Interesting Cases in HIV Medicine Jehan Budak, MD Medical - - PDF document

12/14/19 1

Interesting Cases in HIV Medicine

Jehan Budak, MD Medical Management of HIV/AIDS December 14, 2019 jehan@uw.edu

1

Disclosures

• I have nothing to disclose.

2

12/14/19 2

Roadmap

• ART with M184V
• Anticoagulants and ART
• Doravirine as Salvage
• A Modern Toxo Tale

3

Roadmap

• AR

ART T with M184V

• Anticoagulants and ART
• Doravirine as Salvage
• A Modern Toxo Tale

4

12/14/19 3

Case 1

5

Case 1

• 53M with HIV comes in for regularly scheduled follow-up
• Last CD4 683 cells/mm3, HIV RNA <40 copies/mL
• On TAF/FTC/RPV + DTG since 2016
• HIV History
• Diagnosed 12/2002, started 3TC/AZT + NFV, complicated by nausea/vomiting
• 4/2003 HIV RNA 16K copies/mL, genotype with M184V mutation
• Switched to new regimen and HIV RNA has been suppressed since then
• He has been hesitant to simplify his ART

6

12/14/19 4

ARS: What would you do with his ART in light

• f the M184V?
• A. Continue current regimen (TAF/FTC/RPV + DTG)
• B. Simplify to TAF/FTC/RPV alone
• C. Switch to TAF/FTC + DTG
• D. Switch to BIC/TAF/FTC
• E. Switch to TAF/FTC/c/DRV
• F. Switch to ABC/3TC/DTG

7

What would you do with his ART in light of the M184V?

• A. Continue current regimen (TAF/FTC/RPV + DTG)
• B. Simplify to TAF/FTC/RPV alone
• C. Switch to TAF/FTC + DTG
• D. Switch to BIC/TAF/FTC
• E. Switch to TAF/FTC/c/DRV
• F. Switch to ABC/3TC/DTG

What is the data for use of these ARVs with an M184V?

8

12/14/19 5

Option C: Switch to TAF/FTC + DTG

• Background
• DAWNING (IAS 2017): In 627 patients worldwide failing NNRTI therapy, when

paired with ≥ 1 active NRTI, DTG was superior to r/LPV as salvage

• DAWNING sub-analysis (CROI 2019): Looked at different NRTI mutations and

the impact of those mutations on ≥ 1 active NRTI + DTG or r/LPV

• Patients were NOT virologically suppressed before starting the study but did

have genotypes (GT) available

Aboud M, IAS 2017 #5613; Brown D, CROI 2019 #144.

9

DAWNING Sub-Analysis: Virologic outcomes

84 84 80 70 72 62

10 20 30 40 50 60 70 80 90

Overall M184V present M184V absent

% with HIV-1 RNA < 50 copies/mL

Brown D, CROI 2019 #144.

10

12/14/19 6

DAWNING Sub-Analysis: Results

• DTG maintained virologic suppression when paired with 2 NRTIs regardless of

pre-existing RAM to one of the NRTIs (i.e. ≥ 1 active NRTI)

• Virologic failure lower in DTG arm (11) than r/LPV arm (30)
• RAMs emerged in 2 in DTG and 3 in PI arm
• DTG failures: INSTI-R (G118R, R263K)
• r/LPV failures: No PI-R
• Reaffirms that DTG can fail with INSTI resistance, but b/PIs generally do not

Brown D, CROI 2019 #144.

11

Option D: Switch to BIC/TAF/FTC

• Background
• BIC/TAF/FTC (Biktarvy) has been found to be non-inferior in
• Treatment-naïve individuals (Studies 1489, 1490)1,2
• As switch in virologically suppressed individuals (Studies 1844, 1878)3,4
• Women (1961)5
• But what about its use in people with underlying resistance?

1-Gallant J, Lancet HIV 2017. 2-Sax P, Lancet HIV 2017.3-Molina JM, Lancet HIV 2018. 4-Daar E, Lancet HIV 2018. 5-Kityo, CROI 2018 #500.

