Patients who take a non-nucleoside reverse transcriptase inhibitor (NNRTI) -based regimen after a break from HIV treatment are significantly less likely to achieve an undetectable viral load than patients reinitiating HIV therapy with a protease inhibitor-containing combination, according to the results of a retrospective Spanish study published in the September 15th edition of Clinical Infectious Diseases. The investigators believe that the resistance barriers and pharmacokinetics of NNRTIs could explain these findings and suggest that resistance tests should be performed before a patient recommences NNRTI treatment after a break from HIV therapy.
Researchers from the Hospital Carlos III in Madrid conducted a retrospective analysis of the virologic outcome of 45 patients who stopped taking their HIV treatment in 2002. All the patients had a viral load below 50 copies/ml and a CD4 cell count above 350 cells/mm3 at the time of the treatment break. Prior to taking the treatment interruption, twelve patients were taking a protease inhibitor-containing regimen, with the remaining 33 individuals taking an NNRTI.
After three to seven months the patients had to reinitiate HIV treatment because of a rebound in their HIV viral load.
In total, eleven patients restarted HIV treatment with a regimen containing a protease inhibitor. At the time when HIV treatment was reinitiated these individuals had a median viral load of 33,000 copies/ml. After six months of treatment all had a viral load below 50 copies/ml.
The remaining 34 patients took an NNRTI-containing regimen when they reinitiated treatment. Only 15 (44%) of these individuals experienced a fall in their viral load below 50 copies/ml within six months of the recommencement of treatment. The mean viral load at the time of treatment resumption was comparable between the NNRTI-treated patients who achieved an undetectable viral load and those who did not (22,000 copies/ml versus 25,000 copies/ml).
Wherever possible, phenotypic resistance tests were performed on patients who recommenced treatment with an NNRTI. The investigators found that eight of these nine individuals had drug-resistant HIV within three months of stopping their initial HIV treatment regimen. The investigators found primary resistance mutations conferring resistance to NRTIs in five of these patients and NNRTI-resistant virus in eight.
The investigators note that “the pharmacokinetics of NNRTIs may facilitate the rapid selection of resistance mutations”, explaining, “the long half-life of NNRTIs yields to persistent detectable levels in plasma for as long as 14 – 21 days. In this situation, the pressure for selecting NNRTI resistance mutations is pushed.”
In conclusion the investigators suggest that NNRTI-containing regimens should be used “cautiously in the face of active viral replication, especially in patients who have been previously exposed to nucleoside analogues.” They add “resistance testing may be helpful for choosing the best candidates for NNRTI-based therapies, who, ideally, should be persons without HIV containing reverse-transcriptase resistance mutations.”
Barreiro P et al. Superiority of protease inhibitors over nonnucleoside reverse-transcriptase inhibitors when highly active antiretroviral therapy is resumed after treatment interruption. Clin Infect Dis: 41, 897 – 900, 2005.