What’s new - WHO 2019 recommendations for antiretroviral treatment

Elaine AbramsICAP at Columbia University

Updates of WHO recommendations for antiretroviral treatment regimes, July 2019• Abridged history of WHO 2018 guidelines for antiretroviral

treatment (ART)• Review of WHO 2019 guidance on ART regimens

• First-line ART regimens • Second-line ART regimens• Transition to optimal regimens

oAdults & adolescents, infants & childrenoNew evidence on informing guidelines updateso Considerations and controversies

The introduction of dolutegravir (DTG): an abridged history • Global community identified tenofovir (TDF)+ lamivudine (3TC) +DTG

[TLD] as an optimal ART regimen • Attributes of DTG:

• High virologic potency• High/durable genetic barrier to resistance • Harmonized across populations• Well tolerated• Low toxicity• Low cost • Low pill burden/pill size• Available as generic fixed dose combination (FDC)

The introduction of dolutegravir (DTG): planning for an accelerated transition• In the years leading up to the 2018 WHO clinical ART guidelines

meeting, enormous resources were mobilized to study, produce and introduce DTG for treatment of HIV infection in low- and middle-income countries (LMIC)

• Several countries including Botswana and Brazil introduced DTG into their national guidelines as preferred first-line; other countries piloted DTG through catalytic purchases

• Generic manufacturers accelerated TLD production to meet the anticipated global demand

The introduction of dolutegravir (DTG): monitoring birth outcomes in Botswana• Tsepamo study in Botswana was

an ongoing birth surveillance study established to evaluate the prevalence of selected birth outcomes by maternal HIV and antiretroviral treatment exposure status

• 8 facilities in Botswana including ~ 45% of births

Tsepamo was well positioned to monitor outcomes of pregnant women receiving DTG as the agent was introduced for adults in Botswana

Tsepamo findings: DTG in pregnancy and birth outcomes

• An early look at outcomes among women on DTG at the time of conception identified a ‘signal’ of concern. Neural tube defects (NTDs) were observed in:

• 4 infants of 426 women on DTG ART regimens at conception (0.94%); • 14 infants of 11,200 women on non-DTG ART regimens at conception

(0.12%);• 61 infants of 66,057 HIV-uninfected women (0.09%)

• No significant differences in rates of any adverse event, prematurity, severe prematurity, small for gestational age, low birth weight, stillbirth, neonatal death, birth defects among women initiating DTG during pregnancy compared to EFV initiated during pregnancy

2018 WHO recommendations: First-line ART regimens

Note of caution for using DTG in women and adolescent girls of

childbearing potential

Access to DTG as preferred 1st line among women of childbearing potential (WCBP), May 2019

24 countries

All WCBP NO-DTG based

regimen4 countries

Burundi, Eswatini, Mozambique,

Rwanda

WCBP on Contraception Access DTG15 countries

ANY contraception2 countries

HaitiUkraine

Long Acting Contraception

7 countries

Botswana, Brazil, DRC, Kenya, Nigeria,

South Africa, Venezuela

Consistent reliable contraception

6 countries

Cote d'Ivoire, Ethiopia

Ghana, Niger, Senegal. Zambia

Informed Choice 5 Countries

Lesotho, Malawi, Tanzania, Uganda,

Zimbabwe

Fast Forward 2019 WHO Guidance

• Increased number of observations in Botswana of infants born to women receiving DTG; additional data from other cohorts

• Early results of pathogenesis and basic science studies• New clinical trial results (Advance, NAMSAL, Dolphin)• Cost and cost effectiveness analyses: DTG for WCBP• Additional pharmacologic data: TB, children• Implementation experience• Community input, particularly the voices of women living with HIV • 2019 HIV drug resistance report

2019 WHO recommendations: First-line ART regimens

0

0.5

1

1.5

2

2.5

% w

ith N

TD

0.94%

Tsepamo: Prevalence of NTDs by ARV exposure- May 2018-March 2019

0.12%0.05% 0.09%

Non-DTG preconceptionMay18 July Sept Nov Mar1911300 14792

14 15

EFV pre-conceptionMay18 July Sept Nov Mar195787 7959

3 3

HIV-uninfectedMay18 July Sept Nov Mar1966057 89372

61 70

DTG preconceptionMay18 July Sept Nov Dec Mar19

N 426 1683NTD 4 5

0.11% 0.04% 0.08%

0.30%

Difference 0.20 (0.01, 0.59)Prevalence DifferenceNTD by ARV/HIV Groups:

