The quality of evidence supporting the recommendations (I-III) and the rating scheme for the recommendations (A-E) are defined at the end of the "Major Recommendations" field.
Refer to the original guideline document for information on epidemiology, clinical manifestations, and diagnosis of mycobacterial infections in human immunodeficiency virus (HIV)-exposed and HIV-infected children.
Mycobacterial Infections: Mycobacterium tuberculosis
Prevention Recommendations
Preventing Exposure
Children most commonly are infected with Mycobacterium (M.) tuberculosis from exposure in their immediate environment, usually the household. HIV-infected children may have family members dually infected with HIV and tuberculosis (TB). Homeless children or those exposed to institutional settings (including prolonged hospitalization) may be at increased risk. Risk factors of close contacts of HIV-infected children (e.g., homelessness, incarceration, exposure to institutional settings) should also be considered. Bacille Calmette-Guérin (BCG) vaccine is not routinely administered in the United States and should not be administered to HIV-infected infants and children because of its potential to cause disseminated disease (EII).
Preventing First Episode of Disease
In the United States, where TB exposure is uncommon and BCG is not routinely administered, HIV-infected infants and children should have a tuberculin skin test (TST) (5 tuberculin units purified protein derivative [5-TU PPD]) at 3 months of age, and children should be tested at the time of HIV diagnosis. HIV-infected children should be retested at least once per year (AIII).
HIV-infected infants and children should be treated for latent tuberculosis infection (LTBI) if they have a positive TST (AI) or exposure to a person who has contagious TB (after excluding active TB disease in the infant or child and regardless of the child's TST results) (AII). The duration of preventive therapy for children should be 9 months and the preferred regimen is isoniazid (10 – 15 mg/kg/day [AII] or 20 – 30 mg/kg twice weekly [BII]). Liver function tests should be performed prior to starting isoniazid (AII) for HIV-infected children and further monitoring should be performed if the baseline tests are abnormal, the patient has chronic liver disease, or medications include other potentially hepatotoxic drugs, such as acetaminophen and some antiretroviral drugs. If isoniazid resistance is known or suspected in the source case, rifampin for 4 to 6 months is recommended (BII). A 2-month regimen of rifampin and pyrazinamide was never recommended for children and now is not recommended for any age group because of an increased risk of severe and fatal hepatotoxicity (EII). Children exposed to drug-resistant strains should be managed by an experienced clinician and the regimen should be individualized based on what is known about the source case susceptibility pattern and treatment history.
A randomized, double-blind, controlled trial of isoniazid in HIV-infected children in South Africa was halted when isoniazid administered daily or twice weekly (according to the cotrimoxazole schedule) was found to have a benefit in reducing mortality (hazard ratio 0.46; 95% CI 0.22 – 0.95, p = 0.015). These findings were found across all ages and Centers for Disease Control and Prevention (CDC) HIV disease classification and were independent of TST result, although the study may not have been adequately powered to detect these differences. These results suggest that HIV-infected children in extremely high TB burden areas may benefit from isoniazid preventive therapy irrespective of any known exposure to TB, but this approach is not currently recommended in the United States due to the low prevalence of TB (DII).
Discontinuing Primary Prophylaxis
Not applicable.
Treatment Recommendations
Treatment of Disease
Empiric TB therapy should be started in HIV-infected infants and children in whom the diagnosis is suspected and continued until the diagnosis is definitively ruled out (AII). The use of directly observed therapy (DOT) decreases the rates of relapse, treatment failures, and drug resistance and is recommended for treatment of all children and adolescents with TB in the United States (AII). DOT means that a trained worker, and not a family member, watches the patient ingest each dose of medication. The principles for treatment of TB in the HIV-infected child are the same as for the HIV-uninfected child. However, the treatment of TB in an HIV-infected child is complicated by antiretroviral drug interactions with the rifamycins and overlapping toxicities caused by antiretroviral drugs and TB medications. Rifampin is a potent inducer of the CYP3A family of enzymes. Rifabutin is a less potent inducer but is a substrate of this enzyme system.
