Resistance in the age of Integrases Case presentation

Patient JJ 53yo MSM DSP since diagnosis of HIV and subsequent health issues Diagnosed HIV+ve 5/2002 on presentation with PJP SVH Sydney CD4 Nadir at diagnosis 20 4%, VL 100 000 5/2002 Cigs: 30/day for years, now ex smoker ETOH : Nil Normotensive Substances : nil Not sexually active for years due to ill health Social: Cares for long term chaotic ex partner who has significant crystal addiction and subsequent mental health issues. Also HIV +ve Lives on the Gold Coast but wishes to continue HIV care in Brisbane Returned to Brisbane in September 2015 from Sydney

Past Medical History 2-6/2018 – AIN 1 4/2018 – Moderate OSA 3/2017 – BMI 34 – secondary to inactivity, ill health, steroids post transplant 2015 – Revaccinations post transplant 2014 onwards – monthly IVIG infusions 07/07/2014 – AML : Bone Marrow stem cell transplant Sydney CMV reactivation during treatment 09/04/2013 - AML- Chemotherapy remission 12/2013, relapse 04/2014 19/07/2012 - Lumbar back pain - Large disc protrusion L4/5- chronic LBP 13/10/2011 - Hypertriglyceridaemia 2007 – Hypogonadism – testosterone nadir 2.8. Declines testosterone 2010 – GORD – persisting on endoscopy 2017 2010 – Severe COPD 2009 - Chronic diarrhoea - colonoscopy surveillance – 2017 -2 polyps 2008 – Persistent pulmonary nodules. CT surveillance thought to be benign granulomas 2008-2009 – Anal SCC –chemotherapy, radiotherapy. Colostomy during therapy then reversed. Follow up normal until AIN in 2017 2002 - HIV infection

Sulfonamide antibiotics Vancomycin Gentamycin Bactrim Medications Allergy History Sulfonamide antibiotics Vancomycin Gentamycin Bactrim Medications Panadol Osteo 665 mg Modified release tablets [96 x2] Pantoprazole Tablets 20 mg Tablets [30] Onbrez Breezhaler Powder for inhalation 150 mcg Powder for inhalation [30] – LABA HLAB5701 – no record HIV CORECEPTOR TROPISM GENOTYPE      Specimen Type: Plasma      X4 Viruses:    Detected      Use of CCR5 antagonists not indicated

Antiretroviral History 2002-2004 Abacavir/Lamivudine/Zidovudine- Trizivir 2004 - 2008 Trizivir + Nevirapine 2008- 10/2010 Abacavir/Lamivudine + Nevirapine AZT ceased during chemotherapy for Anal SCC Nevirapine then ceased due to potential for induced metabolism of exogenous testosterone for hypogonadism 2010-2015 Raltegravir, Abacavir/Lamivudine (variable adherence and viral escape 2015 due to medical conditions and social circumstances) 2/2016 -12/2016 Etravirine, Darunavir/r, Dolutegravir, Truvada based on GRA 10/2017-2/2018 Darunavir/r, TAF/FTC, Etravirine (initially minimal nausea but then recurred. Has ceased all meds again due to side effects) Suppressed VL and improving CD4 2006-2014 until AML relapse Adherence generally good 2002-2014 ( Viral escape once in 2011 related to poor adherence) Supressed virus 3/2016 - 12/2016 but significant nausea, vomiting so self ceased 12/16

HIV Monitoring 26/07/2018 CD4: 230 (10%) VL:12325 02/04/2018: CD4: 340 (16%) CD8: 1400 (65%) VL: 1758 5/2/2018 VL: <40 08/01/2018: CD4: 350 (14%) CD8: 1650 (64%) VL: <40 16/10/2017 CD4: 350 (10%) CD8: 2370 (70%) VL: 28007 22/09/2017 CD4: 390 (13%) CD8: 2150 (71%) VL: 38000 18/09/2017 CD4: 480 (16%) CD8: 1950 (66%) VL: 5040 21/08/2017 CD4: 490 (15%) CD8: 2250 (67%) VL <40 26/06/2017 CD4: 480 (16%) CD8: 2090 (69%) VL: <40 29/05/2017 CD4: 440 (16%) CD8: 1870 (70%) VL: <40 03/04/2017 Cd4: 470 (11%) CD8: 3170 (75%) VL: 66890 06/03/2017 Cd4: 350 (15%) Cd8: 1600 (69%) VL: 33978 12/12/2016 CD4: 450 (18%) CD8: 1760 (68%) 14/11/2016 Cd4: 500 (16%) CD8: 2060 (67%) VL: <40 17/10/2016 CD4: 490 (18%) CD8: 1830 (67%) VL: <40 19/09/2016 CD4: 400 (13%) CD8: 2300 (73%) VL: <40 23/08/2016 CD4: 500 (14%) CD8: 2700 (75%) VL: ND 30/05/2016 CD4: 360 (13%) CD8: 2070 (73%) VL: <40 11/04/2016 CD4: 350 (13%) CD8: 1930 (74%) VL: <40 14/03/2016 CD4: 310 (12%) CD8: 1940 (76%) VL: 57 15/02/2016 VL: 19592 18/01/2016 CD4: 360 (12%) CD8: 2310 (76%) VL: 39770 21/12/2015 CD4: 400 (12%) CD8: 2590 (75%) VL: 12561 23/11/2015 CD4: 430 (13%) CD8: 2520 (74%) VL: 2145 04/11/2015 CD4: 350 (11%) CD8: 610 (78%) VL: 53000

