AIDS Trestment News
February 12, 1999

From AIDS Treatment News

Retroviruses Conference, Chicago 1999

by John S. James

The 6th Conference on Retroviruses and Opportunistic Infections, January 31 - February 4 in Chicago, is the largest AIDS scientific meeting of 1999 and provided a complex snapshot of the current state of basic and applied medical science of AIDS. Faster progress in understanding the disease is now being made in many areas, suggesting targets for new treatments. There are promising compounds in the pharmaceutical pipeline, and research with existing treatments is generally going well. But there are serious gaps in applying the new biological knowledge to product development, with most of the new drugs being (hopefully) better versions of existing ones; companies are reluctant to invest in basically new approaches. And much confusion remains concerning the lipodystrophy and metabolic problems which may be side effects of some treatments, especially protease inhibitors -- with little agreement yet on the mechanisms of what is happening, what to do about it, or even how to define and describe these problems consistently.

We believe that HIV-specific immunity is the most important single research area emphasized at this conference; see "Restoring HIV-Specific Immunity," below, for a summary of a few of the many presentations. We will look at clinical trials, and other treatment research, in our following issues.

Besides HIV-specific immunity, other important areas include:

Other immunity studies, including measurements of the lifespan of lymphocytes in the body, understanding and measuring immunity to particular opportunistic infections, and predictors of response to therapy for opportunistic infections;
Lipodystrophy and metabolic problems, including work by lipid experts at Glaxo Wellcome who have provided data on possible causes which had not been identified before;
Viral drug resistance, including new evidence of the value of providing these test results, with expert virology advice, to physicians;
New long-term data from large clinical trials -- both for new drugs, and for new combinations of available ones;
Early information on new compounds just entering human trials;
New information on HIV transmission from mother to child, and on shorter drug regimens to help prevent it;
Virology, especially discoveries of new targets for potential drugs.
And many other important oral and poster presentations which do not fit into a major category.

Restoring HIV-Specific Immunity

by John S. James

When HIV is well controlled with antiretroviral drugs, immunity to infections -- other than HIV -- usually starts to return. As a result, some opportunistic infections go away without specific treatment; and sometimes patients can stop prophylactic treatment for certain opportunistic diseases (although today it is often unclear who can stop prophylaxis safely, and who cannot).

But immunity to HIV itself is different. The CD4 T-helper cell response to HIV usually appears to be eliminated very early in HIV infection, and to return very slowly or not at all, even when HIV has been well suppressed for years with antiretrovirals, and other immunities do return. And without this helper response, the HIV-specific CD8 CTLs (cytotoxic T lymphocytes), which appear to be centrally important to the control of the virus during the initial HIV infection (primary HIV disease), seem to lose their ability to respond effectively to chronic HIV infection.

No one knows for sure why HIV is different from other viruses in this way, but it is likely that because HIV specifically targets activated CD4 T-helper cells, it will selectively kill especially those cells which are able to recognize it and respond. And when HIV is not present due to being suppressed by antiretrovirals, the CD4 T-helper cells genetically able to recognize it usually do not respond -- possibly because they were wiped out earlier, or because they were damaged in some way, or simply because they will not encounter HIV antigens, and therefore not become activated and not mobilize normal immune responses.

The potential importance of the body's failure to restore HIV-specific immunity becomes clear when one realizes that long-term nonprogressors -- the small minority of persons who are infected with HIV but naturally maintain a very low viral load, with a high CD4 count and no evidence of disease progression even after many years -- usually do have a CD4 T-helper cell immune response to HIV, while those who progress and become ill invariably do not. If HIV-specific immunity could be restored, might persons who now have HIV disease become long-term nonprogressors, no longer needing any treatment, or perhaps only needing treatment occasionally if their immune system begins to lose control of the virus again? No one knows at this time, since the research is just beginning. But the results so far are promising, and a handful of patients who had been dependent on antiretrovirals have already been able to stop these drugs entirely, sometimes for more than a year, without having the viral-load rebound that almost always happens when patients stop their antiretroviral treatment (and which did happen to these individuals when they first tried discontinuing their antiretrovirals).