12

12/14/19 7

Switch to BIC/TAF/FTC in Patients with Historical Resistance

• Study GS-4030: Placebo-controlled RCT of 565 virologically suppressed

patients on TAF/FTC + DTG or TDF/FTC + DTG randomized to continue regimen or switch to BIC/TAF/FTC

• Genotypic data obtained from historical + archived GT
• Baseline NRTI-R in 24% of the study (138/565), including M184V in 14% of study (81/565)
• 48 Week Results
• Overall, 93 vs 91% virologic suppression overall
• 98% with M184 (81) maintained suppression
• No treatment-emergent resistance

Acosta R, CROI 2019 #551 and IAS 2019 #MOPEB241.

13

Historical Resistance in Switch Studies 1844 + 1878

• OLE of 570 patients to evaluate virologic outcomes based on analysis of

pre-existing resistance from historical and archived GT (543/570)

• Overall, 16% (89/543) had NRTI resistance, with M184 in 10% (54/543)
• 48 Week Results
• Overall, 98% of B/F/TAF-treated participants were suppressed
• 96% (52/54) with archived M184 were suppressed

Andreatta K, JAC 2019.

14

12/14/19 8

Option E: Switch to TAF/FTC/c/DRV

• Background
• TAF/FTC/c/DRV (Symtuza) was FDA approved July 2018
• EMERALD Study
• Randomized controlled trial switch study of 1,141 virologically suppressed to

TAF/FTC/c/DRV vs continued TDF/FTC + b/DRV (non-inferior)

• 58% had ≥ 5 prior ARV regimens
• 15% with previous virologic failure but not to DRV
• Resistance allowed, but not to DRV (4% with M184 but on archived GT)

Orkin C, Lancet HIV, 2018; Lathouwers E, HIV Glasgow 2018 #P294.

15

ART with M184V: Take-home points

• 1. DAWNING subanalysis affirms the practice of using DTG with <2

active NRTIs, but ≥ 1 active NRTI (to avoid DTG monotherapy)

• 2. If already suppressed with baseline M184, can likely switch to

BIC/TAF/FTC and stay virologically suppressed

• 3. TAF/FTC/c/DRV is a good option for the heavily treatment

experienced with M184 and other baseline RAMs (but not to DRV)

16

12/14/19 9

Roadmap

• ART with M184V
• An

Anticoagu gulants and AR ART

• Doravirine as Salvage
• A Modern Toxo Tale

17

Case 2

18

12/14/19 10

Case 2

• 61M with HIV presents to urgent care with RLE swelling
• Last CD4 348 cells/mm3, HIV RNA <40 copies/mL
• Diagnosed with acute unprovoked DVT, needs anticoagulation
• On ABC/3TC/r/DRV since 2016

19

ARS: Which regimen will you use if he is unable to switch his ART regimen?

• A. Warfarin
• B. Apixaban
• C. Dabigatran
• D. Rivaroxaban

20

12/14/19 11

Background

• Direct-acting oral anticoagulant (DOAC) use is increasing
• Commonly used DOACs - apixaban, rivaroxaban, and dabigatran – are

eliminated either via CYP450 enzymes, P-glycoprotein, or both

• Warfarin is metabolized by CYP2C9

Oral Anticoagulants and Antiplatelet Therapy. National HIV Curriculum.

21

ART & Anticoagulants

DOAC Warfarin Apixaban Rivaroxaban Dabigatran NRTI

✓ ✓ ✓ ✓

NNRTI

Caution Caution Caution Caution

PI ✕ ✕ ✕

Caution

INSTI

*except c/EVG

✓ ✓ ✓ ✓

Oral Anticoagulants and Antiplatelet Therapy. National HIV Curriculum.

22

12/14/19 12

ART & Anticoagulants

DOAC Warfarin Apixaban Rivaroxaban Dabigatran NRTI NNRTI PI INSTI

*except c/EVG

Oral Anticoagulants and Antiplatelet Therapy. National HIV Curriculum.

