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2019 Resistance Mutations Update Volume 27 Issue 3 July/August 2019

Special Contribution 2019 Update of the Mutations in HIV-1

Annemarie M. Wensing, MD, PhD; Vincent Calvez, MD, PhD; Francesca Ceccherini-Silberstein, PhD; Charlotte Charpentier, PharmD, PhD; Huldrych F. Günthard, MD; Roger Paredes, MD, PhD; Robert W. Shafer, MD; Douglas D. Richman, MD

The 2019 edition of the IAS–USA drug resistance mutations list updates the delivering accurate, unbiased, and evi- Figure last published in January 2017. The mutations listed are those that dence-based information on drug re- have been identified by specific criteria for evidence and drugs described. sistance–associated mutations for HIV The Figure is designed to assist practitioners in identifying key mutations clinical practitioners. The group re- associated with resistance to antiretroviral drugs, and therefore, in making views new data on HIV drug resistance clinical decisions regarding antiretroviral therapy. to maintain a current list of mutations associated with clinical resistance to Keywords: HIV, antiretroviral, drug resistance, therapy, mutations HIV-1. This list includes mutations that may contribute to a reduced virologic The 2019 edition of the International long-acting combination of cabote- response to a drug. Antiviral Society–USA (IAS–USA) drug gravir/ for the treatment The group considers only data that resistance mutations list updates the of HIV- in adults who are have been published or have been pre- Figure last published in January 2017.1 virologically suppressed and have sented at a scientific conference. Table In this update: no resistance to the individual com- 1 provides the list of amino acids and ponents of the combination.3 the abbreviations used. Drugs that have • 2 strand transfer inhibitors been approved by the US Food and (InSTIs), and cabotegra- • (formerly MK-1439) was Drug Administration and are generally vir, and the nonnucleoside reverse approved by the FDA in August recommended, as well as any drugs transcriptase inhibitor (NNRTI), do- 2018 for the treatment of HIV-in- ravirine, were added to the Figure. fected, treatment-naive individuals Table 1. Amino acids and in combination with other antiret- their abbreviations. • Bictegravir (formerly GS-9883) was roviral drugs.4 approved by the US Food and Drug A Administration (FDA) in February • Several changes were made to Cysteine C 2018 as part of a fixed-dose combi- drugs already on the Figure. On the Aspartate D nation of bictegravir// / bar, mutations Glutamate E for the treat- at positions 50, 54, and 84 were F ment of HIV-infected, treatment- changed to boldface to indicate rec- Glycine G naive individuals or to replace an ognition as major mutations rather H antiretroviral regimen in those who than minor mutations.5-7 The G118R I are virologically suppressed (HIV-1 mutation was added to the bar for K RNA below 50 copies/mL) on a the InSTI .8,9 L stable antiretroviral regimen for at Methionine M least 3 months with no history of • For antiretroviral drugs that are no N longer recommended, the bars are treatment failure and no known Proline P listed at the bottom of the class and substitutions associated with resis- Q are shaded in gray. tance to the individual components Arginine R 2 of the fixed-dose combination. S Methods • (formerly S/GSK- T 1265744) is an investigational drug The IAS–USA Drug Resistance Muta- Valine V that has been filed for approval at tions Group is an independent, vol- W the FDA as part of a fixed-dose, unteer panel of experts charged with Tryosine Y

Dr Wensing (Group Chair), University Medical Center Utrecht, The Netherlands and University of the Witwatersrand, Johannesburg, South Africa; Dr Calvez, Pierre et Marie Curie University and Pitié-Salpêtrière Hospital, Paris, France; Dr Ceccherini-Silberstein, University of Rome Tor Vergata, Rome, Italy; Dr Charpentier, Paris Diderot University and Bichat-Claude Bernard Hospital, France; Dr Günthard, University Hospital Zurich and Institute of Medical Virology, University of Zurich, Switzerland; Dr Paredes, HIV Unit and IrsiCaixa AIDS Research Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Dr Shafer, Stanford University Medical School, California; Dr Richman (Group Vice Chair), Veterans Affairs San Diego Healthcare System and University of California San Diego. i 2019 Resistance Mutations Update Volume 27 Issue 3 July/August 2019