Strategies for Restoring HIV-Specific Immunity

Several possible approaches for restoring HIV-specific immunity are now being researched:

Therapeutic vaccination while the virus is well suppressed with antiretrovirals. In one study, first reported last summer at Geneva and with new data last week at the Retroviruses conference, volunteers whose viral load had been effectively suppressed with antiretrovirals were also given a killed-virus immunogen (the Remune^TM therapeutic vaccine, which was developed by the late Dr. Jonas Salk); a control group was given the inactive component of the same vaccine but without the HIV. T-helper responses like those of long-term nonprogressors returned in most of those given the real vaccine -- and in none of the control group (see details below).

It is not known that producing an immune response in this way will have clinical benefit, since the results so far have been only laboratory tests, as none of these volunteers has yet chosen to stop their drugs in order to see whether or not their viral load comes back.

Here is one theory of what may be happening in this case. As a person's CD4 count increases after suppression of HIV by antiretroviral drugs, a few of the cells that make up that count are new, "naive" CD4 T-helper cells released by the thymus (naive T-cells are those which have not yet encountered the particular antigen -- such as a protein from a particular virus or bacterium -- which the cell is genetically programmed to recognize). Of these new naive cells, a small minority are, by chance, programmed to recognize HIV. Without the antiretrovirals, these cells would recognize HIV, become activated as they started to respond to it, but then be destroyed by the virus. With only the antiretrovirals, the cells would be protected from infection, but there would be so little HIV present that they would not encounter it and not create an immune response. Adding the vaccine which is made from killed virus apparently allows these cells to safely develop a normal immune response.

It is also noteworthy that the killed-virus vaccine used in this test is made from a virus from Africa which is not clade B -- the variant of HIV which is common in the U.S. and Europe. Even so, the volunteers in this small trial did develop immune responses to purified HIV p-24 antigen from two different clade B viruses, as well as to the immunogen itself -- indicating that this approach might be able to confer a broad protection against many forms of HIV, not limited only to the particular kind of virus which was used to prepare the therapeutic vaccine.

Incidentally, the developers of Remune -- the Immune Response Corporation, later acquired by Agouron Pharmaceuticals -- prefer to call this product an "immunogen" rather than a "vaccine." It is currently being tested in a large phase III trial, separate from the small 43-person trial presented at the Retroviruses conference; data from the phase III study will be available later this year. Remune has never been tested in an HIV-negative person, as a potential preventive vaccine; some experts believe that it should be tested for this purpose.

Another potential way to preserve HIV-specific immunity is to begin antiretroviral treatment very early, during or shortly after primary HIV infection, with the idea of preserving HIV-specific immune responses, by suppressing the virus before it can destroy the cells that recognize it. At the Retroviruses conference, researchers at the Aaron Diamond AIDS Research Center presented examples of two patients who were treated early (within 3 months of HIV infection), had interruptions of therapy due to poor adherence, but now have been off all antiretroviral therapy for over a year without the virus coming back. However, two other patients in the same cohort who tried going off antiretroviral therapy were unsuccessful -- one had a rapid viral load rebound, and the other controlled the virus for four months but then had a rebound (details below).

Incidentally, this team reported the HIV-specific immune responses in CD8 CTLs (cytotoxic T lymphocytes) instead of in CD4 T-helper cells. (The CD4 cells were also measured and were concurrent with the CD8 cells, but that data was not presented at this conference). In all four patients, the strength of their CTL response was associated with how well they controlled the virus when they discontinued antiretroviral therapy.

Another research team is trying to reproduce the example of "the Berlin patient" -- a widely publicized case in which a patient who formerly required antiretrovirals to keep his viral load under control is now able to do so without drugs, and is currently doing well. The Berlin patient was diagnosed early, and began antiretroviral treatment "before complete seroconversion," about two months after the date of infection; he then had to interrupt this treatment because of other medical problems. Viral load returned immediately, and treatment was restarted; viral load again became undetectable. Later, during a second treatment interruption also due to medical problems, viral load did not return. Treatment was restarted, but then this patient decided to stop antiretrovirals permanently. The virus has not returned now for over 18 months.

Researchers from the Research Institute for Genetic and Human Therapy (RIGHT), of Washington D.C. and Pavia, Italy, noted that this patient (1) began treatment very early in the disease course, (2) was treated with indinavir, ddI, and hydroxyurea (any of the three might or might not have mattered), and (3) interrupted and restarted treatment twice (which might have provided occasions for CD4 T-helper cells to recognize HIV antigens while they were protected by the drugs). Later, three volunteers with undetectable viral load agreed to interrupt their therapy, under a protocol which restarted the drugs when their viral load reached 5,000. None of the three have yet been able to control the virus without the drugs; however, the time to viral rebound is getting longer with each subsequent interruption, indicating recovery of HIV-specific immunity.

