December 16, 2005
Heavily treatment-experienced patients who are taking overly complex regimens or dealing with intolerable side effects may benefit from a switch -- at least for a little while -- to a regimen consisting of four nucleoside/tide reverse transcriptase inhibitors (NRTIs), according to a study by German researchers presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy.
One of the more problematic issues in HIV treatment is how to manage treatment-experienced patients who have run out of future treatment options. Although these patients' current regimens may be suppressing their viral load, they may also be highly complex (making adherence difficult and reducing quality of life) or cause intolerable adverse effects. However, it is problematic to design a new regimen, using currently available medications, that would reliably achieve virologic suppression for these patients. What's a frustrated physician (and patient) to do?
One approach would be to temporarily switch the patient to a simple combination that is at least partially effective. This would allow the patient to maintain viral suppression while awaiting new drugs that could become available within the next 12 to 18 months. Such an approach could also be considered for those with good virologic suppression who are unable to tolerate their current, more complex, regimen for any length of time.
With this in mind, Brenda Dauer, of the University of Frankfurt, and colleagues undertook a review of 116 patients to see if switching treatment-experienced patients to a simpler regimen -- in this case, the quadruple-NRTI regimen of zidovudine/lamivudine/abacavir (AZT/3TC/ABC, Trizivir) + tenofovir (TDF, Viread) -- was feasible in clinical practice.
At baseline, the study patients, most of whom (82%) were men, had a nadir CD4+ cell count of 91 cells/mm3 and a current CD4+ cell count of 283 cells/mm3. Median HIV viral load at baseline was 400 copies/mL, but 27 patients had a viral load over 100,000 copies/mL. Patients had received antiretroviral therapy for a median of 6.6 years. The most common reasons for why patients were switching to the study regimen were for simplification or to reduce toxicity.
At 24 weeks, 99 of the 116 patients (85%) remained on the four-NRTI regimen. Only seven patients (6%) experienced a virologic breakthrough; median HIV plasma viral load was 87 copies/mL (versus 400 copies/mL at baseline). The median CD4+ cell count had risen slightly, to 315 cells/mm3. Virologic suppression was associated with less prior exposure to antiretroviral agents (a median of five versus eight drugs), a lower baseline HIV plasma viral load (150 versus 44,000 copies/mL) and a higher baseline CD4+ cell count (361 versus 185 cells/mm3).
Of the 27 patients who had a baseline HIV plasma viral load measure that was greater than 100,000 copies/mL, 44% still achieved good virologic suppression (viral load less than 400 copies/mL) after switching to the four-NRTI regimen.
Pre-treatment genotypic resistance assay results were available for 84 individuals, of which 46 (55%) had at least three mutations associated with nucleoside analog resistance. For these 46 patients, median viral load at 24 weeks was 400 copies/mL. Interestingly, 21 of 22 patients who did not have mutations at codons 210 and 215 responded to therapy, signaling that this combination of mutations is associated with a lack of response to the four-NRTI regimen.
These data are potentially very important. They signal that, for patients who have received multiple courses of therapy and are now achieving virologic suppression on unduly complex or toxic regimens, simplification with NRTI-only regimens may be an option, at least as a six-month respite. Even in patients who are not achieving suppression, this strategy may also be an option, especially if those patients do not have certain resistance mutation patterns, namely the combination of 201W and 215Y/F.
It remains to be seen, however, whether four drugs are actually necessary, or whether using zidovudine/lamivudine/abacavir alone -- or perhaps zidovudine/lamivudine (AZT/3TC, Combivir) + tenofovir -- could achieve the same outcome.
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