1. Marco Vitoria HIV Department Geneva
Overview of first- and second-line ART recommendations in the 2015 WHO guidelines
Marco Vitoria
HIV Department
Geneva
10/11/2018

2. WHO ARV Guidelines Evolution 2002 to 2015
Topic
2002
2003
2006
2010
2013
2015*
When to start
CD4 ≤200
CD4 ≤ 200
Consider 350
- CD4 ≤ 350 for TB
CD4 ≤ 350
-Regardless CD4 for TB and HBV
CD4 ≤ 500
- Regardless CD4 for TB, HBV PW and SDC
- CD4 ≤ 350 as priority
Towards treatment initiation at any CD4 cell count
1st Line ART
8 options
- AZT preferred
4 options
- AZT or TDF preferred
- d4T dose reduction
6 options & FDCs
- d4T phase out
1 preferred option & FDCs
TDF and EFV preferred across all pops
Continue with FDC approach and phased introduction of new options (DTG, EFV400)
2nd Line ART
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
Add more heat stable PI options (DRV/r) and new strategies (NRTI sparing regimens)
3rd Line ART
None
DRV/r, RAL, ETV
Encourage HIV DR to guide
Viral Load
Testing No
(Desirable)
Yes
(Tertiary centers)
(Phase in approach)
(preferred for monitoring, use of PoC, DBS)
Support for scale up of VL using all technologies
Earlier initiation
Simpler treatment
Less toxic, more robust regimens
Since 202, WHO has regularly updating the global recommendation son ART use in a Publci Helath approach. The recommendations has evolved towards earlier initiation, simplification of treatment regimens with les toxic and more robust regimens and better and simpler monitoring.
Better and simpler monitoring
* provisional
WHO, 2015

3. 1st and 2nd line regimens in Adults
10/11/2018

4. What to use in 1st line therapy in adults
MAJOR CHANGES WHO ART GUIDELINES
What to use in 1st line therapy in adults
ARV regimen 1,2
Preferred Option
TDF + XTC3+ EFV600
Alternative Options
AZT + 3TC + EFV600
AZT + 3TC + NVP
TDF + XTC3 + NVP
TDF + XTC3 + DTG 4
TDF + XTC3 + EFV4004
EVIDENCE
RESEARCH GAPS
NEW
NEW
In 2015, two new options were included for 1st line ART: DTG and EFV400. At this stage, they were recommended as alternative drugs to EFV600, as the preferred option for ART initiation continue to be TDF + XTC + EFV as FDC. AZT and NVP also were maintained to be alternative options to repalce TDF or EFV in case of intoekrance or contraindication.
AVAILABILITY
ARV regimens as fixed dose combinations is the preferred approach because of clinical, operational and programmatic benefits.
Countries should discontinue d4T use in 1st line regimens because of its well-recognized metabolic toxicities.
XTC = 3TC or FTC.
These alternative regimens are expected to be available only in Safety data PLHIV with TB co-infection and in HIV+ pregnant women still pending.
WHO, 2015

5. Introduction of new ARVs using a new methodology
Use of network metanalysis (NMA) for direct and indirect comparisons
Efficacy and safety of INSTIs (1st and 2nd line), EFV400 (1st line) and DRV/r (2nd line)
Major outcomes: mortality, AIDS events, CD4 recovery, VL suppression treatment discontinuation and SAE.
76 studies
The rationale for these recommendations were based on 3 major points: review of the evidence, research gaps in critical popualtions of public health interest and availability as generic formulations. For evidence check, WHO used the network metanalyiss, a new methodology that permit a direct and indirect comparative analysis of efficacy and safety of new drugs, considering major outcomes of public helath relevance ( morbidity, mortality, tertament resposne and adverse events)
7 studies
6 studies
Edward Mills, Steve Kanters, M. Eugenia Socias, For WHO ARV GDG, June

6. Safety and Efficacy of INSTIs and EFV400 in 1st line ART (NMA)
major outcomes
INSTI vs EFV 600
DTG vs other INSTI
DTG vs EFV600
DTG vs EFV400
EFV400 vs EFV 600
QUALITY OF EVIDENCE
Viral suppression
INSTI better
DTG better
comparable 1
comparable
moderate
CD4 recovery
INSTI better
EFV400 better
Treatment discontinuation
Mortality
low
AIDS progression
SAE
Evidence: The NMA showed that DTG, was superior to EFV and other INSTIs in terms of viral suppression, CD4 recovery and treatment discontinuation, but comparable with EFV EFV400 was better than EFV 600 in terms of CD4 recovery and treatment discontinuation, but comparable in etrms of viral supression. But all regimens were comparable in terms of SAE. The quality for this evidence was rated as moderate accoding GADE methodology.
Research gaps: Use of DTG and EFV400 was not tested in populatiosn of relevance for this guideliens, as pregannat women and TB. There are concerns that dose adjustment will be necessary to mainatin efficacy and studies are under way.
Availability: Generic formulations DTG and EFV 400 will not be available in the market for clinical use in short term. Several companies are developing standalone and FDCs of this products, which need to be submitted to regulatory agencies for quality assurance. The first standalone products are expected to be available by end 2016 / early 2017, and FDCs during 2017-
1 Estimated effects favored DTG but statistical analysis not significant
WHO, 2015

