IAS and WHO Update HIV/AIDS Treatment Guidelines

By Liz Highleyman

International organizations often take the opportunity of major HIV/AIDS conferences to update their treatment and prevention guidelines.

Coinciding with the XVI International Conference on AIDS, taking place this week in Toronto, the International AIDS Society (IAS) USA Panel issued revised recommendations regarding HIV treatment in adults; the new guidelines were published in the August 16, 2006 Journal of the American Medical Association.

Last week, the World Health Organization (WHO) updated its guidelines for HIV treatment in adults and children in low-income countries, and well as recommendations for preventing mother-to-child transmission.

The new IAS-USA guidelines -- the seventh major revision -- recommend that even for heavily treatment-experienced patients, the goal of therapy should be to reduce HIV viral load to below 50 copies/mL.

“In the case of individuals with multidrug resistant virus and high degrees of treatment experience, regimens should be defined that can drive the virus to undetectable levels," said lead author Scott Hammer, MD.

This goal may be accomplished in many patients – estimated at about 60% --  using new drugs such as tipranavir (Aptivus) and the recently approved protease inhibitor (PI) darunavir (Prezista, formerly TMC114). Whenever possible, second-line regimens should include at least two, and preferably three, new active agents to which the virus has not yet developed resistance.

The recommendations for first-line regimens have not changed: two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) plus either a non-nucleoside reverse transcriptase inhibitors (NNRTIs) – preferably efavirenz (Sustiva) -- or a ritonavir-boosted PI. Studies generally show that four drugs do not work better than three. Triple-NRTI regimens “are inferior to NNRTI- or ritonavir-boosted PI-based regimen,” the panel wrote, “and should only be used in highly selected circumstances.”

Consideration should be given to changing therapy if a patient’s viral load begins to increase, or if drugs are poorly tolerated or inconvenient. In light of conflicting recent data, the panel said strategic treatment interruption should not be done outside of clinical trials. They also said that monotherapy with a boosted PI remains experimental.

As for when to start therapy, the panel continues to recommend initiating treatment when the CD4 cell count falls below 350 cells/mm3. For those with higher CD4 counts, clinical judgment is required, given recent data suggesting that patients may benefit from starting therapy earlier.

“Given the rapid evolution of knowledge, clinicians are challenged to stay abreast of new information that can affect practice,” the panel concluded. “Therapeutic choices rooted in the pathogenesis of HIV disease and individualization of therapy to maximize benefit are the principles that remain constant in a rapidly changing environment.”

WHO Guidelines

The WHO recommended that, due to toxicity, d4T (stavudine, Zerit) should be replaced with less toxic alternatives as part of a NRTI “backbone.” Currently, d4T is a component of several generic fixed-dose antiretroviral coformulations, including the widely used d4T/3TC/nevirapine combination. However, d4T is associated with more side effects than other drugs in its class, including peripheral neuropathy, lipoatrophy (peripheral fat loss), and lactic acidosis (high blood lactic acid levels).

According to the revised guidelines, first-line antiretroviral therapy should include two NRTIs plus a NNRTI. The recommended NRTIs should be 3TC (lamivudine, Epivir) or emtricitabine (FTC, Emtriva) plus either AZT (zidovudine, Retrovir) or abacavir (Ziagen) or tenofovir (Viread). The agency also listed triple-NRTI regimens as an alternative; however, as noted above, such regimens are considered substandard in wealthy countries.

The WHO acknowledged that these guidelines may prove difficult to follow, because fixed-dose pills -- including those containing d4T -- are among the least expensive antiretroviral options in resource-limited countries.

For second-line therapy, the WHO recommended the new formulation of lopinavir/ritonavir (Kaletra), which can be stored without refrigeration. This should be combined with a NRTI not used during first-line therapy.

The WHO also recommended that, to the greatest extent possible, healthcare providers should use CD4 cell counts to guide therapy, rather than relying on symptoms or presence of opportunistic infections.

For prevention of mother-to-child transmission, the WHO recommended more complex regimens rather than single-doses and monotherapy. Single-dose nevirapine (Viramune) monotherapy, now commonly administered during delivery, can lead to drug resistance. Instead, the agency recommends combination therapy (e.g., AZT/3TC/nevirpaine) for mothers during labor and delivery, and AZT for seven days for newborn infants.

The WHO emphasized that antiretroviral therapy should be part of comprehensive healthcare services for women and babies, and that women who require treatment should receive optimal combination therapy for their own benefit, not simpler regimens solely to prevent HIV transmission. Here too, lack of resources may hamper adoption of these recommendations.

In terms of pediatric care, specific regimen recommendations are less definitive. The WHO recommended that first-line treatment should include AZT or d4T or abacavir plus 3TC or d4T plus either nevirapine or efavirenz. However, the agency emphasized that not enough is known about appropriate dosing for infants and children -- the more tolerable tenofovir, for example, is not yet approved for children -- and urged the pharmaceutical industry to conduct further studies.

The full WHO guidelines are available at: http://www.who.int/hiv/pub/guidelines/pmtct/en/index.html

8/15/06 

References

S Hammer, M Saag, M Schechter, and others. 2006 Recommendations of the International AIDS Society–USA Panel. Journal of the American Medical Association 296: 827-843. August 16, 2006.