Co nowego na zjazdach CROI, ICAAC. EACS

clinicaloptions.com/hiv

HIV/AIDS Update From Rio

Co nowego na zjazdach CROI, ICAAC. EACS



Leczenie pierwszego rzutuNowe strategie leczeniaNowe lekiPowikłania leczeniaKoinfekcje



Leczenie pierwszego rzutu&strategie leczenia



Rekomendacje europejskie (EACS)Rekomendacje amerykańskie (DHHS)

Rekomendacje polskie

Kiedy zacząć ?



HAART and Survival Based on Initial CD4+ Cell Count Modeled data from ART

Cohort Collaborative 10,855 patients included 934 progressed to AIDS or

died IDUs excluded from model

Sterne J, et al. CROI 2006. Abstract 525.

Progression and Death According to CD4+ Cell Count (cells/mm3)

< 200 vs 201-350

< 350 vs 351-500

Hazard ratio for AIDS (95% CI)

3.68 (3.01-4.51)

1.52

(1.10-2.10)

Hazard ratio for AIDS or death (95% CI)

2.93 (2.41-3.57)

1.26

(0.94-1.68)

Cumulative Probability of AIDS/Death According to CD4+ Cell Count at Initiation of HAART

Years Since Initiation of HAART

0 1 2 3 4 5

0.00

0.02

0.04

0.06

0.08

0.10

0.12

Pro

bab

ility

of

AID

S o

r D

eath

101-200 cells/mm3

201-350 cells/mm3

351-500 cells/mm3



CD4+ Cell Count Response Based on Baseline CD4+ Cell Count

Keruly J, et al. CROI 2006. Abstract 529. Gras L, et al. CROI 2006. Abstract 530.

Years on HAART

Johns Hopkins HIV Clinical Cohort

Mea

n C

D4+

Cel

l Co

un

t (c

ells

/mm

3 )

1000

800

600

400

200

0

0 48 96 144 192 240 288 336

ATHENA National Cohort

Weeks From Starting HAART

Magnitude of CD4+ cell count increase greatest if therapy started at low CD4+ cell counts, but greater likelihood of CD4+ cell count normalization with earlier therapy

0 1 2 3 4 5

200

400

600

800

0

1000



Związek pomiędzy śmiertelnością a supresją wiremii Prospektywne, Danish HIV Cohort

Study

– N = 3919 HIV(+)

– HAART ≥ 18 miesięcy

Podzieleni na grupy w zależności od proporcji wykrywalnej wiremii w ciągu 18 miesięcy od włączenia leczenia

Większe ryzyko śmierci u osób z niepełną lub brakiem supresji

Lohse N, et al. ICAAC 2005. Abstract H-515.

100% (all values VL ≥ 400)

1%-99% (of values VL ≥ 400)

0% (all values VL < 400)0.25

0.20

0.15

0.10

0.05

0.00

0 18 36 54 72

Months After Baseline (baseline = 18 months after HAART initiation)

Cum

ulat

ive

Mor

talit

y

Proportion of Detectable Viral Loads Over

6-18 Months After Initiation of HAART



Kiedy rozpoczynać HAART : HOPS Cohort

Dane z kohorty >8000pts, obserwacja od 1993 U pacjentów, którzy zaczynali HAART przy wyższym CD4+

– Mniejsza śmiertelność, mniej OI– Lepsza odpowiedź CD4+ na HAART– Rzadziej niewydolność nerek, neuropatia i lipoatrofia

Lepszy efekt immunologiczny u osób stale leczonych HAART vs STI Korzyści z leczenia nawet u osób, którzy rozpoczynali leczenie z CD4+

350-500 kom/mm³ i > 500 kom/mm³

Lichtenstein KA, et al. CROI 2006. Abstract 769.





Czym zacząć ?



Boosted vs Unboosted Atazanavir in Antiretroviral-Naive Patients Randomization 1:1

– ATV 400 mg QD (n = 105)– ATV/r 300/100 mg (n = 95)– Both with d4T-XR 100 mg QD +

3TC 300 mg QD

Trend for more virologic failure in ATV arm*

Patients with VF

– ATV: n = 10– ATV/r: n = 3

Mean CD4+ count change

– ATV: +224– ATV/r: +189

Malan N, et al. CROI 2006. Abstract 107LB.

Weeks

< 400 c/mL

< 50 c/mL

0

20

40

60

80

100

BL2 4 8 12 16 24 32 40 48

86%

75%85%

70%

Res

po

nd

ers

(%)

HIV RNA < 400 c/mL and < 50 c/mL Through Week 48 (ITT)

Difference estimate (95% CI): 1.5 (-8.2 to 11.1)Difference estimate (95% CI): 1.5 (-7.0 to 17.0)

ATV 300/RTV (n = 95)ATV 400 (n = 105)

*Not powered to determine if ATV noninferior to ATV/r



ACTG 5095: Założenia badania

Antiretroviral-Naive VL ≥ 400 copies/mL

(N = 82)

Gulick RM, et al. ICAAC 2005. Abstract H-416a.

