Unit 10: Treating the Dually
Infected Patient
Botswana National Tuberculosis Programme
Manual Training for Medical Officers
Objectives
At the end of this unit, participants will be able to:
• Explain the relationship between TB and HIV
• Describe the effects of immune suppression on TB
progression
• Describe the ways in which TB and HIV care can be
integrated
• Identify and address challenges to integrating TB
and HIV care
• Describe the additional treatments for all TB/HIV
patients
• Manage ART in a patient on TB therapy
Unit 10: Treating the Dually Infected Patient
Slide 10-2
A Deadly Infectious Disease
• HIV/AIDS is the #1
infectious killer in the
world—TB is #2
• Many people have both
infections
• Botswana TB/HIV
co-infection rate is 84%*
Unit 10: Treating the Dually Infected Patient
HIV
HIV & TB
TB
*Source: BNTP, 2007.
Source: WHO, 2006.
Slide 10-3
The TB/HIV Relationship (1)
• TB increases HIV progression
• Dually infected and untreated persons often
have very high HIV viral loads
• Immunosuppression progresses more quickly,
and survival may be shorter despite
successful treatment of TB
• Persons who were co-infected have a shorter
survival period than persons with HIV who
never had TB disease
Unit 10: Treating the Dually Infected Patient
Slide 10-4
The TB/HIV Relationship (2)
• Screen all HIV-infected patients for TB
• Conduct a complete history as well as a
physical examination
• Screen all patients for TB who present in other
situations where there is a high burden of HIV,
such as medical wards, VCT centres and
PMTCT facilities
Unit 10: Treating the Dually Infected Patient
Slide 10-5
Immune Suppression
and TB Progression
• HIV-positive person is more likely to progress to TB
disease following infection
• HIV-positive person has a greater risk of reactivation
• HIV-positive person has a high risk of relapse or
reinfection after treatment
• HIV-positive person has a 10% annual risk of
developing active TB (versus 10% lifetime risk
among HIV negative individuals)
Unit 10: Treating the Dually Infected Patient
Source: WHO, 2004
Slide 10-6
Natural History of TB
Primary
Progressive
TB disease
(children,
rare adults,
HIV+)
HIV -
~ 5%
reactivate
after
2 years
till death
New TB
Infection
Latent
TB Infection
HIV +
Unit 10: Treating the Dually Infected Patient
~5 %
reactivate
In
1-2 years
~ 10%
reactivate
each
year
Slide 10-7
Death within 6 months of TB diagnosis (%)
Mortality from TB
Before Era of ART
16
14
12
10
8
6
4
2
0
HIV-positive
Unit 10: Treating the Dually Infected Patient
HIV negative
Murray J et al, Am J Respir Crit Care Med, 1999.
Slide 10-8
Pattern of TB and Survival
of Patients with HIV-related TB
PTB
EPTB
Both
Days from diagnosis of TB
Unit 10: Treating the Dually Infected Patient
Whalen C, et al. AIDS, 1997.
Slide 10-9
Screening for HIV in TB Patients
• Purpose
• Identify TB suspects and patients who are also HIV
positive
• All TB patients with HIV are eligible for ART, it’s just a
matter of timing of ART initiation
• Method
• At every health care encounter with TB patient:
• Counsel on HIV prevention strategies
• Offer Routine HIV testing if testing not previously done
• CD4 count should be obtained on any HIV positive individual
Unit 10: Treating the Dually Infected Patient
Slide 10-10
Screening for TB at HIV Clinics
• Purpose
• Identify HIV-positive persons eligible for IPT
• Identify HIV-positive persons who may have active
TB
• Method
• At each health care encounter, ask about:
• History of TB and prior treatment for TB
• Current IPT or history of IPT
• TB signs and symptoms
Unit 10: Treating the Dually Infected Patient
Slide 10-11
Early Diagnosis: Better Outcomes
• Decrease in mortality for treated patients
• Decrease in period of transmission to others
especially family members who may be HIV
infected
• Decrease in transmission in the community
• Identification of at-risk contacts in a timely
manner
Unit 10: Treating the Dually Infected Patient
Slide 10-12
TB and HIV Care Strategies
Persons with TB
• Rapid diagnosis and
initiation of TB treatment
• Test all TB patients for HIV
• Maximise treatment
completion rates
• Offer cotrimoxazole
preventive therapy to HIV+
in TB system
• Assess HIV+ for ART
eligibility and refer
Unit 10: Treating the Dually Infected Patient
HIV-positive Persons
• Screen for active TB at
every health system
encounter
• Rapid TB diagnosis and
initiation of TB treatment
• Reduce TB incidence with
IPT
• Reduce TB incidence with
effective ART
• Minimise exposures to
active TB cases
Slide 10-13
TB and HIV Treatment Strategies
TB Care and Treatment
• Individual
• Control their disease
• Restore health and ADL*
• Preserve their position in
family and community
• Community
• Decrease the spread of TB
infection
• Mitigate against TB stigma
from society
• Enforce prevention
Unit 10: Treating the Dually Infected Patient
HIV Care and Treatment
• Individual
• Control their disease
• Restore health and ADL*
• Preserve their position in
family and community
• Community
• Decrease the spread of HIV
infection
• Mitigate against HIV stigma
from society
• Enforce prevention
Slide 10-14
Challenges to Integration
What do you think are
the challenges to
integrating the two
services?
