A US study of structured treatment interruption in salvage therapy has found that people who took a treatment break before starting a new regimen were around two and half times more likely to experience disease progression in the following year when compared with people who switched from one regimen to another with no break. The findings contradict a previous French study of treatment interruption in salvage therapy, called GIGHAART, which found a better CD4 cell response in those who interrupted treatment after 24 weeks on a new regimen.
The US study was designed to test whether a four month break from treatment would allow drug-resistant virus to be `overgrown` by wild-type virus, resulting in a better response to a new regimen when treatment was resumed.
“We had hoped that a structured treatment interruption would be beneficial for people experiencing treatment failure due to multi-drug resistant HIV,” said study investigator Jody Lawrence MD of University of California Department of Medicine (San Francisco). “However, our results indicate that this strategy does not work and should be avoided by this group of HIV-infected individuals. Continuing therapy guided by HIV drug resistance testing proved to be a better approach.”
The findings are published in the August 28th edition of the New England Journal of Medicine, and come from a multicentre trial called CPCRA 064, sponsored by the Terry Beirn Community Programs for Clinical Research on AIDS. The study was originally planned to follow patients for two years, but was halted in June 2002 when an interim analysis showed that patients interrupting treatment were doing less well.
The study recruited 270 patients with viral load above 5,000 copies/ml and genotypic evidence of multidrug resistant virus, receiving a stable antiretroviral regimen. Participants were radomised either to interrupt treatment for four months before starting a new regimen selected after resistance testing (n=138), or to switch immediately to a new regimen optimised through resistance testing (n=132). The new regimen was optimised using both genotypic and phenotypic resistance testing.
At baseline, the median CD4 cell count was 144 cells/mm3 and the median viral load 5 log10 copies/ml (100,000 copies/ml). The median nadir CD4 cell count was 32 cells/mm3 (IQ 10-100). Participants had taken a mean of 10.6 antiretrovirals by the time they were randomised, but only 3.3% had been exposed to tenofovir, 24.8% to lopinavir/ritonavir and 57% to amprenavir. Patients had a mean of 2.5 protease inhibitor mutations (qualifying mutations undefined).
Unlike the GIGHAART study of treatment interruption in salvage therapy, CPCRA 064 used the clinical endpoints of disease progression and death to assess the impact of treatment interruption, and followed patients for longer (a median of 11.6 months).
After a median of 11.6 months, those randomised to treatment interruption were two and half times more likely to experience disease progression (RH 2.57, CI 1.2 – 5.5) depsite receiving standard prophylaxes according to current guidelines. Twenty-two of the treatment interruption group and twelve of the control group experienced further clinical illness or died (p=0.01). Eight deaths occurred in each group. The majority of primary endpoints occurred after the four month treatment interruption was over.
The treatment interruption group had significantly lower CD4 cell counts throughout the study. At the end of the four month treatment interruption, the mean CD4 cell count was 85 cells/mm3 lower (p3 lower (p
The partial or complete loss of drug resistance was observed in 64% of the treatment interruption group after four months, but when a new regimen was selected by reisstance testing, this group of patients were completely sensitive to a median of only 1.5 drugs. The treatment interruption group were significantly more likely to receive lopinavir (68.8% vs 50.8%), but less likely to receive amprenavir (17.4% vs 31.8%) and stavudine (d4T) 36.7% vs 52.3%) (p=0.009 and p=0.02 respectively).
In the treatment interruption group, 21.8% of patients had a viral load below 400 copies/ml four months after resuming treatment, compared with 18.3% of the continuous treatment group, and after eight months on the new regimen, those who interrupted treatment appeared twice as likely to have viral load below 400 copies/ml when compared to the continuous treatment group (19.1% vs 8.3%).
A multivariate analysis showed that the only significant predictors of disease progression or death were structured treatment interruption (HR 2.74) and baseline CD4 count (HR 1.38 for each 50 cell decrement). Baseline viral load and prior AIDS diagnosis were not significant predictors.
Speculating on why their study showed a different outcome from the GIGHAART study, the authors say that the GIGHAART study used a shorter treatment interruption (eight weeks) and used eight or more drugs in the new regimen (compared to an average of 3.6 drugs in CPCRA 064).
Further information on this website
Treatment interruptions - introductory factsheet
Structured treatment interruption - review of research to date
Reference
Lawrence J et al. Structured treatment interruption in patients with multidrug-resistant human immunodeficiency virus. New England Journal of Medicine 349 (9): 837-846, 2003.