Budnik 1 Namibia Presentation Women and Switch

Women and HIV

Piotr Budnik MBBCh FCP(SA)

Medical Lead HIV Southern Africa - GSK

VIIV/DGR/0002/16a August 2016

17.8 million women worldwide

were living with

HIV in 2015

new HIV infections per DAY

among women (≥15 years old)

~ 2,491 of women living

with HIV are aged

15–24 years

15%

of these young

women live in

Sub-Saharan Africa

80%

5–7 yearsIn Sub-Saharan

Africa, women acquire

HIV earlier than men

Young women (15-24 years)

in Sub-Saharan Africa are more

likely to be living with HIV*

of adults living with

HIV globally are

women

50%of adults living with HIV

in Sub-Saharan Africa

are women

x2

Half of the global HIV-infected adult population are women

and the majority are living in Sub-Saharan Africa

*Versus young men UNAIDS GAP Report 2014: http://www.unaids.org/en/resources/publications/2014 Accessed May 2016

59%

There are significant regional differences in the proportions*

women constitute of adults living with HIV

*Proportions calculated from the unrounded 2013 HIV estimates published in UNAIDS, 2014,

The Gap Report, p. A30-A35 See slide notes for reference

58%

39%

30%

50%

38%

36%22%

22%

The proportion of HIV-infected women as compared to men is highest in

Africa, the Caribbean, Asia and Eastern Europe

80%

Young women are facing a HIV epidemic

Key drivers and challenges of the epidemic in young women3

HIV/AIDS is the leading cause of

death worldwide for women aged 15–441

HIV prevalence among adolescent girls

and young women is 7x that of males2

There is a strong link between sociological factors

and the HIV-epidemic in young women

See slide notes for reference

Poverty

Unemployment

Lack of education

Lack of access to healthcare services

Inability to advocate for safe sex

#1

60% of all new HIV infections

among young people aged

15–24, occurred among adolescent

girls and young women1

Living with HIV:

Considerations specific to women

1. Greig JM, Anderson J. Curr Opin Infect Dis 2014;27:46–52; 2. Cejtin H. Am J Obstet Gynecol 2012;207:87–93 3. SHE Programme: Women and HIV; Fertility. Available from: http://www.shetoshe.org/living-well-with-hiv/sexual-and-

reproductive-health/fertility/#.V3ze0vkrJD8 4. SHE Programme: HIV and breastfeeding. Available from: http://www.shetoshe.org/living-well-with-hiv/sexual-and-reproductive-health/hiv-and-breastfeeding/#.V3zfAPkrJD8

5. AVERT: Pregnancy, childbirth and breastfeeding. Available from: http://www.avert.org/hiv-transmission-prevention/pregnancy-childbirth-breastfeeding

Increased barriers to accessing treatment in some

populations1

Barriers to adherence in older women1

Impact of side effects in older women2

Potential early onset of menopause2

DDIs with HRT1,2

Elevated symptom burden in menopause and beyond1,2

Increased barriers to accessing treatment in some

populations1

Choice of contraceptive when partner is serodiscordant1

DDIs with hormonal contraception1,2

Concerns around conception and the HIV status of

partner and baby3

Safety of mother and baby during pregnancy and

breasfeeding3–5

Potential early onset of menopause2

MENOPAUSE

AND OLD AGE

WOMEN OF CHILD

BEARING POTENTIAL

There is a lack of data regarding the efficacy and safety of ARV drugs

during pregnancy as most clinical trials exclude pregnant women

Pregnant women are excluded from

the vast majority of clinical trials1,2

Very few drugs are approved for use during pregnancy;

most drug labels provide little pregnancy data1

The relatively low percentage of women living with HIV who

are pregnant at any given time2 and the length of the gestation

period result in slow generation of pregnancy data

HIV studies involving pregnant women typically

concentrate on outcomes for infants2

1. Blehar M, et al. Womens Health Issues 2013 23(1) e39–e45

2. Westreich D, et al. PLoS ONE 2013;8(8):e73398

Physiological changes during pregnancy alter drug

metabolism and distribution

A variety of physiological changes during pregnancy can

alter the PKs of ARV drugs at all stages of drug

metabolism and may lead to lower plasma levels of drugs

1. Gilbert EM, et al. Pharmacotherapy 2015;35:838–55

2. DHHS. Guidelines for pregnant HIV-1-infected women. August 2015. https://aidsinfo.nih.gov/guidelines Accessed Oct 2015

