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TB & HIV Infection:
Treatment
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International Standards
Standard 8,8,13
15, 16
TB/HIV: Treatment
Objectives: At the end of this presentation,
participants will be able to:
 List the major drug interactions and possible firstline combinations for concomitant TB and
antiretroviral therapy (ART)
 Describe the effect of ART, cotrimoxazole preventive
therapy (CPT), and isoniazid preventive therapy
(IPT) on TB/HIV outcomes
 Describe the circumstances when immune
reconstitution inflammatory syndrome (IRIS) may
present
 List ways that TB/HIV co-infection may negatively
impact adherence
ISTC TB Training Modules 2009
TB/HIV: Treatment
Overview:
 TB regimens in TB/HIV
 Antiretroviral therapy (ART)
and TB treatment
 Cotrimoxazole preventive
therapy (CPT)
 Isoniazid preventive therapy
(IPT)
 Overlapping toxicities
 Immune reconstitution
inflammatory syndrome (IRIS)
 Adherence issues
International Standards 8, 15, 16
ISTC TB Training Modules 2009
Treatment of
HIV-associated
TB
ISTC TB Training Modules 2009
TB/HIV: Treatment Outcomes
In HIV-positive patients:
 TB treatment regimens are the same in
HIV-positive and HIV-negative patients
 HIV is associated with increased
mortality during TB treatment
 Patients with smear-negative TB have a
higher mortality than those with smearpositive TB
ISTC TB Training Modules 2009
TB/HIV: Treatment Outcomes
HIV and MDR/XDR TB: “Perfect Storm”
 Poor treatment outcomes and
exceptionally high mortality rates
• Rapid disease progression
• Delayed diagnosis
• Inadequate initial treatment
 KwaZulu Natal outbreak: 52 of 53 (HIV
+ XDR TB) died within median 16 days
of diagnosis
ISTC TB Training Modules 2009
ART Improves Outcomes
Antiretroviral Therapy (ART)
significantly reduces TB incidence
Decrease in TB
incidence after
starting ART in
resource-limited,
high-burden area
Lawn SD, et al, Am J Respir Crit Care Med, 2008;177:680-685
ISTC TB Training Modules 2009
Standard 8: Treatment*
(1 of 2)
 All patients who have
not been previously
treated should receive
an internationally
accepted treatment
regimen of known
bioavailability:
• Initial phase: 2 months INH, RIF, PZA, EMB
• Continuation phase: 4 months INH and RIF
* Abbreviated version
ISTC TB Training Modules 2009
Standard 8: Treatment
 The doses of anti-TB
drugs used should
conform to international
recommendations
 Fixed-dose combinations
(FDCs) of two (INH, RIF),
three (INH, RIF, PZA),
and four (INH, RIF, PZA,
EMB) drugs are highly
recommended
ISTC TB Training Modules 2009
(2 of 2)
TB/HIV: Treatment
TB/HIV issues to consider:
•
•
•
•
Drug-drug interactions
Role of antiretroviral therapy (ART)
Overlapping drug toxicities
Immune-reconstitution inflammatory
syndrome (IRIS)
• Adherence issues
ISTC TB Training Modules 2009
TB/HIV Treatment: Rifamycins
Drug interactions:
 Rifamycins induce hepatic cytochrome
P450 (CYP3A4) enzymes, accelerating
metabolism of:
• Protease inhibitors (PIs)
• Some non-nucleoside reverse
transcriptase inhibitors (NNRTIs)
• Nucleosides (NRTIs) are not effected
 Rifampicin >> Rifabutin
ISTC TB Training Modules 2009
TB/HIV Treatment: Rifamycins
 Evidence for development of acquired
rifamycin resistance with intermittent
therapy
• Advanced HIV and /or diarrhea: concern
for poor drug absorption
• Intermittent therapy not recommended
during initial phase of TB treatment in
patients with HIV infection
• No twice-weekly continuation phase
with advanced immunosuppression
ISTC TB Training Modules 2009
TB/HIV Treatment: RIF
 Rifampicin (RIF) - based regimens
remain first choice for TB treatment.
