Research Initiative Treatment Action (RITA!); Vol 5, No. 3 July 1999
L. Joel Martinez
Table of Contents
Understanding the dynamics of HIV infection
Presenter: Alan Perelson, PhD
Los Alamos National Laboratories
"We made models where we assumed the therapy was a hundred percent effective. Those models were very idealized."
Three scientists are responsible for the current handle on HIV's in vivo behavior. David Ho, MD, George Shaw, MD, and Alan Perelson, PhD, set aside the prior, erroneous understanding of HIV as a latent virus that became active only after years of infection and replaced it with an appreciation for the relentless rounds of replication that HIV undertakes.
In one of the most erudite presentations of the Conference, Perelson reviewed current concepts in the pathogenesis of HIV infection—concepts that he was one of the first to recognize.
HIV replication is an active, dynamic process that begins with primary infection and lasts, unless interrupted by antiviral therapy, throughout the natural history of the disease. In the months following acute infection, an in vivo equilibrium emerges in which the rate of viral production is roughly equivalent to the rate of viral clearance. This "set point" of viral load, Perelson reported, is heavily influenced by CD8 cytotoxic cells and predictive of time of AIDS. Infected individuals who mount a robust anti-HIV CD8 response will have a lower set point and long interval to AIDS. Those without a vigorous CD8 answer for HIV will have a higher set point and more rapid disease progression.
Productively infected CD4 cells account for 99% of plasma viremia, with long-lived cell populations, such as macrophages, contributing approximately 1%. Plasma virions have an average life span of six hours or less, and an average generation time of 2.6 days. (Generation time is the time it takes for a virion to infect a new cell and for the cell to release more virus into plasma.)
Perelson related the unhappy news, also reported by other Conference presenters, that HIV infection is not eradicated with the use of drugs now available; moreover, he noted that replication persists in some patients, despite maximally suppressive highly active antiretroviral therapy (HAART). Fortunately, this ongoing, low-level replication does not appear to convey drug resistance.
Perelson and Ho, in a mathematical model first published in 1996, had estimated that HIV infection might be eradicated in approximately three years using HAART. That model turned out to be wrong, but it induced people to think seriously about the possibility of curing HIV.
Shortly after his presentation, Perelson returned to his laboratory in Los Alamos, New Mexico. Considering the significance of his work, there is little time to rest.
The use of anti-HIV therapies
Presenter: Martin Markowitz, MD
Aaron Diamond AIDS Research Center
"So the bottom line is, we need new drugs."
Known and respected among those living with HIV for his work on viral eradication, Martin Markowitz, MD, departed from that topic to lecture on the use of antiretroviral therapies. In a moment of false modesty Markowitz pronounced himself not suited to such a presentation (personal communication). But as one of the foremost HIV-treating clinicians in the nation, he is especially qualified to speak on disease management.
He reviewed data showing the clinical value of antiviral therapy. ABT 247, for example, a study of ritonavir (Norvir), demonstrated dramatic reductions in the rate of opportunistic infections and death among patients receiving the drug compared to those who did not. In Merck 035, a trial of indinavir (Crixivan), approximately 80% of subjects taking that protease inhibitor still had unquantifiable viral loads three years after the study started.
Other trials, such as INCAS, show therapy is most impervious in patients who achieve viral loads of less than 50 copies, and that viral load nadir after three months of treatment predicts durability of response.
In a review of data from studies of genotypic resistance testing, Markowitz noted that these assays can tell the clinician what drugs not to use. But resistance testing fails to detect minor viral variants. If those variants are drug-resistant, the assay may report falsely that a patient is drug sensitive. "We need good studies to show us whether or not we can actually use these tests to switch [therapies]," he said.
What to do for patients experienced with antiviral drugs and in need of a new regimen? Markowitz termed the results from studies of second and third-line combinations "depressing." For example, in CNA2007, a study of abacavir (Ziagen), amprenavir (Agenerase) and efavirenz (Sustiva), among patients with a baseline viral load of greater than 40,000 copies who had prior experience with a non-nucleoside reverse transcriptase inhibitor, only 7% achieved unquantifiable viral loads at week 16. "So the bottom line," he said, "is that we need new drugs."