Absorption Changes in digestive processes, nausea and vomiting lead to decreased Cmax,

increased Tmax and reduced absorption/bioavailability

Distribution Alterations to vascular volume and reduced protein concentrations lower Cmax

and increase the free fraction of drug

Metabolism Hormonal alterations to enzyme and biliary functions lead to variable effects on drug

metabolism and reduce biliary drug secretion

Excretion Enhanced renal activity increases clearance of renally eliminated drugs and

decreased steady-state drug concentrations

For HIV-infected women, pregnancy and the associated physiological alterations

may have an impact on their ARV regimens and necessitate increased dosages,

more frequent dosing, or boosting, especially of PIs2

From evidence to policy: Evolution of

WHO MTCT and ART recommendations

See slide notes for references

INITIATION OF LIFELONG MATERNAL ART

MATERNAL ART FOR PREVENTION OF MTCT

20021

AZT or

AZT + 3TC

or SD NVP

No specific

guidance

20042

AZT from

Week 28

+ SD NVP

CD4+

<200 cells/mm3

20063

AZT from

Week 28 +

SD NVP

+ 7 days’

AZT + 3TC

CD4+

<200 cells/mm3

20104

Option A

AZT from Week 14

+ SD NVP +

7 days’ AZT + 3TC

Option B

Triple ART

from Week 14

CD4+

≤350 cells/mm3

20135

Options

B and B+

Triple ART

For B

CD4+

≤500 cells/mm3

20166

Option B+

Lifelong triple ART,

irrespective of CD4+

cell count

N/A

Evolution towards more efficacious treatment schedules and lifelong treatment for all

Impact of ageing is amplified in women living with HIV

particularly due to physiological changes during menopause

Cejtin H. Am J Obstet Gynecol 2012;207:87–93

General

factors

Women-specific

factors

Elevated

burden of

menopausal

symptoms

Possible

early onset of

menopause

Osteoporosis

Cervical

cancer

screening

Burden of

HIV

infection

Burden

of HIV

treatment

Co-morbid

conditions Ageing

1

2

Key considerations for choice of ART during

menopause in women with HIV

1. Andany N, et al. Int J Womens Health 2016;8:1–22; 2. Imai K, et al. Obstet Gynecol Int 2013;2013:340309

3. Loutfy M, et al. J Int AIDS Soc 2013 Oct 1;16:18509

In the era of cART, women with HIV live longer and go through menopausal changes leading to a

continuous increase in complexity in the management of HIV infection2

GENERAL CONSIDERATIONS HRT CONSIDERATIONS

Increased plasma drug concentrations

in elderly patients1

Hepatic and renal functions

may be affected3

Post-menopausal women may respond

differently to ART as oestrogen deficiency

could affect CD4 cell recovery and

HIV replication2

Lower CD4 cell count in previously

untreated menopausal women1

Menopause can lead to metabolic

complications, including osteoporosis,

lipid and glucose disturbances1,3

Depressive symptoms are more

likely during menopause1

Similarity of menopausal symptoms

and ART side effects3

DDIs, e.g. PIs/NNRTIs1

Concerns regarding worsening of HIV

status under hormonal treatment1

Concerns regarding toxicity1

Increased pill burden1

PK and

DDIs

Efficacy and

immunologic

response

Safety and

tolerability

Convenience

Women are under-represented in treatment-naïve,

registrational ART clinical trials1

*or ATV/r (24%)

†DRV/r + RAL (12%) or DRV/r +TDF/FTC (11%)

‡LPV/r + 3TC (16%) or LPV/r + ABC/3TC (17%)

§EVG/c/FTC/TDF vs EVG/c/FTC/TAF

1. Soon GG, et al. AIDS Patient Care STDs 2012;26:444–53; 2. Daar E, et al. Ann Intern Med 2011;154:445–56;

3. Ortiz R, et al. AIDS 2008;22:1389–1397; 4. Molina JM, et al. Lancet 2008;372:646–55; 5. Rockstroh J, et al. J Acquir Immune Defic Syndr

2013;63:77–85. Supplementary file; 6. Molina JM, et al. Lancet 2011;378:238–46; 7. Cohen CJ, et al. Lancet 2011;378:229–37; 8. Landovitz RJ, et al.

CROI 2014. Abstract 85; 9. Sax PE, et al. Lancet 2012;379:2439–48; 10. Dejesus E, et al. Lancet 2012;379:2429–38; 11. Raffi F, et al. CROI 2014.