3-NRTI armZidovudine/lamivudine/abacavir

Median follow-up: 144 weeks

3 NRTIs + EFV armZidovudine/lamivudine/abacavir + efavirenz

2 NRTIs + EFV armZidovudine/lamivudine + efavirenz

Porównanie 2- vs 3 lekowego NRTI backbones i zestawu 3-NRTI vs zawierające EFV

– Ramię 3-NRTI przerwano po analizie danych pokazujących mniejsza efektywność w stosunku do ramion zawierających EFV



ACTG 5095: EFV + ZDV/3TC vs EFV + ZDV/3TC/ABC jako terapia inicjująca Ni stwierdzono różnicy w:

– Czasie osiągnięcia supresji

– Liczbie niepowodzeń terapeutycznych

– Proporcji z VL < 200 or < 50 c/mL

– Odpowiedzi CD4+

– Profilu oporności

Podobne rezultaty u osób z VL > 100,000 Czynniki niepowodzenia wirusologicznego

– HCV (HR: 1.57)

– Black race (HR: 1.67)

– Płeć, wiek, CD4+ nie ma wpływu

Gulick RM, et al. ICAAC 2005. Abstract H-416a.

Viro

logi

c F

ailu

res*

(%

)

0

20

40

60

80

100

25 26

ZDV/3TC + EFV

(n = 382)

ZDV/3TC/ABC + EFV

(n = 383)

* Virologic failure defined as 2 consecutive

VL ≥ 200 copies/mL at ≥ Week 16.



NRTI-Sparing Initial Therapy: LPV/r + SQV Compared With LPV/r + NRTIs Otwarte, randomizowane,

pilotażowe badanie

– N = 30 naive men

– LPV/r (400/100 BID) + SQV (800 BID) or ZDV/3TC (300/150 BID)

Podobne wyniki w 48 tygodniu

Nie różnią się objawami ubocznymi

Mniejsza liczba tabletek nowych postaci LPV/r and SQV

Potrzeba więcej badań nad efektywnością dual-PI

Cameron DW, et al. ICAAC 2005. Abstract H-523.

Week

Pat

ient

s W

ith H

IV-1

RN

A <

50

copi

es/m

L (O

bser

ved

Dat

a) (

%)

0 12 24 36 480

20

40

60

80

100

78%

77%

LPV/r + SQV LPV/r + ZDV/3TC

n = 13 13n = 10 9



Odpowiedź na NNRTIs vs PIs u pacjentów z zaawansowanym AIDS Poprzednie badania sugerowały różnice w efektywności

pomiędzy NNRTIs a PIs u pacjentów z zaawansowaną chorobą

– Jednak oparte na badaniach obserwacyjnych i porównaniu różnych badań

Randomizowane badanie porównujące EFV vs IDV/r u nieleczonych z CD4+ < 100 kom/mm3

– Nie ma statystycznych różnic w odpowiedzi wirusologicznej

– Nie ma statystycznych różnic w odpowiedzi CD4+ w 24 miesiącu

Miro JM, et al. EACS 2005. Abstract PS1/4.



DART: Use of TDF + ZDV + 3TC in Resource-Limited Settings Potential advantages of regimen

– No refrigeration – No hypersensitivity – No pregnancy concerns – No rifampin interactions

Randomized trial: clinical + lab vs clinical monitoring alone in 3315 naive pts starting ZDV/3TC + TDF

48-wk results presented on 300 pts in virology substudy

– BL median CD4+, 100 cells/mm3

– BL median VL, 279,910 copies/mL

0

20

40

60

80

100

55%

65%62%

74%

% o

f S

ub

ject

s

< 50 at Wk 48

< 400 at Wk 48

ITT M=F OT300

3.72

231

4.20Mean log drop:

n =

Kaleebu P, et al. IAS 2005. Abstract WeOaLB0203.





Jak zmieniać? ?



Zmiana na prostszy schemat

SWAN study: efektywność i bezpieczeństwo zmiany z reżimu PI BID i/lub ≥ 3 tabl/dizennie na ATV (n = 253) lub ATV/r, jeśli z TDF (n = 25)

– Kryteria wejścia: na stabilnym HAART z PI-, na 1st lub 2nd zestawie, VL < 50 przez ≥ 3 months

– Randomizowano na dwie grupy-zmiana lub pozostanie na dotychczasowym leczeniu

Patiencji, którzy otrzymali ATV:– Utrzymali supresję wirusologiczną – Mieli poprawę profilu liidów

– Total cholesterol, -16% vs +1% with comparator PI (P < .0001)– Triglycerides, -38% vs +1% with comparator PI (P < .0001)

Gatell JM, et al. IAS 2005. Abstract WePe6.3C15.



Leczenie podtrzymujące monoterapią PI

Monoterapia podtrzymująca stanowi atrakcyjną opcję dla u pacjentów z supresją wiremii

– Jednakże w poprzednich badaniach stwierdzono znaczne ryzyko niepowodzenia wirusologicznego

– PI/r mogą być dobrą opcją: ↑ potencjał, ↓ ryzyko oporności

20/24 miało wiremię nieoznaczalną 48 tygodniu po zmianie LPV/r + 2 NRTIs to LPV/r monoterapię [1]

– Niepowodzenie wirusologiczne nie powodowało rozwoju mutacji , a dodaniem NRTIs uzyskano supresję

1. Arribas JR, et al. IAS 2005. Abstract WePe12.3C05. 2. Vernazza P, et al. IAS 2005. Abstract WeOa0204.



1. von Hentig N, et al. EACS 2005. Abstract PS6/5.2. von Hentig N, et al. EACS 2005. Abstract PS6/6.

