widely available. This dramatic change in disease epidemiology is attributable to a complex interaction between etiologic factors that appear to increase the rate of hepatic fibrosis and accelerate progression to end-stage liver disease (ESLD). Key factors include HAART-related hepatoxicity, frequent coinfection with hepatitis B and C virus, and possibly the direct interaction of HIV virus or soluble protein viral products that interact with hepatocytes and other liver resident cell types. Additionally, there is some evidence that gut permeability is altered during active HIV replication, which affects the complex mix of toxins and growth factors present in the portal circulation. It is critical that hepatologists maintain a strong knowledge base to provide the best possible guidance to HIV-infected patients and their healthcare providers. To this end, the second international forum on HIV and Liver Disease was convened in Jackson Hole, WY, in September 2008. The first forum, held 2 years earlier was previously summarized in HEPATOLOGY, and has been widely cited by experts in the field.1 However, the fast-moving nature of this critical health issue led to development of a second meeting, supported by grants from three institutes of the National Institutes of Health (NIH) (National Institute of Allergy and Infectious Diseases [NIAID], National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK], and the National Institute on Alcohol Abuse and Alcoholism [NIAAA]) and by unrestricted grants provided by the pharmaceutical industry. As before, the meeting sought to bring together basic and clinical researchers representing multiple disciplines including hepatology, infectious diseases, epidemiology, virology, and drug development as well as governmental experts in health policy, research, and research funding. This document provides a summary of key presentations and highlights the current state of knowledge and future directions this field will take. HIV prevalence in the United States is increasing due to the stable incidence of HIV (estimated at 53,600 cases/year in 2006) and the longer life expectancy attributable to widespread use of effective antiretroviral therapies. This pattern permits non-HIV defining processes to predominate as major causes of morbidity and mortality. New infection with HIV is primarily transmitted from persons who do not know that they are infected with HIV, and this observation represents a significant change compared to historical data regarding HIV transmission.2 Furthermore, HIV disproportionately affects African-Americans, Hispanics, men who have sex with men (MSM), and those living in the southern United States. The rate of new infection in MSMs appears to be increasing.3, 4 Recent recommendations from the U.S. Centers for Disease Control and Prevention to broaden screening for HIV may result in an increase in new cases referred to the hepatologist or gastroenterologist. Shared mechanisms of transmission lead to high coinfection rates with both hepatitis C virus (HCV) and hepatitis B virus (HBV) among those with HIV infection. However, rates of infection are highly variable and depend on the nature of shared risk. Current estimates of HCV disease burden suggest that between 250,000 and 300,000 individuals in the United States are coinfected with HCV and HIV.5, 6 Worldwide, rates of coinfection are highly variable. In sub-Saharan Africa, rates of HCV/HIV may be as low as 2%–3% of the HIV-infected population.6 This reflects the predominant mode of HIV transmission, heterosexual exposure, which is relatively inefficient for HCV viral spread. In contrast, reports of acute HCV infection among MSMs appear to be increasing. Small but significant outbreaks of acute HCV have been reported in major cities in Europe and the United States.7, 8 Epidemiological investigation reveals a high risk association with anal-receptive sexual activity including “fisting”, suggesting that anal mucosal trauma is a key element of HCV transmission. The reason that the increase in acute HCV among gay men is being seen now remains contentious. Some investigators believe that widespread use of HAART has created a permissive atmosphere reminiscent of 1980s bathhouse behavior, with multiple sexual exposures in a short window of time. Others do not believe that behaviors have changed, and the perception of increased incidence represents an ascertainment bias. It was suggested that HIV spread in the 1980s was divided into two distinct epidemics: one in MSMs and the other in injection drug users. The MSM spread predominated in the 1980s, and these patients did not have high concomitant rates of HCV infection. Over the years, the risk behaviors of high-risk sexual activity and injection drug use merged, leading to higher prevalence of HCV in the MSM population and contributing to the current acute HCV outbreaks. Additionally, there is evidence that noninjection methamphetamine use may be associated with cases of acute HCV transmission.9 This hypothesis will need to be studied in more detail and represents an important area of epidemiologic research. The natural history of HCV is altered when HIV is present. We have known for some time that low CD4 counts (<200 cells/mm3) are associated with more rapid progression of hepatic fibrosis, development of cirrhosis, and time to appearance of decompensated liver disease.10-13 Recent data suggests that HIV viral load may be an important and independent factor in accelerated disease progression