Resistance to ARV therapy

[Guest guest]

Dear Forum members,

As prices plummet to a reasonable level ARV will be increasingly and more

widely available. This will begin to happen more and more as governments

begin to wake up to their responsibility for the health of their citizens

lest their economies' gains crumble and reverse as huge chunks of the

working adult population die.

It is EXTREMELY important to begin considering three broad areas:

1. The attached article reflects a serious issue with regard to

antiretroviral therapy. I personally know many people who have gone through

every single currently-approved drug in the United States. Assays of

genotype and phenotype both show resistance to every single drug. Some have

died. Others still continue to derive some benefit--leaving the faint but

real hope that perhaps some of the multi-drug resistant HIV is less

pathogenic to the host.

2. The toxicities associated with ARV. These have killed many of my friends

and acquaintances. I have worked on a lengthy document for DAAIR when I

worked for them called Preventing and Managing Drug Side Effects and HIV

Symptoms (go to http://www.daair.org and click Countering Toxicities on the

left for the last draft version). Clearly, many of the more serious,

potentially fatal side effects ARE treatable. India has powerful traditions

including Ayurvedic, Siddhi, Tibetan and Chinese medicinal systems that can

help to minimize these.

3. The need for new ARV therapies and strategies. New antivirals are

necessary. As Sukontikar posted in the " Licensing Under Trips May Affect

Pharma R & D in India, developing nations may find these new products " one

answer may be to investigate indigenous botanicals as well as to bolster

Indian R & D to produce novel anti-HIV treatments. I might boldly suggest

that inhibitors of nef and tat are desperately needed.

As a subset to point 3, the use of judicious Structured Treatment

Interruptions may help to reduce costs, toxicities and even reduce the risk

of resistance developing too quickly, if done correctly. This needs further

investigation. Already, tho, it appears that delaying ARV until CD4 count

hits 350 (and I'd think 200 might even be a safe lower limit) is an

excellent idea. Clearly, tho, the relevance of this in India AT THE MOMENT

is somewhat moot since it would appear that most people come into the

healthcare system already with full-blown AIDS, with the possible exception

of pregnant women.

In any event, I hope these thoughts will stimulate some discussion.

M.

****

HIV's drug resistance increasing rapidly / UC study forecasts 42% of S.F.

cases affected by 2005. San Francisco Chronicle - Friday, August 31, 2001

Sabin , Chronicle Medical Writer.

http://ww2.aegis.org/news/sc/2001/SC010811.html

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Researchers at the University of California are forecasting that

42 percent of HIV infections in San Francisco will be resistant

to current AIDS drugs by 2005, further complicating efforts to

keep the rapidly mutating virus in check.

" Forty-two percent is a lot of resistance. It will certainly be a

challenge if we do not get new drugs developed, " said Dr.

Kahn, an AIDS specialist at San Francisco General Hospital and

senior author of the report, published yesterday in the journal

Nature Medicine.

Resistant strains of HIV are developed when the virus mutates

into forms that aren't suppressed by a combination of powerful

antiviral drugs -- the so- called cocktails that have cut the

AIDS death rate in half since their introduction in 1996.

The model shows drug resistance among all people living with HIV

-- including both new and existing infections -- growing from

zero in 1996 to 28. 5 percent in 1999, and reaching 42 percent in

2005.

Limited data from San Francisco General Hospital clinics suggest

that the model has been accurately tracking the proportion of

drug resistant cases -- which in 1999 accounted for 28 percent of

the hospital's HIV caseload.

Once resistance appears, doctors can switch to new combinations.

But for a patient, it can signal a slide from robust health to a

life with increasingly less desirable medical choices.

" Subsequent treatments rarely work as well as the first, " said

Kahn, an associate professor at the University of California at

San Francisco.

While doctors agree AIDS drug resistance is something to be

avoided, other UCSF researchers have uncovered evidence that the

mutant viral strains resistant to AIDS drugs are less dangerous

than their " wild " counterparts.

WEAKENED VIRUS

" Our work clearly indicates that, as the virus becomes drug

resistant, its capacity to destroy the immune system is also

weakened, " said Dr. Deeks, an AIDS clinician at San

Francisco General Hospital.

Deeks said it is still preferable to have an infection held in

check by effective AIDS drugs, but that the development of a

resistant strain is by no means a return to the days when the

original virus could run amok and wipe out the body's natural

defenses.

" From the onset of drug resistance, it takes a patient an average

of three years to lose the (infection fighting) T-cells they

gained from antiviral therapy, " Deeks said.

That suggests that, while those with resistant virus are worse

off than they were before developing the mutant strains, the

newer viruses will take longer to do their lethal work -- perhaps

long enough for new therapies to come to the rescue.

The prediction is the product of a complex computer modeling

program developed by UCLA biomathematician Sally Blower,

co-author of the paper, who previously conducted her research at

UCSF. Her program is based on systems originally developed to

predict the risk of nuclear plant meltdowns. Blower has been

applying the technique to infectious diseases for nearly a

decade.

" We take her work very seriously, " said San Francisco Department

of Public Health epidemiologist Willi McFarland. The city

estimates there are currently 18,000 residents living with HIV.

" If lives are shortened by a few years because of drug

resistance, it could add up to thousands of years of life lost in

the city, " he said.

ACQUIRING VIRUS

Blower notes that a resistant strain can be acquired in one of

two ways: an existing viral infection that responds to drug

treatment can mutate into an unresponsive one, or an already

drug-resistant strain can be transmitted to a previously

uninfected person.

A key finding of her computer analysis is that the latter

scenario -- transmission of resistant strains -- is " a relatively

minor public health problem. "

Currently, the model estimates that only 8 percent of new HIV

cases in San Francisco in 2000 would be drug-resistant -- a

finding that is also consistent with the 9 percent recorded in

city clinics. By 2005, that number is expected to grow to 16

percent.

The fear that a new epidemic of drug-resistant virus could be

unleashed is largely unfounded, she said.

The computer model did not take into account possible

transmission of drug- resistant strains to those already infected

with virus susceptible to antiviral treatment.

Such " reinfection " is a theoretical risk of unprotected sex

between two HIV positives -- activity that surveys indicate is on

the rise. But Kahn and Blower said there is little clinical

evidence to date to suggest that reinfection is occurring, and

hence it was appropriate to leave that out of the equation.

HEALTH STRATEGY

Based on the model, Blower said the most important public health

strategy is to focus on ways to reduce drug resistance in the

already infected. And she stressed the need to develop new

therapies for patients with drug-resistant strains.

Delaney, founding director of the San Francisco advocacy

group Project Inform, said the prediction of high rates of drug

resistance is not surprising.

" If there were no new drugs in the pipeline, this would be a

significant figure, " he said. However, there are two new

medications under development that appear to work against strains

that resist current protease inhibitors.

" This is a problem that ultimately will be controllable, " he

said.

E-mail Sabin at srussell@.... 010831

SC010811

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