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12th CROI HCV Report
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Reported by Jules Levin
Fatty Liver May be Associated with HIV NRTIs & Can Accelerate HCV Progression
Hepatic steatosis is accumulation of fat in the liver. In HCV monoinfection it is well accepted that fatty liver is common in HCV-infected individuals; that fatty liver can accelerate HCV disease progression; and that fatty liver can have a negative affect on achieving a sustained viral response to peginterferon plus ribavirin therapy. Studies show, however, that weight loss & improved diet can reduce fatty liver. Elevated lipids and diabetes can contribute to fatty liver. Barbara McGovern (abstract 950) reported at the 12th CROI a study suggesting fatty liver can be associated with the use of nucleoside analogs, particularly dideoxynucleosides, and with HCV genotype 3. Of note, the study found 19% of the coinfected patients had moderate to severe fatty liver. This is not a surprising finding, it would be expected. Although the study didn't find this, I would expect elevated lipids associated with HAART, as well as diabetes, to also be associated with fatty liver, steatosis. The study found a borderline association between higher triglycerides & fatty liver. (See abstract below).
Liver Histology, ART, and hyperglycemia in HIV/HCV-co-infected Adults: elevated lipids & glucose can contribute to advancing liver disease
Researchers conducted a cross-sectional analysis that was further confirmed by a prospective study among 203 HIV/HCV-co-infected members of the Johns Hopkins HIV clinic who had a liver biopsy and glucose levels before and after biopsy. In this HIV/HCV-co-infected population, the authors reported "there is a strong relationship between hepatic steatosis (fatty liver), fibrosis, and hyperglycemia". Again this is not a surprising finding; in HCV monoinfection this observation has been found in many studies. Patients in this study tended to have fatty liver, advanced liver disease and elevated glucose (hyperglycemia). The study found this to be more often present among patients who had been on ART for >5 years. The authors said: "If confirmed, these data support efforts to treat HCV and to use ART regimens that have the least associated risk of hyperglycemia in HIV/HCV-co-infected persons". We know from previous reearch that diabetes is associated with having HCV, HCV+ individuals are more likely to have diabetes; we also know that diabetes is associated with obesity & being overweight; and diabetes & obesity is associated with having more advanced liver disease in HCV monoinfection. There is no reason to think this is not also true in coinfected patients; elevated lipids and glucose in coinfection can contribute to advancing HCV liver disease.
CROI ABSTRACT:
The relationship of liver histology and hyperglycemia is unknown. The purpose of this investigation was to examine the relationship between liver histology, ART, and hyperglycemia among HIV/HCV-co-infected individuals attending an urban HIV clinic.
We conducted a cross-sectional analysis that was further confirmed by a prospective study among 203 HIV/HCV-co-infected members of the Johns Hopkins HIV clinic who had a liver biopsy and glucose levels before and after biopsy. Biopsies were evaluated by a single pathologist and scored according to the Ishak modified histological activity index scoring system from F0 (no fibrosis) to F6 (cirrhosis). Steatosis was characterized from no fat, to < 5% fat, 5 to 30% fat, and > 30% fat. Hyperglycemia was defined as plasma glucose > 200 mg/dL. Exposure to ART was prospectively ascertained.
Results: Prevalence of Hyperglycemia: Median age was 55 years, 67% were male, 85% African American, and 18% had prevalent hyperglycemia. Prevalence of hyperglycemia was significantly higher among those with ³ F3 fibrosis (28%) compared with < F3 fibrosis (15%, p = 0.03). Moreover, the prevalence of hyperglycemia increased with higher degree of steatosis, (no fat, 15%; < 5% fat, 23%; 5 to 30% fat, 28%; > 30% fat, 43%; p = 0.02). In multivariate logistic regression analysis, body weight > 190 pounds (OR, 2.3; 95% CI 1.1 to 5.2), ³ 5 years of ART (OR, 2.9; 95% CI 1.3 to 6.3) and ³ F3 fibrosis (OR, 2.2; 95% CI 1.1 to 4.8) were independently associated with hyperglycemia. Prevalence of hyperglycemia was highest in those with ³ F3 fibrosis and ³ 5 years of ART (44%; OR compared with < F3 fibrosis and < 5 years of ART, 6.7; 95% CI 2.3 to 19.2). Incidence of Hyperglycemia: These histologic findings were subsequently confirmed in a prospective analysis. Of 166 individuals without hyperglycemia at biopsy, 11% developed hyperglycemia during follow-up, for a cumulative incidence of 27%. Cumulative incidence of hyperglycemia was higher in persons with ³ F3 fibrosis (40%) compared with < F3 fibrosis (23%, p = 0.02) and in persons with steatosis (38%) compared with without steatosis (21%, p < 0.01).
