AnnaMariaGerettionbehalfofco-authorsProfessorofVirology&InfectiousDiseases,UniversityofLiverpool

ExpertScientist,RochePharmaResearch&EarlyDiscovery

§ Funding:Wellcome Trust,NationalInstitutesofHealth

§ ResearchGovernance:UniversityofLiverpool(UoL)

§ Employment:AMGisemployedbytheUoL andbyRochePharmaResearch&EarlyDiscovery(pRED)– theworkpresentedisindependentofandnotendorsedbyRochepRED

§ AlexanderStockdalea,b

§MatthewSaundersc

§MarkBoydd,e

§ LauraBonnetta

§ VictoriaJohnstonf

§ GillesWandelerg

§ Annelot Schoffelenh

§ LauraCiaffii

§ KristenStaffordj

§ AnnCollierk

§ NicholasPatonl

aUniversity ofLiverpool,UK;bMalawi-

Liverpool-Wellcome TrustCRP,Malawi;cImperial CollegeLondon,UK;dUniversity of

NewSouthWalesandeUniversityofAdelaide,

Australia;fLondon SchoolofHygiene&

TropicalMedicine,UK;gUniversity ofBern,

Switzerland;hUniversity MedicalCentre

Utrecht,Netherlands;iUniversity of

Montpellier,France;jUniversity ofMaryland

SchoolofMedicine,USA;kUniversity of

WashingtonSchoolofMedicine,USA;lNational UniversityofSingapore,Singapore

§ ThenumberofpeoplereceivingARTinSSAincreasedfrom7.5millionin2010to17millionin20151,2

§ Virologicalsuppressionrateswith1st-lineARTinLMICs:67%at12months,65%at24months,62%at48months(meta-analysisof93studies,ITT)3

§ Theneedfor2nd-lineARTprojectedtoincreaseto>4Mby2030,inkeepingwiththeexpansionoftreatmentprovision2,4,5

§ Outcomedatarequiredtoinformpolicy

1.UNAIDS.JointUnitedNationsProgramme onHIV/AIDS,2016;2.UNAIDS.90-90-90AnambitioustreatmenttargettohelpendtheAIDSepidemic,2014;3.Boender etal.Long-termvirologicaloutcomesoffirst-lineantiretroviraltherapyforHIV-1inlow- andmiddle-incomecountries:Asystematicreviewand

meta-analysis.Clin InfectDis2015;4.WHO.ConsolidatedguidelinesontheuseofantiretroviraldrugsfortreatingandpreventingHIVinfection,2016;5.Estilletal.Theneedforsecond-lineantiretroviraltherapyinadultsinsub-SaharanAfricaupto2030:amathematicalmodellingstudy.LancetHIV2016

ART= Antiretroviral Therapy; SSA= Sub-Saharan Africa LMICs= Low-Middle-Income Countries; ITT= Intention-To-Treat

§ Systematicreviewandmeta-analysisofstudiesreportingthevirologicaloutcomesofPI-based2nd-lineARTinSSA

PRIMARYOUTCOMEVirologicalsuppression*after48and96weeksoftreatment

SECONDARYOUTCOMES1. ImpactofNRTIresistance2. ProportionwithPIRAMs

at2nd-linefailure

*Virologicalsuppression:PlasmaHIV-1RNA<400cps/ml

PI= Protease Inhibitor; RAMs= Resistance-Associated Mutations

§ PubMed,EMBASE,CochraneCentralRegisterofControlledTrials,Scopus,WebofScience

§ Terms:“HIV”,“sub-SaharanAfrica”(andcountriestherein),“second-line”,“proteaseinhibitor”,genericandproprietarynamesofdrugsincludedin2nd-lineART

§ Articlespublishedfrom1Jan1996to10Jul2016

Oneprevioussystematicreviewoftheeffectivenessof2nd- lineARTinLMIC(2012);newRCTs(e.g.,SECOND-LINE,EARNEST,2- LADY,SELECT)andcohortstudiespublishedsince

RCTs= Randomised Clinical Trials

§ ReferencescitedinthearticlesandabstractsfromIAS(2014-2015)andCROI(2014-2016)conferences

