Recent Information from the NIH
I thought you'd like to read this in light of the presentations at the 6th Human retrovirus conference on interrupting and stopping therapy. The recently published NATAP Resports newsletter has contains several pages reviewing these presentations. The newsletter is posted to the NATAP web site; if you would like a hard copy of the newsletter you can call the NATAP office at 212 219-02106 or email us at "firstname.lastname@example.org."
HIV Respite Is Brief Subjects Relapse After HaltingTreatment
By David Brown
Washington Post Staff Writer
Sunday, May 9, 1999; Page A01
Mark Deal knows he was never supposed to think he was curedof the AIDS virus. But he couldn't put the idea out of his mind when hevolunteered last January for an experiment in which he stopped taking hisantiviral drugs. The fantasy, however, lasted only 12 weeks. That was thelength of time it took for the human immunodeficiency virus (HIV), heldin check for years by drugs, to reappear in Deal's bloodstream. "Ilasted longer than most," he said last week, putting the best spinon the disappointing news. For some other people in the study, which isunderway at the National Institutes of Health (NIH), the virus bounced backin three weeks.
Deal has restarted his medicines and, once again, HIV isundetectable in his blood. The 37-year-old is healthy, and has every reasonto believe he'll remain so for a very long time. The three-month respitefrom taking 25 pills a day was nice. But it hasn't been hard to go backto the old habits. "It was like not being in class for the summer.It's a pleasant surprise, but then all of a sudden it's time to go backto school. So you do it."
Deal's experience is one stone in the growing mountainof evidence that HIV infection isn't likely to be cured with the antiviraldrugs now in use, as revolutionary as they are.
The NIH study was launched on the theory that some HIVpatients, whose infections had been controlled by drug therapy for longperiods of time, might be able to stop their drugs and keep the virus undercontrol with their immune systems alone. The experiment is ongoing, butearly results suggest that this hopeful hypothesis is wrong.
"Just within a matter of several weeks, a sizableamount of viral relapse is being seen," said Richard Davey, the physicianheading the study at the National Institute of Allergy and Infectious Diseases."My expectation is that the majority of patients will require retreatment."
Davey last week spoke only in general terms about the resultsof the study so far. Later this month, he will present data on the first10 patients to the "institutional review board" that reviews clinicalexperiments at the NIH hospital. Eighteen people are enrolled, and the studycan take up to 50.
The researcher said there are "compelling reasons"to continue the experiment. With the help of elaborate tests on each patient'simmune system, he and his colleagues hope to learn why some people relapsequickly and have high viral "rebounds," while in others HIV returnsmore slowly and remains at relatively lower levels.
It's unlikely that briefly stopping the medicines willhurt, even if it's now certain that virtually everyone will relapse. HIV'sdamage to the immune system -- once infection is firmly established, asit is in all these patients -- occurs over the course of years, not weeks.
Furthermore, as long as a person starts or stops all hisantiviral drugs at once, there's little chance the virus will become resistantto them.
Curiously, there are also theoretical reasons to believethat a brief pause in drug therapy may actually help. The reappearing virusmay stimulate the immune system like the booster shot of a vaccine, givingit new power to suppress the infection.
The rules of Davey's study say that once HIV reaches theconcentration of 5,000 viruses per milliliter of blood, a patient is stronglyurged to resume taking medicines. No one can be compelled to, however.
Richard Shaw, who like Deal signed up for the study inJanuary, is choosing to remain off medicine while his "viral load"bounces around this cutoff.
His virus reappeared quickly. Unlike some patients in thestudy, whose viral loads have risen into the hundreds of thousands, hisinched up slowly. By the sixth week off the medicines, he was advised stronglyto restart them.
"I was pretty depressed about it," said Shaw,40, a construction estimator living outside Philadelphia. "Of course,I wanted to believe that it was gone. And I'm sure somewhere in the backof my mind I was harboring the thought that it wasn't."
One day after he started back on medication, however, hegot a surprising call from one of the NIH investigators. His viral load,which had been as high as 22,000, was back down below the cutoff at whichhe'd agreed to resume antiviral therapy. So, once again, he stopped takingthe drugs.
Both men say the study has given them a chance to experiencesomething they haven't had in years -- a pharmaceutical-free existence.The change is physical and emotional, felt and unfelt.
Shaw says his energy level has increased dramatically.Now that he no longer has to time his meals (and to some extent, their content)to the medicine's dosing schedules, his eating habits have changed. He isworking longer, traveling more, feeling freer.
