Selective acquisition of G190S in HIV-1 subtype A from Russia leading to efavirenz and nevirapine treatment failure

Combination antiretroviral therapy (ART) has transformed HIV and AIDS from a deadly syndrome to a treatable and potentially preventable disease (www.unaids.org). Current treatment guidelines recommend combining three drug classes, including nucleoside and nonnucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs), protease, integrase, and entry inhibitors. The early introduction of ART in 1995 stabilized subtype B epidemics (<10% of the global pandemic) in Western world settings, as epidemics in Africa and Asia continued to expand and diversify to include nine major subtypes (A through D, F through H, J, and K) and many circulating recombinant forms (>62 CRFs) [1,2]. Subtype C infections account for 50% of the global epidemic; subtype A variants, including A sub-subtypes (e.g. A1 and A2), CRF01_AE and CRF02_AG, collectively represent 30% of infections worldwide [1,2]. The scale-up of ART national programs have led to impressive 25–50% declines in HIV incidence in many low-income and middle-income settings, raising optimism for an AIDS-free generation (www.unaids.org). The long-term success of ART programs is dependent on optimizing treatment strategies to limit the acquisition and spread of antiretroviral drug resistance in different population settings. Although current ART options appear to be effective against a broad spectrum of viral subtypes, there is emerging evidence that HIV-1 subtype variation can influence the development of drug resistance and ART susceptibility [2,3]. In this issue of AIDS, Kolomeets et al. have described a genetic difference in the subtype A viruses circulating in the Siberian Federal District of Russia [4]. A signature natural polymorphism (silent mutation) at reverse transcriptase codon position 190 (GGC), unique to this subtype A variant, favors a single G-to-A transition leading to the G190S (GGC → AGC) following treatment failure on efavirenz-based or nevirapine-based regimens. In this subtype A, the appearance of G190S is favored over K103N and Y181C, occurring with respective frequencies of 30, 14, and 6% in patients failing NNRTI-based regimens (n = 182), conferring cross-resistance to efavirenz and nevirapine. In contrast, G190S has been rarely observed in other HIV subtypes (including other subtypes A), in which K103N (AAA → AAC) and Y181C (TAT → TGT) mutations are preferentially selected following treatment failure on efavirenz-based and nevirapine-based regimens. These novel findings are disconcerting insofar as the intravenous drug user subtype A (also referred to as subtype IDU-A) circulating in Russia, former Soviet Union bloc countries and the Balkans is among the fastest growing epidemics worldwide spreading among IDU, perinatal and heterosexual populations [5]. Beyond conferring high-level resistance, studies have shown that G190A and K103N point mutations do not negatively impact on viral fitness and have contributed to the spread of transmitted resistance (3.6–8.1%) and clustered networks of resistance to NNRTIs among drug-naive populations [6–9]. Although efavirenz and nevirapine represent the first-choice components of many ART regimens, there remains a limited availability of routine viral load and drug resistance testing programs in low-income and middle-income settings to monitor the development and spread of drug resistance. Confirmatory data reported in a study from Israel showed G190S in 21% of patients harboring IDU-A viruses failing NNRTI regimens [10]. Although G190S viruses show high-level resistance to efavirenz and nevirapine, they may remain responsive to second-generation NNRTIs, such as etravirine and rilpivirine. Ongoing clinical and basic research studies are warranted to assess the evolution of G190S and cross-resistance to NNRTIs in this viral subtype. Previous clinical and cell culture studies have demonstrated that K65R is selected more frequently and rapidly in subtype C viruses compared with subtype B, particularly in association with the use of stavudine (d4T) and nevirapine [11–14]. This has been mechanistically related to a subtype C-specific nucleotide motif at reverse transcriptase codons 64, 65, and 66, affecting viral template usage [11,15]. The K65R confers resistance to d4T, didanosine (ddI) and tenofovir, seriously limiting the second-line treatment options [11,12,15–17]. The WHO guidelines have recommended the phasing out of stavudine-containing ART based on the toxicity and antiretroviral resistance [17]. An elevated subtype-C-specific selection of V106M has also been reported, although V106M does not confer the same degree of resistance as G190S and frequently appears alongside K103N and Y181C [18]. HIV-1 group O and HIV-2 are innately resistant to the first-generation and second-generation NNRTIs, and genetic determinants in the HIV-2 gag region affect the virological outcome to lopinavir-based regimens [2,19]. Taken together, these findings show that select subtype-specific signature mutations, such as K65R and G190S, may be of clinical relevance in resource-limited settings, in which viral load, genotypic drug resistance testing, and second-line treatment options remain limited. The rise in IDU-A subtype epidemic emphasizes the need for combined harm reduction and prevention strategies, alongside treatment, to limit the acquisition of drug resistance and exacerbate the spread of disease among IDU populations [20,21]. Further studies are essential to determine whether efavirenz and nevirapine are contraindicated for IDU-A subtype epidemics, necessitating costlier protease, integrase or second-generation NNRTIs treatment strategies. Acknowledgements Conflicts of interest There are no conflicts of interest.

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