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Hepatitis Report from ICAAC
Nancy Shulman, MD, Stanford University
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As this year's ICAAC was rescheduled close to the holidays, many people did not attend who had originally submitted posters and abstracts. Therefore some of the abstracts did not have posters presented.
Liver transplantation in HIV+ patients - short-term survival rates are good
Several centers around the world are transplanting HIV+ patients with solid organs, mainly kidneys and livers. Last year, at the Retrovirus conference, early reports of liver transplantation success were good for HIV+ with hepatitis B (HBV), but dismal for hepatitis C+ (HCV). This was mainly due to a rapid recurrence of hepatitis C in the transplanted liver. In a presentation at ICAAC, the results were encouraging. The group from the University of Miami reported their results of 6 HIV+ patients who received cadaveric liver transplants. One additional patient died waiting for a transplant. Three of the transplanted patients had HBV, two had HCV, and one had both.
Two of the patients had acute rejection of the transplanted liver but recovered with increased medications to suppress their immune system. Two of the patients had problems with tacrolimus toxicity (an immunosuppressant used in transplantation) due to higher than desired levels of tacrolimus from interactions with their protease inhibitors, but they both recovered from the toxicity with dose reductions and closer monitoring of the protease inhibitor levels and the immunosuppressants. The 6 patients are at 2, 8, 10, 12, 16, and 30 months out of their transplants. What is different in this group vs. the previously reported groups are that they started the patients who are HCV+ on pegylated interferon and ribavirin after transplant to contain the HCV. When asked how long they will be on therapy, Dr. Neff stated "indefinitely". Dr. Neff also reported that 4 of the 6 patients transplanted at Pittsburgh are also alive, but the exact dates from transplant were not known for that group. One of the two patients who died in the Pittsburgh group had an overwhelming bacterial infection soon after transplantation. The other stopped his immunosuppressive agents for an unclear reason and his liver failed.
This is encouraging news for people with cirrhosis from viral hepatitis who are also HIV+. We all hope to here more about these patients in the future as well as others.
Editorial note: At the AASLD liver meeting (November 2001), 2 posters were reported on using Pegasys for both prophylaxis against HCV after liver transplantation and for patients with recurrent HCV after transplant. For prophylaxis, at week 24 4/9 patients had a 2-log viral load drop, and 2/9 were HCV-RNA negative. For recurrent established HCV, at week 48 4/11 patients receiving Pegasys were HCV-RNA negative. At week 24, 11/19 had a 2-log drop and 6/19 were HCV-RNA negative.
Reference: Neff, et al. Initial successful liver transplantation in patients with HIV-HBV or HCV co-infection: a report of 6 cases. Abstract I-203.
HIV+ patients with decompensated liver disease in the pre-HAART vs. post-HAART era.
Liver disease as a cause of death in HIV+ since the advent of HAART is becoming more important, particularly in places where HCV coinfection rates are high like Spain and Northern Italy. A group from Madrid compared the demographics and outcomes of HIV+ patients admitted to the hospital with their first episode of decompensated liver disease.
Methods: They looked up hospitalization records of patients who developed ascites for the first time (fluid in the abdomen), hepatic encephalopathy (a drunken-like state due to failure of the liver to get rid of toxins), peritonitis (infection of the fluid in the abdomen), bleeding from esophageal varices (dilated veins in the esophagus from cirrhosis), or primary liver cancer. They found 29 patients who were admitted in the pre-HAART era between 1994-1996 and 37 patients in the post-HAART era (1997-2000). 94% had HCV. Similar proportions in each group were former or active substance abusers at the time of admission and more than half of each group were active alcohol users, which we know makes the liver disease of hepatitis worse. The group in the post-HAART era had higher median CD4 counts at the time of admission (239 vs. 84, p=0.002). Fifty-two patients died during follow-up, 26 in each group. More in the pre-HAART era died of opportunistic infections (54% vs. 16%) and more death due to liver disease occurred in the post-HAART era (77% vs. 46%). Median survival in the two groups was not significantly different after first decompensation in the groups as a whole (median 87 vs. 100 days) and in those who died of liver disease (88 vs. 62 days). 50% of all patients died within one year.
The conclusion was that once patients developed decompensated liver disease, survival was no different in the HAART era vs. before. More than half of patients died within one year of their first episode of decompensation. The take home message is to treat the patients for HCV and decrease their alcohol compensation before they develop decompensated disease and to evaluate them for transplantation very soon after they decompensate.