DTG Preconception vs OthersDifference 0.26 (0.07, 0.66)

Difference 0.22 (0.05, 0.61)

Infant without NTD

Infant with NTD

Ordinarily we expect to see 1 NTD out of 1,000 births

In 2018, there were 4 infants with NTDs of 426 births

• Out of 426 births with exposure to DTG around the time of conception in Botswana:• 4 infants had NTD • 422 infants had no NTD

• In other populations this would be the equivalent of:• 9 infants with NTD• 991 infants with no NTD

Infant without NTD

Infant with NTD

In 2019, there were 5 infants with NTDs of 1684 births

• Out of 1684 births with exposure to DTG around the time of conception in Botswana:• 5 infants had NTD • 1679 infants had no NTD

• In other populations this would be the equivalent of:• 3 infants with NTD• 997 infants with no NTD

Infant without NTD

Infant with NTD

CEPA

C-DT

GHI

V SY

NTH

ESIS

Both models show that use of EFV for women of child bearing potential initiating ART rather than DTG in order to avoid NTDs would likely lead to other substantial negative impacts at population level.

Prevalence of pretreatment HIV drug resistance to NNRTI (national surveys)

5 in Africa: South Africa, Uganda, Namibia, Zimbabwe, Eswatini;

5 in Central/South America: Argentina, Honduras, Cuba, Nicaragua, Guatemala;

2 in South East Asia: Nepal, PNG.

2019 WHO HIVDR Report

Nationally representative surveys of pretreatment HIV drug resistance by drug and by country

0-5.7%

0-4.5%

2019 WHO HIVDR Report

Advance Trial: DTG plus two different prodrugs of tenofovir to treat HIV • Open label, 96-week, phase 3 randomized trial

comparing DTG-based ART against local standard of care (SOC)

• 1053 ART-naïve individuals were randomized to receive:

• TDF +Emtricitabine (FTC) +DTG• Tenofovir alafenamide fumarate (TAF)+FTC+DTG• TDF+FTC+EFV (SOC)

• 59% female, 62% South Africa, mean age 32 years, mean CD4 337 cells/mm3 , 78% VL< 100,000 copies/mL at entry

Advance: HIV-1 RNA <50 copies/ml, intention-to-treat population

WD Venter et al. N Engl J Med 2019;381:803-815.

Advance: HIV-1 RNA <50 copies/ml, per protocol population

WD Venter et al. N Engl J Med 2019;381:803-815.

Advance: Individual outcome measures at week 48

WD Venter et al. N Engl J Med 2019;381:803-815.

ADVANCE: Mean change from baseline in body weight by regimen and gender, over time

Female participants

Male participants

WD Venter et al. N Engl J Med 2019;381:803-815.

Patterns of obesity by regimen among females: BMI category (kg/m2), % over time

WD Venter et al. N Engl J Med 2019;381:803-815.

Namsal ANRS 12313: DTG-based or low-dose EFV-based regimen for the treatment of HIV-1

• Open label, multicenter, randomized, phase 3 noninferiority trial in Cameroon

• Trial regimens: TDF+3TC+ DTG vs. TDF+3TC+EFV400

• 613 participants; 66% female, median age 37 years, median VL 5.3 (4.8-5.8) log10copies/ml (30.7% >500,000 copies), median CD4+ 281 (154-444) cells/mm3

Namsal: Viral suppression in intention-to-treat population

The NAMSAL ANRS 12313 Study Group. N Engl J Med 2019;381:816-826.

NAMSAL: Viral suppression according to baseline VL

The NAMSAL ANRS 12313 Study Group. N Engl J Med 2019;381:816-826.

DolPHin 2: DTG vs EFV when starting ART in late pregnancy

• Open-label randomized trial of DTG+2NRTI vs EFV+2NRTI in 268 pregnant ART-naïve women presenting to ANC at ≥28-36 weeks gestation in Kampala and Cape Town.

• Primary endpoint is virologic response (VL <50) at delivery.

