Update on Antiretroviral Therapy:

Current Treatment Guidelines and

What’s on the Horizon

Rajesh T. Gandhi, M.D.Disclosures: grant support from Gilead, Roche, EBSCO

Thanks to Jacqueline Chu, M.D., Joe Eron, M.D. and Neha Patel for assistance with slides

Where Do We Come From? What Are We? Where Are We Going? – Paul Gauguin

Updated: July 28, 2015

http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf

Updated: Sept. 2015

Case

• 55 yo M with HIV infection• Past history: gastroesophageal reflux disease

(GERD), allergic rhinitis, hypertension, smoking, elevated lipids

• Medications: fluticasone, omeprazole• CD4 cell count 550. HIV RNA 125,000• He asks 3 questions:

– “When should I be treated for HIV?”– “What should l be treated with?”– “If I take medicines, will I be cured?”

When to Start

START

• Enrolled 4685 pts from 35 countries• Primary endpoint: serious AIDS-related event, serious non–

AIDS-related event, or death• May 2015: DSMB recommended offering ART to all participants• Median age: 36 yrs; mean follow-up 3 yrs.• Median baseline CD4 count 651. Deferred group: median CD4

count at ART initiation, 408

Insight START Study Group, NEJM, 2015

HIV-infected adults CD4 count >500

Immediate ART (n=2326)

Deferred ART (n=2359)(CD4 Declined to <350 or AIDS-related

event)

START

• Primary endpoint: 57% lower in immediate-ART arm than in deferred arm

• Benefits of immediate ART similar in all patient subgroups, e.g. high-income and low/moderate income regions

• No increase in adverse events associated with immediate vs. deferred ART

Insight START Study Group, NEJM, 2015

Time to primary event

Deferred initiation

Immediate initiation

• 68% of primary endpoints occurred in pts with CD4 >500

Lundgren J, et al. 8th IAS Conference. Vancouver, 2015. Abstract MOSY0301.The INSIGHT START Study Group. N Engl J Med. 2015;July 20..

0

20

40

60

80

100

Nu

mb

er o

f E

ven

ts

AIDS-Related

Non-AIDS Related

Components(Serious Events)

CompositeEndpoint

96Deferred ART (n=2359)

Immediate ART (n=2326)

42

50

14

47

29

Number of Serious Events

57%Reduction(P<0.001)

72%Reduction(P<0.001)

39%Reduction(P=0.04)

START: AIDS- and non-AIDS events

• TB, Kaposi sarcoma, lymphoma — most common AIDS-related events — all less frequent in immediate-ART gp

• Cancer rates (combining AIDS/non-AIDS) lower in immediate-ART gp

• Cardiovascular disease rates similar between 2 gps -- but baseline risk low

Temprano

• Similar benefit to early ART (compared to WHO-guided deferred ART) seen in randomized study performed in Cote d’Ivoire (n=2056, 41% with CD4 count >500)

The TEMPRANO ANRS 12136 Study Group. N Engl J Med 2015

44% reduction in risk with early ART

Sev

ere

HIV

mo

rbid

ity

Severe HIV morbidity: All cause mortality; AIDS-defining event; severe bacterial infection, non-AIDS cancers

WHO on Sept 30, 2015: “Treat-all”

http://www.who.int/hiv/en/

36.9

When to Start: July 2015

US DHHS Guidelines, January 2011.

ART recommended for all HIV+ individuals, regardless of CD4 cell count

AI: strong recommendation, data from randomized clinical trials

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents

in HIV-1-infected adults and adolescents – updated July 28, 2015.

CD4 Cell Count Recommendation

• ≤ 350• 350-500• >500

AIAIAI

“When should I start treatment?”You should start now!

