1. HAIVN Harvard Medical School AIDS Initiative in Vietnam
Tuberculosis and HIV
HAIVN
Harvard Medical School AIDS
Initiative in Vietnam
M1-17-Tuberculosis and HIV-EN
HAIVN Module 1, Revised April 2012

2. Learning Objectives
By the end of this session, participants should be able to:
Explain the significance of TB/HIV co-infection
Describe the clinical presentation of TB in PLHIV
Outline TB treatment regimens
Explain drug-resistant TB
Describe common interactions between ARV and TB drugs

3. TB Epidemiology (1)
Vietnam is ranked 12th in the world for incident TB
The incidence in the general population is 180/100,000
ASK participants, as a review, what the difference is between incidence and prevalence.
ALLOW time for them to answer.
PROVIDE answer as needed: Incident = new cases over a certain time period (e.g. one year); prevalence = total # of cases in a given time period.
REFER participants to Handout M1S17.1: TB Epidemiology so that they can get a closer look at the rankings.
POINT OUT that the HIV prevalence in TB cases is ONLY 4.2% compared with South Africa which is 60%.

4. TB Epidemiology (2) Vietnam Global TB Control. WHO 2010
NOTE that this slide is animated. Do not click through to the answers on the slide until after giving participants the opportunity to answer the question.
EXPLAIN that this map shows TB incidence globally.
ASK participants to find Vietnam on the map and ASK “What is the estimated TB incidence in Vietnam?”
ALLOW time for them to respond.
CLICK through to show Vietnam and the red circle.
EXPLAIN that most of the estimated number of cases in 2009 occurred in Asia (55%) and Africa (30%). Vietnam is one of the 22 countries with the highest rates of TB in the world. >100 cases per 100,000 pop.

5. TB / HIV Epidemiology Vietnam Global TB Control. WHO 2010
EXPLAIN that this map shows HIV prevalence among incident TB cases in the world and in Vietnam.

6. TB/HIV Interaction (1)
TB is the most common OI in developing countries and the most common cause of death among HIV patients
TB infection:
speeds the progression of HIV by increasing viral replication
worsens immunological suppression in HIV patients
HIV increases mortality among patients with TB
EXPLAIN that HIV increases the risk for TB and increases the death rate among patients with TB. TB makes the progression of immunological suppression and the progression to AIDS faster.
REFER to Handout M1S17.2: OI Distribution among PLHIV in Vietnam for further information about OIs in Vietnam.

7. TB/HIV Interaction (2)
Most TB cases are caused by reactivation of latent TB infection
In Vietnam, an estimated 50-60% of the population has latent TB infection
HIV greatly increases the chance for latent TB infection to become active
Status
Risk of active TB infection
HIV negative
10% lifetime risk
HIV negative IDU
1% risk per year
HIV infected
10% risk per year
EXPLAIN that the reason TB is so common in HIV patients in developing countries is the combination of high rates of latent infection with increased risk for latent infection becoming active.
Ref: Am J Resp Crit Care Med 2000 Apr;161 (4 Pt 2 ): S221-47

8. Clinical Presentation of PLHIV with TB
Note that PLHIV stands for People living with HIV/AIDS.
BEFORE moving to the next slide, ASK participants what are the effects (signs and symptoms) of HIV on TB?

9. HIV worsens the signs and symptoms of TB, as shown in the chart
The Effects of HIV on TB
HIV worsens the signs and symptoms of TB, as shown in the chart
Ref: Chest 1994;106:1471-6
Symptom /Sign
HIV Positive
HIV Negative
Dyspnea
97%
81%
Fever
79%
62%
Sweats
83%
64%
Weight loss
89%
Diarrhea
23% 4%
Hepatomegaly
41%
21%
Splenomegaly
40%
15%
Lymphadenopathy
35%
13%
EXPLAIN that the results of this study show that patients with HIV-related TB more often have symptoms and signs of a systemic process – higher rates of fever, sweats, diarrhea, hepatosplenomegaly, and lymphadenopathy.
This suggests that HIV-related immunosuppression doesn’t allow the body to contain TB disease to a single organ system.
Ref: Chest 1994;106:1471-6

10. Clinical Presentation and CD4 (1)
EXPLAIN that in patients with mild immunosuppression (CD4 > 500), the presentation of TB is usually pulmonary with typical symptoms as in patients without HIV.

