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New Treatments for Highly Active Antiretroviral Therapy

Routine use of Highly Active Antiretroviral Therapy (HAART) has led to unprecedented improvement in the clinical outcome of HIV-infected patients.

Pathogenesis of HIV-1 Disease

Infection with HIV-1 causes a slow yet relentless destruction of immune system function over a period of years. The precise mechanisms by which this immune system dysfunction occurs.

Careful evaluation of changes in viral burden response to antiretroviral therapy has yielded direct insight into issues of pathogenesis. Initiation of zidovudine treatment lowers the level of circulating virus by approximately 10-fold within one week. This degree of viral suppression can be sustained over a period of weeks to months and is rapidly reversible upon discontinuation of therapy. The use of nonnucleoside reverse transcriptase inhibitors, such as L-697,661 and nevirapine, lead to comparable changes in viral burden.

Recent results with HIV protease inhibitors (indinavir and ritonavir) has demonstrated suppression of viral burden by over 100-fold coincident with significant elevations in CD4 count responses. Both of these responses are lost when drug therapy is interrupted or when the virus undergoes mutations that render it less susceptible. Kinetic studies of changes in viral load with antiviral therapy demonstrated the half-life of HIV.

Strategies for Continuing Benefit of Antiretroviral Therapy

The recently elucidated mechanisms of HIV pathogenesis along with the development of new antiretroviral therapeutic agents strongly suggest the initiation of antiretroviral therapy early in the course of HIV disease. An increasing body of evidence suggests that monotherapy should be avoided.

When Should Antiretroviral Therapy be Initiated and with What Agents?

The ultimate goal of antiretroviral therapy is to inhibit viral replication to the greatest possible degree. The relative degree of viral suppression, or antiretroviral activity, is best measured through the use of quantitative viral markers, such as plasma HIV RNA. It is assumed that the relative degree of antiretroviral activity is directly related to the clinical outcome, or efficacy, of a given regimen.

What is the Definition of Antiretroviral Treatment Failure?

Simply stated, antiretroviral failure is defined as a loss of antiretroviral effect or development of toxic effects. The return of viral load above the level of detection or a return toward baseline is considered evidence of improvement.

When a patient fails their current regimen, what new antiretroviral regimen represents the best therapeutic alternative?

The appropriate alternative antiretroviral regimen for a patient who has failed initial therapy depends upon several factors, including:

Current stage of disease Previous antiretroviral therapy Known intolerance to specific agents

Underlying disease (eg, history of pancreatitis; history of peripheral neuropathy)

The availability of antiretroviral agents

Cost

Philosophy of the treating physician and the patient

Lessons from ART History

Perhaps the most important factor in deciding the next best regimen is the current regimen on which the patient failed. The drag exposure history influences the viral population with regard to resistance mutations.

What is the Best Strategic Approach to Achieve the Most Durable Antiretroviral Effect Over Time?

The high levels of viral replication throughout all stages of infection, the association of more rapid development of resistance in association with higher levels of viral replication, and the availability of more potent agents used in combination has led to the concept of treating patients with HIV disease aggressively and as early as possible in the course of infection to preserve immunocompetence and significantly delay the development of the resistant viral strains. However, some fundamental questions remain unanswered when applying this new paradigm to clinical practice.

The absence of definite answers to these questions leads to several problems in clinical management of patients at the current time. The most pressing question that clinicians are wrestling with is what viral load threshold should they establish as a therapeutic goal and at what level should they seek changes in antiretroviral therapy after achieving their original therapeutic target? Most clinicians now agree that the initial virologic target of antiretroviral therapy should be "maximum suppression" of viral replication.

The degree of viral suppression may not be complete enough to prevent the development of resistance over time. If protease inhibitors, in particular, are utilized early in the course of disease, virions.