Population Recommendation Strength Evidence

Adults (>19 yr)

Initiate in All Strong Moderate Priority: advanced clinical disease, CD4 ≤350 Strong Moderate

Pregnant/breast-feeding women Initiate in All Strong Moderate

Adolescents(10–19 yo)

Initiate in All Conditional LowPriority: advanced clinical disease, CD4 ≤350 Strong Moderate

Children Initiate in All

1-10 yo: Conditional <2 yo: Strong

1-10 yo: Low <2 yo: Moderate

WHO: When to Start ART

WHO Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV, Sept 2015

When to Start ART after Opportunistic Infection (OI)

OI When to start Cryptosporidiosis,

microsporidiosis, PMLAs part of initial therapy of the OI

PCP, MAC, Toxoplasma, most

other OIs

Within 2 weeks

Tuberculosis If CD4 count <50: within 2 wkIf CD4 count >50: within 8-12 wks

(TB meningitis: careful monitoring/consultation)

Cryptococcal meningitis

4-5 weeks after initiation of anti-fungal therapy

Zolopa A et al, PLoS One. 2009; Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, 2013, WHO Consolidated ARV Guidelines, 2013. Zanoni and Gandhi, Inf Dis Clin N Am, 2014

What to Start

13

http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf

“How should I be treated?”

Case – What to Start?

• 55 yo M with HIV• GERD, allergic rhinitis, HTN, smoking,

elevated lipids. Medications: fluticasone, omeprazole

• CD4 cell count 550. HIV RNA 125,000

Gandhi M, Gandhi RT. N Engl J Med 2014;371:248-259.

Reproductive Cycle of HIV and Sites of Action of Major Classes of Antiretroviral Medications

Gandhi M, Gandhi RT. N Engl J Med 2014;371:248-259.

Reproductive Cycle of HIV and Sites of Action of Major Classes of Antiretroviral Medications

Reverse Transcriptase Inhibitors (RTI)

Nucleoside RTI (NRTIs) – tenofovir, abacavir, 3TC

Nonnucleoside RTI (NNRTIs) -- efavirenz

Fusion Inhibitors

CCR5 Antagonists

Integrase strand transfer inhibitors (INSTI) – dolutegravir, raltegravir, elvitegravir/cobicistat

Protease inhibitors (PI) – lopinavir/ritonavir

http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf

Recommended Regimens (n=5)

Integrase inhibitor + 2 Nucleoside RTI

Dolutegravir/abacavir/3TCDolutegravir + tenofovir/FTCElvitegravir/cobi/Tenofovir/FTCRaltegravir +Tenofovir/FTC

Protease inhibitor + 2 Nucleoside RTI

Darunavir/ritonavir +TDF/FTC

What to Start – 2015

Recommended Regimens

Non-nucleoside RTI + 2 Nucleoside RTI

TDF + (3TC or FTC) + Efavirenz (EFV)

WHO: What to Start

In the U.S. Guidelines, EFV/TDF/FTC Moved to Alternative

• EFV: long track record but, compared with new regimens, decreased tolerability– In SINGLE trial, DTG

+ ABC/3TC superior to EFV/TDF/FTC, largely because of more treatment discontinuations in EFV gp (10% vs. 2%)

Walmsley S et al, NEJM, 2013

DTG + ABC/3TC vs. EFV/TDF/FTC

Efavirenz and Suicidality

• In retrospective analysis of multiple ACTG studies1, increased suicidality in those randomized to EFV-containing regimens as compared to EFV-free regimens

• In a genetic substudy2, those predicted to have slowest clearance of EFV had highest relative risk of suicidality

1Mollan K et al, Ann Int Med, 20142Mollan KR et al, IAS 2015 TUPEB273

HR: 2.28 (95% CI 1.27-4.10; P = .006)

47 events/5817 PY (8.1/1000 PY)

0.05

0.04

0.03

0.02

0.01

0P

rob

abili

ty1920 24 48 72 96 120 144 168

Wks to Suicidality

EFVEFV-free

15 events/4099 PY (3.66/1000 PY)

Integrase Inhibitors for 1st Line HIV Therapy

• Elvitegravir/cobi superior to atazanavir/ritonavir (PI) in HIV+ women (WAVES)

• Raltegravir superior to atazanavir/ritonavir and darunavir/ritonavir (ACTG A5257)

• Dolutegravir superior to darunavir/ritonavir (FLAMINGO)

• Dolutegravir superior to efavirenz (SINGLE)

In U.S. guidelines, 4 of 5 recommended options for initial therapy include integrase inhibitor

Is Efavirenz 400 the Answer?

