Unresolved Issues in Antiretroviral Therapy

Joel E. Gallant, MD, MPH Southwest CARE Center

Santa Fe, NM University of New Mexico School of Medicine Johns Hopkins University School of Medicine

Joel Gallant, MD, MPH

Southwest CARE Center Santa Fe, NM

University of New Mexico School of Medicine Johns Hopkins University School of Medicine

Unresolved Issues in Antiretroviral Therapy

Disclosures

Consulting, Advisory Boards, and DSMBs

Bristol-Myers Squibb

Gilead Sciences

Janssen Therapeutics

Merck & Co.

ViiV Healthcare

Research Support

AbbVie

Bristol-Myers Squibb

Gilead Sciences

Janssen Therapeutics

Merck & Co.

Sangamo BioSciences

ViiV Healthcare

Unresolved issues

• When and how to switch therapy in a suppressed patient

• The role of class-sparing or two-drug regimens

• The roll of induction-maintenance strategies

Switching therapy in suppressed patients When and why?

• To manage side effects

• To manage or prevent drug toxicity

• To simplify regimen (number of doses or pills)

• To address food restrictions

• To address drug interactions

Reasons to consider switching therapy in suppressed patients Older PIs: Maybe

– Reduce pill burden – Decrease metabolic effects – Decrease GI side effects

Older NRTIs: Yes

– d4T, ddI: SWITCH! (toxicity) – AZT: consider switch (toxicity,

side effects, simplification)

TDF: Why not? – Advantages of TAF over TDF

with no known disadvantages and no price difference

Nevirapine: Maybe

– Reduce pill burden – Not toxicity (most toxicity

occurs with initiation)

Efavirenz: Maybe – CNS side effects – No TAF-based

coformulation

Recent switch studies in suppressed pts Trial From To Outcome

GS-123 TDF/FTC + RAL EVG/COBI/FTC/TDF ✔ GS-264 TDF/FTC/EFV RPV/FTC/TDF ✔ Strategy-NNRTI TDF/FTC + NNRTI EVG/COBI/FTC/TDF ✔ Strategy-PI TDF/FTC + PI/r EVG/COBI/FTC/TDF ✔ SPIRIT 2 NRTI + PI/r RPV/FTC/TDF ✔ SPIRAL 2 NRTI + PI/r (exp’d pts) 2 NRTI + RAL ✔ SALT ATV/r + 2 NRTI ATV/r + 3TC ✔ OLE LPV/r + 2 NRTIs LPV/r + 3TC ✔ GS-109 TDF-based ART EVG/COBI/FTC/TAF ✔ STRIIVING Suppressive ART DTG/ABC/3TC ✔ ATLAS-M ATV/r + 2 NRTIs ATV/r + 3TC ✔ GS-119 “Salvage regimen” EVG/COBI/FTC/TAF + DRV ✔ LATTE CAB or EFV + 2 NRTIs CAB + RPV ✔ GS-1089 TDF/FTC + 3rd agent TAF/FTC + 3rd agent ✔

Adapted from David Wohl

STRIIVING: Switch to DTG/ABC/3TC

Ongoing randomized, open-label phase IIIB study

– Primary endpoint: VL < 50 at Wk 24

VL < 50 on stable ART ≥ 6 mos; no previous virologic

failure; HLA-B*5701 negative (N = 551)

DTG/ABC/3TC (n = 274)

Wk 48 Wk 24

Trottier B, et al. ICAAC 2015.

*Containing 2 NRTIs plus NNRTI, PI, or INSTI.

Baseline ART* (n = 277)

DTG/ABC/3TC (n = 277)

PI NNRTI INSTI TDF/FTC BL ART use, % 42 31 26 77

STRIIVING: Study Disposition at Wk 24

Trottier B, et al. ICAAC 2015.