HIV-Specific Immunity: Details of Presentations at Retroviruses Conference

The therapeutic vaccination trial outlined above was presented by Fred Valentine, M.D., of New York University.¹ A total of 43 patients were treated with highly active antiretroviral therapy (HAART), and were randomly assigned the Remune immunogen (a vaccine made from killed HIV) or a placebo (in this case the placebo was IFA, which is an adjuvant -- a substance used to make a vaccine work better -- used in the Remune immunogen). The injections were given at weeks 4, 16, and 28. At week 32, the group receiving the immunogen had a much higher CD4 T-helper response to three different HIV antigens, and a higher production of MIP-1-beta in response to HIV antigen; statistical significance for these four measures was very good, from p=0.007 to p=0.0002 (levels reported in the published abstract). Also, there was a trend toward lower viral load, but it did not reach the p=0.05 level usually taken as statistically significant (p=0.29 and p=0.09 in the abstract, p=0.07 currently). Unfortunately recruitment for this study was cut short over a year ago, before its importance was known, due to financial constraints; if the trial had been fully enrolled, it might have already shown statistical significance for viral load reduction. Note also that statistical proof of viral load effect is hard to prove in this case, simply because both groups did so well.

It is important to note that the volunteers in this trial were not treated during or near primary infection, but could have been infected at any time. They were treatment naive and had a median CD4 count of 493 and a median viral load of about 8,000 copies before they began the study -- not because this approach could not be made to work for more advanced patients, but because it made sense to try the first proof-of-principle study in volunteers who had less immune damage and were easier to treat.

It is also important to remember that there is no proof yet that producing HIV-specific immunity will benefit patients -- since it is possible that long-term nonprogressors are able to resist HIV infection through some other mechanism, and that their HIV-specific immune responses are a consequence of that, not the cause of their remaining well. But the information available today does suggest that HIV-specific immunity is centrally important in the control of this virus.

In the Aaron Diamond study of early treatment, treatment discontinuations, and the CD8 CTL response,² all four patients studied had been treated with ritonavir, AZT, and 3TC within 90 days of infection, and viral load went below the level of quantification (500 copies in this study) within two weeks. Both of the patients who were ultimately successful in stopping antiretroviral drugs and controlling the virus did have a viral rebound the first time they stopped, and restarted the drugs as a result. Both were found to have "broad and strong HIV-1 CTL responses that were boosted at the time of first drug discontinuation, which was associated with HIV-RNA rebound"; apparently the viral rebound boosted an already-strong CTL response. Later they were able to stop drug without viral rebound.

Of the other two patients in this study, both stopped treatment more abruptly. One kept the virus at a low level without drugs for several months, but then "CTL responses faded and plasma virus rebounded." The other "had a rapid viral rebound and a low frequency of HIV-specific CTL."

There is concern that this early work may be misinterpreted to justify casual experiments in drug discontinuation; it is widely agreed that experiments with drug discontinuation to boost HIV-specific immunity should only be done in a research setting. These patients, unlike most, started treatment within 90 days of infection. The researchers had access to tests of HIV-specific immune function, which are not available commercially. And only two of the four who stopped therapy were able to control the virus for over a year without treatment.

The study based on the Berlin patient involved deliberate interruption of therapy in three volunteers;³ viral load was monitored and the drugs were restarted when viral load went over 5,000 copies. None of these patients have yet been able to stop drugs permanently without the virus returning; however, the interval before therapy was required increased substantially with each discontinuation.

All three volunteers started with stable viral loads (719,000, 22,665, and 33,707 copies). They began treatment early, but after primary infection. They were treated for three weeks with indinavir, d4T, ddI, and hydroxyurea; viral load went below 400 copies for all three of them, during this first course of treatment. Then the drugs were stopped for one week, followed by two cycles of treatment for three months, followed by interruption and then resumption of treatment when the viral load reached 5,000.

The first time therapy was stopped for 7 days. On the next interruption, it took an average of 14 days for the viral load to reach 5,000. On the third interruption, it took an average of 37 days for the viral load to reach that level. The trial is ongoing.

