Dolutegravir based regimens in first- and second-line HIV

Treatment

WHO Geneva19 November, 2019

Uptake of major HIV treatment policies

Treat All

DTG transition

Access to DTG as preferred 1st line among WCBP, April 2019

24 countries

All WCBP

NO-DTG based

regimen

4 countries

Burundi, Eswatini, Mozambique, Rwanda

WCBP on Contraception Access DTG15 countries

ANY contraception

2 countries

Haiti

Ukraine

Long Acting Contraception

7 countries

Botswana, Brazil, DRC, Kenya, Nigeria, South

Africa, Venezuela

Consistent reliable contraception

6 countries

Cote d'Ivoire, EthiopiaGhana, Niger, Senegal.

Zambia

Informed Choice

5 Countries

Lesotho, Malawi, Tanzania, Uganda,

Zimbabwe

WHO Recommendations Update

2018 2019

Safety and Efficacy of DTG and EFV600 in 1st line ART(summary 2019 Sys Review & NMA)

major outcomes DTG vs EFV600quality of evidence

Treatment discontinuation (any or due AEs) DTG better high

Viral suppression (4-96 weeks), viral suppression at delivery (PW), transmission (PW)

DTG probably better high to moderate

CD4 recovery (24-144 weeks) DTG probably better high to moderate

Mortality comparable low

Neuropsychiatric AEs (any grade), depression (grade 3 or 4), dizziness (any grade)

DTG probably better moderate to low

Sleep disorders (any grade) comparable very low

Body weight gain EFV probably better moderate

NTD EFV may be better low

HIVDR (overall, NRTI or anchor drug) DTG probably better high to moderate

Reference: Steve Kanters, For WHO ARV GDG, 5-7 June 2019

Tole

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ility

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Safety and Efficacy of DTG and PIs (LPVr) in 2nd line ART(summary 2019 Sys Review & NMA)

major outcomes DTG vs LPVr quality of evidence

Viral suppression (4-96 weeks) DTG better high

Viral suppression baseline VL > 100,000 (48 weeks) comparable moderate

CD4 recovery (24-48 weeks) comparable moderate

Mortality comparable low

Neuropsychiatric AEs (any grade) comparable low

Treatment related SAE comparable low

Treatment emergent AE, related AEs DTG probably better high

Treatment discontinuation (any or due AEs) DTG probably better high

HIVDR ( overall) comparable very low

Reference: Steve Kanters, For WHO ARV GDG, 5-7 June 2019

Tole

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ility

, saf

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&

resi

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Effi

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Topic 2018 interim guidelines 2019 updates

Use of DTG in 1st

line

DTG as preferred option • Conditional recommendation • For adults, adolescents and children

with approved dosing• Moderate certainty evidence for adults• Very low certainty evidence for women

of reproductive age (note of caution on DTG and use of effective contraception)

DTG as preferred option• Strong recommendation• Moderate certainty evidence for all adults

(programmatic considerations and informed by risk/benefit analysis for women of reproductive age)

• Strong focus on women centred approach

Use of EFV in 1st

line

EFV 400 and EFV600 as alternative options• Conditional recommendation• Moderate certainty of evidence• Limited evidence on EFV400 efficacy in

TB and pregnant women

EFV400 as alternative option (including TB and PW)• Strong recommendation • Moderate certainty of evidence

EFV600 used in special situations

Use of DTG in 2nd

line

DTG as preferred option if not used in 1st

line • Conditional recommendation • Moderate certainty of evidence (note of

caution on DTG use for women of reproductive age)

DTG as preferred option if not used in 1st line • Conditional recommendation • Moderate certainty of evidence (informed by

risk/benefit analysis for women of reproductive age )

PI as preferred option if DTG used in 1st line• Strong recommendation • Moderate certainty of evidence