• ENCORE 1: EFV 400 mg vs. EFV 600 mg each in combination with TDF/FTC- EFV 400 non-inferior to EFV 600 mg - ≈90% virologic suppression in both arms- Fewer participants in 400 mg group had

EFV-related side effects• Studies of EFV 400 in pregnant women and with

TB treatment (rifampicin)• Randomized trial to compare TDF/3TC/EFV 400

to TDF/3TC/DTG (NAMSAL)

Encore 1 Study Group, Lancet ID, 2015

Choosing an Antiretroviral Regimen

• Patient-related considerations:- HBV coinfected: choose TDF + 3TC or FTC- Cardiovascular disease: Favor tenofovir over

abacavir- Renal disease: Favor abacavir over tenofovir

• Drug-related considerations:- Food: efavirenz best on empty stomach- Drug interactions: protease inhibitors (and

cobicistat) inhibit CYP3A4 many interactions

Drug Interactions: Exogenous Steroids

• Injectable steroids: levels increased by PIs– 10% of patients on PIs who received a steroid

injection developed clinical evidence of steroid excess or adrenal insufficiency1

• Inhaled fluticasone2 & budesonide3: systemic levels increased by PIs – Beclomethasone is a safer alternative4

1Hyle E et al, JAIDS, 20132DHHS guidelines for use of antiretroviral agents in HIV-1-infected adults and adolescents. Feb 12, 2013.

http://AIDSinfo.nih.gov 3http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm336367.htm

4Boyd S et al, JAIDS, 2013

Case: Salient Considerations

• 55 yo M with HIV. Genotype: no resistance. • Choosing the NRTIs:

– High risk for CV disease (HTN, smoking)– Elevated lipids

Favor TDF/FTC• Choosing between NNRTI, PI, INSTI:

– High VL (>100,000) – don’t choose rilpivirine (RPV)– On omeprazole – reduces ATV, RPV absorption– On fluticasone – interacts with PIs, cobi

Favor Dolutegravir

ART: On the Horizon

Gandhi M, Gandhi RT. N Engl J Med 2014;371:248-259.

Reproductive Cycle of HIV and Sites of Action of Major Classes of Antiretroviral Medications

Reverse Transcriptase Inhibitors (RTI)

Nucleoside RTI (NRTIs) –

TAF

Nonnucleoside RTI

(NNRTIs) –Long-acting Rilpivirine;Doravirine,

Fusion Inhibitors

CCR5 Antagonists

Integrase strand transfer

inhibitors (INSTI) – long-acting Cabotegravir

Protease inhibitors (PI)

New version of current medication:Tenofovir alafenamide (TAF)

• TAF: pro-drug of tenofovir that concentrates in cells, converted to tenofovir (TFV)

• TAF: 90% lower plasma TFV levels compared to TDF (tenofovir disoproxil fumarate)

• TAF compared to TDF for initial therapy:

Sax P et al, Lancet, 2015

n=1733

TAF vs. TDFH

IV-1

RN

A <

50 c

/mL,

%

Success Failure No Data0

20

40

60

80

100 92

4 4

90

4 6

• Virologic efficacy: E/C/F/TAF non-inferior to E/C/F/TDF

• TAF associated with:• Smaller decrease in bone

mineral density (BMD)• Smaller decrease in eGFR• Less proteinuria• Greater increases in

cholesterol, LDL, HDL, TGs (identical changes in TC:HDL)

E/C/F/TAF

E/C/F/TDF

Sax P et al, Lancet, 2015.

.

TAF Switch Studies

• In switch studies, changing from TDF to TAF:• Similar or higher virologic efficacy• Stable/improved renal function; less proteinuria• Increased bone mineral density:

Mills A, et al. IAS 2015. # TUAB0102; Gupta S, et al. IAS 2015. # TUAB0103; Gupta S et al, ICAAC, 2015; Shamblaw D et al, ICAAC 2015; Thompson M et al, IDWeek 2015

432

10

-1

-2

-3

Med

ian

% C

han

ge

in S

pin

e B

MD

(Q

1, Q

3)

Baseline Wk 24

EVG/COBI/FTC/TAFTDF-based regimen

Wk 48

1.79

-0.28

Treatment-experiencedHIV RNA <50eGFR 30-69

Switch to E/C/F/TAF (open-label)(n=242)