Reference: Quereda, et al. Impact of HAART in the natural history of decompensated liver cirrhosis in HIV-infected patients. Abstract I-204
Do people with HCV or HBV have less immunologic responses to HAART?
Prior studies have suggested that patients who have HCV or HBV have a blunted immunologic response to HAART therapy. This study addressed that question using the ICONA cohort from Italy.
Methods: 1320 patients who were antiretroviral naive and had known HCV and HBV status were prospectively followed to see how they did after they started HAART therapy. Factors contributing to CD4 and viral load response were analysed using linear regression and Cox multivariate models. Linear models estimated the change in CD4 count and viral load at the first 2 time points after treatment. Cox models used a categorical (yes or no) measure of achieving a virologic response (<50 copies/ml ), and an immunologic response (CD4 count increase of 100 or more or achieving 500). Patients were also followed for the development of AIDS-defining illnesses and death. The variables that were considered were age, sex, HCV and HBV status, baseline CD4 count, baseline viral load, use of a PI-sparing vs. a PI-based regimen, active IV drug use.
Results: Of the 1320 patients, 75% were male, 8% were active IV drug users, and 15% started a PI-sparing regimen. The median CD4 count was 200 and median viral load was 4.9 log10 copies/ml. 674 patients were HCV-/HBV-, 46 patients were HCV-/HBV+, 556 were HCV+/HBV-, and 44 were both HCV+/HBV+. The median duration of follow-up in the analysis was 3 years. There were 56 new AIDS defining illnesses and 43 deaths: 24 from HIV, 3 from liver disease, and 12 from other causes.
In the linear model, the HCV+ groups had about 30 CD4 cells lower at each time point than the HCV- groups, but were not different in regards to HIV viral load reduction. In the Cox model, HCV+ patients also had a lower chance of achieving an immunologic response than HCV- patients, but not a worse virologic response. Active IV drug use was associated with both worse immunologic and virologic responses.
The conclusion is in agreement with what was previously reported, that HCV+ patients have less immune reconstitution when compared with HCV-, and this study shows this is independent of whether they achieve a virologic response. Of note was despite the relatively high % of HCV+ and HBV+ co-infection in this cohort, there were surprising only 3 liver deaths over the course of follow-up.
Reference: De Luca, et al. The influence of HBV-HCV serostatus on immunologic and virologic responses to HAART in HIV-infected naive individuals. Abstract I-205.
Antiretroviral induced liver toxicity
Co-infected patients have had higher rates of liver toxicity from antiretroviral therapy due to protease inhibitors (Sulkowski, et al, JAMA). 3 abstracts described risk factors for hepatic toxicity in a retrospective study.
221 patients in Madrid with at least 12 months of follow-up were analyzed in the first abstract. 137 (62%) were HCV+, 12 (5%) were HBV+. 34 (15%) developed grade 3 or 4 liver toxicity (>5 times the upper limit of normal ALT) and 9 discontinued due to the liver toxicity (4%). In a multivariate analysis, only baseline ALT was predictive of toxicity (p=0.003), ie: those with high ALTs to start with were more likely to reach the 5x mark. There were trends of higher toxicity with nevirapine (p=0.07) and saquinavir use (p=0.08). HCV status and alcohol consumption were not predictive.
The next abstract, also from Spain, looked at who got grade 3 or 4 liver toxicity in patients who received NNRTIs. 108 patients who were adherent by the discretion of the chart reviewer were included in the study. 46% were HCV+ and 6% were HBV+. 47% were on nevirapine (Viramune) + two nucleosides, 31% on efavirenz (Sustiva) and two nucleosides, 18% were on nevirapine + two nucleosides plus a protease inhibitor, and 4% were on efavirenz + two nucleosides + a protease inhibitor. Patients who were HCV+ (31% developed toxicity) were about 3 times more likely to develop severe toxicity than HCV- (11%). No differences in toxicity rates were seen between the nevirapine +2 nucleosides and the efavirenz + 2 nucleosides. The most risky regimen was nevirapine + a protease inhibitor + two nucleosides which resulted in an almost a 5-fold risk of developing toxicity. The take home message is to be cautious when initiating an NNRTI in HCV+ patients, particularly when giving nevirapine with a PI in this group.
