Version May 2024
INTRODUCTION — The approach to monitoring patients with human immunodeficiency virus (HIV) infection on antituberculous medications must include consideration of the antituberculous regimen, the antiretroviral therapy regimen, potential drug reactions, and complications related to the immune reconstitution inflammatory syndrome.
This topic will cover the issues related to monitoring of patients with HIV infection with tuberculosis (TB), including directly observed therapy, the clinical response to treatment, adverse events related to treatment, duration of treatment, and prognosis.
Issues related to clinical manifestations, diagnosis, and treatment of susceptible TB in patients with HIV infection are discussed elsewhere. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy".)
INITIATION OF THERAPY — Issues related to selection of antituberculous therapy and antiretroviral therapy are discussed separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy".)
DURATION OF THERAPY — Regimens for treatment of TB in patients with HIV infection are discussed separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy", section on 'Regimen selection'.)
All patients with HIV infection should be started on antiretroviral therapy (ART) during treatment of tuberculosis. Issues related to timing of therapy are discussed separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy", section on 'Timing'.)
Traditional regimen (≥6 months) — The duration of therapy for treatment of drug-susceptible pulmonary TB in patients with HIV infection on ART using the traditional regimen is six months. This includes an intensive phase of four drugs (isoniazid, a rifamycin [eg, rifampin or rifabutin], pyrazinamide, and ethambutol) administered for two months, followed by a continuation phase of two drugs (isoniazid and a rifamycin) administered for four months [1,2].
In rare instances in which ART is not administered during antituberculous therapy (ie, if ART is not available or if there are unavoidable concerns regarding drug interactions), the continuation phase of traditional antituberculous therapy should be extended for an additional three months (ie, a continuation phase of seven months, corresponding to a total of nine months of antituberculous therapy); data to support this approach are limited [1].
Further study is needed to address the optimal duration of antituberculous therapy in patients with HIV infection treated with the standard/traditional six-month regimen. In a 2012 meta-analysis including 6 randomized trials and 21 cohort studies, relapse was more common among patients whose regimens included two months of rifamycin than among patients whose regimens included at least eight months of rifamycin (adjusted risk ratio 5.0, 95% CI 1.9-13.2). The risk of relapse was lower with rifampin treatment for ≥9 months compared with 6 months of rifampin (pooled risk difference -9.1 percent, 95% CI -16.5 to -1.8 percent) [3,4]. However, available ART has improved substantially since this study was performed [1].
For patients with cavitary disease and positive sputum cultures after two months of treatment, the duration of the continuation phase should be extended from four to seven months (total duration of treatment extended from six to nine months) [1,2]. No further adjustments in duration of therapy are recommended for patients who did not receive ART during antituberculous therapy (ie, total duration of antituberculous therapy nine months).
Rifapentine-moxifloxacin-based (4-month) regimen — The duration of therapy for treatment with the rifapentine-moxifloxacin-based regimen is four months. This regimen is a potential alternative regimen for patients >12 years and CD4 >100 cells/microL with pulmonary TB. Use of the shortened regimen requires additional attention to drug interactions of ART as well as more intricate and detailed programmatic considerations. The regimen includes isoniazid, high-dose rifapentine, pyrazinamide, and moxifloxacin daily for an eight-week intensive phase followed by a continuation phase of daily isoniazid, high-dose rifapentine, and moxifloxacin for nine weeks [5,6]. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy".)
Completion of the regimen consists of 119 doses (56 intensive phase doses and 63 continuation phase doses). The intensive phase doses should be administered within 70 days from treatment initiation, and the continuation phase doses should be administered within 84 days from intensive phase completion [6]. If these targets are not met, the patient should be considered to have interrupted therapy [1,6].
Thus far, circumstances in which treatment duration should be extended have not been addressed by the available trial data [5].
Treatment failure and relapse — For the traditional regimen, treatment failure refers to positive sputum cultures after four months of antituberculous therapy; for the rifapentine-moxifloxacin-based regimen, lack of improvement at eight weeks should prompt re-evaluation of the patient and the treatment regimen.
Relapse refers to recurrent TB at any time after completion of treatment with apparent or confirmed cure. If treatment failure or relapse is suspected or confirmed, the Mycobacterium tuberculosis isolate should be sent for drug susceptibility testing to first- and second-line agents. (See 'Patients with inadequate clinical response' below.)