23

NNRTIs & Anticoagulants

DOAC Warfarin Apixaban Rivaroxaban Dabigatran NNRTI

• CYP450 enzyme induction by NNRTIs may DECREASE levels of the DOAC
• NNRTIs can alter warfarin levels

Oral Anticoagulants and Antiplatelet Therapy. National HIV Curriculum.

24

12/14/19 13

Protease Inhibitors & Anticoagulants

DOAC Warfarin Apixaban Rivaroxaban Dabigatran PI

• PIs can alter warfarin levels
• CYP450 inhibition by PIs or boosters may INCREASE levels of the DOAC
• Adult and Adolescent ARV Guidelines recommend avoiding DOACs + PIs

Oral Anticoagulants and Antiplatelet Therapy. National HIV Curriculum.

25

ARS: Which regimen will you use if the patient cannot switch ART and cannot adhere to INR monitoring?

• A. Warfarin
• B. Apixaban
• C. Dabigatran
• D. Rivaroxaban

26

12/14/19 14

But what if you HAVE to use a PI and a DOAC?

• Rivaroxaban
• Co-administration not been studied1
• Apixaban
• 50% dose reduction is recommended with close monitoring for bleeding
• No adverse outcomes in 6 PWH on half-dose apixaban while on ritonavir- or

cobicistat-boosted regimens3

• Dabigatran
• Dabigatran administered 2 hours before ritonavir 100mg resulted in dabigatran

AUC decrease by 29%, so requires taking PI simultaneously with dabigatran2

• Cobicistat 150mg with dabigatran increased dabigatran AUC by > 2-fold4

1-Liverpool HIV Drug Interactions; 2-National HIV Curriculum; 3-Nisly SA, Int J STD AIDS, 2019; 4-AIDSinfo.gov

27

Take-Home Points

• In general, NRTIs and INSTIs (except EVG) ok with DOACs and warfarin
• NNRTIs and PIs can alter warfarin levels
• NNRTIs can decrease DOAC levels – use caution
• PIs generally increase DOAC levels – avoid
• If have to use apixaban, use half-dose
• May be able to use dabigatran
• Do not use cobicistat with dabigatran
• If using ritonavir with dabigatran, take PI and dabigatran simultaneously

Oral Anticoagulants and Antiplatelet Therapy. National HIV Curriculum.

28

12/14/19 15

Roadmap

• ART with M184V
• Anticoagulants and ART
• Do

Doravirine as as Salv Salvag age

• A Modern Toxo Tale

29

Case 3

30

12/14/19 16

Case 3

• 65M with HIV and multiple medical problems comes in for follow-up
• Last CD4 388 cells/mm3, HIV RNA undetectable
• On BIC/TAF/FTC + Doravirine

Is this the best regimen for him?

31

Case 3: Prior Genotype Results

• RT: M41L, K103N, Y181C, M184V, T215Y, H221Y
• PI: None
• INSTI: none

M41L, T215Y (TAMs) – resistance to ABC and TDF/TAF M184V – resistance to ABC, 3TC, and FTC K103N – resistance to EFV and NVP Y181C – resistance to EFV, NVP, ETR, and RPV H221Y – some resistance to all NNRTIs

Stanford HIV Drug Resistance Database.

32

12/14/19 17

Doravirine Background

• Doravirine = NNRTI FDA approved in 8/2018
• Available in 100mg dose
• TDF/3TC/DOR (Delstrigo) daily
• DOR (Pifeltro) daily
• No food requirements
• OK with PPIs
• Few drug-drug interactions
• Doravirine. National HIV Curriculum.

33

Doravirine Studies

St Study udy Ou Outcome

• me

DRIVE-AHEAD1 ART start DOR/TDF/3TC non-inferior to TDF/FTC/EFV DRIVE-FORWARD2 ART start DOR + 2NRTI non-inferior to rDRV + 2NRTI DRIVE-SHIFT3 ART switch DOR/TDF/3TC non-inferior at 24w and 48w vs baseline ART at 24w

1- Orkin C, CID, 2018; 2-Molina JM, Lancet HIV, 2018; 3-Johnson M, JAIDS, 2019.

