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AIDS Trestment News
June 4, 1999

Contents:


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Eradication or Immune Control: New Research, Issue of Focus

by John S. James


Four separate publications in the current New England Journal of Medicine(1,2,3,4) and research papers published this month in Nature Medicine(5,6,7) and Journal of Experimental Medicine(8) have brought attention to issue of how much AIDS research should focus on attempting to eradicate HIV by antiretrovirals, vs. seeking long-term immune control even without eradication.

The New England Journal reports have received the most public attention. Two research papers(1,2) and an editorial(3) discussing them, are again illustrating the difficulty of completely eradicating HIV from the body with current drugs. Two years ago it was hoped that if the virus were continually suppressed to undetectable levels with antiretrovirals, maybe the infection would die out by itself within a few years, as infected cells died and were not replaced. Today this hope seems unlikely, at least with current treatments, for two reasons: some cells can live for a long time, and there is evidence of some ongoing viral replication or activity (at least in many patients) despite very good control of viral load with the drugs.

Zhang and others(1) studies eight patients who began treatment soon after infection, and had undetectable viral load for two to three years. They looked for evidence that the virus had changed during this time -- an indication that viral replication was continuing. They did find such evidence in two of the patients, but not in the other six. And even in those two who had low-level replication, drug resistance did not develop.

But this team of 18 scientists at the Aaron Diamond AIDS Research Center and other institutions also estimated the half life of the virus in resting CD4 cells as six months -- meaning that complete eradication in these cells would take many years.

Furtado and others(2) studied five patients with long-standing HIV infection who had undetectable plasma viral load for at least 20 months on antiretroviral treatment. They measured HIV DNA and RNA within CD4 cells, and found that both of these decreased, but then seemed to reach a steady level and not go lower, suggesting that some very low level of viral replication was continuing. They concluded that it might not be possible to eradicate HIV with current treatments.

One benefit of these studies is that they have developed new tools to study very low levels of HIV activity, even in patients whose viral load is completely undetectable.


Another Approach

The letter(4) reports on the well-known "Berlin patient" -- who started treatment soon after acute HIV infection with a regimen which included hydroxyurea, interrupted treatment temporarily on two occasions, and then was able to stop treatment without a rebound in his viral load. While most of the information was already presented at the Retroviruses conference (see "Restoring HIV-Specific Immunity," AIDS Treatment News #312, February 11, 1999), this report after 19 months of treatment notes that very low levels of live virus have been detected by special tests, so the HIV has not been eradicated and it is possible that this patient could have a viral rebound in the future. The importance of this case is that it shows the possibility of immune control of this virus, even in a patient who previously had a high viral load and needed antiretroviral treatment to suppress it.


Comment

Treatment activists are increasingly questioning whether there is too much research emphasis on eradication with antiretrovirals, vs. studies on how to maintain or repair the body's initial ability to control the virus. When HIV infection first occurs, the immune system suppresses the virus very well, much better than any known drugs -- but then this ability is usually lost. Since almost everybody can control this virus for a time -- and some long-term nonprogressors may be able to control it permanently -- and chimpanzees can be infected with HIV, but almost always control the virus and do not become ill -- all of which suggests that immune control of this infection is biologically plausible -- it seems that there should be more research focus on immune responses to HIV, how immune control is lost, and what can be done to maintain or restore it.

Is the research balance is being distorted by the existence of a huge market in antiretrovirals, vs. almost none in immune-based therapies? Or are we only seeing the effects of ongoing progress, as studies planned years ago based on the information of that time are now being reported?


References

1. Zhang L, Ramratnam B, Tenner-Racz K, and others. Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. The New England Journal of Medicine. May 27, 1999; volume 340, number 21, pages 1605- 1613.

2. Furtado MR, Callaway DS, Phair JP, and others. Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy. The New England Journal of Medicine. May 27, 1999; volume 340, number 21, pages 1614-1622.

3. Pomeranatz RJ. Residual HIV-1 disease in the era of highly active antiretroviral therapy. The New England Journal of Medicine. May 27, 1999; volume 340, number 21, pages 1672- 1674.

4. Lisziewicz J, Rosenberg E, Lieberman J, and others. Control of HIV despite the discontinuation of antiretroviral therapy. The New England Journal of Medicine. May 27, 1999; volume 340, number 21, pages 1683-1684.

5. Finzi D, Blankson J, Siliciano JD, and others. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nature Medicine. May 1999; volume 5, number 5, pages 512-517.

6. Pitcher CJ, Quittner C, and Peterson DM. HIV-1-specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression. Nature Medicine. May 1999; volume 5, number 5, pages 518-525.

