Abstract & Commentary

New DHHS Guidelines for Antiretroviral Therapy

By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine. Dr. Winslow serves as a consultant for Siemens Diagnostics, and is on the speaker's bureau for GSK and Cubist.

Synopsis: The revised DHHS guidelines for antiretroviral therapy (ARV) of adults and adolescents were released in December 2009. Significant changes to earlier versions of the guidelines include: recommending possible initiation of ARV at CD4+ lymphocyte counts between 350-500 cells/uL, including raltegravir and darunavir/ritonavir in ARV regimens for treatment-naïve patients, treatment of HIV-2 infection, and guidelines for management of HCV/HIV co-infected patients.

Source: Panel on antiretroviral guidelines for adults and adolescents. Guidelines on the use of antiretroviral agents in HIV-1 infected adults and adolescents. Department of Health and Human Services. 2009;1-161. http://www.aidsinfo.nih.gov/ContentFiles/AdultsandAdolescentGL

The latest iteration of the DHHS guidelines was released December 1, 2009. The major changes to previous versions of the guidelines include a number of changes listed below:

  1. Recommending HIV-1 genotyping as the preferred resistance test for first- or second-regimen failures and consideration of phenotyping for evaluation of known or suspected complex drug resistance patterns, particularly with HIV-1 protease inhibitors.
  2. In addition to the previous recommendation to initiate antiretroviral therapy in all patients with AIDS-defining illness or CD4 < 350, the guidelines clarify the recommendation to initiate ARV in the setting of pregnancy, HIV-associated nephropathy (HIVAN), and hepatitis B virus infection (or when treatment of HBV is otherwise indicated). The Panel also recommended considering institution of ARV when the CD4 count was between 350 and 500 but disagreed on the strength of the evidence supporting the recommendation. The panel was divided on recommending ARV therapy in patients with CD4 > 500.
  3. In addition to the recommendation of tenofovir (TDF) + emtricitabine (FTC) in combination with either efavirenz (EFV) or ritonavir-boosted atazanavir (ATV/r), the panel (following recent FDA approval) also included TDF/FTC + raltegravir and TDF/FTC + ritonavir-boosted darunavir (DRV/r) as preferred initial regimens. Kaletra (LPV/r) is now considered an alternative regimen for treatment-naïve patients.
  4. The warning for clinicians to avoid interrupting ARV is reiterated, and the guidelines make it clear that IL-2 is devoid of clinical utility.
  5. A section on treatment of HIV-2 infection is added, reminding clinicians that non-nucleoside RT inhibitors (nnRTIs) and enfuvirtide are not active against HIV-2.
  6. A section on considerations for management of antiretroviral therapy in HCV coinfected patients is added.

Commentary

The latest version of the DHHS guidelines for antiretroviral therapy represent a large volume of work and immediately become the standard of care for management of HIV-infected patients. The document has grown to 161 pages and contains numerous useful tables, as well as carefully worded explanations for the new recommendations made.

While the document represents an important summary of current knowledge, I have some minor concerns about some of the recommendations made in this iteration. For the record, I have known almost all of the panel members personally (for many years) and they are uniformly excellent clinicians and knowledgeable in the field of HIV medicine. Having participated in similar panel meetings in years past, I am aware of the tendency of many of us in the field to be less than critical in our embracing of new ideas and susceptibility to "group-think." Over the years, I've seen dozens of ideas, accepted as true by the opinion leaders, become "standard of care" only then to finally have the ideas disproved a few years later (i.e., aerosolized pentamidine for PCP, adefovir/ddI/hydroxyurea as an ARV regimen, the notion that PI's are superior to nnRTIs in patients with high viral loads, the utility of in vitro "replication capacity," etc.). At the meetings we all attend, it sometimes seems like unsupported ideas become accepted/true by virtue of us repeating them to each other (with serious expressions on our faces) often enough at different meetings. (Yes, I, too, nod my own head wisely in agreement with my colleagues most of the time!) Fortunately, the DHHS guidelines generally reflect the uncertainty of the quality of evidence if one reads the fine print.

