HIV and Tuberculosis
Neel Gandhi MD
HIV/AIDS Seminar
2 December 2005
Global Burden of HIV
• Greatest burden of HIV/AIDS epidemic is in
developing countries
• At end of 2003, estimated 38 million infected
with HIV
– 25 million in Sub-Saharan Africa
– 7.4 million in Asia
– 2 million in Caribbean & Latin America
Global Tuberculosis Epidemic
• Estimated 2 billion individuals, or one-third of
world’s population, with latent TB infection
• Roughly 9 million new cases of active TB
disease annually
– Greatest burden in developing countries
Number of New TB Cases
Corbett et al. Arch Intern Med. 2003;163:1009-1021
Burden of TB
• Greatest numbers of cases are in Asia
– India, China, Indonesia, Bangladesh, Pakistan
• Greatest rates of TB disease are in Africa
– Zimbabwe, South Africa, Kenya, Tanzania, Uganda
• Number vs Rate
– India: 1.8 million new cases, but only 180 per 100,000
– South Africa: 220,000 new cases vs. 509 per 100,000
HIV and TB
• Increase in rates of TB, particularly in Africa,
attributed to HIV epidemic
• HIV patients more prone to develop active TB
disease due to immunocompromised state
– Latently infected more likely to reactivate
• 7-12% per year vs 10% lifetime risk of reactivation
– More likely to have primary disease after TB infection
– More likely to relapse or become reinfected
Badri et al. Int’l J of TB & Lung Dis. 2002;6:231-7
HIV and TB cont’d
• Impact of TB on HIV disease:
– Increase in HIV replication due to immune activation
– Increased risk other of opportunistic infections
• Mortality among HIV/TB coinfected patients as
high as 40% first year after active TB diagnosis
– Early mortality likely due to TB infection
– Late mortality likely due to immunosuppression and
other opportunistic infections (OIs)
Challenges in Managing Coinfected Patients
• Diagnosis:
– Altered based on level of immunosuppression
• Treatment:
– How should TB be treated?
– How long to treat?
– Should antiretroviral therapy also be given?
• Latent TB infection
– Should isoniazid prevention therapy be given?
Diagnosis of TB in HIV Coinfected
• Clinical presentation of TB varies based on level
of immunosuppression
– Early in HIV: more likely Pulmonary TB, with apical
and cavitary disease, sputum positive
– Late in HIV: extrapulmonary TB more common,
pulmonary disease in lower lobes, sputum negative
Diagnosis of TB in HIV Coinfected (2)
• Common diagnostic tools less helpful
– Clinical symptoms: may also be seen in other OIs
• Eg cough & SOB (PCP), fever (MAC, CMV)
– Sputum Microscopy: may be negative
– Chest X-ray: cavitation less common
• Sputum culture would be most helpful, but not
available in most resource-limited settings
Questions for Group
• Is sputum culture currently available in most
settings?
• Would it be feasible to make sputum culture
routine?
• What type of infrastructure would be needed to
make sputum culture available?
TB Treatment in HIV Coinfected
• TB treatment largely unchanged in HIV+ patients
compared with HIV- patients
• TB treatment with 4 drugs should be initiated at
time of diagnosis of active disease
– Intensive phase: Isoniazid, Rifampicin, Ethambutol,
Pyrazinamide for 2 months
– Continuation phase: INH+RIF for 4 mos (preferred) or
INH+EMB for 6 mos
Directly Observed Therapy
• When possible, TB therapy should be
administered by directly observed therapy (DOT)
• DOT has been associated with greater rates of
treatment completion than self-administration
Questions for Group
• Is directly observed therapy standard practice for
treating TB?
• Where is DOT carried out? In the clinic, at
patients’ homes, or at a convenient community
site?
• Who observes the therapy in DOT? Healthcare
professional? Community member? Family?
• What are the barriers to making DOT standard
and readily available?
Other Issues in TB Management
• Diagnostics and treatment regimens in TB
unchanged for past 3 decades
– Need for better diagnostic tools to identify active TB
and for treatment regimens that are simpler and
shorter
• WHO guidelines recommend cure rate of 85% of
sputum smear positive patients
– Many sites fall short of this goal
– Goal further threatened by increasing case load and
increasing proportion of smear negative and
extrapulmonary TB
Strengthening TB Programs
• Additional resources necessary to strengthen TB
programs
– Not only financial resources, but also human
resources
• What interventions can be made to achieve
higher cure and treatment completion rates?
HIV Coinfection
• Other major factor in improving mortality is
improving outcomes related to HIV infection
• Components of HIV programs
– Voluntary testing
– Prophylactic therapy
– Antiretroviral therapy
Testing for HIV
• Given higher rates of HIV among active TB
patients, HIV testing should be offered to all
patients with active TB
• Is this currently being done?