Conclusions: In this HIV/HCV-co-infected population, there is a strong relationship between hepatic steatosis, fibrosis, and hyperglycemia
HCV/HIV co-infection is associated with impaired visual memory and manual dexterity
A number of studies find that hepatitis C can cause cognitive impairment. A study (Tucker, abstract 949) at the 12th CROI found that HCV/HIV coinfected patients in this study had worse cognitive impairment then HCV monoinfected patients. The study authors suggest cognitive impairment may improve following HAART, but I think HCV associated cognitive impairment can persist until successful therapy with peginterferon plus ribavirin. Studies find that achieving a sustained viral response from peginterferon plus ribavirin can result in improved energy and mental cognitive ability. There have been a number of studies examining cognitive impairment in HCV monoinfected and in coinfected patients, and critics always say the study was not well conducted & there were confounding variables. After numerous studies finding the same, the evidence is convincing that HCV can cause cognitive impairment & coinfected individuals are at risk for cognitive impairment from both HIV & HCV and therefore may suffer more cognitive impairment than HCV monoinfected individuals. (see abstract below).
HAART Controlled HIV May Slow HCV Disease Progression
Numerous studies show HIV can accelerate HCV disease progression. In a study presented at CROI (Stuver, abstract 947) conducted in injection drug users the authors report that coinfected individuals may have faster progression of hepatitis C disease if they have low CD4 count and if they are not doing well on HAART. The study suggests that well controlled HIV (high CD4 counts and low HIV RNA) with HAART may reduce hepatitis C disease progression. Several other recently published studies reported recently suggest this as well. But I think we need more & better studies to examine this question. One of these studies also found that although HAART did not appear to accelerate HCV progression, patients with consistently elevated ALT/AST, above 150, are at risk for accelerated HCV disease progression. (see abstract below).
Effect of Protease Inhibitors and NNRTIs on Liver Histology in HIV/ HCV Co-infection
Richard Sterling reported at the 12th CROI an analysis of the APRICOT Study, in which coinfected individuals were treated with Pegasys plus Copegus (ribavirin). This analysis compared the percent of patients with advanced fibrosis who were taking protease inhibitor or NNRTI therapy. They also compared these patients to patients not taking PI or NNRTI therapy. They found that 25% of patients taking PI therapy and 23% of patients taking NNRTI therapy had advanced fibrosis (Ishak stages 4-6). Thus, they suggested that there was no difference in the effect on disease progression between taking a PI or a NNRTI. This conclusion is not well founded based on this study. There are many potential confounders including that we don't know the past ART treatment history of the patients, we don't know their alcohol use history, as well as other information we don't have about the patients. However, the study authors did say "advanced fibrosis is common in those with HIV/HCV co-infection" and I think this statement is well founded considering that HIV can accelerate HCV disease progression and many coinfected patients have had both diseases for many years, and this alone can translate into advanced disease. The study authors also reported that of those study patients not on a PI or NNRTI they less often (15%) had advanced HCV disease, but 36% were not on any HAART within 2 months prior to liver biopsy. Of note, the study patients had on average 500 CD4s & 65% had undetectable HIV RNA, yet 15-25% of the patients had advanced HCV disease. (See abstract below).
Of note, a recently published study reported:
"that the severity of liver damage could be the most important factor in explaining the risk of hepatoxicity toxicity, that is whether a patient has early HCV disease or less fibrosis found by liver biopsyÉÉ. They observed a 3-fold increase in the risk of liver toxicity among those with advanced chronic liver disease or cirrhosisÉ.but the incidence of toxicity was similar for all of the antiretroviral regimens, including NNRTIs or protease inhibitors, used by coinfected patients with mild or moderate fibrosisÉ." Link to full text of study report:
http://www.natap.org/2005/HIV/020205_03.htm
Does this mean that ART does not contribute to advancing liver disease. I don't think we truly know the answer to this question.
