Upload
katherine-mcdowell
View
223
Download
0
Tags:
Embed Size (px)
Citation preview
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
ISTC Training Modules 2008
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
ISTC Training Modules 2008
Treatment of HIV-associated TB
ISTC Training Modules 2008
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
ISTC Training Modules 2008
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
ISTC Training Modules 2008
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
ISTC Training Modules 2008
* 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)
ISTC Training Modules 2008
* 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)
ISTC Training Modules 2008
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
ISTC Training Modules 2008
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
ISTC Training Modules 2008
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
ISTC Training Modules 2008
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
ISTC Training Modules 2008
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)
ISTC Training Modules 2008
Antiretroviral Therapy with TB
ISTC Training Modules 2008
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)
ISTC Training Modules 2008
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)
ISTC Training Modules 2008
Standard 13: TB/HIV
However, initiation of treatment for tuberculosis should not be delayed.
(3 of 3)
ISTC Training Modules 2008
ISTC Training Modules 2008
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
ISTC Training Modules 2008
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
ISTC Training Modules 2008
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)
ISTC Training Modules 2008
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
ISTC Training Modules 2008
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)
ISTC Training Modules 2008
Rifampicin decreases blood levels of NVP and EFV
NNRTI Effect of Rifampicin
Nevirapine 37–58%
Efavirenz 22%
NNRTIs and Rifampicin
ISTC Training Modules 2008
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)
ISTC Training Modules 2008
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
ISTC Training Modules 2008
*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
ISTC Training Modules 2008
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)
ISTC Training Modules 2008
Other Issues in TB/HIV Treatment
ISTC Training Modules 2008
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
ISTC Training Modules 2008
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
ISTC Training Modules 2008
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
ISTC Training Modules 2008
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
ISTC Training Modules 2008
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
ISTC Training Modules 2008
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
ISTC Training Modules 2008
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
ISTC Training Modules 2008
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)
ISTC Training Modules 2008
IRIS
Clinical presentation: Fever Nodal enlargement Worsening pulmonary
infiltrates (with or without respiratory symptoms)
Local worsening in extrapulmonary sites
ISTC Training Modules 2008
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)
ISTC Training Modules 2008
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
ISTC Training Modules 2008
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
ISTC Training Modules 2008
Source: Tuberculosis Care with TB-HIV Co-management, IMAI
Example: Co-treatment Regimen
ISTC Training Modules 2008
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
ISTC Training Modules 2008
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
ISTC Training Modules 2008
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
ISTC Training Modules 2008
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
ISTC Training Modules 2008
* 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.
ISTC Training Modules 2008
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
ISTC Training Modules 2008
Alternate Slides
ISTC Training Modules 2008
WHO HIV Clinical Stage 1
Asymptomatic Persistent generalized lymphadenopathy (WHO clinical stage 1 conditions are not
HIV specific)
ISTC Training Modules 2008
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
ISTC Training Modules 2008
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
ISTC Training Modules 2008
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
ISTC Training Modules 2008
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
ISTC Training Modules 2008
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
ISTC Training Modules 2008
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 Training Modules 2008
Purpose of ISTC
ISTC Training Modules 2008
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 Training Modules 2008
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
ISTC Training Modules 2008
Questions
ISTC Training Modules 2008
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
ISTC Training Modules 2008
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
ISTC Training Modules 2008
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