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TB & HIV Infection: Treatment. Your name Institution/organization Meeting Date. International Standards 8, 13. TB/HIV: Treatment. Objectives: At the end of this presentation, participants will be able to:

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slide1

TB & HIV Infection: Treatment

Your name

Institution/organization

Meeting

Date

International Standards 8, 13

tb hiv treatment
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
tb hiv treatment1
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

International Standards 8, 13

tb hiv treatment outcomes
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
tb hiv treatment outcomes1
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
arv improves outcomes
ARV Improves Outcomes

Antiretroviral Therapy (ARV) significantly reduces TB incidence

Decrease in TB incidence after starting ART in resource-limited, high-burden area

Lawn SD, et al, Am J Respir Crit Care Med, 2008;177:680-685

standard 8 treatment
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)

* Abbreviated version

standard 8 treatment1
Standard 8: Treatment*

(2 of 2)

  • The doses of anti-TB drugs used should conform to international recommendations.
  • Fixed-dose combinations are highly recommended.

* Abbreviated version

tb hiv treatment2
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
tb hiv treatment rifamycins 1
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
tb hiv treatment rifamycins 2
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
tb hiv treatment rif
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
tb hiv treatment rif alternative
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)
standard 13 tb hiv
Standard 13: TB/HIV

(1 of 3)

  • All patients with TB and HIV infections should be evaluated todetermine if antiretroviral therapy is indicatedduring the course of treatment for TB.
  • Appropriate arrangements for access to antiretroviral drugs should be made for patients who meet indications for treatment.
standard 13 tb hiv1
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 areais recommended before initiation of concurrent treatment for TB and HIV infection, regardless of which disease appeared first.
standard 13 tb hiv2
Standard 13: TB/HIV

(3 of 3)

  • However, initiation of treatment for tuberculosis should not be delayed.

ISTC Training Modules 2008

tb and arv therapy art
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
tb care if already on art
TB Care: If Already on ART

 Key point: Start TB treatment immediately

when to start antiretrovirals 1
When to Start Antiretrovirals (1)

HIV-infected TB patients not yet on ART should be evaluated for ART immediately

when to start antiretrovirals 2
When to Start Antiretrovirals (2)

If CD4 count not available:

art and rif based tb rx 1
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)
nnrtis and rifampicin
NNRTIs and Rifampicin

Rifampicin decreases blood levels of NVP and EFV

art and rif based tb rx 2
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)
pis and rif not recommended
PIs and RIF: Not Recommended

Rifampicin decreases blood levels of all PIs

art options rif based tb rx 1
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

*Tenofovir not recommended in pregnancy

art options rif based tb rx 2
ART options: RIF-based TB Rx(2)
  • Ritonavir boosting of other PIscan achieve adequate blood levels but significant hepatotoxicity risk
    • Can be used in children (<3)
    • Lopinavir/ritonavir (Kaletra) usual dose 400/100 mg twice a day PLUS an extra ritonavir 300 mg twice a day (adult dose)
istc standard 13 tb hiv 3
ISTC Standard 13: TB/HIV (3)
  • Patients with TB and HIV infection should also receivecotrimoxazoleas prophylaxis for other infections.

Pneumocystis jiroveci pneumonia

cotrimoxazole preventative therapy
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
cotrimoxazole preventative therapy1
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
overlapping side effects
Overlapping Side Effects

* May also see rash with cotrimoxazole

Burman et al, Am J Respir Crit Care Med 2001

overlapping side effects1
Overlapping Side Effects

Burman et al, Am J Respir Crit Care Med 2001

progression on tb hiv treatment
Progression on TB/HIV Treatment

What could be happening here?

HIV+ case with TB dx; TB treatment begun

  • After 2 mo. TB treatment,
  • begins ART
  • 6 wks. later symptoms and CXR worsen

slide36
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
slide37
IRIS
  • Risk factors
    • Disseminated TB
    • Shorter delay between onset of TB and ART drugs
    • Low baseline CD4, higher baseline viral load
    • Greater CD4 or viral load response to ART
  • Timing of onset
    • Usually within first 6 weeks of ART (often 2–3 weeks, but can be months after ART started)
slide38
IRIS

Clinical presentation:

  • Fever
  • Nodal enlargement
  • Worsening pulmonary infiltrates (with or without respiratory symptoms)
  • Local worsening in extrapulmonary sites
iris differential diagnosis
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)
iris evaluation and treatment
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
tb hiv adherence
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
example co treatment regimen
Example: Co-treatment Regimen

Source: Tuberculosis Care with TB-HIV Co-management, IMAI

improving adherence
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
infection control
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
summary tb hiv treatment
Summary: TB/HIV Treatment

Summary:

  • Standard TB treatment usually cures TB in TB/HIV co-infection
  • Despite successful TB treatment, mortality among TB/HIV patients remains high
  • Cotrimoxazole prophylaxis (CPT) improves survival and should be used in all TB/HIV patients
summary tb hiv treatment1
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 istc standards covered
Summary: ISTC Standards Covered*

Standard 8:

  • All patients who have not been previously treated should receive an internationally accepted treatment regimen.
  • Initial phase: 2 months INH, RIF, PZA, 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.

* Abbreviated versions

summary istc standards covered1
Summary: ISTC Standards Covered*

Standard 13:

  • 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 receivecotrimoxazolepreventative therapy.

* Abbreviated versions

who hiv clinical stage 1
WHO HIV Clinical Stage 1
  • Asymptomatic
  • Persistent generalized lymphadenopathy
  • (WHO clinical stage 1 conditions are not HIV specific)
who hiv clinical stage 2
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
who hiv clinical stage 3
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
who hiv clinical stage 31
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
who hiv clinical stage 4
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
who hiv clinical stage 41
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
who hiv clinical stage 42
WHO HIV Clinical Stage 4
  • Chronic isosporiasis
  • Disseminated mycosis
  • Recurrent septicemia
  • Lymphoma (cerebral or B cell non-Hodgkin)
  • Invasive cervical carcinoma
  • Atypical disseminated leishmaniasis
  • Symptomatic HIV-associated nephropathy or HIV-associated cardiomyopathy
istc key points
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
istc key points1
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
tb hiv treatment3
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

tb hiv treatment4
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

tb hiv treatment5
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