Despite the obvious benefits of ART, the emergence of drug resistance mutations in HIV genome can severely compromise its long-term efficacy. The possibility of transmission of resistant viral strains and infecting with resistant HIV viruses poses additional challenges for treatment and can compromise public ART programs in settings that use standardized first-line regimens. However, mutations in positions associated with resistance are not always a consequence of treatment or transmission of resistant viruses but may reflect the phenomenon of natural polymorphism and have a subtype-specific nature resulting from the founder effect during the evolutionary formation of subtypes. The knowledge of the impact of such pre-existing mutations on phenotypic HIV drug resistance remains very limited.
A literature review showed that there is no consensus on the significance of pre-existing HIV drug resistance mutations, and the separate analysis of genotype and phenotype in ART-naive subjects may provide conflicting results. For example, the analysis of 18 subjects with minor resistance mutations in HIV-1 protease at baseline showed no signs of clinical resistance during the ongoing ART [19]. No association was found between pre-existing resistance alone to NNRTIs and rates of virological suppression for patients receiving an efavirenz/emtricitabine/tenofovir regimen [20]. It was also shown that antiviral activity of INSTIs (integrase strand transfer inhibitors) was retained in HIV-1 mutants with minor resistance-associated mutations [21]. Although it is a deficit of information regarding mutation E138A we found several publications on this issue. In the SPIRIT Study none of the virologically suppressed patients with single E138A mutation had virological failure through week 48 after switching to rilpivirine/emtricitabine/tenofovir disoproxil fumarate [22]. In a study in patients entering the SENSE trial of first-line ART in Europe, Russia and Israel, 13.9% of patients had one polymorphic mutation in baseline plasma (V90I, V106I or E138A), without any impact on virological outcomes of etravirine-based ART [23]. In a South African cohort, detection of drug-resistant mutations alone including E138A did not predict an increased risk of virological failure [24]. Additionally, in the Eviplera clinical trial there was one patient with mutation E138A at baseline, which maintained virological suppression throughout week 48 [25].
Alternative to these findings, an opinion exists that polymorphic mutations are not fully indifferent for the ART effectiveness and may constitute a kind of support for major resistance mutations. In this role, they can compensate for deleterious effect of major mutations, accelerate their selection, influence the time to resistance development, and the choice of mutational pathways [26].
This is well established that polymorphisms at sites associated with HIV drug resistance occur frequently [27], and the attitude to this issue is different in different countries. In countries where HIV genotyping is routinely performed prior to ART initiation, the presence of any mutations in positions associated with drug resistance ultimately prevents using the appropriate drugs. For example, according to the RPV package insert [28], the presence of E138A prior to therapy may reduce the antiviral activity of RPV, and, in Europe, RPV-based ART will be not recommended to patients with this mutation.
In countries where HIV GRT is not performed before starting treatment, the widespread occurrence of such mutations could potentially lead to ART failure in a significant number of first-line patients. Due to this, it is believed that there is a higher risk of virological failure of RPV-based ART in geographic regions such as sub-Saharan African in which HIV-1 subtype C infections predominate (that is, E138A mutation is widespread) [29]. We observed similar issue in Russia, where the frequency of the E138A polymorphic mutation in patients infected with the dominant HIV A6 virus ranges from 4 to 8%. This mutation is not associated with the transmission of resistant viruses, since the frequency of its occurrence before the use of RPV and ETR in Russia (until 2011) differed marginally from that in the subsequent time period [30].
Since it is planned to expand the use of RPV in Russia, including as part of single-tablet regimens, we were faced with a particular question, namely, whether patients with pre-existing E138A mutation are more prone to rapid failure of first-line RPV-based ART. To explore this issue, we undertook a search for RPV-treated HIV patients in the presence of E138A mutation. Since in Russia GRT is not performed before starting ART, we had to look for such cases outside the country, namely in the largest European database of HIV genotypes EuResist. The data on viral load during the time of the use of first-line RPV-based ART were analyzed in detail in accordance to Russian and international criteria.
Our study demonstrated that virological efficacy of first-line ART regimen based on RPV in HIV-infected patients with pre-existing E138A mutation in reverse transcriptase did not meet the definition of virological failure and corresponded to three out of three criteria of efficient therapy according to the Russian guidelines. At the same time, it did not meet two out of two criteria of virological failure in European and DHHS clinical guidelines. The sustainability of the virological response in all patients in this study suggests that a single pre-existing polymorphic E138A mutation unlikely will reduce the effectiveness of RPV-containing first-line regimens.
Currently, the HIV treatment coverage in Russia is increasing and in 2018 the locally produced generic form of RPV (Lakonivir) was registered. In the absence of the routine HIV GRT before starting ART our results may build background for clinical solutions for prescribing first-line RPV. Our findings provide additional information on the effect of single pre-existing mutations in positions associated with resistance on the ART effectiveness and advocate for expanding studies of this kind.
Our study has several limitations. Only very small number of patients was observed with different observation time. This is retrospective study with the measures of VL and patient examination not been scheduled consistently. Additionally, the HIV patients were infected with different non-A6 HIV-1 subtypes viruses. Investigation of E138A mutation in HIV A6 sub-subtype is pending.
In conclusion, in our investigation of ART naive patients the singleton pre-existing E138A mutation did not result in failure of RPV-based ART. The exact role of this mutation and other singletons in the efficacy of a first-line ART regimens should be clarified and merits further investigation.