A small proof-of-concept study has shown that once-daily treatment with ddI (didanosine), 3TC (lamivudine) and efavirenz in a week on, week off (WOWO) regimen effectively suppresses viral load for up to 72 weeks. However, the regimen does not cause significant increases in CD4 T-cell counts. This study adds to a growing body of evidence to suggest that short-cycle intermittent regimens are unlikely to be of benefit in treating HIV infection.
Following a similar study with twice-daily dosing with an indinavir-based, ritonavir-boosted combination, this study, which was published in the June 1st edition of The Journal of Infectious Diseases, was designed to test the efficacy of a once-daily regimen.
Eight HIV-positive patients who had viral loads below 50 copies/ml were recruited for this study. The patients were given once-daily ddI (200mg), 3TC (300mg) and efavirenz (600mg) for one week, which was followed by a drug-free week. This cycle was repeated up to 36 times, with viral load measurements and CD4 T-cell counts every four weeks during the first 48 weeks of the study, and then at least every twelve weeks. All measurements were taken at the end of the drug-free period. One patient withdrew from the study for personal reasons after 24 weeks.
All of the patients maintained undetectable viral loads (
CD4 T-cell counts remained stable across the study, with a median baseline of 748 cells/mm3, and 740 cells/mm3 at week 48 (p > 0.5). No patients exhibited a decrease in CD4 T-cell counts across this period. However, as the authors point out, “the lack of an increase in CD4 T-cells over 48 weeks may represent an important alteration, compared with continuous therapy.”
The authors claim that the absence of viral load ‘blips’ was due to the persistence of efavirenz in the blood over the seven days of no treatment. Measurements of plasma concentrations of efavirenz on the last day of the drug-free period revealed that the patients had circulating levels of the drug between 70 and 720ng/ml, all of which were below the therapeutic level of around 1000ng/ml.
Despite this, genotypic testing failed to detect any evidence of resistance to antiretroviral drugs in six of seven patients. In one patient, a mutation associated with resistance to 3TC was detected at week 48. This mutation was no longer detectable at week 80, and the patient maintained undetectable viral load for at least 28 weeks after the mutation was detected, casting doubt on the clinical significance of this find.
However, it is not clear how long this drug regimen could be maintained before the development of resistance. The shorter half-lives of ddI and 3TC in comparison to efavirenz suggest that patients on this regimen may be exposed to fewer than three drugs at therapeutic doses towards the end of the drug-free periods.
The authors also argue that this regimen “may have importance in resource-limited settings where the monetary cost of antiretroviral therapy is prohibitive.” However, as was reported in their previous study, maintaining adherence to a short-cycle intermittent regimen may be more difficult than for a continuous regimen, leading to missed doses and the development of drug resistance. “The need for strict adherence to the regimen is necessary, and the feasibility of such an approach will require studies of larger numbers of patients for extended periods.”
Further information on this website
Structured treatment interruption - overview
Treatment interruption - patient information factsheet
Pulse therapy may be an option for a minority on HAART - news story
Should treatment breaks be guided by CD4? Study suggests yes - news story
Use drug holidays cautiously in NNRTI-treated patients - news story
The July 2004 edition of AIDS Treatment Update features a review of the issues around CD4-guided individualised treatment interruption as a long-term strategy for people currently on suppressive HAART. You can subscribe here. If you are an individual personally affected by HIV, you can order a free subscription here.
Reference
Dybul M et al. A proof-of-concept study of short-cycle intermittent antiretroviral therapy with a once-daily regimen of didanosine, lamivudine, and efavirenz for the treatment of HIV infection. J Infect Dis 189:1974-1982, 2004.