HIV in Children and Adolescents

Epidemiology

  • The CDC estimates that 1 million people are living with HIV in the U.S. 
  • Approximately 68,000 young people (ages 13-24 years) in the United States were living with an HIV infection in 2008. Of these, nearly 60% did not know they were infected. In 2009, an estimated 8,300 young people (ages 13-24 years) were newly diagnosed with HIV. 
  • Overall, rates of HIV diagnosis in the U.S. stabilized between 2006-2009. However, HIV diagnosis rates increased for teens and young adults during the same period. Half of all new cases are estimated to occur in persons younger than 25 years old via sexual contact.
  • Perinatal HIV transmission from mother-to-child is the most common route of HIV infection in children <13 years old. Since the mid-1990s, HIV testing and preventative actions have reduced perinatal transmission in the U.S. by more than 90%.
  • In 2010, an estimated 217 children younger than 13 years old were newly diagnosed with HIV in the U.S. It is estimated that approximately 11,000 children under the age of 13 were living with HIV in the U.S. in 2009. Of these, 88% acquired HIV via perinatal transmission. 
  • HIV/AIDS infection rates are disproportionately high among black and Hispanic patients. 

Pathogenesis

  • The HIV virus infects CD4+ lymphocytes, which are essential to the body's immune response to most pathogenic invaders.
  • The virus infects CD4+ cells (lymphocytes, monoctyes and macrophages). It lays latent within the host genome until it is activated by antigens or pathogens. Then, the viral genome replicates. The cell ruptures, and virions exit the cell.
  • Virions infect more CD4+ T-cells, and the process continues. 
  • Measurement of the cell-free virus in the plasma (HIV RNA viral load) is reflective of the total body viral burden. 

Initial Presentation
Infants and Young Children 
- Infants can present during the first few months of life, but many are asymptomatic at birth. 
- Infants have immature immune systems, so they are more likely to suffer from opportunistic infections early on in their illness. Infants often present with PCP pneumonia, lymphoid interstitial pneumonitis, recurrent bacterial infections, failure to thrive, HIV encephalopathy, and refractory thrush or diaper rash. 

Children and Teens (Ages 6-21 years) 
- Older children and teens may present in later years, once their immunity has began to wane. Common presenting signs and symptoms include: candida pneumonia, esophagitis, or vaginitis; varicella zoster; CMV retinitis; HIV wasting; MAC; cryptosporidiosis; severe herpes simplex recurrences; and parotitis
- Teens may also present shortly after infection with an acute retroviral syndrome (30-70% of teens patients may present with this syndrome):

  • Occurs 2-6 weeks after exposure
  • Presenting features: Classically, this is characterized as an infectious mono-like syndrome (fever, sore throat, LAD, malaise, anorexia, rash, myalgias, and fatigue). Symptoms usually resolve in 7-10 days. 
  • The differential diagnosis for patients with an acute retroviral syndrome is quite broad, including: mononucleosis (EBV or CMV), toxoplasmosis, syphilis, disseminated gonococcal infection, and other viral syndromes.
  • The key to diagnosing AIDS in these patients is to suspect it and test for it. A full HEADS assessment is helpful in identifying teens who are at-risk. 

HIV Staging for Pediatric Patients (less than 13 years old)

  • Pediatric HIV is staged using a two-part system that assesses clinical symptoms and immunologic markers
  • Clinical categories
  1. Category N: asymptomatic
  2. Category A: mildly symptomatic
  3. Category B: moderately symptomatic
  4. Category C: severely symptomatic
  • Immunologic categories:
    - Based on age-specific CD4+ cell count and CD4+ percentage (of all T-cells)
    - Three levels:
         - Category 1: no immune suppression
         - Category 2: moderate suppression
         - Category 3: severe suppression