2019 WHO ART Guidelines: What has been changed?

Key change: note of caution removedDTG recommended as preferred ARV for all

▪ Updated systematic review

Safety with DTG – NTD Updates Since 2018

→ May 2018: 12 papers primarily abstracts/case reports

→ June 2019: 24 publications (11 new papers and 19 abstracts (including 2 risk/benefit analyses and 3 basic science studies)

▪ Confidential data from multiple researchers in support of GL update

→ Tsepamo birth surveillance

→ CDC/MOH Botswana birth surveillance

→ Brazil case-control study

→ Antiretroviral Pregnancy Registry update

→ Observational cohorts: PHACS, EPPICC, electronic medical record review US by IMPAACT

→ Basic science studies: ViiV, Gilead, Baylor, U. Toronto, U Nebraska

→ Ongoing DTG trials with unexpected pregnancies: ADVANCE, NAMSAL

0

0.5

1

1.5

2

2.5

% w

ith

NT

D

0.94

Non-DTG preconception

May18 July Sept Nov Mar19

11300 14792

EFV pre-conception

May18 July Sept Nov Mar19

5787 7959

HIV-uninfected

May18 July Sept Nov Mar19

66057 89372

DTG preconception

May18 July Sept Nov Dec Mar19

N 426 1683

Tsepamo: Evolution of NTD Prevalence Over Time

March 2019

0.12 0.05 0.09

→NTD prevalence has decreased but remains significant

→Possible larger number of exposures needed to see

resolution of signal (to detect 3-fold increase in risk of defect

with prevalence 0.1%, need >2,000 exposures)

→Or possible elevated risk will remain at this lower level

Risk vs Benefits of DTG in

Women of Childbearing-Potential at a Population LevelDugdale C et al. Ann Int Med. 2019 – Updated for June 2019 GDG meeting with updated data

Source: C Dugdale/WHO 2019

CEPAC: May 2019 Tsepamo data 0.3% NTD; NNRTI pretreatment drug resistance 10.7%; DTG efficacy per recent trials

For every 1000 South African women of childbearing potential with HIV starting ART, per yr, compared with EFV (average over 5 yrs):

→ “DTG with contraceptive” vs EFV in 1,000 women of childbearing

potential

DTG with contraception vs EFV onlyDTG only vs EFV only

→ “DTG in all” compared to “EFV in all” in 1,000 women of

childbearing potential:

• 1 excess NTD

• More maternal survival, less transmission to sexual partners,

less MTCT, resulting in higher HIV-free survival in infants

• Reducing unintended pregnancies in women using DTG

effectively eliminates NTD concerns

• Still more maternal survival and less transmission to sex partners

• Needs high coverage of effective contraceptive methods

• Reducing unintended pregnancies important goal of integrating

contraceptive & family planning services into ART

INSTI and new story of weight gain among PLHIV

Weight Gain with INSTIs (+ TAF?)

• NAMSAL 48 weeks (baseline BMI 23)

– Significantly more weight/BMI gain & emergent obesity on TDF/3TC + DTG vs TDF/3TC/EFV400

• ADVANCE 96 weeks (baseline BMI 22 in men, 27 in women)

– TAF/F/DTG vs TDF/F/DTG vs TDF/FTC/EFV

– Men +5kg, +4kg, +1kg (DEXA: similar fat/lean mass gain)

– Women +10kg, +5kg, +3kg (DEXA: fat>lean mass gain)

ADVANCE: BMI category over time: women (obese at baseline excluded)%

Par

tici

pan

ts

Weight Gain During Pregnancy in Women with HIV

Starting DTG vs EFV vs Uninfected Women in Botswana, TsepamoCaniglia E et al. IAS July 2019, Mexico City Abs. LBPEB14

▪ Evaluated rate of weekly weight gain and weight gain between 18±2 to 36±2 wk GA

▪ Exposure groups for weight gain analysis

− HIV+ women starting DTG btn conception and 17 wk GA (1st ANC wt 65.6 kg)

− HIV+ women starting EFV btn conception and 17 wk GA (1st ANC wt 65.7 kg)

