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GIGHAART: 8-week Treatment Interruption Improves Viral Response in Deep Salvage
Reported by Jules Levin
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Nelson Mandella addressed the Conference at today's closing ceremony. He took a strong stand in support of taking treatment for HIV. He said AIDS is war against humanity. His speech was compelling. He inspirationally described the affect of AIDS on leaving orphans & the result of this on society and the future of these large numbers of children. He also emphasized the effect of stigma and how people are afraid to admit they have HIV. He encouraged people to reveal they are infected. In Africa, infected people are often fearful of admitting they have HIV.
The results of this French study called GIGHAART suggest that for patients in a deep salvage situation taking a brief 8 week interruption before switching from a virologically failing regimen to the next regimen may improve the CD4 & viral load response.
The purpose of this study was to evaluate the impact of an 8-week treatment interruption on the effectiveness of a subsequent multi-drug regimen in patients with low CD4s (<100) and high viral load (>50,000). The patients in this study were very advanced and had much ART experience. 68% prior AIDS diagnosis. HIV viral load was over 100,000 copies (5.2-5.4 log). They had taken ART therapy for 6-7 years. They had taken a total of 11 drugs: 5 NRTIs, 4 protease inhibitors, 1-2 NNRTIs. The patients had extensive drug resistance. At the start of the study their Cd4 count was 26. The patients were randomized to either take an 8 week interruption after stopping their current regimen before starting the GIGHAART salvage regimen or to switch immediately to the new regimen from the old. The regimen they were switched to was 3-4 NRTIs, hydroxyurea, and 3 protease inhibitors.
RESULTS After 12 weeks of therapy, the 34 patients who switched to immediate GIGHAART had a viral load response of -0.37 log compared to a viral load response of -1.91 for the patients who took an 8-week interruption (reported as an on-treatment analysis). The percent with a 1 log or greater viral load reduction was 26% in the immediate switch GIGHAART arm vs 62% in the deferred therapy arm. Reported using an on-treatment analysis the decrease in viral load was -0.37 in the immediate switch group vs -1.91 in the deferred therapy group.
After 24 weeks of therapy (ITT analysis) the immediate therapy group had a decrease of -0.29 in viral load vs -1.08 in the deferred therapy group. 24% in the immediate group had 1 log or more viral load reduction vs 50% in the deferred therapy group. And 12% had <400 in the immediate group vs 32% in the deferred group. The CD4 increase was 51 in the deferred group vs 8 in the immediate switch group.
In trying to understand why the 8-week interruption may have improved viral response, the study investigators considered two factors. They looked at whether or not patients achieved adequate levels of drug in the blood, and considered if resistance mutations faded during the interruption.
Some patients did not have adequate drug levels in the blood. The researchers also reported that some patients had their mutations become not detectable. 47% of the patients did not experience a loss in detection of their mutations. They reported for 41% of patients the NRTI mutations were no longer detectable; for 35% their NNRTI mutations were not detectable. This does not mean the mutations were gone because previous studies show that when using a more sensitive test you can find the resistance mutations. The French investigators said to me that they detected fading resistance mutations.
It appears to Steve Deeks, MD, a leading researcher in treatment interruption, that the results in this study are impressive but the reason for the results are unclear. In reviewing this study it appears unclear to him why the 8-week interruption produced a better viral load response. He expressed a doubt that drug levels played a role in the difference in viral response between the deferred & immediate treatment arms. He said we need follow-up studies to better understand.
During the 8 week interruption CD4 declined by 40% and viral load increased 0.16 log. In speaking with the study investigators they expressed concern about this and feel that an interruption for longer than 8 weeks would be too risky. The two groups experienced a similar number of grade 3/4 adverse events except that more patients in the immediate group had elevated triglycerides & cholesterol than in the deferred therapy group, suggesting that the break in therapy helped to reduce lipids.
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