What about hydroxyurea, the anti-cancer drug made famous by the so-called "Berlin patient?" "Your guess is as good as mine. I can't figure out whether or not it really has a place in salvage or whether it is truly a drug that should be used early on."
Markowitz closed his talk with a review of "hopeful, encouraging data" about the ability of antiviral therapies to restore immune function. Citing a study presented at the Retrovirus Conference by a group of Spanish researchers, he noted that no case of PCP occurred in a group of 171 patients who first responded to highly active antiretroviral therapy (HAART) and then discontinued PCP prophylaxis.
"The increase," he said, "in CD4 cell count associated with antiretroviral therapy is not cosmetic."
For more information: www.healthcg.com
Interactions involving drugs used in the treatment of HIV/AIDS
Presenter: Charles Flexner, MD
Johns Hopkins Hospital
"Keep up!"
The subject of drug interactions can at times seem overwhelming, but more recently the field seems to be "spinning out of control," according to Charles Flexner, MD. With the exponential growth of anti-HIV drugs—14 approved drugs and two due to be approved before the next millenium-the lives of physicians and patients have reached new levels of complexity. More drugs mean more drug interactions. "That is a given," according to Flexner.
And as if that were not enough, the problem of drug interactions does not start and stop at the pharmacy. Flexner cites the online availability of sildenafil (Viagra) -with little or no physician supervision. This anti-impotency drug shares metabolic pathways with ritonavir (Norvir), nelfinavir (Viracept) and delavirdine (Rescriptor). Coadministration with one of these drugs can result in an increase in the concentrations of sildenafil and an increased risk of cardiovascular side effects.
Even with drugs prescribed at the pharmacy and with physician supervision combining drugs involve some risk as more and more deleterious interactions are identified. For example, nevirapine (Viramune) has recently found to lower the concentration of methadone to such an extent that patients have suffered opiate withdrawal symptoms when the two drugs were administered simultaneously. Similarly, the concentration of oral meperidine (Demerol) has been found to substantially decrease when the drug is coadministered with ritonavir. The effects on intravenous meperidine by ritonavir, on the other hand, are not known.
Despite the deluge of new information, Flexner warns against overplaying drug interactions. He cites three examples of studies that seem to have the interactions field spinning out of control. The first is a study of the coadministration of indinavir (Crixivan) and omeprazole (Prilosec), an anti-ulcer medication. Some of these study patients were found to have higher than normal levels of indivanir; others were found to have lower than normal concentrations. One patient was found to have normal levels of indinavir. Based on an analysis from a single draw of blood the researchers recommended an increase in the dose of indinavir. Adjusting the dose of a critical component of an antiretroviral therapy regimen based on such thin evidence seemed imprecise and careless, to this presenter.
A second study of this same interaction found large variability in indinavir levels and concluded that physicians should "monitor indinavir levels closely." Flexner asked pointedly, "Monitor them for what?" Other studies have shown that indinavir without any other drug affecting its concentration, has great variability of concentration all its own. "Recommendations based on little or no data should be suspect," he adds.
The third example of the field spinning out of control is more complex, involving the interaction of adefovir (Preveon) and delavirdine. Since adefovir is renally cleared and delavirdine is metabolized in the liver there is no reason to expect to find an interaction between these two drugs. In a recent study, however, it was noted that coadministration of adefovir and delavirdine resulted in a 33 to 44% decrease in concentrations of delavirdine. What then is the mechanism for such an interaction? Flexner posits that this interaction may involve a cellular component called P-glycoprotein (P-gp). Simply stated, P-gp is a cellular pump that clears drugs from cells. Adefovir is a P-gp substrate and possibly an inducer of P-gp. As such, it theoretically could be clearing delavirdine and reducing its concentration. The role of P-gp is perhaps too complex to be clinically relevant, according to Flexner. P-gp is expressed in many different cells with different levels of expression. In addition, at least eight other drug transporters have been identified.
