Epidemiology
1. The UN estimates 34.3 million people infected worldwide
 2. 1.3 million of these are children < 15 years of age
3. In the U.S., there has been a stabilization of incidence:  40,000 new cases per year
4. Half of all new cases are estimated to occur in persons younger than 25 y.o. via sexual contact
5. 2% of infections occur in children --90% are vertically transmitted (perinatal > breastfeeding)
6.120,000-160,000 HIV infected women leading to 6000-7000 deliveries of HIV exposed infants each year
 

Changing Demographics
1. Becoming a disease of minority populations
2. New cases predominantly from IVDA and heterosexual contact
3. Increasing number of cases in women:  up from 7% in 1985 to 23% in 1998
4. Decreasing number of cases in children:  down 66% in 1998 from 1993
5.However, adolescents are thought to be a major new high-risk group & infection rates here may well be underestimated
 

Natural History
   Children
    Three distinct patterns of progression
      a. Rapid Progressors:  15-25%.  Onset of sx within first mos. of life and median survival of 6-9 mos.
      b. Long term non-progressors:  represents < 5% of cases.  Minimal progression of disease with low viral loads
      c.The remainder (60-80%) have a median survival of 6 yrs.  Typically have low viral burden at birth, followed by a increase to high levels (>100,000) by 2-3 mos. of age, with a slow decline over 24 mos.

As compared to adults, children tend to have a more rapid course with a higher incidence of HIV encephalopathy, and complications with primary infection, as opposed to reactivation, of opportunisitic infections
 

Natural History
   Adults / Adolescents
      a. Acute seroconversion syndrome
      b. Slow decline of CD4+ T-cells of 50-75/yr
       c. Median time from infection to onset of clinical AIDS is 8-10 yrs. Around 20% progress to AIDS in <5 yrs. and <5% are asymptomatic for 10+ yrs. (long term non-progressors)
 

Clinical Manifestations
     Acute Retroviral Syndrome
        a. Occurs 2-4 weeks after exposure
        b. Presenting features (protean)
        c. Classically, an infectious mono-like syndrome (<20%)
        d. Opportunistic infections occur uncommonly
                 1. Pneumocystis pneumonia
                 2. Candidiasis
                 3. CMV
                 4. TB
       e.Symptoms usually resolve in 7-10 days
       f.  Lab abnormalities (transient)
                1. lymphopenia
                2. Anemia
                3.Thrombocytopenia
                4.+/- increased CRP/ESR
                5. Possible elevation of transaminases
       g.  Differential Dx is very broad
                 1. Mononucleosis (EBV or CMV)
                 2. Toxoplasmosis
                 3. Syphilis
                 4. Disseminated gonococcal infection
                 5. Other viral syndromes

        h. The key to diagnosis is suspecting it
        i. Diagnosis
                1.Serologic conversion 1-3 weeks after onset of symptoms (ELISA/Western)
                 2.Earlier detection available with:
                 3.HIV RNA PCR (of these, the most readily available & in adults/adolescents, not likely to have a false negative because of the high viral loads associated with the acute infection)
                 4. HIV-1 p24 antigen
                 5. HIV DNA PCR
                 6. In children, difficult to know occurrence of seroconversion syndrome, as most cases are perinatally acquired
                 7. Most infants are asymptomatic at birth
 

HIV Staging
      Pediatric
         a. A two-part system including clinical symptoms and immunologic markers
              Clinical categories:
                   1.Category N:  not symptomatic
                   2.Category A:  mildly symptomatic
                   3. Category B:  moderately symptomatic
                   4. Category C:  severely symptomatic

              Immunologic categories:
                   1. Based on age-specific CD4+ cell count & CD4+ % (of all T-cells)
                    2. 3 levels (1, 2, and 3)

Clinical Manifestations
      1. Pediatric -Clinical category A
            a. Not generally subject to opportunistic infections
            b.mildly symptomatic
            c. Defined as 2 or more of the following without meeting criteria for category B or C
                   1.Lymphadenopathy
                   2. Hepatomegaly
                   3. Splenomegaly
                   4.Dermatitis
                   5 Parotitis
                   6. Primarily seen in pediatric HIV
                   7. Usually painless
                   8. If pain/fever occur, secondary infection must be condsidered
                   9. Need to consider lymphoma in the diff dx of enlarging lesions
                  10. Recurrent/persistent URI's, sinusitis, or otitis media
 
 