12 wkPP

24 wkPP

48 wkPP

72 wkPP

Infant VL (dx)

Maternal VL allEFV + 2 NRTI EFV + 2 NRTI

DTG+ 2 NRTI DTG + 2 NRTI

StartEFVART

Randomize median 3 d

4wk2 wkPP

6 wkPP

delivery

ART-naïve

>28-36wksgest

2Khoo S et al. CROI 2019 Seattle, WA Abs 40LB

DolPHin2: More rapid VL decline with DTG than EFV Primary outcome

– Time on medication before delivery, median 55 days

2

Delivery DTG EFV aRR DTG vs EFV* P valueVL <50 73.8% (90/122) 42.6% (49/115) 1.66 (1.2, 2.1) <0.0001

VL <1000 92.6% (113/122) 82.6% (95/115) 1.11 (1.0, 1.2) 0.0513*Adjusted for age, country, VL (<> 100,000), CD4 (<>200), GA at start ART

73.7%78.9%

44.4%

75.9%

57.1%

74.5% 70.8%

42.6%48.9%

14.3%

45.9%

23.5%

44.1%

30.8%

0%

20%

40%

60%

80%

100%

Overall VL <100,000 VL >=100,000 CD4 >=200 CD4 <200 GA <36 wk GA >=36 wk

Perc

ent V

L <5

0 c/

mL

DTG EFV

237 198 39 206 31 200 37VL strata CD4 strata GA at entry strata

Total N

Khoo S et al. CROI 2019 Seattle, WA Abs 40LB

2019 WHO recommendations: First-line ART regimens

2018 Note of caution for using DTG in women and adolescent girls of

childbearing potential

2019 footnote ‘a’: Effective contraception should be offered to adult women and adolescent girls of childbearing age or potential. DTG can be prescribed for adult women and adolescent girls of childbearing age or potential who wish to become pregnant or who are not otherwise using or accessing consistent and effective contraception if they have been fully informed of the potential increase in the risk of NTD. If women identify pregnancy after the first trimester, DTG should be initiated or continued for the duration of the pregnancy

2019 WHO recommendations: Second-line ART regimens

Transitioning to TLD: Individuals newly initiating ART

Treatment scenario Preferred regimen ConsiderationsInitiating ARTAdults and adolescents

TDF+3TC+DTG Providing WCBP with information about NTD risk, access to contraceptive and choice to opt for EFV-based ART

Pregnant and breastfeeding women

TDF+3TC+DTG Providing same information and options during breastfeeding

TB co-infection TDF+3TC+DTG DTG 50mg twice daily if rifampicin is used

*TLD can be used in adolescents >30 kg; DTG 50mg can be used with ABC+3TC in adolescents 20-30kg

*

Transitioning to TLD: Switching only suppressed individuals already on first-line ART• No evidence to support efficacy of DTG when used in combination with an

inactive backbone• Viremic individuals oftentimes harbor NRTI HIV drug resistance mutations(DRM) depending

on duration and height of viremia; observed high levels of NRTI &NNRTI DRM, including dual-class TDF+XTC resistance in HIV DR surveys

• Viral load monitoring is not routinely available in many settings• Requiring VL prior to switching will delay scale-up and delay access to optimized regimens• Population-based surveys indicate high levels of viral suppression among adults on 1st line

ART regimens• Limited evidence to guide viral load cut-offs for failure and switch

• Weak evidence of efficacy of enhanced adherence support to achieve VL suppression

• Further delay access to optimized regimen trying to achieve suppression• Optimizing the NRTI backbone changes regimen characteristics to twice daily

regimen; no currently available FDC

Transitioning to TLD: Switching all individuals unless evidence of failure on first-line ART

• Assumes those currently suppressed will remain suppressed; those off treatment will suppress; those with limited HIVDR will suppress

• For some, efficacy of TLD may be jeopardized resulting in failure to achieve viral suppression; risk of selection of integrase inhibitor mutations, possibly jeopardizing future regimens

• Viral load testing post-transition would identify those failing to suppress, target further intervention (switch backbone, adherence support)

• Programmatically efficient approach to accelerate access to TLD• Programs with the lowest rates of viral suppression are likely to benefit the

most from a rapid transition to TLD

Considerations for transition to TLD among adults and adolescents already using first-line ART, WHO

