1. Unit 10: Treating the Dually Infected Patient
Botswana National Tuberculosis Programme Manual Training for Medical Officers

2. 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
This unit will introduce participants to the synergy of combined HIV and TB infection and treatment options to improve survival of patients with both
The first few slides of this Unit will review and emphasise points made in Units 3 and 4 about the interaction of HIV and TB regarding clinical presentation. The rest of the slide set addresses issues on treatment: both technical and organisational
Ask the participants if they have any questions about the learning objectives before continuing

3. A Deadly Infectious Disease
HIV TB
HIV & TB
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%*
An increasing number of people have both HIV and TB together. HIV/AIDS is the number one infectious cause of death in the world, but many people with HIV/AIDS become ill with TB and die with TB
Rates of co-infected persons, 2004:
Worldwide: 370 thousand
Africa: 300 thousand
Mortality rates in Africa, 2004
586 thousand infected with TB
205 thousand co-infected
The TB/HIV burden in Botswana is estimated as not all TB patients are tested for HIV; it may even be higher than 80%
Our TB case notification rate in Botswana has risen because of HIV
Epidemiologic synergy: HIV and TB often occur in the same populations: the same country, same region, and same households. So there is a lot of opportunity for persons with TB to be exposed to HIV, and for persons with HIV to be exposed to TB. HIV infected persons with latent TB infection are much more likely to develop active disease, so that TB transmission increases in the population as well
*Source: Botswana National Tuberculosis Programme Manual, 2007.
Source: WHO. Global tuberculosis control: surveillance, planning, financing [cited 2008 Jan 30]. Table A2.1, p 143. Available from:
Discuss the following studies with participants:
In an autopsy study of 128 patients done in Francistown in , 81% were HIV-positive
Among HIV-positive patients, 40% had TB, 23 % had bacterial pneumonia 23%, 11% had Pneumocystis carinii pneumonia, and 11% had Kaposi’s Sarcoma. These conditions were the cause of death in 38%, 14%, 11%, and 6%, respectively
Of the 40 pulmonary TB cases, 90% also had disseminated extra-pulmonary TB. Chest radiology could not reliably distinguish the pathologies pre-mortem
Source: Nsari N. Kombe A, Kenyon T, Hone N, Tappero J, Nyirena S, Binkin N, Lucas S. Pathology and causes of death in a group of 128 predominantly HIV-positive patients in Botswana The International Journal of Tuberculosis and Lung Disease, 2002 Jan; 6(1):55-63(9).
*Source: BNTP, 2007.
Source: WHO, 2006.

4. 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
TB and HIV interact in both biological and epidemiological ways. These interactions lead to increases in both conditions
HIV makes TB worse by reducing the immunologic control of TB infection. HIV reduces cell mediated immunity, which leads to higher rates of development of active disease from TB exposure or infection, and to more severe and atypical forms of TB disease
TB has a higher death rate in persons with advanced immunosuppression from HIV, and TB has a higher relapse rate after treatment in HIV-infected persons
Immune system activation by TB increases the rate of HIV growth. Activation of CD4 lymphocytes, macrophages, and other immunologic cells, along with the production of immunologic chemicals called cytokines, increase the growth of HIV. This leads to more rapid development of immunosuppression than with HIV alone

5. 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
Because of the impact that TB has on increasing the progression of HIV to AIDS, it is essential that patients who are newly diagnosed with HIV be educated about tuberculosis and be screened. Further work up is necessary if a patient has positive clinical findings

6. 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)
An HIV-positive person who becomes infected with TB has a 10% annual risk of progressing to active TB disease and a 50% lifetime risk for developing tuberculosis. (Compared with a 2-10% lifetime risk of active TB in an HIV negative person)
HIV infects white blood cells (WBC), which are a part of the body’s immune system. If a person has a weak immune system, she is:
more likely to progress to TB disease immediately following infection
at greater risk for progressing to TB disease from latent infection and
at higher risk of becoming reinfected
Source: World Health Organization. TB/HIV: A Clinical Manual. Second Edition. WHO
Source: WHO, 2004