• Where is it being done? In the TB clinic?
Referred to another site?
• What is the rate of acceptance of HIV test? How
can this be improved?
Initiating HIV Care
• Once patients have been diagnosed with HIV,
how are they linked to HIV care?
• Where does that care take place in relation to
TB care?
Prophylactic Therapy
• Recommended that patients found to be HIV
positive be started on Bactrim or Cotrimoxazole
prophylaxis
• In patients without active TB, US standard is to
test for latent TB infection (LTBI) with a PPD or
tuberculin skin test
– Treat with isoniazid for 9-12 mos if found to have LTBI
– Resistance to this approach in developing countries
Antiretroviral Therapy
• Antiretroviral (ARV) therapy is effective in
reducing morbidity and mortality due to HIV
• Until recently, limited access to ARV in
developing countries
• Now increased availability of ARVs, but issues of
infrastructure and expertise remain
ARV Use in Resource-Limited Settings
• Develop local clinical expertise among
physicians and nurses
• Secure reliable supply (and funds) for ARVs
• Develop program to teach importance of
adherence and to support patients
• Create infrastructure to monitor on ARVs
– Clinical and lab monitoring for adverse reactions
– Laboratory monitoring for effectiveness of therapy
(ie total lymphocyte counts, CD4 counts & viral loads)
ARV use in HIV/TB coinfection
• Use of ARVs in HIV/TB coinfected patients has
additional complications
• Unresolved questions
– Who should be treated with ARVs?
– When should ARVs be started in relation to TB
therapy?
• Immediately? At end of Intensive phase? After TB treatment
completed?
– What ARV regimen should be used?
Problematic Issues
• Drug-Drug interactions
– Rifampicin induces the metabolism of protease
inhibitors making levels difficult to maintain
• Overlapping toxicities
– All the standard TB meds are hepatotoxic, as is
nevirapine
• Pill burden & adherence
– Adherence in both TB and HIV is critical
– Treating both at same time increases number of pills
and may threaten good adherence
Immune Reconstitution Syndrome
• A paradoxical worsening of TB symptoms after
starting ARV therapy
• As patient’s immune system recovers on ARV,
inflammatory response to strengthened against
remaining TB organisms
• If seen, typically occurs 4-8 weeks after initiation
of ARV
Concurrent ARV and TB Therapy
• Little data exist to guide the use of ARV in patients
with active TB
• Generally, a Nevirapine or Efavirenz based ARV
regimen must be used
• WHO recommends that timing of when to start
ARVs be based on degree of immunosuppression
– If CD4 count 200, defer ARV until TB treatment complete
Concurrent ARV and TB Therapy
• Well designed studies are necessary to truly test
the hypotheses regarding timing of ARV therapy
• Studies also necessary to define optimal dosing
of NNRTI regimens and algorithm for nevirapine
vs efavirenz use
Two Diseases, One Patient
• Where should HIV & TB treatments take place?
• What kind of coordination should there be
between the treatment of the two illnesses?
– At what level?
– National? Provincial? Clinic level?
Current TB and HIV Program Paradigms
Current TB and HIV
Programs Paradigm
National National
TB Program HIV Program
Communicatio
n
Collaboration
TB Services HIV Services
VCT
Sputum collection
DOT OI Px
Treatment Support Antiretrovirals
Contact Tracing Adherence
LTBI Treatment Support
Which model of collaboration ?
TB HIV/AIDS
TB AIDS TB AIDS TB/AIDS
Separate Partial Full
TB/ HIV Some mixing One stop service for
patients referral TB-HIV co-infected
Optimal TB and HIV
Programs Paradigm
National National
TB Program HIV Program
Communication
Collaboration
TB Services HIV Services
Sputum collection VCT
DOT OI Px
Treatment Support Antiretrovirals
Contact Tracing Adherence
LTBI Treatment Support
Topics Not Covered
• Multidrug resistant (MDR) TB
• Reinfection with TB after cure or treatment
completion
HIV/TB Treatment Strategy
• Introduce ART by integrating HIV & TB
treatment using existing TB DOT infrastructure:
– Once-daily ART regimen
• Feasibility demonstrated in urban TB clinic
– START pilot study
– Expanded to large Randomized Clinical Trial
(CAPRISA-START study)
Objective
• Test HIV/TB integration strategy in a rural,
resource-poor setting:
– Home-based DOT program
– Community and family support
• Demonstrating effectiveness and safety of
integrated ART & TB treatment by once-daily
DOT in this setting
Methods
• Demonstration project to treat 100 coinfected patients
simultaneously for active TB and HIV disease
• Once-daily ART regimen (didanosine, lamivudine &
efavirenz) with standard TB regimen (isoniazid, rifampin,
ethambutol & pyrazinamide)
