*Indicates presenting author.

POSTER PRESENTATIONS

Treatment Strategies - New Treatments and Targets

P021 Durability and tolerability of first-line combination including two NRTIs and RAL or ATV/r or DRV/r in patients enrolled in the ICONA Foundation cohortd’Arminio Monforte, A*; Lorenzini, P; Cozzi-Lepri, A; Mussini, C; Castagna, A; Baldelli, F; Puoti, M; Mazzotta, F; Abrescia, N; Lo Caputo, S; Gianotti, N; Antinori, A; on behalf of the ICONA Foundation cohort (Milan, Italy)

P022 HIV-1 combinectin GSK3732394: a long-acting inhibitor with multiple modes of actionKrystal, M*; Wensel, D; Sun, Y; Davis, J; McDonagh, T; Li, Z; Zhang, S; Soars, M; Cockett, M (Wallingford, USA)

P025 The integrase strand transfer inhibitor bictegravir has a long integrase/DNA dissociation half-lifeWhite, K*; Majka, A; Novikov, N; Miller, M; Tsiang, M (Foster City, USA)

P026 Durability and prescribing patterns of initial HIV regimens in treatment-naïve patientsEaton, E; Tamhane, A; Prajapati, G*; Goodwin, B; Saag, M (Rahway, USA)

P027 Integrase inhibitor-based antiretroviral therapy in vulnerable populationsConway, B; Kiani, G*; Shahi, R; Raycraft, T; Singh, A; Hakobyan, S; Alimohammadi, A (Vancouver, Canada)

P028 Inhibition of HIV-1 protease and plasmodium falciparum by a modified digold chloroquine derivativeGama, N*; Kumar, K; Reader, J; Gordhan, B; Birkholtz, L; Kana, B; Darkwa, J; Meyer, D (Pretoria, South Africa)

P029 Treatment failure of chronic HCV infection with the new direct-acting antivirals: experience of a Portuguese central hospitalPereira, K*; Dias Grazina, S; Miranda, A; Baptista, T; Borges, F; Nina, J; Peres, S; Aldir, I; Campos, M; Antunes, I; Pereira, J; Ventura, F; Mansinho, K (Lisbon, Portugal)

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241 129 47 22 15RAL1023 701 413 237 119DRV/r986 675 456 306 175ATV/r

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241 147 73 44 32RAL1023 792 545 365 199DRV/r985 795 642 480 307ATV/r

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241 129 47 22 15RAL1023 701 413 237 119DRV/r985 674 455 306 175ATV/r

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ATV/r DRV/rRAL

Background

ICONA Foundation Study Group

d'Arminio Monforte A1, Lorenzini P2, Cozzi-Lepri A3, Mussini C4, Castagna A5, Baldelli F6, Puoti M7, Mazzotta F8, Abrescia

N9, Lo Caputo S10, Gianotti N11, Antinori A2, on behalf of Icona Foundation Study Group1 Department of Health Sciences, University of Milan, Clinic of Infectious and Tropical Diseases, ASST Santi Paolo e Carlo , Milan Italy; 2Clinical Department, National Institute for Infectious Diseases, IRCCS, Lazzaro Spallanzani , Rome Italy; 3Department of Infection and Population Health,

Division of Population Health,UCL Medical School, Royal Free Campus , London United Kingdom; 4Infectious Disease Clinic, University of Modena and Reggio Emilia , Modena Italy; 5Department of Infectious Diseases, San Raffaele Scientific Institute, Università Vita-Salute San Raffaele , Milan Italy; 6Unit of Infectious Diseases, Department of Medicine,University of Perugia , Perugia Italy; 7Department of Infectious Diseases, AO Niguarda Ca' Granda , Milan Italy; 8Division of Infectious Diseases, Ospedale S.M. Annunziata, Antella , Florence Italy; 9Infectious Diseases Unit,

D.Cotugno Hospital-AORN dei Colli , Naples Italy; 10Department of Infectious Diseases, University of Bari , Bari Italy; 11Department of Infectious Diseases, San Raffaele Scientific Institute . Milan Italy;

Durability and tolerability of first-line combination with 2 NRTI and RAL or ATV/r or DRV/r in patients enrolled in the ICONA Foundation cohort

Objectives

Methods

Results

Conclusions

BOARD OF DIRECTORS A d’Arminio Monforte (Vice-President), M Andreoni, G Angarano, A Antinori, F Castelli, R Cauda, G Di Perri, M Galli, R Iardino, G Ippolito, ALazzarin, CF Perno, F von Schloesser, P Viale. SCIENTIFIC SECRETARY A d’Arminio Monforte, A Antinori, A Castagna, F Ceccherini-Silberstein, A Cozzi-Lepri, E Girardi, SLo Caputo, C Mussini, M Puoti. STEERING COMMITTEE M Andreoni, A Ammassari, A Antinori, C Balotta, A Bandera, P Bonfanti, S Bonora, M Borderi, A Calcagno, LCalza, MR Capobianchi, A Castagna, F Ceccherini-Silberstein, A Cingolani, P Cinque, A Cozzi-Lepri, A d’Arminio Monforte, A De Luca, A Di Biagio, E Girardi, N Gianotti, AGori, G Guaraldi, G Lapadula, M Lichtner, S Lo Caputo, G Madeddu, F Maggiolo, G Marchetti, S Marcotullio, L Monno, C Mussini, S Nozza, M Puoti, E Quiros Roldan, RRossotti, S Rusconi, MM Santoro, A Saracino, M Zaccarelli. STATISTICAL AND MONITORING TEAM A Cozzi-Lepri, I Fanti, L Galli, P Lorenzini, A Rodano, M Shanyinde, ATavelli. BIOLOGICAL BANK INMI F Carletti, S Carrara, A Di Caro, S Graziano, F Petrone, G Prota, S Quartu, S Truffa. PARTICIPATING PHYSICIANS AND CENTERS AGiacometti, A Costantini, C Valeriani (Ancona); G Angarano, L Monno, C Santoro (Bari); F Maggiolo, C Suardi (Bergamo); P Viale, V Donati, G Verucchi (Bologna); FCastelli, E Quiros Roldan, C Minardi (Brescia); T Quirino, C Abeli (Busto Arsizio); PE Manconi, P Piano (Cagliari); B Cacopardo, B Celesia (Catania); J Vecchiet, K Falasca(Chieti); L Sighinolfi, D Segala (Ferrara); F Mazzotta, F Vichi (Firenze); G Cassola, C Viscoli, A Alessandrini, N Bobbio, G Mazzarello (Genova); C Mastroianni, V Belvisi(Latina); P Bonfanti, I Caramma (Lecco); A Chiodera, P Milini (Macerata); M Galli, A Lazzarin, G Rizzardini, M Puoti, A d’Arminio Monforte, AL Ridolfo, R Piolini, A Castagna,S Salpietro, L Carenzi, MC Moioli, C Tincati, G Marchetti (Milano); C Mussini, C Puzzolante (Modena); A Gori, G Lapadula (Monza); N Abrescia, A Chirianni, G Borgia, ROrlando, F Di Martino, L Maddaloni, I Gentile, G Bonadies (Napoli); A Cascio, C Colomba (Palermo); F Baldelli, E Schiaroli (Perugia); G Parruti, T Ursini (Pescara); GMagnani, MA Ursitti (Reggio Emilia); R Cauda, M Andreoni, A Antinori, V Vullo, A Cristaudo, A Cingolani, G Baldin, S Cicalini, L Gallo, E Nicastri, R Acinapura, M Capozzi, RLibertone, S Savinelli, A Latini, G Iaiani, L Fontanelli Sulekova (Roma); M Cecchetto, F Viviani (Rovigo); MS Mura, G Madeddu (Sassari); A De Luca, B Rossetti (Siena); DFrancisci, C Di Giuli (Terni); P Caramello, G Di Perri, GC Orofino, S Bonora, M Sciandra (Torino); M Bassetti, A Londero (Udine); G Pellizzer, V Manfrin (Vicenza).

