Contemporary Management of HIV: Modifying ART in Virologically … · 2021. 4. 21. · ‒Switching ART in a Patient With Daily Pill Fatigue ‒Switching ART to Avoid Comorbidities

Saturday, April 24, 2021

10:30 AM ET

Contemporary Management of HIV: Modifying ART in Virologically Suppressed Patients

Supported by an educational grant from ViiV Healthcare.

Provided by Clinical Care Options, LLC.SK3

Speaker and Disclosure Information

David A. Wohl, MDProfessor of MedicineSchool of MedicineSite Leader, AIDS Clinical Trials Unit‐Chapel HillUniversity of North Carolina at Chapel HillDirector, North Carolina AIDS Training and Education CenterChapel Hill, North CarolinaCo‐Director, HIV ServicesNorth Carolina Department of CorrectionRaleigh, North Carolina

David A. Wohl, MD, has disclosed that he has received consulting fees from Gilead Sciences, Janssen, and ViiV Healthcare and funds for research support from Gilead Sciences and ViiV Healthcare.

Let’s Vote!

Poll 1: If you are in practice, what is your degree type?

A. Nurse

B. Nurse practitioner

C. Pharmacist

D. Physician

E. Physician assistant

F. Other healthcare professional

Poll 2: If you are in practice, how do you identify your specialty?A. Infectious disease

B. HIV

C. Family practice/general practice/internal medicine

D. Pharmacy

E. Other

Poll 3: If you treat HIV, how many patients do you provide care for in a typical wk?A. < 10

B. 10‐25

C. 26‐50

D. 51‐100

E. > 100

Poll 4: If you treat HIV, for how many yrs have you done so?A. 0‐2 yrs

B. 3‐5 yrs

C. 6‐10 yrs

D. 11‐15 yrs

E. 16‐20 yrs

F. More than 20 yrs

Presurvey 1: According to the FDA prescribing information, in which of the following patients is LA CAB + RPV indicated?

A. Treatment‐naive or virologically suppressed

B. Treatment naive only

C. Virologically suppressed only

D. Current virologic failure

E. Unsure

JB [2]95

Outcomes Case

You are providing care for a patient with long‐term virologic suppression on first‐line EFV/FTC/TDF who would like to switch to another single‐tablet ART regimen because of neuropsychiatric adverse effects

The patient is at high risk for CVD events and is also receiving a proton pump inhibitor for management of GERD

Presurvey 2: If following current guidelines, which of the following regimens would you recommend as a switch option for this patient?

A. DTG/3TC or BIC/FTC/TAF

B. DTG/ABC/3TC

C. DRV/COBI/FTC/TAF

D. RPV/FTC/TAF or RPV/FTC/TDF

E. Unsure

JB [2]96

Outcomes Case

You are providing care for a patient with a history of drug resistance (M184V and K103N) who is currently virologically suppressed on a 4‐pill twice daily ART regimen

The patient would like to switch to a simpler regimen with fewer pills

Presurvey 3: Based on current DHHS guidelines, how would you counsel this patient?

A. Patients with a history of drug resistance should avoid switching ART except in cases of severe toxicity with the current regimen

B. Switching to a new regimen is recommended only if they are experiencing adverse events (any grade) with their current regimen

C. Switching to a new regimen should be feasible with consideration of their ARV history and resistance testing results

D. Unsure

JB [2]96

Program Overview

Case‐Based Discussion: Modifying ART in Virologically Suppressed Patients

‒ Switching ART in a Patient With Daily Pill Fatigue

‒ Switching ART to Avoid Comorbidities

‒ Simplifying ART in the Context of Known Multidrug Resistance

Question and Answer Session

Switching ART in a Patient With Daily Pill Fatigue

Patient Case 1: Background

39‐yr‐old MSM diagnosed with HIV in 2015 shortly after being found unconscious on the street and brought to hospital by police

Urine toxicology screen positive for cocaine, alcohol, and amphetamines

When he awoke, he acknowledged polysubstance use and selling sex for money

Agreed to HIV testing, which was positive

Laboratory parameters at HIV diagnosis: ‒ CD4+ cell count: 334 cells/mm3

‒ HIV‐1 RNA: 34,000 copies/mL

‒ No HIV drug resistance

‒ Hepatitis serologies negative, including HAV, HBV, HCV

Started on EVG/COBI/FTC/TAF, one pill daily and rapidly achieved viral suppression

Transferred to an inpatient substance use disorder treatment program, has been in recovery since then, with excellent medication adherence

No other medical problems except for intermittent STIs, diagnosed on routine screens

Expresses that he’s tired of taking a daily pill for HIV – reminds him of the time of his diagnosis and difficulties with addiction

Slide credit: clinicaloptions.com

Poll 5: Would you switch this patient to long‐acting injectable CAB + RPV?A. Yes

B. Only after he has completed a hepatitis B vaccine series and shows a response

C. No

D. Unsure

Reasons to Consider an ART Switch During Viral SuppressionAppropriate

To simplify a regimen (eg, reduce pill burden or dosing frequency)

To enhance tolerability or decrease toxicity

To prevent or mitigate drug–drug or drug–food interactions

To eliminate food/fluid requirements

To allow for optimal ART use during pregnancy or where pregnancy may occur

To reduce costs

Inappropriate

To use the “newest” regimen

To reduce costs at the price of a toxicity or intolerance risk for your patient

Slide credit: clinicaloptions.comDHHS Guidelines. December 2019.

