1. TB & HIV Infection: Treatment
Instructor’s Notes
Module: Tuberculosis and HIV Infection: Treatment
ISTC Standards covered: Standard 8,13
Module Time: Approximately 60 minutes
Alternate slides: Slides listing conditions which define WHO HIV clinical stages 1-4, Introductory ISTC slides
Interactive options: Ideas for interactive discussions are offered on many of the slides in this module. Participant discussion can enhance active learning, but will add more time to the lecture and must be planned for.
Additional Material: Slides containing related material may be found in the following modules: Initial Treatment of Tuberculosis; Tuberculosis and HIV Infection.
The full text of the ISTC and all supporting references are available at
Other useful Resources/References:
TB/HIV: A Clinical Manual, second edition. World Health Organization,
Improving the diagnosis and treatment of smear-negative pulmonary and extrapulmonary tuberculosis among adults and adolescents. Recommendations for HIV-prevalent and resource-constrained settings. World Health Organization,
Integrated Management of Adolescent and Adult Illness (IMAI) modules. World Health Organization.
Tuberculosis and HIV Coinfection: Current state of knowledge and research priorities. JID 2007 Supplement; 196:S1
CDC. Managing drug interactions in the treatment of HIV-related tuberculosis, 2007,
Antiretroviral therapy for HIV infection in infants and children : towards universal access : recommendations for a public health approach. World Health Organization
Test Questions: May be attached or inserted within presentation for discussion purposes, or alternatively, combined with questions from other modules to produce evaluation tool.
[Image Credit: Lung Health Image Library /Thierry Falise ]
Your name
Institution/organization
Meeting
Date
International Standards 8, 13

2. TB/HIV: Treatment
Objectives: At the end of this presentation, participants will be able to:
List the major drug interactions and possible first-line combinations for concomitant TB and antiretroviral therapy (ART)
Describe the effect of ART and cotrimoxazole therapy (CPT) 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
It is intended that after completion of this module the student will be able to recognize the major complexities in the treatment of TB and HIV disease as they occur together.
[Review objectives from slide]

3. TB/HIV: Treatment Overview: TB regimens in TB/HIV
Antiretroviral therapy (ART) and TB treatment
Cotrimoxazole preventative therapy (CPT)
Overlapping toxicities
Immune reconstitution inflammatory syndrome (IRIS)
Adherence issues
Overview of Tuberculosis and HIV Infection: Treatment
[Review overview from slide]
Lecture/module includes International Standards 8 and 13
[Image credits: Lung Health Image Library/Jad Davenport]
International Standards 8, 13

4. Treatment of HIV-associated TB
[Transition: Begin by discussing basics of treatment of HIV-associated TB]

5. 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 smear-positive TB
With few exceptions, current recommendations for the treatment of HIV-associated TB are the same as those for treatment of non-HIV associated TB. If treatment is completed, the use of standardized short-course chemotherapy regimens coupled with good case management is as effective in the HIV-infected patient as in patients who are not HIV infected, with the notable exception that the percentage of deaths is greater.
Even with the availability of effective treatment, there is a higher mortality rate for HIV-infected cases during TB treatment. Early deaths (<30 days after TB diagnosis) are often due to TB, while later deaths are often associated with other complications of HIV.
As compared with TB in non-HIV infected persons, smear-negative TB has a higher mortality than smear-positive TB. These findings most likely reflect the difficulty in diagnosis and the greater consequences in HIV-infected individuals associated with delays in initiating appropriate treatment.
In the absence of rapid, simple, and accurate diagnostic tools for smear-negative TB, diagnostic algorithms have been developed through consensus and expert opinion that can help to guide clinicians toward timely TB treatment in these cases.
[Algorithms to assist in the diagnosis of smear-negative TB are included in the module TB and HIV Infection: Introduction and Diagnosis.]

