WHO guidelines

The World Health Organization

The World Health Organization (WHO) is the directing and coordinating authority for health within the United Nations. It provides leadership on global health issues, shapes health research agendas, sets norms and standards, articulates evidence-based policy options, provides technical support to individual countries, and monitors health trends.

The WHO guidelines for antiretroviral therapy in HIV-positive adults and adolescents were originally published in 2002, with revisions published in 2003, 2006 and 2010. The current document, Antiretroviral therapy for HIV infection in adults and adolescents: Recommendations for a public health approach, outlines a public health approach to the delivery of ART in settings with limited health systems capacity and resources.

Four separate working groups are involved in maintaining and updating the WHO guidelines: the Internal WHO ART Guideline Working Group, the ART Guideline Drafting Group, the external ART Peer Review Panel and the full ART Guideline Review Committee. The current recommendations encourage earlier HIV diagnosis and earlier antiretroviral treatment, and promote the use of less toxic regimens and more strategic laboratory monitoring. Separate guidelines are published for antiretroviral treatment of infants and children, and for the prevention of mother-to-child HIV transmission.

The WHO intend that these recommendations be considered in the context of each country's individual HIV epidemic, the capabilities of their health systems, and the availability of resources.

Laboratory monitoring

In developing countries, limited financial and capital resources strongly constrain the use of costly laboratory procedures. Several studies have investigated the costs and benefits of several laboratory monitoring strategies; the WHO guidelines for laboratory monitoring are based in large part on the evidence from these studies. (See Monitoring the immune system – Options in resource-limited settings.)

The WHO guidelines recommend that all patients should have access to CD4 cell count testing, to inform pre-ART care and ART management. Viral load testing is recommended for confirmation of suspected treatment failure (based on clinical or immunological decline). The guideline recommendation is that drug toxicity monitoring should be conducted based on symptoms rather than routinely for all patients.

When to start treatment

Treatment is recommended for all adolescents and adults with HIV, including pregnant women, with:

  • CD4 counts of 350 cells/mm3 or lower, regardless of clinical symptoms,
  • severe or advanced clinical disease (WHO clinical stage 3 or 4), regardless of CD4 cell count,
  • active tuberculosis, regardless of CD4 cell count, or
  • HBV infection requiring treatment, regardless of CD4 cell count.

These recommendations are considerably more aggressive than the 2006 revision, which recommended treatment initiation at CD4 counts of 200 cells/mm3 or lower.

What to start with

First-line therapy should consist of an NNRTI (either efavirenz or nevirapine) plus two NRTIs, one of which should be zidovudine (AZT) or tenofovir. Developing countries are encouraged to progressively reduce the use of stavudine (d4T) in first-line regimens because of its well-recognized toxicities, despite its lower cost.

When to switch

In resource-poor settings, the ability to detect treatment failure (and the resultant need to change regimens) is dependent on the availability of viral load testing. The WHO recommends that viral load testing should be used to confirm treatment failure whenever possible, if the test is available. If possible, routine viral load testing is recommended every six months for patients on ART. A persistent viral load of greater than 5000 copies/ml confirms treatment failure.

When viral load testing is not available, the decision to switch is driven by immunological and/or clinical failure. Immunologic failure is defined as a fall in CD4 count to baseline levels or below, a 50% fall in CD4 count from the on-treatment peak value, or CD4 cell counts persistently below 100 cells/mm3. Clinical failure is defined as a new or recurrent WHO stage 4 condition. The WHO treatment guidelines recommend that immunological criteria be used to confirm clinical failure if viral load is not available.

Second-line regimens

The WHO recommends that second-line ART should consist of a ritonavir-boosted protease inhibitor plus two NRTIs. Ritonavir-boosted atazanavir (ATV/r) or lopinavir/ritonavir (LPV/r) are the preferred protease inhibitors.

If d4T or AZT was used in first-line therapy, tenofovir plus either 3TC or FTC is the recommended second-line NRTI backbone. If tenofovir was used in first-line therapy, the recommended second-line NRTI backbone is AZT plus 3TC.

Third-line regimens

The 2010 revision of the WHO guidelines is the first to begin to address treatment decision-making after multiple treatment failures. These incipient recommendations are that:

  • national programmes should develop policies for third-line therapy that consider funding, sustainability and the provision of equitable access to ART
  • third-line regimens should include new drugs likely to have anti-HIV activity, such as integrase inhibitors and second-generation NNRTIs and PIs
  • patients on a failing second-line regimen with no new ARV options should continue with a regimen that is tolerated.