HIV-Specific Mucosal and Cellular Immunity in HIV-Seronegative Partners of HIV-Seropositive Individuals
|
|
The November 14th issue of Science Magazine carried two important papers detailing
the results of intensive investigation of individuals who have had prolonged suppression of plasma HIV with combination antiretroviral
therapy. All subjects in both these studies had prolonged suppression of plasma HIV-RNA to below 50 copies/mL with protease
inhibitor containing regimens. Both papers reveal highly significant features of these treatment successes.
Replication competent virus is still recoverable from resting CD4 cells even after
highly suppressive regimens of up to 30 months.
The number of such latently infected cells did not decrease significantly with time
on treatment.
Virus recoverable after such long-term suppression was genetically identical to that
seen before antiretroviral treatment suggesting that viral replication and therefore, viral evolution, did not take place over
the 30 months.
HIV in these individuals remained fully sensitive to the antiretroviral drugs used
in their treatment combinations.
A further paper by Wong et al. in the November issue of Proc. Natl. Acad. Sci. also
looks at individuals with good virological control ( < 20 copies/mL) and contrasts them with those who experience poor virological
control on therapy. The two Science papers were accompanied by an editorial which is reproduced below.
HIV survives drug onslaught by hiding out in T cells.
As the war against HIV, the virus that causes AIDS, nears the end of its second decade,
researchers and clinicians have wheeled powerful new cannons onto the battlefield. Potent cocktails of anti-HIV drugs have
led the counterattack, pounding the virus down to undetectable levels in the blood of many HIV-positive patients. But a pair of
papers published in this issue of Science (pp. 1291 and 1295) have both good and bad news for commanders on the front lines.
Two research teams--one led by immunologist Robert Siliciano at The Johns Hopkins
University School of Medicine in Baltimore and the other by virologist Douglas Richman of the University of California, San Diego,
School of Medicine in La Jolla--report that many patients taking the new drug cocktails, known as combination therapy, for as
long as 30 months show no signs of developing drug-resistant strains of HIV. They do, however, still harbour latent virus in a
small number of their T cells--immune cells that are HIV's primary target--despite having undetectable blood levels of HIV. And,
in the test tube at least, these viruses can be induced to wake up and begin reproducing, simply by stimulating the T cells to
become immunologically active--a condition known to be required for HIV to replicate.
Although several research groups had previously demonstrated that HIV was still lurking
in these cells, some scientists had speculated that it might exist in a damaged, nonviable form. But the new findings show
that these viruses are fully capable of replicating and infecting other cells. Moreover, even in patients who adhered rigidly to
their drug regimen for up to 30 months, the percentage of latently infected cells did not decrease significantly. This is not
good news for hopes that combination therapies would be able to eradicate the virus quickly: Either the current drug regimens may
take many years to eliminate HIV totally, or they are not powerful enough to do so. "The idea that the drugs can hit every infected
site in the body is unrealistic," says Simon Wain-Hobson of the Pasteur Institute in Paris.
On the other hand, AIDS researchers are quick to stress the positive side of the results:
The sequences of the viral genomes in the patients' T cells showed little evidence of mutational changes over the course
of their treatment, as would be expected if drug-resistant strains were emerging. "The drugs are doing their job, but the reservoir
is quite slow in its turnover," says David Ho, director of the Aaron Diamond AIDS Research Center in New York City. Ho, who
with Richman is a co-author on the Siliciano paper, adds that the next task will be to "think of strategies to flush out this cellular
compartment." And Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland,
says the results "should not have any impact on what we recommend to patients. We are reaping enormous benefits for patients
by keeping the virus as low as possible for as long as possible."
Despite this optimism, new work from Fauci's laboratory--soon to be published in the
Proceedings of the National Academy of Sciences--will sound yet another cautionary note. Fauci's group found the same hidden
reservoirs as the Siliciano and Richman teams, but also uncovered evidence suggesting that some of the hidden virus may not be latent,
but still replicating at a slow rate.
[Editors comment: Drs. Chun, Fauci and colleagues will report their findings in the
November 25 issue of the Proceedings of the National Academy of Sciences (PNAS). It is important to note that only 9 out of the
thirteen subjects in their study had viral loads less than 500 copies/ml, the cutoff point of the bDNA assay used. They may, therefore,
not be experiencing the same degree of virological control seen in the patients in the Siliciano and Richman studeies.
- PB.]