Doses and side effects of TB medications are included in Tables 1 through 6 in the original guideline document. In the absence of concurrent highly active antiretroviral therapy (HAART), initial empiric treatment of TB disease should generally consist of a four-drug regimen (isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin) (AI). For the first 2 months of treatment, DOT should be administered daily (intensive phase). Modifications of therapy should be based on susceptibility testing, if possible. The drug susceptibility pattern from the isolate of the adult source case can guide treatment in cases when an isolate is not available from the child. If the organism is found to be susceptible to isoniazid, rifampin, and pyrazinamide during the 2-month intensive phase of therapy, ethambutol (or streptomycin) can be discontinued and the intensive phase completed using three drugs (AI).
Following the 2-month intensive phase, for treatment of M. tuberculosis known to be sensitive to isoniazid and rifampin, therapy is continued with isoniazid and rifampin as DOT two to three times weekly (continuation phase) (AI); daily therapy during the continuation phase is also acceptable (AI). Children with severe immunosuppression should only receive daily or thrice weekly treatment during the continuation phase, because TB treatment regimens with once- or twice-weekly dosing have been associated with an increased rate of acquisition of rifamycin resistance among HIV-infected adults with low CD4 cell counts; thus twice-weekly dosing should only be considered for children without immune suppression (e.g., CD4 >15%, or >100 cells/mm3 if >6 years of age) (CIII). Ethionamide can be used as an alternative to ethambutol in cases of TB meningitis (CIII) because ethionamide has better central nervous system (CNS) penetration than ethambutol.
For HIV-infected children with active pulmonary TB disease, the minimum recommended duration of antituberculous drug treatment is 6 months, but some experts recommend up to 9 months (AIII); for children with extrapulmonary disease involving the bones or joints, CNS, or miliary disease, the minimum recommended duration of treatment is 12 months (AIII). These recommendations assume that the organism is susceptible to the medications, that adherence to the regimen has been assured by DOT, and that the child has had a clinical and microbiologic response to therapy.
For HIV-infected children who are diagnosed with TB disease, anti-TB treatment must be started immediately (AIII). However, treatment of TB in the setting of HAART is complicated by unfavorable pharmacokinetic interactions and overlapping toxicities and should be managed by a specialist with expertise in treating both these conditions (AIII). Issues to consider when treating both conditions include (1) the critical role played by rifampin because of its potent bactericidal properties; (2) rifampin's potent induction of the CYP3A enzyme system that precludes treatment with all protease inhibitors (PIs) but may allow treatment with non-nucleoside reverse transcriptase inhibitors (NNRTIs); (3) the CYP3A induction by rifabutin is less potent but there may still be a need for dose adjustments of both rifabutin and possibly the PIs, although there are minimal data in children; (4) overlapping toxicities; and (5) the challenges of adherence to a medication regimen that may include ≥7 drugs.
Given these challenges, some experts have argued that the role of rifamycins for the treatment of TB is so important, the effect of the rifamycins on PI (and possibly NNRTI) levels is so unpredictable, and the subsequent risk of HIV resistance is so great that, in an antiretroviral-naïve child, deferral of HAART until completion of TB therapy should be considered. Others recommend that treatment of TB in an antiretroviral-naïve HIV-infected child should be initiated 2 to 8 weeks before initiating antiretroviral medications to improve adherence and better differentiate potential side effects. Which option to consider must take into account clinical factors, such as clinical stage of HIV, immune status of the child, age, ability to adhere to complicated drug regimens, and other comorbid conditions. For children with severe immune compromise, earlier initiation of HAART (e.g., 2 weeks after antimycobacterial therapy is started) may be advisable (although there is a risk of immune reconstitution inflammatory syndrome [IRIS]), while more delayed initiation of HAART might be considered for children with higher CD4 counts (BII).