Use of RIF straightforward in cases:
• Not on antiretroviral therapy
• For whom PIs or NNRTIs are not
recommended
 RIF may be used with some NNRTIs
(and limited PIs), but requires caution
ISTC TB Training Modules 2009
TB/HIV Treatment: RIF Alternative
 For patients receiving PIs or NNRTIs,
the substitution of rifabutin (for rifampin)
is recommended if available
 Alternative non-rifamycin regimen:
• INH, EMB, PZA, and streptomycin
(but not generally recommended)
ISTC TB Training Modules 2009
Antiretroviral
Therapy with TB
ISTC TB Training Modules 2009
Standard 15: TB/HIV
 All patients with TB and HIV infections
should be evaluated to determine if
antiretroviral therapy is indicated during
the course of treatment for TB.
 Appropriate arrangements for access to
antiretroviral drugs should be made for
patients who meet indications for
treatment.
ISTC TB Training Modules 2009
(1 of 3)
Standard 15: TB/HIV
 However, initiation
of treatment for
tuberculosis should
not be delayed.
ISTC Training
TB Training
Modules
Modules
2008
2009
(2 of 3)
TB and Antiretroviral Therapy
 Indications for ART in TB/HIV patients
depend upon:
• Status of HIV disease (CD4 level)
• Success of current TB treatment
regimen
• Adherence and toxicity issues
• If not on ART at time of TB diagnosis,
use assessment of these issues to
decide when to start ART
ISTC TB Training Modules 2009
TB Care: If Already on ART
If TB develops…
Then
Within 6 months of
starting ART
Start first-line TB rx
and change ART
regimen if necessary
After 6 months of
Consider ART failure
starting ART evidence
and change to secondof clinical
line ART
immunological failure
 Key point: Start TB treatment immediately
ISTC TB Training Modules 2009
When to Start Antiretrovirals
HIV-infected TB patients not yet on ART
should be evaluated for ART immediately
CD4
Consider starting ART
<200
2–8 weeks after start of TB rx
>200 and <350
8 weeks after start of TB rx
>350
Defer ART (re-evaluate at 8
weeks and end of TB rx)
ISTC TB Training Modules 2009
When to Start Antiretrovirals
If CD4 count not available:
Clinical Presentation
ART
Any pulmonary TB and signs of
advanced HIV,
or no clinical improvement;
extrapulmonary TB
Start ART as
soon as TB rx
tolerated
Smear-negative pulmonary TB,
gaining weight on rx, no other
signs/sx of advanced HIV
Start ART after
the intensive
phase of TB rx
Smear-positive pulmonary TB,
gaining weight on rx, no other
signs/sx of advanced HIV
Defer ART until
TB rx done
ISTC TB Training Modules 2009
ART and RIF-based TB Rx
Recommended ART regimen:
 Efavirenz plus two nucleosides
(EFV + two NRTIs)
• Use efavirenz for adults and children
>3 years old
• Avoid 1st trimester of pregnancy
• Efavirenz dose 600mg (or 800mg)
ISTC TB Training Modules 2009
NNRTIs and Rifampicin
Rifampicin decreases blood levels of
NVP and EFV
NNRTI
Effect of Rifampicin
Nevirapine
 37–58%
Efavirenz
 22%
ISTC TB Training Modules 2009
ART and RIF-based TB Rx
Choice of nucleosides (NRTIs) to
combine with efavirenz:
 Usual adult first-line therapy (may also
be used in children >3):
• Zidovudine + lamivudine (AZT/3TC)
• Alternative in case of anemia:
Stavudine + lamivudine (d4T/3TC)
ISTC TB Training Modules 2009
PIs and RIF: Not Recommended
Rifampicin decreases blood levels of all PIs
Protease Inhibitor
Effect of Rifampicin
Saquinavir
 by 84%
Ritonavir
 by 35%
Indinavir
 by 89%
Nelfinavir
 by 82%
Amprenavir
 by 81%
Lopinavir/ritonavir
 by 75%
ISTC TB Training Modules 2009
ART Options: RIF-based TB Rx
More options (consider expert consultation):
 Triple NRTI: abacavir or tenofovir* + 2 NRTIs
• Not as potent, but no drug interactions
• WHO first-line for children >3
 Nevirapine + 2 NRTIs
• Some successful clinical experience
• Concern for low blood levels, toxicity
overlap (hepatitis, rash), and
hypersensitivity reactions
• Preferred WHO alternative in children < 3
*Tenofovir not recommended in pregnancy
ISTC TB Training Modules 2009
ART Options: RIF-based TB Rx
 Ritonavir boosting of other PIs can
achieve adequate blood levels but
significant hepatotoxicity risk
• Can be used in children (<3)
• Lopinavir/ritonavir (Kaletra)
usual dose 400/100 mg twice a day
PLUS an extra ritonavir 300 mg twice
a day (adult dose)
ISTC TB Training Modules 2009
Other Issues in
TB/HIV Treatment
ISTC TB Training Modules 2009
Standard 15: TB/HIV
(3 of 3)
 Patients with TB
and HIV infection
should also receive
cotrimoxazole as
prophylaxis for
other infections.
