February 11, 2004
Several small studies presented at this conference add credence to the growing perception that liver transplants may be as safe for otherwise-healthy, HIV-positive patients as they are for HIV-negative patients. However, they are no panacea for the problems that can cause a patient's liver to fail in the first place.
These three studies, conducted by collaborating researchers at sites across the globe, testify to the short- and mid-term benefits of such transplants in patients with HIV, but leave open the question of potential long-term consequences, such as the severity of hepatitis C recurrence in patients coinfected with both viruses.
Liver Transplants: From Fantasy to Reality
The focus on transplant research in HIV-positive patients is relatively new. Until 1998, very few medical centers would perform a liver transplant in an HIV-positive patient. This was due to a range of reasons, including the high mortality rate of HIV-positive patients, which led most centers to withhold livers for healthier, HIV-negative patients. There was also concern over the risk for HIV progression tied to the use of anti-rejection medications. This combination of factors resulted in an unwillingness on the part of insurance providers and Medicare programs to offer coverage for either the operation or for post-operative patient care, which left patients with no financial recourse even if a medical center was willing to attempt the transplant.1
However, everything changed with the introduction of HAART. Combination drug therapy has extended the lives and improved the overall health of many HIV patients. But this good news has opened up a new can of worms: How do we handle the health problems left behind (or created) when an HIV-positive patient's health has otherwise been stabilized by treatment? (See the latest HOPS results for more on this.) Liver failure, frequently resulting from hepatitis C coinfection, is typically one of these health problems, and has thus garnered an increasing amount of attention since the end of the 1990s.
Study Details: Three Studies Find Satisfactory Results
Three studies presented at CROI 2004 -- one from Spain, one from France and one from the U.S. -- investigated the short- and medium-term outcomes of liver transplant operations in HIV-positive patients, many of whom were coinfected with hepatitis C. They found that, on the whole, patient survival rate was high and HIV disease progression minimal in those receiving liver transplants, provided their CD4 counts and viral loads were relatively good (generally above 200) before the transplant occurred.
The Spanish study was a prospective cohort of the 15 HIV patients in Spain who had received liver transplants since January 2002. All but one had cirrhosis attributable to hepatitis C coinfection. Though only three months of follow-up data were available, researchers found that only one patient had died, a death rate similar to that for HIV-negative patients who receive liver transplants. The patient's death was not attributable to HIV-related causes. In addition, only one patient experienced HIV progression, although hepatitis C reinfection occurred in 10 of the 13 patients for whom more than a month of follow-up data was available -- a rate of reinfection that is also similar to that for HIV-negative transplant recipients. Three of those 10 reinfected patients had initiated hepatitis C treatment by the time the study abstract was submitted.
The French study found similar results. It was a prospective evaluation of 11 hepatitis C/HIV coinfected patients who received liver transplants at Hospital Paul Brousse (a hospital located just outside of Paris) through November 2002. All patients had HIV viral load plasma levels below 400 copies/mL and a median CD4 count of 350 (none were below 103) before their operation, and all had some level of previous exposure to HAART. None had a history of opportunistic infection. After a median of 18 months follow-up, three of the 11 patients had died; two had HAART hepatotoxicity and severe hepatitis C recurrence, while the other died of pancreatic cancer. None of the eight surviving patients developed an opportunistic infection, though one experienced a transient renal insufficiency. The bad news: Nearly all patients developed microvesicular steatosis and five had a significant defect in respiratory chain activity, both of which are early indicators of liver failure. Hepatitis C treatment (consisting of peg-interferon and ribavirin) was subsequently initiated in seven patients.
The U.S. study, the largest of the three, included kidney transplants in its purview. The results closely mirrored the Spanish and French findings: There was little to no HIV progression after a transplant, but high rates of hepatitis C recurrence (which, in one case, was fatal). Conducted by researchers at the University of California-San Francisco (UCSF), this was a longitudinal pilot study of 24 liver and kidney transplant recipients at a single center between March 2000 and September 2003. Nine of the study's subjects received liver transplants alone, 14 received only kidney transplants, and one received both. Four of the liver recipients and four of the kidney recipients were coinfected with hepatitis C. This was a diverse group: All but one subject was male, half were white, a third were African American, 7% were Asian American and 4% were Hispanic. In terms of their HIV infection, these patients were also largely healthy: median pre-transplant CD4 count was 407 (range: 104 to 973), median viral load was below 75 copies/mL (range: less than 75 to 55,100) and only four of the 24 subjects had a prior history of an opportunistic infection.