ATLAS and FLAIR: Long‐Acting Intramuscular CAB + RPV After Initial Virologic Suppression With Oral Therapy Multicenter, randomized, open‐label phase III noninferiority trials

Primary endpoint for both trials: HIV‐1 RNA ≥ 50 copies/mL at Wk 48 by FDA Snapshot in ITT‐E


LA CAB 400 mg + LA RPV 600 mg IM Q4W (n = 303)

Continue Baseline ART(n = 308)

Adults on stable ART (either first or second regimen) with HIV‐1 RNA < 50 copies/mL for ≥ 6 mos with no previous VF

(N = 616)

Comparator arm patients eligible to receive CAB + RPV in extension phase

after Wk 52 (ATLAS‐2M study)

Wk 48 Primary EndpointATLAS

LA CAB 400 mg +LA RPV 600 mg IM Q4W

(n = 278)

Continue DTG/ABC/3TC PO QD(n = 283)

ART‐naive patients withHIV‐1 RNA ≥ 1000 copies/mL,

HBsAg negative, no NNRTI RAMs but K103N permitted

(N = 629)

CAB 30 mg +RPV 25 mg PO QD

(n = 283)

Wk 48 Primary EndpointWk 4

DTG/ABC/3TC PO QD

Wk 96Day 0

Wk 20 FLAIR

1. Swindells. NEJM. 2020;382:1112. 2. Orkin. NEJM. 2020;382:1124.

CAB 30 mg +RPV 25 mg PO QD

(n = 308)

Wk 4Day 0

‐1.2 2.5

0.6

‐10 ‐8 ‐6 ‐4 ‐2 0 2 4 6 8 10

ATLAS: Switch to Long‐Acting CAB + RPV vs Continued 3‐Drug ART in Virologically Suppressed Adults


Patie

nts (%)

Difference (%)

Difference (%)

100

80

40

60

20

01.6 1.0

92.5 95.5

5.8 3.6

LA CAB + LA RPV(n = 308)

Continued BL ART(n = 308)

‐6.7

‐3.0

‐10 ‐8 ‐6 ‐4 ‐2 0 2 4 6 8 10

0.7

Adjusted Treatment Difference (95% CI)*

Key Secondary Endpoint(HIV‐1 RNA < 50 copies/mL)LA CAB + LA RPV noninferior

to continued BL ART

Primary Endpoint(HIV‐1 RNA ≥ 50 copies/mL)LA CAB + LA RPV noninferior

to continued BL ART

6% NImargin

‐10% NImargin

*Adjusted for sex and BL third agent class.

Virologic Outcomes at Wk 48

Virologic Nonresponse (≥ 50 c/mL)

Virologic Success

(< 50 c/mL)

No Virologic Data

Continued ARTLA CAB + LA RPV

Continued ART LA CAB + LA RPV

Swindells. NEJM. 2020;382:1112.

‐2.8 2.1

‐0.46% NImargin

‐10 ‐8 ‐6 ‐4 ‐2 0 2 4 6 8 10Difference (%)

Difference (%)Slide credit: clinicaloptions.com

Patie

nts (%)

100

80

40

60

20

0Virologic

Nonresponse (≥ 50 c/mL)

Virologic Success

(< 50 c/mL)

2.1 2.5

93.6 93.3

4.2 4.2

LA CAB + LA RPV(n = 283)

DTG/ABC/3TC(n = 283)

‐10% NImargin

Difference (%)

‐3.7

0.4

‐10 ‐8 ‐6 ‐4 ‐2 0 2 4 6 8 10

4.5

Virologic Outcomes at Wk 48 Adjusted Treatment Difference (95% CI)*

DTG/ABC/3TCLA CAB + LA RPV

DTG/ABC/3TC LA CAB + LA RPV

Key Secondary Endpoint(HIV‐1 RNA < 50 copies/mL):LA CAB + LA RPV noninferior

to DTG/ABC/3TC

*Adjusted for sex, BL HIV‐1 RNA (< vs ≥ 100,000 c/mL).

FLAIR: Long‐Acting CAB + RPV Maintenance After Oral DTG/ABC/3TC Induction

Primary Endpoint(HIV‐1 RNA ≥ 50 copies/mL)LA CAB + LA RPV noninferior

to DTG/ABC/3TC

No Virologic Data

Orkin. NEJM. 2020;382:1124.

ATLAS and FLAIR: Treatment‐Emergent Resistance With Long‐Acting CAB + RPV

101/483 patients had BL L74I in FLAIR: n = 64 from Russia, n = 60 with subtype A[3]

‒ Presence of this polymorphism did not negatively affect proportion achieving HIV‐1 RNA < 50 copies/mL at Wk 48

1. Swindells. CROI 2019. Abstr 139. 2. Orkin. CROI 2019. Abstr 140LB. 3. Overton. IAS 2019. Abstr MOPEB257. Slide credit: clinicaloptions.com

Study Sex Country HIV‐1 Subtype

Wk of Failure

NNRTI RAMs INSTI RAMs*

Baseline Failure Baseline Failure

ATLAS[1]F Russia A/A1 8 E138E/A E138A L74I L74I

F France AG 12 V108V/I, E138K V108I, E138K None None

M Russia A/A1 20 None E138E/K L74I L74I, N155H

FLAIR[2]F Russia A1 20 None E138E/A/K/T L74I L74I, Q148R

M Russia A1 28 None K101E L74I L74I, G140R

F Russia A1 48 None E138K L74I L74I, Q148R*L74I not considered an INSTI RAM by IAS‐USA guidance; not expected to affect CAB sensitivity.

ATLAS and FLAIR: Patient‐Reported Preference for Drug Delivery in Patients Receiving Long‐Acting CAB + RPV

1. Swindells. CROI 2019. Abstr 139. 2. Swindells. NEJM. 2020;382:1112. 3. Orkin. CROI 2019. Abstr 140LB. 4. Orkin. NEJM. 2020;382:1124. Slide credit: clinicaloptions.com

*Per single question in Wk 48 participant survey.

Study PopulationPreferred Regimen,* % (n/N)

Long‐Acting IM Daily PO

ATLAS[1,2] ITT‐E 86 (266/308) 2 (7/308) Responding participants 97 (266/273) ‐‐

FLAIR[3.4] ITT‐E 91 (257/283) 1 (2/283) Responding participants 99 (257/259) ‐‐

Long‐Acting CAB + RPV Approved by FDA January 21, 2021 FDA indication:

‒ As complete regimen for HIV‐1 infection treatment switch in adults who are virologically suppressed on a stable ART regimen

‒ No history of treatment failure and no known or suspected resistance to either CAB or RPV

Requires oral lead‐in dosing for ~ 1 mo to assess tolerability

Initiate IM gluteal injection of CAB 600 mg + RPV 900 mg on last day of oral lead‐in period and continue injections every mo thereafter

https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212888s000lbl.pdf. Slide credit: clinicaloptions.com

Assessment 1: According to the FDA prescribing information, in which of the following patients is LA CAB + RPV indicated?

A. Treatment‐naive or virologically suppressed

B. Treatment naive only

C. Virologically suppressed only

D. Current virologic failure

E. Unsure

JB [2]95

Questions to Consider

Which of your patients will be good candidates for this novel treatment?

How would you counsel them about the pros and cons?