6. TB/HIV: Treatment Outcomes
HIV and MDR/XDR: “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) died within median 16 days of diagnosis
While the presence of HIV infection does not increase the risk for TB drug resistance, the combination of HIV and multidrug-resistant (MDR) or extensively drug-resistant (XDR) TB has been a very deadly one.
Many have likened this combination to the “Perfect Storm,” an analogy referring to the convergence of significant factors that can lead to dire outcomes.
Poor outcomes may be directly related to the advanced state of HIV/AIDS and what is essentially untreated TB.
As an example: In the face of HIV-related immunosuppression, 52 of 53 cases of XDR TB died within a median of 16 days from the time of diagnosis in a rural area of South Africa. [Gandhi NR et al, Lancet 2006;368: ]

7. Antiretroviral Therapy (ARV) significantly reduces TB incidence
ARV Improves Outcomes
Antiretroviral Therapy (ARV) significantly reduces TB incidence
Decrease in TB incidence after starting ART in resource-limited, high-burden area
The initiation of appropriate antiretroviral therapy (ARV) has proven to be a major intervention, reducing the incidence of TB within HIV-infected populations.
As an example: In a community-based ART cohort in South Africa (median baseline CD4 96), the initiation of ART reduced the incidence of TB in the cohort from 23 cases per 100 person-years to 7 cases during the first year of treatment. This decline in the risk for TB was strongly associated with improving immune status.
Lawn SD, et al, Am J Respir Crit Care Med, 2008;177:

8. Standard 8: Treatment*
(1 of 2)
All patients who have not been previously treated should receive an internationally accepted treatment regimen:
Initial phase: 2 months INH, RIF, PZA, and EMB
Continuation phase: 4 months INH and RIF, or
6 months of INH and EMB (higher failure in HIV)
As noted, basic TB treatment recommendations in the International Standards for TB Care (ISTC) Standard 8 hold true for both HIV and non-HIV associated TB.
Specifically: [Read Standard 8, abbreviated – for slides with full text see Initial Treatment of Tuberculosis module.]
[Image credits: Lung Health Image Library/Gary Hampton]
* Abbreviated version

9. Standard 8: Treatment*
(2 of 2)
The doses of anti-TB drugs used should conform to international recommendations.
Fixed-dose combinations are highly recommended.
ISTC Standard 8 continued:
[Review content of slide]
[Note: one major difference with HIV-positive cases is that the option to omit EMB is not recommended for smear-negative disease. This statement from Standard 8 has not been included here in the abbreviated version.]
[Image is of a four-drug fixed-dose combination pill pack.]
[Image credit: Stop Tb Partnership, Global Drug Facility,
* Abbreviated version

10. 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
Although the general principles of TB therapy are the same as in patients without HIV, special areas of consideration that add to the complexity of the clinical management and treatment of HIV-associated TB include the following:
[Review slide contents]

11. TB/HIV Treatment: Rifamycins (1)
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
Drug Interactions:
The rifamycin family of drugs is the most frequent cause of drug-drug interactions with antiretroviral drugs.
[Review content of slide]
Rifampicin is a much more potent inducer of cytochrome P450 enzymes than rifabutin. While rifabutin may be used in some countries in the treatment of TB in HIV-infected individuals on ART, it is not available in many parts of the world.
[Long-acting rifapentine is nearly as potent an inducer of the P450 system as rifampicin and is not recommended for use in HIV-associated TB treatment - see next slide regarding risk for acquired resistance with rifapentine.]

12. TB/HIV Treatment: Rifamycins (2)
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
[Review content of slide]
Studies of HIV-associated TB cases have shown an association between intermittent anti-TB treatment (rifapentine once weekly, and rifabutin or rifampicin twice weekly) with the development of acquired rifamycin resistance.
This association was strongest in the groups with severe immunosuppression (CD4 < 100).
Patients with advanced HIV and those with significant diarrhea appear to be at risk for lower concentrations of the orally administered first-line anti-TB medications compared to non-HIV TB patients (but some conflicting data). However, the doses remain the same.
Because of the risk of acquired drug resistance, intermittent therapy during the initiation phase of treatment using a rifamycin drug is generally not recommended in HIV-associated TB.