Unit 10: Treating the Dually Infected Patient
What strategies can
you suggest to
address these
potential challenges?
Slide 10-15
Treating a Person with HIV and TB
• Common scenario in Botswana
• TB case definitions are the same regardless of
HIV status
• TB treatment is the priority
• Clinician should decide the optimal timing for
initiation of ART during TB treatment guided
by National policy
Unit 10: Treating the Dually Infected Patient
Slide 10-16
When to Start ART
During TB Therapy
• All HIV-infected TB patients qualify for ART
• CD4<100 should start ART within one to two weeks after
start of ATT
• CD4 100 – 200 should start ART within two to four weeks
after start of ATT
• CD4s>200 may defer ART until end of ATT
• HIV-infected patients already on ART who develop
TB should begin anti-TB meds immediately
• Management of TB patients on ART is complex and
patient care needs to be coordinated with IDCC
Unit 10: Treating the Dually Infected Patient
Slide 10-17
ART in the Botswana
National Programme
NRTIs
AZT (Zidovudine)
3TC (Lamivudine)
d4T (Stavudine)
ddI (Didanosine)
(AZT+3TC) (Combivir)
NNRTIs
EFV (Efavirenz)
NVP (Nevirapine)
PIs
LPV/r (Kaletra or Alluvia)
RTV (Ritonavir)
SQV (Saquinavir)
Special Order:
ABC (Abacavir), TDF (Tenofovir)
Unit 10: Treating the Dually Infected Patient
Slide 10-18
TB Disease Progression
with HIV Co-infection
• TB progresses more rapidly with HIV co-infection
• Up to 10% of co-infected individuals develop active
tuberculosis each year
• 10%–20% lifetime risk among those without HIV infection
• ART alone can reduce the risk of progression to
active tuberculosis in latently infected individuals by
as much as 80%–92%
• Patients on or about to start ART should still be
offered IPT if they meet the criteria
Unit 10: Treating the Dually Infected Patient
Source: de Jong BC et al, Annu Rev Med, 2004.
Slide 10-19
HIV Disease Progression on
TB Treatment, ART
CPCRA/ACTG
TBTC 23
No ARV
ARV
1993-1995
1999-2002
Baseline CD4 cell count
85
90
Use of ART during TB
treatment
0%
80%
Death within 1 year of start
of TB therapy
20%
4.5%
Death or new OI within 1
year of start of TB therapy
38.9%
15.7%
Years of enrollment
Source: Burman et al, CROI, 2003.
Unit 10: Treating the Dually Infected Patient
Slide 10-20
How To Improve
Outcomes of HIV-Related TB?