34

12/14/19 18

DOR as Salvage: Questions

• 1. What mutations arise with Doravirine use?
• 2. With what NNRTI mutations can we use Doravirine?
• 3. What is Doravirine’s role in salvage therapy?
• 4. What data exists for use of BIC/TAF/FTC + Doravirine?

35

Emergent Resistance in ART Naïve Studies with Doravirine

Lai M-T, IAS 2018. Abstract THPDB101.

36

12/14/19 19

Effect of Resistance in DRIVE-SHIFT

• Baseline resistance
• Of 24 patients with baseline NNRTI resistance (K103N, Y181C, or

G190A), virologic suppression maintained in 24 patients

• Virologic failure
• Occurred in 7 people in DOR arm, 1 in baseline ART
• Treatment-emergent resistance?
• No resistance in DOR group, one person in baseline ART had a M184

Johnson M, JAIDS 2019.

37

DOR as Salvage: Answers

1.

• 1. Wh

What mu mutatio ions ar aris ise e wit ith Dor Doravirine use use?

• V106, P225, F227, H221

2.

• 2. Wit

With what NNRTI TI mu mutatio ions can an we e use e Dor Doravirine?

• Can use with a K103, Y181, G190, and K103N/Y181C combo
• Beware E138, and do not use with other NNRTI mutations

3.

• 3. Wh

What is is Dor Doravirine’ e’s ro role in salvage thera rapy?

• Can use in a TRIO-like regimen, with 3 Ds = DTG/b/DRV/DOR

4.

• 4. What data exi

xists for use of Bi Biktarvy + + Dor Doravirine?

• None

38

12/14/19 20

Roadmap

• ART with M184V
• Anticoagulants and ART
• Doravirine as Salvage
• A

A Modern To Toxo Ta Tale

39

Case 4

A Modern Toxo Tale

40

12/14/19 21

Background

• Toxoplasma gondii is a protozoan parasite can be acquired congenitally,

through consumption of cysts in undercooked meats, and exposure to cat feces

• In immunocompromised hosts, it can reactivate and cause encephalitis,

but can also disseminate to eyes, heart, lungs, etc.

• Today, it is rarely seen due to ART and effective prophylaxis, but

toxoplasmosis made the news in 2015 due to the cost of pyrimethamine

Toxoplasma Encephalitis. National HIV Curriculum.

41

10/2018 Urinary retention and low back pain, new dx HIV (CD4 11/3%)

A young man from West Africa presents with…

42

12/14/19 22

Avidly ring-enhancing intramedullary spinal cord lesion at T12 with adjacent abnormal cord signal and cord expansion.

43

10/2018 Urinary retention and low back pain, new dx HIV (CD4 11/3%)

A young man from West Africa is admitted with…

11/2018 Spinal cord lesion vastly improved

Pyrimethamine + Leucovorin Sulfadiazine

44

12/14/19 23

45

10/2018 Urinary retention and low back pain, new dx HIV (CD4 11/3%)

A young man from West Africa is admitted with…

11/2018 Spinal cord lesion vastly improved, but experiences medication side effects

Pyrimethamine + Leucovorin Sulfadiazine Clindamycin BIC/TAF/FTC Atovaquone

46

12/14/19 24

Toxoplasmosis Treatment

Image from National HIV Curriculum.

