Unmet needs and challenges of current ART in South Africa. Michelle Moorhouse 21 Nov PDF Free Download

Unmet needs and challenges of current ART in South Africa Michelle Moorhouse 21 Nov 2015

SA Snapshot Òct 2015 6-7 million HIV-positive: 18% world total, 25% of Southern Africa 3.2 on first line ART: consume 25% of global generic ART 160 000 children: PMTCT working well 200 000 on second-line, 400 on third-line

ART coverage significantly decreased individual risk, KwaZulu Natal, South Africa (2004-11) Africa Centre longitudinal surveillance cohort with community and individual data Between 2004 and 2011, 1395 HIV seroconversions and over 53,042 person-years of observation (crude HIV incidence rate of 2.63 (95% C.I. 2.50 to 2.77) per 100 person-years Maps showing the estimated percentage of HIV + adults ( 15 years of age) on ART across the Africa Centre s surveillance area (2004 to 2011) Every % point increase in ART coverage among all HIV+ adults in a community, was associated with a 1.7% decline in the hazard of HIV acquisition (p <0.001)

Changing disease severity over time Thanks: Andrew Boulle Source: Consolidated National report covering monthly and quarterly ART data to end March 2014

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

Still too many people start ART late % people starting ART with CD4 < 100 IeDEA Collaboration, JAIDS 2014

Still too many people start ART late % people starting ART with CD4 < 100 1 in 5 start ART at CD4 <100 IeDEA Collaboration, JAIDS 2014

Evolution of WHO ART Guidelines in Adults Topic 2002 2003 2006 2010 2013 When to start 1 st Line 8 options - AZT preferred 2 nd Line Boosted and non-boosted PIs CD4 200 CD4 200 CD4 200 - Consider 350 - CD4 350 for TB 4 options - AZT preferred Boosted PIs -IDV/r LPV/r, SQV/r 8 options - AZT or TDFpreferred - d4t dose reduction Boosted PI - ATV/r, DRV/r, FPV/r LPV/r, SQV/r CD4 350 -Irrespective CD4 for TB and HBV 6 options &FDCs - AZT or TDF preferred - d4t phase out Boosted PI - Heat stable FDC: ATV/r, LPV/r CD4 500 -Irrespective CD4 for TB, HBV, PW and SDC - CD4 350 as priority 2 options & FDCs - TDF and EFV preferred across all populations Boosted PI - Heat stable FDC: ATV/r, LPV/r 3 rd Line None None None DRV/r, RAL, ETV DRV/r, RAL, ETV Viral Load Testing No Earlier initiation Simpler treatment Less toxic, more robust regimens No (Desirable) Yes (Tertiary centers) Better monitoring Yes (Phase in approach) Yes (preferred for monitoring, use of PoC, DBS) HIV/AIDS Department

A widening menu of ARV use for treatment and prevention 34,000,000 30.000.000 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 HIV+ IDU >500 HIV+ MSM >500 25.000.000 20.000.000 2013 HIV+ FSW >500 Sero Discordant Couples >500 Pregnant women >500 Children HIV+ (aged 2-4) 15.000.000 Adults 350-500 HIV+/HBV+ >350 10.000.000 5.000.000 2010 TB+/HIV+ >350 <350 not on ART Children in need (aged <2) - On ART (adults and children)

Some key messages from the 2015 WHO ARV guidelines Treat all (at any CD4) - PLHIV across all ages, but the sickest remain a priority (symptomatic disease and CD4 < 350). Phased introduction of optimized drug regimens and formulations (DTG, low dose EFV, DRV/r). Establishment of care packages to optimize the care cascade (reduce late presentation, improve retention). PrEP recommended as an additional prevention choice for all people at substantial risk of HIV infection.