Pharmacokinetics of double-boosted PI therapy assessed in observational Frankfurt HIV cohort– Compared to each single-boosted PI + NRTIs

ATV also reduces RTV levels when combined with LPV/r– Secondary boosting effect of ATV on LPV

Pharmakokinetyka of Double-Boosted zestawów z ATV

AUCss After 3 Days of Treatment (ng·hr/mL)

Effect on Concomitant Drug[1]

Effect on ATV[2]

Recommendation

Lopinavir/ritonavir (400/100 BID)

↓ 16% (P = .21)

↓ 22% (P = .077)

Use with TDM

Saquinavir/ritonavir (1000 BID/100 QD)

↑ 40% (P = .001)

↑ 16% (P = .11)

Use with low-dose ritonavir (100 mg QD)

Fosamprenavir/ritonavir (700/100 BID)

neutral ↓ 31% (P = .003)

Further investigation required

P values for PI/r + ATV vs PI/r alone.



Week 24 copies/mL (n)

BL VL copies/mL > 400 50–400 < 50

50–400 (n = 78)

< 50 (n = 111)

By Week 24 after switch

– 26 (14%) had increases in VL

– 114 (60%) maintained VL

– 49 (26%) had decreases in VL

COMET: Switch From ZDV/3TC to TDF/FTC 189 suppressed patients switched

from ZDV/3TC to TDF/FTC

– Primary reason for switch: simplification (86%)

– All had BL VL < 400 copies/mL

Small, but significant improvement in lipids

– TC ↓ 13 mg/dL at Week 12

– TG ↓ 12.5 mg/dL at Week 12

Hb increased 0.6 g/dL by Week 24

Ruane P, et al. EACS 2005. Abstract PE7.3/5.

9

3 14

4920

94





Jak nie zmieniać?



COL40263: Once-Daily ZDV/3TC/ABC + Tenofovir

Cohen C, et al. ICAAC 2005. Abstract H-521.Elion R, et al. ICAAC 2005. Abstract H-1068.

*≥ 400 copies/mL at ≥ 24 weeks

14%

21%

7%29%

29%

Pat

ient

s W

ith H

IV-1

RN

A

< 5

0 co

pies

/mL

(IT

T: M

=F

) (%

)

Study Week

0 44 16 24 32 40 48

100

80

60

40

20

08

All patientsBL VL < 100,000 BL VL ≥ 100,000

K65R/K (2 of 14 isolates)

≥ 1 TAMs only (3 of 14 isolates)

M184V only (1 of 14 isolates)

≥ 1 TAMs + M184V (4 of 14 isolates)Wild type (4 of 14 isolates)

Genotypes of Nonresponders*



Problemy z Didanosine + Tenofovir + Efavirenz

1. van Lunzen J, et al. IAS 2005. Abstract TuPp0306.2. Barrios A, et al. IAS 2005. Abstract WePe12.3C16.

Badanie TEDDI potwierdziło poprzednie doniesienia o większym odsetku pacjentów z niepowodzeniem wirusologicznym przyjmujących ddI + TDF + EFV [1]

– VF: 25% po 12 tygodniach of TDF + ddI + EFV

Badanie EFADITE pts ze stabilną supresją, którzy przestawieni zostali na TDF + ddI + EFV albo zostali na dotychczasowym leczeniu [2]

– Utrzymano stłumienie wiremii u większości pts

– Jednak, CD4+ ↓ na TDF + ddI + EFV

– Median change in CD4+ at Yr 1, -25 vs +46 in controls (P = .007)

– Significantly larger CD4+ declines in pts on high vs low ddI doses



3TC Alone vs Treatment Interruption in Patients Failing 3TC-Based HAART

Castagna A, et al. IAS 2005. Abstract WeFo0204.

-300

4 12 24 36 48

Mea

n C

ha

ng

e in

HIV

-1

RN

A (

log

10 c

op

ies/

mL

) Weeks

Mea

n C

ha

ng

e in

CD

4+

Cel

l C

ou

nt

(cel

ls/m

m3)

Weeks

04 12 24 36 48

P = NS-250

-200

-150

-100

-50

0

Mean CD4+ Decrease (ITT)Mean VL Increase (ITT)

P = .0015

0.5

1.0

1.5

2.0 3TC TI

In contrast to treatment interruption arm, 3TC alone resulted in:– Smaller recovery in replication capacity– No further selection of resistance mutations

3TC TI



Lower Incidence of M184V/I Following Virologic Failure With FTC vs 3TC 1363 treatment-naive patients

experiencing virologic failure in 1 of 3 phase III studies

– FTC-301A: FTC QD + ddI + EFV vs d4T + ddI + EFV

– GS-903: 3TC BID + TDF + EFV vs 3TC BID + d4T + EFV

– GS-934: FTC QD + TDF + EFV vs 3TC BID + ZDV + EFV

Significantly ↓ rate of M184V/I emergence with FTC QD vs 3TC BID (both in combination with another NRTI and EFV)

McColl D, et al. EACS 2005. Abstract PE7.3/17.

0

0.5

1.0

1.5

2.0

2.5

3.0

Inci

den

ce o

f M

184V

/I in

3

Po

ole

d P

has

e III

Tri

als

(%)

0.6

2.4P = .015

FTC (n = 522)

3TC (n = 841)



TOPS: Reducing Emergence of Resistance After Single-Dose NVP

Arm 3

Arm 2

Arm 1sdNVP

sdNVP

ZDV/3TC x 4d

ZDV/3TC x 4d

ZDV/3TC x 7d

ZDV/3TC x 7d

Intrapartum Postpartum

Mother

Baby

Mother

Baby

Mother

Baby

sdNVP

sdNVP

sdNVP

sdNVP

McIntyre JA, et al. IAS 2005. Abstract TuFo0204.



