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Revised U.S. Antiretroviral Therapy Guidelines Call for Earlier Treatment and Promote Raltegravir (Isentress) to a Preferred First-line Option

On December 1, the U.S. Department of Health and Human Services (DHHS) updated its guidelines for antiretroviral therapy (ART) for HIV positive adults and adolescents. In keeping with recent research, the revision calls for earlier treatment. ART is now recommended for people with 350-500 cells/mm3, and half the expert panel favored treatment even for those with more than 500 cells/mm3. For first-line therapy, the integrase inhibitor raltegravir (Isentress) was added to the list of "preferred" options, while lopinavir/ritonavir (Kaletra) was changed to an "alternative" due to side effects.

The revised guidelines include the following key changes from the November 3, 2008 version:

• New section on management of patients with HIV-2 infection.
• Revised section on drug resistance testing, with more specific recommendations on when to use genotypic vs phenotypic tests.
• Recommendation for earlier initiation of antiretroviral therapy:
  • ART should be initiated in all patients with a CD4 count < 350 cells/mm³ or history of an AIDS-defining illness.
  • ART should also be initiated, regardless of CD4 count, for pregnant women, people with HIV-associated nephropathy (kidney disease), and hepatitis B virus (HBV) coinfection that requires treatment.
  • ART is "recommended" for patients with CD4 counts between 350 and 500 cells/mm³.
  • ART is "favored" or "optional" for individuals with > 500 cells/mm³.
• Revised list of drugs to start as initial therapy for treatment-naive patients:
  • Raltegravir + tenofovir/emtricitabine added as a “preferred” regimen.
  • Lopinavir/ritonavir now listed as "alternative," except for pregnant women.
• Substantially updated sections and related tables on:
  • What drugs not to use;
  • Management of treatment-experienced patients;
  • Treatment simplification;
  • Hepatitis C coinfection;
  • Antiretroviral-associated adverse effects;
  • Antiretroviral drug interactions;
  • Preventing transmission of HIV to others.

When to Start

The recommendation to start ART sooner reflects a growing body of evidence accumulated over the past few years indicating that earlier treatment has considerable benefits.

Although opportunistic infections and cancers typically occur at a CD4 count < 200 cells/mm³, studies show that the risk of both AIDS-related and non-AIDS conditions (including cancers caused by infectious agents such as human papillomavirus) increases as CD4 count falls, even at relatively high levels.

Other studies have shown that people who start ART with a relatively high CD4 cell -- above 350, 500, or even 700 cells/mm³ in various studies -- have a significantly better chance of eventually achieving a normal level.

Even low-level HIV can lead to previously unrecognized problems throughout the body. Ongoing viral replication triggers immune activation and chronic inflammation, which can contribute to conditions including cardiovascular disease, liver and kidney damage, neurocognitive impairment, and bone loss, and may accelerate the aging process. The SMART study suggested that allowing viral levels to rise and fall with CD4-guided treatment interruption may be particularly harmful.

Taking this evidence into account, a slim majority (55%) of the DHHS expert panel thought that ART initiation between 350 and 500 cells/mm³ deserved a "strong" recommendation, while 45% gave it a "moderate" recommendation.

Studies are less clear about the benefits of ART at high CD4 counts > 500 cells/mm³ -- within the normal range for HIV negative people. Given that modern ART is generally well-tolerated and any amount of HIV replication appears harmful, 50% of the panel members "favored" treatment above this threshold, while the other half considered it "optional."

The panel acknowledged that early ART can have drawbacks and may not be appropriate for everyone.

"Patients initiating antiretroviral therapy should be willing and able to commit to lifelong treatment and should understand the benefits and risks of therapy and the importance of adherence," they wrote. "Patients may choose to postpone therapy, and providers may elect to defer therapy, based on clinical and/or psychosocial factors on a case-by-case basis."

What to Start

With regard to what drugs to start for first-line therapy in treatment-naive patients, the major change is the addition of raltegravir, the first approved integrase inhibitor, as a preferred drug.