Comparing preferred and alternative first-line ART options (IAS,DHHS, EACS and WHO ART guidelines) GUIDELINES NRTI BACKBONE NNRTI INSTI PI TDF/XTC ABC/3TC AZT/3TC EFV NVP RIL DTG EVG RQL ATV DRV LPV IAS (2014) DHHS (2015) EACS (2015) WHO (2015) preferred alternative not recommended/ special situations GUIDELINES preferred 1 st line options alternative 1 st line options IAS (2014) 11 16 DHHS (2015) 05 07 EACS (2015) 06 13 WHO (2015) 01 05 M Vitoria, 2015,

Major guidelines for initiation of ART Guideline AIDS or HIV-Related Symptoms CD4+ Cell Count < 200/mm 3 CD4+ Cell Count 200-350/mm 3 CD4+ Cell Count 350-500/mm 3 CD4+ Cell Count > 500 cells/mm 3 DHHS-USA, 2014 Yes Yes Yes Yes 1 Yes 2 International AIDS Society-USA, 2014 Yes Yes Yes Yes 1 Yes 2 Brazil, 2014 Yes Yes Yes Yes 1 Yes 2 European AIDS Clinical Society, 2014 British HIV Association, 2014 World Health Organization, 2014 Yes Yes Yes Consider 3 Consider 3 Yes Yes Yes Consider 3 Defer 5 Yes Yes Yes Yes 4 Defer 5 (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 SA Government, 2015 Yes Yes Yes Defer Defer Yes Yes Yes Yes Defer

So what we got?

Individualised vs Population Approach Major characteristics Individual perspective Population perspective Type of management Clinical management Programme management Target audience Characteristics of recommendations Type of interventions Screening goals Physicians and other health care providers Evidence based interventions considering most effective options according patient profile Tailored interventions according patient profile Identify Individual risk factors associated with susceptibility or disease progression Programme managers and policy makers Evidence based interventions considering best cost-effectiveness options according population /group profile (feasibility and cost) Standardized interventions across populations/ groups Identify risk factors associated with susceptibility or disease progression across groups, populations or regions Prevention goals Impact on HIV acquisition Impact on HIV transmission Treatment and care goals Impact on disease progression, complications and death Impact on mortality, morbidity and transmission M Vitoria, 2015,

ART eligibility and timing: adults CD4 count <500 cells/mm 3 irrespective of clinical stage (prioritise CD4 <350 cells/mm 3 ) OR Severe or advanced HIV disease (WHO clinical stage 3 or 4), regardless of CD4 count OR Irrespective of CD4 or clinical stage Active TB disease HIV-positive pregnant and breastfeeding women Known HBV co-infection ART should be started within 2 weeks after the CD4 count is done In TB co-infection: TB treatment first, then ART ASAP, within 8 weeks CD4 <50 cells/mm 3 start ART within 2 weeks TB treatment, when symptoms improving and TB treatment tolerated Defer ART 4-6 weeks in TBM or cryptococcal meningitis (defer for 2 weeks for asymptomatic cryptococcal antigenaemia) Immediate initiation: All HIV-positive pregnant or breastfeeding women Within 7 days: Patients with low CD4 <200 cells/mm 3 HIV stage 4, even if CD4 not available

Is sex safe? HPTN 052 % HR = 0.37 or 96.3% reduction in transmission Deferred Immediate

Is sex safe? HPTN 052 % And confirmed in Partners study HR = 0.37 or 96.3% reduction in transmission Deferred Immediate

Thorn in T&T side: Individual benefit Conflicting observational studies 052 not convincing re individual data

START and Temprano fixed this Thanks: Simon Collins

START and Temprano fixed this David Barr: It s easy to say that we always knew the answer we would have a very different answer if we lived in the d4t or AZT era Thanks: Simon Collins

