Medical Highlights of the 12th World AIDS Conference
"The essential message of the Geneva meeting is that while much of the developed world is making progress in slowing HIV infection and treating those with HIV disease, enormous regions of the world, that are home to literally billions of people, are being allowed to slip further and further behind," declared Conference chairman, Dr. Bernard Hirschel, head of HIV/AIDS, Cantonel University Hospital, Geneva, Switzerland.
"Millions of people are becoming infected with HIV in the developing world every year -- 10 million since we last met two years ago, with an anticipated figure of 40 million individuals infected by the year 2000."
"There is a great deal of progress to report, however," Dr. Hirschel continued. "Yet in some ways, the enthusiasm which greeted medical progress at the last meeting in Vancouver is tempered by medical and social realities. HIV/AIDS still is one of the most devastating global pandemics of modern times."
"On the positive side," said Dr. Scott Hammer, Beth Israel Deaconess Hospital, Boston, Massachusetts, "advances in antiretroviral therapy are substantial and have been borne out in population-based studies around the world."
This article provides highlights of some of the long-awaited data on new HIV/AIDS therapies, the new vaccine trials, and research demonstrating both longer-term benefits, potential side-effects of antiviral therapy, and methods of combating these complications.
HIV Vaccines Under Active Investigation
Because there is a major need for an effective vaccine, researchers are attempting to move more quickly in pursuit of this elusive goal, pointed out Dr. Hans Wigzell, an investigator at the MTC-Karolinska Institute, Stockholm, Sweden. In this regard, the upcoming VaxGen Thailand and U.S. trials are justified, because nothing can be learned if one continues to wait.
While these large-scale phase III studies obviously are a step in the right direction, it should be noted that AIDS/VAX B/B for the U.S. and AIDS/VAX B/B for Thailand are really second-generation gp120 vaccines, the first generation of which were tested in more than 1200 volunteers without real success. Although no one can predict for certain how effectively gp 120 vaccines will protect healthy individuals from contracting HIV, few scientists have high hopes. On the other hand, if the vaccine proves to be effective in only a few individuals, the trials will be worth the effort. If the vaccine is 30% or 40% effective, it may be possible to identify what immunological parameters correlate with protection.
The next type of vaccine to progress to clinical efficacy trials most likely will be a live vector vaccine that places a portion of the HIV virus in a harmless virus, such as canarypox, explained Seth Berkeley, president of the International AIDS Vaccine Initiative in the U.S. It may be at least the year 2000 before the canarypox virus vaccine moves forward, however, and there still is some question as to whether it will progress into clinical trials.
Other forms of HIV vaccine are even further away from actual testing in humans, including live attenuated vaccines, those considered most promising but also most controversial, noted Dr. Ronald Derosiers, New England Regional Private Research Center and Harvard Medical School, Boston, Massachusetts. Vaccines that inject live but weakened forms of primate HIV have been most effective in protecting monkeys and chimpanzees from subsequent infection.
Although these live attenuated HIV vaccines outperform other vaccines in terms of efficacy in animals, the vaccines may be dangerous due to their potential to actually cause HIV infection, pointed out Dr. Ruth Ruprecht, associate professor of medicine, Harvard Medical School, Boston, Massachusetts. While it was thought that these live attenuated vaccines might provide long-term protection against subsequent challenge with HIV, it was found that the primate version of HIV-simian immune deficiency virus causes AIDS in animals. Of eight newborn monkeys who received the HIV vaccine, five died of AIDS, one has full-blown AIDS, and two have signs of early HIV disease.
Most researchers still are not sure which vaccine avenue to pursue or for how long. There is little doubt, however, that prevention efforts must continue on all fronts until an effective HIV vaccine is accessable to all people at risk for HIV.
Women First Study Demonstrates Value of Nelfinavir-Based Regimen
A dual protease inhibitor, quadruple drug therapy regimen consisting of nelfinavir (Viracept®, Agouron) saquinavir (Invirase®, Roche), stavudine (d4T) (Zerit®, Bristol Meyers Squibb) and lamivudine (3TC) (Epivir®, Glaxo Wellcome) has proved to be safe, well-tolerated and effective in HIV-infected women, resulting in potent antiviral and immunologic activity, according to Kathleen E. Squires, M.D., associate professor of medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama and a spokesperson for the Women First Study.