Clinical Manifestations

  • Pediatric Clinical Category A ( asymptomatic)
    - Category A patients do not have symptoms
    - Chronic LAD is often present
  • Pediatric Clinical Category B (moderately symptomatic)
    -Category B is defined as  the presence of any of the following:
         - Moderate unexplained weight loss (<10% of body weight) 
         - Papular itchy skin eruptions
         - Extensive molluscum contagiosum 
         - Recurrent oral ulcerationss
         - Unexplained persistent parotid gland enlargement
         - Linear gingival erythema
         - Herpes zoster
         - Recurrent or chronic respiratory tract infections (sinusitis, otorrhoea,    
         tonsillitis, otitis media)
         - Fungal nail infections
  • Pediatric Clinical Category C (severely immunocompromised)
    -Category C is defined as the presence of any of the following: 
         - Unexplained severe weight loss (>10% of body weight) 
         - Unexplained persistent diarrhea for longer than 14 days
         - Unexplained persistent fever above 37.5 (intermittent or constant for
         more than one month)
         - Persistent oral candida (in patients > than 6-8 weeks old)
         - Oral hairy leukoplakia
         - Acute necrotizing ulcerative gingivitis or periodontitis
         - TB lymphadenopathy or pulmonary tuberculosis
         - Severe bacterial infections (pneumonia, empyema, pyomyositis, bone
         or joint infection, bactemia, or meningitis)
         - Symptomatic lymphoid interstitial pneumonitis (LIP)
         - Unexplained anaemia (<8g/dl), neutropenia (<500/mm3) or  
          thrombocytopenia (<50,000/mm3)
    - It is important to remember that children with perinatal infections can qualify for clinical category C very early on (as early as 1 month of age).
    - The possibility of drug therapy side effects should be considered in the differential of many of these complaints
  • Pediatric Clinical Category D (severely symptomatic)
    -Category D is defined as the presence of any of the following:
         - Unexplained severe wasting, stunting, or severe malnutrition not
         responding to treatment
         - Pneumocystis carinii (jeroveci) pneumonia
         - Recurrent severe bacterial pneumonia
         - Toxoplasmosis of the brain
         - Cryptosporidiosis with diarrhea for longer than 1 month
         - Isosporiasis with diarrhea > 1 month
         - Extrapulmonary cryptococcosis
         - Cytomegalovirus of an organ other than liver, spleen or lymph node
         - Chronic herpes simplex infection (lesions present for >1 month)
         - Progressive multifocal leukoencephalopathy
         - Candidiasis of the esophagus, trachea and bronchus
         - Atypical mycobacteriosis, disseminated
         - Extrapulmonary tuberculosis excluding TB lymphadenopathy
         - Lymphoma (cerebral or B cell non-Hodgkin)
         - Recurrent salmonella bacteremia
         - Kaposi’s sarcoma
         - HIV encephalopathy:HIV encephalopathy may present as
         developmental delay, symmetric motor deficits, or loss of milestones.
         Children suffer from impaired brain growth and acquired microcephaly. 
         - Symptomatic HIV-associated cardiomyopathy or HIV-associated
         nephropathy

Diagnosis of HIV

  •  Infants: Infants born to HIV+ mothers will have positive antibody tests (ELISA or Western blot), reflecting placental transfer of IgG from mom.  The presence of these antibodies may persist for 18 months after birth. As a result, the preferred tests for infants of seropositive mothers are virus-specific (HIV DNA PCR, HIV culture, HIV RNA PCR, or HIV p24 antigen). HIV DNA PCR is the test that is most often used. 
    -The schedule for testing an infant of an HIV+ mother is as follows: 
         - Initial test: within 48 hrs. of life
         - 2nd test:  1-2 mos. of age
         - 3rd test:  3-6 mos. of age
    -Two positive HIV DNA PCR's are diagnostic of infection. All positive tests should be confirmed with a second test.
    -The child is not infected if:
         - Two negative PCRs are obtained, one at or after 1 month of age and 
         another after 4 months of age
         - Negative HIV serologic tests after 6 months of age
  • For all other children and teens with suspected HIV, the HIV ELISA is the initial test, with a confirmatory Western blot

