Suboptimal CD4 Increases in HIV-infected Patients Receiving Didanosine plus Tenofovir

The combination of nucleos(t)ide analogues (NAs) is essential for the design of effective antiretroviral regimens. Although there are currently many options for the selection of such drug backbones, not all combinations produce optimal results.

As the number of these compounds has increased, it has become clear that the concomitant administration of certain NAs should be avoided due to high rates of toxicity and/or greater risk of virological failure. As an example, the combination of didanosine (Videx) and tenofovir (Viread) has recently been associated with a paradoxical depletion of CD4+ T cells in the face of complete viral suppression.

Interference between the pathways leading to the intracellular activation of didanosine and tenofovir, and their blocking of the purine nucleoside phosphorylase, seems to explain this phenomenon, according to Pablo Barreiro and Vincent Soriano, authors of a study published online in The Journal of Antimicrobial Chemotherapy (Epub April 10, 2006) [1].

The association of tenofovir (tenofovir disoproxil fumarate) with didanosine seemed to be very attractive at first sight as a nucleos(t)ide analogue (NA) backbone, given that both drugs are administered once a day, they show a relatively high genetic barrier for resistance, they are relatively well tolerated and food restrictions can be avoided.

The first unexpected problem using this combination came from the recognition of a pharmacokinetic interaction between the two drugs, which causes a significant elevation (40–60%) in plasma didanosine levels.

Soon after this finding, it was recommended that the didanosine dose be reduced to 250 mg daily [2] in order to minimize the risk of developing complications such as pancreatitis and hyperlactatemia.

Two main mechanisms have been proposed to explain the pharmacokinetic interaction between didanosine and tenofovir. First, tenofovir seems to increase the gastrointestinal absorption of didanosine [3]. Although the underlying mechanism for this has not been fully elucidated, the lack of an effect of tenofovir on didanosine half-life and renal clearance, together with an increase in the C_max, AUC and cumulative urinary excretion of didanosine when given along with tenofovir, is a strong argument in favor of this hypothesis.

Alternatively, recent data have been released proving that tenofovir may reduce the intracellular metabolism of didanosine. This second pathway, which is not incompatible with the first, has gained credibility over recent months and may provide some insights into other problems that have arisen when using the combination of didanosine and tenofovir.

Purine nucleoside phosphorylase (PNP) is a cellular enzyme present in many tissues, but especially in lymphocytes. It is responsible for the metabolism of purines (inosine and guanine). As didanosine is a purine analogue, it is metabolized intracellularly, at least partially, through PNP. On the other hand, the phosphorylated forms of tenofovir (which is also a purine analogue) are potent PNP inhibitors, which may cause increased didanosine levels.

In a similar way, other antivirals that act as PNP inhibitors, such as ganciclovir, are known to elevate didanosine concentrations. Interestingly, the reduction in the dose of didanosine from 400 to 250 mg, when combined with tenofovir, normalizes not only plasma levels of didanosine but also the concentration of intracellular active forms of didanosine, including dideoxyadenosine triphosphate (ddATP) [4].This observation indirectly supports the hypothesis that the main mechanism involved in the didanosine–tenofovir interaction occurs at the intracellular level.

Paradoxical CD4+ T Cell Declines under Didanosine plus Tenofovir

In simplification regimens compared with first-line regimens. This may be because in first-line regimens a CD4 recovery is primed due to the reduction in viral load; in simplification regimens the viral load is already undetectable.

In patients with high CD4 counts at baseline. There is no clear explanation for this, although it may be that the more CD4 cells present the easier it is to detect an absolute decrease.

In subjects receiving high didanosine doses. Mitochondrial didanosine toxicity may be one of the causes of CD4 cell decay, and higher didanosine doses are more toxic.

In patients with low weight (which may cause higher didanosine levels).

If the third drug was an NA rather than a NNA (as all NAs may produce mitochondrial toxicity).

Tenofovir interference with purine metabolic pathways may again be responsible for this unexpected finding. Alternatively, the accumulation of dGTP would preferentially cause the inhibition of mitochondrial RNR. The diminution in the capabilities for mitochondrial DNA repair caused by RNR malfunction would finally precipitate cellular apoptosis and CD4+ T cell depletion.

In summary, the association of didanosine plus tenofovir might produce unexpected toxicities by two different pathways: first, by enhancing didanosine-mediated mitochondrial toxicities (pancreatitis, hyperglycemia, hyperlactataemia, etc.); second, through PNP inhibition mediated by tenofovir (i.e. CD4+ T cell depletion).

High Rate of Mitochondrial Toxicity with Didanosine plus Tenofovir

The interference of tenofovir in the metabolism of didanosine could explain the observed higher rate in subjects taking these drugs in combination of didanosine-related toxicities, such as pancreatitis, severe weight loss mimicking rapid progression of lipoatrophy and hyperglycemia.

In vitro studies have shown a direct relationship between didanosine levels and the intracellular concentration of ddATP, the active form of didanosine. This metabolite is a potent inhibitor of the mitochondrial Ÿ-DNA polymerase. Hypothetically, the reduction in the cellular catabolism of didanosine, through the inhibition of PNP by tenofovir, might enhance didanosine-related toxicities as a result of the inhibition of mitochondrial activity by ddATP.

In fact, pancreatic toxicity and lipoatrophy are side effects already known to occur in subjects exposed to other NAs due to their deleterious influence on mitochondrial metabolism.

Didanosine plus tenofovir should be considered as a combination with a low genetic barrier for resistance, as selection of just one mutation, K65R, compromises the antiviral activity of both the drugs.

In summary, the combination of didanosine plus tenofovir is associated with CD4+ T cell depletion in HIV-infected patients despite complete virus suppression. Although the reduction of didanosine doses seems to mitigate this paradoxical effect, the effect does not vanish. The recognition of this side effect, along with a greater risk of pancreatitis, hyperglycemia and virological failure, should discourage the use of this NA combination.

Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain.

04/14/06

Source

Barreiro and Soriano. Suboptimal CD4 gains in HIV-infected patients receiving didanosine plus tenofovir. The Journal of Antimicrobial Chemotherapy [Epub ahead of print: April 10, 2006].

References

 1.    P Barreiro and V Soriano. Suboptimal CD4 gains in HIV-infected patients receiving didanosine plus tenofovir. Journal of Antimicrobial Chemotherapy [Epub ahead of print: April 10, 2006].

2.    B Kearney, J Flaherty and J Shah. Tenofovir disoproxil fumarate: clinical pharmacology and pharmacokinetics. Clin Pharmacokinet 43: 595–612. 2004.

3.    P Pecora and M Kirian. Effect of TDF on ddI absorption in patients with HIV. Ann Pharmacother 37: 1325–1328. 2003.

4.    A Pruvost, E Negredo, H Benech, et al. Measurement of intracellular didanosine and tenofovir phosphorylated metabolites and possible interaction of the two drugs in HIV-infected patients. Antimicrob Agents Chemother 49: 1907–1914. 2005.