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Questions Linger on Initiating and Switching HIV Treatment

tagline 2008 Fall

When and how to start antiretroviral therapy—and how to respond down the line when changes become necessary—remain unsettled questions.

Amid a plethora of therapeutic options, gaps remain in our understanding about when and how to start antiretroviral therapy—and how to respond down the line, when changes become necessary.

By 1996, HIV treatment had been revolutionized by using a wave of effective new antiretroviral drugs in combination, and by the development of viral load testing that showed HIV dropping to undetectable levels after treatment was started. Within months, the falling death rate from AIDS confirmed the impact of the treatment revolution beyond question. A dozen years later, better drugs and refined treatment strategies have made antiretroviral therapy much safer and even more effective. However, despite a flood of information from drug approval trials and treatment strategy studies, key questions have yet to be settled, such as: When is the optimal time to start HIV treatment? Which drugs should be used first? And which drugs should be used after the first have failed?

In April 1998, the first U.S. HIV treatment guidelines were issued. These guidelines were intended to avert therapeutic chaos by identifying preferred drug regimens. Since then, the U.S. Health and Human Services HIV Treatment Guidelines panel’s recommendations for when to start HIV treatment by CD4 cell count have veered from <500 cells/mm3 (1998) to anywhere between 200 and 350 cells/mm3 (2001). As of 2007, the guidelines recommend initiating treatment when CD4 cell counts fall to 350 cells/mm3. But the primary goal of therapy—suppression of HIV replication to the lowest possible level—has remained constant.

It has become increasingly clear that in addition to the deadly opportunistic infections and cancers of AIDS, longterm, untreated HIV infection also increases a person’s risk for kidney, cardiovascular, and liver disease, as well as for certain non-AIDS cancers. This is alarming news given that so many people in the United States are not diagnosed with HIV until they already have very low CD4 cell counts. In 2005, the Centers for Disease Control (CDC) reported, a staggering 38% of people testing HIV-positive were diagnosed with AIDS within 12 months of their HIV diagnosis.

Many doctors and activists now argue that the serious non-AIDS consequences of untreated HIV—along with advances such as drug combinations that are more convenient, less toxic, and require less-frequent dosing—call for starting treatment much earlier than current guidelines recommend. Yet the fundamental question—when to start— has not been formally studied in a large randomized controlled trial designed to produce strongly convincing data. Instead, experts interpret results from cohort studies, treatment interruption trials, and nonrandomized studies to inform treatment guidelines.

With a lull in new HIV drug approvals expected over the next few years, a perfect opportunity exists to do some serious research on these key treatment strategy questions: When should HIV treatment be started? What drug regimen should one start with? And how should subsequent drug regimens be chosen?

The latest HIV drugs to enter the market (darunavir, maraviroc, raltegravir, and etravirine) were initially studied in treatment-experienced people who had multidrug-resistant virus. Unlike some of their predecessors, these drugs may also be appealing options for treatmentnaive people due to favorable side effect profiles, potency, and the (yet to be proven) assumption that they will remain effective and easy to tolerate for a long time.

Obviously, the first HIV regimen a person chooses has important implications for subsequent treatment options. So far, HIV drug development has focused mainly on treatment-naive people or people with multidrugresistant HIV. Less is known about optimizing what comes between these two poles: second- and thirdline regimens. Current guidelines offer comprehensive information on drug characteristics, side effects, and potential drug-to-drug interactions, and recommend resistance testing in case of virologic failure. But the choice of what drugs should be used after the first regimen fails is more by default than by design, leaving many doctors to guess.

More data on incorporating the latest generation of drugs into the most effective, durable, and least toxic regimens—and what to follow them with—are urgently needed. Studies are currently examining some of these new combinations for first-line therapy, but they aren’t designed to shed light on questions about subsequent treatment sequencing. Trials are needed that investigate switching to improve tolerability and avoid metabolic side effects, in addition to those that study how to respond to treatment failure.

HIV treatment is a lifelong prospect. It is time to examine treatment strategies that can be relied upon for the long haul, not just at the beginning and the end of therapy.