Possible Explanation for CD4+ Cell Decline in HIV Patients with Complete Virus Suppression Taking Tenofovir and Didanosine

Current treatment guidelines for HIV infection call for the use of two nucleoside (or nucleotide) analogues (NA) in combination with a protease inhibitor (PI) or a non nucleoside analogue (NNA). Tenofovir/TDF (Viread) and didanosine/ddI (Videx) are frequently recommended due to the convenience of their combination (one pill each daily), their high genetic barrier, their acceptable toxicity profile, and their potency.

In spite of all these advantages, the safety and potency of co-administration of these two NAs has been questioned, based on the fact that TDF significantly increases ddI levels. As a result the recommendation has been to reduce the dose of ddI from 400 to 250 mg daily in patients weighing more than 60 kg who take both drugs concomitantly.

In addition, some reports have shown an increase in the risk of pancreatitis and hyperglycemia in individuals using the combination.

In the current report, researchers evaluate the evidence of an unexpected decline in the CD4 T cell count among patients with an undetectable HIV viral load taking TDF/ddI.

In a large multicenter study (570 patients), researchers assessed the CD4 cell outcome in patients receiving different NA combinations, including TDF plus ddI, ddI alone, TDF alone, and others. In addition, data were analyzed according to the third anti-HIV agent administered and the dose of ddI. Finally, the relationship to plasma levels of ddl was further examined.

HIV-infected individuals who initiated a protease inhibitor-sparing regimen between September 2002 and June 2003 at five hospitals, and had at least one subsequent visit within the next 12 months, always with complete virus suppression, were retrospectively assessed. Only drug-naive individuals and patients who simplified a prior successful antiretroviral regimen were analyzed.

Based on their findings, the investigators propose a new mechanism by which TDF plus ddI may cause CD4+ T-cell depletion in HIV-infected individuals despite providing complete virus suppression.

Results

· Outcomes were analyzed in 570 individuals according to treatment modality (98 drug-naive versus 472 simplified); the nucleoside analogue (NA) backbone (298 with TDF + ddI, 88 with ddI, 44 with TDF, and 140 with neither ddI nor TDF); and the third agent used (378 with non-nucleoside analogues versus 192 with NA).

· Significant CD4+ T-cell declines were seen in patients taking ddI + TDF with respect to all other NA combinations, including ddI or TDF separately.

· Patients exposed to high ddI doses or taking a third NA showed more pronounced CD4 declines; and

· Plasma levels of ddI correlated with the extent of CD4+ T-cell loss.

“Patients receiving ddI + TDF-based combinations,” write the authors, “show CD4+ T-cell declines despite achieving complete virus suppression. This effect generally progresses with time.” They continue, “An imbalance in adenosine metabolites within CD4+ T lymphocytes may explain this phenomenon, which resembles the genetic purine nucleoside phosphorylase deficiency syndrome” they add.

Discussion

This study demonstrates that HIV-infected individuals receiving ddI + TDF-based combinations show CD4+ T-cell declines (in both absolute number and percentages) despite complete virus suppression. This effect generally occurs after 6 months of therapy and worsens with time. It occurs earlier and is more pronounced when TDF + ddI are taken together with another NA as third agent as well as when using high ddI doses.

High ddI plasma levels correlated with loss of CD4+ T cells. Finally, CD4+ T-cell declines were not seen in patients receiving any other antiretroviral regimen, including those in which either TDF or ddI were included.

Given that ddI and TDF are both adenosine analogues, the investigators hypothesize that a synergistic effect of their metabolites might cause an imbalance in the purine pool within CD4+ T lymphocytes. As these cells experience a rapid turnover in HIV infection, any impairment in cell replication might translate into loss of CD4+ T cells by a mechanism which is independent of virus replication.

This cytostatic effect of TDF + ddI combinations on CD4+ T lymphocytes essentially resembles the T-cell immunodeficiency seen in the purine nucleoside phosphorylase (PNP) deficiency, a rare recessive genetic disorder.

The greater CD4+ T-cell decline seen in patients who took ddI + TDF with a third NA is a remarkably finding, say the researchers. The fact that other triple NA combinations did not cause CD4+ T-cell drops, including those in which TDF or ddI were provided separately, suggests that administration of additional NAs might further exacerbate the metabolic interaction between ddI and TDF within the cells.

Higher ddI doses were associated with more profound CD4+ T-cell declines in patients undergoing ddI + TDF-based combinations. Even more, time on high ddI doses was independently associated to loss of CD4+ T cells in the multivariate analysis.

In conclusion, the authors state,

· These findings are relevant for selection of antiretroviral combinations and discourage the use of TDF and ddI in combination;

· The recognition of CD4+ T-cell declines in patients taking these medications together adds to the other recently discussed concerns about other side effects, including a higher risk of pancreatitis, hyperglycemia, and lactic acidosis, as well as of higher risk of virological failure with selection of the K65R mutation;

· When possible, the combination of TDF and ddI should be avoided.

04/08/05

Reference
A Barrios and others. Paradoxical CD4+ T-cell decline in HIV-infected patients with complete virus suppression taking tenofovir and didanosine. AIDS 19(6): 569-575. April 8, 2005.