The Siliciano and Richman teams adopted the same basic approach in looking for HIV
in so-called memory T cells, which help lead the attack when the body encounters microbial invaders it has seen before. The researchers
took blood cells from HIV-positive patients who were on a strict regimen of combination therapy and cultured them together
with blood cells from HIV-negative donors, along with reagents that trigger memory T cells to become immunologically activated.
The researchers observed virus from latently infected memory cells quickly replicating and infecting the HIV-negative cells,
even though the original level of infection of the HIV-positive cells was very low--the Siliciano team measured no more than 16
infected cells per 1 million T cells.
Researchers say these results clearly indicate that it is much too early to consider
taking patients off combination therapy. "The results are not surprising," says retrovirologist John Coffin of Tufts University
in Medford, Massachusetts. "We knew that patients over this time frame would become virus positive if treatment is removed. The
virus has to still be somewhere." Adds Wain-Hobson: "We must assume that HIV infection is forever until we know to the contrary."
Researchers are far from sure how long infected memory T cells will live before finally
dying out, perhaps taking the virus into oblivion with them. Several years ago, immunologists Angela McLean of Oxford University
and Colin Michie at London's Ealing Hospital showed that while the average memory T cell lives for about 200 days, some individual
cells could survive for many years. "If these cells are left on their own, they are going to last at least a decade, or
maybe two or more," says Richman. But leaving these cells on their own is the last thing AIDS researchers intend to do. "We must
hasten the demise of these cells," says Coffin.
Fauci suggests that some patients, particularly those treated early in their infection,
might be able to mount an effective immune response against the few infected memory cells once they are taken off combination
therapy--especially if their immune systems could be boosted with an anti-HIV vaccine. Another approach, Fauci says, would be
to develop new drugs against HIV enzymes called integrases--which allow the virus to take over the genetic machinery of its target
cells--hence stopping the formation of hidden HIV reservoirs. Says Ho: "These new results tell us what we must do in the upcoming
year. They shed light on the path to eliminating the virus from an infected person, the ultimate goal for those of us working
on HIV therapeutics."
Author: M. Balter
Ref: Science, 278(5341):1227 (Nov 14 1997).
Return to Contents
Recovery of replication-competent HIV despite prolonged suppression of plasma viraemia
In evaluating current combination drug regimens for treatment of human immunodeficiency
virus (HIV) disease, it is important to determine the existence of viral reservoirs. After depletion of CD8 cells from the
peripheral blood mononuclear cells (PBMCs) of both patients and normal donors, activation of patient CD4 lymphocytes with immobilised
antibodies to CD3 and CD28 enabled the isolation of virus from PBMCs of six patients despite the suppression of their plasma
HIV RNA to fewer than 50 copies per millilitre for up to 2 years. Partial sequencing of HIV pol revealed no new drug resistance
mutations or discernible evolution, providing evidence for viral latency rather than drug failure.
Ref: Wong JK, Hezareh M, Guenthard HF, Havlir DV, Ignacio CC, Spina CA, Richman DD.
Science, 278(5341):1291 - 1295 (Nov 14 1997).
Return to Contents
Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy
The hypothesis that quiescent CD4+ T lymphocytes carrying proviral DNA provide a reservoir
for human immunodeficiency virus-type 1 (HIV-1) in patients on highly active antiretroviral therapy (HAART) was examined.
In a study of 22 patients successfully treated with HAART for up to 30 months, replication-competent virus was routinely recovered
from resting CD4+ T lymphocytes. The frequency of resting CD4+ T cells harbouring latent HIV-1 was low, 0.2 to 16.4 per 106 cells, and, in cross-sectional analysis, did not decrease with increasing time on
therapy. The recovered viruses generally did not show mutations associated with resistance to the relevant antiretroviral drugs.
This reservoir of nonevolving latent virus in resting CD4+ T cells should be considered in deciding whether to terminate treatment
in patients who respond to HAART.
Ref: Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE, Quinn TC,
Chadwick K, Margolick J, Brookmeyer R, Gallant J, Markowitz M, Ho DD, Richman DD, Siliciano RF. Science, 278(5341):1295-1300 (Nov
14 1997).
Interestingly the siliciano study contained two subjects who were newly infected and
treated within 10 weeks of the onset of symptomatic primary infection. Despite 11 and 17 months of HAART respectively, replication
competent virus was still recoverable from their latent CD4+ lymphocytes. This suggests that the latently infected CD4+ T
cell compartment can become established very early in infection. The findings revealed in these papers have obvious implications
for treatment strategies:
A plasma viral load of < 20 copies/mL should be the preferred treatment response.