Initial Studies for Children

  • HIV-exposed infantz
    - Establish diagnosis as noted above
    - Check a CBC at 2 weeks and 6 weeks of age, as the child will be on AZT
  • HIV-positive child/teen
    - Baseline serologies for HIV, Toxoplasma, CMV, EBV, VZV, HSV, hepatitis B and C, and Rubella
    - CMV, EBV, and Toxoplasma should be repeated annually if negative
    - CBC, CD4+ count, viral load, CMP, pancreatic enzymes, QUIGs, UA
    - As in adults, the CD4+ count and viral load should be repeated every three months. CBC, hepatic function, and pancreatic enzymes are also repeated on a quarterly basis. 
    -Baseline Head CT
    -Baseline CXR: repeated annually
    - PPD: should be repeated annually in endemic areas
    - Ophthalmologic exam: annually until immune category 3, then every six months
    - Pap smear when age-appropriate
    - Dental evaluation

Immunizations

  • DTaP, IPV, HiB, and Hepatitis B as in all children
  • Pneumococcal vaccination
    - Children <24 months old should be immunized the same as all children 
    - In addition, the 23 valent vaccine shuld be given at 2 years of age and then repeated in 3-5 years
  • MMR
    -Administered at 12 months of age unless in immune category 3 -- these children should not receive the MMR
    - A booster dose may be given as soon as 4 weeks after the first dose
  • The varicella vaccination is only given to children classified as N1 or A1
  • Influenza vaccination should be given annually. Children <9 years old require 2 doses with the initial vaccination

Treatment

  • Combination anti-retroviral therapy (ART) is the mainstay of treatment. 
  • ART is recommended for all HIV-infected infants under 12 months of age regardless of their clinical status. 
  • ART is recommended for all infants and children with AIDS or significant symptoms (Clinical category C and some Clinical category B patients as well).
  • In other HIV-infected children, recommendations for starting ART therapy depend on the child's CD4+ count, CD4+ lymphocyte percentage, and clinical status. 
  • Initial treatment regimens include: combination therapy with a nucleoside/nucleotide reverse transcriptase inhibitor PLUS either a non-nucleoside reverse transcriptase inhibitor OR a protease inhibitor.  
  • The goal of therapy is to reduce plasma HIV RNA levels below what can be detected by the most sensitive assays and to normalize immune status.
  • ART resistance testing is recommended for all infants, children and teens beginning ART therapy.
  • Current treatment guidelines, with frequently updated and specific recommendations for therapy, can be found at www.aidsinfo.nih.gov/guidelines
  • Compliance to therapy is a huge issue for infants, children and teens with HIV. Compliance is incredibly important because of the possibilty of resistance, but can it can be very difficult for families to adhere properly to ART regimens. Discuss compliance issues early and often. 

Prophylaxis for Opportunistic Infections

  • Prevention of opportunistic infections is a mainstay of managment of HIV-infected patients. 
  • In general, prophylaxis against PCP, MAI, candida, HSV, cryptococcus, and invasive CMV begins when patients enter immune category 3, though these indications vary somewhat by disease. 
  • Infants under 12 months of age also require PCP prophylaxis. 
  • Brief descriptions of common OIs and treatment regimens used in children:
    - PCP: typically prevented with TMP-SMX or dapsone
    - Mycobacterium Avium Intracellulaire (MAI): clarithromycin or azithromycin
    - CMV: ganciclovir or valganciclovir
    - Candida: fluconazole 
    - HSV: acyclovir 
    - Cryptococcus: fluconazole 

