Mutations in the Reverse Transcriptase Gene Associated With Resistance to Reverse Transcriptase Inhibitors Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors (nRTIs) 69 Insertion Complex (affects all nRTIs currently approved by the US FDA) Multi-nRTI Resistance 151 Complex (affects all nRTIs currently approved by the US FDA except tenofovir) Multi-nRTI Resistance Thymidine Analogue-Associated Mutations (TAMs; affect all nRTIs currently approved by the US FDA other than emtricitabine and lamivudine) This slide summarizes NNRTI resistance patterns. There is a clustering of mutations between codons 100 and 106 and codons 181 and 190, with several others occurring in the low 200s. There is broad cross-resistance in these patterns, although subtle differences can be seen.1 Multi-nRTI Resistance 1. D’Aquila RT, Schapiro JM, Brun-Vezinet F, et al. Drug resistance mutations in HIV-1. Top HIV Med. 2002;10:11-15. ´

Mutations in the Reverse Transcriptase Gene Associated With Resistance to Reverse Transcriptase Inhibitors (cont’d) Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine This slide summarizes NNRTI resistance patterns. There is a clustering of mutations between codons 100 and 106 and codons 181 and 190, with several others occurring in the low 200s. There is broad cross-resistance in these patterns, although subtle differences can be seen.1 1. D’Aquila RT, Schapiro JM, Brun-Vezinet F, et al. Drug resistance mutations in HIV-1. Top HIV Med. 2002;10:11-15. ´

Mutations in the Reverse Transcriptase Gene Associated With Resistance to Reverse Transcriptase Inhibitors (cont’d) Nonnucleoside Analogue Reverse Transcriptase Inhibitors (NNRTIs) Etravirine Efavirenz Nevirapine Rilpivirine This slide summarizes NNRTI resistance patterns. There is a clustering of mutations between codons 100 and 106 and codons 181 and 190, with several others occurring in the low 200s. There is broad cross-resistance in these patterns, although subtle differences can be seen.1 1. D’Aquila RT, Schapiro JM, Brun-Vezinet F, et al. Drug resistance mutations in HIV-1. Top HIV Med. 2002;10:11-15. ´

Mutations in the Protease Gene Associated With Resistance to Protease Inhibitors Atazanavir +/-ritonavir Darunavir/ ritonavir Fosamprenavir/ ritonavir Indinavir/ ritonavir Lopinavir/ ritonavir Many mutations in the protease gene, as shown in this recent representation,1 confer significant cross-resistance across the entire class. The mutations highlighted in yellow generally develop in patients who receive the individual PIs for the first time with or without nucleosides. Indinavir—46 and 82 Ritonavir—84 and 82 Saquinavir—48 and 90 Nelfinavir—30 and 90, occasionally 88 Amprenavir—50, 54, and 84 Lopinavir/ritonavir—It is unclear which mutation develops first in patients, but the mutations shown all contribute to lopinavir resistance, based on phenotypic and genotypic analyses of clinical isolates. It has been suggested that as few as 4 mutations may be associated with high-level resistance to lopinavir/ritonavir. Although L63P causes no appreciable increase in IC50, it is shown for only lopinavir/ritonavir because, along with other mutations, it predicts a lack of viral load response to regimens containing this agent. 1. D’Aquila RT, Schapiro JM, Brun-Vezinet F, et al. Drug resistance mutations in HIV-1. Top HIV Med. 2002;10:11-15. ´

Mutations in the Protease Gene Associated With Resistance to Protease Inhibitors (cont’d) Nelfinavir Saquinavir/ ritonavir Tipranavir/ ritonavir Many mutations in the protease gene, as shown in this recent representation,1 confer significant cross-resistance across the entire class. The mutations highlighted in yellow generally develop in patients who receive the individual PIs for the first time with or without nucleosides. Indinavir—46 and 82 Ritonavir—84 and 82 Saquinavir—48 and 90 Nelfinavir—30 and 90, occasionally 88 Amprenavir—50, 54, and 84 Lopinavir/ritonavir—It is unclear which mutation develops first in patients, but the mutations shown all contribute to lopinavir resistance, based on phenotypic and genotypic analyses of clinical isolates. It has been suggested that as few as 4 mutations may be associated with high-level resistance to lopinavir/ritonavir. Although L63P causes no appreciable increase in IC50, it is shown for only lopinavir/ritonavir because, along with other mutations, it predicts a lack of viral load response to regimens containing this agent. 1. D’Aquila RT, Schapiro JM, Brun-Vezinet F, et al. Drug resistance mutations in HIV-1. Top HIV Med. 2002;10:11-15. ´

Mutations in the Envelope Gene Associated With Resistance to Entry Inhibitors Enfuvirtide Maraviroc User Notes available at www.iasusa.org This slide summarizes NNRTI resistance patterns. There is a clustering of mutations between codons 100 and 106 and codons 181 and 190, with several others occurring in the low 200s. There is broad cross-resistance in these patterns, although subtle differences can be seen.1 1. D’Aquila RT, Schapiro JM, Brun-Vezinet F, et al. Drug resistance mutations in HIV-1. Top HIV Med. 2002;10:11-15. ´

Mutations in the Integrase Gene Associated With Resistance to Integrase Strand Transfer Inhibitors Dolutegravir Elvitegravir Raltegravir This slide summarizes NNRTI resistance patterns. There is a clustering of mutations between codons 100 and 106 and codons 181 and 190, with several others occurring in the low 200s. There is broad cross-resistance in these patterns, although subtle differences can be seen.1 1. D’Aquila RT, Schapiro JM, Brun-Vezinet F, et al. Drug resistance mutations in HIV-1. Top HIV Med. 2002;10:11-15. ´

2017 Update of the Drug Resistance Mutations in HIV-1 IAS–USA Drug Resistance Mutations Group 2017 Update of the Drug Resistance Mutations in HIV-1 Annemarie M. Wensing, MD, PhD; Vincent Calvez, MD, PhD; Huldrych F. Günthard, MD; Victoria A. Johnson, MD; Roger Paredes, MD, PhD; Deenan Pillay, MD, PhD; Robert W. Shafer, MD; Douglas D. Richman, MD Top Antivir Med. 24(4). Updates available at www.iasusa.org. IAS–USA is a not-for-profit, HIV clinical specialist–education organization. It is entirely different from and not affiliated with the International AIDS Society.