If pyrimethamine unavailable or there is a delay in obtaining it, TMP-SMX should be used in place

• f pyrimethamine-sulfadiazine (BI

BI). 47

10/2018 Urinary retention and low back pain, new dx HIV (CD4 11/3%)

A young man from West Africa is…

11/2018 Spinal cord lesion vastly improved, but experiences medication side effects 12/2018 Discharged to SNF

Pyrimethamine + Leucovorin Sulfadiazine Clindamycin BIC/TAF/FTC Atovaquone

48

12/14/19 25

10/2018 Urinary retention and low back pain, new dx HIV (CD4 11/3%)

A young man from West Africa returns with…

11/2018 Spinal cord lesion vastly improved, but experiences medication side effects 12/2018 Discharged to SNF 4/2019 New headaches and vision loss, abnormalities on brain MRI

Pyrimethamine + Leucovorin Sulfadiazine Clindamycin BIC/TAF/FTC Atovaquone

49

Interval development of numerous ring and punctate enhancing lesions in bilateral cerebral hemispheres, right greater than left basal ganglia, bilateral cerebellar hemispheres.

50

12/14/19 26

10/2018 Urinary retention and low back pain, new dx HIV (CD4 11/3%)

A young man from West Africa returns with…

11/2018 Spinal cord lesion vastly improved, but experiences medication side effects 12/2018 Discharged to SNF 4/2019 New headaches and vision loss, abnormalities on brain MRI 6/2019 Discharged to self- care after DOT and symptomatic improvement

Pyrimethamine + Leucovorin Sulfadiazine Clindamycin BIC/TAF/FTC Atovaquone

51

10/2018 Urinary retention and low back pain, new dx HIV (CD4 11/3%)

A young man from West Africa returns with…

11/2018 Spinal cord lesion vastly improved, but experiences medication side effects 12/2018 Discharged to SNF 4/2019 New headaches and vision loss, abnormalities on brain MRI 6/2019 Discharged to self- care after DOT and symptomatic improvement 7/2019 Presents to drop-in clinic

Pyrimethamine + Leucovorin Sulfadiazine Clindamycin BIC/TAF/FTC Atovaquone

52

12/14/19 27

Toxoplasmosis Primary Prophylaxis

• For PWH with CD4 < 100 cells/mm3 & Toxoplasma seropositivity (IgG)

Image from National HIV Curriculum.

53

Take-Home Points

• Toxoplasmosis is a rare but treatable infection with a high likelihood of

dissemination and recurrence.

• Treatment includes induction (at least 6 weeks), followed by chronic maintenance

(or secondary prophylaxis) until immune reconstitution.

• Many options exist for toxoplasmosis treatment and prophylaxis, even in the

setting of high pyrimethamine costs.

54

12/14/19 28

Case Recap

• Case 1: In a patient with a history of M184 who is already virologically

suppressed, ART simplification options include TAF/FTC or TDF/FTC + DTG, TAF/FTC/c/DRV, and maybe BIC/TAF/FTC.

• Case 2: Beware DOACs with NNRTIs, and avoid DOACs with PIs.

Communicate with pharmacist!

• Case 3: There is no data regarding use of BIC/TAF/FTC + Doravirine.
• Case 4: Toxoplasmosis is rare, but if treatment or prophylaxis is needed,

alternative options to pyrimethamine exist. Communicate with pharmacist!

55

Supplementary Slides

56

12/14/19 29

DAWNING: Baseline Characteristics

• Resistance
• 80% received <2 fully active NRTIs
• 90% with NRTI-R
• 82% with a M184V (+/- other RAMs)
• 30% with a K65R
• 24% with ≥ 1 TAM
• Baseline NRTI regimen, post randomization
• AZT + 3TC (41%)
• TDF + XTC (42%)
• TDF + AZT (12%)
• ABC + 3TC (2%)

Brown, CROI 2019 #144

57

DAWNING Sub-Analysis: Results

Brown, CROI 2019 #144

58

12/14/19 30

Toxoplasmosis Treatment cont.

• If pyrimethamine is unavailable or there is a delay in obtaining it, TMP-

SMX should be used in place of pyrimethamine-sulfadiazine (BI BI).

• For patients with a history of sulfa allergy, sulfa desensitization should

be attempted (BI BI).

• Atovaquone should be administered until therapeutic doses of TMP-

SMX are achieved (CI CIII).

Image from National HIV Curriculum.

59

Chronic maintenance therapy

Image from National HIV Curriculum.

60