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1. Why should we be concerned about TB-HIV co-infection?
Worldwide, HIV infection is the foremost risk factor for development of active tuberculosis (TB). TB is now the most common opportunistic infection among patients infected with HIV in Africa. For this reason, you should offer all patients with tuberculosis, regardless of their perceived risk of HIV infection, an HIV test as part of their tuberculosis treatment package.
The clinical and radiographic presentation of this individual’s disease may be atypical. Compared to the immune competent
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general population, HIV-infected patients with active pulmonary tuberculosis are more likely to have smear-negative TB. The clinician caring for HIV-infected patients, therefore, needs to have a high index of suspicion for tuberculosis in symptomatic individuals. This is important because, as with patients who are not infected with HIV, the principles of TB treatment in HIV-infected individuals remain the same despite some challenges, which are explained below.
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2. What is the approach to diagnosis of TB in HIV?
As pointed out above, the diagnosis of TB in HIV is challenging because the presentation is atypical. A high index of suspicion is the key to early diagnosis. However, as with TB in HIV-negative individuals, the principles of diagnosis are the same. Microscopic sputum smears remain an essential part of TB diagnosis. Early morning samples are preferable for admitted patients. But for outpatients, three spot samples increase the likelihood of a positive smear when TB is present. In patients with a CD4 count <100cell/dl, a positive smear for any of the samples should be enough to confirm the diagnosis. A negative sputum smear does not rule out a diagnosis of TB.
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Sputum culture is the gold standard whenever the facilities can support this; however, it should not delay initiation of treatment.
X-ray presentations are often atypical and can take any form. With a relatively high CD4 count (>350cell/dl), x-ray features of TB are the same as for non HIV-infected patients, including hilar lymphadenopathy, upper zone infiltrates, or consolidation. From more severely immune-suppressed individuals, however, the presentation takes the form of primary infection, many times with a millially picture, plural fluid, cavitations, multilobular consolidation, or lung collapse, for example.
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3. What is the goal of treatment of TB-HIV co-infection?
The aim of TB therapy is:
- To cure the patient of TB; and
- To minimize the transmission of Mycobacterium tuberculosis (MTB), to both immune-suppressed and immune-competent persons.
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4. What is the type and duration of treatment of TB in patients co-infected with HIV?
The principle of therapy remains the same for both HIV-positive and HIV-negative TB patients. Thus, in most circumstances, the treatment regimen for all adults with previously untreated tuberculosis should consist of two phases:
- A two-month initial phase of isoniazid, rifampicin, pyrazinamide and ethambutol. This is followed by a continuation phase of treatment for either four or seven months. The four-month continuation phase should be used in the majority of patients.
- Whenever possible, the six-month short course drug combination should be recommended to all HIV-positive patients with pulmonary tuberculosis. All patients should be given 10-25 mg of pyridoxine (vitamin B6) with isoniazid dosing.
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There are important exceptions:
- Patients with cavitary pulmonary disease who remain sputum culture positive at month two of treatment should get a prolonged first and second phase of treatment (at least 9 month of treatment).
- A 10-month continuation phase is recommended for patients with central nervous system (CNS) involvement, such as meningitis or tuberculomata, and for patients presenting with other forms of extra pulmonary TB
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5. Many patients inevitably interrupt treatment for various reasons even when properly counseled. When this occurs, how should I proceed?
All efforts should be made to avoid interruptions in treatment since this can lead to multi-drug resistance (MDR). However, if this occurs. then the following guideline should be followed. Remember this is only a guide and should be used as such.
- If the interruption occurs during the initial phase of treatment and the interruption is for 14 days or more, restart treatment from the beginning.
- If the interruption is less than 14 days, continue the treatment regimen. NB In both 1) and 2) the total number of doses prescribed for the initial phase should be given.
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- For patients who were smear-positive initially, it is necessary to continue treatment to complete the planned total number of doses. Thus, 1) If the patient has received less than 80% of the planned total doses and the lapse is three months or more in duration, restart treatment from the beginning. 2) If the interruption is less than three months in duration, continue treatment to complete a full course.
- Regardless of the timing and duration of the interruption, use DOT (or modified DOT).
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6. What common drug/drug interactions should I be aware of?
Most drugs used by HIV-infected patients for various reasons are metabolized in the liver by a group of enzymes referred to as hepatic cytochrome P450 system. Rifamycins (in particular rifampicin) act as inducers of this system, thereby accelerating the metabolism of some drugs like the protease inhibitors, some nonnucleoside reverse transcriptase inhibitors (NNTIs),
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and contraceptives. So when given together, the blood levels of such drugs will be markedly reduced thus reducing their effective dose. However, the level of rifampicin will be increased, thus raising the risk of toxicities. Also many antiretroviral and anti-TB drugs in common use can cause hepatic damage. When this occurs, it becomes difficult to tell which of them is the cause.
