%PDF-1.6
%
1 0 obj
<>
endobj
2 0 obj
<>stream
Loreta A. Kondili, Giovanni Battista Gaeta, Donatella Ieluzzi, Anna Linda Zignego, Monica Monti, Andrea Gori, Alessandro Soria, Giovanni Raimondo, Roberto Filomia, Alfredo Di Leo, Andrea Iannone, Marco Massari, Romina Corsini, Roberto Gulminetti, Alberto Gatti Comini, Pierluigi Toniutto, Denis Dissegna, Francesco Paolo Russo, Alberto Zanetto, Maria Grazia Rumi, Giuseppina Brancaccio, Elena Danieli, Maurizia Rossana Brunetto, Liliana Elena Weimer, Maria Giovanna Quaranta, Stefano Vella, Massimo Puoti
Real-life data on potential drug-drug interactions in patients with chronic hepatitis C viral infection undergoing antiviral therapy with interferon-free DAAs in the PITER Cohort Study
www.plosone.org
www.plosone.org
endstream
endobj
3 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 12 0 R/Annots 13 0 R/Contents 14 0 R/TrimBox[0 0 612 792]>>
endobj
13 0 obj
[15 0 R 16 0 R 17 0 R 18 0 R 19 0 R 20 0 R 21 0 R]
endobj
15 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172159.ref001)>>
endobj
16 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172159.ref003)>>
endobj
17 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172159.ref004)>>
endobj
18 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172159.ref005)>>
endobj
19 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172159.ref006)>>
endobj
20 0 obj
<>/Border[0 0 0]/Dest(Rpone.0172159.ref007)>>
endobj
21 0 obj
<>/Border[0 0 0]/A 22 0 R>>
endobj
22 0 obj
<>
endobj
14 0 obj
[23 0 R 24 0 R 25 0 R 26 0 R 27 0 R 28 0 R 29 0 R 30 0 R 31 0 R 32 0 R]
endobj
23 0 obj
<>stream
q
0.45 0.36 0.35 0.01 k
0 w
575.9997 435.9396 m
199.9998 435.9396 l
199.9998 436.4396 l
575.9997 436.4396 l
f*
0.83 0.64 0.02 0 k
557.4047 364.8756 m
562.1669 364.8756 l
h
f*
200.0126 351.8929 m
204.7748 351.8929 l
h
f*
429.1654 299.9055 m
433.9276 299.9055 l
h
f*
436.1386 299.9055 m
440.9008 299.9055 l
h
f*
203.4142 182.8913 m
208.1764 182.8913 l
h
f*
557.5181 156.8693 m
562.2803 156.8693 l
h
f*
0 g
1 j
1 J
11.4998 0 0 11.4998 200.0125 706.3937 cm
BT
/F2 1 Tf
1 TL
-0.0035 Tc
0 0 Td
(Results)Tj
ET
Q
q
1 j
1 J
0 w
9.5 0 0 9.5 200.0125 689.3858 cm
BT
/F0 1 Tf
1 TL
-0.0042 Tc
0 0 Td
(Of)Tj
1.277 0 Td
(the)Tj
1.5934 0 Td
(449)Tj
1.8679 0 Td
(patients)Tj
3.676 0 Td
(evaluated,)Tj
4.7801 0 Td
(86)Tj
1.3189 0 Td
(had)Tj
1.8679 0 Td
(mild)Tj
2.029 0 Td
(liver)Tj
2.023 0 Td
(disease)Tj
3.6224 0 Td
(and)Tj
1.8678 0 Td
(363)Tj
1.862 0 Td
(had)Tj
1.8678 0 Td
(moderate-to-se)Tj
6.7136 0 Td
(vere)Tj
-36.3668 -1.474 Td
(disease.)Tj
3.8968 0 Td
(The)Tj
1.9335 0 Td
(use)Tj
1.8142 0 Td
(of)Tj
1.0444 0 Td
(a)Tj
0.7698 0 Td
(single)Tj
2.7928 0 Td
(comedication)Tj
6.0393 0 Td
(was)Tj
1.9813 0 Td
(more)Tj
2.4766 0 Td
(frequent)Tj
3.8491 0 Td
(among)Tj
3.2464 0 Td
(patients)Tj
3.682 0 Td
(with)Tj
1.9753 0 Td
(mild)Tj
2.029 0 Td
(liver)Tj
-37.5305 -1.468 Td
(disease)Tj
3.6223 0 Td
(\(p)Tj
1.0981 0 Td
(=)Tj
0.7996 0 Td
(0.03\),)Tj
2.7511 0 Td
(whereas)Tj
3.9566 0 Td
(utilization)Tj
4.3265 0 Td
(of)Tj
1.0444 0 Td
(more)Tj
2.4765 0 Td
(than)Tj
2.1484 0 Td
(three)Tj
2.4706 0 Td
(drugs)Tj
2.6914 0 Td
(among)Tj
3.2464 0 Td
(those)Tj
2.6377 0 Td
(with)Tj
1.9813 0 Td
(moder-)Tj
-35.2509 -1.474 Td
(ate-to-severe)Tj
6.0452 0 Td
(disease)Tj
3.6283 0 Td
(\(p)Tj
1.0981 0 Td
(=)Tj
0.7996 0 Td
(0.05\).)Tj