Although PI/r including regimens are no longer indicated as preferential regimensin the first line cART, in a number of situations they are still used as first lineregimens, due to their high genetic barrier and potency.

We aimed to conduct an analysis similar to that of the ACTG 5257 trial,comparing durability and safety of first line raltegravir (RAL) including regimens toregimens including either darunavir/ritonavir (DRV/r) or atazanavir/r (ATV/r) in theobservational setting.

Participants in the Icona Foundation Cohort who started cART after the 1st ofJanuary 2008 with 2NRTI (either TDF+FTC or ABC+3TC) + ATV/r or DRV/r or RALwhen ART-naïve were included.Primary end-point: treatment failure (TF) defined by the composite endpoint ofvirological failure (VF) (confirmed HIV-RNA >200 copies/mL after 6 months oftherapy) or discontinuation of the regimen for any causeSecondary end-points:- confirmed HIV-RNA>50 copies/mL after 6 months of therapy (VF50)- discontinuation of DRV/r or ATV/r or RAL for any reasons- discontinuation of DRV/r or ATV/r or RAL because of intolerance/toxicity

(as reported by the treating physician)Statistical analyses:For the comparison of characteristics at time of treatment initiation among thethree groups, Chi-square or Kruskal-Wallis test were used as appropriate.Survival analysis with Kaplan-Meier curves and Cox regression model with timefixed covariates at cART initiation stratified by clinical site was used. Participants’follow-up accrued from the date of cART initiation to the date of the event or tothe date of last available visit/viral load.

A total of 2,249 persons in Icona Foundation Cohort were enrolled: 985 started2NRTI+ATV/r, 1023 2NRTI+DRV/r and 241 2NRTI+RAL when ART-naïve, on averagein 2012 (IQR:2011-2014). Most of subjects started FTC/TDF (86.5%) as NRTIbackbone. Median age was 40 years, 21% females, 44% heterosexuals. Patientsstarting ATV/r were less frequently males (p=0.003), less likely of Italiannationality (p=0.022), more frequently hepatitis C co-infected (p=0.001), and theystarted cART earlier than the other two groups (p<0.001). Subjects on DRV/r-based regimens had the lowest median CD4 cell count (p<0.001) and the highestmedian viral load at cART starting (p=0.001), and also the higher proportion ofpatients who experienced an AIDS event (p<0.001). RAL group started cART withthe highest median value of CD4 count and lowest viral load (p<0.001) (Table 1).

Table 1. Main characteristics of patients according to the third drug startedCHARACTERISTICS ATV/r DRV RAL p Total

N=985 N=1023 N=241 N=2249Male gender, n(%) 745 (75.6%) 835 (81.6%) 196 (81.3%) 0.003 1776 (79.0%)Age, yrs, median (IQR) 39 (32-47) 40 (33-49) 43 (35-50) <0.001 40 (32-48)Migrants, n(%) 240 (24.4%) 209 (20.4%) 42 (17.4%) 0.022 491 (21.8%)Mode of HIV transmission, n(%)

heterosexual 450 (45.7%) 426 (41.6%) 106 (44.0%) <0.001 982 (43.7%)PWID 118 (12.0%) 62 (6.1%) 14 (5.8%) 194 (8.6%)MSM 354 (35.9%) 436 (42.6%) 102 (42.3%) 892 (39.7%)other/unknown 63 (6.4%) 99 (9.7%) 19(7.9%) 181 (8.0%)

AIDS diagnosis, n(%) 88 (8.9%) 164 (16.0%) 29 (12.0%) <0.001 281 (12.5%)Time from HIV diagnosis to date of starting cART, months, median (IQR) 4 (1-32) 2 (1-17) 3 (1-24) <0.001 3(1-24)HCV co-infection, n(%)

positive 125 (12.7%) 80 (7.8%) 19 (7.9%) 0.001 224 (10.0%)negative 769 (78.1%) 830 (81.1%) 188 (78.0%) 1787 (79.5%)not tested 91 (9.2%) 113 (11.1%) 34 (14.1%) 238 (10.5%)

HBV co-infection, n(%)positive 41 (4.2%) 37 (3.6%) 14 (5.8%) 0.311 92 (4.1%)negative 818 (83.1%) 833 (81.4%) 190 (78.8%) 1841 (81.9%)not tested 126 (12.8%) 153 (15.0%) 37 (15.4%) 316 (14.0%)

CD4 cell/mmc, n(%)0-200 267 (27.1%) 378 (37.0%) 55 (22.8%) <0.001 700 (31.1%)201-350 284 (28.8%) 207 (20.2%) 43 (17.8%) 534 (23.7%)351-500 209 (21.2%) 192 (18.8%) 45 (18.7%) 446 (19.8%)501+ 133 (13.5%) 119 (11.6%) 62 (25.7%) 314 (14.0%)not available 92 (9.3%) 127 (12.4%) 36 (14.9%) 255 (11.3%)

