The rise and fall of triple nucleoside reverse transcriptase inhibitor (NRTI) regimens

Triple nucleoside reverse transcriptase inhibitor (NRTI) regimens have attracted much interest due to their potential to (1) simplify dosing, with potential gains in adherence to treatment, and (2) reduce or even reverse dyslipidaemia associated with protease inhibitor (PI) therapy. A variety of triple NRTI combinations have been investigated, in both antiretroviral-naive and antiretroviral-experienced HIV-infected patients. Many of these trials have generated disappointing results, and some have been prematurely discontinued due to poor efficacy. This article reviews the background to the development of triple NRTI regimens, and the mounting evidence that this approach is suboptimal for antiretroviral-naive patients. Indeed, some triple NRTI regimens should never be used in this population. A role for triple NRTI combinations as a simplification strategy in treatment-experienced patients whose HIV is well controlled has been suggested, but emerging evidence indicates that such an approach can, under adequate selection pressure, lead to the emergence of mutations and viral load rebound. This commentary discusses the factors that appear to influence patients' responses to triple NRTI therapy, and their implications for patient selection.