Michael Keep awoke in the University of Pittsburgh Medical Center (UPMC) recovery room in October 2001 worrying about his liver—and his lover. “When I open my eyes, if I can see Max, I’ll be OK,” he thought. For Keep, 50, it was (he hoped) the end of an arduous journey. In 1999, coinfected with HIV, hepatitis B and hepatitis C, he was running out of options…and time. Fatigued, bloated, confused and “very toxic,” the Los Angeleno was referred to UPMC, then the only center in the U.S. willing to perform liver transplants on HIVers. By the summer of 2001, his condition had worsened, and he and his partner, Max Bruno, had found a temporary apartment in Pittsburgh. Two weeks before moving, Keep got “a very startling call to reality.” At 11 o’clock one night, UPMC announced that a liver was waiting. But Keep couldn’t cross the country in time—and the organ was lost to him. Once settled into his new Pittsburgh digs, he waited some more. By October, bored and frustrated, he wanted to leave.
Then another call came. “I raced around, packed my bag, cleaned my apartment, took out the trash and fell asleep,” Keep recalls. Later that night he took the bus to the hospital. But he knew not to be too optimistic—some patients get to the operating-room door only to discover that the new liver is a bad match or is in poor condition. On a gurney the next morning, drowsy with anaesthesia, he realized he’d hit the surgical suite. A doctor leaned down and said, “This is it, guy.” The next face Keep saw was Max’s. If he’d had to wait much longer, Keep might not be here to tell his tale. And it’s an increasingly common one—for HIV positives and negatives alike—as hepatitis C ravages livers across America, creating what many public-health officials are calling the first major epidemic since AIDS. Even more important to HIVers, liver failure due to chronic hepatitis has become a leading killer, worse than advanced AIDS and opportunistic infections. But in the savage transplant sweepstakes, HIV can still be a handicap.
Calling All Coinfecteds
The liver carries out many vital functions, such as helping digest food, storing nutrients, processing drugs, producing proteins and filtering out toxins. When it fails—as a result of, say, viral hepatitis, or booze—scar tissue piles up (fibrosis, then cirrhosis), compromising blood flow and function. Now the situation can turn really ugly: exhaustion and jaundice, excess abdominal fluids (ascites), burst internal blood vessels, poor clotting, severe itching and brain dysfunction (encephalopathy). In the gravest cases, confusion progresses to coma—then death.
An estimated four million Americans have contracted the blood-borne hepatitis C virus, the vast majority from IV-drug use, though other culprits include sex, accidental needle pricks, tattoos, pre-’90s blood transfusions and even shared razors or toothbrushes. A minority “clear” the virus naturally, but up to 80 percent become chronic—and up to one-quarter of these develop serious liver damage. Hep C can take decades to show up; many infected in the 1970s are only now symptomatic. Some 1.5 million Americans, meanwhile, have hep B, which becomes chronic in only 5 percent of cases but can cause damage equal to hep C’s, also after many years or decades. Prognosis? Hep C is already the main cause of U.S. liver transplants, and, says University of Miami liver specialist Guy Neff, MD, “we’re just seeing the tip of the iceberg.”
But when HIV and hep B or C (or both) shack up, you have a whole new 2+2=5 condition called coinfection. Some 25 to 40 percent of HIVers have hep C, and among people with hemophilia and former drug-shooters, the rate skyrockets. Meanwhile, as many as 15 percent of HIVers have chronic hep B—triple the rate in neggies. Most studies have shown that HIV spurs hep B or C progression and, therefore, liver damage. But the longest-term studies began before HAART, and more recent findings suggest that patients coinfected with well-controlled HIV may do nearly as well as those with hep B or C alone.
HIV or no, few heppers hit the transplant-or-die point. Even without treatment, only 10 to 25 percent watch their livers go south. The latest hep C treatment combo, pegylated interferon plus ribavirin, clears the virus about half the time—and new research suggests that coinfected folks with well-controlled HIV can respond to it nearly as well as neggies. And even if it doesn’t clear C completely, ongoing low-dose interferon may still keep you from a transplant. Plus, new drugs are in the pipeline, including protease inhibitors for hep C. For B, the HIV cocktail mixers Epivir (3TC) and Viread (tenofovir) look good, as do Hepsera and 3TC cousin Coviracil.
Although treatment for C is famous for causing the “flu from hell,” the real problem is initial detection. “Hep C can be silent,” says Neff—exactly why HIVers should test for it so that they “don’t know till it’s too late and transplant is the only option.”