Drug interactions have a positive potential. Flexner ended by listing the potential pharmacokinetic advantages that can be derived from combining some protease inhibitors. The right combination of protease inhibitors can result in increased trough levels, decreased peaks and decreased variability leading to more predictable and manageable drug levels. He cites as an example the combination of ritonavir and indinavir—a combination that produces all of the above results and eliminates indinavir's food effect.
Flexner's final recommendations were as follow. Keep up. Discriminate between the statistically and clinically significant interactions-not all interactions have clinical implications. Be cautious in adjusting doses of antiretroviral therapies and when possible, minimize polypharmacy.
The last of these is easier said than done, according to Flexner.
For drug interaction calculator and scheduler: www.medscape.com
HIV disease in children
Presenter: Mark Kline, MD
Baylor College of Medicine
"The new therapies have had an enormous impact in restoring children to health and in prolonging their lives."
Mark Kline, MD, reported statistics from the World Health Organization showing 590,000 new cases of pediatric HIV worldwide in 1997, equaling 1,600 new cases of HIV infection in children every day. Transmission from mother to child, commonly referred to as vertical transmission, accounts for 95% of these infections, with the remaining 5% being attributable to transfusion.
In the case of vertical transmission, a child can become HIV-infected at three points: in the womb, during delivery or after birth usually through breast feeding. A recent study confirmed that breast feeding doubles the risk of transmission. The World Health Organization recommends avoiding breast feeding if there is suitable alternative to breast milk.
Clinical trials have shown that vertical transmission can be reduced approximately 66% with the use of zidovudine (Retrovir). Generally, zidovudine is given using a three pronged approach: first zidovudine is given orally to the mother; intravenous infusion of zidovudine is subsequently given during labor and delivery; and finally, a six-week course of the drug is given to the infant. By following this protocol, transmission rates drop from approximately 25% to 8.3%. In Houston, the number of infants testing HIV positive dropped from 20% in 1994 to about 2% today.
Kline stressed that an HIV-infected infant cannot be recognized by physical examination. All infants born to an HIV-infected mother test positive to HIV antibodies at birth. Therefore, a true diagnosis of HIV infection must employ either a DNA polymerase chain reaction test or an HIV culture.
As with adults, Pneumocystis carinii pneumonia is the most common AIDS-defining illness in children. In other respects pediatric HIV is different. Common opportunistic infections in children include lymphoid interstitial pneumonitis, bacteremia and septic arthritis. Wasting, failure to thrive and encephalopathy continue to plague children with HIV, with many experiencing severe developmental delay and loss of cognitive milestones.
The National Institutes of Health recommends initiating therapy for all infants infected with HIV. This recommendation is based on the inability to predict an infant's rate of progression. Past infancy, therapy is indicated for any child with symptomatic HIV or with evidence of immunological compromise.
There is debate about the initiation of therapy in older children with stable CD4 T cell counts and low viral loads. Some doctors suggest "watchful waiting." Others feel this is risky and cite a study showing that even children with the lowest viral load (under 10,000 copies) and a stable CD4 T cell count experience a 25% risk of death over three years. This study was done largely before the advent of highly active antiretroviral therapy (HAART), but results have been confirmed in subsequent studies.
The treatment of children is similar to the treatment of adults. Children generally start with two nucleoside analogs combined with a protease inhibitor. The use of protease inhibitors in children has been problematic because many are only available as pills. Only three protease inhibitors are available for children too young to swallow pills. Ritonavir (Norvir) is produced in a liquid, nelfinavir (Viracept) is provided in a powder and amprenavir (Agenerase) has a liquid formula. Children and adults experience the same barriers in treatment with failure resulting primarily from nonadherence, toxicity and viral resistance.
Kline concluded by discussing options for children who have failed current therapies. Ideally, doctors would begin a whole new drug regimen, but for children, as for adults, the ability to create whole new regimens is limited. Ongoing studies are exploring the use of dual protease inhibitors and megadosing of antivirals, as well as investigating the effects of hydroxyurea (Hydrea) in children. Many strides have been made to improve the life span and quality of life in children living with HIV in this country. Challenges await children who need third-line therapy and for those in other countries who have minimal access to treatment.