The final abstract evaluated the incidence and risk of developing severe, life-threatening hepatitis from nevirapine. 394 patients who received at least 1 week of nevirapine were included. Small elevations (grade 1-2) in ALT were common (28%). 5 patients developed acute icteric hepatitis, all gay men with CD4 counts >200 and only one had concurrent HBV. They all developed a mild eosinophilia (an increase in the cells associated with allergic reactions). Within 8 weeks of stopping therapy, all 5 patients recovered. HCV/HBV does not appear associated with the worst cases of nevirapine-induced liver toxicity.
Reference:
1. Moreno, et al. Hepatotoxicity associated with antiretroviral therapy in HIV-infected adults: seriousness and predictive factors. Abstract I-207.
2. Ena, et al. Risk and determinants of developing severe hepatic cytolysis during therapy with NNRTI combinations in HIV-infected patients. Abstract I-208.
3. Fernandez-Guerrero, et al. Nevirapine induced acute hepatitis. Abstract I-209.
Why does HCV progress faster in HIV+?
An interesting abstract was presented addressing the question of why HCV progresses faster in HIV patients. HCV damage to the liver is thought to be immune-mediated. If that was the case in HIV, one would expect less damage with lower CD4 counts, but that is not the case in past studies. Cytokines like tumor necrosis alfa (TNF-alpha) mediate HIV symptoms, correlate with the levels of HIV viral loads and mediate liver damage. TNF and soluble TNF receptor II and TNF-alpha (sTNFRII) are involved with fibrosis. Transforming growth factor beta (TGFB) inhibits hepatocyte (liver cell) proliferation. This group from Albany Medical Center looked at the levels of TNF-alpha, sTNFRII, and TGFB in the blood from HCV+ patients (24 HIV- and 28 HIV+ patients). These patients also had liver biopsies to compare histopathology with the cytokine results. TNF alfa levels were substantially higher in co-infected patients. In the HIV- group, sTNFRII correlated with the Knodell score. In the co-infected group, HIV viral load, TGF-beta levels, and the degree of apoptosis (programmed cell death or cell "suicide") in the liver cells were each independently associated with pathology.
The investigators conclude that in HCV+ HIV-, the liver disease is caused by an immune mediated reaction to HCV. In HIV co-infected patients this is not the case, but appears to be a cytokine-mediated direct affect. Patients with higher HIV viral loads had worse liver pathology. Control of the HIV may improve that although those studies have not been reported/performed.
Reference: Stellrecht, et al. Pathogenesis of HCV in HIV positive patients. Abstract
H-456.
Optimal Peginterferon - Alfa 2a (Pegasys) doses for HCV
This was a study using Pegylated interferon monotherapy, which is not the current standard of care. It tested two different doses of Peg-IFN, 135mg and 180mg per week injected subcutaneously into about 600 HCV monoinfected patients and compared these to standard IFN 3million units three times per week. Overall sustained viral responses were 28%, 28%, and 11% in the three groups, with 22%, 19%, and 7% in patients with Genotype I. The histologic responses were substantially better with the highest Peg-IFN dose, 58% vs. 48% and 45% in other three groups. Toxicity rates were similar in the three groups. Take home: 180mg of Pegasys is better since it had better histologic responses, but 135mg is a step-down option to reduce to if toxicity is seen in with 180mg as the sustained response rates are the same.
Reference: Pockros, P, et al. Evaluation of two doses of Pegylated Interferon Alfa-2a for the treatment of chronic HCV. Abstract H-457.
Preliminary data on low-dose peg-Intron with ribavirin for HIV/HCV coinfected
A group from Spain presented end-of-treatment response and toxicity data on treatment of HCV in 35 HIV+ patients with a low dose Pegylated interferon alpha 2b (Peg-Intron) plus ribavirin. They used a timid dose of Peg-IFN, due to fear of toxicity, of 50mcg per week. The standard dose is 1.5mcg per kg per week. In addition to the Peg-IFN, patients received 800mg of ribavirin per day.
Patients: All patients had CD4 counts of >300, had HIV viral loads of <10,000, and had ALT levels of 1.5 times the upper limit of normal, had compensated liver disease, and were interferon naive to qualify for the study. 35 patients were enrolled. The median age was 38, and most were male. 54% had HCV genotype 1. 32 patients were on antiretroviral therapy.
