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Studies Find Low-Level HIV Drug Resistance During Therapy and Interruptions; Does 3 month Interruption Help or Harm?
Reported by Jules Levin
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There were several interesting studies on the development of resistance during therapy and during treatment interruption; and there were 2 interesting studies on whether or not taking a 3 month interruption helps response to therapy after restarting a new regimen.
Low Level PI Resistance Found During Therapy
In one study reported at the Resistance Wksp, Alan Hance (Hopital Bichat Claude Bernard, Paris, France) looked at 7 patients who had virologic failure while on A PI regimen, and for whom standard genotype testing showed a major PI mutation -- the L90M. Hance used a very sensitive test to look at blood samples taken from them during therapy. This same L90M mutation was found (as a minority population) in viruses for 3-34 months prior to viraologic failure and the detection of the L90M by standard genotype testing. Hance concluded there is low level HIV drug resistance that can be overlooked by standard resistance testing. We know from before that even while patients have <50 copies of viral load on therapy HIV continues to produce at low levels. This study suggests there is low level resistance developing while still <50 copies. He also found there are additional protease inhibitor mutations that were detected when using the sensitive test (including V82I, I54V, M36I, M46L). Although Hance suggested these results suggest you may be less susceptible to future therapy, this has not been proven. You need to do studies in HIV-infected who are undetectable (<50) with these types of low level resistance mutations to evaluate responses to their next regimen after failing the other. And, the presence of low level mutations does not mean patients are going to fail the therapy they are currently taking or are more likely to fail their regimen. Studies are needed to better understand and characterize this information.
Drug Resistance During Interruptions
Karen Metzner studied found the emergence of drug resistance in 25 chronically-infected patients undergoing multiple Structured Therapy Interruptions in the well known Spanish Swiss Therapy Interruption Trial. She used a sensitive to look for resistance mutations L90M (protease) and M184V (3TC). Patients in the SSTIT study had <50 copies for 6 months or greater, >300 CD4s, and was treatment-naive prior to entering the study. None of the study patients were permitted to be taking NNRTIs because of their long half-life, which means after other drugs are eliminated after stopping therapy decreasing levels of NNRTIs remain in the blood for several days and could lead to resistance. In addition one mutation (K103N) can lead to NNRTI resistance.
Therapy was stopped for 2 weeks followed by 8 weeks back on therapy, and this cycle was repeated 4 times. After week 40 patients took a 3 month interruption, and therapy rsumed if necessary according to study rules. Metzner found low levels (minor populations) of drug resistance in several patients during the 2 week interruptions. In 1 patient both mutations were detected as minor populations during the first 2 week interruption, but the mutations disappeared during future interruptions. In one patient the L90M was detected during the 4th 2 week STI and in a second patient the L90M showed up in the 4 month STI. 36% of patients (9/25) were found to have the 3TC (M184V) mutation at low levels (minority population) at different times during the STIs. Overall, 40% (10/25) were found to have a low level mutation. However, so far none of the study patients developed failure to therapy after resuming treatment. Metzner concluded that drug resistance can develop during an interruption, even one as short as 2 weeks. She suggested that this could be because when you stop a regimen HIV replication increases but HIV drug levels are decreasing. The presence of suboptimal drug levels in the face of increasing HIV viral replication can cause resistance for some individuals. Resistance is most likely to occur to drugs for which resistance can develop easy such as when 1 resistance mutation leads to drug resistance. One mutation leads to resistance to NNRTIs and for 3TC.
Does a 3 Month Interruption Harm or Help Response to Next Regimen
In a relatively small study presented at the Resistance Workshop, Lydia Ruiz found that heavily treated patients responded the same to the next regimen following a 3 month interruption. In a small study presented at Barcelona Christine Katlama's GIGHAART study found that patients who were much more advanced than those in the Ruiz study responded better in terms of CD4s & viral load after a 3 month interruption. At this point it's not understood why the responses in the 2 studies are different as these data were just presented and researchers have not had the opportunity yet to discuss the results.
In the Ruiz study 22 patients with viral failure were switched immediately to a new regimen and 24 took a 3 month interruption before starting the new regimen. The new regimen was Kaletra, 3TC, saquinavir, abacavir and DDI. The 46 patients had average viral load of 20,000 copies, and CD4swere about 350 on average. During the 3 month break viral load increased by an average of 0.9 log and Cd4s decreased by an average of 131. Clinical complications were not observed during the break. The average number of mutations was almost 10 before patients switched therapy, but during the 3 month break these patients only had 4 mutations detected. This is important information because it has been suggested that taking a 3 month break might cause mutations to fade and might be the reason for better viral response after restarting therapy. However, in this study no matter whether patients took a 3 month break or not the viral load response was about the same. After 48 weeks on the new salvage regimen 45% in the interruption patients and 43% in the non-interrupting patients had <80 copies of viral load. Cd4s increased a little more on therapy for the group who did not take a break (73 vs 31) but it's uncertain if this difference is significant.
The shift to wild-type virus (disappearance of resistance mutations) was not associated with a better viral response in the Ruiz study. But Christine Katlama suggests that the disappearance of resistance mutations in her study appears to be associated with the better viral response in the patients taking an interruption. Ruiz found that patients with <20,000 viral load in her study had a better response than patients with higher viral load, and patients who were adherent had a better response.
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. These patients were much more advanced than in the Ruiz study: 68% had prior AIDS diagnosis, viral load was >100,000 copies, CD4s on average were 26. 68 patients were randomized to switch immediately to new regimen or take an 8 week interruption before restarting therapy with the same new regimen. The new regimen consisted of 3 protease inhibitors, 3-4 nukes, and hydroxyurea. After 12 weeks on the new regimen the immediate switch patients had a viral load reduction of -0.37 vs -1.91 for the patients taking 8 week break. After 24 weeks on the new regimen, the immediate switch patients had a -0.30 log reduction vs -1.08 for the patients taking an interruption.
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 had good drug levels & some did not. For some patients mutations were no longer detectable during the 8 week break. Katlama suggested the better response may be due to the disappearance of mutations during the break. But it remains unclear why there was a better response for patients taking the break. During the break CD4s declined by 40% and viral load increased by 0.16 log. In this advanced population, the investigators said they would not want to have an interruption longer than 8 weeks due to the CD4 decline and viral load increase. The reported number of grade 3/4 adverse events was the same in both groups. But it appeared as though the break led to improvements in cholesterol & triglycerides.
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