Antiretroviral therapy failure
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Antiretroviral therapy failure
- 1. ANTIRETROVIRAL THERAPY IN 2012 AND ANTIRETROVIRAL THERAPY RESISTANCE DR AMEET DRAVID M.D (Med) AAHIVS (USA) RUBY HALL CLINIC and NOBLE HOSPITAL,PUNE
- 2. Antiretrovirals approved for use NRTI NNRTI PI Newer drugs Zidovudine(AZT) Nevirapine (NVP) Nelfinavir CCR5 inhibitors :Maraviroc Stavudine(d4T) Efavirenz (EFV) Indinavir Integrase inhibitors : Raltegravir Lamivudine(3TC) Etravirine Saquinavir Fusion inhibitors : enfuvirtide Didanosine(ddI) Ritonavir Abacavir(ABC) Atazanavir/Ritonavi r Tenofovir(TDF) Lopinavir/Ritonavir Emtricitabine(FTC) Darunavir Tipranavir Fosamprenavir
- 3. When to start ?
- 4. NACO GUIDELINES 2012 Classification of HIV-associated clinical disease WHO STAGE CD4 NOT AVAILABLE Asymptomatic 1 CD4 AVAILABLE Do not treat Treat if CD4 <350 Mild symptoms 2 Do not treat Advanced symptoms 3 Treat Consider treatment if CD4 <350 and initiate ART before CD4 drops below 200 Severe/advanced symptoms 4 Treat Treat irrespective of CD4 count
- 5. API-ART Guidelines : When to start ? Classification of HIV-associated clinical disease WHO STAGE Asymptomatic 1 Mild symptoms 2 CD4 AVAILABLE CD4 <350 /mm3 Initiate ART CD4 > 350/mm3 Defer unless HBV/HCV Rx HIV nephropathy Cytotoxic therapy Advanced symptoms 3 Severe/advanced symptoms 4 Treat irrespective of CD4 count
- 6. When to Start: 2012 DHHS Guidelines
- 7. WHAT TO START ?
- 8. NACO GUIDELINES 2012 Preferred regimen (2NRTI’s + 1 NNRTI) AZT + 3TC + NVP (Zidovudine + Lamivudine + Nevirapine ) Alternative regimen (2NRTI’s + 1 NNRTI) AZT + 3TC + EFV (Zidovudine + Lamivudine + Efavirenz) TDF + 3TC + NVP/EFV (Tenofovir + Lamivudine + Nevirapine/Efavirenz ) Other options Stavudine (d4T) + 3TC/FTC + NVP/EFV Pi’s not recommended for first line therapy
- 9. API-ART GUIDELINES 2008: WHAT TO START ? • • • • • • • • NRTI Preferred Tenofovir + Lamivudine Abacavir + Lamivudine Zidovudine + Lamivudine Alternative Stavudine + Lamivudine Didanosine + Lamivudine • • • • NNRTI Preferred Efavirenz Nevirapine
- 10. Commonly used 1st line ART regimens in India NAME OF DRUG TRADE NAME Zidovudine + Lamivudine + Nevirapine Duovir-N/Zidolam N/Virocomb N Stavudine+ Lamivudine + Nevirapine Triomune-30/Emtri 30/Virolans 30 Zidovudine + Lamivudine + Efavirenz Duovir + Efavir Stavudine+ Lamivudine + Efavirenz Lamivir-S(30 )+ Efavir Tenofovir + Lamivudine + Efavirenz Tenolam E/Trioday/Dinmek Tenofovir + Emtricitabine + Efavirenz Viraday/Trustiva/Vonavir
- 11. Monitoring patients on antiretroviral therapy
- 12. 1st line antiretroviral treatment failure • • • • • Virologic failure : inability to achieve or maintain suppression of viral replication to HIV-1 RNA levels < 50 copies/mL 2 consecutive tests indicating HIV-1 RNA > 400 copies/mL after 24 weeks or > 50 copies/mL at 48 weeks Immunologic failure Inability of CD4 count to increase > 100 cells/mm3 in 1st year of ART Fall in CD4 count from peak level by > 50 % Clinical failure AIDS defining illness occurring more than 3-6 months after starting antiretroviral therapy
- 13. Difference between viral rebound and viral blip • • • • Viral blip : defined as a single, low-level plasma HIV-1 RNA level of 50-1000 copies/mL) that is immediately preceded and followed by an undetectable HIV-1 RNA false elevations of HIV-1 RNA related to erroneous laboratory findings or to release of archived virus from activated cells. not associated with the development of resistance mutations temporally linked to nonadherence to therapy
- 14. Recommended methods for determining virologic failure • HIV-1 viral load measurements should be done by any one of the following US FDA recommended tests: • Roche Cobas Amplicor • Branched DNA method • Nucleic acid sequence based assay (NASBA)
- 15. Causes of ARV Treatment Failure Social/personal issues Regimen issues Poor potency Wrong dose Toxicities Host genetics Poor adherence Poor absorption Drug pharmacokinetics Transmitted resistance Insufficient drug level Drug interactions Viral replication in the presence of drug Resistant virus ART resistance testing. AETC National Resource Center.