§ Authorscontactedtoobtainandclarifydata

§ RCTs(n=5)andobservationalcohortstudiesreportingvirologicaloutcomesofPI-based2nd-lineARTinSSA

EXCLUSIONSStudieswith<20participantsParticipantsoutsideSSAinmulti-centre trialsPIsornon-standardregimensusedas1st-lineARTNoclearlydefinedcriteriaforswitchingfrom1st- to2nd-lineART

INCLUSIONSHIV-1positivesubjectsaged>10years1st-lineART(2NRTIs+NNRTI)for≥6monthspriortostarting2nd-lineARTClinical,immunologicalorvirologicalcriteriaforstarting2nd-lineARTViralloadmeasuredatleastannually

§ DatafromSouthAfrica,Nigeria,Uganda,Zimbabwe,Kenya,Malawi,Zambia,BurkinaFaso,Cameroon,Senegal,Tanzania

§MostpatientsreceivedLPV/r;oneRCTrandomised onethirdofpatientstoDRV/r(800mgod)

CI= Confidence Interval

*ITTanalysis

VirologicalfailurebyWHOdefinition(>1000cps/ml):2.5-26.6%atwk 48,4.1-11.1%atwk 96

Virologicalsuppression70.0%*[95%CI56.7,81.7]

Virologicalsuppression61.5%* [95%CI47.2,74.9]

WEEK48:13studies3408participants

WEEK96:8studies2145participants

48 weeks, ITT

Observed:83.3%[76.7,89.0] Proportion<400cps/ml

Heterogeneity between groups: p 0·0< 01

Overall (I^2 = 98·3 %, p 0· 0 );6 < 0 1

La Rosa

Gross

Subtotal (I^2 = 81· %, p 0· 0 )50 < 0 1

Paton

Boyd/Amin

Ciaffi

Randomised trials

2012−13

2009−11

2010−14

2010−14

2010−13

162

132

426

100

451

148

112

336

85

399

Hosseinipour

Castelnuovo

Subtotal (I^2 = 96·14%, p 0·0 )< 01

Boender/ Sigaloff

Johnston

Murphy

Observational studies

Schoffelen

Osinusi−Adekanmbi

Wandeler

2006−08

2004−06

2007−11

2003−08

2006−10

2004−10

2008−11

2006−12

101

40

243

417

136

156

73

971

75

30

178

174

94

70

36

368

69·97 1 7(56·7 , 81· 4)

74·26 (64·95, 81·78)

75·00 (59·81, 85·81)

58·06 (46·00, 69·65)

73·25 (67·36, 78·42)

41·73 (37·09, 46·51)

69·12 (60·92, 76·27)

91·36 (86·02, 94·78)

44·87 (37·28, 52·71)

49·32 (38·17, 60·53)

84·85 (77·75, 89·97)

85·87 (80·76, 90·32)

78·87 (74·75, 82·48)

8 00 (7 , )4· 5·58 89·90

88·47 (85·19, 91·10)

37·90 (34·90, 40·99)

12·34

10·99

100·00

12·95

13·15

12·60

19·30

12·70

11·97

18·29

100·00

22·75

16·77

22·89

13·31

0 10 20 30 40 50 60 70 80 90 100

Proportion with <400 copies/ml (%)viral load

Study Year Total VL <400 Proportion (95% CI) Weight (%)

A: 48 weeks

Heterogeneity between groups: p 0·00< 1

Overall (I^2 = 97· %, p 0·0 );32 < 01

Schoffelen

Randomised trials

Osinusi−Adekanmbi

Observational study

Murphy

Boender/ Sigaloff

Wandeler

Subtotal (I^2 = 94·45%, p 0·00 )< 1

Paton

Castelnuovo

Boyd/Amin

2004−10

2008−11

2006−10

2007−11

2006−12

2010−14

2004−06

2010−14

156

73

136

243

971

426

40

100

67

41

74

150

361

326

34

76

61·48 7· 5 4· 7(4 1 , 7 8 )

42.95 (35.44, 50.79)

56.16 (44.76, 66.95)

7 . (7 . , . 4)6 49 2 75 80 0

54.41 (46.03, 62.55)

61.73 (55.48, 67.61)

37.18 (34.19, 40.26)

55.66 (43.14, 67.82)

76.53 (72.27, 80.30)

85.00 (70.93, 92.94)

76 66.77 83.31.00 ( , )

.