MUTATIONS Insertion tagenesis; (2) susceptibility testing of scriptase inhibitors, or first generation laboratory or clinical isolates; (3) nu- InSTIs (, ). wild-type K ▼ Amino acid position 65 cleotide sequencing of from The absence of detectable viral re- Amino acid substitution R conferring resistance patients in whom the drug is failing; (4) sistance after treatment failure may association studies between genotype result from any combination of the fol- at baseline and virologic response in lowing factors: the presence of drug- Figure 1. Display of the Figure Bar: Amino patients exposed to the drug. resistant minority viral populations, a acid position, wild type, mutation confer- The development of more recently prolonged interval between the time of ring resistance, and indication of insertion approved drugs that cannot be tested antiretroviral drug discontinuation and mutation. as monotherapy precludes assessment genotypic testing, nonadherence to of the impact of resistance on anti- , laboratory error, lack of available in expanded access programs retroviral activity that is not seriously current knowledge of the association are included (listed in alphabetic order confounded by activity of other drug of certain mutations with drug resis- by drug class). Drugs that are no longer components in the background regi- tance, the occurrence of relevant mu- recommended are listed at the bottom men. Readers are encouraged to con- tations outside the regions targeted by of the class and are shaded in gray. sult the literature and experts in the routine resistance assays, drug-drug User notes provide additional infor- field for clarification or more informa- interactions leading to subtherapeutic mation. Although the Drug Resistance tion about specific mutations and their drug levels, and possibly compartmen- Mutations Group works to maintain a clinical impact. Polymorphisms as- tal issues, indicating that drugs may complete and current list of these mu- sociated with impaired treatment re- not optimal levels in specific cel- tations, it cannot be assumed that the sponses that occur in otherwise wild- lular or tissue reservoirs. list presented here is exhaustive. type viruses should not be used in epi- For more in-depth reading and an The magnitude of the reduction in demiologic analyses to identify trans- extensive reference list, see the 2018 susceptibility conferred by drug resis- mitted HIV-1 drug resistance. Conse- IAS–USA panel recommendations for tance mutations varies widely, and is quently, only some of the resistance resistance testing11 and 2018 IAS–USA modulated by the genetic context of mutations depicted on the Figure can panel recommendations for antiret- the HIV sequence in which the muta- be used to identify transmitted drug roviral therapy.12 Updates are posted tion occurs. Despite the fact that mu- resistance.10 periodically at www.iasusa.org. tations result in a spectrum of degrees of resistance, mutations have been ar- bitrarily designated as major (bolded) Clinical Context Comments or minor (not bolded) (see Figure 1). The Figure is designed for practitioners Please send your evidence-based com- Those defined as major tend to occur to use in identifying key mutations ments, including relevant reference earlier during treatment failure and associated with antiretroviral drug re- citations, to [email protected]. generally confer larger reductions in sistance and in making therapeutic susceptibility. Those defined as minor decisions. In the context of making tend to accrue after the emergence of Reprint Requests clinical decisions regarding antiretro- a major mutation, confer some incre- viral therapy, evaluating the results of The Drug Resistance Mutations Group mental resistance, may occur as well as HIV-1 genotypic testing includes: (1) welcomes interest in the Figure as an polymorphisms in wild-type , and assessing whether the pattern or ab- educational resource for practitioners in some cases do not reduce suscep- sence of a pattern in the mutations is and encourages dissemination of the tibility but restore replication fitness consistent with the patient’s history material to as broad an audience as to viruses with resistance mutations of antiretroviral therapy; (2) recogniz- possible. However, permission is re- that impair fitness. In general, a major ing that in the absence of current drug quired to reprint the Figure and no mutation should raise concern that a treatment that is conferring selection alterations in format or content can drug is at least partially compromised; pressure, resistant strains may be pres- be made. a minor mutation on its own may not ent at levels below the limit of detec- Requests to reprint the material raise such a concern, but it should tion of the test (analyzing stored sam- should include the name of the pub- add concern in the presence of other ples, collected under selection pressure, lisher or sponsor, the name or a de- mutations. could be useful in this setting); and (3) scription of the publication in which recognizing that virologic failure of the material will be reprinted, the fund- Identification of Mutations a first-line regimen typically involves ing organization(s), if applicable, and The mutations listed are those that have HIV-1 isolates with resistance to only 1 the intended audience. Requests to been identified by 1 or more of the fol- or 2 of the drugs in the regimen. In this make any minimal adaptations of the lowing criteria: (1) in vitro passage ex- setting, resistance emerges most com- material should include the former, periments or validation of contribution monly to or emtricitabine, plus a detailed explanation of the adap- to resistance by using site-directed mu- nonnucleoside analogue reverse tran- tation(s) and, if possible, a copy of the

