July 13, 2000
This symposium was divided into three parts: a review of the scientific principles that underlie our current understanding of how to manage chronic HIV infection, an argument for why and how to make antiretroviral therapy available in the developing world ("resource-poor countries"), and a view of the future of antiretroviral therapy. I will reprise some of the most novel areas covered.
Dr. Joep Lange of Amsterdam, who has previously worked at UNAIDS in Geneva and is the president-elect of the International AIDS Society, made a compelling argument for why treatment needs to be made accessible. The number of infected people who are not receiving any treatment will result in an "unacceptable" number of casualties, and it is morally indefensible for the developed world to be complacent about this. He also made a case for treatment that went beyond that of compassion. The economies of developing countries will be seriously endangered when so many adults die in their prime adult years, leaving behind only the very young and the very old to fend for themselves. In the West, HAART is one of the most cost-effective interventions in modern medicine, because it allows adults in their peak earning years to remain robust and to contribute to the economy.
Dr. Lange went on to say that the use of sub-optimal therapy (for example, two NRTIs) should not be condoned on the basis of cost. Sub-optimal therapy will lead to resistance (and cross-resistance to related drugs) which has its own costly consequences. Moreover, sub-optimal therapy has less immediate and less profound clinical benefit in terms of restoring the immune system and a sense of well being. Dr. Lange described a collaborative clinical research project that the Netherlands and Australia are doing with physicians in Thailand. Local research needs to be done to answer questions about therapy pertinent to the needs of the developing world.
In order to bring treatment to resource-poor settings, there are a number of hurdles to overcome: drug costs, shortage of health care personnel with AIDS expertise, development of an appropriate infrastructure (clinics, labs, information management), and with whom to collaborate. He voiced considerable skepticism that targeting the public sector is the right way to proceed, characterizing some sub-Saharan governments as incompetent, corrupt, or both. Although governments will need to give their blessing to any planned projects and will need to be involved at some point, he feels that focusing instead on the private and not-for-profit sectors will get projects going faster and more efficiently, and will save more lives.
Funding might come from "decent" governments, international donor organizations, and large employers who should be motivated to maintain a healthy workforce. Appropriate goals would include cheap drugs, cheap laboratory monitoring, infrastructure development, and continuous education of the public and health care providers. Ultimately there would be sufficient knowledge to develop relevant treatment guidelines that don't compromise effectiveness of HIV treatment. Guidelines would need to include the management of tuberculosis, one of the biggest HIV-associated problems in the developing world, and prevention strategies for opportunistic infections.
He reviewed a number of new drugs in various stages of development. In the nucleoside reverse transcriptase inhibitor class, FTC and DAPD -- both drugs that can be given once a day -- are being studied. DAPD has the advantage of being active against HIV strains that are resistant to AZT and 3TC. Among the "second generation" of non-nucleoside reverse transcriptase inhibitors (NNRTIs), capravirine is the furthest along; in addition, emivirine and newer drugs being developed by DuPont all look promising.
There are a number of new protease inhibitors (PIs) in development. Lopinavir, formerly known as ABT-378/r, has been submitted to the FDA for approval, which is expected later this year. This drug has the potential for once-a-day dosing and is active against many strains of HIV that are resistant to the currently-available protease inhibitors. Tipranavir is another "second generation" PI that has broad activity against resistant strains. Like lopinavir, tipranavir blood levels are boosted by using a small dose (in this case, 200mg) of ritonavir, BMS 232,632 that may be able to be given once a day and is currently entering the second phase of testing. Tenofovir belongs to a unique class called nucleotide reverse transcriptase inhibitors. It is also active against hepatitis B and can be given once a day. Tenofovir is active against AZT and ddI-resistant viruses, as well as the multi-drug resistant strain that carries the Q151M mutation.
There are a number of attachment/entry inhibitors. T-20 is entering the final phase of testing later this summer; so far, it has been reasonably successful as part of a salvage regimen. A follow-up drug from the same company called T-1249 is in early testing. PRO 542, recombinant human CD4/IgG2, is a potential attachment inhibitor. Inhibitors of various receptors on the surface of CD4 cells that are used by HIV to enter an uninfected cell, such as SCH-C and AMD 3100, are a completely novel approach, however, these agents have not been tested yet in humans.