Case Discussion: HIV resistance and salvage regimens

The 3rd HIV-NAT Symposium Series

Wasana Prasitsuebsai, MD, MPH25th July 2013

Case 1

• A 6 year-old Thai boy presented at HIV-NAT clinic with poor weight gain and chronic cough and dyspnea. Perinatally HIV infection with lymphocytic interstitial pneumonitis were identified (CDC B).

• d4T/3TC/NVP were initiated and switched to AZT/3TC/NVP when he was 8 year-old.

• His father and mother died since he was young. He lives with grandparents and aunts in the slum. His home is a gambling house.

Progression

Age (years)

BW (kg)

CD4% (CD4 count; cells/mm3)

HIV-RNA (copies/mL)

HAART Remark

6 12 1 (22) 132,000 d4T/3TC/NVP Start treatment

8 15.5 16 (451) <50 AZT/3TC/NVP To prevent LD

13 22.7 21 (472) <40 AZT/3TC/NVP(GPO-vir Z)

14 30.4 19 (439) 149 GPO-vir Z Pill count 66%

14 y 6 m 31.4 21 (411) 2719 GPO-vir Z Pill count 83%

VOTE now

Question

What is next step?1.Continue GPO-vir Z with adherence counselling and

HIV status disclosure2. Switch to once daily regimen (EFV-based HAART)3. Genotypic resistance testing then switch to

second-line HAART 4. Switch to second-line HAART without genotypic

resistance testing

Answer discussion

1. Continue GPO-vir Z with adherence counselling with disclosure Incorrect. HIV disclosure should be considered. Adherence counsellingshould be performed continually. But a failing regimen should not be continued. 2. Switch to once daily regimen (EFV-based HAART)Incorrect3. Genotypic resistance testing then switch to second-line HAARTCorrect 4. Switch to second-line HAART without genotypic resistance testingIncorrect. Genotyping can be performed under the National Program. Genotyping should be performed before switching to the next regimen.

Progression

• Genotypic resistance testing was performed at last visit. His resistance testing identified:– M184V– V108I– Y181C

• Which ARV will be affected by these mutations?

NNRTI Mutations

Question

What should be the best second-line regimen?

1. TDF + AZT + LPV/r

2. TDF + 3TC + LPVr once daily regimen

3. AZT + 3TC + LPV/r

4. TDF + 3TC + ATV/r

VOTE now

Answer Discussion

1. TDF + AZT + LPV/rOptional. Patient has to take ARVs twice daily.

2. TDF + 3TC + LPV/r once daily regimenBest option as this is once daily regimen. It may help to improve adherence to ART.

3. AZT + 3TC + LPV/r Optional. Patient has to take ARVs twice daily.

4. TDF + 3TC + ATV/rATV/r is not co-formulated and harder to take.Not a good option for this child since he had poor adherence.

d4T or AZT + 3TC + NVP or EFV

Select 2NRTI according to genotyping*/ARV history+

1 Protease inhibitor LPV/r (preferred)

ATV/r (alternative)

Treatment Failure

2010 Thai MOPH Guidelines

*Send genotyping when VL > 2000 copies/ml

Recommended Second-line Regiments in Children with Treatment Failure of First-line Regimens

Clinical Progression

Age (years)

BW (kg) CD4% (CD4 count; cells/mm3)

HIV-RNA (copies/mL)

HAART Remark

6 12 1 (22) 132,000 d4T/3TC/NVP Start treatment

8 15.5 16 (451) <50 AZT/3TC/NVP To prevent LD

13 22.7 21 (472) <40 AZT/3TC/NVP(GPO-vir Z)

14 30.4 19 (439) 149 GPO-vir Z Pill count 66%

14 y 6 m 31.4 21 (411) 2719 GPO-vir Z Pill count 83%

15 33.9 3TC/TDF/LPV/r OD

15 y 3 m 36.4 18 (497) <20 3TC/TDF/LPV/r OD Pill count 92%

16 y 40.8 15 (344) 65,870 3TC/TDF/LPV/r OD Pill count 90%

Question

What is your management plan?

