Yes - Istituto Superiore di Sanità

Report
HIV Treatment
for Adults and Adolescents
Stefano Vella MD
Istituto Superiore di Sanità - Rome - Italy
www.ias2013.org
Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Treatment gap
WHO 2013 Guidelines contribution
to fill the treatment gap
PLHIV in need of ART
15 000 000
9 000 000
6 000 000
3 000 000
2003
•
•
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
Receiving antiretroviral therapy
12 000 000
2004
2005
2006
2007
2008
2009
2010
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!
When to start ART: what is new since 2010 ?
• 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
morbidity
o 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
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
Major Guidelines for Initiation of Antiretroviral Therapy
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
Guideline
(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
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)
2013 WHO consolidated Guidelines
One regimen cannot fit all: alternative, special situations
1st Line ART
Preferred (FDC) Regimen(s)
Adults and Adolescents
(including pregnant women, TB coinfection and HBV co-infection)
TDF+3TC (or FTC) + EFV
AZT+ 3TC + EFV (or NVP)
Alternative Regimens
Special situations
TDF+ 3TC (or FTC)+ NVP
ABC +3TC
+EFV (or NVP)
AZT (or ABC)+ 3TC
+ LPV/r or ATV/r
Challenges ahead (i): current NRTIs
Major parameters
Major toxicities
Major drug Interactions
Convenience
(once vs twice daily regimen)
Safety in pregnancy
Availability as triple FDCs
GI intolerance
Consistency with pediatric
regimens (all ages)
Cost (generic, annual, per patient)
TDF
ABC
ABC
Renal and bone
hypersensitivity
toxicity
syndrome
AZT
Anemia and
neutropenia
d4T
Lipodystrophy
and neuropathy
Boosted PIs
Not significant
IFN
RBV
INH
ddI
once daily
once or twice
daily
twice daily
twice daily
Yes
Yes
Yes
yes
Yes
No
Yes
Yes
Not common
Not common
Frequent
Not common
No (only for 3
years and older)
Yes
Yes
Yes
US$ 57
US$ 169
US$ 75
US$ 19
Phasing out d4T: trends of d4T, AZT and TDF use
in adults first line ART (2006 – 2012 )
Evolution in the APIs use in adults, 2006 - 2012
80.0
70%
d4T in 1st line
AZT in 1st lline
TDF in 1st line
70.0
% of treated patients
60.0
50.0
44%
40.0
30.0
24.9%
27.9%
20.0
10.0
27.9%
< 0.1%
0.0
2006
N= 12 countries
HIV/AIDS Department
2007
2009
2010
2011
2012
Challenges ahead (ii): second-line regimens
Preferred second-line regimen
Target population
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
Adults
Pregnant
women
HIV and TB
coinfection
HIV and HBV
coinfection
Same regimens recommended for adults and adolescents
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)
AZT + TDF + 3TC (or FTC) + (ATV/r or LPV/r)
Comparative Analysis of ATV/r , LPV/r and DRV/r
Major parameters
Consistency with pediatric regimens
Number of pills per day (standard dose as
FDC)
Convenience (once vs twice daily regimen)
Safety in pregnancy
GI intolerance (diarrhea)
Availability of heat stable FDCs
Use with TB treatment regimen that contains
rifampin
Hyperbilirrubinemia
Dyslipidemia
Reduction cost potential
Accessibility in countries (registration status)
Availability of generic formulations
ATV/r
LPV/r
DRV/r
no
yes
no
1
4
2-4
once daily
twice daily
Once or twice
daily
yes
Not frequent
yes
yes
common
yes
yes
Not frequent
no
no
yes
no
+
±
low
+
low
±
high
low
high
low
yes
yes
yes
Need to move forward: towards the 2015 guidelines…..