• Appropriate treatment of TB
• TB treatment regimens are the same for HIVinfected patients as for non-infected patients
• Assure adherence with TB treatment (use of
directly observed therapy, DOT)
• Cotrimoxazole prophylaxis
• ART
Unit 10: Treating the Dually Infected Patient
Slide 10-21
TB Treatment and
Outcome of HIV-Related TB
• Poor adherence to TB treatment is associated with
the following adverse outcomes
• Treatment failure: patient suffers morbidity or mortality of
TB
• Increased risk of TB drug resistance or MDR complicating
future treatment of the patient
• Continued transmission of TB and development of new
cases of active TB
• Possible transmission of drug resistant or MDR TB
• DOT can lead to improved outcomes by supporting
better adherence practices
Unit 10: Treating the Dually Infected Patient
Slide 10-22
Cotrimoxazole Preventative
Therapy (CPT) (1)
• Reduces the risk of
• Pneumocystis jiroveci pneumonia (PCP)
• Toxoplasmosis
• Bacterial infections
• Reduces deaths and hospitalisations
• Also effective against:
• Pneumococcus, salmonella, nocardia and malaria
Unit 10: Treating the Dually Infected Patient
Slide 10-23
CPT (2)
• All HIV-positive TB patients should
receive CPT regardless of the CD4 count
for, at least, the duration of anti-TB
treatment
• Extend CPT beyond the end of anti-TB
treatment if the CD4 cell count is less
than 200 cells/mm3
Unit 10: Treating the Dually Infected Patient
Source: WHO, 2006
Slide 10-24
Cotrimoxazole Dosing
AGE (weight)
OF CHILD
RECOMMENDED
DAILY DOSE
SUSPENSION
(5ML syrup =
200mg/40mg)
Child tablet
(100mg/20mg)
Single strength
adult tablet
(400mg/80mg)
6 weeks to 6
months
(<5kg)
100mg
sulfamethoxazole/
20mg trimethoprim
2.5ml
One tablet
6 months – 5
years (515kg)
200mg
sulfamethoxazole/
40mg trimethoprim
5ml
Two tablets
Half tablet
6 to postpubertal
400mg
sulfamethoxazole/
80mg trimethoprim
10ml
Four tablets
One tablet
Post-pubertal 800mg
Adolescents sulfamethoxazole/
160mg trimethoprim
and Adults
Unit 10: Treating the Dually Infected Patient
Two tablets
Slide 10-25
Issues in Using
ART During TB Therapy
• Identification of patients who will benefit from
antiretroviral therapy
• Drug-drug interactions
• Immune reconstitution events
• Overlapping ARV and TB medicine side effect
• Adherence with multi-drug therapy for two infections
• Coordinating care between TB and HIV care
providers
Unit 10: Treating the Dually Infected Patient
Slide 10-26
Immune Function and
Survival During TB Treatment
• Survival during TB treatment is associated with level
of immune function
• ART can substantially reduce mortality among
HIV/TB co-infected patients
• Initiation of ART within six months of TB diagnosis
can improve survival
Unit 10: Treating the Dually Infected Patient
Source: Mansouthi W et al., J Acquir Immune Defic Syndr, 2006.
Slide 10-27
Who Would Benefit from ARVs
During TB Therapy?
• HIV is associated with markedly increased
mortality during TB treatment
• Early deaths (< 30 days after TB diagnosis)
often due to TB; later deaths - other
complications of HIV
• All HIV+ patients with TB are stage 3
(pulmonary) or 4 (extra-pulmonary) and are
eligible for ART
Unit 10: Treating the Dually Infected Patient
Slide 10-28
Benefits and Risks
• Benefits:
• Strengthen immune system for fighting TB and other
infections
• Avoid deaths due to OIs and AIDS during TB therapy
• Risks
• Drug interactions limit ART regimens
• Immune reconstitution inflammatory syndrome
• Drug toxicity
Unit 10: Treating the Dually Infected Patient
Slide 10-29
Treatment of TB for HIV-Positive
Persons
Initial treatment phase should consist of
• Isoniazid (H)
• Rifampicin (R)
• Pyrazinzamide (Z)
• Ethambutol (E)