2.7511 0 Td
(Of)Tj
1.2711 0 Td
(the)Tj
1.5994 0 Td
(142)Tj
1.8619 0 Td
(comedications)Tj
6.5405 0 Td
(used)Tj
2.3632 0 Td
(in)Tj
0.9847 0 Td
(86)Tj
1.3188 0 Td
(patients)Tj
3.6821 0 Td
(with)Tj
1.9753 0 Td
(mild)Tj
2.029 0 Td
(dis-)Tj
-37.9483 -1.474 Td
(ease,)Tj
2.6377 0 Td
(27)Tj
1.3188 0 Td
(\(20%\))Tj
2.8585 0 Td
(may)Tj
2.0947 0 Td
(require)Tj
3.2881 0 Td
(dose)Tj
2.3632 0 Td
(adjustment/closer)Tj
7.9728 0 Td
(monitoring,)Tj
5.1083 0 Td
(none)Tj
2.4169 0 Td
(was)Tj
1.9813 0 Td
(contraindicated.)Tj
-32.0403 -1.474 Td
(Of)Tj
1.277 0 Td
(the)Tj
1.5934 0 Td
(322)Tj
1.8679 0 Td
(comedications)Tj
6.5346 0 Td
(used)Tj
2.3631 0 Td
(in)Tj
0.9847 0 Td
(363)Tj
1.8679 0 Td
(patients)Tj
3.682 0 Td
(with)Tj
1.9753 0 Td
(moderate-to-se)Tj
6.7136 0 Td
(vere)Tj
2.1424 0 Td
(liver)Tj
2.0231 0 Td
(disease,)Tj
3.9028 0 Td
(82)Tj
-36.9278 -1.474 Td
(\(25%\))Tj
2.8585 0 Td
(were)Tj
2.3631 0 Td
(classified)Tj
4.2789 0 Td
(with)Tj
1.9753 0 Td
(potential)Tj
3.9505 0 Td
(DDIs)Tj
2.4229 0 Td
(that)Tj
1.8739 0 Td
(required)Tj
3.8372 0 Td
(only)Tj
2.029 0 Td
(monitoring)Tj
4.8278 0 Td
(and)Tj
1.8679 0 Td
(dose)Tj
2.3632 0 Td
(adjust-)Tj
-34.6482 -1.4741 Td
(ments;)Tj
3.1986 0 Td
(10)Tj
1.3189 0 Td
(\(3%\))Tj
2.3094 0 Td
(were)Tj
2.3632 0 Td
(contraindicated)Tj
6.9166 0 Td
(in)Tj
0.9846 0 Td
(severe)Tj
3.1867 0 Td
(liver)Tj
2.0231 0 Td
(disease.)Tj
3.9028 0 Td
(In)Tj
1.0444 0 Td
(patients)Tj
3.682 0 Td
(with)Tj
1.9753 0 Td
(mild)Tj
2.029 0 Td
(liver)Tj
2.029 0 Td
(dis-)Tj
-36.9636 -1.474 Td
(ease)Tj
2.3631 0 Td
(30%)Tj
2.1961 0 Td
(\(26/86\))Tj
3.3539 0 Td
(used)Tj
2.3632 0 Td
(at)Tj
1.0443 0 Td
(least)Tj
2.3095 0 Td
(one)Tj
1.8619 0 Td
(drug)Tj
2.1961 0 Td
(with)Tj
1.9812 0 Td
(a)Tj
0.7639 0 Td
(potential)Tj
3.9506 0 Td
(DDI)Tj
1.9275 0 Td
(whereas)Tj
3.9566 0 Td
(of)Tj
1.0503 0 Td
(the)Tj
1.5934 0 Td
(363)Tj
1.8678 0 Td
(patients)Tj
-34.7794 -1.474 Td
(with)Tj
1.9752 0 Td
(moderate-to-se)Tj
6.7137 0 Td
(vere)Tj
2.1423 0 Td
(liver)Tj
2.0231 0 Td
(disease,)Tj
3.9028 0 Td
(161)Tj
1.8619 0 Td
(\(44%\))Tj
2.8645 0 Td
(were)Tj
2.3632 0 Td
(at)Tj
1.0443 0 Td
(risk)Tj
1.7545 0 Td
(for)Tj
1.3786 0 Td
(one)Tj
1.8678 0 Td
(or)Tj
1.0981 0 Td
(more)Tj
2.4766 0 Td
(DDI.)Tj
ET
Q
q
1 j
1 J
0 w
11.4998 0 0 11.4998 200.0125 536.4283 cm
BT
/F2 1 Tf
1 TL
-0.0035 Tc
0 0 Td
(Conclusions)Tj
ET
Q
q
1 j
1 J
0 w
9.5 0 0 9.5 200.0125 519.4204 cm
BT
/F0 1 Tf
1 TL
-0.0042 Tc
0 0 Td
(Based)Tj
3.0256 0 Td
(on)Tj
1.3188 0 Td
(these)Tj
2.6377 0 Td
(results,)Tj
3.4075 0 Td
(we)Tj
1.486 0 Td
(can)Tj
1.8142 0 Td
(estimate)Tj
3.9625 0 Td
(that)Tj
1.8738 0 Td
(3044%)Tj
3.8492 0 Td
(of)Tj
1.0443 0 Td
(patients)Tj
3.682 0 Td
(undergoing)Tj
5.1501 0 Td
(DAA)Tj
2.2677 0 Td
(and)Tj
1.8619 0 Td
(tak-)Tj
-37.3813 -1.474 Td
(ing)Tj
1.5336 0 Td
(comedications)Tj
6.5346 0 Td
(are)Tj
1.6471 0 Td
(at)Tj
1.0503 0 Td
(risk)Tj
1.7545 0 Td
(of)Tj
1.0503 0 Td
(a)Tj
0.7639 0 Td
(clinically)Tj
3.8849 0 Td
(significant)Tj
4.607 0 Td
(DDI.)Tj
2.2081 0 Td
(This)Tj
2.0886 0 Td
(data)Tj
2.1424 0 Td
(indicates)Tj
4.1177 0 Td
(the)Tj
1.5934 0 Td
(need)Tj
2.4169 0 Td
(for)Tj
-37.3933 -1.474 Td
(increased)Tj
4.4996 0 Td
(awareness)Tj
5.0009 0 Td
(of)Tj
1.0503 0 Td
(potential)Tj
3.9446 0 Td
(DDI)Tj
1.9275 0 Td
(during)Tj
2.96 0 Td
(DAA)Tj
2.2617 0 Td
(therapy,)Tj
3.8014 0 Td
(especially)Tj
4.5474 0 Td
(in)Tj
0.9846 0 Td