CD4 cell/mmc, median (IQR) 305 (171-180) 254 (91-409) 369 (180-540) <0.001 289 (134-429)HIV RNA cp/mL, n(%)

50-20.000 234 (23.8%) 192 (18.8%) 66 (27.4%) 0.001 492 (21.9%)20.000-10.000 265 (26.9%) 232 (22.7%) 60 (24.9%) 557 (24.8%)10.000-250.000 150 (15.2%) 171 (16.7%) 30 (12.4%) 351 (15.6%)250.000+ 190 (19.3%) 240 (23.5%) 38 (15.8%) 468 (20.8%)not available 146 (14.8%) 188 (18.4%) 47 (19.5%) 381 (16.9%)

HIV RNA log10 cp/mL, median (IQR) 4.8 (4.2-5.3) 5.0 (4.4-5.5) 4.7 (4.1-5.3) <0.001 4.9 (4.3-5.4)Calendar year of cART start, n(%)

2008-2009 98 (9.9%) 12 (1.2%) 14 (5.8%) <0.001 124 (5.5%)2010-2011 354 (35.9%) 265 (28.7%) 28 (11.6%) 647 (28.8%)2012-2013 356 (36.1%) 403 (39.4%) 52 (21.6%) 811 (36.1%)2014-2015 177 (18.0%) 343 (33.5%) 147 (61.0%) 667 (29.7%)

NRTI pair, n(%)Tenofovir/Emtricitabine 852 (86.5%) 886 (86.6%) 207 (85.9%) 0.958 1945 (86.5%)Abacavir/Lamivudine 133 (13.5%) 137 (13.4%) 34 (14.1%) 304 (13.5%)

P-021

Figure 1: Kaplan Meier estimates of reaching the different end-points stratified by third drug

Outcome: discontinuation because of toxicityOutcome: confirmed viral load>50 cp/mL Outcome: discontinuation for any reasons

After controlling for a number of confounders (footnote of Table 3) subjects treated with ATV/r showed ahigher rate of treatment failure and of risk of discontinuation (for any reasons and due to toxicity) thanthe DRV/r group. In contrast, still compared to DRV/r, patients who started a RAL-based regimen showeda lower rate of discontinuation due to toxicity and a lower rate of virological failure (VF50)(Table 3).

Table 3. Relative hazards from fitting 4 separate Cox regression modelsOUTCOMES Crude RH

(95%CI) P-valueAdjusted* RH

(95%CI) P-valueTF (HIV-RNA >200 cp/mL or discontinuation)DRV/r 1.00 1.00ATV/r 1.10 (0.97-1.25) 0.138 1.19 (1.04-1.36) 0.009RAL 0.99 (0.79-1.25) 0.950 0.91 (0.72-1.15) 0.428VF50 (HIV-RNA>50 cp/mL)DRV/r 1.00 1.00ATV/r 0.92 (0.71-1.18) 0.496 0.99 (0.75-1.30) 0.932RAL 0.35 (0.17-0.72) 0.004 0.42 (0.20-0.86) 0.018Discontinuation for any reasonDRV/r 1.00 1.00ATV/r 1.09 (0.95-1.24) 0.213 1.20 (1.05-1.38) 0.008RAL 1.08 (0.86-1.35) 0.527 0.97 (0.77-1.23) 0.811Discontinuation due to toxicityDRV/r 1.00 1.00ATV/r 1.77 (1.37-2.28) <0.001 1.97 (1.51-2.57) <0.001RAL 0.47 (0.24-0.94) 0.033 0.42 (0.21-0.85) 0.017*Adjusted for age, gender, nation of birth, mode of HIV transmission, hepatitis co-infection status, AIDS diagnosis, nucleoside pair started, baseline CD4 count and viral load and year of starting cART

Over a median follow-up of 2.9 years (IQR: 1.5-4.3), the 2 year-probability of treatmentfailure was 45.9% (95%CI: 42.7-49.2) for persons receiving ATV/r, 43.7% (95%CI: 40.4-47.0)for persons receiving DRV/r and 49.6% (95%CI: 41.3-58.4) for those receiving RAL (p=0.89)

Figure 2: Distribution of reasons for discontinuation stratified by third drug

Our data were somewhat different from those observed in the ACTG5257 randomized comparison:-when the composite endpoint of treatment failure was considered, ATV/r-based regimens showed a 19% higher risk than DRV/r -when considering virological failure, with a threshold of 50 copies/mL, data are suggesting a lower rate of virological failure for RAL than DRV/r.

In contrast, regarding the discontinuation end-point, our results seem to be consistent with those ofthe ACTG 5257, indicating a higher propensity to discontinue ATV/r for reasons due to toxicity vs. DRV/rgroup.

We found also a lower rate of discontinuation for toxicity in RAL-based regimens compared to DRV/r. ATV/r showed also a higher risk of discontinuation regardless the reason as compared to DRV/r. The comparison between analyses conducted in the observational settings and those coming from RCT

is always a difficult one to make and we cannot rule out possible bias due to unmeasured confoundingor other introduced by the subjective nature of the data reported (e.g. the reason for stopping a drug).

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241 126 42 21 15RAL1023 665 384 225 112DRV/r985 629 419 282 159ATV/r

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ATV/r DRV/rRAL

KM estimates ATV/r (N=985)

DRV/r (N=1023)

RAL (N=241)

P Total (N=2249)

VF>50 copies/mL2 yrs 15.0% (12.6-17.9) 15.6% (13.1-18.5) 5.5% (2.4-12.3) 0.004 14.4% (12.8-16.4) 3 yrs 19.4% (16.4-22.8) 19.8% (16.7-23.4) 5.5% (2.4-12.3) 18.6% (16.5-20.9)Discontinuationfor any reason2 yrs 41.1% (37.9-44.4) 39.2% (36.0-42.6) 45.7% (37.8 -54.4) 0.784 40.4 % (38.3-42.7)3 yrs 51.6% (48.2-55.1) 52.9% (49.3-56.6) 57.9% (48.5-67.6) 52.5% (50.1-54.9)Discontinuationdue to toxicity2 yrs 16.9% (14.5-19.7) 10.5% (8.5-12.8) 5.3% (2.7-10.3) <0.001 12.9% (11.4-14.6)3 yrs 18.4% (15.8-21.3) 13.0% (10.6-15.9) 5.3% (2.7-10.3) 14.8% (13.1-16.7)

