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Home > Topics > Care of HIV-Exposed and Infected Children > Summary and Recommendations
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Summary and Recommendations: Cotrimoxazole Prophylaxis for HIV-Related Infections in Adults, Infants, and Children in Resource-Limited Settings

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Prophylaxis for Adults and Adolescents

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Starting Prophylaxis

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All HIV-infected adults and adolescents, including pregnant women and those receiving antiretroviral therapy (ART), should receive prophylaxis against HIV-related infections such as Pneumocystis jiroveci pneumonia (PCP) and toxoplasmosis according to the criteria in Table 1.

Table 1. Starting Cotrimoxazole Prophylaxis for Adults and Adolescents Living with HIV
Situation Action
WHO Clinical Stage 3 or 4 Start prophylaxis regardless of CD4 count or percent
WHO Clinical Stage 2 Start prophylaxis only if CD4 count or percent is not available
CD4 Count <350 cells/µL Start prophylaxis regardless of clinical stage
Source: World Health Organization. Guidelines on Cotrimoxazole Prophylaxis for HIV-Related Infections among Children, Adolescents and Adults in Resource-Limited Settings: Recommendations for a Public Health Approach . Geneva: World Health Organization; August 7, 2006.
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Countries, particularly those with a high HIV prevalence and a weak public health infrastructure, also may choose to adopt universal cotrimoxazole (CTX) prophylaxis for HIV-infected patients regardless of their clinical stage or CD4 status.

CTX, also known as trimethoprim-sulfamethoxazole (TMP-SMX), Bactrim, Septra, and Septrin, is the recommended prophylactic agent. The World Health Organization (WHO) recommends 1 double-strength tablet (TMP 80 mg/SMX 400 mg) or 2 single-strength tablets (TMP 160 mg/SMX 800 mg) per day as the preferred regimen.( 1 ) However, 1 single-strength tablet per day also is effective and might be better tolerated.( 2 ) Likewise, 1 double-strength tablet 3 times per week may be effective, but adherence to such intermittent regimens may be difficult.

CTX at a dosage of 1 double-strength tablet per day confers cross-protection against toxoplasmosis and some common respiratory bacterial infections and as well as intestinal tract pathogens and malaria.( 2 ) Lower dosages of CTX also might confer such protection. Recent studies have found a 40% reduction in mortality among HIV-infected adults and children who received cotrimoxazole prophylaxis but were not on ART.( 3 , 4 )

Table 2. Prophylactic Drugs for Pneumocystis jiroveci Pneumonia in Adults
Preferred Prophylaxis

The total daily dosage is 960 mg (trimethoprim 160 mg + sulfamethoxazole 800 mg)

  • Cotrimoxazole 1 double-strength tablet each day
  • Cotrimoxazole 2 single-strength tablets each day
Alternative Prophylaxis
  • Dapsone 50 mg orally twice each day or 100 mg orally once each day
  • Dapsone 50 mg orally each day + pyrimethamine 50 mg orally each day + leucovorin 25 mg orally each week
  • Dapsone 200 mg orally each day + pyrimethamine 75 mg orally each day + leucovorin 25 mg orally each week
  • Aerosolized pentamidine 300 mg via Respirgard II nebulizer once each month
  • Atovaquone 1,500 mg orally once each day

Modified from: (1) U.S. Public Health Service and Infectious Diseases Society of America; Guidelines for the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus ; June 14, 2002. (2) World Health Organization. Guidelines on Cotrimoxazole Prophylaxis for HIV-Related Infections among Children, Adolescents and Adults in Resource-Limited Settings: Recommendations for a Public Health Approach . Geneva: World Health Organization; August 7, 2006.

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Adverse Reactions

CTX prophylaxis should be continued for patients who have an adverse reaction that is not life threatening, if it is clinically feasible. For those who have discontinued prophylaxis because of an adverse reaction, reinstitution of CTX should be strongly considered after the adverse event has resolved. Patients who have experienced adverse events, especially fever and rash, might better tolerate reintroduction of the drug if they are given a gradual increase in dosage (desensitization) or if each dose of the drug or the frequency of administration is reduced. Up to 70% of patients who stop taking CTX because of an adverse reaction can tolerate the reinstitution of prophylaxis.( 5 )