13% of subjects withdrawn (n = 35)

Adverse event 10 (4%)

Lack of efficacy (virologic failure) 0

Protocol deviation 15 (5%)

Stopping criteria met 0

Lost to follow-up 3 (1%)

Investigator discretion 3 (1%)

Withdrew consent 4 (1%)

87% completed (n = 239)

Screened (N = 841)

12% of subjects withdrawn (n = 32)

Adverse event 0

Lack of efficacy (virologic failure) 0

Protocol deviation 17 (6%)

Stopping criteria met 0

Lost to follow-up 3 (1%)

Investigator discretion 3 (1%)

Withdrew consent 9 (3%)

Randomized and treated Baseline ART (n = 277)

88% completed (n = 244) 1 with missing information

Randomized and treated DTG/ABC/3TC (n = 274)

5 2

STRIIVING: Virologic Outcomes at Wk 24

Switch noninferior to maintaining baseline ART No protocol-defined virologic failure

– 3 pts in DTG/ABC/3TC arm (1%) and 4 pts in BL ART arm (1%) had VL 50-100 through Wk 24

Trottier B, et al. ICAAC 2015.

Primary Efficacy Analysis: ITT-Exposed and Per Protocol Populations

100

80

60

40

20

0 Virologic Success

Virologic Nonresponse

No Virologic Data

VL <

50

(%)

DTG/ABC/3TC (ITT-E, n = 274) Baseline ART (ITT-E, n = 277) DTG/ABC/3TC (PP, n = 220) Baseline ART (PP, n = 215)

85 88 93 93

14 10 6 1 1 < 1

12 -12 -8 -4 0 4 8

12 -12 -8 -4 0 4 8

-4.9

-0.3

4.4

2.3 -9.1

ITT-E Population

PP Population

-3.4

DTG/ABC/3TC Baseline ART

STRIIVING: Adverse Events and Treatment Satisfaction

10 pts discontinued for AEs in DTG/ABC/3TC arm vs 0 in baseline ART arm

Greater increase in treatment satisfaction score from baseline to Wk 24 in DTG/ABC/3TC arm vs baseline ART arm: adjusted mean difference: 2.4 (P < .001)

Trottier B, et al. ICAAC 2015.

AEs in 10 Pts Who Withdrew* Grade Insomnia 2

Diarrhea, flatulence, rash Abdominal pain, anxiety, nausea, body ache

1 2

Euphoric mood Headache

1 2

Abdominal cramps, chills, diarrhea, dizziness, headache

2

Pruritus 2

Abdominal pain, diarrhea, flulike syndrome, profuse sweating, change in body odor Fatigue,† malaise, depression

1 2

Nasal congestion Worsening fatigue Nausea

1 2 3

Alopecia 1

Fatigue† 1

Homicide† N/A

*None serious AEs except homicide.

GS-109: Switching to E/C/F/TAF from TDF- based regimens

100

80

60

40

20

0

Wk

48 V

L <

50, %

All Prior Regimens

Prior EFV/TDF/FTC

Prior Boosted

ATV + TDF/FTC

Prior EVG/COBI/ FTC/TDF

EVG/COBI/FTC/TAF TDF-Based Regimen Primary Endpoint

P < .001 P = .02 P = .02 P = NS

97 93 96 90

97 92 98 97

932/ 959

444/ 477

241/ 251

112/ 125

390/ 402

183/ 199

301/ 306

149/ 153 n/N =

Mills A, et al. Lancet Infect Dis 2016;16:43-52

GS 109: Switch from TDF-based Regimens to E/C/F/TAF : Renal and Bone Outcomes

BMD changes: spine

Hip BMD was similarly increased for pts treated with TAF regimen

Mills A, et al. Lancet Infect Dis 2016;16:43-52

Regimen Renal Events Leading to Discontinuation

EVG/COBI/ FTC/TAF (n = 959)

Acute renal failure

Interstitial nephritis

TDF-Based Regimen (n = 477)

Chronic kidney disease

Elevated serum creatinine

Fanconi syndrome (mild jaundice)

Increased creatinine

Nephretic colic (nephrolithiasis)

4 3 2 1 0

-1 -2 -3

Med

ian

% C

hang

e

in B

MD

(Q1,

Q3)

Baseline Week 24

EVG/COBI/FTC/TAF TDF-Based Regimen

Week 48

1.79

-0.28

P < .001

GS-112: Switching to E/C/F/TAF Regimen With Renal Impairment (eGFR 30-60)

• Changes in eGFR from baseline to Wk 48

• Changes in spinal BMD from baseline to Wk 48

Gupta S, et al. IAS 2015. Abstract TUAB0103.

