1. HIV Treatment for Adults and Adolescents
Stefano Vella MD
Istituto Superiore di Sanità - Rome - Italy

2. 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. 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!
WHO first published guidelines on the use of ART for HIV infection among adults and adolescents in 2002, revised in 2003 and on the use of ARV drugs for PMTCT in 2004.
The 2006 updates of the guidelines introduced the concept of a public health approach, with simplified and harmonized ART regimens.
These publications and their updates – most recently in 2010 – have provided important guidance to countries that have scaled up national ARV programmes during the past decade.
In 2013, for the first time, WHO has revised and combined these and other ARV-related guidance documents into one set of consolidated guidelines that addresses the use of ARV drugs for HIV treatment and prevention across all age groups and populations, based on the broad continuum of HIV care.

4. When to start ART: what is new since 2010 ?
Strong evidence of the impact of ART on HIV transmission:
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:
Observational studies showing impact on HIV mortality and morbidity
Scientific insights on HIV immunopathogenesis and on the effects of chronic inflammation associated with HIV infection
Better regimens:
Better tolerable drugs
Better formulations
New classes

5. Evaluating Risks & Benefits of earlier ART initiation
When to start ART WHO consolidated Guidelines
Evaluating Risks & Benefits of earlier ART initiation
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
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)

6. Threshold moved to < 500 CD4
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

7. Major Guidelines for Initiation of Antiretroviral Therapy
AIDS or HIV-Related Symptoms
CD4+ Cell Count < 200/mm3
CD4+ Cell Count /mm3
CD4+ Cell Count /mm3
CD4+ Cell Count > 500 cells/mm3
DHHS-USA, 2013
Yes
Yes1
Yes2
International AIDS
Society-USA, 2012
British HIV
Association, 2012
Consider 3
Defer3
European AIDS
Clinical Society, 2012
Consider3
World Health
Organization, 2013
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

8. What ARV regimens to be used in adults
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)

9. One regimen cannot fit all: alternative, special situations
2013 WHO consolidated Guidelines
One regimen cannot fit all: alternative, special situations
1st Line ART
Adults and Adolescents
(including pregnant women, TB co-infection and HBV co-infection)
Preferred (FDC) Regimen(s)
TDF+3TC (or FTC) + EFV
Alternative Regimens
AZT+ 3TC + EFV (or NVP)
TDF+ 3TC (or FTC)+ NVP
Special situations
ABC +3TC
+EFV (or NVP)
AZT (or ABC)+ 3TC
+ LPV/r or ATV/r
For adults, use of d4T as an option in first-line treatment should be discontinued and restricted to special cases where other ARVs cannot be usedand to the shortest time possible, with close monitoring.
In adults witn concomitant use of boosted PIs and TB treatament containg rifampicin, ATV/r is contraindicated and LPV/r dose need to be adjsuted. If rifabutin is used, ATV/r or LPV/r can be used and no dose adjustment is needed
For children, d4T use should be restricted to those situations where there is suspected or confirmed toxicity to AZT and lack of access to ABC or TDF. The duration of therapy with this drug should be  limited to the shortest time possible.

10. Challenges ahead (i): current NRTIs
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
Safety in pregnancy
Yes
yes
Availability as triple FDCs No
GI intolerance
Not common
Frequent
Consistency with pediatric regimens (all ages)
No (only for 3 years and older)
Cost (generic, annual, per patient)
US$ 57
US$ 169
US$ 75
US$ 19

11. Phasing out d4T: trends of d4T, AZT and TDF use in adults first line ART (2006 – 2012 )
70%
44%
27.9%
27.9%
N= 12 countries
HIV/AIDS Department

12. Challenges ahead (ii): second-line regimens

13. Comparative Analysis of ATV/r , LPV/r and DRV/r
Major parameters
ATV/r
LPV/r
DRV/r
Consistency with pediatric regimens no
yes
Number 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 daily
Safety in pregnancy
GI intolerance (diarrhea)
Not frequent
common
Availability of heat stable FDCs
Use with TB treatment regimen that contains rifampin
Hyperbilirrubinemia + -
Dyslipidemia
Reduction cost potential
low
high
Accessibility in countries (registration status)
Availability of generic formulations

14. Need to move forward: towards the 2015 guidelines…..
New drugs and new combinations shall be made available,
globally,
at affordable price,
when possible as FDCs
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
so easier for adult clinicians to prescribe  inc access

15. 2013 WHO ART Guidelines in Adults: a summary
Topic
2002
2003
2006
2010
2013
When to start
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 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
- Heat stable FDC: ATV/r, LPV/r
Heat stable FDC:
ATV/r, LPV/r
3rd Line
None
DRV/r, RAL, ETV
Viral Load
Testing No
(Desirable)
Yes
(Tertiary centers)
(Phase in approach)
(VL preferred for monitoring)
Earlier initiation
Simpler treatment
Less toxic, more robust regimens
Better monitoring
HIV/AIDS Department

16. 2013 WHO ART Guidelines in Adults: a summary
Topic
2002
2003
2006
2010
2013
When to start
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 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
- Heat stable FDC: ATV/r, LPV/r
Heat stable FDC:
ATV/r, LPV/r
3rd Line
None
DRV/r, RAL, ETV
Viral Load
Testing No
(Desirable)
Yes
(Tertiary centers)
(Phase in approach)
(VL preferred for monitoring)
Earlier initiation
Simpler treatment
Less toxic, more robust regimens
Better monitoring
Evidence-based, but intentionally aspirational…
HIV/AIDS Department

17. 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 >1000
copies/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

18. A “game changer” document, and an important step
2013 WHO consolidated Guidelines
A “game changer” document, and an important step
towards the global alignment of the HIV standard of care

19. 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
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)
WHO Department of HIV
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)