HIV-2: diagnostic tools and antiretroviral therapy Jean Ruelle - PowerPoint PPT Presentation

HIV-2: diagnostic tools and antiretroviral therapy Jean Ruelle AIDS Reference Laboratory – UCLouvain Bruxelles 2012 May 3d Arevir Meeting - Bonn

AIDS Reference Laboratory (ARL) Missions: - Confirm HIV positivity: Serology Molecular tests for children born to positive mothers - Follow-up of positive patients: Plasma viral load Resistance tests (genotype) PR/ RT, IN, tropism - Collect epidemiological data Research projects : some ARLs are part of an university UCL Bruxelles: - Research projects focus on HIV-2 - Development of diagnostic tools for HIV-2 monitoring, in collaboration with others (CRP-Santé Luxembourg, AcHIeV2e collaboration,… ) - Centralisation of HIV-2 samples (Be-Lu)

Crosstalk between clinical and research activities Data, sam ples Specific questions ARL « Translational » Fondamental clinical activity research research (routine) guidelines m odels

AcHIeV 2 e collaboration The ACHIEV2E Collaboration has been created in 2005. It regroups 12 HIV-2 reference cohorts or centres, 10 from Europe and 2 from West-Africa. The main objectives of this collaboration are: • To evaluate the response to antiretroviral treatment in HAART-treated HIV-2 infected patients • study the natural history of HIV-2 infection in those patients with a reliable estimated date of seroconversion • study resistance mutations on HIV-2 • elaborate international recommendations on medical management of HIV2- infected patients

HIV-2 origins Retroviridae Spumavirus Alpharetrovirus Betaretrovirus Gammaretrovirus Lentivirus Deltaretrovirus Epsilonretrovirus  Human immunodeficiency virus type 1 (HIV-1)  HIV-2  Simian immunodeficiency virus (SIV)  FIV, EIAV, CAEV, …

Phylogeny of lentiviruses , from Sharp and Hahn, Cold Spring Harb Perspect Med 2011

Origins of AIDS viruses , from Sharp and Hahn, Cold Spring Harb Perspect Med 2011

Each HIV group is related to a cross-species transmission from monkey to man Sharp and Hahn, Cold Spring Harb Perspect Med 2011

Phylogeographic model used to infer the place and the date of HIV-2 appearence in human population (maximum clade credibility genealogies) Faria et al., J Gen Virol 2012: The phylogeographic footprint of colonial history in the global dispersal of HIV-2 group A

Faria et al., J Gen Virol 2012

HIV-2: a natural model of attenuated HIV disease HIV-2 is the second virus causing AIDS. Compared to HIV-1: • Asymptomatic phase is longer (mean) • Transmission rates are lower (same routes) • Slower evolution of genomes within the quasi- specie • Plasma viral load is lower • Proviral load is similar (at low CD4 counts)

Ret roviridae replicative cycle De novo infections or clonal multiplication of infected cells ? What is the predictive value of plasma viral load in the follow-up ?

Soares et al. , 2011: « cell associated » viral load indicates a continous replication in aviraemic HIV-2 patients. Compared to HIV-1 patients, equal amount of gag mRNA although plasma VL is lower, but less tat mRNA suggesting less de novo infections.

No Vpu in HIV-2, but Gp41 assumes Vpu antagonises the antiviral cellular factor the tetherin tetherin (BST-2, CD317) (Neil et al., Nature 2008) antagonism: in a less efficient LTR Vpu, Vpr - Vpx manner ? Env glycoproteins: co-receptor usage, glycosylations

Survival probability (without ART). Two different HIV-2 “populations”: long term non-progressors, for whom infection doesn’t affect survival, and progressors, in a way similar to HIV-1 van Tienen et al , Plos One 2011.

Relationship between plasma viral load and immune activat ion (Leligdowicz et al ., 2010) HIV-2 patients with undetectable VL = no differences in activation markers between HIV-2 and HIV negative. HIV-2 patients with detectable viral load = activation comparable to HIV-1 patients. Positive correlation between pVL and HLA-DR and CD38.

AIDS stage : AIDS defining conditions seem to appear at higher CD4 counts in HIV-2 patients (compared to HIV-1) but symptoms are similar. (Martinez-Steele et al ., 2007) Median Median HIV-1 HIV-2 CD4 CD4 AIDS- defining condition patients patients count count (n = 341) (n = 87) Wasting syndrome 34 % 76 45,9 % 140 Pulmonary tuberculosis 35,8 % 123 27,6 % 161 Life-threatening pneumonia 13,5 % 148 16,1 % 287 Neurological impairment 13,2 % 103 10,3 % 106 Kaposi’s sarcoma 11,4 % 165 3,4 % 72 Extra-pulmonary tuberculosis 4,7 % 177 1,1 % - Cryptococcal meningitis 1,2 % 54 4,6 % 36 Invasive cervical carcinoma 1,2 % 381 3,4 % 419 Candidiasis of the oesophagus 1,2 % 563 0 -