      2. Pediatric-Clinical Category B
                  a.Moderately symptomatic
                  b.Defined as  the presence of any of the following:
                          1. Anemia, neutropenia, or thrombocytopenia >30 days
                           2.  ITP is relatively common
                 c. Single episode of bacterial meningitis, pneumonia, or sepsis
                 d.Thrush lasting > 2 months in a child >6 m/o
                 e. Cardiomyopathy - typically a dilated cardiomyopathy, though other lesions are seen
 sinus tachycardia
                 f. Clinical CMV infection prior to 1 month of age
                 g. Recurrent/chronic diarrhea
                 h. Hepatitis
                 i. Recurrent HSV stomatitis (>2 episodes/yr.)
                 j. HSV bronchitis, pneumonitis, or esophagitis occurring prior to 1 month of age
                 k. Shingles occurring more than once or involving more than one dermatome
                  l. Leiomyosarcoma
                  m. Lymphoid interstitial pneumonitis (LIP)
                         1.  Primarily a disease of children with HIV
                          2. Chronic process (years) with slow onset of tachypnea, cough, and hypoxia
                          3. Physical exam findings can be minimal
                          4. Diffuse interstitial infiltrate without LAD on CXR
                          5. Diagnosis usually made presumptivel
                  n. HIV nephropathy
                  o. Nocardiosis
                  p.  Fever > 1 month
                  q. Toxoplasmosis prior to the age of 1 month
                  r. Disseminated VZV infection

       3. Pediatric:  Clinical Category C
                  a. Severely immunocompromised
                  b. Defined as the occurrence of any of:
                            1. 2 or more episodes (within 2 yrs.) of bacterial sepsis, pneumonia, meningitis, septic arthritis, osteomyelitis, visceral abscess
                            2. Esophageal or pulmonary Candidiasis
                            3.  Disseminated Coccidioidomycosis
                            4. Extrapulmonary Cryptococcosis
                            5. Disseminated histoplasmosis
                            6. Clinical CMV infection after age 1 month
                            7. HIV encephalopath
                                        a. Developmental delay or loss of milestones
                                        b. Impaired brain growth/acquired microcephaly
                                        c. Acquired symmetric motor deficit
                                        d. Consider infections (e.g., Cryptococcus, Toxoplasma, Mycobacterial infections, CMV, HSV, VZV, and neurosyphilis) and neoplasms in the diff dx
                             8.HSV bronchitis/pneumonitis, or esophagitis OR mucocutaneous ulcer lasting > 1 month in a child over 1 month of age
                             9. Diarrhea > 1 month secondary to Cryptosporidium or Isospora
                           10.Kaposi's sarcoma (exceedingly rare in children)
                           11. CNS lymphoma
                           12. Non-Hodgkin Lymphoma (typically EBV-associated)
                           13. Disseminated tuberculosis
                            14.Pneumocystis carinii pneumonia
                            15. Progressive multifocal leukoencephalopathy
                            16. Recurrent Salmonella bacteremia
                            17. CNS Toxoplasmosis after 1 month of age
                             18. FTT/wasting syndrome associated with chronic diarrhea or FUO

 It is important to remember that children with perinatal infection can reach this stage of disease very quickly (as early as 1 month of age)
 The possibility of drug therapy side effects needs to be considered in the differential of many of these complaints
 

Diagnosis of HIV

 1. ELISA is the initial test, with a confirmatory Western blot
 2.Viral load (RNA PCR) is not recommended as a diagnostic test because of the possibility of false negatives
 3. CD4+ counts are not diagnostic because they can be decreased in a number of illnesses
 4. Infants < 18 mos.:
         a. HIV DNA PCR is the preferred diagnostic test
         b. From age 1-36 mos.:  sens 95% / spec 97%
          c. Only 30% will be positive at <48 hours of age
 5. Schedule of testing in perinatal HIV exposure
          a. Initial test:  within 48 hrs. of life
          b. 2nd test:  1-2 mos. of age
          c. 3rd test:  3-6 mos. of age
          d. Any positive test should be confirmed as soon as possible
          e. Two positive HIV DNA PCR's are diagnostic of infection
          f. The child is not infected if:
                     1. 2 negative PCR's are obtained, at or after 1 month of age and 1 was done after age 4 mos.
                      2. 2 negative HIV serologic tests after 6 mos. of  age
          g. Most would recommend confirming HIV status in a patient with a report of HIV positivity and no documentation
 

Initial Studies - Children
   1. HIV-exposed infant
         a. Establish diagnosis as noted above
         b. CBC at 2 wks and 6 wks, as will be on AZT
    2. HIV-positive child
         a. Baseline serologies for HIV, Toxoplasma, CMV, EBV, VZV, HSV, hepatitis B and C, and Rubella
         b. CMV, EBV, and Toxo should be repeated annually if negative
         c. CBC, CD4+ count, viral load, CMP, pancreatic enzymes, QUIGs, UA
         d. As in adults, the CD4+ count and viral load should be repeated Q3 months
         e. CBC, hepatic function, and pancreatic enzymes are also repeated quarterly
         f. Baseline Head CT
         g. Baseline CXR - repeated annually
         h. PPD - should be repeated yearly in endemic areas
         i.  Ophthalmologic exam - annual until immune category 3, then Q6 months
         j. Pap smear when age-appropriate
         k. Dental evaluation

Immunizations
1.  DTaP, IPV, HiB, and Hepatitis B as in all children
2. Pneumococcal vaccination
         a. Children <24 mos. old should be immunized as all children with the heptavalent vaccine
         b.  In addition, the 23 valent vaccine shuld be given at 2 yrs of age & repeated in 3-5 years
3.  MMR
         a. administered at 12 mos. unless in immune category 3 -- these children should not receive the MMR
         b. Booster dose may be given as soon as 4 weeks after the first dose
4. Varicella vaccination is given only to children classified as N1 or A1
5.  Influenza annually -- children <9 y/o need 2 doses with the initial vaccination
 