The choice of antiretroviral regimen in an HIV-infected child being treated for TB disease is complex, and advice should be obtained from an expert in the treatment of these two diseases. Starting antiretroviral therapy with an NNRTI-based rather than a PI-based regimen is preferred because NNRTI regimens have fewer interactions with rifampin-based TB therapy (BII). However, NNRTIs are also metabolized via the CYP3A enzyme system and efavirenz and nevirapine are both CYP3A4 enzyme inducers. Efavirenz is the preferred NNRTI in HIV-infected children aged >3 years, while nevirapine is the preferred NNRTI for children aged <3 years, as the dosing for efavirenz in younger children has not been defined and there is no pediatric formulation. There are currently no data in children on the pharmacokinetics of either drug in combination with rifampin to make specific recommendations regarding potential need for an increase in dose of the NNRTI. If a PI is used, a ritonavir-boosted PI such as lopinavir/ritonavir is required. There are no pharmacokinetic data to address whether additional ritonavir boosting is needed in children receiving rifampin and lopinavir/ritonavir-based regimens.
For children already receiving antiretroviral therapy who have had TB diagnosed, the issues are equally complicated and similar considerations must be taken into account. Treatment for TB must be started immediately (AIII) and the child's antiretroviral regimen should be reviewed and altered, if needed, to ensure optimal treatment for both TB and HIV and to minimize potential toxicities and drug-drug interactions. These recommendations are limited because of the paucity of data on the optimal dosing of medications to treat TB in children, especially in children who are HIV infected. Guidelines and recommendations exist for dose adjustments necessary in adults when treated with rifabutin and PIs, but the absence of data precludes extrapolating these to HIV-infected children being treated for TB. Consultation with an expert in pediatric HIV and TB infection is recommended. More data are needed on the pharmacokinetics of anti-TB medications in both HIV-infected and -uninfected children.
For treatment of drug-resistant TB, a minimum of three drugs should be administered, including two or more bactericidal drugs to which the isolate is susceptible (AII). Regimens can include three to six drugs with varying levels of activity. Children infected with multidrug-resistant (MDR) TB (e.g., resistance to at least isoniazid and rifampin) should be managed in consultation with an expert in this condition (AIII). If the strain is resistant only to isoniazid, isoniazid should be discontinued and the patient treated with 9 to 12 months of a rifampin- or rifabutin-containing regimen (e.g., rifampin, pyrazinamide, and ethambutol) (BII). If the strain is resistant only to rifampin, risk for relapse and treatment failure is increased. Rifampin should be discontinued and a 2-month induction phase of isoniazid, pyrazinamide, ethambutol, and streptomycin should be administered, followed by an additional continuation phase of isoniazid, pyrazinamide, and ethambutol to complete a minimum of a 12- to 18-month course of therapy, with the exact length of therapy based on clinical and radiologic improvement (BIII). Among older adolescents with rifampin-monoresistant strains, isoniazid, ethambutol, and a fluoroquinolone can be administered, with pyrazinamide added for the first 2 months (BIII); an injectable agent (e.g., aminoglycoside such as streptomycin or amikacin) also can be included in the first 2 to 3 months for patients with severe disease (BIII). When the strain is resistant to isoniazid and rifampin (i.e., MDR TB), therapeutic regimens must be individualized based on the resistance pattern, treatment history of the patient or the source case, relative activities of the drugs, extent of disease, and any comorbid conditions. The duration of therapy should be at least 12 months, and usually longer. In children who are smear or culture positive at treatment initiation, therapy should generally be continue for 18 to 24 months after smear and culture conversion. Among children with paucibacillary disease (e.g., smear and culture negative), therapy may be of shorter duration but should be ≥12 months.
Extensively drug-resistant tuberculosis (extremely drug-resistant [XDR] TB) has emerged globally as an important new threat, particularly in persons infected with HIV. XDR TB is a strain of TB resistant to isoniazid and rifampin (which defined MDR TB) plus additional resistance to any fluoroquinolone and ≥1 of 3 injectable drugs: capreomycin, kanamycin, and amikacin. Of the 49 cases of XDR TB identified in the United States from 1993 to 2006, 1 (3%) occurred in a child aged <15 years. However, this number possibly underestimates the burden in children, as many TB cases in children are not culture positive and thus a definitive diagnosis of drug resistance (including MDR or XDR) is not possible. Children with suspected or confirmed XDR TB should be managed in consultation with an expert, as such cases are associated with rapid disease progression in the presence of HIV coinfection and a high mortality rate.
