TB & HIV Infection: Treatment Your name Institution/organization Meeting Date International Standard 8, 13 TB & HIV Infection: Treatment Your name Institution/organization.

TB & HIV Infection: Treatment

Your name Institution/organizationMeetingDate

International Standard 8, 13

TB & HIV Infection: Treatment

Your name Institution/organizationMeetingDate

International Standards 8, 13

ISTC Training Modules 2008

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: Treatment

International Standards 8, 13

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

Treatment of HIV-associated TB

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 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

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

ARV Improves Outcomes

* Abbreviated version

• 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)

Standard 8: Treatment*

All patients who have not been previously treated should receive an internationally accepted treatment regimen:

(1 of 2)

* Abbreviated version

Standard 8: Treatment*

The doses of anti-TB drugs used should conform to international recommendations.

Fixed-dose combinations are highly recommended.

(2 of 2)

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

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)

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

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

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)

Antiretroviral Therapy with TB

Standard 13: TB/HIV

All patients with TB and HIV infections should be evaluated to determine if antiretroviral therapy is indicated during the course of treatment for TB.

Appropriate arrangements for access to antiretroviral drugs should be made for patients who meet indications for treatment.

(1 of 3)

Standard 13: TB/HIV

Given the complexity of co-administration of anti-TB treatment and antiretroviral therapy, consultation with a physician who is expert in this in this area is recommended before initiation of concurrent treatment for TB and HIV infection, regardless of which disease appeared first.

(2 of 3)

Standard 13: TB/HIV

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

(3 of 3)

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

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

Key point: Start TB treatment immediately

TB Care: If Already on ART

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)

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

When to Start Antiretrovirals (1)

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

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)

ART and RIF-based TB Rx (1)

Rifampicin decreases blood levels of NVP and EFV

NNRTI Effect of Rifampicin

Nevirapine 37–58%

Efavirenz 22%

NNRTIs and Rifampicin

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)

Protease Inhibitor Effect of Rifampicin

Saquinavir by 84%

Ritonavir by 35%

Indinavir by 89%

Nelfinavir by 82%

Amprenavir by 81%

Lopinavir/ritonavir by 75%

Rifampicin decreases blood levels of all PIs

PIs and RIF: Not Recommended

*Tenofovir not recommended in pregnancy

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

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)

Other Issues in TB/HIV Treatment

ISTC Standard 13: TB/HIV (3)

Patients with TB Patients with TB and HIV infection and HIV infection should also receiveshould also receive cotrimoxazolecotrimoxazole as as prophylaxis for prophylaxis for other infections.other infections.

Pneumocystis jiroveciPneumocystis jiroveci pneumonia pneumonia

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

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

Cotrimoxazole Preventative Therapy

Overlapping Side Effects

Side Effect TB Drug ARV

Skin rash* PZA, RIF, INHNevirapineEfavirenzAbacavir

Nausea,vomiting

PZA, RIF, INHZidovudineRitonavirAmprenavir Indinavir

Burman et al, Am J Respir Crit Care Med 2001

* May also see rash with cotrimoxazole* May also see rash with cotrimoxazole

Side Effect TB Drug ARV

Hepatitis PZA, RIF, INH

Nevirapine Protease

inhibitors IRIS

(with chronic hepatitis)

Leukopenia,anemia RIF Zidovudine

Overlapping Side Effects

Burman et al, Am J Respir Crit Care Med 2001

Progression on TB/HIV Treatment

What could be happening here?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

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

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)

Clinical presentation: Fever Nodal enlargement Worsening pulmonary

infiltrates (with or without respiratory symptoms)

Local worsening in extrapulmonary sites

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

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

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

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

Example: Co-treatment Regimen

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: 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: 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 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

* Abbreviated versions

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.

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 receive cotrimoxazole preventative therapy.

* Abbreviated versions

Alternate Slides

WHO HIV Clinical Stage 1

Asymptomatic Persistent generalized lymphadenopathy (WHO clinical stage 1 conditions are not

HIV specific)

Moderate unexplained weight loss (<10%) Recurrent respiratory tract infections Herpes zoster Angular cheilitis Recurrent oral ulceration Papular pruritic eruptions Seborrhoeic dermatitis Fungal nail infections

Unexplained severe weight loss >10%

Unexplained chronic diarrhea > 1 month

Unexplained persistent fever > 1 month

Persistent oral candidiasis

Oral hairy leukoplakia

Pulmonary tuberculosis

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

HIV wasting syndrome Pneumocystis pneumonia Recurrent severe bacterial pneumonia Chronic herpes simplex infection Esophageal candidiasis Extrapulmonary tuberculosis Kaposi’s sarcoma Cytomegalovirus infection

Central nervous system toxoplasmosis HIV encephalopathy Extrapulmonary cryptococcosis, including

meningitis Disseminated non-tuberculous

mycobacterial infection Progressive multifocal

leukoencephalopathy Chronic cryptosporidiosis

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

Purpose of ISTC

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

Audience: all health care practitioners, public and private

Scope: diagnosis, treatment, and public health responsibilities; intended to complement local and national guidelines

Rationale: sound tuberculosis control requires the effective engagement of all providers in providing high quality care and in collaborating with TB control programs

ISTC: Key Points

Questions

TB/HIV: Treatment

1. A 45 year-old man with AIDS had documented clinical improvement after two months of standard TB treatment and subsequently began ART. After one month of combined TB treatment and ART, symptoms of cough with new infiltrates on chest radiograph are discovered. Which of the following need to be considered in the differential diagnosis at this time:A. TB treatment failure

B. New opportunistic respiratory infection

C. Immune reconstitution inflammatory syndrome

D. All of the above

TB/HIV: Treatment

2. The antiretroviral therapy regimen of choice for a patient on first-line TB treatment with isoniazid, rifampicin, ethambutol, and pyrazinamide would be: A. A triple nucleoside (NRTI) regimen

B. Ritonavir “super-boosted” protease inhibitor (PI) regimen

C. A dual protease inhibitor (PI) regimen

D. Efavirenz plus two nucleosides (NRTIs) if not pregnant

TB/HIV: Treatment3. A 50 year-old woman with sputum smear-positive TB

and new HIV infection is started on both a standard four-drug TB regimen and a three-drug ART regimen at the same time. The patient’s adherence is spotty and one week later she complains of severe nausea and vomiting. All of the following statements are correct except:A. Nausea and vomiting can be side effects seen with either TB

or ART drugsB. The initial high pill burden may be contributing to the patient’s

poor adherenceC. Starting both TB and HIV treatments together has made the

job of finding the cause of the symptoms more complicatedD. Prioritizing the start of ART first, with a delay in TB treatment

would have been the recommended sequence

TB & HIV Infection: Treatment Your name Institution/organization Meeting Date International Standard 8, 13 TB & HIV Infection: Treatment Your name Institution/organization.

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