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, >20% in 55 80 age group) Highest prevalence in Europe: Portugal, followed by France Sara Rowland-Jones, CROI 2007
HIV-2 is a zoonosis Different groups of HIV-2 (A-H) : the result of multiple independent cross-species transmissions of SIV sm 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. Cercocebus atys Sooty Mangabey 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
HIV-2: clinical evolution ~ 80% slow progressors ~ 20% progression similar to HIV-1 Caio Cohort, Sarah Rowland-Jones et al, CROI 2007
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/mm 3-40% in patients with CD4 between 200 and 500 cells/mm 3-13% in patients with > 500 cells/mm 3
HIV-2: clinical evolution Predictors of disease progression: symptoms CDC stage B age > 40 CD4 cell count < 200/mm 3 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 and clinical response 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: % Similarity between Retroviral Proteins gag pol env Weighted Average SIV sm and HIV-2 82 76 70 72 SIV sm and HIV-1 51 53 34 43 HIV-2 and HIV-1 52 55 35 43 Franchini G, et al. Nature 1987;328:539-542
HIV-2 and NNRTIs : natural resistance 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 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
HIV-2 and Drug Resistance 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
Protease Inhibitors
Phenotypic susceptibility of HIV-2 to Protease Inhibitors 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 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
HIV-2 and Protease Inhibitors Variable sensitivity among PIs has been reported, with lopinavir, saquinavir, and darunavir having greater activities than other approved PIs Smith et al, CROI 2010, Abs 579
Protease Inhibitors Commonly used in first-line regimens: Lopinavir/r Darunavir/r Salvage regimens: Saquinavir/r
NRTIs
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) 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)]. 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, 7 th European Workshop on HIV Drug Resistance, 24-27 March, Stockholm, Sweden, abstract nº 60
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.
HIV-2 and NRTIs NRTIs recommended for first-line regimens Tenofovir + Emtricitabine Abacavir + Lamivudine Salvage regimens: Zidovudine
Integrase Inhibitors
Raltegravir and HIV-2 Efficacy is similar in HIV-1 and HIV-2 in vitro Roquebert B, Damond F et al: XVI International HIV Drug Resistance Workshop, Barbados, 2007 Efficacy in the short term in vivo in salvage therapy Damond F, Lariven S et al: AIDS 2008, Vol 22, Nº5, 665-666 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 Delelis O et al, CROI 2011, Boston,USA, abstr 608 Other mutations are specific for HIV-2: K46R, Q19R, A153G. Their impact on resistance to INstI is still unknown 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
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.
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.
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
CCR5 Antagonists
HIV-2: broad use of co-receptors HIV-2 HIV-1 SIV CCR5 BOB BONZO CCR5 CXCR4 CXCR4 CCR3 CCR3 CCR5 BOB BONZO Azevedo Pereira JM et al Virology. 2003 Aug 15;313(1):136-46. Unutmaz D, et al. Sem in Immunol 1998;10:225-236
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 IC 50 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
NRTIs Fewer potent ARV drugs HIV-2 HIV-1 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
Cercocebus atys Sooty Mangabey GUILTY! Photo credit: Kathelijne Koops : http://pin.primate.wisc.edu/factsheets/links/cercocebus