For more information: www.bayloraids.org
Immune based therapies
Presenter: Brenda Lein
Project Inform
"Thus far, antiviral approaches do not appear to result in immune restoration for many people."
Viral load, viral mutations, antiviral therapy, viral reservoirs, etc.—the field of HIV/AIDS is replete with concepts and concerns regarding the human immunodeficiency virus. Yet, as Brenda Lein is quick to point out, "AIDS is a disease of primary immune deficiency caused by a virus." The goal of much research has been to find a way to stop HIV. Indeed, Lein readily admits, antiviral therapies are the most potent immune based therapies. Immune markers have been improved, the overactivation of the immune system has been dampened and the incidence of opportunistic infections and death has declined—all indicators that the antiviral strategy has had some success.
Why then is it necessary to pursue other strategies aimed at augmenting or improving the immune system? Simply because, Lein remarks, antiviral strategies have limitations. With the exception of a few individuals who have been treated within days of being infected with HIV, most individuals are unable to preserve a complete repertoire of immune responses. Inevitably some immune function is lost, even in those treated at a time when they have greater than 500 CD4 T cells. In addition, it is becoming clear that eradication of the virus will not be accomplished with antivirals alone and that these drugs may have time-limiting side effects. Finally, there are individuals with declining health status or advanced disease despite these potent antivirals.
Immune based therapies generally fall into one of four categories: improving the environment where cells are produced and mature; increasing the immune cell numbers; protecting newly produced cells; and augmenting immune function by replenishment and maintenance of the repertoire of immune cells.
Aside from the complementary therapies such as good nutrition, exercise, etc. that enhance immunity generally, pharmaceutical and scientific approaches have made some headway into exploring this area of medicine. Research into the role of the thymus in HIV disease has recently determined that persons fighting HIV have detectable thymus masses. It has been thought that damage to the thymus of HIV-infected persons might prevent the creation of new immune fighting cells. Thymic transplantation has been done in HIV-infected individuals, with varied and unclear results. Lein suggests that thymic hormones, which have been previously studied in HIV, might be worth another look in the era of highly active antiretroviral therapy.
Interleukin-2 (IL-2), a potent stimulator of CD4 T cell reproduction, is finally starting phase III efficacy studies. Two of these studies will be conducted in Houston. The studies will help determine if the CD4 T cells that are produced through the administration of IL-2 are functional and whether they augment the immune response.
Studies using immunosuppressive approaches are being undertaken to see if HIV can be eliminated in certain tissues and as a way of dampening what appears to be an overactive immune system. Oncologists treating HIV-infected patients for cancers have incidentally noted that the types of cytoablative (cell killing) therapies used for treating cancer can have beneficial results in HIV disease. This is a new era of study in HIV.
Other strategies for augmenting cells are also under consideration. Granulocyte macrophage colony stimulating factor (sargramostim), interleukin-12 and WF10 are among the compounds being studied for augmenting the function of macrophages, a critical type of immune cell. Finally, scientists have begun to work to find ways to modify cells to make them resistant to HIV and then reintroduce them into an infected person.
It seems that the incomplete success of antivirals has led the scientific and medical community to revisit with renewed interest this critical area of immune based therapies.
For more information regarding IL-2 trials in Houston: Stephen Garcia, RN, 713.500.6751
Sargramostim: an ivestigational agent for the prevention of opportunistic infections
Presenter: Mark Gilbert, MD
Immunex Corporation
"Efforts to augment immune function are the next frontier in AIDS research."
Opportunistic infections and malignancies, and not HIV itself, are the true killers of people with AIDS. Although antiretroviral therapies have produced sharp reductions in the number of clinical events among people living with the virus, disease progression still occurs. Efforts to augment immune function are the next frontier in AIDS research.
Mark Gilbert, MD, of Immune Corporation reported on his company's study of granulocyte macrophage colony stimulating factor (GM-CSF), also known as sargramostim (brand name Leukine). He began by noting the similarities between oncology, where GM-CSF is already used, and HIV. Both cancer and HIV infection are settings of immune suppression, and both are notable for the presence of a "foreign" agent, namely malignant cells or a virus.