17.12

15.90

100.00

16.95

17.55

18.16

100.00

80.93

14.33

19.07

.

0 10 20 30 40 50 60 70 80 90 100

B: 96 weeks

Study Year Total VL <400 Proportion (95% CI) Weight (%)

Proportion with <400 copies/ml (%)viral load

Figure 3

96 weeks, ITT

Observed84.8%[78.8,89.9]

Proportion<400cps/ml

48 weeks, ITT

RCTsvs.Observationalstudies85.9%[80.8,90.3]vs.58.1%[46.0,69.7]

p<0·001

Proportion<400cps/ml

Heterogeneity between groups: p 0·0< 01

Overall (I^2 = 98·3 %, p 0· 0 );6 < 0 1

La Rosa

Gross

Subtotal (I^2 = 81· %, p 0· 0 )50 < 0 1

Paton

Boyd/Amin

Ciaffi

Randomised trials

2012−13

2009−11

2010−14

2010−14

2010−13

162

132

426

100

451

148

112

336

85

399

Hosseinipour

Castelnuovo

Subtotal (I^2 = 96·14%, p 0·0 )< 01

Boender/ Sigaloff

Johnston

Murphy

Observational studies

Schoffelen

Osinusi−Adekanmbi

Wandeler

2006−08

2004−06

2007−11

2003−08

2006−10

2004−10

2008−11

2006−12

101

40

243

417

136

156

73

971

75

30

178

174

94

70

36

368

69·97 1 7(56·7 , 81· 4)

74·26 (64·95, 81·78)

75·00 (59·81, 85·81)

58·06 (46·00, 69·65)

73·25 (67·36, 78·42)

41·73 (37·09, 46·51)

69·12 (60·92, 76·27)

91·36 (86·02, 94·78)

44·87 (37·28, 52·71)

49·32 (38·17, 60·53)

84·85 (77·75, 89·97)

85·87 (80·76, 90·32)

78·87 (74·75, 82·48)

8 00 (7 , )4· 5·58 89·90

88·47 (85·19, 91·10)

37·90 (34·90, 40·99)

12·34

10·99

100·00

12·95

13·15

12·60

19·30

12·70

11·97

18·29

100·00

22·75

16·77

22·89

13·31

0 10 20 30 40 50 60 70 80 90 100

Proportion with <400 copies/ml (%)viral load

Study Year Total VL <400 Proportion (95% CI) Weight (%)

A: 48 weeks

Heterogeneity between groups: p 0·00< 1

Overall (I^2 = 97· %, p 0·0 );32 < 01

Schoffelen

Randomised trials

Osinusi−Adekanmbi

Observational study

Murphy

Boender/ Sigaloff

Wandeler

Subtotal (I^2 = 94·45%, p 0·00 )< 1

Paton

Castelnuovo

Boyd/Amin

2004−10

2008−11

2006−10

2007−11

2006−12

2010−14

2004−06

2010−14

156

73

136

243

971

426

40

100

67

41

74

150

361

326

34

76

61·48 7· 5 4· 7(4 1 , 7 8 )

42.95 (35.44, 50.79)

56.16 (44.76, 66.95)

7 . (7 . , . 4)6 49 2 75 80 0

54.41 (46.03, 62.55)

61.73 (55.48, 67.61)

37.18 (34.19, 40.26)

55.66 (43.14, 67.82)

76.53 (72.27, 80.30)

85.00 (70.93, 92.94)

76 66.77 83.31.00 ( , )

.

17.12

15.90

100.00

16.95

17.55

18.16

100.00

80.93

14.33

19.07

.

