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CROI Report- HIV/HCV Co-Infection: Organ Transplantation and Liver Cancer
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Reported by Jules Levin
There were 3 posters on liver transplantation in HIV-infected individuals at the 11th Retrovirus Conference (Feb 8-11, 2004, San Francisco). As well, there was a poster at the conference looking at the difference in liver cancer progression comparing coinfected patients to HCV monoinfected patients.
It is fairly well accepted now that liver transplantaion in HIV-infected patients can be successful due to HAART. Prior to the HAART era there were concerns about survival and tolerability of the transplantation procedure and the immunosuppressive drugs liver transplant recipients have to undergo. There is still concern about the drug-drug interactions between the immunosuppressive drugs needed post-transplantation and HAART. Further long term followup is needed as the followup time after transplant in coinfected patients should be better and in general there is less experience transplanting coinfected patients with livers. But most liver transplant centers are providing data from transplants that support the notion that response in coinfected patients is similar to those who are moninfected, based on limited followup and numbers of patients.
Transplants due to HBV are more successful in general than for HBV. Another problem is the recurrence of HCV in transplanted patients. A significant number of HCV transplant recipients experience recurrence of HCV and have to undergoe HCV therapy. There is no doubt about it the transplant experience is difficult and hard to obtain. Insurers are not excited to reimburse for transplants in coinfected patients. This is why Michelle Roland and her team at at UCSF have initiated a study to establish the efficacy of liver and kidney transplants in coinfected patients. Sites at UCSF, University of Pittsburgh, and University of Miami are known for their programs. As well Mt Sinai in NYC has a program for coinfection liver transplants.
The best way to avoid the a liver transplant is to receive good care.
When HCV treatment is appropriate, consider it carefully. Undue delay of therapy may lead to advanced liver disease which can include risk for liver cancer and decompensated cirrhosis. Once a person has decompensated cirrhosis, it is_difficult to start HCV therapy. Although peginterferon/ribavirin therapy is difficult to tolerate and we would like better response rates, treatment can be successful in curing HCV. Hepatitis C virus is curable. 98-99% of patients who achieve a sustained viral response, undetectable viral load 6 months after stopping therapy, appear cured of HCV.
Clinical Presentation and Outcome of Hepatocellular Carcinoma in HIV-infected Patients: liver cancer appears to progress more quickly in HIV-infected individuals than in those with HCV moninfection
M Puoti*1, R Bruno2, V Soriano3, E Vaccher4, F Donato1, G B Gaeta5, G P Quinzan6, D Precone5, C Filice2, F Suter6, G Carosi1, U Tirelli4, and GICAT, Brescia HCC Study Group, CLIP 1Univ. of Brescia, Italy; 2Univ. of Pavia, Italy; 3Inst. de Salud Carlos III, Madrid,Spain; 4CRO, Aviano, Italy; 5SUN, Napoli, Italy; and 6Hosp. Riuniti, Bergamo, Italy
Hepatocellular carcinoma (HCC) is an increasing cause of mortality in HIV+. The aim of the study is to identify clinical characteristics of HCC in HIV+ persons and to compare them with those observed in anti-HIV- subjects.
In this non-concurrent prospective case control study, we enrolled HIV+ subjects with a diagnosis of HCC defined according to EASL guidelines notified to 2 registries for tumors. All cases of HCC diagnosed in HIV- subjects in the town of Brescia from 1995 to 1998 and all HIV- cases from the registry of the Cancer of the Liver Italian Project (CLIP) were enrolled as control groups. Data on each eligible case were collected through a standardized case record form. All patients were followed up for at least 2 years. Clinical characteristics at presentation and survival were compared between HIV+ and HIV- subjects by logistic regression and Cox's proportional hazard regression analysis.
Of the 41 cases of HIV+ subjects with HCC, 1 received the first diagnosis in 1989, 2 in 1997, 2 in 1998, 2 in 1999, 6 in the year 2000, and 10 in the first 6 months of the year 2001; 33 cases have been observed in Italy and 8 in Spain. Their individual data have been compared with those of the 384 HIV- from the Brescia HCC study group registry and those of the 701 HIV- from the CLIP registry.
Multivariate analysis adjusted for age and gender identified an association between HIV infection and higher prevalence of HCV infection (OR 11 vs Brescia HCC study group; p = 0.005 and 9 p = 0.006 vs CLIP registry), and higher frequency of infiltrating tumors or extranodal metastasis at presentation (OR 11,8; p <0.001 vs Brescia HCC study group and 17,3 p = 0.001 vs CLIP registry).