as well. These data are primarily derived from large treatment or observational cohort studies (e.g., SMART, EUROSIDA, GESIDA) which show decreased progression to ESLD when HIV viral loads are low or undetectable.14, 15 Clearly, it is difficult to separate the effect of CD4 from HIV viral load because these are highly related covariates, but study of large cohorts does permit some insight into the independent effects of these variables. Furthermore, there are biological data regarding the effect of HIV on cells residing in the liver that support the epidemiologic associations. These data are described more fully in the section on Pathogenesis below. Unpublished data presented by Dr. Tuma demonstrated that rates of progression to cirrhosis in a HAART-treated Spanish cohort did not differ significantly from those with HCV alone. Similarly, Dr. Rimland provided data from a cohort in Atlanta, Georgia, indicating that liver-related deaths among HCV/HIV-coinfected patients are decreasing. Taken together, these data suggest a role for effective HIV treatment in HCV/HIV-coinfected patients, but additional supporting data is clearly needed. Despite these observations, several meeting participants noted that abnormal liver enzyme levels in HCV/HIV-coinfected patients often discourage continuation of potentially hepatotoxic HAART agents, leading to undertreatment.16 Dr. Sterling presented data regarding the high frequency of serum aminotransferase abnormalities among those with HIV infection absent of known viral coinfections, or use of hepatotoxic drugs.17 It is clear that hepatology input regarding the etiology, significance, and severity of the underlying liver disease is a critical element in the comprehensive management of HIV-infected patients. ESLD, end-stage liver disease; HAART, highly active antiretroviral therapy; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; MSM, men who have sex with men; NIH, National Institutes of Health; RVR, rapid viral response; SVR, sustained viral response. The observation of more rapidly progressive liver disease in HCV/HIV coinfection, despite the fundamental role of the immune response in chronic viral disease pathogenesis, suggests a paradox, because the depletion of CD4 cells might be expected to attenuate such responses in advancing HIV disease. However, available evidence suggests that HIV coinfection is attended by immune dysregulation rather than depletion. For instance, although there appears to be no clear quantitative differences in intrahepatic CD4 or CD8 T cell responses against HCV, there are qualitative differences, including increases in interleukin-10 secretion compared with HCV monoinfection.18 Another important contributor to accelerated HCV-related liver disease is alteration of the fibrogenic cytokine environment. In this regard, it has been demonstrated that HCV-induced transforming growth factor-β secretion by hepatocytes is augmented by addition of recombinant HIV envelope protein gp120 or HIV infection itself, implying that HIV is capable of altering the hepatocyte cytokine environment without necessarily directly infecting hepatocytes.19 There is additional experimental evidence that HIV may also impact hepatic stellate cells, the prime movers of hepatic fibrogenesis.20 HIV may also increase fibrogenesis indirectly through promotion of hepatocyte apoptosis.21 Finally, HIV may alter the hepatocyte environment indirectly through promotion of microbial translocation, immune activation, and alteration of local levels of tumor necrosis factor-α, which promotes hepatocyte injury.22 Alcohol has been demonstrated to accelerate viral liver injury. Ethanol is well-known to induce direct hepatic injury through its principal metabolite, acetaldehyde, but also induces steatosis through alterations in the hepatic oxidation-reduction state. Oxidative stress also induces mitochondrial injury, which predisposes to hepatocyte apoptosis. Alcohol may also enhance the injury associated with microbial translocation, promoting production of tumor necrosis factor-α These findings suggest a direct interaction between HIV infection and alcoholic liver disease pathogenesis.23, 24 Hepatic steatosis can also be observed under nonalcoholic conditions as well, and is particularly frequent among HIV-infected persons. Steatosis has been suggested to have an association with accelerated rates of HCV fibrosis progression.25 Persons infected with HIV have multiple predispositions to hepatic steatosis, including use of protease inhibitors and nucleoside analogs, hyperlipidemia, lipodystrophy with increased visceral fat deposition, and insulin resistance, though the prevalence may not be more than in HCV monoinfection.26 HCV infection itself contributes to insulin resistance and indirectly to steatosis. In the case of genotype 3 infection, HCV can directly promote steatosis. Reversal of steatosis has been considered when antiviral therapy for HCV fails or cannot be tolerated. In this regard, the use of insulin-sensitizing agents may have a role in not only ameliorating steatosis, but also in improving antiviral response rates, because elevated insulin resistance is associated with diminished interferon response. However, this concept has not been proven in clinical trials. A clinical trial investigating whether pioglitazone pretreatment of previously treated HCV/HIV nonresponder subjects improves retreatment response is actively enrolling in the AIDS Clinical Trials Group (ACTG) at this time. Antiretroviral