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HIV

Published On June 17, 2019

POLICY

Rethinking the Perfect Organ

The critical shortage of organs isn’t going away. Revising the current guidelines about who should be a donor—and who should be a recipient—might save lives.

AT 74, STEPHEN FARRELL was the second oldest person to receive a heart transplant at Massachusetts General Hospital—and among the first to receive a heart infected with hepatitis C (HCV). It was offered to Farrell in April 2018, and came with the certainty that he would be exposed to the virus. Farrell had been waiting three years for a new heart, and he reasoned that this one was better than the alternative—the ventricular assist device that he relied on to keep his own heart beating. He decided to go through with the surgery, and before long he was able to carry his own clubs through a full game of golf for the first time in nearly a decade. Now he also walks his dog every day and has returned to his position as sweeper on his curling team. As for the HCV, Farrell got the first dose of a curative therapy on his way to the operating room, and there is no sign of the disease now. “It turned out to be a great heart,” he says.

Just a few years ago, that heart would have gone to waste or perhaps been transplanted into someone whose own organs were failing because of advanced HCV. Farrell might well have died before getting a transplant—the fate of 5,000 patients in the United States in 2018 who never received the organs they needed. Waiting lists for hearts, lungs, kidneys and livers now contain more than 110,000 people, and hospitals are working against the clock to find healthy, suitable matches.

One solution may be to review the rules for organ transplants and bring them in line with changing clinical realities. Now that HCV has an effective cure, organs from donors with the virus can be transplanted into any willing recipient. “We have such a critical shortage of organs that we need to find new solutions, including intentionally giving patients an infection along with a new organ,” says surgeon Julie Heimbach, chair of the division of transplantation surgery at Mayo Clinic in Rochester, Minn. Another surprising candidate may be organs from donors infected with HIV—an infection that’s manageable though not yet curable. More than a million people in the United States are now estimated to be living with the virus and may be candidates for organs that are also HIV positive.

On the other side of the donor-recipient equation, rethinking current guidelines also expands those who may be candidates to receive a new organ. Several conditions—obesity, alcoholism and certain kinds of drug use among them—often lead to failing organs, but people who have these conditions have generally been considered poor candidates to draw on the scarce supply of new organs. Yet increasing evidence shows that some of these patients do very well after transplant surgery, which can mean the difference between years of suffering and a chance to thrive.

These and other changes are upending longstanding approaches to which organs can be transplanted and who should receive them. “There has been a sea change in how we think about allocating organs today,” says Joren Madsen, the cardiac surgeon who directs the transplant center at MGH. “By broadening the criteria for what constitutes an acceptable organ, patients who need organs the most will now have a greater chance of getting them.”

UNTIL RECENTLY PEOPLE LIVING with HCV were in the queue waiting for transplants. The condition slowly destroys the liver through a progression to cirrhosis, an irreversible scarring, or to liver cancer.

Treatments have existed since shortly after the disease was discovered in 1989. But they had a success rate of less than 50% and required weekly injections with side effects that included depression and anxiety. As a result, many avoided or abandoned them.

That situation changed in 2014 with the arrival of antivirals that could directly attack the virus, curing up to 98% of HCV infections. The new therapy not only reduces the need for liver transplants in these patients, but it has also meant that organs from HCV-infected donors, which had been discarded, can now be used for transplants more broadly. “We transplant organs with other viruses all the time—glandular fever virus and cytomegalovirus, for instance, which you have for life and require treatment after transplant,” says Cameron Wolfe, associate professor of medicine at Duke University School of Medicine. “With thousands of people on organ waiting lists, it’s egregious not to use high-quality organs from donors with hepatitis C.”

Transplanting those organs into HCV-negative candidates is not yet standard practice. But all 30 kidney transplant recipients of HCV donor organs in pilot trials at Johns Hopkins and the University of Pennsylvania were cured of HCV, and outcomes for those patients at one year were just as good as for those who received HCV-negative kidneys. In addition, a study published in The New England Journal of Medicine in April 2019 looked at 44 patients who received hepatitis C–infected hearts or lungs. Researchers found that the transplants were safe and that the transmitted HCV was eradicated with a four-week course of treatment post-transplant. “If people run into any problems with a transplant, they tend to happen within the first year,” says Wolfe, who believes these early results are likely to hold up, encouraging wider use of HCV-infected organs.

All told there have been just over 100 HCV-positive organs transplanted into uninfected U.S. patients in the published literature, estimates Christine Durand, transplant researcher and associate professor of medicine at Johns Hopkins Medicine. “HCV-infected organs may provide an additional 500 to 1,000 kidneys annually, and they could make a big impact in liver, lung and heart transplantation, too,” she says. “Wait times may drop from years to months for candidates willing to accept these organs.” And while a recent survey of Chicago patients waiting for transplants showed many were reluctant to take an HCV-infected organ, 46% of people were willing, says Raymond Chung, medical director of the liver transplant program at MGH, who conducted the study.

