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CROI Resistance Report 6: Single Drug Interruption Strategy--nrti, nnrti, pi
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Written for NATAP by Andrew Zolopa, MD
Stanford University
Strategies for Managing Patients with Multi-drug Resistant HIV: Can we use fewer drugs?
In the past year we have begun seeing reports evaluating the impact of stopping part of a patient's antiretroviral regimen who has MDR HIV and partial viral suppression. The idea is to reduce the burden of ARV in patients who are not able to achieve full viral suppression without subjecting the patient to the risks of a complete structured treatment interruption (STI). Some of the clinical questions that are being addressed in these studies include what kind of regimen is required and what is the minimum number of drugs required to maintain clinical stability in patients with partial viral suppression? Moreover, what role do PI's versus nRTI's play in maintaining partial suppression and CD4 stability?
In the COLATE study, investigators evaluated the impact of removing 3TC in patients with 184V. [abstract 549] Many practitioners maintain 3TC as part of salvage regimens even in patients with resistance to the drug. The main justification for keeping 3TC as part of salvage regimens is to maintain the 184V mutation which has been shown in vitro to diminish viral fitness. In this randomized controlled study, patients who were on failing ARV regimens with viral loads >1000 copies/ml (stratified by first regimen failure vs. subsequent failures) and who had evidence of the 184V mutation present were randomly assigned to a new ARV based on resistance testing with or without 3TC as part of the new regimen. There was no difference in virologic outcomes seen in the study and the study was stopped early by a data safety monitoring board who felt that continuing the study would lead to a null result (ie, no difference). In the 131 subjects enrolled, 41% were failing their first regimen and two thirds of the patients achieved <400 copies by week 48. In the group in which a follow up sequence could be obtained, those that received 3TC did maintain the 184V mutation while the 184V mutation became undetectable after 12-24 weeks in those who did not continue 3TC.
Although this study did not show any benefit to maintaining 3TC in patients with 184V, it does not prove that continued 3TC is ineffective in improving virologic response in patients unable to achieve complete suppression -- thru it's impact on viral fitness. The main limitation with this study is that the majority of subjects had very good virologic responses. Fitness impacts are not particularly relevant in patients who are able to achieve full suppression as was seen in this study. This study needs to be repeated in more treatment experienced patients who would be more likely to remain viremic while on a ARV regimen.
Maldarelli and colleagues from the NCI reported results on 6 patients who had ongoing viremia while on ARV and stopped 1 of their nucleosides (3 d4T, 1 ddI) or the NNRTI (2 stopped EFV). [abstract 623] All patients were on ARV regimens with stable viral loads >5,000 and CD4 counts >50. After close monitoring for 10 days, patient stopped one drug in their regimens while continuing the rest of the regimen. Over 14 days frequent sampling was performed. There were increases in viral load seen in all the patients who stopped a nRTI while those who stopped the NNRTI experienced no increase. Interestingly, in 2 subjects who stopped d4T had multiple TAM's at baseline and yet it appeared that d4T was still contributing to antiviral activity of the regimen. When d4T was reinstituted viral loads decreased promptly.
This study along with others reported at last year's meetings seem to indicate that nucleoside inhibitors continue to exert an antiviral effect in patients with partial viral suppression even though it appears from their resistance profile that these drugs should not have any activity. From these studies it is probably reasonable to continue at least one nRTI in most salvage regimens to attempt to take advantage of any residual antiviral effects this class may have in the setting of " pan-resistant" HIV. However, further study in larger cohorts and randomized controlled studies are required to better define the impact of nRTI's in the setting of salvage therapy and how best to optimize treatment for these patients.
Hunt and colleagues from UCSF reported on the immunological and virological impact of selectively stopping PI's ("partial treatment interruption or PTI") in patients with multi-drug resistant HIV and partial virologic suppression. [abstract 663] In this uncontrolled study, investigators stopped the PI in 17 patients with PI --resistance and partial viral suppression. They measured changes in CD8 activation, CD4 counts, viral load and resistance profile over time. CD4 counts declined at an average of 2 cells/ month of PI PTI and this rate of decline accelerated when there was loss of PI resistance. After adjusting for viral loads, the investigators found that CD8 activation markers increased and that there seemed to be an association with loss of PI resistance. Although the cause and effect relationships between viral load, PI resistance and CD8 activation are not clear from this study, the investigators suggest that CD8 activation as well as virologic factors determine the profile of change in CD4 counts and viral load during PI PTI's. Again randomized controlled studies are called for to better delineate the role of PI's in the setting of MDR-HIV in patients experiencing partial viral suppression.
Launay and colleagues from Paris, presented results from the "Vista study" (ANRS 109) in which investigators identified 26 patients with MDR HIV, who were viremic while on their ARV's and were put on "low dose" IDV/RTV with 3TC. The IDV doses were adjusted such that patients were to have Cmins of IDV that were calculated to be 50% of the patients IC50 (ie, a dose that would not expect to be fully suppressive). At 24 weeks viral loads increased by 0.22 log and CD4 counts dropped by 50 cells. The study was stopped early as a result of these findings. Although the CD4 declines were disappointing, the rate of decline was not statistical significantly different from the decline seen prior to entering the study. Furthermore, there was little evolution of resistance over the course of the study. This thoughtful approach to minimizing long term ARV toxicities while maintaining virologic and immunologic benefit by using a "minimal" ARV regimen deserves further study.
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