Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children

The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.

Mycobacterium tuberculosis

Last Updated: November 6, 2013; Last Reviewed: November 6, 2013

Panel's Recommendations for Mycobacterium Tuberculosis
Panel's Recommendations

Detection of Latent TB Infection

  • Diagnostic methods for latent tuberculosis (TB) infection (LTBI) include the tuberculin skin test (TST), administered by the Mantoux method with an Food and Drug Administration (FDA)-approved purified protein derivative, or FDA-approved interferon gamma release assays (IGRA) (QuantiFERON®-TB Gold In-Tube, and T SPOT®.TB); TST is preferred over IGRA in children aged <5 years (Bll)
  • TST and IGRA should NOT be used to rule out disease and cannot replace regular screening for TB exposure (AII). In high-TB-burden settings, screening for TB exposure and for signs or symptoms suggestive of TB disease is universally applicable and should occur at every health care visit (AII)

Treatment for LTBI

  • HIV-infected children should receive preventive therapy if they have a positive TST or IGRA result or if they are exposed to an individual with infectious TB (regardless of previous treatment for TB or the TST or IGRA result), after TB disease has been excluded (AII).
  • The preferred preventive therapy regimen is isoniazid daily for 9 months (AII). If adherence with daily isoniazid cannot be ensured, then consider twice-weekly isoniazid by directly observed therapy (DOT) by a trained worker, not a family member (BII).
  • With exposure to an isoniazid mono-resistant source case, preventive therapy consisting of daily rifampin for 6 months is recommended, with adjustment of combination antiretroviral therapy (cART) as required (BII).
  • A 12-dose combination regimen of once-weekly isoniazid and rifapentine by DOT is as safe and effective as other regimens in preventing TB disease, and the completion rate is greater than for longer regimens. However, pediatric experience with this regimen is limited, and drug-drug interactions between rifapentine and other antiretroviral drugs have not been determined. This regimen is not recommended for children aged <2 years, nor for HIV-infected adults or children who are receiving cART or individuals who have LTBI with presumed isoniazid or rifampin resistance; the preferred regimen for children aged 2 to 11 years remains daily isoniazid for 9 months.

Treatment of TB Disease 

  • In children diagnosed with TB, DOT must be started immediately (AII) and all cases of suspected and confirmed TB disease must be reported to the relevant health authorities.
  • All children diagnosed with TB should be tested for HIV infection (AIII).
  • In HIV-infected children, the recommended treatment for fully-drug-susceptible TB is a 4-drug regimen consisting of isoniazid, rifampin, pyrazinamide, and ethambutol given daily during the 2-month intensive phase, followed by a 7-month continuation phase using only isoniazid and rifampin (AII), with adjustment of cART as required. With good adherence and treatment response, thrice-weekly treatment under DOT during the continuation phase can be considered (CII)
  • For children with extrapulmonary disease caused by drug susceptible TB involving the bones or joints, central nervous system (CNS), or disseminated/miliary disease, the recommended duration of treatment is 12 months (AIII).
  • For TB meningitis (TBM), pending drug-susceptibility testing results, ethionamide can replace ethambutol (or an injectable aminoglycoside) as the fourth drug because of its superior cerebrospinal fluid penetration (CII).
  • Children with suspected and confirmed multidrug resistant (MDR) TB (i.e., resistance to both isoniazid and rifampin) should be managed in consultation with an expert. In the United States, treatment of MDR-TB should be individualized based on drug susceptibility test (DST) results (in cases where DST results for the child are not available, then DST results for the source case should be used to guide initial choice of regimen) (AII).
  • Treatment for TB must commence as soon as the diagnosis is established in HIV-infected children, both those who are already on cART and those not yet receiving cART; those not yet on cART should be evaluated for early cART initiation, preferably within 2 to 8 weeks of starting TB therapy (AII).
  • Depending on age and previous cART exposure, an efavirenz-based regimen usually is preferable because such regimens are associated with better treatment outcomes (AII). Nevirapine with potential dose adjustment with concomitant rifampin administration can also be considered (CIII)
  • If a protease inhibitor-based regimen is used, superboosting with ritonavir (using a ritonavir dose equal to the lopinavir dose) for the full duration of rifampin treatment (and 2 weeks after termination) is required (AII).
  • Pyridoxine supplementation (1-2 mg/kg body weight/day, max 50 mg/day) is recommended for all HIV-infected children who are taking isoniazid (AII) or cycloserine (AIII)
  • Adjunctive corticosteroids treatment (with ongoing treatment for TB) is indicated for children with TBM or pericardial effusion (AII). It can also be considered with severe immune reconstitution inflammatory syndrome, airway compression, or pleural effusion (BII).
  • Liver chemistry tests should be performed before initiation and after 2, 4, and 8 weeks of treatment for TB (the same for cART initiation while receiving treatment for TB) (BIII). Beyond 2 months, routine testing every 2 to 3 months is advisable for all children receiving cART, or more frequently if clinically indicated (BIII).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials in children with clinical outcomes and/or validated endpoints; I* = One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying data in children from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; II = One or more well-designed, nonrandomized trials or observational cohort studies in children† with long-term outcomes; II* = One or more well-designed, nonrandomized trials or observational studies in adults with long-term clinical outcomes with accompanying data in children from one or more similar nonrandomized trials or cohort studies with clinical outcome data; III = Expert opinion