Adjunctive treatment with corticosteroids is indicated for children with TB meningitis; dexamethasone lowers mortality and long-term neurologic impairment (AII). These drugs might be considered for children with pleural or pericardial effusions, severe miliary disease, and substantial endobronchial disease (BIII). Anti-TB therapy must be administered concomitantly. Most experts use 1 – 2 mg/kg/day of prednisone or its equivalent for 6 to 8 weeks.
Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome
Monthly monitoring of clinical and bacteriologic response to therapy is important (AII). For children with pulmonary TB, chest radiographs should be obtained after 2 to 3 months of therapy to evaluate response (AIII). Hilar adenopathy might persist for as long as 2 to 3 years despite successful anti-TB therapy and a normal radiograph is not a criterion to discontinue therapy. Follow-up radiographs after completion of therapy are not necessary unless clinical symptoms recur.
Common side effects associated with TB medications are listed in Table 5 in the original guideline document. Isoniazid is available as syrup, but some specialists advise against using it because the syrup is unstable and frequently causes diarrhea. Gastric upset during the initial weeks of isoniazid treatment occurs frequently and can often be avoided by having some food in the stomach when isoniazid is given. Hepatotoxicity is the most common serious adverse effect. It includes subclinical hepatic enzyme elevation, which usually resolves spontaneously while treatment is continued and clinical hepatitis that usually resolves when the drug is discontinued; it rarely progresses to hepatic failure, but the likelihood of life-threatening liver damage is increased by continuing isoniazid in spite of hepatitis symptoms. Hepatotoxicity is less frequent in children than in adults, but no age group is risk free. Transient asymptomatic serum transaminase elevations have been noted in 3% – 10% and clinical hepatitis in <1% of children receiving isoniazid, although <1% of children required treatment discontinuation. However, the rate of hepatotoxicity might be greater in children taking multiple hepatotoxic medications and those who have HIV infection. Pyridoxine (150 mg/day) is recommended for all symptomatic HIV-infected children treated with isoniazid (AII).
HIV-infected children on anti-TB medications should have liver enzymes obtained at baseline and monthly thereafter (AIII). If symptoms of drug toxicity develop, a physical examination and repeat liver enzyme measurement should be performed (AIII). Mild elevations in serum transaminases (e.g., 2 to 3 times the upper limit of normal) do not require discontinuation of drugs if other findings are normal (AII), but they do require more frequent rechecks until they resolve—as often as weekly.
The most ominous toxicity associated with ethambutol is optic neuritis, with symptoms of blurry vision, central scotomata, and red-green color blindness, which is usually reversible and rare at doses of 15 – 25 mg/kg among children with normal renal function. Assessments of renal function, ophthalmoscopy, and (if possible) visual acuity and color vision should be performed before starting ethambutol and monitored regularly during treatment with the agent (AIII). Hypothyroidism has been associated with ethionamide and periodic (e.g., monthly) monitoring of thyroid hormone serum concentrations is recommended with its use (AIII).
Major adverse effects of aminoglycoside drugs are oto- and nephrotoxicity. Periodic audiometry, monitoring of vestibular function (as possible), and blood urea nitrogen and creatinine are recommended (AIII).
Secondary drugs used in treatment of resistant TB have not been well studied in children. These medications should be used in consultation with a TB specialist (AIII). Coadministration of pyridoxine (150 mg/day) with cycloserine is recommended (AII). Thiacetazone can cause severe and often fatal reactions among HIV-infected children, including severe rash and aplastic anemia, and should not be used (EIII).
An IRIS in patients receiving anti-TB therapy in the setting of HAART has been reported in HIV-infected adults. New onset of systemic symptoms, especially high fever, expanding CNS lesions, and worsening adenopathy, pulmonary infiltrates, or pleural effusions have been reported in HIV-infected adults in the setting of HAART up to several months after starting TB therapy. These cases have also been reported in children and should be suspected in children with advanced immune suppression who initiate HAART and subsequently develop new symptoms.