7. Robinson HL, Montefiori DC, Johnson RP, and others. Neutralizing antibody-independent containment of immunodeficiency virus challenges by DNA priming and recombinant pox virus booster immunizations. Nature Medicine. May 1999; volume 5, number 5, pages 526-534.

8. Hockett RD, Kilby JM, Derdeyn CA, and others. Constant mean viral copy number per infected cell in tissues regardless of high, low, or undetectable plasma HIV RNA. Journal of Experimental Medicine. May 17, 1999; volume 189, number 10, pages 1545-1554.



Treatment Interruption Research: The Trial Most Needed Now

by David Scondras


Note: Treatment activist David Scondras, of Search for a Cure in Boston, outlined a research proposal in a May 27 email to the Treatment list.(1) We also talked with him for additional information for this article. Essentially he is outlining a comprehensive approach which brings together the various tools which may help the immune system improve its control of HIV. The problem is that it is hard to organize and fund a comprehensive trial; instead we get fragmented trials as different companies, groups, and individuals pursue their own agendas. JSJ

* * *

If you look at the ideas so far on how to get immune control of HIV, and put them together, they are not antagonistic. You could use antiretrovirals to suppress the virus, wait until there are naïve cells, and then use an immunogen like Remune(TM), or a DNA vaccine, to cause replication of the naïve cells which recognize peptides associated with HIV. When that has been done well, use IL-2 to copy all of the clones, including those which recognize HIV, until there is a significant rise in LPA (lymphoproliferative assay, a measure of immune function) in response to HIV.

Then set a viral load threshold, low enough that one is comfortable it will not wipe out those clones; interrupt antiretroviral therapy, and go back on therapy when the viral rebound reaches that pre-determined threshold. See if long cycles of interruption followed by therapy when needed can prolong the time a person can be drug-free and still below the viral threshold.

A similar companion trial could test a regimen which is easier to take, such as ddI plus hydroxyurea, instead of the treatment interruption, to see if a simpler therapy is enough to keep the virus suppressed, after this effort to reconstitute the immune response against HIV.

This is not the only trial that should be done; far from it. But it is the one trial that must be done. We need to support trials that give a person the best chance to be able to stay off drugs for the longest possible time.


References

1. For information about joining the Treatment list, send email to listproc@CritPath.Org, with "info treatment" (without the quote marks) in line 1.



HE2000 Begins Clinical Trials

Interview with James Frincke, Ph.D.

by John S. James


HE2000 is a chemical relative of DHEA which was selected for development after it showed antiretroviral activity in laboratory tests. The immediate reason for interest in this compound today is that it apparently saved the lives of all three monkeys treated in a small animal study.(1) A phase I/II human trials will be starting soon in Chicago, Houston, Palo Alto (California), and San Francisco in the U.S., and is ongoing in Cape Town, Johannesburg, and Pretoria in South Africa; for more information about the U.S. study, call Bob Marsella at Hollis Eden, 619-587-9333. HE2000 is currently given by injection for five successive days followed by a 30-day observation period, but oral and other formulations are being developed. The mechanism of action is largely unknown at this time.

Hollis Eden sees HE2000, if it works in people, as pioneering a new approach to treating the cells of the host, not the virus. It hopes to develop a treatment which could be affordable worldwide, avoid viral resistance, and be easier to administer, reducing adherence problems.

On May 24 we interviewed James M. Frincke, Ph.D., executive vice president for research and development at Hollis-Eden Pharmaceuticals (San Diego, California), the company which is developing HE2000.

ATN: What is HE2000, and what is its rationale or mechanism of action?

Frincke: HE2000 is an injectable formulation of a compound called alpha-epi-bromide. We are using an injectable form in this study to avoid clouding the results due to variable absorption with oral use. Eventually we hope to use the injectable form for a loading dose when a patient is first treated, but then switch to an oral drug for most other times. If the oral dose is insufficient for any reason, the patient could return to the clinic for injections to boost the effect again.

HE2000 has also shown activity in laboratory tests against malaria, CMV, polio, and influenza. It is possible that these infections and others use some similar mechanism to permit the infection to establish itself and persist in the human body. [On May 26 the company announced that it will work with the Navy on preclinical testing of the active ingredient in HE2000 for malaria.]

ATN: What is known about the toxicity of HE2000?

Frincke: We studied the drug both in rats and rabbits, and found minimal drug-induced toxicity up to a 160 mg/Kg dose; injection-site irritation may have been exacerbated by the drug, in a very sensitive rabbit species. The formulation used -- a proprietary mixture of ingredients -- at high volumes became toxic in rabbits before the drug itself did. So the drug toxicity appears to be low.