After a median follow-up of about 68 weeks, only two of the 24 subjects had died: one liver-transplant patient from a hepatitis C relapse, and one kidney-transplant patient from congestive heart failure. Median viral load remained undetectable (below 75 copies/mL) and median CD4 count dropped to 255 (range: 8 to 902), though one of the study's authors, Michelle Roland, M.D., noted that this study was too small and the data too preliminary to draw any conclusions from this apparent decline. Two patients developed an opportunistic infection, though both were relatively minor: One liver-transplant patient developed cytomegalovirus esophagitis and one diabetic kidney-transplant patient developed candida esophagitis. It was unknown whether these infections were attributable to the anti-rejection immune suppressants or to HIV infection itself. Two of the four liver patients with hepatitis C experienced a recurrence of the infection; at the time this study was presented, one had been placed on hepatitis C treatment.
Discussion: Evidence Favors Transplants, but Long-Term Impact Remains Unknown
Observed together, these studies support earlier findings2-5 that liver transplants can be relatively safe and successful in HIV-positive patients with low pre-transplant viral loads and relatively high CD4 counts. Although no study has directly compared the outcomes of HIV-negative and HIV-positive transplant recipients, these findings do not differ significantly from what is known about short-term transplant success in HIV-negative patients, Dr. Roland says. All three studies were limited, however, by their small sizes and generally brief follow-up periods.
In addition, many issues remain unresolved. Hepatitis C recurrence is a significant concern. As earlier studies have indicated2-4 and these small studies corroborate, patients coinfected with hepatitis C are highly likely to experience a recurrence of the disease over time. Although this outcome may not be different for coinfected patients than for HIV-negative patients with hepatitis C, long-term studies will need to identify just how widespread and severe these relapses can be, and whether it is a more or less dangerous problem in HIV-positive patients than HIV-negative patients.
It should be noted that liver transplants, much like any other organ transplant, are a treatment of last resort for end-stage organ disease and are not without complications of their own. For instance, a patient's new liver can be rejected despite the use of immune-suppressant drugs. In addition, the potential interactions between immune suppressants (which must be taken for life), HAART and hepatitis C therapy have not been conclusively laid out. Lastly, the long-term effects of immune suppressants on HIV-positive transplant recipients are still unknown.
Though the medical community has recently become more amenable to them, organ transplants in HIV-positive patients are still rare, Dr. Roland says. Many U.S. centers are still unwilling to perform the operation, and many U.S. insurance providers -- as well as Medicare -- remain reluctant to cover it in the absence of truly conclusive supportive evidence.6 For HIV-positive patients in need of liver transplants, or for physicians looking to help their patients receive them, their best bet by far is still to seek enrollment in a clinical trial.
Dr. Roland, who was an investigator for the UCSF study, has written widely on transplants in HIV-positive patients. She and her colleagues are currently coordinating a prospective, 17-site U.S. study that will observe liver and kidney transplant patient outcomes over the course of several years. This study is actively enrolling patients throughout the U.S.; Dr. Roland said she encourages referrals from patients while they are still in the early stages of liver or kidney disease.
Results from the new UCSF study will not be available for several years. Smaller studies such as the three presented at this conference, however, are at least able to provide reassurance that successful liver transplants in HIV-positive patients have moved squarely out of the realm of idle fantasy. Hopefully that new reality will continue to spread through the medical and insurance communities over the months and years to come, allowing more HIV-positive patients with liver failure to obtain a new lease on life.
Abstract: Patient and Graft Outcomes Following Solid Organ Transplantation (Poster 826)
Authored by: M. Roland, L. Carlson, N. Terrault, C. Freise, R. Hirose, R. Rogers, P. Stock
Affiliations: Univ. of California, San Francisco, CA
View poster: Download PDF
Abstract: Orthotopic Liver Transplantation in 15 HIV-1-Infected Recipients: Evaluation of Spanish Experience in the HAART Era (2002-2003) (Poster 827)
Authored by: G. Rufi, R. Barcena, V. Vargas, A. Valdivieso, J. M. Miro, M. Salcedo, A. Rafecas, F. X. Xiol, E. de Vicente, J. Fortun, C. Margarit, A. Pahissa, M. Montejo, A. Rimola, A. Moreno, P. Miralles, the Spanish OLT-HIV Working Group
Affiliations: Hosp. Univ. Bellvitge, Barcelona, Spain; Hosp. Ramón y Cajal, Madrid, Spain; Hosp. Univ. Vall d'Hebrón, Barcelona, Spain; Hosp. Cruces, Bilbao, Spain; Hosp. Clin. -- IDIBAPS, Barcelona, Spain; Hosp. Gregorio Marañon, Madrid, Spain
Abstract: Liver Transplantation in HIV-HCV Co-Infected Patients (Poster 828)
Authored by: E. Teicher, D. Vittecoq, J. Duclos-Vallés, D. Azulay, D. Castaing, H. Bismuth, A. Roque-Afonso, E. Dussaix, D. Samuel
Affiliations: Hosp. Paul Brousse, Villejuif, France
View poster: Download PDF