What concerns do you have?

Case Report: Acute Hepatitis B in a Patient on CAB/RPV

31‐yr‐old MSM diagnosed with HIV 11/16; started induction ART in 2/17 with DTG, 3TC, and ABC in FLAIR study; no markers of prior HBV infection, no history of HBV vaccination at screening

‒ 4/17: HIV‐1 plasma viral load undetectable

9/17: randomized to 4‐wk oral CAB/RPV, followed by monthly LA CAB/RPV injection

HBV vaccine and HAV vaccine: 7/17, 8/17, 4/18; treated 12/16 and 4/18 for syphilis, urethral and anal chlamydia, and shigellosis

6/18: increased AST (78 IU/L) and ALT (162 IU/L); continued increase in ALT to 594 IU/L

‒ Diagnosis acute HBV infection: HBsAg+, HBsAb‐, HBc IgM+, HBeAg+, HBeAb‐, high HBV DNA level of 229,000,000 IU/mL (8.36 log10)

Retrospective testing of 1/18 serum found no detectable anti‐HBsAb

7/18: switched to TDF,FTC, and DTG; after 3 mos, normal ALT, decreased HBV DNA level to 170 IU/mL (2.23 log10)

Slide credit: clinicaloptions.comPintado. Open Forum Infect Dis. 2020;7:ofaa367.

Factors That May Contribute to Risk of Treatment Failure With Long‐Acting CAB/RPV Post‐hoc analysis of phase III data (Wk 48)

‒ ATLAS and FLAIR (Q4W dosing)

‒ ATLAS‐2M (Q4W and Q8W dosing)

Logistic regression model (10 covariates)

Factors associated with increased odds of confirmed virologic failure:‒ Rilpirivine RAMs at baseline: OR 37.2 (P < .001)

‒ Log2 of post‐hoc Wk 8 rilpirivine trough concentration: OR 4.2 (P = .004)

‒ Baseline HIV‐1 subtype A1/A6: OR 6.6 (P = .005)

‒ BMI ≥ 30 kg/m2 at baseline: OR 1.1 (P = .001)

Q8W dosing was not a significant factor

Slide credit: clinicaloptions.comMargolis. J Int AIDS Soc. 2020;23(suppl 7):17.

Baseline Factors

Confirmed Virologic Failure (%)

HIV‐1 RNA < 50 Copies/mL (%)

None 0.4 951 0.4 96≤ 2 26 71Total 1.3 94

“Direct to Inject”: Switching to CAB/RPV Without an Oral Lead‐In FLAIR extension study

‒ Participants on DTG/ABC/3TC arm achieving virologic suppression (HIV‐1 RNA < 50 copies/mL) in 20‐wk induction phase could switch to monthly CAB/RPV at Wk 100

‒ Switchers randomized to groups with (n = 121) or without (n = 111) an oral CAB + RPV lead‐in

Slide credit: clinicaloptions.comD’Amico. J Int AIDS Soc. 2020;23(suppl 7):15.

Patie

nts (%)

99.193.4

0.9 0.8 05.8

Virologic Outcomes at Wk 124 Following Switch to CAB/RPV at Wk 100

No lead‐inLead‐in

Virologic Nonresponse

Virologic Suppression

No Virologic Data

100

80

40

60

20

0

Questions for Discussion

Would you still consider injectable CAB/RPV for the case patient if …

‒ He had a history of treatment interruptions?

‒ He had transmitted K103N (resistance to efavirenz)?

‒ This was a woman of childbearing potential?

‒ This was a time with a COVID‐19 surge?

‒ If he was a frequent traveler who spent wks at a time out of the country?

‒ He was not HBV immune?

Switching ART to Avoid Comorbidities


66‐yr‐old woman diagnosed with HIV in 2008 when her husband was hospitalized with PJP

Her initial CD4+ cell count was 480 cells/mm3, HIV‐1 RNA 67,000 copies/mL, with no transmitted resistance

Started EFV/FTC/TDF, later switched to ATV/RTV + FTC/TDF because of CNS adverse effects

Ended up on DRV/RTV + FTC/TDF because she needed to take acid‐reducing medication for reflux

Switched to single pill DRV/COBI/FTC/TAF in 2019, which she tolerates well

Additional medical history

‒ HTN

‒ Type 2 DM

‒ Renal impairment (eGFR 45 mL/min/1.73m2)

‒ Obesity

Current other medications: atorvastatin, amlodipine, valsartan, metformin, pantoprazole

Nonsmoker

Strong family history of cardiac disease


Considerations When Switching Regimens in Virologically Suppressed Patients

Comorbidity: HBV coinfection Cardiovascular disease or risk Renal function Bone mineral density Pregnancy Other coinfections

Safety:

Review ART history for intolerance Must be HLA‐B*5701 negative if considering ABC Consider drug–drug interactions with

comedications

Drug Resistance:

Review ART history for possible VF Review all available resistance test results If earlier resistance uncertain, only consider switch if new regimen likely to maintain suppression of resistant virus

Within‐class switches usually maintain virologic suppression if no resistance to drugs in that class are present

Caution when switching from boosted PI to another class if full treatment/resistance history not known

Consult an expert when switching if resistance to ≥ 1 class

DHHS ART Guidelines. December 2019. Slide credit: clinicaloptions.com







To reduce costs

Inappropriate




Data Collection on Adverse Events of Anti‐HIV Drugs (D:A:D) Study: DRV Associated With Increased CVD Risk Prospective, multinational analysis

previously showed that longer, cumulative use of older PIs IDV and LPV/RTV associated with CVD risk[1]

Adequate data available for 35,711 participants; during mean follow‐up of ~ 7 yrs, 1157 developed CVD[1]

‒ 379 stroke

‒ 454 type 1 myocardial infarction

‒ 459 angioplasty

‒ 93 bypass

‒ 15 endarterectomy

‒ 0 sudden cardiac deaths

*After adjustment for potential confounders.

Slide credit: clinicaloptions.com1. Ryom. Lancet HIV. 2018;5:e291. 2. Saag. JAMA. 2020;324:1651.

