New HIV Treatment Guidelines Issued

August 4, 2008 (Mexico City) — New HIV treatment guidelines issued by the International AIDS Society–USA urge starting therapy sooner. The guidelines incorporate both newly approved drugs and a greater understanding of disease pathology.

They were unveiled here at a news conference in Mexico City prior to the start of the AIDS 2008: XVII International AIDS Conference and are published in the August 6 issue of the Journal of the American Medical Association.

The recommendations "are built on the precept of integrated pathogenesis of HIV infection along with the best evidence that we have got to individualized therapy," said Scott Hammer, MD, Columbia University College of Physicians and Surgeons in New York, NY, who made the presentation on behalf of the panel that developed the guidelines. The 15 members were drawn from 6 different countries.

While written for wealthier nations, Dr. Hammer said, "The principles that we espouse are universally applicable to middle income countries and hopefully, eventually are translatable to low resource settings." The goal is to achieve maximum suppression of the virus, with minimal toxicity, and maximum simplicity. "When you do this you promote adherence and minimize resistance."

The 3 drugs approved since the last version of the guidelines in 2006 are maraviroc, which Dr. Hammer called "a very important addition to the armamentarium" because it is the first drug to target the CCR5 co-receptor on the surface of the cell; raltegravir, the first drug in the integrase inhibitor class; and etravirine, a second-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) "with clear activity against some NNRTI-resistant viruses."

The emergence during the past 2 years of "regimens that are potent, durable, more simple than they were before, and safer, [plus] better formulations with improved pharmacokinetics which enhance adherence and therefore diminish resistance — overall present us with more treatment options, not just to start but most importantly on the second, third, and fourth rounds of treatment."

The guidelines move aggressively toward earlier initiation of antiretroviral therapy, prior to a decline in CD4 cell count less than 350/μL, if certain other clinical conditions are present.

Referring to the SMART (The Strategies for Management of Antiretroviral Therapy) study, he said, "Uncontrolled HIV replication (>100,000 copies/mL) and resulting immune activation are associated with non-AIDS illnesses — cardiovascular, hepatic, and renal events, and non-AIDS malignancies, really a potpourri of issues that are not classically thought of as HIV disease related disease progression." Individuals with incomplete virologic suppression have greater morbidity and mortality than those who more completely suppress it.

Dr. Hammer said the definition of HIV disease progression has broadened because "HIV viremia and the immune activation that accompanies that intersects with the host and organ systems in a number of different ways."

When to Start

Unchanged are the recommendations to start therapy in any patient with symptomatic HIV disease, regardless of CD4 count or viral load, and asymptomatic patients with less than 200/μL CD4 cell count.

Initiation of therapy in patients within the 200 to 350/μL CD4 cell count range should be strongly considered and individualized. Dr. Hammer said, "This recommendation is simplified and strengthened."

Previous guidelines capped consideration of starting therapy at 500/μL CD4 cell count, but in the revised version, "We are specifically not putting in an upper limit threshold," he said.

Above 350/μL CD4 cell count, initiation of therapy should be strongly considered "where there are correlates of faster HIV disease progression such as high viral loads, such as >100,000 copies/mL or rapid CD4 decline, over 100 per year." High risk for cardiovascular disease, coinfection with hepatitis B or C (resulting in faster progression of liver disease), and the occurrence of HIV-associated nephropathy are also suggestive of the need to begin treatment.

Choosing a Regimen

"Clinicians are encouraged to evaluate the whole patient, not just the status of HIV disease, but all coexisting conditions," said Dr. Hammer. "Resistance testing should be conducted in all patients as part of their baseline workup."

There is little change in recommendations for an initial regimen in patients who are not infected with resistant virus. The first-line choice is a backbone of either an NNRTI or a ritonavir-boosted protease inhibitor (PI), combined with a dual nucleoside reverse transcriptase inhibitor (NRTI) component. He said there is "a wealth of evidence" of randomized comparative trials of the available options.

Dr. Hammer suggested not using darunavir as part of an initial regimen but holding it in reserve to use with patients who develop resistance to other PIs.

Recent findings on abacavir hypersensitivity, possible lower efficacy in patients with high viral loads (>100,000 copies/mL), and increased risk for cardiovascular disease suggest caution in using this drug in a regimen.

First-line failure of a NNRTI-based regimen should be treated with 2 active NRTIs plus a ritonavir-boosted PI. Depending on the NRTI mutations present, one might want to consider use of etravirine.

Failure of a PI-based regimen can be more complicated, "depending upon the genetic barriers." If caught early, changing the NRTI component to 2 active drugs might be sufficient to save the regimen. But as resistance points accumulate, one should consider use of darunavir or tipranavir.

One change in the recommendations is a greater emphasis on full virologic suppression. "Approval of raltegravir has taken us another leap forward in achieving virologic suppression in patients with multiple drug resistance HIV," Dr. Hammer said.

Enfurvitide remains an important option for the heavily treatment experienced population, but problems associated with daily injections and the emergence of other therapeutic alternatives such as raltegravir or maraviroc have reduced its use.

"Raltegravir looks great in naive subjects," he said. "It has raised the question of, down the line, might integrase inhibitors replace existing classes. I don't think we are ready to be there yet." Current first-line regimens are good and simple to use, and there is still concern about holding some drugs in reserve for patients who develop resistance to existing drugs.

Broader Application

Dr. Hammer believes these changes in the guidelines "substantially increases the eligible group" of those who would benefit from treatment. "In the United States that probably translates to a few hundred thousand more people."

Broader application of these guidelines to less affluent parts of the world is hampered by the availability of sophisticated diagnostics and the cost of follow-up regimens. He said, "The gap is widening. It is not just in monitoring...Going from a generic, fixed-dose combination NNRTI-based first line regimen to a ritonavir-boosted protease inhibitor regimen, increases the cost 4-to-6-fold in most non-US or European countries."

Given the increased prominence that these guidelines give to historically non-HIV identified factors in the decision of whether to initiate therapy, Medscape HIV asked Dr. Hammer what was the role of the HIV specialist in this new paradigm.

"HIV is a humbling organism," he began. "You need multispecialty expertise to take care of complex individuals. You still need the HIV specialist to integrate information, interpret drug resistance information, and choose the regimens. It is still an individualized decision. It is not that everybody above 350 [CD4 cell count] should be treated, the issue is to think about comorbid conditions, and then make a decision."

AIDS 2008: XVII International AIDS Conference. Antiretroviral Treatment of Adult HIV Infection, 2008 Recommendations of the International AIDS Society–USA Panel. Presented August 3, 2008.

JAMA. 2008;300:555-570.