Integrase Inhibitor Based Antiretroviral Therapy in Botswana; a Case Report

Transcription

1 Detection of Four-Class Resistant HIV-1C in a patient on Integrase Inhibitor Based Antiretroviral Therapy in Botswana; a Case Report Kaelo K. Seatla MPhil / PhD Student Supervisors: Dr. Simani Gaseitsiwe Prof. Kasvosve Dr. Ava Avalos Advisory committee: Joe Jarvis Mark Brockman Chris Rowley

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4 Botswana HIV Guidelines since 2002

5 How HIV Drug Resistance arises Viral factors Viral subtype/clade e.g. NVP resistance in D vs A TAM pathways different in C More K65R s in C etc. Replicative capacity Genetic mutations Patient Factors Poor adherence Stigma Substance abuse ARV treatment access barriers Drugs Low potency Drug-drug interactions Low genetic barrier to resistance Side effects ART Clinic Site Issues Inadequate staffing Poor retention rates Poor support to treatment adherence Delays in switching National ART programme issues Suboptimal drug procurement Poorly managed programmes Limited Human resources Hostile Political climates WHO, Global action plan on HIV drug resistance Geneva: World Health Organization; Licence: CC BY-NC-SA 3.0 IGO, no. February

6 Types of HIV Drug Resistance Transmitted Drug Resistance (TDR) Patients are newly infected with a virus with drug resistant mutations Acquired Drug Resistance (ADR) Patients on ART develop mutations due to errors in viral replication or inadequate ARV pressures etc. Pre-treatment HIVDR (PDR) Detected in ARV naïve patients initiating ART or those with prior ART exposure e.g. sdnvp being reinitiated. Can be TDR,ADR or both WHO, Global action plan on HIV drug resistance Geneva: World Health Organization; Licence: CC BY-NC-SA 3.0 IGO, no. February

7 What do we know about HIV DR in Botswana? 2007 TDR rates in Gaborone Botswana; 0/33 = None 2014/2015 TDR Rates in Gaborone Botswana; 6/62=9.7%

8 Case Report Conducted as part of the Botswana Epidemiological ART Treatment Cohort Study Retrospective chart review September August 2017 Genotypic Resistance testing (GRT) at Reverse Transcriptase (RT), Protease and Integrase genes was done as per National ART Guidelines Raw sequences were edited using Sequencher 5.0 Stanford University HIV Drug resistance database used to asses for drug resistance mutations

9 Case Report, cont 51-year-old man enrolled into ART care on 8 September 2003 prior Hx for treatment for Pulmonary TB and Cryptococcal Meningitis ARV Switches over 14 years 08-Sep-03 AZT \ 3TC \ NVP 03-Nov-04 d4t \ ddi \ NFV 07-Feb-06 AZT \ TDF \ LPV/r 14-Jan-08 AZT \ 3TC \TDF \ LPV/r 10-Jun-09 AZT \ ABC \ TDF \ LPV/r 05-Aug-09 TDF \ FTC \ SQV/r 21-Oct-09 TDF \ FTC \DRV/r \ RAL 28-May-15 TDF \ FTC \ DRV/r 20-Apr-16 DRV/r \ DTG 02-Sep-16 TDF \ FTC \DRV/r \ DTG Reason for Switch

10 Case Report, cont Follow-up period clinically uneventful with no OI s Poor adherence to ARV s and clinic appointments Experienced one episode of drug stock-out DRV for about 2 weeks in March 2012 Social life has been tumultuous characterized by; conflicts within family retirement from his Job Death of one of his children dedication to his subsistence farming activities that are far away from his ART clinic.

11 Results Plasma HIV-1 RNA (Viral Loads) Log 10 copies/ml Sep-03; AZT,3TC, NVP Plasma Viral Loads, CD4 cell count and HAART regimens at different time points over a 14 year period for One Patient Viral Loads Log 10 copies/ml 03-Nov-04; d4t,ddi, NFV 07-Feb-06; AZT,TDF, LPV/r 14-Jan-08; AZT,3TC,TDF,L PV/r 10-Jun-09; AZT,ABC,TDF, LPV/r 05-Aug-09; TDF,FTC, SQV/r 21-Oct-09; TDF,FTC, DRV/r, RAL Timeline, years 28-May-15; TDF,FTC, DRV/r ART regimen CD4 Absolute Count cells/µl 20-Apr-16; DRV/r,, DTG bd 0 02-Sep-16; TDF,FTC, DRV/r,DTG DTG bd CD4+ Absolute Count cells/µl