- 16. 1st line Antiretroviral therapy treatment failure • • • • • • • • Should be confirmed by 2 plasma viral load reports (plasma viral load > 400 copies/ml) after 6 months on 1st line ART. 2nd line ART should not be started on immunologic (CD4)/clinical evidence alone. Genotypic resistance testing should ideally be recommended while patient is on failing 1st line antiretroviral regimen. Reason for 1st line ART failure and cost of 2nd line antiretroviral regimen should be discussed in detail. Adding at least two (preferably three) fully active agents to an optimized background antiretroviral regimen can provide significant antiretroviral activity Boosted PI regimens well studied, expected to be effective Backbone of 2 NRTI’s can be decided from resistance testing report Goal of 2nd line ART is to re-suppress plasma viral load to undetectable levels.
- 17. Assessing treatment failiure • Genotypic resistance testing • Phenotypic resistance testing • Virtual phenotype
- 18. Genotypic resistance testing • Identifies mutations within reverse transcriptase and protease genes that have been associated with impaired virologic response • Readily available • Quick turnaround time (1-2 weeks) • Confers short-term virologic benefits • Useful for mixtures of wild type and drug resistant virus • Genotype testing is suitable for straightforward situations, such as testing for drug-resistant virus in treatment-naive subjects or evaluating resistance in a patient with viral rebound after their first regimen
- 19. Common reverse transcriptase inhibitor resistance (NRTI/NtRTI/NNRTI) mutations TYPE OF DRUG DRUGS INCLUDED SIGNATURE MUTATIONS THYMIDINE ANALOGS ZIDOVUDINE 41L, 67N,70R,210W,215Y,219Q (TAM’s) STAVUDINE 41L, 67N,70R,210W,215Y,219Q NON-THYMIDINE ANALOGS TENOFOVIR K65R ABACAVIR L74V,K65R DIDANOSINE L74V,K65R NEVIRAPINE K103N,Y181C EFAVIRENZ K103N,Y181C LAMIVUDINE M184V NNRTI NRTI EMTRICITABINE
- 20. Dynamics of resistance development DRUG K103N,Y181C LAMIVUDINE M184V ZIDOVUDINE TAM’s EFAVIRENZ TRUSTIVA/VIRADAY RESISTANCE MUTATION NEVIRAPINE ZIDOLAM N/ DUOVIR N COMPONENTS K103N,Y181C EMTRICITABINE M184V TENOFOVIR K65R
- 21. Higher Mortality and Disease Progression in MDR HIV • Drug-resistant virus associated with poorer prognosis and higher mortality • Factors correlating with increased risk of death – Lower CD4+ cell count ― Higher viral load – Treatment history with greater number of anti-HIV agents – Earlier diagnosis of MDR HIV Class-Wide Resistance Mutations Parameter, % 0 1 2 3 P Value All-cause death 8.9 11.7 13.4 27.1 .0286 AIDS-related death 6.1 9.9 13.4 21.5 .0299 New AIDS event or death 16.0 17.7 19.3 35.9 .0155 Zaccarelli M, et al. AIDS. 2005;19:1081-1089.
