New Guidelines for When to Start Antiretroviral Therapy - An Optimistic View

As we approach the 20th anniversary of the original description of the clinical syndrome now known as AIDS, treatment paradigms (patterns) continue to evolve and the pendulum still swings. Nowhere is this more evident than in the guidelines for when to start antiretroviral therapy for HIV. In fact, the only constant regarding the recommendations for initiating treatment is that they keep changing. In February 2001, the Department of Health and Human Services Panel on Clinical Practices for Treatment of HIV Infection, to much fanfare, changed these recommendations once again. In this article, I will summarize the new guidelines, place them into historical perspective, and then clarify what the modifications mean in clinical practice.

Details of the most recent guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents can be found at The recommendations for starting antiretroviral therapy have been modified to reflect a trend towards delaying the initiation of treatment. These current guidelines for initiation of therapy are summarized in the table below.

Clinical Category

CD4 Cells







(no symptoms)







Offer Treatment
Controversy Exists



>30,000 (bDNA) or
>55,000 (RT-PCR)

Experts Differ,
but Many Treat



<30,000 (bDNA)
<55,000 (RT-PCR)

Many Experts Defer,
With Observations

TABLE: Guidelines for starting antiretroviral therapy. The number of CD4 cells reflects the status of the body's immune (defense) system. (Over 500 = normal; under 200 = suppressed immune system.) The bDNA and RT-PCR are different methods for measuring the amount (load) of virus.

Shifting guidelines on starting therapy date back to a time when the issues were whether or not to use zidovudine and whether therapy should be started at less than 200 or less than 500 CD4 cells/uL. While the regimens have changed since then, the lack of convincing data on the optimal time to start therapy has not. Moreover, it is unlikely that a study will ever be performed that will definitively demonstrate when treatment should be initiated. Therefore, the recent modification in recommendations could be looked at as either a positive or negative reflection on the state-of-the-art of antiretroviral treatment. I will explain why I see the shift as a positive reflection.

The rationale for deferring therapy comes from several key observations made during the last few years. First, we now know it is highly unlikely that current therapies will be able to eradicate the virus from the body. Thus, life-long treatment is required for HIV. Second, current therapies are associated with significant short-term toxicity, such as nausea, diarrhea, and fatigue, as well as long-term toxicity. The long-term toxicity includes peripheral neuropathy and metabolic abnormalities such as diabetes and increased cholesterol levels. Additionally, many people have an even greater concern that antiretroviral therapy may be contributing to certain body changes that have been described, such as sunken cheeks, thinning of the arms and legs, and an increase in waist size. A third observation leading to the trend in delaying treatment is that many individuals are not able to strictly adhere to the therapy for a many year duration. What's more, this non-compliance results in drug resistance and, ultimately, treatment failure.

Although the above issues are all important, I would argue that a compelling reason to consider deferring therapy is related to the success of current antiretroviral treatments. Yes, some data suggests that the virologic response to treatment is better in those who start early. Studies are not convincing, however, that a difference in response exists between those starting treatment at less than 350 versus 350 to 500 CD4 cells/uL. Furthermore, there is even a question among experts as to how convincing the data is that starting at 200 to 350 is better than starting at less than 200 CD4 cells/uL. Finally, increasing evidence suggests that even severely immunosuppressed individuals experience substantial immunologic improvement after starting treatment. Accordingly, the modifications in the current recommendations for when to start antiretroviral therapy should, at least in part, be seen as a tribute to the potency of current regimens, and not simply a response to their limitations.

How should these recommendations be employed in the clinic? First of all, they are now, as they have always been, guidelines only. As a clinician, I must never forget that I am treating individuals and that no cookbook recipe will apply to all. Some people, for a variety of reasons, may choose to initiate treatment early. After being counseled as to the potential risks and benefits, such patients should not necessarily be discouraged from early therapy.


What is HIV? See Answer

In contrast, delaying therapy may be preferable for other people. This is especially so for those who, for any one of a number of reasons, may not be able to adhere to therapy. In particular, those individuals suffering from substance abuse or depression may be at increased risk for nonadherence and the consequent development of drug resistance. These patients are better off deferring therapy until they have dealt with these underlying problems, rather than rushing on to a drug regimen that may be doomed for failure. In general, I would prefer to have a patient with lower CD4 cells and/or a higher viral load (more advanced disease), but who is ready and able to commit to therapy and has no drug resistance. I can be more optimistic for such a patient than for one with higher CD4 cells and/or a lower viral load (less advanced disease), but who has developed extensive drug resistance with limited treatment options.

What about patients who started therapy based upon previous guidelines, such as when their CD4 cells were between 350 and 500 cells/uL? It is natural that these patients may now consider discontinuing therapy. Whether this is the best strategy for any given person, however, will need to be individualized. Certainly, those who are experiencing significant drug-related toxicity that is impairing their quality of life, or those who are struggling to maintain a high level of adherence to their regimen can consider stopping the treatment. They, however, should work closely with their medical providers to determine if therapy can be altered or should be discontinued. In contrast, most clinicians would agree that patients doing well with treatment should stay on their current regimen until we learn more about the consequences of interrupting treatment in this setting.

Recommendations for the use of antiretroviral therapy in adults and adolescents will continue to evolve. Each paradigm shift in treatment raises new questions and concerns for patients. Placed in the proper context, however, these changes often empower the patients and their clinicians to individualize therapy. Thus, the most recent guidelines for the initiation of therapy allow patients to consider the impact of treatment on their quality of life, while recognizing that delayed therapy is still highly effective. In the case of treatment guidelines for antiretroviral therapy, change is good and we should only be concerned when the changing stops.

Medical Author: Eric S. Daar, M.D.
Medical Editor: Leslie J. Schoenfield, M.D., Ph.D.

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