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.

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Malaria

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

Panel's Recommendations for Malaria
Panel's Recommendations
  • Families traveling to malaria-endemic countries should receive pre-travel counseling, including information on insecticide-treated bed nets, N,N-Diethyl-meta-toluamide, and country-specific antimalarial prophylaxis (AII).
  • Trimethoprim-sulfamethoxazole is not recommended for antimalarial prophylaxis (AIII).
  • Treatment of malaria is based on disease severity, patient age, parasite species, pregnancy status, and local resistance patterns where the malaria infection was acquired (AI).
  • The choice of malaria therapy is not affected by HIV status but can be modified based on potential interactions between antiretroviral and antimalarial drugs (AIII). Quinidine is not recommended for patients who are taking ritonavir (AIII) (ritonavir may be replaced if quinidine is needed for severe malaria) and should be administered with caution with atazanavir, darunavir and fosamprenavir (AIII).
  • The treatment options for uncomplicated chloroquine-susceptible Plasmodium falciparum malaria include chloroquine phosphate, atovaquone-proguanil, artemether-lumefantrine, and quinine sulfate plus either doxycycline, tetracycline (in children aged ≥8 years), or clindamycin. Mefloquine is considered an alternative regimen (AIII).
  • Chloroquine should not be used to treat malaria infections acquired in areas with chloroquine resistance (AIII).
  • Treatment of uncomplicated chloroquine-resistant malaria may include atovaquone-proguanil, quinine sulfate plus either doxycycline or tetracycline (specifically in children aged ≥8 years) or clindamycin or artemether-lumefantrine (AIII).
  • Treat for presumptive chloroquine-resistant P. falciparum malaria in symptomatic patients who have traveled to a region with chloroquine-resistant P. falciparum and for whom reliable identification of the malaria species is not possible or who are severely ill (AIII).
  • After initial treatment for Plasmodium vivax and Plasmodium ovale (same as for uncomplicated P. falciparum), primaquine is recommended for treatment of the dormant liver stage (hypnozoites) (AIII). 
  • Glucose-6-phosphate dehydrogenase deficiency must be excluded before use of primaquine because of risk of severe hemolytic anemia (AIII)
  • Treatment of severe malaria includes both IV quinidine gluconate plus either doxycycline OR clindamycin OR tetracycline. Alternatives include artesunate IV (under Investigational New Drug protocol: Contact the Centers for Disease Control and Prevention Malaria Hotline at (770) 488-7788) followed by either doxycycline OR atovaquone-proguanil OR mefloquine OR clindamycin (AIII).
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

Potential Clinically Relevant Interactions between Antimalarial and Antiretroviral Drugs*
Antimalarial Drug
 Protease Inhibitors NRTI NNRTI
Quinine
 PIs: increase quinine levels
 No available data
 Efavirenz, Nevirapine: reduces quinine levels
Atovaquone/Proguanil
 Lopinavir/Ritonavir, Atazanavir/Ritonavir: reduces atovaquone and proguanil levels
   Efavirenz: reduces atovaquone and proguanil levels
Mefloquine
 Ritonavir: reduces ritonavir levels
   Efavirenz, Nevirapine: reduces mefloquine levels
Lumefantrine, Halofantrine
 PIs: increase lumefantrine or halofantrine levels, which can prolong QT interval
   Efavirenz, Nevirapine: increases lumefantrine or halofantrine levels, which can prolong QT interval
Amodiaquine plus Artesunate
     Efavirenz: increases amodiaquine concentration which can increase hepatic toxicity; do not co-administer
Chloroquine, Pyrimethamine, Sulfadoxine-Pyrimethamine
 Ritonavir: alters anti-malarial drug metabolism, may increase chloroquine levels
    
Sulfadoxine-Pyrimethamine
   Zidovudine: possibly increases risk of anemia
 Nevirapine: possibly increases adverse skin or liver adverse reactions; do not start both drugs simultaneously
Artemisinin
 PIs: alter artemisinin metabolism
   Nevirapine: may decrease artemisinin levels
Dapsone
 Saquinavir: alters dapsone metabolism
    
Key to Acronyms: NRTI=nucleoside reverse transcriptase inhibitor; NNRTI=non-nucleoside reverse transcriptase inhibitor; PI= protease inhibitor

* Modified from: Flateau, C., G. Le Loup, et al. Consequences of HIV infection on malaria and therapeutic implications: a systematic review. Lancet Infect Dis. 2011. 11(7);541-556.