- 22. CASE 1 • • • • • Mr A.B Resident of Phaltan, married with two kids Farmer by occupation Occasional Smoker Was diagnosed HIV-1 positive in March 2008 when he suffered from disseminated TB • Pt was put on 4 drug ATT, Septran and responded well • Investigations done were as follows :
- 23. INVESTIGATIONS Haemoglobin 12.3 g/dl T. Bil 1 mg/dl TLC 6500 cells/mm3 D. Bil 0.3 mg/dl Lymphocyte count 2500 cells/mm3 I.Bil 0.7 mg/dl Platelet count 189,000 AST/ALT 34/34 BUN 20 mg/dl CD4 132 cells/mm3 Creat 1 mg/dl CD8 987 cells/mm3 HBsAg Positive XRC P/A Lower zone infiltrates VDRL negative USG Abdomen Mesentric lymphadenopathy
- 24. Further course • Pt was started on Zidovudine/Lamivudine in July 2008 along with ATT • Pt was shifted to Zidovudine/Lamivudine/Nevirapine in October 2008 by his physician on completion of his ATT • Pt took treatment extremely regularly over the next 6 months although he was having AZT induced gastritis and myalgia • He presented to Noble Hospital, Pune in April 2009 • His investigations revealed :
- 25. INVESTIGATIONS Haemoglobin 10.1 g/dl T. Bil 1.1 mg/dl TLC 6500 cells/mm3 D. Bil 0.3 mg/dl Lymphocyte count 1600 cells/mm3 I.Bil 0.8 mg/dl Platelet count 549,000 AST/ALT 84/114 BUN 32 mg/dl CD4 32 cells/mm3 Creat 1.2 mg/dl PVL+ 123,000 copies/ml HBsAg Positive XRC P/A WNL VDRL negative USG Abdomen WNL
- 26. QUESTIONS • • • • • • What type of ART failure does the pt. have ? Virologic failure Immunologic failure Clinical failure Virologic + Immunologic failure All of the above
- 27. QUESTIONS • What will be your next step ? • Pt has failed 1st line therapy change to second line therapy immediately • Continue same treatment • Do a genotypic resistance testing pending which shift the pt to 2nd line ART • Refer the pt to a ID specialist
- 28. Further course • Plasma viral load is reconfirmed and the value is 125,000 copies/ml • Pt was willing to submit his plasma sample for Genotypic HIV-1 resistance testing • Pt is counseled about need for second line ART regimen and was willing for the same
- 29. QUESTIONS • What are the precautions to be taken while sending plasma sample of pt for genotypic resistance testing ? • Resistance testing should be done when pt is on failing ART regimen or within 4 weeks of discontinuation • Might not detect resistance mutations when viral load is very low i.e < 5000 copies/ml • Might not detect minority variants
- 30. Genotypic resistance testing • HIV-1 subtype C • NRTI : M184V • NNRTI : K103N • PI : None
- 31. Common reverse transcriptase inhibitor resistance (NRTI/NtRTI/NNRTI) mutations TYPE OF DRUG DRUGS INCLUDED SIGNATURE MUTATIONS THYMIDINE ANALOGS ZIDOVUDINE 41L, 67N,70R,210W,215Y,219Q (TAM’s) STAVUDINE 41L, 67N,70R,210W,215Y,219Q NON-THYMIDINE ANALOGS TENOFOVIR K65R ABACAVIR L74V,K65R DIDANOSINE L74V,K65R NEVIRAPINE K103N,Y181C EFAVIRENZ K103N,Y181C LAMIVUDINE M184V NNRTI NRTI EMTRICITABINE
- 32. QUESTIONS • M184V mutation confers hypersusceptibility to which NRTI/NtRTIs ? • Zidovudine • Stavudine • Tenofovir • All of the above
- 33. QUESTIONS • Which nucleoside/nucleotide analogue is most likely to retain maximum activity in this pt ? • Zidovudine • Didanosine • Abacavir • Tenofovir
- 34. QUESTIONS • Would you keep lamivudine/Emtricitabine in second line ART regimen ? • What would be the preferred second line ART regimen in above pt ?
