HIV-2 Therapy Ricardo Jorge Camacho KU Leuven, Rega Institute for - - PowerPoint PPT Presentation

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HIV-2 Therapy Ricardo Jorge Camacho KU Leuven, Rega Institute for - - PowerPoint PPT Presentation

Dec 15, 2023 567 likes •861 views

HIV-2 Therapy Ricardo Jorge Camacho KU Leuven, Rega Institute for Medical Research, Leuven, Belgium World distribution ~1.000.000 2.000.000 people infected in West Africa Highest prevalence : Guinea-Bissau (8-10% general population,

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HIV-2 Therapy

Ricardo Jorge Camacho KU Leuven, Rega Institute for Medical Research, Leuven, Belgium

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World distribution

~1.000.000 – 2.000.000 people infected in West Africa Highest prevalence : Guinea-Bissau (8-10% general population, >20% in 55 – 80 age group) Highest prevalence in Europe: Portugal, followed by France

Sara Rowland-Jones, CROI 2007

AREVIR 2015 Ricardo J Camacho

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  • Different groups of HIV-2 (A-H) : the result of

multiple independent cross-species transmissions of SIVsm into the human population.

  • Only groups A and B are largelly represented in

the HIV-2 epidemic. The other groups seem to represent “dead-end” or limited transmission with no demonstrable spread.

Heuverswyn FV, et al. Curr Infect Dis Reports 2007;9:338-346 Hahn B, et al. Science 2000;287:607-614 http://pin.primate.wisc.edu/factsheets/links/cercocebus

Cercocebus atys Sooty Mangabey

HIV-2 is a zoonosis

AREVIR 2015 Ricardo J Camacho

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  • ~ 80% slow progressors
  • ~ 20% progression similar to HIV-1

Caio Cohort, Sarah Rowland-Jones et al, CROI 2007

HIV-2: clinical evolution

AREVIR 2015 Ricardo J Camacho

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Viral Load in HIV-2 infection

  • 2 – 3 logs lower than in matched HIV-1 cases
  • Viral load is only detected in:
  • 57% of patients with CD4 < 200 cells/mm3
  • 40% in patients with CD4 between 200 and 500

cells/mm3

  • 13% in patients with > 500 cells/mm3

AREVIR 2015 Ricardo J Camacho

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  • Predictors of disease progression:

– symptoms CDC stage B – age > 40 – CD4 cell count < 200/mm3 – detectable viral load

  • Viral load >100 copies/ml: RR of progression 26% vs 6%

– high serum β2 – microglobulin

– high CD14s

  • Mortality rate 2-4 X uninfected individuals; the difference

disappears for people >55 years

French HIV-2 cohort, 2006, CROI 2011, CID 2012 Caio Cohort, Sarah Rowland-Jones et al, CROI 2007

HIV-2: clinical evolution

AREVIR 2015 Ricardo J Camacho

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61 patients, starting triple combination therapy at a median count of 136 cells/ul 61 pts BL CD4 < 200 BL CD4 > 200 Month 12: +41 +9 +65 Month 24: +62 +45 +79

Matheron S and the ANRS CO5 HIV-2 Cohort Study Group: AIDS 20(3) 459-462, 2006

HIV-2 and clinical response

AREVIR 2015 Ricardo J Camacho

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HIV-2: % Similarity between Retroviral Proteins

Franchini G, et al. Nature 1987;328:539-542

gag pol env Weighted Average SIVsm and HIV-2 SIVsm and HIV-1 HIV-2 and HIV-1 82 51 52 76 53 55 70 34 35 72 43 43

AREVIR 2015 Ricardo J Camacho

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HIV-2 and NNRTIs : natural resistance

NNRTI EC 50 (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

In vitro activities of NNRTIs on HIV-1, HIV-2 and SIV isolates Amino acids in HIV-2 WT RT related with HIV-1 NNRTI drug resistance: 181I, 188L, 190A

AREVIR 2015 Ricardo J Camacho

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Comparative study on the development of resistance to PIs in HIV-1 and 2

  • By 15 weeks of culture, resistance mutations were already present in HIV-2

isolates: I82L (TPV), I54M and I82F (IDV), L90M (NFV) and a new motif V62A + l99F which conferred resistance to all PIs (except SQV)

  • No mutations were seen in HIV-1 before 25 weeks of culture (exception.

