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Liver transplants in HIV-HCV co-infection-results from a U.S. study

3 May 2012 - The American National Institutes of Health (NIH) is the world's largest biomedical research organization, both funding research and carrying it out. Thanks to NIH funding, researchers in the U.S. have conducted a study of carefully selected HIV-positive people who were also co-infected with hepatitis C virus (HCV) and who needed a liver transplant. After the transplant and an average of three years of monitoring, researchers found that 60% of participants were still alive. By contrast, among a similar group of HCV-mono-infected (HCV infection alone) participants, three-year survival rates after a liver transplant were about 80%. The NIH study has yielded important information that could be used by transplant teams to improve the survival of HIV-HCV-infected people who need a liver transplant.

Study details

Starting in 2003 and ending in 2010, researchers across the U.S. recruited 89 participants who were HIV positive and who were co-infected with HCV. All participants were ill from complications due to severe liver damage.

For the purposes of comparison, the study team compared reviewed databases that had collected health-related information from other groups of people, including those with HCV mono-infection (235 participants).

This report focuses on co-infected people.

At the time the co-infected people entered the study, their average profile was as follows:

  • age - 49 years
  • 75% men, 25% women
  • body mass index (BMI-an assessment of body weight relative to a person's height) - 25
  • liver cancer - 34%
  • common HCV strains or genotypes present (genotypes 1 or 4) - 80%
  • co-infection with hepatitis B virus (HBV) - 3%
  • CD4+ count - 283 cells
  • undetectable HIV viral load - 88%

The use of potent combination therapy for HIV (commonly called ART or HAART) was suspended shortly before surgery and then resumed when recipients began to recover-they could swallow medications, their overall condition had stabilized and the functioning of key organs such as the kidneys had improved. In most cases, ART was resumed within a week of surgery. Usually the same regimen used prior to transplantation was reinitiated.

In eight cases there were combined liver and kidney transplants. Kidney transplants were needed because some participants' kidneys were dysfunctional for a number of reasons, as follows:

  • diabetes
  • higher-than-normal blood pressure
  • other causes (such as cardiovascular disease)

Results - Survival

One year after transplantation, survival rates were as follows:

  • HIV-HCV co-infection - 76%
  • HCV mono-infection - 92%

Three years after transplantation, survival rates were as follows:

  • HIV-HCV co-infection - 60%
  • HCV mono-infection - 79%

In general, after organ transplants, bacterial infections are common in the first month, particularly in surgical wounds. In the present study, deaths were often due to bacterial infections that had overwhelmed participants, leading to blood poisoning and failure of vital organs. Deaths arising from bacterial infections were more common among co-infected people.

None of the deaths among co-infected people arose because of AIDS-related infections or cancers. Furthermore, having a pre-transplant history of such infections/cancers did not affect survival after transplantation.

The only factor that was associated with an increased risk of death was HIV infection.

Balancing risks

As the transplanted organ comes from a different person, there is a risk of the recipient's immune system attacking the new organ. Such attacks are called "rejection," as the immune system rejects the organ. To minimize episodes of rejection and damage to the new organ, recipients of transplanted organs are given drugs to help weaken their immune systems. Yet a balance in the level of immune suppression must be found, otherwise the immune system will become too weak and the risk of developing serious infections (and subsequently dying) increases.

In the present study, low doses of one the following transplant medicines were used:

  • cyclosporine (Neoral, Sandimmune)
  • sirolimus (Rapamune)
  • tacrolimus (Prograf)

The levels of these drugs in the blood must be regularly assessed, particularly once participants resume ART, as transplant drugs can interact with protease inhibitors and non-nukes (NNRTIs) and vice versa.

In cases of an episode of rejection, a change in immune-suppressing medicine could be made, another transplant drug such as mycophenolate mofetil (CellCept) could be added, or corticosteroids could be used. The transplant team attempted to avoid the use of very powerful immuno-suppressing drugs (such as antibodies that attacked the immune system), unless the episode of rejection was severe.

Organ damage

Even with good care and adequate immune suppression, sometimes the transplanted organ, or graft, can suffer damage as it increasingly comes under attack by the immune system. Researchers found that the following factors placed co-infected participants at significantly increased risk for severe damage to the graft:

  • receipt of two transplanted organs (liver and kidney)
  • having a BMI at the start of the study of less than 21
  • receipt of an organ from a donor who was infected with HCV

Overall, seven out of eight participants who received both a liver and kidney died.

Co-infected people who did not have these three factors had survival rates similar to those seen among HIV-negative people aged 65 years or older in the U.S. who received an organ transplant.