ii IAS–USA Topics in Antiviral Medicine

proposed adaptation. To ensure the in- Healthcare. Dr Günthard has served , Inc. tegrity of the Figure, IAS–USA policy is as a consultant to Merck & Co, Inc, 3. Margolis DA, Gonzalez-Garcia J, Stellbrink HJ, et al. Long-acting intramuscular cabo- to grant permission for only minor, pre- ViiV Healthcare, Sandoz, Teva Pharma- tegravir and rilpivirine in adults with HIV-1 approved adaptations of the Figure (eg, ceutical Industries, and Gilead Sciences, infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non- an adjustment in size). Minimal adap- Inc, and has received research grants inferiority trial. Lancet. 2017;390(10101): tations only will be considered; no al- from Gilead Sciences, Inc. Dr Paredes has 1499-1510. terations of the content of the Figure or received research grants from and has 4. Merck & Co Inc. Doravirine [prescribing information]. 2018.Whitehouse Station, user notes will be permitted. served as an advisor for ViiV Health- NJ, Merck. Permission will be granted only for care, Gilead Sciences, Inc, and Merck 5. Lam E, Parkin NT. resis- requests to reprint or adapt the most Sharp & Dohme, Inc. Dr Richman has tance imparted by the I50V mutation in HIV-1 can be suppressed by current version of the Figure as they been a consultant to Antiva Biosci- the N88S mutation. Clin Infect Dis. 2003; are posted at www.iasusa.org. Because ences, Gilead Sciences, Inc, and Viriome, 37(9):1273-1274. scientific under-standing of HIV drug Inc. Dr Shafer has received research 6. Rhee SY, Taylor J, Fessel WJ, et al. HIV-1 protease mutations and protease inhibi- resistance evolves and the goal of the grants from Janssen Therapeutics, Vela tor cross-resistance. Antimicrob Agents Drug Resistance Mutations Group is to Diagnostics, and InSilixa, Inc, and con- Chemother. 2010;54(10):4253-4261. 7. Hermans LE, Steegen K, ter Heine R, et maintain the most up-to-date compila- sulting fees from Abbott Diagnostics. Dr al. PI drug-level testing as screening tool tion of mutations for HIV clinicians and Wensing has served on advisory boards for drug resistance in 2nd-line ART fail- researchers, publication of out-of-date for ViiV Healthcare, Merck & Co, Inc, ure. Top Antivir Med. 2019;27(1s):169s. 8. Smith SJ, Zhao XZ, Burke TR, Jr., Hughes figures is counterproductive. If you Janssen Therapeutics, and Gilead Sci- SH. Efficacies of cabotegravir and bicte- have any questions about reprints or ences, Inc, and has received research or gravir against drug-resistant HIV-1 inte adaptations, please contact IAS–USA. unrestricted educational grants from grase mutants. Retrovirology. 2018;15(1):37. 9. Quashie PK, Mesplede T, Han YS, et Janssen Therapeutics, ViiV Healthcare, al. Biochemical analysis of the role of Financial affiliations in the past 12 Merck & Co, Inc, and Gilead Sciences, G118R-linked dolutegravir drug resistance substitutions in HIV-1 integrase. Anti- months: Dr Calvez has served as an advi- Inc. microb Agents Chemother. 2013;57(12): sor or consultant to and has received re- Funding/Support: This work was funded 6223-6235. search grants from Bristol-Myers Squibb, 10. Pingen M, Nijhuis M, de Bruijn JA, Bouch- by IAS–USA. No commercial company er CA, Wensing AM. Evolutionary path- Johnson & Johnson, ViiV Healthcare, and or government funding was used to sup- ways of transmitted drug-resistant HIV-1. Gilead Sciences, Inc, and is a founder port the effort. Panel members are not J Antimicrob Chemother. 2011;66(7):1467- of SkinDermic Pharma. Dr Ceccherini- 1480. compensated. 11. Gunthard HF, Calvez V, Paredes R, et Silberstein has been a consultant to ViiV The authors thank Jose Francisco for ad- al. Human immunodeficiency virus drug Healthcare, Bristol-Myers Squibb, and resistance: 2018 recommendations of ministrative support for the work. the International Antiviral Society–USA Merck Sharp & Dohme, Inc, and has re- panel. Clin Infect Dis. 2018;67:1-11. ceived research grants from ViiV Health- 12. Saag MS, Benson CA, Gandhi RT, et al. care, Gilead Sciences, Inc, and Merck References Antiretroviral drugs for treatment and prevention of HIV infection in adults: Sharp & Dohme, Inc. Dr Charpentier 1. Wensing AM, Calvez V, Gunthard HF, et 2018 recommendations of the Interna- serves as an advisor for ViiV Healthcare, al. 2017 Update of the Drug Resistance tional Antiviral Society-USA panel. JAMA. Gilead Sciences, Inc, Janssen Therapeu- Mutations in HIV-1. Top Antivir Med. 2017; 2018;320(4):379-396. 24(4):132-133. tics, and Merck Sharp & Dohme, Inc, and 2. Gilead Sciences Inc. BIKTARVY [prescrib- Top Antivir Med. 2019;27(3). has received research grants from ViiV ing information]. 2018.Foster City, CA, ©2019, IAS–USA. All rights reserved

iii 2019 Resistance Mutations Update Volume 27 Issue 3 July/August 2019

MUTATIONS IN THE GENE ASSOCIATED WITH RESISTANCE TO REVERSE TRANSCRIPTASE INHIBITORS Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors (nRTIs)1 69 Insertion Complex2 (affects all nRTIs currently approved by the US FDA) M A ▼ K L T K Multi-nRTI 41 62 69 70 210 215 219 Resistance L V Insert R W Y Q F E 151 Complex3 (affects all nRTIs currently approved by the US FDA except tenofovir) A V F F Q Multi-nRTI 62 75 77 116 151 Resistance V I L Y M Thymidine Analogue-Associated Mutations4,5 (TAMs; affect all nRTIs currently approved by the US FDA other than emtricitabine and lamivudine) M D K L T K Multi-nRTI 41 67 70 210 215 219 Resistance L N R W Y Q F E

K L Y M Abacavir1,6 65 74 115 184 R V F V E N

K M Emtricitabine 65 184 R V E I N

K M Lamivudine 65 184 R V E I N

K K Tenofovir1,7 65 70 R E E N

M D K L T K Zidovudine4,5,8,9 41 67 70 210 215 219 L N R W Y Q F E

K L Didanosine1,10,21 65 74 R V E N M K D K L T K Stavudine1,4,5,8,9 41 65 67 70 210 215 219 L R N R W Y Q E F E N

Nonnucleoside Analogue Reverse Transcriptase Inhibitors (NNRTIs)1,11 V Y G P F M L Doravirine12 106 188 190 225 227 230 234 A C E H C L I I L L M H R T

L K K V V Y Y G P M 100 101 103 106 108 181 188 190 225 230 I P N M I C L S H L S I A

V A L K V E V Y G M Etravirine13 90 98 100 101 106 138 179 181 190 230 I G I E I A D C S L H G F I A P K T V Q

L K K V V Y Y G M 100 101 103 106 108 181 188 190 230 I P N A I C C A L S M I L H

L K E V Y Y H F M Rilpivirine14 100 101 138 179 181 188 221 227 230 I E A L C L Y C I P G I L K V Q R iv IAS–USA Topics in Antiviral Medicine

MUTATIONS IN THE PROTEASE GENE ASSOCIATED WITH RESISTANCE TO PROTEASE INHIBITORS(PIs)15,16,17 L G K L V L E M M G I F I D I I A G V I I N L I 10 16 20 24 32 33 34 36 46 48 50 53 54 60 62 64 71 73 82 84 85 88 90 93 +/- ritonavir18 I E R I I I Q I I V L L L E V L V C A V V S M L F M F L L Y V M I S T M V I V V M V T T F C T T L A I V A

V V L I I I T L I L / 11 32 33 47 50 54 74 76 84 89 ritonavir19 I I F V V M P V V V L

