Understanding the unmet medical needs with current ART Thanks: Polly Clayden, Francesca Conradie, Loyd Mulenga, Gary Maartens, Andrew Hill, David Ripin, Elli Katabira, Chris Duncombe, Nathan Ford, Marco Vitoria, WHO, Trip Gullik Industry: Gilead , Janssen, Viiv, Abbott, Merck, GSK Understanding the unmet medical needs with current ART Francois Venter Wits Reproductive Health & HIV Institute

28 approved drugs Up to 10 recommended first-line regimens

What is coming next from WHO? ?Test and Treat – vs staying at 500 ?use of integrase inhibitors Both are linked

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, 2014 Yes Yes1 Yes2 International AIDS Society-USA, 2014 Brazil, 2014 European AIDS Clinical Society, 2014 Consider3 British HIV Association, 2014 Defer5 World Health Organization, 2014 Yes4 (1) Strong strength recommendation based on observational data (A-II) (2) Moderate strength recommendation based on expert opinion (B-III). (3 ) But treat all symptomatic patients, HIV+ pregnant women, HBV co-infection, HCV co-infection, HIVAN, HIV related neurocognitive disorders, ITP, non-AIDS cancers (including HPV) 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 couples SA HIV Clinicians Society 2014 Yes Defer SA Government , 2015

UNAIDS Gap Report 2014 <unaids.org>

ART Trials: Virologic Responses 114 studies through 2012, up to 3 years of f/u: ITT analyses 78% 43% Carr PLoS One 2014;9:e97482

ART Trials: Safety and Tolerability 114 studies, through 2012, up to 3 years of f/u: ITT analyses 14% 4% Carr PLoS One 2014;9:e97482

A widening menu of ARV use for treatment and prevention Despite immediate increase from currently 17 million to 26 million people eligible for ART , the preventive effect will lead to decrease of number eligible after 2020 2013 This slide shows breakdown in numbers accessing and needing ART according to different eligibility criteria. At the end of 2011 there were 8 million people on ART. An additional 6.4 million adults and 1.4 million children were eligible for treatment under 2011 criteria but not on ART. (15.8 Million) The new guidelines proposed for 2013 would increase those eligible for ART by adding 4.5 million adults with CD4 counts 350-500, 750,000 HIV+ children between the ages of 2 and 5, an 5.2 million in special population groups with CD4 count above 500 700,000 pregnant women, 3.9 million sero-discordant couples, 500,000 HIV+/TB+ adults) and another 1.2 million key populations (SW, MSM, PWID) would be eligible if offered early treatment. TOTAL ~ 26 MILLION Conclusions: New guidelines on eligibility for ART, if adopted by all countries, would dramatically increase the number eligible for treatment. National programs will need to consider how to effectively reach these new population groups and maintain high quality treatment while expanding the numbers on treatment. 2010

Pipeline Report http://www.pipelinereport.org

Think… Many HIV testing programmes performing well – issues such as TB and high VL less of an issue Pregnancy always an issue

So what we got?

Evolution of WHO ART Guidelines in Adults 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) (preferred for monitoring, use of PoC, DBS) Earlier initiation Simpler treatment Less toxic, more robust regimens Better monitoring HIV/AIDS Department

Evolution of WHO ART Guidelines in Adults 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) (preferred for monitoring, use of PoC, DBS) Earlier initiation Simpler treatment Less toxic, more robust regimens Better monitoring HIV/AIDS Department

Evolution of WHO ART Guidelines in Adults 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) (preferred for monitoring, use of PoC, DBS) Earlier initiation Simpler treatment Less toxic, more robust regimens Better monitoring HIV/AIDS Department

Evolution of WHO ART Guidelines in Adults 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) (preferred for monitoring, use of PoC, DBS) Earlier initiation Simpler treatment Less toxic, more robust regimens Better monitoring HIV/AIDS Department

Drug optimization Science evolved: smarter and better HIV treatment options are now available

In terms of first line therapy (TDF+XTC+EFV) Was 2013 just a brief harmonisation event? EFV now routinely substituted in developed world due to side effects (where TB less of a problem) Increasing concern about CNS side effects (also lipids, hepatitis, rash, gynaecomastia)

With limited resources, a public health approach needs to balance both costs and effectiveness in order to maximize efficiencies Drugs that have been prioritized as having clinical superiority have shown dramatic price reductions over short periods of time even since CADO in 2010 21% price reduction 77% price reduction 72% price reduction EFV – 2 year savings of approx $107 TDF – 2 year savings of approx $ 128million in 2011 and 2012, ATV/r – 3 year expected savings of $40million for 2013-2015 Method for EFV and TDF - patient numbers of 2011,2012 in found in market report (unrounded). Savings=2011 patient volume * 2010 price-2011 price + 2012 patient volume * 2010price-2012price, does not differentiate between those on FDCs or not. Method for ATV/r – CHAI forecasted ATV/r patient volumes and CHAI forecasted price difference compared to 2010 price in 2013 , 2014, 2015 Prices citation – 2006, from CADO1 and from CHAI case studies. 2010 from CHAI ceiling report July 2010, 2012 from CHAI ceiling report, May 2012. EFV TDF ATV/r