Survival did not change over the course of the study.

Women and participants who had severe episodes of rejection were more likely to have had severe HCV-related liver damage.

Rejection

Episodes of acute rejection that required treatment were more common among co-infected people (39%) compared to people with HCV mono-infection (24%). About half of the episodes of acute rejection among co-infected people happened within the first three weeks after transplantation.

Most (82%) co-infected people who developed acute rejection were treated with corticosteroids.  HIV infection was the only factor linked to having an acute episode of rejection within the first month after transplantation.

Changes in assessments of HIV disease

Compared to their pre-transplant levels, CD4+ cell counts at different points after transplant were as follows:

  • six months after transplantation - 83 less cells
  • 12 months after transplantation - 11 less cells
  • 36 months after transplantation - 2 less cells

This trend shows that the immune systems of co-infected people gradually recovered from the trauma of major surgery and the impact of immune-suppressing drugs.

Cases of fungal infections occurred as follows:

  • 3 cases of yeast infections of the throat and mouth
  • 2 cases of yeast infections of the lungs

All five participants recovered when treated with anti-fungal drugs.

One person developed Kaposi's sarcoma (KS) lesions on his skin. When doctors changed his immunosuppressant drug to sirolimus (which appears to also have some anti-KS activity), his lesions cleared without further treatment.

Upon entering the study, 11 participants had detectable levels of HIV in their blood samples. Three months after transplantation, 10 of these 11 participants had an undetectable level of HIV. The 11 th person had detectable HIV for several more months but his last viral load test was less than 50 copies/ml.

Overall, 78 participants entered the study with an undetectable level of HIV in their blood. Of these, 14 participants (18%) had "two or more consecutive detectable [HIV viral load tests after transplantation]."

These detectable bouts of viral load ranged between 7,000 and 43,000 copies/ml. At their most recent lab test, nine of these participants had detectable viral load. This was likely due to inflammation and activation of their immune systems brought about by an episode of rejection of the graft.

Key points

The research team made these points in evaluating its research:

  1. Survival three years after liver transplant is reduced in HIV-HCV infected people compared to people infected with HCV alone who have also received a liver transplant.
  1. Care must be taken to select the right donors of organs. In the present study, researchers found that organs from people with HCV or from older people were less likely to thrive once transplanted into co-infected patients. This finding is important, as a similar result has not been found in HIV-negative people who receive an organ from HCV-positive people.
  1. Early referral for evaluation for transplantation and using living donors are likely to shorten the time spent on a transplant waiting list. Reduced wait times will likely result in better chances of survival after transplantation.
  1. Relatively high rates of acute rejection occurred among co-infected participants. The study team thinks that this problem occurred because participants were given low doses of immune-suppressing medicines. This was probably due to the transplant team being wary of weakening the immune system to a dangerous degree.
  1. The study suffered from a relative weakness: The type of ART used was not standardized and neither was there a uniform regimen for suppressing the immune system. The study team suggested that newer drugs, such as the HIV integrase inhibitor raltegravir (Isentress), may be useful in HIV-positive patients undergoing organ transplantation in the future, as this drug is not likely to interact with immune-suppressing medicines (and vice versa).

The results of the present study provide a useful experience that organ transplant centres can use when managing the medical needs of HIV-HCV co-infected patients in the future.

For general information on organ transplantation and HIV infection, see TreatmentUpdate 183 .

-Sean R. Hosein

REFERENCES:

  1. Terrault NA, Roland ME, Schiano T, et al. Outcomes of liver transplantation in HCV-HIV coinfected recipients. Liver Transplantation . 2012; in press .
  2. O'Grady JG. Liver transplantation in HIV-HCV co-infected patients: Response needed! Liver Transplantation . 2012; in press .
  3. Tricot L, Teicher E, Peytavin G, et al. Safety and efficacy of raltegravir in HIV-infected transplant patients cotreated with immunosuppressive drugs. American Journal of Transplantation . 2009 Aug;9(8):1946-52.
  4. Bickel M, Anadol E, Vogel M, et al. Daily dosing of tacrolimus in patients treated with HIV-1 therapy containing a ritonavir-boosted protease inhibitor or raltegravir. Journal of Antimicrobial Chemotherapy . 2010 May;65(5):999-1004.
  5. Moreno A, Bárcena R, Quereda C, et al. Safe use of raltegravir and sirolimus in an HIV-infected patient with renal impairment after orthotopic liver transplantation. AIDS. 2008 Feb 19;22(4):547-8.

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