Studies that include children or children/adolescents, but not studies limited to post-pubertal adolescents

Table: Summary of Recommendations for Concurrent Use of Antiretroviral Therapy and TB Treatment
Age/Weight Combination Antiretroviral Therapy (cART)a
Aged <3 years 
or weight <10 kg
Retain or Start the Following Regimens:
  • NRTI backbone; use 2 NRTIs
Third Drug
If Receiving NVP, Consider: 
  • Switching to lopinavir/ritonavir (Kaletra®) with additional ritonavir to achieve mg-for-mg parity with lopinavir and continue for 1–2 weeks after treatment for TB has been stopped
  • If not possible, continue NVP dose at the upper end of the dosage scale
If Receiving Lopinavir/Ritonavir (Kaletra®): 
  • Use additional ritonavir as above 
  • If ritonavir boosting is not possible, substitute NVP for lopinavir/ritonavir (preferably only if undetectable viral load and if not previously exposed to NVP through PMTCT or prior treatment regimen) dose at the upper end of the dosage scale
For cART Initiation:
  • Triple NRTI therapy is an option, if baseline viral load <100,000 copies/mL
Aged ≥3 years
and weight ≥10 kg

Retain or Start the Following Regimens:
  • 2 NRTIs as backbone
Third drug
If Receiving EFV: 
  • Retain efavirenz (no dosage adjustment necessary)
If Receiving NVP: 
  • Substitute efavirenz for nevirapine
  • If efavirenz not available, continue nevirapine; dose at the upper end of the dosage scale
If Receiving Lopinavir/Ritonavir (Kaletra®): 
  • Consider substituting efavirenz for lopinavir/ritonavir, preferably only if viral load is undetectableb and no prior NNRTI exposure
  • Alternatively use additional ritonavir as above
  • If starting efavirenz or ritonavir boosting is not possible, start NVP in place of lopinavir/ritonavir, preferably only if undetectable viral load and no prior NNRTI exposure; dose at the upper end of the dosage scale
For Initiation:
  • Triple NRTI therapy is an option if baseline viral load <100,000 copies/mL 
Treatment for TB is not adjusted and should be initiated as soon as the diagnosis is made.
No cART adjustment is necessary with INH preventive therapy

Monitoring:
  • If previously on cART, monitor clinically for signs of drug toxicity; routine liver function testing every 2-3 months is advisable for all children on cART; no routine additional testing beyond what is done for routine HIV care and treatment is advised unless clinically indicated (BIIl)
  • If cART newly initiated-Liver chemistry tests (such as serum ALT concentration) should be performed before initiation and after 2, 4, and 8 weeks of treatment for TB (the same for cART initiation while receiving treatment for TB) (Blll). Beyond 2 months, routine testing every 2-3 months is advisable for all children on cART; no routine additional testing beyond what is done for routine HIV care and treatment is advised unless clinically indicated (BIIl).
TB patients newly diagnosed with HIV should receive cART as soon as possible, after completing the first 2 weeks of treatment for TB (earlier if clinically justified); efavirenz is preferred third drug with concurrent rifampin-based treatment for TB, but alternative options need to be considered in children aged <3 years and in those for whom efavirenz is not a preferred option. 
Children established on cART should be assessed for therapeutic failure. Do not exchange only a single drug in children whose viral load is not suppressed; rather, consider a full regimen change.