Pneumocystis jiroveci pneumonia
ISTC TB Training Modules 2009
Cotrimoxazole Preventive Therapy
 Reduces the risk of
• Pneumocystis jiroveci pneumonia (PCP)
• Toxoplasma
• Bacterial infections
 Reduces deaths and hospitalizations
 Also effective against:
• Pneumococcus, salmonella, nocardia
and malaria
ISTC TB Training Modules 2009
Cotrimoxazole Preventive Therapy
 All HIV-positive TB patients should receive
Cotrimoxazole Preventive Therapy
regardless of the CD4 count, for at least
the duration of anti-TB treatment.
 CPT is recommended for all patients with
CD4 cell count less than 200 cells/mm3
ISTC TB Training Modules 2009
Standard 16: Isoniazid Preventive Therapy
Persons with HIV
infection who, after
careful evaluation, do
not have active
tuberculosis should be
treated for presumed
latent tuberculosis
infection with isoniazid
for 6-9 months
ISTC TB Training Modules 2009
TB Risk with HIV Infection
 Exceptionally high rate of reactivation of
latent infection (7-10% per year)
 Rapid progression to TB following new
infection
 Increased risk begins soon after HIV infection
and increases as immunosuppression
increases
 Increased risk is reduced but not eliminated
by antiretroviral treatment
 Increased potential for reinfection after
successful treatment for TB
ISTC TB Training Modules 2009
Overlapping Side Effects
Side Effect
Skin rash*
Nausea,
vomiting
TB Drug
PZA, RIF, INH
PZA, RIF, INH
ARV
 Nevirapine
 Efavirenz
 Abacavir
 Zidovudine
 Ritonavir
 Amprenavir
 Indinavir
* May also see rash with cotrimoxazole
Burman et al, Am J Respir Crit Care Med 2001
ISTC TB Training Modules 2009
Overlapping Side Effects
Side Effect
Hepatitis
Leukopenia,
anemia
TB Drug
ARV
 Nevirapine
 Protease
inhibitors
PZA, RIF, INH
 IRIS
(with chronic
hepatitis)
RIF
 Zidovudine
Burman et al, Am J Respir Crit Care Med 2001
ISTC TB Training Modules 2009
Progression on TB/HIV Treatment
HIV+ case with
TB dx; TB
treatment begun

After 2 mo.
TB treatment,
begins ART

6 wks. later
symptoms and
CXR worsen
What could be happening here?
ISTC TB Training Modules 2009
IRIS
Immune Reconstitution
Inflammatory Syndrome (IRIS)
 Clinical worsening in the setting of an
adequate response to ART
• “Paradoxical” worsening of previously
known treated (completed or ongoing)
opportunistic pathogen
• “Unmasking” of subclinical opportunistic
pathogen
ISTC TB Training Modules 2009
IRIS
 Risk factors
• Disseminated TB
• Shorter delay between onset of TB and ART
drugs
• Low baseline CD4, higher baseline viral load
• Greater CD4 or viral load response to ART
 Timing of onset
• Usually within first 6 weeks of ART (often 2–3
weeks, but can be months after ART started)
ISTC TB Training Modules 2009
IRIS
Clinical presentation:
 Fever
 Nodal enlargement
 Worsening pulmonary
infiltrates (with or
without respiratory
symptoms)
 Local worsening in
extrapulmonary sites
ISTC TB Training Modules 2009
IRIS Differential Diagnosis
Differential diagnosis of IRIS:
 TB treatment failure
 Drug-resistant TB
 Other opportunistic (or non-opportunistic)
infections
 Lymphoma, Kaposi’s sarcoma
 Hypersensitivity drug reactions
 ART failure (if symptoms occur late in the
course of ART therapy)
ISTC TB Training Modules 2009
IRIS Evaluation and Treatment
 TB treatment should be continued
 Exclude TB treatment failure
• Adequate treatment and adherence?
