Clinical Resolution and CSF Viral Suppression Following Switching - PowerPoint PPT Presentation

Clinical Resolution and CSF Viral Suppression Following Switching to a Genotype-guided South African Antiretroviral Third Line Regimen with Good CSF Penetration Cerebrospinal Fluid HIV Viral Escape Kabengele Kayembe D. ; Nxele N.P.; Famoroti T.; Gordon M.

matter lives Brain #

Individual and programmatic impact and management implications Clinical and virologic Objective Escape Cerebrospinal fluid Neuro-symptomatic outcomes

Figure 1. Geographic distribution of cohorts presented at the Global HIV-1 CSF Escape Meeting 2016 among ART-experienced estimated at 4%‒ 20 % of CSF viral escape The prevalence HIV+ adults Uncommon or unrecognized or under reported 1 in 5 South Africa ART experienced HIV infected €€ € € € UNAIDS Data 2017 | Journal of Virus Eradication 2016; 2: 243–250 | J Acquir Immune Defic Syndr 2017;75:246–255

Deep rural Zulu Kingdom | KwaZulu-Natal province | South Africa The setting Eshowe District hospital

Clinical Suspicion “With a high suspicion, every effort to obtain these assessments should be made since they are essential for diagnosis and rational management . ” at the onset of new or progress of CNS symptoms Escape Cerebrospinal fluid Neuro-symptomatic Clin Infect Dis. 2010; 50:773–8 | AIDS. 2012 September 10; 26(14) | J Neurovirol . 2013 August ; 19(4): 402–405 | AIDS. 2016;30(7):1143–1144 | Curr HIV/AIDS Rep (2015) 12:280–288 | Clin Infect Dis 2017;64(8):1059–65 | J Acquir Immune Defic Syndr 2017;75:246–255) | AIDS 2016, Vol 30 No 7:1143-1144 | AIDS. 2012 September 10; 26(14)

Escape Cerebrospinal fluid Neuro-symptomatic Plasma/CSF viral loads Genotyping Magnetic resonance imaging September 2016 October 2016* December 2016 January 2017 *October 2016 plasma genotyping not reported (viral load 386 copies/mL)

HIV infection diagnosis in February 2010 and viremia of 156,162 copies/mL (cpm) (5.20 Log) Shift worker process control officer at a pulp and containerboard mill since 1987 Married (spouse optimally suppressed on NNRTI based ART) and father to six children The patient 55-year-old male Baseline CD4 cell count (%) of 264 cells/ µ L (6%)

0.0 ATV/r CD4 percentage % CD4 p-Log VL Suboptimal and labile Mar-2010* Jul-2015** D4T, 3TC, NVP TDF, FTC, ATV/r TDF, FTC, LPV/r TDF, FTC, TDF, FTC, 1.0 LPV/r Initiation Switch ART regimen exposure Intermittent Severe adherence immune suppression viral suppression History of HIV care Figure 2. Viremia & immune suppression levels Viral load Log Figure 3. Antiretroviral therapy regimens 12 7.5 13.5 4.5 6 0 6.0 5.0 9 3 15 4.0 3.0 2.0 10.5 1.5 0 1 2 2 6 0 0 1 1 2 3 3 4 4 5 5 6 6 6 7 7 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 - - - - - - - - - - - - - - - - - - - - - b n c n n c n g v r t r p l t n l p c n r u u p c p c p e e o e e u a u u u e u e a J J O O A A A D J D N S S D J F J J J A J Oct-2015 ⋊ Apr-2016 ∅ Jun-2016 ⋕

History of HIV care Ritonavir boosted protease Inhibitor based antiretroviral therapy months 14

“Established” neurologic impairment despite improvement viremia control Worsening unremarkable brain computed tomography Spectrum & severity fluctuated with viremia Tremors & Unsteadiness Progressive Insidious onset

“Established” neurologic impairment Culminated with status epilepticus Incapacitation Semi-consciousness Total dependence Neurogenic dysphagia Worsening Tremors & Unsteadiness Progressive Insidious onset

4.0 4.5 Figure 5. CSF/Plasma dissociation >2 times** >0.5 Log*** than paired plasma levels HIV-1 RNA higher Cerebrospinal fluid Definition criteria Cerebrospinal fluid Escape CSF Plasma Discordance Dec-16 4.4 Sep-16 4.0 3.5 2.3 3.4 1.7 1 -1.0 -0.5 Figure 4. CSF escape criteria 0.0 0.5 1.0 1.5 2.0 2.5 3.0 ≥ 1 Log* *AIDS. 2012 September 10; 26(14) | *Clin Infect Dis. 2010; 50:773–8 | **Curr HIV/AIDS Rep (2015) 12:280–288 | ***J Acquir Immune Defic Syndr 2017;75:246– 255) | ***J Infect 2012;65(3):239–245 | ***J. Neurovirol. (2016) 22:852–860

Escape 3.5 0.5 1.0 1.5 2.0 2.5 3.0 4.0 -0.5 4.5 Sep-16 Dec-16 Discordance Plasma CSF Figure 5. CSF/Plasma dissociation 0.0 -1.0 Cerebrospinal fluid 1 Confirmation Meningeal inflammation Neuro-Imaging HIV encephalitis Absence of alternative neuro-pathology diagnosis 4.0 4.4 2.3 3.4 1.7 Cerebrospinal fluid J Acquir Immune Defic Syndr 2017;75:246–255) | Curr HIV/AIDS Rep (2015) 12:280–288 | AIDS. 2012 September 10; 26(14) | Clin Infect Dis. 2010; 50:773–8 | J Infect Dis. 2010; 202:1819–25 | J Virus Erad. 2016 Oct; 2(4): 242 | Clin Infect Dis. 2017;64(8):1059–65 | J. Neurovirol. (2016) 22:852–860 | AIDS. 2016;30(7):1143–1144

