r. montejano sanchez , mª luisa montes, ignacio...
TRANSCRIPT
R. Montejano Sanchez, Mª Luisa Montes, Ignacio Perez-Valero, Silvia Garcia-Bujalance, Jose R Arribas
Hospital Universitario La Paz
CC_09
CLINICAL CASE
• 56-year-old man • HIV diagnosed 1993. Sexual transmission • Recurrent genital Herpes simplex • 2003- Herpes zoster infection • 2006- Oral candidiasis • B3 CDC stage • Transferred to our Hospital in 06/2006 because of
difficult management due to multiple resistance – Never supressed, despite great adherence – CD4 Nadir 20 cell/ml
Date ART
15/02/1993 NAÏVE 15/03/1993 AZT 15/03/1995 AZT ddI 15/04/1996 ddI d4T SAQ 15/02/1997 AZT 3TC SAQ RIT 15/06/1998 d4T ABC NEV NFV 15/01/1999 ddI d4T EFV IDV RIT 15/02/2001 3TC TDF LOP/r FAMP T20 15/11/2004 ddI 3TC TDF TPV T20 15/01/2006 TDF/FTC TPV RIT
ART HISTORY
RESISTANCE MUTATIONS GENOTYPE
• Reverse transcriptase: M41L, K43E, E44A, S68G, L74I, K101E, K103R, V108I, V118I, V179F, Y181C, M184V, G190A, G196E, E203K, L210W, R211K, T215Y, K219N, K223Q, L228R, L238I – High-level resistance to all NRTI and NNRTI
• Protease: L10Y, V11I, I13V, A22V, L33I, I54L, Q58E, I62V, L63P, A71V, G73S, V82L, I84V, L89V, L90M – High-level resistance to all PI
• Fusion inhibitor resistance - Previous hospital: V38M, V38A – Reduce enfuvirtide susceptibility by more than 10-fold in site-directed
mutants and most clinical isolates. • HIV tropism test performed – Previous hospital (Trofile): Dual tropic
virus – CCR5 partially active
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Viral load - CD4 count evolution
Viral load (log 10 copies/ml) CD4 count (cells/ml)
ddI + 3TC/ZVD + DRV RIT + ETV
ddI + 3TC/ZVD + DRV RIT DUET-1 Clinical trial
DUET Rollover Clinical trial
VIRAL & IMMUNOLOGICAL SITUATION
ETV + DRV RIT + T20 + RAL
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03/0
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01/0
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/01/
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19/0
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/10/
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27/0
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Viral load - CD4 count evolution
Viral load (log 10 copies/ml) CD4 count (cells/ml)
VIRAL & IMMUNOLOGICAL SITUATION
Early access to RAL: RAL- MK-0518-023
3TC/ZDV + ETV + DRV RIT + RAL
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/01/
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26/0
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/06/
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22/0
9/20
1017
/01/
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13/0
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1125
/04/
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03/0
5/20
1117
/05/
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01/0
6/20
1117
/06/
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11/0
7/20
1121
/09/
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12/0
1/20
1222
/02/
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13/0
6/20
1212
/12/
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26/0
6/20
1308
/01/
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19/0
3/20
1408
/10/
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27/0
5/20
15
Viral load - CD4 count evolution
Viral load (log 10 copies/ml) CD4 count (cells/ml)
VIRAL & IMMUNOLOGICAL SITUATION
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/06/
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/01/
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13/0
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1125
/04/
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/02/
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/12/
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/01/
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/10/
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Viral load - CD4 count evolution
Viral load (log 10 copies/ml) CD4 count (cells/ml)
TDF/FTC + DRV RIT + MVC
TDF/FTC + DRV RIT + RAL + MVC
VIRAL & IMMUNOLOGICAL SITUATION
RESISTANCE MUTATIONS GENOTYPE
• Reverse transcriptase: M41L, 101E, V108I, V118I, Y181C, M184V, G190A, L210W – High-level resistance to all NRTI and NNRTI
• Protease: V32I, I54L, Q58E, L63P, G73S, V82L, I84V, L90M, V11I, I15V, M36L, I62V, A71I, L89V – High-level resistance to all protease inhibitors.
• Fusion inhibitor resistance: V38M, V38A – Reduce enfuvirtide susceptibility by more than 10-fold in site-directed
mutants and most clinical isolates. • Integrase Inhibitor: E92Q, N155H
– High-level resistance to raltegravir and elvitegravir and low-level resistance to DTG.