HIV GENOTYPE RESISTANCE 4/12/15 Stanford HIV subtype: D (PR 94 HIV GENOTYPE RESISTANCE 4/12/15      Stanford HIV subtype: D (PR 94.9%)  B (RT 96.2%): SUBTYPE B      HIV Viral Load .....:                  copies/mL      Protease Inhibitor Resistance Mutations:      PI Major Resistance Mutations      PI Minor Resistance Mutations      L10I      Other Mutations      I15V E35D M36I R41K L63T I93L      Protease Inhibitors ...:      ATV/r  Susceptible      DRV/r  Susceptible      FPV/r  Susceptible      IDV/r  Susceptible      LPV/r  Susceptible      NFV/r  Susceptible      SQV    Susceptible      TPV/r  Susceptible      Reverse Transcriptase Resistance Mutations:      NRTI Resistance Mutations      M184MV      NNRTI Resistance Mutations      Other Mutations      V21I V60I K122E T128IT I142V G196E E203D R211K      NRTIs                             NNRTIs      3TC High-Level Resistance          RPV Susceptible      ABC Low-Level Resistance           EFV Susceptible      AZT Susceptible                    NVP Susceptible      D4T Susceptible                    ETR Susceptible      DDI Potential Low-Level Resistance      FTC High-Level Resistance      TDF Susceptible      Comments      "RTPOS184VI NRTI": M184V/I cause high-level resistance to 3TC and FTC      and low-level resistance to DDI and ABC. However, M184V/I are not      contraindications to continued treatment with 3TC or FTC because they      increase susceptibility to AZT, TDF and D4T and are associated with      clinically significant reductions in HIV-1 replication. In combination      with K101E or E138K, M184I synergistically reduces RPV susceptibility.      "PRPOS10IV PIMinor": L10I/V are polymorphic, PI-selected accessory      mutations that reduce PI susceptibility of increase the replication of      viruses with other PI-resistance mutations.       

HIV INTEGRASE RESISTANCE 4/12/15 Stanford HIV Subtype: B (IN 95 HIV INTEGRASE RESISTANCE 4/12/15      Stanford HIV Subtype: B (IN 95.1%)      HIV Viral Load......:              copies/mL      Integrase Inhibitor Resistance Mutations:      Integrase Major Resistance Mutations      N155H      Integrase Accessory Mutations      T97A      Other Mutations      E11D A21T V31I C40CY D41N K71R A91T S119R T125A V201I I208L S230N      L234I D256E R284G      Integrase Inhibitors      Dolutegravir..:  Low-Level Resistance      Elvitegravir..:  High-Level Resistance      Raltegravir ..:  High-Level Resistance      Comments:      "INPOS155H Major": N155H is a nonpolymorphic mutation selected in      patients receiving RAL and EVG. Alone, it reduces RAL susceptibility      15-fold and EVG susceptibility 30-fold. Susceptibility is further      reduced when N155H occurs in combination with E92Q and other primary      or accessory INI-reistance mutations. N155H has been selected by DTG      in RAL-experienced patients but does not reduce DTG susceptibility by      itself.      "INPOS97A Accessory": T97A is a polymorphic accessory INI-resistance      mutation that, depending on subtype, occurs in 1% to 5% of viruses      from untreated persons. It is selected by RAL and EVG. Alone, it has      minimal effect on any INI susceptibility but in combination with      Y143C/R it markedly reduces RAL susceptibility.      "INPOS230N None": S230N is a polymophism that is not associated with      reduced INI susceptibility. HIV CORECEPTOR TROPISM GENOTYPE      Specimen Type: Plasma      X4 Viruses:    Detected           

4/11/11

HIV INTEGRASE RESISTANCE 27/10/17 Stanford HIV subtype:  B (3.86)      HIV Viral load......:               copies/mL      Protease Inhibitor Resistance Mutations:      PI Major Resistance Mutations      PI Minor Resistance Mutations:      Other Mutations      L10I I15V E35D M36I R41K L63T I93L      Protease Inhibitors....:      ATV/r      Susceptible      DRV/r      Susceptible      FPV/r      Susceptible      IDV/r      Susceptible      LPV/r      Susceptible      NFV/r      Susceptible      SQV/r      Susceptible      TPV/r      Susceptible      Reverse Transcriptase Resistance Mutations:      NRTI Resistance Mutations      NNRTI Resistance Mutations      Other Mutations      V21I V60I K122E I142V G196E E203D R211K      NRTIs                       NNRTIs      3TC       Susceptible       RPV     Susceptible      ABC       Susceptible       EFV     Susceptible      AZT       Susceptible       NVP     Susceptible      D4T       Susceptible       ETR     Susceptible      DDI       Susceptible      FTC       Susceptible      TDF       Susceptible      Comments:      PRPOS10IV Other: L10I/V are polymorphic, PI-selected accessory      mutations that increase the replication of viruses with other      PI-resistance mutations.

Integrase Inhibitors Dolutegravir. : Susceptible Elvitegravir Integrase Inhibitors      Dolutegravir..:     Susceptible      Elvitegravir..:     Potential Low-Level Resistance      Raltegravir...:     Potential Low-Level Resistance      Comments:      INPOS97A Accessory: T97A is a polymorphic accessory mutation that,      depending on subtype, occurs in 1% to 5% of viruses from untreated      persons. It is selected by RAL and EVG. Alone, it has minimal effects      on INI susceptibility but in combination with other primary resistance      mutations, particularly Y143C/R, it synergistically reduces      susceptibility to EVG and RAL.      INPOS230N Other: S230N is a polymorphism that is not associated with      reduced INI susceptibility.

Options Aim for viral suppression Limit adverse events Which Integrase Which PI Which NNRTI/NRTI Biktarvy + Prezcobix + Rilpivirine Dolutegravir bd + Descovy + Prezcobix + Rilpivirine