In adapting biologics for use in the treatment of HIV, what approaches are relevant? Gilbert noted four:
GM-CSF may be useful for most of these approaches. By blocking the co-receptor used by HIV for cell entry, GM-CSF can prevent cell destruction. As a growth factor, GM-CSF stimulates production of neutrophils and macrophages, promoting cell renewal; it also increases both the number and activity of dendritic cells, which play an important role in presenting antigens to T cells. Finally, GM-CSF is known to penetrate the central nervous system, and may have activity in that site.
By way of reviewing clinical data on GM-CSF for the treatment of HIV infections, Gilbert noted two trials. In these studies, patients who received GM-CSF had viral load decreases of between 0.5 log and 0.75 and concomitant rises in T cell count. Patients given placebo had a viral load reduction of only 0.01 log.
At the time of Gilbert's presentation, data from the company's phase III study of GM-CSF were still embargoed. The company has since made those data public, which again show that GM-CSF produces statistically significant reductions in viral load compared to placebo. The data also show that time to antiretroviral treatment failure is delayed in patients receiving the immune modulator.
For more information: www.immunex.com
Pentafuside (T-20): a novel investigational treatment for HIV infection
Presenter: Alex Dusek
Trimeris, Inc.
"Fusion is a viable target."
Presenter Alex Dusek, PhD, began his presentation with a simple statement, "T-20 is the first of a class of anti-HIV drugs called fusion inhibitors." Simple though that sentence may sound, Dusek was announcing the introduction of a possible new type of AIDS drug—a drug with a different mechanism of action. For many in the affected community who had long seen the limited utility of targeting the same two targets—reverse transcriptase and protease—the news of a drug with a new target was a welcome relief.
Because of the novelty of its action pentafuside (T-20) has been anticipated for quite some time in the hopes that its activity will augment the actions of nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors. Unlike the members of these classes of drugs that must perform their inhibition intracellularly, fusion inhibitors work outside the cell. Pentafuside's mechanism of action involves interfering with a conformational change that glycoprotein 41 must make before the virus can fuse with the target cell. (See "Interfering with Greg Louganis, Your Sister's Bobby Pins and Glycoprotein 41," RITA!, 5:2, p.11, April 1999.)
Dusek reported on the earliest trial of pentafuside that found that the drug had activity against HIV and was safe. The second trial of the drug tackled the problem of how best to administer the drug. Since pentafuside is a large peptide, oral administration is not possible. The stomach would see the peptide as food and proceed to break it down. This second study, which involved 78 patients, was designed in part to determine if the drug could be administered by subcutaneous injection or if continuous infusion with a small pump would be required.
Pentafuside was given for 28 days as monotherapy or with a backdrop of stable antiretroviral therapy. One group received pentafuside by continuous infusion by a pump; another set of patients administered pentafuside by subcutaneous injection. There was no limitation on the number of prior antiretrovirals taken and participants had to have a viral load of at least 5,000 copies. The average number of antiretroviral that the participants had taken prior to starting the trial was nine and the median number of failed protease inhibitors was 3 per patient.
The pharmacokinetics of pentafuside indicated that subcutaneous injections given every 12 hours were sufficient to maintain drug levels above the therapeutic threshold. Greater than one log drops in viral load were seen in both the 100 and 50 mg twice a day doses, with better results seen in the 100 mg twice a day dose. There were no discontinuations of the drug due to severe adverse events.
Resistance in this group of patients may be evidenced by a trend toward baseline. Three mutations have been associated with the use of pentafuside. According to Dusek, developing two of these mutations is sufficient to confer significant resistance. Trimeris has begun working on a second-generation fusion inhibitor, T-1249, which is expected to work against pentafuside resistant virus.