7. Natural History of TB New TB Infection Latent TB Infection Primary
Progressive
TB disease
(children,
rare adults,
HIV+)
~ 10%
reactivate
each
year
~ 5%
after
2 years
till death
~5 % In
1-2 years
HIV +
HIV -
Among persons with TB infections and without HIV, there is a 10% lifetime risk of active disease, whereas among HIV-positive persons with TB infection there is about an average 10% risk per year of developing active disease

8. Mortality from TB Before Era of ART
This slide shows the effect of HIV infection on the death rate of TB during treatment (6 months)
The vertical axis shows the percent of patients who died during the first 6 months of TB diagnosis
The horizontal axis divides patients by HIV status
Patients with HIV/TB co-infection had a much higher death rate – 14% vs. 0.5%
The high death rate suggests that treatment of HIV, in addition to treatment of TB, could improve outcomes of patients with HIV-TB
Source: Murray J, Sonnenberg P, Shearer SC, Godfrey-Faussett. Human immunodeficiency virus and the outcome of treatment for new and recurrent pulmonary tuberculosis in African patients. Am J Respir Crit Care Med Mar;159(3):
There seems to be a lack of data regarding the impact of ART on morbidity and mortality of TB patients. A study in Malawi showed little difference in short-term mortality in TB patients with or without ART. Most co-infected patients died during the first two months of TB treatment
However, most patients in the study were started on ART after the intensive phase, and ART might need to be started early to have an impact on short-term mortality
Source: Zachariah R, Fitzgerald M, Massaquo M et al. Does ART reduce case fatality among HIV-positive patients with tuberculosis in Malawi? Int J Tuberc Lung Dis 2007; 11(8):
Data might be scarce for Botswana but ART could reduce mortality significantly, though to what extent it is unknown
Other references:
Manosuthi W, Chottanapand S, Thongyen S, Chaovavanich A, Sungkanuparph S. Survival Rate and Risk Factors of Mortality Among HIV/Tuberculosis-Coinfected Patients with and without Antiretroviral Therapy. J Acquir Immune Defic Syndr Sep;43(1):42-6.
Lawn SD; Myer L; Bekker LG; Wood R. Burden of tuberculosis in an antiretroviral treatment programme in sub-Saharan Africa: impact on treatment outcomes and implications for tuberculosis control. AIDS. 2006; 20(12):
Murray J et al, Am J Respir Crit Care Med, 1999.

9. Pattern of TB and Survival of Patients with HIV-related TB
PTB
EPTB
Both
This slide shows that the clinical pattern of TB disease is associated with survival among people with HIV-related TB. HIV-infected persons who have both pulmonary and extra-pulmonary TB have the poorest survival in general, perhaps because they have more severe immunosuppression. Knowledge of the patient’s extent of TB may help prioritise who should be considered for ART
Orient participants to this graph
The vertical axis shows survival after the diagnosis of HIV-related TB
The horizontal axis shows time since that diagnosis, in days
Patients with pulmonary-only TB had the best survival, patients with pulmonary + extrapulmonary TB had the worst survival
This relationship is probably due to the effect of CD4 count and presence of extrapulmonary TB – the lower the CD4 cell count, the more the chance of extrapulmonary involvement
The results of this study suggest that presence of extrapulmonary TB can be one way of targeting patients to receive potent antiretroviral therapy
Source: Whalen C, Horsburgh CR Jr, Hom D, Lahart C, Simberkoff M, Ellner J. Site of disease and opportunistic infection predict survival in HIV-associated tuberculosis. AIDS Mar 15;11(4):
Days from diagnosis of TB
Whalen C, et al. AIDS, 1997.

10. 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
Compare the purpose and methods of TB and HIV screening (HIV screening listed on the next slide)

11. 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
Health care encounters include:
Mother-to-child (PMTCT)
IDCC/ART Clinic
Other health unit
TB symptoms: cough >2-3 weeks, weight loss, fatigue, night sweats, loss of appetite, haemoptysis, TB contact, chest pain, fever....
Ask the group: If you had 50 patients waiting to be seen and you had 3 questions you could ask each patient, what would they be?