• HIV tropism test performed – (Trofile): non typeable – Other hospital: Dual tropic virus – CCR5 partially active
23/03/2008
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7/20
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/01/
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7/20
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/01/
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26/0
5/20
1022
/06/
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22/0
9/20
1017
/01/
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13/0
4/20
1125
/04/
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03/0
5/20
1117
/05/
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01/0
6/20
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/06/
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11/0
7/20
1121
/09/
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12/0
1/20
1222
/02/
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13/0
6/20
1212
/12/
2012
26/0
6/20
1308
/01/
2014
19/0
3/20
1408
/10/
2014
27/0
5/20
15
Viral load - CD4 count evolution
Viral load (log 10 copies/ml) CD4 count (cells/ml)
TDF/FTC + LOP/r+ MVC
TDF + DRV RIT + MVC TDF/FTC + DRV RIT + MVC
VIRAL & IMMUNOLOGICAL SITUATION
CLINICAL EVOLUTION
• AIDS event – Wasting syndrome
• Oral candidiasis
• Neurosyphilis • Permanently non suppressed
– Last Viral load 2.9 10e6 copies/ml
• Current CD4 count 20 cell/mm3
RESISTANCE MUTATIONS GENOTYPE
• Reverse transcriptase: M41L, K101E, V108I, V118I, Y181C, M184V, G190A, L210W, T215Y, V179F. – High-level resistance to all NRTI and NNRTI
• Protease: L10F, L10Y, I13V, M36L, V32I, I54L, Q58E, A71I, G73S, V82L, I84V, L89V, L90M, V11I, M36L, L89V. – High-level resistance to all PI.
• Fusion inhibitor resistance: V38M, V38A, V38E. – Reduce enfuvirtide susceptibility by more than 10-fold in site-directed
mutants and most clinical isolates. • Integrase Inhibitor: E92Q, N155H , N155I.
– High-level resistance to raltegravir and elvitegravir and low-level resistance to DTG.
• HIV tropism test performed - April 2009 (Trofile): CX4 tropic virus. – CCR5 inhibitors not active.
13/04/2011
What could we do?
• Compassionate use dolutegravir (ViiV®) • Expert opinion • Reinforce adherence
Peg-INF as a ART?
0.46 (0.30, 0.63; P = 0.024)
0.39 (0.24, 0.55; P=0.008)
0.53 (0.36, 0.69; P<0.001)
The proportion of patients with greater than 0.65 log10 decrease in plasma viral load, was significantly higher in the arms that received PegIntron, as compared with the placebo recipients (32%, 31%, and 42% versus 8% in the placebo group)
d4T + TDF/FTC + DRV RIT + DTG + Peg-INF 2α + T20
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26/0
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13/0
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1125
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5/20
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Viral load - CD4 count evolution
Viral load (log 10 copies/ml) CD4 count (cells/ml)
VIRAL & IMMUNOLOGICAL SITUATION
d4T 40 mg + TDF/FTC 300/200 mg + DRV/R 1000/100 mg BID + DTG 50mg BID + PEG-IFN-α2a 180 mcg weekly + T20 90 mg BID
DTG: Compassionate use program
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Viral load - CD4 count evolution
Viral load (log 10 copies/ml) CD4 count (cells/ml)
VIRAL & IMMUNOLOGICAL SITUATION
d4T + TDF/FTC + DRV RIT + DTG + Peg-INF 2α + MVC
d4T + TDF/FTC + DRV RIT + DTG + Peg-INF 2α + T20 + Foscarnet
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9/20
1017
/01/
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13/0
4/20
1125
/04/
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03/0
5/20
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/05/
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01/0
6/20
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7/20
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/09/
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1/20
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/02/
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/10/
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Viral load - CD4 count evolution
Viral load (log 10 copies/ml) CD4 count (cells/ml)
VIRAL & IMMUNOLOGICAL SITUATION
d4T + DRV RIT + DTG + MVC + Valaciclovir
d4T + DRV RIT + DTG + Peg-INF 2α + MVC
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/01/
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/04/
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03/0
5/20
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Viral load - CD4 count evolution
Viral load (log 10 copies/ml) CD4 count (cells/ml)
VIRAL & IMMUNOLOGICAL SITUATION
d4T + DRV RIT + DTG + Peg-INF 2α + MVC
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/04/
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1/20
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/02/
