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CLINICAL SCIENCE AND CARE: TRACK 'B' HIGHLIGHTS

12th World AIDS Conference to Address
New Therapies, Drug Resistance,
Challenges of Drug Adherence, and Increasing Gaps Between
Developed and Developing Worlds

ENGLISH    FRENCH

(GENEVA, SWITZERLAND) - Track B, the Clinical Care track at the 12^th World AIDS Conference, will include long-awaited research data on new HIV/AIDS therapies including efavirenz, ABT 378, abacavir (ABC,1592), hydroxyurea and interleukin-2 (IL-2), and new research demonstrating both the longer-term benefits and potential side-effects of combination antiviral therapy.

Also included in the Clinical Care track are data on the explosion of HIV/AIDS in new parts of the developing world, particularly India, news on the transmission of drug-resistant HIV variants, and promising data on the reduction, in the developed world, of some HIV-related conditions such as dementia.

"The Clinical Science presentations at the 12^th World AIDS Conference represent an increasingly expanding global knowledge base about HIV treatment and care," said Dr. Scott Hammer of Beth Israel Deaconess Medical Centre, and Track B Co-Chair. "Advances in antiretroviral therapy (ART) are substantial and have now been borne out in population-based studies around the world," Dr. Hammer continued. "Yet, within the parts of the developed world with access to these treatments, questions remain about the long term efficacy and toxicities of the new therapies, the complexity of adherence, and the issue of drug resistance."

"We are learning that the world desperately needs more simplified, less toxic, and less costly regimens to treat HIV/AIDS," Dr. Hammer continued. "The research to be presented in Geneva thrusts before us a clear moral imperative to deliver cost effective care to the developing world."

As with the entire 12^th World AIDS Conference, much of the science that makes up the Clinical Care Track will include a particular emphasis on the growing gap between the developed and developing worlds in HIV research and treatment, as well as on strategies to narrow that increasing divide.

Track B research will document the interconnection of epidemics of HIV and tuberculosis in the developing world and differential HIV/AIDS treatment and death rates between the two hemispheres, as well as low-cost and highly effective HIV treatment interventions in areas too poor to afford combination therapy.

Among the noteworthy clinical science abstracts selected for presentation at the Conference are:

Clinical Studies of New and Existing Therapies

Session B 17, "ART I: Clinical Trials" (Monday, 15.00-17.00, Arena) will include long-awaited data on the "Safety and Activity of abacavir (ABC,1592) with 3TC/ZDV in Antiretroviral Naïve Subjects". This is the first presentation of phase III data on the new nucleoside analog, and the first presentation of data on a triple nucleoside combination that includes abacavir. The experience of children treated with abacavir will also be addressed in this session in the presentation, "Antiretroviral Activity and Safety of abacavir (ABC,1592) with 3TC/ZDV in Therapy-Experienced Children".

In another presentation on abacavir, Session B44, "Neurological Complications of HIV" (Thursday, 13.00-14.30) includes "Safety and Efficacy of abacavir (ABC, 1592) in AIDS Dementia Complex", the first major study to examine whether the drug may be helpful in treating neurological HIV disease.

Efavirenz (EFV) is a new type of non-nucleoside retrotranscriptase inhibitor, and phase II studies of this agent will also be presented in session B17 "A Phase II, Multicenter Randomised, Open-Label Study to Compare the Antiretroviral Activity and Tolerability…" (presentation 130/poster number 22336). The study found that the combination of efavirenz plus zidovudine plus 3-TC was as good, or better than standard triple therapy with indinavir plus zidovudine plus 3-TC.

In addition, a Late Breaker paper, "Safety & Efficacy of ABT-378/Ritonavir in Antiretroviral-Naïve HIV Patients: Preliminary Phase II Results" (Friday, 08.30-10.30, Arena) presents data on ABT-378, a novel HIV protease inhibitor which the authors state has superior in vitro activity compared to other protease inhibitors. According to the paper authors, preliminary phase II data presented here indicate that ABT-378/ritonavir is a convenient regimen that is well-tolerated and displays high in vivo potency in antiretroviral naïve patients.

Also in Session B17, a presentation titled "A Multicentre Randomised Study Comparing Ritonavir and Indinavir in 1251 Previously Treated Patients with CD4 Below 50/mm3" presents data from a large study that focused on patients with advanced HIV disease. The report is significant because of its scope, and because it provides a head-on comparison, with a large number of clinical endpoints, of two widely prescribed drugs.