Abstract 84LB; 12. Raffi F, et al. Lancet 2013;381:735–43; 13. Cahn P, et al. EACS 2013. Abstract LBPS7/6; 14. Cohen C, et al. HIV Therapy Glasgow

2012. Abstract O425; 15. Walmsley S, et al. N Engl J Med 2013;369:1807–18. Supplementary appendix;

16. Clotet B, et al. Lancet 2014;383:2222–31; 17. Sax PE, et al. Lancet 2015;385:2606–15

Time (by start date)2005 2013

EVG

DRV/r

Pro

po

rtio

n o

f w

om

en

recru

ite

d (

%)

RAL

EFV

DTG

RPV

LPV/r

ATV/r

ATV

Third agent

ART clinical trials since 2005 have recruited on average ~18% women1

Importance of women in clinical trials

Heidari S, et al. J Int AIDs Soc 2011;14:11

SCIENTIFIC RATIONALE

Biological and hormonal

gender differences

Bodyweight/fat distribution differences

and their effects on drug absorption,

distribution, metabolism and excretion

Drugs should be tested in populations

that reflect the end-users

(including age, gender, ethnicity)

More biologically susceptible

to HIV transmission

Different ARV toxicity profiles reported

SOCIAL RATIONALE

Understanding and addressing

the barriers to inclusion

Ensuring equal access to treatment

More vulnerable due to gender-based

power relationships

Access to testing, counselling,

prevention and treatment programmes

of the HIV population

are women50%

ABC/3TC/DTG

TDF/FTC + DTG

EVG/c/FTC/TDF

TDF/FTC + RAL

ABC/3TC/DTG

TDF/FTC + DTG

EVG/c/FTC/TAF

EVG/c/FTC/TDF

TDF/FTC + RAL

TDF/FTC + DTG†

TDF/3TC + DTG†

TDF/FTC + DRV/r TDF/FTC + DRV/r

TDF/FTC/RPV – TDF/FTC/EFV

TDF/3TC/EFV

TDF + 3TC + EFV†

TDF + FTC + EFV†

AZT + 3TC + EFV‡

AZT + 3TC + NVP‡

TDF + 3TC + NVP‡

TDF + FTC + NVP‡

Treatment guidelines do not differentiate

between men and women*

*Except for women planning pregnancy and those who are pregnant; †Alternative options to initiate ART; ‡If TDF/3TC/EFV or TDF/FTC/EFV contra-indicated or not available See slide notes for references

INI-BASED REGIMENS

PI-BASED REGIMENS

NNRTI-BASED REGIMENS

RECOMMENDED/PREFERRED REGIMENS FOR TREATMENT-NAÏVE WOMEN

EACS1 WHO3DHHS2

Some RCTs show elevated rates of specific AEs in women:

NNRTIs, PIs and INIs1

*Please see slide notes for details and trials

Similarities in AEs in women vs men*

Elevated AEs in women vs men*

PIs

More discontinuations

due to AEs (ATV/r, LPV/r)2

or for reasons other than

virologic failure (DRV/r)3

Similar overall AE

profiles (DRV/r)5

Larger increases in anthropometric

measurements (DRV/r)4

NNRTIs

Hepatotoxicity (NVP)6

Similar overall safety

profiles (EFV, RPV)9

Nausea (EFV, RPV)9

CNS side effects (EFV)7

Rash (NVP, EFV, ETR)6,8,10

INIs

More drug-related

AEs (RAL)11

No specific AE

increases

reported (RAL,

EVG, DTG)11–14

Similar rates of

Grade 2–4 or 3/4 AEs

and discontinuations

(DTG, EVG)13,14

DTG/ABC/3TC STR QD

N=~237

ARIA – Phase IIIB trial in HIV-1-infected ART-naïve women:

Study design

Orrell C, et al. AIDS 2016. Oral THAB0205LB

Randomisation (1:1) Primary analysis Week 48 Screening Visit

Primary endpoint: proportion of subjects with HIV-1 RNA <50 c/mL at Week 48 (snapshot algorithm) with a 12% non-

inferiority margin.

Stratification: by HIV-1 RNA (≤ or >100,000 copies/mL), CD4+ count (≤ or >350 cells/mm3).

Women who became pregnant were withdrawn and, if possible, offered entry into a DTG/ABC/3TC pregnancy study

International, multicentre, Phase IIIb, randomised, open-label, non-inferiority clinical trial

HIV-1-infected,

ART-naïve women

HIV-1 RNA

≥500 c/mL

Negative for

HLA-B*5701 allele

Hepatitis B negative

N=~474

ATV/r + TDF/FTC QD

N=~237

DTG/ABC/3TC

STR QD

ARIA: Global enrolment


ARIA enrolled from September 2013 to September 2014; 499 women have been randomised across 13 countries. The

study is ongoing.