Coadministration of 4-7 days of ZDV/3TC with single-dose NVP reduced incidence of NVP resistance

– 41/68 (60%) vs 15/135 (11%); P = .0001

TOPS Update on NVP Resistance

Study Arm N Maternal NVP Resistance*, n (%)

sdNVP 68 41 (60%)

sdNVP + ZDV/3TC x 4d 67 8 (12%)

sdNVP + ZD/3TC x 7d 68 7 (10%)

McIntyre JA, et al. IAS 2005. Abstract TuFo0204.

* Incidence determined by standard genotyping, which is not sensitive to minority variants



RESIST-1 i -2: wyniki 48 tygodni

Cahn P, et al. EACS 2005. Abstract LBPS3/8.

TPV/r similar toxicity profile to CPI/r, with 2 exceptions– Elevated ALT (9.7% vs 4.2%), AST (6.1% vs 1.8%) – Elevated TGs (24.9% vs 13.0%), TC (2.1% vs 0.4%)

80

0

20

40

All Patients First-Time ENF Use

Pat

ien

ts W

ith

HIV

-1 R

NA

<

50

cop

ies/

mL

(%

)

TPV/r CPI/r

22.810.2

35.8

14.4

n =746n = 737 n = 123n = 97

60

100

80

0

20

40

All Patients First-Time ENF Use

Pat

ien

ts W

ith

HIV

-1 R

NA

<

400

co

pie

s/m

L (

%)

TPV/r CPI/r

30.4

13.8

52.0

19.6

n =746n = 737 n = 123n = 97

60

100



Niewystępowanie oporności na PI po niepowodzeniu leczenia PI/r No primary PI resistance mutations in pts with failure of

SQV/r regimen

– Staccato trial: Of 10 patients failing SQV/r 1600/100 mg QD + d4T/ddI (or TDF/3TC), none had primary PI mutations at failure [1]

Consistent with previous reports on FPV/r, LPV/r

– SOLO trial: Of 32 pts failing FPV/r + ABC + 3TC, none developed primary or secondary PI mutations at failure [2]

– M98-863 trial: Of 51 pts failing LPV/r + d4T + 3TC, none had primary PI mutations at failure [3]

1. Ananworanich J, et al. IAS 2005. Abstract WePe4.4C12. 2. MacManus S, et al. AIDS. 2004;18:651-655. 3. Kempf DJ, et al. J Infect Dis. 2004;189:51-60.



Pharmacokinetics of Dual-boosted PI Regimens Substantial reductions in APV and LPV levels previously

shown when FPV and LPV/r coadministered [1]

However, new study showed no apparent adverse PK effect with ATV (300 or 400 QD) + LPV/r (400/100 BID) [2]

– 20 treatment-experienced pts; 3 PI naive; 14 LPV/r naive

– Median ATV and LPV Cmin in target range

– 69% < 400 copies/mL at Week 24

Further formal drug interaction studies and clinical trials are warranted

1. Kashuba A, et al. AIDS. 2005;19:145-152. 2. Duvivier C, et al. IAS 2005. Abstract WePe3.2C10.



NRTIs/NtRTIs

– SPD 754 (DOTC)

– Amdoxovir (DAPD)

– D-d4FC

– Racivir (± FTC)

– SN1212

– Compound X

Protease inhibitors

– TMC114

– GW0385

Entry inhibitors

– Aplaviroc

– Maraviroc

– Vicriviroc

– BMS-488043

– TNX-355

– NB-2, NB-64

NNRTIs

– TMC125

– GW678248 (prodrug = GW695634)

– TMC278

– BILR 355 BS

– CSIC

– DAPY/DATA

– UC781

– TMC120 (as microbicide)

Nowe leki



Antiretrovirals Potentially Active in Treatment-Experienced Patients

EnfuvirtideCCR5 inhibitors

TipranavirTMC114

D-d4FC (NRTI)TMC125 (NNRTI)

PA-457

MK-0518GS-9137



Virologic Response to D-d4FC

Randomized, dose-ranging trial of D-d4FC vs placebo in 199 experienced pts with VL > 2000 copies/mL

D-d4FC active against NRTI-resistant viruses

Cohen C, et al. IAS 2005. Abstract WeOaLB0103.

Response to D-d4FC (200 mg QD) during initial 2-wk add-on phase

0-3 TAMs

4-6 TAMs

M41L+L210W

M184V alone

M184V+TAMs L74V/I K65R

-0.00

-0.75

-0.50

-0.25

-1.00

Ch

ang

e i

n H

IV-1

RN

A

at W

k 2

(lo

g1

0 c

op

ies/

mL

)



Activity of Novel NNRTI GW695634

Becker S, et al. IAS 2005. Abstract WePe6.2C03.