Adapted from Marais, Rabie, Cotton (2011)


Key to Acronyms: cART = combined antiretroviral therapy; EFV = efavirenz; NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine; TB = tuberculosis 

Dosing Recommendations for Preventing and Treating TB in HIV-infected Children
Indication First Choice Alternative Comments/Special Issues
Prophylaxis
Post-exposure
Source Case Drug Susceptible:
  • Isoniazid 10–15 mg/kg body weight (maximum 300 mg/day) by mouth daily for 9 months 
Source Case Drug Resistant:
  • Consult expert and local public health authorities. 
  • If adherence with daily isoniazid cannot be ensured, consider isoniazid 20–30 mg/kg body weight (maximum 900 mg/day) by mouth 2 times a week by DOT for 9 months 
  • Isoniazid 10–15 mg/kg body weight (maximum 300 mg/day) and rifampin 10–20 mg/kg/body weight (maximum 600 mg/day) by mouth daily for 3–4 months
  • Rifampin 10–20 mg/kg body weight (maximum 600 mg/day) by mouth daily for 4–6 months
Drug-drug interactions with cART should be considered for all rifamycin containing alternatives.

Indication
  • Positive TST (TST ≥5 mm) or IGRA without previous TB treatment
  • Close contact with any infectious TB case (repeated exposures warrant repeated post-exposure prophylaxis)
  • TB disease must be excluded before starting treatment.
  • No indication for pre-exposure and post-treatment prophylaxis.
Criteria for Discontinuing Prophylaxis:
  • Only with documented severe adverse event, which is exceedingly rare.
Adjunctive Treatment
  • Pyridoxine 1–2 mg/kg body weight once daily (maximum 25–50 mg/day) with isoniazid; pyridoxine supplementation is recommended for exclusively breastfed infants and for children and adolescents on meat- and milk-deficient diets; children with nutritional deficiencies, including all symptomatic HIV-infected children; and pregnant adolescents and women.
Treatment Intrathoracic Disease
Drug-Susceptible TB
Intensive Phase (2 Months):
  • Isoniazid, 10–15 mg/kg body weight (maximum 300 mg/day) by mouth once daily, plus 
  • Rifampin 10–20 mg/kg body weight (maximum 600 mg/day) by mouth once daily, plus
  • Pyrazinamide 30–40 mg/kg body weight (maximum 2 g/day) by mouth once daily, plus
  • Ethambutol 15–25 mg/kg body weight (maximum 2.5 g/day) by mouth once daily
Continuation Phase (7 Months)
  • Isoniazid 10–15 mg/kg body weight (maximum 300 mg/day) by mouth once daily, plus
  • Rifampin 10–20 mg/kg body weight (maximum 600 mg/day) by mouth once daily 
Extrathoracic Disease
Note: Depends on disease entity
  • Lymph node TB—treat as minimal intrathoracic disease
  • Bone or joint disease–consider extending continuation phase to 10 months (for total duration of therapy of 12 months).
TB Meningitis:
  • As alternative to ethambutol or streptomycin, 20–40 mg/kg body weight (maximum 1 g/day) IM once daily—during intensive phase, consider ethionamide, 15–20 mg/kg body weight by mouth (maximum 1 g/day), initially divided into 2 doses until well tolerated) 
  • Consider extending continuation phase to 10 months (for total duration of therapy of 12 months). 
  • Discuss with an expert.
Drug-Resistant TB
MDR-TB:
  • Therapy should be based on resistance pattern of child (or of source case where child’s isolate is not available); consult an expert.
  • Treatment Duration:
    • 18–24 months after non-bacteriological diagnosis or after culture conversion; ≥12 months if minimal disease
    • Discuss with an expert.
Alternative for Rifampin
  • Rifabutin 10–20 mg/kg body weight (maximum 300 mg/day) by mouth once daily (same dose if 3 times a week) 
  • Discuss with an expert.
Alternative Continuation Phase 
If Good Adherence and Treatment Response:
  • Isoniazid 20–30 mg/kg body weight (maximum 900 mg/day) by mouth, plus
  • Rifampin 10–20 mg/kg body weight (maximum 600 mg/day) three times a week.
  • In children with minimal disease with fully drug-susceptible TB in the absence of significant immune compromise, a 3-drug intensive phase regimen (excluding ethambutol) and a continuation phase of 4 months can be considered (total duration of therapy of 6 months).
Only DOT.