(patients)Tj
3.6821 0 Td
(with)Tj
1.9753 0 Td
(mod-)Tj
-36.6354 -1.468 Td
(erate-to-severe)Tj
6.9284 0 Td
(liver)Tj
2.023 0 Td
(disease.)Tj
3.8969 0 Td
(For)Tj
1.7127 0 Td
(several)Tj
3.4016 0 Td
(drugs,)Tj
2.9719 0 Td
(the)Tj
1.5933 0 Td
(recommenda)Tj
5.7827 0 Td
(tion)Tj
1.8082 0 Td
(related)Tj
3.2345 0 Td
(to)Tj
1.0503 0 Td
(the)Tj
1.5933 0 Td
(DDI)Tj
-35.9968 -1.474 Td
(changes)Tj
3.9565 0 Td
(from)Tj
2.208 0 Td
(dose)Tj
2.6915 0 Td
(adjustment/closer)Tj
7.9727 0 Td
(monitoring,)Tj
5.4366 0 Td
(in)Tj
0.9846 0 Td
(mild)Tj
2.029 0 Td
(to)Tj
1.0444 0 Td
(moderate)Tj
4.4041 0 Td
(liver)Tj
2.023 0 Td
(disease,)Tj
3.8969 0 Td
(to)Tj
1.0503 0 Td
(the)Tj
-37.6976 -1.474 Td
(use)Tj
1.8141 0 Td
(is)Tj
0.931 0 Td
(contraindicated)Tj
7.2447 0 Td
(in)Tj
0.9847 0 Td
(severe)Tj
3.1867 0 Td
(liver)Tj
2.029 0 Td
(disease.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 395.9433 cm
BT
/F2 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Introduction)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 378.9921 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(The)Tj
1.7801 0 Td
(new)Tj
1.8765 0 Td
(generation)Tj
4.5071 0 Td
(of)Tj
1.0148 0 Td
(oral)Tj
1.7801 0 Td
(direct-acting)Tj
5.3178 0 Td
(antivirals)Tj
3.9004 0 Td
(\(DAAs\))Tj
3.3676 0 Td
(has)Tj
1.542 0 Td
(transformed)Tj
5.1704 0 Td
(the)Tj
1.4683 0 Td
(treatment)Tj
4.1386 0 Td
(of)Tj
-35.8637 -1.3039 Td
(hepatitis)Tj
3.6113 0 Td
(C)Tj
0.8844 0 Td
(virus)Tj
2.2053 0 Td
(\(HCV\))Tj
3.0217 0 Td
(infection,)Tj
4.0195 0 Td
(demonstrating)Tj
6.0888 0 Td
(both)Tj
2.0579 0 Td
(high)Tj
2.007 0 Td
(efficacy)Tj
3.2258 0 Td
(and)Tj
1.7291 0 Td
(high)Tj
2.0069 0 Td
(tolerability)Tj
4.5411 0 Td
([)Tj
0.83 0.64 0.02 0 k
(1)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
-35.3988 -1.2982 Td
(3)Tj
0 g
(].)Tj
1.2585 0 Td
(However,)Tj
4.0762 0 Td
(none)Tj
2.2507 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(DAAs)Tj
2.6873 0 Td
(are)Tj
1.4456 0 Td
(completely)Tj
4.5808 0 Td
(free)Tj
1.7291 0 Td
(of)Tj
1.0148 0 Td
(drug-drug)Tj
4.354 0 Td
(interactions)Tj
4.9663 0 Td
(\(DDIs\),)Tj
3.2995 0 Td
(which)Tj
-34.1459 -1.2983 Td
(can)Tj
1.627 0 Td
(significantly)Tj
5.0853 0 Td
(alter)Tj
1.9956 0 Td
(the)Tj
1.4684 0 Td
(drugs')Tj
2.6872 0 Td
(exposure)Tj
3.8154 0 Td
(and)Tj
1.7348 0 Td
(thus)Tj
1.9332 0 Td
(their)Tj
2.109 0 Td
(efficacy)Tj
3.2201 0 Td
(and)Tj
1.7291 0 Td
(toxicity.)Tj
3.4299 0 Td
(Studies)Tj
3.1011 0 Td
(on)Tj
1.2756 0 Td
(inter-)Tj
-35.2117 -1.3039 Td
(actions)Tj
3.0557 0 Td
(between)Tj
3.5319 0 Td
(DAAs)Tj
2.6816 0 Td
(and)Tj
1.7348 0 Td
(some)Tj
2.33 0 Td
(key)Tj
1.5931 0 Td
(drugs)Tj
2.4718 0 Td
(have)Tj
2.0636 0 Td
(been)Tj
2.1203 0 Td
(performed)Tj
4.4674 0 Td
(in)Tj
1.0375 0 Td
(the)Tj
1.4683 0 Td
(development)Tj
5.4141 0 Td
(of)Tj
1.0148 0 Td
(all)Tj
-34.9849 -1.2983 Td
(DAAs.)Tj
2.9083 0 Td
(However,)Tj
4.0762 0 Td
(the)Tj
1.474 0 Td
(majority)Tj
3.6283 0 Td
(of)Tj
1.0148 0 Td
(clinical)Tj
3.0727 0 Td
(trial)Tj
1.8369 0 Td
(participants)Tj
4.9606 0 Td
(have)Tj
2.0579 0 Td
(been)Tj
2.126 0 Td
(healthy)Tj
3.1294 0 Td
(volunteers)Tj
4.3823 0 Td
(with)Tj
-34.6674 -1.2982 Td
(few)Tj
1.6157 0 Td
(comorbidities)Tj
5.7656 0 Td
(and)Tj
1.7291 0 Td
(limited)Tj
3.0728 0 Td
(concomitant)Tj
5.2951 0 Td
(medications)Tj
5.0966 0 Td
([)Tj
0.83 0.64 0.02 0 k
(4)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(5)Tj
