HIV Resistance John E. McKinnon, MD, MSc

HIV Resistance John E. McKinnon, MD, MSc
Senior Staff Infectious Diseases Henry Ford Hospital Associate Professor Wayne State University

Conflicts None for this talk
All drug names will be provided in both commercial and generic names to avoid confusion and for ease of description

What Will You Learn? Why HIV virus develop resistance so easily?
What tests to order and when? What resistance can occur in your patients? Common approaches to patients with HIV resistance

CASE 1 45 yo Male presents to your clinic with a history of positive HIV testing at home. He says he “kind of knew” he was positive for about 10 years. What tests do you order on the first visit? HIV viral load and CD4 T cell accounts HIV 4th or 5th generation test with confirmatory testing HIV genotype HIV ELISA and Western Blot

Case 1 You have confirmed that the patient is HIV positive. You obtain an HIV viral load and CD4 T cell counts. Are you required to obtain an HIV Genotype? Yes No

Resistance in Treatment Naive
Oette M, Kaiser R, Daumer M, et al. Primary HIV drug resistance and efficacy of first-line antiretroviral therapy guided by resistance testing. J Acquir Immune Defic Syndr. 2006:41:

US HIV Resistance Overall rate of 14% IAS-USA resistance in treatment naïve seeking care 8% in 2000 17% in 2007 (highest) 13% in 2009 IAS-USA Resistance by Class: NNRTI 9.5% NRTI 4% PI 3% Overall prevalence of DRM to: Two classes 2% Three classes 1% Ross LL, et al. AIDS Res Hum Retroviruses. 2018

Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. Downloaded from on 12/27/2017

Who to Test for Resistance?
Acute or recent HIV infection ART naïve with chronic HIV infection Patients with virologic failure Suboptimal virologic suppression after ART Pregnant patients with HIV not on therapy DON’T TEST MORE THAN 4 WEEKS AFTER THEY STOP THERAPY

Resistance Testing Generally there are three types of resistance test
Genotypic Tests ViroSeq, Trugene, etc NGS or UDS Phenotypic Tests PhenoSense Genotype/Phenotype tests PhenoSense GT

Case 1 Your patient tells you he has an HIV seropositive partner that has been on the same one pill for 10 years. What does this mean to your patient’s treatment options? What pills can he take? Are there any new pills for him?

Every step in the virus cycle is a target for drug therapy
Figure 3. The Essential Steps in the Life Cycle of HIV-1. The first step is the attachment of the virus particle to receptors on the cell surface. The HIV-1 RNA genome then enters the cytoplasm as part of a nucleoprotein complex. The viral RNA genome is reverse-transcribed into a collinear DNA duplex, which has terminal duplications known as long terminal repeats (LTRs) that are not present in HIV-1 RNA. Once the viral DNA has been synthesized, the linear viral DNA molecule is incorporated into a preintegration complex that enters the nucleus. In the nucleus, unintegrated viral DNA is found in both linear and circular forms. The unintegrated circular forms of viral DNA have either one or two long terminal repeats, are byproducts of the integration process, and are found exclusively in the nucleus. The linear unintegrated viral DNA is the precursor of integrated proviral DNA, which is a stable structure that remains indefinitely in the host-cell genome and serves as a template for viral transcription. Transcription of the proviral DNA template and alternative mRNA splicing creates spliced viral mRNA species encoding the viral accessory proteins, including Tat, Rev, and Nef, and the unspliced viral mRNA encoding the viral structural proteins, including the gag-pol precursor protein. A shift in the transcriptional pattern from the expression of predominantly multiply spliced viral mRNA to predominantly unspliced viral mRNA is indicative of active viral replication. All the viral transcripts are exported into the cytoplasm, where translation and assembly and processing of the retroviral particle take place. The cycle is completed by the release of infectious retroviral particles from the cell. Modified from Furtado M et al. N Engl J Med 1999;340:

Antiretroviral Medications 2018
Nucleoside Reverse Transcriptase Inhibitors (NRTI) Abacavir ABC Didanosine DDI Emtricitabine FTC Lamivudine 3TC Stavudine D4T Tenofovir TDF Zidovudine ZDV (AZT) Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI) Efavirenz EFV Nevirapine NVP Etravirine ERV or ETV Delavirdine DLV Rilpivirine RPV Fusion Inhibitors Enfuvirtide T-20