1. Follow-up and continue TDF/3TC/LPV/r with adherence counselling and repeat VL next 3 months

2. Switch to a third-line regimen3. Stop ART4. Therapeutic drug monitoring (TDM)5. Genotypic resistance testing

VOTE now

Answer Discussion

1. Follow-up with adherence counselling and repeat VL Correct

2. Switch to a third-line regimenIncorrect

3. Stop ARTIncorrect

4. Therapeutic drug monitoring (TDM)Optional if accessible. TDM can help identify poor adherence.

5. Genotypic resistance testingIncorrect. It should be performed in case of persistent detectable VL

after adherence strengthening.

Progression

• Adherence problem was discussed with patient and his grandfather. Social worker team helped call patient to remind his ARV schedule randomly

• TDF/3TC/LPV/r regimen was continued. VL was repeated every 6 months

• Genotypic resistance testing was performed with TDM at next visit. Results revealed:– LPV Cmin level – undetectable– RTV Cmin level – undetectable– Resistance: no NRTI, NNRTI and PI mutations identified

Progression

• Adherence problem was discussed with patient and his grandfather. Social worker team helped call patient to remind his ARV schedule randomly.

• TDF/3TC/LPV/r regimen was continued. VL was repeated every 6 months.

• Genotypic resistance testing was performed with TDM at next visit. Results revealed:– LPV Cmin level – undetectable– RTV Cmin level – undetectable– Resistance: no NRTI, NNRTI and PI mutations identified

What should we do next?

Case 2

• A 15 years 6 months boy with perinatally HIV infection • Refer to HIV-NAT after failing the 2nd line regimen• BW 38 kg, height 159 cm• CDC A, No active HIV-related illness

Age ART Start-Stop Date Reason to Stop

2 AZT monotherapy 1998-2004 Switched to HAART

8 d4T/3TC/NVP 2004-2005 Unknown

9 d4T/3TC/EFV 2005-2006 Virologic failure

10 d4T/3TC/NFV 2006-2007 Virologic failure

11 IDV/LPV/r 2007-2011 IDV toxicity

15 3TC/LPV/r 2011-going on

CD4, VL and Genotypic Resistant Mutations

• The patient were receiving 3TC plus LPV/r

Date Age (yr) ART CD4% (cells/mm3) HIV RNA (copies/ml)

Feb 2009 13 IDV/LPV/r 30 (963) <40

Jan 2011 15 3TC/LPV/r 26 (596) 52,200

Mar 2011 15 3TC/LPV/r 18 (284) 86,800

Mutations

NRTI M41L, D67N, T69D, K70R, M184V, K219Q

NNRTI A98G, K101H, Y181C, G190A

PI L10F, K20R, L33I, M36I, M46L, I54V, T74S, N83D, I84V

Genotypic Mutations

What is your third-line HAART for this patient?

1. ddI/3TC/darunavir/r

2. TDF/3TC/darunavir/r

3. TDF/3TC/etravirine/darunavir/r

4. TDF/3TC/darunavir/r/raltegravir

Mutations

NRTI M41L, D67N, T69D, K70R, M184V, K219Q

NNRTI A98G, K101H, Y181C, G190A

PI L10F, K20R, L33I, M36I, M46L, I54V, T74S, N83D, I84V

•69 insertion complex + TAMs at 41, 210 or 215•151 complex (Q151M+others, TDF not resistant)•Multi-NRTI resistance (≥ 4 thymidine analog mutations)

Johnson VA, Topics in Antiviral medicine, March 2013

Multi-NRTI Mutations

NRTI Mutations

•K65R = tenofovir resistance (mainly selected by TDF, d4T)•AZT prevents K65R when used with TDF•M184V = 3TC, FTC resistance (delays TAMs)•TAMs = M41L, D67N, K70R, L210W, T215Y/F, K219Q/E

NNRTI Mutations

•Resistance to NVP and EFV = require 1 major mutation•Universal cross resistance between NVP and EFV•Resistance to etravirine = require > 1 major mutation•K103N = no resistance to etravirine

PI Mutations

•Multiple mutations required for reduced activity •ATV/r and LPV/r have different patterns of resistance•DRV = negative impact by I47V (LPV), I84V (ATV) •but positive impact by V82A (LPV)