− HIV-uninfected women of similar age, presenting for ANC <17 wk (1st ANC wt 66.5 kg)

Adjusted Mean Difference Weight Gain 18-36 wk (kg)Adjusted Mean Difference Weekly Weight Gain (kg/wk)

Adjusted for: age, CD4, employment, education, parity, gravidity, marital status, site, smoking, alcohol, pre-pregnancy weight, weight at ART initiation (or first ANC), gestational age at ART initiation (or first ANC)

Weight Gain During Pregnancy in Women with HIV

Starting DTG vs EFV vs Uninfected Women in Botswana, TsepamoCaniglia E et al. IAS July 2019, Mexico City Abs. LBPEB14

▪ Evaluated rate of weekly weight gain and weight gain between 18±2 to 36±2 wk GA

▪ Exposure groups for weight gain analysis

− HIV+ women starting DTG btn conception and 17 wk GA (1st ANC wt 65.6 kg)

− HIV+ women starting EFV btn conception and 17 wk GA (1st ANC wt 65.7 kg)

− HIV-uninfected women of similar age, presenting for ANC <17 wk (1st ANC wt 66.5 kg)

Adjusted Mean Difference Weight Gain 18-36 wk (kg)Adjusted Mean Difference Weekly Weight Gain (kg/wk)

Adjusted for: age, CD4, employment, education, parity, gravidity, marital status, site, smoking, alcohol, pre-pregnancy weight, weight at ART initiation (or first ANC), gestational age at ART initiation (or first ANC)

Women initiating DTG compared to

EFV gained more weight However,

neither group gained as much weight as

HIV-uninfected women

Important drug-drug interactions with DTGKey drug interaction Suggested management

Amiodaquine Use an alternative antimalarial agent

Carbamazepine Use DTG twice daily or substitute with an alternative anticonvulsant agent

Phenytoin and phenobarbital Use an alternative anticonvulsant agent

Dofetilide Use an alternative antiarrhythmic agent

Metformin Limit daily dose of metformin to 1000mg when used with DTG & monitor glycemic control

Polyvalent cation products containing Al, Ca, Fe, Mg and Zn (eg: antacids, multivitamins & supplements)*

Use 2 hours before or 6 hours after DTG

Rifampicin Use DTG twice daily or substitute with rifabutin

* There is no drug interaction of DTG with folic acid. However, folic acid is frequently included in multivitamin preparations which may also

contain polyvalent cations.

Pharmacovigilance and toxicity monitoring for ARVsGaps and specific population groups

Toxicity Monitoring & Pharmacovigilence• Need to monitor long-term and unexpected complications (incl. weight gain) and

address gaps in ARV toxicity monitoring in pregnant women, children & adolescents

• WHO supporting via following:

• Normative: Advisory Committee on Safety of Medicinal Products (ACSoMP), ART

guidelines

• Guidance: implementation tools, systematic evidence reviews,

• Global ARV toxicity database and central pregnancy: pooling data collected at

country level for rapid signal detection

• Country support: PV preparedness and toxicity surveillance at sites

• Convening: advisory committee on implementation of surveillance and toxicity

monitoring

Country implementation of ARV toxicity monitoring

Source: Global AIDS Monitoring (UNAIDS/WHO/UNICEF) and WHO HIV country intelligence tool, 2018

Majority of countries (18/37) reported monitoring ARV toxicity via routine HIV patient monitoring system

*ARV toxicity

monitoring approaches

Routine monitoring

Active surveillance

(general population)

Pregnancy registry/birth

defect surveillance

Country implementation of toxicity monitoring approaches to monitor ADRs to DTG

Source: Global AIDS Monitoring (UNAIDS/WHO/UNICEF) and WHO HIV country intelligence tool, 2018