This recommendation is based on data from the STARTMRK trial, which found that raltegravir suppressed viral load as well as efavirenz (Sustiva), but was better tolerated overall, and especially in terms of central nervous system (CNS) side effects.

There are now 4 regimens listed as "preferred" options for initial therapy:

• Efavirenz + tenofovir/emtricitabine (Truvada)(all 3 drugs are in the Atriplacoformulation)
• Ritonavir-boosted atazanavir (Reyataz)+ tenofovir/emtricitabine;
• Ritonavir-boosted darunavir (Prezista)+ tenofovir/emtricitabine;
• Raltegravir + tenofovir/emtricitabine.

Lopinavir/ritonavir was "demoted" to an "alternative" primarily due to the fact that it causes more side effects that the other regimens, including gastrointestinal side effects and blood lipid elevations, which may increase the risk of cardiovascular disease. But efavirenz, as noted, often causes CNS symptoms, and atazanavir can cause elevated bilirubin, potentially resulting in jaundice (yellowing of the skin and eyes).

Twice-daily lopinavir/ritonavir, in combination with zidovudine/lamivudine (Combivir) remains a preferred regimen for pregnant women, since efavirenz is contraindicated during pregnancy, lopinavir/ritonavir has been more extensively studies than the newer agents, and this regimen lowers the risk of mother-to-child HIV transmission.

Tenofovir/emtricitabine is the sole preferred NRTI "backbone" (except for pregnant women, as noted above). Abacavir/lamivudine (Epzicom)was included in a previous version of the guidelines, but was removed due to concerns about inferior efficacy in patients with high baseline viral load and increased risk of heart attacks. Both concerns remain subject to debate, due to conflicting study data; recently updates European guidelines still include abacavir along with tenofovir.

Guidelines Comparison

On November 30, the World Health Organization (WHO) also issued updated guidelines, which are widely adopted in low- and middle-income countries. These guidelines raised the threshold for starting therapy from 200 to 350 cells/mm³. They also called for replacing older, more toxic drugs -- in particular stavudine (d4T; Zerit)-- with more tolerable alternatives such as tenofovir.

WHO and the International AIDS Society have endorsed universal access to ART as a strategy for reducing the rate of new HIV infections, given that people on effective treatment have much lower viral loads and therefore are less likely to transmit the virus.

Updated guidelines from the European AIDS Clinical Society (EACS) released at the group's annual meeting in November, indicated that starting ART in the 350-500 cells/mm³ range, or even higher, should be considered for several groups including pregnant women, people older than 50 years, patients with high HIV viral load or rapidly declining CD4 count, and people with co-existing conditions including hepatitis B or C coinfection, kidney disease, cancer, and elevated cardiovascular risk -- as well as individuals outside these groups who seek and are ready for therapy. However, they did not go as far as the new DHHS guidelines in issuing a blanket recommendation for ART initiation under 500 cells/mm³.

While the worldwide trend is clearly toward earlier antiretroviral treatment, side effects and development of resistance remain a concern, especially for people who have no signs of HIV disease progression. In addition, dramatically increasing the number of patients eligible for ART will increase the strain on resources, both in poor countries where millions of people lack access even using the old 200 cells/mm³ threshold, and in the U.S. where the ongoing recession is putting a strain on AIDS Drug Assistance programs (ADAPs).

12/4/09

Reference

U.S. Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. December 1, 2009.

Other Sources

R Klein and K Struble (U.S. Food and Drug Administration). Updated Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents available. HIV/AIDS Update. December 1, 2009.

L Highleyman. U.S. and WHO guidelines
call for earlier HIV treatment. Bay Area Reporter. December 3, 2009.

P Dalton. My Thoughts on the New Guidelines. POZ Blog. December 1, 2009.

Merck & Co. U.S. Department of Health & Human Services Recommends Merck's First-in-Class Integrase Inhibitor Isentress (raltegravir) Tablets, in Combination Therapy, as a Preferred Regimen for Treatment-Naïve Patients with HIV-1 Infection. Press release. December 1, 2009.