Antiretroviral Medications 2018
Protease Inhibitors (PI) Fosamprenavir fAPV Atazanavir ATV Indinavir IDV Lopinavir/ritonavir LPV/r Nelfinavir NFV Ritonavir RTV Saquinavir SQV Tipranavir TPV Darunavir DRV Post-Attachment Inhibitors Ibalizumab Integrase Strand Transfer Inhibitors (INSTI) Raltegravir RAL Elvitegravir EVG Dolutegravir DTG Bictegravir BIC CCR5/chemokine receptor antagonists Maraviroc MVC Boosting agents-no anti-HIV effect Cobicistat COBI

Combination Tablets Combination pills Once daily ART / STR
Combivir TM (AZT/3TC) Epzicom TM (ABC/3TC) Trizivir TM (ABC/AZT/3TC) Truvada TM (FTC/TDF) Descovy TM (FTC/TAF) Prezcobix TM (DRV/cobi) Evotaz TM (ATV/cobi) Kaletra TM (LPV/r) Once daily ART / STR ATRIPLA TM (EFV/TDF/FTC) Complera TM (RPV/TDF/FTC) Odefsey TM (FTC/RPV/TAF) Stribild TM (EVG/COBI/TDF/FTC) Genvoya TM (EVG/COBI/TAF/FTC) Triumeq TM (ABC/DTG/3TC) Juluca TM (DTG/RPV) Biktarvy TM (BIC/FTC/TAF)

DHHS 2017 ART Recommendations
2017 DHHS Adult and Adolescent Guidelines

Why HIV virus develop resistance so easily?

Case 1 Your patient indicates that his partner’s pill has efavirenz/TDF/FTC and that they have unprotected sex and occasionally his partner doesn’t take his medications. What is the most likely resistance mutation that the patient may have acquired? M184V K103N M46I Q148R

What is Resistance? Latin- ‘resistens’
“The native or acquired ability of an organism to maintain its immunity to antagonistic agents in its environment” Resistance may be absolute or relative.

HIV Replication Daily virion production is between 1010 to virion/day High rate of virion replication plus low fidelity for HIV RT (error rate 3.4x10-5) In other words for every round of replication, one nucleotide is misincorporated randomly This in theory will result in the production of every possible single-based variant daily.

HIV Replication For every misincorporation event a new variant is produced that may have: A lethal mutation: virion not be able to replicate or severely cripple and the virion becomes non-viable A mutation with little or no effect of viral phenotype A mutation that affects either replicative capacity or infectivity and produces a growth disadvantage A mutation that affects ART binding and provides a growth advantage under drug pressure The variant with the greatest advantage in replication or infectivity will emerge as the predominant plasma strain

HIV ART Resistance Price to ART Resistance Exceptions to the rule
Some mutations may reduce RT activity and protease processing, thereby lowering the replication capacity as compared to wild type As a consequence, resistance mutations are seldom seen in untreated individuals or if they are off medications for a prolonged period* Exceptions to the rule Mutations that do not reduce replicative capacity or infectivity Patients infected with resistant HIV strains

HIV ART Resistance In individuals with HIV ART resistance who stop their antiretrovirals retain their resistant quasispecies long after the therapy has stopped Resistant mutations may be archived in proviral genomes or persist in low frequency mutants. *THEY JUST DON’T GO AWAY!!

Nucleoside Reverse Transcriptase Inhibitors Resistance Mutations

NRTI Mutations Multiple mutations have been identified in the RT region of the Pol gene Nucleoside associated mutations or thymidine associated mutations are the same Mutations/Insertions can be seen in the following positions: 41, 44, 62, 65, 67,69, 70, 74, 75, 77, 115, 116, 118, 151, 184, 210, 215, 219…. Just to name a few.