0 g
(].)Tj
-21.3787 -1.304 Td
(Clinical)Tj
3.3165 0 Td
(implications)Tj
5.176 0 Td
(of)Tj
1.0148 0 Td
(established)Tj
4.5978 0 Td
(or)Tj
1.0998 0 Td
(potential)Tj
3.7587 0 Td
(DDIs)Tj
2.3981 0 Td
(between)Tj
3.5263 0 Td
(DAAs)Tj
2.6872 0 Td
(and)Tj
1.7291 0 Td
(comedications)Tj
-30.5005 -1.2982 Td
(vary,)Tj
2.1599 0 Td
(as)Tj
1.0148 0 Td
(do)Tj
1.2529 0 Td
(the)Tj
1.4684 0 Td
(effects)Tj
2.7269 0 Td
(of)Tj
1.0148 0 Td
(hepatic)Tj
3.1124 0 Td
(and)Tj
1.7291 0 Td
(renal)Tj
2.2451 0 Td
(impairment)Tj
4.9889 0 Td
(on)Tj
1.2699 0 Td
(DAAs)Tj
2.6872 0 Td
(and)Tj
1.7292 0 Td
(other)Tj
2.3527 0 Td
(drugs.)Tj
2.6929 0 Td
(Interactions)Tj
-32.4451 -1.2983 Td
(may)Tj
1.9275 0 Td
(lead)Tj
1.8482 0 Td
(to)Tj
1.0261 0 Td
(decreased)Tj
4.1386 0 Td
(concentrations)Tj
6.1795 0 Td
(resulting)Tj
3.7303 0 Td
(in)Tj
1.0318 0 Td
(decreased)Tj
4.1386 0 Td
(efficacy)Tj
3.2201 0 Td
(\(i.e)Tj
1.4797 0 Td
(lack)Tj
1.8198 0 Td
(of)Tj
1.0148 0 Td
(therapeutic)Tj
-31.555 -1.2983 Td
(effect\))Tj
2.7042 0 Td
(or)Tj
1.0998 0 Td
(increased)Tj
3.9968 0 Td
(peak)Tj
2.092 0 Td
(concentrations)Tj
6.1795 0 Td
(associated)Tj
4.2576 0 Td
(with)Tj
1.9956 0 Td
(increased)Tj
4.0025 0 Td
(drug)Tj
2.1089 0 Td
(toxicity.)Tj
-27.2407 -1.3039 Td
(In)Tj
1.1111 0 Td
(patients)Tj
3.3676 0 Td
(with)Tj
1.9956 0 Td
(severe)Tj
2.6815 0 Td
(liver)Tj
1.9786 0 Td
(disease,)Tj
3.2485 0 Td
(determining)Tj
5.176 0 Td
(the)Tj
1.474 0 Td
(effect)Tj
2.3641 0 Td
(of)Tj
1.0148 0 Td
(DDIs)Tj
2.3924 0 Td
(between)Tj
3.5263 0 Td
(DAAs)Tj
2.6872 0 Td
(and)Tj
-34.2139 -1.2982 Td
(comedications)Tj
6.0264 0 Td
(remains)Tj
3.4469 0 Td
(a)Tj
0.6519 0 Td
(challenge.)Tj
4.184 0 Td
(This)Tj
1.9842 0 Td
(challenge)Tj
3.9628 0 Td
(is)Tj
0.8447 0 Td
(further)Tj
3.0274 0 Td
(complicated)Tj
5.108 0 Td
(by)Tj
1.1849 0 Td
(ageing)Tj
2.8233 0 Td
(and)Tj
1.7291 0 Td
(addi-)Tj
-34.9736 -1.2983 Td
(tional)Tj
2.5171 0 Td
(comorbidities)Tj
5.7713 0 Td
(in)Tj
1.0318 0 Td
(chronic)Tj
3.2882 0 Td
(HCV)Tj
2.347 0 Td
(patients,)Tj
3.5944 0 Td
(often)Tj
2.2847 0 Td
(resulting)Tj
3.7303 0 Td
(in)Tj
1.0375 0 Td
(polypharmacy.)Tj
-24.4061 -1.3039 Td
(There)Tj
2.5795 0 Td
(is)Tj
0.8504 0 Td
(limited)Tj
3.067 0 Td
(data)Tj
1.9162 0 Td
(available)Tj
3.6624 0 Td
(that)Tj
1.7801 0 Td
(addresses)Tj
4.0139 0 Td
(DDIs)Tj
2.3924 0 Td
(in)Tj
1.0318 0 Td
(patients)Tj
3.3732 0 Td
(with)Tj
1.9956 0 Td
(chronic)Tj
3.2881 0 Td
(HCV)Tj
2.3471 0 Td
(infection)Tj
-33.4939 -1.2983 Td
([)Tj
0.83 0.64 0.02 0 k
(6)Tj
0 g
(].)Tj
1.5987 0 Td
(The)Tj
1.7858 0 Td
(objective)Tj
3.7814 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(present)Tj
3.1635 0 Td
(study)Tj
2.3867 0 Td
(was)Tj
1.7008 0 Td
(to)Tj
1.0261 0 Td
(assess)Tj
2.5229 0 Td
(the)Tj
1.4683 0 Td
(potential)Tj
3.7587 0 Td
(DDIs)Tj
2.3924 0 Td
(of)Tj
1.0148 0 Td
(DAAs)Tj
2.6873 0 Td
(with)Tj
1.9955 0 Td
(medica-)Tj
-33.766 -1.2982 Td
(tions)Tj
2.1996 0 Td
(used)Tj
2.0636 0 Td
(in)Tj
1.0318 0 Td
(outpatients)Tj
4.6998 0 Td
(that)Tj
1.7802 0 Td
(began)Tj
2.5965 0 Td
(anti-HCV)Tj
4.2463 0 Td
(Interferon)Tj
4.3426 0 Td
(\(IFN\)-free)Tj
4.3597 0 Td
(therapy)Tj
3.2485 0 Td
(as)Tj
1.0148 0 Td
(part)Tj
1.8368 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
-34.435 -1.304 Td
(PITER)Tj
2.9196 0 Td
(Cohort)Tj
3.0954 0 Td
(Study)Tj
2.5058 0 Td
(\(Piattaforma)Tj
5.2668 0 Td
