Virological failure and development of new resistance mutations according to CD4 count at combination antiretroviral therapy initiation

Objectives No randomized controlled trials have yet reported an individual patient benefit of initiating combination antiretroviral therapy (cART) at CD4 counts > 350 cells/μL. It is hypothesized that earlier initiation of cART in asymptomatic and otherwise healthy individuals may lead to poorer adherence and subsequently higher rates of resistance development. Methods In a large cohort of HIV‐positive individuals, we investigated the emergence of new resistance mutations upon virological treatment failure according to the CD4 count at the initiation of cART. Results Of 7918 included individuals, 6514 (82.3%), 996 (12.6%) and 408 (5.2%) started cART with a CD4 count ≤ 350, 351–499 and ≥ 500 cells/μL, respectively. Virological rebound occurred while on cART in 488 (7.5%), 46 (4.6%) and 30 (7.4%) with a baseline CD4 count ≤ 350, 351–499 and ≥ 500 cells/μL, respectively. Only four (13.0%) individuals with a baseline CD4 count > 350 cells/μL in receipt of a resistance test at viral load rebound were found to have developed new resistance mutations. This compared to 107 (41.2%) of those with virological failure who had initiated cART with a CD4 count < 350 cells/μL. Conclusions We found no evidence of increased rates of resistance development when cART was initiated at CD4 counts above 350 cells/μL.


Introduction
Although morbidity and mortality benefits of starting combination antiretroviral therapy (cART) at CD4 counts > 350 cells/lL have been reported in cohort studies [1,2], there is little randomized evidence on the individual risk-benefit ratio of initiating combination antiretroviral therapy (cART) at higher CD4 counts [3]. The randomized controlled Strategic Timing of AntiRetroviral Treatment (START) trial has recently investigated the optimal timing of cART initiation in order to improve morbidity and mortality outcomes in HIV-positive individuals [4]. Nevertheless, there have already been changes to national and international HIV treatment guidelines [5,6], largely driven by the impact of cART on viral transmission [7] and a pragmatic approach to cART roll out programmes.
As adherence to cART has been associated with perceived "need" for treatment [8], there is concern that a recommendation to start cART at higher CD4 counts may be met with patients' ambivalence to cART, leading to suboptimal adherence and antiretroviral resistance. However, there are no data reported in support of this hypothesis to date [9,10] This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. antiretroviral resistance development as a secondary endpoint, and will report these findings after 2016.
Previously, we reported on laboratory-defined adverse events (LDAEs) according to the CD4 count at initiation of cART [11]. We now describe rates of new antiretroviral resistance mutations in those experiencing virological failure, according to the CD4 count at treatment initiation.

Methods
The UK Collaborative HIV Cohort (CHIC) Study collates routinely collected clinical data on HIV-positive individuals accessing care across several centres in the UK. The study was approved by a multicentre research ethics committee and by local ethics committees and does not require informed consent. Similarly, the UK HIV Drug Resistance Database (HDRD) collates results of routine resistance testing of HIV-positive individuals accessing care. A combined UK CHIC -UK HDRD dataset was used for analysis. Individuals were included who initiated cART (≥ 3 antiretroviral drugs) between 2000 and 2011 with a baseline CD4 count and resistance test result available, and who achieved an undetectable viral load on cART. Pregnant women were excluded.
Virological rebound was defined at the first occurrence of two consecutive viral loads > 400 HIV-1 RNA copies/ mL following an undetectable viral load. Virological rebound occurring while on cART was classed as treatment failure and evaluated for resistance development. Virological rebound that occurred immediately following a treatment discontinuation was not evaluated for resistance development. The earliest resistance test result available up to 1 month before or 6 months after the date of virological failure was used. We defined new resistance as the presence of any new major resistance mutation [12] not present in the baseline genotype, stratifying results according to the CD4 count at cART initiation (≤ 350, 351-499 and ≥ 500 cells/lL).

Discussion
Our results do not demonstrate an increased risk of virological failure on cART when therapy is initiated at CD4 counts > 350 cells/lL. In fact, there appeared to be a reduced risk of developing a major resistance mutation when cART was initiated at CD4 counts > 350 cells/lL. Greater use of PI/r-based regimens with a higher genetic barrier to resistance in this group may explain the effect of seeing fewer resistance mutations emerge when virological failure occurred [13]. However, our findings are consistent with other studies [9,10].
Higher rates of virological rebound were observed in the group that started cART at CD4 counts above 500 cells/lL. The majority of rebounds in this group occurred following treatment discontinuation, with the proportion of patients experiencing rebound while reportedly still receiving cART being similar across groups. Reasons for treatment discontinuation in this group are unknown; however, it is possible that some of these individuals were enrolled in trials of treatment interruption strategies that were undertaken during this time period [14]. However, this trend towards more treatment interruption in those starting cART with a high CD4 count raises some concerns. Depending on the specific drugs included in the regimen as well as the timing of stopping, there is the potential for viral replication to occur in the presence of sub-optimal levels of cART following treatment discontinuation, thus leading to selection of drug-resistant virus, particularly for regimens containing NNRTIs [15]. Fewer resistance tests appeared to be undertaken in individuals experiencing virological failure who had initiated treatment with CD4 counts > 350 cells/lL, raising concerns that resistance mutations may be missed in this group. However, this may be a chance finding and reasons for a lower rate of testing in this group are unclear; lower viral load at virological failure did not appear to explain this and no significant predictors of resistance testing at virological failure were found in any CD4 strata.
Our analyses are limited because reasons for starting cART at high CD4 counts outside current national guidelines are not known. Caucasians and MSM were overrepresented amongst those starting therapy with CD4 counts > 350 cells/lL, indicating that subgroups traditionally presenting to HIV services earlier in the United Kingdom tend to initiate treatment earlier [16]. This may indicate an underlying selection bias amongst those starting therapy early, as native English speakers and UK nationals with greater access to healthcare and of potentially higher educational status may opt to start therapy earlier. However, repeating our analysis including only MSM, we saw similar patterns by CD4 count strata, with 35. 1, 12.5 and 11.1% of those with CD4 counts < 350, 351-499 and > 500 cells/lL (respectively) having new resistance mutations when tested at virological rebound. Furthermore, in this observational setting, those who have been motivated to start cART at higher CD4 counts may be more likely to have better adherence to treatment and may therefore be less likely to either experience virological rebound or develop resistance to antiretrovirals.
Despite certain limitations, we have not found evidence of an increased risk of resistance development at virological failure amongst people initiating cART at CD4 counts > 350 cells/lL. Caroline Sabin has received honoraria participation in Data Safety and Monitoring Boards and Advisory Boards, for preparation of educational materials and for membership of speaker panels for Gilead Sciences, Bristol-Myers Squibb, ViiV Healthcare/GlaxoSmithKline, Janssen-Cilag and Abbvie. Sarah Fidler has worked in research collaborations with MSD and GlaxoSmithKline and as a speaker for Viiv Healthcare, Janssen-Cilag and MSD.