Understanding the Mutation List
A- alanine C- cysteine D- aspartate E- glutamate F- phenylalanine G- glycine H- histidine I- isoleucine K- lysine L- leucine M- methionine N- asparagine P- proline Q- glutamine R- arginine S- serine T- threonine V- valine W- tryptophan Y- tyrosine

Understanding the Mutation List

NRTI Associated Mutations-NAMs
First mutations ever identified: First NAMs (TAMs) were: D67N, K70R, T215Y/F and K219Q (1989) Expanded (1992) to include M41L and L210W (1996) They produce from fourfold to >100-fold increase in resistance to AZT Other like K70E is assoc. with adefovir which is similar to tenofovir

NRTI Associated Mutations-NAMs
NAMs don’t appear randomly, there’s two clusters The M41L, L210W and T215Y (± D67N) The D67N, K70R and K219E/Q (± T215F) These work by Excision Pathway Tenofovir is affected by NAMs with M41L or L210W mutations Abacavir is tolerant of NAMs except in the presence of a M184V mutation

Other NRTI Assoc. Mutations
Extended NAMs may include mutations in E44D/A and V118I They are often associated with mutations in 215 position Together they can give moderate resistance to lamivudine

Reverse Transcriptase
67 70 219 41 118 215 TAMs or NAMs 210

62 69 75 74 65 77 116 151 184 NRTI Mutations

Other Key RT Mutations M184V
Selected by 3TC, FTC and ABC (rarely, DDI) and can occur within days with mono-therapy fold resistance to 3TC, FTC (Discrimination Pathway) For ABC, M184V is usually the first to emerge along with L74V, K65R and Y115F Low ABC resistance is conferred by single M184V mutation As for ddI, NAMs must compensate for the M184V to produce resistance in clinical isolates It confers increase susceptibility to AZT, TDF and adefovir It reverses some NAM resistance and also reduces RT processivity, thereby reducing the replicative capacity

Other RT Mutations L74V The primary mutation associated with ddI monotherapy (also seen with ddC) The second most common selected mutation with ABC therapy occurring with or after M184V Three to 4 fold resistance to ABC by itself, increasing above 10 fold if K65R or NAMs present Emergence is suppressed by concomitant use of AZT Other ABC resistance: K65R, Y115F, M184V

Other RT Mutations K65R Other TDF mutations: K70E
Selected by TDF/TAF therapy Resistance partially reversed by M184V Initially associated with extended ddI monotx Significant cross-resistance to 3TC (~20 fold) Emergence blocked by AZT containing regimens Reduces affinity for the analogs Other TDF mutations: K70E TAMs with TDF resistance: M41L, L210W, T215Y

Multi-Nucleoside Resistance
Q151M Complex Includes Q151M, A62V, V75I, F77L, F116Y Resistance to most NRTIs 3TC and TDF/TAF are only slightly affected, but still active Selective decrease in the rate of incorporation of the inhibitors

Multi-Nucleoside Resistance
Codon 69 Insertions Insertions in codons 67 and 69 confer high-level resistance for all NRTIs currently in use Associated with 6 base in-frame insertions Rare The changes confer higher level of NRTI excision than NAMs provide

Mutations in the Reverse Transcriptase Gene Associated With Resistance to Reverse Transcriptase Inhibitors Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors (nRTIs) Multi-nRTI Resistance: 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 TDF Multi-nRTI Resistance: Thymidine Analogue-Associated Mutations (TAMs; affect all nRTIs currently approved by the US FDA) 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) 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.

Non-Nucleoside Reverse Transcriptase Inhibitor Resistance Mutations

Non-Nucleoside RTI Mutations
NNRTI mutations tend to confer high-cross resistance to multiple drugs in the class They affect the NNRTI pocket binding site Y181C and K103N are the prototypical NNRTI mutations NNRTI mutations that can emerge in following positions: 100, 103, 106, 108, 181, 188, 190, 225, 230, 236

NNRTI Mutations 188 108 225 181 106 236 190 100 103

Y181C Selected primarily by NVP or DLV K103N may also co-exist at failure >100 fold resistance Suppresses NAM resistance through T215Y/F similar to M184V Emergence maybe suppressed with co-administration of a thymidine analog (AZT)

K103N Most commonly selected NNRTI mutation by EFV but also with NVP Not affected by thymidine analog usage 30-40 fold resistance to all agents Multi-NNRTI Resistance Two main patterns: K103N+V106M, or Y188L May accumulate other cross-resistance mutations: L100I, V106A, Y181C, G190S/A, and M230L Antiviral activity is abolished to all current NNRTIs

Rilpivirine: Resistant mutations: V90I, L100I, K101E/P, E138K, V179L, Y181C, Y188L, V189I, H221Y, F227C and M230I/L E138K (and other aa subs) is a novel NNRTI resistant mutation with high level resistance to RPV and can give cross resistance to ETR, EFV & NVP E138K associated with M184I and improves replication capacity