HIV-2 epidemiology • Round 1 million people infected worldwide • Prevalence is declining but concerns remain, particularly in West African urban areas • Highest prevalence country = Guinea-Bissau. Among pregnant women, decline from 3 to 2% during the last decade. Only 3 countries with documented data of prevalence > 1%. • Portugal and France: respectively 5 and 2% of HIV cases

HIV-1 HIV-2 Norrgren H et al. Trends and interaction of HIV-1 and HIV-2 in Guinea-Bissau, west Africa: no protection of HIV-2 against HIV-1 infection. AIDS. 1999; 13:701-7. van der Loeff MF et al. Sixteen years of HIV surveillance in a West African research clinic reveals divergent epidemic trends of HIV-1 and HIV-2. Int J Epidemiol. 2006; 35:1322-8. Mansson et al . Prevalence and incidence of HIV-1 and HIV-2 before, during and after a civil war in an occupational cohort in Guinea-Bissau, West Afica. AIDS 2009; 23:1575-82. Gianelli et al ., Prevalence and risk detreminants of HIV-1 and HIV-2 infections in pregnant women in Bissau, Journal of infection 2010.

Gianelli et al , 2010: HIV prevalence among pregnant women, Bissau.

Be/ Lu HIV-2 epidemiology • In Belgium and Luxembourg, 110 cases were described (less than 1% of HIV cases). • M/ F ratio close to 1 • Heterosexual transmission dominates (87%) • Country of origin: more than 60% from West African countries (others from Belgium and Europe, central and south Africa, and Asia) • In clinical follow-up today: 83 had at least one VL in 2011 (27 LTFU), 69 Be -14 Lu 28 are ARV treated (34%).

HIV-1/ 2 diagnostic: Inno-Lia line immuno-assay

HIV-1/ 2 diagnostic: algorithm * Alternatively one single test if high HIV prevalence ** Alternatively a rapid test discriminant for HIV type *** If not available, retest a new sample 2 to 4 weeks later. Not informative about HIV type in case of positivity

Plasma VL assays • No commercial kit available on HIV-1 VL platforms. Most labs use in-house assays. • HIV- 2 plasma viral load assays: comparative studies published (Damond et al, J. Clin. Microb. 2008) , agreement on a shared standard for HIV-2 quantification, at least for group A. Group B quantifications remain problematic (Damond et al, J. Clin. Microb. 2011).

AcHIeV 2 e VL inter-laboratory QC (Damond et al., 2011)

ART - HIV-2 Be/ Lu database • The data collection started in 2004. It followed the set up of a quantitative VL assay. Use of the ARL network, and centralisation of the HIV-2 molecular tests at the ARL-UCL. • Up to 2006, heterogeneity of ARV regimens, poor efficacy (measured by the number of failures and CD4 gains: 60% of virological failures after 1 year)

ART and CD4 counts (retrospective cohort analysis) BASELINE CD4 DELTA CD4 (cells /mm 3 ) after 12 months Mean Median Interval Mean Median Interval Non-treated (N=10) 402 427 193 660 -16 -21 -112 64 ARV therapies (n=22) 263 226 10 737 64 50 -62 323 - with PIs (n=15) 230 237 10 527 106 89 -31 323 p = 0,0003 - without PIs (n=7) 333 195 150 737 -25 -53 -62 57 - undetectable VL (n=8) 248 195 40 630 137 141 12 323 p < 0,0001 - detectable VL (n=14) 272 226 10 737 23 16 -62 180 Suboptimal therapies: CD4 gain round 50 cells/ mm 3 / year Ruelle et al ., BMC Infect. Dis. 2008; 8: 21

Antiretroviral therapy • Recommended ART: no RCT, cohort data, case series, expert opinion… • AcHIeV 2 e: first data merger in 2008 (next slides) Second merger in 2011 (analysis under way – evolution of HIV-2 disease is compared to HIV-1 within the CHAIN project)

First line cART in the AcHIeV2e cohort merger (2008) cART N (%) Triple NRTI Abacavir + AZT + 3TC 32 (72) DDI + AZT + 3TC 3 (7) DDI + 3TC + d4T 3 (7) Abacavir + DDI + d4T 2 (5) Other 4 (9) Rtv-boosted PI Lopinavir 76 (61) Indinavir 18 (14) Saquinavir 16 (13) Atazanavir 8 (6) Fos-amprenavir 7 (5) Darunavir 1 (1) EACS 2009 cART in antiretroviral-naïve HIV-2-infected patients

Estimated HIV-2 RNA changes in patients with detectable values at treatment initiation (n=67) M0 -M3 M4-M12 Boosted PI: -0.4 log 10 cp/ ml/ month Boosted PI: -0.12 log 10 cp/ ml/ year 3 NRTI: -0.2 log 10 cp/ ml/ month 3 NRTI: +1.2 log 10 cp/ ml/ year p =0.02 p =0.19 Benard et al., CID 2011.

Estimated CD4 cell count changes (n=158) M0 -M3 M4-M12 Boosted PI: +12/ mm 3 / month Boosted PI: +76/ mm 3 / year 3 NRTI: + 6/ mm 3 / month -60/ mm 3 / year 3 NRTI: p =0.24 p =0.002 Sam e trends after adjustm ent for baseline HIV-2 RNA and geographical origin Benard et al., CID 2011.