Cumulative use of RTV‐boosted DRV, but not RTV‐boosted ATV, was independently associated with small, but progressively increasing risk of CVD events[1]

IAS‐USA ART guidelines recommend switching from ABC‐based or PI‐containing regimens (except ATV) in patients with or at high for CVD event[2]

Regimen[1] Incidence Rate Ratio/5 Yrs* (95% CI)

RTV‐boosted DRV 1.59 (1.33‐1.91)

RTV‐boosted ATV 1.03 (0.90‐1.18)

Poll 6: What would you recommend for the case patient’s ART regimen?A. Continue DRV/COBI/FTC/TAF

B. Switch to BIC/FTC/TAF

C. Switch to DTG/3TC

D. Switch to DTG/RPV

E. Switch to long‐acting injectable CAB and RPV

F. Something else

Switching From Suppressive ART to an STR: Noninferior Efficacy Across Phase III Studies

1. Daar. Lancet HIV. 2018;5:e347. 2. Molina. Lancet HIV. 2018;5:e357. 3. Sax. IAS 2019. Abstr MOAB0105. 4. Kityo. CROI 2018. Abstr 500. 5. Johnson. JAIDS. 2019;81:463. 6. Orkin. Lancet HIV. 2017;4:e195. 7. DeJesus. Lancet HIV. 2017;4:e205. 8. Trottier. Antivir Ther. 2017;22:295. 9. Mills. Lancet Infect Dis. 2016;16:43. 10. Orkin. Lancet HIV. 2018;5:e23 11. van Wyk. Clin Infect Dis. 2020;71:1920. 12. Llibre. Lancet. 2018;391:839. 13. Hagins. CROI 2020. Abstr 36. Slide credit: clinicaloptions.com

Key Studies* Switch to† Switch From

380‐1878,[1] 380‐1844,[2] 380‐4030‡,[3] 380‐1961,‡[4] and BRAAVE‡[13] BIC/FTC/TAF

Boosted PI + 2 NRTIs, DTG/ABC/3TC, DTG + FTC/(TAF or TDF), or EVG/COBI/FTC/(TAF or TDF),

2 NRTIs + third agent

DRIVE‐SHIFT[5] DOR/3TC/TDF Boosted PI, EVG/COBI, or NNRTI + 2 NRTIs

GS‐1216[6] and GS‐1160[7] RPV/FTC/TAF RPV/FTC/TDF or EFV/FTC/TDF

STRIIVING[8] DTG/ABC/3TC Third agent + 2 NRTIs

GS‐109[9] EVG/COBI/FTC/TAF TDF‐based regimen

EMERALD‡[10] DRV/COBI/FTC/TAF Boosted PI + FTC/TDF

TANGO[11] DTG/3TC 3‐drug or 4‐drug TAF‐based ART

SWORD‐1/2[12] DTG + RPV Third agent + 2 NRTIs*Listed studies not head to head. †Most recent FDA approvals: for BIC/FTC/TAF, DTG/RPV, DOR/3TC/TDF, and DTG/3TC must have no history of treatment failure and no resistance to regimen components; for DRV/COBI/FTC/TAF, must have no resistance to DRV, TFV. ‡Patients with resistance permitted.

SWORD‐1 and ‐2: Switch to DTG + RPV vs Continuation of Baseline ART in Virologically Suppressed Adults Parallel, randomized, open‐label, multicenter phase III noninferiority studies in adults on stable ART (INSTI,

NNRTI, or PI + 2 NRTIs) with HIV‐1 RNA < 50 copies/mL for ≥ 6 mos[1,2]

Primary endpoint: HIV‐1 RNA < 50 copies/mL maintained in 95% of patients in each arm at Wk 48; adjusted treatment difference: ‐0.2% (95% CI: ‐3.0 to 2.5)[2]

10/990 (1%) confirmed virologic withdrawals through Wk 100[1]

‒ Treatment‐emergent NNRTI resistance mutations documented in 3/10, all from early switch arm*

Time of Failure

Previous Regimen

Mutations at Baseline Mutations atConfirmed Virologic Withdrawal

NNRTI INSTI NNRTI INSTI

Wk 36 EFV/FTC/TDF None None K101K/E None

Wk 88 DTG/ABC/3TC None None E138E/A None

Wk 100 EFV/FTC/TDF K101E, E138A G193E K101E, E138A, M230M/L Assay failure


*For these 3 patients, HIV‐1 RNA at last measurement: < 50 copies/mL, 55 copies/mL, 300 copies/mL, respectively.1. Aboud. AIDS 2018. Abstr THPEB047. 2. Llibre. Lancet. 2018;391:839.

Comorbidity, n (%)Treatment Experienced

Suppressed (n = 671)

Not Suppressed (n = 197)

Any 587 (87.5) 159 (80.7)

Autoimmune disease 29 (4.3) 8 (4.1)

Cardiovascular disease 89 (13.3) 20 (10.2)

Invasive cancer 80 (11.9) 15 (7.6)

Endocrine disorder 422 (62.9) 94 (47.7)

Mental health disorder 232 (34.6) 58 (29.4)

Liver disease 115 (17.1) 40 (20.3)

Bone disorder 52 (7.7) 17 (8.6)

Peripheral neuropathy 83 (12.4) 27 (13.7)

Renal disease 198 (29.5) 51 (25.9)

Hypertension 290 (43.2) 77 (39.1)

Substance use 92 (13.7) 31 (15.7)

Real‐World Experience With DTG/RPV in the United States Retrospective analysis of clinical characteristics and

outcomes in PWH switching to DTG/RPV between Jan 2018 and Dec 2018 in OPERA study (N = 880)

BL characteristics: 68% had CD4+ cell count > 500 cells/mm3, 63% initiated ART after 2013

88% remained on drug at 12 mos, virologic failure occurred in 1.5%; of 42 patients who discontinued, 41% were virologically suppressed

Pierone. IDWeek 2019. Abstr 2483. Slide credit: clinicaloptions.com

Region (South)

Age (50+)

Risk Factor (MSM)

Race (Black)

Ethnicity (Hispanic)

Sex (Female)

0 10 20 30 40 50 60 70 80 90 100

Baseline Demographics of Patients Switching to DTG/RPV (N = 880)DTG/RPV switchOverall OPERA population

63%57%

54%38%

35%60%

35%44%

28%25%

18%17%

Rilpivirine and Acid‐reducing Therapies

Agent Effect on RPV Concentration Clinical Comment

Antacids: aluminum or magnesium hydroxide, calcium carbonate

No change if antacid taken ≥ 2 hrsbefore RPV or ≥ 4 hrs after RPV

Use antacid + RPV with caution; may cause decreases in RPV plasma

concentration

H2‐receptor antagonists: cimetidine, famotidine*, nizatidine, ranitidine

No change if famotidine taken ≥ 12 hrs before RPV or ≥ 4 hrs after RPV; decreased RPV if famotidine taken

2 hrs before RPV

Use H2‐receptor antagonists + RPV with caution; may cause decreases

in RPV plasma concentration

Proton pump inhibitors: esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole

Decreases in RPVplasma concentrations may occur

due to gastric pH increase

Do not coadminister proton pump inhibitors with RPV

1. Rilpivirine PI. 2. Crauwels. J Int AIDS Soc. 2008;11(Suppl1:239). Slide credit: clinicaloptions.com

*RPV‐famotidine interaction assessed in a clinical study.[2]

Switch from Boosted PIs to BIC/FTC/TAF

Daar. Lancet HIV. 2018;5:e347.