Treatment Failure2 yrs 45.9% (42.7-49.2) 43.7% (40.4-47.0) 49.6% (41.3-58.4) 0.891 44.9% (42.7-17.2)3 yrs 55.4% (52.0-58.8) 55.6% (52.0-59.3) 58.5% (49.1-68.2) 55.5% (53.1-57.9)

Outcome: Treatment Failure

log rank p=0.891

log rank p=0.004 log rank p=0.784 log rank p<0.001

6,4%9,6%

19,4%

22,3%

42,4%

ATV/r

5,1% 5,6%

18,4%

41,2%

29,7%

DRV/r

14,7%5,3%

25,3%42,7%

12,0%

RAL

ATV/r DRV/r RAL(N=173) (N=105) (N=9)

Hepatotoxicity / Hyperbilirubinemia 40,5% 5,7% 0,0%

Gastrintestinal Toxicity 14,5% 30,5% 22,2%

Allergic Reactions / Rash 13,3% 20,0% 33,3%

Others 8,1% 16,2% 22,2%

Lipidic Metabolism Toxicity 6,4% 20,0% 0,0%

Nephroxicity 13,3% 2,9% 0,0%

Toxicity Not Specified 3,5% 1,9% 11,1%

Osteopenia / Osteporosis 0,6% 2,9% 11,1%

Table 2. Causes of discontinuation for toxicity

HIV Glasgow; October 23-26, 2016; Glasgow, UK

In vitro susceptibility GSK3732394 demonstrated a broad spectrum of coverage in a cell-cell fusion assay with

functional envelope clones from 124 clinical isolates compared to a control envelope (Figure 2)

Mouse model of infection Humanized mice were infected with YU2 virus and treated every 3 days subcutaneously (SC) with

4, 12.5, or 32 mg/kg GSK3732394; samples were taken every 9 days for analyses Extent of CD4 binding in vivo (receptor occupancy) was analyzed (Figure 3)

Dose-dependent increase in receptor occupancy on CD4 At 32 mg/kg, receptor occupancy ranged from 40% to 60% Measurement of virus titers at each collection point were performed (Figure 4) Dose-dependent decreases in viral titers observed

The efficacy observed at the highest dose of GSK3732394 was similar to that observed with HAART By Day 63, viral titers were present in all of the mice exposed to the 4 mg/kg dose and in 7 of the

8 mice exposed to the 12.5 mg/kg dose In the 32 mg/kg dose group, viral titers were present in 3 of 7 remaining animals by Day 63

Viral titers remained undetectable in the other mice All samples with viral titers were assessed at Day 63, and the only change present (in all viruses)

was Q577R, which is the resistance mutation to the α-N17 Adnectin

Introduction Long-acting antiretrovirals could provide a useful alternative to daily oral therapy for

HIV-1–infected individuals Adnectins™ (Bristol-Myers Squibb, Waltham, MA, USA) are small proteins derived from the

10th type III fibronectin domain of the human fibronectin protein that possess modifiable binding loops akin to the complementarity-determining region of an antibody1

Using Adnectins and a peptide fusion inhibitor, we developed the Combinectin inhibitor GSK3732394 (BMS-986197), a biologic with 3 independent and synergistic modes of HIV entry inhibition that could potentially be self-administered as a long-acting subcutaneous injection

We present preclinical data on the antiviral potency and efficacy of GSK3732394 in a mouse model of infection

MethodsDrug design Adnectins targeting CD4 and a region of gp41 were isolated and optimized for antiviral potency

and biophysical characteristics The α-CD4 Adnectin (EC50=8.5 nM) allows gp120 to bind but inhibits conformational changes needed for

coreceptor binding The α-gp41 Adnectin (EC50=5.4 nM) targets the conserved N17 pocket in heptad repeat 1 (HR1) The peptide fusion inhibitor (EC50=0.4 nM) targets the region just upstream (N-terminal) of N17

The α-gp41 Adnectin was joined at its amino terminus to the α -CD4 Adnectin via a peptide linker, and the peptide was joined to the α-gp41 Adnectin via a linker (Figure 1)

Last, a human serum albumin (HSA) molecule was attached via a linker to the amino terminus of the α-CD4 Adnectin to optimize in vivo pharmacokinetics (PK)

Efficacy of GSK3732394 The in vivo activity of GSK3732394 was tested by TransCure Biosciences (Archamps, France) in

a mouse model of infection

ResultsAntiviral potency Various synergies were obtained by linking all 3 inhibitors into a single molecule. Optimally

combining the 2 Adnectins increased the potency over 100 fold to ~20 pM (Table 1) Addition of HSA enables a projected half-life of GSK3732394 of ~40 hours

Accompanying decrease in the potency to 0.27 ± 0.17 nM for full molecule

Resistance profile Resistance to each individual component was generated in vitro, and recombinant viruses

containing mixtures of these resistance mutations were examined No significant change in susceptibility to GSK3732394 was observed with recombinant viruses

constructed to contain resistance substitutions to one of the inhibitors (Table 2) Only viruses resistant to both α-gp41 inhibitors or all 3 inhibitors exhibited high fold changes

compared with wild-type virus

P022

Mark Krystal,1 David Wensel,2 Yongnian Sun,3 Jonathan Davis,2 Zhufang Li,1Thomas McDonagh,2 Sharon Zhang,1 Matt Soars,3 Mark Cockett1

1ViiV Healthcare, Wallingford, CT, USA; 2Bristol-Myers Squibb, Waltham, MA, USA; 3Bristol-Myers Squibb, Wallingford, CT, USA

HIV Combinectin GSK3732394: A LongHIV Combinectin GSK3732394: A Long-HIV Combinectin GSK3732394: A Long-Acting

Mark Krystal,1 David Wensel,2 Yongnian Sun,3 Jonathan Davis,2 Zhufang Li,1

HIV Combinectin GSK3732394: A LongHIV Combinectin GSK3732394: A LongHIV Combinectin GSK3732394: A Long Acting Acting Inhibitor With Multiple Modes of Action

Acknowledgments: This study was sponsored by ViiV Healthcare. The Combinectin team would like to thank Bristol-Myers Squibb, former members of the team from Bristol-Myers Squibb, and current members from ViiV Healthcare and GlaxoSmithKline for their support of this program. Reference: 1. Lipovsek D. Adnectins: engineered target-binding protein therapeutics. Protein Eng Des Sel. 2011;24:3-9.

