PEDIATRIC AIDS - A GENERATION CHALLENGED!
Dr.S.N. Mothi*, Dr.V.H.T. Swamy**
Department of Pediatrics.*, Department of Pediatrics.**
Introduction:

The wave of Pediatric AIDS has arrived and becoming increasingly visible. If we allow the HIV/AIDS epidemic to slowly but surely wipe away this very precious generation from the face of the earth, we are going to be sorry in the future. This will impact our nation, continent and the world at large. It will adversely affect the health statistics, the economic growth and above all the morale of nations. Are we doing enough to prevent all these effects of the global epidemic of HIV/AIDS, which is now predominantly affecting the developing world? Are we geared up to care for the children affected with this deadly virus?

Though children represented only 6% of all people infected with HIV/AIDS as of December 2005, they accounted for 18% of the 3.1 million AIDS deaths in 2005. And only 40,000 or 4% of the one million people now on antiretroviral treatment are children. This means that one in every six AIDS deaths each year is a child, yet children represent less than one of every twenty-five persons getting treatment in developing countries today.

The estimated number of children living with HIV/AIDS in India is 202,000 as per UNAIDS report published in July 2004. Half of HIV-positive children die undiagnosed before their 2nd birthday as they are not tested by nucleic acid tests which are expensive. To compound the problems, even among diagnosed children, very few have access to antiretroviral therapy (ART). Additionally, pediatric drug formulations cost ten times as much as adult formulations, and pediatric formulations are not widely available. The prices remain high as pharmaceutical companies do not perceive a market for children as huge as for adults.

Therefore, it is important for us to draw a Road Map to be followed for the prevention and management of Pediatric HIV in India. The main thrust areas include the newborn component of PPTCT; follow up of the HIV exposed baby in infancy, providing the HIV exposed babies with the right infant feeding choices, PCP prophylaxis and appropriate diagnosis of infected children. Once HIV infection is confirmed and for the older children, who have contracted HIV through other routes, the areas of importance include correct diagnosis, nutritional support, immunization, both routine and special vaccines, antiretroviral therapy, prevention and management of opportunistic infections (OIs), and last but not the least access to appropriate counseling services. We also need to focus on adolescents and HIV, especially with regard to primary prevention of HIV amongst the teens by providing them with the family life education including scientific and right messages on prevention of HIV.

Mode of HIV transmission in Children:
The reported cases of pediatric AIDS is doubling every year. The primary means through which HIV is acquired in children are:

  1. Perinatal transfer - The efficiency of transmission is 20-45 % by this route,
  2. However the transmission rate is higher in a symptomatic mother.
  3. Transmission of virus through contaminated blood or blood products particularly in infants with recurrent blood transfusions or blood products seen in hemophiliacs and Thalassemic children efficiency of transmission is 95%.
  4. Breast feeding [12 - 21%]
  5. Sexual abuse of children and high risk behavior in adolescents also contribute HIV infection among youth.

Clinical Picture in Pediatric AIDS:
A variety of signs and symptoms presenting in a child in whom HIV infection was not previously suspected should alert the clinician to the possibility of the disease. The presentations include recurrent bacterial infections, unrelenting fever, diarrhea, thrush, recurrent pneumonia, chronic parotitis, generalized lymphadenopathy,delay in development with failure to thrive and significant pruritic dermatomes. Mucocutaneous eruptions may be the first sign of HIV and may vary in presentation depending on Childs immune status. The age of presentation can be highly variable in high risk child who was previously unidentified. Children can be asymptomatic for many years, and the appearance of an opportunistic infection in a 10 year old child in whom AIDS is subsequently diagnosed is not rare. Children who acquire HIV by means of non vertical transmission may have an illness during the acute phase of the retroviral syndrome or they may present many years later with opportunistic or recurrent infections.
Opportunistic Infections:
  1. Pneumocystis carinii (PCP)
  2. Candida
  3. Mycobacterium Tuberculosis
  4. Recurrent Bacterial infections
  5. Mycobacterium avium complex
  6. Chronic or recurrent diarrhea (Cryptosporidium, Microsporidia, Isospora belli, Cyclospora)
  7. Herpes zoster and varicella zoster
  8. Herpes simplex
  9. Cytomegalovirus
  10. Cryptococcal meningitis
  11. Toxoplasmosis
  12. REGIONAL SPECIFIC OI: Penicilliosis