Investigation of less arduous maintenance regimens is urgently needed.
As eradication looks increasingly less likely consideration must be given that the
patient may eventually fail their current regimen. Planning for subsequent regimens must, therefore, be considered.
Although latency establishes early, there are still arguments for treatment of seroconverters
(eg. lowering the viral load set point).
If the patient must remain on treatment indefinitely, hitting HIV too early condemns
many patients to inconvenient regimens, risk of morbidity from drug side effects (including diabetes, raised blood lipids, lipodystrophy,
kidney stones, chronic gastro-intestinal discomfort, myopathies and neuropathies). Early treatment may not necessarily
provide benefit different from delaying therapy until risk of illness is greater than risk of toxicity.
|
Return to Contents
Reduction of HIV-1 in blood and lymph nodes following potent antiretroviral therapy and the virologic correlates of treatment failure
Potent antiretroviral therapy can reduce plasma HIV RNA levels below the threshold
of detection for periods of a year or more. The magnitude of HIV RNA reduction in the lymphoid tissue in patients with suppression
of HIV RNA levels in plasma beyond 6 months has not been determined. We evaluated levels of HIV RNA and DNA and characterised
resistance mutations in blood and inguinal lymph node biopsies obtained from 10 HIV-infected subjects who received 36-52 weeks
of indinavir (IDV)/zidovudine (ZDV)/lamivudine (3TC), IDV, or ZDV/3TC. After 1 year of therapy, viral RNA levels in LN of individuals
remained detectable but were log10 = 4 lower than in subjects on the triple drug regimen with interruption of therapy
or in those treated with ZDV/3TC alone, who had viral loads in their lymph nodes indistinguishable from those expected for untreated
patients. In all cases viral DNA remained detectable in lymph nodes and peripheral blood mononuclear cells (PBMC). When plasma
virus suppression was incomplete, lymph node and PBMC cultures were positive and drug resistance developed. These studies
indicate that pronounced and sustained suppression of plasma viraemia by a potent antiretroviral combination is associated with
low HIV RNA levels in the lymph nodes 1 year after treatment. Conversely, the persistence of even modest levels of plasma virus
after 1 year of treatment reflects ongoing viral replication, the emergence of drug resistance, and the maintenance of high burdens
of virus in the lymph nodes.
Ref: Wong JK, Guenthard HF, Havlir DV, Zhang Z-Q, Haase AT, Ignacio CC, Kwok S, Emini
E, Richman DD. Proc. Natl. Acad. Sci. USA 94:12574-12579 (Nov 11 1997).
This study gives the following results:
Treatment with the triple drug regimen of ZDV, 3TC, and IDV can result in plasma viral
suppression to <20 copies per mL at a year of therapy.
Virus RNA is greatly reduced but remains detectable in lymph nodes after 1 year of
therapy in those with complete suppression of plasma virus.
In subjects with even modest plasma viraemia, very significant virus loads were detectable
in the corresponding lymph nodes.
HIV DNA remained detectable in lymph node and PBMC from all patients.
Quantity of HIV RNA and DNA in lymph node correlated well with plasma HIV RNA after
1 year of therapy.
Recovery of virus by co-culture and detection of phenotypic and genotypic drug resistance
occurred in all subjects with incompletely suppressed plasma virus.
The Science papers outlined above show the significance of this viral DNA.
|
Return to Contents
HIV Research Overview: Interview with David Ho, M.D.
On October 30 AIDS TREATMENT NEWS interviewed David D. Ho., M.D., director of the
Aaron Diamond AIDS Research Center in New York City, and a professor at The Rockefeller University. Aaron Diamond, the world's largest
independent AIDS research laboratory, "focuses on basic research efforts to increase understanding of the structure and function
of HIV and to define the mechanism by which it destroys the immune system." We asked Dr. Ho to tell our readers what he
believes is most important now in HIV treatment research.
Hit Hard Hit Early
AIDS TREATMENT NEWS: Some see a backlash against the "hit hard hit early" philosophy.
Some physicians say that is right for some people, but that others, especially those who have an excellent prognosis anyway
for several years, maybe we should hold the fort with a regimen such as d4T plus ddI, and reserve protease inhibitors, non-nucleoside
RT inhibitors, and other treatments where viral resistance can develop rapidly, until we have better drugs and combinations
available. How do you answer?