• Drug resistance?




Exclude additional/new diagnosis
Continue ART (unless life-threatening)
Consider NSAIDS, steroids
Drainage of lesions
ISTC TB Training Modules 2009
TB/HIV: Adherence
Increased difficulties for adherence:
 Higher pill burden
 Greater number of potential drug side
effects
 Dual social stigma
 Additional illness (opportunistic infections)
 Difficult medical access, drug-supply
interruptions
ISTC TB Training Modules 2009
Example: Co-treatment Regimen
Source: Tuberculosis Care with TB-HIV Co-management, IMAI
ISTC TB Training Modules 2009
Improving Adherence
 DOTS
 Patient-centered care
 Incentives, enablers
 Patient education and
counseling
 Collaboration between
TB and HIV providers
 Joint TB and HIV
medication dispensaries
 Patient support groups
ISTC TB Training Modules 2009
Infection Control
Infection Control: Important in facilities
providing services for patients with TB,
especially in high HIV prevalence areas
 Establish an infection control plan
 Maximize natural ventilation of patient care
and waiting areas
 Identify and separate coughing patients
 Ensure rapid sputum smear results (24 hours)
 Consolidate TB services in time and place
ISTC TB Training Modules 2009
Summary: TB/HIV Treatment
Summary:
 Standard TB treatment usually cures TB in
TB/HIV co-infection
 Despite successful TB treatment, mortality
among TB/HIV patients remains high
 Cotrimoxazole prophylaxis (CPT)
improves survival and should be used in
all TB/HIV patients
 Latent TB infection should be treated with
isoniazid (IPT) in HIV-infected patients
ISTC TB Training Modules 2009
Summary: TB/HIV Treatment
Summary (continued):
 ART for eligible patients greatly improves
survival
 Different ART regimens may be required
because of drug interactions with rifampicin
 Coordination between the TB and HIV
programs is needed to improve treatment of
both conditions and will reduce disease and
death
ISTC TB Training Modules 2009
Summary: ISTC Standards Covered*
Standard 8:
 All patients who have not been previously
treated should receive an internationally
accepted treatment regimen.
 Initial phase: 2 months INH, RIF, PZA, EMB.
 Continuation phase: 4 months INH and RIF.
 EMB may be omitted in the initial phase for
non-HIV smear-negative cases without severe
disease.
 The doses of anti-TB drugs used should
conform to international recommendations.
Fixed-dose combinations are highly
recommended.
* Abbreviated versions
ISTC TB Training Modules 2009
Summary: ISTC Standards Covered*
Standard 15:
 All TB/HIV patients should be evaluated to
determine if ART is indicated during the
course of TB treatment.
 Appropriate arrangements for access to
ART should be made.
 However, initiation of treatment for
tuberculosis should not be delayed.
 TB/HIV patients should also receive
cotrimoxazole preventative therapy.