PI(lopinavir or atazanavir) TDF XTC EFV AZT XTC PI(lopinavir or atazanavir) XTC, other nukes Darunavir Raltegravir Etravirine

Dual NRTI + INSTI + booster Currently available (or near-available) co-formulated antiretroviral agents and regimens Agent Regimen D4T/3TC Dual NRTI D4T/3TC/NVP NNRTI + dual NRTI ZDV/3TC ZDV/3TC/ABC Triple NRTI LPV/RTV Boosted PI ATV/RTV DTG/ABC/3TC INSTI + dual NNRTI ABC/3TC TDF/XTC TDF/XTC/EFV TDF/FTC/RPV TDF/FTC/EVG/COBI Dual NRTI + INSTI + booster 3TC, lamivudine; ABC, abacavir; COBI, cobicistat; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; LPV, lopinavir; RPV, rilpivirine; TDF, tenofovir; ZDV, zidovudine. There are currently numerous coformulated antiretroviral agents and regimens available. Some of the earliest coformulations included the dual-NRTI combination of zidovudine/lamivudine and the triple NRTI combination zidovudine/lamivudine/abacavir, both of which have been available for more than a decade. The first (and currently only) fixed-dose combination boosted PI, lopinavir/ritonavir, also has been available for almost a decade.   In 2007, the first single‑tablet preferred regimen—TDF/emtricitabine/efavirenz—was introduced. That was followed recently by 2 other complete regimens, TDF/emtricitabine/rilpivirine and TDF/emtricitabine/elvitegravir/cobicistat. As discussed later in this program, additional complete regimens and other coformulated agents are in development.

PI(lopinavir or atazanavir) TDF XTC EFV AZT XTC PI(lopinavir or atazanavir) XTC, other nukes Darunavir Raltegravir Etravirine

Tenofovir has taken over the world! 1st line recommendation by WHO; feature in EVERY guideline (some have ABC) Well tolerated, FDCs galore, daily Cheap (only alternative that is cheaper is d4T) Hep B for free

WHO Guidelines: 2013 Update Recommended Regimens NNRTI based EFV + (TDF/FTC or AZT/3TC) Alternative Regimens NVP + (TDF/FTC or AZT/3TC) 2013 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. WHO; 2013 June.

Changes in D4T, AZT & TDF use (2006-2012) Between 2 to 4 million people using AZT containing regimen in 2012 2006 2007 2008 2009 2010 2011 2012 WHO AMDS database, 2014 (preliminary data) 11/8/2018

Now add PrEP TDF…

Is API production capacity a potential treatment bottleneck? Situation of API production capacity for TDF and EFV with major API producers ( WHO API manufacturer survey, May 2013) Major parameters TDF EFV Number of API producers in 2012 7 8  API production capacity in 2012 (in metric tons)* >1,500 >2,210 Estimated number of patients using regimens containing the API in end of 2012 3,500,000 3,700,000 Number of patients that could be treated in end of 2012 >13,800,000 >10,000,000 The manufacturers also mentioned that they are all in the process of increasing capacity. WHO HIV/AMDS, 2014 (preliminary data) (*) Data from some major manufacturers were not reported.

Is API production capacity a potential treatment bottleneck? Concern: API may become a huge problem if ’20 by 20’ AND PrEP come into play… Situation of API production capacity for TDF and EFV with major API producers ( WHO API manufacturer survey, May 2013) Major parameters TDF EFV Number of API producers in 2012 7 8  API production capacity in 2012 (in metric tons)* >1,500 >2,210 Estimated number of patients using regimens containing the API in end of 2012 3,500,000 3,700,000 Number of patients that could be treated in end of 2012 >13,800,000 >10,000,000 The manufacturers also mentioned that they are all in the process of increasing capacity. WHO HIV/AMDS, 2014 (preliminary data) (*) Data from some major manufacturers were not reported.

