Increasing proportions of HIV-1 non-B subtypes and of NNRTI resistance between 2013 and 2016 in Germany: Results from the national molecular surveillance of new HIV-diagnoses

Abstract

BackgroundMolecular surveillance of newly diagnosed HIV-infections is important for tracking trends in circulating HIV-variants, including those with transmitted drug resistances (TDR) to sustain ART efficacy.MethodsDried serum spots (DSS) are received together with the statutory notification of a new diagnosis. 'Recent infections' (<155 days) classified by a 'recent infection test algorithm' (BED-CEIA and clinical data) are genotyped in HIV-protease (PR), reverse transcriptase (RT) and integrase (INT) to determine the HIV-1 subtype, to calculate prevalence and trends of TDR, to predict baseline susceptibility and to identify potential transmission clusters for resistant variants.ResultsBetween January 2013 and December 2016, 1,885 recent infections were analysed regarding the PR/RT genomic region, with 43.5% of these also being subjected to the analysis of INT. The proportion of HIV-1 non-B viruses (31.3%; 591/1,885) increased from 21.6% to 36.0%, particularly the subtypes A (5.0% to 8.3%) and C (3.2% to 7.7%; all ptrends < 0.01). The subtype A increment is mainly due to transmissions within men who have sex with men (MSM) while subtype C transmissions are associated with heterosexuals and people who inject drugs. The prevalence of TDR was stable at 11.0% (208/1,885) over the study period. Resistances to nucleotide RT inhibitors (NRTI) and PR inhibitors (PI) were 4.5% and 3.2%, respectively, without identifiable trends. In contrast, resistances to non-NRTIs (NNRTI, 4.7%) doubled between 2014 and 2016 from 3.2% to 6.4% (ptrend = 0.02) mainly due to the K103N mutation (from 1.7% to 4.1%; ptrend = 0.03) predominantly detected in recently infected German MSM not linked to transmission clusters. Transmitted INSTI mutations were present in only one case (T66I) and resistance to dolutegravir was not identified at all. Reduced susceptibility to recommended first-line therapies was low with 1.0% for PIs, 1.3% for NRTIs and 0.7% for INSTIs, but high for the NNRTIs efavirence (4.9%) and rilpivirine (6.0%) due to the K103N mutation and the polymorphic mutation E138A. These trends in therapy-naïve individuals impact current first-line regimens and require awareness and vigilant surveillance.

Reconstruction of the Genetic History and the Current Spread of HIV-1 Subtype A in Germany

“…For decades, subtype B has been the dominating HIV-1 subtype in many European countries. However, in recent years the incidence and prevalence of other subtypes have been increasing in Western and Southern European countries, such as Great Britain, France, Italy, and Germany (2,14,16,(18)(19)(20)(22)(23)(24)(25). Hence, non-B infections are becoming a more serious public health issue, which necessitates a deeper understanding of the non-B epidemics in these countries.…”

“…Hence, non-B infections are becoming a more serious public health issue, which necessitates a deeper understanding of the non-B epidemics in these countries. Among HIV-1 non-B subtypes in Germany, subtype A is one of the most abundant subtypes showing increasing prevalence rates (19,20,26).…”

“…As all RKI sequences were obtained from treatment-naive patients, this allows us to get a nationwide view on SDRM in German subtype A. The analysis of these sequences revealed a higher proportion of SDRM (13.3% and 18.9% with E138A) than the nationwide level of 11% for all subtypes (19,20). Resistance mutations against protease inhibitors as well as the E138A NNRTI mutation occur exclusively in clusters.…”

“…This subepidemic strain, here termed the Eastern European lineage or A Former Soviet Union (A FSU ), is estimated to have arrived in the town of Odessa (Ukraine) around 1984 from the DRC, and since 1993, it has spread explosively among people who inject drugs (PWID) all over the Former Soviet Union (13). The geographic range of the Eastern European clade is increasing, and this lineage has now been found in several other European countries, including Great Britain, Poland, Italy, and Germany (14,(16)(17)(18)(19)(20). Analysis of HIV-1 sequences from recently infected individuals in Germany revealed HIV-1 subtype A, with an increasing frequency from 5.1% in 2013/2014 to 8.3% in 2016, to be the most abundant non-B subtype among newly infected individuals in Germany (19,20).…”

An Evolutionary Model-Based Approach To Quantify the Genetic Barrier to Drug Resistance in Fast-Evolving Viruses and Its Application to HIV-1 Subtypes and Integrase Inhibitors

“…Here, we demonstrate our approach by the application to the HIV-1 INSTIs. With the rollout of INSTIs in LMICs, an increasing introduction of non-B subtypes in highincome countries (26)(27)(28)(29), and the anticipated approval of additional INSTIs, this study addressed the need for an in-depth understanding of the dynamics underlying INSTI resistance development across HIV-1 subtypes. We derived an optimized genetic barrier score based on empirical substitution costs, which contrasts with previous approaches that used arbitrary costs differing from in vivo estimates (30).…”