7.  EFV600 vs DTG comparable  Major parameters EFV600 DTG
Occurrence of SAEs
comparable
Better virologic suppression 
Better CD4 recovery
Less treatment discontinuation
Less occurrence of subjective side effects
Lower potential for drug-dug interactions
Efficacy in HIV-2 infection
Efficacy in TB co/infection
Efficacy and safety in pregnant/breastfeeding women
Availability as generic formulations
This table is a summary of the comparison between EFV 600 and DTG. It highlights the DTG research gaps and availability of generic formulations only in 2017 

8.  EFV600 vs EFV400 comparable  Major parameters EFV600 EFV400
Virologic suppression
comparable
Occurrence of SAEs
Better CD4 recovery 
Less Treatment discontinuation
Less occurrence of subjective side effects
Efficacy in TB co/infection
Safety in pregnant /breastfeeding women
Availability as generic formulations 
This table is a summary of the comaprions between EFV 600 and EFV 400. It highlights the EFV400 research gaps and availability of generic formulations only in 2017

9. What we need to know about DTG?
There are several ongoing studies on DTG, which aims to fill the current gaps. Particularly o studies on safety in pregnant women and efficacy in TB patients using rifampin , expected in 2016/2017.
ViiV, 2013

10. Safety of EFV use in 1st Line ART
42 studies included
90% of patients remaining on EFV (78 weeks)
Higher relative risk of discontinuation due AEs when compared with other ARVs , but the absolute differences was low (< 5%).
No difference in terms of SAEs
In a recent systematic review and metanalysis conducted by WHO, safety and CNS adverse events in patients using EFV were evaluated. The results showed that among 42 studies checked, 90% of patients remaining on EFV and despite a higher relative risk for discontinuation , the absolute differences with other ARVs used in 1st line were small., and no difference in etrms of SAEs was found, supporting the resulst of the NMA.
Ford et al, JAIDS 2015

11. What to use in 2nd line therapy in adults
MAJOR CHANGES WHO ART GUIDELINES
What to use in 2nd line therapy in adults
ARV regimen
Preferred Options
2 NRTI1 + ATV/r or LPV/r 2
Alternative Options
2 NRTI1 + DRV/r2 3
LPV/r2 + RAL
EVIDENCE
NEW
RESEARCH GAPS
NEW
WHO also revised the recommendations for 2nd line ART and have added DRV/r as an additional PI option to be used with NRTI backbone, and a NRTI sparing regimen containing RAL and LPV/r. The NMA also evaluated the different dose rages of DRV/r for 2nd line ART ( 800/100 OD, 600/100 OD and 600/100 BD)
The following sequence of 2nd line NRTI backbone options is recommended:
If failure with TDF + XTC in 1st line, use AZT+3TC
if failure with AZT + 3TC in 1st line, use TDF + XTC
Use of NRTI backbones as FDCs is recommended as the preferred approach.
Heat stable fixed dose combinations of boosted PIs are the preferred approach.
DRV/r as FDC tablet (400/50mg) expected to be available in
AVAILABILITY
WHO, 2015

12. RAL + LPVr vs 2 NRTIs + ATVr or LPV/r
Safety and Efficacy of DRV/r and INSTI/PI regimens in 2nd line ART (NMA)
major outcomes
DRV/r vs ATV/r or LPV/r
DRV800 OD vs DRV600 OD
DRV800/100 OD vs DRV600/100 BD
RAL + LPVr vs NRTIs + ATVr or LPV/r
QUALITY OF EVDIENCE
Viral suppression
comparable
comparable 3
comparable 1
equivalent
moderate
CD4 recovery
comparable 2
comparable 4
low
Treatment discontinuation
Mortality
AIDS progression
SAE
Similarly to 1st line, the main apsetcs evalaued were evidence, research gaps and availability of generic formulations. The NMA showed that DRV/r is comparable to ATV/r and LPV/r as a 2nd line option, and OD and BD regimens also seams to be comparable in terms of viral suppression. However, confidence interval were too large for establish equivalence. However DRV/r coforumualtions are expecting to be available only in 2017.
DRV cannot be used in patients with TB and rifampin and studies on RAL in TB/HIV patients is also ongoing (phase 2 studies sugegst that dose can be maintained)
Regarding NRTI sparing regimen, only RAL + LPVr was compared and , the NMA showed equivalence, when compared with 2 NRTI + Pis, but the cost is substantially higher. The quality of evidence for these comparisons were moderate.
1 Confidence interval too large to establish equivalence
2 Estimated effects favored DRV/r 800/100 but statistical analysis not significant
3 Estimated effects favored DRV/r 800/100 but statistical analysis not significant
4 Estimated effects favored LPV/r + RAL but statistically not significant
WHO, 2015