Multicenter, double blind, randomized 7-day add-on study

N = 44 NNRTI-exp pts

27 ≥ 1 NNRTI mutation at BL

Remaining 17 had history of NNRTI mutations

– Most common NNRTI mut: K103N, V108I, Y181C

BL VL, 4.4-4.6 log

BL CD4+, 230-345

-0.4

0.0

0.4

0.8

-2.0

-1.6

-1.2

-0.8

1 2 3 4 5 6 7 8

Placebo 100 mg 200 mg300 mg 400 mg

Ch

ang

e i

n P

las

ma

HIV

-1 R

NA

(l

og

10 c

op

ies/

mL

)

Study Day



TMC125-C223: Virologic Response in Pts With NNRTI and PI Resistance

TMC125 active in patients with no other active drugs

– -0.59 log10 reduction in HIV-1 RNA with 800 mg BID dose

Nadler JP, et al. EACS 2005. Abstract LBPS3/7a

-1.6

-1.2

-0.8

-0.4

0

0.4

Mea

n (

± S

E)

Ch

ang

e in

HIV

-1

RN

A (

log

10 c

op

ies/

mL

)

Control(n = 40)

400 mg BID(n = 80)

800 mg BID(n = 79)

0 21 4 8 12 16 20 24

–0.19

–1.04*

–1.18*

*P < .05



POWER-2: Darunavir/r (TMC114/r) in PI-Experienced Patients Ongoing 96-week randomized trials

of 3-class experienced patients

– 1 primary PI mutation

– BL HIV-1 RNA: 4.6-4.7 log10 c/mL

– BL CD4+: 99-113 cells/mm3

24-week data previously reported from POWER-1 cohort[1]

Current analysis presented 24-week data from POWER-2 cohort[2]

– Same arms and entry criteria in POWER-1 and POWER-2

Darunavir 400 mg QD +Ritonavir 100 mg QD + OBR

(n = 57)

Darunavir 800 mg QD +Ritonavir 100 mg QD + OBR

(n = 56)

Darunavir 400 mg BID +Ritonavir 100 mg BID + OBR

(n = 55)

Darunavir 600 mg BID +Ritonavir 100 mg BID + OBR

(n = 57)

Investigator-selected PI + OBR

(n = 53)

POWER-2 Treatment Arms

1. Katlama C, et al. IAS 2005. Abstract WeOaLB0102.2. Wilkin T, et al. ICAAC 2005. Abstract H-413.



Brecanavir (GW640385): PI Susceptibility vs Other PIs Brecanavir retains in vitro susceptibility against virus

resistant to commonly used PIs

In vitro study of 55 isolates from PI-experienced patients

Drug Mean IC50 (nM) Range (nM)

Brecanavir 1.3 0.1 to 14.9

Amprenavir 404 61 to > 1500

Indinavir 515 27 to > 1500

Lopinavir 448 10 to 1455

Nelfinavir 368 69 to 1309

Reddy S, et al. ICAAC 2003. Abstract A-1800.

Viruses selected based on presence of protease mutations at codons 10, 32, 46, 47, 50, 54, 84, and/or 90 (mean: 8; range: 4-14)



Brecanavir (GW640385) Novel PI Active in HIV-Infected Patients Open-label, single-arm study in

HIV-infected subjects

– N = 31 naive and experienced

– BL VL: 4.7 log10 copies/mL– BL CD4+: 311 cells/mm3

– Brecanavir/r 300/100 BID + 2 NRTIs

77% achieved VL < 50 copies/mL at Week 24 (ITT: missing = failure)

– 81% < 400 copies/mL at Week 24

Ward D, et al. ICAAC 2005. Abstract H-412.

0

1

2

3

4

5

6

0 4 8 12 16 20 24

Study Week

Med

ian

Pla

sma

HIV

-1 R

NA

(lo

g 10

copi

es/m

L)

PI sensitive at BL (n = 23)

PI resistant at BL (n = 6)

Median change at Week 24

• PI sensitive: -3.3 log10 c/mL • PI resistant: -2.2 log10 c/mL



Virologic Response to Novel Integrase Inhibitor Monotherapy MK-0518, novel integrase inhibitor

– Active against HIV resistant to current antiretrovirals

Randomized, placebo-controlled 10-day monotherapy trial in treatment-naive patients– BL VL: 4.53-4.97 log10 c/mL– BL CD4: 256-569 cells/mm3

Good response seen with 10-day monotherapy– No dose response

All doses generally well tolerated

Morales-Ramirez JO, et al. EACS 2005. Abstract LBPS1/6.

Day on Therapy

Ch

ang

e F

rom

Bas

elin

e in

H

IV-1

RN

A (

log

10 c

op

ies/

mL

)

1 2 3 4 5 8 10

MK-0518 100 mg (n = 7)MK-0518 200 mg (n = 7)MK-0518 400 mg (n = 6)MK-0518 600 mg (n = 8)Placebo (n = 7)

-3

-2

-1

0

1



MK-0518: Adverse Events

Adverse events similar to placebo

Serious drug-related adverse events

– Acute pancreatitis, considered secondary to OBT, n = 1

– Lipoatrophy, n = 1

– Anemia, metabolic acidosis, renal insufficiency, death, n=1

– Hepatomegaly, tenderness, fever (600 mg arm), n = 1

2 discontinuations

– Lack of efficacy (1); death (1)

– Most AEs mild to moderateGrinsztejn B, et al. CROI 2006. Abstract 159LB.



Integrase Inhibitor: GS-9137 10-day monotherapy study

N = 40, HIV positive, HCV/HBV negative

ARV naive or experienced off treatment

Randomized 1:1 vs placebo

Dosing – 200 mg BID

– 400 mg BID

– 800 mg QD

– 800 mg BID

– 50 mg/RTV 100 mg QD

PK studies – Days 1 and 10

– Trough sampling through Day 21

No serious adverse events Once-daily dosing with RTV to be investigated

in phase II trial with experienced patients

DeJesus E, et al. CROI 2006. Abstract 160LB.

BL1 2 3 4 7 1011 14 21-2.5

-2.0

-1.5

-1.0

-0.5

0.0

200 BID400 BID800 BID50 + RTV QD

Placebo800 QD

Day

Lo

g1

0 C

han

ge

HIV

-1 R

NA

Dosing



Next-Generation Fusion Inhibitors

Delmedico M, et al. CROI 2006. Abstract 48.

