Resistance to Antiretroviral Drugs HIV-2 HIV-2: Background 1986 - - PDF document

HIV-2 Resistance to Antiretroviral Drugs

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

• f

transmission.

• 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: Background

HIV HIV-

• 2

2 Naturally Naturally attenuated attenuated HIV infection: HIV infection: why why? ?

– 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 ???

Shi et al ARHR 2002

• Large in-vitro coreceptors usage: CCR1, CCR2, CCR3, GPR15,

CXCR6 , BOB… .Activity of the CCR5 inhibitors?

• Tropism assays not available in clinical practice

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 et CRF_02; C 50% , 65R 65R : 70% , 151M : 30% 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

• 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: Mutations K65R and Q151M

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

NNRTI EC50 (nM) median (IQR) 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) NVP 34,09 (26,23-44,90) > 31 250 (29 980-32 000) > 31 250 (31 250-100 000)

Rimsky LT, XVIII IHDRW 2009, Abs. 120

Resistance to Rilpivirine

In vitro activity of RIL on HIV-1, HIV-2 and SIVmac In In vitro vitro activity activity of

• f RIL on HIV

RIL on HIV-

• 1, HIV

1, HIV-

• 2 and

2 and SIVmac SIVmac

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

Smith et al, CROI 2010, Abs 579

HIV-2 and Protease Inhibitors

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 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 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 C Terminal residues N Terminal residues Enzyme Active site region Top of flaps residues Second loop of  sheet residues

• 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

Differences between HIV-1 and HIV-2 protease genes (Los Alamos database and F Damond, 2005)

EACS 2009 cART in antiretroviral-naïve HIV-2-infected patients 20

Immuno-virological response to triple NRTI and ritonavir-boosted PI in treatment-naïve HIV-2-infected patients The ACHIEV2E collaboration study group

Antoine BENARD

1, Audrey TAIEB 1, Ard

van SIGHEM 2, Francisco ANTUNES 3, 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 ACHIEV2 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

HIV-2 and Integrase inhibitors

Polymorphisms : 38% difference in sequence between HIV-1 and HIV-2 integrase genes (52 clinical isolates)

2008

HIV-2 and INIs: in vitro phenotypic susceptibilities to raltegravir and elvitegravir is similar to HIV-1

Roquebert, JAC 2008 Median IC50 : RAL 2.4 nM and EVG 0.7nM

(Roquebert et al,AIDS 2008, CROI 2010)

HIV-2 and in vivo RAL mutations patterns

(Garrett AIDS 2008)

Other mutations at codons 72, 84, 153, 160 and 163

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????

GH Bichat-Claude Bernard /EA 4409 Virologie

Dr Florence DAMOND, Dr Bénédicte ROQUEBERT Dr Lucile LARROUY Benoit VISSEAUX Gilles COLLIN Alexandre STORTO Guylaine CASTOR Pr Diane DESCAMPS Pr Françoise BRUN-VEZINET

SMIT

Pr Sophie MATHERON Pr Patrick YENI

INSERM U897, Bordeaux Centre Coordination

Dr Antoine BENARD Marie BERTENCELLO Audrey TAIEB Pr Geneviève CHENE

Virologie Hôpital Saint-Louis

Pr François SIMON

Immunologie GH Pitié-Salpêtrière

Pr Brigitte AUTRAN

MAY 2010 Sept 07 PMLE