Unit 10: Treating the Dually Infected Patient
Slide 10-30
Rifampicin Decreases
Blood Levels of NVP and EFV
NNRTI
Effect of rifampicin
Nevirapine
 37-58%
Efavirenz
 13-26%
Unit 10: Treating the Dually Infected Patient
Slide 10-31
ART and Rifampicin-Based
TB Therapy
• AZT/3TC/EFV*
• Men
• Women outside of child bearing years
• Children >3 years old
• AZT/3TC/NVP*
• Women of child bearing age
• Children < 3 years old
*Note: if Hb < 7.5, substitute AZT with d4T
Unit 10: Treating the Dually Infected Patient
Slide 10-32
Rifampicin Markedly
Decreases Blood Levels of all PIs
Protease Inhibitor
Rifampicin effect
Saquinavir
 by 80%
Ritonavir
Indinavir
 by 35%
 by 90%
Nelfinavir
 by 82%
Lopinavir/ritonavir
 by 75%
Unit 10: Treating the Dually Infected Patient
Slide 10-33
Treatment Options: ART During
Rifampicin-Based TB Therapy
Ritonavir boosting of other PIs can achieve
adequate blood levels:
• Lopinavir/ritonavir, 400mg/400mg BD
• = 3 capsules Kaletra + 3 capsules ritonavir BD
• =2 tablets Alluvia* + 3 capsules ritonavir BD
• Lopinavir/ritonavir, 800mg/200mg BD
• =6 capsules Kaletra BD
• =4 tablets Alluvia* BD
Unit 10: Treating the Dually Infected Patient
Slide 10-34
Case Study: M.L. (1)
• 31 year old female with HIV infection
diagnosed 5 years ago
• She has been non-adherent to ART
• She presented with fever and cough of 2-3
weeks duration
• Exam: a small (1 cm) submandibular lymph
node was found on the right side
• Lab: CD4 count 26, Sputum smears x 2
positive for AFB
Unit 10: Treating the Dually Infected Patient
Slide 10-35
Case Study: M.L. (2)
• M.L. was started on TB medications (EHRZ)
plus ART as inpatient
• 2 wks after starting medications, she
developed increased cervical
lymphadenopathy with worsening respiratory
symptoms
• Repeat CD4 count was 120
• A CXR was done
Unit 10: Treating the Dually Infected Patient
Slide 10-36
Case Study: M.L. (3)
What do you think
is happening?
What would you
do next?
Unit 10: Treating the Dually Infected Patient
Courtesy of: © M. Narita, 2006.
Slide 10-37
Case Study: M.L. (4)
• HIV medications were
discontinued
• TB medications were
continued
• Repeat CXR was done
• M.L.’s CD4 decreased
to 34
Courtesy of: © M. Narita, 2006.
Unit 10: Treating the Dually Infected Patient
Slide 10-38
Case Study: M.L. (5)
• ART resumed 3 months into TB
treatment
• TB was cured
• At the end of TB treatment her CD4 was
342
Unit 10: Treating the Dually Infected Patient
Slide 10-39
Immune Reconstitution
Inflammatory Syndrome (IRIS)
• Improved immune response against MTB leads to
new or worsening signs or symptoms despite
effective TB treatment
• Closely associated with starting ARV (days to
weeks), but rarely associated with starting TB
therapy
• Natural history
• Duration - days to months
• Waxing and waning is common
Unit 10: Treating the Dually Infected Patient
Slide 10-40
IRIS Among Patients with HIV/TB
• Fever
• New or worsening lymphadenitis - peripheral or
central nodes
• New or worsening pulmonary infiltrates, including
respiratory failure
• New or worsening pleuritis, pericarditis, or ascites
• Intracranial tuberculomas, worsening meningitis
• Disseminated skin lesions
• Epididymitis, hepatosplenomegaly, soft tissue
abscesses
Unit 10: Treating the Dually Infected Patient
Slide 10-41
Risk Factors for IRIS
• Shorter time from the initiation of TB therapy
to the initiation of antiretroviral therapy (e.g.,
within six weeks)
• Low initial CD4 count or high viral load at ART
initiation
• CD4 count rises rapidly on ART
• Good immunological and virological response
during ART
• Extrapulmonary or disseminated disease
Unit 10: Treating the Dually Infected Patient
Source: Colebunders R, et al., Int J Tuberc Lung Dis, 2006.
