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
• thers (CRP-Santé Luxembourg, AcHIeV2e collaboration,…

)

• Centralisation of HIV-2 samples (Be-Lu)

Crosstalk between clinical and research activities

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

AcHIeV2e 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

Spumavirus

Lentivirus

Retroviridae

Alpharetrovirus Betaretrovirus Deltaretrovirus Epsilonretrovirus Gammaretrovirus

 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

Sharp and Hahn, Cold Spring Harb Perspect Med 2011

Each HIV group is related to a cross-species transmission from monkey to man

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)

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

Ret roviridae replicative cycle

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.

Vpu, Vpr - Vpx LTR Env glycoproteins: co-receptor usage, glycosylations

Vpu antagonises the antiviral cellular factor tetherin (BST-2, CD317) (Neil et al., Nature 2008)

No Vpu in HIV-2, but Gp41 assumes the tetherin antagonism: in a less efficient manner ?

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)

AIDS- defining condition HIV-1 patients (n = 341) Median CD4 count HIV-2 patients (n = 87) Median CD4 count

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

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

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.

HIV-2 HIV-1

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).

AcHIeV2e 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%

• f virological failures after 1 year)

ART and CD4 counts (retrospective cohort analysis)

BASELINE CD4 (cells /mm3) DELTA CD4 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

• without PIs (n=7)

333 195 150 737

• 25
• 53
• 62

57 p = 0,0003

• undetectable VL (n=8)

248 195 40 630 137 141 12 323

• detectable VL (n=14)

272 226 10 737 23 16

• 62

180 p < 0,0001

Ruelle et al., BMC Infect. Dis. 2008; 8: 21

Suboptimal therapies: CD4 gain round 50 cells/ mm 3/ year

Antiretroviral therapy

• Recommended ART: no RCT, cohort data, case

series, expert opinion…

• AcHIeV2e:

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 Boosted PI: -0.4 log10 cp/ ml/ month 3 NRTI:

• 0.2 log10 cp/ ml/ month

p=0.02 M4-M12 Boosted PI: -0.12 log10 cp/ ml/ year 3 NRTI: +1.2 log10 cp/ ml/ year p=0.19

Benard et al., CID 2011.

Estimated CD4 cell count changes

(n=158)

M0 -M3 Boosted PI: +12/ mm 3/ month 3 NRTI: + 6/ mm 3/ month p=0.24 M4-M12 Boosted PI: +76/ mm 3/ year 3 NRTI:

• 60/ mm 3/ year

p=0.002 Sam e trends after adjustm ent for baseline HIV-2 RNA and geographical origin

Benard et al., CID 2011.

Estimated CD4 cell count changes stratified on baseline CD4 cell count

Baseline CD4 count <200/ mm 3 (n=71) Baseline CD4 count ≥200/ mm 3 (n=63)

M0 – M3 p=0.56 M4 – M12 p=0.26 M0 – M3 p=0.45 M4 – M12 p=0.02

Benard et al., CID 2011.

Achiev2e – best ART options

• Largest observational study of treatment-naïve HIV-2 infected

patients starting cART in Europe

• Triple NRTI regimens are associated with a smaller CD4 cell

recovery, not sustained beyond 3 months, regardless

– baseline CD4 cell counts – baseline HIV-2 RNA or geographical origin

• Patients receiving PI/ r were at more advanced stage, which

reinforces our conclusion

• Highest level of evidence for the treatment of naïve HIV-2

infected patients

Natural resistance to NNRTIs

(Ren et al., 2002) 106I, 181I, 188L, 190A

Prot ease: st ruct ure is comparable t o HIV-1 but t here are differences in sensit ivit y t o PIs and genet ic barrier t o resist ance

Kovalevsky et al., 2009

Recommandations – HIV-2 ART

• Active drugs :

NRTIs: all, but TDF/ FTC and ABC/ 3TC are the most convenient PIs: LPV/ r, SQV/ r, DRV/ r, no APV-FPV (consensus); no ATV and TPV (no consensus in the literature) INIs: RAL, EVG, DTG

• No NNRTIs – including 2d generation, no enfuvirtide
• Tropism assay in development (in house, F): CCR-5

antagonists will probably be useful: new phenotypic data available, but only 2 case-reports up to now

Back to Belgium: impact of ART- efficacy knowledge on treatment

• In Belgium: improvements noted in the efficacy of ARV

therapies Before 2006: 60% of virological failures after 1 year of ARV In 2008: 60% of patients under therapy have a VL < 50 cop/ ml In 2010 and 2011: 70% of patients under therapy < 50 cop/ ml

• But it is still less than values recorded for HIV-1

patients…

HIV-2 resistance to antiretrovirals

• Pattern of resistance may differ: genotypic

interpretation rules used for HIV-1 cannot be applied

• Problem of lower genetic barrier
• New algorithm (HIV Grade, Genotypic

Resistance-Algorithm Deutschland) available with on-line interpretation report

Discussion - Take home messages

• The HIV-2 incidence is declining, but the model of HIV

attenuated disease is quite neglected and could help to develop new strategies against HIV-1

• National and international collaborations for uncommon

pathogens help to set up guidelines or recommendations, followed by measurable results in clinic

• HIV-2: a correct diagnosis is important to ensure an

adapted follow-up of the patient. Best treatment option includes a PI/ r (LPV, SQV, DRV), and RAL as second line.

Acknowledgements

ARL UCLouvain AcHIeV2e collaborators

• Perrine Triqueneaux
• Nordine Bakouche
• Anne-Thérèse Vandenbroucke
• Philippe de Sany
• Armelle Duquenne
• Patrick Goubau
• Cliniques St-Luc and UCL

Mont Godinne

• UGent
• ITG
• KULeuven – Rega institute
• UZ Brussel
• CHU St-Pierre/ UMC St-Pieter
• Hôpital Erasme
• CHU Liège
• CRP-Santé and CHL

Luxembourg

Belgian/ Lu ARLs and ARCs