66

2050 Russia

Canada

South Africa

54Spain

44Argentina

40Thailand

28Italy

25UK

16France

9Portugal

11Mexico

2Puerto Rico

134USA

ARIA: Snapshot outcomes at Week 48: ITT-E and

PP populations


82

6

12

71

14 15

86

6 8

76

11 13

0

20

40

60

80

100

Virologicsuccess

Virologicnon-response

No virologicdata

HIV

-1 R

NA

<5

0 c

/mL

, %

DTG/ABC/3TC (ITT-E, n=248)

ATV/r+TDF/FTC (ITT-E, n=247)

DTG/ABC/3TC (PP, n=230)

ATV/r+TDF/FTC (PP, n=225) ITT-E (primary)

PP

3.1 17.8

16.82.6

DTG/ABC/3TC is superior to ATV/r+TDF/FTC with respect to snapshot in the ITT-E (<50 c/mL) at Week 48, p=0.005

ATV/r + TDF/FTC DTG/ABC/3TC

Virologic outcomes Treatment differences (95% CI)

21st International AIDS Conference, 18-22 July 2016, Durban, South Africa

DTG/ABC/3TC

(n=248)

ATV/r +TDF/FTC

(n=247)

Virologic response 203 (82%) 176 (71%)

Virologic non-response 16 (6%) 35 (14%)

Data in window not below threshold 4 (2%) 16 (6%)

Discontinued while VL not <50* 12 (5%) 19 (8%)

No virologic data 29 (12%) 36 (15%)

Discontinued study due to AE or death 9 (4%) 18 (7%)

Discontinued study for other reasons 15 (6%) 14 (6%)

Missing data during window but on study 5 (2%) 4 (2%)

ARIA: Snapshot outcomes at Week 48: ITT-E

*Includes categories: Discontinued for lack of efficacy and Discontinued for other reason while not below threshold


Differences in response rates driven by Snapshot virologic non-response and lower rates of both

discontinuations due to AEs in the DTG/ABC/3TC group


ARIA: Snapshot outcomes by baseline randomisation

strata at Week 48: ITT-E


HIV-1 RNA c/mL CD4+ count cells/mm3

248 247 179 181 69 66 130 123 118 124

HIV

-1 R

NA

<5

0 c

/mL

, %

DTG/ABC/3TC (n) ATV/r + TDF/FTC (n)


ARIA: Treatment emergent mutations in patients with

confirmed virologic withdrawal

• The resistance analysis was performed on subjects meeting

confirmed virologic withdrawal (confirmed ≥400 c/mL on or after

Week 24)

*Two subjects receiving DTG/ABC/3TC had either K219K/Q (TAM) or E138E/G at CVW with no reduced

susceptibility to DTG/ABC/3TC. K219K/Q is not selected for by ABC or 3TC nor does it affect their fold change


Resistance Analysis

DTG/ABC/3TC

(n=6)

ATV/r + TDF/FTC

(n=4)

INI 0 0

NRTI 0* 1

M184V 0 1

PI 0 0

No subject receiving DTG/ABC/3TC developed INI or ABC/3TC resistance-associated mutations


ARIA: Most frequent AEs and relative risk

*Randomised phase (up to Week 48); All AEs reported by >5% in at least one treatment group Orrell C, et al. AIDS 2016. Oral THAB0205LB

0 5 10 15 20 25

Most frequent AEs* (%)

DTG/ABC/3TC, n=248 ATV/r + TDF/FTC, n=247

0 .125 .25 .5 1 2 4

Relative risk with 95% CI

Favors

DTG/ABC/3TC

Favors

ATV/r + TDF/FTC

Nasopharyngitis

Nausea

Upper respiratory tract infection

Headache

Dizziness

Vomiting

Urinary tract infection

Diarrhoea

Back pain

Rash

Fatigue

Abdominal pain

Cough

Dyspepsia

Hyperbilirubinemia

Jaundice

Ocular icterus


ARIA: Conclusions

• In treatment-naïve women, DTG/ABC/3TC (Triumeq) was superior to

ATV/r+TDF/FTC at 48 weeks of treatment

– Adjusted difference 10.5%, 95% CI: 3.1% to 17.8%, p=0.005

– Difference driven by lower rate of virologic non-response (Snapshot) and

fewer discontinuations due to AEs in DTG/ABC/3TC arm

• DTG/ABC/3TC had a favourable safety profile compared to ATV/r + TDF/FTC

– Similar to overall safety profile for DTG from previous studies

• There were no treatment-emergent primary INI or ABC/3TC resistance

mutations in the DTG/ABC/3TC group

• The study provides important information to help guide treatment decisions

in women


In treatment-naïve women, DTG/ABC/3TC (Triumeq) was superior to ATV/r + TDF/FTC at