Dosing Recommendations for Prevention and Treatment of Malaria
Indication First Choice
 Comments/Special Issues
Primary Prophylaxis
 For Travel To Chloroquine-Sensitive Areas:
  • Chloroquine base 5 mg/kg body weight base by mouth, up to 300 mg once weekly (equivalent to 7.5 mg/kg body weight chloroquine phosphate). Start 1–2 weeks before leaving, take weekly while away, and then take once weekly for 4 weeks after returning home
  • Atovaquone/proguanil once daily started 1–2 days before travel, for duration of stay, and then for 1 week after returning home
    • 11–20 kg; 1 pediatric tablet (62.5 mg/25 mg)
    • 21–30 kg, 2 pediatric tablets (125 mg/50 mg)
    • 31–40 kg; 3 pediatric tablets (187.5 mg/75 mg)
    • >40 kg; 1 adult tablet (250 mg/100 mg)
  • Doxycycline 2.2 mg/kg body weight (maximum 100 mg) by mouth once daily for children aged ≥8 years. Must be taken 1-2 days before travel, daily while away, and then up to 4 weeks after returning
  • Mefloquine 5 mg/kg body weight orally given once weekly (max 250 mg)
For Areas with Mainly P. Vivax:
  • Primaquine phosphate 0.6 mg/kg body weight base once daily by mouth, up to a maximum of 30 mg base/day. Starting 1 day before leaving, taken daily, and for 3–7 days after return 
 Recommendations are the same for HIV-infected and HIV-uninfected children. Please refer to the following website for the most recent recommendations based on region and drug susceptibility: http://www.cdc.gov/malaria/
 
For travel to chloroquine-sensitive areas. Equally recommended options include chloroquine, atovaquone/proguanil, doxycycline (for children aged ≥8 years), and mefloquine; primaquine is recommended for areas with mainly P. vivax.
 
G6PD screening must be performed prior to primaquine use.

Chloroquine phosphate is the only formulation of chloroquine available in the United States; 10 mg of chloroquine phosphate = 6 mg of chloroquine base.

For travel to chloroquine-resistant areas, preferred drugs are atovaquone/proguanil, doxycycline (for children aged ≥8 years) or mefloquine.
For Travel to Chloroquine-Resistant Areas:
  • Atovaquone/proguanil once daily started 1–2 days before travel, for duration of stay, and then for 1 week after returning home
    • 11–20 kg; 1 pediatric tablet (62.5 mg/25 mg)
    • 21–30 kg, 2 pediatric tablets (125 mg/50 mg)
    • 31–40 kg; 3 pediatric tablets (187.5 mg/75 mg)
    • >40 kg; 1 adult tablet (250 mg/100 mg)
  • Doxycycline 2.2 mg/kg body weight (maximum 100 mg) by mouth once daily for children aged ≥8 years. Must be taken 1–2 days before travel, daily while away, and then up to 4 weeks after returning
  • Mefloquine 5 mg/kg body weight orally given once weekly (maximum 250 mg)
Secondary Prophylaxis
 For P. vivax or P. ovale:
  • Primaquine 0.5 mg/kg base (0.8 mg/kg salt) up to adult dose orally, daily for 14 days after departure from the malarious area
 This regimen, known as PART, is recommended only for individuals who have resided in a malaria-endemic area for an extended period of time. Adult dose: 30 mg base (52.6 mg salt) orally, daily for 14 days after departure from the malarious area.