As of a May 27, 1998 cut-off date, 53 HIV-positive women were enrolled in a randomized, open-label multicenter trial, designed to assess a twice-daily regimen of nelfinavir (1250 mg) plus saquinavir (1000 mg) plus standard doses of d4T and 3TC, or a three-times daily regimen of nelfinavir (750 mg) plus saquinavir (600 mg) plus standard doses of d4T and 3TC for a 12 month period. Of these, one-third had a mean duration of 20-to-25 months of prior antiretroviral therapy, but all were protease inhibitor-naive.
The twice daily treatment regimen of nelfinavir saquinavir, d4T and 3TC produced similar levels of treatment compared to the three-times-a-day approach, producing mean increases in CD4 cell counts of 138 and 149 cells/mm3 and 77% and 75% of patients below 400 copies/ml of HIV-RNA, as well as 62% and 63% below 50 copies/ml through 24 weeks of treatment. Furthermore, women responded very well to this regimen, with no difficulty adhering to the protocol. Diarrhea, commonly reported as a common side effect in men, was not a problem in these women.
Abacavir Plus Amprenavir Proving Highly Potent
Preliminary results from a small phase II study point out that a potent new second-generation protease inhibitor, amprenavir (AgeneraseTM, Glaxo Wellcome) in combination with the new nucleoside reverse transcriptase inhibitor abacavir (ZiagenTM, Glaxo Wellcome) may effectively suppress HIV replication and may have a major role in helping the recovery of the immune system of HIV-infected persons, asserted Dr. Pierre-Alexander Bart, AIDS specialist in the clinical unit, Hôpital de Beaumont, Lausanne, Switzerland.
In an open-labeled, non-randomized study, 41 treatment-naive patients were given abacavir (300 mg orally twice daily) and amprenavir (1200 mg orally twice daily) for a planned period of 72 weeks. Early results indicate that 89% of patients (25 of 28), who at the time of analysis had completed 24 weeks of therapy, had undetectable levels of virus (less than 500 copies/ml). Moreover, 78% of persons (32 of 41) who had completed four weeks of treatment had undetectable virus, as did 97% (37 of 38) of patients who completed eight weeks of treatment. At 48 weeks, viral load was undetectable with an ultrasensitive assay (less than 50 copies/ml) in eight of nine persons tested.
Furthermore, a comparison of CD4 and CD8 T-cells was carried out in the lymph nodes of eight trial participants and 15 HIV-negative individuals, at baseline and 48 weeks. While there were major differences between the two study groups at baseline, at 48 weeks, the values were similar, suggesting a normalization of the CD4 to CD8 cell ratios and return to nearly normal values.
Once Daily Efavirenz plus Triple Combo Highly Active in Previously Treated Patients
Combining the investigational anti-HIV drug efavirenz (SustivaTM, Dupont Pharma) with a standard three-drug regimen of the protease inhibitor indinavir (Crixivan®, Merck) plus two nucleoside analogues significantly reduced the HIV viral load in therapy-experienced patients to below detectable levels (400 copies/ml) compared to those on the three-drug regimen alone, stated Dr. W. Jeffrey Fessel, director, HIV research unit, Kaiser Permanente, San Francisco, California.
In an interim assessment of the first 184 persons enrolled in this study, treatment with efavirenz plus the triple combo was compared to the triple combo alone, a current standard-of-care regimen. As early as eight weeks after beginning treatment, patients in the efavirenz-based treatment group demonstrated a significantly greater reduction in HIV viral load than those on the three-drug combination. Furthermore, persons taking the four-drug regimens containing efavirenz had superior reduction in HIV-RNA levels to below 50 copies/ml using an ultrasensitive assay with 74% compared to 45% of those taking the standard three-drug protocol.
Immune-Based Therapy Shows Great Promise
In an interim report, patients treated with highly active antiretroviral drug therapy (HAART) developed large immune responses and had more frequent drops in plasma HIV below the level of detection when their drug therapy was by an inactivated HI immunogen (RemuneTM, The Immune Response Corporation and Agouron Pharmaceutical Inc.), declared Dr. Fred T. Valentine, professor of medicine, New York University Medical Center, New York, New York.