One minor concern in this document includes the recommendation for phenotypic resistance testing in patients who have failed multiple regimens. While intuitively this recommendation makes sense (and most HIV doctors, including me, occasionally order phenotypic testing in this situation), no data from controlled trials have ever shown that phenotypic testing is useful in this group of patients. In fact, phenotypic testing is probably least useful in patients who have failed multiple regimens. While both the European VIRADAPT study1 and the U.S. CPCRA-sponsored GART study2 demonstrated that one sees a 0.5 log incremental benefit of genotypic testing (vs. standard of care — educated guessing) in selecting a new regimen in patients failing therapy, no virologic benefit of phenotyping has ever been demonstrated except in the Virco-sponsored VIRA 3001 study (which was limited to patients failing their first ARV regimen). The European NARVAL study did demonstrate a benefit of genotyping but no benefit of phenotyping in patients failing therapy.3 Even the Monogram Biosciences-supported CCTG 575 study (chaired by a member of the Monogram Advisory Board) failed to demonstrate that phenotyping was any better than educated guessing in selecting a new regimen in patients failing ARV therapy.4 (When I order a phenotype in a highly treatment-experienced group, I always think of the joke about the man frantically searching for his lost car keys under the streetlight — because that's where the light is best — rather than in the dark part of the parking lot where he probably lost them!) It should be noted that the Europeans don't order phenotypes at all — which I believe reflects their willingness to critically look at the data and to be better stewards of limited healthcare resources than we are in the United States. Despite this lack of data, American HIV-treating physicians continue to order these incredibly expensive assays ($1,200 or more per test) and, now, the DHHS panel has enshrined this practice based on paltry evidence. A much more useful (and inexpensive) alternative to phenotyping in treatment-experienced patients is the Virco "Virtual Phenotype," which gives information complementary to the genotype at a fraction of the cost of a true phenotype and with greater reliability since it is derived from the genotype sequence.

Another concern regarding this latest version of the DHHS guidelines is the firm recommendation to initiate ARV therapy in all patients with CD4 between 350 and 500, and a recommendation to even consider this in patients with CD4 > 500. This recommendation is largely based on the recently published NA-ACCORD trial, which purported to show reduced mortality in patients who initiated ARVs with higher CD4 counts.5 This case-control study was seriously flawed by the self-selection of patients who chose to initiate earlier ARV therapy also generally having other "healthier" lifestyle features; hence, fewer deaths from cardiovascular disease, homicide, suicide, and drug overdose rather than AIDS-defining events. Despite this concern that the panel's recommendation was made based on misleading evidence, the favorable toxicity profile of newer ARVs probably makes earlier initiation of therapy appropriate in the developed world, especially in those co-infected with hepatitis B, hepatitis C, and those patients with risk factors for cardiovascular disease where more evidence is accumulating that the heightened inflammatory state associated with untreated HIV infection causes more rapid progression of these non-AIDS-defining diseases.

References

  1. Durant J, et al. Drug-resistance genotyping in HIV-1 therapy: The VIRADAPT randomised controlled trial. Lancet 1999;353:2195-2199.
  2. Baxter JD, et al. A randomized study of antiretroviral management based on plasma genotypic antiretroviral testing in patients failing therapy. AIDS. 2000;14:83-93.
  3. Meynard JL, et al. Phenotypic or genotypic resistance testing for choosing antiretroviral therapy after treatment failure: A randomized trial. AIDS. 2002;16:727-736.
  4. Haubrich RH, et al. A randomized prospective study of phenotype susceptibility testing versus standard of care to manage antiretroviral therapy: CCTG 575. AIDS. 2005;19:295-302.
  5. Kitahata MM, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med. 2009;360:1815-1826.