(Italiana)Tj
3.2258 0 Td
(per)Tj
1.5307 0 Td
(lo)Tj
0.9751 0 Td
(studio)Tj
2.7042 0 Td
(della)Tj
2.0977 0 Td
(Terapia)Tj
3.2825 0 Td
(delle)Tj
2.0862 0 Td
(Epatiti)Tj
2.8687 0 Td
(viRali\))Tj
2.8516 0 Td
([)Tj
0.83 0.64 0.02 0 k
(7)Tj
0 g
(].)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 131.0173 cm
BT
/F2 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Patients)Tj
4.0724 0 Td
(and)Tj
1.9937 0 Td
(methods)Tj
/F0 1 Tf
-6.0661 -1.5023 Td
(Patients)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 95.9811 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(For)Tj
1.627 0 Td
(the)Tj
1.4684 0 Td
(present)Tj
3.1634 0 Td
(prospective)Tj
4.7849 0 Td
(multicentric)Tj
5.1363 0 Td
(real)Tj
1.6951 0 Td
(life)Tj
1.44 0 Td
(study,)Tj
2.6192 0 Td
(we)Tj
1.3266 0 Td
(evaluated)Tj
3.9912 0 Td
(data)Tj
1.9105 0 Td
(from)Tj
2.2053 0 Td
(patients)Tj
3.3676 0 Td
(who)Tj
-34.7355 -1.2982 Td
(were)Tj
2.1203 0 Td
(initiated)Tj
3.5546 0 Td
(a)Tj
0.6519 0 Td
(DAA)Tj
2.3244 0 Td
(IFN-free)Tj
3.6794 0 Td
(regimen)Tj
3.5433 0 Td
(in)Tj
1.0318 0 Td
(the)Tj
1.4683 0 Td
(period)Tj
2.8346 0 Td
(from)Tj
2.2054 0 Td
(March)Tj
2.8743 0 Td
(2015)Tj
2.1203 0 Td
(to)Tj
1.0261 0 Td
(March)Tj
2.8687 0 Td
(2016)Tj
2.1203 0 Td
(and)Tj
ET
Q
q
1 j
1 J
0 w
576 737.1 m
36 737.1 l
36 737.6 l
576 737.6 l
f*
36 741.2598 107.1496 23.6976 re
W* n
q
107.0929 0 0 23.6409 36 741.3165 cm
q
/I0 Do
Q
Q
Q
q
0 0 612 792 re
W* n
1 j
1 J
0 w
7.9999 0 0 7.9999 403.4834 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(Real-life)Tj
3.8055 0 Td
(data)Tj
2.1331 0 Td
(on)Tj
1.311 0 Td
(potentia)Tj
3.4867 0 Td
(l)Tj
0.4322 0 Td
(DDI)Tj
1.9205 0 Td
(during)Tj
2.941 0 Td
(DAA)Tj
2.2536 0 Td
(therapy)Tj
ET
Q
q
1 j
1 J
0 w
36 48.0002 m
576 48.0002 l
576 47.5002 l
36 47.5002 l
f*
7.9999 0 0 7.9999 36 36 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(PLOS)Tj
2.8559 0 Td
(ONE)Tj
2.3669 0 Td
(|)Tj
0.4748 0 Td
(DOI:10.137)Tj
5.0387 0 Td
(1/journal.po)Tj
5.1236 0 Td
(ne.0172)Tj
3.5434 0 Td
(159)Tj
2.6362 0 Td
(February)Tj
4.1599 0 Td
(28,)Tj
1.5874 0 Td
(2017)Tj
37.3538 0 Td
(2)Tj
0.7654 0 Td
(/)Tj
0.496 0 Td
(11)Tj
ET
Q
q
0.83 0.64 0.02 0 k
1 j
1 J
0 w
59.1874 696.6425 m
113.8961 696.6425 l
h
f*
0 g
7.9999 0 0 7.9999 36 708.7181 cm
BT
/F8 1 Tf
1 TL
-0.025 Tc
0 0 Td
(reasons.)Tj
3.3874 0 Td
(Interest)Tj
2.8063 0 Td
(ed)Tj
1.1197 0 Td
(reader)Tj
2.3457 0 Td
(s)Tj
0.6449 0 Td
(may)Tj
1.8142 0 Td
(contact)Tj
2.948 0 Td
(Carlo)Tj
-15.0662 -1.3748 Td
(Petrini)Tj
2.5866 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(carlo.petrin)Tj
4.4717 0 Td
(i@iss.it)Tj
0 g
(\))Tj
3.2031 0 Td
(from)Tj
2.0127 0 Td
(the)Tj
1.3677 0 Td
(Ethical)Tj
-13.6418 -1.3748 Td
(Committe)Tj
3.6283 0 Td
(e)Tj
0.6449 0 Td
(of)Tj
0.9496 0 Td
(Istituto)Tj
2.7993 0 Td
(Superiore)Tj
3.8197 0 Td
(di)Tj
0.8858 0 Td
(Sanit)Tj
/F9 1 Tf
[( j)]TJ
/F8 1 Tf
2.5087 0 Td
(to)Tj
0.9496 0 Td
(request)Tj
-16.1859 -1.3748 Td
(access)Tj
2.7496 0 Td
(to)Tj
0.9496 0 Td
(patient)Tj
2.7142 0 Td
(level)Tj
1.8709 0 Td
(data.)Tj
/F7 1 Tf
-8.2843 -2.126 Td
(Funding:)Tj
/F8 1 Tf
3.5716 0 Td
(The)Tj
1.5874 0 Td
(authors)Tj
3.0473 0 Td
(received)Tj
3.3024 0 Td
(no)Tj
1.1622 0 Td
(specific)Tj
3.026 0 Td
(funding)Tj
-15.6969 -1.3748 Td
(for)Tj
1.2543 0 Td
(this)Tj
1.5661 0 Td
(work.)Tj
2.282 0 Td
(However,)Tj
3.7205 0 Td
(the)Tj
1.3677 0 Td
(PITER)Tj
