Guidelines for Prevention and Treatment of Opportunistic Infections among HIV-Infected Children

1. Guidelines for Prevention and Treatment of Opportunistic Infections among HIV-Infected Children Recommendations from Centers for Disease Control and Prevention, the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics

2. About This Presentation These slides were developed using the April 2008 Guidelines. The intended audience is clinicians involved in the care of patients with HIV. Users are cautioned that, because of the rapidly changing field of HIV care, this information could become out of date quickly. Finally, it is intended that these slides be used as prepared, without changes in either content or attribution. Users are asked to honor this intent. Expert opinion should be sought for complex treatment regimens. – AETC NRC www.aidsetc.org

3. Contents • Introduction (slide 7) • Bacterial infections (slide 13) • Serious and recurrent bacterial infections, bartonellosis, syphilis • Mycobacterial infections (slide 45) • TB, MAC • Fungal infections (slide 76) • Aspergillosis, candidiasis, coccidiomycosis, cryptococcosis,histoplasmosis, PCP • Parasitic infections (slide 138) • Cryptosporidiosis/microsporidiosis, malaria, toxoplasmosis • Viral infections(slide 167) CMV, HBV, HCV, HHV-6/7, HHV-8, HSV, HPV, PML, VZV www.aidsetc.org

4. Diagnosis of HIV in HIV-Exposed Infants HIV infected: HIV positive by HIV DNA or RNA PCR on 2 separate samples or If >18 months and not breast-fed, positive by either antibody or PCR www.aidsetc.org

5. ART and Management of OIs • Highly active antiretroviral therapy (ART) reduces the incidence of OIs and improves survival independent of antimicrobial prophylaxis • ART does not replace the need for OI prophylaxis in children with severe immunosuppression • ART in the setting of acute or latent OIs can lead to immune reconstitution inflammatory syndrome (IRIS) www.aidsetc.org

6. Immune Reconstitution Inflammatory Syndrome (IRIS) • Definition: temporarily worsening of symptoms of inflammation or infection related to starting ART • Occurs after initiation of ART as immunity is restored • Results from an exaggerated immune response (eg, activation of latent or occult TB) • Treatment consists of nonsteroidal antiinflammatory drugs for moderate cases and corticosteroids for severe cases www.aidsetc.org

7. Introduction • Mother-to-child transmission of OI is an important mode of acquisition • HIV-infected women coinfected with OI are more likely to transmit (eg, CMV, HCV) • HIV-infected women or HIV-infected family members are sources of horizontal transmission (eg, TB) www.aidsetc.org

8. Differences between Adults and Children • OI in children often reflects primary infection rather than reactivation • OI occurs at a time when infant’s immune system is immature • Different disease manifestations (eg, children more likely to have nonpulmonic and disseminated TB) • Classical features of infection may not be present www.aidsetc.org

9. Difficulty of Diagnosing OI in Children • Inability to describe symptoms • Antibody-based tests confounded by maternal transfer of antibody • Sputum difficult to obtain without invasive procedures www.aidsetc.org

10. Frequency of OI among HIV-Infected Children • Pre-HAART era, most common OIs occurring at >1 events/100 child years • Serious bacterial infections (bacteremia and pneumonia), herpes zoster, Pneumocystis jiroveci (carinii) pneumonia, candidiasis, Mycobacterium avium complex • Pre-HAART era, most common OIs occurring at <1 events/100 child years • Cytomegalovirus, toxoplasmosis, cryptosporidiosis, TB, systemic fungal infections www.aidsetc.org

11. Changes in Frequency of OI among HIV-Infected Children www.aidsetc.org

12. Treating OI among HIV-Infected Children • Letter indicating strength of recommendation (eg, A, B, C) • Roman numeral indicating nature of evidence (eg, I, II, III) Rating of treatment recommendations is based on opinion of working group www.aidsetc.org

13. Serious Recurrent Bacterial Infections: Epidemiology • Most common infection in pre-HAART era (15/100 child years) • Because of difficulties in obtaining appropriate diagnostic specimens, bacterial pneumonia is often a presumptive diagnosis in a child with fever, pulmonary symptoms, and an abnormal chest radiogram • Bacteremia more common in HIV-infected children with pneumonia www.aidsetc.org

14. Serious Recurrent Bacterial Infections:Epidemiology (2) • Bacteria isolated include Streptococcus pneumoniae, Haemophilus influenzae type B, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, nontyphoid Salmonella • S pneumoniae accounts for >50% of bacteremia • Incidence of S pneumoniae and H influenzae may be lower in regions where vaccines are administered www.aidsetc.org

