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By Mark Harrington

Safer and more effective drug combinations included in new guidelines…

Unusually, there was something to celebrate on World AIDS Day in 2009, even if it was only on paper. The World Health Organization (WHO) updated its antiretroviral treatment (ART) guidelines for adults, adolescents, pregnant women, mother-to-child transmission, and breast- feeding. These guidelines were issued in late November 2009.1 The new WHO guidelines are progressive and reflect changes in knowledge and practice which have also been reflected over the past year in revised ART guidelines in Europe, South Africa, the United Kingdom, and the United States, among others. TAGline will cover the new WHO ART guidelines for adults and adolescents here; future articles will examine issues related to children, pregnancy, breastfeeding, and evolving ART guidelines in specific countries.

The new WHO ART guidelines are the first to be released since 2006. Among the key changes in the new guidelines are a higher CD4 cell level for initiating ART from ≤200 to ≤350 CD4 cells, including pregnant women and people with tuberculosis (TB). This move brings the WHO guidelines more in synch with the most recent ART recommendations in developed nations. The panel addressed several other key issues with this update:

  • Replacing stavudine (d4T) in first- line therapy with tenofovir or AZT, something advocates have long called for. The writing group “… placed high value on avoiding the disfiguring, unpleasant and potentially life threatening toxicity of d4T”
  • Starting ART as soon as possible after initiating TB treatment for HIV- positive people with active tuberculosis (TB) disease, which kills 500,000 people with HIV each year • Starting ART regardless of CD4 count for people coinfected with hepatitis B (HBV) and HIV, using regimens containing both tenofovir and lamivudine (3TC) or emtricitabine (FTC) to reduce the risk of HBV resistant mutations. However, the lack of viral hepatitis screening in many parts of world remains a major barrier. The management of both HBV and hepatitis C virus (HCV) must be integrated into the global standards of care for HIV, as hundreds of millions of people worldwide are infected with these killer hepatitis viruses.
  • Using HIV RNA (viral load) testing to guide the decision to switch to second- line ART. This change will support the scale-up of viral load testing in developing countries. HIV RNA monitoring is critical for diagnosing HIV infection among newborns and to avert the 50% mortality seen within two years when they are untreated. HIV RNA measurement is useful to detect non-adherence or virologic treatment failure. In developed countries, repeated detectable viral load increases demonstrate treatment failure and lead to a therapy switch. Hitherto most developing countries (though Brazil and South Africa are exceptions) have not widely used viral load testing because of its cost. However recent data demonstrate that when people are switched to second- line ART on the basis of CD4 cell loss or clinical progression, virologic failure is often advanced and the virus may have developed additional resistance mutations. Yet, the main reason for reluctance to switch in many countries may be the expense or lack of access to second-line therapy, which usually includes a boosted protease inhibitor (such as atazanavir or lopinavir with ritonavir) plus two nucleoside analogue reverse transcriptase inhibitors (NRTIs). In the absence of viral load technology, the WHO strongly recommends initiating HIV therapy regardless, and switches based on CD4 cell loss or clinical progression.
  • National programs should consider introducing third-line therapies when first- and second-line regimens fail. While this could be expensive, introducing third-line regimens would bring the global standard of care much closer to that prevailing in developed countries. The WHO panel suggested including more recently approved treatments in third-line therapy such as an integrase inhibitor or newer non- nucleoside RTIs (NNRTIs) or protease inhibitors. Unfortunately, many of these agents are not yet approved or affordable in most developing countries.

The new WHO guidelines do not change the recommended first-line ART anchor NNRTI agent—either efavirenz or nevirapine—with a background of tenofovir (TDF) or zidovudine (AZT) with 3TC or FTC. This presents new complications when starting treatment at higher CD4 counts. Nevirapine is not safe to initiate in women with over 250 CD4 cells (or in men with over 400) due to a higher risk of liver toxicity, while efavirenz is contraindicated in the first trimester of pregnancy due to concerns of neural tube defects in the fetus. Since many women do not know they are pregnant during their first trimester, this complicates the selection of the safest treatment choice when starting ART at a CD4 count of over 250. Data from the antiretroviral pregnancy registry do not suggest that there is an excess of such defects in babies born to mothers taking efavirenz. However, new options that lack either danger would be welcome in this situation.

These new guidelines are more progressive than those of the previous version, and will vastly increase the estimated number of people who need treatment. This in turn makes the achievement of universal access to HIV treatment—defined as treating at least 80% of those who need ART—by the end of 2010 even more unlikely. Meeting the universal access target under the 2006 guidelines would have required putting 6 million more people on treatment by the end of 2010. With the new higher CD4≤350 as the ART starting recommendation, one would need to perhaps quadruple the number currently on therapy from 4 to 16 million.

In the next five years, over 10 million people will die of AIDS unless treatment scale-up —enrollment of new ART participants— continues and those on current programs stay enrolled. There is an AIDS funding backlash which claims that treating people with ART is too expensive. It is necessary to point out, however, that for every increase in the proportion of HIV-positive people put on therapy, there is in fact a certain (but not yet precisely measured) decrease in the likelihood of onward transmission of HIV. If applied widely enough, this approach (treating HIV earlier) has the potential, when combined with other effective prevention methods, to reverse the spread of HIV and even perhaps to bring the epidemic under control, though it is unlikely that in the absence of a vaccine that the HIV pandemic can ever be fully eliminated.

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