Date Published: April 16, 2018
Publisher: BioMed Central
Author(s): Oliver T. Stirrup, David T. Dunn, Anna Tostevin, Caroline A. Sabin, Anton Pozniak, David Asboe, Alison Cox, Chloe Orkin, Fabiola Martin, Patricia Cane.
The prevalence of HIV-1 resistance to antiretroviral therapies (ART) has declined in high-income countries over recent years, but drug resistance remains a substantial concern in many low and middle-income countries. The Q151M and T69 insertion (T69i) resistance mutations in the viral reverse transcriptase gene can reduce susceptibility to all nucleoside/tide analogue reverse transcriptase inhibitors, motivating the present study to investigate the risk factors and outcomes associated with these mutations.
We considered all data in the UK HIV Drug Resistance Database for blood samples obtained in the period 1997–2014. Where available, treatment history and patient outcomes were obtained through linkage to the UK Collaborative HIV Cohort study. A matched case–control approach was used to assess risk factors associated with the appearance of each of the mutations in ART-experienced patients, and survival analysis was used to investigate factors associated with viral suppression. A further analysis using matched controls was performed to investigate the impact of each mutation on survival.
A total of 180 patients with Q151M mutation and 85 with T69i mutation were identified, almost entirely from before 2006. Occurrence of both the Q151M and T69i mutations was strongly associated with cumulative period of virological failure while on ART, and for Q151M there was a particular positive association with use of stavudine and negative association with use of boosted-protease inhibitors. Subsequent viral suppression was negatively associated with viral load at sequencing for both mutations, and for Q151M we found a negative association with didanosine use but a positive association with boosted-protease inhibitor use. The results obtained in these analyses were also consistent with potentially large associations with other drugs. Analyses were inconclusive regarding associations between the mutations and mortality, but mortality was high for patients with low CD4 at detection.
The Q151M and T69i resistance mutations are now very rare in the UK. Our results suggest that good outcomes are possible for people with these mutations. However, in this historic sample, viral load and CD4 at detection were important factors in determining prognosis.
The online version of this article (10.1186/s12981-018-0198-7) contains supplementary material, which is available to authorized users.
Highly potent and effective antiretroviral therapies (ART) to treat HIV-1 infection are now available and although drug resistance was a considerable problem in the early years of ART use, its impact has now declined in high-income countries. In the UK HIV Drug Resistance Database (UK-HDRD) only about 30% of treated patients receiving resistance tests following virological failure in 2014 showed any drug resistance, compared with 72% in 2002 . Likewise, a decline in drug resistance in treated patients has been observed in Canada  and overall in Western Europe . In Switzerland it is now considered that the emergence of new drug resistance “can be virtually stopped with new potent therapies and close monitoring” . However, drug resistance remains a considerable problem in the successful treatment of HIV infection in many low- and middle-income countries (LMICs) [5–7]. This is in part due to limited drug options, but also to a lack of (or limited) routine viral load (VL) monitoring  as patients continuing to use ART while failing to suppress viral replication may develop resistance mutations. This has led to calls for improved provision of VL monitoring and resistance testing [9–11].
We have found that the prevalence of multi-drug resistance mutations Q151M and T69i has declined to almost zero in the UK and, as such, it is likely that observation of these mutations will now be very rare in any high-income country. However, the more recent introduction of widespread ART in LMICs has been associated with an increase in transmitted drug resistance  and whilst it may be expected that the phase-out of older drug regimens  and improved access to VL monitoring  will lead to an eventual reduction, the overall levels of drug resistance have yet to show such a decline . Our analysis regarding the risk factors and outcomes associated with these mutations may therefore be relevant for drug resistance monitoring and clinical management of any observed cases in such settings.
Our data confirm that modern ART and laboratory monitoring have greatly reduced the occurrence of multi-NRTI resistance due to T69i and Q151M in the UK, a change that is very likely to have also occurred in other developed countries. It remains to be seen whether similar progress can be achieved in LMICs. In addition this report demonstrates that ART regimen changes can be successful despite these mutations, although whether outcomes in patients with the poorest prognosis can be improved with more modern ART regimens also remains to be determined.