L K L V L M I I F I L A G L V I L Lopinavir/ 10 20 24 32 33 46 47 50 53 54 63 71 73 76 82 84 90 ritonavir20 F M I I F I V V L V P V S V A V M I R L A L T F R A T V M S T S

L L M K M I I Q H T V N I L / 10 33 36 43 46 47 54 58 69 74 82 83 84 89 ritonavir V F I T L V A E K P L D V I L M R T M V V V

L V M I I I G L V I L / 10 32 46 47 50 54 73 76 82 84 90 ritonavir21 F I I V V L S V A V M I L V F R M S V T

L K L V M M I A G L V V I L / 10 20 24 32 36 46 54 71 73 76 77 82 84 90 ritonavir 21 I M I I I I V V S V I A V M R R L T A F V T

L D M M A V V I N L 21,22 10 30 36 46 71 77 82 84 88 90 F N I I V I A V D M I L T F S T S

L L G I I A G V V I L / 10 24 48 54 62 71 73 77 82 84 90 ritonavir 21 I I V V V V S I A V M R L T F V T S

MUTATIONS IN THE ENVELOPE GENE ASSOCIATED WITH RESISTANCE TO ENTRY INHIBITORS G I V Q Q N N Enfuvirtide23 36 37 38 39 40 42 43 D V A R H T D S M E

Maraviroc24 See User Note

MUTATIONS IN THE INTEGRASE GENE ASSOCIATED WITH RESISTANCE TO INTEGRASE STRAND TRANSFER INHIBITORS25 G E G Q R Bictegravir 26 118 138 140 148 263 R K S H K

T G E G Q S N R Cabotegravir27 66 118 138 140 148 153 155 263 K R A A H F H K K C K Y T R R S

G F E G Q N R Dolutegravir28 118 121 138 140 148 155 263 R Y A A H H K K S K T R

T E T F S Q N R Elvitegravir 29 66 92 97 121 147 148 155 263 I Q A Y G H H K A G K K R

L E T F E G Y Q N R Raltegravir30 74 92 97 121 138 140 143 148 155 263 M Q A Y A A R H H K K S H K C R v 2019 Resistance Mutations Update Volume 27 Issue 3 July/August 2019