Table 3. Protocol for Cotrimoxazole Desensitization among Adults and Adolescents
Step Dose
Day 1 Trimethoprim 16 mg + sulfamethoxazole 80 mg (2 mL of oral suspension)*
Day 2 Trimethoprim 16 mg + sulfamethoxazole 80 mg (2 mL of oral suspension)*
Day 3 Trimethoprim 48 mg + sulfamethoxazole 240 mg (6 mL of oral suspension)*
Day 4 Trimethoprim 64 mg + sulfamethoxazole 320 mg (8 mL of oral suspension)*
Day 5 1 single-strength trimethoprim-sulfamethoxazole tablet (trimethoprim 80 mg + sulfamethoxazole 400 mg)
Day 6 and Beyond 2 single-strength trimethoprim-sulfamethoxazole tablets or 1 double-strength tablet (trimethoprim 160 mg + sulfamethoxazole 800 mg)
Source: World Health Organization. Guidelines on Cotrimoxazole Prophylaxis for HIV-Related Infections among Children, Adolescents and Adults in Resource-Limited Settings: Recommendations for a Public Health Approach . Geneva: World Health Organization; August 7, 2006.
* Cotrimoxazole oral suspension is trimethoprim 40 mg + sulfamethoxazole 200 mg per 5 mL.
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If CTX cannot be tolerated, other prophylactic regimens can be recommended for prevention of PCP and toxoplasmosis. However, there have been no clinical trials to evaluate the efficacy of these alternative regimens in preventing other types of bacterial infections.

Alternatives to CTX include dapsone, dapsone + pyrimethamine + leucovorin (folinic acid), aerosolized pentamidine administered by the Respirgard II nebulizer (Marquest, Englewood, CO), and atovaquone.( 6 ) Because dapsone causes hemolytic anemia in individuals with low levels of the enzyme G6PD in their red blood cells, levels of this enzyme should be checked before using dapsone.( 7 ) Atovaquone appears to be as effective as aerosolized pentamidine or dapsone but is substantially more expensive than the other regimens. For patients who are seropositive for Toxoplasma gondii and cannot tolerate CTX, recommended alternatives to CTX for prophylaxis against both PCP and toxoplasmosis include dapsone + pyrimethamine or atovaquone with or without pyrimethamine. Regimens containing pyrimethamine must include leucovorin.( 6 )

The following regimens generally cannot be recommended as alternatives because data regarding their efficacy for PCP prophylaxis are insufficient for a firm recommendation: aerosolized pentamidine administered by other nebulization devices, intermittently administered parenteral pentamidine, oral pyrimethamine + sulfadoxine, oral clindamycin + primaquine, and intravenous trimetrexate.( 6 ) However, clinicians may consider using these agents in unusual situations in which the recommended agents cannot be administered.

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Stopping Prophylaxis

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Because there is limited information on the safety of discontinuing CTX prophylaxis in resource-poor settings, caution should be used when considering this option. In the United States and Europe, although optimal criteria for discontinuing PCP prophylaxis are still being assessed, providers generally stop prophylaxis when patients have sustained a CD4 count of >200 cells/µL for at least 3-6 months. Additional criteria might include sustained reduction in viral load for at least 3-6 months.( 8 )

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Pregnant Women

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CTX for HIV-related infections should be administered to pregnant women according to the same criteria used for other adults and adolescents. CTX is the recommended prophylactic agent; dapsone is an alternative. There is little evidence that CTX administered during pregnancies results in congenital abnormalities. It is recommended, therefore, that prophylaxis be initiated in all women who meet the initiation criteria regardless of stage of pregnancy and that it be administered throughout pregnancy. However, caution should be exercised when using CTX during pregnancy by women who may be nutritionally deprived, as the drug may result in folic acid deficiency.

Women receiving CTX prophylaxis do not need additional sulfadoxine/pyrimethamine-based intermittent presumptive therapy for malaria. Breast-feeding women should continue to receive CTX prophylaxis, but clinicians may consider discontinuing it for 1 week after delivery in order to avoid jaundice developing in the infant.( 2 )

For additional information on PCP, see the HIV InSite Knowledge Base chapter Pneumocystosis and HIV , which provides a comprehensive discussion on the subject, and the Pneumocystis Pneumonia chapter in the Clinical Manual for Management of the HIV-Infected Adult , which provides an overview on managing patients who may have PCP.
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Prophylaxis in Infants and Children

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Starting Prophylaxis

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All children born to HIV-infected mothers should receive prophylaxis with CTX beginning at 4-6 weeks of age (Table 4).

CTX prophylaxis should be discontinued only for children who are found to be uninfected with HIV after they have stopped breast-feeding for at least 3 months. HIV-infected children and children whose infection status remains unknown should continue to receive prophylaxis indefinitely.( 1 )

HIV infection can be excluded in children who have had 1 or more negative result using HIV viral assays (eg, HIV RNA or DNA polymerase chain reaction) or 2 or more negative HIV antibody test results.

  • HIV viral assays are definitive from age 6 weeks.
  • Antibody tests are definitive only if they are performed when the child is 18 months of age or older.
  • Both viral and antibody assay results are definitive only for children who have completely stopped breast-feeding for 6 weeks or longer.

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Stopping Prophylaxis

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Because of the lack of data on the safety of discontinuing CTX prophylaxis in children living in resource-limited settings, the WHO's general recommendation is to continue CTX prophylaxis for HIV-infected children indefinitely, unless an adverse reaction occurs.