Total TDF Non-TDF

Med

ian

Cha

nge

from

Bas

elin

e

10

0

-10

-0.6

+0.2

-1.8 -1.8* -1.5 -2.7*

Baseline: 56 58 53 54 56 50 eGFRCG mL/min

eGFRCKD-EPI Cr mL/min/1.73m2

*P < 0.05.

Total TDF Non-TDF

*P < 0.05.

4

2

0

-2

Mea

n %

Cha

nge

S

pine

BM

D

2.95* 2.29*

0.99

Multicenter, open-label phase III trial, N=242

GS 1089: Switch from F/TDF to F/TAF

Randomized, double-blind, double-dummy, active-controlled study

*F/TAF Dose: • 200/10 mg with boosted PIs • 200/25 mg with unboosted third agents

Secondary Endpoint

n=333

n=330

Primary Endpoint HIV-1 RNA <50 c/mL

BL Wk 96 Wk 48

F/TAF (200/10 or 200/25 mg)* QD

F/TDF Placebo QD

Continue Third Agent

F/TDF (200/300 mg) QD

F/TAF* Placebo QD

Continue Third Agent

VL <50 on F/TDF + Third Agent

eGFR ≥50 mL/min

Gallant J, et al. Lancet HIV 2016;3:e158-65

GS 1089: Efficacy at Week 48 (Snapshot)

F/TDF F/TAF

0

VL

<50,

%

‒10% +10%

5.1 -2.5

1.3

Non-success

Treatment Difference (95% CI) Virologic Outcome

Gallant J, et al. Lancet HIV 2016;3:e158-65

GS 1089: Switch from F/TDF to F/TAF Changes in eGFR

*eGFR calculated with Cockcroft-Gault equation

Me

dia

n (

Q1

, Q

3)

ch

an

ge

eG

FR

* (m

L/m

in)

8.4 mL/min

2.8 mL/min

p <0.001

Gallant J, et al. Lancet HIV 2016;3:e158-65

RBP, retinol-binding protein; β2M, β2-microglobulin.

GS 1089: Switch from F/TDF to F/TAF Change in Renal Biomarkers at Week 48

All differences between treatments statistically significant (p <0.001)

F/TAF

F/TDF

Albumin Protein β2M RBP

Urine Protein to Creatinine Ratio

Med

ian

% c

hang

e

Gallant J, et al. Lancet HIV 2016;3:e158-65

GS 1089: Switch from F/TDF to F/TAF: Bone density changes

≥ 3% BMD increase at Week 48 F/TAF 30.3%

p<0.001 16.7%

p=0.003 F/TDF 13.7% 8.6%

321 310 300

320 310 306

321 309 300

317 305 303

F/TAF, n

F/TDF, n

Mea

n %

cha

nge

(95%

CI)

Spine

1.5

-0.2

1.1

-0.2

Weeks Weeks

p <0.001

Hip

p <0.001

Gallant J, et al. Lancet HIV 2016;3:e158-65

Recent switch studies in suppressed pts Trial From To Outcome

GS-123 TDF/FTC + RAL EVG/COBI/FTC/TDF ✔ GS-264 TDF/FTC/EFV RPV/FTC/TDF ✔ Strategy-NNRTI TDF/FTC + NNRTI EVG/COBI/FTC/TDF ✔ Strategy-PI TDF/FTC + PI/r EVG/COBI/FTC/TDF ✔ SPIRIT 2 NRTI + PI/r RPV/FTC/TDF ✔ SPIRAL 2 NRTI + PI/r (exp’d pts) 2 NRTI + RAL ✔ SALT ATV/r + 2 NRTI ATV/r + 3TC ✔ OLE LPV/r + 2 NRTIs LPV/r + 3TC ✔ GS-109 TDF-based ART EVG/COBI/FTC/TAF ✔ STRIIVING Suppressive ART DTG/ABC/3TC ✔ ATLAS-M ATV/r + 2 NRTIs ATV/r + 3TC ✔ GS-119 “Salvage regimen” EVG/COBI/FTC/TAF + DRV ✔ LATTE CAB or EFV + 2 NRTIs CAB + RPV ✔ GS-1089 TDF/FTC + 3rd agent TAF/FTC + 3rd agent ✔ SWITHCMRK 2 NRTI + LPV/r (exp’d pts) 2 NRTI + RAL ✗