Conclusions GSK3732394 is a long-acting (projected: weekly SC dose) biologic molecule containing

3 individual inhibitors of HIV-1 entry The combination of inhibitors in a single molecule provides multiple advantages

Synergistic potency derived from localization of inhibitors at the cell surface Excellent potency at low receptor occupancy (CD4 binding; not shown) GSK3732394 exhibits good inhibitory activity against viruses resistant to a single component

GSK3732394 is extremely effective at lowering viral loads in a mouse model Selection of resistance to one of the components (α-N17 Adnectin) was observed over the

2-month dosing period Selection of resistance mutations could be due to a suboptimal level of receptor occupancy

This molecule has biophysical characteristics that are amenable to a self-administered subcutaneous weekly injection regimen

Table 2. Resistance Barrier: Fold Change vs Wild-Type Virus

Inhibitor α-CD4R α-N17R pepR α-N17R/pepR α-CD4R/α-N17R/pepR

α-CD4 Adn 6.8a 0.1 1.2 0.8 3.2α-N17 Adn 0.4 >660 1.8 >799.8 >660Peptide 0.4 1.4 7.0 83.1 39.9GSK3732394 1.1 1.9 2.1 89.1 98.0R, resistant virus. aFold change vs WT virus.

Figure 1. Design of Combinectin GSK3732394

Virus-CellFusionFusion

CD4Binding

CellMembrane

CoreceptorBinding

CCR5/CXCR4

Binding

CD4

HSA α-CD4α-gp41

α-gp41NH2

COOH

CCR5, C-C chemokine receptor 5; CXCR4, C-X-C chemokine receptor 4; HSA, human serum albumin.

Table 1. Potency of Individual and Fused Components

Protein Description EC50 (nM)α-CD4–α-N17 tandem 0.02 ± 0.01

Peptide 0.40 ± 0.27Combinectin minus HSA 0.09 ± 0.01

Full-length CombinectinGSK3732394

0.27 ± 0.17

EC50, half-maximal effective concentration; HSA, human serum albumin.

Figure 2. Spectrum of GSK3732394 Against Clinical Envelopes

B C A F

Others0

15

30

Fold

Cha

nge

B C A F Others

0

20

40

60

80

100

9 18 27 36 45 54 63

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, %

Days after treatment initiation

Figure 3. Receptor Occupancy of GSK3732394 on CD4 In Vivo

32 mg/kg

12.5 mg/kg

4 mg/kg

Figure 4. Efficacy of GSK3732394 Over 63 Days in an In Vivo Mouse Model of Infection

*Number undetectablemice/total mice alive in cohort

Subtype

B (64)C (26)A (9)F (8)D (4)G (1)CRF01_AE (3)CRF02_AG (5)CRF08_BC (1)CRF12_BF (3)

Fold

cha

nge

2.0

1.0

0

-1.0

-2.0

-3.0

-4.0

-5.0

Cha

nge

in m

edia

n H

IV-1

RN

A,lo

g 10

c/m

L

0 9 18 27

Days after treatment initiation

45 54 6336

The Integrase Strand Transfer Inhibitor Bictegravir has a Long Integrase/DNA Dissociation Half-life

K White, A Niedziela-Majka, N Novikov, M Miller, and M Tsiang

Gilead Sciences Inc, Foster City, CA

•Bictegravir is a potent INSTI with a high barrier to resistance and improved potency against HIV-1 with INSTI resistance mutations

•Bictegravir has the longest reported dissociation half-life from wild-type HIV-1 IN/DNA complexes compared to DTG, RAL, and EVG

• Long residence times of INSTIs on the integrase/DNA complex have been correlated with potent antiretroviral activity against wild-type HIV-1 integrase and a high barrier to resistance in vitro5

•Phase 3 clinical studies of the single tablet regimen of BIC/FTC/TAF are ongoing and will examine the relationship of high resistance barrier associated with long dissociation half-life in vitro with clinical outcomes

� Bictegravir (BIC; GS-9883) is a novel potent once-daily unboosted INSTI currently in clinical development in combination with tenofovir alafenamide (TAF) and emtricitabine (FTC) as a single-tablet regimen for the treatment of HIV-1 infection1,2,3

� Bictegravir has an improved resistance profile compared to elvitegravir (EVG), raltegravir (RAL), and dolutegravir (DTG) in patient isolates, particularly for isolates with high-level INSTI resistance containing combinations of mutations such as E92Q+N155H or G140C/S+Q148R/H/K4

� In biochemical studies, the apparent dissociation rate constant of DTG from integrase/DNA complexes was shown to be longer than RAL or EVG and was predicted to correlate with potent antiretroviral activity and a higher genetic barrier to resistance5

� In this study, we report the dissociation kinetics of bictegravir and other INSTIs from wild-type HIV-1 integrase/DNA complexes in vitro

� SPA Assay: The apparent association and dissociation kinetics of 3H-labelled bictegravir, dolutegravir, elvitegravir, and raltegravir were measured using wild-type HIV-1 integrase/DNA complexes and a scintillation proximity assay as previously described (Figure 1)5

� Equilibrium Binding Model Analysis: We observed that the competition binding phase deviates significantly from the single exponential decay because the SPA beads gradually sediment over time (Figure 2). For this reason, the on- and off-rate constants appear to change over time. The equilibrium binding model incorporates a correction for this gradual sedimentation by replacing kon and koff with decreasing hyperbolic functions of time (zon and zoff) where tc is the time of cold competitor addition and r and n are correction factors.