Animal data

Enhanced pharmacokinetic properties

Potential with once-weekly dosing

In vitro data

High genetic barrier

Active against ENF-resistant virus

Fo

ld D

ecre

ase

in A

ctiv

ity

Number of Mutations

Pla

sma

Co

nce

ntr

atio

n(m

m3/m

L)

Time (Hours)

ENF TRI-1144

TRI-999

Cynomolgus monkeyIV, 1 mg/Kg

0 10 20 30 400

1

10

100 Clearance (mL/kg/hr) ENF 40

TRI-1144 11 TRI-999 7

(6) (7) (8) (9)

> 4321

TRI-999

ENF

TRI-1144

1000

100

10

0

(n)



Novel Maturation Inhibitor, PA-457

Podawany doustnie; 70 godzin okres półtrwania u HIV (+)

Efekt leczenia koreluje z poziomem w surowicy i trough concentration

Liniowa farmakokinetyka prz różnych dawkach

Badania In vitro oporności potwierdzają efekt działania studies confirm mode of action

We wstępnych badaniach nie stwierdzono oporności

Smith P, et al. CROI 2006. Abstract 52.



TNX-355: Novel CD4+ Attachment Inhibitor Anti-CD4 monoclonal antibody blocks

gp120 attachment to CD4+ receptor

– Delivered by IV infusion

Phase II randomized trial in 823-class–experienced patients[1]

– TNX-355 + OBR or OBR alone

– TNX-355 doses:

– 15 mg/kg IV every 2 weeks

– 10 mg/kg IV every week x 8 weeks, then 10 mg/kg every 2 weeks

Active against R5- and X4-tropic HIV[2]

-0.8

-0.4

0

-1.2

Mea

n C

han

ge

in H

IV-1

RN

A a

t W

eek

24 (

log

10 c

op

ies/

mL

)

OBR Alone

15 mg/kg

10 mg/kg

1. Norris D, et al. ICAAC 2005. Abstract LB2-26.2. Godofsky E, et al. ICAAC 2005. Abstract LB26.

-0.20

-0.95(P = .003)

-1.16(P < .001)

TNX-355 + OBR



PA-457: Virologic Response to Novel Maturation Inhibitor Monotherapy PA-457 first in new class called

maturation inhibitors

– Targets late step in HIV life cycle

– Reduces viral load by disrupting production of HIV capsid protein, necessary for infecting other cells

Randomized, phase IIa study of PA-457 10-day monotherapy in 32 HIV-infected patients

– Median 1 log10 VL reduction with PA-457 200 mg/day

Generally well tolerated

-0.8

-0.4

0

-1.2Med

ian

Cha

nge

in H

IV-1

RN

A a

t D

ay 1

0 (lo

g 10

copi

es/m

L)

PL(n = 8)

25(n = 6)

50(n = 6)

100(n = 6)

200(n = 6)

PA-457 Dose (mg/day)

Beatty G, et al. ICAAC 2005. Abstract H-416d.

+0.03 +0.05

-0.17(P = .02)

-0.48(P = .004)

-1.03 (P < .0001)



Zaburzenia metaboliczne i inne objawy uboczne



Prevalence of Metabolic Syndrome in MACS Cohort

Palella F, et al. IAS 2005. Abstract TuPe2.2B18.

Estimated Odds Ratio for HIV+ vs HIV- Pts (95% CI) P Value

Metabolic syndrome 1.50 (1.14-1.98) .004 Elevated fasting triglycerides 2.81 (2.25-3.52) < .001 Elevated fasting glucose 1.81 (1.38-2.38) < .001 Increased waist circumference 0.38 (0.28-0.53) < .001 Low HDL cholesterol 3.15 (2.53-3.92) < .001 High blood pressure 1.04 (0.84-1.29) .715

HIV-positive men more likely to have metabolic syndrome than HIV-negative men

– Low HDL, elevated TGs, elevated glucose more likely in HIV+

– Increased waist circumference less likely in HIV+



Swiss HIV Cohort Study (N = 1065; FU 17-18 mos)

– ↑ cholesterol with either PIs or NNRTIs

– ↑ triglycerides with PIs, particularly with RTV regimens

– Patients primarily on LPV/r, IDV/r, or NFV

– ↑ HDL-C with NNRTIs

Young J, et al. IAS 2005. Abstract TuPe2.2B16.

Lipid Effects of First-line Regimens



Dyslipidemia: Lipid-Lowering Therapy vs PI to NNRTI Switch

Calza L, et al. AIDS. 2005;19:1051-1058. TuFo0105

PravastatinBezafibrate

Mea

n T

ota

l C

ho

lest

ero

l (m

g/d

L)

129630

300

250

200

150

100

Months

EFVNVP

50

-10%

-27%

-46%

-38%



RAVE: Switch Thymidine Analogue to ABC or TDF Suppressed patients with

self-defined lipoatrophy on thymidine analogue NRTI

105 patients randomized to replace TA with

– Tenofovir, or

– Abacavir

Total limb fat increased to similar extent in both arms over 48 weeks

Moyle G, et al. CROI 2005. Abstract 44LB.