Results: Five patients discontinued therapy: 2 from anemia, one from lactic acidosis, one from depression, and one from severe flu-like symptoms. All patients had at least one adverse event. 88% had flu-like symptoms, 82% malaise, 20% headache, 14% depression, and 28% had an injection site reaction. 23% dose reduced due to hemoglobin <10 g/dL, and 6% discontinued. 14% dose reduced due to neutropenia, none discontinued. 1 (3%) patient discontinued due to hyperlactatemia. Of the 30 that remained on therapy for 6 months, 46% had an undetectable HCV RNA including 31% of the Genotype 1 group and 67% of the genotype 2/3 group. This is somewhat higher than the end-of treatment responses in other studies of coinfected patients using interferon and interferon-ribavirin combination, but we will have to wait 6 months to see who remains HCV RNA negative off of therapy.
Reference: Moreno, et al. Early response to combination therapy with low-dose pelylated interferon alpha 2b and ribavirin for chronic hepatitis C in HIV-infected patients. Abstract 458.
Pancreatitis in HIV-HCV coinfected patients on HCV treatment
The group at Parkland hospital in Dallas described asymptomatic and symptomatic pancreatitis in their patients treated for HCV with interferon and ribavirin therapy. 22 patients received therapy for HCV, all with normal lipase (a pancreatic enzyme) levels prior to treatment. 10/25 had significant elevations of their lipase and amylase during therapy including 5 with clinical pancreatitis. Four of these 5, were on D4T/DDI and one was on D4T/3TC. The other 5 with asymptomatic elevations in amylase/lipase were on D4T, DDI or both. None were active alcohol users. All of the patients with clinical pancreatitis improved with stopping both HCV and HIV treatments. IFN and ribavirin should be used with caution in patients on the combination of D4T/DDI as the risk of pancreatitis seems to be increased.
Reference: Hester, et al. Pancreatitis: an emerging complication of HCV treatment in HIV co-infected patients treated with DDI/D4T containing regimens. Abstract H-739.
Diabetes more a problem in HIV+ with HCV than without HCV
Diabetes has been associated with HIV therapies, particularly the protease inhibitors and diabetes has also associated with HCV. A report of a retrospective case control study looking at 53 HIV/HCV and 53 HIV only control patients. Control patients were matched for body mass index, age, sex, CD4 count, and viral loads prior to the onset of therapy. They were also matched to HAART regimen. They did not match for race and wound up with 60% Latinos in the coinfected vs. 38% in the control with HIV only and 30% Caucasians in the coinfected vs. 45% in the controls. Latinos are known to be more prone to type diabetes than Caucasians so this may have affected the results. 5 patients developed diabetes and one hyperglycemia in the coinfected group vs. none in the control group. All 6 with diabetes/hyperglycemia were significantly overweight with BMIs of >25 and 5 of 6 were on PI-based regimens.
Reference: Terry. Factors associated with hyperglycemia in HAART treated HIV/HCV coinfected patients. Abstract 740.
Consensus Interferon monotherapy in HIV
A study of consensus interferon (Infergen) monotherapy in HIV/HCV which enrolled patients before combination therapy with IFN and ribavirin became the standard of care and long before pegylated interferon hit the market. This study explored high-dose infergen. 96 patients who were previous interferon non-responders were randomized to receive either Infergen 15mcg subcutaneously three times a week or daily for four weeks followed by TIW for 48 weeks. Daily, high-dose interferon is difficult to tolerate, perhaps more in coinfected patients as indicated by the 40% dropout rate. Only 39 completed at least 24 weeks of therapy. Most of the dropouts were due to side affects and ineffectiveness. 3 of 32 (9%) patients in who received the 4 week induction had a sustained viral response vs. 0 of 7 in the arm without the induction. Take home message: Interferon monotherapy of any type (2a, 2b, or consensus) has very little bang for the buck.
Reference: Infergen treatment of HCV in patients co-infected with HIV who failed a previous course of interferon. Abstract H-459.