This IRIS occurs in two common clinical scenarios. First, patients with occult TB prior to initiating HAART may have unmasking of their TB by immune recovery following antiretroviral drug initiation. This is referred to as "unmasking IRIS" or incident TB-IRIS, usually occurs within the first 3 to 6 months after initiation of HAART, and the infectious pathogen is typically detectable. Second, IRIS can also occur as paradoxical exacerbation of TB after initiating HAART in a patient already receiving anti-TB treatment, through a clinical recrudescence of a successfully treated infection or symptomatic relapse despite initial clinical improvement and continued microbiologic treatment success; this is referred to as "paradoxical IRIS." In paradoxical IRIS, persons are already on TB treatment at the time of antiretroviral treatment initiation, and treatment failure due to microbial resistance or poor adherence must be ruled out.
The literature on IRIS in children consists largely of case reports and small series, so it is not clear whether IRIS occurs more often in children than in adults. Persons with mild-to-moderate symptoms of IRIS have been treated symptomatically with nonsteroidal anti-inflammatory drugs while continuing anti-TB and HIV therapies. In certain cases, use of systemic corticosteroids for 1 to 2 weeks results in improvement while continuing to receive TB/HIV therapies (CIII). However, no controlled trials of the use of corticosteroids have been published. TB therapy should not be discontinued.
Management of Treatment Failure
Most children with TB respond well to medical therapy. If response is not good, then an evaluation that includes assessment of adherence to therapy, drug absorption, and drug resistance should be carried out. Mycobacterial culture, drug susceptibility testing, and antimycobacterial drug levels should be performed whenever possible. Drug resistance should be suspected in any child who fails to convert their smear or culture after 2 months of anti-TB therapy as DOT. In the absence of bacteriologic confirmation of disease in the first place, failure should be suspected in children who do not have resolution of clinical symptoms, including failure to gain weight, and who have radiographic evidence of disease progression on therapy. As described above, drug-resistant TB should be managed in consultation with an expert.
Prevention of Recurrence
Risk of recurrence is rare in children with drug-susceptible TB who are treated under direct observation. If TB recurs, the child is at high risk of drug resistance and should be managed accordingly.
Chronic suppressive therapy for a patient who has successfully completed a recommended regimen of treatment for TB is unnecessary (DII). Secondary prophylaxis is not recommended for children who have had a prior episode of TB. However, HIV-infected children who were treated for LTBI or TB and who come into contact with contagious TB again should be treated for presumed latent infection, after diagnostic evaluation excludes current disease.
Discontinuing Secondary Prophylaxis
Not applicable.
Mycobacterial Infections: Mycobacterium avium Complex (MAC) Disease
Prevention Recommendations
Preventing Exposure
MAC is ubiquitous in the environment. Available information does not support specific recommendations regarding exposure avoidance. Person-to-person transmission is not believed to be common.
Preventing First Episode of Disease
The most effective way to prevent disseminated MAC among HIV-infected children is to preserve immune function through use of effective antiretroviral therapy. HIV-infected children who have advanced immunosuppression should be offered prophylaxis against disseminated MAC disease according to the following CD4 count thresholds (AII):
- Children aged ≥6 years: <50 cells/mm3
- Children aged 2 to 5 years: <75 cells/mm3
- Children aged 1 to 2 years: <500 cells/mm3
- Children aged <1 year: <750 cells/mm3
For the same reasons that clarithromycin and azithromycin are the preferred prophylactic agents for adults, either one should be considered for prophylaxis in children (AII); oral suspensions of both agents are commercially available in the United States. Before prophylaxis is initiated, evaluation for the presence of disseminated MAC disease should be carried out, which should usually include obtaining a blood culture for MAC (AIII).
Although detecting MAC in stool or respiratory tract may precede disseminated disease, no available data support initiating prophylaxis in patients with detectable organisms at these sites in the absence of a positive blood culture for MAC. Therefore, routine screening of respiratory or gastrointestinal (GI) specimens for MAC is not recommended (DIII).