http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter-3-infectious-diseases-related-to-travel/malaria.htm#1939
Treatment Uncomplicated P. Falciparum or Unknown Malaria Species, from Chloroquine-Resistant Areas (All Malaria Areas Except Those Listed as Chloroquine Sensitive) or Unknown Region:
  • Atovaquone-proguanil (pediatric tablets 62.5 mg/25 mg; adult tablets 250 mg/100 mg), dosed once daily: 
    • 5–8 kg; 2 pediatric tablets for 3 days;
    • 9–10 kg; 3 pediatric tablets for 3 days;
    • 11–20 kg; 4 pediatric tablets or 1 adult tablet for 3 days;
    • 21–30 kg; 2 adult tablets for 3 days;
    • 31–40 kg; 3 adult tablets for 3 days;
    • >40 kg; 4 adult tablets for 3 days
Uncomplicated P. Falciparum OR Unknown Malaria Species From Chloroquine-Sensitive Region (See Comments for Link to Resistance Map): 
  • Chloroquine phosphate: 16.6 mg/kg body weight (10 mg/kg body weight chloroquine base) (maximum 1000 mg) by mouth once, then 8.3 mg/kg body weight (maximum 500 mg) by mouth at 6, 24, and 48 hours (total dose = 41.6 mg/kg body weight chloroquine phosphate [maximum 2500 mg] = 25 mg/kg body weight chloroquine base)
P. vivax, P. ovale, P. malariae, P. knowlesi (All Areas Except Papua New Guinea, Indonesia; See Comments)
Initial Therapy (Followed by Anti-Relapse Therapy for P. Ovale and P. Vivax):
  • Chloroquine phosphate 16.6 mg/kg body weight (10 mg/kg body weight chloroquine base) (maximum 1000 mg) by mouth once, then 8.3 mg/kg body weight (maximum 500 mg) by mouth at 6, 24, and 48 hours (total dose = 41.6 mg/kg body weight chloroquine phosphate [maximum 2500 mg] = 25 mg/kg body weight chloroquine base)
Anti-Relapse Therapy for P. ovale, P. vivax:
  • Primaquine 0.5 mg base/kg body weight (max 30 mg base) by mouth once daily for 14 days
Uncomplicated P. falciparum or Unknown Malaria Species from Chloroquine-Resistant Areas (All Malaria Areas Except Those Listed as Chloroquine Sensitive) or Unknown Region:
  • Mefloquine (250-mg tablets only): 15 mg/kg body weight (maximum 750 mg) by mouth once, then 10 mg/kg body weight (maximum 500 mg) by mouth given 12 hours later
  • Quinine sulfate 10 mg/kg body weight (maximum 650 mg) per dose by mouth every 8 hours for 3 to 7 days, plus Clindamycin 7 mg/kg body weight per dose by mouth every 8 hours for 7 days, or doxycycline: 2.2 mg/kg body weight per dose (maximum 100 mg) given by mouth every 12 hours, or tetracycline 6–12.5 mg/kg body weight per dose by mouth given every 6 hours (maximum dose: 500 mg per dose given 4 times daily) for 7 days.
  • Artemether-lumefantrine: 1 tablet=20 mg Artemether and 120 mg lumefantrine, a 3-day treatment schedule for a total of 6 doses. The second dose follows the initial dose 8 hours later, then 1 dose twice daily for the next 2 days.
    • 5 to <15 kg; 1 tablet per dose
    • 15 to <25 kg; 2 tablets per dose
    • 25 to <35 kg; 3 tablets per dose
    • >35 kg; 4 tablets per dose
 For quinine-based regimens, doxycycline or tetracycline should be used only in children aged ≥8 years. An alternative for children aged ≥8 years is clindamycin 7 mg/kg body weight per dose by mouth given every 8 hours. Clindamycin should be used for children aged <8 years.

