Back grey_arrow_rt.gif
'Salvage Therapy' - New AIDS drug offers hope, but too late for one man
  note from Jules Levin: this is an unprecedented time in HIV treatment because there are many new HIV drugs available either because they were recently approved or are expected to be soon approved: approved this year were TMC114, a protease inhibitor; available through expanded access and expected to be approved soon: MK-0518, integrase inhibitor, TMC125, a NNRTI; available soon through expanded access: Maraviroc, a CCR5 antagonist; approved in last 2 years: tipranavir, a protease inhibitor, Fuzeon, a fusion inhibitor. It is important to remember that when composing a new regimen it is crucial to have an adequately potent regimen that will potently suppress the resistant HIV the patient has. This means at least 2 new drugs and preferrably three new drugs should be used. There are 3 new classes of drugs among thos mentioned above (Maravitoc, a CCR5 anatagonist, MK-0518, an integrase inhibitor, and Fuzeon, a fusion inhibvitor). Patients with resistance to current classes of drugs (protease inhibitors and NNRTIs) should consider using 2 drugs from new classes of drugs along with TMC114 and/or TMC125 to put together a potent regimen for long-term success.
By James Ricci,
LA Times Staff Writer
January 2, 2007
2006 was destined to be the year Warren Ratcliffe lost his desperate race to survive AIDS, and the year Mark McClelland appeared, finally, poised to win his.
The two Bay Area men were among an estimated 40,000 Americans whose illness could not be controlled by modern HIV drugs because they'd developed a bedeviling resistance to them. Known as "salvage therapy" patients, they had only one hope: that a complicated and ever-changing witch's brew of existing medications, aimed at stalling the famously mutational virus, would keep them alive long enough for entirely new drugs to arrive via the pharmaceutical research pipeline.
In 2006 just such a drug - one that some researchers are calling "truly phenomenal" - did come along, in time, doctors hope, to save the 45-year-old McClelland but too late for Ratcliffe, who was overtaken by AIDS-related cancer and died April 27 at age 58.
The new drug, called an integrase inhibitor, was a highlight of the summer's annual international AIDS conference in Toronto. Newly published clinical studies showed that it, in combination with two existing drugs, reduced the virus to undetectable levels in nearly 100% of HIV patients taking, for the first time, a regimen targeting their condition. It had a similar effect on the virus in up to 72% of salvage therapy patients.
"They tested it on some people who were in deep, deep salvage therapy, and even those people did remarkably well," said Dr. Steven Deeks, a UC San Francisco salvage therapy authority who treated Ratcliffe and still treats McClelland. "It seems to be a truly phenomenal drug that everyone is sort of a little bit in awe of right now and is changing the whole way we think about the management of these patients."
The drug essentially prevents the virus from integrating its DNA with that of a host's cells, thus short-circuiting its ability to replicate itself.
McClelland had several friends in salvage therapy who were part of the integrase inhibitor studies. "They all did extremely well," he said.
The knowledge of how they fared was immensely encouraging to him. And his own recent negative experience propelled him in the same direction.
In October, he came down with a fungal infection that took advantage of his lowered immune defenses.
"It was semi-serious but treatable," he said. "Getting sick hit me emotionally, however. I was just coasting along, and it was an opportunistic infection, and I hadn't had one of those in 11 years. And that was tough and gave me some renewed determination."
What was more, McClelland's count of infection-fighting T-cells, a principal indicator of immune system compromise, hit zero. "It wasn't too different from four, which I've hit before, but there's something about hitting zero that was a little upsetting."
Ratcliffe could not be included in the clinical studies of the integrase inhibitor. Kaposi's sarcoma, the early AIDS epidemic's portentous and deadly calling card, was overwhelming him.
"Warren really couldn't qualify for the drug, because his Kaposi's was progressing and because he had pretty significant side effects from the chemotherapy," Deeks said. "Mark is doing well, however, and I'm trying to get him on the integrase inhibitor right now. We're trying to get as many people in our research cohort as possible on this."
