Drug level monitoring succesful at reducing treatment failure in nelfinavir-treated HIV patients

Patients taking the protease inhibitor nelfinavir who receive therapeutic drug monitoring (TDM) are significantly more likely to maintain an undetectable viral load, according to the ATHENA study, the findings of which are published in the May 23^rd edition of AIDS.

The Dutch ATHENA study recruited 147 patients HIV-treatment naïve patients who were starting HAART with regimens based on either the protease inhibitor nelfinavir or indinavir. Nelfinavir can be poorly absorbed by the body if not taken with food, resulting in poor blood concentrations of the drug to fight HIV. Indinavir can cause unpleasant side-effects, particularly when taken with ritonavir.

The object of the study was to see if TDM improved the success of therapy, by allowing doctors to intervene to boost the amount of antiretroviral in the blood of patients who had insufficient quantities to achieve a clinical benefit, or to reduce the dose in those patients where levels of the drug were likely to cause side-effects. Patients were followed for a year, in an intention-to-treat analysis which regarded treatment discontinuation as failure.

After starting HAART patients were randomly assigned to a TDM or a non-TDM control arm. There were no significant baseline differences between the two arms of the study. Patients returned to the clinic for blood tests at weeks four, twelve and then at twelve weekly intervals. At these visits patients were also asked to complete a questionnaire to assess their adherence. An HIV viral load above 500 copies/mL was regarded as virological failure.

At the end of the study, 12 of the 69 patients in the TDM arm had discontinued due to treatment failure or toxicity compared to 31 of the 78 patients in the non-TDM arm. Fewer patients discontinued nelfinavir because of treatment failure in the TDM arm than in the non-TDM arm (2.4% versus 17.6% p=0.02) and fewer indinavir patients who had stopped treatment due to side-effects than non-TDM patients (14.3% versus 29.6%, p=0.17).

Significantly more patients who received TDM had a viral load below 500 copiesmL at both six and twelve months than the patients who did not have TDM testing (94.2% versus 79.5% after six month, 78.2% versus 55.1% after twelve months p=0.009, p=0.003 respectively).

As a similar level of patients, 24%, in both the TDM and control arms reported poor adherence, drug absorption appeared to be the cause.

Patients taking indinavir were treated with one of three doses of the drug: 800 mg every eight hours; or 800 mg of indinavir boosted by 100mg of ritonavir every twelve hours; or 400 mg indinavir with 400 mg of ritonavir every twelve hours. Investigators found that TDM patients were significantly less likely to discontinue due to toxicity than patients in the control arm.

Investigators also found that the use of TDM allowed them to target interventions to boost the amount of nelfinavir in the blood, or reduce potentially toxic doses of indinavir. Of the 63% of nelfinavir patients in the TDM arm with at least one concentration of the drug below therapeutic levels, just under half (12 of 26) achieved a therapeutic concentration on the second test as a result of a reminder about the importance of taking nelfinavir with food. As a result, 34% maintained sub-therapeutic nelfinavir levels compared to 59% of the control arm.

Amongst the indinavir-treated patients, TDM allowed doses to be reduced in all six patients experiencing side-effects due to toxic levels of the drug. In contrast three out of four control patients maintained toxic levels of the drug and eventually stopped treatment due to side-effects.

The investigators conclude that their study demonstrated that “TDM of protease inhibitors…improves therapeutic response”, with fewer nelfinavir patients discontinuing treatment because of virological failure and fewer indinavir-treated patients because of side-effects.

Further information on this website

Testing drug levels - menu of information

Nelfinavir - overview

Indinavir - overivew