Issues related to duration of therapy for patients with HIV infection and drug-resistant TB are discussed separately. (See "Treatment of drug-resistant pulmonary tuberculosis in adults".)
CLINICAL MONITORING — Patients with HIV infection with TB generally respond well to therapy if the diagnosis is made promptly and standard therapy instituted. Fever usually resolves within one month; improvement in chest radiograph findings may take longer. Lack of weight gain during the first two months of TB treatment predicts poor treatment outcomes, independent of HIV status [7].
Sputum monitoring — Sputum should be obtained for acid-fast bacilli (AFB) smear and culture at monthly intervals until two consecutive cultures are negative (algorithm 1 and algorithm 2 and algorithm 3) [1]. Sputum AFB smear and culture after two months of treatment is particularly important for assessing relapse risk and for determining the duration of the continuation phase. A positive sputum culture at two months should prompt drug susceptibility testing of that M. tuberculosis isolate and a search for reasons for persistently positive sputum cultures, including poor adherence or malabsorption [6].
The approach in the setting of persistently positive sputum culture is discussed below. (See 'Persistently positive sputum culture' below.)
After the sputum smear has converted to negative, at least one sputum should be collected at the completion of therapy to confirm that the patient has remained smear and culture negative [2].
Drug-related side effects — Antituberculous drugs are associated with a broad array of adverse effects, and the likelihood of adverse effects may be increased in patients with HIV infection [8].
Patient education regarding symptoms of hepatitis and other possible drug toxicities should be reinforced at each return visit, at least monthly. Patients should be instructed to report signs or symptoms of toxicity immediately and stop antituberculous medications until advised to resume treatment.
Issues related to adverse effects associated with antituberculous drugs are discussed separately. (See "Antituberculous drugs: An overview", section on 'Manifestations and their management'.)
Issues related to laboratory monitoring for patients on antituberculous drugs are discussed separately. (See "Antituberculous drugs: An overview", section on 'Clinical and laboratory monitoring'.)
It may be beneficial to check liver function tests after two weeks of antituberculous therapy for early detection of toxicity [9]. Thereafter, patients with HIV infection who warrant serial liver function test monitoring may be followed monthly.
Issues related to regimen adjustment for drug intolerance and management of hepatotoxicity associated with antituberculous therapy are discussed separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection", section on 'Regimen adjustments for drug intolerance'.)
Isoniazid is associated with peripheral neuropathy; the risk may be further increased in patients with diabetes mellitus or alcohol abuse. Vitamin B6 decreases the risk of peripheral neuropathy.
Therapeutic drug monitoring — Therapeutic drug monitoring need not be performed routinely. Drug concentration monitoring may be useful for patients with advanced HIV, diabetes, alcohol abuse, slow response to therapy (eg, positive sputum smear or culture after two months of therapy), and/or in the setting of potential for drug-drug interactions [10-12]. Among more than 260 patients with TB and HIV infection TB in Uganda, low levels of isoniazid and rifampin were associated with delayed sputum culture conversion, but did not translate to a high proportion of patients with treatment failure [13].
Issues related to drug monitoring are discussed further separately. (See "Antituberculous drugs: An overview", section on 'Serum drug concentration monitoring'.)
PATIENTS WITH INADEQUATE CLINICAL RESPONSE
General principles — Inadequate clinical response or clinical deterioration in an patients with HIV and TB infection may be attributable to poor adherence, poor drug absorption, emergence of drug resistance, an intercurrent opportunistic infection, or the immune reconstitution inflammatory syndrome (IRIS).
The approach to distinguishing between causes of inadequate clinical response depends in part on the timing relative to initiation of antituberculous therapy:
●Drug hypersensitivity (usually manifesting as rash or systemic reactions) generally occurs in the first few weeks of therapy.
●IRIS usually occurs approximately three weeks after starting antiretroviral therapy (ART), though it can occur later. (See 'Immune reconstitution inflammatory syndrome' below.)
●Treatment failure is defined as positive sputum culture after four to five months of treatment. Persistently positive sputum culture may be attributable to poor adherence, poor drug absorption, and/or emergence of drug resistance. (See 'Persistently positive sputum culture' below.)
●Recurrence is defined as recurrent signs and symptoms after successful completion of treatment. This may be due to either relapse (with the same M. tuberculosis strain as the original episode) or reinfection (with a different M. tuberculosis strain).
●Intercurrent opportunistic infection is possible at any time during treatment and must be included routinely in the differential diagnosis and clinical evaluation. (See 'Intercurrent opportunistic infection' below.)