Escape Cerebrospinal fluid CNS drug resistance Cerebrospinal fluid had developed unique and significant resistance mutations in the CSF Suggesting failure of the current treatment regimen in the central nervous system some*, many **, majority ***, all # cases **J Acquir Immune Defic Syndr 2017;75:246–255) | Curr HIV/AIDS Rep (2015) 12:280–288 | *AIDS. 2012 September 10; 26(14) | ***Clin Infect Dis. 2010; 50:773–8 | J Infect Dis. 2010; 202:1819–25 | J Virus Erad. 2016 Oct; 2(4): 242 | Clin Infect Dis. 2017;64(8):1059–65 | # J. Neurovirol. (2016) 22:852–860 | AIDS. 2016;30(7):1143–1144

Escape K238T based second-line ART regimen in the CSF October 2016 : Failure of boosted PIs Cerebrospinal fluid L10F M46I (PR) gene Protease K103N Compartmentalized, asynchronous, “discordant” ? M184V T215F K70R D67N (RT) gene transcriptase Reverse CNS drug resistance

Escape K238T based second-line ART regimen in the plasma December 2016 : Failure of boosted PIs V82A/V L10F M46I (PR) gene Protease K103N Cerebrospinal fluid M184V T215F K70R D67N (RT) gene transcriptase Reverse Plasma drug resistance

Escape 15 K103N, K238T K103N, Low Low 15 TDF EFV High High 60 60 3TC High High K238T 90 60 90 Susceptible 0 0 RPV High High 90 NVP 90 Susceptible Susceptible 0 0 ETR High High 60 FTC Cerebrospinal fluid CSF* K70R, D67N, Plasma CSF Plasma CSF Plasma** Resistance Levels*** T215F Mutation Scoring Drugs Mutations Table 1. Reverse transcriptase (RT) gene drug resistance mutations & levels drug resistance? Asynchronous, discordance Compartmentalized, M184V, D67N, High 80 High 65 65 D4T High High 80 AZT K70R, Intermediate Intermediate 40 40 ABC T215F M184V, Susceptible

Escape NFV Low Intermediate IDV/r 20 60 Low High LPV/r 15 55 Low Intermediate 45 25 85 Intermediate High SQV/r 10 35 Potential Low Intermediate TPV/r 5 5 Susceptible Susceptible 50 FPV/r Cerebrospinal fluid CSF Compartmentalized, Asynchronous, discordance drug resistance? Table 2. Protease (PR) gene drug resistance mutations & levels Mutations Drugs Mutation Scoring Resistance Levels*** CSF* Plasma** CSF Plasma Plasma Susceptible M46I, L10F M46I, V82A/V L10F ATV/r 10 35 Potential Low Intermediate DRV/r 5 5 Susceptible Plasma PIs resistance one or two levels relatively higher

Escape Cerebrospinal fluid Rational management A CABBAGE !!!!!!!! Our Father

Escape Cerebrospinal fluid Rational management Antiretroviral therapy alteration Drug resistance* & previous exposure Central nervous system drug penetration** Patient’s adherence motivation, support & sustainment Regimen switch and/or intensification *J. Neurovirol. (2016) 22:852–860 | *Curr HIV/AIDS Rep (2015) 12:280–288** | *AIDS. 2012 September 10; 26(14)** | *Clin Infect Dis. 2010; 50(5):773–8**| J Virus Erad. 2016 Oct; 2(4): 242 | AIDS. 2016;30(7):1143–1144** | J Acquir Immune Defic Syndr 2017;75:246–255) | *J Neurol (2017) 264:1715–1727 **

Escape Cerebrospinal fluid South African third line antiretroviral therapy two months earlier Protease inhibitor resistance mutations scoring than in the plasma in the central nervous system Eligibility “criteria” on the Stanford University HIV Drug resistance Database ≥ 15 S Afr J HIV Med. 2017;18(1), a776. https://doi.org/10.4102/ sajhivmed.v18i1.776

Escape scoring less than 29 80 Additional InSTI and/or ETV not required with respectively TDF and DRV mutations and 15 AZT Third line option CSF plasma DRV DRV TDF TDF 80 15 Cerebrospinal fluid Plasma South African third line antiretroviral therapy Building the regimen according to the algorithm Drug CSF score score 15 ATV 10 35 LPV 15 55 TDF S Afr J HIV Med. 2017;18(1), a776. https://doi.org/10.4102/ sajhivmed.v18i1.776

Escape TDF 09/04/2017 Treatment started 09/05/2017 Authorization granted 09/02/2017 Application submitted FTC TDF DRV 80 80 AZT 15 15 55 Cerebrospinal fluid Plasma South African third line antiretroviral therapy Building the regimen according to the algorithm Drug CSF score score 15 From the committee ATV 10 35 LPV S Afr J HIV Med. 2017;18(1), a776. https://doi.org/10.4102/ sajhivmed.v18i1.776