These variables were independently associated with HIV infection in both comparisons. HIV infection was associated with reduced survival independently from treatment, Child-Pugh status, portal invasion, serum alfa-fetoprotein, tumor morphology, and size (HR 1,63 p = 0.015 vs Brescia HCC study group and HR 1,5 p = 0.013 vs CLIP registry).
Our data suggest that HCC in HIV+ has a more aggressive clinical course that reduces the chances for cure. Thus preventive strategies for HCC should beimplemented in the management of HIV-infected subjects.
Patient and Graft Outcomes following Solid Organ Transplantation at UCSF
M Roland*, L Carlson, N Terrault, C Freise, R Hirose, R Rogers, and P Stock
Univ. of California, San Francisco, USA
The team at UCSF has previously reported their experience at conferences, as have the liver transplant team from the University of Pittsburgh. The response rates have been similar to those seen in moninfected patients. Still, there are many difficulties in undergoing transplants. Patients can get sick and experience severe health concerns following transplantation, but the transplantation can be successful.
HIV-infected patients undergoing transplantation may experience HIV disease progression induced by immunosuppressants and/or accelerated graft failure due to HIV or its treatment. Alternatively, they may experience patient and graft survival rates similar to other patients.
A pilot, single center, non-randomized, longitudinal evaluation was started at UCSF to follow for patient and graft survival and post-transplant complications in subjects who received a liver or kidney transplant and were treated with antiretrovirals and immunosuppressants.
Of the total, 14 subjects received kidney transplants, 9 received liver transplants, and 1 received a liver/kidney transplant (n = 24) between 3/00 and 9/03.
Subjects included 23 men and 1 woman, with a median age of 45 (15 to 64); 54% were white, 33% African American, 8% Asian, and 4% Latino. Four (17%) subjects had a prior history of 5 opportunistic complications (CMV, cryptococcal meningitis, MAC, KS, and TB).
Median pre-transplant CD4+ T-cell count was 407 (104 to 973). HIV RNA was undetectable in kidney recipients; median HIV RNA was <75 (<75 to 55,100) in liver recipients.
HCV infection was present in 4 (40%) liver and 4 (29%) kidney recipients. Median follow-up as of October 1, 2003, is 480 days (8 to 1254). Two subjects died: 1 liver recipient with recurrent HCV infection (15 months) and 1 kidney recipient with pneumonia (6 months).
There was one case each of the following: Candida esophagitis, CMV esophagitis, and pulmonary Aspergillus infection. There was no recurrence of prior opportunistic infections.
At follow-up, the median CD4+ T-cell count was 255 (8 to 902) and HIV RNA was <75 (<75 to 9600). Rejection occurred in 10 (71%) kidney recipients, the liver/kidney recipient, and one liver recipient.
There were 5 cases of delayed graft function in kidney recipients and 1 kidney graft loss due to rejection. Median creatinine is 1.6 (1.1 to 3.2) in kidney recipients.
One liver recipient required re-transplantation due to a small for size graft lesion. Recurrent HCV has been documented in 2 liver recipients, 1 of whom received HCV treatment, and progressive HCV in no kidney recipients.
Roland concluded that liver and kidney transplantation appears to be associated with good patient and graft survival (relative to experience in moninfected) and minimal evidence of HIV disease progression despite CD4+ T-cell declines with rejection treatment. There is an unexpectedly high rate of kidney rejection. A multi-site study will definitively address the safety and efficacy of this intervention, which appears to have started.
Orthotopic Liver Transplantation in 15 HIV-1-infected Recipients: Evaluation of Spanish Experience in the HAART Era (2002-2003)
Rufi1, R Barcena2, V Vargas3, A Valdivieso4, J M Miro*5, M Salcedo6, A Rafecas1, F X Xiol1,2, E de Vicente2,3, J Fortun2,4, C Margarit3,5, A Pahissa3,6, M Montejo4, A Rimola5, A Moreno5, P Miralles6, and the Spanish OLT-HIV Working Group
1Hosp. Univ. Bellvitge, Barcelona, Spain; 2Hosp. Ramón y Cajal, Madrid, Spain; 3Hosp. Univ. Vall d'Hebrón, Barcelona, Spain; 4Hosp. Cruces, Bilbao, Spain; 5Hosp. Clin. - IDIBAPS, Barcelona, Spain; and 6Hosp. Gregorio Marañon, Madrid, Spain
ABSTRACT: The safety and efficacy of orthotopic liver transplantation (OLT) in HIV-1-infected patients is currently being re-evaluated in the HAART-era.