•
Additional 1st line options
•
Better 2nd / 3rd lines
•
New strategies
(if proven effective)
Nucleosides
Integrase Inhibitors
New drugs and new
combinations shall be
made available,
globally,
at affordable price,
when possible as FDCs
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
2013 WHO ART Guidelines in Adults: a summary
Topic
When to
start
2002
CD4 ≤200
2003
CD4 ≤ 200
2006
2010
CD4 ≤ 200
CD4 ≤ 350
CD4 ≤ 500
- Consider 350
- CD4 ≤ 350 for TB
-Irrespective CD4 for
TB and HBV
-Irrespective CD4 for TB,
HBV, PW and SDC
- CD4 ≤ 350 as priority
Earlier initiation
1st Line
2013
8 options
4 options
8 options
6 options &FDCs
2 options & FDCs
- AZT preferred
- AZT preferred
- AZT or TDFpreferred
- d4T dose reduction
- AZT or TDF preferred
- d4T phase out
- TDF and EFV preferred
across all populations
Simpler treatment
2nd Line
Boosted and
non-boosted
PIs
Boosted PIs
Boosted PI
Boosted PI
Boosted PIs
-IDV/r LPV/r,
SQV/r
- ATV/r, DRV/r, FPV/r
LPV/r, SQV/r
- Heat stable FDC:
ATV/r, LPV/r
- Heat stable FDC:
ATV/r, LPV/r
Less toxic, more robust regimens
3rd Line
None
None
None
DRV/r, RAL, ETV
DRV/r, RAL, ETV
Viral Load
Testing
No
No
Yes
Yes
(Desirable)
(Tertiary centers)
(Phase in approach)
Yes
(VL preferred for
monitoring)
Better monitoring
HIV/AIDS
Department
17 April
2013
2013 WHO ART Guidelines in Adults: a summary
Topic
When to
start
2002
CD4 ≤200
2003
CD4 ≤ 200
2006
2010
CD4 ≤ 200
CD4 ≤ 350
CD4 ≤ 500
- Consider 350
- CD4 ≤ 350 for TB
-Irrespective CD4 for
TB and HBV
-Irrespective CD4 for TB,
HBV, PW and SDC
- CD4 ≤ 350 as priority
Earlier initiation
1st Line
2013
8 options
4 options
8 options
6 options &FDCs
2 options & FDCs
- AZT preferred
- AZT preferred
- AZT or TDFpreferred
- d4T dose reduction
- AZT or TDF preferred
- d4T phase out
- TDF and EFV preferred
across all populations
Simpler treatment
2nd Line
Boosted and
non-boosted
PIs
Boosted PIs
Boosted PI
Boosted PI
Boosted PIs
-IDV/r LPV/r,
SQV/r
- ATV/r, DRV/r, FPV/r
LPV/r, SQV/r
- Heat stable FDC:
ATV/r, LPV/r
- Heat stable FDC:
ATV/r, LPV/r
Less toxic, more robust regimens
3rd Line
None
None
None
DRV/r, RAL, ETV
DRV/r, RAL, ETV
Viral Load
Testing
No
No
Yes
Yes
(Desirable)
(Tertiary centers)
(Phase in approach)
Yes
(VL preferred for
monitoring)
Better monitoring
Evidence-based, but intentionally aspirational…
HIV/AIDS
Department
17 April
2013
MONITORING ART RESPONSE
Targeted viral load
monitoring (suspected
clinical or immunological
failure)
Routine viral load
monitoring (early
detection of
virological failure)
70% greater resuppression
rate after adherence intervention
Test viral load
Viral load >1000
copies/ml
Evaluate for
adherence concerns
Repeat viral load
testing after 3–6
months
Viral load ≤1000
copies/ml
Viral load >1000
copies/ml
Maintain first-line
therapy
Switch to second-line
therapy
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
2013 WHO consolidated Guidelines
A “game changer” document, and an important step
towards the global alignment of the HIV standard of care
Acknowledgements
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.
Guideline Development Group
WHO Department of HIV
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)
Andrew Ball
Philippa Easterbrook
Meg Doherty
Eyerusalem Kebede Negussie
Nathan Shaffer
Lulu Muhe
Nathan Ford
Marco 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)

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