If cART-naive, start TB therapy immediately and initiate cART within 2–8 weeks. 

Already on cART; review to minimize potential toxicities and drug-drug interactions; start TB treatment immediately.

Potential drug toxicity and interactions should be reviewed at every visit.

Adjunctive Treatment
  • Co-trimoxazole prophylaxis 
  • Pyridoxine 1–2 mg/kg/ body weight/day (maximum 25–50 mg/day) with isoniazid or cycloserine/terizidone or, if malnourished; pyridoxine supplementation is recommended for exclusively breastfed infants and for children and adolescents on meat- and milk-deficient diets; children with nutritional deficiencies, including all symptomatic HIV-infected children; and pregnant adolescents and women.
  • Corticosteroids (2 mg/kg body weight per day of prednisone [maximum, 60 mg/day] or its equivalent for 4–6 weeks followed by tapering) with CNS disease or pericardial effusion; may be considered with pleural effusions, severe airway compression, or severe IRIS.
Second-Line Drug Doses
  • Amikacin 15–30 mg/kg body weight (maximum 1 g/day) IM or IV once daily 
  • Kanamycin 15–30 mg/kg body weight (maximum 1 g/day) IM or IV once daily
  • Capreomycin 15–30 mg/kg body weight (maximum 1 g/day) IM once daily 
  • Ofloxacin 15–20 mg/kg body weight (maximum 800 mg/day), or levofloxacin 7.5–10 mg/kg body weight (maximum 750 mg/day) by mouth once daily. Because some fluoroquinolones are approved by the FDA for use only in people aged 18 years and older, their use in younger patients necessitates careful assessment of the potential risks and benefits.
  • Cycloserine/Terizidone 10–20 mg/kg body weight (maximum 1 g/day) by mouth once daily
  • Ethionamide/prothionamide, 15–20 mg/kg body weight (maximum 1 g/day) by mouth in 2–3 divided doses
  • Para-aminosalicylic acid 200–300 mg/kg body weight by mouth divided into 3–4 doses per day (maximum 10 g/day).
  • Thiacetazone can cause severe reactions in HIV-infected children including rash and aplastic anemia, and should not be used.
Key to Acronyms: cART = combined antiretroviral therapy; CNS = central nervous system; DOT = directly observed therapy; FDA = Food and Drug Administration; IGRA = interferon-gamma release assay; IM = intramuscular; IRIS = immune reconstitution inflammatory syndrome; IV = intravenous; MDR-TB = multi-drug-resistant tuberculosis; TB = tuberculosis; TST = tuberculin skin test

References:
Pickering LK, Baker CJ, Kimberlin DW, Long SS, and the American Academy of Pediatrics. Tuberculosis. Red Book: 2009 Report of the Committee on Infectious Diseases. Elk Grove Village, IL: American Academy of Pediatrics; 2009:680-701

Centers for Disease Control and Prevention. Tuberculin Testing and Treatment of Latent Tuberculosis Infection. MMWR 49(RR06);1-54. 2003.

Centers for Disease Control and Prevention. Treatment of Tuberculosis. MMWR 52(RR11);1-77. 2003.

Schaaf HS, Marais BJ. Management of multidrug-resistant tuberculosis in children: a survival guide for paediatricians. Paediatr Respir Rev. 2011; 12: 31-38

World Health Organization. Rapid Advice: treatment of tuberculosis in children. Paper presented at Geneva, Switzerland: (WHO/HTM/TB/2010.13). 

World Health Organization. Guidance for national tuberculosis and HIV programmes on the management of tuberculosis in HIV-infected children: recommendations for a public health approach. Paper presented at: Paris, France: IUATLD , 2010

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