HARNESS 2 NRTI + 3rd Agent ATV/r + RAL ✗

Adapted from David Wohl

HIV+ pts with viral suppression on LPV/r-based

ART for ≥ 3 mos. Not required to

be initial regimen

(N = 702) (SWITCHMRK 1: 348 SWITCHMRK 2: 354)

SWITCHMRK 1 & 2: From LPV/r + NRTIs to RAL + NRTIs

Switch to RAL + other BL ARVs*

(SWITCHMRK 1: n = 174 SWITCHMRK 2: n = 176)

Continue LPV/r + other BL ARVs*

(SWITCHMRK 1: n = 174 SWITCHMRK 2: n = 178)

Wk 12 lipid analysis

Wk 24 efficacy analysis

*All patients continued background regimen including ≥ 2 NRTIs.

Eron JJ, et al. Lancet. 2010;375:396-407.

Inferior efficacy of RAL appeared driven by more failure among pts with previous virologic failure

SWITCHMRK: Prior failure predicts failure

Eron JJ, et al. Lancet. 2010;375:396-407.

Outcome SWITCHMRK1 SWITCHMRK 2

RAL (n = 174)

LPV/r (n = 174)

RAL (n = 176)

LPV/r (n = 178)

Patients without previous virologic failure

VL < 50 at Wk 24, % 85.1 85.8 92.5 93.5

Treatment difference, % (95% CI) -0.7 (-9.9 to 8.6) -1.0 (-8.5 to 6.3)

Patients with previous virologic failure

VL < 50 at Wk 24, % 72.3 89.7 79.7 93.8

Treatment difference, % (95% CI) -17.3 (-33.0 to -2.5) -14.2 (-26.5 to -2.6)

Switching: Caveats

Know the treatment and resistance history

Avoid switching from high barrier to lower barrier agents when you don’t

Switching and simplifying therapy

“Vertical Switches”: switch to drug with lower resistance barrier

Most drug discontinuations

Boosted PI → NNRTI

Boosted PI → INSTI

Boosted PI → any STR

DRV/r twice daily → once daily

“Horizontal Switches”: switch to drug with equal or higher resistance barrier

RTV → COBI (boosters)

Switches within INSTI class

EFV or NVP → RPV or ETR

LPV/r or ATV/r → DRV/r

ABC or AZT → TDF/TAF

TDF → TAF

Toma J, et al. ICAAC 2015, September 17-21, 2015, San Diego.

• Concordance with historical resistance (individual ARVs): 85%

• NNRTIs: 93% • PIs: 84% • NRTIs: 76%

• Identified major wild-type (nonmutant) variants at 97% • False omission rate 3%.

Class-sparing regimens, 2-drug regimens, and induction-maintenance strategies

• “Class-sparing” is an misnomer: All recommended and alternative initial regimens still contain 2 classes (sparing the other classes)

• The real questions: • Are 2 drugs ever enough?

• Can you treat HIV without NRTIs?

• Can you “de-intensify therapy” after suppression?

Nuke-sparing regimens

The need for “nuke-sparing regimens”: a brief history

• 1986-2001: NRTIs caused lipoatrophy, neuropathy, anemia, pancreatitis, lactic acidosis, hepatic steatosis, and death

• 2001-2015: NRTIs better tolerated, but still caused nephrotoxicity, decreased bone density, hypersensitivity, and possible increase in MI risk

• 2015-present: There are few patients who cannot take either TAF or ABC

NEAT 001: DRV/r + either RAL or TDF/FTC: Primary endpoint at W96 by baseline characteristics

n = 805

n = 530

n = 275

n = 123

n = 682

Overall

< 100,000 c/ml

> 100,000 c/ml

< 200/mm3

> 200/mm3

Baseline HIV-1 RNA

Baseline CD4+

17.4 %

7 %

36 %

39.0 %

13.6 %

13.7 %

7 %

27 %

21.3 %

12.2 %

RAL + DRV/r

TDF/FTC + DRV/r

10 0 -10 20 30

9

Difference in estimated proportion (95% CI) RAL – TDF/FTC; adjusted

p = 0.09

p = 0.02

-1.1 8.6

-3.9 3.5

-0.05 19.3

4.7 30.8

-3.4 6.3

Raffi et al, CROI 2014, Abstract 84LB

GARDEL: LPV/r + 3TC noninferior to LPV/r + 2 NRTIs at Wk 48

CD4 increase similar

Grade 2-3 AEs more frequent in triple-ART arm (88 vs 65 events)