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7. When should I be concerned that hepatotoxicity has occurred, and what should I do?
Hepatotoxicity is a common and potentially serious adverse event. It is defined as:
- A serum AST or ALT level of more than three times the upper limit of normal in the presence of symptoms, or
- A serum AST or ALT greater than five times the upper limit of normal in the absence of symptoms.
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All drugs should be put on hold while searching for the culprit +/- desensitization, where possible. Hepatitis B and/or C infection (or IRIS) should be ruled out.
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8. Whan should I begin ART in newly diagnosed TB patients with HIV?
The optimal time to initiate HAART in an HIV-positive patient with TB is not known. Every physician uses a different approach. A balance must be reached between preventing the progression of the HIV disease when HAART is delayed and the risk of toxicities and/or IRIS if HAART is concurrently administered with the anti-TB therapy. In general the following can guide the physician's decision (although one needs to use the right judgment).
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- If CD4 count is <100/dl, initiate HAART as soon as possible, dependent on physician assessment. (Some physicians delay up to two months).
- If the CD4 count is 100-200/dl, you may initiate HAART after two months of TB treatment.
- If the CD4 count is >250/dl, you can delay HAART until the completion of TB treatment. In this case regular monitoring of the CD4 count is recommended where possible and ART initiated as soon as there is an indication that the CD4 count is declining.
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9. How do I proceed with a patient already on ART but is now diagnosed with TB?
TB in a patient already on HAART should trigger the suspicion of ART failure. If a patient is on a boosted PI, TB therapy can be intiated without altering the ART regimen. If a patient is on nevirapine, this should be substituted with Efavirenz or a
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boosted protease inhibitor (PI). If rifabutin is available, it should be used in preference to rifampicin. If a patient has not been on HAART for more than two months, consider IRIS, in which case you continue with HAART plus anti-TB therapy depending on the severity of IRIS (see below).
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10. What are the overlapping toxicities between ART and anti-TB drugs?
Most anti-TB drugs cause skin reactions that may be indistinguishable from those of an NNRTI and co-trimoxazole
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skin reactions. Hepatotoxicity is common to both HAART and anti-TB drugs. Gastrointestinal disturbances, especially during the early days of therapy are common to most drugs used to manage HIV-positive patients.
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11. What is the role of tuberculin skin testing in screening HIV-infected patients for the risk of developing TB?
A tuberculin test is performed to identify those patients who may have latent TB infection; then treatment may be given in order to prevent reactivation. In HIV and TB co-infection, there is a reduction in the proportion of those reacting to purified protein derivative (PPD) as the CD4 count falls; it decreases
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from 50%-90% in those who have a CD4 count of ≥500 cells/uL down to 0%-20% in patients who have AIDS or advanced HIV infection and a CD4 count of ≥200cells/uL. This limits the usefulness of the tuberculin test as a diagnostic tool. Since a negative skin test does not rule out latent TB, its usefulness in endemic areas such as Africa is difficult to determine.
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12. Is there a role for chemoprophylaxis against TB? What should be the approach?
Patients with a positive skin test but no evidence of active TB disease will benefit from chemoprophlaxis with anti-TB drugs. All efforts should be made to rule out active TB before chemophlaxis begins. If a decision has been made to administer chemoprohlaxis to a patient the following is recommended:
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- Isoniazid for a total of six-nine months, or
- Rifampicin with isoniazid for a total of three months, or
- Rifampicin alone for four months.
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13. How should I go about managing a patient with TB relapse, treatment failure or suspected/confirmed resistance?
Answer pending.
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14. When should I recognize the symptoms of Immune Reconstitution Syndrome (IRIS) in patients being treated for TB and HIV?
Answer pending.
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15. How should I manage an HIV positive pregnant mother newly diagnosed with TB?
The HAART regimen should contain AZT in the backbone. Efavirenz (teratogenic effects) and Nevirapine (increased risk of hepatotoxicity) should be avoided. Consider a triple NRTI
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with abacavir, AZT, d4T. A boosted PI if available can be used. Avoid streptomycin. You can safely use ethambutol, rifampicin, isoniazid and pyrizinamide. Watch out for lactic acidosis, which commonly complicates pregnancy in the presence of an NRTI.
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