Persistently positive sputum culture — The approach to sputum monitoring is described above. (See 'Sputum monitoring' above.)
Persistently positive sputum culture may be attributable to poor adherence, poor drug absorption, and/or emergence of drug resistance:
●Adherence should be reviewed; directly observed therapy should be implemented if this has not already been done. (See "Adherence to tuberculosis treatment".)
●Therapeutic drug monitoring should be pursued since poor drug absorption is common among patients with advanced HIV disease. This is particularly true in the setting of diarrhea and/or malabsorption but may occur even in the absence of these symptoms [14-17]. Issues related to drug monitoring are discussed further separately. (See "Antituberculous drugs: An overview", section on 'Serum drug concentration monitoring'.)
●Drug susceptibility testing on a current isolate should be pursued [1]. Patients with drug-resistant isolates should be treated as discussed separately. (See "Treatment of drug-resistant pulmonary tuberculosis in adults".)
For patients treated with the rifapentine-moxifloxacin-based regimen who have delayed clinical or microbiologic response with persistent positive sputum cultures beyond two months, the optimal duration of treatment is uncertain [6]. Options (to be considered on a case-by-case basis) might include transition to the traditional or alternative regimen with extension of treatment beyond four months. In such instances, consultation with a TB expert or a CDC Center of Excellence is warranted [18].
Persistent symptoms and/or radiographic findings — Persistent symptoms and/or radiographic findings may be attributable to an intercurrent opportunistic infection, IRIS, and/or the causes of persistently positive sputum discussed in the preceding section (eg, poor adherence, poor drug absorption, and/or emergence of drug resistance).
Intercurrent opportunistic infection — New clinical findings such as fever, cough, or weight loss or new radiographic abnormalities in a patient with HIV infection on appropriate TB therapy whose sputum smear becomes negative suggest the development of an intercurrent opportunistic infection [8]. Diagnostic considerations include Pneumocystis jirovecii pneumonia, pneumonia due to other bacterial, viral, or fungal causes, and lymphoma. (See "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV".)
Immune reconstitution inflammatory syndrome
●Clinical manifestations – Clinical and/or radiographic deterioration despite appropriate antituberculous chemotherapy may reflect IRIS, a paradoxical worsening of a pre-existing inflammatory process following immune recovery associated with administration of ART [19-24].
Among patients with TB, IRIS has been described in 8 to 43 percent of cases [19,21,25,26]. The risk is increased in patients with an initial CD4 count <100/microL [25] and in patients with a significant reduction in viral load and a large increase in CD4 count [26].
IRIS usually occurs approximately three weeks after starting ART, though it can occur later. Clinical manifestations of IRIS in patients with HIV infection with TB include new or expanding lymph nodes or abscesses, enlarging intracranial tuberculomas, persistent pyrexia, worsening pulmonary infiltrates, and new serositis [23].
●Management – IRIS is usually self-limited and in general does not require alteration or interruption of the antituberculous or antiretroviral regimens. For IRIS causing significant symptoms, treatment should be undertaken only after a thorough evaluation to exclude other potential causes of clinical deterioration. Initial management consists of nonsteroidal anti-inflammatory drugs, if symptoms persist, a short course of corticosteroids is warranted [2]. For patients with symptoms refractory to corticosteroids, some case reports have described use of tumor necrosis factor-alpha inhibitors [27,28].
For management of symptomatic involvement such as impingement of the airway or major vessel (eg, vena cava) by enlarged mediastinal lymph nodes, use of corticosteroids (prednisone 1 mg/kg orally per day) is reasonable. The dose should be tapered as symptoms allow; worsening of symptoms with tapering should prompt reversion to a higher dose.
For patients with IRIS that is not responsive to corticosteroids, particularly patients with neurological manifestations of TB, tumor necrosis factor alpha inhibitors may be a useful treatment tool; further clinical data are needed [29].
●Prevention – Issues related to timing of ART to minimize the likelihood of IRIS are discussed separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy", section on 'Timing'.)
Issues related to prevention of TB-associated IRIS are discussed separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy", section on 'Preventing IRIS'.)
OUTCOMES — Patients with HIV infection and drug-sensitive tuberculosis generally respond well to therapy if the diagnosis is made promptly and standard therapy instituted. Fever usually resolves within one month and the chest radiograph typically improves at two to three months [8,30,31]. In a series published prior to the antiretroviral therapy (ART) era including 82 patients with HIV infection and drug-susceptible TB, treatment failure occurred in only 5 percent of cases; all failures were attributable to poor adherence [32].
