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CROI Resistance Report, Part 2; Transmission of Drug Resistance, it Persists; Global Trends; Impact of Transmitted Resistance on Initial Response to HAART
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Written for NATAP by Andrew Zolopa, MD Stanford University
--Transmitted HIV Drug Resistance Persists --Transmission of Drug Resistance: Is There a Global Trend and what are the Implications for Treatment?-- What is the impact of transmitted resistance on response to initial treatment?
Resistance Transmitted is anything but Transient: so far seen to last up to 3 years
It remained unclear, until recently, how long transmitted resistant variants would remain detectable in the plasma of newly infected individuals who were not on antiretroviral treatment. Little and colleagues presented 12 subjects that are part of the multi-center acute infection cohort - the characteristics of which have been previously published [abstract 36LB]. These 12 subjects were first enrolled into the cohort a median of 56 days after acute infection and were followed off ARV for a median of 255 days. All subjects were infected with HIV that had resistance to at least one class of antiretrovirals, 10 had NNRTI-related resistance, 5 had nRTI-related resistance (nukes) and 4 had PI-related resistance. The investigators monitored the time to mixture in which a wild-type virus variant was first detectable along with the resistant variant that was transmitted. The mean time to mixture was 375 days for NNRTI mutations, 362 days for nRTI mutations and no reversions were seen for the PI mutations. Even the M184V mutation which is thought to "disappear" relatively rapidly because of it's negative impact on viral fitness was actually seen to persist at least in one subject with a time to mixture of 327 days. Furthermore, there was only 1 patient who had a "complete reversion" to wild-type (that is no mixtures or mutations detected by standard genotyping techniques) and that occurred after 1019 days of follow up. These findings were supported by similar findings in study from the UK [abstract 684].
Resistance testing is now recommended in patients who are treatment naïve and have been infected in the past 1-2 years, this recent change in the guidelines is in part related to the data from Little and colleagues showing that resistance that is transmitted tends to persist in the plasma and is detectable by standard resistance testing methods. Even if the patient is not necessarily going to start antiretroviral therapy immediately, it is probably useful to obtain the genotype as part of the initial evaluation if the timing of infection falls with in this 1 to 2 year window and maybe longer.
Transmission of Drug Resistance: Is There a Global Trend and what are the Implications for Treatment?
There was a poster session [session 95, abstracts 676-685] devoted to the epidemiology of transmitted drug resistance from around the world. Taken as a whole, there was no overall dominant trend, of say increasing transmission of drug resistance worldwide. Rather, the results of the studies presented were quite heterogeneous and apparently conflicting. The prevalence of transmitted drug resistance varies by HIV subtype (usually lower levels in non-B clades), risk group (generally higher levels in MSM compared to heterosexuals), geographic location of infection (lower levels in countries or regions with less ARV available), and cluster outbreaks within "core" groups in a given country (eg IDU cluster in Switzerland). Given the wide variation in these factors world wide, it is not terribly surprising that there is not a dominate trend across the globe, particularly when one adds to these sources of variation - variation in definitions of drug resistance used in the various studies, convenience sampling and relatively small sample sizes.
What is the impact of transmitted resistance on response to initial treatment?
Previously published studies have indicated that transmitted resistance impacts response to first line ARV. In published studies by Little [NEJM 2001] and Grant [JAMA 2002], there was a slower rate of virologic response in those patients who had been infected with drug resistant viruses. In the CASCADE study, presented at this year's conference no such negative impact was observed. [abstract 685] Time to viral suppression was no different in the group who had transmitted drug resistance compared to the group with no resistance. Nor did the investigators find any impact on virologic response related to resistance to a particular class of ARV. However, the investigators caution that longer-term follow-up is required to determine the durability of response in patients with transmitted drug resistance.
Why did this study show no difference in response in those patients who had drug resistance while older studies did demonstrate a negative impact? In part this may reflect better treatment options available now compared those used in the earlier studies. In the CASCADE study, the over all response rate was quite impressive with 87% of subjects achieving viral loads of <500 copies within 3 months of initiating treatment. Use of potent boosted PI's and more convenient once a day regimens may have been better able to overcome transmitted resistance compared to older ARV regimens used in the earlier studies. Most transmitted resistance is limited to a single class -- and most commonly it is one or two mutations to the nucleoside reverse transcriptase inhibitors. It is likely, that potent regimens that contain boosted PI's and some of the newer nucleoside/tide RTI's will be able to over come this level of resistance and achieve good virologic suppression at least initially.
However, there may have been analytical differences between the studies that evaluated impact of transmitted resistance on initial treatment response that also help explain the differences in outcomes. In the CSCADE study, investigators state that there was no difference in time to viral suppression "after adjusting for individuals without a fully active HAART regimen". It would be of interest to know the response rates in the two groups (those with and without transmitted resistance) without statistical adjustment for number of active drugs. Furthermore, it is not clear how much access the treating physicians had to the resistance results in crafting an ARV regimen for the patients enrolled in the CASCADE cohort, but if the treating physicians had the resistance tests results in hand this would obviously influence the outcome of the study.
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