ABSTRACTS
"Hepatic Steatosis Is Associated with Dideoxynucleoside Analogue Use and HCV Genotype 3 in HIV/HCV Co-infected Patients"
Barbara McGovern*1, J Ditelberg2, L Taylor3, R Gandhi4, K Christopoulos4, J Fiore2, F Graeme-Cook4, B Schwartzapfel3, S Chapman3, A M Fiorino5, E Rindler2, P Taglienti1, T Zaman1, P Sax6, and P Hibberd2
1Lemuel Shattuck Hosp, Jamaica Plain, MA, USA; 2Tufts-New England Med Ctr, Boston, MA, USA; 3Miriam Hosp, Providence, RI, USA; 4Massachusetts Gen Hosp, Boston, USA; 5Tufts-New England Med Ctr, Boston, MA, USA; and 6Brigham and Women's Hosp, Boston, MA, USA
Background: In patients with HCV alone, hepatic steatosis is associated with genotype 3 infection and increased fibrosis progression rates. Little is known about the prevalence of steatosis in HIV/HCV-co-infected patients or the role which antiretroviral medications may play as potential risk factors in the development of fatty liver.
Methods: Retrospective chart reviews of 179 subjects with liver biopsies were conducted in 4 teaching hospitals in New England serving community and incarcerated patients. Data on demographics, medications, and laboratories were abstracted from medical records; all biopsies were read by 1 pathologist who was blinded to the clinical information. Steatosis was graded as absent, minimal, mild, moderate, or severe. Data were analyzed using SPSS version 11.5.
Results: Characteristics of the 179 patients were: mean age, 43 ± 7 years; male 79%; mean CD4 446 ± 248 cells/mm3, and median and interquartile range HIV RNA 68 (< 50 to 2683 copies/mL). Racial diversity was: Hispanic 27%; African American 24%; other 49%; 58% were taking HAART; 69% were taking nucleoside analogs. The distribution of HCV genotypes were 1 (68%), 2 (9%), 3 (19%), and 4 (5%).Steatosis was absent (31%), minimal (23%), mild (28%), and moderate to severe (19%). Patterns of steatosis were macrovesicular (4%), microvesicular (17%), and mixed (52%). On univariate analysis, factors associated with the presence of steatosis included use of dideoxynucleosides (p = 0.029) and the number of nucleoside analogs used (p = 0.042). Borderline associations with higher triglycerides (OR 1.0, 95% CI 1.00 to 1.01, p = 0.08), male gender (OR 2.0, 95% CI 0.97 to 4.3, p = 0.06), and HCV genotype 3 (OR 2.5, 95% CI 0.9 to 6.9, p = 0.09) were also found. Age, race, duration of HIV, alcohol, CD4, HIV RNA, HCV RNA, cholesterol, and use of protease inhibitors were not associated with steatosis. On multivariate analysis, associated with the presence of steatosis were the use of dideoxynucleosides (OR 6.0, 95% CI 1.9 to 18.9; p = 0.002) and other nucleoside analogs (OR 3.0, 95% CI 1.05 to 8.4; p = 0.04) and HCV genotype 3 (OR 3.7, 95% CI 0.92 to 14.5; p = 0.065).
Conclusions: Hepatic steatosis was prevalent in this racially diverse population of HIV/HCV co-infected patients and was associated with the use of nucleoside analogs, particularly dideoxynucleosides, and with HCV genotype 3. Through their deleterious effects on mitochondria and oxidative phosphorylation, the use of nucleoside analogs may increase hepatic steatosis thereby contributing to liver fibrosis progression.
"Neuropsychological Functioning in HCV/HIV-co-infected Subjects"
K Tucker1, T Parsons1, A Parente1, T Dickens1, M Fried1, J Eron1, K Straits-Tršster2, A Tršster1, C Hall1, and Kevin Robertson*1
1Univ of North Carolina at Chapel Hill, USA and 2Duke Univ, Durham, NC, USA
Background: Co-infection with HIV and hepatitis C virus (HCV) has been associated with an increased risk of liver cirrhosis and more rapid progression to end-stage liver disease. Cognitive changes associated with HIV/HCV co-infection have not been adequately evaluated.