Tenofovir alafenamide Slightly better safety profile than TDF ( at 10 or 25mg vs 300mg). But being tested as co-formulations Preliminary results promising – will it simply replace TDF? Less API, less toxicity (?co-formulations – estimated availability to LMIC 2020) TDF analogue – CHAI – 200mg vs 300mg: may be available

Studies 104/111: Tenofovir Alafenamide Fumarate vs TDF in Treatment-Naive Pts Parallel, randomized, double-blind, active-controlled phase III studies Primary endpoint: HIV-1 RNA at Wk 48 Stratified by HIV-1 RNA, CD4+ cell count, geographic region Wk 48 Primary endpoint Wk 144 TAF/FTC/EVG/COBI* single-tablet regimen (n = 866) COBI, cobicistat; eGFR, estimated glomerular filtration rate; EVG, elvitegravir; FTC, emtricitabine; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil fumarate. For more information about this study, go to http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202015/Highlights/Capsules/113LB.aspx. Treatment-naive HIV-infected pts with HIV-1 RNA ≥ 1000 copies/mL, eGFR ≥ 50 mL/min (N = 1733) TDF/FTC/EVG/COBI† single-tablet regimen (n = 867) *10/200/150/150 mg once daily. †300/200/150/150 mg once daily. Wohl DA, et al. CROI 2015. Abstract 113LB.

Studies 104/111: TAF Noninferior to TDF at Week 48 TAF also noninferior to TDF at Wk 48 in each study (104 and 111) Results similar across all baseline virologic and demographic subgroups 7 pts in TAF arm and 5 pts in TDF arm with NRTI resistance at VF 1 in TAF arm and 2 in TDF arm with combined M184V/I + K65R 5 pts in TAF arm and 3 pts in TDF arm with INSTI resistance at VF 0.9% in TAF arm and 1.5% in TDF arm discontinued due to AE CD4+ increases greater in TAF arm: 211 vs 181 (P = .024) Δ +2.0% (95% CI: -0.7% to +4.7) 100 92 90 TAF/FTC/EVG/COBI (n = 866) 80 TDF/FTC/EVG/COBI(n = 867) 60 Pts (%) 40 AE, adverse event; COBI, cobicistat; EVG, elvitegravir; FDA, US Food and Drug Administration; FTC, emtricitabine; TAF, tenofovir alafenamide fumarate; tenofovir disoproxil fumarate; VF, virologic failure. For more information about this study, go to http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202015/Highlights/Capsules/23LB.aspx. 20 6 4 4 4 n = 800 784 Virologic Success* Virologic Failure No Data *HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm Discontinued for AE, death, or missing data. Wohl DA, et al. CROI 2015. Abstract 113LB. Reproduced with permission.

Renal Markers With TAF and TDF at Wk 48 In separate single-arm trial of virologically suppressed pts with eGFR 30-69 mL/min switched to open-label TAF/FTC/EVG/COBI[2] 65% on TDF at BL At Wk 48 after switch: 92% maintained virologic suppression No change in eGFR Reduction in proteinuria and markers of renal tubular function Improvement in hip and spine BMD Smaller decreases in eGFR with TAF[1] Smaller changes in proteinuria with TAF[1] TAF/FTC/EVG/COBI (n = 866) TDF/FTC/EVG/COBI (n = 867) 20 10 -10 -20 P < .001 Mean Δ From BL in eGFR, mL/min (Cockcroft-Gault) -6.6 -11.2 12 24 36 48 Time (Wks) Median % Change From BL in Urine Protein:Creatinine Ratio Marker TAF (n = 866) TDF (n = 867) P Value Protein -3 +20 < .001 Albumin -5 +7 Retinol-binding protein +9 +51 β2-microglobulin -32 +24 BL, baseline; BMD, bone mass density; COBI, cobicistat; eGFR, estimated glomerular filtration rate; EVG, elvitegravir; FTC, emtricitabine; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil fumarate. For more information about this study, go to http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202015/Highlights/Capsules/143.aspx. 1. Sax P, et al. CROI 2015. Abstract 143. Reproduced with permission. 2. Pozniak A, et al. CROI 2015. Abstract 795.

Studies 104/111: Significantly Smaller Decline in Hip and Spine BMD With TAF Higher lipid levels with TAF, but TC:HDL-C ratio same as TDF[1] TAF/FTC/EVG/COBI (n = 866) TDF/FTC/EVG/COBI (n = 867) Change in Spine BMD Change in Hip BMD -8 -6 -4 -2 2 -8 -6 -4 -2 2 -0.66 -1.30 Mean % Change From BL -2.86 -2.95 P < .001 P < .001 BL, baseline; BMD, bone mass density; COBI, cobicistat; EVG, elvitegravir; FTC, emtricitabine; HDL-C, high density lipoprotein cholesterol; TAF, tenofovir alafenamide fumarate; TC, total cholesterol; TDF, tenofovir disoproxil fumarate. For more information about this study, go to http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202015/Highlights/Capsules/143.aspx. 24 48 24 48 Wk Wk n n = 845 = 850 797 816 784 773 836 848 789 815 780 767 Sax P, et al. CROI 2015. Abstract 143. Reproduced with permission.