User Notes recommended with tenofovir or the double and triple mutants V106A and in the presence of TAMs. The degree to which F227L; V106A and L234I; V106A and F227L 1. Mutations at the C-terminal reverse tran- cross-resistance is observed depends on the and L234I; and V106A and 190A and F227L, scriptase domains (amino acids 293-560) out- specific mutations and number of mutations are all associated with substantial resis- side of regions depicted on the Figure Bar involved.21-24 tance to doravirine.39,41,44 may contribute to nucleoside (or nucleotide) analogue reverse transcriptase inhibitor (nRTI) 5. Although reverse transcriptase changes as- 13. Resistance to has been ex- and nonnucleoside analogue reverse transcrip- sociated with the E44D and V118I mutations tensively studied only in the context of co- tase inhibitors (NNRTI) HIV-1 drug resistance. may have an accessory role in increased resis- administration with ritonavir-boosted daruna- The clinical relevance of these connection do- tance to nRTIs in the presence of TAMs, their vir. There, mutations associated with virologic 25-27 main mutations arises mostly in conjunction clinical relevance is very limited. outcome were assessed and their relative with thymidine analogue–associated muta- weights (or magnitudes of impact) assigned. 6. The M184V mutation alone does not ap- tions (TAMs) and M184V and they have not In addition, phenotypic cutoff values were pear to be associated with a reduced virologic been associated with increased rates of viro- calculated, and assessments of genotype- response to in vivo. When associ- logic failure of etravirine or rilpivirine in clinical phenotype correlations from a large clinical 1-3 ated with TAMs, M184V increases abacavir trials. K65E/N/R variants are reported in database have determined relative importance resistance.5,28 patients experiencing treatment failure with of the various mutations. These 2 approaches tenofovir (meaning fu- are in agreement for many, but not all, muta- [ ] [ ]) 7. The presence of K65R is associated with marate TDF or tenofovir alafenamide TA F 4 tions and weights.45-47 The single mutations , or . The K65R/N vari- a reduced virologic response to tenofovir. L100I, K101P, and Y181C/I/V have high relative ants may be selected by tenofovir, didanosine, A reduced response also occurs in the pres- weights with regard to reduced susceptibility abacavir, or stavudine and are associated with ence of 3 or more TAMs inclusive of either 4 and reduced clinical response compared with decreased viral susceptibility to these drugs.4-8 M41L or L210W. The presence of TAMs or other mutations.48,49 The presence of K103N 65R may be more easily selected in subtype C combined treatment with zidovudine prevents alone does not affect etravirine response.49 clades.9 K65E usually occurs in mixtures with the emergence of K65R in the presence of 29-31 Accumulation of several mutations results in wild-type virus. Patient-derived viruses with tenofovir. greater reductions in susceptibility and viro- K65E and site-directed mutations replicate 8. The presence of M184V appears to delay or 50-52 very poorly in vitro; as such, no susceptibil- logic response than do single mutations. prevent emergence of TAMs.32 This effect may ity testing can be performed.10,11 Some nRTI be overcome by an accumulation of TAMs or 14. Fifteen mutations have been associated mutations, like T215Y and H208Y,12 may lead other mutations. with decreased rilpivirine susceptibility to viral hypersusceptibility to nonnucleoside (K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, reverse transcriptase inhibitors (NNRTIs), includ- 9. The T215A/C/D/E/G/H/I/L/N/S/V substitutions H221Y, F227C, and M230I/L).53-55 A 16th mu- ing etravirine,13 in nRTI-treated individuals. are revertant mutations at codon 215 that tation, Y188L, reduces rilpivirine susceptibility The presence of these mutations may improve confer increased risk of virologic failure of zid- 6 fold. The K101P and Y181I/V mutations re- subsequent virologic response to NNRTI-con- ovudine or stavudine in antiretroviral-naive duce rilpivirine susceptibility approximately taining regimens (nevirapine or efavirenz) in patients.33,34 The T215Y mutant may emerge 14-18 50 fold and 15 fold, respectively, but are NNRTI-naive individuals, although no clin- quickly from one of these mutations in the 35 not commonly observed in patients receiv- ical data exist for improved response to etra- presence of zidovudine or stavudine. 56-58 virine in NNRTI-experienced individuals. ing rilpivirine. Mutations at position 138 10. The presence of 3 of the following muta- (most notably E138A) may occur as natural 2. The 69 insertion complex consists of a sub- polymorphisms, especially in non-B subtype tions—M41L, D67N, L210W, T215Y/F, K219Q/E— 59 stitution at codon 69 (typically T69S) and an is associated with resistance to didanosine.36 virus. The K101E, E138K, and Y181C mu- insertion of 2 or more amino acids (S-S, S-A, The presence of K70R or M184V alone does tations, each of which reduces rilpivirine S-G, or others). The 69 insertion complex is not decrease virologic response to didano- susceptibility 2.5 fold to 3 fold, occur com- associated with resistance to all nRTIs cur- sine.37 However, the mutations depicted on monly in patients receiving rilpivirine. E138K rently approved by the US Food and Drug the Figure Bar cannot be considered compre- and to a lesser extent K101E usually occur in Administration (FDA) when present with 1 or hensive because little relevant research has combination with the nRTI resistance–associ- 4 more TAMs at codons 41, 210, or 215. Some been reported in recent years to update the ated mutation M184I, which alone does not other amino acid changes from the wild-type resistance and cross-resistance patterns for reduce rilpivirine susceptibility. When M184I T at codon 69 without the insertion may be this drug. is combined with E138K or K101E, rilpivirine associated with broad nRTI resistance. susceptibility is reduced about 7 fold and 4.5 11. There is no evidence for the utility of efavi- fold, respectively.58,60-62 The combinations of 3. Tenofovir retains activity against the Q151M renz, nevirapine, or rilpivirine in patients with reverse transcriptase–associated mutations complex of mutations.4 Q151M is the most NNRTI resistance.38 L100I plus K103N/S and L100I plus K103R important mutation in the complex (ie, the plus V179D were strongly associated with re- other mutations in the complex [A62V, V75I, 12. Doravirine is active in vitro against var- duced susceptibility to rilpivirine. However, for F77L, and F116Y] in isolation may not reflect iants containing the common NNRTI muta- 39,40 isolates harboring the K103N/R/S or V179D as multidrug resistance). Since no differences tions K103N, E138K, Y181C, and G190A. single mutations, no reduction in susceptibil- in resistance patterns have been observed Doravirine selects for mutations at positions ity was detected.55,63 between TDF and TAF, both drugs are re- 106, 108, 227, and 234, with more than ferred to as “tenofovir” on the Figure Bar.19 1 mutation usually required for substan- 15. Often, several mutations are necessary to 41 tial levels of resistance. Mutations V106A, substantially impact virologic response to a 4. Mutations known to be selected by TAMs Y188L, and M230L are associated with a 10- ritonavir-boosted protease inhibitor (PI).64 (ie, M41L, D67N, K70R, L210W, T215Y/F, and or greater fold reduced susceptibility to dora- K219Q/E) also confer reduced susceptibil- virine. V106A and Y188L have also been se- 16. Mutations in Gag cleavage sites may con- ity to all currently approved nRTIs20 except lected in vivo.42,43 In 1 clinical isolate, G190E fer or contribute to resistance to PIs and may emtricitabine and lamivudine, which in fact was associated with about 20-fold reduced even emerge before mutations in protease.65 reverse the magnitude of resistance and are susceptibility to doravirine.40 Furthermore, A large proportion of virus samples from