- 35. Further course • Pt was started on Tenofovir/Emtricitabine/Lopinavir/Ritonavir as second line regimen • He tolerated the regimen well and investigations done in December 2009 were as follows : • CD4 count : 323 cells/mm3 • Plasma viral load < 400 copies/ml • Serum Creatinine – 1.2 mg/dl
- 36. CASE 2 • • • • • Mr X.Y Resident of Pune, married with 3 kids Police constable by occupation Heavy drinker and chain smoker Was diagnosed HIV-1 positive in May 2003 when he went for routine health check • Investigations done were as follows :
- 37. INVESTIGATIONS Haemoglobin 9.3 g/dl T. Bil 1.3 mg/dl TLC 10500 cells/mm3 D. Bil 1 mg/dl Lymphocyte count 3500 cells/mm3 I.Bil 0.6 mg/dl Platelet count 413,000 AST/ALT 83/31 BUN 32 mg/dl CD4 66 cells/mm3 Creat 0.6 mg/dl CD8 432 cells/mm3 HBsAg Negative XRC P/A WNL VDRL negative USG Abdomen WNL
- 38. Further course • Pt was started on Zidovudine/Lamivudine/Nevirapine in May 2003 • Pt took treatment extremely regularly but developed AZT induced anemia in November 2003 • Pt was shifted to Stavudine/Lamivudine/Nevirapine which he continued to take till July 2010 • During episodes of binge drinking pt used to skip ART • Pt also gave history of taking drugs once daily instead of twice daily when on official duty • His self reported adherence was around 75 % • He presented to Ruby Hall Clinic, Pune in July 2010 with h/o high grade fever,anorexia,wt. loss since 20 days • His past investigations revealed :
- 40. INVESTIGATIONS Haemoglobin 10.7 g/dl T. Bil 1.3 mg/dl TLC 14300 cells/mm3 D. Bil 1 mg/dl Lymphocyte count 6700 cells/mm3 I.Bil 0.3 mg/dl Platelet count 549,000 AST/ALT 96/31 BUN 32 mg/dl CD4 4 cells/mm3 Creat 0.6 mg/dl Plasma viral load 111,000 copies/ml HBsAg Negative VDRL negative XRC P/A WNL USG Abdomen WNL HRCT chest Mediastinal necrotic lymphadenopathy CT abdomen Splenic microabcesses
- 41. FINAL DIAGNOSIS • 1ST LINE ART FAILURE WITH DISSEMINATED TUBECULOSIS
- 42. QUESTIONS • What will be the drugs to be included in antitubercular regimen of this patient ? • When will you initiate second line antiretroviral therapy in this pt ? • What dose of rifabutin is recommended to be used with Lopinavir-Ritonavir ?
- 43. Timing of ART initiation in patients with tuberculosis CD4 count < 50 cells /mm3 Time to initiate antiretroviral therapy within 2 weeks 50 – 200 cells/mm3 (low Karnofsky 2-4 weeks score, body mass index, haemoglobin, or albumin, organ system dysfunction) 50 – 200 cells/mm3 (no severe markers) 200 – 500 cells/mm3 Within 8-12 weeks > 500 cells/mm3 Within 8-12 weeks Tubercular meningitis irrespective of CD4 count Delay ART till meningitis under control Within 8-12 weeks
- 44. Recommendations for Coadministering Antiretroviral Drugs with RIFAMPICIN DRUG WITH WHICH RIFAMPIN IS COADMINISTERED DOSE OF COADMINISTERED DRUG DOSE OF RIFAMPIN EFAVIRENZ 600 mg/day (recommend NO CHANGE 800 mg for patients > 50 kg) NEVIRAPINE 200 mg twice daily NO CHANGE RITONAVIR BOOSTED INDINAVIR should not be used together should not be used together RITONAVIR BOOSTED ATAZANAVIR should not be used together should not be used together RITONAVIR BOOSTED LOPINAVIR should not be used together should not be used together • SQV 400/RTV 400, LPV/RTV 4 tab BD, Super boosted LPV/RTV