Science on Your Side
Doctors have long resisted transplants in HIVers. Some feared the immune-suppressing drugs transplantees must take to fight organ rejection would kill them. But more important was the prejudice that AIDS was a death sentence: Why waste a perfectly good organ on someone due to die soon? Now, of course, HIVers on HAART are living longer—and ironically, in coinfected ones, the very meds that sustain them can further stress their livers. Surgeons have also feared catching HIV (or hep C, which is easier to transmit), a risk Neff calls “a major concern when doing a lengthy, difficult, bloody procedure in a person who may be infected.” But, says University of California/San Francisco (UCSF) transplanter Peter Stock, MD, “If you think you’ll benefit the patient, there’s an obligation to do it. You take the same precautions [that you do] with everybody.”
Michelle Roland, MD, an HIV specialist at UCSF and, with Stock, a co-leader of a National Institutes of Health (NIH) study looking at transplants in HIVers (see “Liver Spots,” below), says that many HIV doctors and liver specialists still don’t know that transplants are a viable option for HIVers. About a dozen transplant facilities accept HIVers now, with 40 such transplants performed in America and more than 60 worldwide. Most patients have been men in their 40s or 50s; they were equally divided between hep B and C. Silencing the many naysayers, the results are exceedingly promising so far: At the Conference on Retroviruses and Opportunistic Infections in February, researchers reported that HIVer transplantees do just as well as neggies, with one-year survival rates of about 85 percent. Two HIVers who had transplants done at UPMC in the early ’80s, long before HAART, survived over 12 years.
In late 2001, science got a boost from celebrity when activist and author Larry Kramer, long infected with HIV and hep B, became the most famous (and, at 66, the oldest) HIVer to have a liver transplant. Earlier that year, he had boldly posed for Newsweek with an abdomen so bloated from liver disease that he looked eight months pregnant. “The Angry Prophet Is Dying,” blared the headline. “When the doctors told me my liver only had about six months left, I accepted that I was close to death,” Kramer recalls. “But then one day, out of the blue, I was told I might be eligible to get a transplant. From that moment on, I knew I would live. I just knew it.”
Belynda Dunn had less luck. A charismatic, outspoken African-American AIDS activist in Boston, Dunn was coinfected with HIV and hep C. Although she was deemed medically eligible for a transplant in the spring of 2001, her HMO refused her three times, claiming that transplants in HIVers were “experimental.” Dunn brought a widely publicized federal lawsuit, but a medical review panel sided with the HMO. After another coinfected HIVer successfully sued the state Medicaid program for transplant coverage, though, Dunn’s HMO relented. But after two failed transplants in March 2002, Dunn died at 49 from multiorgan failure—unrelated to HIV. Still, she and Kramer put in headlines an idea that surprised many: Having HIV should in no way rule out the “gift of life.”
And what’s the magic ingredient for a successful HIVer transplant? Patients and docs insist it’s complete, constant communication among all parties. “Make sure all your doctors— at the transplant center, at home, your HIV doc, your primary—are on the same network,” Kramer says. UCSF’s Roland agrees: “There’s no way any one of us can have all that expertise.”
CD4s, HMOs and SOBs
All transplant-seekers face a long and winding road, HIVers more so. Candidates—ideally via an HIV-savvy primary-care doc—must first find a center that takes HIVers, then brave an exhaustive medical evaluation and the center’s HIV criteria. Most centers prefer an undetectable viral load—but many understand that a failing liver sometimes can’t tolerate HIV meds. Bottom line? “We want to be able to predict that the person can achieve a low or undetectable viral load after the transplant,” says UPMC’s John Fung, MD, the pioneering surgeon who performed the transplants for Keep, Kramer and Dunn. UCSF, for instance, seeks patients with a CD4 count of at least 100 and no past opportunistic infections—but it will bend the infections rule for a CD4 count of 200 or more.
A select few bypass this process. HIVer Barry Carpenter, 42, was working double shifts as a mortgage broker when he became suddenly ill the day after Thanksgiving 2001, his fever hitting 105 degrees. A liver biopsy revealed fulminant hepatitis A—a rare, acute form of the disease that can lead to rapid cell death and liver failure. He became instantly eligible for a transplant and got his new liver early that December.
Each transplant center also considers substance abuse and family and social support. Roland says candidates “must be able to follow a complex and demanding medical program” after the transplant. HIVers—many already used to taking multiple meds on a strict schedule—may have an edge here.