Dr. Ho: Some people are looking at failures on combination therapies which include
a protease inhibitor, as an indication that the concept of hit early hit hard is incorrect. My view is the opposite, given what
we have seen over the past year. The failures on combination therapy have generally occurred when patients are more advanced in
the disease process, and have taken prior antiretroviral therapy, usually as monotherapy or dual therapy. And one must consider
the issue of compliance or adherence; poor adherence is akin to hitting inadequately hard.
Those are the principal reasons for failure on combination therapy. Our experience
suggests that when treatment is successful, patients maintain control of HIV replication on combination therapy. Most of them were
drug naive, or at least without extensive antiretroviral drug experience. The earlier you start, the greater the chance of sustaining
the
antiretroviral effect. So the practical experience does support the hit-hard-hit-early
notion.
ATN: When you are the treating physician, who if anybody would you suggest should
not start treatment at all?
Dr. Ho: There are certain patients who are HIV infected, but have either a normal
or slightly depressed CD4 count, and a viral load which is spontaneously quite low. Their prognosis without treatment is quite good,
based on those numbers, and there is no reason to rush into any form of therapy. One could comfortably monitor their viral
load and CD4, and delay making any decision on starting treatment.
ATN: A big concern is that many people are not ready to start this complex regimen,
and do not have the commitment they will need to see it through for year after year after year. The fear is that they will start
something and not be ready to maintain it.
Dr. Ho: This is obviously a very important decision. If the commitment is not completely
there, then I would agree. If a patient cannot face a very complicated regimen for several years at least, then starting
therapy may in fact be bad. Without the commitment, adherence will likely be poor, leading to drug failure, and many drugs will
be used up. That would not be in the patient's best interest.
ATN: What would you say about treatments like d4T plus ddI that are not recommended
in the guidelines, but are picked to be drugs where resistance tends to develop slowly--as intermediate between no treatment,
and the full hit hard hit early?
Dr. Ho: I think if the situation were not as desperate, if somebody is pretty well
off and wants to take that sort of approach, of reserving stronger drugs for later use, I think an argument could be made in support
of that strategy. However, with a drug combination such as the one you mentioned, it is fairly clear that you cannot adequately
control the virus, there will be residual ongoing replication, and some variant forms will eventually emerge. So the antiviral
effect is unlikely to be very durable. And even though ddI may not be the most crucial drug to have in your arsenal, you will
still use it up. It takes away one card that we may want to play in the future. Overall, I cannot endorse such an approach.
Maintaining Blood Levels
ATN: At the recent ICAAC conference there were posters on the correlation of the nadir
of indinavir blood levels [the trough or lowest concentration of indinavir), for example, in the blood between doses--which
usually occurs just before the next dose], with how durable the effect was. If the drug level became too low between doses, viral
resistance and rebound would likely develop. So there has been an interest in the community--maybe less so in industry- -in individualising
doses, by checking blood levels when a person starts on a drug, to make sure it is being absorbed, and that the nadir
stays high enough to maintain an antiviral effect. What do you think of this approach? Does it make even theoretical sense?
And if so, what about the practicalities of getting it introduced.
Dr. Ho: It makes a lot of theoretical sense. When we first tested protease inhibitors,
we noticed that there are lots of individual variations in drug concentrations. In those days we were doing pharmacokinetics
regularly. The same dose could achieve concentrations that vary considerably between patients, suggesting significant individual
differences in drug absorption and metabolism.
We found quite a bit of individual variation in how these drugs are absorbed and metabolised.
If those concentrations could be measured easily and dosing could be tailored on an individual basis, this would certainly
make sense. But on a practical level, even for researchers, it is not easy or inexpensive to get these measurements made.
In clinical practice, it would be even more difficult.
ATN: Some researchers have told us that companies have not been co-operative with
them in developing these tests--for example, refusing to provide pure samples of the drug to calibrate their tests. Have you had
any such experience?
Dr. Ho: I do not know much about that. Many of the companies do not even do these
assays [for drug levels in blood] themselves; they contract out to certain commercial laboratories that measure these drug concentrations
by specialised chemical techniques. I find that on a practical level, it is difficult to get these measures done.
After Virological Failure
ATN: When there is virological failure with a triple combination, what can people
do next? We hear many anecdotal reports of people whose treatment has "failed" virologically with some of the protease inhibitor
combinations, in that viral load comes back up but usually not all the way to baseline; however their CD4 count seems to stay high,
and they seem to be doing well clinically. What do we know about what's going on? And how should these people continue their
treatment?
