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HIV Resistance

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.

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HIV Resistance

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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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. 2006:41:573-581.

  7. US HIV Resistance 2000-2009 • Overall rate of 14% IAS-USAresistance 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

  8. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. Downloaded from https://aidsinfo.nih.gov/guidelines on 12/27/2017

  9. 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

  10. 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

  11. 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?

  12. Every step in the virus cycle is a target for drug therapy Modified from Furtado M et al. N Engl J Med 1999;340:1614-1622

  13. Nucleoside Reverse Transcriptase Inhibitors (NRTI) Abacavir ABC Didanosine DDI EmtricitabineFTC Lamivudine 3TC Stavudine D4T TenofovirTDF Zidovudine ZDV (AZT) Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI) Efavirenz EFV Nevirapine NVP Etravirine ERV or ETV Delavirdine DLV Rilpivirine RPV Fusion Inhibitors EnfuvirtideT-20 Antiretroviral Medications 2018

  14. Protease Inhibitors (PI) FosamprenavirfAPV AtazanavirATV Indinavir IDV Lopinavir/ritonavir LPV/r Nelfinavir NFV Ritonavir RTV Saquinavir SQV TipranavirTPV DarunavirDRV 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 Antiretroviral Medications 2018

  15. Combination Tablets • Combination pills • CombivirTM (AZT/3TC) • EpzicomTM (ABC/3TC) • TrizivirTM (ABC/AZT/3TC) • Truvada TM (FTC/TDF) • DescovyTM (FTC/TAF) • PrezcobixTM (DRV/cobi) • EvotazTM (ATV/cobi) • KaletraTM (LPV/r) • Once daily ART / STR • ATRIPLA TM (EFV/TDF/FTC) • Complera TM (RPV/TDF/FTC) • Odefsey TM (FTC/RPV/TAF) • StribildTM (EVG/COBI/TDF/FTC) • GenvoyaTM (EVG/COBI/TAF/FTC) • TriumeqTM (ABC/DTG/3TC) • JulucaTM (DTG/RPV) • BiktarvyTM (BIC/FTC/TAF)

  16. DHHS 2017 ART Recommendations 2017 DHHS Adult and Adolescent Guidelines

  17. Why HIV virus develop resistance so easily?

  18. 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

  19. 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.

  20. HIV Replication • Daily virion production is between 1010 to 1011 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.

  21. 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

  22. HIV ART Resistance • Price to ART Resistance • 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

  23. 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!!

  24. Nucleoside Reverse Transcriptase Inhibitors Resistance Mutations

  25. 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.

  26. 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

  27. Understanding the Mutation List

  28. 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

  29. 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

  30. 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

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

  32. 62 69 75 74 65 77 116 151 184 NRTI Mutations

  33. Other Key RT Mutations • M184V • Selected by 3TC, FTC and ABC (rarely, DDI) and can occur within days with mono-therapy • 100-1000 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

  34. 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

  35. Other RT Mutations • K65R • Selected by TDF/TAF therapy • Resistance partially reversed by M184V • Initially associated with extended ddImonotx • 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

  36. 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

  37. 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

  38. 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)

  39. Mutations in the Reverse Transcriptase Gene Associated With Resistance to Reverse Transcriptase Inhibitors (cont’d) Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine

  40. Non-Nucleoside Reverse Transcriptase Inhibitor Resistance Mutations

  41. 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

  42. NNRTI Mutations 188 108 225 181 106 236 190 100 103

  43. Non-Nucleoside RTI Mutations • 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)

  44. Non-Nucleoside RTI Mutations • K103N • Most commonly selected NNRTI mutation by EFVbut also withNVP • 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

  45. Non-Nucleoside RTI Mutations • 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

  46. Non-Nucleoside RTI Mutations • 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

  47. Mutations in the Reverse Transcriptase Gene Associated With Resistance to Reverse Transcriptase Inhibitors (cont’d) Nonnucleoside Analogue Reverse Transcriptase Inhibitors (NNRTIs) Efavirenz Etravirine Nevirapine Rilpivirine

  48. 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.

  49. 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

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