48 weeks of treatment and had a favourable safety profile compared to ATV/r + TDF/FTC

Parameter % (n/N) Dolutegravir Comparator Comparator Favours DTG

Overall

88 (361/411) 85 (351/411)

88 (364/414) 81 (338/419)

90 (217/242) 83 (200/242)

Baseline viral load ≤100,000 c/mL

90 (267/297) 89 (264/295)

90 (252/280) 83 (238/288)

88 (160/181) 87 (157/181)

Baseline viral load >100,000 c/mL

82 (94/114) 75 (87/116)

83 (111/134) 76 (100/131)

93 (57/61) 70 (43/61)

CD4+ T-cell count <200 cell/mm3

78 (43/55) 68 (34/50)

79 (45/57) 77 (48/62)

91 (21/23) 79 (19/24)

CD4+ T-cell count 200-350 cell/mm3

89 (128/144) 85 (118/139)

88 (143/163) 79 (126/159)

86 (63/73) 80 (41/51)

CD4+ T-cell count ≥350 cell/mm3

90 (190/212) 90 (199/222)

91 (176/194) 83 (164/198)

91 (133/146) 84 (140/167)

Background NRTI: ABC/3TC86 (145/169) 87 (142/164)

90 (71/79) 85 (68/80)

Background NRTI: TDF/FTC89 (216/242) 85 (209/247)

90 (146/163) 81 (132/162)

Female

84 (53/63) 82 (46/56)

85 (57/67) 75 (47/63)

84 (26/31) 73 (30/41)

Age <36 years

87 (162/186) 83 (181/219)

87 (175/202) 80 (171/215)

89 (117/131) 81 (108/134)

Age ≥36 years

88 (199/225) 89 (170/192)

89 (189/212) 82 (167/204)

90 (100/111) 85 (92/108)

African American/African heritage

84 (41/49) 85 (33/39)

82 (80/98) 75 (74/99)

85 (51/60) 77 (41/53)

DTG-based regimens effective across key subgroups,

including women

Adapted from Raffi F, et al. AIDS 2015;29(2):167–174

DTG showed consistent efficacy across key subgroups regardless of sex, viral load, age, race, CD4+ T-cell count and NRTI backbone (Week 48)

-10-15-20 -5 0 5 10 15 20 25 30 35 40

SPRING-2

SINGLE

FLAMINGO

INI-naïve: DTG-based regimens effective across key subgroups,

including women

Hagins D, et al. ICAAC 2013. Abstract H-1460

Subgroup

Response rates Difference (DTG-RAL) and 95% CI

DTG RAL

no. with response/total no. (%) In favour of RAL In favour of DTG

Overall 251/354 (71) 230/361 (64)

Gender

Female

Male

79/107 (74)

172/247 (70)

74/123 (60)

156/238 (66)

Race

White

Non-white

African

American/

African heritage

133/178 (75)

118/175 (67)

98/143 (69)

125/175 (71)

105/185 (57)

92/160 (58)

Age

<50

≥50

196/269 (73)

55/85 (65)

172/277 (62)

58/84 (69)

32% womenN=715

Treatment-experienced: DTG-based regimens

effective across key subgroups, including women

Hagins D, et al. ICAAC 2013. Abstract H-1460

23% womenN=183

Subgroup

DTG

no. with response/total no. (%) DTG response rate and 95% Cl

Overall 126/183 (69)

Gender

Female

Male

30/42 (71)

96/141 (68)

Race

White

Non-white

African

American/

African heritage

91/130 (70)

35/53 (66)

32/49 (65)

Age

<50

≥50

80/110 (73)

46/73 (63)

Observational data on the use of DTG during pregnancy

*Trimester of DTG exposure

1. Data on file (Maternal Dolutegravir Pharmacokinetics, Safety, and Pregnancy Outcomes of Patients who Received a Dolutegravir-Based Regimen)

2. Antiretroviral Pregnancy Registry International Interim Report December 2015. www.APRegistry.com; 3. Data on file (Medical comment: Maternal Dolutegravir (Pharmacokinetics, Safety and

Pregnancy Outcomes); 4. Simons R, et al. BHIVA 2016. Poster 9

Although DTG is assigned an FDA pregnancy category B (no evidence of human risk), there

are currently insufficient data in the APR to detect an increase in risk of birth defects2

37 pregnancies occurred

in subjects taking DTG

as part of clinical trials:

18 produced normal infants

1 infant born with congenital anomaly:

double-outlet right ventricle plus

ventricular septal defect (trimester* 1)