Prevention of Perinatal Transmission

  • Preconception counseling is important for HIV+ women who are considering becoming pregnant. Issues that should be discussed include: options if the partner is serodiscordant; avoidance of drugs, alcohol, cigarettes, and other  risky behaviors; the possibility of initiation of ART prior to conception, and optimization of immune status prior to conception.
  • For women who become pregnant but are not on ART therapy, ART therapy can be started immediately or after the first 12 weeks. Initiation of therapy depends on the woman's CD4+ count, viral load and clinical status. 
  • Plasma HIV RNA levels and CD4+ lymphocyte counts should be monitored at initial visits and throughout the pregnancy, at least every 3 months. HIV RNA levels should be checked at 34-36 weeks gestation to inform decisions about the delivery.
  • For women with HIV RNA levels >400 copies/mL OR if their HIV RNA levels are unknown, IV zidovudine should be given near delivery (regardless of mode of delivery and antepartum regimens). 
  • Women with unknown HIV status who present in labor should be given rapid HIV testing. If the initial test is positive, a confirmatory test should be ordered. The mother should be started immediately on IV zidovudine, and the infant will need ART treatment. If the confirmatory test is negative, the drugs can be stopped. 
  • Scheduled c-section at 38 weeks reduces the risk of transmission during delivery for mothers with HIV RNA levels >1,000 or unknown HIV levels. 
  • It is unclear whether c-section delivery prevents transmission from mothers with HIV RNA levels <1,000 OR if the mother presents after ROM. Treatment of women who present after ROM should be individualized at the time of labor depending on the duration of their labor, HIV RNA levels, and current ART regimen. 
  • The following should be avoided unless absolutely necessary:
    - Artificial ROM
    - Fetal scalp electrodes
    - Operative delivery with forceps, vacuum or episiotomy 
  • Breastfeeding is not recommended for HIV-positive women in the U.S., even if the woman is on ART. 
  • All infants born to HIV-positive mothers should be started on zidovudine within 6-12 hours after birth. Treatment continues for six weeks. Infants born to women who did not receive ART during pregnancy require zidovudine for six weeks as well as three doses of nevirapine (at birth, 48 hours of life, and 96 hours after the second dose). 

Nutritional Issues

  • In both adults and children with HIV/AIDS, malnutrition is a major clinical concern. There are many contributing factors that make maintaining good nutrition difficult in these patients: poor intake, frequent diarrhea, increased basal metabolic rate, AIDS-related wasting, and frequent mouth sores/thrush.
  • In children, growth delay and overt failure to thrive is common.
  • Nutritional supplementation may be provided with multivitamins and nutritional drinks.
  • Appetite stimulation with medications such as Megace is common.
  • Nasogastric feedings or gastrostomy-tube feedings may become necessary.

Prognosis

  • Many HIV+ children now do well. Fewer children are progressing to AIDS-defining illnesses, and children who present with low CD4+ counts are able to recover their CD4+ counts and avoid further OIs. 
  • Adherence to medication regimens is the major barrier to successful long-term treatment of these patients.
  • Many children have the potential to live for many years, with their HIV/AIDS being managed as a chronic disease. 

References

  1. www.aidsinfo.nih.gov/guidelines
  2. Buchanan AL et al. Barriers to Medication Adherence in HIV-Infected Children and Youth Based on Self- and Caregiver Report. Pediatrics. 2012;129:e1244. 
  3. Burchett SK and Pizzo PA. HIV Infection in Infants, Children and Adolescents. Pediatrics in Review. 2003;24:186. 
  4. Cohen M, et al. Acute HIV-1 Infection. NEJM. May 19, 2011.
  5. Committee on Pediatric AIDS. Adolescents and HIV Infection: The Pediatrician's Role in Promoting Routine Testing. Pediatrics. 2011;128:1023. 
  6. Committee on Pediatric AIDS. HIV Testing and Prophylaxis to Prevent Mother-to-Child Transmission in the United States.  Pediatrics. 2008;122:1127. 
  7. Hammer SM. Management of Newly Diagnosed HIV Infection.  NEJM. Oct 20, 2005. 
  8. Huang L. et al. Intensive Care of Patients with HIV. NEJM. July 13, 2006. 

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