Methods: In this study, 32 HIV+/HCV- (mono-infected) and 14 HIV+/HCV+ (co-infected) patients underwent neuropsychological evaluation before and after 6 months of treatment with HAART. We hypothesized that co-infected patients would demonstrate worse neuropsychological performance than mono-infected patients. Furthermore, we expected the test scores of both the mono-infected and co-infected groups to improve with HAART. Repeated measures multivariate analysis of variance (MANOVA) was used to evaluate group differences and treatment effects. The dependent variables were six cognitive domains derived from neuropsychological test scores (attention, psychomotor speed, executive functioning, verbal memory, visual memory, and fine motor functioning).
Results: Overall, there was a significant difference in cognitive functioning related to HCV status (p < 0.03). In contrast, neither treatment time (pre- vs post-treatment) nor the interaction between HCV status and treatment time contributed significantly to cognitive functioning. Further examination of the significant finding with follow up tests showed that HCV status was significantly related to visual memory (p < 0.03) and fine motor speed (p < 0.002), with worse performance found in the co-infected group relative to the mono-infected group. Of the 6 cognitive domains, 4 and the summary score fell within the impaired range in the co-infected group, whereas, none of the cognitive domains, nor the summary score, were impaired in the mono-infected group at baseline.
Conclusions: The results suggested HCV/HIV co-infection is associated with impaired visual memory and manual dexterity. Thus, it cannot be assumed that HIV fully accounts for these types of cognitive deficits in co-infected patients. Studies with larger sample sizes are needed to determine whether other cognitive deficits and improvement following treatment would become apparent in co-infected groups, since there was a non-significant trend for co-infected patients to perform worse than mono-infected patients on other cognitive domains and to improve following treatment with HAART.
"Predictors of Liver Disease Progression in a Cohort of HIV/HCV-co-infected Drug Users"
Sherri O Stuver*1, C Fleming2, D Nunes3,8, C Reed1, S Tumilty4, J Murray1, C Graham5,7, M Koziel5,7, D Craven6, P Skolnik3,8, and C Horsburgh1
1Boston Univ, MA, USA; 2Univ Coll Hosp, Galway, Ireland; 3Boston Med Ctr, MA, USA; 4Boston Med Ctr, MA, USA; 5Beth Israel Deaconess Med Ctr, Boston, MA, USA; 6Lahey Clin Med Ctr, Burlington, MA, USA; 7Harvard Med Sch, Boston, MA, USA; and 8Boston Univ Sch of Med, MA, USA
Background: Injection drug users (IDU) experience significant morbidity and mortality related to HIV and hepatitis C virus (HCV) infection. Data are limited with respect to predictors of progressive liver disease among IDU infected with both viruses. We examined the effect of viral and nonviral factors on the rate of liver disease progression and liver-related mortality in a cohort of HIV/HCV-co-infected drug users.
Methods: We performed a prospective analysis of liver-related events (i.e., clinical progression of, or death from, liver disease) in 231 HIV/HCV-co-infected IDU enrolled in the Hepatitis C, HIV, and Related Morbidity (CHARM) study cohort, who had at least 1 year of follow-up between August 2002 and January 2004. Cox regression analysis was used to estimate hazard ratios (HR) for demographic (gender, age, race), HCV (age at infection, viral load), HIV (nadir CD4, viral load, ART), hepatitis B virus (HBV) carrier status, and current substance abuse (injection drug use, hazardous drinking) variables.