2.537 0 Td
(platform)Tj
3.352 0 Td
(has)Tj
-16.0796 -1.3748 Td
(been)Tj
2.0126 0 Td
(supporte)Tj
3.2953 0 Td
(d)Tj
0.6945 0 Td
(by)Tj
1.1126 0 Td
(Italian)Tj
2.4378 0 Td
(Ministry)Tj
3.2386 0 Td
(of)Tj
0.9496 0 Td
(Health)Tj
2.5725 0 Td
(Grant)Tj
-16.3135 -1.3748 Td
(Research)Tj
4.0535 0 Td
(Project)Tj
2.8205 0 Td
(PITER2010)Tj
4.7835 0 Td
(RF-2010-23)Tj
4.4646 0 Td
(15839)Tj
-16.1221 -1.3748 Td
(to)Tj
0.9496 0 Td
(SV.)Tj
/F7 1 Tf
-0.9496 -2.126 Td
(Competing)Tj
4.3795 0 Td
(interests)Tj
3.3307 0 Td
(:)Tj
/F8 1 Tf
0.4819 0 Td
(The)Tj
1.5875 0 Td
(authors)Tj
3.0401 0 Td
(have)Tj
1.963 0 Td
(declared)Tj
-14.7827 -1.3749 Td
(that)Tj
1.6228 0 Td
(no)Tj
1.1693 0 Td
(competing)Tj
4.1599 0 Td
(interests)Tj
ET
endstream
endobj
24 0 obj
<>stream
endstream
endobj
25 0 obj
<>stream
endstream
endobj
26 0 obj
<>stream
endstream
endobj
27 0 obj
<>stream
endstream
endobj
28 0 obj
<>stream
endstream
endobj
29 0 obj
<>stream
endstream
endobj
30 0 obj
<>stream
endstream
endobj
31 0 obj
<>stream
endstream
endobj
32 0 obj
<>stream
BT
10.3394 -15.2505 Td
(exist.)Tj
ET
Q
endstream
endobj
33 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 12 0 R/Annots 37 0 R/Contents 38 0 R/TrimBox[0 0 612 792]>>
endobj
35 0 obj
<>
endobj
39 0 obj
<>
endobj
42 0 obj
<>stream
MinionPro-Regular 6 )
H? HD H\ ' - 3 > H N T Z ` j q t { +2=CIU[cnz~
"(.9CIOU[elov|&-8>DPV^iuy &+/49@DGLPU[]_ahjmru|
&-4;BIPW^elsz
")07>ELSZahov} %,3:AHOV]dkry#/;JTey ! ( / 6 = D K R Y ` g n u |
$
+
2
9
@
G
N
U
\
c
j
q
x
'.5<CJQX_fmt{ #*18?FMT[bkry
"
)
0
7
>
E
J
O
W
d
q
v
$+29@GNU\cjqx '.5<CJQX_fmt{ #*18?FMT[bipw~
&-4;BIPW^elsz !(/6=DOVcpuz-B\v$<Tdy*5@Tanz!2>O_fmt{ $-6?HQZclu~ )2;DMV^gpy $-6?HQZclu~ )2;DM\enwcommaaccentAbreveAmacronAogonekAEacuteCacuteCcaronCcircumflexCdotaccentDcaronDcroatEbreveEcaronEdotaccentEmacronEngEogonekGbreveGcircumflexGcommaaccentGdotaccentHbarHcircumflexIbreveIJImacronIogonekItildeJcircumflexKcommaaccentLacuteLcaronLcommaaccentLdotNacuteNcaronNcommaaccentObreveOhungarumlautOmacronOslashacuteRacuteRcaronRcommaaccentSacuteScedillaScircumflexScommaaccentTbarTcaronTcommaaccentUbreveUhungarumlautUmacronUogonekUringUtildeWacuteWcircumflexWdieresisWgraveYcircumflexYgraveZacuteZdotaccentIdotaccentabreveamacronaogonekaeacutecacuteccaronccircumflexcdotaccentdcarondcroatebreveecaronedotaccentemacronengeogonekgbrevegcircumflexgcommaaccentgdotaccenthbarhcircumflexibreveijimacroniogonekitildejcircumflexkcommaaccentlacutelcaronlcommaaccentldotnacutencaronncommaaccentobreveohungarumlautomacronoslashacuteracutercaronrcommaaccentsacutescedillascircumflexscommaaccenttbartcarontcommaaccentubreveuhungarumlautumacronuogonekuringutildewacutewcircumflexwdieresiswgraveycircumflexygravezacutezdotaccentkgreenlandiclongsnapostrophetonosdieresistonosAlphaBetaGammaDeltaEpsilonZetaEtaThetaIotaKappaLambdaMuNuXiOmicronPiRhoSigmaTauUpsilonPhiChiPsiOmegaAlphatonosEpsilontonosEtatonosIotatonosIotadieresisOmicrontonosUpsilontonosUpsilondieresisOmegatonosuni1FBBuni1F09uni1F0Duni1F0Buni1F0Funi1FB8uni1FBAuni1FBCuni1F89uni1F8Duni1F8Buni1F8Funi1F88uni1F8Cuni1F8Auni1F8Euni1F08uni1F0Cuni1F0Auni1F0Euni1FB9uni1FC9uni1F19uni1F1Duni1F1Buni1FC8uni1F18uni1F1Cuni1F1Auni1FCBuni1F29uni1F2Duni1F2Buni1F2Funi1FCAuni1FCCuni1F99uni1F9Duni1F9Buni1F9Funi1F98uni1F9Cuni1F9Auni1F9Euni1F28uni1F2Cuni1F2Auni1F2Euni1FDBuni1F39uni1F3Duni1F