- 45. Recommendations for Coadministering Antiretroviral Drugs with RIFABUTIN DRUG WITH WHICH RIFABUTIN IS CO-ADMINISTERED DOSE OF RIFABUTIN EFAVIRENZ 450-600 mg/day NEVIRAPINE 300 mg/day RITONAVIR BOOSTED DARUNAVIR 150 mg daily RITONAVIR BOOSTED ATAZANAVIR 150 mg daily RITONAVIR BOOSTED LOPINAVIR 150 mg daily
- 46. Genotypic resistance testing report • NRTI : M41L, D67N, M184V, T215Y, K219Q • NNRTI : Y181C, H221Y, Y318F • PI : none
- 47. Common reverse transcriptase inhibitor resistance (NRTI/NtRTI/NNRTI) mutations TYPE OF DRUG DRUGS INCLUDED SIGNATURE MUTATIONS THYMIDINE ANALOGS ZIDOVUDINE 41L, 67N,70R,210W,215Y,219Q STAVUDINE 41L, 67N,70R,210W,215Y,219Q TENOFOVIR K65R ABACAVIR L74V,K65R DIDANOSINE L74V,K65R NEVIRAPINE K103N,Y181C EFAVIRENZ K103N,Y181C LAMIVUDINE M184V NON-THYMIDINE ANALOGS NNRTI NRTI EMTRICITABINE
- 48. Genotypic resistance testing report DRUG MUTATION SCORE DRUG MUTATION SCORE ZIDOVUDINE 68 NELFINAVIR 0 STAVUDINE 62 INDINAVIR 0 LAMIVUDINE 68 ATAZANAVIR 0 TENOFOVIR 25 LOPINAVIR 0 ABACAVIR 45 DARUNAVIR 0 DIDANOSINE 52 SAQUINAVIR 0 NEVIRAPINE 90 EFAVIRENZ 40
- 49. QUESTIONS • What are Thymidine analog mutation (TAM) pathways and why are they important? • 41L, 67N,70R,210W,215Y,219Q • 41,210,215 pathway • 67,70,219 pathway
- 50. QUESTIONS • What will be the second line ART regimen chosen for this pt ? • What are the recommended PI regimens for second line therapy ?
- 51. Further course • Pt was started on Tenofovir/Emtricitabine/Lopinavir/Ritonavir as second line regimen • He tolerated the regimen well and investigations done in Jan 2011 were as follows : • CD4 count : 493 cells/mm3 • Plasma viral load < 400 copies/ml • Serum Creatinine – 0.8 mg/dl
- 52. CASE 3 • • • • • Mr G.B Resident of Dhule, married Businessman by occupation Tobacco chewer Was diagnosed HIV-1 positive in April 2009 when he went to a dermatologist regarding recurrent penile ulcers and oral apthous ulcers • Investigations done were as follows :
- 53. INVESTIGATIONS Haemoglobin 11.1 g/dl T. Bil 0.5 mg/dl TLC 4600 cells/mm3 D. Bil 0.2 mg/dl Lymphocyte count 1600 cells/mm3 I.Bil 0.3 mg/dl Platelet count 138,000 AST/ALT 84/34 BUN 27 mg/dl CD4 132 cells/mm3 Creat 1.3 mg/dl CD8 1148 cells/mm3 HBsAg NEGATIVE XRC P/A WNL VDRL negative USG Abdomen WNL
- 54. Further course • • • • • • • Pt was started on Stavudine/Lamivudine/Nevirapine in January 2009 Pt developed severe itching and erythematous rash within 15 days of starting treatment and took tablets alternate day for 20 days and then stopped them altogether Pt presented to local physician in April 2009 who shifted him to Tenofovir/Emtricitabine/Efavirenz which he continued to take till December 2009 Pt took the treatment extremely regularly and had no side-effects His self reported adherence was around 95 % He presented in January 2010 with h/o weight loss of 5 kgs over 1 month His investigations revealed :
- 55. INVESTIGATIONS Haemoglobin 8.7 g/dl T. Bil 1.3 mg/dl TLC 10300 cells/mm3 D. Bil 0.3 mg/dl Lymphocyte count 5700 cells/mm3 I.Bil 1 mg/dl Platelet count 143,000 AST/ALT 23/31 BUN 32 mg/dl CD4 14 cells/mm3 Creat 0.6 mg/dl Plasma viral load 141,000 copies/ml HBsAg Negative Serum Cryptococcal Antigen negative XRC P/A WNL USG Abdomen WNL HRCT chest WNL CT abdomen WNL