Discontinuing Primary Prophylaxis
Primary prophylaxis for MAC can be safely discontinued in HIV-infected adults who respond to antiretroviral therapy with an increase in CD4 count based upon both randomized controlled trials and observational data. In a study of discontinuing opportunistic infection (OI) prophylaxis among HIV-infected children whose CD4 percentages were ≥20% for those aged >6 years and ≥25 % for those aged 2 to 6 years, 63 HIV-infected children discontinued MAC prophylaxis, and no MAC events were observed during ≥2 years of follow-up. Based on these findings and data from studies in adults, primary prophylaxis can be discontinued in HIV-infected children aged >2 years receiving stable HAART for ≥6 months who experience sustained (>3 months) CD4 cell recovery well above the age-specific target for initiation of prophylaxis (e.g., similar to adults, >100 cells/mm3 for children aged ≥6 years and >200 cells/mm3 for children aged 2 to 5 years) (BII).
Treatment Recommendations
Treatment of Disease
Treatment of disseminated MAC infection should be done in consultation with a pediatric infectious disease specialist with expertise in pediatric HIV infection (AIII). Combination therapy with a minimum of two drugs is recommended to prevent or delay the emergence of resistance (AI). Monotherapy with a macrolide results in emergence of high-level drug resistance within weeks.
Improved immunologic status is important for control of disseminated MAC disease; potent antiretroviral therapy should be initiated among children with MAC disease who are antiretroviral naïve. However, the optimal time to start HAART in this situation is unknown; many experts treat MAC with antimycobacterial therapy for 2 weeks before starting HAART to try to minimize the occurrence of IRIS, although whether this makes a difference is unknown (CIII). For children already receiving HAART, it should be continued and optimized unless drug interactions preclude the safe concomitant use of antiretroviral and antimycobacterial drugs.
Doses and side effects of MAC medications are included in Tables 1 through 6 of the original guideline document. Initial empiric therapy should include two or more drugs (AI): clarithromycin or azithromycin plus ethambutol. Some experts use clarithromycin as the preferred first agent (AI), reserving azithromycin for patients with substantial intolerance to clarithromycin or when drug interactions with clarithromycin are a concern (AII). PIs can increase and efavirenz can decrease clarithromycin levels but no data are available to recommend dose adjustments for pediatric patients. Azithromycin is not metabolized by the cytochrome P450 (CYP450) system; therefore, it can be used without concern for significant drug interactions with PIs and NNRTIs.
Because a study in adult patients demonstrated a survival benefit with the addition of rifabutin to clarithromycin plus ethambutol, some experts would add rifabutin as a third drug to the clarithromycin/ethambutol regimen (CI); however, drug interactions should be checked carefully, and more intensive toxicity monitoring might be warranted if such drugs are given concomitantly (AIII). Because rifabutin increases CYP450 activity that leads to increased clearance of other drugs (e.g., PIs and NNRTIs), and increased toxicity might be observed with concomitant administration of drugs, other experts recommend against the use of this third agent in children (CIII). Guidelines and recommendations exist for dose adjustments necessary in adults who are treated with rifabutin and PIs, but the absence of pediatric data precludes extrapolating these to HIV-infected children being treated for disseminated MAC. There is no pediatric formulation of rifabutin, although the drug can be administered mixed with foods such as applesauce. Limited safety data are available from use in 22 HIV-infected children (median age, 9 years) who received rifabutin in combination with two or more other antimycobacterial drugs for treatment of MAC for periods of 1 to 183 weeks; doses ranged from 4 to 18.5 mg/kg/dose, and reported adverse effects were similar to those reported in adults.
Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome
Most patients demonstrate substantial clinical improvement during the first 4 to 6 weeks of therapy. A repeat blood culture for MAC should be obtained 4 to 8 weeks after initiation of antimycobacterial therapy in patients who fail to have a clinical response to their initial treatment regimen. Improvement in fever can be expected within 2 to 4 weeks after initiation of appropriate therapy. However, for those with more extensive disease or advanced immunosuppression, clinical response might be delayed and elimination of the organism from the blood might require up to 12 weeks of effective therapy.