The researchers believe that the treatment interruptions may have prolonged the time to viral rebound. Also, Dr. Lori, who presented the results at the conference, believes that hydroxyurea may have some immune benefit, as well as enhancing the antiretroviral activity of ddI and some other drugs. The mechanism of any possible immune benefit is not known.

A followup on the Berlin patient was also presented at the Retroviruses conference.⁴

Measuring HIV-Specific CD4 and CTL Activity

Dr. Valentine, who presented the HAART plus Remune experiment, measured the ability of patients' CD4 T-helper cells to respond to HIV; the Aaron Diamond study measured the response to HIV of CD8 CTLs (cytotoxic T lymphocytes), instead of CD4 T-helper cells. What is the contribution of these two kinds of immune cells?

The ultimate answer is unknown, but there is strong evidence that CD8 CTLs are critically important for controlling HIV. It also appears that during primary HIV infection, when the level of virus is very high, CTLs may be able to control the virus with little or no help from the CD4 T-helper cells -- but that this help is essential for mobilizing the CTLs to keep the long-lasting chronic infection under control.

The HIV-specific CD4 T-helper cells (a small minority of the total T-cell count) may be especially important to measure -- and to restore -- because they are highly vulnerable to HIV infection -- which may explain why the HIV-specific T-helper response usually does not come back on its own.

References

1. Valentine F, DeGruttola V, and the Remune 816 Study Team. Immunological and virological evaluations of the effects of HAART compared to HAART plus an inactivated HIV immunogen after 32 weeks. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, January 31 - February 4, 1999 [abstract #346].

2. Ortiz GM, Jin X, Demoitie MA and others. Containment of breakthrough HIV plasma viremia in the absence of antiretroviral drug therapy is associated with a broad and vigorous HIV specific cytotoxic T lymphocyte (CTL) response. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, January 31 - February 4, 1999 [abstract #256].

3. Lori F, Zinn D, and Varga G. Intermittent drug therapy increases the time to HIV rebound in humans and induces the control of SIV after treatment interruption in monkeys. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, January 31 - February 4, 1999 [abstract #LB5].

4. Lisziewicz J, Rosenberg E, Lieberman H and others. Immune control of HIV after suspension of therapy. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, January 31 - February 4, 1999 [abstract #351].

Note: For instructions on how to obtain these abstracts, see "HIV-Specific Immunity: Major Conference Sessions," below.

HIV-Specific Immunity: Major Conference Sessions

"Restoring HIV-Specific Immunity," above, discussed four research presentations at the Retroviruses conference. There were also dozens of other presentations in this area. Here are the main categories most relevant to HIV-specific immunity, and the abstract numbers in each category.

You can read these abstracts on the Web. Go to http://www.retroconference.org/99/abstract.htm, and select 'Conference Abstracts.' Search for 'abstract nnn', where nnn is the abstract number given in the list below: e.g. 'abstract 256', or 'abstract 21' (without the single quotes). You will see the title and authors; click the underlined abstract number to see the full abstract.

Immunologic Reserve and Reconstitution: abstracts 21-30;
HIV Specific Humoral and Cell Mediated Immunity: abstracts 31-38;
Topics in Immunology and Immunopathogenesis: abstracts 51-57B;
Cellular Immunity to HIV, SIV, and HHV-8: abstracts 252-261;
HAART: Effects on Repertoire, Lymphocyte Dynamics, and General Immune Response: abstracts 317-338;
HAART: Reconstitution of HIV-Specific Immunity: abstracts 339-353;
Immune Based and Genetic Therapies: abstracts 354-361;
Immunopathogenesis of Primary HIV Infection: abstracts 553-559;
In the Late Breaker session, abstracts LB 3a, LB 3b, and LB 5. These cannot be searched by abstract number, but can be found by searching for a word or phrase from the title. The titles are:
- Potent and Aberrant CD4 Responses in Lymphoid Tissue (LT) during Primary HIV-1 Infection (PHI);
- Defect in Cytolytic Effector Molecules in Lymphoid Tissue (LT) during Primary HIV-1 Infection (PHI) is a Very Early Mechanism of Immune Dysfunction; and
- Intermittent Drug Therapy Increases the Time to HIV Rebound in Humans and Induces the Control of SIV after Treatment Interruption in Monkeys.

You can also search the abstracts for a word or phrase. However, searching on authors' names is not reliable at this time (since any superscript which appears must be typed as part of the name).