Results: Of the total 22 HIV/HCV-co-infected subjects experienced liver-related events, at a rate of 5.1/100 person-years. Statistically significant univariate predictors of increased liver disease progression or death included Hispanic race (HR = 5.2; 95% CI 1.1 to 24.3) and nadir CD4 < 100 (HR = 15.8; 2.0 to 122); ART with viral load < 75 (copies/mL) was associated with a significant decreased rate (HR = 0.29; 0.08 to 1.00). The effect of black race (HR = 3.1; 0.69 to 13.8), nadir CD4 100 to 199< (HR = 7.4; 0.86 to 63.0), and current injection drug use (HR = 1.9; 0.80 to 4.6) were of borderline significance. Neither age at HCV infection, HBV infection, nor current hazardous drinking (AUDIT score ³ 8) predicted liver disease progression. In multivariate analysis, nadir CD4 < 200 (< 100, HR = 19.1; 2.1 to 177; 100 to 199, HR = 10.9; 1.2 to 101) was significantly associated with liver disease progression or death; ART and non-white race also appeared to be strong predictors of the rate of liver-related events.
Conclusions: Liver-related morbidity and mortality occurred primarily among persons of non-white race in this urban, IDU cohort. The results demonstrate that low nadir CD4 count strongly predicts HCV-related liver disease progression and death in IDU with HIV co-infection. Moreover, receipt of ART may significantly reduce morbidity. Strategies to increase availability of and adherence to ART may decrease progression of HCV liver disease among HIV co-infected IDU.
"Effect of Protease Inhibitors and Non-nucleoside Reverse Transcriptase Inhibitors on Liver Histology in HIV/ HCV Co-infection: Analysis of Patients Enrolled in the AIDS PEGASYS Ribavirin International Co-infection Trial (APRICOT)"
Richard Sterling*1, E Lissen2, N Clumeck3, R Sola4, M Correa5, J Montaner6, M Sulkowski7, F Torriani8, D Dieterich9, D Messinger10, and M Nelson11
1Virginia Commonwealth Univ Hlth System, Richmond, USA; 2Virgen del Roc’o Univ Hosp, Seville, Spain; 3Ctr Hosp Univ St-Pierre, Brussels, Belgium; 4Hosp del Mar, Univ Aut—noma de Barcelona, Spain; 5HCFMUSP, Casa da AIDS, Sao Paulo, Brazil; 6Univ of British Columbia, Vancouver, Canada; 7Johns Hopkins Univ Sch of Med, Baltimore, MD, USA; 8Univ of California, San Diego, Treatment Ctr, USA; 9Mt Sinai Sch of Med, New York, NY, USA; 10IST GmbH, Mannheim, Germany; and 11Chelsea and Westminster Hosp, London, UK
Background: The effect of HAART on hepatitis C virus (HCV) disease severity remains controversial. Although early studies suggested that protease inhibitors (PI) are associated with slower fibrosis progression, more recent data show no significant difference in liver histology between patients on PI and those on non-nucleoside reverse transcriptase inhibitors (NNRTI) as part of their HAART regimen. These studies, however, were small. We aimed to determine the effect of PI or NNRTI on liver histology in the large cohort of patients in APRICOT.
Methods: Retrospective analysis of liver histology in patients entering APRICOT. The design and results of APRICOT were recently published. In 178 of 868 randomized patients no pre-biopsy HAART data were available (liver biopsies obtained until 15 months prior to the study were eligible). Patients were stratified by use of PI, NNRTI, or both within 2 months prior to biopsy. Liver histology was assessed by Ishak score and significant histology was defined as advanced fibrosis (Ishak 4 to 6). Data are expressed as mean (± SD).
Results: Of 690 patients with evaluable data, 312 (45%) were taking PI, 205 (30%) were taking NNRTI, 53 (8%) were taking both, and 120 (17%) were on neither (see the table). Of those not on a PI or NNRTI, 43 (36%) were not on any HAART within 2 months prior to liver biopsy. These groups had similar demographic characteristics (age, race, weight, body mass index, and HCV RNA titer), and mode of infection. Overall, advanced fibrosis (Ishak score 4 to 6) was more frequent in patients receiving PI/NNRTI than in patients not receiving PI/NNRTI (24% vs 15%, p = 0.026) independent of the type (NNRTI or PI).
Conclusions: Advanced fibrosis is common in those with HIV/HCV co-infection. While there were no significant differences in liver histology between patients receiving a PI- compared with a NNRTI-containing regimen, these data suggest that the choice of HAART should be based on potency and durability of the ART regimen and not as much on the potential for hepatotoxicity and progression to fibrosis.
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