Dr. Ho: There are several scenarios. Take the patient who is previously antiretroviral
naive, who gets treated with a triple combination, who has good suppression for a while, then after some period of time, say
a year, the viraemia reappears. In that case, you could have viraemia that bounced back to the prior baseline--which means that
the virus is resistant to two or three of the drugs. The thing to do there is to change to a new regimen. Since the patient is
previously drug naive, the doctor still has several other options to work with.
There is another scenario, however--closer to the one you presented. Viraemia reappears,
but at a much lower level. Therefore, that lower level does not seem to impact the CD4 count or the clinical picture. What
do you do?
This is a difficult issue. Clinically and immunologically, you are still benefiting
the patient by continuing the medications--because the viraemia is suppressed compared to the baseline, and the CD4 count is still
at a higher level. The concern here is that there is now residual virus replication; we are all aware of the possibility that
resistant viruses will eventually emerge, and the question is, will that take a few more months, or will that take another year
or two?
We do not know what the right answer is. For those inclined to be more aggressive,
they may go ahead and add a drug, and see if they could get it back down to undetectable levels--to arrest the evolution of viral
sequences, and therefore block the further development of resistant virus. Others do not like to add just a single drug; they
would rather change the whole regimen. We do not have enough experience to know how persistent such a situation could be.
Then there are patients who have taken several drugs before, and begin a more powerful
combination and suppress viraemia for a period of time, but then the viraemia comes back at some intermediate level. Here it
is hard to make pronouncements or general guidelines about what to do; you have to deal with it case by case, depending on the
specifics of the situation, the prior drug experience, and what options are left to come up with a combination of drugs that a
patient has not seen before.
ATN: What could be said about the odds or percentages--either for naive patients starting
a hit-hard-hit-early regimen, or people who have had much prior experience and have been through most of the drugs besides
protease inhibitors, and then start their first protease-inhibitor-containing regimen? Are there any situations where we have
fairly good data to let people know what their chances may be? And to what extent are the problems due to lack of adherence, and
therefore under control to some extent by the patient?
Dr. Ho: We have some indications, but not much cohort or trial data to guide us. In
drug naive patients who start these combinations reasonably early, and adhere to the combinations, in our experience clearly over
80% to 90% have durable suppression for over a year, and some have been on treatment successfully now for over two years. But
adherence to these difficult regimens is a very real problem. And often it is hard to predict in advance who will stick to the
regimen, and who will not. In addition to the true drug failure, we are going to have somewhere around a third who will be significantly
non-adherent to the regimen--even in motivated patients such as our trial subjects.
But if someone is very confident that they can stick to a twice-daily regimen for
several years, and if that patient is drug naive and reasonably early in disease progression, the chances of prolonged suppression
are quite good.
On the other extreme are patients who are in and out of the hospital, who have taken
several of the reverse transcriptase inhibitors in the past, and then start on a typical triple combination. I think the recent
San Francisco General data suggests that about half of those patients will fail. That takes into consideration everything: the
prior drug experience, the more advanced disease status, and includes any adherence problems.
ATN: Yet so far I have heard that most of those patients are doing well, even the
ones who have virologically failed.
Dr. Ho: That is a very important point--what do you mean by failure? That failure
in the San Francisco study was defined as any virus being detectable; it was a virological definition. If you have ongoing, detectable
virus, the concern is that the result will be more resistant virus, more viral load, and clinical failure. But having a little
bit of viraemia but still having the virus under reasonable control is clinically very beneficial.
The San Francisco study was portrayed in the lay press as terrible news. It is certainly
not great news, but not so bad if you consider the clinical perspective.
And you need to realise that was a chart review study, looking back at the early experience
with these treatments, in a hospital setting with advanced patients. That study design was prone to yield a more pessimistic
view of combination therapy including a protease inhibitor.
Viral Load--More Sensitive Tests
ATN: Now there is data suggesting that a viral load below 400 copies may not be good
enough; for the most durable viral control, you would really like to know that you are below a much lower cut-off, for example
below 20 copies. The practical problem is that most patients cannot get the Ultrasensitive test that goes down to 20. As a stopgap,
would it make sense to use the available test and look for a result of zero, no virus detected at all, instead of a number
which is above zero but below the quantification limit of 400?
Dr. Ho: If the threshold of detection is 400, then there is no point in reporting
a specific number below that 400; that would confuse people, and is not reliable.
You can find some patients who consistently have a result between 20 and the lower
limit of the more available viral load tests [400 or 500]. Some people on the modern combination therapies are in that category.