Then, of course, there’s the money. All centers require that candidates be able to pay for their transplant—a tab that runs a cool quarter of a million (not including meds, which can add thousands of dollars per month for the rest of one’s life). Insurance coverage varies widely among plans. Medicare paid for Kramer’s transplant after a single appeal, and many plans have followed its lead. But Carpenter says that his HMO gave him grief, and UCSF ultimately covered his procedure. Moral of story? You may have to fight for coverage. But, as Kramer, a champion fighter, notes, “If you know you’re going to die if you don’t get it, you’d be surprised what a motivation this can be.”
Living on The List
Getting accepted by a center is only half the battle. Candidates then join what many reverentially call The List—the national transplant waiting list maintained by the nonprofit United Network for Organ Sharing (UNOS). Due to a severe shortage of donor organs, the list is long—and getting longer (see “Pay It Forward”). As of February 2003, more than 17,000 people were awaiting livers. In 2002, only about 5,200 transplants were done and 1,590 people on The List died.
UNOS’ former priority system confusingly mixed quantitative criteria such as lab markers with “soft” ones such as bloating and itching. Within priority categories, organs were first-come, first-serve by geographical region to get them to recipients fast, because the organs “die”after 24 hours. You could game the old system: Some centers immediately listed patients at the first sign of liver damage, offering a better crack at reaching the top—and hobbling sicker contenders with less access to health care. But in 2002, UNOS debuted its Model for End-Stage Liver Disease (MELD) system, which prioritizes patients solely by three objective lab tests of liver function: bilirubin, creatinine and prothrombin time (a blood-clotting gauge). Since then, the number of listed patients who have either died waiting or were dropped because they were too sick has fallen by nearly 25 percent. Top priority remains for those whose first transplant fails, like Dunn, or those with fulminant liver failure, like Carpenter, whose coma popped him to the top of the list.
How long you have to wait also depends on blood type. Type ABs, who can accept organs from any other type, leap up the list (landing a liver after a nationwide average of about six months), while As and Bs take about twice as long and Os—who can receive only from other Os—four times as long. In the Southeast, a person with A or B waited about 210 days in 2000–2001, while one in the mid-Atlantic states waited about 770 days. List-waiters must always be “on call,” able to drop everything and get to the hospital pronto. Many centers offer low-cost housing for patients and families just for this reason.
List Early, List Often?
In theory, The List doesn’t discriminate—UNOS says it hasn’t denied an organ because of HIV since 1987. But some wait-listed HIVers face a dilemma: If they table the HIV meds that hurt their livers, CD4 counts can fall, nixing their transplant eligibility. Such was the case with Glen Hillson, 51, chair of the British Columbia Persons With AIDS Society, who cycled on and off HIV meds for years due to liver problems. When he approached the British Columbia Transplant Society (BCTS), it didn’t race to his side. “I wasn’t very sick, as far as they were concerned,” Hillson recalls. But when he had to stop his HIV meds last fall, his CD4s dropped below the eligibility cutoffs of both the BCTS (300) and UCSF (200 for a person with a past OI). “A day earlier I had been too healthy to expedite screening,” he says. “The next day I was too sick to be eligible.” (His CD4s have crept up to 171 on their own, so he may still make the cut.) Also, because hep B and C may progress faster in HIVers, the interval between “too healthy” and “too sick” seems shorter for coinfected folks—which is why The List should prioritize them, says Jules Levin, who runs the National AIDS Treatment Advocacy Project and himself has HIV and hep C: “As activists, we should push this.”
Should HIVers aim to get on The List early? Brian Klein of the Hepatitis C Action and Advocacy Coalition thinks not: “It’s traumatic, exhausting and expensive to go through the entire work-up, only to sit there for years and worry. Wait until there is a clear likelihood of needing a transplant.” He and Alan Franciscus of the Hepatitis C Support Project think HIVers with early-stage cirrhosis should try hep C or hep B treatment first. But the top doctors stress not waiting too long. “The earlier you’re referred, the better your chance of getting through the work-up in time,”says Roland. Fung agrees:“Don’t wait till you’re bloated and yellow. Then it’s probably too late.”
The Big Day
“When they finally called me to come to the hospital, I was euphoric and couldn’t wait to get there,” Kramer recalls. “I was all bubbly and said, ‘Hey, let’s get this show on the road!’ The admitting doc looked at me like I was crazy.”