Nutritional Issues
1.  In both adults and children, malnutrition is a major clinical concern
2. Etiologies are multifactorial:  poor intake, diarrhea, increased metabolic rate, AIDS-related wasting, etc.
3.  In children, growth delay and overt failure to thrive is common
4.  Nutritional supplementation with multivitamins is a common practice
5.  Appetite stimulation with medications such as Megace is common
6. Testosterone can be tried empirically in adult males
7.  Recombinant human GH is approved for treatment of HIV-associated wasting in adults
8.  Nasogastric feedings or Gastrostomy-tube feedings may become necessary

Opportunistic Infection Prophylaxis - Children
1.  Pneumocystis carinii- Indications
          a. Gestational exposure -- begin at 4-6 wks of age and continue until definitively HIV-negative or 1 year of age (if not otherwise indicated)
          b. Immunologic category 3 at any age
          c. Medication:
                  1. TMP-SMX 150/750 mg/m2/d  BID 3x/wk on consecutive days
                  2.  BID or alternate day regimens also acceptable
                  3. Alternative regimens (dapsone/atavaquone...)available for pts. not able to tolerate bactrim
2.  Tuberculosis
     a. PPD > 5mm
     b. Contact with known case of active TB
      c. Medications
                1. INH 10-15 mg/kg QD x 9 mos. or 20-30 mg/kg 2x/week x 9 mos.
                 2.  Rifampin may be used as an alternative if indicated
3. Disseminated Mycobacterium avium complex
     a.  Indications
                  1. Age <1 yr:  CD4 < 750
                  2. Age 1-2 yrs:  CD4 < 500
                 3.  Age 2-6 yrs:  CD4 < 75
                  4. Age 6+ yrs:  CD4 < 50
      b. Medications
                  1. Clarithromycin 7.5 mg/kg BID or Azithromycin 20 mg/kg Q Weekly
                  2. Alternative regimes available, but more complex
4. Toxoplasma gondii
     a.Indications-Immunologic class 3 and seropositive
     b.Medications
                   1. TMP-SMZ 150/750 mg/m2/d divided BID
                    2. Dapsone plus pyrimethamine is the second choice and others are available

Antiretroviral Therapy
1. Indications for Treatment
                 a. In both adults and children, the patient / family need to be ready to be COMPLIANT!!!
                 d.  Children
                       1.  Symptomatic HIV infection, OR
                        2. Immune category 2 or 3, OR
                        3. Age < 12 mos., regardless of category
                        4. Asymptomatic children D 1 year of age:
                        5.Initiate Therapy in all patients (preferred)
                        6. Defer therapy until symptoms develop IF immune status normal and viral load <10,000
2. General Principles
           a. Multiple drugs are required - three is the standard starting number now
           b. The goal of therapy is suppression of viral load to undetectable levels
           c. A single log reduction (10x) should be seen at 4 weeks
           d. In children with very high viral loads (>100,000), virologic response may not be seen until 8-12 weeks
           e. Maximal suppression is achieved by 4-6 mos.
           f. Not all patients will achieve undetectable viral loads & whether to change therapies at this point is subjective
           g. There are a myriad of drug interactions that must be considered
           h. Most antiretrovirals have many side effects, some potentially severe
           i. Compliance is absolutely essential to avoid development of resistance

Prevention of Perinatal Transmission
1.  Principles
      a. PACTG 076 showed a decrease in transmission from 22.6% to 7.6% with a 3-part ZDV regimen:
      b. Maternal ZDV monotherapy initiated at 14-34 wks GA
      c. ZDV administered IV during labor
      d.Postpartum admin of ZDV to the neonate x 6 wks
2. Permutations of this regimen have led to multiple variations & options of treatment depending on the clinical circumstance
3. Changes in standard of care for adults have led to different maternal regimens
4. Delaying therapy during the 1st trimester is acceptable
5.  Recommendations
      a. Pregnant women without prior treatment:  should be offered standard triple-therapy including ZDV
      b. Women already on appropriate therapy:  continuation of current tx with either substitution of a current NRTI with ZDV or addition of ZDV as another drug
      c. Presentation in labor without prior therapy:
            1. Nevirapine as a single dose for the mother followed by a single dose for the child at age 48 hrs.
             2. ZCV and 3TC during labor and 1 wk of ZDV/3TC for the child
             3. intrapartum ZDV followed by 6 wks of ZDV for the child
             4 Nevirapine regimen + the ZDV regimen
6. Infants born without peripartum prophylaxis:  ZDV regimen x 6 wks
7.  C-section is recommended (elective, prior to onset of labor) for patients with a viral load >1000 (some controversy)
8. The recommended therapy for neonates prior to confirmation of HIV status is the 6 week ZDV regimen -- however, some would treat with a combination regimen
9.Breastfeeding is contraindicated in the US