What next on TDF? d4T study will part-answer bone and renal worries; otherwise, just wait TAF likely to replace it; TDF-CHAI 200mg Lower doses AZT, d4T; ABC, other drugs unlikely to displace it

PI(lopinavir or atazanavir) TDF XTC EFV AZT XTC PI(lopinavir or atazanavir) XTC, other nukes Darunavir Raltegravir Etravirine

Efavirenz Daily, cheap, co-formulated, huge experience base, TB (and most everything else)-friendly EFV side effects predictable, treatable, substitutions easy Everyone pretty happy re teratogenicity

BUT… Increasing recognition of CNS side effects - ?Africans stoic? More nb in asymptomatics Rash, hepatitis, gynaecomastia, lipids ENCORE (Lancet 2013)– 400mg vs 600mg – less discontinuations, but very little change in side effects Concerns about 400 mg dose in PMTCT and TB

Depression Efavirenz (6%) 2x higher risk for suicidality Meta-analysis n=5332, 4 RCT Efavirenz (6%) 2x higher risk for suicidality Rilpivirine (8%) Elvitegravir/COBI (5%) Raltegravir (6%) Atazanavir/r (2%) For composite endpoint ‘Only’ trend for completed/attempted suicide (17 events occured) EFV EFV-free Lack of association between use of efavirenz and death from suicide: evidence from the D:A:D study #O315 Wednesday 5 November C. Smith; L. Ryom; A. d’Arminio Monforte; P. Reiss; A. Mocroft; W. El-Sadr; R. Weber; M. Law; C. Sabin; J. Lundgren. Cohen et al., Lancet 2011; Molina et al, Lancet 2011; Elion et al., JAIDS 2013; Mollan et al, Ann Intern Med 2014

Alternatives… Integrase inhibitors Rilprivirine

What about: Dolutegravir (raltegravir and elvitegravir expensive) Wunderkind of the moment 50 mg once-daily (in naïve patients) Very good efficacy Minimal toxicity Pregnancy category B Superior to EFV at 48 weeks in naïve patients– SINGLE study (compared ABC/3TC/DTG with TDF/FTC/EFV. ) – but safer, not virologically better Potential to be low cost and coformulated Walmsley SL et al. N Engl J Med. November 2013 FDA press statement.  August 2013

What is the cost if we switch from EFV to DTG? Millions of patients will need to be switched (assuming stable patients on EFV will move, seems likely) – huge undertaking – and the manufacturing changes will likely be slightly chaotic Moving from EFV to DTG unlikely to be a big deal (?VL) ; reverse a problem “Training” – how big an issue if all you lose is side effects? ?harmonisation between and within different countries – private vs public sector, cross borders Pregnancy – limited data TB – studies are needed Studies largely done in men It’s a new agent – what happens if: it doesn’t work in TB? Pregnancy? New side effect?

PI(lopinavir or atazanavir) TDF XTC EFV AZT XTC PI(lopinavir or atazanavir) XTC, other nukes Darunavir Raltegravir Etravirine

AZT Toxic ???any role for AZT in future??? EARNEST – does it matter what the nukes are? Could we recycle TDF/FTC?

PI(lopinavir or atazanavir) TDF XTC EFV AZT XTC PI(lopinavir or atazanavir) XTC, other nukes Darunavir Raltegravir Etravirine

?: Darunavir in 2nd line ‘Best PI’ – better side effects If we get the dose down from 800/100… ? 600/100 ?400/100 – lower cost, less side effects BUT – will the virological potency be maintained? BUT – is lopinavir all we need? EARNEST was very successful Will we even need a second line if DTG in 1st? Studies planned

(Short term) future dream? (photo credit John Mellors)

Pill "A" to Pill "B" – two single tablet regimens? Pill "A" TDF/3TC/EFV400 $100 Pill "B" DRV400/r/DTG $250 Two pills, used in sequence Simple treatment rule – task shifting No overlapping drug resistance Mass generic production Low cost: $100 and $250 per person-year

Pill "A" to Pill "B" – two single tablet regimens? Pill "A“TAF/FTC/DTG (275mg) TDF/3TC/EFV400 $100 Pill "B" DRV400/r/DTG $250 Two pills, used in sequence Simple treatment rule – task shifting No overlapping drug resistance Mass generic production Low cost: $100 and $250 per person-year Pil?/FTC/darunavir (400mg)/rit 700+?) TDF/3TC/EFV400 $100

What about the children? Granules and sprinkles – lpv/rit, raltegravir, others Low dose d4T planned – ABC/TDF concerns

Conclusions New drugs likely to be in play in our area EFV 600mg - ?if will be displaced