Same Data, Contradictory HIV Guidelines

Daniel M. Keller, PhD

October 22, 2014

PHILADELPHIA — Five sets of HIV treatment guidelines from expert organizations around the world have been issued or updated this year, but the recommendations are inconsistent.

"What these guidelines have in common is that they get a group of experts together, they review all available data, and then they make recommendations for clinicians," said Roy Gulick, MD, from Weill Cornell Medical College in New York City, and cochair of the US Department of Health and Human Services antiretroviral guidelines panel. He was speaking during an antiretroviral therapy guideline update here at IDWeek 2014.

"One of the most remarkable things is they're all looking at the same data, yet some of these guidelines come to different conclusions," he pointed out. The methodologies that the organizations use and the way they synthesize the information can lead to different conclusions.

Among the organizations that have issued or updated their treatment guidelines in the past year are the US Department of Health and Human Services (DHHS), the International Antiviral Society–USA, the British HIV Association (BHIVA), the European AIDS Clinical Society (EACS), and the World Health Organization (WHO).

One of the most fundamental questions is when to start antiretroviral therapy. Several recent clinical trials and cohort studies have looked at the CD4+ T-cell count at which to start therapy, and thresholds have ranged from below 200/mm³ to above 500/mm³.

The fact that antiretroviral therapy has become less toxic, more potent, and more convenient might also influence the recommended threshold for the initiation of therapy. Some of the older regimens involve up to 20 pills a day, but there are now 4 regimens that involve one pill a day, and a fifth once-daily pill is in phase 3 clinical trials.

 
A lot of different numbers, and we're all looking at the same data here.
 

Current American guidelines recommend starting antiretroviral therapy even when the CD4+ T-cell count is above 500/mm³, so essentially anyone infected with HIV. European guidelines say to consider or offer antiretroviral therapy when the count is in the 350 to 500/mm³ range, and they and the WHO guidelines recommend starting antiretroviral therapy if the CD4+ T-cell count is below 350/mm³.

Recommendations on the CD4+ threshold for the initiation of therapy in these three sets of guidelines were compiled last year (N Engl J Med. 2013;368:886-889). The most divergence was seen for counts above 350/mm³, but all agree that antiretrovirals should be initiated if someone has AIDS or symptomatic disease, regardless of the CD4+ count.

The EACS and BHIVA guidelines recommend therapy on the basis of comorbid conditions for certain patients with CD4+ T-cell counts exceeding their thresholds, such as those with malignancies, serious viral infections, tuberculosis, neurocognitive impairment, or pregnancy.

That's almost everyone being recommended for therapy, said Dr Gulick.

All five guidelines are in relative agreement that tenofovir and emtricitabine should be the initial nucleoside reverse-transcriptase inhibitor (NRTI). Abacavir and lamivudine can be used as an alternative, but it is less effective at high viral loads.

For non-nucleoside reverse-transcriptase inhibitors (NNRTIs), they recommend efavirenz, or rilpivirine at lower viral loads. The recommended first-line protease inhibitors are ritonavir-boosted atazanavir and ritonavir-boosted darunavir, and the recommended first-line integrase inhibitors are elvitegravir or raltegravir (plus dolutegravir in the two American guidelines).

"We really see a convergence of first-line recommended therapies around the world," said Dr Gulick. He noted, however, that the WHO makes no recommendation for a protease inhibitor or an integrase inhibitor.

There are currently at least seven first-line therapies recommended in the United States, but the list will likely narrow after results are released from current head-to-head comparisons that take into account virologic or composite virologic and toxicity end points, he explained.

The guidelines have slightly different criteria for what constitutes virologic failure. The threshold in both the DHHS and IAS–USA guidelines is 200 copies/mL, in the EACS guidelines is 50 copies/mL, in the BHIVA guidelines is 400 copies/mL, and in the WHO guidelines is 1000 copies/mL. "Again, a lot of different numbers, and we're all looking at the same data here," Dr Gulick said.

All the treatment guidelines except EACS make recommendations for pre-exposure prophylaxis (PrEP). Because the European Medicines Agency has not approved PrEP, no European country has approved it. The BHIVA recommends using PrEP only in the context of a clinical study.

At the end of his presentation, Dr Gulick thanked anyone in the audience who has ever served on a guidelines panel, because "we all really go by guidelines. We trust that experts are synthesizing and making informed and intelligent recommendations."

He recommended that young clinicians in the audience serve on a guidelines panel. "It's an unrivaled opportunity to be with some of the best people in the field and really get to carefully look at what available data there are," he said.

New Drugs, New Guidelines

New drugs, "especially new integrase inhibitors," have been approved recently, so it was essential to update guidelines, said Joel Gallant, MD, chair of the HIV Medicine Association and associate medical director of the Southwest CARE Center in Santa Fe, New Mexico.

An important change in American guidelines has been the inclusion of a recommendation for combinations of any of the three integrase inhibitors (elvitegravir, raltegravir, and dolutegravir), he told Medscape Medical News. "Personally, I think the evidence is becoming pretty convincing that integrase inhibitor-based regimens are going to be the way to go for most people," he said. In "virtually every study," they proved superior to the standard of care, or noninferior but with better tolerability.

Already, providers are starting to favor these regimens over NNRTIs or protease inhibitor-based regimens. Integrase inhibitor-based regimens appear to work at all HIV viral loads and at any stage of the disease.

Another change has been that DHHS has dropped its terminology indicating "preferred, alternative, and other regimens," and instead adopted "recommended and alternative." There are now so many good regimens, it is no longer necessary to have a "third and fourth class of regimens that really nobody would recommend using anymore," Dr Gallant explained. In addition, the DHHS added some recommended, but not "preferred," regimens that are appropriate for people with lower baseline viral loads.

It is worth noting that the American guidelines continue to recommend antiretroviral therapy for anyone infected with HIV, regardless of CD4+ T-cell count, "both for the benefit of the individual and for the prevention benefits," he said.

Unfortunately, the guidelines offer no recommendation when it is not possible to prescribe tenofovir or abacavir. Dr Gallant said he hopes to see "a newer, better" tenofovir in the form of tenofovir alafenamide, which appears not to have the bone and kidney toxicity of the current formulation of tenofovir disoproxil fumarate.

He said he is looking forward to results from a North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) study that might establish whether or not abacavir increases the risk for myocardial infarction. "Of course, our hope is that it doesn't, in which case we'll have tenofovir alafenamide, and we'll have abacavir without the concern about myocardial infarction, and we probably won't need NRTI-sparing regimens in the future," he said.

One of the drugs in the pipeline is doravirine, which has advantages over existing NNRTIs. Although the pipeline is somewhat limited, new coformulations will appear, and tenofovir alafenamide will replace tenofovir disoproxil fumarate in current combinations. Tenofovir alafenamide might also offer some advantages over tenofovir disoproxil fumarate in terms of resistance because intracellular levels are higher with tenofovir alafenamide and in terms of toxicity because plasma levels are lower.

Dr Gulick has disclosed no relevant financial relationships. Dr Gallant reports financial relationships with Bristol-Myers Squibb, CytoDyn, Gilead Sciences, Merck & Co., Takara Bio, Sangamo BioSciences, Vertex Pharmaceuticals, ViiV Healthcare, and Janssen Therapeutics.

IDWeek 2014. Presented October 10, 2014.

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