therapy can be associated with acceleration of hepatic injury as well, further fomenting hepatic disturbances among HIV-infected persons. Hepatotoxicity can be observed with all classes of HAART, and grade 3–4 elevations of alanine aminotransferase can be observed in about 5% of patients in patients receiving nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside RTIs, and protease inhibitors (PIs). NRTIs, in particular, because they bind mitochondrial DNA polymerase-γ, increase the risk for mitochondrial toxicity, promoting apoptosis and microvesicular steatosis, though not all NRTIs demonstrate similar levels of toxicity. Stavudine and didanosine (ddI) are particularly troubling in this regard, but their use has been replaced in most practice settings with lower toxicity agents. In addition, immune reconstitution injury can be observed in persons with chronic HBV infection who experience resurgent immune responses. Immune reconstitution may occur with HCV as well; however, this entity has been more difficult to distinguish, because immune responses to HCV are attenuated in general. The direct effects of HIV on the liver remain unclear, but will constitute an important area of research activity as the field moves forward.27 There are data suggesting that HIV can directly (infection) and indirectly (gp120 binding) interact with hepatocytes, stellate cells, and Kuppfer cells. Furthermore, it seems likely that active infection of intrahepatic CD4 cells with HIV also occurs. Details regarding HIV tropism and specific adaptations remain to be explored. Finally, there is recent recognition of “new” forms of liver disease in HIV-infected patients. Several groups around the world have noted cases of nodular regenerative hyperplasia or hepatoportal sclerosis.28, 29 In many cases, these were thought to represent a form of cryptogenic cirrhosis, but appropriate biopsy or evaluation of the liver following liver transplantation provided the correct diagnosis. The etiology remains uncertain. Some investigators suggest a strong association with prior use of didanosine, but the nearly ubiquitous use of this agent in patients during the late 1990s until the mid-2000s raises the possibility that this is a spurious finding. Research is required to determine if persistent mitochondrial injury can lead to this pathologic finding. The widespread use of HAART has dramatically changed the prognosis of HIV infection since its introduction in the mid 1990s. During the early HAART era, encouraging responses led to the treatment of nearly all infected individuals, following the principle of “hit hard, hit early”.30 However, appreciation of the short-term and long-term side effects of the oldest antiretrovirals, particularly of “d-drugs” such as didanosine, and and protease inhibitors (e.g., and of when to and a until CD4 counts a critical which the risk of was significantly The recent of antiretroviral agents many of with a toxicity to new drug with a appreciation of the by HIV has a to an earlier introduction of HIV treatment is in all HIV patients with CD4 counts as well as in many patients with higher CD4 A study in suggests that early of HAART the CD4 is associated with A of suggests that all patients with coinfection who HBV treatment be on antiretroviral therapy HBV Some experts also earlier treatment of HIV in the of The current antiretroviral by the U.S. of Health and or AIDS Clinical of two NRTIs with a (e.g., first a protease Some experts support use of following its recent for patients. these around of patients at However, with a of patients experience viral as result of and of this drug resistance is and a in antiretroviral be in to viral be with no to prior agents and include to drug classes (e.g., or with high to resistance (e.g., antiretroviral both HIV and HCV are and some similar in the the HCV is not into the infected hepatocyte as with HIV DNA in infected Furthermore, the of HCV is higher than HIV or HBV This HCV can be with therapy HIV infection for life despite of viral with antiretroviral observation is that HIV seems to and liver cell on the other of HCV, in has been this it is to of in these might the and clinical in of HIV, HCV, and HBV with from of of Infectious of Current treatment have the 2 patients are treated with a of and although therapy has not been by in the United States. data from which higher early viral response rates when compared to historical who at a of The trial also supported use of for patients for those trial was in of both studies supported the of the The of a large trial of in HCV/HIV-coinfected subjects are at this time. were presented suggesting that rapid viral response as HCV viral at 4 of was a of sustained viral response in coinfected patients. However, there was for of treatment in the of was an There was of the role of and this meeting the of the were presented at the on and The findings did not support use of interferon therapy in HCV/HIV The study did in HCV treatment with lower rates of seen in and The of new direct against HCV is for patients, in current therapy with interferon provides in than of HCV genotype which are the most The new for HCV, however, may in the coinfected population in the risk of drug resistance might be increased due to higher viral loads and lower activity of Furthermore, there is a high for interaction and with antiretroviral due to shared for many experimental agents. Despite these the U.S. and that studies in HCV/HIV-coinfected patients be prior to of a