CC_9 R. Montejano Sanchez, Mª Luisa Montes, Ignacio Perez- Valero, Silvia Garcia-Bujalance, Jose R Arribas Hospital Universitario La Paz
CLINICAL CASE 56-year-old man HIV diagnosed 993. Sexual transmission Recurrent genital Herpes simplex 3- Herpes zoster infection 6- Oral candidiasis B3 CDC stage Transferred to our Hospital in 6/6 because of difficult management due to multiple resistance Never supressed, despite great adherence CD4 Nadir 2 cell/ml
ART HISTORY Date ART 5/2/993 NAÏVE 5/3/993 AZT 5/3/995 AZT ddi 5/4/996 ddi d4t SAQ 5/2/997 AZT 3TC SAQ RIT 5/6/998 d4t ABC NEV NFV 5//999 ddi d4t EFV IDV RIT 5/2/ 3TC TDF LOP/r FAMP T2 5//4 ddi 3TC TDF TPV T2 5//6 TDF/FTC TPV RIT
RESISTANCE MUTATIONS GENOTYPE Reverse transcriptase: M4L, K43E, E44A, S68G, L74I, KE, K3R, V8I, V8I, V79F, Y8C, M84V, G9A, G96E, E23K, L2W, R2K, T25Y, K29N, K223Q, L228R, L238I High-level resistance to all NRTI and NNRTI Protease: LY, VI, I3V, A22V, L33I, I54L, Q58E, I62V, L63P, A7V, G73S, V82L, I84V, L89V, L9M High-level resistance to all PI Fusion inhibitor resistance - Previous hospital: V38M, V38A Reduce enfuvirtide susceptibility by more than -fold in site-directed mutants and most clinical isolates. HIV tropism test performed Previous hospital (Trofile): Dual tropic virus CCR5 partially active
4 2 25/6/6 4//6 27/2/7 2/7/7 23//7 27/3/8 9/5/8 23/7/8 7//9 2/7/9 5//2 26/5/2 22/6/2 22/9/2 7//2 25/4/2 3/5/2 7/5/2 /6/2 7/6/2 /7/2 2/9/2 2//22 22/2/22 3/6/22 2/2/22 26/6/23 8//24 9/3/24 8//24 27/5/25 Viral load (log copies/ml) ddi + 3TC/ZVD + DRV RIT DUET- Clinical trial ddi + 3TC/ZVD + DRV RIT + ETV DUET Rollover Clinical trial
4 2 25/6/6 4//6 27/2/7 2/7/7 23//7 27/3/8 9/5/8 23/7/8 7//9 2/7/9 5//2 26/5/2 22/6/2 22/9/2 7//2 25/4/2 3/5/2 7/5/2 /6/2 7/6/2 /7/2 2/9/2 2//22 22/2/22 3/6/22 2/2/22 26/6/23 8//24 9/3/24 8//24 27/5/25 Viral load (log copies/ml) ETV + DRV RIT + T2 + RAL Early access to RAL: RAL- MK-58-23
4 2 25/6/6 4//6 27/2/7 2/7/7 23//7 27/3/8 9/5/8 23/7/8 7//9 2/7/9 5//2 26/5/2 22/6/2 22/9/2 7//2 25/4/2 3/5/2 7/5/2 /6/2 7/6/2 /7/2 2/9/2 2//22 22/2/22 3/6/22 2/2/22 26/6/23 8//24 9/3/24 8//24 27/5/25 Viral load (log copies/ml) 3TC/ZDV + ETV + DRV RIT + RAL
4 2 25/6/6 4//6 27/2/7 2/7/7 23//7 27/3/8 9/5/8 23/7/8 7//9 2/7/9 5//2 26/5/2 22/6/2 22/9/2 7//2 25/4/2 3/5/2 7/5/2 /6/2 7/6/2 /7/2 2/9/2 2//22 22/2/22 3/6/22 2/2/22 26/6/23 8//24 9/3/24 8//24 27/5/25 Viral load (log copies/ml) TDF/FTC + DRV RIT + RAL + MVC TDF/FTC + DRV RIT + MVC
RESISTANCE MUTATIONS GENOTYPE Reverse transcriptase: M4L, E, V8I, V8I, Y8C, M84V, G9A, L2W High-level resistance to all NRTI and NNRTI Protease: V32I, I54L, Q58E, L63P, G73S, V82L, I84V, L9M, VI, I5V, M36L, I62V, A7I, L89V High-level resistance to all protease inhibitors. Fusion inhibitor resistance: V38M, V38A Reduce enfuvirtide susceptibility by more than -fold in site-directed mutants and most clinical isolates. Integrase Inhibitor: E92Q, N55H 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 23/3/8