Figure 1. SPA-Based INSTI Binding Assay

Figure 4. Time Course of the Binding and Competition Binding (Association and Dissociation) of INSTIs from WT HIV-1 Integrase/DNA Complexes and Exponential Decay Fit

Figure 5. Time Course of the Binding and Competition Binding (Association and Dissociation) of INSTIs from WT HIV-1 Integrase/DNA Complexes and Equilibrium Binding Model Fit

Table 1. Apparent Association/Binding Half-life of INSTIs from WT HIV-1 Integrase/DNA Complexes

© 2016 Gilead Sciences, Inc. All rights reserved.HIV Glasgow, 23-26 October 2016, Glasgow, UK

Gilead Sciences, Inc.333 Lakeside Drive

Foster City, CA 94404 Tel: (650) 574-3000

Fax: (650) 578-9264

Introduction

Methods

Methods (cont’d)

Conclusions

References

INSTIApparent Association of INSTI from IN/DNA Complexes

Association t1/2 (min)* p-value vs BICBIC 35 ± 5 –

DTG 36 ± 4 0.648

RAL 24 ± 8 0.020

EVG 15 ± 6 0.00003

*Average ± standard deviation from 5 to 7 experiments; values have been updated since the abstract was submitted.

Figure 2. Gradual Sedimentation of the SPA Beads Leads to Rate Constants of Association and Dissociation that Appear Decreased Over Time

Figure 3. Structure of Bictegravir (BIC) and other INSTIs

Single Exponential Decay Fit (red lines) of the Competition Binding Phase Deviates from the Experimental Data (black plot)

1. Lazerwith et al., “Discovery of Bictegravir (GS-9883), a Novel, Unboosted, Once-Daily HIV-1 Integrase Strand Transfer Inhibitor (INSTI) with Improved Pharmacokinetics and In Vitro Resistance Profile.” ASM Microbe, June 19, 2016, Boston, MA, Poster #414.

2. Tsiang et al., “Antiviral Activity of Bictegravir (GS-9883), a Potent Next Generation HIV-1 Integrase Strand Transfer Inhibitor.” ASM Microbe, June 19, 2016, Boston, MA, Poster #416.

3. Gallant et al., “Novel Integrase Strand Transfer Inhibitor Bictegravir 10 Day Monotherapy in HIV-1-Infected Patients.” ASM Microbe, June 19, 2016, Boston, MA, Poster #415.

4. Jones et al., “Bictegravir (GS-9883), a Novel HIV-1 Integrase Strand Transfer Inhibitor (INSTI) with Optimized In Vitro Resistance profile.” ASM Microbe, June 19, 2016, Boston, MA, Poster #413.

5. Hightower et al., “Dolutegravir (S/GSK1349572) Exhibits Significantly Slower Dissociation then Raltegravir and Elvitegravir from Wild-Type and Integrase Inhibitor-Resistance HIV-1 Integrase-DNA Complexes.” Antimicrobial Agents and Chemotherapy. (2011) 55(10):4552-4559.

kon determined from direct binding of 3H-INSTIkoff determined from competition binding of 3H-INSTI with cold/non-radioactive compound

� Exponential Decay Analysis: The apparent association t1/2 was determined by curve fitting the binding phase using equation (1): y = M(1 – e-kt) (1) where M is the plateau and t1/2 = (ln 2)/ k

� The apparent dissociation t1/2 was determined by curve fitting the competition binding phase using equation (2): y = M(e-kt) (2) where M is the starting value and t1/2 = (ln 2)/ k

� The kon and koff values of the compounds were determined by curve fitting an equilibrium binding model (scheme A) simultaneously to both the binding and competition binding phases. The actual dissociation t1/2 was calculated as (ln 2)/koff

where E = integrase/donor DNA complex, L = 3H-INSTI, C = cold (non-radioactive) INSTI, EL = 3H- intermediate complex, ELf = 3H final complex, EC = cold intermediate complex, ECf = cold final complex, kon and koff = on- and off-rate constants for L and C , k2 & k-2 = kforward and kreverse for EL and EC, i = rate of addition of C and Q = dosing function for C, (0 or 1)

(scheme A)

Results

Table 2. Apparent Dissociation Half-life of INSTIs from WT HIV-1 Integrase/DNA Complexes

INSTI

Apparent Dissociation of INSTI from IN/DNA Complexes*

By Exponential Decay By Equilibrium Binding Model

t1/2 (hr) [**] p-value vs BIC t1/2 (hr) p-value vs BICBIC 135 ± 20 [na] – 38 ± 19 –

DTG 79 ± 13 [71] < 0.0001 16 ± 9 0.017

RAL 14 ± 3 [8.8] < 0.0001 5.2 ± 0.6 0.003

EVG 3.6 ± 0.7 [2.7] < 0.0001 1.5 ± 0.2 0.0006*Average ± standard deviation from 5 to 7 experiments; values have been updated since the abstract was submitted.**Published t1/2 values from Hightower et al., Antimicrobial Agents and Chemotherapy. (2011) 55(10):4552-4559.

Results (cont’d)

Equilibrium Binding Model Fit of the Competition Binding Phase (smooth lines stating at 800 min) are Consistent with the Experimental Data

� This deviation correction, enabled the determination of an initial half-life (i.e. actual dissociation t1/2 = (ln2)/ koff ) and a terminal half-life (i.e. a prolonged t1/2 = r(ln2)/ koff ) due to the gradual sedimentation of the SPA beads)

Poster Number P025

Passcode: P025

3’ 3’

Bound RadiolabeledINSTI

Integrase Dimer

3’-processed donor DNA

SPA Bead Surface Light

particles

IN/DNA Assembly

Biotin/Streptavidin interaction

P026.indd 1 16/11/2016 13:34

www.postersession.com

HIV Support Group Within a Multidisciplinary Healthcare Delivery Model as a Treatment Strategy for People Who Inject

Drugs

Rajvir Shahi1, Ghazaleh Kiani1, Arshia Alimohammadi1, Tyler Raycraft1,2, Syune Hakobyan, Brian Conway11

1. Vancouver Infectious Diseases Centre, Vancouver, BC, Canada2. University of British Columbia, Faculty of Medicine

Brian Conway, MD, FRCPC Vancouver Infectious Diseases Centre 201-1200 Burrard StreetVancouver, BC V6Z 2C7 Canada Tel: (604) 642-6429 Fax: (604) 642-6419 Email: brian.conway@vidc.ca

Background TABLE 1: CHARACTERISTICS OF HIV INFECTED PATIENTS ATTENDING THE EDUCATIONAL SUPPORT GROUP (N=74)

Methods

Among the 18,000 residents living on the Downtown EastSide (DTES) of Vancouver, over 20% are infected with HIV.An innovative approach is needed to engage theseindividuals in care to fulfill the goals of the "90-90-90"program endorsed by the World Health Organization toaddress the global HIV pandemic.

