www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013

HIV Treatment for Adults and Adolescents

Stefano Vella MDIstituto Superiore di Sanità - Rome - Italy

WHO 2013 Guidelines contribution to fill the treatment gap

• Operational / Programmatic Guidance – Improve testing coverage, address late presentation

– Optimize care delivery models:

• offer something meaningful in the pre-art period,

• task sharing, decentralization and integration of care, address attrition

• community involvement

• procurement

• Clinical Guidance– Improve the quality of drugs

– Simplify and harmonize 1st line regimens

– Perfect monitoring

– Streamline subsequent treatment lines

– Consider co-infections and co-morbidities

3 000 000

6 000 000

9 000 000

12 000 000

15 000 000

2003 2004 2005 2006 2007 2008 2009 2010

PLHIV in need of ART

Treatment gap

Receiving antiretroviral therapy

WHO’s 2013 Guidelines: the challenge

To find the right balance between:

the “individualized” approach to ART…..

and

the “public health” approach needed to start and maintain on

ART over 20 million persons….…

….considering the different HIV epidemics

….while keeping the same - evidence-based - standard of care!

• Strong evidence of the impact of ART on HIV transmission: o HPTN 052 study

• Emerging data on the impact of ART on HIV incidence at the population level

• Increasing evidence on clinical benefits of early ART initiation: o Observational studies showing impact on HIV mortality and

morbidityo Scientific insights on HIV immunopathogenesis and on the

effects of chronic inflammation associated with HIV infection

• Better regimens: o Better tolerable drugs o Better formulations o New classes

When to start ART: what is new since 2010 ?

When to start ART 2013 WHO consolidated Guidelines

Evaluating Risks & Benefits of earlier ART initiation

Potential benefits

• ↓ risk of HIV transmission (sexual and vertical)

• ↓ risk of TB disease• ↓ risk of serious non-AIDS conditions

(HBV disease, cardiovascular disease, renal disease, liver disease, cancers)

• linkage to care• chance to achieve higher CD4

values (immune recovery)• ↓ long term costs (infections and co

morbidities averted)

Potential risks

• long-term adverse effects / toxicities

• limitation of future treatment options (with drug resistance concerns)

• stigma & discrimination

• ↓ long term adherence ?

• burden on healthcare infrastructure / feasibility

• immediate cost

When to start in adults: what is new in the 2013 Guidelines

Considering both the individual and the Public Health benefit….

• Threshold moved to < 500 CD4 • Priority for reaching all HIV+ symptomatic persons

and those with CD4 ≤ 350 • More CD4-independent situations for ART initiation (in

addition to HIV/TB coinfection and HBV advanced liver disease):– HIV serodiscordant couples, – Pregnancy– Children less than 5 years of age

GL are a “tool” for countries to produce their own guidelines: they will adapt the new threshold(s) with operational / programmatic local context

Guideline AIDS or HIV-Related Symptoms

CD4+ Cell Count < 200/mm3

CD4+ Cell Count 200-350/mm3

CD4+ Cell Count 350-500/mm3

CD4+ Cell Count > 500 cells/mm3

DHHS-USA, 2013 Yes Yes Yes Yes1 Yes2

International AIDS Society-USA, 2012 Yes Yes Yes Yes1 Yes2

British HIV Association, 2012 Yes Yes Yes Consider 3 Defer3

European AIDS Clinical Society, 2012 Yes Yes Yes Consider3 Defer3

World Health Organization, 2013 Yes Yes Yes Yes4 Defer5

(1) Strong strength recommendation based on observational data (A-II)(2) Moderate strength recommendation based on expert opinion (B-III).(3 ) But treat all HIV+ pregnant women, HBV co-infection, HCV co-infection, HIVAN, HIV related neurocognitive disorders, ITP, non-AIDS cancers and serodiscordant couples

(4) Individuals with CD4 < 350 as a priority.(5) But treat all HIV+ pregnant women ,TB co-infection with active disease and HBV co-infection with severe liver disease, and serodiscordant copuls

Major Guidelines for Initiation of Antiretroviral Therapy

2013 WHO consolidated Guidelines

What ARV regimens to be used in adults

One-pill-a-day FDC as preferred 1st line(s)

Reducing the number of preferred regimens

Defining substitution regimens

Harmonizing regimens across different target populations

(TB, Hepatitis B, Pregnant Women)

1st Line ARTAdults and Adolescents

(including pregnant women, TB co-infection and HBV co-infection)

Preferred (FDC) Regimen(s)TDF+3TC (or FTC) + EFV

Alternative RegimensAZT+ 3TC + EFV (or NVP)

TDF+ 3TC (or FTC)+ NVP

Special situationsABC +3TC

+EFV (or NVP)