13. 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
Despite the potential for drug-drug interactions, a rifampicin-based TB regimen used throughout both the initial and continuation phase remains the first-line choice for treatment of TB in patients with HIV infection.
Therefore, when combining both TB and ART regimens, one may look toward alterations in choices for ART first.
[Review slide content]

14. 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)
Because of its reduced effect on hepatic microsomal enzymes compared with rifampin, rifabutin is often preferred in first-line TB regimens used in conjunction with ART. Unfortunately, rifabutin is not readily available in many parts of the world. [Rifabutin can be used with most PIs, but the clinician must also be aware that certain antiretrovirals can increase or decrease rifabutin serum levels necessitating dose adjustments.]
Another alternative regimen that avoids the use of rifampin is INH, EMB, PZA, and streptomycin. Use of this combination requires extending treatment duration to 9 months and may not be used in pregnancy (streptomycin contraindicated).
[Additional regimen to consider is an all oral regimen with INH, EMB, PZA, + a fluoroquinolone for 9-12 months.]
[Drug dosage recommendations for ARV used in conjunction with rifabutin may be found at: CDC. Managing drug interactions in the treatment of HIV-related tuberculosis, 2007, http//

15. Antiretroviral Therapy with TB
[Transition: The diagnosis of TB is an indication for initiating ART – an important point underscored in International Standard 13.]

16. Standard 13: TB/HIV
(1 of 3)
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 Standard 13:
[Review content of slide]

17. Standard 13: TB/HIV
(2 of 3)
Given the complexity of co-administration of anti-TB treatment and antiretroviral therapy, consultation with a physician who is expert in this area is recommended before initiation of concurrent treatment for TB and HIV infection, regardless of which disease appeared first.
ISTC Standard 13:
[Review content of slide]
Note: while expert consultation is optimal – the lack of expert consultation should not discourage the use of ART in appropriate circumstances in accordance with local/national guidelines.

18. Standard 13: TB/HIV
(3 of 3)
However, initiation of treatment for tuberculosis should not be delayed.
ISTC Standard 13 (continued)
[Review content of slide]
[Image Credit: Francis J. Curry National Tuberculosis Center, University of California San Francisco]
ISTC Training Modules 2008

19. TB and ARV Therapy (ART)
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
The use of antiretroviral therapy in the setting of TB therapy can be complex and must take into consideration many issues including:
[Review content of slide]
Particularly difficult, is the appropriate timing of starting ART (if not already begun) while on treatment for TB.
If not already receiving ART, early initiation of ART at the time of TB drug initiation may decrease HIV progression, but may be associated with both side effects and paradoxical reactions (IRIS). With many new drugs initiated together, discovering which drug is responsible for an adverse event becomes more complex.
Bad reactions or clinical worsening may be severe enough to halt both TB and ART drugs during the critical initial time period of TB treatment.
Dual initiation of both TB treatment and ART also introduces a significantly large pill burden from the onset and therefore may make early adherence a problem.
Therefore, a step-wise approach to starting TB treatment, followed by ART initiation may help to avoid some of the confusion and potential pitfalls in treatment.

20. 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 starting ART evidence of clinical immunological failure
Consider ART failure and change to second-line ART
In cases where ART has already been started, the issues under consideration when TB treatment is started include questions of drug compatibility (desire to reduce drug-drug interaction), and efficacy of ART (does the finding of TB imply a worsening of patient’s immune status while on ART)?
In patients with HIV-related TB, the priority is to begin TB treatment to improve outcomes for the patient and to reduce disease transmission. Therefore, HIV-infected patients already on ART who develop TB should begin anti-TB medications immediately.
If recently started on ART (<6 months), consider whether the regimen needs to be changed due to incompatibility with the TB regimen.
If already on ART therapy for more than 6 months, the development of TB, particularly extrapulmonary or disseminated TB, may be suggestive of ART failure and a need for re-evaluation of the ART regimen. History of ART adherence, immune response on ART (CD4 count), and other clinical parameters (weight) since starting ART should factor into the assessment for possible ART failure.
Seek expert consultation if available or refer patient in cases of suspected ART failure.
 Key point: Start TB treatment immediately