Some who argue for using organs with HCV want to go a step further and advocate wider use of organs from “increased risk” donors. The federal government requires that label when a donor was recently in prison, had a sexually transmitted disease in the past year or was a sex worker, an intravenous drug user or a man who had sex with men. Such situations and behavior statistically correlate with higher rates of HCV, hepatitis B and HIV infection. About one in four deceased organ donors falls into one or more of those categories—and though “increased risk” organs can be used if a recipient consents, a large proportion end up being declined.

Yet the donor may not have had any of those infections, and now, with better tests, the actual risk is very low. All deceased organ donors are screened, and that catches most if not quite all possible infections, leaving an approximately 0.2% chance that a donated organ might transmit a disease physicians didn’t anticipate, Wolfe estimates. There has been no unintentional transmission of HIV through transplant since 2009, and only a handful of missed early infections of HCV.

How many viable organs in this classification go to waste? In a recent study, Durand found that more than 2,300 were discarded from 2000 through 2007 after being procured from increased-risk donors or those who tested positive for HCV. Another study found that 20% of kidneys from such donors in 2016 weren’t transplanted. “This is just the tip of the iceberg,” Durand says. “Many more of these organs are never even offered to those on the waiting lists.”

Among patients who were offered a heart from an increased-risk donor—and chose not to take it—21% were still waiting for a transplant a year later, and 8% had died or were near death, according to research by Michael Mulvihill, a transplant surgery resident at Duke University School of Medicine. “By declining the organ, there was a real risk that they wouldn’t live to receive another offer,” says Mulvihill, who also found reduced survival rates among patients who turned down lungs from increased-risk donors.

BECAUSE THERE'S NOT YET a cure for HIV, organs from donors with that virus are in a special category. Transplants from HIV-infected donors were illegal until the law changed in 2013, and it wasn’t until 2016 that physicians at Johns Hopkins conducted the first transplants of kidneys and livers from HIV-positive donors to recipients who also had the virus. (South Africa, with the world’s highest incidence of HIV, began HIV-to-HIV transplants in 2008.) Such transplants remain rare in this country, with only about 100 performed to date, in part because of strict certification rules that require centers to have experience transplanting HIV-negative organs into HIV-positive recipients—operations that didn’t begin until the early 2000s and have remained relatively rare. “Fewer than 30 centers have been approved, and only 15 have done the transplants so far,” Wolfe says.

Most transplant physicians believe those restrictions are excessive and hope they’ll be relaxed soon. But there are also medical barriers, which include potential complications affecting people with HIV who receive organs, even when the donated livers or kidneys aren’t infected with HIV. Those patients’ immune systems seem to reject new organs at marginally higher-than-normal rates, possibly because antiretroviral HIV medications interact with the immunosuppressant drugs necessary after a transplant. Also, the immune system of patients living with HIV may be more reactive in general, and therefore prone to recognizing the donated organ as foreign. In an HIV-to-HIV transplant, there’s also a very small chance of “superinfection,” in which the organ recipient gets infected with a different strain of HIV that resists treatment.

Some questions about the safety of HIV-to-HIV transplants may be answered by the results of two five-year trials now getting started. One will enroll 160 HIV-positive patients who will receive a kidney from an infected or uninfected donor, and a similar study will look at liver transplants. The results may further pave the way to a lifesaving role for HIV-positive donors.

IF TRANSPLANTED ORGANS ARE to save lives, they must make their way to people who can make the best use of them. But the rules for deciding who that may be could also be outdated. In the past, people with alcohol-associated liver disease had to achieve complete sobriety before becoming transplant candidates, including completion of addiction treatment and a prolonged period of abstinence. People who suffered from obesity, which can damage the liver and other organs, were also denied transplants unless they lost weight. Those recovering from drug addictions and using maintenance therapies, such as methadone, typically weren’t considered at all. But now those rules are tentatively being rethought.

“Until very recently, most transplant programs wouldn’t even consider people if they hadn’t been sober for at least six months,” says Norah Terrault, professor of medicine and chief of gastroenterology and liver diseases at the University of Southern California. Many people with alcoholic hepatitis die within months of the onset of their disease, leaving them no opportunity to stop drinking, let alone wait in line for a new liver. But it turns out that giving those patients new livers may do more than give them a temporary reprieve. In 2011, an influential French study of 26 carefully selected patients with alcoholic hepatitis who received transplants without a requisite period of abstinence from alcohol found that only three of the 26, who had been chosen because of their supportive families and a strong commitment to stop drinking, resumed drinking within two years of their surgery. Moreover, 77% of those who got transplants were still alive two years later, a dramatically better survival rate than the 23% of a control group of patients who didn’t receive early transplants.