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Table 4. Recommendations for Prophylaxis for HIV-Related Infections in Exposed Infants and Children
HIV Infection Status Age Action
HIV Exposed Birth to 4-6 weeks None
From 4-6 weeks until HIV infection can be ruled out Prophylaxis
Newly Diagnosed HIV Infection 1-4 years Prophylaxis if:
  • WHO Stage II, III, or IV regardless of CD4 percentage
  • CD4 percentage <25%
>5 years Follow adult guidelines
Source: World Health Organization. Guidelines on Cotrimoxazole Prophylaxis for HIV-Related Infections among Children, Adolescents and Adults in Resource-Limited Settings: Recommendations for a Public Health Approach . Geneva: World Health Organization; August 7, 2006.
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Table 5. Cotrimoxazole Formulations and Dosage for HIV-Exposed and HIV-Infected Children
Age Infant Weight (kg) Dosage Amount of Suspension (single daily dose in mL) Single-Strength Tablet (single daily dose) Double-Strength Tablet (single daily dose)
<6 months 3-5 Trimethoprim 20 mg/ sulfamethoxazole 100 mg 2.5 1/4 --
6 months-5 years 5-15 Trimethoprim 40 mg/ sulfamethoxazole 200 mg 5 1/2 --
6-14 years 15-30 Trimethoprim 80 mg/ sulfamethoxazole 400 mg 10 1 1/2
>14 years >30 Trimethoprim 160 mg/ sulfamethoxazole 800 mg -- 2 1
Note:
  • Single-strength tablets are trimethoprim 80 mg and sulfamethoxazole 400 mg.
  • Double-strength tablets are trimethoprim 160 mg and sulfamethoxazole 800 mg.
  • Cotrimoxazole pediatric suspension: 5 mL = trimethoprim 40 mg and sulfamethoxazole 200 mg.
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Alternative regimens for PCP prophylaxis if CTX is not tolerated ( 6 ):

  • Dapsone (children >1 month of age): 2 mg/kg (maximum 100 mg) administered orally once a day, or 4 mg/kg (maximum 200 mg) orally every week. Because dapsone causes hemolytic anemia in individuals with low levels of the enzyme G6PD in their red blood cells, levels of this enzyme should be checked before using dapsone. In terms of side effects and survival, weekly dosing of dapsone may be safer than daily dosing in children, but weekly dosing appears less effective in preventing PCP.
  • Aerosolized pentamidine (children aged 5 years or older): 300 mg administered via Respirgard II inhaler monthly.
  • Atovaquone (children 1-3 months of age and >24 months of age): 30 mg/kg orally once a day; (children 4-24 months of age): 45 mg/kg orally once a day.
  • If dapsone, aerosolized pentamidine, and atovaquone are not tolerated, some clinicians use intravenous pentamidine (4 mg/kg) administered every 2-4 weeks.

These alternative regimens should be used only for preventing PCP; their efficacy for preventing other HIV-related infections has not been established.

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References

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  1. World Health Organization. Guidelines on Cotrimoxazole Prophylaxis for HIV-Related Infections among Children, Adolescents and Adults in Resource-Limited Settings: Recommendations for a Public Health Approach. Geneva: World Health Organization; August 7, 2006.
  2. U.S. Public Health Service and Infectious Diseases Society of America. Guidelines for the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus; June 14, 2002.
  3. Walker AS, Mulenga V, Sinyinza F, et al. Determinants of survival without antiretroviral therapy after infancy in HIV-1-infected Zambian children in the CHAP Trial. J Acquir Immune Defic Syndr. 2006 Aug 15;42(5):637-45. PMID: 16868501
  4. Mermin J, Ekwaru JP, Liechty CA, et al. Effect of co-trimoxazole prophylaxis, antiretroviral therapy, and insecticide-treated bednets on the frequency of malaria in HIV-1-infected adults in Uganda: a prospective cohort study. Lancet. 2006 Apr 15;367(9518):1256-61. PMID: 16631881
  5. Carr A, Penny R, Cooper DA. Efficacy and safety of rechallenge with low-dose trimethoprim-sulphamethoxazole in previously hypersensitive HIV-infected patients. AIDS. 1993 Jan;7(1):65-71. PMID: 8442919
  6. U.S. Centers for Disease Control and Prevention. Guidelines for prophylaxis against Pneumocystis carinii pneumonia for persons infected with human immunodeficiency virus. MMWR Morb Mortal Wkly Rep. 1989 Jun 16;38 Suppl 5:1-9. PMID: 2524643
  7. Sin DD, Shafran SD. Dapsone- and primaquine-induced methemoglobinemia in HIV-infected individuals. J Acquir Immune Defic Syndr Hum Retrovirol. 1996 Aug 15;12(5):477-81. PMID: 8757424
  8. Furrer H, Egger M, Opravil M, et al. Discontinuation of primary prophylaxis against Pneumocystis carinii pneumonia in HIV-1-infected adults treated with combination antiretroviral therapy. Swiss HIV Cohort Study. N Engl J Med. 1999 Apr 29;340(17):1301-6. PMID: 10219064
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