Multicenter, randomized, open‐label, active‐controlled, phase III noninferiority trial

BIC/FTC/TAF(n = 290)

Continue Baseline Boosted PI (n = 287)

Adults with HIV‐1 infection with eGFR ≥ 50 mL, plasma HIV‐1

RNA < 50 copies/mL ≥ 6 mos; on regimen of boosted PI* (N = 578; 1 randomized participant

was not treated)*ATV or DRV + FTC/TDF or 3TC/ABC.

Wk 48 Primary Endpoint


Primary endpoint: HIV‐1 RNA ≥ 50 copies/mL at Wk 48 by FDA snapshot algorithm with 4% prespecified noninferiority margin

HIV‐1 RNA ≥ 50 copies/mL at Wk 48: 2% with BIC/FTC/TAF or continued boosted PI

Stratified by use of TDF or ABC at screening

Key Secondary Endpoint(HIV‐1 RNA < 50 c/mL)DTG/3TC noninferior to continued TAF‐based ART

TANGO: Switch to DTG/3TC vs Continuing TAF‐Based 3‐Drug Regimen


0.5

Patie

nts (%)

100

80

40

60

20

0 HIV‐1 RNA ≥ 50 c/mL

HIV‐1 RNA < 50 c/mL

No Virologic Data

0.3

93.293.0

6.5 6.5

Switch to DTG/3TC(n = 369)

Continue TAF‐based ART(n = 372)

Virologic Outcomes by FDA Snapshot (ITT‐E) at Wk 48 Adjusted Treatment Difference (95% CI)*

Primary Endpoint(HIV‐1 RNA ≥ 50 c/mL)DTG/3TC noninferior to continued TAF‐based ART

*Adjusted for baseline third agent class.Difference (%)

‐3.4

0.2

‐8 ‐6 ‐4 ‐2 0 2 4 6 8

3.9‐8% NImargin

TAF‐Based ARTDTG/3TC

TAF‐Based ART DTG/3TC

‐1.2 0.7

‐0.3

‐8 ‐6 ‐4 ‐2 0 2 4 6 8

4% NImargin

van Wyk. IAS 2019. Abstr WEAB0403LB.

No CVW in DTG/3TC arm, CVW in 1 (< 1%) patient in TAF‐based ART arm; no resistance detected at failure

All 7 patients (4 in DTG/3TC group, 3 in TAF‐based ART group) with proviral M184V/I mutation at baseline maintained HIV‐1 RNA < 50 c/mL at Wk 48

International, randomized, open‐label phase III noninferiority study in adults with HIV‐1 RNA < 50 c/mL for > 6 mos on TAF‐based ART

In analysis excluding those with BL lipid‐modifying agent use, lipid changes favored switch to DTG/3TC (n = 275) vs continued TAF‐based ART (n = 263) in overall population‒ When stratified by previous use of boosting agents, statistically favorable changes with

DTG/3TC vs TAF‐based ART persisted in boosted subgroup

TANGO: Lipid Changes at Wk 48

Slide credit: clinicaloptions.comvan Wyk. Clin Infect Dis. 2020;71:1920. van Wyk. AIDS 2020. Abstr OAB0606.

Change From BL to Wk 48, %

Overall Boosted Subgroup Unboosted Subgroup

DTG/3TC (n = 275)

TAF‐Based ART (n = 263)

PValue

DTG/3TC (n = 202)


PValue

DTG/3TC (n = 97)


PValue

Total cholesterol ‐4.5 2.3 < .001 ‐5.7 2.2 < .001 ‐0.8 2.0 ‐‐

HDL ‐1.2 1.7 ‐‐ ‐0.8 1.02 ‐‐ ‐2.3 0.1 ‐‐

LDL ‐5.5 2.2 < .001 ‐6.6 2.9 < .001 ‐2.0 ‐0.3 ‐‐

Triglycerides ‐11.2 6.0 < .001 ‐14.1 4.0 < .001 ‐1.6 12.2 ‐‐

TC:HDL ratio ‐3.3 0.5 .017 ‐4.8 0.1 .007 1.4 1.8 ‐‐

TANGO: HbA1c, Fasting Glucose, and Fasting Insulin Changes at Wk 48 A1C and fasting glucose changes minimal, comparable between treatment arms;

fasting insulin changes statistically favored switch to DTG/3TC vs continued TAF‐based ART in boosted subgroup (P = .006), with trend for unboosted subgroup

Slide credit: clinicaloptions.comvan Wyk. AIDS 2020. Abstr OAB0606.

Metabolic Parameter, % DTG/3TC TAF‐Based ARTMedian change from BL in A1C 5.3 5.4Adjusted mean change from BL in fasting glucose* Boosted baseline regimen Unboosted baseline regimen

2.3‐0.2

3.82.1

Adjusted mean change from BL in fasting insulin† Boosted baseline regimen Unboosted baseline regimen

‐11.70.9

‐7.25.1

*DTG/3TC (boosted, n = 222; unboosted, n = 82); TAF‐based ART (boosted, n = 221; unboosted, n = 60).†DTG/3TC (boosted, n = 222; unboosted, n = 83); TAF‐based ART (boosted, n = 218; unboosted, n = 61).

Poll 7: If you switch this patient’s ART regimen to DTG/3TC, would you expect her to lose weight?A. Yes

B. No

C. Not sure

TANGO: Weight Change at Wk 48

Overall weight gains minimal, comparable between treatment arms

Slide credit: clinicaloptions.comvan Wyk. AIDS 2020. Abstr OAB0606.