11. Clinical Presentation and CD4 (2)
Signs and Symptoms of Pulmonary TB
CD4 > 500
“Typical” presentation:
Fever
Cough
Weight loss
Bloody sputum
CD4 < 200
“Atypical” presentation:
fever of unknown etiology
weight loss
minimal cough
Extra-pulmonary disease more likely
Sputum sample more likely to be negative
EXPLAIN that when CD4 is low (<200), atypical presentations of TB are more common: extra-pulmonary disease (lymph nodes or disseminated) with fewer or no respiratory symptoms. Sputum AFB negative is more common.
EXPLAIN further that wasting syndrome is a common presentation in patients with advanced AIDS. (In a study in HCMC, 50% of pts with a diagnosis of wasting syndrome, later had positive cultures for MTB)
NOTE The next few slides will display chest x-rays of TB (Pulmonary TB – typical/atypical and Miliary TB)

12. Typical Chest X Ray Infiltrates predominantly in upper lobes
Early stages of HIV (CD4 > 500):
Infiltrates predominantly in upper lobes
Pulmonary cavities present
Pleural effusions
EXPLAIN Typical CXR of patients with pulmonary TB and high CD4.
EXPLAIN what is shown in each of the CXRs on the slide:
CXR 1: Shows left upper lobe pulmonary cavity
CXR 2: Shows right upper lobe infiltrate
CXR 3: Shows right pleural effusions

13. Atypical Chest X Ray Advanced stages of HIV (CD4 < 200):
Pulmonary cavities absent
Infiltrates in middle and lower lobes
Nodular infiltrates
Effusions can be pleural and pericardial
Mediastinal lymphadenopathy with no pulmonary infiltrates
Normal CXR in 10 %
EXPLAIN atypical CXR in patients with low CD4.
EXPLAIN what is shown in each of the CXRs on the slide:
CXR 1: Mediastinal lymphadenopathy
CXR 2: Infiltrate in middle lobe
CXR 3: Miliary pattern

14. Chest X Ray – Miliary (Disseminated) TB
EXPLAIN Miliary TB, as needed:
Miliary (or disseminated) TB: wide dissemination of TB disease throughout the body
Presents radiologically as many tiny spots (like millet seeds) throughout the lungs
May involve several organs, including lungs, liver, and spleen

15. Extra-pulmonary TB (1)
Extra-pulmonary Tuberculosis (EPTB) occurs when bacteria spread outside of the lung and cause disease
Occurs more commonly in people with weak immune systems e.g. PLHIV
May occur with or without concomitant pulmonary TB

16. Extra-pulmonary TB (2) Occurs most often when a person’s CD4 < 100
Most commonly manifests as:
Abdominal and lymph node TB (very often)
TB meningitis (5-10%), Tuberculoma
Pericarditis
Pleural effusion
Cutaneous
Renal
EXPLAIN that when the CD4 <100 the presentation of TB may be anywhere in the body.
Lymph node disease and disseminated disease are common.

17. Extra-pulmonary TB (3)
EXPLAIN that these are pictures of patients with extra-pulmonary TB in different sites on their bodies.

18. Extra-pulmonary TB (4)
NOTE that this slide is animated. Click once to show the first picture (5 all together) and ASK participants to guess what type of extra-pulmonary TB each picture represents.
PROVIDE each answer, before going on to the next picture.
1-TB Pericarditis
2-Cutaneous TB (diagnosis by biopsy) in general associated with disseminated TB (milliary)
3-Cutaneous TB (diagnosis by biopsy) in general associated with disseminated TB (milliary)
4- Tuberculoma (DD: toxo, lymphoma)
5- Articular TB

19. Sputum Smear and HIV Status (1)
Diagnose TB by examining stained sputum samples for presence of acid fast bacilli (AFB)
Sputum smear is the most rapid and inexpensive diagnostic test for TB
The sensitivity of TB sputum smears depends on many factors including HIV status
EXPLAIN that the sensitivity of the TB sputum smears depends on many factors such as the type of TB (pulmonary vs. extra-pulmonary), the quality of the sputum specimen, the experience of the laboratory, the HIV status.

