US panel updates antiretroviral treatment guidelines

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On October 14th the US Department of Health and Human Services (DHHS) issued updated guidelines for the use of antiretroviral therapy (ART) in adults and adolescents, coinciding with the release of revised European AIDS Clinical Society (EACS) guidelines at the 13th European AIDS Conference last week in Belgrade.

The key changes in this version of the US guidelines focus on which drugs to start in a first-line regimen for treatment-naive patients.

In the non-nucleoside reverse transcriptase inhibitors (NNRTI) class, efavirenz (Sustiva, Stocrin) plus tenofovir/emtricitabine (the drugs in the Truvada coformulation) continues to be the "preferred" first-line regimen, except for pregnant women.

Glossary

reverse transcriptase

A retroviral enzyme which converts genetic material from RNA into DNA, an essential step in the lifecycle of HIV. Several classes of anti-HIV drugs interfere with this stage of HIV’s life cycle: nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). 

nucleoside

A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 

naive

In HIV, an individual who is ‘treatment naive’ has never taken anti-HIV treatment before.

first-line therapy

The regimen used when starting treatment for the first time.

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

Regimens containing nevirapine (Viramune) are now classified as "acceptable" for appropriate patients - that is, women with pre-treatment CD4 cell counts below 250 cells/mm3 and men below 400 cells/mm3 (people with higher counts are at greater risk for hypersensitivity reactions).

The recently approved NNRTI rilpivirine (Edurant) was included as an "alternative" component of initial therapy thanks to accumulated data supporting its safety and efficacy. The new EACS guidelines rate efavirenz and nevirapine equally as recommended options, but do not include rilpivirine, which still awaits final marketing approval in the European Union.

Turning to protease inhibitors, once-daily ritonavir-boosted atazanavir (Reyataz) or boosted darunavir (Prezista) plus tenofovir/emtricitabine are the "preferred" options. Darunavir plus abacavir/lamivudine (the drugs in the Kivexa and Epzicom coformulations) was reclassified as an "alternative" due to additional data. But unboosted fosamprenavir (Telzir, Lexiva) was removed due to inferior potency and risk of drug resistance.

Similarly, raltegravir (Isentress) - the sole approved integrase inhibitor - plus tenofovir/emtricitabine remains the "preferred" regimen, whilst raltegravir plus abacavir/lamivudine was upgraded to "alternative" with accumulation of favourable data.

With regard to nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbones, the DHHS guidelines keep tenofovir/emtricitabine as the sole "preferred" option (except for pregnant women) and abacavir/lamivudine as an "alternative".

The DHHS panel demoted abacavir/lamivudine from "preferred" to "alternative" status in 2008 due to concerns that abacavir may increase the risk of heart attacks and may not be as effective for people with high pre-treatment viral load.

By now, numerous studies have produced conflicting data about the comparative risks and benefits of abacavir/lamivudine and tenofovir/emtricitabine. The new DHHS guidelines include more extensive discussion of this issue, concluding that abacavir/lamivudine "remains a good alternative dual-NRTI option for some ART-naive patients". The EACS guidelines recommend the two backbones equally.

Certain other dual NRTI backbones were demoted or removed entirely due to toxicities. The first-ever NRTI combinations - zidovudine/lamivudine (the drugs in the Combivir coformulation) - was reclassified from "alternative" to "acceptable" overall, but remains the preferred NRTI combination for pregnant women receiving antiretroviral drugs to prevent mother-to-child HIV transmission.

As for when to initiate HIV treatment - a subject of ongoing controversy - the US guidelines continue to advise starting when a person's CD4 cell count falls below 500 cells/mm3. Above that level the panel was split on whether to start or wait.

The EACS guidelines are more conservative, recommending treatment initiation at a threshold of 350 cells/mm3, although ART is advised below 500 cells/mm3 - or even sooner - for several patient groups including pregnant women and people with co-existing conditions such as HIV-associated kidney disease, neurocognitive impairment and hepatitis B or C.

The full revised DHHS guidelines are available online at http://aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=7&ClassID=1. Changes are summarised in an introductory section, "What's New in the Guidelines?"

References

US Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. October 14, 2011.