12. 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
HIV and TB often occur in the same populations: the same country, same region, and same households. So there is a lot of opportunity for persons with TB to be exposed to HIV, and for persons with HIV to be exposed to TB
HIV infected persons with TB are much more likely to develop active disease, so that TB transmission increases in the population as well
Therefore, diagnosing TB early among HIV patients is even more important to improving outcomes in all of these ways

13. 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
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
Review the strategies to confront HIV and TB by looking at the tasks directed at HIV-positive persons and the tasks directed at persons with TB

14. 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
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
Ask participants to share their observations about the content of the past two slides
Answer: the tasks for addressing TB and those for addressing HIV are very similar and have a lot of overlap
*ADL = Activities of Daily Living
Note the similarity between the two columns– we need coordination of efforts

15. Challenges to Integration
What do you think are the challenges to integrating the two services?
What strategies can you suggest to address these potential challenges?
Coordination needed between HIV and TB programs and clinics to:
Prevent HIV among TB patients
Prevent TB among HIV patients
Test patients and contacts for both conditions
Coordinate therapy
Manage drug interactions
Maximise adherence with DOT/treatment supporters
Divide participants into small groups of about 4-5 people
Ask each group to select a reporter and recorder
Distribute flip chart paper to each group
Ask the groups to list challenges they see to integrating these two services. For each challenge listed, the groups should try to brainstorm a potential strategy to address these potential challenges
Allow participants 5-10 minutes to work as a small group
Ask each group to share 2-3 of their responses (challenge and strategy). If groups had trouble coming up with a strategy, ask the rest of the group for other ideas
Discuss as a large group for about 5 minutes.
Give example that at Marina Hospital, all TB/HIV co-infected patients are seen on Fridays (for ART refills, episodic visits, etc.) so that it becomes a “TB/HIV integration day”
Another example of integration is provision of cotrimoxazole preventive therapy to HIV positive patients at clinics where TB services (but not ART) are provided

16. 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
Decision on when to start ART after starting TB treatment involves a balance between the pill burden, potential drug interactions, overlapping toxicities and possible immune reconstitution syndrome versus the risk of further progression of immune suppression with its associated increase in mortality and morbidity

17. 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
This has been a source of confusion for many
It’s controversial and a lot of people have different ways of doing this
Current first-line ARVs used in Botswana are AZT + 3TC with either efavirenz or nevirapine (women of childbearing age). If the patient is anaemic with a haemoglobin<7.5, d4T is used instead of AZT
In the next 6 months, the first line ART regimen is going to be changed to TDF + FTC instead of combivir. It will be in a fixed dose combination like combivir, but will be taken once daily. FTC has the same mechanism of action as 3TC, and tenofovir (TDF) has fewer side effect and complications & is a nucleotide reverse transcriptase inhibitor
Risks of starting ARVs early:
Toxicity
Pill burden
IRIS
Drug-drug interaction

18. ART in the Botswana National Programme
NRTIs
NNRTIs
PIs
AZT (Zidovudine)
3TC (Lamivudine)
d4T (Stavudine)
ddI (Didanosine)
(AZT+3TC) (Combivir)
EFV (Efavirenz)
NVP (Nevirapine)
LPV/r (Kaletra or Alluvia)
RTV (Ritonavir)
SQV (Saquinavir)
The drugs listed in the slide are from 3 classes:
NRTI=nucleoside reverse transcriptase inhibitor TDF & ABC are both NRTIs; NRTIs act by competing with natural occurring deoxynucleotides in building the viral DNA chain and cause chain termination.
NNRTI=non-nucleoside reverse transcriptase inhibitor; NNRTIs are non-competitive inhibitors of reverse transcriptase. They do not actually become incorporated into viral DNA chain like NRTIs.
PI=protease inhibitor; PIs work by prohibiting HIV from cutting up the protein molecule into viral particles (virions)
Alluvia is a tablet form of lopinavir/ritonavir and is now available in the Botswana HIV treatment programme. Patients take 2 tablets BD rather than 3 capsules BD. It does not need to be stored in the refrigerator, therefore it is more appropriate for patients in under-resourced settings.
With the impending ART guideline revision, AZT/3TC is going to be replaced with FTC/TDF as the “backbone” of the first line regimen. (with EFV or NVP). FTC has a similar mechanism of action as 3TC.
Special Order:
ABC (Abacavir), TDF (Tenofovir)

19. 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
Source: de Jong BC, Israelski DM, Corbett EL, Small PM. Clinical Management of Tuberculosis in the Context of HIV Infection. Annu Rev Med ; 55:
Source: de Jong BC et al, Annu Rev Med, 2004.