AZT (or ABC)+ 3TC+ LPV/r or ATV/r

One regimen cannot fit all: alternative, special situations

2013 WHO consolidated Guidelines

Major parameters TDF ABC AZT d4T

Major toxicities Renal and bone toxicity

ABC hypersensitivity

syndrome

Anemia and neutropenia Lipodystrophy

and neuropathy

Major drug Interactions Boosted PIs Not significant IFN RBV

INH ddI

Convenience (once vs twice daily regimen)

once daily once or twice daily twice daily twice daily

Safety in pregnancy Yes Yes Yes yesAvailability as triple FDCs Yes No Yes Yes

GI intolerance Not common Not common Frequent Not common

Consistency with pediatric regimens (all ages)

No (only for 3 years and older) Yes Yes Yes

Cost (generic, annual, per patient) US$ 57 US$ 169 US$ 75 US$ 19

Challenges ahead (i): current NRTIs

Phasing out d4T: trends of d4T, AZT and TDF use in adults first line ART (2006 – 2012 )

2006 2007 2009 2010 2011 20120.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

Evolution in the APIs use in adults, 2006 - 2012

d4T in 1st line Linear (d4T in 1st line) AZT in 1st lline TDF in 1st line

% o

f tre

ated

pati

ents

24.9%

< 0.1%

N= 12 countries

44%

27.9%

70%

27.9%

HIV/AIDS Department

Challenges ahead (ii): second-line regimens

Target population Preferred second-line regimen

Adults

If d4T or AZT was used in first -line ART TDF + 3TC (or FTC) + ATV/r or LPV/r

If TDF was used in first-line ART AZT + 3TC + ATV/r or LPV/r

Pregnant women Same regimens recommended for adults and adolescents

HIV and TB coinfection

If rifabutin is available Standard PI-containing regimens as recommended for adults and adolescents

If rifabutin is not available

Same NRTI backbones as recommended for adults and adolescents plus double-dose LPV/r (that is, LPV/r 800 mg/200 mg twice daily) or standard LPV dose with an adjusted dose of RTV (that is, LPV/r 400 mg/400 mg twice daily)

HIV and HBV coinfection AZT + TDF + 3TC (or FTC) + (ATV/r or LPV/r)

Comparative Analysis of ATV/r , LPV/r and DRV/r

Major parameters ATV/r LPV/r DRV/rConsistency with pediatric regimens no yes noNumber of pills per day (standard dose as FDC) 1 4 2-4

Convenience (once vs twice daily regimen)once daily twice daily Once or twice

dailySafety in pregnancy yes yes yesGI intolerance (diarrhea) Not frequent common Not frequentAvailability of heat stable FDCs yes yes noUse with TB treatment regimen that contains rifampin no yes no

Hyperbilirrubinemia + - -Dyslipidemia ± + ±Reduction cost potential low low highAccessibility in countries (registration status) low high lowAvailability of generic formulations yes yes yes

• Additional 1st line options

• Better 2nd / 3rd lines

• New strategies (if proven effective)

Nucleosides Integrase Inhibitors Non-nucleosides Protease Inhibitors

Available agents / combinations

Raltegravir Rilpivirine (FDC) Darunavir (boosted FDC)

Elvitegravir (FDC)

Investigational agents / combinations

TAF (TDF prodrug) Dolutegravir (FDC) MK-1439 TMC 310911

New drugs and new combinations shall be

made available, globally,

at affordable price,when possible as FDCs

Need to move forward: towards the 2015 guidelines…..

17 April 2013

2013 WHO ART Guidelines in Adults: a summary

Topic 2002 2003 2006 2010 2013When to start

CD4 ≤200 CD4 ≤ 200 CD4 ≤ 200- Consider 350 - CD4 ≤ 350 for TB

CD4 ≤ 350-Irrespective CD4 for TB and HBV

CD4 ≤ 500-Irrespective CD4 for TB, HBV, PW and SDC- CD4 ≤ 350 as priority

1st Line 8 options- AZT preferred

4 options- AZT preferred

8 options- AZT or TDFpreferred- d4T dose reduction

6 options &FDCs- AZT or TDF preferred- d4T phase out

2 options & FDCs- TDF and EFV preferred

across all populations

2nd Line Boosted and non-boosted PIs

Boosted PIs-IDV/r LPV/r, SQV/r

Boosted PI- ATV/r, DRV/r, FPV/r LPV/r, SQV/r

Boosted PI - Heat stable FDC: ATV/r, LPV/r

Boosted PIs - Heat stable FDC: ATV/r, LPV/r

3rd Line None None None DRV/r, RAL, ETV DRV/r, RAL, ETV

Viral LoadTesting

No No (Desirable)

Yes(Tertiary centers)

Yes(Phase in approach)

Yes(VL preferred for monitoring)