The new drug is on track for FDA approval by mid-2007, but its manufacturer, Merck & Co., is making it available sooner to patients in desperate straits.
Ratcliffe and McClelland were featured last January in a Times article about their unlucky subgroup and the obscure corner of AIDS treatment it occupies.
Like most others in their category, they had the misfortune of being diagnosed with HIV when single-drug treatment, called monotherapy, was the only help available. With monotherapy, the virus had to mutate past only one drug, which made a patient resistant to that medication and all others of its type.
Multi-drug therapy, which became available a decade ago, usually presents HIV with too many obstacles for it to mutate past. This therapy became the gold standard of treatment, suppressing the virus and allowing patients to live normal lives.
The multi-drug "cocktail" failed to work for monotherapy veterans like Ratcliffe and McClelland, because in them, the virus had already become resistant to one of the cocktail's components and was more likely to resist other drugs in the mix, as well.
Ratcliffe's deterioration and death just as a potentially saving drug was becoming available has inflicted an added measure of pain on Alex Kazan, his domestic partner of 10 years and friend of 25.
"Watching him go was pretty difficult, because he was such a wonderful, caring person," Kazan said. "You wonder why he couldn't have been spared. I thought I'd grow old with him, but he just didn't hit the right part of the wave, I guess."
Suffering from effects of the disease and the toxicity of the pharmacist's catalog of medications he took over the years was a constant theme in Ratcliffe's life. It too had a special poignancy for the 55-year-old Kazan, himself a veteran of monotherapy, albeit one whom multi-drug therapy has kept in good heath.
"I guess there was always a little bit of guilt that I was doing better than he was," Kazan said. "But he was always excited about me doing better. He probably wouldn't have gone through all the heroics, in terms of all the therapies, if it wasn't for me. He took care of me. He fought so hard and rarely complained."
In late March, his once-fit body reduced to boniness by chemotherapy, Ratcliffe admitted himself to a hospital because of a persistent, intense headache. Over the next month, infections appeared in his brain and, knowing the end was near, he decided to die at home.
"They thought he'd make it another eight or nine weeks, but he made it only five days," Kazan recalled.
At a memorial service July 15, the day before Ratcliffe would have turned 59, the 150 people in attendance heard the Mississippi native and Navy veteran of the Vietnam War memorialized as a homebody, a perfectionist, an expert cook and gardener, a man who looked after elderly friends, remained close to his four siblings and was especially kind to children.
"Before he died, he sat down his goddaughter and other kids he knew and told them that after he was gone, they had to go on living," Kazan said. "And he sat me down too and said that I had to go on. I'm not sure I have. Not yet."
It is in the hope of preventing similar loss that Deeks and other researchers have such profound interest in the new AIDS drug, especially in combination with other new drugs they hope to have available by the end of this year.
His recent infection convinced McClelland that he has to begin taking the new integrase inhibitor - probably in combination with two other new drugs - sooner rather than later, probably in February.
He's had promising medicine regimes before, and all of them ended up disappointments, "but this seems to be so much better than anything that's come before," he said.
"It could be the Holy Grail - or just give me the next five years, which would be fine with me."
For surviving salvage therapy patients like McClelland, Deeks said, "2007 may change everything. We're shooting for lifelong undetectable viral loads, and once we achieve that, the immune system rebuilds itself. That's what we're shooting for with Mark and everyone like him."
'Salvage Therapy' for The ones HIV left in limbo
Salvage therapy is the last resort of a largely unknown and unlucky minority who began treatment before multidrug 'cocktails.

By James Ricci,
Jan 1, 2007 LA Times Staff Writer
SAN FRANCISCO -- In a consultation room at San Francisco General Hospital, Warren Ratcliffe rolls up the leg of his jeans to display an anachronism. Purplish brown, leech-shaped splotches cover his left shin and calf.
They exist also, he says, on his stomach and chest, and he fears they might appear on his hands and face, where clothing won't obscure them.