• Administered by DOT at home by volunteer community
health workers and patients’ family members
• Patients transitioned to self-administration at completion
of TB therapy
Setting
Msinga district:
– 2,000 sq km rural district in KwaZulu Natal
– 200 km northeast of Durban
– Home to 300,000 traditional Zulu people
Local Healthcare
Tugela Ferry:
• 335 bed hospital in center of district
– 40% hospital beds occupied by HIV patients
• Comprehensive HIV program:
– Voluntary counseling and testing program
– Hospice, Orphan’s program, Mother to Child
Transmission program
– HIV clinic: provides opportunistic infection
prophylaxis, but no ART
TB DOT program
• Initiated in 1993
– Follows WHO recommended treatment guidelines
• Administered by volunteer community health
workers (“DOT supporters”) and family members
– Trained in importance of adherence and recognition
of adverse reactions
– Observe daily TB dose in patient’s home
– Report to TB program nurse weekly
Phases of Project
1. Create an ART treatment program by using
and strengthening existing TB DOT
infrastructure
2. Simultaneous ART & TB treatment in 100
HIV/TB coinfected patients and follow for
safety and effectiveness
Strengthening TB DOT program
• Struggling with increase in active TB cases:
– 350 in 1995 to 1000 in 2003
– Treatment completion rate in 2002: 59%
• Increased resources provided to TB program:
– 2 additional TB program coordinators
– Number of DOT supporters increased by training
120 additional supporters
– Additional transportation resources
Challenges in Creating ART Program
• Clinical expertise
• Access to medications
• Patient preparation & adherence
• Patient monitoring
Access to Medications
• Reliable and “affordable” supply of ART
secured:
– National wholesale pharmacy and pharmaceutical
companies “direct access” programs
• Cost of once-daily ART regimen
(didanosine, lamivudine & efavirenz):
– varied between $800 & $1400 per patient per year
Patient Preparation & Adherence
• 4-session curriculum on HIV infection, ART use and
adherence before starting ART
• DOT supporter & family member divide responsibility for
administrating daily TB & ART dose in patient’s home
• Patients prepare monthly dose “calendars”
– Consistent with Zulu culture
Patient Monitoring
• Clinical monitoring for treatment response,
adverse reactions & adherence carried out:
– Daily by family members and DOT supporters
– Monthly by physicians at HIV clinic
• Laboratory monitoring:
– Common tests: Hospital lab in Tugela Ferry
– CD4 and viral load: Virology labs in Durban
Phases of Project
1. Create an ART treatment program by
strengthening and utilizing existing TB DOT
infrastructure
2. Simultaneous ART & TB treatment in 100
HIV/TB coinfected patients and follow for
safety and effectiveness
Phases of Project
1. Create an ART treatment program by
strengthening and utilizing existing TB DOT
infrastructure
2. Simultaneous ART & TB treatment in 100
HIV/TB coinfected patients and follow for
safety and effectiveness
Entry Criteria
• Active tuberculosis; documented HIV infection
• CD4 less than 350 cells/mm3
• No prior ART exposure or TB treatment default
• Completed 1 month of TB DOT
• No clinical contraindications
• Disclose HIV diagnosis to a family member
• Women must be on reliable form of contraception
Interim Enrolment as of June 2005
161 HIV/TB co-infected patients approached
-died during screening
- CD4 too high
- abnormal LFTs
79 Ineligible - poor attendance
- Suspected MDR TB
-1 year commitment
82 Initiated on ARV - family disclosure
-Geographical area
8 patient deaths
1 dropped out
1 Relocation
72 patients
8 months mean follow-up period
Baseline Data (n=82)
• 42 Women , 40 Men
• Mean Age 34.31 years, range 23-54 years
• Weight: mean 55.62 kg, range 41– 83 kg
• CD4 count: mean 105 cells/mm3, range 1 – 338
• ( 27 (32%) patients less than CD4 50, 70 (85% patients 5000 copies 5 (9%)
Summary of Interim Results
BL 3m 6m 12m 15m
Number of patients 82 53 33 13 5
Mean weight (Kg) 55,6 62 62 63 64
Mean CD4 count (cells/mm3) 105 271 267 332 349
Viral Load (# of Patients)
5000 copies 5 (9%) 3 (9%) 2 (14%)
CD4 count with Time
Cd4 Count with Time
400
350
300
CD4 count
250
200
150
100
50
0
0 3 6 12 15
Months
Adherence & Acceptance (n= 82)
• Patients exhibited high level of commitment
– Out of 708 patient follow-up visits appointments (only 17 missed
exact appointment dates (2 %) but all did collect treatment
within 3 days grace period)
– Excellent adherence (99% )
• Disclosure facilitated family support and partner
enrollment to Rollout
• Project well accepted by patients, families and
community at large
• Staff Confidence in ARV therapy led to fast accreditation
( first site in KZN to rollout)