20. HIV Disease Progression on TB Treatment, ART
Years of enrollment
Baseline CD4 cell count
Use of ART during TB treatment
Death within 1 year of start of TB therapy
Death or new OI within 1 year of start of TB therapy
TBTC 23
ARV 90
80%
4.5%
15.7%
CPCRA/ACTG
No ARV 85 0%
20%
38.9%
This study illustrates the 75% reduction in death rates (from 20% to about 5%) and reductions in new opportunistic infections when TB therapy is combined with antiretroviral therapy in persons who started with low CD4 cell counts. Details follow. However, this analysis does not provide information regarding the best time to start ART among patients on TB treatment
To evaluate the clinical outcomes of using antiretroviral therapy during TB treatment, we compared the outcomes in a study in which patients were encouraged to take potent antiretroviral therapy (TBTC Study 23) to the outcomes of patients enrolled in study of treatment of HIV-related TB taking place before the availability of potent antiretroviral therapy (CPCRA 019 / ACTG 223). Both studies were done in the United States. As this slide shows, the two cohorts had very similar baseline CD4 cell counts at the time of TB diagnosis, but differed in the expected manner in the use of ART – 80% of the patients in the present trial received ART compared to none of the patients in the CPCRA/ACTG study. The differences in clinical outcomes were dramatic – decreases in the risk of death and new opportunistic infections
So, among patients with advanced HIV disease, use of potent antiretroviral therapy appears to markedly decrease the risk of death during and shortly after TB treatment
Source: Burman W. et al. Use of Antiretroviral Therapy During Treatment of Active Tuberculosis with a Rifabutin-based Regimen. 10th Conference on Retroviruses and Opportunistic Infections (CROI) Abstract No. 136, 2003.
Source: Burman et al, CROI, 2003.

21. How To Improve Outcomes of HIV-Related TB?
Appropriate treatment of TB
TB treatment regimens are the same for HIV-infected patients as for non-infected patients
Assure adherence with TB treatment (use of directly observed therapy, DOT)
Cotrimoxazole prophylaxis
ART
Outcomes can be improved with appropriate treatment of TB (the purpose of this entire course) as well as by maximizing other factors
We will discuss adherence, opportunistic infection prophylaxis and ART in the next several slides
State that this was a change in the revised guidelines

22. 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

23. 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
New guidelines state that everybody with HIV and TB should be put on cotrimoxazole, regardless of CD4 count

24. 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
Where CD4 cell testing is available, co-trimoxazole prophylaxis is recommended for everyone with a CD4 cell count <350 per mm3, particularly in resource-limited settings where bacterial infections and malaria are prevalent among people living with HIV.
Bacterial infections are prevalent in individuals living with HIV in all settings, which supports the use of the 350 cells per mm3 threshold
People with WHO clinical stage 3 or 4 HIV disease (including people with pulmonary as well as extrapulmonary TB) should, however, still initiate co-trimoxazole prophylaxis irrespective of the CD4 cell count
Source: Guidelines on co-trimoxazole prophylaxis for HIV-related infections among children, adolescents and adults in resource-limited settings: Recommendations for a public health approach. World Health Organization, 2006.
Source: WHO, 2006

25. Cotrimoxazole Dosing 2.5ml One tablet 5ml Two tablets Half tablet 10ml
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 (5-15kg)
200mg sulfamethoxazole/ 40mg trimethoprim
5ml
Two tablets
Half tablet
6 to post-pubertal
400mg sulfamethoxazole/ 80mg trimethoprim
10ml
Four tablets
Post-pubertal Adolescents and Adults
800mg sulfamethoxazole/ 160mg trimethoprim
Paediatric dosing does not need to be addressed here, it was discussed in previous paediatric unit

