Key developments in HIV/TB research

Zeena Nackerdien

STOP

TB

TB classification based on drug resistance (1-2)*

*Categories are not mutually exclusive..(1) WHO/HTM/TB/2013.2. Guidelines for the programmatic management of drug-resistant tuberculosis: Definitions and reporting framework for tuberculosis – 2013 revision http://apps.who.int/iris/bitstream/10665/79199/1/9789241505345_eng.pdf?ua=1.(2) Parida SK, Axelsson-Robertson R, Rao MV, et al. Totally-drug resistant tuberculosis and adjunct therapies. Journal of Internal Medicine. 2014 (e-pub).

DirectorPolydrug resistance:to >1 first-line anti-TB drug(other than both isoniazid and rifampicin)

Monoresistance:To 1 first-line anti-TBdrug only

Multidrug resistance:To at leastboth isoniazid and rifampin

Extensive resistance:To any fluoroquinolone and to at least one of three second-line injectable drugs (capreomycin, kanamycin and amikacin), in addition to multidrug resistance

Rifampicin resistance:To rifampicin detected using phenotypic or genotypic methods, with or without resistance to other anti-TB drugs

Total drug resistance (‘XXDR-TB’): To allfirst- & second-line drugstested in vitro

MOA:Inhibits cell wall assembly

Novel therapies for TB treatment (2)

MOA, mechanism of action(21 Parida SK, Axelsson-Robertson R, Rao MV, et al. Totally-drug resistant tuberculosis and adjunct therapies. Journal of Internal Medicine. 2014 (e-pub).

DirectorBedaquilin

e

Phase II

MOA:↓ATP levels

Diaryquinolines

SQ109

Phase II

1,2-diamine

Nitroimidazoles

Oxazolidinones

Delamanid

PA-824

Phase III

Phase II

MOA:Generate NO, block mycolic

acid synthesis, destabilize

cellMembrane

Linezolid

Phase II

Phase II

Phase II

Sutezolid

AZD5847

MOA:Inhibits different

components of protein synthesis

Investigational TB vaccines (2013)(3)

3. Frick M. The TB Vaccines Pipeline Report. http://www.pipelinereport.org/2013/tb-vaccine..

M. indicus pranii

M. vaccae

Dar-901

MVA85A/ AERAS-485

Crucell Ad35/ AERAS-402

Ad5Ag85A

M72 + AS01

Hybrid 1 + IC31

Hybrid 56 + IC31

Hybrid 4 + IC31/ AERAS-404

ID93 + GLA-SE

VPM1002

RUTI

MTBVAC

14 investigational vaccines (Prime-boost/immunotherapeutic): M. vaccae and

M. indicus pranii completed Phase III trials; 8 have reached Phase II to show safety & immunogenicity & 4 have reached Phase I to show safety

HIV: Host genetic factors(4)

Natural resistance/non- or slow progression phenotype

Protective HLA alleles e.g., HLA-B51, HLA-B57 CCR532, CCR2-641 mutations and KIR polymorphisms

TRIM-5, APOBEC3G, SAMHD1, tetherin

Other correlates of immune-mediated protection

APOBEC3G, apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3G ; CCR2-641, chemokine co-receptor 2-641 mutation; CCR5, C-C chemokine receptor type 5; HLA,Human leukocyte antigen; KIR, Killer-cell immunoglobulin-like receptor ; S;AMHD1, SAM domain and HD domain-containing protein 1; TRIM-5, Tripartite motif-containing protein 5 alpha isoform 4. Borthwick N, Ahmed T, Ondondo B, et al. Vaccine-elicited human T cells recognizing conserved protein regions inhibit HIV-1. Molecular therapy 2014;22(2):464-75.

Global epidemiology of HIV/AIDS (2012) (5-6)

35.3 millionPeople with HIV

~69% of HIV+-peoplelive in

Sub-Saharan Africa

Low- and middle-income countries

>9.7 millionHIV+-people got ARTs

5. HIV/AIDS, Fact sheet N°360, Updated October 2013: World Health Organization: http://www.who.int/mediacentre/factsheets/fs360/en/6. AIDS.gov. Global AIDS overview. updated 2013 : http://aids.gov/federal-resources/around-the-world/global-aids-overview/.

3.34 millionHIV+-children, mostly infected

By HIV+-mothers duringPregnancy, childbirth &

breastfeeding

HIV-associated TB facts(7)

7. HIV-Associated TB Facts. 2013: World Health Organization; http://www.who.int/tb/challenges/hiv/tbhiv_factsheet_2013_web.pdf?ua=1.

HIV

TB

TB is the most common presenting illness among

people living with HIV

TB is the leading

cause of death among people living with HIV1 in 5 HIV-related

deaths

At least one-third of the 35.3 million HIV+-people worldwide are infected with latent TB; >deaths among women than men in African region

CDC (2012): Concomitant treatment of TB & HIV (8)

Preferred: Efivarenz-based ART +RIF-based TB mgmt

Preferred for patients unable to take efavirenz  with pre-specified precautions: PI-based ART * + rifabutin-containing tuberculosis treatment TB mgmt

Alternative for patients who cannot take efivarenz (with added recommendations): NVP-based ART + RIF-based TB mgmt

NNRTIs/PIs Alternative for patients

who cannot take efavirenz/NVP & if rifabutin not available: Zidovudine / lamivudine / abacavir / tenofovir + RIF-based TB mgmt

Alternative for patients who cannot take efavirenz and abacavir and if rifabutin not available: Zidovudine / lamivudine / tenofovir with RIF-based TB mgmt

Alternative for patients who cannot take efavirenz or NVP and if rifabutin not available: Zidovudine / lamivudine / abacavir  + RIF-based TB treatment

NRTIsAlternative if rifabutin not available :Super-boosted lopinavir-based ART or double-dose lopinavir/ritonavir based ART + RIF-containing TB treatment

Alternative at higher doses for patients who cannot take efavirenz and who have baseline viral load <100,000 copies/mL:Raltegravir-based ART* + RIF-based TB mgmt

NRTSs/PIs/Int.

