An unexpectedly high failure rate was seen in patients taking boosted lopinavir (lopinavir/ritonavir: Kaletra) as their only HIV drug, according to a Swiss study presented at the Sixteenth Conference on Retroviruses and Opportunistic Infections last week.
The study was stopped when six out of 29 (21%) patients randomised to lopinavir/r developed detectable HIV viral loads on the drug after periods of eight to 24 weeks on therapy.
All six patients had a CD4 nadir (lowest-ever CD4 count) of below 200 (range: 7 to 160). Two had nearly undetectable levels of lopinavir/r in their blood, despite claiming full adherence, but the other four had average levels.
The study also measured viral load in patients’ cerebro-spinal fluid (CSF). All the patients who failed had high viral loads in their CSF as well (the patient who had the highest blood viral load refused the necessary lumbar puncture) and three other patients also developed detectable viral loads in their CSF.
The MOST study was intended to be a 96-week study which randomised patients who had been on combination antiretroviral therapy (cART) for more than six months (average, nearly four years) with an undetectable viral load either to continue on cART or to switch to lopinavir/r monotherapy.
The patients were aged 44 on average; about 70% were male. Three-quarters were already on protease-inhibitor (PI) based cART while most of the other quarter were on non-nucleoside reverse transcriptase inhibitors (NNRTIs).
The study was terminated prematurely when it breached a failure criterion of more than 10% of patients with viral rebound. No patients who continued cART failed therapy. All patients who failed did so in the first 24 weeks.
The mean CD4 nadir in the failing patients was 77, compared with 166 in the patients who remained virally suppressed. CD4 nadir was the only patient characteristic associated with failure.
All patients received a lumbar puncture at baseline and at that point all but one (who continued on cART and did not fail treatment) also had undetectable HIV in their CSF. After 54 out of 60 patients consented to another lumbar puncture at the termination of the study, it was found that all the failing patients had viral loads in their CSF ranging from 1300 to 130,000 copies/ml. Another three patients had CSF viral loads ranging from 2500 to 20,000 copies/ml though they were still undetectable in blood: these patients did not have low CD4 nadirs.
At the time of failure, three failing patients had neurological symptoms including headache, dizziness, concentration problems, visual disturbance and loss of muscle co-ordination. Measurements of viral loads in genital secretions are ongoing. No patients who failed developed any drug resistance mutations.
The investigators conclude that "PI monotherapy should probably not be initiated in patients who experienced a CD4 nadir below 200”.
Gutmann C et al. Low-nadir CD4 count predicts failure of monotherapy maintenance with ritonavir-boosted lopinavir: results after premature termination of a randomized study due to unexpectedly high failure rate in the monotherapy arm. Sixteenth Conference on Retroviruses and Opportunistic Infections, Montreal, abstract 578. 2009.