26. 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
Despite the dramatic benefits of treating HIV during TB treatment, there are a number of factors which make it complicated to use potent antiretroviral therapy during TB treatment

27. 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
Highest risk of death during TB treatment is among patients with poor immune function (equivalent to CD4 count <200)
Very low rate of death among patients with relatively good immune function (high CD4 values) at the time of TB diagnosis
Source: Manosuthi W, Chottanapand S, Thongyen S, Chaovavanich A, Sungkanuparph S. Survival Rate and Risk Factors of Mortality Among HIV/Tuberculosis-Coinfected Patients With and Without Antiretroviral Therapy. J Acquir Immune Defic Syndr Sep;43(1):42-46.
Source: Mansouthi W et al., J Acquir Immune Defic Syndr,

28. 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
Large international randomized controlled trial of immediate versus delayed antiretroviral therapy among persons with HIV and TB are underway in South Africa and elsewhere, and others are being planned. Until then, the guideline on when HIV/TB patients should start ARVs will be based on limited data and expert opinion
All HIV patients with TB are eligible for ART because they are either in stage 3 or stage 4

29. Benefits and Risks Benefits: Risks
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
A large international randomized controlled trial of immediate versus delayed antiretroviral therapy among persons with HIV and TB is being planned. Until then, the guideline on when HIV/TB patients should start ARVs will be based on limited data and expert opinion

30. Treatment of TB for HIV-Positive Persons
Initial treatment phase should consist of
Isoniazid (H)
Rifampicin (R)
Pyrazinzamide (Z)
Ethambutol (E)
There is no change in TB treatment in HIV positive individuals, whether on ART or not. The same drug, and the same dose, for the same duration is to be used

31. Rifampicin Decreases Blood Levels of NVP and EFV
NNRTI
Effect of rifampicin
Nevirapine
 37-58%
Efavirenz
 13-26%
Rifampicin is a strong inducer of the cytochrome p450 cytochrome system and substantially lowers the levels of nevirapine. It lowers the levels of efavirenz less.

32. 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
There is no dose escalation of efavirenz recommended.
There is some concern that rifampicin lowers level of NVP to below therapeutic levels, but there is successful clinical experience in Spain, and Botswana ART programme recommends that NVP be used.
*Note: if Hb < 7.5, substitute AZT with d4T

33. Rifampicin Markedly Decreases Blood Levels of all PIs
Protease Inhibitor
Rifampicin effect
Saquinavir
 by 80%
Ritonavir
 by 35%
Indinavir
 by 90%
Nelfinavir
 by 82%
Lopinavir/ritonavir
 by 75%
The effects of rifampicin on blood levels of protease inhibitors means that protease inhibitors should not be used among people on rifampicin – the blood levels would be so low that the protease inhibitors would be ineffective in suppressing HIV
Ritonavir is not used by itself, instead is used in combination with other PIs
It’s the combinations that you need to worry about

34. 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
This slide lists alternatives to efavirenz-based antiretroviral therapy
These would have to be considered for pregnant patients (efavirenz is a teratogen), if there is efavirenz intolerance, or probable resistance to efavirenz (prior failure of efavirenz-based therapy)
There is limited experience with these alternatives
As mentioned previously, high-dose ritonavir is not well-tolerated by most patients
*Alluvia is now available in Botswana – it is a tablet form of Kaletra and does not need to be refrigerated

35. 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
Tell participants that this case illustrates how IRIS can present in the setting of HIV-related TB
Ask participants what they would do now before moving to next slide

36. 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
Ask the participants what her ART regimen was likely to have been

37. What do you think is happening?
Case Study: M.L. (3)
What do you think is happening?
What would you do next?
Ask participants what they think is happening and what they would do next.
Answer: Diffuse nodular infiltrates bilaterally with right pleural effusion
Source: © M. Narita, 2006
Courtesy of: © M. Narita, 2006.