- 56. Genotypic resistance testing report • NRTI : K65R, K70T, M184V • NNRTI : V90I, L100I, K103N, V108IV • PI : none
- 57. Common reverse transcriptase inhibitor resistance (NRTI/NtRTI/NNRTI) mutations TYPE OF DRUG DRUGS INCLUDED SIGNATURE MUTATIONS THYMIDINE ANALOGS ZIDOVUDINE 41L, 67N,70R,210W,215Y,219Q STAVUDINE 41L, 67N,70R,210W,215Y,219Q TENOFOVIR K65R ABACAVIR L74V,K65R DIDANOSINE L74V,K65R NEVIRAPINE K103N,Y181C EFAVIRENZ K103N,Y181C LAMIVUDINE M184V NON-THYMIDINE ANALOGS NNRTI NRTI EMTRICITABINE
- 58. Genotypic resistance testing report DRUG MUTATION SCORE DRUG MUTATION SCORE ZIDOVUDINE -12 NELFINAVIR 0 STAVUDINE 15 INDINAVIR 0 LAMIVUDINE 90 ATAZANAVIR 0 TENOFOVIR 28 LOPINAVIR 0 ABACAVIR 42 DARUNAVIR 0 DIDANOSINE 35 SAQUINAVIR 0 NEVIRAPINE 110 EFAVIRENZ 110
- 59. QUESTIONS • What will be the second line ART regimen chosen for this pt ? • What is the commonest side-effect of Atazanavir- ritonavir ?
- 60. Further course • Pt was started on Zidovudine/Lamivudine/Tenofovir/Atazanavir/ Ritonavir as second line regimen • He tolerated the regimen well and investigations done in Sept 2010 were as follows : • CD4 count : 189 cells/mm3 • Plasma viral load < 400 copies/ml • Serum Creatinine – 0.6 mg/dl • T.Bil – 4.3 • I.Bilirubin – 3.7 • SGPT/SGOT- 39/37
- 61. CASE 4 • • • • • Mr S.J Resident of Akluj, married Farmer by occupation Non- addict Was diagnosed HIV-1 positive in June 2004 when he was admitted for pile banding surgery at Solapur • Investigations done were as follows :
- 62. INVESTIGATIONS Haemoglobin 7.1g/dl T. Bil 0.8 mg/dl TLC 4500 cells/mm3 D. Bil 0.5 mg/dl Lymphocyte count 2200 cells/mm3 I.Bil 0.3 mg/dl Platelet count 643,000 AST/ALT 14/34 BUN 34 mg/dl CD4 201 cells/mm3 Creat 0.7 mg/dl CD8 1029 cells/mm3 HBsAg negative XRC P/A WNL VDRL negative USG Abdomen WNL
- 63. Further course • • • • • • • • • • • • Pt was started on Zidovudine/Lamivudine/Nevirapine in July 2004 Pt continued treatment till January 2008 His self reported adherence was around 80 % He used to take multiple gaps in treatment especially during visits to other villages for work He was also unhappy with the gastritis and myalgia he developed on consuming ART tablets. Pt’s CD4 count done in January 2008 was 219 cells/mm 3 He was shifted to Tenofovir/Emtricitabine/Efavirenz by local physician in January 2008 He took treatment extremely regularly till July 2008 His repeat CD4 count done was 159 cells/mm3 Pt was disappointed by falling CD4 count and stopped all drugs He presented to Noble Hospital, Pune in May 2009 Pt was asymptomatic on presentation
- 64. INVESTIGATIONS Haemoglobin 9.6g/dl T. Bil 0.9 mg/dl TLC 2300 cells/mm3 D. Bil 0.6 mg/dl Lymphocyte count 1200 cells/mm3 I.Bil 0.3 mg/dl Platelet count 419,000 AST/ALT 54/44 BUN 21 mg/dl CD4 78 cells/mm3 Creat 0.5 mg/dl CD8 1349 cells/mm3 HBsAg negative XRC P/A WNL Cryptococcal Antigen negative USG Abdomen WNL
- 65. QUESTIONS • What will be your next step ? • What will be the second line ART regimen chosen for this pt ?