Infants & childrenIn brief

Substantial Gaps in First and Third 90, 0-14y (n=487), PHIA

60

94

53

0

20

40

60

80

100

Eswatini Malawi Tanzania* Uganda* Zambia Zimbabwe Overall

%

Diagnosed On Treatment VLS* N<25

Low rates of viral load suppression among children, 0-14 years, compared with adults, PHIA surveys

Source: Saito, 10th pediatric workshop, 2019*Pooled estimates from 6 countries, PHIA 2016-2018

WHO national HIV PDR surveys among infants newly diagnosed with HIV and treatment naïve 2012-2018: NNRTI resistance

WHO HIV Drug Resistance Report 2019

NEONATES CHILDREN

Preferred AZT+3TC+RAL1 ABC+3TC+DTG2

Alternatives AZT+3TC+NVPABC+3TC+LPV/rABC+3TC+RAL1

Special circumstances3 AZT+3TC+LPV/r

ABC (or AZT)+3TC+EFVABC (or

AZT)+3TC+RALAZT+3TC+LPV/rAZT+3TC+RALAZT+3TC+NVP

1 For the shortest time possible, until a solid formulation of LPV/r or DTG can be used2 For age and weight groups with DTG approved dosing and where LPV/r is not available3 In cases where no other alternatives are available

WHO 2018 Recommendations and Guidance carried forward in 2019

Move away from NNRTI-based

regimens

Introduce DTG as soon as possible

Use the most potent non-NNRTI

option

Only age <2 wks

2TLD can be used in adolescents >30 kg; DTG 50mg can be used with ABC+3TC in adolescents 20-30kg

Goal of transition • Improve outcomes• Harmonization• Simplification• Supply security

Children eligible for transition • Already on ART • Clinically stable

(defined as per national guidelines)

• Prioritize children on NNRTI based regimen

Approach to transitioning children to optimal regimensCurrent regimen Weight Optimal regimen for

transition Considerations

AZT/3TC/NVP AZT/3TC/EFVABC/3TC/NVP

<20 kg ABC/3TC/LPVr If still stable these can be transitioned to DTG when they reach 20 kg

20-30kg ABC/3TC/DTG If still stable these can be transitioned to TLD when they reach 30 kg

> 30kg TLD -

ABC/3TC/EFV

<20 kgNo change until reach 20

kg unless treatment failure occurs

Of value once reached 20 kg when DTG can be used so that OD administration is preserved.

20-30kg ABC/3TC/DTG If still stable these can be transitioned to TLD when they reach 30 kg

> 30kg TLD

ABC/3TC/LPVrAZT/3TC/LPVr

<20 kgNo change until reach 20

kg unless treatment failure occurs

Important to ensure use of tablets as soon as possible to reduce pill burden. Transition from AZT/3TC/LPVr to ABC/3TC/LPVr can also be considered to reduce pill burden

20-30kg ABC/3TC/DTG If still stable these can be transitioned to TLD when they reach 30 kg

> 30kg TLD -

Kid considerations

• Enormous progress determining DTG dosing in children, an unusually accelerated timeline

• Adolescents and children >20kg can start receiving DTG today! • ART for children has not yet achieved simplification; infant

formulations remain problematic• New formulations and helpful guidance are on the way

• Preventing new pediatric infections is critical to improve child health outcomes; TLD for pregnant women should accelerate efforts to prevent new pediatric infections

In summary

• WHO 2019 guidelines strongly endorsed TLD as the preferred first-line ART and TLE400 as alternative

• Removed the note of caution for women of reproductive potential• Confirmed 2018 recommendations for second-line treatment regimens• Identified a need for more data on TAF and DTG-associated weight gain• Provided further guidance on transition to optimal regimens• Community of people living with HIV played an important role

• The work is ongoing, recognizing that many questions remain unanswered

• Need for additional research and carefully documented implementation experiences and outcomes to inform the next guidelines

Thank you for your attention!

Thank you to Nandita Sugandhi, Martina Penazzato, Meg Doherty, Lynne Mofenson. Francois Venter and the countless other individuals doing this difficult work

GRAND ROUNDS

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