21. When to Start Antiretrovirals (1)
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)
Although the optimal timing of ART initiation is not known, general recommendations based on the CD4 cell count (reflecting the degree of immunosuppression at the onset of TB treatment) from 2006 WHO consensus guidelines are outlined here.
In patients with HIV-related TB, the priority is to treat TB and ideally antiretroviral (ARV) treatment can be safely postponed.
However, in more severely immunosuppressed patients with HIV-related TB there may be need for the earlier initiation of ART and this may be done with careful oversight within the first 2-4 weeks of starting TB treatment.

22. When to Start Antiretrovirals (2)
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
If the CD4 cell count is not known or available, clinical indicators for more advanced HIV disease can be used as above.

23. ART and RIF-based TB Rx (1)
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)
As mentioned before, the choice of first-line TB treatment includes the use of rifampicin. Due to the known drug interactions with many of the ART drugs, the choice of ART regimen requires careful consideration.
The primary recommended ART regimen uses efavirenz (NNRTI) plus two NRTI choices.
[Some experts recommend Efavirenz 800mg for adults >60kg.]
[Resources: TB/HIV: A Clinical Manual, second edition. World Health Organization,
CDC: Managing drug interactions in the treatment of HIV-related tuberculosis, 2007,

24. Rifampicin decreases blood levels of NVP and EFV
NNRTIs and Rifampicin
Rifampicin decreases blood levels of NVP and EFV
NNRTI
Effect of Rifampicin
Nevirapine
 37–58%
Efavirenz
 22%
In choosing an NNRTI as part of the ART regimen, efavirenz is favored over nevirapine (see below).
In several cohort studies, standard-dose efavirenz + two NRTIs was well-tolerated and efficacious in achieving complete viral suppression.
Rifampicin has a greater effect on serum nevirapine levels. Despite the interaction with RIF, there is reasonable data that ART with nevirapine can be effective, but there are more concerns for overlap of common side effects (skin rash and hepatitis).
[Reference:CDC. Managing drug interactions in the treatment of HIV-related tuberculosis, 2007,

25. ART and RIF-based TB Rx (2)
Choice of nucleosides (NRTIs) to combine with efavirenz:
Usual adult first-line therapy (may also be used in children >3):
Zidovudine + lamivudine (AZT/3TC)
Alternate in case of anemia: Stavudine + lamivudine (d4T/3TC)
The following are recommended choices of NRTIs that may be combined with efavirenz:
[Review slide content]
Efavirenz is highly active among older children and may be combined with the listed NRTIs.
Efavirenz is not available for children under 3 years of age or under 10 kg. Often ART for children in this age group is generally postponed until completion of TB treatment.
[If young children are severely immunosuppressed and it is felt necessary to start ART, can use kaletra plus “super-boosted” ritonavir or “Triple NRTIs” (ABC + d4T/AZT + 3TC): see slide on ART options.]
[Resources: TB/HIV: A Clinical Manual, second edition. World Health Organization,
CDC: Managing drug interactions in the treatment of HIV-related tuberculosis, 2007,

26. 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%
The notable effect of rifampicin on blood levels of most protease inhibitors means that protease inhibitors (whether boosted or not with ritonavir) generally should not be used for patients receiving rifampicin – the blood levels would be so low that the protease inhibitors would be ineffective in suppressing HIV.
[Exception discussed on upcoming slide: Lopinavir/ritonavir (Kaletra) combined with rifampicin resulted in hepatitis in all adult healthy volunteers. Kaletra “super-boosted” with extra ritonavir has had some favorable pharmacokinetic and clinical data among young children.]
[Slide credit: MTCT-plus: Diagnosis and management of TB/HIV (

