US guidelines update (2010): treat when CD4 is less than 500 cells/mm3

On 1 December 2009, the US Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents were updated.

Changes are highlighted in yellow on the PDF file and include:

New section

Based on interests and requests from HIV practitioners, a new section entitled  Considerations in Managing Patients with HIV-2 Infection” has been added to the guidelines. This new section briefly reviews the current knowledge on the epidemiology and diagnosis of HIV-2 infection and the role of antiretroviral therapy in the management of patients with HIV-2 mono-infection and HIV-1/HIV-2 coinfection.

Key updates

Drug resistance testing ?In this revision, the Panel provides more specific recommendations on when to use genotypic versus phenotypic testing to guide therapy in treatment-experienced patients with viremia while on treatment.

  • Genotypic testing is recommended as the preferred resistance testing to guide therapy in patients with suboptimal virologic responses or virologic failure while on first or second regimens (AIII).
  • Addition of phenotypic testing to genotypic testing is generally preferred for persons with known or suspected complex drug resistance mutation patterns, particularly
    to protease inhibitors (BIII).

Initiation of antiretroviral therapy

In this updated version of the guidelines, the Panel recommends earlier initiation of antiretroviral therapy with the following specific recommendations:

  • Antiretroviral therapy should be initiated in all patients with a history of an AIDS-defining illness or with CD4 count < 350 cells/mm3 (AI).
  • Antiretroviral therapy should also be initiated, regardless of CD4 count, in patients with the following conditions: pregnancy (AI),
    HIV-associated nephropathy (AII), and hepatitis B virus (HBV) coinfection when treatment of HBV is indicated (AIII).
  • Antiretroviral therapy is recommended for patients with CD4 counts between 350 and 500 cells/mm3. The Panel was divided on the strength of this recommendation: 55% of Panel members for strong recommendation (A) and 45% for moderate recommendation (B) (A/B-II).
  • For patients with CD4 counts >500 cells/mm3, 50% of Panel members favor starting antiretroviral therapy (B); the other 50% of members view treatment as optional (C) in this setting (B/C-III).
  • 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 (AIII). 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 in antiretroviral-naive patients

Increasing clinical trial data in the past few years have allowed for better distinction between the virological efficacy and safety of different combination regimens. Instead of providing recommendations for individual antiretroviral components to use to make up a combination, the Panel now defines what regimens are recommended in treatment naive patients.

Regimens are classified as “Preferred,” “Alternative,” “Acceptable,” “Regimens that may be acceptable but more definitive data are needed,” and “Regimens to be used with caution.

The following changes were made in the recommendations:

  • Raltegravir + tenofovir/emtricitabine” has been added as a “Preferred” regimen based on the results of a Phase III randomised controlled trial (AI).
  • Four regimens are now listed as “Preferred” regimens for treatment-naive patients:

i)    efavirenz/tenofovir/emtricitabine;

ii)    ritonavir-boosted atazanavir + tenofovir/emtricitabine;

iii)    ritonavir-boosted darunavir + tenofovir/emtricitabine; and

iv)    raltegravir + tenofovir/emtricitabine.

  • Lopinavir/ritonavir-based regimens are now listed as “Alternative” (BI) instead of “Preferred” regimens, except in pregnant women, where twice-daily lopinavir/ritonavir + zidovudine/lamivudine remains a “Preferred” regimen (AI).

Additional updates

The following sections and their relevant tables have been substantially updated:

  • What not to use
  • Management of treatment-experienced patients
  • Treatment simplification
  • Hepatitis C coinfection
  • Antiretroviral-associated adverse effects
  • Antiretroviral drug interactions
  • Preventing secondary transmission of HIV

These and other DHHS guidelines are available on the NIH aidsinfo website:

Direct download (PDF):


The main concern in these guidelines is the strength of the statement for new recommendations for starting treatment.

Currently the document states that the whole panel recommends starting treatment for people with a CD4 count 350-500 cells/mm3. This leaves no indication of support for the view that there is insufficient data to balance the risks against the benefits.

Although this is discussed in the main document in more detail, the summary of the guidelines does not accurately reflect the later discussion. The summary is far more widely read than the entire document, and it would therefore be helpful for this wording to be reconsidered.

This years recommendations are especially important as they coincide with the enrollment of the NIH-funded START study which may be the only opportunity to look at both the risks and benefits from a randomised study.

So while there is data supporting short-term safety, there is no data based on long-term risk.

An example of risk comes from the trials of the preferred regimens referenced with the latest data (STARTMRK, ARTEMIS etc). Viral suppression to <50 copies/mL (the primary goal of treatment) was not achieved by around 15% patients at 48 weeks and 20% by week 96. In the context of lifelong treatment, low levels of resistance currently reported, may become more serious if second-line treatment also fails. Population-based uptake of treatment in Western countries is also frequently associated with higher rates of failure.

A second example is that no combination has been shown not to cause fat accumulation, itself associated with additional longer-term health complications, as well as reduced quality of life. This complication may also be related to race and gender.

These potential risks from earlier treatment are not addressed in the main guidelines.

In addition, while the summary states that ‘some people may defer treatment’, this is suggested for ‘clinical or psychosocial factors’ and is tied to an earlier sentence about people who might have difficulty with adherence.

While the document is only produced as guidance, the DHHS guidelines are widely interpreted as indicating the minimum recommended standard of care, based on the best available evidence. Clinical trials, especially NIH funded trials, become unethical if they recommend less that the current standard of care for any participant.

While many doctors, researchers and advocates believe that there is still equipoise on the use of treatment by people with counts 350-500, the current summary brings them into conflict with what are otherwise, one of the most useful documents for the management of HIV infection.

Given the summary has already been widely distributed and publicised, it would help if any subsequent update addresses whether a randomised trial in people with CD4 counts lower than 500 cells/mm3 remains ethical. Currently the guideline summary states that expert opinion believes that further research is unnecessary.

This is important in the context of the START trial which is just enrolling patients and which will be the most important study to inform on this and many other questions.

The history of previous recommendations from the DHHS panel on the when treatment should be started shows the importance of collecting evidence from a randomised study. Earlier recommendations to start at 500 and 350 have probably resulted in widespread complications from side effects and resistance.

Other changes in the guidelines are positive, especially the inclusion of a new section on HIV-2.

Links to other websites are current at date of posting but not maintained.