New in subjects due to the significant disease burden and rapid progression observed in HCV/HIV-coinfected from multiple suggest that only a of subjects with HCV/HIV coinfection treatment for The low rate of hepatitis C therapy among patients in many U.S. in those including with treatment rates of in in genotype genotype 2 and 3 in to and variable appear to for this but it seems clear that further evaluation of this is of HIV patients show persistent serum levels of hepatitis B serum The rate is higher in than in to ESLD in in the of significant elevated liver because are in the liver of individuals with HIV, despite the accelerated nature of There are HBV of including multiple in HBV is by the of the and of However, and coinfection may immune and of In with or and appear to show a high to resistance, although use is in patients with prior due to the clinical of hepatitis B viral The of in patients has been widely with more than of patients with HBV at years, with significant in liver and of liver fibrosis the recognition of a activity for the use of this drug in patients with the activity of against HIV and HBV this when with or with the for coinfected Another is a nucleoside with HBV but with a resistance similar to There are case reports of HIV activity and as with use of this agent in patients without other concomitant HAART therapy cannot be at this time. In addition to accelerated there may be additional clinical that liver disease. A of reports have cases of portal in the of cirrhosis, by nodular regenerative in persons with HIV and no other clear liver disease clinical findings and with development of Several of these patients liver The most was the of didanosine, which raises the of a by the drug or its that the response of nodular regenerative study is required to the frequency and factors underlying this For those persons with fully decompensated ESLD, an important is when to for liver reports suggest that infectious disease do not include international in their evaluation of HIV-infected patients. studies have and their in among ESLD patients with The has demonstrated that HIV viral load and CD4 are associated with increased for Liver Disease was the only independent of suggests that mortality did not appear to be higher among persons than in individuals for and it appear that is an in individuals as it is in the population and be to HIV-infected patients with the about the of liver disease in possibility is that the may be more from the to the decompensated however, more the of may more study is to the clinical factors that the are now in the United States and Europe regarding of liver transplantation in HIV-infected patients. the that have been have been for ESLD, the other for have been with of HIV with HAART, and no progression to AIDS observed among persons who have been to HAART the use of with hepatitis B immune and antiviral with or the rates of ESLD have been and on with In contrast, the rates for those liver transplantation for HCV ESLD have been lower in both the United States and and with The major reason for the in and has been in a but of patients, of HCV has been The factors that this have not been Clearly, is required to the and viral factors that the widely of persons liver for HCV The management of liver disease in the of HIV into and that impact disease transmission, and most are a high of patients with HIV infection are and their is by that provide with for These behaviors lead to increased risk of HIV, HCV, and HBV as well as drug and studies have clearly demonstrated the of agents such as and this of patients is highly to drug and to be critical in the management of such patients, both in of management and in the to maintain antiretroviral or HCV The most effective development of a that the to a There is significant in the of new research activity in the area of HIV and liver disease. This several institutes of the and has led development of multiple for and that are on the for In addition, several institutes support development to provide early to to investigators with an in this There is in the development of studies that use of and data derived from cohorts including the AIDS Clinical Trials Group the AIDS the HIV and to research include the relatively low rate of though this may be by increased due to the of Furthermore, an environment has increased related to research. key remain with to development and management of liver disease in the of HIV infection. The development of new agents for treatment of hepatitis C represents both an and an increased of as of HCV viral and drug toxicity, and drug Furthermore, it has clear that HCV/HIV-coinfected patients are treatment and the for that include all infected patients remains The direct and role of HIV and its soluble on hepatic cells and remains and of gut of and the effect on the liver remain at this time. epidemiologic data suggest that HIV may be the of liver disease but this hypothesis be supported by of mechanisms that these B therapy seems more but of long-term and resistance remain and of new for The described was supported by from the and by the and the The is the of the and does not necessarily represent the of or the The meeting participants the following The was of The were and The and were of AIDS of of National Institute of Allergy and Infectious Diseases Centers for Disease Control and of of of of at of of and Institute of of of of of of AIDS of of of Health of at and of of

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.