9 elective terminations and

3 spontaneous abortions

(no obvious abnormalities)

7 outcomes unknown

74 pregnancies reported

by 16 Jan 2016 as post-

marketing surveillance

18 produced normal infants

2 infants born with congenital

anomaly: intracranial calcifications

(trimesters* 2 and 3), polydactyly

(trimesters 1, 2 and 3)

14 spontaneous abortions

(1 with congenital anomaly: fetal

dystrophy, trimester* 1)

1 still birth (normal infant)

39 outcomes unknown

28 pregnancies

registered with the

APR by 31 Jul 2015

10 infants exposed to DTG during

1st trimester: 10 normal infants

18 infants exposed to DTG during

2nd or 3rd trimesters: 17 normal

infants, 1 with congenital anomaly:

Hypoglossia hypodacylia syndrome

(trimester 3*)

9 pregnancies

in 54 women

treated with DTG

1 infant exposed to DTG

during first Trimester

8 infants exposed to DTG

during 2nd or 3rd trimester

No birth defects observed

Retrospective

real-world

data3

Antiretroviral

Pregnancy

Registry

(APR)2,3

DTG

post-marketing

surveillance1

DTG clinical

development

program1

http://www.apregistry.com/

Observational data on the use of ABC and/or 3TC

during pregnancy (APR data)

The Antiretroviral Pregnancy Registry finds no apparent increases in frequency of specific defects with first trimester

exposures and no pattern to suggest a common cause; however, potential limitations of registries should be recognised

Antiretroviral Pregnancy Registry International Interim

Report December 2015. www.APRegistry.com

With ABC, sufficient

numbers of 1st trimester exposures have been

monitored to detect at

least a 2-fold increased risk of

overall birth defects

With 3TC, sufficient numbers of

1st trimester exposures have

been monitored to detect at least a

1.5-fold increased risk of overall birth

defects…and a 2-fold increased risk of

cardiovascular or genitourinary defects

No such increases in

risk have been detected

No such increases in

risk have been detected

Birth defects ABC-exposed infants Birth defects 3TC-exposed infants

29 infants from

993 live births

143 infants from

4566 live births

VIIV/DGR/0125/15 – October 2015


Why switch a stable regimen?


Initial regimens have grown simpler and more tolerable since

the beginning of triple-drug cART

1998 2003 2008 2015

One ofPlus

one of

EFV ZDV+ddI EFV + FTC + (TDF, ZDV or d4T)a EFV + TDF/FTCa DTG/3TC/ABC (TRIUMEQ)c

IDV d4T+ddI LPV/r + (3TC or FTC) + (ZDV or d4T) ATV/r + TDF/FTCEVG/c/FTC/TDF

(STRIBILD)

NFV ZDV+ddC ABC + 3TC + (ZDV or d4T)b DRV/r + TDF/FTV DTG + TDF/FTC

RTV ZDV+3TC FPV/r + TDF/FTC RAL + TDF/FTC

SQV (sqc) d4T+3TC LPV/r + TDF/FTC DRV/r + TDF/FTC

SQV+RTV

a Except in pregnancy/potential for pregnancy.b Only if NNRTIs or PIs are unsuitable.c Only if HLA-B*5701-negative.

3TC, lamivudine; ABC, abacavir; ATV, atazanavir; c, cobicistat; cART, combination antiretroviral therapy; d4T, stavudine; ddC, zalcitabine; ddI,

didanosine; DTG, dolutegravir; DRV, darunavir; EFV, efavirenz; EVG, elvitegravir; FPV, fosamprenavir; FTC, emtricitabine; IDV, indinavir; NFV,

nelfinavir; r, ritonavir (minidose); RAL, raltegravir; RTV, ritonavir (400 mg); SQV, saquinavir; TDF, tenofovir disoproxil fumarate; ZDV, zidovudine.

DHHS Guidelines for the use of antiretroviral agents in HIV-1-infected adults

and adolescents – Dec 1 1998; Nov 10, 2003; Nov 3, 2008, and April 8, 2015.

Available at https://aidsinfo.nih.gov/guidelines (accessed June 2015).

DHHS recommended/preferred regimens 1998–2015

https://aidsinfo.nih.gov/guidelines


Why switch a regimen that works?