This study was a prospective cohort study of all Spanish HIV-1-infected patients who underwent OLT. The liver criteria used to determine eligibility were the same as for the non-HIV-1-infected population; no previous CDC stage C events except tuberculosis, pre-OLT CD4 cell count greater than 100 cells/mm3 and undetectable plasma RNA HIV-1 viral load on HAART or detectable plasma viral load off HAART with post-transplant suppression predicted; and no heroin or cocaine abuse for the last 2 years and no alcohol abuse for the last 6 months.
The first OLT in an HIV-1-infected patient was performed in January 2002. Six sites have transplanted 15 HIV-infected patients, 10 in the year 2003. Median (range) age was 38 (35 to 51) years, 80% of recipients were male and former drug use (73%) was the most common HIV-1 risk factor. HCV-related cirrhosis (93%) was the leading indication for OLT. Pre-OLT Child-Pugh class was C, B or A in 6, 7 and 2 cases, respectively. The latter two cases had hepatocellular carcinoma. Pre-OLT antiretroviral therapy was given in 13 cases (efavirenz-based HAART in 9, three NRTI in 3 and protease-inhibitor-based HAART in 1 patient). Median (range) CD4 cell count pre-OLT was 247 (142 to 589) cells/mm3 and 12 patients (80%) had undetectable plasma viral load.
13 recipients received a cadaveric graft and two a graft from a living donor. Immunosuppression therapy was the standard in each center.
There was no operative mortality. Median (range) follow-up was 6 (1 to 21) months. None of the patients required re-transplantation. All patients received HAART after OLT. Only one patient died (7%) at 3 months. Death was non-HIV related. One patient had to stop HAART at 4 months because of massive liver steatosis. There was neither clinical nor immunological HIV-1 progression in the remaining cases except in one.
Four subjects (27%) experienced rejection and 10 out of 13 (77%) patients with more than one month of follow-up have became HCV re-infected. Therapy with peg-interferon plus ribavirin was started in 3 cases.
The study authors concluded that OLT is a safe and effective procedure at short/mid-term for selected HIV-1-infected patients in the HAART era. However, HCV re-infection is a cause for concern.
Liver Transplantation in HIV-HCV Co-infected Patients; French Report
E Teicher*, D Vittecoq, J Duclos-Vallés, D Azulay, D Castaing, H Bismuth, A Roque-Afonso, E Dussaix, and D Samuel
Hosp. Paul Brousse, Villejuif, France
ABSTRACT: End stage liver disease in HIV-HCV co-infected patients is an emerging problem requiring to assess the benefit risk ratio of liver transplantation (LT). We started a prospective evaluation of LT in co-infected patients in December 1999 assessing several parameters: impact on the immune system and HIV replication, drug interactions, mitochondrial toxicity and incidence of HCV relapse.
Up to December 2002, eleven HIV-HCV co-infected patients without history of opportunistic infection, were transplanted. At time of LT all patients were exposed to HAART, HIV plasma viral load was < 400 copies/mL and the median CD4 lymphocyte count was 350 cells/mm3 (range: 103-659).
Immunosuppression therapy consisted of steroids and Tacrolimus. Anti HCV viral therapy was used when necessary and its benefit risk ratio was prospectively evaluated. Lastly, mitochondrial toxicity on the graft was studied by spectrophotometric analyses of the respiratory chain complexes and molecular analysis of mitochondrial DNA (mtDNA).
At time of evaluation, the median follow-up is 18 months (range 3 to 45): 3 patients died, 4, 11, and 19 months after LT. Seven patients are in good condition and one patient is in poor condition. None on the patients developed opportunistic infection. Drug interaction was under control, only one patient developed a transient renal insufficiency.
HCV replication started promptly after LT in all patients. Seven patients began pegylated interferon (PEG-IFN) and ribavirin therapy. This treatment was stopped in three patients because of intolerance.
One patient showed a virological response and another a biochemical response and a decrease of liver fibrosis. At last biopsy, METAVIR score was staged F4 in 2 patients, F3 in 1, F2 in 2. Microvesicular steatosis was observed in nearly all patients. The ratio mtDNA nuclear DNA was low in 4 patients. A significant defect on the activities of respiratory chain was noted in five patients.
Liver transplantation in HV/HCV co-infected patients is feasible in a very selected population. Our experience do not suggest a deterioration of immune deficiency. Drug interaction is not a limiting problem. The early and severe relapse of hepatitis C suggest to start promptly an association of PEG-IFN and ribavirin. LT requires a multidisciplinary partnership.
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