Earlier initiation

Simpler treatment

Less toxic, more robust regimens

Better monitoring

HIV/AIDS Department

17 April 2013

2013 WHO ART Guidelines in Adults: a summary

Topic 2002 2003 2006 2010 2013When to start

CD4 ≤200 CD4 ≤ 200 CD4 ≤ 200- Consider 350 - CD4 ≤ 350 for TB

CD4 ≤ 350-Irrespective CD4 for TB and HBV

CD4 ≤ 500-Irrespective CD4 for TB, HBV, PW and SDC- CD4 ≤ 350 as priority

1st Line 8 options- AZT preferred

4 options- AZT preferred

8 options- AZT or TDFpreferred- d4T dose reduction

6 options &FDCs- AZT or TDF preferred- d4T phase out

2 options & FDCs- TDF and EFV preferred

across all populations

2nd Line Boosted and non-boosted PIs

Boosted PIs-IDV/r LPV/r, SQV/r

Boosted PI- ATV/r, DRV/r, FPV/r LPV/r, SQV/r

Boosted PI - Heat stable FDC: ATV/r, LPV/r

Boosted PIs - Heat stable FDC: ATV/r, LPV/r

3rd Line None None None DRV/r, RAL, ETV DRV/r, RAL, ETV

Viral LoadTesting

No No (Desirable)

Yes(Tertiary centers)

Yes(Phase in approach)

Yes(VL preferred for monitoring)

Earlier initiation

Simpler treatment

Less toxic, more robust regimens

Better monitoring

HIV/AIDS Department Evidence-based, but intentionally aspirational…

MONITORING ART RESPONSE

Targeted viral load monitoring (suspected

clinical or immunological failure)

Routine viral load monitoring (early

detection of virological failure)

Switch to second-line therapy

Maintain first-line therapy

Viral load ≤1000 copies/ml

Viral load >1000 copies/ml

Repeat viral load testing after 3–6

months

Evaluate for adherence concerns

Viral load >1000copies/ml

Test viral load

70% greater resuppression rate after adherence intervention

Viral load as a tool to reinforce adherence and discriminate between treatment failure and non-adherence:

need to expand the availabity of point-of care diagnostics

A “game changer” document, and an important steptowards the global alignment of the HIV standard of care

2013 WHO consolidated Guidelines

Acknowledgements

Guideline Development Group

Co-chairs:

Anthony Harries, Gottfried Hirnschall

Elaine Abrams (International Center for AIDS Care and Treatment Programs, Mailman School of

Public Health, Columbia University, USA)

Tsitsi Apollo (Ministry of Health and Child Welfare, Zimbabwe)

Kevin De Cock (United States Centers for Disease Control and Prevention, USA)

Serge Eholie (ANEPA/Treichville Hospital, Abidjan, Côte d’Ivoire)

Adeeba Kamarulzaman (University of Malaya, Malaysia)

Yogan Pillay (National Department of Health, South Africa)

Denis Tindyebwa (African Network for the Care of Children Affected by AIDS, Uganda)

Stefano Vella (Istituto Superiore di Sanità, Italy)

Special thanks to all members of the Guideline Development Groups, the Peer Review panel and to those who contributed to the GRADE systematic reviews and supporting evidence which informed the

guidelines process.

WHO Department of HIV

Andrew Ball Philippa Easterbrook

Meg Doherty Eyerusalem Kebede Negussie

Nathan Shaffer Lulu Muhe

Nathan FordMarco Vitoria

Joseph Perriëns

Guideline Development Group

Pedro Cahn (Fundación Huesped, Argentina), Alexandra Calmy (University of Geneva, Switzerland), Frank

Chimbwandira (Ministry of Health, Malawi), David Cooper (University of New South Wales and St Vincent’s Hospital, Australia), Judith Currier (UCLA Clinical AIDS Research & Education Center, USA), François Dabis (School of Public

Health (ISPED) of the University Bordeaux Segalen, France), Charles Flexner (Johns Hopkins University, USA), Tendani Gaolathe (Princess Marina Hospital, Botswana), Beatriz Grinsztejn (Fundação Oswaldo Cruz – FIOCRUZ,

Brazil), Diane Havlir (University of California at San Francisco, USA), Charles Holmes (Centre for Infectious

Disease Research in Zambia, Zambia), John Idoko (National Agency for the Control of AIDS, Nigeria), Kebba Jobarteh

(Centers for Disease Control and Prevention, Mozambique), Elly Katabira (Makarere University, Uganda),

Nagalingeswaran Kumarasamy (Y.R. Gaitonde Centre for AIDS Research and Education, India), Volodymyr Kurpita

(All-Ukrainian Network of People Living with HIV, Ukraine), Karine Lacombe (Agence Nationale de Recherche sur le

Sida et les Hépatites Virales (ANRS), France), Albert Mwango (Ministry of Health, Zambia), Leonardo Palombi

(DREAM Program, Community of Sant’Egidio, Rome, Italy), Anton Pozniak (Chelsea and Westminster Hospital, United Kingdom), Luis Adrián Quiroz (Derechohabientes Viviendo

con VIH del IMSS, Mexico), Kiat Ruxrungtham (Chulalongkorn University, Chula Vaccine Research Center, King Chulalongkorn Memorial Hospital, Thailand), Michael Saag (University of Alabama at Birmingham, USA), Gisela

Schneider (German Institute for Medical Mission, Germany), Yanri Subronto (Universitas Gadjah Mada, Indonesia) and Francois Venter (University of the Witwatersrand, South

Africa)