D30N, not selected by HIV-2)

Michel Ntemgwa et al: Antimicrob Agents Chemother, 2007(Feb);51(2) 604-610

HIV-2 and Drug Resistance

AREVIR 2015 Ricardo J Camacho

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Protease Inhibitors

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Phenotypic susceptibility of HIV-2 to Protease Inhibitors

FAPV ATV TPV NFV IDV SQV LPV DRV 31 X 8 X 7 X 3-4 X 3 X

  • Boosted Saquinavir, Lopinavir and Darunavir are the

recommended PIs in HIV-2 infection

Delphine Desbois, Bénédicte Roquebert1 Gilles Peytavin, Florence Damond, Gilles Collin, Antoine Bénard5 Pauline Campa, Sophie Matheron, Geneviève Chêne, Françoise Brun-Vézinet and Diane Descamps for the French ANRS HIV-2 Cohort8 (ANRS CO 05 VIH-2).

  • Antimicrob. Agents Chemother. doi:10.1128/AAC.01284-07

AAC Accepts, published online ahead of print on 28 January 2008

AREVIR 2015 Ricardo J Camacho

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Smith et al, CROI 2010, Abs 579

HI HIV-2 a and Pro rotease Inhibitors

Variable sensitivity among PIs has been reported, with lopinavir, saquinavir, and darunavir having greater activities than other approved PIs

AREVIR 2015 Ricardo J Camacho

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Protease Inhibitors

Commonly used in first-line regimens:

  • Lopinavir/r
  • Darunavir/r

Salvage regimens:

  • Saquinavir/r

AREVIR 2015 Ricardo J Camacho

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NRTIs

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HIV-2 and NRTIs

  • There’s no natural resistance of HIV-2 to any of the drugs of this class

M Witvrouw et al, Antiviral Therapy 9:57 - 65, 2004

  • Some resistance mutations are the same as in HIV-1: M184V (lamivudine,

emtricitabine), K65R (tenofovir, stavudine, didanosine, abacavir)

  • K65R is selected faster than in HIV-1 and antagonize the selection of

mutations at codon 215 by Zidovudine

Cavaco-Silva J et al, 2009, 7th European Workshop on HIV Drug Resistance, 24-27 March, Stockholm, Sweden, abstract nº 60

Damond, F., et al.. 2005. Letter. Antivir.Ther. 10:861-865. Jallow S., et al.. 2005. 10th European AIDS Conference/EACS-Nov. 17-20. Dublin, Ireland (abstract nº PE7.8/2)]. AREVIR 2015 Ricardo J Camacho

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Mutation Q151M

  • Mutation Q151M is selected by Didanosine> Stavudine and confers

different levels of cross resistance to all NRTIs, except Tenofovir Adje Toure CA et al: AIDS 17 Supplement 3, S49-S54, July 2003

  • 151M + V111I = High level resistance to all NRTIs

Damond, F., et al.. 2005. Letter. Antivir.Ther. 10:861-865.

