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Conference
"Future Treatment Perspectives" Dr. Stephano Vella (biography) English - 2002-04-15 - 36 minutes
Summary : Future treatment advances need to be addressed both from a short term and a mid-long term perspective.
1. Short Term Perspectives
1.1. Reconsidering the best time to initiate therapy
With "eradication" not in the horizon, the goal of therapy has been redirected towards a less ambitious goal: the long-term management of a chronic infection. As of today, consensus has been reached that treatment should be initiated only when risk of progression becomes relevant (e.g. CD4+ approaching 300 / mm3). However, we shouldn't lose sight of remarkable progress made in controlling HIV disease progression in the developed world. Very probably, when simple, potent, durable, non-toxic regimens become the norm, pendulum will swing again toward more aggressive (early) approach. In the meantime, we need to consider that delaying therapy may not be the only option. Alternatives may be dependent on the discovery of "new" predictors of progression and of genetic correlates of drug metabolism and toxicity, on toxicity prophylaxis and treatment, and on the use of intermittent therapy to reduce toxicity.
1.2 Refining the clinical use of resistance testing assays
Data from the eight controlled studies performed so far are somehow conflicting, with only 3 out of eight giving a short-mid term advantage of using resistance testing to guide the selection of second and third line treatment options. Despite numerous justifications for the negative results, its clear that more research is needed, keeping in mind that genotypic tests are more similar in their complexity to an EKG, a biopsy, or MRI than to a typical antimicrobial susceptibility test.
1.3 Management of metabolic toxicities
Although lack of a standard case definition complicates characterization, diagnosis, and tracking, the reality is that morphologic changes have a substantial impact on quality of life and cardiovascular sequelae of dyslipidemia appears minimal short-term but long-term outcome is unknown.
So far, management approaches of fat redistribution syndromes and of metabolic toxicies are largely empirical. Only few of them are based on short term controlled studies: antiretroviral therapy switches, exercise and diet, anabolic steroids, recombinant human growth hormone (rhGH), testosterone, metformin, tiazolidinediones and plastic surgery for fat redistribution syndromes; lifestyle modification (diet, exercise), use of lipid-lowering agents and switching to non-PI regimens for dislypidemic syndromes.
1.4. New drugs of existing classes
New drugs belonging to the existing classes are eagerly awaited to address issues of toxicity, potency, resistance and to improve convenience and tolerability. Indeed, new formulations/dosing schedules of "old" drugs have been recently introduced, while new members of each available class have been or are expected to enter the clinic in the next few months. The following are just a few examples of drugs in advanced stage of clinical investigation:
HIV protease inhibitors
-Tipranavir (TPV), BMS 232,632, mozenavir (DMP-450), Ag 1776, DPC 681, DPC 684, Tibotec compounds
1.5. New Strategies
The major advances are indeed expected to come not from the availability of new drugs, but, as it happened in the recent history of antiretroviral therapy, from the careful evaluation of new treatment strategies such as revisiting induction / maintenance or treatment simplification strategies or the careful testing of Structured (Strategic) Treatment Interruptions (STIs). In fact, many patients now being treated had marginal indications for therapy based on current guidelines and may be able to remain off therapy for a substantial period of time following a period of full viral suppression and CD4+ gain.
Structured or strategic treatment interruption (STI) has raised many practical and theoretical questions. As a way of re-exposing the immune system to HIV antigens after periods of prolonged suppression on successful antiretroviral therapy, STI becomes a form of auto-vaccination. This strategy has worked well in a preliminary study in patients with acute or extremely recent HIV infections. The results in established infection have been less promising. A more recent type of STI, named structured intermittent therapy (SIT), has recently been suggested. Here, therapy is used intermittently, for example on alternate weeks, simply to decrease or delay cumulative drug doses and hence toxicity. However, this must be seen as a research strategy and cannot be recommended apart from controlled trials.
2. Mid-Long Term Perspectives
2.1 New drugs classes
In addition to the new more potent and safe drugs belonging to the existing classes, there is an urgent need to develop antiretroviral drugs directed against new HIV replicative targets. Among these, the more advanced are the HIV entry inhibitors (attachment inhibitors; co-receptor inhibitors; fusion inhibitors) and the HIV integrase inhibitors.
2.2 Immune interventions
The failure rate of drug combinations due to either lack of efficacy or unacceptable toxicity has also necessitated development of long term strategies which optimize efficacy but minimize toxicity and cost: the use of pharmacologic monitoring, resistance testing, and novel drug schedules need more examination. The inability of many patients to derive long term benefit from antiretroviral drugs should also stimulate renewed interest in approaches which augment immune response to determine if such strategies may allow longer preservation of immune competence with an acceptable rate of toxicity. Although effective suppression of HIV-1 replication has been the major focus of the therapeutic research effort in recent years, there has been increasing interest in the concept of manipulating the immune response to the benefit of the host. The combination of HAART and immune-based therapies presently appear as the most appealing approach for achieving a long term, stable containment of HIV replication. These approaches should include attempts to augment or to dampen the immune response generally, and those designed to stimulate relevant HIV-1 specific immune effector mechanisms.
2.3 HIV Eradication
The great hope of eradicating HIV seems to be definitely out of our perspective, because all the pharmacological attempts at eliminating any form of virus from an infected individual so far have failed. In fact, there exist two major types of reservoirs, i.e. sanctuary sites of viral replication poorly accessible to antiretroviral therapies: anatomical reservoirs (CNS, male and female genital tract…) and cellular reservoirs (latently infected, resting memory CD4+ T lymphocytes carrying an integrated copy of viral DNA; persistently infected macrophages; follicular dendritic cells trapping extracellular virions). However, we cannot lose sight of the importance of continuing research on HIV eradication, despite the delusions of the recent past.
Various strategic approaches can be envisaged to clear these reservoirs: eliminating anatomical sanctuaries appears to be a more pharmacological issue, dealing with problems such as bioavailability, penetration into blood-brain barrier, reduced protein binding, etc. On the other hand, attacking cellular reservoirs of HIV is a major and so far unmet challenge, requiring complex and innovative approaches.
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