The decision about when to initiate combination antiretroviral therapy (cART) in asymptomatic HIV-infected
older children, adolescents, and adults continues to generate controversy among HIV experts. Aggressive
therapy in the early stages of HIV infection has the potential to control viral replication before the evolution of
HIV in that individual into a diverse and potentially more pathogenic quasispecies. Initiation of therapy at
higher CD4 T lymphocyte (CD4) cell counts has been associated with fewer drug resistance mutations at
virologic failure in adults.1 Early therapy also slows immune system destruction and preserves immune
function, preventing clinical disease progression.2 Ongoing viral replication may be associated with persistent
inflammation and development of cardiovascular, kidney, and liver disease and malignancy; studies in adults
suggest that early control of replication may reduce the occurrence of these non-AIDS complications.2-8
Conversely, delaying therapy until later in the course of HIV infection, when clinical or immunologic
symptoms appear, may result in reduced evolution of drug-resistant virus due to a lack of drug selection
pressure, improved adherence to the therapeutic regimen due to perceived need when the patient becomes
symptomatic, and reduced or delayed adverse effects of cART. Because therapy in children is initiated at a
young age and will likely be life-long, concerns about adherence and toxicities are particularly important.
The Department of Health and Human Services (HHS) Adult and Adolescent Antiretroviral Guidelines Panel
(the Panel) has recommended initiation of therapy for all adults with HIV infection, with the proviso that the
strength of the recommendations is dependent on the pre-treatment CD4 cell count.9 Randomized clinical
trials have provided definitive evidence of benefit with initiation of therapy in adults with CD4 cell counts
<350 cells/mm3
.
10 Observational cohort data have demonstrated the benefit of treatment in adults with CD4
cell counts between 350 and 500 cells/mm3 in reducing morbidity and mortality; therefore, adult treatment
guidelines recommend initiation of lifelong cART for individuals with CD4 cell counts ≤500 cells/mm3
.
9,11-14
For adults with CD4 counts >500 cell/mm3
, observational data are less conclusive regarding the potential
survival benefit of early treatment.11,12,15 The recommendation for initiation of therapy at CD4 counts
>500/mm3 (BIII evidence) in adults is based on accumulating data that untreated HIV infection may be
associated with development of many non-AIDS-defining diseases, the availability of more effective cART
regimens with improved tolerability, and evidence that effective cART reduces sexual HIV transmission.16
However, the Adult Guidelines Panel acknowledges that the amount of data supporting earlier initiation of
therapy decreases as the CD4 cell count increases above 500 cells/mm3
, and that concerns remain over the
unknown overall benefit, long-term risks, cumulative additional costs, and potential for decreased medication
adherence associated with earlier treatment in asymptomatic patients
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