Resistance to Antiretroviral Drugs HIV-2
HIV-2: Background • 1986 • Restricted to West Africa with decreasing prevalence even in Guinea Bissau – ≈ 1million persons infected by HIV-2 • Portugal: HIV-2 accounts for 4.5% AIDS cases (2004) • France (2006): HIV-2 represented 1.8% of newly diagnosed HIV patients ( F Barin et al. AI DS 2 0 0 7 )
HIV-2: Background • 1986 • Restricted to West Africa with decreasing prevalence even in Guinea Bissau – ≈ 1million persons infected by HIV-2 • Portugal: HIV-2 accounts for 4.5% AIDS cases (2004) • France (2006): HIV-2 represented 1.8% of newly diagnosed HIV patients ( F Barin et al. AI DS 2 0 0 7 ) • Low frequency of RNA plasma detection: in ≈ 50% of patients – Low plasma titers (rarely >4 log c/ml) – lower rates and levels of HIV-2 RNA in the female genital tract than HIV-1 – low semen viral load ( Gottlieb, AIDS 2006, 2008 ) • Similar total proviral DNA titers (integrated and unintegrated) ≈ 3 log c/106 cells • Less pathogenic: longer incubation period, lower rate of disease progression, reduced frequency of transmission.
HIV-2: Background • HIV-1 and HIV-2 share less than 50 % genomic homology HIV-2 close to SIV (SIVsm) 8 clades characterized (A to H): A and B more prevalent
HIV- - 2 2 HIV Naturally attenuated attenuated HIV infection: HIV infection: why why? ? Naturally – SIVmac is not a model for human HIV-2 infection – Non-pathogenic SIVs are not a model for human HIV-2 infection (high VL)
Entry Inhibitors
CCR5 inhibitors: Maraviroc and Vicriviroc ??? Large in-vitro coreceptors usage: CCR1, CCR2, CCR3, GPR15, CXCR6 , BOB… .Activity of the CCR5 inhibitors? Tropism assays not available in clinical practice Shi et al ARHR 2002
Association between V3 loop amino-acids global charge and coreceptors usage V3 loop amino-acid global charge: : CCR5 + : +5 or +6 CCR5 - : +7 CXCR4 + : +7 , CXCR4 - : +5 or +6. Shi et al; J Gen Virol 2005
Fusion Inhibitor: Enfuvirtide • Enfuvirtide (Poveda, ARHR 2004) – Not active – Gp36 HIV-2 transmembrane (TM) protein very different from gp 41 HIV-1TM protein to allow enfuvirtide fixation to HR-2 Susceptibility of HIV-2, SIV to various anti-HIV-1 compounds M Witvrouw et al, Antiviral Therapy, 2004 T20: EC50 Fold Increase HIV2 ROD X 70 HIV2 EHO X 90
HIV-2 and RT Inhibitors
HIV-2 and NRTIs • In vitro natural suceptibilities similar to HIV-1 for all licensed NRTIs: ZDV, d4T, 3TC, FTC, ddI, TDF, ABC • Natural polymorphism at 6 positions with amino acids sometimes associated with HIV-1 resistance: – 69N, 75I, 118I, 210N, 215S, 219 E – facilitating different mutational pathways at failure compared to HIV-1?
HIV-2 and NRTIs : selection of mutations at failure HIV-1 HIV-2 ZDV 215 and TAMs 65R: 70% ; 151M : 30% (Descamps, 04) 65R: 20% ; 151M: 78% (Camacho, 09) D4T 215 and TAMs 100% B 65R : 70% , 151M : 30% et CRF_02; C 50% , 65R 3TC/ FTC 184V/ I 184V/ I ddI 74V, 65R 65R TDF 65R 65R ABC 74V, 115, 184V 65R Preferential selection of K65R and Q151M mutations at failure No TAMs except 70R Decrease in NRTI incorporation to the benefice of natural nucleosides
HIV-2: Mutations K65R and Q151M K65R: The mechanism of selection seems to be very close to HIV- 1 subtype C with the « signature » K64 K65 K66 which probably promotes the selection of K65R Q151M : No known mechanism facilitating the selection of 151M
HIV-2 and NNRTI : natural resistance • HIV-1 (grey) and HIV-2 (colored) RT structures seem to be similar • But different AA at codons 101, 181, 188, 190 • HIV-2 is naturally resistant to all licensed NNRTIs (nevirapine, efavirenz, etravirine as well as rilpivirine Ren, PNAS 2002
Resistance to Rilpivirine In vitro vitro activity activity of of RIL on HIV RIL on HIV- - 1, HIV 1, HIV- - 2 and 2 and SIVmac SIVmac In In vitro activity of RIL on HIV-1, HIV-2 and SIVmac EC50 (nM) median (IQR) NNRTI HIV-1 (IIIB) HIV-2 (ROD) SIV (mac251) RIL 0,73 (0,30-0,98) 5 220 (2 510-10 830) 4 310 (2 210-8 410) EFV 1,73 (1,14-2,42) 24 840 (14 490-32 000) 45 110 (22 780-45 860) ETR 2,73 (2,06-3,49) 5 670 (3 100-7 340) 3 330 (3 120-7 960) > 31 250 (29 980-32 NVP 34,09 (26,23-44,90) > 31 250 (31 250-100 000) 000) Rimsky LT, XVIII IHDRW 2009, Abs. 120
HIV-2 and Protease Inhibitors