Dusek pointed out a single patient observation where a patient has been on 50 mg twice a day of pentafuside for over 30 weeks, adding nevirapine (Viramune), nelfinavir (Viracept) and saquinavir (Fortovase) and achieving a 2.5 log drop in viral load and an increase of 380 CD4 T cells. At the time of the presentation, the patient had rolled over to the study of pentafuside, abacavir (Ziagen), amprenavir (Agenerase) and efavirenz (Sustiva).
It appears that these inhibitors, like other antiretrovirals, will work best when used in combination with other drugs.
For more information: www.trimeris.com
Recent progress in the clearing of the HIV reservoirs
Presenter: Robert Siliciano, MD
Johns Hopkins Hospital
"It doesn't mean that current therapies are not effective. It doesn't mean that HIV can't be cured. It doesn't mean patients are going to eventually fail therapy."
Robert Siliciano, MD, began with a warning. The news, he said, "was a bit depressing." Indeed, despite the success of highly active antiretroviral therapy (HAART)—its ability to suppress HIV to levels that are unquantifiable—the sobering news Siliciano brought to this conference was that a small pool of virus may persist and that this viral reservoir may be stable and not diminishing.
Why is this news depressing? Earlier, scientists had speculated that eradication of HIV would be a matter of stopping viral replication and waiting for chronically infected cells to die out. An initial steep decay in viral replication would be followed by a slower decay and then eradication of all virus would be complete. One problem, Siliciano points out, is the existence of a pool of latently infected resting CD4 T cells in which the virus persistmdash;a pool which seems to persist for longer than anyone anticipated.
Activated CD4 T cellsmdash;those cells that have encountered their antigen and have begun their immunologic fightmdash;are a primary target of HIV. Once infected most cells either begin to produce HIV and eventually die either through the cell-killing properties of HIV or as a result of the immune system's recognition that they are infected cells. A few cells become activated and infected but then return to a resting state. These cells are referred to as "memory" cells and their function is to persist and recognize the invader if it ever should present itself again.
The problem lies in the fact that HIV has integrated itself into the DNA of these memory cells and lies in wait, undetected by the immune system and unaffected by HAART. By their very nature memory cells are intended to persist for a very long time. Siliciano cites the example of a child infected with the measles virus at a young age still being protected 60 years later. The long persistence of these HIV-infected memory cells becomes a major stumbling block for eradication. These cells, once reactivated, start to produce HIV again.
The question then becomes does this pool of memory cells decay when a patient is able to suppress viral replication to unquantifiable levels with combination therapy? If the pool does decay, at what rate does it do so? Siliciano summarized results of a study in which thirty-four patients who had been on combination therapy and had had unquantifiable viral load for 2 to 2.5 years. In this study, scientists were able to isolate and measure over a period of time the number of latently infected resting CD4 T cells with replication-competent HIV. The participants were heterogeneous with respect to age, sex, risk factor, different regimens and stage of disease. As a result, Siliciano posits, they were representative of the diversity of the AIDS epidemic.
Siliciano was able to find evidence of a viral reservoir of replication competent CD4 T cells in all but two of the 34 participants. Using a series of measurements this researcher estimates the size of the reservoir at between 1,000,000 to 100,000 cells. The rate of decay was found to be extremely slow, with slopes in most cases approximating zero. The half-life of the cells was found to be approximately 43 months. With these measurements Siliciano estimates that if the reservoir consists of 1,000,000 cells, it would take 70 years of effective combination therapy to eliminate this reservoir. If the reservoir consists of only one hundred thousand cells, it would take 60 years for complete decay.
Other scientists have estimated that the half-life of memory cells to be 5 to 6 months. Why then is this pool of latently infected memory cells so much more persistent? The body, according to this speaker, has established a homeostatic mechanism for maintaining immunologic memory and it may be that HIV has found a way to tap into this mechanism and maintain itself. This pool of latently infected cells may be renewed by occasional proliferation of the infected cells or by entry of new cells into the reservoir or as a result of low levels of ongoing viral replication.