Etravirine Common mutations: V90I, A98G, L100I, K101P/E/H, V106I, E138K+, V179D/F, Y181C/I/V/Y, G190S/A and M230L Increasing number of mutations lead to increase resistance but no single mutation with high level resistance But Y181 codon mutations lead to intermediate resistance

Mutations in the Reverse Transcriptase Gene Associated With Resistance to Reverse Transcriptase Inhibitors (cont’d) Nonnucleoside Analogue Reverse Transcriptase Inhibitors (NNRTIs) Efavirenz Etravirine Nevirapine 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 Rilpivirine 1. D’Aquila RT, Schapiro JM, Brun-Vezinet F, et al. Drug resistance mutations in HIV-1. Top HIV Med. 2002;10:11-15.

Case 2 36 yo HIV positive female was started on atazanavir/ritonavir/TDF/FTC regimen because of a recent pregnancy. She has not followed up since her delivery and presents 8 months later for refills. You speak with her and she indicates that she stopped ART about 2 months ago after she stopped breast feeding.

Case 2 You plan to restart ART and you obtain an HIV genotype, what is the most likely finding? M184V mutation I50L, N88S K103N No mutations

Protease Inhibitors Resistance Mutations

Protease Inhibitor Resistance
Resistance patterns are very complex and overlap between agents Mutations can occur in two different sites: Protease gene Protease cleavage sites in Gag polyprotein (not normally tested) Primary mutations At or close to the protease active site, affect binding of the inhibitor

Primary Mutations Changes in the active site affect can produce decreased enzymatic activity and reduce replicative capacity Secondary Mutations Increase the level of resistance conferred by 1ry mutations Provide cross-resistance Partially restore lost enzymatic activity

Multi-PI Resistance Mutations: L10F/I/R/V, M46I/L, I54V/M/L, V82A/F/T/S, I84V, L90M Other positions associated with resistance: 20, 24, 30, 32, 33, 36, 47, 48, 50, 53, 63, 71, 73, 77, 88… Caveat: Some changes at some positions are considered polymorphisms, and may be more prevalent in wild type than in resistant mutants

Saquinavir (SQV) First protease inhibitor approved by the FDA Primary mutations L90M and G48V, usually occurring in succession G48V is SQV specific mutation L90M is common for all PIs and is associated with significant cross-resistance However, presence of L90M alone does not preclude the use of other PIs or even SQV if no secondary mutations present

Fosamprenavir (FPV) (amprenavir) FPV is a pro-drug of APV and allows for BID dosing and better absorption Four major pathways of resistance I50V or I84V, +/- secondary mutations I50V + M46I/L and/or I47V, +/- sec. mutations I47V + V32I I54L/M All pathways confer low/mod cross-resistance to other PIs

Lopinavir (LPV) Co-formulated with RTV Two patterns of resistance First: I84V followed by M46I, V32I and I47V Similar to IDV, RTV and APV Second: I50V followed by M46I, similar to FPV Very low incidence of LPV resistance in ART naïve failures with first regimen containing LPV/r

Atazanavir (ATV or AZV) Usually given with RTV or Cobi Several primary mutations with different resistance patterns N88S or I84V Unique I50L, frequently associated with A71V and with hypersucceptibility to other PIs Drug experienced failures with ATV do have cross-resistance to other PIs First time failures with ATV regimen tend not to have PI resistance mutations at the time of failure

Darunavir (DRV) Mutations: L1I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, L89V Resistance profile: I50V, I54L and L76V confer significant resistance DRV but hypersusceptibility to Tipranavir Tipranavir (TPV) Mutations: 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, I47V, I54A/M/V, 58E, 69K, 74P, I82L/T, 83D, I84V 3-10 mutations partial susceptibility, 11+ resistance TPV resistance has no impact on DRV susceptibilities

Flexible Flaps Protease Substrate Binding Tunnel Active Site

Protease Resistant Mutations
G48 I50

V82 D30 I84 L10 L90

V77 K20 I63 A71

Mutations in the Protease Gene Associated With Resistance to Protease Inhibitors
Atazanavir +/-ritonavir Darunavir/ ritonavir Fosamprenavir/ ritonavir Indinavir/ 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. Lopinavir/ ritonavir 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.

