Antiretroviral therapy failure

ANTIRETROVIRAL THERAPY IN 2012 AND ANTIRETROVIRAL THERAPY RESISTANCE

DR AMEET DRAVIDM.D (Med) AAHIVS (USA)

RUBY HALL CLINIC and NOBLE HOSPITAL,PUNE

Antiretrovirals approved for useNRTI 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/Ritonavir

Tenofovir(TDF) Lopinavir/Ritonavir

Emtricitabine(FTC) Darunavir

Tipranavir

Fosamprenavir

When to start ?

NACO GUIDELINES 2012Classification ofHIV-associated clinical disease

WHO STAGE CD4 NOT AVAILABLE

CD4 AVAILABLE

Asymptomatic 1 Do not treatTreat 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

API-ART Guidelines : When to start ?Classification of

HIV-associated clinical disease

WHO STAGE CD4 AVAILABLE

Asymptomatic 1 CD4 <350 /mm3

Initiate ART

CD4 > 350/mm3 Defer unlessHBV/HCV Rx HIV nephropathyCytotoxic therapy

Mild symptoms 2

Advanced symptoms 3Treat irrespective of CD4

countSevere/advanced symptoms

4

When to Start: 2012 DHHS Guidelines

WHAT TO START ?

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

API-ART GUIDELINES 2008: WHAT TO START ?

• NRTI• Preferred • Tenofovir + Lamivudine• Abacavir + Lamivudine• Zidovudine + Lamivudine • Alternative • Stavudine + Lamivudine• Didanosine + Lamivudine

• NNRTI• Preferred• Efavirenz • Nevirapine

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

Monitoring patients on antiretroviral therapy

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

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

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)

Resistant virus

Insufficient drug level

Social/personal issues

Regimen issues

Toxicities

Poor potency

Wrong dose

Host genetics

Poor absorption

Drug pharmacokinetics

Transmitted resistance

Drug interactions

Poor adherence

Viral replication in thepresence of drug

Causes of ARV Treatment Failure

ART resistance testing. AETC National Resource Center.

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.

Assessing treatment failiure

• Genotypic resistance testing• Phenotypic resistance testing• Virtual phenotype

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

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

NNRTI NEVIRAPINE K103N,Y181C

EFAVIRENZ K103N,Y181C

NRTI LAMIVUDINE M184V

EMTRICITABINE

Dynamics of resistance development

DRUG COMPONENTS RESISTANCE MUTATION

NEVIRAPINE K103N,Y181C

ZIDOLAM N/ DUOVIR N LAMIVUDINE M184V

ZIDOVUDINE TAM’s


TRUSTIVA/VIRADAY EMTRICITABINE M184V

TENOFOVIR K65R

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

Zaccarelli M, et al. AIDS. 2005;19:1081-1089.

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

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 :

INVESTIGATIONSHaemoglobin 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

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 :

INVESTIGATIONSHaemoglobin 10.1 g/dl T. Bil 1.1 mg/dl





Creat 1.2 mg/dl PVL+ 123,000 copies/ml

HBsAg Positive XRC P/A WNL

VDRL negative USG Abdomen WNL

QUESTIONS

• What type of ART failure does the pt. have ?• Virologic failure• Immunologic failure• Clinical failure• Virologic + Immunologic failure• All of the above

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

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

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

Genotypic resistance testing

• HIV-1 subtype C

• NRTI : M184V

• NNRTI : K103N

• PI : None




(TAM’s) STAVUDINE 41L, 67N,70R,210W,215Y,219Q


ABACAVIR L74V,K65R





EMTRICITABINE

QUESTIONS

• M184V mutation confers hypersusceptibility to which NRTI/NtRTIs ?

• Zidovudine• Stavudine• Tenofovir• All of the above

QUESTIONS

• Which nucleoside/nucleotide analogue is most likely to retain maximum activity in this pt ?

• Zidovudine• Didanosine• Abacavir• Tenofovir

QUESTIONS

• Would you keep lamivudine/Emtricitabine in second line ART regimen ?

• What would be the preferred second line ART regimen in above pt ?

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

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 :


TLC 10500 cells/mm3 D. Bil 1 mg/dl




Creat 0.6 mg/dl CD8 432 cells/mm3

HBsAg Negative XRC P/A WNL


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 :

INVESTIGATIONSDATE 1/4/2005 10/8/2007 27/12/2008

CD4 83 100 53

CD8 1586 2101 1455

PVL Not done Not done Not done


TLC 14300 cells/mm3 D. Bil 1 mg/dl




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

FINAL DIAGNOSIS

• 1ST LINE ART FAILURE WITH DISSEMINATED TUBECULOSIS

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 ?

