Women and HIV Piotr Budnik MBBCh FCP(SA) Medical Lead HIV Southern - - PowerPoint PPT Presentation

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

• f women living

with HIV are aged 15–24 years

15%

• f these young

women live in Sub-Saharan Africa

80% 5–7 years

In 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*

• f adults living with

HIV globally are women

50%

• f 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-

• 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

• r 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

• f 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

• 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

• 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

Proportion of women recruited (%)

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

• f the HIV population

are women

50%

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;

See slide notes for references

 INI-BASED REGIMENS  PI-BASED REGIMENS  NNRTI-BASED REGIMENS

RECOMMENDED/PREFERRED REGIMENS FOR TREATMENT-NAÏVE WOMEN

EACS1 WHO3 DHHS2

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

• r 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

Orrell C, et al. AIDS 2016. Oral THAB0205LB

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

66 20 50 Russia

Canada

South Africa 54 Spain 44 Argentina 40 Thailand 28 Italy 25 UK 16 France 9 Portugal 11 Mexico 2 Puerto Rico 134 USA

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

Orrell C, et al. AIDS 2016. Oral THAB0205LB

82 6 12 71 14 15 86 6 8 76 11 13 20 40 60 80 100 Virologic success Virologic non-response No virologic data HIV-1 RNA <50 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 16.8 2.6

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 Orrell C, et al. AIDS 2016. Oral THAB0205LB

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

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

ARIA: Snapshot outcomes by baseline randomisation strata at Week 48: ITT-E

Orrell C, et al. AIDS 2016. Oral THAB0205LB

HIV-1 RNA c/mL CD4+ count cells/mm3 248 247 179 181 69 66 130 123 118 124 HIV-1 RNA <50 c/mL, % DTG/ABC/3TC (n) ATV/r + TDF/FTC (n)

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

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 Orrell C, et al. AIDS 2016. Oral THAB0205LB

Resistance Analysis DTG/ABC/3TC (n=6) ATV/r + TDF/FTC (n=4) INI NRTI 0* 1 M184V 1 PI No subject receiving DTG/ABC/3TC developed INI or ABC/3TC resistance-associated mutations

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

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

5 10 15 20 25 Most frequent AEs* (%)

DTG/ABC/3TC, n=248

ATV/r + TDF/FTC, n=247 .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

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

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

Orrell C, et al. AIDS 2016. Oral THAB0205LB

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/3TC 86 (145/169) 87 (142/164) 90 (71/79) 85 (68/80) Background NRTI: TDF/FTC 89 (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

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% women

N=715

Treatment-experienced: DTG-based regimens effective across key subgroups, including women

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

23% women

N=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

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

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

• verall 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 VIIV/DGR/0125/15 – October 2015

Why switch a stable regimen?

VIIV/DGR/0125/15 – October 2015

Initial regimens have grown simpler and more tolerable since the beginning of triple-drug cART

1998 2003 2008 2015

One of Plus

• ne 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/FTC EVG/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

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

VIIV/DGR/0125/15 – October 2015

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.

VIIV/DGR/0125/15 – October 2015

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

Proportion of toxicity switches (%)

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.

VIIV/DGR/0125/15 – October 2015

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.

VIIV/DGR/0125/15 – October 2015

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



VIIV/DGR/0125/15 – October 2015

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

VIIV/DGR/0125/15 – October 2015 VIIV/DGR/0125/15 – October 2015

STRIIVING

VIIV/DGR/0125/15 – October 2015

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

Week 24 Screening Week 48

Countries: US, Canada, Puerto Rico

Current ARTa

≥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.

VIIV/DGR/0125/15 – October 2015

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

2 4 6 8 10 12

• 9.1

2.3 ITT-E Population

• 0,3
• 12 -10 -8
• 6
• 4
• 2

2 4 6 8 10 12

• 4.9

4.4 PP Population

85 1 14 88 1 10 93 <1 6 93 2 5 20 40 60 80 100

Virologic success Virologic non- response No virologic data

HIV-1 RNA <50 c/mL, %

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.

VIIV/DGR/0125/15 – October 2015

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 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.

VIIV/DGR/0125/15 – October 2015

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.

0,5 1 1,5 2 2,5 3 3,5 4 Triumeq (n=269) CAR (n=276) Adjusted mean Change in score at Week 24

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.

VIIV/DGR/0125/15 – October 2015

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.

VIIV/DGR/0125/15 – October 2015

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.