27. ART options: RIF-based TB Rx (1)
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
These two slides list alternatives to efavirenz-based antiretroviral therapy.
There is limited experience with these alternatives.
Triple-nucleoside therapy is less effective than 2 nucleosides + an NNRTI, but could be considered because there are no major drug interactions between these drugs (AZT, 3TC, and abacavir). Listed as first-line ART for children >3 years old by WHO.
Nevirapine (+ 2 nucleosides) has been used successfully in two small studies from Spain – because of the decrease in nevirapine blood levels (some experts recommend increasing the dose of nevirapine to 300 mg (1½ tablets) twice-daily, but may have increased risk for hypersensitivity). Common toxicities with nevirapine overlap with some of the first-line anti-TB medications (hepatitis and skin rash). There is also an increased risk for severe hypersensitivity reactions in patients with higher CD4 cell counts (>350 for men and >250 for women).
Also listed as preferred alternative for very young children (<3 years old) in WHO guidelines).
Alternatives without efavirenz or tenofovir are options in pregnancy.
[Resources: 1). TB/HIV: A Clinical Manual, second edition. World Health Organization,
2).CDC: Managing drug interactions in the treatment of HIV-related tuberculosis, 2007,
3). Antiretroviral therapy for HIV infection in infants and children : towards universal access : recommendations for a public health approach.
World Health Organization
*Tenofovir not recommended in pregnancy

28. ART options: RIF-based TB Rx (2)
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)
(Continuation of list of alternatives to efavirenz-based antiretroviral therapy)
As noted on the previous table of PIs, standard doses of most PIs coupled with rifampicin would result in ineffective antiretroviral activity. Standard boosting of PIs with ritonavir (at 100 mg) still does not result in adequate PI levels when used with rifampicin.
Combining PIs with higher dose ritonavir “super-boosting” (Kaletra plus extra ritonavir) can overcome the effects of rifampicin, but is poorly tolerated in most due to hepatotoxicity (use with caution under close supervision in adults). Young children are the exception and appear to tolerate this combination better with favorable results in limited studies.
[Resource: Managing drug interactions in the treatment of HIV-related tuberculosis, 2007,

29. Other Issues in TB/HIV Treatment
[Top image: Drug-related skin rash; Middle image: Chest radiograph with right upper lobe infiltrate; Bottom image: IRIS-related enlarged cervical adenopathy]
[Image credit: (top) Catalog of Clinical Images/ Charlie Goldberg, MD, (middle) Francis J. Curry National Tuberculosis Center, University of California, San Francisco; (bottom) Bob Colebunders, MD]

30. ISTC Standard 13: TB/HIV (3)
Patients with TB and HIV infection should also receive cotrimoxazole as prophylaxis for other infections.
Final part of ISTC Standard 13:
[Review content of slide]
[CXR: Chest radiograph of an HIV-infected patient, CD4 count of <200 cells/µL, revealing bilateral, diffuse granular opacities. This radiographic presentation is characteristic of Pneumocystis jiroveci pneumonia, which was microscopically confirmed by examination of induced sputum.]
[Image Credit: Laurence Huang, MD, University of California San Francisco]
Pneumocystis jiroveci pneumonia

31. Cotrimoxazole Preventative Therapy
Reduces the risk of
Pneumocystis jiroveci pneumonia (PCP)
Toxoplasma
Bacterial infections
Reduces deaths and hospitalizations
Also effective against:
Pneumococcus, salmonella, nocardia and malaria
In addition to ART, patients infected with HIV and TB benefit from the cotrimoxazole preventative therapy (CPT).
Through the presumed reduction in concomitant infections, use of CPT has been shown to reduce both mortality and morbidity in HIV-positive patients with sputum smear-positive pulmonary TB in randomized placebo controlled trials in both Cote d’Ivoire (1999) and Zambia (2008).