vi IAS–USA Topics in Antiviral Medicine

patients with confirmed virologic failure on repeat (HR1) region of the envelope with TAF/emtricitabine, which may protect a PI-containing regimen is not found to have gene. However, mutations or polymorphisms the drug from mutations such as those ob- PI resistance–associated mutations. in other regions of the (eg, the HR2 region served during virologic failure of dolutegravir or those yet to be identified), as well as co- monotherapy.93-97 17. Ritonavir is not listed separately, as it is receptor usage and density, may affect suscep- currently used only at low doses as a pharma- tibility to .81-83 27. Cabotegravir is an investigational, long- cologic booster of other PIs. acting InSTI. In clinical trials, Q148R (fold 24. The activity of CC chemokine receptor 5 changes, 5.2-9.4) and G140R (fold change, 18. Several mutations are associated with (CCR5) antagonists is limited to patients with 6.7) have been observed particularly in HIV-1 atazanavir resistance. Their impacts differ, virus that use only CCR5 for entry (R5 virus). A1 subtype harboring the L74I integrase 93,98-101 with I50L, I84V, and N88S having the great- Viruses that use both CCR5 and CXC chemo- polymorphism. The G118R mutation est effect. Mutations that are selected during kine receptor 4 (CXCR4; termed dual/mixed has been selected in macaques receiving unboosted atazanavir are not different from [D/M] virus) or only CXCR4 (X4 virus) do not cabotegravir (long-acting) for pre-exposure those selected during boosted atazanavir, but respond to treatment with CCR5 antagonists. prophylaxis during acute simian/human im- 102 the relative frequency of mutations may differ. Virologic failure of these drugs is frequently munodeficiency virus infection. Higher atazanavir levels obtained with ritona- associated with outgrowth of D/M or X4 vi- 28. vir boosting increase the number of muta- Several mutations are required in HIV rus from a preexisting minority population integrase to confer high-level resistance to tions required for loss of activity. The presence present at levels below the limit of assay de- 103 of M46I plus L76V might increase suscepti- dolutegravir. Cross-resistance studies with tection. Mutations in HIV-1 gp120 that allow raltegravir- and elvitegravir-resistant viruses bility to atazanavir when no other related mu- the virus to bind to the drug-bound form of tations are present.66 indicate that Q148H/R and G140S in combi- CCR5 have been described in viruses from nation with mutations L74I/M, E92Q, T97A, some patients whose virus remained R5 after 19. Virologic response to ritonavir-boosted E138A/K, G140A, or N155H are associated virologic failure of a CCR5 antagonist. Most of darunavir correlates with baseline suscepti- with 5-fold to 20-fold reduced dolutegravir these mutations are found in the V3 loop, the 104 bility and the presence of several specific PI 84 susceptibility and reduced virologic sup- major determinant of viral tropism. There 105-108 resistance–associated mutations. Reductions pression in patients. is as yet no consensus on specific signature in response are associated with increas- mutations for CCR5 antagonist resistance, so 29. Seven elvitegravir codon mutations have ing numbers of the mutations indicated they are not depicted on the Figure Bar. Some been observed in InSTI treatment–naive and on the Figure Bar. The negative impact of CCR5 antagonist–resistant viruses selected in –experienced patients in whom therapy is the protease mutations I47V, I54M, T74P, and 109-115 vitro have shown mutations in gp41 without failing. T97A, which may occur as a poly- I84V and the positive impact of the prote- 116 mutations in V3;85 the clinical significance of morphism, results in only a 2-fold change ase mutation V82A on virologic response to such mutations is not yet known. in elvitegravir susceptibility and may require ritonavir-boosted darunavir were shown inde- 114,115 67,68 additional mutations for resistance. The pendently in 2 data sets. Some of these 25. In site-directed mutants and clinical iso- sequential use of elvitegravir and raltegravir mutations appear to have a greater effect on lates, the mutation F121Y has a profound effect (in either order) is not recommended because susceptibility than others (eg, I50V vs V11I). on susceptibility to elvitegravir and raltegravir of cross-resistance between these drugs.114 The presence at baseline of 2 or more of the and to a lesser extent to dolutegravir. R263K substitutions V11I, V32I, L33F, I47V, I50V, can be selected in vivo during treatment 30. Raltegravir failure is associated with inte- I54L/M, T74P, L76V, I84V, or L89V was asso- with dolutegravir and raltegravir and results grase mutations in at least 3 distinct, but not ciated with a decreased virologic response to exclusive, genetic pathways defined by 2 or 69 in a 2- to 5-fold reduction in susceptibility to ritonavir-boosted darunavir. dolutegravir, elvitegravir, and raltegravir.86-91 more mutations including (1) a mutation at 263K has been selected in vitro under pres- Q148H/K/R, N155H, or Y143R/H/C; and (2) 20. Virologic response to ritonavir-boosted sure with bictegravir and cabotegravir.92 1 or more additional minor mutations. Minor lopinavir is affected by the presence of 3 or mutations described in the Q148H/K/R path- more of the following amino acid substitu- 26. Bictegravir is a second-generation inte- way include L74M plus E138A, E138K, or tions in protease at baseline: L10F/I/R/V, grase strand transfer inhibitor (InSTI), like G140S. The most common mutational pattern K20M/N/R, L24I, L33F, M36I, I47V, G48V, dolutegravir, with higher genetic barrier to in this pathway is Q148H plus G140S, which I54L/T/V, V82A/C/F/S/T, and I84V. In addition, resistance than raltegravir and elvitegravir. also confers the greatest loss of drug suscep- the combination of 47A/V with V32I is associ- tibility. Mutations described in the N155H 66,70-76 Bictegravir has only been studied in detail in ated with high-level resistance. I50V is treatment-naive individuals and those with pathway include this major mutation plus only occasionally selected in vivo but has suppressed viremia (<50 HIV-RNA copies/mL) either L74M, E92Q, T97A, E92Q plus T97A, 77-79 117 a clear impact on susceptibility. Subtype who have been on stable antiretroviral ther- Y143H, G163K/R, V151I, or D232N. The 118-122 C patterns with M46L, I54V, L76V, and V82A apy for at least 3 months without a history of Y143R/H/C mutation is uncommon. are frequently observed in patients receiving treatment failure and without relevant resis- E92Q alone reduces susceptibility to elvite- ritonavir-boosted lopinavir. tance to bictegravir or its coformulated drugs. gravir more than 20 fold and causes limited (<5 fold) cross-resistance to raltegravir.123-125 21. The mutations depicted on the Figure Bar Susceptibility studies in vitro and in animal models93 show that mutations G118R and N155H mutants tend to predominate early in cannot be considered comprehensive because the course of raltegravir failure, but are gradu- little relevant research has been reported in re- R263K confer 14-fold and 6-fold increases in 50% effective concentration (EC50), whereas ally replaced by viruses with higher resistance, cent years to update the resistance and cross- often bearing mutations G140S plus Q148H/ resistance patterns for this drug. the G140S and Q148H combination of muta- tions decreases HIV-1 susceptibility to bicte- R/K, with continuing raltegravir treatment. 22. In some nonsubtype-B HIV-1, D30N is gravir 4.8 fold. Bictegravir dose-escalation tis- selected less frequently than are other PI re- sue culture experiments also showed the se- References to the User Notes sistance–associated mutations.80 lection of the M50I and R263K mutations. In combination with Q148 and G140A mu- 1. von Wyl V, Ehteshami M, Demeter LM, 23. Resistance to enfuvirtide is associated tations, E138K reduces bictegravir suscepti- et al. HIV-1 reverse transcriptase connection primarily with mutations in the first heptad bility 10 fold.94 Bictegravir is coformulated domain mutations: dynamics of emergence