Treatment for drug-susceptible TB in patients with HIV infection is associated with rates of culture conversion and completion of therapy comparable to rates in HIV-uninfected patients [1,33]. This was illustrated in an observational study of 280 patients with TB; patients whose HIV status was positive, negative, and unknown had relapse rates of 6.0, 5.5, and 3.0 percent, respectively [34].
ART has significantly decreased mortality related to TB; this is most evident in resource-limited settings where TB is endemic. In a prospective study in Thailand including 290 patients with HIV infection and TB, survival was more likely among patients who received ART than those who did not (7 versus 43 percent) [35].
Treatment for HIV infection appears to be as effective in the HIV/TB coinfected patients as in patients with HIV alone. This was illustrated in an observational study including 111 patients with HIV and TB and 45 patients with HIV infection in the absence of concomitant TB (matched for gender, ethnicity, and baseline CD4 cell count) [36]. Viral suppression was achieved at six months in similar proportions of HIV/TB-coinfected patients and patients with HIV alone (87 versus 88 percent). Similar improvements in CD4 cell counts were also noted between patients with HIV and TB infection and patients with HIV infection in the absence of TB (97 versus 89 cells/microL). Most patients in the study were taking a nonnucleoside reverse transcriptase inhibitor along with two nucleoside analogs.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Opportunistic infections in adults with HIV".)
SUMMARY
●The approach to monitoring patients with HIV infection and pulmonary tuberculosis (TB) on antituberculous medications must include consideration of the antituberculous regimen, the antiretroviral therapy (ART) regimen, potential drug reactions, and complications related to the immune reconstitution inflammatory syndrome (IRIS). (See 'Introduction' above.)
●Issues related to selection of antituberculous therapy and antiretroviral therapy are discussed separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy".)
●Duration of therapy (See 'Duration of therapy' above.)
•The traditional duration of therapy for treatment of drug-susceptible pulmonary TB in patients with HIV infection on ART is six months. This includes an intensive phase of four drugs (isoniazid, a rifamycin [eg, rifampin or rifabutin], pyrazinamide, and ethambutol) administered for two months, followed by a continuation phase of two drugs (isoniazid and a rifamycin) administered for four months.
•The duration of therapy for the rifapentine-moxifloxacin-based regimen is four months. The regimen includes isoniazid, high-dose rifapentine, pyrazinamide, and moxifloxacin daily for an eight-week intensive phase followed by a continuation phase of daily isoniazid, high-dose rifapentine, and moxifloxacin for nine weeks.
●In rare instances in which ART is not administered during antituberculous therapy (ie, ART is not available or there are unavoidable concerns regarding drug interactions), the continuation phase should be extended for an additional three months (ie, a continuation phase of seven months), corresponding to a total of nine months of antituberculous therapy. (See 'Duration of therapy' above.)
●During treatment of pulmonary TB, sputum should be obtained for acid-fast bacilli (AFB) smear and culture at monthly intervals until two consecutive cultures are negative. Sputum AFB smear and culture after two months of treatment is particularly important for assessing relapse risk and for determining the duration of the continuation phase (algorithm 1 and algorithm 2 and algorithm 3). (See 'Sputum monitoring' above.)
●Patient education regarding symptoms of hepatitis and other possible drug toxicities should be reinforced at each follow-up visit, at least monthly. Patients should be instructed to report signs or symptoms of toxicity immediately and stop antituberculous medications until advised to resume. (See 'Drug-related side effects' above.)
●Issues related to adverse effects and laboratory monitoring for patients on antituberculous drugs are discussed separately. (See "Antituberculous drugs: An overview", section on 'Manifestations and their management' and "Antituberculous drugs: An overview", section on 'Clinical and laboratory monitoring'.)
●Issues related to regimen adjustment for drug intolerance and management of hepatotoxicity associated with antituberculous therapy are discussed separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection", section on 'Regimen adjustments for drug intolerance'.)
●Inadequate clinical response or clinical deterioration in an patients with HIV infection and TB may be attributable to poor adherence, poor drug absorption, emergence of drug resistance, an intercurrent opportunistic infection, or the immune reconstitution inflammatory syndrome. (See 'Patients with inadequate clinical response' above.)
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