How we interpret this situation, and whether we should do anything about it, is a
grey area now. It is unlikely that a viral load of, say, 150 copies per mL will be associated with rapid progression and clinical
disease. So clinically, you probably do not need to do very much to modify whatever the patient is on. However, this test result
tells us that there is continuing viral replication; the virus will continue to evolve, and we have to be careful about a breakthrough
later on. Since there is not a lot of clinical experience to guide us, some people are saying we should just follow these
people carefully; others, if there is flexibility, would add a drug to see if the virus could be dropped below 20 copies per
mL.
Viral Resistance Testing
ATN: On viral resistance testing, what role do you see for these tests--both now,
and in the future, for selecting which drugs to start somebody on, or which drugs to change to?
Dr. Ho: I think these tests probably could be very helpful, if they could be made
simpler, with faster turnaround, and at some reasonable cost, say equivalent to a viral load test, or only slightly above that.
We do not have anything today that meets these criteria; however, a number of people and companies are working toward those goals.
These assays will most likely be useful when a patient goes on combination and is
failing it, and you need to need to know what to do next. While the patient is still taking the failing regimen, so that the viruses
are breaking through despite the presence of the drugs, you could take the virus and measure their resistance profile, and
get a reasonable reflection of what is going on. Then if the viruses are, say, resistant to two of the drugs the patient is taking,
and sensitive to the third, you would use that drug in combination with two or three other new drugs. In that setting, resistance
testing will be fairly useful.
One has to be careful about using any of these tests on a patient who has gone off
the drugs already. Say the patient has taken AZT plus 3TC in the past, and has resistant virus to those two drugs, but the drugs
are no longer being used. The resistant virus would revert back to a minority population, say only accounting for 5% of the viruses.
The resistance assays used today are not sensitive enough to pick that up; you would miss it, and get a false sense of security,
and may use drugs that would be doomed to fail.
So while the patient is on the medication, I think the tests are useful. But once
the patient has gone off the drugs, and he resistant virus is the minor population, the tests we have now would not be reliable.
There are ways to deal with this; surely the companies will come up with such strategies in the future, but they are not there
yet.
Therefore, at the start of therapy, I think that taking a history [of previous antiretroviral
drug use, where some of those drugs are likely to have been discontinued] may be at least as useful as measuring the
virus--unless you are dealing with a patient who was infected with a drug-resistant virus in the beginning.
ATN: Looking ahead maybe three to five years in the future, do you think most of the
usefulness will be from the phenotypic tests [which see how well the virus can grow in the presence of drugs] or the genotypic
tests [which look for mutations associated with resistance to particular drugs]?
Dr. Ho: I think that ultimately we would like to have a phenotypic assay--the same
approach used successfully for testing antibiotic resistance very quickly in the laboratory, to strep and staph and other pathogens.
The genotypes are quite difficult to interpret; because of mutational interactions, their clinical consequences are often
very difficult to predict. We want a phenotypic assay in the long run.
Targeting Resistant Protease
Dr. Ho: Here is one project I would like to see pharmaceutical companies take on.
They know how to make protease inhibitors now. They could take a very resistant virus--for example, a virus highly resistant to
indinavir-- and crystallise that protease, and start the whole effort over, and develop a second generation protease inhibitor that
will attack the drug-resistant variants. Companies have been through the process [of developing protease inhibitors], they know
the strategy, and these strategies have been quite successful over the last few years. Why not repeat it, and come up with compounds
that would be active against the viruses that are resisting the first generation protease inhibitors? I think that would
add a lot to the arsenal for our patients.
ATN: Isn't this the approach that Abbott used to develop its second generation?
Dr. Ho: I am not sure if that is the strategy they used. ABT- 378 has greater potency
against the wild-type virus, and good pharmacokinetics. It tries to overcome the resistant virus through greater potency and
higher drug concentration. To my knowledge, it was not designed against a resistant virus.
I think this process might work better if we start from scratch, with a drug-resistant
viral protease.
Is Eradication Possible?
ATN: What do you see, in the next several years, on eradication possibilities?
Dr. Ho: We are learning quite a bit. Eradication is still a goal; it is not something
we or anyone else has achieved so far. But we are learning a lot about different viral compartments, and how quickly they could
be eliminated once strong therapies are applied.
