Paradoxical CD4+ T-Cell Decline in HIV-Infected Patients With Complete Virus Suppression Taking Tenofovir and Didanosine

Abstract

Purpose of the Study. Tenofovir and didanosine are adenosine analogs commonly used in highly active antiretroviral therapy combinations. Although virologically effective, this combination is theoretically associated with pharmacokinetic interactions and increased risks of pancreatitis and hyperglycemia. The study examined the CD4+ T-cell effects of the use of these 2 drugs as part of a highly active antiretroviral therapy regimen. Methods. Data from 570 individuals were analyzed retrospectively according to the nucleoside analog “backbone” of protease inhibitor–containing regimens: tenofovir + didanosine in 298 subjects, didanosine in 88, tenofovir in 44, and neither didanosine nor tenofovir in 140. Results. Significant CD4+ T-cell declines were noted in patients taking the combination of tenofovir + didanosine relative to all other nucleoside analog combinations including didanosine or tenofovir only. Patients exposed to higher didanosine doses showed a more pronounced CD4+ T-cell decline, and plasma levels of didanosine correlated with the extent of T-cell loss. Conclusions. Although patients receiving tenofovir + didanosine–based combinations generally achieved excellent viral suppression, their CD4+ T cells often paradoxically declined. This effect generally progressed over time. It is hypothesized that the use of these 2 agents together results in a condition that metabolically resembles purine nucleoside phosphorylase deficiency, a rare but well-described primary immunodeficiency syndrome. Reviewer Comments. Tenofovir and didanosine frequently are the only nucleoside analog agents available to patients with drug-resistant virus. This combination with either a nonnucleoside reverse transcriptase inhibitor or a protease inhibitor is often effective in suppressing virus in patients with limited options. However, the paradoxical decline in T-cell numbers is of great concern. Patients on this regimen must be monitored carefully for this potential complication.