.

In 2013, structured HIV support groups were designed as an innovative strategy to engage this vulnerable population in a multidisciplinary program of care. The group is held once a week for four hours, led by medical doctors, nurses and other community-based workers. Individuals attending the group are given a presentation on a topic related to HIV/AIDS, such as HIV transmission, therapy or substance abuse. They are also able to ask medical questions and voice their health-related concerns in an open and safe environment. Two meals are provided as well as services to address medical, psychological, social and addiction-related needs. A retrospective analysis to assess characteristics of individuals attending the group regularly (at least once per month) was performed, and commitment to HIV treatment was evaluated.

ResultsA total of 74 HIV-infected patients (mean age 52 years, 12% females, 14% First Nations) regularly attended the group. Among these HIV-positive individuals attending the group, 55 (74.3%) were people who actively inject drugs (PWID), 36 (48.6%) self-identified as being homeless, and 25 (33.8%) had an underlying psychiatric disease. The majority (73/74, 98.6 %) were receiving antiretroviral therapy and 58/73 (79.4%) of these individuals had a suppressed HIV plasma viral load (<40 copies/mL). The remaining 15/73 (20.5%) are on treatment, but have not yet suppressed.

Conflict of InterestAdvisory committees of Review Panel: Vertex Pharmaceauticals, Merck, Boehringer Ingelheim,Jannsesn Pharmaceauticals; Grant/Research Support: Vertex Pharmaceauticals,Abbvie,Gilead Scienes

ConclusionThis HIV support group model has shown to be effective at engaging and retaining HIV-infected patients in care, with the vast majority having a maximal response to antiretroviral therapy. These individuals were previously undiagnosed or not receiving care. Approaches such as the one we have developed will be essential to reaching the goal of "90-90-90" especially in more vulnerable populations.

Characteristic QuantityMean Age 52Female 9 (12%)First Nations 10 (14%)PWID 55 (74.3%)Homeless/Unstable Housing 36 (48.6%)

Psychiatric Condition 25 (33.8%)Receiving ARV 73 (98.6%)Suppressed HIV Viral Load 58 (79.4%)Active HCV-Infection 29 (39.2%)

FIGURE 2: GENOTYPE DISTRIBUTION OF HIV INFECTED INDIVIDUALS WITH ACTIVE HCV INFECTION (N=29)

62

21

17

GT 1aGT 3aOther

www.up.ac.za

Inhibition of HIV-1 Protease and Plasmodium falciparum by a modified digold chloroquine derivative

N.Gama a, Kamlesh Kumar b,c, Erik Ekengard b, Matti Hukka d, J. Reader a, B Gordhan e, L. Birkholtz a, B Kana e, Ebbe Nordlander c, J. Darkwa b, D.Meyer f

Introduction

Objectives1. Investigate the HIV-1 protease inhibition abilities of 1.2. Determine the effects of the complex on associated

infections: M.tuberculosis and P.falciparum.3. Determine effects on cell viability using viability dyes and

real-time cell electronic sensing (RTCES).

Methods

ResultsComplex 1 showed HIV-1 protease inhibition values of above 50% at25µg/mL (Figure 1). Higher concentrations of the complex behavedsimilarly to the control, acetyl-pepstatin.

Figure 1. The inhibition of HIV-1 protease by complex 1. The complex showed an IC50 value of 26,69 μg/mL, and kinetic studies suggest that the complex is a mixed inhibitor. Conclusion

A complex with inhibitory abilities against HIV-1 replication, M.tuberculosis and P. falciparum is presented here. Tuberculosis andMalaria play a major role in the mortality of HIV-1 infected patients inAfrica, and the development of drugs with dual activities that cancontrol both the viral and opportunistic infections could contribute tothe alleviation of the fatal prognosis associated with HIV in the Sub-Saharan region.

References1. World Health Organisation (WHO); 2014, World Health Statistics Report, Geneva, Switzerland. 2. Canaday, D. H. et al. Induction of HIV type 1 expression correlates with T cell responsiveness to mycobacteria in patients coinfectedwith HIV type 1 and Mycobacterium tuberculosis. AIDS Res. Hum. Retroviruses 25, (2009).3. H. N. Luma, H.N. et al. Adverse drug reactions of Highly Active Antiretroviral Therapy (HAART) in HIV infected patients at the GeneralHospital , Douala , Cameroon : a cross sectional study. Pan Afr. Med. J. 12, 2012.4.Oprea, T. I. & Mestres, J. Drug repurposing: far beyond new targets for old drugs. AAPS J. 14, 759–63 (2012).5.Gama, N. et al. Gold(I) complex of 1,1′-bis(diphenylphosphino) ferrocene–quinoline conjugate: a virostatic agent against HIV-1. BioMetals 29, 389–397 (2016).6. Pavan, F. R. et al. Understanding Tuberculosis– New Approaches to Fighting Against Drug Resistance (ed. Cardona, P.) 137–146 (InTech, 2012).

Table 1. Minimal inhibitory concentrations of the complex at 7 and 14 days post incubationwith M. tuberculosis.

Figure 2. : RTCES analysis of compound 3 on TZM-bl cells. All tested concentrationsresulted in profiles similar to cells indicating non-toxicity 5.

Complex 1 exhibited MIC values ≤ 10 μg/mL in M.tuberculosis (Table 1),warranting further investigation as an anti-TB drug as stated in therecommendations by Pavan et al. (2012). The complex was also activeagainst P. falciparum, with an IC50 of 0.593 μM.

aDepartment of Biochemistry, University of Pretoria, Hatfield Campus, Pretoria 0002, South AfricabChemistry Department, University of Johannesburg, Kingsway Campus, Johannesburg, Auckland Park 2006, South AfricacInorganic Chemistry Research Group, Chemical Physics, Center for Chemistry and Chemical Engineering, Lund University, Box 124, SE-22100 Lund, Sweden.dDepartment of Chemistry, University of Jyväskylä, FI-40014, FinlandeDST/NRF Centre of Excellence for Biomedical TB Research (CBTBR), National Health Laboratory Service (NHLS), University of the Witwatersrand, Johannesburg 2000, South Africaf Dean’s Office, Faculty of Science, University of Johannesburg, Kingsway Campus, Johannesburg, Auckland Park 2006, South Africa

