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

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

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

What to use in 1st line therapy in adults MAJOR CHANGES - 2015 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 2017. Safety data PLHIV with TB co-infection and in HIV+ pregnant women still pending. WHO, 2015

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 1-5 2015

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 EFV400. . 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

 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 

 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

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

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

What to use in 2nd line therapy in adults MAJOR CHANGES - 2015 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 2017 . AVAILABILITY WHO, 2015

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 2 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

Research gaps and availability Raltegravir for treatment of TB in PLHIV (ANRS 12 180 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

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

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

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

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

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