Primary EndpointWk 24: Change From

Baseline in eGFR

Switch to E/C/F/TAF in Patients With Renal Impairment (Study 112)

• Median age: 58. Median eGFR 56. HTN 40%; DM: 14%. 65% on TDF prior to switch

• GFR unaffected by switch to E/C/F/TAF• After switch to E/C/F/TAF, improved:

– Spine and hip BMD– Albuminuria and proteinuria

Gupta S, et al. J Int AIDS Soc. 2015;18(suppl 4):35-36. IAS 2015 Abstract TUAB0103

HIV+/HBsAg positiveHBV DNA <9 log10 IU/L

HIV RNA <50

Switch to E/C/F/TAF(n=242)

Switch to E/C/F/TAF in HIV/HBV Coinfected Patients (Study 1249)

Switch to E/C/F/TAF(n=72)

Primary Endpoint Wk 24: HIV RNA <50; HBV DNA <29 IU/mL

Gallant J, et al. 8th IAS Conference. Vancouver, 2015. Abstract WELBPE13.

• Pre-switch: 96% on TDF; 42% HBeAg+

• Following switch to E/C/F/TAF:– HIV suppression maintained– HBV suppression maintained– No HBV flares

HIV-1 RNA <50c/mL

HBV DNA<29 IU/mL

Fibrosis (mod/severe)

0

20

40

60

80

100100

86

62

92 92

58†

Wk 48

Elvitegravir/cobicistat/FTC/TAF – Approved in U.S. on Nov. 5, 2015

FTC/TAF – April 2016

Rilpivirine/FTC/TAF – July 2016

Darunavir/cobi/FTC/TAF – phase III

DTG/FTC/TDF vs. DTG/FTC/TAF in treatment naïve pts– WITS RHI

• For initial therapy– LPV/r + 3TC; GARDEL– DRV/r + RAL; NEAT001– DTG + 3TC3 – being studied (PADDLE, ACTG 5353)

• Switching after patient virologically suppressed (maintenance therapy)– Switch to LPV/r + 3TC/FTC (OLE)– Switch to ATV/r + 3TC (SALT)– DTG + 3TC3 (ASPIRE) – being studied– DTG/RPV – being studied (SWORD-1 and -2)

On the Horizon: Nuc-lite or Nuc-sparing regimens

Cahn, Lancet ID 2014; Gatell, Lancet ID 2015; Perez-Molina, Lancet ID 2015. 2. Raffi, Lancet 2014; Boyd Lancet 2013. 3. Girouard, IAS 2015 TULBPE12; PADDLE, ASPIRE, ACTG A5353

• Long-acting agents: cabotegravir, LA-rilpivirine, broadly-neutralizing antibodies

• Cabotegravir (CBG) and rilpivirine (RPV) available in long-acting nanosuspension formulations which have half-lives of months

ART: Long-acting Agents

Spreen, JAIDS 2014; Margolis CROI 2015 #554LB; Jackson, Clin Pharmacol Ther 2014; Caskey, Nature 2015, Viiv press release, Nov 2015

Latte-2

At wk 32, VL <50 in 95% of q8 wk arm, 94% of q4 wk arm, 91% of oral arm. Only 1 pt in an injection arm had virologic failure: no resistance.

Gandhi M, Gandhi RT. N Engl J Med 2014;371:248-259.

Reverse Transcriptase Inhibitors (RTI)

Nucleoside RTI (NRTIs)

Nonnucleoside RTI (NNRTIs)

Integrase strand transfer inhibitors (INSTI)

Protease inhibitors (PI)

New Drugs in New Classes

Fusion Inhibitors

CCR5 Antagonists

Gandhi M, Gandhi RT. N Engl J Med 2014;371:248-259.