Toxicity/Intolerance • To resolve acute intolerance

• To reduce long-term, chronic inconvenience

• To proactively avoid potential future issues (e.g. renal, bone, cardiovascular disease)

Simplification • To reduce pill count or dosing frequency

• To reduce or eliminate food or timing restrictions

Drug–drug

interactions

• To reduce the risk of unsafe or treatment-limiting interactions with other drugs

• To prevent or simplify dose adjustments

Pregnancy • To avoid or reduce teratogenic risk

• To optimise therapeutic drug levels in pregnancy

Cost • To reduce the copayer cost to patients

• To reduce healthcare system costs

Patient preference

• Despite tremendous improvements in convenience and tolerability, no regimen is ideal for every

patient who receives it, even if it is fully effective

• Therapy is life-long, and given the growing population of older adults with HIV, there is a need to

ensure ease of use if treatment adherence is to be maintained

• There are many instances where virologically suppressed patients may benefit from a change of

regimen

• Switching regimens remains common, but mostly for reasons other than virological

failure

DHHS guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. April 08, 2015. Available at

https://aidsinfo.nih.gov/guidelines (accessed June 2015); British HIV Association. HIV Medicine 2014;15 (Suppl. 1):1-85.

https://aidsinfo.nih.gov/guidelines


0

5

10

15

20

25

30

CNS GI Cardiac Hepatic Metabolic Renal Other

27.0

14.2

11.9 11.9

9.3 8.4

17.3

EFV

Other

PIs

Other

ABC

SQV

Other

ATV

EFV

Other

TDF

ATV

PI

Other

Pro

po

rtio

n o

f to

xic

ity s

wit

ch

es

(%

)

Why do people switch in the real world?

• 6211 patients assessed

• 923 regimen switches in 722 patients over 18 months Annual switch rate: 8%

– 83% of switchers on therapy >6 months

• Half of switches were for drug toxicity/intolerance

– 23% EFV switches for CNS (20%) or hepatic (3%) concerns

– 14% PI switches for GI or metabolic disturbance

– 7% ATV for hepatic or renal concerns

– 6% TDF for renal concerns

– 5% ABC or SQV for cardiac concerns

Toxicity

49%

Simplification

15%Clinical

Trial

8%

Virological

Failure

8%

Drug

Interaction

4% Other

16%

Boyle A, et al. HIV Med 2012;13 (Suppl. 1):10 [abstr].

Regimen changes at Chelsea and Westminster Hospital (UK) 2009–2011

ABC, abacavir; ATV, atazanavir; CNS, central nervous system; DTG, dolutegravir; DRV,

darunavir; EFV, efavirenz; GI, gastrointestinal; PI, protease inhibitor; SQV, saquinavir;

TDF, tenofovir disoproxil fumarate.


Many factors contribute to adherence

• Drug/alcohol abuse

• Male sex

• Youth

• Non-white race

• Depression

• Low education

• Low confidence in ability to self-medicate

• Extreme anxiety

• Extreme pain

• No change in health status

• Dosing frequency more than BID

• Pill burden

• Type of drug

• Inability to take medication away from home

• Food requirements

• Side effects

• Poor relationship with healthcare provider

• Dissatisfaction with healthcare system

Patient factors

Medication factors Poor

adherence

Chesney MA. Clin Infect Dis 2000;30 (suppl 2):S171-6.


Barriers to switching can lie with the physician, the patient or

the healthcare system

Barrier to switching Physician Patient System

Fear of possible consequences

Assumption that all is well

“Virocentricity” (undetectable is the only relevant outcome)

Inertia

Inconvenience

Infrequent visits

Lack of specific data

Lack of guidelines algorithms

Lack of experience

Lack of physician time

No label indication

Cost


Any change to a stable regimen carries both potential risks and

potential benefits

Potential benefits include...1

• Improved drug levels

• Prevention or reversal of toxicity

• Prevention or reduction of drug

interactions or comorbidities

• Improved confidentiality (e.g. no

refrigeration or dosing at work)

• Reduced costs to patient, lower

pharmacy costs and/or expanded

community coverage for the same

healthcare expenditure

Potential risks include...1

• Loss of virological control

• Short- and long-term toxicities

• Unforeseen drug interactions

• Increased costs due to greater

virological failure or toxicity

• Pharmacy prescription error or patient

dosing error

1. Adapted from Carr A, et al. PLoS Med 2012;9:e1001240.

The risk-to-benefit balance of switching depends on

individual patient circumstances as well as on the

characteristics of the drugs involved



STRIIVING


Primary endpoint at

24 weeks: VL <50 c/mL

(Snapshot)

STRIIVING study design

Inclusion criteria

• Virologically suppressed

(confirmed HIV-1 RNA

<50 c/mL)

• HLA-B*5701 negative

Open-label,

randomised

1:1

Triumeq

0 Week 24Screening Week 48

Countries: US, Canada, Puerto Rico

Current ARTa

a Stable suppressive current ART with 2 NRTIs plus either a PI, an NNRTI, or an INI.

