"You've gotta have HAART"*

Highly active antiretroviral therapies have changed the prospects for people living with HIV

MJA 1998; 169: 456-457

The past two years have seen extraordinary advances in the practice of HIV medicine. In Australia, this is reflected in a dramatic drop in morbidity and mortality associated with the introduction of highly active antiretroviral therapy (HAART), as reported by Correll and colleagues in this issue of the MJA .1 The advent in 1996 of the very potent protease inhibitors and the growing list of reverse transcriptase inhibitors enabled the development of combination therapy with three or four drugs aimed at durable suppression of viral replication. Durability is a critical aspect of treatment, as HIV is capable of rapidly developing resistance to single agents. Fortunately, in 1997 the measurement of HIV plasma RNA concentration (viral load) became routine practice, allowing physicians and patients to monitor the effectiveness and durability of combination therapy. Publications on the efficacy of HAART have mostly reported its effects on the important surrogate markers (viral load and CD4+ T-cell count), although there are already clinical endpoint data showing a reduction in progression to AIDS and death.2,3 Clinical trials, however, do not always reflect clinical practice. How effective have these drugs been in the real world? In this regard, the report in this issue from the National Centre for HIV Epidemiology and Clinical Research (NCHECR)1 is of particular importance. In the years 1994-1997 there were 80% fewer deaths and 43% fewer AIDS cases among a cohort of people with advanced HIV infection (CD4+ T-cell count below 200/µL) than in a matched patient cohort from 1990-1993.1 These findings are similar to those reported from Switzerland4 and the United States.5 Although such studies have methodological difficulties, the emerging pattern is very clear. Moreover, the benefits escalate each year.5 This is not surprising as the change in prescribing has been stepwise: the first phase, sequential monotherapy, ended with the publication in 1996 of the definite but modest advantage of combining two reverse transcriptase inhibitors (eg, zidovudine-didanosine).6 In the same year, protease inhibitors became accessible, and the practice of multiple drug regimens including a protease inhibitor became widespread during 1997. It is likely that the analyses for 1998 will show even greater benefits.   "What you really need is HEART"* The highly active regimens become highly effective antiretroviral therapy (HEART) by slowing the damage to the immune system and, in part, by restoring lost function. HAART leads to an immediate rise in the CD4+ T-cell count, due initially to a redistribution and expansion of memory T-cells followed by a very gradual replenishment of naive T-cells, the latter filling in gaps in the T-cell repertoire and providing the host with the ability to respond to a broader range of invaders.7,8 While the goal for HAART is to reduce the viral load to an undetectable level, a rise in CD4+ T-cell count occurs in patients in which this is not achieved.9 Moreover, the elevated CD4 cell count and clinical benefit from HAART may persist long after virological failure (rising viral load) in some patients. Yet much remains to be learned. For HAART to remain HEART in 1999 and beyond, three major problems must be overcome: drug resistance, long term side effects, and compliance with difficult regimens that may be taken for many years. A sizeable proportion of patients have developed some resistance to each of the current drug combinations. Many agents are available (see Table, below), but a high rate of cross-resistance exists within members of each class of antiretroviral drugs. Second generation protease inhibitors are in development, as are nucleotide analogues and inhibitors of viral integrase. However, the use of the powerful protease inhibitors is limited in some patients by metabolic toxicity, involving lipodystrophy, hyperlipidaemia and insulin resistance, the mechanisms for which are still a matter of hypothesis.10 Poor compliance encourages drug resistance; a strong commitment to HAART is necessary before starting treatment. Simple, easily tolerated regimens are still years away. These issues are driving the need for new approaches. In this regard, the past two years have brought remarkable advances in HIV science with the discovery of the major co-receptors used by HIV (with CD4) to infect and damage the cells of the immune system. Mutations in the genes encoding these receptors are associated with protection against HIV infection in homozygotes (about 1% of Caucasians are all but uninfectable with HIV-1) and a slower rate of progression to AIDS and death in heterozygotes.11 These discoveries are underpinning a frenzy of commercial activity12 aimed at developing a range of antireceptor agents, several of which have reached phase I/II clinical trials.13 The future looks promising for those early in the course of their HIV infection; for those whose infections are already overcoming HAART, it is a major challenge to find the best approach to "salvage therapy" while awaiting new drugs.   A HAART-less world In Australia, HIV physicians have the option of prescribing HAART, despite its expense, for all appropriate patients. But there is no access to HAART for the vast majority of the world's 30-40 million people living with HIV, mostly in Africa and Asia. In a US study, Medicaid patients were less likely to receive a protease inhibitor and had a higher mortality rate than privately insured patients.5 The remarkable success of HAART has brought into focus the disparity in healthcare between rich and poor and between the developed and developing countries -- gaps to be bridged in the new millennium.   Critical research question In addition to the benefits for patients, the positive effect on HIV doctors has been considerable, both through relief from sadness and through the affirmation of the scientific paradigm under which we practice. The viagra-like change in therapeutic potency carries, however, the danger of assuming that because we have a proud new tool we know exactly how to use it. In reality, it is still not known when to start HAART, which agents to start with, when to change and to what. National treatment guidelines depend, by necessity, on the lowest level of evidence: consensus opinion of experts.14 There is high biological plausibility to justify striving for an undetectable viral load from early in infection, but there are no data to support the long term benefits of "going early and going hard", nor long term data on side effects. There are few data on whether virological failure (rising viral load) equals clinical failure, or on what best to do for patients who have "failed" all available drugs. It is essential that clinical trials continue to address these questions, but the benefits of HAART and the licensing of many drugs makes this more difficult.   Future prospects While there are strong grounds for expecting that simple, well-tolerated, effective and durable conbination regimens will emerge from current science, the real therapeutic hope is that HAART might eventually eradicate the virus in HIV-infected individuals. This outcome requires effective viral suppression beyond the life span of the long-lived cells that form a reservoir of latent virus. Initial enthusiasm15 has been tempered by a gradual realisation of the difficulties,16 but it is not an unrealistic hope given the extraordinary pace of discovery in HIV science and medicine. Graeme J Stewart Chairman, Research Advisory Committee Australian National Council on AIDS and Related Diseases Westmead Hospital, Sydney NSW

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