The available therapies have helped us eliminate over 99% of the virus in infected
individuals. But we are learning about additional viral compartments. In our patients who have been treated very early and very
hard, and have received this treatment two years now, we are still finding a residual pool of virus resting in certain CD4 cells,
in a very quiescent way. This poses a new obstacle to deal with.
Some people would say it means eradication is not possible. But those of us who are
working on the science look at it differently, and say this is information we need to achieve eradication. Now with this information,
how do we move on? How do we flush that residual pool out, how do we protect the individual from that virus reactivating
and spreading the infection?
Much fairly exciting basic research is underway, by several groups. If we go back
a few years to 1994 or 1995, we would not have predicted that we would be dealing with such a small pool of virus after a year and
a half or two years. But on the other hand, the cells that contain this virus are quiescent, so they will not turn themselves
over very fast. So we need to think about continuing antiviral therapy, but also using certain immunological strategies to activate
those cells so they could be flushed out. It poses a new obstacle; but it is a scientific challenge which has certain theoretical
solutions. The research groups engaged in these issues are taking that on. It is quite exciting from a scientific perspective.
Can One Be Re-Infected with a Second Strain of HIV
ATN: Is there much re-infection with a different strain of HIV, after one strain has
become established?
Dr. Ho: We can show in monkeys that re-infection occurs; we do know from the various
recombinant viruses that we find in people throughout the world, that dual infection or superinfection must occur on occasion.
But on a practical level, within our patients, there have been precious few documented cases of superinfection. Some groups have
looked for evidence that this has occurred, and have not found it.
Treatments to Watch
ATN: Over the next three to five years, what are some of the particular drugs and
treatment strategies and approaches that you think we should be keeping an eye on?
Dr. Ho: Some of my answers will be the standard ones you hear from others. We will
have several more reverse transcriptase inhibitors, both nucleoside and non-nucleoside. We should have a few more protease inhibitors.
But I also think that the companies that are making these drugs will come up with equivalent ones that are less toxic and
easier to take. If we could move some of the protease inhibitors from three times a day to one time a day, it would be a major
advance. Some of the companies are working toward these goals.
Also, a couple major pharmaceutical companies are working on integrase inhibitors,
a potentially very important class of drugs.
The recent breakthroughs in chemokine receptors, as cofactors necessary for viral
entry, have led to much screening to find drugs that might inhibit one or several of these co- receptors. At the screening stage,
the effort has been quite successful; there are many "hits" [compounds that work in the laboratory screening tests], and they
are being pursued. We probably will not hear much about them for another year or two, when they get to toxicity testing, and some
to clinical studies. But there is much activity already.
And there are other new kinds of drugs being developed, such as T-20 that attacks
the envelope fusion process, and other drugs that attack the viral protein.
Key Issues
ATN: What do you see as the most important issues to leave with our readers?
Dr. Ho: The issue of eradication, the goal, what we are learning about the obstacles,
and the strategies to deal with those. The failures: it is important that patients understand what are the principal causes
of failure; many of them involve treating advanced-stage patients who have prior antiretroviral therapy. And the issue of adherence.
When we hear statistics, we have to understand under what setting were the numbers
generated--and not just walk away and say that study says it's 90% successful, and this study says it's 50%, so somebody is wrong.
One has to interpret all of these results in the context of the patient population that is being studied.
Also, the word "failure" is being thrown around without a precise definition. Is
it virologic failure, is it clinical failure? We need to keep this difference in mind.
Ref: Author John S. James. AIDS Treatment News Issue No. 282, November 7, 1997;
Subscription and Editorial Office: P.O. Box 411256 San Francisco, CA 94141 office number fax: 415/255-4659 Internet: aidsnews@aidsnews.org
NOTES: d4T/ddI failure - although it is rare to detect genotypic resistance, this
combination can, and does, stop working for patients. Most researchers believe this is probably due to cellular resistance (the
slowing of cellular phosphorylation, or cell membrane becoming impermeable to the parent compounds). It is assumed that such cellular
resistance is reversible. After a period of not taking these nucleoside analogues (in the absence of HIV genotypic change),
the response to the same combination may be restored. This theory is untested at present. Some UK physicians have raised the idea
of taking a drug holiday, say of one month, between regimens, to allow a reversion of possible cellular resistance. This may
strengthen the initial virological response to the new regimen.
|
Return to Contents
Saquinavir Soft Gel Approved in the US
On November 7, 1997, the US Food and Drug Administration approved the sale of the
new soft-gel formulation of saquinavir, which will be marketed under the name Fortovase. The drug's approval was based on the results
of clinical trials that achieved better drops in viral load in patients taking Fortovase than in those using Invirase, the
original hard-gel form of saquinavir. Administered in combination with 2 nucleoside analogues at a dose of 1200 mg 3 times daily,
Fortovase resulted in viral loads below 400 copies/mL in a greater percentage of patients than did Invirase. Twice as many patients
who took Fortovase had undetectable levels of plasma HIV RNA at 16 weeks compared to those who took Invirase.