The Late Breaker paper, "ADAM Study: Inferior Viral Suppression with Maintenance Therapy After a Quadruple Induction Therapy in HIV-1 Infected Individuals" (Friday, 08.30-10.30, Arena) finds that, although the quadruple induction regimen provided a rapid suppression of viral replication to below 50 copies/mL, only patients with a relatively high initial viral clearance rate succeeded in sustaining suppression of viral replication during maintenance therapy with stavudine plus nelfinavir, or with saquinavir plus nelfinavir. The authors conclude that it is currently inadvisable to continue attempts at induction-maintenance therapy in clinical practice.

Hydroxyurea

Three studies reported in Session B26, "ARTII: Clinical Trials" (Tuesday, 15.00-17.00, Arena) present important new data on hydroxyurea, a drug that has gained considerable attention in the past two years. The data presented should be useful in determining whether hydroxyurea is a useful adjunct in antiretroviral regimens, and in designing additional research to study the drug's usefulness.

Interleukin-2 and Immune Restoration

Three studies reported in Session B32, "Clinical Immunology in HIV-1 Infection", (Wednesday, 11.00-12.30, Hall VII) review immunological response and tolerance for IL-2, a widely discussed immunologic adjunctive therapy. The studies demonstrate good CD4 response, and show that IL-2 can be administered over the long term. The data presented here can provide important information on which to base a major multinational clinical endpoint trial.

Two Late Breakers (Friday, 08.30-10.30) address related issues. "Effects of HAART Compared to HAART Plus an Inactivated HIV Immunogen on Lymphocyte Proliferative Responses (LPR) to HIV Antigens" concludes that, in subjects on HAART, inactivated HIV immunogen can induce LPR to HIV antigens comparable to those observed in some long term nonprogressors.

An additional Late Breaker in this session, "Restoration of T cell Renewal Capacity Coincides with Naïve CD4⁺T Cell Repopulation After Anti-Retroviral Therapy," concludes, from studying the difference in T cell development profiles between progressors and long-term asymptomatics, that a decline in T cell progenitor capacity may contribute to CD4⁺T cell depletion and progression to AIDS. The authors state their conclusion is further strengthened by the increase in the number of naïve CD4⁺T cells concurrent with increases in T cell progenitor capacity during therapy.

Combination Therapy Side-Effects

As the number of individuals treated and length of treatment with protease inhibitors increases, side effects and difficulties of protease inhibitor use are becoming better known. Session B22, "Complications of Protease Inhibitors" (Tuesday, 11.00-12.30, Hall VII) includes several studies addressing these complications, including "Changes in Body Habitus in HIV+ Women After Initiation of Protease Inhibitor Therapy". This study, which examines lipid abnormalities and body changes in women, is noteworthy because many of the initial studies examining protease inhibitor side-effects have focused on men.

A Late Breaker paper, "Prevalence and Severity of Protease Inhibitor (PI) Induced Lipodystrophy (LD) and Insulin Resistance" concludes that LD is common, progressive and does not reverse spontaneously in most patients receiving prolonged protease inhibitor therapy. Hyperlipidemia and insulin resistance were not found to worsen, not to correlate with LD severity.

Some researchers attempt to avoid protease inhibitors in early HIV infection. Session B17, "ART I: Clinical Trials" (Monday, 15.00-17.00, Arena) will feature trial results of combination therapy with three reverse transcriptase inhibitors: efavirenz+3TC+zidovudine (Number 22336), or abacavir+3TC+zidovudine (12230), or delavirdine + 3TC + zidovudine (12219).

Antiretroviral Resistance and Transmission of Drug-Resistant HIV

One of the key scientific concerns, as HIV is more aggressively treated in the developed world, is the emergence of drug-resistant strains of the virus. Session B24, "Antiretroviral Resistance" (Tuesday, 13.00-14.30, Arena) includes several research presentations on development and transmission of resistant virus. Among these is "Patterns of Phenotypic and Genotypic Cross-Resistance Among Protease Inhibitors in Over 1,000 Clinical HIV-1 Isolates". This very large study provides substantial basic data on protease inhibitor resistance and cross-resistance, demonstrates a fair degree of class cross-resistance, and should focus additional attention on the potential use of resistance assays in clinical medicine.