Kaposi's sarcoma, once the familiar and portentous calling card of the deadly AIDS epidemic, has all but disappeared over the last decade, during which multidrug "cocktail" therapy has drained HIV of much of its ferocity and returned many patients to normal lives.
The markings on Ratcliffe's skin, however, tell of a grim exception.
For an estimated 40,000 Americans such as Ratcliffe, the newer treatments have not subdued the disease. Most members of that group had the bad fortune of being diagnosed with HIV when single-drug treatment -- or monotherapy -- was all that was available.
Monotherapy gave the virus only one obstacle to mutate past, and as researchers later discovered, resistance to the drug often developed. Multidrug therapy, which was initiated in 1996 and usually consists of three medications, usually presents the virus with a virtually insurmountable mutational challenge.
But longtime monotherapy patients are an unfortunate exception. Because the drug they have taken is one of the three types used in the multidrug cocktails, if their virus has already become resistant, it can more easily become resistant to other drugs in the mix too.
That leaves veterans of monotherapy playing a fearsome waiting game, trying to stay alive long enough for new drugs -- which their infection might not be resistant to -- to become available while their doctors repeatedly improvise with existing medications to slow their progress toward death.
This little-known corner of HIV medicine is called salvage therapy, the last resort of this unlucky minority.
Warren Ratcliffe's arduous journey through disease and treatment illustrates the plight of those who wind up in salvage therapy.
A 58-year-old native of Mississippi, he settled in San Francisco after serving four years in the Navy during the Vietnam War. He thinks he was infected in 1976.
The disease lay dormant for a dozen years, but in 1988 he took an HIV test and was found to have the virus. Ratcliffe was immediately put on AZT, a drug that is in one of the three major classes of current HIV medications.
Although he had stomach problems with AZT, he had no symptoms of the disease itself for three more years, and his infection-fighting T-cells were, at 400 per milliliter of blood, near normal numbers -- a sign that his immune system was operating effectively.
In 1991, however, a dermatologist discovered a lesion from Kaposi's sarcoma on the back of his right leg -- proof that the AZT was no longer working.
Ratcliffe was then put on daily alpha interferon injections that had him "feeling like I'd been run over by a bus, and it backed up and ran over me again. Basically I had one day a week -- maybe two -- when I felt human."
What ensued over the following years was a cascade of medications sequentially and in combinations, none of which succeeded in knocking the virus down to undetectable levels. Two experimental drugs Ratcliffe has taken as part of clinical trials have failed.
Now his salvage therapy regimen reads like a pharmaceutical catalog: Neupogen (three injections a week to boost his white blood cell count); Fuzeon (two injections a day to help prevent the virus from fusing with normal cells); Crixivan (two pills a day; a protease inhibitor that interferes with HIV's replication process); Kaletra (three capsules twice a day; another protease inhibitor); Viread, Epzicom and Zerit (one pill a day each to interfere with the virus' ability to make DNA); Zithromax (one pill a week to prevent opportunistic infections); and Bactrim (one pill a day to combat infections).
Despite all this, his T-cell count is down to 37. Anything below 200 is considered an indicator of full-blown AIDS. His weight is low, and he sometimes has difficulty giving himself injections because of a lack of fat beneath the skin.
"I've had every drug out there and the virus keeps building resistance to them," Ratcliffe said. "My problem is, I need three new drugs.... So, we try to maintain until there are additional drugs available and I can take more than one at a time."
Through sleeplessness and constant bone pain, Ratcliffe is still able to attend to errands and other aspects of normal life, thanks in large part, he says, to the support of his partner, who is also a veteran of monotherapy but whose virus has been suppressed to undetectable levels by multidrug treatment.
Ratcliffe says the fact he is still alive is due to the level of HIV expertise among doctors in San Francisco, and especially to the talent of Dr. Steven Deeks, possibly the world's leading authority on salvage therapy.
Deeks has shown that drug-resistant HIV strains are less "fit" than original "wild-type" viruses and do their damage more haltingly, especially when up against numerous drugs in a salvage-therapy regimen.