38. Case Study: M.L. (4) HIV medications were discontinued
TB medications were continued
Repeat CXR was done
M.L.’s CD4 decreased to 34
Source: © M. Narita, 2006
Courtesy of: © M. Narita, 2006.

39. 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
What ART regimen would M.L. be started on now?
Answer: the same regimen – AZT/3TC/NVP
Ask the group what the criteria are for M.L. to be considered “cured”

40. 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
Immune Reconstitution Inflammatory Syndrome (IRIS) can occur in persons with HIV and a variety of opportunistic infections. For this course, we are discussing ONLY immune reconstitution events related to TB
Immune reconstitution events are relatively common among HIV/TB co-infected patients starting ART in resource-limited settings
Small cohort studies found that 11-45% of HIV-infected patients with active TB experienced TB IRIS upon ART initiation
Source: Colebunders R, John L, Huyst V, Kambugu A, Scano F, Lynent L. Tuberculosis immune reconstitution inflammatory syndrome in countries with limited resources. Int J Tuberc Lung Dis Sep;10(9):

41. 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
Immune Reconstitution Inflammatory Syndrome is a syndrome of increased immune reaction against an infection that occurs shortly after ART is begun. In sub-Saharan Africa, it is most often an immune response against MTB, which may or may not have been diagnosed before the ART treatment began.
This slide focuses on immune reconstitution against TB. In the ARV course and OI course, immune reconstitution against TB and other opportunistic pathogens is discussed.
Disseminated skin lesions are not that common in Botswana

42. 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
Only small cohort studies have been done to date on TB IRIS on initiation of ART. The risk factors listed on this slide have been suggested by some studies, but not found to be significant in others.
Source: Colebunders R, John L, Huyst V, Kambugu A, Scano F, Lynent L. Tuberculosis immune reconstitution inflammatory syndrome in countries with limited resources. Int J Tuberc Lung Dis Sep; 10(9):946-53
Source: Colebunders R, et al., Int J Tuberc Lung Dis, 2006.

43. 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
Before concluding that an event is an immune reconstitution event, it is important to consider other possible explanations – failure of TB treatment or the occurrence of another process (a new opportunistic infection, a tumor, etc.)
There are many uncertainties about the optimal management of immune reconstitution events
Relatively mild events may be managed with reassurance and encouragement – the event is a sign that the HIV treatment is working
Fevers and pain may respond to non-steroidal anti-inflammatory drugs, like Aspirin
Severe manifestations – enlarging lymph nodes that compromise ability to move the neck, swallow or breath, an enlarging tuberculoma in the central nervous system, worsening meningitis, respiratory failure – should be treated with corticosteroids. In addition, it may be necessary to stop antiretroviral therapy for a time
The duration of steroid therapy has not been studied, but most experts would try to taper the steroids after several weeks, if there has been a good response
Remember that not all worsening of patients may be due to IRIS

44. 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
Ask a participant to read case study presented on this slide.
Ask the group, “What medications do you start this patient on?”
Allow the group to discuss treatment options for this and come to consensus about what the treatment regimen would be
Once the group has come to consensus, give them the answer. If it is different than what they determined, discuss why this is the appropriate regimen
Answer: Start patient on rifampicin, isoniazid, pyrazinamide and ethambutol plus cotrimoxazole

45. 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
Ask a participant to read case study, part 2 presented on this slide.
Ask the group, “Do you agree with the ARVs that Mika has started? Why or why not? What ARVs would make up his regimen?”
Facilitate a discussion for a few minutes
Answer: AZT/3TC/EFV
Source: I-TECH, Tanzania
X-ray shows improvement

46. 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
Ask a participant to read case study, part 3 presented on this slide. Ask the group, “What else would you want from a history and physical?”
Answers:
Was Mika adherent to all his medications?
Does Mika have other symptoms including nausea, vomiting, diarrhoea, which may indicate other infections or malabsorption?
Ask the group, “What further tests would you order?”
Blood pressure, heart rate, temperature, respiratory rate and oxygen saturation
Additional labs: sputum smear for AFB and bacteria, sputum culture, FBC, liver tests, CD4 count. Viral load if available
Ask the group, “What is you’re your differential diagnosis?”
TB IRIS
Drug-resistant TB
Failure of TB therapy due to poor adherence or malabsorption of medications
Bacterial pneumonia
PCP
Drug toxicity
Ask the group, “What will you look for on physical examination?”
Detailed physical examination concentrating on the chest
Enlarged lymph nodes
Body swelling (edema)
Abdominal distention
Jaundice (icterus)
Neurologic exam