15. Serious Recurrent Bacterial Infections:Epidemiology (3) • Increased risk of Haemophilus influenzae B, invasive meningococcal disease • Gram-negative bacteremia more common in children with advanced disease • Case mortality with gram-negative bacteremia >40% • Central venous catheter increases risk of bacterial infections www.aidsetc.org

16. Serious Recurrent Bacterial Infections:Clinical Manifestations • Clinical presentation dependent on type of bacterial infection(eg, bacteremia, sepsis, vasculitis, septic arthritis, pneumonia, meningitis, sinusitis) • Presentation similar to that of HIV-uninfected children • Classical signs, symptoms, and laboratory tests may be missing in many HIV-infected children www.aidsetc.org

17. Serious Recurrent Bacterial Infections:Diagnosis • Isolation of pathogenic organism from normally sterile sites: blood, bone marrow, CSF • Diagnosis of pneumonia by radiograph and physical findings • Culture of catheter tips • Sputum cultures may be difficult to obtain • Additional studies such as ultrasound should be considered • Assays for detection of bacterial antigens when available may be helpful www.aidsetc.org

18. Serious Recurrent Bacterial Infections:Prevention • Routine use of conjugated pneumococcal and Haemophilus influenzae B vaccine (not routinely available in resource-poor countries) • Avoid raw and undercooked foods, unsterilized water, unpasteurized milk products • Hand washing and other precautions • Avoid pets • Caution with all foods when traveling www.aidsetc.org

19. Serious Recurrent Bacterial Infections:Prevention –H influenza B • Children <5 years of age should be given H influenza B (Hib) conjugate vaccine • Consider use in children >5 years • Incompletely immunized children should receive 2 doses >8 weeks apart • Pneumococcal conjugate vaccines (A II) • >5 years: consider Hib conjugate vaccine 2 doses 1-2 months apart • Children 2-59 months should receive the heptavalent pneumococcal vaccine (PCV) at 2, 4, 6, and 12-15 months www.aidsetc.org

20. Serious Recurrent Bacterial Infections:Prevention –S pneumoniae • Previously unimmunized children aged 7-23 months should receive 2-3 doses of PCV • Incompletely immunized children should receive 2 doses of PCV >8 weeks apart • Children >2 years of age should receive 23 valent PCV (>2 months after last conjugate vaccine) • Reimmunize with PCV in 3-5 years in children aged <10 years or after 5 years in children aged >10 years www.aidsetc.org

21. Serious Recurrent Bacterial Infections:Prevention • Trimethoprim sulfamethoxazole (TMP-SMX) prophylaxis reduces bacterial infection and new and recurrent episodes of malaria • Atovaquone plus azithromycin provides prophylaxis for MAC as well as PCP • Discontinue prophylaxis in children on ART with CD4 percentage >15% with caution www.aidsetc.org

22. Serious Recurrent Bacterial Infections:Treatment • Patients with suspected serious bacterial infections should be treated empirically and promptly without waiting for laboratory results • Consider local prevalence of resistance of common infectious agents • Response of mildly immunodeficient children is similar to that of HIV-uninfected children www.aidsetc.org

23. Serious Recurrent Bacterial Infections:Treatment (2) • Treat HIV-infected children outside the neonatal period with empiric therapy until cultures are available (A III) • Use extended spectrum cephalosporin such as ceftriaxone or cefotaxime • Consider addition of azithromycin for hospitalized patients with pneumonia • Add clindamycin or vancomycin if MRSA is suspected www.aidsetc.org

24. Serious Recurrent Bacterial Infections:Treatment Failure • Consider bacterial resistance if treatment failure occurs • Consider nonbacterial cause such as TB, PCP, meningitis (Cryptococcus or TB) • Look for catheter-related infections • Occult abscess www.aidsetc.org

25. Bartonellosis: Epidemiology • Bartonella henselae and Bartonella quintana are primary species causing bacillary angiomatosis and peliosis • Bartonella bacteremia also occurs in HIV-infected individuals but is relatively uncommon in HIV-infected children • Bartonella henselae is associated with cat scratch disease in the general population www.aidsetc.org

26. Bartonellosis: Epidemiology (2) • Household cat is the primary vector • Eradication of flea infestation may be important in preventing infection, as contamination of cat claws is a possible mechanism of human infection • 90% of patients with cat scratch disease have a history of recent contact with cats • The vector for Bartonella quintana is the human body louse www.aidsetc.org