32. Cotrimoxazole Preventative Therapy
All HIV-positive TB patients should receive Cotrimoxazole Preventative Therapy (CPT) 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
WHO recommendations for use of CPT:
Use CPT for all cases with WHO HIV clinical stage 3 or 4 disease*, which includes both pulmonary and extrapulmonary TB, regardless of CD4 count.
In all settings, particularly where prevention of PCP and toxoplasmosis are the major targets, the recommended CD4 threshold to start CPT is 200.
In settings where bacterial infections and malaria are prevalent, some studies suggest that a threshold of CD4 350 is more adequate.
Some expert opinions considered a recommendation for CPT in patients with CD4 < 500 considering operational simplicity, cost-effectiveness analysis and some data on the effectiveness of CTX in reducing severe morbidity at early stages.
[Alternative slides: * WHO HIV clinical stages are outlined]
[Resource: WHO 2006,

33. Overlapping Side Effects
TB Drug
ARV
Skin rash*
PZA, RIF, INH
Nevirapine
Efavirenz
Abacavir
Nausea,
vomiting
Zidovudine
Ritonavir
Amprenavir
Indinavir
Adverse reactions to both TB and ARV drugs are common among patients with HIV-related TB and there are significant overlaps in the toxicity profiles between the drugs.
To simplify the clinical management, it is often recommended that ARV initiation be deferred until there has been time to identify and manage side effects from the TB treatment – usually 2-8 weeks. [Recommendations for when to start ARVs reviewed in earlier slides.]
Listed on two slides are the major areas of overlapping toxicities:
[Review content of slide]
* May also see rash with cotrimoxazole
Burman et al, Am J Respir Crit Care Med 2001

34. Overlapping Side Effects
TB Drug
ARV
Hepatitis
PZA, RIF, INH
Nevirapine
Protease inhibitors
IRIS (with chronic hepatitis)
Leukopenia,
anemia
RIF
Zidovudine
Overlapping side effects continued:
[Review content of slide]
Burman et al, Am J Respir Crit Care Med 2001

35. 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
[Review slide content]
After an initial apparent response to TB treatment, ART is begun in this patient. The clinical picture worsens – what are the possible causes?
[Interactive option: Ask audience the question and discuss possible differential diagnoses at this time. Possibilities include treatment failure, a new opportunistic infection, drug reaction, – then lead into topic of immune reconstitution inflammatory syndrome (IRIS).]
[Note: CXRs show initial right lower lobe infiltrate that improves after initial TB treatment. A new infiltrate appears in the same area after ART is added to the treatment regimen.]
[Image Credit: Francis J. Curry National Tuberculosis Center, University of California, San Francisco]  
What could be happening here?

36. 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
Immune reconstitution inflammatory syndrome (IRIS), also known as immune restoration disease, is described as a phenomenon of clinical worsening that may occur in association with an appropriate immune recovery after the initiation of antiretroviral therapy (ART).
An IRIS response may be seen in association with a wide range of infectious agents or with autoimmune disease, but is most commonly seen in relation to tuberculosis.
Two mechanisms may occur with TB-associated IRIS:
A paradoxical worsening of clinical and/or radiographic findings of known active TB after the start of ART.
Or, due to the restoration of the immune response seen on ART, subclinical TB may be “unmasked”, manifesting the clinical signs and symptoms of TB once the immune response is recovered.

37. IRIS Risk factors Timing of onset 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)
Risk factors for the development of IRIS:
[Review slide content]
Timing of onset of IRIS is typically relatively early in the course of ART, but has been reported as many as several months after ART initiation.
Reported incidence rates for TB-related IRIS are highly variable (8% - 43%).

