No One Left Behind: HIV and
Tuberculosis co-infection
Diane Havlir, University of California, San Francisco
Thank you to my co-authors
Mark Harrington
Soumya Swaminathan
Haileyesus Getahun
In 2014… We have



Evidence based prevention for HIV/TB
New TB diagnostics
Ability to cure most TB in 6 months and to
reduce mortality with ART
Over 1 million new TB cases in HIV+ persons
and 320,000 HIV/TB deaths EVERY YEAR
Why do we still have so much
death and suffering from TB in the
HIV epidemic?
1. We are not maximally implementing evidence
based interventions
2. Most at risk populations (MARPS) for HIV/TB
have not received adequate attention
3. Our care delivery is often disease (ie HIV or TB )
and NOT patient centric
2004: HIV/TB rampant overwhelming
communities and health systems
Rapid, unabated increase in TB
caseload due to HIV/TB interaction
TB risk increase
12-20 fold in
HIV+
Karim, Lancet, 2009
2014: Policy, advocacy and
implementation have produced results
•
•
Source: Global tuberculosis report 2013. Geneva, World Health Organization, 2013 .
Diagnose
and treat
TB
Diagnose
and treat
HIV
Over 40%
decline in
HIV/TB
deaths and
over 1.3
million lives
saved
Moving forward in 2014: Combination
Prevention for HIV/TB

ART

IPT
• NO TB SKIN TEST NEEDED

Transmission
reduction strategies
ART: 65% reduction in TB(1)
ART + isoniazid preventive
therapy (IPT) additional 35%
reduction in TB in high TB
transmission areas(2)
Transmission reduction
strategies
• Enhanced case finding (3)
• Infection control
Combination Prevention
1. Suthar, PLOS Medicine , 2012; 2. Rangaka, Lancet, 2014 3. Lorent PLOS One, 2014
2014: New and better diagnostics

XPERT MTBRIF: 2 hour
molecular test for M.TB
diagnosis and rifampin
resistance(1)
• More sensitive than AFB smear
• Works in children and
extrapulmonary TB
• Screen for MDR and XDRTB

LAM: POC urine test(2)
• 85% TB cases detected in
HIV+ persons with < 100
CD4+ cells entering hospital
with new TB diagnosis
1. Lawn, Lancet ID, 2013 ;2. Lawn, CROI, 2014
2014: Treatment strategy of immediate TB therapy
+early ART (2 vs 8 weeks) that saves lives and
reduces HIV complications
CAMELIA
(Cambodia)
SAPIT (South
Africa)
STRIDE (multicontinent)
WHOPolicy–
2010 ART
Guidelinesto
WHO
Harmonized
optimize outcomes in HIV and TB
•
•
•
Start ART at CD4 <500
Provide IPT for HIV-positive
patients without active TB
For those with TB, ART initiated
as soon as possible after the start
of TB treatment
• At 2 weeks when CD4<50;
no later than 8 weeks
Prevent and Treat HIV
and Prevent TB
Reduce HIV/TB deaths
And HIV morbidity
Stepping up the pace requires we:




Understand who is dying and why they are dying
Adapt care delivery systems so we can apply the
evidence
Pay more attention to HIV/TB MARPs
Invest in research to improve prevention,
diagnosis and treatment of TB and HIV/TB
Who is dying from HIV/TB?
TOP 10 COUNTRIES WITH HIV/TB DEATHS
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
South Africa
Mozambique
India
Nigeria
Zimbabwe
Uganda
Kenya
Tanzania
DRC
Ethiopia
88,000
45,000
42,000
19,000
18,000
9,200
7,700
7,000
6,300
5,600
Global TB report, 2012 data
TOP 8 COUNTRIES WHERE ELIMINATION
OF HIV/TB DEATHS IS WITHIN REACH
1.
2.
3.
4.
5.
6.
7.
8.
Cambodia
China
Russia
Indonesia
Viet Nam
Thailand
Brazil
Myamar
560
1,200
1,800
2100
2100
2200
2500
4600
Global TB report, 2012 data, high burden countries
Reasons for HIV/TB Deaths
Some reasons for
HIV/TB Deaths





TB not recognized
(until autopsy)
HIV not diagnosed
TB not diagnosed
TB not treated
HIV not promptly
treated
MDRTB
CROI, 2013
HIV is not diagnosed in TB; ART
cannot be started
Globally, Only 40%
TB cases HIV
status known
Global TB report, 2012
ART start lags behind guidelines




