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The Clinical Edge

Insights and commentary from the HIV/AIDS Division at UCSF/San Francisco General Hospital

Should Elite Controllers Be Offered Antiretroviral Therapy?

Dr. Steven Deeks discusses the rationale for initiating antiretroviral therapy to treat "elite controllers."

Although the question seems to be settled in our local clinics, there is an ongoing passionate debate on the global level as to when to initiate antiretroviral therapy (ART). The Europeans are the most conservative. Both the European and UK guidelines recommend therapy only for those adults whose CD4+ T-cell counts drop below 350 cells/µL, or those who want to initiate ART to prevent transmission to others. The World Health Organization (WHO) is a bit more forceful and recommends therapy for anyone below 500 cells/µL, but acknowledges that treatment is costly and not all countries can provide treatment for all who meet this indication.

The U.S. guidelines are decidedly more aggressive. In the past few years, two large longstanding panels of experts (the DHHS and IAS-USA) have come out with controversial recommendations that treatment be encouraged for essentially everyone. The strength of the evidence for treating those with high CD4+ T-cell counts is weak, as noted in the guidelines, and is based largely on data suggesting that that the short- and long-term harm associated with exposure to ART (eg, drug toxicity) is probably lower than the harm associated with ongoing HIV replication (eg, inflammation, end-organ damage, irreversible immunologic progression). If faced with a choice of high-level HIV replication or ART, the latter might prove to be safer.

I tell patients I would be inclined to start therapy, particularly if there is any evidence of chronic inflammation.

One question left largely unaddressed by any guideline is what to do about those individuals fortunate enough to naturally control their virus without therapy. These so-called controllers have either no detectable virus ("elite controllers") or very low levels of detectable virus ("viremic controllers"). Most maintain high CD4+ T-cell counts for years to decades. Their risk of progressing to AIDS is vanishingly small.

Is there any reason to offer ART to such individuals? If the underlying philosophy of current U.S.-based guidelines is that the virus is more harmful than the drugs, why would we give ART to a person with essentially no detectable virus?

How HIV causes disease is not fully known. It is clear, however, that HIV causes a chronic inflammatory state, and that this inflammation very likely causes harm. HIV-associated inflammation has been consistently associated with cardiovascular disease, nervous system disease, cancer, osteopenia/osteoporosis, and renal disease. One of the major rationales for early ART is to prevent inflammation and the harm it likely causes.

When considered in this context, there may very well be a strong rationale to treat elite controllers. At San Francisco General Hospital, Peter Hunt showed years ago that controllers have high levels of inflammation. Priscilla Hsue subsequently showed that elite controllers have higher than normal levels of cardiovascular disease. Hiroyu Hatano found that treating controllers with ART reduces the level of residual viremia and reduces inflammation. All of these observations have been confirmed by other groups. There is now a consensus that elite control is marked by chronic inflammation and that the health of controllers eventually may be affected by this inflammation.

Based on this admittedly limited evidence, I think ART should at least be considered. Personally, when I meet a controller in the clinic who is interested in starting ART, I first emphasize that there is no solid evidence one way or the other. I also inform the patient up front that the vast majority of experts have until recently never really considered treating controllers, and most probably do not believe it is indicated. Finally, I make it clear that one can take months to years to make a decision about ART, and that as far as we know, those who start ART can later stop it safely, without fear of losing control of their virus.

With all of those caveats, I then outline the pros and cons of therapy. The decision essentially comes down to the known toxicities, costs, and inconvenience of therapy versus the theoretical harm associated with HIV-related inflammation. I then tell patients I would be inclined to start therapy, particularly if there is any evidence of chronic inflammation (including a high CD8+ T-cell count) or CD4+ T-cell loss. I have found most patients to be open to treatment, but most have chosen to take their time in making this decision.