Entry Inhibitor Resistance
Fusion inhibitors T-20 Story not completely told yet Mutations in gp41 Between codons 36 to 45 Codons 36, 37 and 38 were seen early in vitro and in early clinical studies More mutations, more resistance Mutations associated with decreased replicative capacity (reduced viral entry) Co-receptors resistance-(Maraviroc) CXCR4 use confers resistance (2%) Tropism assays are require (Trofile Assay)

Mutations in the Envelope Gene Associated With Resistance to Entry Inhibitors
Enfuvirtide Maraviroc 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.

Post-Attachment Inhibitor
Ibalizumab (TNX-355) is a humanized IgG4 monoclonal antibody that binds to CD4 receptor’s domain 2 on the cell surface It is a non-competitive, allosteric inhibitor of HIV-1 cell entry Dose via infusion every 2 weeks (first loading) Resistance can occur with virus due to fewer N-linked glycosylation sites in gp120 Multientry inhibitor resistance (including enfuvirtide) can occur. Bettiker RL. Curr Opin HIV AIDS. 2018

Ibalizumab Bettiker RL. Curr Opin HIV AIDS. 2018

Integrase Inhibitors Raltegravir Elvitegravir Dolutegravir
Signature mutations: Q148H/K/R, Y143C and N155H N155H and Q148H/K/R pathways are present Elvitegravir Signature mutations: Q148R, E92Q, and T66l. Additional mutations at codons 92, 138, and 147 Dolutegravir Active against Y143C, N155H Reduce activity against Q148 mutations but may be overcome by BID dosing

Major Pathways of Resistance with Raltegravir
Early N155H Delayed Q148H/K/R Secondary Mutations (L74M, E92Q, T97A, V151I, G163R) Secondary Mutations (L74M, G140A/S, E138K) Source: Fransen S, et al. J Virol. 2009;83:

Mutations in the Integrase Gene Associated With Resistance to Integrase Strand Transfer Inhibitors
Dolutegravir Raltegravir Elvitegravir 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.

Bictegravir Newly approved by the FDA in 2017
Only available in the US as Biktarvy combination Key mutations in vitro M50I 1.3 fold T66I 0.4 fold S153F 1.9 fold R263K 2.2 fold T66I+S153F 0.5 fold M50I+R263K 2.9 fold

Case 3 55 yo Male, history of HIV diagnosis in He has been on multiple regimens, he can’t recall. He is incarcerated for several years and is treated with an unknown regimen. He presents to clinic with an HIV viral load of 76,582 copies/mL and a CD4 counts of 98 cells/mm3.

Case 3 PMHX Allergies Substance abuse DM Hyperlipidemia Pneumonia
Herpes Zoster Polyneuropathy Asthma/COPD Allergies Aztreonam Carbapenems Cephalosporins Penicillins Zidovudine

Case 3 His prior HIV genotype using ViroSeq from 2013 showed no resistance to NRTI, NNRTI or PI agents. A repeat genotype in 2017 using next generation sequencing shows again no primary resistance mutations to NRTI, NNRTI or PI. Integrase does not show mutations. No minority species detected with resistance. He is placed on a EVG/Cobi/FTC/TAF plus Darunavir regimen in 2017 due to concern for possible underlying resistance.

Case 3 The patient tolerates his regimen well.
He is able to achieve viral load reduction below 50 copies/mL and raise his CD4 counts. He relapses in his alcohol and drug abuse. He intermittently takes his medication and eventually stops it. DATE CD4 Cells Counts HIV Viremia 7/25/2018 98 76,582 7/13/2017 72 154 8/28/2017 128 46 11/27/2017 143 133,550 3/12/2018 53 95,163

Case- Minority Resistance
NNRTI: V106A Confers high level of resistance to nevirapine and intermediate to efavirenz Integrase resistance Major mutations: Y143L, S147T, Q148R Accessory mutations: P145K, Q146R Q148R confers major high level resistance to elvitegravir and raltegravir. Intermediate resistance to dolutegravir and bictegravir

Integrase Resistance This is a case of high level resistance to all integrase inhibitors. Prior NNRTI resistance missed on prior genotypes emerged under ART drug pressure. Additional mutations and minority species were identified as part of majority and minority viral populations Key mutations were only found on minority populations that clearly impact treatment options

What Did You Learn? The HIV virus can easily develop resistance to ART. HIV testing, genotypes and other tests needed for management HIV resistance mutations will depend of the current and past ART regimens Complicated HIV resistance patterns will require HIV expert consultation for management

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HIV Resistance John E. McKinnon, MD, MSc

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