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and implications for success of combination 12. Clark SA, Shulman NS, Bosch RJ, Mel- to zidovudine. Proc Natl Acad Sci USA. 1992; antiretroviral therapy. Clin Infect Dis. 2010; lors JW. Reverse transcriptase mutations 118I, 89(5):1934-1938. 51(5):620-628. 208Y, and 215Y cause HIV-1 hypersusceptibil- ity to non-nucleoside reverse transcriptase in- 23. Calvez V, Costagliola D, Descamps D, et 2. Gupta S, Vingerhoets J, Fransen S, et al. hibitors. AIDS. 2006;20(7):981-984. al. Impact of stavudine phenotype and thymi- Connection domain mutations in HIV-1 re- dine analogues mutations on viral response verse transcriptase do not impact etravirine 13. Picchio G, Vingerhoets J, Parkin N, Azijn to stavudine plus lamivudine in ALTIS 2 ANRS susceptibility and virologic responses to H, de Bethune MP. Nucleoside-associated trial. Antivir Ther. 2002;7(3):211-218. etravirine-containing regimens. Antimicrob mutations cause hypersusceptibility to etra- Agents Chemother. 2011;55(6):2872-2879. virine. Antivir Ther. 2008;13(Suppl 3):A25. 24. Kuritzkes DR, Bassett RL, Hazelwood JD, et al. Rate of thymidine analogue resistance 3. Rimsky L, Van Eygen V, Vingerhoets J, 14. Shulman NS, Bosch RJ, Mellors JW, Al- mutation accumulation with zidovudine- or Leijskens E, Picchio G. Reverse transcriptase brecht MA, Katzenstein DA. Genetic correlates stavudine-based regimens. JAIDS. 2004;36(1): connection domain mutations were not as- of efavirenz hypersusceptibility. AIDS. 2004; 600-603. sociated with virological failure or phenotypic 18(13):1781-1785. resistance in rilpivirine-treated patients from 25. Romano L, Venturi G, Bloor S, et al. Broad the ECHO and THRIVE Phase III trials (week 15. Demeter LM, DeGruttola V, Lustgarten nucleoside-analogue resistance implications 96 analysis). Antivir Ther. 2012;17(Suppl 1):A36. S, et al. Association of efavirenz hypersus- for human immunodeficiency virus type 1 ceptibility with virologic response in ACTG reverse-transcriptase mutations at codons 44 4. 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Svarovskaia ES, Margot NA, Bae AS, et al. outcome in nucleoside-experienced patients rectional antagonism between K65R and Low-level K65R mutation in HIV-1 reverse tran- receiving three or four antiretroviral drugs. thymidine analog mutations in HIV-1 reverse scriptase of treatment-experienced patients AIDS. 2003;17(6):821-830. transcriptase. AIDS. 2007;21(11):1405-1414. exposed to abacavir or didanosine. JAIDS. 2007; 46(2):174-180. 19. Margot N, Cox S, Das M, McCallister S, 30. Parikh UM, Barnas DC, Faruki H, Mel- 8. Hawkins CA, Chaplin B, Idoko J, et al. Clini- Miller MD, Callebaut C. Infrequent develop- lors JW. Antagonism between the HIV-1 re- cal and genotypic findings in HIV-infected ment of drug resistance in HIV-1–infected verse-transcriptase mutation K65R and thymi- patients with the K65R mutation failing first- treatment-naive subjects after 96 weeks of dine-analogue mutations at the genomic level. J line antiretroviral therapy in Nigeria. 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34. Chappey C, Wrin T, Deeks S, Petropoulos efficacies against NNRTI-resistant HIV-1 mu- 56. Cohen CJ, Andrade-Villanueva J, Clotet CJ. Evolution of amino acid 215 in HIV-1 re- tants. JAIDS. 2016;72(5):485-491. B, et al. Rilpivirine versus efavirenz with two verse transcriptase in response to intermittent background nucleoside or nucleotide reverse drug selection. Antivir Ther. 2003;8:S37. 45. Benhamida J, Chappey C, Coakley E, transcriptase inhibitors in treatment-naive Parkin NT. HIV-1 genotype algorithms for adults infected with HIV-1 (THRIVE): a phase 3, 35. Garcia-Lerma JG, MacInnes H, Bennett D, prediction of etravirine susceptibility: novel randomised, non-inferiority trial. Lancet. 2011; Weinstock H, Heneine W. Transmitted human mutations and weighting factors identified 378(9787):229-237. immunodeficiency virus type 1 carrying the through correlations to phenotype. Antivir D67N or K219Q/E mutation evolves rapidly Ther. 2008;13(Suppl 3):A142. 57. Molina JM, Cahn P, Grinsztejn B, et al. Ril- to zidovudine resistance in vitro and shows a pivirine versus efavirenz with tenofovir and high replicative fitness in the presence of zid- 46. Coakley E, Chappey C, Benhamida J, et emtricitabine in treatment-naive adults infected ovudine. J Virol. 2004;78(14):7545-7552. al. Biological and clinical cut-off analyses for with HIV-1 (ECHO): a phase 3 randomised dou- etravirine in the PhenoSense HIV assay. Anti- ble-blind active-controlled trial. Lancet. 2011; 36. Marcelin AG, Flandre P, Pavie J, et al. vir Ther. 2008;13(Suppl 3):A134. 378(9787):238-246. Clinically relevant genotype interpretation of resistance to didanosine. Antimicrob Agents 47. Vingerhoets J, Tambuyzer L, Azijn H, et 58. Rimsky L, Vingerhoets J, Van Eygen V, et Chemother. 