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/01/
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/10/
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27/0
5/20
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Viral load - CD4 count evolution
Viral load (log 10 copies/ml) CD4 count (cells/ml)
VIRAL & IMMUNOLOGICAL SITUATION
DRV RIT + DTG + Peg-INF 2α + MVC
Reduced doses Peg-INF, 135 mcg weekly
VIRAL & IMMUNOLOGICAL SITUATION
DRV RIT + DTG + MVC
0
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/01/
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02/0
7/20
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/01/
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26/0
5/20
1022
/06/
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22/0
9/20
1017
/01/
2011
13/0
4/20
1125
/04/
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03/0
5/20
1117
/05/
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01/0
6/20
1117
/06/
2011
11/0
7/20
1121
/09/
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12/0
1/20
1222
/02/
2012
13/0
6/20
1212
/12/
2012
26/0
6/20
1308
/01/
2014
19/0
3/20
1408
/10/
2014
27/0
5/20
15
Viral load - CD4 count evolution
Viral load (log 10 copies/ml) CD4 count (cells/ml)
VIRAL & IMMUNOLOGICAL SITUATION
0
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1000000025
/06/
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7/20
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3/20
0809
/05/
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23/0
7/20
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/01/
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02/0
7/20
0905
/01/
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26/0
5/20
1022
/06/
2010
22/0
9/20
1017
/01/
2011
13/0
4/20
1125
/04/
2011
03/0
5/20
1117
/05/
2011
01/0
6/20
1117
/06/
2011
11/0
7/20
1121
/09/
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12/0
1/20
1222
/02/
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13/0
6/20
1212
/12/
2012
26/0
6/20
1308
/01/
2014
19/0
3/20
1408
/10/
2014
27/0
5/20
15
Viral load - CD4 count evolution
Viral load (log 10 copies/ml) CD4 count (cells/ml)
DRV RIT + DTG + MVC
VIRAL & IMMUNOLOGICAL SITUATION
0
50
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450
1
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1000000
1000000025
/06/
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04/1
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/02/
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21/0
7/20
0723
/10/
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27/0
3/20
0809
/05/
2008
23/0
7/20
0807
/01/
2009
02/0
7/20
0905
/01/
2010
26/0
5/20
1022
/06/
2010
22/0
9/20
1017
/01/
2011
13/0
4/20
1125
/04/
2011
03/0
5/20
1117
/05/
2011
01/0
6/20
1117
/06/
2011
11/0
7/20
1121
/09/
2011
12/0
1/20
1222
/02/
2012
13/0
6/20
1212
/12/
2012
26/0
6/20
1308
/01/
2014
19/0
3/20
1408
/10/
2014
27/0
5/20
15
Viral load - CD4 count evolution
Viral load (log 10 copies/ml) CD4 count (cells/ml)DRV RIT + DTG + MVC
d4T + DRV RIT + DTG + Peg-INF 2α + MVC
d4T + DRV RIT + DTG + MVC + Valaciclovir
d4T + DRV RIT + DTG + Peg-INF 2α + MVC
d4T + TDF/FTC + DRV RIT + DTG + Peg-INF 2α + MVC
d4T + TDF/FTC + DRV RIT + DTG + Peg-INF 2α + T20
d4T + TDF/FTC + DRV RIT + DTG + Peg-INF 2α + T20 + Foscarnet
TDF/FTC + LOP/r+ MVC
TDF + DRV RIT + MVC
TDF/FTC + DRV RIT + MVC
TDF/FTC + DRV RIT + MVC
TDF/FTC + DRV RIT + RAL + MVC
ddI + 3TC/ZVD + DRV RIT + ETV
ddI + 3TC/ZVD + DRV RIT
3TC/ZDV + ETV + DRV RIT + RAL
3TC/ZDV + ETV + DRV RIT + RAL DRV RIT + DTG + Peg-INF 2 α + MVC
ART REGIMENS
Date ART
15/03/1993 AZT 15/03/1995 AZT ddI 15/04/1996 ddI d4T SAQ 15/02/1997 AZT 3TC SAQ RIT 15/06/1998 d4T ABC NEV NFV 15/01/1999 ddI d4T EFV IDV RIT 15/02/2001 3TC TDF LOP/r FAMP T20 15/11/2004 ddI 3TC TDF TPV T20 15/01/2006 TDF/FTC TPV RIT 11/07/2006 ddI 3TC/ZDV DRV RIT 19/09/2007 ddI 3TC/ZDV ETV DRV RIT 23/10/2007 ETV DRV RIT T20 RAL 23/01/2008 3TC/ZDV ETV DRV RIT RAL 11/04/2008 TDF/FTC DRV RIT RAL MRC 09/05/2008 TDF/FTC DRV RIT MRC 31/05/2010 TDF DRV RIT MRC 28/06/2010 TDF LOP/r MRC 31/01/2011 TDF/FTC DRV RIT MRC 13/04/2011 d4T TDF/FTC DRV RIT DTG INF T20 23/05/2011 d4T TDF/FTC DRV RIT DTG INF T20 Foscarnet 01/07/2011 d4T TDF/FTC DRV RIT DTG INF MRC 14/12/2011 d4T DRV RIT DTG MRC Valaciclovir 26/01/2012 d4T DRV RIT DTG INF MRC 18/04/2012 DRV RIT DTG MRC INF 15/01/2014 DRV RIT DTG MRC
41 months suppresed: • 21 months DRV/r+DTG+MVC+PEG-IFN-α2a • 20 months DRV/r+DTG+MVC
050100150200250300350400450
1
10
100
1000
10000
100000
1000000
10000000
Viral load - CD4 count evolution
Viral load (log 10 copies/ml)
CD4 count (cells/ml)
CONCLUSIONS
• The combination of Dolutegravir plus Peg–
interferon alfa-2a could be able to achieve long-term virologic control if there are no Q148 integrase drug resistance mutations.
• This combination could be an option in exceptionally difficult to treat cases