4 2 25/6/6 4//6 27/2/7 2/7/7 23//7 27/3/8 9/5/8 23/7/8 7//9 2/7/9 5//2 26/5/2 22/6/2 22/9/2 7//2 25/4/2 3/5/2 7/5/2 /6/2 7/6/2 /7/2 2/9/2 2//22 22/2/22 3/6/22 2/2/22 26/6/23 8//24 9/3/24 8//24 27/5/25 Viral load (log copies/ml) TDF + DRV RIT + MVC TDF/FTC + DRV RIT + MVC TDF/FTC + LOP/r+ MVC
CLINICAL EVOLUTION AIDS event Wasting syndrome Oral candidiasis Neurosyphilis Permanently non suppressed Last Viral load 2.9 e6 copies/ml Current CD4 count 2 cell/mm3
RESISTANCE MUTATIONS GENOTYPE Reverse transcriptase: M4L, KE, V8I, V8I, Y8C, M84V, G9A, L2W, T25Y, V79F. High-level resistance to all NRTI and NNRTI Protease: LF, LY, I3V, M36L, V32I, I54L, Q58E, A7I, G73S, V82L, I84V, L89V, L9M, VI, M36L, L89V. High-level resistance to all PI. Fusion inhibitor resistance: V38M, V38A, V38E. Reduce enfuvirtide susceptibility by more than -fold in site-directed mutants and most clinical isolates. Integrase Inhibitor: E92Q, N55H, N55I. High-level resistance to raltegravir and elvitegravir and low-level resistance to DTG. HIV tropism test performed - April 9 (Trofile): CX4 tropic virus. CCR5 inhibitors not active.
What could we do? Compassionate use dolutegravir (ViiV ) Expert opinion Reinforce adherence
Peg-INF as a ART?.46 (.3,.63; P =.24).39 (.24,.55; P=.8).53 (.36,.69; P<.) The proportion of patients with greater than.65 log decrease in plasma viral load, was significantly higher in the arms that received PegIntron, as compared with the placebo recipients (32%, 3%, and 42% versus 8% in the placebo group)
4 2 25/6/6 4//6 27/2/7 2/7/7 23//7 27/3/8 9/5/8 23/7/8 7//9 2/7/9 5//2 26/5/2 22/6/2 22/9/2 7//2 25/4/2 3/5/2 7/5/2 /6/2 7/6/2 /7/2 2/9/2 2//22 22/2/22 3/6/22 2/2/22 26/6/23 8//24 9/3/24 8//24 27/5/25 Viral load (log copies/ml) d4t + TDF/FTC + DRV RIT + DTG + Peg-INF 2α + T2 d4t 4 mg + TDF/FTC / mg + DRV/R / mg BID + DTG mg BID + PEG-IFN-α2a 8 mcg weekly + T2 9 mg BID DTG: Compassionate use program
4 2 25/6/6 4//6 27/2/7 2/7/7 23//7 27/3/8 9/5/8 23/7/8 7//9 2/7/9 5//2 26/5/2 22/6/2 22/9/2 7//2 25/4/2 3/5/2 7/5/2 /6/2 7/6/2 /7/2 2/9/2 2//22 22/2/22 3/6/22 2/2/22 26/6/23 8//24 9/3/24 8//24 27/5/25 Viral load (log copies/ml) d4t + TDF/FTC + DRV RIT + DTG + Peg-INF 2α + T2 + Foscarnet d4t + TDF/FTC + DRV RIT + DTG + Peg-INF 2α + MVC
4 2 25/6/6 4//6 27/2/7 2/7/7 23//7 27/3/8 9/5/8 23/7/8 7//9 2/7/9 5//2 26/5/2 22/6/2 22/9/2 7//2 25/4/2 3/5/2 7/5/2 /6/2 7/6/2 /7/2 2/9/2 2//22 22/2/22 3/6/22 2/2/22 26/6/23 8//24 9/3/24 8//24 27/5/25 Viral load (log copies/ml) d4t + DRV RIT + DTG + Peg-INF 2α + MVC d4t + DRV RIT + DTG + MVC + Valaciclovir