Before primaquine is given, G6PD status must be verified. Primaquine may be given in combination with chloroquine if the G6PD status is known and negative, otherwise give after chloroquine (when G6PD status is available)

For most updated prevention and treatment recommendations for specific region, refer to updated CDC treatment table available at http://www.cdc.gov/malaria/resources/pdf/treatmenttable.pdf

For sensitive and resistant malaria map: http://cdc-malaria.ncsa.uiuc.edu/

High treatment failure rates due to chloroquine-resistant P. vivax have been documented in Papua New Guinea and Indonesia. Treatment should be selected from one of the three following options:
  • Atovaquone-proguanil plus primaquine phosphate
  • Quinine sulfate plus EITHER doxycycline OR tetracycline PLUS primaquine phosphate. This regimen cannot be used in children aged <8 years.
  • Mefloquine plus primaquine phosphate
 
Severe Malaria Quinidine gluconate 10 mg/kg body weight IV loading dose over 1–2 hours, then 0.02 mg/kg body weight/minute infusion for ≥24 hours (Treatment duration: 7 days in Southeast Asia, Oceania, otherwise 3 days) 

PLUS One of the Following:
  • Doxycycline 100 mg per dose by mouth every 12 hours for 7 days; for children <45 kg, use 2.2 mg/kg body weight per dose
             OR
  • Clindamycin 7 mg/kg body weight per dose by mouth given every 8 hours for 7 days. 
             OR
  • Tetracycline 6–12.5 mg/kg body weight per dose every 6 hours (maximum dose 500 mg per dose given 4 times daily) for 7 days 
Artesunate 2.4 mg/kg body weight IV bolus at 0, 12, 24, and 48 hours            

PLUS One of the Following:
  • Doxycycline (treatment dosing as above), or Atovaquone-proguanil (treatment dosing as above), or
  • Mefloquine 15 mg/kg body weight (maximum 750 mg) by mouth once, then 10 mg/kg body weight (maximum 500 mg) by mouth once given 12 hours later, or
  • Clindamycin (dosing as above)
 Quinidine gluconate is a class 1a anti-arrhythmic agent not typically stocked in pediatric hospitals. When regional supplies are unavailable, the CDC Malaria hotline may be of assistance (see below). Do not give quinidine gluconate as an IV bolus. Quinidine gluconate IV should be administered in a monitored setting. Cardiac monitoring required. Adverse events including severe hypoglycemia, prolongation of the QT interval, ventricular arrhythmia, and hypotension can result from the use of this drug at treatment doses.

IND: IV artesunate is available from CDC. Contact the CDC Malaria Hotline at (770) 488-7788 from 8 a.m.–4:30 p.m. EST or (770) 488-7100 after hours, weekends, and holidays. Artesunate followed by one of the following: Atovaquone-proguanil (Malarone™), clindamycin, mefloquine, or (for children aged >8 years) doxycycline.

Quinidine gluconate: 10 mg = 6.25 mg quinidine base.

Doxycycline (or tetracycline) should be used in children aged ≥8 years. For patients unable to take oral medication, may give IV. For children <45 kg, give 2.2 mg/kg IV every 12 hours and then switch to oral doxycycline. For children >45 kg, use the same dosing as per adults. For IV use, avoid rapid administration.

For patients unable to take oral clindamycin, give 10 mg base/kg loading dose IV, followed by 5 mg base/kg IV every 8 hours. Switch to oral clindamycin (oral dose as above) as soon as a patient can take oral medication. For IV use, avoid rapid administration.

Drug Interactions: 
  • Avoid co-administration of quinidine with ritonavir
  • Use quinidine with caution with other protease inhibitors.
Key to Acronyms: CDC = Centers for Disease Control and Prevention; G6PD = glucose-6-phosphate dehydrogenase; IND = investigational new drug; IV = intravenous; PART = presumptive anti-relapse therapy

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