The Human Immunodeficiency Virus-1 (HIV-1) remains a major threat to public health 1. Sub-Saharan Africa has the highest prevalence ofHIV/AIDS and the overlap of this infection with other major pandemics that plague the region has become a major challenge in thetreatment of the infection. These include tuberculosis and malaria 2. Although Highly Active Antiretroviral Therapy (HAART) have beensuccessful in the treatment of the virus, these drugs are associated with a number of adverse effects often resulting in non-compliance bythe patients and increasing an individual’s susceptibility to opportunistic infections that are prevalent in the region 3. It is, therefore, crucialto develop novel treatments that are not only effective against HIV, but also against opportunistic infections. Indeed, multi-target drugs arebecoming increasingly popular with the rise in syndemic diseases in most parts of the world. Finding novel drugs that are effective againsttwo or more different infections or diseases, targeting various pathways within the microorganism /pathology is where research is movingtowards, and in this study metal modified chloroquine (Complex 1) was investigated in a type of repurposing approach for this well-knownmalaria drug 4.

Complex 1

HIV-1 Protease fluorescence

assay

MIC on M.tuberculosis

H37Rv

IC50 on P.falciparum

3D7TZM-bl viability

MTT tetrazolium dye

xCelligenceRTCES

20 40 60 80 100-0.5

0.0

0.5

1.0

1.5

2.0Cells20 g/ml10 g/ml5 g/ml2 g/ml

Time(Hour)Nor

mal

ized

Cel

l Ind

ex

6.125

12.25

0

24.50

0

46.00

0

98.00

0

196.0

006.1

250

50

100

150

200Complex 1Acetyl-pepstatin

[g/ml]

Perc

enta

ge P

rote

ase

Inhi

bitio

n

MIC at 7 days (μg/mL)

MIC at 14 days (μg/mL)

Complex 1 10 5

The CC50 of the complex on TZM-bl cells, as determined by the MTTassay, was 24.34 ± 0.68 μg/mL. This was confirmed by RTCES, withconcentrations below 20 μg/mL resulting in profiles similar to untreatedcells, indicating non-toxicity 5.

TTREATMENTREATMENT FAILUREFAILURE OFOF CHRONICCHRONIC HCV HCV INFECTIONINFECTION WITHWITH THETHE NEWNEW DIRECTDIRECT-DIRECT-ACTINGANTIVIRALS

FAILUREFAILURE OFOFOFANTIVIRALSANTIVIRALSANTIVIRALS: : : : : EXPERIENCEEXPERIENCEEXPERIENCEEXPERIENCE OFOFOF A

INFECTIONINFECTIONAAA PPPPPPPPORTUGUESEORTUGUESEORTUGUESE CENTRALCENTRALCENTRAL HOSPITAL

Karen Pereira, Sara Dias Grazina, Ana Cláudia Miranda, Teresa Baptista, Fernando Borges, Jaime Nina, Susana Peres, Isabel Aldir, Maria JoséCampos*, Isabel Antunes, João Pereira**, Fernando Ventura, Kamal Mansinho.

Serviço de Doenças Infecciosas e Medicina Tropical, Hospital de Egas Moniz, Centro Hospitalar de Lisboa Ocidental, E.P.E. Lisbon - Portugal*Serviço de Urgência Geral, Hospital de Egas Moniz, Centro Hospitalar de Lisboa Ocidental, E.P.E. Lisbon - Portugal

** Serviço de Medicina Interna, Hospital de Egas Moniz, Centro Hospitalar de Lisboa Ocidental, E.P.E. Lisbon - Portugal

P029

BACKGROUNDSince the emergence of new direct-acting agents, Hepatitis C treatment has undergone a rapid evolution, bringing about a radical change in the clinicalparadigm. Oral treatment regimens with high virologic efficacy, great tolerability, favorable safety profiles, high genetic barriers and an easy posology are nowavailable. Despite this, challenges remain to patients who fail the treatment. This study aims to characterize this group of patients in an infectious diseasesclinic in Lisbon.

PATIENTS AND METHODSRetrospective observational study of a cohort of HCV chronically infected patients with or without HIV infection, given new direct-acting agents, from01/01/2015 to 30/04/2016. Demographic, epidemiological, clinical and laboratory data were collected. Statistical analysis was performed using Microsoft Oficce® - Excel 2012.

RESULTS_ 426 patients were eligible to start HCV treatment with DAA regimens; 138 HCV monoinfected vs 288 HCV/HIV coinfected.

CONCLUSIONSIn this preliminary analysis, the 8 patients with non SVR 12, were male and 7 had HIV infection. These factors may be associated withresponse and outcome with the new direct-acting agents. Regarding the efficacy of these drugs, uncertainties and challenges remain, inaddition to continued necessity of identifying response predictive factors and individual strategies for special patient groups.

Contact: medina.karen10@gmail.com

327 STARTED THE TREATMENT (77%)

HCV vs HCV/HIV n= 97 n= 230

VIRAL LOAD 12 WEEKS AFTERTREATMENT ENDED (n=

WEEKS AFTER(n=134; 61%)

n=n=126 (((9494%) n=

219 CONCLUDED (51%)

HCV vs HCV/HIV n= 56 n= 163

SVR12 Detectable

MONOINFECTEDn= 1

COINFECTEDn=7

All portuguese males MeanAge (years) 57 49,8Time of diagnosis (years) 6 12HCV RNA at baseline (IU/mL) 425 677 8 057 446TCD4+ lymphocyte at baseline (cells/μL) - 627

Transmission Route IV drug users 1 5Unknow - 2

Previously treatedN = 6

Null responders 1 4Relapser 1

8 ((6%)

GENOTYPE CHARACTERIZATION IL28B POLYMORPHISM

FIBROSIS STAGINGby elastography (METAVIR score)

4

1

2

1

1a 1b 3a 4acd

Coinfected

Monoinfected

n pa

tient

s

4

2

11

CC CT TT

Coinfected

Monoinfected

1

2

4

1

F2 F2/F3 F3

Coinfected

Monoinfected

n pa

tient

s

n pa

tient

s

TREATMENT REGIMENS TREATMENT DURATION

FOLLOWW-W-UP

5

21

Coinfected

Monoinfected

5

2

1

Coinfected

Monoinfected

n pa

tient

s

- One patient died at the end of treatment, with hepatocellular carcinoma.

- The others are waiting for retreatment options.

n pa

tient

s