Ch

ang

e in

Fat

Mas

s b

y D

EX

A a

t W

eek

48 (

g)

393

522

1061

316

791

1046

0

200

400

600

800

1000

1200

Limb Trunk Total Fat

TDFABC

Within-group change in limb fat from baseline: TDF (P = .01), ABC (P = .001)


HIV/AIDS Update From RioR

isk o

f Disea

se P

rog

ression

or D

eath

No. of Patients With EventsSubgroups Relative Risk (95% CI)

All Patients 1642.5

SexMale

Female

RaceBlack

Nonblack

118

46

2.3

3.4

71

93

3.6

2.0

Severe Complications 1141.5

CVD, liver, or renal deaths

Nonfatal CVD events

31

63

1.4

1.5

Nonfatal hepatic events

Nonfatal renal events

14

7

1.4

2.5

1.0 10.00.1 Favors TI Favors CT

El-Sadr W, et al. CROI 2006. Abstract 106 LB.

Risk

of

Co

mp

licatio

ns

SMART: HIV Progression by Sex and Race; Severe Complications



CD4+ Cell Count–Guided TIs: Summary TI may be safe if patient has CD4+ cell count > 350 cells/mm³ and remains

above that level

In these trials, TI has led to some risk of progression and/or resistance and may potentially lead to increased risk of transmission

In the US, if therapy is indicated, the best results are seen in patients who are on continuous therapy

In developing countries, further investigation of TI is warranted due to limited ART availability

In SMART, increased risk of poor outcome noted unexpectedly early in the interruption period

In SMART, presence of viremia at baseline associated with poorer outcomes regardless of arm

– In viremic patients, no increased risk with CD4+-guided TI (RR 1.1)

– In aviremic patients, ↑ risk of progression or death with TI (RR 3.8)



Koinfekcje



*HCV/HIV coinfection linked to IDU

Hepatitis C: A Global Health Problem

170-200 million carriers worldwide10 million HIV coinfected*

USAUSA3-4 M

30% HIV+*

AmericasAmericas12-15 M

AfricaAfrica30-40 M

W. EuropeW. Europe5 M

30-50% HIV+*

E. EuropeE. Europe10 M

South South East AsiaEast Asia30-35 M

AustraliaAustralia0.2 M

Far EastFar East60 M

HBV350 M

HCV170-200 M

HIV40 M

WHO. 1999.



Increase in Sexual Transmission of HCVGreat Britain; 3 cities; 2002-2005[1]

111 HIV-positive MSM with acute HCV

Phylogenetic analysis of 91 E1/E2 sequences indicated common source transmission of HCV

Risk factors for HCV infection by case-control analysis

– Meeting sexual partners in bathhouses or over the Internet

– Body piercing or tattooing

– Sexual partners and unsafe sex practices, including group sex

– Recreational drug use and drug use during sex

– STDs1. Danta M, et al. CROI 2006. Abstract 86. 2. Coutinho R, et al. CROI 2006. Abstract 87.

Amsterdam Cohort Study[2]

10-fold increase in HCV since 2000

29 cases of HIV-positive MSM with acute HCV

Phylogenetic analysis (n = 24) identified 2 clusters, which are not related to other Dutch risk groups

18 reported unsafe sex practices or mucosal-damaging STDs

Out of 20 surveyed, all denied IDU



Increase in HCV RNA Detection After HAART Initiation Analysis of HCV/HIV-

coinfected pts in the HOMER cohort

20% of patients who were HCV-Ab (+)/HCV RNA (-) pre-HAART became HCV RNA (+) after HAART

Possible explanations

– Blips

– Laboratory variation, error

– Immune restorationBraitstein P, et al. IAS 2005. Abstract TuPe1.1C30.

Baseline samples tested with unambiguous results

(n = 1186)

PCR (+): 70%(n = 425)

PCR (-): 30%(n = 179)

HCV Ab (+) and PCR (+) after 6-12 mos of HAART: 20%

(n = 24 of 118 evaluable samples)

HCV-Ab (+): 51%(n = 606)

HCV-Ab (-): 49%(n = 580)



Complications in HCV/HIV-Coinfected vs HCV-Monoinfected Patients

Miro J. IAS 2005. Abstract TuFo0303; Pineda JA et al, Hepatology. 2005, 41:779-89

Encepha-Encepha-lopathylopathy

VaricealVaricealbleedingbleeding

HCV/HIV coinfected

HCV monoinfected

Fre

qu

ency

as

Fir

st H

epat

ic

Dec

om

pen

sati

on

(%

)

0

10

20

30

40

50

60

70

14%

8%4%

27%

66%

38%

11%

2% 3% 2% 2%

17%

1%4%

AscitesAscites JaundiceJaundice SBPSBP HCCHCC Hepatorenal Hepatorenal syndromesyndrome

P = .01

P < .001

P < .001

P < .001

P = NS

P < .001

P = .02



HCV-3 Coinfection Associated With Greater Risk of Hepatotoxicity N = 388 HIV/HCV-coinfected

patients in Italian cohort

– 132 had HCV genotype 3

Factors associated with ↑ risk of grade ≥ 3 hepatotoxicity

– Male sex

– HBsAg positivity

– Baseline ALT

– HCV genotype 3

0.9

1.0

0.8

0.7

0.6

0.0 0.5 1.0 1.5 2.0 2.5 3.0

0.5

0.4

Time Since Entry (Years)

Cum

ulat

ive

Pro

port

ion

of P

atie

nts

Fre

e of

≥ G

rade

3 H

epat

otox

icity

P < .001

HCV ≠ 3

HCV-3

Torti C, et al. ICAAC 2005. Abstract H-1484.