3Buni1F3Funi1FD8uni1FDAuni1F38uni1F3Cuni1F3Auni1F3Euni1FD9uni1FFBuni1F69uni1F6Duni1F6Buni1F6Funi1FFAuni1FFCuni1FA9uni1FADuni1FABuni1FAFuni1FA8uni1FACuni1FAAuni1FAEuni1F68uni1F6Cuni1F6Auni1F6Euni1FF9uni1F49uni1F4Duni1F4Buni1FF8uni1F48uni1F4Cuni1F4Auni1FECuni1FEBuni1F59uni1F5Duni1F5Buni1F5Funi1FE8uni1FEAuni1FE9alphabetagammadeltaepsilonzetaetathetaiotakappalambdanuxiomicronpirhosigmatauupsilonphichipsiomegaalphatonosepsilontonosetatonosiotatonosiotadieresisomicrontonosupsilontonosupsilondieresisomegatonosiotadieresistonosupsilondieresistonosuni03C2uni0374uni0375uni037Euni03D0uni03DAuni03DEuni03E0uni03F0uni1FBDuni1FBEuni1FC1uni1FCDuni1FCEuni1FCFuni1FDDuni1FDEuni1FDFuni1FEDuni1FEEuni1FFEuni1F00uni1F01uni1F02uni1F03uni1F04uni1F05uni1F06uni1F07uni1F10uni1F11uni1F12uni1F13uni1F14uni1F15uni1F20uni1F21uni1F22uni1F23uni1F24uni1F25uni1F26uni1F27uni1F30uni1F31uni1F32uni1F33uni1F34uni1F35uni1F36uni1F37uni1F40uni1F41uni1F42uni1F43uni1F44uni1F45uni1F50uni1F51uni1F52uni1F53uni1F54uni1F55uni1F56uni1F57uni1F60uni1F61uni1F62uni1F63uni1F64uni1F65uni1F66uni1F67uni1F70uni1F71uni1F72uni1F73uni1F74uni1F75uni1F76uni1F77uni1F78uni1F79uni1F7Auni1F7Buni1F7Cuni1F7Duni1F80uni1F81uni1F82uni1F83uni1F84uni1F85uni1F86uni1F87uni1F90uni1F91uni1F92uni1F93uni1F94uni1F95uni1F96uni1F97uni1FA0uni1FA1uni1FA2uni1FA3uni1FA4uni1FA5uni1FA6uni1FA7uni1FB0uni1FB1uni1FB2uni1FB3uni1FB6uni1FB7uni1FC2uni1FC3uni1FC4uni1FC6uni1FC7uni1FD0uni1FD1uni1FD2uni1FD3uni1FD6uni1FD7uni1FE0uni1FE1uni1FE2uni1FE3uni1FE4uni1FE5uni1FE6uni1FF2uni1FF3uni1FF4uni1FF6uni1FF7uni1FB4uni1FE7uniEFD5anoteleiauni03D1uni03D5uni03D6franclirapesetaEuroafii61289estimatedpartialdiffproductsummationuni2219radicalinfinityintegralapproxequalnotequallessequalgreaterequallozengeuni02C9uniEFEDuniEFEEuniEFF1uniEFF2uniEFF3uniEFF5uniEFF7AcuteCaronDieresisDieresisAcuteDieresisGraveGraveHungarumlautMacroncyrBrevecyrFlexdblGravecyrbrevecyrflexdblgravedieresisacutedieresisgraveuniF635uniF637uniF638uniF639uniF6DCuniF63AuniF63BuniF63CuniF63DuniF63EuniF63FuniF640uniF641uniF642uniF628uniF643uniF644uniF645uniF646uniF647uniF648uniF649uniF64AuniF64BuniF64CuniF64DuniF64EuniF64FuniF650uniF651uniF652uniF653uniF654uniF655uniF656uniF657uniF658uniF659uniF65AuniF65BuniF65CuniF65DuniF65EuniF65FuniF660uniF629uniF62AuniF62BuniF62CuniF62DuniF661uniF662uniF663uniF664uniF665uniF666uniF667uniF668uniF669uniF66AuniF66BuniF66CuniF62EuniF62FuniF630uniF631uniF632uniF66DuniF66EuniF66FuniF670uniF671uniF672uniF673uniF674uniF675uniF676uniF677uniF678uniF679uniF67AuniF67BuniF67CuniF67DuniF67EuniF67FuniF680uniF681uniF682uniF683uniF684uniF685uniF686uniF687uniF688uniF689uniF68AuniF68BuniF68CuniF68DuniF68EuniF68FuniF690uniF691uniF692uniF693uniF694uniF695uniF696uniF697uniF698uniF699uniF69AuniF69BuniF69CuniF69DuniF69EuniF69FuniF6A0uniF6A1uniF6A2uniF6A3uniF6A4uniF6A5uniF6A6uniF6A7uniF6A8uniF6A9uniF6AAuniF6ABuniF6ACuniF6ADuniF6AEuniF6AFuniF6B0uniF6B1uniF6B2uniF6B3uniF6B4uniF6B5uniF6B6uniF6B7uniF6B8uniF6B9uniF6BAuniF6BBuniF6BCuniF6BDuniF633c_hc_kc_tf_bf_f_bf_f_hf_f_kf_f_tf_hf_jf_f_jf_kf_ts_puniFB06T_hlongs_blongs_hlongs_ilongs_klongs_llongs_longsuniFB05longs_longs_ilongs_longs_la.ende.endm.endn.endr.endK.altR.altk.altcaron.altcommaaccent.altpeseta.altAlphaiotasub.altAlphaiotasubasper.altAlphaiotasubasperacute.altAlphaiotasubaspergrave.altAlphaiotasubaspertilde.altAlphaiotasublenis.altAlphaiotasublenisacute.altAlphaiotasublenisgrave.altAlphaiotasublenistilde.altEtaiotasub.altEtaiotasubasper.altEtaiotasubasperacute.altEtaiotasubaspergrave.altEtaiotasubaspertilde.altEtaiotasublenis.altEtaiotasublenisacute.altEtaiotasublenisgrave.altEtaiotasublenistilde.altOmegaiotasub.altOmegaiotasubasper.altOmegaiotasubasperacute.altOmegaiotasubaspergrave.altOmegaiotasubaspertilde.altOmegaiotasublenis.altOmegaiotasublenisacute.altOmegaiotasublenisgrave.altOmegaiotasublenistilde.altEuro.fittedcent.fittedcolonmonetary.fitteddollar.fittedflorin.fittedfranc.fittedlira.fittednumbersign.fittedsterling.fittedyen.fittedEuro.oldstylecolonmonetary.oldstyleestimated.oldstyleflorin.oldstylefranc.oldstylelira.oldstylenumbersign.oldstylesterling.oldstyleyen.oldstylefranc.taboldstylelira.taboldstyleorn.001orn.002orn.003orn.004orn.005orn.006orn.007orn.008orn.009orn.010orn.011orn.012orn.013orn.014orn.015orn.016orn.017orn.018orn.019orn.020orn.021orn.022orn.023afii10023afii10031afii10022afii10049T_h.caronafii10070afii10196afii10026afii10021afii10846afii10193afii10107afii10024afii10195afii10041afii10037afii10109afii10053afii10045afii10108afii10040afii10104afii10036afii10078afii10074afii10060afii10046afii10052afii10087afii10050afii10145afii10057afii10059afii10146afii10088afii10101afii10054afii10058Rholenisafii10025afii10099afii10068afii10035afii10048afii10089afii10105afii10085afii10020afii10077afii10106afii10019afii10076afii10110afii10100afii10090afii10028afii10095afii10147afii10066afii10098afii10082afii10061afii10103afii10102afii10083afii10027afii10072afii10039afii61352afii10069afii10094afii10038afii10034afii10148afii10032afii10194afii10033afii10075afii10017afii10081afii10056afii10084afii10044afii10030afii10051afii10047afii10018afii10080afii10042afii10071afii10029afii10062afii10065afii10097T_h.commaaccentafii10096afii10079afii10091afii10093afii10064afii10043afii10092uni2215uni021Bafii10073afii10067uni00A0uni021Aafii10086afii10055uni0394uni03BCuni03A9uni00ADCopyright 2000 Adobe Systems Incorporated. All Rights Reserved. U.S. Patent Des. 337,604.Minion is either a registered trademark or a trademark of Adobe Systems Incorporated in the United States and/or other countries.Minion Pro RegularMinion Pro% i WZ5:`v22> % I
/
2
I
o
#3p~U
D
e
!o#]emE %<Jeov~EMfjtFp|,S-AZ0=DK +^&7NQy(/S_dl 5Rk$=Valsz"'-@T_gos{ ) . > N ^ d n v ~ !!!!'!3!?!H!Q!Z!]!c!i!n!s!x!!!!!!!!!!!!!"""#"'"3"?"K"W"c"k"s"{""""""""""""""c&oEr^7 JB@H *W2c~sp&m!1= 4:$kYyywRvzwrZnon?˘iNUddLoLݪ
~}}vywS6vO(Zp^TrǕ؍8x`?NYwUVYWE}zyMhummR~Kfowx}|txcBzuyBpOwTxql[LPҩy}~Bxxhzqlc#T0@9
5/j,X^M8Uruuoquvqiff{bE<H8XUo^bb_rMG'Н=[W}yQSSۚ$P|TzTyT'
ajqyzx||rrpwttozpj`lWHrʥaiqyo
|rqpxt@tpyqjalVHr]yt/m'mDx]pIsn8AgmxpQAz4wv~s}~vstzf|oęgfeoszvwzxu$wny|YgJO-ʆea]>9+ZhchAB_\?#^|m[5v-<<[FL LHHq˂~XxAo4uFabfqaf%f+rrs}ǔcqW "* ڟŇՊvx|po~}wUJN<0o-כtzr[ {"!coч~^o]/6'orsBp0ZlZqRoGt{_Fpq|iiMkTratap`DabuvCICpAϦ{~{lpˇBDDpӐ qoكtYoNU)gI_Z`yӔodžF/INlw71oC
ŸԱȗГnoՆ3$811xrdcQD:0] ;hJjp~djmplXhZfYxnmmyf^#MR:AgszvT]jjZ?_ynZQ{sNHyZdƨ]O틯֯}ޣDyZ{kvumofFMk_VYЄ#ms^@L A_!Z Z|蒯}~rqyg|usqrwgmazԬqbfZBoل5|%69o<3oZMZJuׇ3c T{ddmvrjY_VpŇkrkGpφ}8Fgsmy]pWSy/OBR7WXjfeolw}v84o~}xUGP~72pC
~㿊IK
NϪb98IPq
`y[~XsłI\FL
ދ.R۲vhl_@oۅ8(85oq͗ƫ>(3XOG7]_\i^%"Ba:Jy.}eu}|wzq]is|~ґϐuCDDEp
ؑ~P|xhcMp^},
qkuGuzwv~s}~ust}e{nęgfR5BcH
蠓`
i
`c
v
y
蠚}xsnyvrpyh&T~Y|S|Q4xrqxvrpyhrqVVrm