- 66. Further course • Pt was started on Stavudine/Lamivudine/Tenofovir/Atazanavir/ Ritonavir as second line regimen • He tolerated the regimen well and investigations done in Feb 2010 were as follows : • CD4 count : 514 cells/mm3 • Plasma viral load < 400 copies/ml • Serum Creatinine – 0.9 mg/dl
- 67. CASE 5 • • • • • Mr R.M. Resident of Belgaon, married businessman by occupation Non- addict Was diagnosed HIV-1 positive in June 1998 when he was admitted for Road traffic accident at local hospital • Investigations done were as follows :
- 68. INVESTIGATIONS Haemoglobin 13.5g/dl T. Bil 1.1 mg/dl TLC 14500 cells/mm3 D. Bil 0.5 mg/dl Lymphocyte count 8200 cells/mm3 I.Bil 0.6 mg/dl Platelet count 315000 AST/ALT 14/34 BUN 48 mg/dl CD4 345 cells/mm3 Creat 1.2 mg/dl CD8 1176 cells/mm3 HBsAg negative XRC P/A WNL VDRL Not done USG Abdomen WNL
- 69. Further course • • • • Pt was started on Zidovudine/Lamivudine in July 1998 Pt continued treatment extremely regularly till May 2005 His self reported adherence was around 100 % Serial investigations were as follows : DATE 21/1/2003 166 141 85 CD8 2787 976 946 Plasma viral load • 18/9/2011 CD4 • 10/10/2000 73551 79443 88200 Pt was started on Stavudine/Lamivudine/Nevirapine in June 2005 which he continued to take regularly till July 2009 Investigations done during that period were as follows :
- 70. Further course DATE 12/10/2007 14/11/2008 CD4 103 CD8 885 Plasma viral load 13400 750000 • He was shifted to Tenofovir/Emtricitabine/Efavirenz by local physician in July 2009 • He took treatment extremely regularly till March 2010 when he was admitted in Poona Hospital with chronic diarrhea (cryptosporidial) • His repeat CD4 count done was 37 cells/mm3 and Plasma viral load >750000 copies/ml
- 71. Genotypic resistance testing report • NRTI : M41L, E44D, D67N, M184V, L210W, T215Y, K219N • NNRTI : K101P, Y188L • PI : none
- 72. Genotypic resistance testing report DRUG MUTATION SCORE DRUG MUTATION SCORE ZIDOVUDINE 79 NELFINAVIR 0 STAVUDINE 89 INDINAVIR 0 LAMIVUDINE 77 ATAZANAVIR 0 TENOFOVIR 28 LOPINAVIR 0 ABACAVIR 66 DARUNAVIR 0 DIDANOSINE 77 SAQUINAVIR 0 NEVIRAPINE 100 EFAVIRENZ 100
- 73. Further course • Pt was started on Tenofovir/Emticitabine/Lopinavir/Ritonavir in March 2010 • His diarrhea subsided and he started improving clinically with 8 kg weight gain in 6 months • We repeated investigations in October 2010 which were as follows
- 74. INVESTIGATIONS Haemoglobin 12.9g/dl T. Bil 1.1 mg/dl TLC 6800 cells/mm3 D. Bil 0.5 mg/dl Lymphocyte count 1100 cells/mm3 I.Bil 0.6 mg/dl Platelet count 198000 AST/ALT 14/34 BUN 21 mg/dl CD4 66 cells/mm3 Creat 1.1 mg/dl CD8 796 cells/mm3 Viral load 87500
- 75. Genotypic resistance testing report • NRTI : M41L, D67N, M184V, L210W, T215Y, K219N • NNRTI : K101Q, Y188L • PI : M46I, I54V, L76V, V82T
- 76. Genotypic resistance testing report DRUG MUTATION SCORE DRUG MUTATION SCORE ZIDOVUDINE 77 NELFINAVIR 99 STAVUDINE 87 INDINAVIR/r 88 LAMIVUDINE 72 ATAZANAVIR/r 43 TENOFOVIR 41 LOPINAVIR/r 76 ABACAVIR 64 DARUNAVIR/r 15 DIDANOSINE 57 SAQUINAVIR 29 NEVIRAPINE 65 EFAVIRENZ 65
- 77. Further course • Pt gave history of being exposed to Tenofovir/Lamivudine/low dose Indinavir/ Ritonavir in 2008 for 6 months which he stopped due to financial constraints • Pt was given an option to start 3rd line ART in form of Darunavir/Ritonavir/Lamivudine/Raltegravir which he started in Jan 2011 • His reports after 6 months of the same were as follows