Weight Parameter DTG/3TC(n = 343)

TAF‐Based ART(n = 343)

Adjusted mean weight change from BL, kg (SE) Prior TAF duration < 1 yr* Prior TAF duration ≥ 1 yr† Boosted baseline regimen Unboosted baseline regimen

0.81 (0.23)1.45 (0.46)0.60 (0.26)0.81 (0.27)0.81 (0.45)

0.76 (0.22)1.35 (0.47)0.60 (0.25)0.88 (0.25)0.40 (0.44)

Weight increase ≥ 10% from BL, n (%) 11 (3) 13 (4)*DTG/3TC, n = 83; TAF‐based ART, n = 76. †DTG/3TC, n = 260; TAF‐based ART, n = 267.

The Do IT Study: Doravirine in PWH With Significant Weight Gain on INSTIs + TAF ACTG 5391: randomized, open‐label phase IV trial

Primary endpoint: Differences in weight change over 48 wks

Secondary endpoints: metabolic outcomes, viral load, safety

Overweight/obese (BMI ≥ 27.5 kg/m2) patients on RAL, DTG, or BIC + FTC/TAF (or 3TC/TAF) withunintentional > 10% weight gain

over prior 1‐3 yrs(N = 222) Continuation of entry INSTI + FTC/TAF (or

3TC/TAF)

Wk 48

DOR 100 mg QD +FTC/TAF (or 3TC/TAF)

DOR 100 mg QD +FTC/TDF (or 3TC/TDF)

NCT04636437. Slide credit: clinicaloptions.com

The DEFINE Study: Switch to D/C/F/TAF in PWH With Rapid Weight Gain on INSTI Randomized, open‐label, phase IV trial

Primary endpoint: Percent change from baseline in body weight at Week 24

Secondary endpoints: metabolic outcomes, viral load, safety, antiretroviral resistance, adherence

PWH on INSTI + FTC/TAF with rapid and significant body

weight gain(N = 110)

Wk 48

Darunavir 800 mg/cobicistat 150 mg /emtricitabine 200 mg/tenofovir alafenamide

10 mg (D/C/F/TAF)

D/C/F/TAFContinuation of entry INSTI + FTC/TAF

Wk 24

NCT04442737.

Safety of Full‐Dose Lamivudine in Patients with eGFR < 50 mL/min* Primary end points: mean model‐simulated 3TC AUC (0–24 hr) and mean observed 3TC

concentrations predose (Cmin) and 0.5‐1.5 hours postdose (Cmax)

Observed 3TC Cmax values comparable across CrCl cohorts; simulated 3TC AUC values in participants with impaired renal function consistent with historical data

Lactic acid levels all within normal limits; no adverse effects

Men and nonpregnant, nonlactating women age

≥ 18 yrs with HIV receiving 3TC for ≥ 3 mos

(N = 34)

CrCl > 50 mL/min; 3TC 300 mg daily(n = 5)

CrCl 30‐49 mL/min; 3TC 300 mg daily (n = 16)

Stratified by renal function

CrCl 15‐29 mL/min; 3TC 150 mg daily(n = 4; 1 on dialysis)

Hemodialysis; 3TC 100 mg or 150 mg daily(n = 10)

Slide credit: clinicaloptions.com*As of March 2021, DTG/3TC is indicated for patients with eGFR < 30 mL/min Fischetti. Open Forum Infect Dis. 2018;5:ofy225.

Outcomes Case

You are providing care for a patient with long‐term virologic suppression on first‐line EFV/FTC/TDF who would like to switch to another single‐tablet ART regimen because of neuropsychiatric adverse effects

The patient is at high risk for CVD events and is also receiving a proton pump inhibitor for management of GERD

Assessment 2: If following current guidelines, which of the following regimens would you recommend as a switch option for this patient?

A. DTG/3TC or BIC/FTC/TAF

B. DTG/ABC/3TC

C. DRV/COBI/FTC/TAF

D. RPV/FTC/TAF or RPV/FTC/TDF

E. Unsure

JB [2]96

Simplifying ART in the Context of Known Multidrug Resistance


60‐yr‐old man diagnosed with HIV in 1990 when he experienced weight loss, thrush, and dysphagia

Treated with fluconazole and improved rapidly; no HIV‐related complications since then

Initial CD4+ cell count: 110 cells/mm3

Treated with NRTIs (ZDV, ddI, d4T, 3TC) until 1996, when he began various combination regimens that included “recycled” NRTIs plus unboosted PIs (SQV, IDV) and NNRTIs (NVP, EFV)

Never consistently achieved viral suppression

HIV genotype in 2007 while receivingLPV/RTV + ABC/3TC (HIV‐1 RNA: 1200 c/mL; CD4+ cell count: 300 cells/ mm3)

‒ NRTI: M184V, L74V (resistance to 3TC, FTC, ABC)

‒ NNRTI: K103N (resistance to EFV, NVP)

‒ PI: D30N, L90M (resistance to NFV, SQV)

Placed on new regimen of DRV/RTV twice daily + RAL twice daily + etravirine twice daily

Viral suppression since then (2007)

Asks if he can take a simpler regimenSlide credit: clinicaloptions.com

Poll 8: How would you manage this patient’s ART regimen?A. Continue current therapy (4 pills twice daily)

B. Switch to once daily DRV/COBI + DTG + DOR (3 pills once daily)

C. Switch to DRV/COBI/FTC/TAF (1 pill once daily)

D. Switch to BIC/FTC/TAF (1 pill once daily)

E. Switch to long‐acting CAB and RPV (2 injections once a month)

F. Something else







To reduce costs

Inappropriate




DHHS: Switching Regimens in Patients With Viral Suppression and Drug Resistance “Patients with prior drug resistance can be switched to a new regimen based

on their ARV history and resistance testing results”

Some data on within‐class switch from 1 high resistance barrier drug to another (DTG BIC): Study 380‐4030

No direct data on between‐class switch from 1 high resistance barrier drug to another (boosted PI to a BIC or DTG‐containing regimen + fully active NRTI)

‒ Theoretical support from Study 380‐4030

‒ Indirectly supported by superior efficacy of DTG compared with boosted PI in patients with first‐line failure and resistance: DAWNING study

DHHS ART Guidelines. December 2019. Slide credit: clinicaloptions.com

Outcomes Case

You are providing care for a patient with a history of drug resistance (M184V and K103N) who is currently virologically suppressed on a 4‐pill twice daily ART regimen

The patient would like to switch to a simpler regimen with fewer pills

Assessment 3: Based on current DHHS guidelines, how would you counsel this patient?