* Abbreviated versions
ISTC TB Training Modules 2009
Summary: ISTC Standards Covered
Standard 16:
• Persons with HIV infection who, after
careful evaluation, do not have active
tuberculosis should be treated for
presumed latent tuberculosis infection with
isoniazid for 6-9 months
ISTC TB Training Modules 2009
Alternate Slides
ISTC TB Training Modules 2009
WHO HIV Clinical Stage 1
 Asymptomatic
 Persistent generalized lymphadenopathy
 (WHO clinical stage 1 conditions are not
HIV specific)
ISTC TB Training Modules 2009
WHO HIV Clinical Stage 2








Moderate unexplained weight loss (<10%)
Recurrent respiratory tract infections
Herpes zoster
Angular cheilitis
Recurrent oral ulceration
Papular pruritic eruptions
Seborrhoeic dermatitis
Fungal nail infections
ISTC TB Training Modules 2009
WHO HIV Clinical Stage 3
 Unexplained severe weight loss >10%
 Unexplained chronic diarrhea > 1 month
 Unexplained persistent fever > 1 month
 Persistent oral candidiasis
 Oral hairy leukoplakia
 Pulmonary tuberculosis
ISTC TB Training Modules 2009
WHO HIV Clinical Stage 3
 Severe bacterial infections
 Acute necrotizing ulcerative
stomatitis, gingivitis or periodontitis
 Unexplained:
• Anemia <8 g/dl
• Neutropenia < 0.5 x 109/l
• Chronic thrombocytopenia <50 x 109 /l
ISTC TB Training Modules 2009
WHO HIV Clinical Stage 4








HIV wasting syndrome
Pneumocystis pneumonia
Recurrent severe bacterial pneumonia
Chronic herpes simplex infection
Esophageal candidiasis
Extrapulmonary tuberculosis
Kaposi’s sarcoma
Cytomegalovirus infection
ISTC TB Training Modules 2009
WHO HIV Clinical Stage 4
 Central nervous system toxoplasmosis
 HIV encephalopathy
 Extrapulmonary cryptococcosis, including
meningitis
 Disseminated non-tuberculous
mycobacterial infection
 Progressive multifocal
leukoencephalopathy
 Chronic cryptosporidiosis
ISTC TB Training Modules 2009
WHO HIV Clinical Stage 4




Chronic isosporiasis
Disseminated mycosis
Recurrent septicemia
Lymphoma
(cerebral or B cell non-Hodgkin)
 Invasive cervical carcinoma
 Atypical disseminated leishmaniasis
 Symptomatic HIV-associated nephropathy
or HIV-associated cardiomyopathy
ISTC TB Training Modules 2009
Purpose of ISTC
ISTC TB Training Modules 2009
ISTC: Key Points
 21 Standards (revised/renumbered in 2009)
 Differ from existing guidelines: standards
present what should be done, whereas,
guidelines describe how the action is to be
accomplished
 Evidence-based, living document
 Developed in tandem with Patients’ Charter
for Tuberculosis Care
 Handbook for using the International
Standards for Tuberculosis Care
ISTC TB Training Modules 2009
ISTC: Key Points
 Audience: all health care practitioners,
public and private
 Scope: diagnosis, treatment, and public
health responsibilities; intended to
complement local and national guidelines
 Rationale: sound tuberculosis control
requires the effective engagement of all
providers in providing high quality care and
in collaborating with TB control programs
ISTC TB Training Modules 2009
Questions
ISTC TB Training Modules 2009
TB/HIV: Treatment
1.
A 45 year-old man with AIDS had documented
clinical improvement after two months of standard
TB treatment and subsequently began ART. After
one month of combined TB treatment and ART,
symptoms of cough with new infiltrates on chest
radiograph are discovered. Which of the following
need to be considered in the differential diagnosis
at this time:
A. TB treatment failure
B. New opportunistic respiratory infection
C. Immune reconstitution inflammatory syndrome
D. All of the above
ISTC TB Training Modules 2009
TB/HIV: Treatment
2. The antiretroviral therapy regimen of choice for
a patient on first-line TB treatment with
isoniazid, rifampicin, ethambutol, and
pyrazinamide would be:
A. A triple nucleoside (NRTI) regimen
B. Ritonavir “super-boosted” protease inhibitor (PI)
regimen
C. A dual protease inhibitor (PI) regimen
D. Efavirenz plus two nucleosides (NRTIs) if not
pregnant
ISTC TB Training Modules 2009
TB/HIV: Treatment
3.
A 50 year-old woman with sputum smear-positive TB
and new HIV infection is started on both a standard
four-drug TB regimen and a three-drug ART regimen at
the same time. The patient’s adherence is spotty and
one week later she complains of severe nausea and
vomiting. All of the following statements are correct
except:
A.
B.
C.
D.
Nausea and vomiting can be side effects seen with either TB
or ART drugs
The initial high pill burden may be contributing to the patient’s
poor adherence
Starting both TB and HIV treatments together has made the
job of finding the cause of the symptoms more complicated
Prioritizing the start of ART first, with a delay in TB treatment
would have been the recommended sequence
ISTC TB Training Modules 2009