San Francisco Health Officials Announce New Policy of Universal HIV Treatment Regardless of CD4 Cell Count

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Providers at San Francisco General Hospital (SFGH) and other facilities run by the San Francisco Department of Public Health (SFDPH) are now offering antiretroviral therapy (ART) to all patients who test HIV positive, regardless of CD4 cell count. At a community forum this week, health officials and researchers discussed the policy change, the scientific evidence supporting earlier therapy, and potential concerns including increased cost and need for adherence support. 

As first described in an April 2 article in the New York Times, newly diagnosed individuals are now being given the opportunity to start ART immediately, rather than waiting until their CD4 cell count falls into the 350-500 cells/mm3 range specified in the current U.S. treatment guidelines.

"Based on accumulated data we believe all HIV-infected persons should be treated with antiretroviral therapy unless there is a strong reason not to," said SFDPH director Mitch Katz. "A strong reason could be that the patient or the primary care provider feels it is not best for that particular patient. Although this is a policy change, we don't dictate medical practice by policy; no one will be in the examination room other than the patient and the provider."

The new policy is supported by a growing body of evidence showing that early HIV treatment can help prevent non-AIDS complications that may occur well before a person's CD4 cell count falls into the danger zone for opportunistic infections (OIs). Recent research has also clarified that HIV has detrimental effects throughout the body from the earliest stages of infection.

"Now we know that HIV from the start is causing damage to more than just the immune system," explained Diane Havlir, chief of the UCSF Division of HIV/AIDS at SFGH. "The virus is causing damage to multiple organs including the heart, liver, kidneys, and probably the brain, even when people have high CD4s and feel fine." This is "not surprisingly from a biological standpoint," she added, since it is "probably pretty unlikely" that unchecked viral replication is not doing any harm.

When to start HIV treatment has been a controversial issue since the early years of the epidemic. Soon after the advent of combination ART, David Ho and others proposed a "hit early, hit hard" strategy, hoping that very early therapy could eradicate the virus. But as it became apparent that ART could cause long-term side effects including body shape changes and metabolic abnormalities, patients and providers began to favor delaying treatment as long as possible.

The large SMART treatment interruption trial was designed to test whether people could safely stop therapy when their CD4 cell count was above 350 cells/mm3 in an effort to minimize drug exposure and toxicity. On the contrary, as first reported at the 2006 Conference on Retroviruses and Opportunistic Infections, participants who periodically stopped treatment not only had more AIDS-related OIs than those who stayed on continuous therapy, but also had more non-AIDS cardiovascular, liver, and kidney disease, as well as a higher risk of death due to any cause.

An analysis of the large NA-ACCORD cohort, which included more than 17,500 asymptomatic HIV positive patients receiving care in the U.S. and Canada since the start of the ART era, found that participants who started treatment immediately had a lower risk of death than those who deferred therapy, even at relatively high CD4 counts of 350-500 or > 500 cells/mm3.

Based on these and other studies, this past December the U.S. Department of Health and Human Services updated its ART guidelines to recommend earlier treatment, raising the threshold from below 350 to the 350-500 cells/mm3 range; above this level, half the expert panel favored treatment initiation and half said it was optional.

In the years since the SMART findings were first reported, numerous studies have implicated excessive immune activation and chronic inflammation due to ongoing HIV replication as a cause of non-AIDS complications and what appears to be accelerated aging in people with HIV.

"I'm going to argue that we should perhaps think of AIDS as acquired inflammatory disease syndrome," said Steven Deeks, also with the UCSF Division of HIV/AIDS. "From the get-go HIV is causing high level inflammation and inflammation-associated disease. Antiretroviral therapy can make people live longer, but it does not restore health and they do not have a normal lifespan."

While HIV treatment dramatically reduces inflammation, it does not completely normalize, and the degree of residual inflammation is determined in part by when a person starts treatment, Deeks explained. Even "elite controllers" who naturally maintain an extremely low viral load without therapy show detrimental effects that are likely due to low-level HIV replication.

