Bstantially reducing efficacy of TFV, ddI and ABC [29-33]. Rarer active
Bstantially reducing efficacy of TFV, ddI and ABC [29-33]. Rarer active site mutations such as Q151M can emerge with use of thymidine analogues and confer high-level resistance to all NRTI [31,32]. Connection domain resistance mutations such as G335C/D, N348I, A360I/V, V365I, and A376S have been identified and N348I, in particular, emerges following nevirapine (NVP) exposure [34]. These mutations reduce and/or delay RNAseH activity thereby allowing more time for Procyanidin B1 site primer unblocking [35]. The effect is to reduce susceptibility to NRTI, in particular to ZDV [36]. As this region of the HIV-1 genome is not routinely sequenced in drug resistance surveys, there are few data on whether these mutations are transmitted, and thus whether they may compromise treatment as prevention strategies. Second-generation drugs in various classes with activity in the face of mutations associated with drug resistance to first generation drugs have been developed (for example the NNRTI etravirine, the PIs darunavir and tipranavir, and the INSTI dolutegravir). As ABC and TFV are compromised by mutations selected by older NRTI, these drugs are potentially vulnerable in regard to future use in prevention in areas in which ART scale up has occurred.NNRTI and resistanceTwo currently licensed NNRTI are efavirenz (EFV) and NVP, and both are highly effective when combined with 2NRTI [37]. Both bind in a hydrophobic pocket and arrest DNA synthesis through allosteric effects. Highlevel resistance is conferred by various single mutations, includingK103N, Y181C, Y188C/L/H, V106A/M, G180A/ S and A98G (reviewed in [38]). HIV-2 and HIV-1 group O are not sensitive to this class of agents due to RT polymorphisms [39,40]. The long plasma half-life of NNRTI predisposes them to development of resistance, particularly when a fixed dose tablet is stopped [41]. This may occur due to sub optimal adherence or drug stock-outs, recently reported to be common across Africa [42]. PI and NNRTI based regimens appear to be largely equivalent in terms of viral suppression rates [43]. However, when virologic failure occurs, NNRTI are associated with higher rates of drug resistance to both the NRTI and NNRTI components of regimens as compared to failure occurring following PI treatment [44]. If PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28250575 transmitted, NNRTI resistance is of particular concern as PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/26266977 the odds of viral failure when a major NNRTI mutation pre-exists is approximately two in the first year of therapy, based on data from both Europe [45] and sub-Saharan Africa [46]. There is evidence that drug resistance to NRTI and in particular NNRTI has been rising since ART scale up, with the greatest increases being seen in East African countries [47].Gupta et al. Retrovirology 2013, 10:82 http://www.retrovirology.com/content/10/1/Page 3 ofRTI-based treatment outcomes in the era of HAARTWide scale availability of ART outside industrialized countries has been largely possible through generic production of fixed dose combinations (FDC) and accreditation/quality control by the World Health Organization. Thymidine analogues have featured in the most widely used regimens along with 3TC/NVP with good outcomes [48,49]. However, NVP interacts with rifampicin-containing tuberculosis therapies and is also associated with potentially serious skin reactions and liver toxicity [50]. Data suggest that EFV may have equivalent or superior efficacy as NVP, and this agent has gradually replaced NVP. EFV itself had been avoided due to concerns regarding congenital.