Also included in this session is the presentation "Frequency of Transmission of Drug-Resistant Variants in Individuals with Primary HIV-1 Infection". This long-term study examines the circulation of drug resistant strains of HIV, including strains resistant not just to nucleoside analogs, but to non-nucleoside analogs and protease inhibitors. The circulation of drug resistant strains of HIV increases the possibility that individuals will be infected with these strains, may reduce the overall effectiveness of currently available therapies, and focuses attention on the need to consider resistance testing in patients with new infection before a therapy is prescribed.

Adherence

The challenge of adhering to complex, expensive, and difficult to take treatment regimens is limiting the benefit of new therapies for many, and presents a tremendous challenge to care providers. Sessions B25 "Adherence to Antiretroviral Therapy" (Tuesday, 15.00-17.00) features experts addressing the fundamental issues of adherence. Session B35 "Adherence to ART: New Research" (Wednesday, 13.00-14.30, Arena) examines adherence behaviour among a variety of patient, socio-economic and HIV risk groups.

Bridging the Gap: HIV/AIDS in the Developing World

As with the entire 12^th World AIDS Conference, several Track B sessions will also focus on the growing divide between the developed and developing world, and on the need for global action to address this growing disparity.

One of these, Session B14, "Care in Resource-Limited Settings" (Monday, 13.00-14.30, Hall VII) includes several important research papers, including "Clinical Profile of 1800 HIV/AIDS Patients at the Only Comprehensive AIDS Clinic in Bombay, India". This very large study dramatically highlights the explosion of HIV/AIDS in Asia, where it is affecting people in the most economically productive age groups, and makes it unmistakably clear that India is now a major new epicentre of the global HIV/AIDS epidemic.

Session B36 includes a paper from the group that hosted the XI International Congress on AIDS in Vancouver titled "One World, One Hope: The Cost of Making Antiretroviral Therapy Available to All Nations". This study provides an intriguing analysis of the cost of antiretroviral therapy as portion of the GNP of different countries.

The Link Between Tuberculosis and HIV

The epidemics of HIV and tuberculosis (TB) are inexorably linked in the parts of the world where both infections are spreading most rapidly and most devastatingly. Presentations in Session B37, "Tuberculosis: Prevention and Management" (Wednesday, 15.00-17.00, Arena) examine the interconnectedness of the epidemics, and of the need for outreach, education, prevention and treatment to address both.

"Increasing Burden on Tuberculosis and High Rate of Drug Resistance in an HIV Epicentre in Northern Thailand, 1989-1997" provides a ten-year overview of the dual epidemics in one of the hardest hit areas of the world, and provides a substantial man-year analysis of the burden of disease and the challenges of drug resistance.

While both tuberculosis and HIV continue to spread, particularly in the developing world, many HIV-infected individuals go without detection or treatment for TB. Yet, a number of highly cost-effective and prevention interventions are available. The presentation "Cost-Effectiveness of Isoniazid

Preventive Therapy for HIV-Infected People in Sub-Saharan Africa" demonstrates one of these, a prophylaxis programme that saves lives at a cost of $36 per life year saved.

A Late Breaker paper, "Significant Reduction in Mortality Attributable to Cotrimoxazole Prophylaxis Among HIV-Infected Tuberculosis Patients in Abidjan, Côte d’Ivoire", (Friday, 08.30-10.30, Arena) finds that cotrimoxazole prophylaxis significantly reduces morbidity and mortality in HIV-infected tuberculosis patients -- findings that the authors state may have important implications for enhancing the clinical management of HIV-infected tuberculosis patients in Africa.

Low-Cost HIV Therapeutic Interventions

As many parts of the world struggle with the overwhelming cost of combination therapy, some studies to be presented in Geneva provide clear data indicating that low cost interventions can improve health and save lives. Session B21, "Pediatrics Care and Treatment" (Tuesday, 11.00-12.30, Hall III) includes the presentation "Vitamin A Supplements and Mortality Among HIV Positive and Negative Children in Tanzania". This study demonstrates that, even in resource poor countries that have been unable to afford antiretroviral therapy, differences in outcome can be achieved with low-cost interventions such as nutritional supplements.