2005;49(5):1739-1744. al. Resistance profile of etravirine: combined al. 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Clin Infect Dis. 2016;62(5):655-663. verse transcriptase inhibitors limits recycling correlation with matched phenotype. Poster efavirenz after nevirapine failure. AIDS Res presented at: 17th Conference on 60. Kulkarni R, Babaoglu K, Lansdon EB, et Hum Retroviruses. 2002;18(12):835-838. and Opportunistic (CROI); February al. The HIV-1 reverse transcriptase M184I mu- 16-19, 2010; San Francisco, CA. tation enhances the E138K-associated resis- 39. Feng M, Wang D, Grobler JA, Hazuda DJ, tance to rilpivirine and decreases viral fitness. Miller MD, Lai MT. In vitro resistance selec- 49. Etravirine [prescribing information]. 2013. JAIDS. 2012;59(1):47-54. tion with doravirine (MK-1439), a novel Titusville, NJ, Janssen Therapeutics. nonnucleoside reverse transcriptase inhibitor 61. Hu Z, Kuritzkes DR. Interaction of re- with distinct mutation development path- 50. Scherrer AU, Hasse B, Von Wyl V, et al. verse transcriptase (RT) mutations conferring ways. Antimicrob Agents Chemother. 2015; Prevalence of etravirine mutations and impact resistance to lamivudine and etravirine: ef- 59(1):590-598. on response to treatment in routine clinical fects on fitness and RT activity of human care: the Swiss HIV Cohort Study (SHCS). HIV immunodeficiency virus type 1. J Virol. 2011; 40. Lai MT, Xu M, Ngo W, et al. Characteriza- Med. 2009;10(10):647-656. 85(21):11309-11314. tion of doravirine-selected resistance patterns from participants in treatment-naive phase 3 51. Tambuyzer L, Nijs S, Daems B, Picchio G, 62. Xu HT, Asahchop EL, Oliveira M, et al. clinical trials. Poster presented at: 22nd Inter- Vingerhoets J. Effect of mutations at position Compensation by the E138K mutation in national AIDS Conference; July 23-27, 2018; E138 in HIV-1 reverse transcriptase on pheno- HIV-1 reverse transcriptase for deficits in viral Amsterdam, The Netherlands. typic susceptibility and virologic response to replication capacity and enzyme processiv- etravirine. JAIDS. 2011;58(1):18-22. ity associated with the M184I/V mutations. J 41. Lai MT, Feng M, Falgueyret JP, et al. In Virol. 2011;85(21):11300-11308. vitro characterization of MK-1439, a novel 52. Tudor-Williams G, Cahn P, Chokephaibulkit HIV-1 nonnucleoside reverse transcriptase in- K, et al. Etravirine in treatment-experienced, 63. Haddad M, Napolitano LA, Frantzell A, et hibitor. Antimicrob Agents Chemother. 2014; HIV-1–infected children and adolescents: 48- al. Combinations of HIV-1 reverse transcrip- 58(3):1652-1663. week safety, efficacy and resistance analysis tase mutations L100I + K103N/S and L100I + K103R + V179D reduce susceptibility to rilpi- 42. Orkin C, Squires KE, Molina JM, et al. of the phase II PIANO study. HIV Med. 2014; 15(9):513-524. virine. Poster presented at: 53rd Interscience Doravirine/lamivudine/tenofovir disoproxil Conference on Antimicrobial Agents and Che- fumarate is non-inferior to efavirenz/em- motherapy (ICAAC); September 10-13, 2013; tricitabine/tenofovir disoproxil fumarate in 53. Rilpivirine [prescribing information]. 2015. J Denver, CO. treatment-naive adults with human immuno- Titusville, NJ, anssen Therapeutics. deficiency virus-1 infection: week 48 results of 64. Hirsch MS, Günthard HF, Schapiro JM, et 54. Azijn H, Tirry I, Vingerhoets J, et al. TMC278, the DRIVE-AHEAD trial. Clin Infect Dis. 2019; al. Antiretroviral drug resistance testing in a next-generation nonnucleoside reverse tran- 68(4):535-544. adult HIV-1 infection: 2008 recommendations scriptase inhibitor (NNRTI), active against of an International AIDS Society-USA panel. wild-type and NNRTI-resistant HIV-1. Antimi- 43. Molina JM, Squires K, Sax PE, et al. Dora- Clin Infect Dis. 2008;47(2):266-285. virine versus ritonavir-boosted darunavir in crob Agents Chemother. 2010;54(2):718-727. antiretroviral-naive adults with HIV-1 (DRIVE- 65. Fun A, Wensing AM, Verheyen J, Nijhuis FORWARD): 48-week results of a randomised, 55. Picchio GR, Rimsky LT, Van Eygen V, et al. M. Human Immunodeficiency Virus Gag and double-blind, phase 3, non-inferiority trial. Prevalence in the USA of rilpivirine resistance- protease: partners in resistance. Retrovirology. Lancet HIV. 2018;5(5):e211-e220. associated mutations in clinical samples and 2012;9:63. effects on phenotypic susceptibility to rilpiv- 44. Smith SJ, Pauly GT, Akram A, et al. Rilpi- irine and etravirine. Antivir Ther. 2014;19(8): 66. Young TP, Parkin NT, Stawiski E, et al. virine and doravirine have complementary 819-823. Prevalence, mutation patterns, and effects on

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