A recent large U.S. study has shown similar findings. “Data to support the use of the mandated six months of sobriety are weak, but many transplant centers adhere to it,” Terrault says. Taking a step away from that rule, a pilot study at MGH is providing liver transplants for a few patients with alcoholic hepatitis who fall short of the sobriety rule but meet other strict criteria. They can’t have been previously hospitalized for the disease and must have good family support. “These are patients who haven’t been fully educated on the ramifications of heavy drinking and haven’t been given a chance to get sober,” says James Markmann, chief of the division of transplantation at MGH. “Alcoholic hepatitis is a disease, and if the outcome is that 90% of patients abstain from drinking after transplant, why wouldn’t we give them a new liver?”

Rules based on obesity might also need to be rethought. The condition often comes with a buildup of fat in the liver, which can cause scarring similar to that found in alcoholic cirrhosis. Nonalcoholic fatty liver disease often destroys that organ, leaving these patients in need of a new one, but their obesity typically means they can’t get a transplant. “We found that obese patients who got a transplant often didn’t do well,” says the Mayo Clinic’s Julie Heimbach. “Recovery is difficult, complications are more prevalent and the fatty liver disease could return, along with other problems related to obesity, such as heart disease or diabetes.”

Standard care is to encourage weight loss before someone is added to a transplant list, but many people fail to shed the pounds. In 2009, in tandem with a liver transplant, Heimbach began to perform a sleeve gastrectomy—a type of bariatric surgery—so that patients would have a better chance of maintaining a healthy weight after receiving a new liver. These patients had been too sick for bariatric surgery before a transplant, but because the stomach is next to the liver, combining a liver transplant with a sleeve gastrectomy is “very straightforward” surgery, Heimbach says. Three years later, all of the patients who had the combined operations have maintained a healthy weight versus just 29% of patients who had shed sufficient pounds to meet the normal requirements for a transplant. Now patients from around the country who have been rejected as transplant candidates because of their obesity are lining up for the surgery. “One patient in his fifties had been in hospice. He had the combined surgery and is doing great now,” Heimbach says.

Changing rules for those who have struggled with addiction may also have outsized benefits. Former intravenous drug users who keep their addiction at bay with opioid agonist therapy (OAT), taking prescribed methadone or buprenorphine, are often not considered suitable candidates for organ transplants. An estimated 30% of transplant centers require that people stop the maintenance therapy for at least six months before they can go on a transplant list. This is a harmful policy not based on evidence, says MGH addiction specialist and psychiatrist Ana Ivkovic. “Asking people to come off OAT to be listed for transplant is like asking a diabetic to stop taking insulin before transplant,” Ivkovic says.

One study followed 36 patients on methadone maintenance therapy for five years after liver transplant. Only 11% went back to taking intravenous drugs, and transplant outcomes for the group matched overall national averages. The best predictors of successful transplants among former drug users are solid social support networks and treatment for substance abuse disorder as well as for concurrent psychiatric illnesses such as depression and anxiety, Ivkovic says. “We want to give everyone with opioid use disorder a solid chance,” she says.

The timing for revisiting these rules could not be more important. Rates of chronic liver disease are on the rise, and in 2018, a record 36,527 U.S. transplants were performed, continuing a five-year upward trend. Someday, transplants may not need to be governed by laws of scarcity, says MGH’s James Markmann. “There are some amazing new technologies coming that have the potential to dramatically change how we do transplantation, such as reducing the need for immunosuppression, genetic editing to make animal organs suitable for use in humans, and stem cell technologies that will eliminate the need for some transplants,” he says. “I can see a time when there will be no shortage of organs for transplantation.”

Until then, however, it’s incumbent on transplant physicians to find ways to use every available organ, and to get them to the patients who are desperately waiting. Says Christine Durand of Johns Hopkins: “Donors and their families give organs to save lives. It’s up to us to find the best ways to honor those gifts.”

DOSSIER

Personal Viewpoint on Opioid Agonist Therapy and Transplantation,” by Ana Ivkovic and Sarah Wakeman, American Journal of Transplantation, September 2018. This editorial argues that transplant centers that require people with opioid use disorders to discontinue opioid agonist therapy are employing an outdated and harmful policy.

The Drug Overdose Epidemic and Deceased-Donor Transplantation in the United States,” by Christine M. Durand et al., Annals of Internal Medicine, April 2018. This study found that patients who received organs from overdose death donors did as well as patients who received organs from non-overdose death donors.

Heart and Lung Transplants from HCV-Infected Donors to Uninfected Recipients,” by Ann E. Woolley et al., The New England Journal of Medicine, April 2019. This study shows that treatment immediately after a transplant can wipe out the infection from hepatitis C–positive lungs and hearts.