An IRIS in patients receiving MAC therapy in the setting of HAART has been reported among HIV-infected adults and children. New onset of systemic symptoms, especially fever or abdominal pain, leukocytosis, and focal lymphadenitis (cervical, thoracic, or abdominal) associated with pre-existing but relatively asymptomatic MAC infection has been seen after starting HAART. Before initiation of HAART among HIV-infected children with low CD4 counts, consideration should be given for an assessment for MAC and treatment if MAC is identified. However, recent data indicate that MAC prophylaxis with azithromycin did not prevent the development of immune reconstitution disease. Children with moderate symptoms of IRIS can be treated symptomatically with nonsteroidal anti-inflammatory drugs or, if unresponsive to nonsteroidals, a short course (e.g., 4 weeks) of systemic corticosteroid therapy while continuing to receive HAART (CIII).
Adverse effects with clarithromycin and azithromycin include nausea, vomiting, abdominal pain, abnormal taste, and elevations of liver transaminase levels or hypersensitivity reactions. The major toxicity associated with ethambutol is optic neuritis, with symptoms of blurry vision, central scotomata, and red-green color blindness, which is usually reversible and rare at doses of 15 – 25 mg/kg among children with normal renal function. Assessments of renal function, ophthalmoscopy, and (if possible) visual acuity and color vision should be performed before starting ethambutol and monitored regularly during treatment with the agent (AIII).
Patients receiving clarithromycin plus rifabutin should be observed for the rifabutin-related development of leucopenia, uveitis, polyarthralgias, and pseudojaundice. Tiny, almost transparent, asymptomatic peripheral and central corneal deposits that do not impair vision have been observed in some HIV-infected children receiving rifabutin as part of a multidrug regimen for MAC.
Management of Treatment Failure
Treatment failure is defined by the absence of clinical response and the persistence of mycobacteremia after 8 to 12 weeks of treatment. Repeat susceptibility testing of MAC isolates is recommended in this setting, and a new multidrug regimen of two or more drugs not previously used and to which the isolate is susceptible should be administered (AIII). Drugs that should be considered under this scenario include rifabutin, amikacin, and a quinolone. In HIV-infected adults, based on data from treating MAC in HIV-uninfected patients, an injectable agent such as amikacin or streptomycin should be considered (CIII). Because dosing of these agents in pediatrics can be problematic, treatment for drug-resistant disseminated MAC should be carried out with input from an expert in this disease (AIII). Optimization of antiretroviral therapy is an especially important adjunct to treatment of patients who have failed initial MAC therapy.
Prevention of Recurrence
Children with a history of disseminated MAC should be administered lifelong prophylaxis to prevent recurrence (AII).
Discontinuing Secondary Prophylaxis
Based upon immune reconstitution data in adults and data in children discontinuing primary prophylaxis, some experts recommend discontinuation of secondary prophylaxis in HIV-infected children aged >2 years who have completed a course of ≥12 months of treatment for MAC, remain asymptomatic with respect to signs and symptoms of MAC, and are receiving stable HAART who experience sustained (≥6 months) CD4 cell recovery well above the age-specific target for initiation of primary prophylaxis (e.g., similar to adults, >100 cells/mm3 for children aged >6 years and >200 cells/mm3 for children aged 2 to 6 years) (CIII). Secondary prophylaxis should be reintroduced if the CD4 count falls below the age-related threshold.
Definitions:
| Rating Scheme for Prevention and Treatment Recommendations |
| A |
Both strong evidence for efficacy and substantial clinical benefit support recommendation for use. Should always be offered. |
| B |
Moderate evidence for efficacy - or strong evidence for efficacy but only limited clinical benefit - supports recommendation for use. Should generally be offered. |
| C |
Evidence for efficacy is insufficient to support a recommendation for or against use. Or evidence for efficacy might not outweigh adverse consequence (e.g., drug toxicity, drug interactions) or cost of the treatment under consideration. Optional. |
| D |
Moderate evidence for lack of efficacy or for adverse outcome supports a recommendation against use. Should generally not be offered. |
| E |
Good evidence for lack of efficacy or for adverse outcome supports a recommendation against use. Should never be offered. |
| Quality of Evidence Supporting the Recommendation |
| I |
Evidence from at least one randomized, controlled trial. |
| II |
Evidence from at least one well-designed clinical trial without randomization, from cohort or case-controlled analytic studies (preferably from more than one center), or from multiple time-series studies. Or dramatic results from uncontrolled experiments. |
| III |
Evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees. |