A. Patients with a history of drug resistance should avoid switching ART except in cases of severe toxicity with the current regimen

B. Switching to a new regimen is recommended only if they are experiencing adverse events (any grade) with their current regimen

C. Switching to a new regimen should be feasible with consideration of their ARV history and resistance testing results

D. Unsure

JB [2]96

Between Class Switching With Underlying Resistance

SWITCHMRK results warned of switching from high barrier to low barrier resistance drug in patients with underlying resistance[1]

Viral suppression can be maintained by boosted PIs and high resistance barrier INSTIs (DTG and BIC) when only 1 accompanying NRTI is fully active, unlike lower resistance barrier drugs (eg, EVG, RAL, NNRTIs)[2]

Switching 1 low barrier drug for another is effective in those with multidrug resistance (eg, EVG for RAL as with switch to DRV + EVG/COBI/FTC/TAF)[3]

What about boosted PI to high barrier INSTI switch with underlying resistance?

1. Eron. Lancet. 2010;375:396. 2. DHHS ART Guidelines. December 2019. 3. Huhn. JAIDS. 2017;74:193. Slide credit: clinicaloptions.com

SWITCHMRK: A Cautionary Tale of Between Class Switches Randomized, double‐blind trials in which virologically suppressed patients continued

LPV/RTV‐based regimen or switched to RAL‐based regimen (N = 702)

Underlying resistance matters: % with HIV‐1 RNA < 50 c/mL for RAL vs LPV/RTV by investigator report of previous virologic failure: no, 89% vs 90%; yes, 77% vs 92%

Switch to RALContinue LPV/RTV

50

60

70

80

90

100

0 4Wks

HIV‐1 RNA < 50

c/m

L (%

)

8 12 24

87%

81%

∆: ‐6.6 (95% CI: ‐14.4 to 1.2)*

SWITCHMRK‐1 94%

88%

*Prespecified noninferiority margin: ‐12%.

Slide credit: clinicaloptions.comEron. Lancet. 2010;375:396.

50

60

70

80

90

100

0 4Wks

HIV‐1 RNA < 50

c/m

L (%

)8 12 24

∆:‐5.8 (95% CI: ‐12.2 to 0.2)*

SWITCHMRK‐2

Evidence of High Resistance Barrier With DTG and BIC

No emergent resistance with virologic failure in either treatment naive or switch studies of DTG or BIC plus 2 NRTIs[1]

Rare reports of emergent resistance in clinical practice or with DTG plus 3TC[2]

DTG superior to RAL and LPV/RTV in treatment‐experienced patients with resistance[1,3]

BIC/FTC/TAF noninferior to DTG + FTC/TAF or FTC/TDF in suppressed patients with NRTI resistance[4,5]

1. Cahn. Lancet. 2013;382:700. 2. Mahomed. South Afr J HIV Med. 2020;21:1062. 3. Aboud. Lancet Infect Dis. 2019;19:253. 4. Acosta. CROI 2019. Abstr 0551. 5. Hagins. CROI 2020. Abstr 36. Slide credit: clinicaloptions.com

DAWNING: Virologic Response at Wk 48

Patients with VF on first‐line NNRTI + 2 NRTIs switched to DTG or LPV/RPV + 2 NRTIs (≥ 1 fully active NRTI per GT resistance testing at screening); no primary resistance to INSTIs or PIs Emergent INSTI and INSTI + NRTI

resistance at CVW with DTG: n = 2

Emergent NRTI resistance but no PI resistance at CVW with LPV/RTV: n = 3

1. Aboud. Lancet HIV. 2019;6(9):e576‐e587. Slide credit: clinicaloptions.com

DTG + 2 NRTIsLPV/RTV + 2 NRTIs

*P < .0001 for superiority.

HIV‐1 RNA < 50

c/m

L(%

)[1]

ITT‐E PP

219/312

84

70

261/312

219/312

246/283

204/274

87

74

100

80

60

40

20

0n/N =

Δ 13.8*(7.3‐20.3)

Δ 12.3(5.8‐18.7)

DTG Arm BL At VF

Patient 1 RT: K70E, M184V

RT: M184V;INSTI: H51H/Y, G118R; E138E/K: R263K

Patient 2 RT: M184V, K219K/E

RT: D67N,* M184V;INSTI: G118R

*Did not confer resistance to either NRTI taken during trial.

DAWNING: Virologic Response by Presence of M184V/I and Use of 3TC or FTC at Wk 48

Slide credit: clinicaloptions.comBrown. CROI 2019. Abstr 144.

DTG + 2 NRTIsLPV/RTV + 2 NRTIs

Virologic Outcomes (ITT‐E)

219/312

85

72

187/220

152/210

33/41

30/42

8071

HIV‐1 RNA < 50

c/m

L(%

)

100

80

60

40

20

0n/N =

Use of3TC or FTC

No use of3TC or FTC

12.6 Δ 9.1

41/51

37/60

Δ 18.7

80

62

No M184V/I

M184V/I Other NRTI Mutations

Study 380‐4030: Switch to BIC/FTC/TAF From DTG + FTC/(TAF or TDF) Randomized, double‐blind, active‐controlled phase III noninferiority trial

Sax. Clin Infect Dis. 2020;[Epub]. Slide credit: clinicaloptions.com

Adults receiving DTG + FTC/(TAF or TDF) with HIV‐1 RNA < 50 copies/mL for ≥ 3‐6 mos,* no known

INSTI resistance,† and no previous VF on INSTI(N = 565)

BIC/FTC/TAF QD(n = 284)

DTG + FTC/TAF QD(n = 281)

Wk 48

*3 mos if no known NRTI resistance mutations, 6 mos with known/suspected resistance. †Documented or suspected NRTI, NNRTI, or PI resistance permitted.

Stratified by known/suspected NRTI resistance at BL (K65R or ≥ 3 TAMS vs other NRTI RAMs vs none)

Primary endpoint: HIV‐1 RNA ≥ 50 c/mL at Wk 48 by FDA Snapshot algorithm

‒ Noninferiority margin: 4%

Study 380‐4030: Virologic Outcomes at Wk 48

Patients with viral suppression on stable triple DTG‐based ART switched to BIC/FTC/TAF or continued DTG‐based ART; documented or suspected NRTI, NNRTI, or PI resistance permitted‒ Preexisting NRTI resistance: 25% in BIC/FTC/TAF arm and 24% in DTG‐based ART arm

Sax. Clin Infect Dis. 2020;[Epub].