38. IRIS Clinical presentation: Fever Nodal enlargement
Worsening pulmonary infiltrates (with or without respiratory symptoms)
Local worsening in extrapulmonary sites
While the clinical manifestations of IRIS may present much like the spectrum of TB in general within the HIV-infected population, in some instances the onset may be unusually rapid with an intense inflammatory component.
Common clinical manifestations may include:
[Review slide content]
It has been suggested that the rate and intensity of IRIS presentation is likely related to the underlying mycobacterial load and reflects the rate and intensity of the immune recovery response to ART.
[Interactive option: Ask participants to give examples of IRIS presentation that they may have encountered.]
[Upper photo: IRIS-related enlarged cervical adenopathy]
[Lower photo: IRIS-related development of TB skin abscesses]
[Image credit: Bob Colebunders, MD]

39. 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)
There is no diagnostic test to confirm the presence of IRIS. The diagnosis of IRIS is one of exclusion and can be challenging, particularly in resource limited settings.
To complicate the matter further, the differential diagnosis for IRIS can be broad and includes:
[Review slide content]
Of major concern during the course of TB treatment is the possibility for treatment failure or drug-resistant disease. Re-evaluation of patient adherence and repeat sampling of sputum or extrapulmonary sites would be indicated.
If IRIS appears later in the course of ART, a further consideration would be the possibility of ART failure. Evaluation of CD4 and/or viral load would be helpful here to differentiate failure of ART (falling CD4) vs. IRIS associated with immune recovery (rising CD4).

40. 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
If clinical indicators raise the suspicion for IRIS:
[Review slide content]
A significant point is that TB (and ART if status not life-threatening) treatment should continue during the evaluation.
Median symptom duration has been reported to be approximately 57 days, but can be significantly longer in cases of lymphadenopathy (median 195 days).
Cases are usually self-limiting (although rare reports of death due to IRIS).
Symptomatic relief can often be achieved using non-steroidal anti-inflammatory drugs (NSAIDS) if needed, or with the use of corticosteroids in more severe disease presentations.
On some occasions, more direct interventions, ex. aspiration of abscesses, placement of biliary stents, may be indicated.

41. 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
The additive issues that can complicate adherence for patients undergoing treatment for both TB and HIV infections include:
[Review slide content]
[Interactive option: Ask participants for further examples that may be particular to their location or situation.]

42. Example: Co-treatment Regimen
Example regimen: Illustrates a sample of the potential pill burden associated with the combination of TB treatment and ART.
(In this example scenario, ARV started as soon as TB treatment is tolerated)
[Resource: Tuberculosis Care with TB-HIV Co-management, IMAI
Source: Tuberculosis Care with TB-HIV Co-management, IMAI

43. 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
Interventions that may enhance patient adherence:
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TB/HIV patients may receive care in different settings. These settings include the patient's home, local health center, district hospital, and tertiary referral hospital. Coordination of care in different settings promotes continuity of care for the patient.
Closer collaboration between caregivers may also result in co-location of some services such as medication dispensaries which can improve the ease and efficiency of care for the patient.
[Image Credit: Lung Health Image Library/(top photo) Pierre Virot; (bottom photo) Gary Hampton]

44. 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
Infection control is important in facilities providing services for patients with TB, especially in high HIV prevalence areas.
All facilities should have an infection control plan.
Natural ventilation of patient care and waiting areas should be maximized.
Coughing patients should be promptly identified and separated
Sputum smear results should be available within 24 hours.
Whenever possible, cohorting of patients with TB should be used.

45. Summary: TB/HIV Treatment
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
To summarize, the key points of this presentation were:
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46. 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
[Summary continued]
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47. Summary: ISTC Standards Covered*
All patients who have not been previously treated should receive an internationally accepted treatment regimen.
Initial phase: 2 months INH, RIF, PZA, and EMB.
Continuation phase: 4 months INH and RIF, or 6 months of INH and EMB (higher failure in HIV).
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.
And in summary, the International Standards reviewed:
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* Abbreviated versions

48. Summary: ISTC Standards Covered*
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.
Consult with an expert in this area before initiation of concurrent treatment for TB and HIV infection. However, initiation of treatment for tuberculosis should not be delayed.
TB/HIV patients should also receive cotrimoxazole preventative therapy.
And in summary, the International Standards reviewed:
[Review content of slide]
* Abbreviated versions

49. Alternate Slides
Alternate Slides: Offer additional options that may be added or substituted into module.
See Facilitator Guide for further information.