HIV-2 and Protease Inhibitors • Variable sensitivity among PIs has been reported, • Lopinavir, saquinavir, and darunavir having greater activities than other approved PIs Desbois et al. AAC 2008
HIV-2 and Protease Inhibitors Smith et al, CROI 2010, Abs 579
Differences between HIV-1 and HIV-2 protease genes (Los Alamos database and F Damond, 2005) N Terminal residues Enzyme Active site region Amino acid number 3 4 7 10 12 13 14 16 19 20 22 24 30 31 32 33 HIV-2 Clade A P Q F S L W K R P V V T A Y I E G Q P V E V L L D T G A D D S I V HIV-2 Clade B R K C S HIV-1 consensus B I T Q L T I K G L K A T V L Top of flaps residues 34 35 36 37 39 40 41 42 43 46 47 48 50 54 55 56 57 58 60 61 62 63 64 65 66 HIV-2 Clade A A G I E L G S N Y S P K I V G G I G G F I N T K E Y K N V E I K V HIV-2 Clade B T D E HIV-1 consensus B E E M N P G R W K M I K V R Q D Q I L E I Second loop of sheet residues C Terminal residues 67 68 69 70 71 72 73 75 76 77 79 82 84 85 89 90 91 92 93 95 96 99 HIV-2 Clade A L N K R V R A T I M T G D T P I N I F G R N I L T A L G M S L N L HIV-2 Clade B V G N T T F HIV-1 consensus B C G H K A I G V L V P V I L T Q I C T F Positions involved in minor mutations for HIV-1 Positions involved in major mutations for HIV-1 • Concerned 55/ 99 aminoacids • 3 positions described as major resistance mutations in HIV-1: at codons 46I, 47V and 82I • 10 positions described as minor resistance mutations in HIV-1 : 10, 20, 32, 33, 36, 63, 71, 73 and 77
Immuno-virological response to triple NRTI and ritonavir-boosted PI in treatment-naïve HIV-2-infected patients The ACHI E V 2 E collaboration study group 1 , Audrey TAIEB 1 , Ard van SIGHEM 2 , Francisco ANTUNES 3 , Antoine BENARD Jean RUELLE 4 , Vicente SORIANO 5 , Alexandra CALMY 6 , Claudia BALOTTA 7 , Florence Damond 8 , Françoise BRUN-VEZINET 8 , Geneviève CHENE 1 , Sophie MATHERON 9 and the ACHIEV 2 E study group 1. INSERM, U897, CIC-EC 7, Bordeaux, France; 2. Stichting HIV Monitoring, Amsterdam, Netherlands; 3. Hospital de Santa Maria, Lisbon, Portugal; 4. AIDS Reference Laboratory, Louvain, Belgium; 5. Hospital Carlos III, Madrid, Spain; 6. Hôpitaux Universitaires de Genève, Switzerland; 7. University of Milan, Italy; 8. APHP, Hôpital Bichat – Claude Bernard, Paris, France; 9. APHP, Hôpital Bichat – Claude Bernard, Paris, France EACS 2009 cART in antiretroviral-naïve HIV-2-infected patients 20
HIV-2 and Integrase inhibitors
2008 Polymorphisms : 38% difference in sequence between HIV-1 and HIV-2 integrase genes (52 clinical isolates)
HIV-2 and INIs: in vitro phenotypic susceptibilities to raltegravir and elvitegravir is similar to HIV-1 Roquebert, JAC 2008 Median IC 50 : RAL 2.4 nM and EVG 0.7nM
HIV-2 and in vivo RAL mutations patterns Other mutations at codons 72, 84, 153, 160 and 163 (Garrett AIDS 2008) (Roquebert et al,AIDS 2008, CROI 2010)
HIV-2: Conclusions • Less therapeutic options than for HIV-1 • Natural resistance to fusion inhibitor and NNRTIs • CCR5 inhibitors? • NRTIs – Natural susceptibility conserved – Mutation patterns responsible for broad cross resistance among this class (K65R and Q151M) • INIs – To be studied in first line regimens – Mutations patterns similar to HIV-1 • PI/ rs – in first line regimens – Variable sensitivity among PIs has been reported, with lopinavir, saquinavir, and darunavir having greater activities than others
HIV-2 Conclusions – Several small studies showed poor responses among HIV-2 infected individuals treated with some ARV regimes including: dual-NRTI regimens , and some unboosted PI-based regimens including NFV or IDV + ZDV and 3TC (Gotlieb AIDS 2008; Gottlieb Clin Infect Dis. 2009; Jallow AIDS. 2006; Adje- Toure AIDS. 2003) – utility of triple-NRTI regimens: conflicting data (Matheron AIDS. 2006; Ruelle BMC Infect Dis. 2008) – Boosted PI-containing regimens have resulted in more favorable virologic and immunologic responses (Ruelle BMC Infect Dis. 2008; Benard AIDS 2009 and EACS 2009)
French National Recommendations for HIV-2 infected patients (2010) • When to start? – CD4< 500/ mm3 whatever the VL – CD4> 500/ mm3: consider when detectable VL • Close follow up • CD4 slope • First line? – 2NRTIs + 1 PI/ r (LPV, DRV, SQV) – 3 NRTIs not recommended • Second line? – As for HIV-1: tolerance, adherence, PK and genotype – PI or INIs • CCR5 inhibitors????
Recommend
More recommend