VF in 22 pts, of whom 2 had resistance (M184V)

– Both on dual ART Patie

nts

(%)

88.3 83.7

Δ 4.6 (95% CI: -2.2 to 11.8;

P = .171)

Dual ART (n = 214) Triple ART (n = 202)

189 169 0

20

40

60

80

100

4.7 5.9 0.9 4.9

n = 2 10 12 Virologic Success*

Virologic Non-

response

D/C Due to AE or Death

D/C for Other

Reasons

6.1 5.4 10 13 11

Cahn P, et al. Lancet Infect Dis 2014;14:572-80

*VL< 50 c/mL by FDA Snapshot algorithm.

Phase IV open-label single-arm exploratory trial

– Primary endpoint: VL < 50 at Week 48 (ITT-e, FDA snapshot analysis)

PADDLE: Dolutegravir + Lamivudine in Treatment-Naive Pts

Figueroa MI, et al. EACS 2015. Abstract 1066.

Treatment-naive pts with VL 5000-100,000 and

CD4 ≥ 200 HBsAg negative

(N = 20)

DTG 50 mg QD + 3TC 300 mg QD

PADDLE: All Pts Virologically Suppressed by Wk 8 of DTG + 3TC Included 4 pts with VL > 100,000 at BL

Figueroa MI, et al. EACS 2015. Abstract 1066.

Pt # HIV-1 RNA (copies/mL)

Screen BL Day 2 Day 4 Day 7 Day 10 Wk 2 Wk 3 Wk 4 Wk 6 Wk 8 Wk 12 Wk 24 1 5584 10,909 3701 383 101 71 < 50 < 50 < 50 < 50 < 50 < 50 < 50 2 8887 10,233 5671 318 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 3 67,335 151,569 37,604 1565 1178 266 97 53 < 50 < 50 < 50 < 50 < 50 4 99,291 148,370 11,797 3303 432 179 178 55 < 50 < 50 < 50 < 50 < 50 5 34,362 20,544 4680 1292 570 168 107 < 50 < 50 < 50 < 50 < 50 < 50 6 16,024 14,499 3754 1634 162 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 7 37,604 18,597 2948 819 61 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 8 25,071 24,368 6264 1377 Not done 268 105 < 50 < 50 < 50 < 50 < 50 < 50 9 14,707 10,832 Not done 516 202 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

10 10,679 7978 5671 318 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 11 50,089 273,676 160,974 68,129 3880 2247 784 290 288 147 < 50 < 50 < 50 12 13,508 64,103 3496 3296 135 351 351 84 67 < 50 < 50 < 50 < 50 13 28,093 33,829 37,350 26,343 539 268 61 < 50 < 50 < 50 < 50 < 50 < 50 14 15,348 15,151 3994 791 198 98 < 50 61 64 < 50 < 50 < 50 < 50 15 23,185 23,500 15,830 4217 192 69 < 50 < 50 < 50 Not done < 50 < 50 < 50 16 11,377 3910 370 97 143 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 17 39,100 25,828 11,879 1970 460 147 52 < 50 < 50 < 50 < 50 < 50 < 50 18 60,771 73,069 31,170 2174 692 358 156 < 50 < 50 < 50 < 50 < 50 < 50 19 82,803 106,320 35,517 2902 897 352 168 76 < 50 < 50 < 50 < 50 < 50 20 5190 7368 3433 147 56 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