4 2 25/6/6 4//6 27/2/7 2/7/7 23//7 27/3/8 9/5/8 23/7/8 7//9 2/7/9 5//2 26/5/2 22/6/2 22/9/2 7//2 25/4/2 3/5/2 7/5/2 /6/2 7/6/2 /7/2 2/9/2 2//22 22/2/22 3/6/22 2/2/22 26/6/23 8//24 9/3/24 8//24 27/5/25 Viral load (log copies/ml) d4t + DRV RIT + DTG + Peg-INF 2α + MVC
25/6/6 4//6 27/2/7 2/7/7 23//7 27/3/8 9/5/8 23/7/8 7//9 2/7/9 5//2 26/5/2 22/6/2 22/9/2 7//2 25/4/2 3/5/2 7/5/2 /6/2 7/6/2 /7/2 2/9/2 2//22 22/2/22 3/6/22 2/2/22 26/6/23 8//24 9/3/24 8//24 27/5/25 4 2 Viral load (log copies/ml) DRV RIT + DTG + Peg-INF 2α + MVC Reduced doses Peg-INF, 35 mcg weekly
4 2 25/6/6 4//6 27/2/7 2/7/7 23//7 27/3/8 9/5/8 23/7/8 7//9 2/7/9 5//2 26/5/2 22/6/2 22/9/2 7//2 25/4/2 3/5/2 7/5/2 /6/2 7/6/2 /7/2 2/9/2 2//22 22/2/22 3/6/22 2/2/22 26/6/23 8//24 9/3/24 8//24 27/5/25 Viral load (log copies/ml) DRV RIT + DTG + MVC
4 2 25/6/6 4//6 27/2/7 2/7/7 23//7 27/3/8 9/5/8 23/7/8 7//9 2/7/9 5//2 26/5/2 22/6/2 22/9/2 7//2 25/4/2 3/5/2 7/5/2 /6/2 7/6/2 /7/2 2/9/2 2//22 22/2/22 3/6/22 2/2/22 26/6/23 8//24 9/3/24 8//24 27/5/25 Viral load (log copies/ml) DRV RIT + DTG + MVC
4 2 25/6/6 4//6 27/2/7 2/7/7 23//7 27/3/8 9/5/8 23/7/8 7//9 2/7/9 5//2 26/5/2 22/6/2 22/9/2 7//2 25/4/2 3/5/2 7/5/2 /6/2 7/6/2 /7/2 2/9/2 2//22 22/2/22 3/6/22 2/2/22 26/6/23 8//24 9/3/24 8//24 27/5/25 ddi + 3TC/ZVD + DRV RIT ddi + 3TC/ZVD + DRV RIT + ETV TDF/FTC Viral + load DRV (log RIT + MVC copies/ml) 3TC/ZDV + ETV + DRV RIT + RAL TDF + DRV RIT + MVC d4t + TDF/FTC + DRV RIT + DTG + Peg-INF 2α + T2 3TC/ZDV + ETV + DRV RIT + RAL TDF/FTC + LOP/r+ MVC TDF/FTC + DRV RIT + RAL + MVC TDF/FTC + DRV RIT + MVC d4t + TDF/FTC + DRV RIT + DTG + Peg-INF 2α + T2 + Foscarnet d4t + TDF/FTC + DRV RIT + DTG + Peg-INF 2α + MVC DRV RIT + DTG + MVC DRV RIT + DTG + Peg-INF 2 α + MVC d4t + DRV RIT + DTG + Peg-INF 2α + MVC d4t + DRV RIT + DTG + MVC + Valaciclovir d4t + DRV RIT + DTG + Peg-INF 2α + MVC
ART REGIMENS Viral load (log copies/ml) 4 months suppresed: 2 months DRV/r+DTG+MVC+PEG-IFN-α2a 2 months DRV/r+DTG+MVC 4 2 Date ART 5/3/993 AZT 5/3/995 AZT ddi 5/4/996 ddi d4t SAQ 5/2/997 AZT 3TC SAQ RIT 5/6/998 d4t ABC NEV NFV 5//999 ddi d4t EFV IDV RIT 5/2/ 3TC TDF LOP/r FAMP T2 5//4 ddi 3TC TDF TPV T2 5//6 TDF/FTC TPV RIT /7/6 ddi 3TC/ZDV DRV RIT 9/9/7 ddi 3TC/ZDV ETV DRV RIT 23//7 ETV DRV RIT T2 RAL 23//8 3TC/ZDV ETV DRV RIT RAL /4/8 TDF/FTC DRV RIT RAL MRC 9/5/8 TDF/FTC DRV RIT MRC 3/5/2 TDF DRV RIT MRC 28/6/2 TDF LOP/r MRC 3//2 TDF/FTC DRV RIT MRC d4t TDF/FTC DRV RIT DTG INF T2 23/5/2 d4t TDF/FTC DRV RIT DTG INF T2 Foscarnet /7/2 d4t TDF/FTC DRV RIT DTG INF MRC 4/2/2 d4t DRV RIT DTG MRC Valaciclovir 26//22 d4t DRV RIT DTG INF MRC 8/4/22 DRV RIT DTG MRC INF 5//24 DRV RIT DTG MRC
CONCLUSIONS The combination of Dolutegravir plus Peg interferon alfa-2a could be able to achieve long-term virologic control if there are no Q48 integrase drug resistance mutations. This combination could be an option in exceptionally difficult to treat cases