Harder-to-treat and more lethal tubercle bacilli continue to emerge across the globe, especially in the African region. Together with HIV, these infectious killers continue to have profound effects on the productive workforce in different countries. The deck is a brief overview of developments in disease management and research, with an emphasis on medications and vaccines.

1. Key developments in
HIV/TB research
Zeena Nackerdien
STOP
TB

2. 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).
Director
Polydrug resistance:
to >1 first-line
anti-TB drug
(other than both
isoniazid and rifampicin)
Monoresistance:
To 1 first-line anti-TB
drug only
Multidrug resistance:
To at least
both 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 all
first- & second-line drugs
tested in vitro

3. 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).
Director
Bedaquiline
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 cell
Membrane
Linezolid
Phase II
Phase II
Phase II
Sutezolid
AZD5847
MOA:
Inhibits
different
components
of protein
synthesis

4. 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

5. HIV: Host genetic factors(4)
Natural resistance/non- or slow progression
phenotype
Protective HLA alleles e.g., HLA-B51, HLA-B57
CCR532, 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.

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

7. 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 cause of
death among people living with
HIV
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

8. 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
NRTIs
Alternative 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 analogs
8. 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

9. WHO HIV/TB Activities(7)
*(Intensified case finding for TB, Isoniazid preventive therapy (IPT), and Infection control; ART, antiretroviral therapy); CPT, co-trimoxazole preventive therapy
7. 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 to
reduce the burden of TB among HIV+-people
WHO ACTIVITIES: PROGRESS & RECOMMENDATIONS

10. 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 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%
efficacy

11. 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 pathways
AID, 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-cells
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.

12. 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 pathways
AID, 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-cells
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.
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
sterilizing
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 cells
HEPS also have
↑NK-cells, pro-
inflammatory – and
beta-cytokines