47. 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
You get the chest x-ray back and you see that he has right side infiltration
Ask the group, “What would you do now?”
Answer: Advise him to continue ART and the TB continuation regimen. You reassure him and discuss the importance of taking all of his medications as prescribed. Schedule him to come back in two weeks or sooner if he gets worse
Source: I-TECH, Tanzania
New CXR

48. 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
Ask the group, “What do you think is happening?”
Answer: This is TB IRIS. The immune system is reacting to dead mycobacteria in the system. The inflammation is worsening as his immune system reconstitutes itself on ART
Ask the group, “How you would manage this patient?”
Answer: Admit him to the hospital. Give oxygen. Check blood work, CBC, chemistry panel. Administer steroids at this point to reduce inflammation. (Consider administration of treatment for community-acquired pneumonia, in addition to steroids). If he continues to worsen despite steroid treatment, stop ART until he has clinically improved (resolution of chest x-ray, respiratory distress). Restart ART once clinically stable. Continue TB treatment continuation regimen throughout. If culture turned positive, then you would suspect drug resistance and you would do sensitivity testing.
Source: I-TECH, Tanzania
X-ray shows worsening

49. 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
Adverse events and treatment interruption (TB and/or HIV) are common
Because of the degree of immunodeficiency and the use of multiple medications, it isn’t surprising that adverse events are common among patients being treated for HIV-related TB
In one cohort study from London, 34% of patients stopped TB or HIV therapy, at least temporarily
The most common adverse events were peripheral neuropathy, skin rash, and hepatitis
Source: Dean GL et al. Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy. AIDS Jan 4;16(1):75-83.
Source: Dean GL, et.al., AIDS, 2002.

50. Overlapping Side Effects of Anti-TB and ARV Drugs
Possible Causes
Antituberculosis
Drugs
Antiretroviral
drugs
Skin rash
S, Z, R, H
nevirapine, efavirenz, abacavir
Nausea, vomiting
Z, R, H
zidovudine, ritonavir, protease inhibitors
Hepatitis
nevirapine, efavirenz, protease inhibitors
Leukopenia, anemia R
zidovudine
A problem with starting many drugs at the same time is that of knowing which of the drugs is the cause, if a side effect occurs
This is particularly a problem in the treatment of HIV-related TB, because both diseases have to be treated with multi-drug therapy and because the drugs used to treat these two diseases can have the same side effects
An additional factor is that many patients also need to receive other drugs, most often cotrimoxazole for PCP prophylaxis, and this can cause rash, hepatitis, and anemia/leukopenia

51. 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!
Emphasize severe and reoccurring side effects; don’t give up on first-line ATT
Source: Dean GL et al. Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy. AIDS Jan 4;16(1):75-83.
Source: Dean GL, et.al., AIDS,

52. 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
If there are severe reactions (such as Stevens Johnsons), then you need to stop everything

53. 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
The key is a good relationship between the TB and HIV programs, and an overlap regarding adherence issues. Coordination is essential. Practical planning in most countries however, is lacking.

54. Preventing Active TB Among HIV-Infected Persons
Four strategies:
INH Preventive Treatment
Antiretroviral Therapy
Infection Control
HIV+ Health Care Workers should avoid TB exposure (medical and TB wards)
TB case finding
Early case-detection and effective TB therapy (effective DOTS program)
The issue of keeping HIV+ health care workers away from TB patients is quite difficult in practice although it is a useful goal.
TB is widespread among patients in Botswana, HIV is widespread even among health care workers, and usually health care workers have either not been tested for HIV or have not disclosed their status with their employer

55. 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
Summarise the presentation and review the Key Points
Ask participants if they have any questions