Slide 10-42
Managing IRIS
• Inform patients about the possibility of an event after
starting ART– may feel like the “TB is coming back”
• Evaluate for possible TB treatment failure
• Drug resistance, non-adherence, malabsorption
• Assess for other HIV-related complications, e.g.,
another opportunistic infection
• Management of symptoms, e.g., use non-steroidal
anti inflammatory drugs
• For severe symptoms may need to use steroids
(prednisolone), 1 mg/kg or even stop ART
temporarily
Unit 10: Treating the Dually Infected Patient
Slide 10-43
Case Study: Mika
• A 40 year-old male from Gaborone
presents with fever for 4 weeks, cough with
bloody sputum, sweats and weight loss of
7kg
• Chest X-ray shows right lobe infiltrate
• Sputum AFB x 1 results “scanty”
• His HIV test is positive and CD4 is180
cell/cu mm
Unit 10: Treating the Dually Infected Patient
Slide 10-44
Case Study:
Mika at 2 months ATT
• Mika returns after two
months
• His fevers, cough, and night
sweats have stopped and
he has gained 5kg
• His TB regimen is changed
to the continuous phase
(R/H)
• He is started on ART
Source: I-TECH, Tanzania
X-ray shows improvement
Unit 10: Treating the Dually Infected Patient
Slide 10-45
Case study: Mika at 4 Months ATT
• Mika comes back for his 2nd ART monitoring
visit
• He reports fever, cough and night sweats have
returned
• He has taken his ARTs as prescribed but
thinks they are making him more sick and
would like to stop them
Unit 10: Treating the Dually Infected Patient
Slide 10-46
Case Study: Mika
Findings at 4 Months ATT
• Mika reports excellent
adherence and denies
nausea, vomiting or
diarrhoea
• His oxygen saturation is
96% on room air
• Heart rate, respiratory rate
and other vital signs are
normal
• Remainder of physical
exam is normal
• Sputum smear is 1+ for AFB
Source: I-TECH, Tanzania
New CXR
Unit 10: Treating the Dually Infected Patient
Slide 10-47
Case Study: Mika
2 Weeks Later
• He is worse
• Sputum culture from last visit
shows no growth to date (2
weeks)
• Sputum smear is still 1+ AFB
• On physical exam is
tachypnoeic
• Oxygen saturations is 90% on
room air
• Crackles heard in right lung
field
Source: I-TECH, Tanzania
X-ray shows worsening
Unit 10: Treating the Dually Infected Patient
Slide 10-48
Adverse Events During
Combined TB+HIV Treatment (1)
Common adverse events include:
• Peripheral neuropathy - more common with
use of ddI & d4T
• Skin rash
•
•
•
•
TB drugs
Cotrimoxazole
Nevirapine
Other drugs
• Hepatitis, due to TB drugs or unknown causes
Unit 10: Treating the Dually Infected Patient
Source: Dean GL, et.al., AIDS, 2002.
Slide 10-49
Overlapping Side Effects of
Anti-TB and ARV Drugs
Possible Causes
Side Effect
Antituberculosis
Drugs
Antiretroviral
drugs
Skin rash
S, Z, R, H
nevirapine, efavirenz, abacavir
Nausea, vomiting
Z, R, H
zidovudine, ritonavir, protease
inhibitors
Hepatitis
Z, R, H
nevirapine, efavirenz, protease
inhibitors
Leukopenia, anemia
R
Unit 10: Treating the Dually Infected Patient
zidovudine
Slide 10-50
Adverse Events During
Combined TB+HIV Treatment (2)
• Some adverse events related to advanced AIDS,
some to other infections or malignancies, and some
to their treatment
• Few events result in permanent discontinuation of
first-line TB drugs, even though therapy may have
been temporarily discontinued
Do not give up on the first-line TB drugs
unless it is clear that one of them is causing a
severe side effect!
Unit 10: Treating the Dually Infected Patient
Source: Dean GL, et.al., AIDS, 2002.
Slide 10-51
Managing Adverse Events
• Do one thing at a time-- makes it easier to decide the
cause of an event
• Stop medications for severe adverse events
• Use sequential re-challenge to decide the cause of
an event
• Don’t switch from the first-line TB drugs (especially
INH and RIF) without evidence of an association with
a significant side effect
• Remember IRIS as a possible cause of adverse
events during treatment
Unit 10: Treating the Dually Infected Patient
Slide 10-52
Increasing TB/HIV
Treatment Adherence
• TB treatment uses directly observed therapy
(DOT)-- use DOT visits for TB treatment to
enhance adherence to antiretroviral therapy
• Try to coordinate medication pickups where
possible
Unit 10: Treating the Dually Infected Patient
Slide 10-53
Preventing Active TB
Among HIV-Infected Persons
Four strategies:
1. INH Preventive Treatment
2. Antiretroviral Therapy
3. Infection Control
•
HIV+ Health Care Workers should avoid TB exposure
(medical and TB wards)
4. TB case finding
•
Early case-detection and effective TB therapy
(effective DOTS program)
Unit 10: Treating the Dually Infected Patient
Slide 10-54
Key Points
• Both TB and HIV increase the other’s disease
progression
• Early Diagnosis of TB has better outcomes for
patients, families and community
• Standard TB treatment correctly implemented cures
TB in TB/HIV
• ART for eligible patients greatly improves survival
• Different ART regimens are required because of drug
interactions with rifampicin
Unit 10: Treating the Dually Infected Patient
Slide 10-55