In most patients, immune responses against HIV produced by infection do not result in control of the disease. There is, however, a group of rare individuals who maintain low levels of plasma HIV and are long-term nonprogressors without therapy. These individuals appear to have strong lymphocytic proliferative responses (LPRs). Results from this study strongly suggest that the Remune immunogen can induce the same LPR immune responses observed in the long-term nonprogressors.
To reach these conclusions, 43 HIV-infected patients were treated with HAART consisting of zidovudine, lamivudine and indinavir. After four weeks, these persons were randomly assigned to an inactivated gp 120 depleted whole virus immunogen, based on the theoretical concepts of the late, great Jonas Salk, or a placebo given intramuscularly every three months.
Sixteen weeks into the trial, 86% of patients who received both Remune and HAART had viral loads below the level of detection by ultrasensitive assay (less than 40 copies/ml) versus 67% of those on HAART alone. Furthermore, the HAART plus HIV immunogen-treated patients showed a significant improvement in major markers of immunologic response from baseline to week 20, as well as significant increases in the production of a substance in the blood (a beta-chemokine) associated with viral suppression, compared to HAART alone.
Recombinant Human Erythropoietin Improves Survival in HIV-Related Anemia
Recombinant human erythropoietin (r-HuEPO) (Procrit®, Ortho Biotech, Inc.) has been demonstrated to offer a safer, better tolerated, and more effective approach for the treatment of HIV-associated anemia than the traditional use of blood transfusions, according to Dr. Richard D. Moore, associate professor of medicine, and director, pharmaco-epidemiology and pharmacoeconomics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Anemia in HIV-infected persons has consistently been associated with early death. In a study of 31,534 HIV-positive patients carried out by the U.S. Centers for Disease Control and Prevention, the one-year incidence of anemia in persons with clinical AIDS was 36.9%. Survival rates were positively associated with hemoglobin levels (being 83% when baseline hemoglobin was more than 12 g/dL but only 56% with baseline hemoglobin less than 10 g/dL). Recovery from the anemia, however, substantially reduced this excess risk of death.
While blood transfusions have been the treatment of choice in the past, this approach carries the risk of transfusion reaction, may transmit additional infections such as hepatitis or cytomegalovirus, and may down-regulate immune function. In contrast, in the most recent prospective survival analysis, treatment of 500 HIV-infected patients with anemia using r-HuEPO resulted in a significantly decreased risk of dying, producing a survival rate comparable to that of HIV-positive individuals who had never been anemic.
Zidovudine Is Drug of Choice in Managing HIV-Associated Dementia
Based on current data, zidovudine (ZDV) (Retrovir®, Glaxo Wellcome) is presently the drug of choice in the management of HIV-associated dementia, according to Dr. David M. Simpson, associate professor of neurology and director, department of clinical neurophysiology, Mount Sinai Medical Center, New York, New York.
Neurological complications are among the most frequent and damaging of the problems that face HIV-infected persons, with both children and adults being stricken at any stage of the illness. In fact, 40 to 70% of all HIV-infected persons develop symptomatic neurologic disorders, particularly HIV-associated dementia. Furthermore, in the past, most patients succumbed to this severe complication within six months or less.
Now, several studies have found that early treatment with ZDV may protect patients from the development of HIV-associated dementia. In one small trial, 40 HIV-infected persons were randomly assigned to receive either ZDV 1000 mg or 2000 mg or placebo and were followed for an average of 64 weeks. The most improvement in neurological functioning was seen among the individuals receiving 2000 mg/day of ZDV, with an intermediate level of improvement noted in the group receiving 1000 mg daily. Also, in a study of 25 children with symptomatic HIV infection, significant improvements from baseline were seen in all neurodevelopment areas, except motor skills, measured after six months of ZDV therapy. Thus maintenance of patients on ZDV appears to be consistent with an enhanced quality of life in long-term survivors.
This article was provided by Body Positive. It is a part of the publication Body Positive.