Interferon as an HIV drug
Interferon is known to have activity against HIV as well as HCV. Two studies looked at the potency of interferon against HIV. One study evaluated Peg-Intron in 4 different doses over placebo in patients failing their antiretroviral therapy. The highest doses of Peg-Intron gave a 0.4-0.5 median log reduction in HIV RNA after 4 weeks. The second study looked at the affect of HIV RNA in those with detectable virus who began IFN and ribavirin therapy for HCV (the same study as reported above with low dose Peg-IFN + ribavirin, Moreno, et al). The patients with detectable virus dropped a median of about 0.6 logs of HIV, which appeared to be sustained for 3 months or longer. Interferon has activity against HIV, but less than other licensed drugs and it is associated with substantial side affects. In addition, long term tolerability data is lacking.
References:
1. Rodriguez, et al. Virologic and Immunologic impact of pegylated interferon alfa 2B in HIV-infected patients. Abstract I-1938.
2. Moreno, et al. Antiretroviral efficacy of pegylated-alfa 2B interferon. Abstract I-1939.
Ribavirin antagonizes 3TC in vitro
Ribavirin has been shown to antagonize the anti-HIV affects of AZT and D4T in vitro and increase the affects of DDI and Abacavir. Its affect on 3TC was explored in this in vitro study. The amount of 3TC required to inhibit half of the virus population (IC50) was 8 times higher in the presence of ribavirin, suggesting an antagonistic affect of ribavirin on 3TC. This shows 3TC effectiveness may be reduced. Of note, even though these antagonisms with AZT, 3TC, and D4T occur in vitro, it has not been clinically significant in studies of HCV treatment in coinfected patients. Generally, there is a reduction of HIV viral load from the baseline during HCV treatment, probably from the anti-HIV affect of the IFN.
Reference: Huh, et al. Antagonistic effect of ribavirin on lamivudine against HIV-1 infection. Abstract I-1939.
Hepatitis B drugs
Entecavir is a drug in development from BMS for the treatment of HBV. It is a guanosine nucleoside analog. It has potent anti-HBV activity, at least comparable to lamivudine in clinical trials. A study was reported to look at the in vitro activity of entecavir against HBV with resistance to 3TC. These resistant isolates also had substantially reduced susceptibility to entecavir (23-fold with M550V, L526M and 107 fold with M550V, L526M, and V553I) but less than 3TC. The BMS groups claim that the potency is higher so entecavir may be able to overcome these levels of resistance. At the AASLD liver meeting (November 2001), BMS reported on 40 patients with 3TC resistance who received 1 of 3 entecavir doses. Mean HBV-DNA was about 9 log. 79% in the high dose arm (1.0 mg) had undetectable HBV-DNA at week 24 by bDNA, and a 4.4 log reduction in HBV-DNA. By PCR 17% had undetectable HBV-DNA. 93% had 2 or more log reduction.
www.natap.org/2001/aasld2/day13.htm
A dose escalation study of LdT for HBV was presented that tested 25mg, 50mg, 100mg, and 200mg per day in treatment naive patients. Most patients achieved a rapid 2-log first phase decay, while the second phase of clearance (between 2-4 weeks) revealed a better response at the higher doses. No toxicity was observed so higher doses will be tested.
Adefovir was initially developed as an HIV drug, but failed FDA approval due to its excess of renal toxicity at 60mg and 120 doses. It is also a potent HBV drug with activity against 3TC-resistant HBV. A late-breaker study compared 10mg and 30mg of adefovir per day was with placebo for the treatment of HBV over 48 weeks. 515 subjects were randomized 1:1:1. Most were Asian. At 48 weeks the median viral load reductions were highest in the 30mg dose (not given in the abstract), -3.52 logs in the 10mg group and -0.55 in the placebo group. 12% of the combined adefovir groups seroconverted (became E antigen negative and E antibody positive- a good thing) vs. 6% of the placebo group. The 30mg group had an excess number of renal side affects whereas the 10mg side affect profile was similar to placebo. Due to the excess renal toxicity with the 30mg, the 10mg dose will be studied further. Unfortunately, the study ended at 48 weeks and therefore long-term renal toxicity in the 10mg dose cannot be assessed. It may be cumulative.
References:
1. Levine, et al. Efficacy of entecavir against lamivudine-resistant hepatitis B virus and recombinant polymerases. Abstract H-463.
2. Zhou, et al. Dose optimization for LdT and other hepatitis B antivirals: importance of second-phase clearance and viral dynamics modeling. Abstract H-464.
3. Lim, et al. Antiviral activity of adefovir dipivoxil in HbeAg+ chronic hepatitis B infection. LB-20.
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