20. Sputum Smear and HIV Status (2)
EXPLAIN that TB Smear is not useful for excluding TB in HIV positive patients.
In addition, a negative smear should not unduly delay TB treatment.
Patients with HIV-related pulmonary TB more often have negative sputum smears (43% vs. 24%) compared to those without HIV co-infection.
EXPLAIN that this will be a challenge for sites that do not have access to AFB culture (which is most sites in Vietnam).
For patients with smear-negative TB to be treated appropriately, it is extremely importance to recognize the clinical and chest radiographic characteristics of HIV-TB.
Tubercle Lung Dis 1993;75:191-4

21. TB HIV Co-infection Key Clinical Practice Points
“Typical” pulmonary TB less common
“Atypical”, smear negative and extra-pulmonary TB more common
WHO and Vietnam MOH guidelines allow TB treatment on clinical suspicion without positive smear test
EXPLAIN that again, atypical presentations of TB are more common in HIV patients with low CD4.
Lack of positive AFB should not delay TB treatment in patients with strong clinical suspicion for TB.

22. MOH and WHO Recommend: “THE ANTIBIOTIC TRIAL”
When indicated, use one course of broad spectrum antibiotics including coverage for typical and atypical causes of community acquired pneumonia
Under such circumstances, avoid Fluoroquinolones to prevent undue delay in diagnosis of TB
EXPLAIN that fluoroquinolones have activity against TB. If they are used in the ‘antibiotic trial’ the patient may have a partial initial clinical response thereby confusing the picture and possibly leading to a delay in the diagnosis of TB.
EXPLAIN further that fluoroquinolones are part of the 2nd line TB treatment in case of MDR TB.

23. Treatment Regimens for PLHIV with TB
BEFORE moving to the next slide, ASK participants “What drugs are typically used for treating TB?”

24. TB National Treatment Protocol (1)
Guidelines for the Diagnosis and Treatment of HIV/AIDS. Ministry of Health, 2009.
Drug
Dosage
Isoniazid (H)
5 mg/kg/day
Rifampin (R)
10 mg/kg/day
Pyrazinamide (Z)
20-30 mg/kg/day
Streptomycin (S)
15 mg/kg/day
Ethambutol (E)
15-25 mg/kg/day
EXPLAIN that dosages of TB drugs are the same for HIV infected patients as for HIV-negative patients.

25. TB National Treatment Protocol (2)
For newly diagnosed TB cases, regimen 1:
2 S(E)HRZ / 6 HE
2 S(E)RHZ / 4 RH*
* applied only if direct observation continued in maintenance phase
EXPLAIN that in HIV patients, the course of TB treatment is the same as that for HIV negative patients.
However, for the first two-months, also known as the “attack” phase of treatment Ethambutol is often substituted for Streptomycin due to
High rates of SM resistance in new patients (29%)
Desire to prevent need for injections
EXPLAIN that the use of EH in the maintenance phase of TB is associated with higher rates of treatment failure and TB relapse. However, due to concerns for development of rifampin resistance, RH is only recommended if directly observed therapy (DOT) can be used for the duration of the TB treatment course.
Guidelines for the Diagnosis and Treatment of HIV/AIDS. Ministry of Health, 2009.

26. TB National Re-Treatment Protocol (3)
For recurrent TB and failure to Regimen 1, there is Regimen 2:
2 SHRZE for 2 months: 5 drug
THEN
1 HRZE for 1 month: 4 drugs
5 H3R3E3 for 5 months: 3 drugs given 3 times per week
Total duration: 8 months
Guidelines for the Diagnosis and Treatment of HIV/AIDS. Ministry of Health, Vietnam

27. TB Treatment: Special Situations
Some special situations require a more aggressive course of treatment, including:
Miliary TB
Pericarditis
Meningitis
Spondilitis with neurological complications
For pregnant women: avoid streptomycin - can cause permanent deafness in baby
Use ethambutol instead
EXPLAIN that TB treatment can be prolonged to months in patients with severe extra-pulmonary or disseminated TB.

28. Small Group Activity: Case Study 1
Instructions:
DIVIDE participants into groups of 5-6 people.
REFER to Worksheet M1S17.3: TB Case Study to complete the case study.
ALLOW 15 minutes for the group work. At the end of the 15 minutes have the groups of 5-6 report their results to the larger group.
ASK participants if they have any questions, concerns.