ATN: What dose will you be using in people?

Frincke: Our highest dose will be 3 mg/Kg -- about 200 mg for a 70 Kg person. In pharmacology, one adjusts dose by using body surface area, so an equivalent dose for small animals is larger than if body weight only were used. Still, there is at least a 10-fold safety margin in the first and second human dose, and possibly in the third dose as well. Because in animals we found toxicity from the vehicle, not the drug (although the drug may have exacerbated the toxicity), we will be monitoring for all possible toxicities in the trial.


Mechanism of Action

Frincke: We also had to demonstrate that the drug has antiviral activity in animals. That was especially important for HE2000, since unlike the standard antiretrovirals, we could not do rational drug design on a computer screen against a viral target.

ATN: Because you don't know what the target is?

Frincke: Yes; the mechanism of action is still uncertain at this time. We know from the literature that the compound interacts with certain enzymes, including G6PDH (glucose 6 phosphate dehydrogenase); these enzymes could be involved in the mechanism. Also, the compound is in the steroid hormone series, and involved in control mechanisms in our cells that are much more complex, interacting with receptors and therefore changing the biochemistry of cells. This compound may have many modes of action; we are trying to understand what they may be.


The Primate Study

ATN: Describe the animal study that had the unexpected survival result.

Frincke: Retroviruses which infect mice would not have reflected the human situation. So to study antiretroviral activity in animals and make sure we had a sufficient therapeutic index (margin of safety between active and toxic doses), we used a virus called SHIV229 -- an artificially created virus which is a combination of HIV and SIV (simian immunodeficiency virus). This virus was created for vaccine studies, a virus which could infect monkeys and cause illness quickly. (HIV itself will not infect most primates; and when it does, it usually does not cause illness. SIV does cause illness in some monkeys, but that usually takes years -- which would greatly slow the research.)

Eight animals were infected with SHIV229, and six were used for a small controlled study. In two to three weeks after infection, the animals' CD4 counts would drop to less than 100. And there was an increase in viral load to about 10 million, independent of the dose of virus which was given.

The six animals had been infected 24 weeks before we started treatment, so they were in end-stage disease. There had been no successful treatment of end-stage disease in any primates. But because we were looking for changes in viral load, we decided to go ahead and see if the drug had an effect.

Three of the six animals received an HE2000 injection daily for ten days, and then went without further treatment until eight weeks after the treatment began. We found only a modest effect on the virus, but the animals were doing quite well. So we decided to try another treatment regimen.

So we gave another 10 daily injections at a higher dose, and studied the animals for 11 weeks without further treatment; at that time the animals started to progress again. But what was important was that they were still alive.

So we went to a third dosing, giving it for ten consecutive days of a month, then repeated that treatment in the following month. At that point the primate center which was conducting the study told us that we had found something that might be very important -- because the animals were still alive when they would not be expected to be. The three control animals which had not received HE2000 had a mean time from infection to death of 193 days; the three which had been treated had lived about 350 days at that time. So it appeared we had found a survival advantage, even though the viral load had not moved in ways seen with other antiretroviral drugs.

So we decided to continue this research as a survival study. We next administered the drug for five days and observed without treatment for 25 days. At that time we lost the most healthy of the three animals to an anesthesia death -- the animals are anesthetized for blood draws, for the safety of the handlers working with them.

We treated the other two out to about 420 days; we had more than doubled their survival time, compared to the untreated controls. Then we stopped treatment to see how rapidly the animals declined. About five weeks later we lost the sickest monkey, who had a viral load of a billion and a CD4 count around 9. The final animal is still alive today, but is beginning to decline. So this experiment is about at an end.

The control animals had wasting syndrome, like that seen in AIDS. The animals which received the HE 2000, because they were in end-stage disease, had also begun to waste before their treatment started. After receiving HE2000, two of them went on to gain weight at a rate which would be expected of their age group. The wasting was halted and reversed in two of the three animals; in the third, the wasting stopped, but there was no increase in weight.

ATN: What is the next step?

Frincke: That study is now being repeated, with nine animals, four in the control arm. Five are receiving HE2000 for five days at a higher dose, about equivalent to the highest human dose planned, according to the surface-area dose calculations. After the five days, the animals are observed for the rest of the month, and then the monthly treatment is repeated. This study also includes extensive analytical work on the mechanisms of action of the drug.


Clinical Trials

Frincke: A phase I/II clinical trial is ongoing in South Africa, and a U.S. trial will begin enrolling patients in the first dose group.