Answer Discussion

1. ddI/3TC/darunavir/rIncorrect

2. TDF/3TC/darunavir/rCorrect

3. TDF/3TC/etravirine/darunavir/rIncorrect. ETR score is 6.

4. TDF/3TC/darunavir/r/raltegravirThe best option

Progression

Date ART CD4% (cells/mm3)

HIV RNA (copies/ml)

Remark

Mar 2011 3TC/LPV/r 18 (284) 86,800

Jan 2012 3TC/LPV/r 16 (288) 104,201 Refer to HIV-NAT

Feb 2012 TDF/3TC/DRV/r

May 2012 TDF/3TC/DRV/r 17 (302) 24705 Pill count 99%

Aug 2012 TDF/3TC/DRV/r 19 (314) 45849 Pill count 99%

What is your management?1. Continue TDF/3TC/DRV/r with VL monitoring and adherence counseling2. Perform genotypic resistance testing3. Add AZT and RAL4. Add ETR, RAL and AZT

PI MutationsMajor V32I, M46L, I54L, I84V

Minor L10F, L33I, N83D

Others I13V, L19LV, A22V, E35D, M36I, R41K, I62IV, I64V, H69K, K70KR, G73DG, T74S, I85IV, L89I, T91s

Progression

Date ART CD4% (cells/mm3)

HIV RNA (copies/ml) Remark

Mar 2011 3TC/LPV/r 18 (284) 86,800

Jan 2012 3TC/LPV/r 16 (288) 104,201 Refer to HIV-NAT

Feb 2012 TDF/3TC/DRV/r

May 2012 TDF/3TC/DRV/r 17 (302) 24705 Pill count 99%

Aug 2012 TDF/3TC/DRV/r 19 (314) 45849 Pill count 99%

Jan 2013 AZT/TDF/3TC/RAL/DRV/r

Apr 2013 AZT/TDF/3TC/RAL/DRV/r 20 (308) <20

Take Home Message

• Children have fewer ARV options than adults especially for treatment of first- and second-line treatment failure.

• TDF may be used in children with multi NRTI failure who do not have K65R and have wt>30 kg or Tanner >4.

• Use of new drugs should be done with expert advice. • Viral load monitoring after switching to a new

regimen is recommended to detect early failure.

Back Up Case

Case 3

• A 12 year-old HIV-infected girl• CDC clinical classification B (TB lung)• Underlying Homozygous HbE disease• Live with parents, good adherence to ARVs, disclosed by mom• Hb 9.4%, CD4 34% (1085), VL 3370 copies/mL

Age (years) ART

2 ddI / AZT

4 d4T / 3TC / NVP

9 AZT / 3TC / NVP

12 3TC

Genotypic Mutations

Mutations

NRTI M41L, D67N, L210W, T215Y, K219E, M184V

NNRTI K103N

What is your second-line HAART for this patient?

1. TDF + AZT + LPV/r

2. TDF + 3TC + LPVr

3. ABC + ddI + LPV/r

4. ABC + 3TC + LPV/r

•69 insertion complex + TAMs at 41, 210 or 215•151 complex (Q151M+others, TDF not resistant)•Multi-NRTI resistance (≥ 4 thymidine analog mutations)

Johnson VA, Topics in Antiviral medicine, March 2013

Multi-NRTI Mutations

NRTI Mutations

•K65R = tenofovir resistance (mainly selected by TDF, d4T)•AZT prevents K65R when used with TDF•M184V = 3TC, FTC resistance (delays TAMs)•TAMs = M41L, D67N, K70R, L210W, T215Y/F, K219Q/E

NNRTI Mutations

•Resistance to NVP and EFV = require 1 major mutation•Universal cross resistance between NVP and EFV•Resistance to etravirine = require > 1 major mutation•K103N = no resistance to etravirine

Answer Discussion

1. TDF + AZT + LPV/rIncorrect. Patient had anemia.

2. TDF + 3TC + LPVr Correct

3. ABC + ddI + LPV/rOptional (ABC is not available through the National Program)

4. ABC + 3TC + LPV/rOptional

Progression

• ART was switched to TDF/3TC/LPV/r BID regimen

Month of 2nd line HAART

BW (kg)CD4%

(CD4 count; cells/mm3)HIV-RNA

(copies/mL)

0 41 40 (971) 5552

3 41 35 (1298) <40