Malawi Program Data – before and after new 2011
country guidelines (1)
685 HIV/TB cases
ART at any time increased from 70% to 78%
ART within 2 weeks increased from 30% to 46%
1. Best case scenarios: Less than half patients
receiving ART in timely way to reduce mortality
2. Time to ART start not routinely collected in
country programs
1. Tweya, BMC Public Health, 2014, 2014
Stepping up the pace requires we:




Understand who is dying and why they are dying
Adapt care delivery systems so we can apply the
evidence
Pay more attention to HIV/TB MARPs
Invest in research to improve prevention,
diagnosis and treatment of TB and HIV/TB
The HIV/TB Care Cascade needs
to be monitored and fixed
Undiagnosed TB
Active TB
late ART start
Diagnose Treat
TB
TB
Start ART
2 weeks
bad care
Complete Transition
TB
to HIV care
treatment
What is the best model for HIV/TB
care?

The one that is convenient for the patient and
delivers quality care
• There is no one size fits all
• Will vary according to HIV and TB prevalence

Possible HIV/TB clinic models
• Referral models- 2 separate clinics
• Integrated and co-located models

Considerations
• Integrated models are optimal but require more effort on
staff training and considerations such as infection control
• Co-location not sufficient for optimal delivery of care
• Most systems are still burdensome to the patient
Legidor Quigley, Trop Med Int Health, 2013; Schwartz, IJTLD, 2013; Uyei, Health
Policy and Planning, 2014
Adapting Care: Xpert MTB/Rif for
Faster TB detection
•
Nurses coordinated
Xpert use
• Time to TB diagnosis less
with Xpert and smear vs
TB culture
• More TB cases detected
from Xpert vs smear
• Time to TB treatment
reduced
with Xpert
We
now need
to
Theron, Lancet, 2013
overcome logistical
challenges of Xpert
scale up
Adapting Care: Increase in HIV
testing in TB patients in India
Challenge: HIV testing in low prevalence setting
Adapting Care: Isoniazid
preventive therapy (IPT) in Brazil
Globally, Only 1/3 patients in HIV care prescribed IPT (1)



THRIO Goal: increase IPT uptake for among
HIV+ persons
12,816 persons in 29 HIV clinics in Rio de Janeiro
Intervention
• Operational training on TB skin test and IPT
• Active TB screening within ART program
• Supply chain fortification

27% reduction in TB; 31% reduction in TB or
death during the intervention period
1. Global TB report, 2012; 2. Durovni, Lancet ID 2013
Stepping up the pace requires we:



Understand who is dying and why they are
dying
Adapt care delivery systems so we can apply
the evidence
Develop strategies for HIV/TB MARPs
•
•
•
•

Children
Miners and their families and contacts
Persons who inject drugs (PWID)
Incarcerated populations
Invest in research to improve prevention,
diagnosis and treatment of TB and HIV/TB
Children– Left Behind
530,000 TB cases; 78,000 deaths in children*




Children have more rapid progression of
TB from infection to disease vs adults
TB diagnosis is more difficult in children
than adults
TB/ART dosing and dose adjustments are
more complex
Cascade of care even more challenging for
children
*WHO estimate; Recent estimates by Dodd,( Lancet 2014 ) 650,000;Jenkins,
(Lancet, 2014) 1 million
Children– Some sobering data
High TB Burden and
Mortality



32% HIV + children
enrolled in Malawi cohort
2004-2010 diagnosed with
TB
20% with TB died
8.8 fold increase in death
in those not starting ART
vs those starting ART
within 2 months
Buck, IJTLD, 2013
Broken care cascade



1713 children
presented with cough
>2 weeks duration in
rural Uganda clinics
Only 17.5% referred for
microscopy
Among those found to
be AFB smear positive,
only approximately half
started TB therapy
Marquez, submitted
Children– What Next?



Prevent all HIV transmission (MTCT B+)
Start ART in all children
IPT for all children exposed to TB cases
Childhood TB infection relevant to all of HIV/TB and TB
control because much of global TB reservoir is established in
childhood
Roadmap for Childhood tuberculosis – Towards Zero Deaths, WHO 2013
Miners – “a public health
catastrophe”



Extraordinary rates of TB 4000-7000/100,000 in
miners vs general population in SSA
Second largest driver of TB in South Africa (after
HIV) is mining
HIV and mining lethal combination
•
•
•
•

Silica exposure– increase risk 3 fold
HIV + increase risk greater than 10 fold
HIV + silica- exposure - increased risk 15 fold
Poor living conditions– increased risk many fold
All forms of TB are a problem
• Latent TB- 89% in miners!
• New TB infections and TB re-infections
• MDRTB 3.6% (miners) vs 1.9% non miners
Dharmadadhikari, Int J Health Services, 2013
Miners– What next?
Declaration on tuberculosis in the Mining Industry
Zero deaths from TB, Maputo, 2012