START and Temprano fixed this Thanks: Simon Collins

First line regimens Who? What? Comments Adults Pregnant and breastfeeding women TB co-infection HBV co-infection Adolescents >15 years and weighing >40kg Adolescents <40kg (except pregnant: FDC) TDF + FTC (or 3TC) + EFV (FDC preferred) ABC + 3TC + EFV Replace EFV with NVP if significant psychiatric comorbidity or intolerance to EFV and where the neuropsychiatric toxicity of EFV may impair daily functioning, e.g. shift workers.. Remember CD4 count restrictions for NVP Evidence supports the efficacy and safety equivalence of 3TC and FTC If adolescent s weight <40kg, align with paediatric regimen

Substituting contraindicated drugs in first line Contraindicated drug EFV NVP TDF Currently on d4t Substitute TDF + FTC (or 3TC) + NVP TDF + FTC (or 3TC) + LPV/r ABC + 3TC + EFV (or NVP) TDF + FTC (or 3TC) + EFV FDC preferred Comments Replace EFV with NVP if significant psychiatric comorbidity or intolerance to EFV and where the neuropsychiatric toxicity of EFV may impair daily functioning, e.g. shift workers. Remember CD4 count restrictions for NVP Avoid NVP in women if CD4 count >250 cells/mm 3, and men with CD4 count >400 cells/mm 3 Renal disease or the use of other nephrotoxic drugs, e.g. aminoglycosides MDR treatment d4t to be discontinued in all patients, even if well tolerated. If patient is not virally suppressed, consider switching to second line

DHHS Guidelines, April 2015: What to start? Recommended Regimens INSTI based PI based DTG/ABC/3TC* DTG + TDF/FTC EVG/COBI/TDF/FTC RAL + TDF/FTC DRV/r + TDF/FTC *Only for pts who are HLA-B*5701 negative. Only for pts with pre-art CrCl 70 ml/min. NNRTIs and ATV/r, previously classified as recommended, are now alternative regimens DHHS Guidelines. April 2015.

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

$ PPPY Drugs that have been prioritised as having clinical superiority have shown dramatic price reductions over short periods of time even since CADO in 2010 $400 $350 $300 $250 $200 $150 $100 $50 PH approach needs to balance costs and $0 effectiveness to maximise efficiencies 77% price reduction 72% price reduction 2006 2010 2012 2006 2010 2012 2006 2010 2012 EFV TDF ATV/r 21% price reduction

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)

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

First line: What is good? First line a single tablet, relatively well tolerated, relatively cheap, can use in TB pregnancy TDF XTC EFV

What is bad? SA will spend R10 billion on ART in 2018 Significant toxicity Low resistance barrier Active pharmaceutical ingredients TDF XTC EFV

TDF XTC EFV AZT XTC PI(LPV or ATV) 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

Changes in d4t, AZT and 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)

Now add PrEP TDF

What about API production capacity? 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 Number of patients that could be treated in end of 2012 3,500,000 3,700,000 >13,800,000 >10,000,000 (*) Data from some major manufacturers were not reported. The manufacturers also mentioned that they are all in the process of increasing capacity. WHO HIV/AMDS, 2014 (preliminary data)

Major parameters Number of API producers in 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) TDF EFV 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 Number of patients that could be treated in end of 2012 Concern: API may become a huge problem if 20 by 20 AND PrEP come into play 3,500,000 3,700,000 >13,800,000 >10,000,000 (*) Data from some major manufacturers were not reported. The manufacturers also mentioned that they are all in the process of increasing capacity. WHO HIV/AMDS, 2014 (preliminary data)

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 (?coformulations estimated availability to LMIC 2020) TDF analogue CHAI 200mg vs 300mg: may be available

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 d4t; ABC, other drugs unlikely to displace it

TDF XTC EFV AZT XTC PI(LPV or ATV) 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? Rash, hepatitis, gynaecomastia, lipids ENCORE (Lancet 2013): 400mg versus 600mg less discontinuations, but very little change in side effects Concerns about 400 mg dose in PMTCT and TB