- 78. Further course • CD4 : 165 cells/mm3 • CD8 : 1729 cells/mm3 • Plasma viral load < 400 copies/ml • Pt has tolerated ART very well and is currently symptom free however is distressed about the stiff cost of treatment
- 79. THANK YOU
Editor's Notes
- ARV, antiretroviral. This slide reviews the causes for antiretroviral treatment failure. There are many factors that affect treatment failure and they are primarily associated with insufficient drug levels. If drug levels are not sufficient, viral replication occurs in the presence of the drug, thereby permitting emergence of resistant virus and subsequent treatment failure. Poor adherence is one cause of insufficient drug levels, but poor adherence has a negative connotation that implies the patient has done something wrong. Frequently, there are social or personal issues that may be out of the patient’s control. For example, if their state of residence closes the AIDS Drug Assistance Program, patients may have difficulty obtaining their medication. There may also be regimen issues, including tolerability problems that do not reach the level of toxicity. In addition, toxicity issues involving serious adverse effects may interrupt therapy. However, there are other reasons for insufficient drug levels. For example, the clinician may choose a regimen with low potency. Alternatively, the wrong dose may be prescribed or dispensed and even though the patient may be perfectly adherent, this suboptimal dose may be the cause for treatment failure. There might be differences in host genetics that affect drug metabolism. Likewise, there might be issues affecting drug absorption. We have also mentioned drug pharmacokinetics and drug-drug interactions. Transmitted resistance is another factor affecting the ability to achieve sufficient drug level. If the patient is infected with an NNRTI-resistant virus, for example, any level of efavirenz will be insufficient. This results in viral replication in the presence of the drug and may lead to emergence of further drug resistance even to other classes of drugs. However, if the patient does not take his or her medication, he or she is unlikely to develop a resistant virus but treatment failure would still occur.
- A study of 623 individuals who had genotype resistance testing during antiretroviral failure demonstrated a heightened risk of death with viral drug resistance. These highly experienced patients had a median 24 months of HAART before genotype testing, and a median of 3 failed regimens. Approximately half of these patients (50.9%) had at least 1 class-wide resistance mutation according to genotype results, and 24 (3.9%) had resistance to all 3 classes. Over 48 months of observation from the time of genotype resistance testing, 28 new AIDS events were documented and 38 deaths occurred, of which 29 were AIDS related. The incidence of death in patients with 0, 1, 2, or 3 class-wide resistance mutations was found to be 3.50, 2.79, 3.97, and 11.90 per 100 person-years of follow-up, respectively. Multivariate statistical analysis correlated triple-class resistance with an increased risk of death (hazard ratio [HR], 5.34; 95% CI, 1.76- 16.24; P < .01); AIDS-related death (HR, 4.14; 95% CI, 1.17-14.68; P = .03); and new AIDS diagnosis or death (HR, 5.36; 95% CI, 2.16-13.32; P < .01). Other factors associated with increased morbidity and mortality were higher current HIV-1 RNA level and pregenotype AIDS diagnosis. Higher CD4+ cell count at the time of genotype resistance testing significantly reduced the risk of death.