Improved housing and mining conditions
HIV/TB prevention and screening as part of
employee health contract
•
•
•
•
•
•
HIV testing
Offer ART start for all HIV+ persons (best TB prevention!)
Routine TB screening symptoms and radiograph
IPT (not just 6 months!) while in high risk setting
Continuity in care when miners come and go from employment
Xpert accessible for rapid diagnosis and identification of high risk
for MDRTB
Persons who inject drugs:
intersection of HIV/TB/HCV



One third PWID are HIV-infected; two thirds are
HCV infected
High rates of TB infection
Human rights violations drive PWID away from
care
Getahun, Curr Opin HIV/AIDs, 2012; Grenfell Drug and Alcohol Dependence,
2013; Schluger, Drug and Alcohol Dependence, 2013
Incarcerated Populations- Left
Behind

High rates of incarceration exacerbate TB
spread
• 1/11 of TB transmission in prison on high income countries
• 1/16 of TB transmissions in low and middle income
countries


Crowded conditions
Limited health access
Declaration on tuberculosis for PWID or incarcerated
populations
DOES NOT EXIST
PWID and Prisoners -Next Steps


Improved housing
On-site HIV/TB prevention and screening
•
•
•
•
•
Routine HIV/TB screening
ART offered for all HIV+
IPT (not just 6 months!) while in high risk setting
Opioid substitution therapy and compatible TB therapy/ART
Xpert accesible for rapid diagnosis and identification of high
risk for MDRTB
• Rapid ART start for new cases of TB in HIV+ patients
Getahun, Curr Opin HIV/AIDs, 2012; Grenfell Drug and Alcohol Dependence,
2013; Schluger, Drug and Alcohol Dependence, 2013
Stepping up the pace requires we:




Understand who is dying and why they are
dying
Adapt care delivery systems so we can apply
the evidence
Pay more attention to HIV/TB MARPs
Invest in research to improve prevention,
diagnosis and treatment of TB and HIV/TB
TAG TB Research and Development Report, 2013
TB reservoir– it matters

What is TB reservoir?
• Persistent infection with
TB that can reactivate
• HIV and aging both risk
factors for this reservoir to
develop into active disease

Lung granulomas are dynamic and
independent in metabolic activity and size
Why does it matter?
• Estimated that 1/3 worlds
population is infected with
TB
• Achilles heal of elimination
of TB
Lin, AAC, 2013
Shorter TB prevention for ALL populations


Standard– Isoniazid 6-9 months
New 3 month regimen works!
• INH/Rifapentine once per week – total 12 doses
• Works in HIV+ population
• Rifapentine can be administered with efavirenz

Even shorter- 1 month regimen under study
Daily high dose INH + rifapentine (ACTG 5279)
We need to answer the question if even these more
potent short course regimens work and are sufficient
in high transmission settings.
Sterling, NEJM 2011: Sterling, CROI, 2014
Shorter TB treatment

What do we want? Once daily, few pills, few side
effects, compatible with ART, TB cures at 2 weeks,
treatment for children
THE BAD NEWS

We cannot shorten TB treatment to 4 months
with current drugs at standard doses
• OFLOTUB study (gatifloxacin)
• RIFAQUIN study (moxifloxacin/rifapentine )


We cannot rely on the week 8 culture results to
tell us if we need to extend treatment
Some of the TB agents in development interact
with HIV medications and some are stalled in
development
The good news… (with more not
so good news)

We may be able to combine available drugs using
higher doses to shorten TB therapy
• Rifapentine
• Rifampin

We may be able to design regimens with new drugs
that treat both drug sensitive and drug resistant TB
TB Research and Development Investment
•
Reduced by 4.6% from 2011-2012
•
Fell short of projected need in 2012 by over 1.2 billion USD
Summary




HIV/TB rates are declining- but there are still over 1
million HIV/TB cases and 300,000 HIV/TB deaths
We need to deploy targeted strategic approaches
,
• Combination prevention for HIV/TB
• New diagnostics
• Rapid ART start
Stepping up the pace requires structural changes
• Fix HIV/TB care cascade with a patient centric system
• New HIV/TB MARPS programs- children, miners, PWID,
prisoners
Research investment and renewed advocacy
Conclusion
“Every HIV/TB case is a public health failure”
Helen Ayles, 2014
Every HIV/TB case prevented and every death
averted is a public health success and puts us one
step closer to ending the dual epidemic of HIV and
TB
Melbourne IAC, 2014
WHO Post 2015 Strategy and Targets for TB; TB Elimination by 2035
Endorsed by World Health Assembly, May 2014