13. Research gaps and availability
Raltegravir for treatment of TB in PLHIV (ANRS Reflate TB)
DRV/r cannot be used in TB patients on RMP
Studies with RAL in TB patients are ongoing (phase 3 is needed)
Generic heat stable coformulations of DRV/r expected in 2017
Virologic response ( 48 weeks)
Grinsztejn et al. Lancet Infect Dis 2014; 14: 459–67
DRV cannot be used with rifampicin, which is a important limitation in RLS, where TB is stil very prevalent, even in patients in 2nd lien ART. INSTI has been studies as an aletrnative in this situation, and phase 2 resultsa from REFLATE showed that regular dose can be maintained. However a phase 3 studied is needed ( and ongoing).
DRV/r 400mg/50 mg HS tablets
10/11/2018

14. 1st and 2nd line regimens in Adolescents and Children
10/11/2018

15. Starting ART in adolescents
First-line ART
Preferred first-line regimens
Alternative first-line regimens
Adults
TDF + 3TC (or FTC) + EFV
AZT + 3TC + EFV (or NVP)
TDF + 3TC (or FTC) + DTG
TDF + 3TC (or FTC) + EFV400
TDF + 3TC (or FTC) + NVP
Adolescents
TDF (or ABC) + 3TC (or FTC) + DTG
TDF (or ABC) + 3TC (or FTC) + EFV400
TDF (or ABC) + 3TC (or FTC) + NVP 
In summary … LIKE ADULTS
As you can see from this slide we were able to maintain harmonisation between adult and adolescents for which use of more tolerable and forgiving drugs are particularly important due to the challenges attached to adherence. In this context DTG-based and EFV400-based regimen were included as potential alternative to the currently preferred regimen.
Introducing more potent and tolerable regimens as alternatives
Simplifying regimens for adolescents who started Tx in childhood
Maintaining harmonisation with adults

16. Starting ART in children
Children < 3 years
Children 3 years to < 10 years
Preferred
ABC + 3TC + LPV/r or
AZT + 3TC + LPV/r
ABC + 3TC + EFV
Alternative
ABC + 3TC + NVP
AZT + 3TC + NVP
AZT + 3TC + EFV
TDF + 3TC (or FTC) + EFV
TDF + 3TC (or FTC) + NVP
In summary …NO CHANGE
Overall no change was made to 1st line recommendations for children so enphasis remains on the need to provide more potent options to younger children (LPV-based regimen in younger than 3) and once daily regimen for children older than 3 years. Unfortunately these recommendations are not being adopted as well as expected an newer formulations to delivery the recommended drug are awated. You will hear more from Nandita later.
Using the most potent regimen available for young children (LPVr)
Simplifying where feasible (substitute LPVr with EFV)
Using RAL-based regimen in special circumstances
Keeping ABC + 3TC as preferred NRTIs
Maintaining EFV-based regimen to harmonise with adults

17. Offering better options for 2nd line
Children including adolescents
First-line ART regimen
Second-line ART regimen
LPV/r-based first line
Younger than 3 years
ABC + 3TC + LPV/r
AZT or ABC + 3TC + RAL
AZT + 3TC + LPV/r
3 years and older
AZT + 3TC + EFV or RAL
ABC or TDF + 3TC + EFV or RAL
NNRTI-based first-line regimen
All ages
ABC + 3TC + EFV (or NVP)
AZT + 3TC + ATV/r or LPV/r
TDF + 3TC + EFV (or NVP)
AZT + 3TC + EFV (or NVP)
ABC or TDF + 3TC + ATV/r or LPV/r
In summary … MORE OPTIONS
The 2015 WHO guidelines however will take advantage of some of the new drugs available and work towards further rationalization and harmonization of second line recommendations. We’ll see RAL for second line with LPV/r failure and the introduction of atazanvir as an alternative to lopinavir, recognizing that formulation issues are still problematic for all but adolescents.
Introducing more potent options for children failing on LPVr (RAL)
Promoting use of once daily bPI such as ATV

18. http://www.who.int/hiv/pub/arv/policy-brief-arv-2015/en/ 10/11/2018
More information available at WHO website.  
10/11/2018