ART, anti-retroviral therapy; CDC, US Centers for Disease Control and Prevention; INT, integrase inhibitors; mgmt., management; NVP, nevaripine; NRTI/NNRTI, nucleoside & non-nucleoside reverse transcriptase inhibitors; PIs, protease inhibitors; RIF, rifampin; * with 2 nucleoside analogs8. US Centers for Disease Control and Prevention. Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis. 2013 http://www.cdc.gov/tb/publications/guidelines/tb_hiv_drugs/table1a.htm.

Drug-drug interactions, drug-

resistant TB & patient sub-groups

need special considerations

WHO HIV/TB Activities(7)

*(Intensified case finding for TB, Isoniazid preventive therapy (IPT), and Infection control; ART, antiretroviral therapy); CPT, co-trimoxazole preventive therapy7. HIV-Associated TB Facts. 2013: World Health Organization; http://www.who.int/tb/challenges/hiv/tbhiv_factsheet_2013_web.pdf?ua=1.

• Lives saved (2005-2011): ~1.3 million• Globally, in 2012, 46% of TB patients (2.8 million)were tested or accessed HIV care services versus 40% (2.5 million) in 2011• Of the known HIV-TB co-infected people in 2012, 57% (0.3

million) were enrolled on ART and 80% (0.4 million) were enrolled on CPT • Intensified case finding increased from 3.5 million in 2011

to 4.1 million in 2012

• Early diagnosis & treatment important • Three I’s* for HIV/TB need to be urgently adopted

toreduce the burden of TB among HIV+-people

WHO ACTIVITIES: PROGRESS & RECOMMENDATIONS

T cell and antibody responses

(non-neutralizing antibodies to the V1/V2

loop)

Prophylactic HIV vaccines(9)

9..Chanzu N, Ondondo B. Induction of Potent and Long-Lived Antibody and Cellular Immune Responses in the Genitorectal Mucosa Could be the Critical Determinant of HIV Vaccine Efficacy. Frontiers in Immunology. 2014;5:202...

HVTN 502/Merck 023 STEP/

Phase IIB

HVTN 503 Phambili Study/Phase IIB

VAX 003/Phase III

RV144Phase III

VAX 004/Phase III

HVTN 505/Phase IIB

T-cell responses in HVTN502, 503 and 505 trials and Ab responses (gp140 binding IgG) in

latter study; Ab (binding and Nabs to gp120 )

responses in VAX003 & 004 trials

31.2% efficac

y

Strategies to improve HIV vaccine immunogenicity & efficacy (9)

Vaccines & vectors

B-cell

Mosaic

Live vectors

Rep. vectors + T-cell & Ab-

inducing mosaic vaccines

Adjuvants

Cytokines

Chemokines

Genetic

To overcome issue of HIV

diversity: May also include concurrent depletion of

Tregs & blockade of inhibitory pathways*

AID

vectors that induce stable effector memory rather than central memory CD8+-T-cell responses; *programmed death-1-ligand & T-cell immunoglobulin & mucin protein-3 pathwaysAID, activation-induced cytidine deaminase; (targeting enzymes that regulate somatic mutations may increase the chances of generating broadly neutralizing antibodies)Ab, antibody; rep., replicating; Treg, regulatory T-cells9. Chanzu N, Ondondo B. Induction of Potent and Long-Lived Antibody and Cellular Immune Responses in the Genitorectal Mucosa Could be the Critical Determinant of HIV Vaccine Efficacy. Frontiers in Immunology. 2014;5:202...

Which factors/correlates of immune protection may contribute to HIV vaccine efficacy? (9)

vectors that induce stable effector memory rather than central memory CD8+-T-cell responses; *programmed death-1-ligand & T-cell immunoglobulin & mucin protein-3 pathwaysAID, activation-induced cytidine deaminase; (targeting enzymes that regulate somatic mutations may increase the chances of generating broadly neutralizing antibodies)Ab, antibody; bNAbs, broadly neutralizing antibodies; CTLs, cytotoxic lymphocytes; ECs, elite controllers; HEPS, highly –exposed persistently seronegative; rep., replicating; Tcm , central memory T-cells; Tem, effector memory T-cells; Treg, regulatory T-cells9. Chanzu N, Ondondo B. Induction of Potent and Long-Lived Antibody and Cellular Immune Responses in the Genitorectal Mucosa Could be the Critical Determinant of HIV Vaccine Efficacy. Frontiers in Immunology. 2014;5:202..

For sustained HIV surveillance: Need stable long-lasting B- & T-cell memory

in genitorectal mucosa, possibly

via vectored immunoprophylaxis

or sustained antigen-release

strategies

Delivery route:

muscular, genitorectal mucosa,

oral

BNAbs critical

for sterilizin

g immunity

Host genetics, viral

determinants, immunological

parameters, unknown factors

HIV-specific CD8+ CTLs

requirement for elimination of

latent viral reservoirs after

reactivation

ECs have potent Tem rather than

Tcm cellsHEPS also have ↑NK-cells, pro-inflammatory –

and beta-cytokines