HIV‐1 RNA< 50 c/mL

HIV‐1 RNA≥ 50 c/mL

No VirologicData

1/284

3/281

265/284

256/281

22/281

18/284

Virologic Outcomes (FDA Snapshot)

BIC/FTC/TAF (n = 284)DTG + FTC/TAF (n = 281)

Patie

nts (%)

n/N =

100

80

40

60

20

0< 1 1

93 91

6 8

‐4 ‐2 0 2 4

Favors DTG + FTC/TAFFavors BIC/FTC/TAF

‐0.71.0‐2.8

HIV‐1 RNA ≥ 50 copies/mLTreatment Difference, % (95% CI)


Study 380‐4030: Viral Suppression After Switch From DTG to BIC by Baseline NRTI Resistance HIV‐1 RNA ≥ 50 c/mL not observed in any patient with preexisting NRTI resistance

Sax. Clin Infect Dis. 2020;[Epub]. Slide credit: clinicaloptions.com

Virologic Outcomes at Wk 48 (FDA Snapshot) BIC/FTC/TAF (n = 284)DTG + FTC/TAF (n = 281)

100

80

60

40

20

0Overall K65R or ≥ 3 TAMs Other NRTI Resist. No NRTI Resist. No M184V/I M184VI ± Other

Resist.

91 8694 93

87 87 9185

91 86 87 85

Data suggest switching 1 high‐resistance barrier drug for another may be effective in patients with viral suppression, even in the setting of underlying resistance

HIV‐1 RNA < 20

c/m

L(%

)

257/284

241/281n/N =

15/16

13/14

48/55

46/53

194/213

182/214

216/237

212/247

41/47

29/34

BRAAVE 2020: Impact of BL Resistance on Outcomes Following Switch to BIC/FTC/TAF in Black PLWH 2:1 randomized, open‐label, active‐controlled

phase III study

Evaluated switch from BL regimen (2 NRTIs + third agent) to BIC/FTC/TAF in virologically suppressed black PLWH (N = 495)

Switch to BIC/FTC/TAF noninferior to remaining on BL regimen at Wk 24‒ Wk 24 was primary efficacy endpoint

Patients with BL NRTI resistance remained suppressed at Wk 24

Hagins. CROI 2020. Abstr 36. Slide credit: clinicaloptions.com

BL ARV Resistance, %

BIC/FTC/TAF(n = 330)

Continue BL Regimen(n = 165)

NRTI M184V/I

139

1612

NNRTI 21 19PI 11 15

Wk 24 Virologic Outcomes

HIV‐1 RNA < 50

c/m

L (%

) 100

80

40

60

20

0YesNRTI Resistance

98 96

BIC/FTC/TAFBL regimen

No YesM184V or M184I

No

96 95 97 95 96 95

n = 44 26 269 132 31 20 282 138

99 98 99 100 100

Series 1

Switching to BIC/FTC/TAF in Patients With HIV and Pre‐Existing M184V/I Pooled analysis of 6 phase III studies:

N = 2034

‒ Viral suppression at baseline

‒ M184V/I detected in 10%

HIV‐1 RNA < 50 copies/mL at last visit post‐switch

‒ All patients: 99%

‒ With vs without M184V/I: 99% vs 98%

‒ No treatment‐emergent resistance

Patie

nts (%)

HIV‐1 RNA < 50 Copies/mL at Last Visit

M184V/I*Patients with baseline data.

Andreatta. J Int AIDS Soc. 2020;23(suppl 7):105. Slide credit: clinicaloptions.com

All Patients* (n = 1825)

100

80

40

60

20

0All

(n = 182)+NNRTI‐R (n = 97)

+PI‐R (n = 58)

+INSTI‐R (n = 4)

Poll 9: If you did not have historical genotype data for this patient, would you order a proviral HIV genotype?A. Yes

B. No

C. Not sure

Proviral HIV DNA Genotype: Acquiring Resistance Data

DNA (archive) genotype[1,2]

‒ Sequences mutations in cell‐associated proviral DNA

‒ Can be assessed at any HIV‐1 RNA level, including undetectable

‒ Less sensitive than cumulative RNA genotypes

Concordance between DNA and RNA genotypes varies by study and ARV class (26% to 84%)[2,3]

Study 1824: switch to EVG/COBI/FTC/TAF among virologically suppressed patients with M184V/I mutation on RNA assay[4]

‒ M184V/I detected with DNA assay in only 48% (40/84) of screened patients

1. Delaugerre. HIV Med. 2012;13:517. 2. Wirden. J Antimicrob Chemother. 2011;66:709. 3. Derache. PLoS One. 2015;10:e0117430. 4. Margot. IAS 2019. Abstr MOPEB249. Slide credit: clinicaloptions.com

DHHS Guidelines: Recommendations on Proviral DNA Genotyping Proviral DNA genotyping can be considered for individuals with a suppressed viral load, particularly if complex or semi‐complex preexisting resistance is suspected

Results should be interpreted with caution; proviral genotyping may miss some or all preexisting mutations

“… for individuals who have experienced multiple prior failures, a prolonged history of prior ARV regimens, and/or for whom genotypic resistance test results are not available, it

may be appropriate to utilize proviral DNA genotypic testing.”


Review of Our 3 Cases and Proposed Switch Strategies

Switching ART in a Patient With Daily Pill Fatigue

‒ Optimal switch: Long‐acting injectable CAB and RPV, monthly

‒ Need to monitor adherence, vaccinate against hepatitis B

Switching ART to Avoid Comorbidities

‒ Optimal switch: DTG/3TC, one pill daily

‒ Not approved for eGFR < 50 mL/min, but likely safe

Simplifying ART in the Context of Known Multidrug Resistance

‒ Optimal switch: BIC/FTC/TAF, one pill daily

‒ Limited data on use of this strategy with multiclass resistance, but encouraging data from switches with active TAF and BIC


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Documents

Contemporary Management of HIV: Modifying ART in Virologically … · 2021. 4. 21. · ‒Switching ART in a Patient With Daily Pill Fatigue ‒Switching ART to Avoid Comorbidities