So what happens behind the surgical doors? After sedation and prep work, the surgeon makes a boomerang-shaped incision under the ribcage. The old liver—usually lumpy, fatty and scarred—is cut from its moorings and removed. Then the shiny new liver is removed from the cold storage it was placed in mere hours ago after being recovered from the donor, stitched to the recipient’s blood vessels and bile ducts and slipped into place. The whole affair can take from four to 12 hours.
But, as Kramer notes, that’s the easy part. Recovery time varies, but a transplantee might expect to spend three days in intensive care, three weeks in the hospital and three months at home. During that time, much can go wrong. First, there’s “primary nonfunction”—an uncommon condition in which the new liver just doesn’t work. Then there’s possible wound infections, excessive bleeding, leaking bile and scarred, narrowed bile ducts (stenosis). Stock says that major problems are rare and can often be fixed (he’s lost just one patient in 100 transplants). Such was Keep’s case: A month after his transplant, he returned to the hospital to drain excess abdominal fluids and returned the following year for artery-repair surgery.
According to Stock, the worst complication for all hep C patients is the recurrence of the virus, which almost always stays in the body and infects the new liver (even, it seems, in those who appeared to clear the virus with treatment before the transplant; though unmeasurable, C is still lurking). Keep found out his new liver was infected even before he left Pittsburgh. Those who’ve responded well to interferon and ribavirin before may do so again, Stock says, and low-dose interferon maintenance therapy is being studied. Those with hep B are luckier: a drug called HBIG can usually prevent recurrence (but sadly won’t cure the initial case).
Yet another post-transplant possibility? Organ rejection. Seeing the newcomer as a foreign invader, the immune system attacks it and can kill it. To prevent this, transplantees must take immune-suppressing drugs, such as Prograf, CellCept, cyclosporine and prednisone, usually for life. Hence another Catch-22: Your HIV must be tamed to win a transplant, but the subsequent meds can encourage some of the same nasties that plague people with out-of-control HIV—like CMV, shingles, PCP and fungal infections. Transplantees and their docs must often rely on trial and error to find just the right amount of meds to stop rejection. Still, most transplantees have some rejection, often within the first few months. Detected early, it can usually be controlled with more or stronger drugs. Do HIVers generally need fewer drugs, though, because they’re already immune-compromised? Not always. HIVers “have the same rejection rates as HIV negative people,” says Neff; some need less, some need more.
Things can get even messier when you throw HIV meds into the mix. Docs agree that most post-transplant HIVers should start or resume HAART within days—even those who’d enjoyed low viral load and high CD4s without HAART beforehand. Carpenter, who hadn’t taken HIV drugs since 1998, needed two large shopping bags to tote a month’s med supply home from his transplant. “The sight was a bit overwhelming,” he admits. At first he took 14 different meds—almost 30 pills—a day. Today, he’s down to eight meds, his anti-rejection drug doses have been cut, and he’ll soon stop prednisone.
Many HIVers who had trouble tolerating HIV therapy with their battered old livers do fine once the new filters are in place. But HIV meds and anti-rejection drugs can “interact very dramatically,” Fung says—something many primary-care HIV docs may not know. Protease inhibitors can send Prograf levels sky-high. One UPMC patient died of liver rejection after his hometown doc took him off HIVmeds, sending his Prograf levels plummeting—a chilling reminder of the need for communication within the care team.
Also, anti-rejection drugs can cause some of the same side effects as HIV meds: nausea, diarrhea, and high blood fat and blood sugar. So far, Larry Kramer’s been lucky. “I have had no physical reaction at all to Prograf, which is a transplant wonder drug,” he says.
Patients may begin to wonder if all the waiting and worrying is worth it—until they leave the hospital. “I felt pretty darn good when I left Pittsburgh in December 2001,” Michael Keep recalls. “A year later, I couldn’t believe how good I felt. I don’t remember when I last had real quality of life.” Carpenter ditched San Francisco and his high-stress job for a ranch near Yosemite. “It’s a whole new world,” he raves. “I don’t care about money—friends and family are what’s important.” Kramer advises, “Don’t be afraid of the process. Learn all you can. As in any illness, the patient must be proactive!”
When Susan (not her real name), 40, of Miami, first sought a transplant, she was told they weren’t done in HIVers. A veteran HIV–hep C coinfectee, she thought she should hang it up. She had even entered a hospice program and was making tapes for her 9-year-old son to remember her by—but still she never gave up. Susan waited a year and a half to get on the waiting list, then six months for a liver—at the University of Miami in September 2000, making her one of the few coinfected women to have had the procedure. “Never, ever give up,”she says. “My doctors told me to. If I had, I’d be dead.”