Rapid Fibrosis Progression in HCV/HIV-Coinfected Patients

Bonnard P, et al. EACS 2005. Abstract PE13.2/2.

0

20

40

60

80

100

F0/1 F2 F3 F4

Pat

ien

ts (

%)

First biopsy Second biopsy

Fibrosis Stage

91

900

40*33

189

Mean time between biopsies: 50 months

*All patients were F1 at second biopsy.

9/32 (28%) of HCV/HIV-coinfected patients progressed ≥ 2 fibrosis points between biopsies



HAART and Liver Enzyme Elevations Meta-analysis of 20 publications of HIV-infected patients ± HCV coinfection

Grade 2 or higher liver elevations noted

Drug Class

Pat

ien

ts W

ith

LE

E,%

NNRTI0

10

32.00

18.44 15.9620

30

40

13.62

5.26

14.67

PI Mixed BPI NRTI Overall

P = .004

P = .025

P = .009

% LEE in HCV-Coinfected Patients by Drug Class

Benhamou Y, et al. CROI 2006. Abstract 88.



Response to Treatment During Acute HCV in HIV-Coinfected Patients 59% SVR among pts with

acute HCV treated with 24 wks Peg-IFN alfa 2b + RBV

– Similar to overall rate in treatment of chronic HCV in coinfected pts

– Better for genotype 1 coinfected pts vs treatment during chronic infection

– Lower than that with treatment of acute HCV in monoinfected pts

High rate of spontaneous clearance w/o therapy (24%)

Nelson M, et al. IAS 2005. Abstract TuPe1.1C10.

0

20

40

60

80

100

All Patients(n = 27)

Genotype 1(n = 20)

Genotype non-1(n = 4)

67% 65%

100%

59% 55%

SVRETR

Viro

logi

c R

espo

nse

(%)

Peg-IFN (1.5 g/kg/wk) + RBV (800-1200 mg/day) for 24 weeks



Low Numbers of HCV/HIV Patients Achieve SVR in an Urban HIV Clinic Retrospective analysis of Johns Hopkins HIV Clinic

n = 6 (21%) of these attained SVR

This represents 2.1% of those referred, or 0.7% of those with

HCV

Mehta S, et al. CROI 2006. Abstract 884.

n = 125 entered evaluation for treatment

n = 277 referred (33%)

n = 29 initiated treatment

n = 845 with HCV



Use of QuantiFERON-TB Goldin HIV-Infected Patients QuantiFERON-TB Gold, new blood-

based diagnostic test for TB infection

– Uses peptides absent from BCG and common non-tuberculous mycobacteria

– CDC recommends that QFT-G be used in all circumstances in which the TB skin test is currently used[1]

– Sensitivity unknown in HIV population

Evaluated in 590 HIV-infected pts[2]

– 27 QFT-G positive

Limitations– No comparison with skin testing – No means of assessing true TB infection

rate

1. Mazurek GH, et al. MMWR Morb Mortal Wkly Rep. 2005;54(RR- 15):49-55. 2. Brock I, et al. ICAAC 2005. Abstract H-1494.

Pat

ient

s (%

)

100-199 200-300 > 3000

20

40

60

0-99

QTF-G(-) (n = 543)

QTF-G(+) (n = 27)80

100

Mean CD4+ Cell Count (cells/mm3)

2 046

10 7

81

89



Hepatotoxicity with Rifampin + SQV/r

2/05 FDA letter warning of ↑ risk of hepatotoxicity when hard-gel SQV/r taken with rifampin in healthy volunteers

Confirmed by data in TB/HIV-coinfected patients

– Prospective study of 20 coinfected patients who began SQV/RTV (400/400 BID) 30 days into TB treatment [1]

– 14 pts discontinued during TB-HIV therapy phase due to ARV intolerance (mostly hepatic and gastrointestinal events)

– Chart review of 12 coinfected pts on rifampin who began SQV/r (1000/100 BID) + 2 NRTIs during induction phase [2]

– 6 experienced hepatotoxicity – 3 cases moderate to severe; all had HCV

– 1 pt permanently discontinued antiretroviral treatment

1. Rolla V, et al. IAS 2005. Abstract WePe3.3C03. 2. Duran A, et al. IAS 2005. Abstract TuPe7.1C22.



EuroSIDA: Liver-Related Deaths in HIV-Infected Patients Death rates from liver-related disease appear to have

decreased in Europe (1995-2004/5)

– After adjusting for CD4+ cell count, small ↑ in liver disease–related deaths noted

↑ HAART exposure associated with ↑ liver disease–related death after adjusting for CD4+ cell count

– May be due to ARV-induced liver toxicity, progression of liver disease in HBV- or HCV-coinfected patients as patients survive longer, or other factors

Lundgren J, et al. EACS 2005. Abstract PS7/2.



Predictors of Anal Dysplasia in HIV-Positive and HIV-Negative MSM UCSD anal dysplasia screening clinic[1]

– Pap screening not associated with decreased prevalence of invasive anal cancer, although earlier stage at detection suggested

– Pap correlated with biopsy (increasingly so with increased operator experience)

Anal dysplasia referral population study[2]

– 36% of HIV-positive men and 30% of HIV-negative men had high-grade anal dysplasia

– Pap results did not correlate with biopsy

– ARV use and duration not predictive of high-grade anal dysplasia

1. Press N, et al. CROI 2006. Abstract 808. 2. Montaner J, et al. CROI 2006. Abstract 807.

Documents

Co nowego na zjazdach CROI, ICAAC. EACS