In South Africa the protocol is five sequential days of injections, followed by observation for the remainder of a month. Testing includes viral load, proviral DNA, infectious virus in cells and serum, cytokine levels -- TNF, gamma interferon, and a few others, standard chemistries, and markers for vehicle-related toxicity.

Three doses are being studied in South Africa: 50, 100, and 200 mg. There are 12 volunteers at each dose level. They are treatment naïve; few individuals in that country can afford the treatments used in the U.S. to control the disease.

These patients are often co-infected with another illness, such as malaria, hepatitis B, hepatitis C, or tuberculosis; often they present with one of those at a clinic, and then when they are tested, they are found to also have HIV. Despite the co-infection, they may be able to enter the HE2000 trial.

These volunteers are eligible to receive a second and third monthly administration of HE 2000. At the end of that period, all patients who have received treatment are eligible to continue with the optimum dose, if the medicine is useful to them. So the protocol covers three administrations, but after the protocol closes, we will continue to observe the volunteers, and continue to provide drug.

ATN: Is there a placebo in this trial?

Frincke: No, everyone receives HE2000. There may be a placebo later in a phase II/III trial.

ATN: How is the U.S. trial different?

Frincke: In the U.S., the patient population that the FDA allowed is those who are failing their second HAART [highly active antiretroviral therapy] treatment, and have few viable treatment options. The FDA and the ethics committees felt that ethically these patients could be studied [while others who did have good options should use the approved treatments instead].

Because the U.S. volunteers will be further along in their disease and usually sicker than those in South Africa, we are starting with a lower 25 mg. dose; so there will be four doses, 25, 50, 100, and 200 mg, given for five sequential days, with an observation period for 30 days. In the U.S., the current protocol has only one treatment cycle. We will submit another protocol to the FDA to permit additional cycles if patients show a benefit with HE2000.

We are requiring a CD4 count greater than 100; this might be important as it is possible that there is an immune component in the action of the compound, and we want to make sure that the patients have enough immune potential so that we would not miss such an effect if it exists. Later, in a different study, we will test with volunteers who have a CD4 count less than 100.

We are also requiring a viral load between 5,000 and 250,000 copies, so that we can measure changes. And the patients' viral loads need to be stable, not moving drastically.

Exclusion criteria, both in the U.S. and South Africa, include G6PDH deficiency, any active serious infection, or current use of anabolic steroids, testosterone, DHEA, hydroxyurea or other metabolic inhibitors, or chemotherapy for malignant conditions. Volunteers must be at least 18 years of age, and have liver-function and certain other blood tests within normal range.


Comment

At this time the main evidence supporting HE2000 is from three monkeys. Why do we devote much space to a drug so early in development? There are three reasons:

  1. The monkey survival data is credible, and hard to explain away. And there is a good chance it will apply to people, although it might not.

  2. While HE2000 is not DHEA, and may have very different effects, the two are chemically related. We are glad to see more research attention in this area.

  3. When facing uncertainty, a useful way to judge a course of action is to compare the consequences of being right vs. the consequences of being wrong. If HE2000 does work as very early data suggests it might, it would be a fundamentally new drug suitable for use worldwide, with a survival benefit, little toxicity, little manufacturing difficulty, and no need for use every day. Also, it would establish a new mechanism of action, opening additional opportunities for medical research and drug development.

If HE2000 does not work, the down side would be the same as for the failure of any experimental medication -- the inevitable risks of human research with a new drug.


References

(1) Frincke J, Ahlem C, Anderson D, Beck T, Agy M, Moton B, and Prendergast P. Treatment of SHIV229 in pigtailed macaques with HE2000. ICAR (12th International Conference on Antiviral Research), March 24, 1999, Jerusalem, Israel [late breaker abstract].



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Salvage Therapy Workshop in Toronto: Reports on Web


Reports on selected highlights from the Second International Workshop on Salvage Therapy for HIV, Toronto, May 19-21, 1999, can be found at:

www.HIVandHepatitis.com (look under 'Features'), and at: www.natap.org/52699.html.



Threat to Compounding of Topical Testosterone, Other Pharmaceuticals

FDA Proposes Limit on Interstate Shipment

by John S. James


"Compounding" means that a pharmacist or physician custom-mixes a drug according to an order from a physician, instead of dispensing medication which has been mass produced. Originally most prescriptions were filled by compounding; today, few are. AIDS Treatment News twice noted the availability of compounded drugs: DHEA in 1996, before it was widely sold in the U.S., and testosterone last year during a supply shortage of the approved generic injectable forms, since topical cream and gel formulations remained available at little cost from compounding pharmacies, and may be more suitable than testosterone injections or patches for some patients.