LOVE TO LOVE YOU, LIVER
So far, 40 HIVers have had liver transplants in the United States. Meet these fab four:
Irascible author-activist LARRY KRAMER, 67. “My surgeon said,‘You’re as old as your liver,’ and mine came from a 45-year-old. I haven’t felt like this since I was a kid.”
Boston AIDS activist BELYNDA DUNN. She died at 50 after her second transplant, but not before putting HMO coverage of HIVer transplants on the radar.
BARRY CARPENTER, 42. A hep A coma shot him to the top of The List. Now “I feel like I have my whole life ahead of me. I’m living proof that this can work in HIVers.”
MICHAEL KEEP, 50. “I couldn’t believe how good I felt” a year after his transplant, he says—and calls his new liver “truly the most selfless gift someone can make.”
NIH study: http://spitfire.emmes.com/study/hiv-l (lowercase L)
NIH study sites:
Georgetown University, Washington, DC (202.687.6043)
University of California, San Francisco (415.502.8322)
University of Minnesota, Minneapolis (612.626.3877)
University of Pennsylvania, Philadelphia (215.662.6857)
University of Virginia, Charlottesville (434.924.0311)
Other centers that do liver transplants for HIVers:
Columbia University, New York City (212.305.0914)
Mayo Clinic, Jacksonville, Florida (904.296.5876)
Mt. Sinai School of Medicine, New York City (212.659.8053)
St. Vincent’s Medical Center, Los Angeles (213.484.5551)
University of Chicago (773.702.3244)
University of Cincinnati (513.558.7200)
University of Miami (305.243.6251)
University of Pittsburgh (412.648.3309)
United Network for Organ Sharing (national waiting list): www.unos.org
National Organ Procurement and Transplantation Network (OPTN): www.optn.org
Liver transplant information:
USC Patient’s Guide: www.livertransplant.org/patientguide
UPMC transplant info: www.sti.upmc.edu/liver
Hep C and coinfected education and advocacy:
HALT-C Trial (interferon maintenance): www.haltctrial.org
More and more surgeons are hip to doing liver transplants in HIVers. Some pioneers:
The University of Miami’s GUY NEFF, MD. He calls the hep C-related transplant stampede “the tip of the iceberg,” because hep C " can be a silent disease.”
UCSF HIV guru and NIH researcher MICHELLE ROLAND, MD. She invites curious surgeons to “call us, and we’ll share all our data and expertise” on HIVer transplants.
UPMC’s JOHN FUNG, MD, PhD. He counts HIVers Kramer, Dunn and Keep among his transplantees—and urges HIVers to get on “The Liver List” early.
PAY IT FORWARD
The biggest obstacle for transplant-seekers with or without HIV is the lack of donated organs. In the U.S., willing donors mark their driver’s license, but the surviving family still makes the final decision. Senate majority leader Bill Frist (R-TN), a transplant surgeon himself, has prepared a bill to probe a “presumed consent” system in which everyone’s organs are up for grabs unless they explicitly opt out. Also needed are full-time hospital coordinators who monitor failing patients and start the consent process early. “The current way we’re doing donations is 30 years old,” says John Fung, MD. “Most people believe in donation, but the way we time it—asking bereaved family members for organs—makes no sense.”
Some hope also lies with new transplant technologies such as split-liver procedures (dividing a liver between two recipients), transplants using part of a liver from a live donor, “xenotransplants”from such species as pigs and the use of organs from “high risk” groups like gay men, whose organs, like their blood, are currently not accepted even if they test HIV negative.
One thing is certain. Those who donate will receive undying gratitude. “Not a day goes by that I don’t think about the family who lost their 22-year-old son,” says Barry Carpenter, who is starting a foundation called Carry On to encourage more donations (e-mail him at firstname.lastname@example.org).
What can activists do? First, browse www.transweb.org, www.organdonor.org and www.organdonor.gov to learn more, then alert your legislators. Support advocacy groups like www.shareyourlife.org working on the issue. Finally, if you’re HIV negative, become an organ donor—just call your local Department of Motor Vehicles for info—and get others to do the same. HIVers, don’t feel left out! The NIH-funded HIV Research Program (HIVRP; call 800.222.6374) desperately needs HIVer organs to study. Indirectly, you may help save far more lives than one!