Reverse Transcriptase Inhibitors (RTI)

Nucleoside RTI (NRTIs)

Nonnucleoside RTI (NNRTIs)

Integrase strand transfer inhibitors (INSTI)

Protease inhibitors (PI)

Maturation inhibitor:

BMS 955176: phase IIb (with DTG + ATV +/- RTV) in treatment-experienced pts

GSK2838232 (phase I)

New Drugs in New Classes

Fusion Inhibitors

CCR5 AntagonistsAttachment inhibitor: BMS-663068 (prodrug)

Promising phase IIb results (n=251)

Phase 3 trial of 068* + optimized background therapy vs. OBT in treatment experienced pts with multidrug resistant HIV*600 mg bid

Hwang et al, IAS 2015, TUAB0106LB, Jeffrey et al, CROI 2015 538; Lataillade, IAS 2015 TUPEB284; Lalezari Lancet HIV, 2015

• Ending the epidemic with ART?

--90/90/90

• Cure?

Challenges and Opportunities

Ending the Epidemic with ART?

1. Cohen MS, et al. N Engl J Med 2011;10.1056. 2. Cohen MS, et al. IAS 2015, MOAC0101LB. 3. UNAIDS, 2014

• Treatment and virologic suppression markedly reduce transmission1,2 (“Treatment as prevention”)

• Modeling suggests that treating a high proportion of infected patients could end the epidemic by 20303

• UNAIDS Treatment Targets:

= 73% suppressed

A. U.S.

B. Russia

C. Britain

D. Rwanda

E. Switzerland

In which country is the highest proportion of HIV-infected patients

virologically suppressed?

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

68%

62% 61% 59%

52% 52%

40%35%

32% 30% 30%

9%

UNAIDS Target: 73% of all HIV+ people achieving viral suppression

(*SSA = Regional average From 30 countries)

Adapted from Levi J, et al. IAS 2015. MOAD0102.

Percentage of HIV+ People with HIV RNA Suppression

Case

• 55 yo M with HIV infection• “If I take medicines, will I be cured?”

• Only 1 known case of HIV cure:– HIV+ man with leukemia who underwent allogeneic

stem cell transplant with a CCRdelta32 homozygous bone marrow

– Following the transplant, he stopped ART and has remained without any evidence for infection

Why Should We Try to Cure HIV?

• Although life expectancy has improved, HIV+ patients, especially if diagnosed late, don’t live as long as HIV-negative people -- perhaps because of persistent inflammation in HIV+ patients

• Cost, side effects, and impact on quality of life of life-long ART

• Need to maintain high level of adherence to ART to prevent drug-resistant virus

• Stigma, discrimination, fear of transmission, isolation

Adapted from slide by Joe Eron, MD

Long-lived latent reservoir

0.00001

0.0001

0.001

0.01

0.1

1

10

100

1000

10000

0 1 2 3 4 5 6 7 8

Time on HAART (years)

Fre

qu

enc

y(I

UP

M)

Frequency of Latently Infected CD4+T Cells as a Function of Time on HAART

-

t ½ = 44.2 months73.4 years

Why does ART not Cure HIV?

Siliciano J, Nature Medicine, 2003

“If I take medicines, will I be cured?”

100 copies

10 copies

1 copy

Persistent HIV Production Despite ART

50 copies

Using extremely sensitive assays, plasma viremia detectable in most patients on ART, often below the detection limit of commercial assays (<20 copies/mL)

Maldarelli F, et al. PLoS Pathog. 2007;3:e46.

Treatment intensification?

Adding 4th Drug (raltegravir) to 3-drug ART does not reduce low-level viremia

♦ Arm A: RAL first (immediate intensification)● Arm B: Placebo first (deferred intensification)

Gandhi R et al, PLoS Med, 2010

+RAL No RALNo RAL

Can we cure HIV?

“It's tough to make predictions, especially about the future”

Can we cure HIV? “ART-Plus”

• HIV cure remains an aspirational goal• Clinical trials are testing ways to:

• Reverse latency• Enhance killing of infected cells• Make cells impervious to infection• Combination therapy!!

• Increased knowledge of mechanisms of HIV persistence needed

• Given safety of current ART and uncertainties regarding risks of novel interventions, cure studies must adhere to highest scientific and ethical standards

World AIDS Day, 2013: . . . the United States should be at the forefront of new discoveries into how to put HIV into long-term remission without requiring lifelong therapies -- or, better yet, to eliminate it completely. 

Patient: One day I’d love to say, “I used to have HIV.”