Two-drug maintenance with tenofovir-efavirenz less effective than triple therapy

A team of French investigators have found a two-drug maintenance regimen of tenofovir (Viread) and efavirenz (Sustiva) to be less effective than a three-drug combination of the same two drugs plus 3TC (lamivudine, Epivir) over 48 weeks of follow-up.

Antiretroviral drug treatment often results in long-term toxicities. Although 3TC is generally regarded as one of the least toxic antiretrovirals, nucleoside analogues – the class of drugs to which 3TC belongs – can contribute to many forms of metabolic complications, such as lipodystrophy (the redistribution of body fat), and elevated levels of lactic acid in the blood.

As a possible way of reducing long-term toxicities, the COOL study team specifically looked at the effectiveness and toxicity of 3TC as part of one specific drug combination. In this study, researchers at various sites in France took participants already on successful therapy, and switched them to either a standard three-drug regimen – tenofovir, 3TC and efavirenz – or a simplified regimen of only tenofovir and efavirenz.

To enter the 48-week trial, patients needed to have already been on a stable treatment regimen for at least three months, with a viral load below 50 copies/ml, and no history of treatment failure. They needed to weigh over 45kg, and to show no significant toxicities at the time of entering the trial. Since tenofovir may be toxic to the kidneys in people with reduced kidney function, laboratory markers of kidney health had to be normal (creatinine clearance over 60 ml per minute). There were no restrictions on CD4 cell count.

The COOL trial enrolled 143 patients, who were randomised to receive either tenofovir, efavirenz, and 3TC (TDF/EFV/3TC), or tenofovir and efavirenz only (TDF/EFV). Characteristics of the two groups were very similar, with the following overall average values: 40 years of age, 69kg, CD4 cell count of 473 cells/mm³, and 3.7 years on therapy (43.5% NNRTI-based, 45.5% PI-based, 71% including AZT/3TC). Twenty-eight per cent of the participants were female.

Intent-to-treat (ITT) analysis included all 143 original participants; cases where data was missing for any reason (including those who dropped out of the study) were treated as ‘treatment failures”. Results, by both methods, were as follows:

Six participants were “lost to follow-up” in the TDF/EFV arm, but only two in the TDF/EFV/3TC arm. Somewhat oddly, all four dropouts due to side-effects were in the TDF/EFV arm. (No kidney toxicity or drop in blood phosphate levels was seen.)

All three of the virologic failures were also in the two-drug, TDF/EFV arm: all three of these people acquired NNRTI resistance mutations. (One case was likely due to very poor treatment adherence, but the adherence levels for the other two were not known.) There was no explanation as to why more side-effects and dropouts would be seen in the group taking fewer medications.

The researchers concluded that “TDF + 3TC + EFV demonstrates an optimal success rate (97%) as a maintenance regimen when compared to TDF + EFV (82%). Switching to a … tenofovir based regimen can significantly improve lipid profile even when lipids are within the median normal range at baseline. Other improvements in biological parameters were observed following a switch from [twice-daily] HAART to TDF-based HAART.”