"After I had been off the drugs for 10 weeks, my doctortold me, 'Don't try to pack the last 10 years into this time,' " herecalled recently.
Deal, too, says his energy "went through the roof"when he stopped taking the four antiviral drugs he was on. Who knows, hesays, it may have been from the emotional high. He tires more easily now.The spontaneity was also nice, such as deciding to go out to dinner andnot worrying whether it was 7 p.m. or 10 p.m.
"That was a pleasant experience," he recalledlast week. "But I'm not the sort of person who spends time now thinkingabout how difficult my life is. Because the fact is, it isn't."
There are some things, however, that he'd like to avoidon his return to "highly active antiretroviral therapy" (HAART),as combination drug therapy is generically called.
Like many people, he developed abnormally high bloodstreamfats, as well as signs of incipient diabetes, while on a protease inhibitordrug. Although for the moment he has agreed to take the medicines he usedbefore the study began, he eventually plans to switch to a new combination.Unlike people with HIV infection just a few years ago, he's now worriedabout diseases that take decades to develop.
"I have no intention of dropping dead of a heart attack,"he said.
The NIH study was never conceived as a test of whetherHIV could be eradicated from an infected person's body with the drugs available.Research on patients, combined with mathematical projections, suggests thatHIV persists in tissue "reservoirs" long after replication stops.A study in this month's issue of the journal Nature Medicine says that "eradicationcould take as long as 60 years."
Ironically, the very success of HAART may contribute tothe longevity of infection. That's because, over time, immune system cellsespecially primed to kill cells infected with HIV disappear. Scientistshope that if the immune system can be periodically "reeducated,"it might be able to hasten the demise of the virus.
With that idea in mind, Bruce D. Walker, head of the AIDSresearch center at Massachusetts General Hospital in Boston, is recruitingpeople newly infected with HIV. They are immediately started on HAART. Thismay prevent the damage to the immune system that occurs in the first monthsafter infection.
Periodically thereafter, HAART will be stopped until thevirus reappears. Then it will be restarted. Eventually, Walker and his colleagueshope, the jazzed-up immune system may be able to control the infection onits own. There are scattered reports that this has happened, although notin clinical trials.
"This is something that should only be done in a verycarefully controlled clinical setting," Walker said last week. "Forone thing, there's no evidence that it works."
Such a strategy, if successful, might give thousands ofpeople with HIV infection a second shot at a life without antiviral medicines.
Meanwhile, life goes on.
Deal was a hotel concierge in New Orleans from 1986 to1992, when he quit to care for his longtime partner, who had AIDS and diedin October 1994. In the years since, he's lived in other places and hadother jobs (and no job).
Now, he's back home in New Orleans again. He's just accepteda new position as a concierge. It's at the one hotel where he's always wantedto work.
Commentary by Jules Levin
You should read the article I wrote for the recent issueof NATAP Reports. It discusses all the related issues in detail and includesanimal and human data. It's available on this web page a few articles belowor in hard copy by calling our office (212 219-0106). The data suggeststhat "priming" the immune system may help stimulate a CTL responseto HIV. Hopefully after several interruption the immune system might respondto control HIV. But in experiments reported at Retrovirus this good responsewas seen in individuals who initially had a broad and strong CTL responsebefore starting HAART during acute infection only. In the NIH study theydid not interrupt therapy but only discontinued it. As well, the patientswere not treated during acute infection. And they haven't reported on thisbut we don't know if they had any CTL responses present.
Bruce Walker started his study recently to treat individualsduring acute infection and follow with brief interruptions. At this point,this approach is more likely to see some successes than the NIH study butwe have to wait and see. At Retrovirus Rosenberg (from Walker's lab) talkedabout one patient who appeared to be a great candidate but they did notinterrupt therapy several times, they only discontinued his therapy. Andhis viral load rebounded after stopping HAART. The priming may be important.
So in summary, the NIH study is a first attempt to lookat stopping therapy. Usually in a pilot study they design a protocol thatis most likely to be successful: narrow entry criteria, etc. This was notdone in the NIH study. There already was data presented at Retrovirus (discussedon p.13 in NATAP Reports) on 8 individuals with early but chronic infectionwho had <20 copies/ml and all 8 rebounded immediately after stopping.The NATAP article on interrupting and disct therapy in the newsletter givesa full perspective of the story.