27. Bartonellosis: Clinical Manifestations • Clinical manifestations determined by host response • Localized disease consisting of suppurative regional lymphadenopathy is most common in patients with an intact immune system • Systemic infection is more common among immunocompromised individuals www.aidsetc.org

28. Bartonellosis: Clinical Manifestations – Bacillary angiomatosis • Rare disorder occurring in severely immunocompromised individuals • Characterized by cutaneous and subcutaneous angiomatous papules • Can be confused with Kaposi sarcoma • Nodules may be observed in the subcutaneous tissue and can erode to the skin www.aidsetc.org

29. Bartonellosis: Clinical Manifestations – Bacillary peliosis • Characterized by angiomatous masses in the visceral organs • The liver is most frequently infected • Individuals with bacillary peliosis and bacillary angiomatosis may have relapsing fevers • Dissemination can result in osteomyelitis, endocarditis, encephalopathy, seizures, neuroretinitis, and transverse myelitis • Nonspecific symptoms include fever, chills, night sweats, anorexia, weight loss, abdominal pain, vomiting, and diarrhea www.aidsetc.org

30. Bartonellosis: Diagnosis • Diagnosis usually made by means of a biopsy with demonstration of small gram-negative bacilli • Isolated with difficulty from blood and tissue culture • Indirect fluorescent antibody and enzyme immunoassay tests are available at some laboratories • Cross-reactivity among Bartonella species and other bacteria is common • PCR is the most sensitive means of diagnosis www.aidsetc.org

31. Bartonellosis: Prevention • Reduce exposure to cats and cat fleas • Treat infestations of body lice • Consider risk of ownership of cats, especially for individuals who are severely immunocompromised www.aidsetc.org

32. Bartonellosis: Treatment • Treatment of cat scratch disease in immunocompetent individuals is mainly supportive • In vitro and in vivo antibiotic susceptibilities do not correlate well with efficacy • Drug of choice is erythromycin or doxycycline • Clarithromycin and azithromycin treatment has been associated with clinical responses www.aidsetc.org

33. Bartonellosis: Treatment (2) • Severe disease requires IV administration • Treatment should be given for 3 months for bacillary angiomatosis and 4 months for bacillary peliosis central nervous system disease, osteomyelitis and other severe systemic infections • Add rifampin to either erythromycin or doxycycline for severely infected immunocompromised individuals www.aidsetc.org

34. Bartonellosis: Treatment Failure • Immunocompromised individuals who experience treatment failure should be re-treated for 4-6 months • Immunocompromised HIV-infected adults who experience relapse have been treated with long-term suppression with doxycycline or a macrolide when CD4 counts are <200 cells/µL • There are no data for children www.aidsetc.org

35. Syphilis: Epidemiology • Perinatal transmission of Treponema pallidum at any stage of pregnancy or during delivery • Illicit drug use during pregnancy increases risk of maternal and congenital syphilis • Rate of congenital syphilis 50 times greater among infants born to HIV-infected mothers • Half of new infections are in women 15-24 years of age www.aidsetc.org

36. Syphilis: Clinical Manifestations • Untreated early syphilis in pregnancy leads to spontaneous abortion, stillbirth, hydrops, preterm delivery, death in up to 40% of pregnancies • 47% of infants born to mothers with inadequately treated syphilis have clinical, radiographic, or laboratory findings consistent with congenital syphilis www.aidsetc.org

37. Syphilis: Clinical Manifestations (2) • 60% of infants with congenital syphilis have hepatomegaly, jaundice, skin rash, nasal discharge, anemia, thrombocytopenia, osteitis, periostitis, osteochondritis, or pseudoparalysis • Late manifestations include mental retardation, keratitis, deafness, frontal bossing, Hutchinson teeth, saddle nose, Clutton joints www.aidsetc.org

38. Syphilis: Diagnosis • Use combination of physical, radiologic, serologic, and direct microscopic results, as standard serologic tests detect only IgG • All infants born to mothers with reactive nontreponemal and treponemal tests should be evaluated with a quantitative nontreponemal test (eg, slide test, RPR, automated reagin test) www.aidsetc.org

39. Syphilis: Diagnosis (2) • Darkfield microscopy or direct fluorescent antibody staining • Presumptive diagnosis – any infant, regardless of physical findings, born to an untreated or inadequately treated mother with syphilis www.aidsetc.org

