An unexpected significant fall in CD4, CD8 and total lymphocyte counts has been seen in people combining full dose ddI with tenofovir, according to a study from Spain published in a recent edition of the journal AIDS.
The study took place prior to the news, reported here here, that tenofovir interacts with ddI, causing, on average, 60% higher total ddI levels. This can increase the risk of serious side-effects such as lactic acidosis and pancreatitis. Since then, a ddI dose reduction to 250mg when taken at the same time as tenofovir and with food, has become standard practice, and, so far, no unusual CD4 declines have been reported.
In this study, investigators from a major HIV hospital in Badalona, Spain, were prompted to review all their patients’ records when they observed a significant decline in CD4 cells in people on ddI, tenofovir and nevirapine, despite their viral loads remaining undetectable. They identified 302 individuals on ddI and tenofovir in combination or used without the other, and looked at a variety of cell counts in the 48 weeks prior to and after receiving these drugs.
In the 48 weeks prior to ddI and/or tenofovir therapy, CD4 counts increased or remained stable in all 302 individuals. After 150 of these individuals began ddI 400mg with tenofovir, a significant decrease was seen in CD4 and CD8 counts, with more than 50% seeing a 1-100 CD4 cell decline, 30% seeing a 101-200 CD4 cell decline and only 15% seeing an increase in CD4 cell counts. By contrast, 85-90% of those individuals taking ddI or tenofovir separately in other HAART combinations experienced CD4 increases.
The CD4 decline was seen whether the ddI/tenofovir was taken alongside nevirapine (P=0.05), efavirenz (P=0.05) or Kaletra (P=0.048). Additionally, those individuals who weighed less than 60kg and were given the recommended ddI dosing for their weight (250mg), also saw CD4 declines when the ddI/tenofovir combination was used with any other HAART drug (P=0.035).
Significant CD8 declines were only seen in individuals taking ddI/tenofovir with efavirenz (P=0.038), or in those who weighed less than 60kg and took reduced-dose ddI/tenofovir with any other HAART drug (P=0.036).
However, total lymphocyte count fell significantly in all ddI/tenofovir-based HAART; specifically with nevirapine (P=0.04), efavirenz (P=0.029), Kaletra (P=0.034), and any HAART drug in those who weighed less than 60kg and took reduced dose ddI/tenofovir (P=0.05).
Adverse effects and events led to some ddI discontinuation during the study period. Most surprisingly (and leading to the most discontinuations) was dry mouth, which was experienced by ten percent, and led five percent to stop ddI. Asymptomatic increases in amylase (used to measure likelihood of pancreatitis) leading to discontinuation of ddI were seen in four per cent of individuals receiving any ddI/tenofovir-based HAART combination. Moderate or severe peripheral neuropathy serious enough to stop ddI was experienced by two percent (although 25% experienced mild neuropathy and did not stop ddI).
Eight individuals on 400mg ddI, tenofovir and nevirapine underwent pharmacokinetic evaluation, and it was found that when the ddI dose was reduced to 250mg, the median total exposure (AUC) of ddI fell from 5520ng/ml (range, 1760-8280) to 2340ng/ml (range, 1590-4700). Similarly, the median maximum exposure (Cmax) dropped from 1390ng/ml (range, 640-3070) to 750mg/ml (range, 300-1560).
Prior to these eight individuals’ dosage reduction, their mean CD4 cell count had declined by 163 cells/mm3. Twelve weeks after the ddI dose reduction, the majority experienced a mean CD4 count rise of 60 cells/mm3, although two continued to experience a mean CD4 count decline of 72 cells/mm3.
The authors suggest that lymphocyte toxicity is the most plausible reason for the unexpected CD4 declines seen when full dose ddI is taken with tenofovir, since no other significant changes were seen regarding viral load, nor in leukocyte, neutrophil, haemoglobin or platelet counts. This is most likely due to the high ddI levels seen both here and in other studies, although other causes cannot be ruled out. They suggest that it is important to understand exactly how tenofovir increases ddI plasma levels, since at present is it not clear if this results from an increase in ddI absorption, a decrease in ddI clearance, or “a modification of tissular distribution”.
The authors recommend that individuals weighing more than 60kg reduce their ddI dose to 250mg when combined with tenofovir, and that those weighing less than 60kg reduce their ddI dose to between 125mg and 200mg. Currently, Bristol Myers Squibb does not recommend a further ddI dose reduction below 250mg for people weighing less than 60kg.
Further information on this website
Warning on Kaletra, tenofovir and ddI interaction after case of multiple severe toxicities - news story
Further case report of lactic acidosis linked to tenofovir/ddI - news story
HIV-positive man dies of kidney failure and lactic acidosis due to tenofovir/ddI interaction - news story
BMS data confirm potential for dosing ddI and tenofovir with food - news story
ddI dosing with tenofovir defined - news story
Negredo et al. Unexpected CD4 cell count decline in patients receiving didanosine and tenofovir-based regimens despite undetectable viral load AIDS 18(3), 459-463, 2004.