12 Table 1: Various HIV drug resistant mutations from different time points and the affected ARV drug class Drug Class Mutations Date of test 18-May Aug Aug-16 Nucleoside Reverse Transcriptase Inhibitor s (NRTI's) D67N,K70R, M184V D67N, K70R, M184V, K219N D67N,K70R,M184V Nonnucleoside Reverse Transcriptase Inhibitor s (NNRTI's) Y181C Y181C None Protease Inhibitor s (PI's) Major Minor V32I, I47V,I54L, I84V V32I, I47V,I54L, I84V V32I, I47V,I54L, I84V L10V, L33F,G73V, T74S L10V, L33F,G73V, T74S L10V, L33F,G73V, T74S Integrase Strand Transfer Inhibitor s Not tested Not tested Q148R, E138K, G140A Fusion Inhibitor s Not tested Not tested None Entry Inhibitor s -CCR5 co-receptor antagonist's Not tested Not tested R5 tropic

13 Discussion Over the course of his treatment, the patient was seen by over 24 Doctors highlighting the critical importance of continuity of care and expertise when managing highly treatment experienced patients received inadequate psycho-social support To our knowledge, this is the first reported case of four-class HIV-1C drug resistance in a patient exposed to DTG cart in SSA

14 What should we do? Rilpivirine(RPV) based cart remains unattractive because; Patient has prior RAMs to NNRTI s, NRTI s and is not Virologicaly suppressed S. Gallien et al.,. E. Wilson and J. E. Gallant., Etravirine (ETR) has some activity against NNRTI resistant virus with an OBR; But it s a CYP3A4 inhibitor with many contraindications, needs bid dosing, side effects... E. Wilson and J. E. Gallant., Potential benefit from continuation of DTG at bid BUT with optimization of OBR; Viking-3 Benefit from being motivated for Maraviroc ( MVC) with an OBR? data is lacking on an R5-1C virus with an Integrase Q major mutations as in this case MVC is bid Enfuvirtide (T-20) might be a better option; Its Efficacious and durable in Rx experienced Pts with OBR But needs time consuming reconstitution, can cause painful reaction site reactions, its very costly

15 Challenges MVC, RPV,Etravirine (ETR)and Enfuvirtide (T-20) are not available in the national public ART programme A potential public health concern is the introduction of a multidrug resistant HIV-1C virus into the circulating pool as despite extensive counselling the patient is still condomlessly sexually active with one partner and virologicaly unsuppressed.

16 Conclusion We need to proactively address the rising levels of resistance to HIV drugs if we are to achieve the global target of ending AIDS by Dr Tedros Adhanom Ghebreyesus WHO Director-General (accessed 22 Oct 2017)

17 References [1] L. E. Wilson and J. E. Gallant, The Management of Treatment-Experienced HIV- Infected Patients : New Drugs and Drug Combinations, Clin. Infect. Dis., vol. 48, pp , [2] S. Gallien et al., Archived hiv-1 dna resistance mutations to rilpivirine and etravirine in successfully treated hiv-1-infected individuals pre-exposed to efavirenz or nevirapine, J. Antimicrob. Chemother., vol. 70, no. 2, pp , [3] S. Gazaignes et al., Efficacy and safety of a switch to rilpivirine-based regimens in treatment- experienced HIV-1-infected patients: A cohort study, Antivir. Ther., vol. 21, no. 4, pp , [4] A. Castagna et al., Dolutegravir in antiretroviral-experienced patients with raltegravirand/or e lvitegravir-resistant HIV-1: 24-week results of the phase III VIKING-3 study, J. Infect. Dis., vol. 210, no. 3, pp , [5] H. Bussmann et al., Prevalence of Transmitted HIV Drug Resistance in Botswana: Lessons Learned from the HIVDR-Threshold Survey Conducted Among Women Presenting for Routine Antenatal Care as Part of the 2007 National Sentinel Survey, AIDS Res. Hum. Retroviruses, vol. 27, no. 4, pp , [6] C. F. Rowley et al., Sharp increase in rates of HIV transmitted drug resistance at antenatal clinics in botswana demonstrates the need for routine surveillance, J. Antimicrob. Chemother., vol. 71, no. 5, pp , 2016.

18 Acknowledgements Prof. Thumbi Ndungu Dennis Chopera Sipho Khumalo Kim Wallidove SANTHE Team Dr. Ava Avalos Dr. Madisa Mine Simani Gaseitsiwe Sikhulile Moyo Rosemary Musonda Joe Jarvis Thabo Diphoko BHP HIV Drug Resistance Group Research Lab Team Prof. Kasvosve Mosepele Mosepele Tendani Gaolatlhe Miriam Haverkamp PMH IDCC staff and Patients