4 countries reported DTG pregnancy registries/birth defect surveillance

• Botswana• Brazil• Malawi• Uganda

0.7%

0.4%

0.3%0.3%

0.1% 0.1% 0.1%

0.2%

1,394 852 613 525 202 168 140 4130.0%

0.1%

0.2%

0.3%

0.4%

0.5%

0.6%

0.7%

0.8%

Brazilian experience on active pharmacovigilance of dolutegravir

• Active pharmacovigilance was implemented through patient interviews and a specific form was incorporated in the national ARV system

• Pharmacovigilance system coverage: 95% (190K/199K)

Sources: (1) Batista et al. The Brazilian experience of implementing the active pharmacovigilance of dolutegravir. Medicine (Baltimore). 2019 Mar;98(10):e14828.; and (2) Ministérioda Saúde. Relatório de Monitoramento Clínico do HIV 2018 [Internet]. Available from: http://www.aids.gov.br/pt-br/pub/2018/relatorio-de-monitoramento-clinico-do-hiv-2018.

Prevalence of adverse reactions: 1.5% (~3K)

1.3%

1.4%

1.4%

1.7%

1.9%

1.7%

1.5%

1.9%

1.0%

0.0% 0.5% 1.0% 1.5% 2.0%

60+

50-59

40-49

25-39

18-24

Female

Male

Naïve

Switch

Age

Sex

Pre

vio

us

AR

T u

se

WHO response to safety signal with DTG starting from May 2018

• Sub-committee on safety of dolutegravir established - July 2018

• Report to WHO Advisory Committee on Safety of Medical Products (ACSoMP) and ART Guidelines Development Group

• Review and assess data and ongoing studies in relation with the NTD signal and any safety issues in pregnancy

• Potential INSTIs class effect • Last meeting in May 2019 and regularly

convened as new data become available• Next meeting November 2019 – new

Botswana Tsepamo and CDC data

Objective: refute or confirm the safety signal

https://www.who.int/medicines/regulation/medicines-safety/publications/ACSoMP_16.pdf?ua=1

• Review of case reports • ART national policy adoptions and

adaptations - HIV• Procurement issues - HIV• PV system preparedness and DTG active

monitoring – EMP & HIV

• researchers and partners engaged in surveillance and trials - HIV

• regulatory authorities esp. FDA and EMA - EMP

• marketing authorization holders (MAHs) - HIV and EMP

• Consultation with civil society – HIV • public: Media Centre, Pharmaceutical

Newsletter, technical updates – HIV & EMP

• Interrogation of global or national PV databases incl. Vigibase

WHO normative work on potential safety issue with DTG

WHO technical and convening role WHO Country support work

Emerging ADRs➢ Rapidly adaptable process with DTG sub-

group of experts/partners ➢ invitation of clinical experts e.g.

endocrinogists➢ clinic assessors to support reporting

country to review case reports ➢ Inform 2020 revisions

WHO permanent role

WHO support to countries for implementation of active toxicity monitoring and safe introduction of DTG and other new ARVs – guidance, tools and technical assistance

new indicators for toxicity in case surveillance &

routine monitoring

1. Guidance and tools inc.WHO ARV toxicity

monitoring implementation tool and

training materials

WHO global ARV toxicity monitoring database

Central registry for drug safety in pregnancy

General population inc.

children & adolescents

Pregnant women

Pregnancy & birth defect registry tools

Toolkit with PV module for children

WHO global databases

Generic DTG ADR notification form

AcknowledgementsAll members Guidelines Development Group members

• Elaine Abrams & Serge Eholie

• Tamara Kredo

WHO Treatment and Care team

• Marco Vitoria

• Martina Penazzato

• Francoise Renaud

• Nathan Ford

• Silvia Bertagnolio

• Lara Vojnov

• Vindi Singh

• Morkor Newman

• Serena Brusamento

• Chantal Migone

• Ajay Rangaraj

• Anisa Ghadrshenasa

• PEPFAR, Unitaid, Global Fund, Gates, CDC, USAID, UNAIDS, UNICEF

• AFROCAB, iBASE, ITPC, Salamander Trust, ICW, GPN+, APN+