Other Sessions Available by Computer

There is also a half-hour lecture with slides, "T-Cell Immunity During Acute and Chronic Viral Infection," which can be heard and seen in full on the Web, although no abstract was published. At the http://www.retroconference.org Web site, select 'Hear the Lectures', then select this one from the list.

A symposium, Immune Reconstitution and Clinical Implications, consisting of five lectures and slide presentations, can also be heard and viewed at the site. Select 'Hear the Symposia', then select this one, under Thursday, Feb. 4.

Houston, April 30: Eleventh Annual Houston Conference on AIDS in America

Leading treatment experts will address a one-day AIDS meeting focusing on clinical information, in Houston, Texas, on April 30. Judging from previous years, about 2,000 people are expected to attend. Topics and speakers include:

"The Use of Antiretroviral Therapies" by Martin Markowitz, M.D., Aaron Diamond AIDS Research Center;
"Interactions Involving Drugs Used in the Treatment of HIV/AIDS" by Charles Flexner, M.D., Johns Hopkins Hospital;
"HIV Disease in Children" by Mark Kline, M.D., Baylor College of Medicine;
"Immune Based Therapies" by Brenda Lein of Project Immune Restoration at Project Inform;
"Recent Progress in the Clearing of HIV Reservoirs" by Robert Siliciano, M.D., Johns Hopkins Hospital;
"Ethics: Advertising, Access and Research" by Mark Harrington, Treatment Action Group, New York;
"Immune Reconstitution in the Era of Highly Active Antiretroviral Therapy" by Fred Valentine, M.D., New York University School of Medicine; and
"Vaccines for the Prevention of HIV Infection" by Sam Avrett, M.P.H., AIDS Vaccine Advocacy Coalition.

This event is free and open to the public. Continuing medical education credit is available (there is a $25 fee for the credit). The meeting will be held at the George R. Brown Convention Center, Friday April 30, with registration and continental breakfast starting at 7:00 a.m. and the first talk at 8:00 a.m. Advance registration is recommended; call International Meeting Managers Inc. at 713-965-0566.

3rd International Conference on Nutrition and HIV Infection (Focusing on Metabolic Complications)

Cannes, France, April 22-25

The 3rd International Conference on Nutrition and HIV Infection, focusing this year on Metabolic Complications of Antiretroviral Therapy: Clinical Implications, will take place in Cannes, France, April 22-25, 1999. The preliminary program includes the following sessions:

Changing Face of AIDS Wasting;
Longitudinal Nutritional Study on HAART;
Unique Adverse Effects of HAART;
Body Composition: Measurement and Manipulation;
Appetite Regulation;
Lipid Metabolism;
Endocrine Disorders in HIV Infection;
Oxidative Stress and Micronutrients;
From Insulin Sensitivity to Resistance;
Developing Countries and Pediatric AIDS;
Also, there will be a Late Breaker session, and several meetings for discussion of selected abstracts.

The official languages of the conference will be French and English, with simultaneous translation during the plenary sessions, slide sessions, and workshops. Slides and posters will be in English.

Advance registration is recommended, but there will also be on-site registration. For registration, fee, and hotel information, contact:

ECOR
c/o The European Heart House
2035 route des Colles
Les Templiers - BP 179
06903 SOPHIA ANTIPOLIS cedex - FRANCE
Tel. 33 (0) 4 92 94 76 00
Fax 33 (0) 4 92 94 76 01

Or to obtain a copy of the Second Announcement of the meeting, send an email request to: asymptote@hol.fr

International Health: Preparing for the 21st Century

San Francisco, February 27

A one-day conference "to promote scholarship, public awareness, and practical action in the field of international health" will take place Saturday, February 27, 1999, 8:00 a.m. to 5:00 p.m. in San Francisco. This meeting, not focused specifically on AIDS, will address major themes of health, poverty, and development; family planning and reproductive health; and emerging infections and continuing plagues.

Registration is $35 general, $15 student, and $50 exhibitor. For more information, contact Claire Norris, Conference Coordinator, International Health Office, 313 Warren Hall, School of Public Health, University of California, Berkeley, CA 94720-7360; telephone 510-642-6915, fax 510-643-8236, email cnorris@uclink4.berkeley.edu.

Note: Registration deadline is February 19; use the email address to request a copy of the registration form.

ISSN # 1052-4207

This article was provided by AIDS Treatment News.

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AIDS Trestment News February 12, 1999

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