"Five years ago we said drugs are no fun and we should wait, but the consequence of waiting is that people develop irreversible harm to the immune system," Deeks continued. "The old paradigm was that drugs are toxic so we should wait as long as possible. The new paradigm is that while today's drugs are not totally benign, they are less toxic than the virus."

Acknowledging that much remains to be learned, Deeks indicated that he would rather err on the side of treating too early than too late. "If I'm wrong, we'll start people [on treatment] a couple years earlier than we otherwise would. But if I'm right and we don't start early, there's no going back."

The San Francisco policy change was motivated by benefits to the individual patient, but Katz noted that earlier treatment might also help reduce HIV incidence. A mathematical model recently published by World Health Organization researchers showed that HIV transmission could potentially be eliminated if universal testing were implemented and all people who test positive received prompt treatment regardless of CD4 count, as the San Francisco policy recommends.

"This is not a discussion primarily about prevention, but we do believe from a public health perspective that early treatment will drive down community viral load and reduce transmission," he said. "We know treatment doesn't eliminate transmission, but we believe this policy will ultimately result in fewer new infections."

Dana Van Gorder, executive director of Project Inform, recognized that none of the evening's panelists represented experts who oppose earlier treatment, for reasons ranging from insufficient data to concerns about cost, adherence, and drug resistance. The day before the forum, Project Inform issued a position statement -- the first in its 25-year history -- on when to start therapy.

"Based upon a careful review of currently available data, Project Inform believes that all HIV positive people who are ready to begin treatment should start at least before their CD4 counts fall below 500," the statement reads in part. "Deciding whether to start treatment above 500 CD4s is an individual choice to be made with a qualified medical provider."

But not everyone agrees with this assessment. Van Gorder noted that the Treatment Action Group in New York City has chosen not to take position until more data are available. The aforementioned New York Times article quoted long-time UCSF HIV researcher Jay Levy as saying that the immediate treatment policy is "just too risky" given the unknown side effects of taking antiretroviral drugs for decades.

The Strategic Timing of Antiretroviral Treatment (START) trial may provide more definite answers. The study, which began enrolling participants last year, will compare immediate versus deferred therapy in individuals with high CD4 counts. START is not expected to provide data until at least 2015, however. "When people come in with seroconversion, they want treatment," said Stephen Follansbee, director of HIV services at Kaiser San Francisco. "I don't want to wait, and I don't think our patients want to wait for data that might not even apply to them."

With regard to the risk of drug resistance if people start treatment sooner, Havlir noted that the proportion of resistant HIV in San Francisco has actually been decreased as more people have started effective treatment, from 28% in 2000 to just 15% in 2009. Likewise, recent data from Vancouver showed that expanded treatment was accompanied by an increased rate of viral suppression and a decreased rate of resistance.

During the discussion following the panel presentations, most questions concerned the added costs of treating more people at a time when federal, state, and local resources devoted to health care are already stretched to the breaking point.

Brad Hare, medical director of SFGH's Positive Health Program, suggested that the new policy probably would not lead to a surge of new people starting treatment. Of the more than 2,600 patients (500 of them new) seen at SFGH last year, more than 80% are already on therapy. The average CD4 count of people accessing care is about 425 cells/mm3, indicating that more than half would qualify for treatment even under the previous threshold. Similarly, Michelle Roland, chief of the California Office of AIDS, said that many providers already made the shift to earlier therapy when the revised federal guidelines came out last year.

While noting that prompt therapy often proves cost-effective in the long run, panelists argued that budgetary constraints should not discourage state-of-the-art care.

"Since beginning of the epidemic San Francisco has always been on the leading edge," Katz said. "We've never debated about whether we think low-income people are entitled to the same advances as everyone else."

"I am confident that even in this economy, our leaders can make the case that this is an effective intervention," said Havlir.

4/16/10

Sources

L Highleyman. SF health officials advise early treatment for people with HIV. Bay Area Reporter. April 15, 2010.


S Russell. City Endorses New Policy for Treatment of H.I.V. New York Times. April 2, 2010.

Project Inform. Project Inform's position on when to start HIV treatment. April 2010.