Depression 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 Rilpivirine

Safety/tolerability Study (reference) ECHO/THRIVE Cohen AIDS 2013 SPRING-2 Raffi Lancet Infect Dis 2013 GS US 236 0103: Rockstroh JAIDS 2013 ACTG 5257 Lennox Ann Intern Med 2014 Study arm (N) Regimen % d/c for adverse events at 96 wks 682 2 NRTI + EFV 9% 686 2 NRTI + RPV 4% 411 2 NRTI + DTG 2% 353 TDF/FTC/EVG/c 4% 605 2 NRTI + ATV/r 14% 601 2 NRTI + DRV/r 5% 603 2 NRTI + RAL <1%

Viral load monitoring of first line Viral load Recommended response <400 copies/ml 6-monthly VL monitoring and routine adherence support 400-1000 copies/ml Assess adherence carefully Repeat viral load in 6 months, and manage accordingly >1000 copies/ml Adherence assessment and intense adherence support Repeat VL in 2 months and check HBV status and Hb, if not already done If <1000 copies/ml, return to 6-monthly VL monitoring If >1000 copies/ml and adherence issues addressed, switch to second line therapy after checking HBV status and Hb UNLESS KNOWN HBV-POSITIVE, CHECK HBV (HBSAG) STATUS OF PATIENTS ON TDF AND 3TC/FTC BEFORE STOPPING THESE DRUGS Can result in severe hepatitis flare, therefore continue TDF in second line Check cholesterol before switching to second line If >6 mmol/l, do NOT switch to Aluvia; switch to boosted atazanavir instead

Recommended second line regimens Second line treatment regimens Zidovudine (AZT) if previously on tenofovir (TDF) or abacavir (ABC)* OR TDF if previously on d4t or AZT AND Lamivudine (3TC) or emtricitabine (FTC) AND Lopinavir/ritonavir (LPV/r) replaces efavirenz or nevirapine *IF HBSAG POSITIVE, CONTINUE TDF IN ADDITION TO THE NEW ART REGIMEN [4 DRUGS] Monitoring CD4 count only if clinically indicated VL at 6 months after starting second line. Then 12 monthly if virologically suppressed Contraindications Contraindication Contraindicated drug Replacement drug GI intolerability (diarrhoea) Serum total cholesterol >6 mmol/l Anaemia and renal failure LPV/r ATV/r (ritonavir boosted atazanavir) Use ABC

Second line: What is good? Works like a bomb! AZT XTC PI(lopinavir or atazanavir)

Second line: What is bad? Expensive Toxicity much higher than first LOTS of tablets Small % still fail AZT XTC PI(lopinavir or atazanavir)

TDF XTC EFV AZT XTC PI(LPV or ATV) XTC, other nukes Darunavir Raltegravir Etravirine

AZT Toxic, dose reduction not successful???any role for AZT in future??? EARNEST does it matter what the nukes are? Could we recycle TDF/FTC?

TDF XTC EFV AZT XTC PI(LPV or ATV) XTC, other nukes Darunavir Raltegravir Etravirine

Darunavir in second-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

Perspectives for improving ART ART Optimisation Strategy Tolerabilit y Robust Convenient PW, TB, children Cost Reductio n What is needed? Timelin e Low dose EFV?? PK studies (PW and TB) 1-2 yrs Low dose DRV/r (as FDC) Use of DTG (as FDC)??? Use of TAF?? Long-acting formulations? PK studies (DRV:RTV ratio) RCT (standard vs low dose) Studies in PW, TB and children Comparative trials RCT (DRV/r + DTG in second-line) Comparative trials using DTG Studies in PW, TB and children Phase II/III studies (treatment and prevention trials) 1-2 yrs 2-5 yrs 2-5 yrs > 5 yrs

Losses occur everywhere, but at different steps in the cascade Hill et al. CROI 2015 [abstr 1118]

Unmet needs and challenges of current ART in South Africa. Michelle Moorhouse 21 Nov 2015