This increased antiviral activity is due to the improved bioavailability of Fortovase
over Invirase. In simpler terms, more of the drug is absorbed and used by the body to battle HIV replication. Results from clinical
trials have also revealed Fortovase to be relatively well tolerated by patients, causing side effects of mainly mild intensity
including nausea, diarrhoea, abdominal discomfort and dyspepsia (digestive difficulty).
Some compassionate access to Fortovase is expected for Europe in Jan/Feb 98, although licensing is unlikely to be granted earlier than June 98.
|
Return to Contents
Salvage Therapy Using Six Drugs in Heavily Pretreated Patients
A latebreaker abstract at the recent Hamburg conference reported on salvage therapy
in 12 heavily pretreated patients using a combination of six antiretrovirals. The twelve patients had been exposed to all three
protease inhibitors (indinavir, ritonavir and saquinavir) and who were virological failures. Mean viral load at baseline was 170,065
copies/mL The six drugs used were d4T 40mg bd, ddI 400mg once daily, 3TC 150mg bd, nevirapine 200mg bd, nelfinavir 1000mg
tds and saquinavir 600mg tds.
Nine of the twelve patients remained on all six drugs and all nine achieved a viral
load <400 copies/mL by week 12. CD4 counts increased by 30 to 370 cells/mm3. Three patients who had been previously intolerant
to components in the combination were again intolerant to them. Side-effects ceased when the offending agents were removed.
The authors conclude that having failed all three protease inhibitors previously some cross-resistance to nelfinavir
may have been expected. Nevirapine is known to select for resistance rapidly when used as monotherapy. On the basis of
these being the only new agents in this combination, the sustained effect seen in this group is surprising. They go on to suggest that ...recycling of drugs may be possible if enough drugs are used.
Ref: LB 926, Sixth European Conference on Clinical Aspects of HIV Infection. Hamburg
99.
Return to Contents
|
PATHOGENESIS
|
Global Distribution of the CCR5 Gene 32-Basepair Deletion
A study--reported by Jeremy J. Martinson and colleagues of John Radcliffe Hospital's
Institute of Molecular Medicine in the United Kingdom in a recent issue of Nature Genetics--has found a 10 percent gene frequency
for a CCR5 mutation in populations of European descent. Martinson et al. used a rapid PCR assay to screen 3,342 individuals
from a globally distributed population for CCR5 with a 32-basepair deletion, which has been shown to prevent cell invasion by
the primary transmitting strain of HIV-1. No mutant alleles for the gene were reported among indigenous non-European groups. Martinson
and colleagues suggest that these differences in mutated CCR5 occurrence should be taken into consideration in future predictions
of HIV transmission rates.
Ref: Journal of the American Medical Association (11/05/97) Vol. 278, No. 17, P.
1388 ad
Source: CDC NCHSTP Daily News Update.
Return to Contents
HIV-Specific Mucosal and Cellular Immunity in HIV-Seronegative Partners of HIV-Seropositive Individuals
An analysis of HIV-specific mucosal and cellular immunity in heterosexual couples
with only one seropositive partner found HIV-specific immunoglobulins A (IgA) but not IgC in urine and vaginal wash samples from
seronegative, HIV-exposed individuals (ESNs). In the seropositive partners, both IgA and IgC were present; neither of the antibodies
was detected in a low-risk control group. Peptide-stimulated production of interleukin-2 was detected in nine of 16 ESNs,
five of 16 HIV-positive individuals, and one of 50 controls. According to the researchers, the findings indicate that humans
can exhibit a "compartmentalised" immune system response, and raises the possibility of protective roles for cell-mediated immunity
and mucosal IgA in seronegative individuals exposed to HIV. Mucosal and systemic immunity has previously been observed to protect
primates from SIV infection.
Ref: Nature Medicine (11/97) Vol. 3, No. 11, P. 1250; Mazzoli, Sandra; Trabattoni,
Daria; Lo Caputo, Sergio; et al.
Source: CDC NCHSTP Daily News Update.
Return to Contents