The FDA Modernization Act, the reform law currently in effect, requires the FDA to draft a "memorandum of understanding" (MOU) on compounding, to be signed by each state; the purpose of this section seems to be to impose more uniform regulation of compounding by the states. The current controversy concerns a provision of the FDA's draft MOU that would prevent a pharmacy or physician from filling more than 20% of its compounded prescriptions out of state. This provision will make it difficult for some patients to obtain the medicine their doctor recommends.

Apparently the FDA is concerned about how to draw a line between compounding and manufacturing (which is subject to higher regulatory standards of quality control). The fear seems to be that some pharmacies could use the compounding exception, which was "grandfathered" into current practice years ago, to set up manufacturing not subject to all of the usual safeguards. The limit on out-of-state shipments seems designed to choke the compounding industry and keep it small.

We are concerned that this limit may be both unnecessary and harmful. Compounding is unlikely to encroach significantly on drug manufacturing, since there is seldom an incentive to compound drugs unless they are otherwise unavailable. And the arbitrary limit proposed will impact patients directly, since it only works by blocking them from obtaining treatments their physicians want them to have.

For background, see the FDA's Web page on this issue, http://www.fda.gov/cder/pharmcomp/. Note the link to the "Draft MOU"; also note the link to Section 127 of the FDA Modernization Act. Also see the Women's International Pharmacy site, www.wipws.com, which includes suggestions on how to oppose the out-of-state prescription limits.

AIDS Treatment News submitted the following letter to the FDA last week. We did not learn about the issue until shortly before the public comment period closed on May 31.

* * *

Dockets Management Branch (HFA-305)
Food and Drug Administration
5630 Fishers Lane, rm. 1061
Rockville, Maryland 20852

Re: Docket No. 98N-1265

The 12/23/98 Draft Memorandum of Understanding on Interstate Distribution of Compounded Drug Products, in its current form, threatens access to important medications for some persons with AIDS and other illnesses.

Last November AIDS Treatment News investigated a serious shortage of FDA-approved injectable testosterone, apparently the unintended result of an FDA enforcement action against a manufacturer (see "U.S. Testosterone Shortage: Call for Information," AIDS Treatment News #306, and "Testosterone Cream and Gel Available; Prices Vary Widely," Issue #307). Many patients and physicians were unable to obtain the products they had been using, or a suitable equivalent. As one alternative, we investigated compounded testosterone cream or gel for topical use. We found a more than 10-fold difference in price, and fortunately were able to locate a reliable compounding pharmacy which could supply these products for $20 per month.

The 20% ceiling on out-of-state shipment of a compounded drug (in the 12/23/98 Memorandum of Understanding) is likely to make reliable products much harder to obtain. This figure is not included in legislation, and was apparently picked arbitrarily. It will mean that patients will rely on less experienced compounders, or will need to travel to other states to obtain their medication.

A "memorandum of understanding with the FDA that addresses the interstate distribution of inordinate amounts of compounded drug products" does not require an arbitrary ceiling or other provisions which will make it difficult for patients to obtain necessary care.

Sincerely yours,
John S. James Editor and publisher,
AIDS Treatment News



Panama: Modern Antiretroviral Treatment Will Be Available


About 1,500 people in Panama will now potentially have access to triple antiretroviral therapy under a decision made earlier this month by the Panamanian national health service. Panama and Costa Rica now provide modern HIV treatment; the other Central American nations do not. Orlando Quintero, a physician in Panama living with AIDS, led the efforts for treatment access for the last 15 months.

The decision followed a week of major protests, legal action, and growing public awareness and support.

For more information contact treatment activist Richard Stern, rastern@sol.racsa.co.cr, who works extensively on access issues in Central America.



AEGIS Nominated to UNESCO "Memory of the World"


On May 26 the online AIDS database AEGIS (AIDS Education Global Information Service), www.aegis.com, was nominated to the United Nations Educational, Scientific, and Cultural Organization's "Memory of the World Programme"; UNESCO created this program to encourage the preservation of valuable archives and library holdings throughout the world. AEGIS, build since 1990 by Sister Mary Elizabeth of the Sisters of St. Elizabeth of Hungary, is the largest AIDS database in the world. The nomination can be viewed on the UNESCO site at: www.unesco.org/webworld/mdm/1999/index.html.



ISSN # 1052-4207

Copyright 1999 by John S. James. Permission granted for noncommercial reproduction, provided that our address and phone number are included if more than short quotations are used.




  
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