50. WHO HIV Clinical Stage 1 Asymptomatic
Persistent generalized lymphadenopathy
(WHO clinical stage 1 conditions are not HIV specific)
Note: WHO stage 1 conditions in general are not HIV specific, and in low prevalence settings do not suggest HIV infection. WHO stage 4 manifestations are much more likely to occur in HIV positive than in HIV negative patients.

51. 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
Weight loss should be measured from usual or ideal body weight.
Recurrent respiratory infections are: sinusitis, tonsillitis, otitis media, and pharyngitis.

52. 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
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53. 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
[Review content of slide]

54. 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
Chronic herpes simplex infection is defined as: orolabial, genital or anorectal of more than one month’s duration or visceral at any site.
Esophageal candidiasis (or candidiasis of trachea, bronchi or lungs) are considered stage 4.
Cytomegalovirus infection refers to symptomatic infection with evidence of end organ damage. (retinitis, esophagitis, colitis, or infection of other organs).

55. 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
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56. 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
Disseminated mycosis refers to (extrapulmonary histoplasmosis, coccidiomycosis, and penicilliosis).

57. Purpose of ISTC
The International Standards for Tuberculosis Care (ISTC):
Are intended to unite public and private sectors in providing a uniformly accepted level of care for all patients with, or suspected of having, TB.
Describes the essential elements of TB care that should be available everywhere.
Provides a vehicle for mobilizing professional societies globally in support of TB programs.
Serves as a powerful advocacy tool to ensure that the essential elements are available.
[Image Credit: Lung Health Image Library/Gary Hampton]

58. ISTC: Key Points 17 Standards
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
The ISTC consist of 17 evidence-based standards.
Standards differ from existing guidelines in that standards present what should be done, whereas, guidelines describe how the action is to be accomplished.
To meet the requirements of the Standards, approaches and strategies, determined by local circumstances and practices and developed in collaboration with local and national public health authorities, will be necessary. There are many situations in which the level of care can, and should, go beyond what is specified in the Standards.
The Standards should be viewed as a living document that will be revised as technology, resources, and circumstances change. Revisions to the original document released December 2005 are currently underway.
Funded (Oct 1, 2004) by USAID via TBCTA, development was supervised by an international steering committee (28 members / 14 countries) chosen to represent perspectives relevant to tuberculosis care and control.
The Standards are also intended to serve as a companion to and support for the Patients’ Charter for Tuberculosis Care developed in tandem with the Standards.
A Handbook for using the International Standards for Tuberculosis Care is also available (2007). The Handbook presents suggestions and guidance, based mainly on country-level experiences, for using the ISTC as a tool to foster and guide the delivery of high-quality care by all practitioners providing TB care.
[Resource:

59. 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
The Standards are addressed to all healthcare providers, private and public, who care for persons with proven tuberculosis or with symptoms and signs suggestive of TB.
Three categories of activities are addressed by the Standards: diagnosis, treatment, and public health responsibilities of all providers. The ISTC are intended to be complementary to local and national TB control policies that are consistent with the World Health Organization (WHO) recommendations.
In many parts of the world there is great variability in the quality of tuberculosis care, and poor quality care continues to plague global tuberculosis control efforts. Effective engagement of all providers in providing high quality care in collaboration with TB control programs is key to the promotion of sound tuberculosis control.

60. Questions
Questions: May be used for interactive discussion, course evaluation, or continuing medical education purposes.
See Facilitator Guide for further information.

61. TB/HIV: Treatment
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:
TB treatment failure
New opportunistic respiratory infection
Immune reconstitution inflammatory syndrome
All of the above
Correct Answer: D

62. 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 triple nucleoside (NRTI) regimen
Ritonavir “super-boosted” protease inhibitor (PI) regimen
A dual protease inhibitor (PI) regimen
Efavirenz plus two nucleosides (NRTIs) if not pregnant
Correct Answer: D

63. 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:
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
Correct Answer: D