29. Drug Resistant TB (1) Type Meaning
Drug resistant TB is TB for which anti-TB drugs have little or no effect against the TB causing agent
Type
Meaning
Mono-resistance
Resistant to only 1 anti-TB drug
Poly-resistance (PDR)
Resistant to more than 1 anti-TB drug, but not INH and RIF combination
Multi-drug resistance (MDR)
Resistant to at least INH and RIF, the 2 most effective anti-TB drugs
Extensively drug-resistant (XDR)
MDR and further resistance to any fluoroquinolone and at least one of three injectable second-line drugs: amikacin, kanamycin, or capreomycin
EXPLAIN that drug resistant TB is increasing throughout the world. These are the definitions of the terms.

30. Drug Resistant TB (2) Causes of drug resistant TB include:
Inadequate treatment regimens
Interrupted availability to drug treatment
Poor quality of drug treatment
Incomplete treatment adherence
Results from spontaneous mutations of MTB exposed to drugs
NOTE that this slide is animated. Do not click through to the answers on the slide until after giving participants the opportunity to answer the question below.
ASK participants “What are some reasons that TB is sometimes resistant to drugs?”
ALLOW time for them to respond.
CLICK through to show answers.
EXPLAIN that all of the same factors can lead ARV drug resistance in the context of HIV.
Quy HT, Buu TN et al Int J Tuberc Lung Dis 2006;10(2):

31. Multi Drug-Resistant (MDR) TB in Vietnam
Among reported cases in 2008, it is estimated that:
2.7% of new TB cases had MDR-TB
19% of re-treatment cases had MDR-TB
3500 MDR-TB cases among reported pulmonary TB cases in 2009
EXPLAIN that patients with a history of previous TB treatment have higher rates of resistance compared new TB cases.
Global TB Control. WHO 2010

32. TB and ARV Drug Interactions (1)
Rifampicin decreases drug levels of some ARVs:
ARV
Effect
Treatment/Solution
NVP
 37%
Switch to EFV, if available
(NVP OK, if necessary*)
EFV
 25%
EFV still effective PI
(LPV/r, IDV)
 80-90%
Do not use PI with RIF: refer to specialty center for treatment
EXPLAIN that Rifampicin decreases drug levels of some ARV by increasing metabolism in the liver by the Cytochrome P450 enzyme system.
Protease inhibitors (PIs) can be given with RIF if extra ritonavir is used to “super-boost” the PI. This is available in some referral clinics (Tropical Disease Hospital in HCMC).
*Vietnam MOH HIV/AIDS Guidelines, 2009

33. TB and ARV Drug Interactions (2)
Note overlapping toxicities of TB and ARV drugs TB
ARV
Toxicity
INH
d4T
Peripheral neuropathy: prevent with pyridoxine (B6) mg/day
INH, RIF, PZA
NVP, EFV
Hepatotoxicity
EXPLAIN that it is important to beware of overlapping toxicities of TB and ARV drugs.
The drugs can be used together, but the doctor must follow for signs or symptoms of side effects.
All patients on INH should be given pyridoxine (vitamin B6) mg per day to prevent neuropathy.

34. Case Study 2 (1)
26 year old patient with HIV and a CD4 count of 15 presents with prolonged fever and wasting
CXR shown to right
You suspect TB but sputum AFB/BK is negative
Note that this case study can be done in a large group.
ASK for a volunteer to read the case study on the slide. 34

35. Case Study 2 (2) What does the CXR show?
How do you interpret negative sputum smear? 
How would you manage the patient?
ASK for a volunteer to read the case study questions on the slide.
ASK participants to respond to the questions.
ALLOW time for them to respond to each one.
PROVIDE answers, as needed:
1) What does the CXR show?
Left upper lobe consolidation
Mediastinal and hilar lymphadenopathy
2) How do you interpret the negative sputum smear?
A negative sputum smear does not rule out TB particularly in an HIV+ patient with a very low CD4 count
3) How would you manage the patient?
A trial of a course of broad spectrum antibiotics
If no response, refer for TB treatment 35

36. Key Points TB/HIV co-infection is common among PLHIV in Vietnam
HIV infection increases risk for active TB infection by over 100 fold
Clinical presentation of TB varies by CD4 count
TB treatment regimens are the same for both HIV+/- patients

37. Thank you!
Questions?