Revised WHO Staging:
Revised WHO Clinical Staging Of HIV/AIDS For Infants And Children With Confirmed HIV Infection (> 18 Months - HIV Ab Test Positive, <18 Months - Virologic Test Positive)
Primary HIV infection
Asymptomatic
Acute retroviral syndrome
Clinical Stage 1
Asymptomatic
Persistent generalized lymphadenopathy
Clinical Stage 2
Unexplained persistent hepatosplenomegaly
Papular pruritic eruptions
Extensive wart virus infection
Extensive molluscum contagiosum
Recurrent oral ulcerations
Unexplained persistent parotid enlargement
Lineal gingival erythema
Herpes zoster
Recurrent or chronic respiratory tract infections (otitis media, otorrhoea, sinusitis, tonsillitis )
Fungal nail infections
Clinical Stage 3
Moderate unexplained malnutrition not adequately responding to standard therapy
Unexplained persistent diarrhoea (14 days or more )
Unexplained persistent fever (above 37.5 intermittent or constant, for longer than one month)
Persistent oral candida (outside first 6- 8 weeks of life)
Oral hairy leukoplakia
Acute necrotizing ulcerative gingivitis/periodontitis
TB lymphadenitis
Pulmonary tuberculosis
Severe recurrent presumed bacterial pneumonia
Symptomatic lymphoid interstitial pneumonitis
Chronic HIV-associated lung disease including bronchiectasis
Unexplained anaemia (<8g/dl ), neutropenia (<500/mm 3) or chronic thrombocytopenia (<50 000/ mm 3)
HIV-associated cardiomyopathy or HIV-associated nephropathy
Clinical Stage 4
Unexplained severe wasting, stunting or severe malnutrition not responding to standard therapy
Pneumocystis pneumonia
Recurrent severe presumed bacterial infections (e.g. empyema, pyomyositis, bone or joint infection, meningitis, but excluding pneumonia)
Chronic herpes simplex infection; (orolabial or cutaneous of more than one month's duration or visceral at any site)
Extrapulmonary tuberculosis
Kaposi sarcoma
Oesophageal candidiasis (or candida of trachea, bronchi or lungs)
Central nervous system toxoplasmosis (outside the neonatal period)
HIV encephalopathy
Cytomegalovirus (CMV) infection; retinitis or CMV infection affecting another organ, with onset at age over 1 month
Extrapulmonary cryptococcosis including meningitis
Disseminated endemic mycosis (extrapulmonary histoplasmosis, coccidiomycosis, penicilliosis)
Chronic Cryptosporidiosis
Chronic Isosporiasis
Disseminated non-tuberculous mycobacteria infection
Acquired HIV-associated rectal fistula
Cerebral or B cell non-Hodgkin lymphoma
Progressive multifocal leukoencephalopathy

Diagnosis:
Persistence of maternal antibodies until 15-18 months of age will render the report of ELISA for HIV antibodies irrelevant for early diagnosis. HIV DNA -PCR is reliable and has >95% sensitivity after 12 weeks of age but this test is quite expensive.

Treatment:
CLINICAL AND IMMUNOLOGICAL CRITERIA FOR INITIATING ART IN INFANTS AND CHILDREN:


Clinical Criteria:

WHO stage I &II

Do not unless CD4 suggest severe immune suppression

WHO stage III & IV

Treat all (Irrespective of CD4)



CD4 criteria
CD4 criteria of severe HIV Immunodeficiency

Immunological marker a

Age-specific recommendation to initiate ART b

=11 months

12 months-

35 months

36 months-

59 months

=5 years

CD4 % c

< 25%

< 20%

< 15%

< 15%

CD4 count c

< 1500 cells/mm 3

< 750 cells/mm 3

< 350 cells/mm 3

< 200 cells/mm 3

Notes:
  • Immunological markers supplement clinical assessment and should therefore be used in combination with clinical staging; ideally, CD4 is measured after stabilization of acute presenting conditions.
  • ART should be initiated by these cut-off levels, regardless of clinical stage; a drop of CD4 below these levels significantly increases the risk of disease progression and mortality.
  • % CD4 is preferred for children <5 years of age.