Timing of ART initiation in patients with tuberculosis

CD4 count Time to initiate antiretroviral therapy

< 50 cells /mm3 within 2 weeks

50 – 200 cells/mm3 (low Karnofsky score, body mass index, haemoglobin, or

albumin, organ system dysfunction)

2-4 weeks

50 – 200 cells/mm3 (no severe markers)

Within 8-12 weeks

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

Recommendations for Coadministering Antiretroviral Drugs with RIFAMPICIN

• SQV 400/RTV 400, LPV/RTV 4 tab BD, Super boosted LPV/RTV

DRUG WITH WHICH RIFAMPIN IS CO-

ADMINISTERED

DOSE OF CO-ADMINISTERED DRUG

DOSE OF RIFAMPIN

EFAVIRENZ 600 mg/day (recommend 800 mg for patients > 50 kg)

NO CHANGE

NEVIRAPINE 200 mg twice daily NO CHANGE

RITONAVIR BOOSTED INDINAVIR

should not be used together


RITONAVIR BOOSTED ATAZANAVIR



RITONAVIR BOOSTED LOPINAVIR



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

Genotypic resistance testing report

• NRTI : M41L, D67N, M184V, T215Y, K219Q

• NNRTI : Y181C, H221Y, Y318F

• PI : none




STAVUDINE 41L, 67N,70R,210W,215Y,219Q


ABACAVIR L74V,K65R





EMTRICITABINE

Genotypic resistance testing reportDRUG 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

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

QUESTIONS

• What will be the second line ART regimen chosen for this pt ?

• What are the recommended PI regimens for second line therapy ?


Tenofovir/Emtricitabine/Lopinavir/Ritonavir as second line regimen

• He tolerated the regimen well and investigations done in Jan 2011 were as follows :



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 :







HBsAg NEGATIVE XRC P/A WNL


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 :



Lymphocyte count 5700 cells/mm3 I.Bil 1 mg/dl



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


• NRTI : K65R, K70T, M184V

• NNRTI : V90I, L100I, K103N, V108IV

• PI : none




STAVUDINE 41L, 67N,70R,210W,215Y,219Q


ABACAVIR L74V,K65R





EMTRICITABINE


ZIDOVUDINE -12 NELFINAVIR 0






NEVIRAPINE 110

EFAVIRENZ 110

QUESTIONS


• What is the commonest side-effect of Atazanavir- ritonavir ?


Zidovudine/Lamivudine/Tenofovir/Atazanavir/ Ritonavir as second line regimen

• He tolerated the regimen well and investigations done in Sept 2010 were as follows :


• Plasma viral load < 400 copies/ml• Serum Creatinine – 0.6 mg/dl• T.Bil – 4.3• I.Bilirubin – 3.7• SGPT/SGOT- 39/37

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 :

INVESTIGATIONSHaemoglobin 7.1g/dl T. Bil 0.8 mg/dl






HBsAg negative XRC P/A WNL


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/mm3

• 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








Cryptococcal Antigen

negative USG Abdomen WNL

QUESTIONS

• What will be your next step ?



Stavudine/Lamivudine/Tenofovir/Atazanavir/ Ritonavir as second line regimen

• He tolerated the regimen well and investigations done in Feb 2010 were as follows :



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 :




Platelet count 315000 AST/ALT 14/34




VDRL Not done USG Abdomen WNL

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 :

• 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 :

DATE 10/10/2000 18/9/2011 21/1/2003

CD4 166 141 85

CD8 2787 976 946

Plasma viral load

73551 79443 88200

Further course

• 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

DATE 12/10/2007 14/11/2008

CD4 103

CD8 885

Plasma viral load 13400 750000


• NRTI : M41L, E44D, D67N, M184V, L210W, T215Y, K219N

• NNRTI : K101P, Y188L

• PI : none








NEVIRAPINE 100

EFAVIRENZ 100


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




Platelet count 198000 AST/ALT 14/34



Viral load 87500


• NRTI : M41L, D67N, M184V, L210W, T215Y, K219N

• NNRTI : K101Q, Y188L

• PI : M46I, I54V, L76V, V82T



STAVUDINE 87 INDINAVIR/r 88

LAMIVUDINE 72 ATAZANAVIR/r 43

TENOFOVIR 41 LOPINAVIR/r 76

ABACAVIR 64 DARUNAVIR/r 15


NEVIRAPINE 65

EFAVIRENZ 65

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

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

THANK YOU

Health & Medicine

Antiretroviral therapy failure