Do the results mean the end of the dream of eradication? Siliciano indicates there may be ways to induce and purge this latent reservoir of cells. He cites the study of interleukin-2 as a possible way of purging the reservoir. He ended his talk by pointing out that eradication may not be necessary at all if researchers can figure out a way to train the immune system to contain the virus. He cites the now famous example of the Berlin patient as an encouraging sign that the total elimination of viral reservoir may not be the ultimate and only goal of controlling HIV/AIDS.
For more information: www.hopkins-aids.edu
Ethics: advertising, access and research
Presenter: Mark Harrington
Treatment Action Group
"Marketing drives research."
In the most humor-filled presentation of the Conference, Mark Harrington, senior policy director for Treatment Action Group (TAG) and a MacArthur Fellow, addressed the ethical implications of HIV research, pharmaceutical advertising and access to experimental drugs.
He began by noting that the pharmaceutical industry is the stronger partner in the "strange symbiosis" that exists between HIV-infected patients, community service organizations and treatment advocates. Patients need the industry's drugs and community-based groups need its money. For example, last year TAG received $180,000mdash;30% of its budgetmdash;from pharmaceutical companies.
Harrington identified the multiplemdash;and successfulmdash;methods of direct to consumer marketing used by industry, including billboards, bus shelter displays and glossy advertisements. Indeed, he suggested that some of the publications aimed at people living with HIV, including POZ, Arts and Understanding and Out, emerged, at least in part, in response to the industry's need for additional advertising outlets.
In a recent issue of POZ, for example, 85% of the advertisements were for antivirals, drugs for wasting or viatical settlement companies, which, Harrington remarked wryly, reflects the natural progression of the disease.
He cited three ethically suspect ads for HIV drugs: Roche's "strategy ad" for the now defunct Invirase brand saquinavir, which promoted a suboptimal protease inhibitor (PI) that failed to suppress viral load adequately and also promoted cross-resistance to other PIs; Bristol-Myers Squibb's campaign to promote stavudine (Zerit) by capitalizing on the distrust of zidovudine (Retrovir) among African Americans; and GlaxoWellcome's misuse of its partnership with the National Minority AIDS Council by turning a generic "Be Smart About HIV" campaign into a campaign for Combivir.
Beyond advertising, industry has also allowed its marketing needs to take precedence in research over the need for new agents and better clinical information. Harrington noted that drug company studies have not answered the questions of when to start therapy or what combinations work best.
In view of the industry's enormous power, what can activists and community-based organizations (CBOs) do to ensure their own ethical integrity? Harrington had several suggestions:
For more information: www.aidsinfonyc.org/tag
Immune reconstitution in the era of highly active antiretroviral therapy
Presenter: Fred Valentine, MD
New York University School of Medicine
"It's very clear that with potent antiretroviral therapy that many, many folks are doing better."
Fred Valentine, MD, of New York University School of Medicine, discussed immune reconstitution, one of the most gratifying results of highly active antiretroviral therapy (HAART). He noted, however, that full immune restoration would include effective responses against HIV itselfmdash;something not yet seen, but the focus of current research.
Generally, the immune system either eliminates a viral infection or at the very least contains it. With HIV, that is not the case. The goal of our efforts, Valentine suggested, should therefore be to turn HIV into a "conventional viral disease." But how?
Valentine began by reviewing what is known about immune reconstitution in the era of HAART. Following the initiation of therapy, T cell counts often rise rapidly. Much of this rise probably reflects a redistribution of cells from the lymph nodes to peripheral circulation, but naive cells do emerge. Valentine also noted that, for some patients, the T cell count remains elevated even after virologic failuremdash;a phenomenon not seen in the prior era of two drug nucleoside treatment.
Of course, number does not equal function. Do these new cells work? Relying on a sports analogy, Valentine remarked that the number of players on the field is not the only factor that decides the outcome of game. How well they play is also important. "The same thing is true if you look at the immune system," he said. In vivo immune function can be measured by a lymphocyte proliferate response assay (LPA), which measures the ability of a cell to divide when encountering the antigen against which the cell is directed.