0 10 20 30 40 50 60 70 80 90 100

B: 96 weeks

Study Year Total VL <400 Proportion (95% CI) Weight (%)

Proportion with <400 copies/ml (%)viral load

Figure 3

96 weeks, ITT

RCTsvs.Observationalstudies76.5%[72.8,80.4]vs.55.7%[43.1,67.8]

p<0·001

Proportion<400cps/ml

NOTE: Weights are from random effects analysis

Overall (I−squared = 62·8%, p = 0·020)

Paton

Boyd

Hosseinipour

Castelnouvo

Sigaloff

Johnston

22

4

3

11

69

18

33 (66·6)

10 (40·0)

5 (60·0)

12 (91·7)

80 (86·3)

35 (51·4)

310

71

84

4

95

62

358 (86·6)

81 (87·7)

89 (94·4)

4 (100)

112 (84.8)

79 (78·5)

0·31 (0·14, 0·70)

0·31 (0·14, 0·68)

0·09 (0·02, 0·39)

0·09 (0·01, 0·66)

0·85 (0·03, 25·05)

1·12 (0·49, 2·55)

0·29 (0·12, 0·68)

100·00

23·56

15·48

10·49

4·75

23·09

22·63

10·1 0·2 0·5 1 2 5 10 30

Odds ratio

Study VL<400 Total (%) VL<400 Total (%) OR (95% CI) Weight (%)

Fully active Partially active

Higher odds of virological suppressionwith fully active regimen

Lower odds of virological suppressionwith fully active regimen

Figure 5

IMPACTOFNRTIRESISTANCEResistancetestresultsatstartof2nd-lineARTavailablein6studies

OddsRatio

§ Unbiasedselectionmethodforresistancetestingrequired:• eitherallpatientsmeetingadefinedviralloadthreshold,or

• arandomselectionofthetotalfailurepopulation

• 11studies

• Thresholdforresistancetesting400-5000cps/ml

• Durationof2nd-lineARTatresistancetesting:6-31months

• 0-7%ofat-riskpopulation,0-25%offailurepopulation

• 0-7%at6-12months;0-29%at16-24months0

510

15

20

25

Pro

port

ion w

ith m

ajo

r P

I m

uta

tion(%

)

0 4 8 12 16 20 24 28 32

Cohort median duration of second−line ART at failure (months)

Maigi

CourtPaton

WallisSigaloff

ReynoldsLevison

Boyd

Johnston

Ciaffi

Ndahimana

Figure 6

Mediandurationof2nd-lineARTattimeoffailure

Prop

ortio

nwith

PIR

AMs

25

20

15

10

5

0

048121620242832

§ PI-based2nd-lineART(withcontinuedNRTIuse)resultsinvirologicalsuppressioninmostpatientsinSSAandcarriesarelativelylowriskofPIresistance

§ PI-based2nd-lineART(withcontinuedNRTIuse)resultsinvirologicalsuppressioninmostpatientsinSSAandcarriesarelativelylowriskofPIresistance

§ Substantialheterogeneityacrossobservationalstudies

ØOnesource:variableproportionofmissingviralloaddatanotexplainedbydeathorlosstofollow-up

§ Virologicaloutcomessignificantlybetter(andlosstofollow-uplower)amongRCTparticipantsvs.observationalstudies

§ NRTIresistancepredictedhigheroddsofvirologicalsuppression

ØResistanceasaproxyforhigheradherence

ØZDVandTDFretainsignificantresidualactivitydespiteTAMs,enhancedbycontinuationof3TC

§ Long-termdata

§ Standardised reportingØE.g.,sizeof1st-lineARTpopulation,rateof1st-lineARTfailure,rateofswitchingto2nd-lineART,NRTIsusedin1st- and2nd-lineregimens,rateofadverseevents,contributionoftolerabilitytotreatmentdiscontinuation

§ OnethirdofpatientsdidnotachievevirologicalsuppressionØRiskofdiseaseprogressionandonwardHIVtransmission

§ Optimalstrategiesforpreventing,defining,andmanaging2nd-lineARTfailure,bothwithandwithoutPIresistance,representaresearchpriorityforSSA