≥40% PIs, at least 25% INIs.

90% power based on 10% non-inferiority margin (estimated response rate = 85%).

Assessments

• CD4 cell count changes

• Clinical and laboratory safety

• Lipids, renal, bone, and

cardiovascular changes

• Development of resistance

• Treatment satisfaction

Triumeq

Trottier B, et al. Presented at ICAAC, 17-21 September 2015,

San Diego.

ART, antiretroviral; c/mL, copies/mL; INI, integrase inhibitor; NRTIs, nucleoside

reverse transcriptase inhibitors; PI, protease inhibitor; VL, viral load.


Snapshot outcomes at week 24: ITT-E and PP populations

CAR, current antiretroviral therapy; CI, confidence interval;

ITT-E, intent-to-treat exposed; PP, per protocol.

CAR Triumeq

Virological outcomes Treatment differences (95% CI)

-3,4

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

-9.1 2.3

ITT-E Population

-0,3

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

-4.9 4.4

PP Population

85

1

14

88

1

10

93

<1

6

93

25

0

20

40

60

80

100

Virologicsuccess

Virologic non-response

No virologicdata

HIV

-1 R

NA

<50

c/m

L, %

Triumeq (ITT-E, n=274)

CAR (ITT-E, n=277)

Triumeq (PP, n=220)

CAR (PP, n=215)

Trottier B, et al. Presented at ICAAC, 17-21 September 2015,

San Diego.


Virological endpoints

• No subjects met protocol-defined virological failure in either study arm

a Triumeq VLs: 58, 64, 71 c/mL b CAR VLs: 55, 55, 61, 85 c/mL

• Subjects with HIV-1 RNA ≥50 c/mL at any visit (scheduled or unscheduled)

will require further testing

• Subjects with HIV-1 RNA ≥400 c/mL on 2 consecutive assessments any time after

randomization are withdrawn = meets “confirmed virological withdrawal criterion”

Triumeq

(n=274)

CAR

(n=277)

PDVF 0 0

VL ≥50 in W24 window 3 (1%)a 4(1%)b

Trottier B, et al. Presented at ICAAC, 17-21 September 2015, San Diego.

c/mL, copies/mL; CAR, current antiretroviral therapy;

PDVF, pre-defined virological failure.


Treatment satisfaction–total score

• At baseline, overall treatment satisfaction scores were similar between groups.

• HIV TSQ total scores increased in both groups, with a statistically significant

difference favouring Triumeq.

0

0,5

1

1,5

2

2,5

3

3,5

4

Triumeq (n=269) CAR (n=276)

Ad

juste

d m

ean

Ch

an

ge

in

sco

re a

t W

eek 2

4

Adjusted mean difference at

Week 24 (95% CI): 2.4 (1.3–3.5)

P<0.001

Trottier B, et al. Presented at ICAAC, 17-21 September 2015, San Diego.

CAR, current antiretroviral therapy; TSQ, treatment

satisfaction questionnaire.


Conclusions

• Switching to Triumeq from a variety of regimens was demonstrated to be safe and

effective

• Switching to Triumeq met non-inferiority endpoints for all population analyses

• No subjects met the protocol-defined virological failure endpoint through 24 weeks

• Discontinuations due to AEs in the Triumeq arm were infrequent and mostly due to

low grade adverse events

• Greater improvements in treatment satisfaction were demonstrated in subjects

switching to Triumeq

Trottier B, et al. Presented at ICAAC, 17-21 September 2015, San Diego. AEs, adverse events.


Summary

• Toxicity is still a key reason for switching a virologically successful regimen in 2015

– Simplification and avoiding drug interactions are also important

• A significant minority of patients fail to inform their HCP about the regimen toxicities

they suffer

• Virological suppression will likely be preserved when switching first-line patients and

those without previous virological failure to either NNRTI- or INSTI-based regimens,

provided attention is paid to

– New regimen requirements and patient acceptance thereof

– Patient acceptance of possible new adverse events

– Potential new drug interactions

• Successful switching of experienced patients with a history of virological failure also

requires case-by-case attention to

– Previous treatment history

– Documented or possible drug resistance based on prior history

• Successful switches can significantly reduce or resolve metabolic or symptomatic

toxicities

• Dolutegravir is a potentially promising option for future switch regimens

INSTI, integrase inhibitors; NNRTI, non-nucleoside reverse transcriptase inhibitors.

Budnik 1 Namibia Presentation Women and Switch

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