AREVIR 2015 Ricardo J Camacho

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HIV-2 and NRTIs

NRTIs recommended for first-line regimens

  • Tenofovir + Emtricitabine
  • Abacavir + Lamivudine

Salvage regimens: Zidovudine

AREVIR 2015 Ricardo J Camacho

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Integrase Inhibitors

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Raltegravir and HIV-2

  • Efficacy is similar in HIV-1 and HIV-2 in vitro
  • Efficacy in the short term in vivo in salvage therapy
  • Major resistance mutations are the same as in HIV-1: N155H, Q148K/R/H and
  • Y143C. But Y143C alone doesn’t confer resistance to Raltegravir, as it happens

in HIV-1; the accumulation of other mutations, such as T97A, is necessary for resistance to arise

  • Other mutations are specific for HIV-2: K46R, Q19R, A153G. Their impact on

resistance to INstI is still unknown

Roquebert B, Damond F et al: XVI International HIV Drug Resistance Workshop, Barbados, 2007 Damond F, Lariven S et al: AIDS 2008, Vol 22, Nº5, 665 - 666 Bercoff DP et al, Retrovirology. 2010 Nov 29;7:98. Cavaco Silva J et al, 9th European Workshop on HIV & Hepatitis 23-25 March 2011, Paphos, Cyprus, abstract O_04 Delelis O et al, CROI 2011, Boston,USA, abstr 608 AREVIR 2015 Ricardo J Camacho

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Raltegravir and HIV-2

  • Raltegravir is a potent drug in the context of HIV-2
  • However, its low genetic barrier recommends its

usage in the context regimens with, at least, two other fully active drugs.

  • As a consequence, Raltegravir should be used in first

line therapy.

AREVIR 2015 Ricardo J Camacho

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Elvitegravir and HIV-2

  • Potent inhibition of HIV-2 replication in vitro
  • No clinical experience with this drug
  • As ETG is only available co-formulated with TDF + FTC

+ COBI, it’s role (if any) would be as a first line regimen.

AREVIR 2015 Ricardo J Camacho

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Dolutegravir

  • High efficacy against HIV-2 in vitro
  • Tested in 11 multiresistant patients (including resistance to

raltegravir and elvitegravir) almost as funcional monotherapy.

  • Only in four patients the viral load become undetectable: All

had mutations in integrase codon 143 (in vitro and in vivo contradictory results). There was no virological response in patients with any other mutational pattern

Descamps D, Matheron S et al: CROI 2014, Abstract 572

AREVIR 2015 Ricardo J Camacho

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CCR5 Antagonists

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HIV-2 SIV HIV-1 CCR5 CCR5 CCR5 CXCR4 BOB BONZO CCR3 BOB BONZO CXCR4 CCR3

Unutmaz D, et al. Sem in Immunol 1998;10:225-236 Azevedo Pereira JM et al Virology. 2003 Aug 15;313(1):136-46.

HIV-2: broad use of co-receptors

AREVIR 2015 Ricardo J Camacho

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CCR5 antagonists

  • Given the broad use of co-receptors by HIV-2, the theoretical potential of

CCR5 antagonists as an effective agent against this virus seem low

  • However, it was demonstrated that HIV-2 uses CCR5 until late stages of

infection.

  • There is a potent inhibition of some HIV-2 strains in vitro by this class of

drugs, but the IC50 is higher than in HIV-1, and not all CCR5 strains are equally inhibited.

  • There are now several cases of maraviroc use in salvage therapy reported so

far: in most of them, there was a good short term response

AREVIR 2015 Ricardo J Camacho

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Fewer er po poten ent A ARV dr drugs

HIV-2 HIV-1 NRTIs NNRTIs RAL EVG DTG SQV/r LPV/r DRV/r ATV/r NFV fAPV/r Enfuvirtide (T20)

Maraviroc

Delelis O. Retrovirogy 2011, Charpentier C. AAC 2011, Charpentier C.AIDS 2010, Roquebert B. JAC 2008, Roquebert B. AIDS 2008, Desbois D. AAC 2008, Damond F. AVT 2005, Damond F. JCM 2005, Descamps D. JCM 2004

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Cercocebus atys

Sooty Mangabey

Photo credit: Kathelijne Koops : http://pin.primate.wisc.edu/factsheets/links/cercocebus

GUILTY!

AREVIR 2015 Ricardo J Camacho