Following an explanation of the assay itself, Valentine reviewed data on pathogen-specific responses as measured by LPA. In the natural history of HIV infection, lymphocyte proliferative responses to a range of microorganisms are diminished, and an lymphocyte proliferative response to HIV itself is almost always absent. But it is precisely the presence of this response " ... that correlates with the control of most infections." HAART can reconstitute immune reactions to a number of pathogens, but not to HIV itself.
How, then, can we persuade the immune system to treat HIV like any other virus, and either eliminate or at least suppress it? It is plain, Valentine noted, that the immune system does react to HIV; indeed, the detection of antibodies to HIV is how the infection is diagnosed. But the "vast majority" of infected individuals have poor lymphocyte proliferation responses to HIV antigens.
Valentine is a leading investigator of HIV-1 immunogen (Remune), a therapeutic vaccine that may stimulate lymphocytes to react against the virus. His work shows that when given to infected individuals receiving HAART, Remune produces significant lymphocyte proliferation responses to HIV.
A data and safety monitoring board recently halted a phase III study of Remune when it failed to show any reduction in the number of clinical events among patients receiving the vaccine. However, the use of Remune did result in statistically significant reductions in viral load when combined with HAART compared to HAART alone.
Researchers will make the specifics of the data from the phase III study available later this year. If Remune lives up to its promise, it may be the vehicle by which the immune system is enticed to suppress HIV.
For more information: www.imnr.com
Vaccines for the prevention of HIV infection
Presenter: Sam Avrett, MPH
AIDS Vaccine Advocacy Coalition
"The HIV epidemic is not inevitable. We could end this epidemic and there is no better work we could be doing."
Sam Avrett, the director of the AIDS Vaccine Advocacy Coalition (AVAC), presented a general overview of the current status of HIV preventive vaccine development. AVAC, is a national coalition of volunteer advocates that strives to have an independent voice and works to have community imput into current research on HIV preventive vaccines. The coalition's goal is to analyze obstacles to HIV preventive vaccine research and explore and find solutions for overcoming these obstacles.
Avrett began by asking the question, "Do we need an HIV preventive vaccine?" Everyday sixteen thousand new infections occur globally. This year approximately one million more people will be infected with HIV. Currently, prevention efforts rely entirely on behavioral changemdash;safer sex or clean needles. "That is not enoughmdash;we need better, we deserve better," Avrett contends.
According to this presenter a successful HIV vaccine must have the following characteristics. First, it must be safe. To work as an effective protective stratagem the vaccine must be given to millions of people. There will be little, if any chance to test for compromised immunity or existing infection. An HIV vaccine must not lead to further complications or create harm where none exists.
Secondly, a vaccine must be effective. The ideal vaccine would require a single inoculation and provide complete protection against all routes of transmission for a person's lifetime. The reality may be that an HIV preventive vaccine may end up being only partially protective, may require multiple boosts and may work for some people and not for others.
Thirdly, a vaccine should be easy to administrate. It may be possible to replace the traditional injection with oral or nasal administration. Some scientists are exploring the possibility of developing plants that carry the vaccine antigen. In this case it may be possible to vaccinate a person through the consumption of the plant or its fruit.
Finally, a vaccine must be stable. Refrigeration in many parts of the world where an HIV vaccine is needed is an expensive, untenable luxury.
Vaccine technology has changed dramatically. Before the early 1980s and the development of the hepatitis B vaccine, all vaccines were either live-attenuated vaccines or whole-killed vaccines. Today, vaccines are being constructed using recombinant proteins, synthetic peptides, naked DNA and live-recombinant vectors.
Approximately 25 preventive vaccine trials have been tested for safety in people. Four vaccines have progressed to phase II testing for safety and efficacy. Two efficacy trials are currently testing in phase III.
Avrett pressed people to become more involved in vaccine advocacy. In the final analysis he concluded, "Each of us has the same goal: to end the epidemic."
For more information: www.avac.org
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Copyright © 1999 - Research Initiative Treatment Action (RITA!). Reproduced with permission. RITA! is published by The Center for AIDS. Contact Thomas Gegeny, MS, ELS, Editor, RITA! for permission to reproduce RITA!. tom@centerforaids.org. http://www.centerforaids.org
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