“Nuke-sparing” and “nuke-lite” regimens Regimen Results

DRV/r + RAL (ACTG 52621) Poor performance at high VL DRV/r + RAL (NEAT2) Less effective at high VL, low CD4 DRV/r + MVC (MODERN3) Less effective than standard ART ATV/r + RAL (HARNESS4 – switch) Less effective than standard ART LPV/r + RAL (PROGRESS5) Small study; few pts with high VL LPV/r + EFV (ACTG 51426) Poorly tolerated but effective LPV/r + 3TC (GARDEL7) As effective as standard ART LPV/r + 3TC or FTC (OLE8 – switch) As effective as standard ART ATV/r + 3TC (SALT9 – switch) As effective as standard ART DTG + 3TC (PADDLE10) Promising but preliminary

1. Taiwo B, et al. AIDS. 2011;25:2113-22 2. Raffi et al. CROI 2014, Abstract 84LB 3. Stellbrink H-J, et al. IAD 2014. Abstract MOAB0101 4. Van Lunzen J et al. IAC 2014. Abstract A-641-0126-11307 5. Reynes J, et al. AIDS Res Hum Retroviruses. 2013;29:256-65

6. Daar ES et al. Ann Intern Med 2011 7. Cahn P, et al. Lancet Infect Dis 2014;14:572-80 8. Gatell J, et al. AIDS 2014. Abstract LBPE17. 9. Perez-Molina, JA, et al. IAC 2014. Abstract LBPE18. 10 Figueroa MI, et al. EACS 2015. Abstract 1066.

LATTE-2: IM Cabotegravir + Rilpivirine For Long-Acting Maintenance ART Phase IIb, multicenter, open-label study

– Primary endpoints: VL < 50 by FDA snapshot, PDVF, and safety at maintenance Wk 32

Margolis DA, et al. CROI 2016. Abstract 31LB.

CAB 400 mg IM + RPV 600 mg IM Q4W (n = 115)

CAB 600 mg IM + RPV 900 mg IM Q8W (n = 115)

*Pts with VL < 50 from Wk 16 to Wk 20 continued to maintenance phase.

ART-naive HIV+ pts with

CD4 > 200 (N = 309)

CAB 30 mg PO + ABC/3TC PO QD (n = 56)

CAB 30 mg PO QD + ABC/3TC

Wk 32 primary analysis; dose selection

Wk 20

Induction Phase* Maintenance Phase

Wk 1 Wk 96

LATTE-2: Maintenance Wk 32 Virologic Efficacy (ITT-Maintenance Exposed) Efficacy of Q4W and Q8W IM regimens similar to oral regimen

No INSTI, NNRTI, or NRTI resistance mutations detected

Margolis DA, et al. CROI 2016. Abstract 31LB.

95 94 91

4 < 1 4 < 1 5 5

Virologic success

Virologic non-

response

No virologic data

VL

<50

, %

100

80

60

40

20

0

IM CAB + RPV Q4W (n = 115) IM CAB + RPV Q8W (n = 115) Oral CAB + ABC/3TC (n = 56)

Treatment Differences (95% CI)

Q8W

-4.8 3.7

12.2

IM Oral

-12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12

Q4W

-5.8

2.8

11.5 -12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12

The rationale for 2-drug regimens

• (To avoid NRTI toxicity)

• Reduce cost (e.g. 3TC + X)

• Allow for long acting therapy (e.g. CAB + RPV)

Evolution of Integrase Mutations in 2 DTG Monotherapy Switch Studies

All 4 pts with virologic failure had history of INSTI use before switch

1 pt had previous RAL failure but no INSTI resistance

1. Rojas J, et al. EACS 2015. Abstract 1108. 2. Katlama C, et al. EACS 2015. Abstract 714.

VL at VF, c/mL

INSTI Resistance by Timepoint (Detection Source) Day 0 Wk 4 Wk 12/13 Wk 24

155[1] - None (DNA) - 118R (DNA)

469[2] L74I (DNA) - L74I, E92Q (RNA)

R: EVG RAL -

291[2] None (DNA) - - 155H (RNA) R: EVG RAL

2220[2] None (DNA) None (RNA)

None (DNA)

E138K / G140A, Q148R (RNA)

R: DTG EVG RAL

Induction maintenance

• Some studies start therapy with 2-drug regimens (e.g. PI/r + 3TC, DTG + 3TC)

• Some studies use induction-maintenance strategy (e.g. LATTE)

• Is induction necessary? Would the 2-drug maintenance regimen have worked just as well from the start?

• What we eventually do in clinical practice will depend on study design