40. Syphilis: Prevention – Congenital Syphilis • Routinely screen all pregnant women with serologic testing during first prenatal visit • Obtain information regarding the treatment of sexual partners for sexually transmitted diseases • Serologic testing of mothers serum is preferable • Routine screening of newborns’ serum or umbilical cord blood is not recommended www.aidsetc.org

41. Syphilis: Prevention – Acquired Syphilis • Routine discussion of sexual behaviors that place individuals at risk of syphilis and HIV • Routine serologic screening for syphilis annually for all sexually active HIV-infected individuals • The occurrence of syphilis in an HIV infected individual is an indication of high-risk behavior • Individuals undergoing screening or treatment for syphilis should be evaluated for all sexually transmitted diseases www.aidsetc.org

42. Syphilis: Treatment – Congenital Syphilis • Treat all infants whose mothers have untreated or inadequately treated syphilis; not treated or initiated treatment 4 weeks prior to delivery • Treat if mother treated with penicillin but no 4-fold decrease in nontreponemal antibody titer, or a 4-fold increase suggesting relapse or reinfection • Treat infants regardless of maternal history if examination suggests syphilis; darkfield or fluorescent antibody test positive or nontreponemal serologic titer = 4-fold higher than maternal level (A II) www.aidsetc.org

43. Syphilis: Treatment – Congenital Syphilis (2) • Aqueous crystalline penicillin G: 100,000-150,000 units/kg/day given as 50,000 units/kg/dose IV Q12H for 7 days, followed by Q8H for a total of 10 days (A II) • Diagnosis after 1 month of age, increase dosage to 50,000 units/kg IV Q6H for 10 days www.aidsetc.org

44. Syphilis: Treatment – Acquired Syphilis • Treat acquired syphilis with single dose of benzathine penicillin G 50,000 units/kg IM • Treat late latent disease with benzathine penicillin G 50,000 units/kg IM once weekly for 3 doses (A III) • Alternative therapies among HIV-infected patients have not been evaluated • Treat neurosyphilis with aqueous penicillin G 200,000 to 300,000 units/kg IV Q6H for 10-14 days • Follow up with examinations at 1, 2, 3, 6, and 12 months and serologic tests at 3, 6, and 12 months; if titers continue to be positive or increase, consider retreatment (A III) www.aidsetc.org

45. Mycobacterium tuberculosis:Epidemiology • 14,000 new cases of TB in United States in 2006 (6% among children <15 years of age) • 1.1% of these were HIV infected • Incidence of TB in HIV-infected children 100 times higher than in uninfected • In South Africa, as many as 48% of children with TB were coinfected with HIV www.aidsetc.org

46. Mycobacterium tuberculosis: Epidemiology (2) • CD4 count is not a sufficient indicator of TB risk • Primarily infection by contact with adults in daily environment • In most cases, TB represents the progression of primary infection rather than a reactivation of disease • All confirmed and suspected TB cases should be reported to health authorities www.aidsetc.org

47. Mycobacterium tuberculosis: Epidemiology (3) • BCG induced M tuberculosis has been reported in HIV-infected children vaccinated at birth • In the United States, resistance to any of the first-line anti-TB drugs occurs in 15% of children • Internationally, rate of multiple drug-resistant (MDR) TB is increasing www.aidsetc.org

48. Mycobacterium tuberculosis: Epidemiology (4) • Extrapulmonary and miliary TB more common in children <4 years old • Congenital TB has been reported • Drug-resistant TB can be transmitted • Patients should be treated under assumption that drug resistance profiles of source and patient are similar www.aidsetc.org

49. Mycobacterium tuberculosis:Clinical Manifestations • Younger children progress more rapidly (possibly due to delayed diagnosis) • Nonspecific symptoms: fever, weight loss, failure to thrive • Pulmonary TB most likely appears as infiltrate with hilar adenopathy • Clinical presentation of TB similar in HIV-infected and HIV-uninfected children • Extrapulmonary: marrow, lymph node, bone, pleura, pericardium, peritoneal www.aidsetc.org

50. Mycobacterium tuberculosis:Diagnosis • Difficult to diagnose; maintain a degree of suspicion • M tuberculosis detected in up to 50% of gastric aspirate in HIV-uninfected children (obtain 3 consecutive morning gastric aspirates) • Usually requires linking TB in child to contact along with positive radiograph, positive skin test (TST), or physical examination www.aidsetc.org