"The basic principle of therapy is that one should have three fully effective drugs in any new regimen. But this is rarely possible in heavily pretreated patients," Deeks said.
"Hence, we often try to get two fully effective options and combine this with other 'partially effective' options. The need to add up all of these partially effective options is why many salvage regimens contain five or more drugs."
Salvage therapy is a machine of many moving parts. Matters are complicated by the fact that a patient's resistance to a given drug often means resistance to all the other drugs in its class.
"Salvage therapy in this point of time is an art," said Jeff Sheehy, communications director for the AIDS Research Institute at UC San Francisco, where Deeks is an associate professor of medicine. "It's almost like Steve Deeks is a magician. He's like a wizard concocting potions .... You have to understand the meds, the side effects, the resistance profiles of each drug and the resistance profile of the virus in the individual you're treating."
Like Ratcliffe, Mark McClelland credits salvage therapy with keeping him alive. Despite low T-cell counts, he is able to exercise regularly and practice yoga. His apparent good health belies a history of high hope and bitter disappointment with HIV treatments.
McClelland, a 44-year-old former healthcare policy analyst, tested positive for HIV in 1990 and immediately was placed on AZT, then on another AZT-class drug he found more tolerable. Six years later, he went on a three-drug regimen and his T-cells jumped from 12 to 250 in two weeks. "I felt great," he said. "I had normal energy and I even considered going back to work. I did some traveling."
After about eight months, however, he began to decline again.
In 1998, he was placed on a new four-drug regimen that succeeded in suppressing his virus to undetectable levels. After two years, however, the drugs became toxic to his liver and he was put on an altered regimen to which his virus quickly became resistant.
His two brushes with success took their psychological toll. "You think, 'Hey, maybe this is it. Maybe I'm going to be OK,' " he said.
"So, there's a letdown. I mean, there are people who went on three-drug therapy the same time I did and they've been doing great ever since, which is not a happy comparison for me."
Now McClelland takes six drugs of various classes. Although his T-cell count has dipped as low as 4, he says, "I'm clinically stable, have good energy, am not getting any infections."
Like everyone connected with salvage therapy, McClelland keeps a vigilant eye on the drug pipeline, waiting for at least two new ones that he is not resistant to and that can be combined. The temptation is to leap on each drug as it emerges, but that carries a greater risk of developing resistance to it.
Two new drugs from one pharmaceutical company are being combined in clinical trials. Further back in the pipeline is an entirely new class of drugs called integrase inhibitors. Together, these developments might offer the chance of a new three-drug combination in a couple years. Another intriguing new class called R-5 drugs is already being tested, but has run into problems with liver toxicity.
Of concern to Deeks and his colleagues is the fact that drug-resistant strains of HIV increasingly are showing up in newly infected patients. In San Francisco, recent studies indicate that between 5% and 27% of new cases involve HIV strains that are resistant to at least one of the three classes typically used in multidrug therapy. In one study, about 13% were resistant to two of the classes.
This, Deeks says, shows the importance of testing new patients for drug resistance, which is routinely done in San Francisco but not elsewhere and is not covered by medical insurance. "It says something about our health system that insurance will cover $30,000 to $40,000 a year worth of medications but will not spend a few hundred dollars for a resistance test to tell us which drugs to use," he said.
Knowing which drugs new patients are resistant to is critical. It enables doctors to avoid including them in multidrug regimens, which would predestine failure and speed patients into salvage therapy and the harrowing wait for medical science to catch up before it's too late.
That wait, McClelland says, has to be managed with the proper attitude. "One of the main life lessons is not to give in to anxiety, but to live in the moment, to enjoy being healthy today," he said.
After discussing his case, Ratcliffe puts on his jacket and slips his backpack over a shoulder. As he leaves, he says to a visitor: "I never thought I would live this long with this disease. I hope you can come back five years from now and interview me."
  icon paper stack View Older Articles   Back to Top