 |
|
|
| |
CROI: HIV-1 Drug Resistance Review Report 1: Low Level NNRTI Resistance May Not Be Detected by Standard Genotype Tests; Sensitive Genotype Tests
|
| |
| |
Andrew Zolopa, MD
Stanford University
This is the first of a series of reports on HIV- Drug resistance from the 11th Retrovirus Conference written for NATAP by Andrew Zolopa, a leading HIV drug resistance researcher. Following is an Index of topic to be covered in the series.
--Inability of Standard Resistance Tests to Detect Low Level ("Minority") Resistance in Treatment Naïve & Experienced Patients
--New Drugs: Reyataz & the 50L mutation, may limit resistance to other protease inhibitors; TMC-114 for patients with resistance to protease inhibitors; Reverset: a new NRTI with in vitro activity against HIV with NRTI resistsnce
--Single Drug Interruption Strategy: nrti, nnrti, & PI interruption strategies
--Transmitted Drug Resistance May Persist
--Impact of Transmitted Drug Resistance on ARV
--Single Dose Nevirapine & its Impact on Subsequent Treatment of Mother
--Select Triple Nucleoside/tide Regimens Have Led to High Viral Failure Rates (but Not All Triple Nuke Regimens) & HIV Drug Resistance
--K65R Mutation: its prevalence, mechanism of resistance, and mutational interactions
Introduction
The problem of drug resistance continues to challenge HIV providers and at this year's conference, we learned that in patients who experience virologic failure on antiretroviral (ARV) therapy have even more drug resistance than meets the eye from standard resistance test results. Attendees learned about the problem of so-called "minority variants" and their contribution to treatment failure. We also learned that drug resistant variants that are transmitted persist in some cases up to 3 years and maybe longer. We saw conflicting reports on the prevalence of transmitted resistance across countries and heard a discussion as to the potential causes of this global heterogeneity. The impact of transmitted resistance on response to ARV therapy was also the subject of a new study. We will review important results from Thailand on the resistance associated with single dose neviripine and the impact on subsequent treatment of the mother.
In this report we will review the virologic and resistance outcomes from several clinical trials of "all nucleoside/tide" ARV regimens that were presented at the conference with special attention to the prevalence, mechanism of resistance and mutational interactions of the K65R mutation. We will also review results of studies that explore the treatment strategy of removing one or more drugs from treatment regimens in patients with partial viral suppression, so-called "partial treatment interruption". And finally, we review a select few new drugs that either have unique resistance profiles and/or a potential role in treatment strategies of within class sequencing.
Minority Populations making a Big Impression: standard genotype resistance tests may not detect all drug resistance
Although resistance testing is now standard of care, the current technologies have shortcomings. Both phenotype and genotype tests are unable to detect "minority variants" which are HIV quazi-species that comprise less than 20-30% of the total HIV population circulating in the plasma of a patient. There are technologies that are more sensitive -- with a level of detection of minority variants down to <1% - however these technologies are not widely available and furthermore, it has remained unclear what the clinical impact of minority populations are on response to ARV therapy.
Mellors analyzed minority variants and the impact on treatment response using samples from the ACTG 398 trial. [abstract 39] Recall that the trial evaluated response to a "salvage regimen" that consisted of efavirenz, adefovir and various PI's in treatment experienced patients who had ongoing viremia (viral loads of >1000 copies) on their ARV regimen. Over half of the patients where naïve to NNRTI's while 44% were NNRTI experienced.
In the published results of the study, it was observed that patients who were NNRTI experienced did not respond to the treatment regimen as well as those who were NNRTI naive. Mellors showed that even in NNRTI-experienced patients with no NNRTI-related mutations detected at baseline by standard population-based sequencing did no better than those experienced patients with baseline mutations. This observation raised the possibility that there was NNRTI-associated resistance in the experienced patients that was simply not being detected by standard techniques. Using two different highly sensitive techniques to measure minority variants, the investigators found that many of the NNRTI-experienced patients with no detectable mutations by standard techniques indeed had NNRTI mutations at baseline detected by the more sensitive techniques. Furthermore, by phylogenetic mapping the investigators showed that in many cases these minority variants were the same mutations that emerged in the dominant population at treatment failure.
Note from Jules Levin: Mellors compared the frequency of minor NNRTI resistant variants among NNRTI naïve and experienced patients with negative standard genotypes for NNRTI mutations at baseline. He looked at 12 NNRTI-naïve and 11 NNRTI-experienced patients in study ACTG 398. Of the 12 naïve patients they were able to look at 9 of them, 9 had amplifiable samples. None of the 12 NNRTI-naïve study patients had detectable mutations by standard genotype testing. Using the sensitive test 2 patients had identifiable NNRTI resistance mutations: 1 patient had the K103N (this mutation was found in 1 of 41 genomes); a second patient had 2 mutations (100I + 225L) (these 2 mutations were present in 2 of 33 genomes, one in each). It appears that NNRTI resistance in naïve patients was at a low level, and clinical implications need further research. In the 11 NNRTI-experienced patients no mutations were detected by standard genotype; but in samples available for 10 patients, 6 patients had NNRTI mutations.
Hance and colleagues demonstrated that minority variants present at baseline in protease inhibitor experienced patients were selected for and emerged as the dominate variants at failure on a subsequent PI-containing regimen. [abstract 57] However, phylogenetic mapping revealed that the further out treatment failure occurred on the new regimen the less closely did the failure genotype map to the baseline sequence. It appears from this study that pre-existing minority variants are more likely to explain early virologic failures but there is also de novo resistance which develops while on a failing regimen and this mechanism of resistance becomes more common the longer the patient is on a failing ARV regimen.
Taken together these two studies clearly demonstrate that minority variants which can not be detected by standard resistance tests are responsible for treatment failure in at least some treatment experienced patients who go onto a new ARV regimen. These studies document that drug resistance in the setting of treatment failure is even more prevalent and complex than we have come to learn from using resistance testing in practice over that past several years.
To use the analogy that Mellors used in his presentation, we are only seeing the tip of the resistance iceberg with currently available resistance technologies. This of course is further bad news for patients trying to achieve virologic control after treatment failure and makes the need for new drugs that are not cross resistant to currently available agents ever more obvious.
However, being able to detect minority variants with more sensitive tests has not been shown to improve treatment choices for patients who are experiencing treatment failure compared to treatment choices that are based on standard resistance test results. The other point to emphasize here is the importance of a careful treatment history in accessing resistance test results. For example, in a patient who has had an NNRTI --containing regimen in the past and who was viremic during that exposure (even if only for a couple of weeks), it is likely they have NNRTI-associated resistance even if the current resistance tests does not detect any resistance.
|
|
| |
| |
|
| |
|
|
|
|
|