Management of Pediatric HIV/AIDS:
  • HIV infected children will be evaluated using history, review of records, physical examination and laboratory tools for their suitability to commence ART.
  • Children would be classified into various categories depending upon the revised WHO clinical grading for HIV infected infants and children.
  • Immune status would be categorized on the basis of WHO classification of immunodeficiency associated with HIV infection in infants and children.
  • The caregiver would be counseled regarding importance of adherence, possible side effects of the drugs and steps to be taken and would be provided linkages with community based organizations for adherence support
  • ART would be initiated as per revised WHO clinical staging and immunologic categories in infants and children (revised Feb 2006) [mentioned in detail in the complete document]
  • The detailed guidelines for initiating therapy would include the clinical criteria along with CD4% and/or counts. All children in WHO stage 4 would be started on ART irrespective of CD4 counts. Stage 3 warrants treatment for all infants and children, however, in children with TB, LIP, thrombocytopenia and OHL, treatment has to be CD4 guided (discussed in the complete document).
  • The primary regimen would consist of three drugs, which would include 2 NRTIs and 1 NNRTI. The NRTIs include AZT or d4T + 3TC + NVP or EFV. EFV would be used preferably only in those co-infected with TB.
  • Pediatric formulations of fixed dose combinations (FDC) are preferred. However, in the absence of availability of FDC, other alternatives that can be used include:
  • Single drug pediatric formulations
  • Preferably scored adult FDC tablets cut with the pill cutter (only into halves)


Change in therapy could be warranted under the following counts:
A)Toxicity to an individual drug in the combination:
B)Failure of treatment: If there is evidence of clinical, immunologic or virologic failure , a second line regimen would be initiated as per the guidelines by WHO.
  • The drugs that would be used for second-line treatment for failure of first line drugs would include change of NRTI and NNRTI to a different combination and addition of a PI (Protease Inhibitor)
  • Monitoring for treatment efficacy, monitoring adverse events, adherence and drug-drug interaction should be undertaken. Clinical and laboratory tools should be used for this purpose.


For Adverse Events:
a) Clinical Monitoring: Skin rashes, fever, signs of infections s/o neutropenia, pallor, symptoms and signs of peripheral neuropathy, lactic acidosis, pancreatitis etc.
b)Laboratory Monitoring: Hemoglobin, hematocrit, total WBC count, differential count, AST, BUN, creatinine, glucose and any other clinically indicated tests (e.g. ABG, serum lactate/ pyruvate for lactic acidosis), serum bilirubin, serum amylase, serum lipids

For Treatment Efficacy:
a)Clinical Monitoring: Assess growth and development and Look for any illnesses
b)Laboratory monitoring: CD4 counts 6 monthly
c)Virologic monitoring: not available, but may be useful in some centers for research

Contraindications and Drug Interactions:

Tuberculosis and HIV are the commonest co-infections encountered in our country. It is extremely important to be aware that these two cannot be easily treated together due to the p450 inducer drug Rifampicin which alters the drug levels of several of the commonly prescribed antiretroviral drugs. Therefore in children co-infected with TB, ART needs to be deferred, if possible, until ATT is completed. In case, the clinical stage of HIV is advanced and one needs to initiate ART almost simultaneously (Possibly after the intensive phase of 2 months or after 2 weeks of ATT), the recommendations include use of ABC + 3TC + ZDV/d4T for all children irrespective of age. However, since ABC is not available in pediatric formulation in our country, the alternative recommendation would be implemented till such time. This includes EFV based regimen for all children> 3 years and for below 3 years, NVP based regimen.

Salient features in Pediatric HIV/AIDS
  • Early diagnosis of HIV in children
  • Early identification and diagnosis of opportunistic infections
  • Effective prevention and management of opportunistic infections
  • Early initiation of ART to prevent OI
  • TMP/SMX prophylaxis against multiple OI
  • Integration of HIV in IMNCI programme especially for management of ARI and acute diarrhea
  • Immunization for vaccine preventable diseases as per IAP Immunization Technical Committee recommendations

References :
  1. AIDS Epidemic Update. 2005, UNAIDS.
  2. De Cock K et al. Prevention of mother to child transmission in resource poor countries: Translating research into policy and practice. JAMA, 2000. 283 (9). 1175-1182.
  3. Coutsoudis A. et al. Influence of infant feeding practices on early mother to child transmission of HIV-1 in Durban, South Africa: a prospective study. Lancet, 1999. 354 (9177): 471-476.
  4. Nduati R et al. Effect of breastfeeding and formula feeding on transmission of HIV1: a randomized trial. JAMA 2000. 283 (9) : 1167-1174.
  5. Petra Study team. Efficacy of three short course regimens of ZDV and 3TC in preventing early and late transmission of HIV-1 from mother to child in Tanzania ,South Africa and Uganda (Petra Study) : a randomized ,double blind placebo controlled trial. Lancet 2002. 359 (99313) : 1178-86.
  6. Shaaffer N, Chuachoowong R, Mock PA, et al.Short course ZDV for perinatal HIV-1transmission in Bangkok Thailand: A randomized controlled trial .Lancet 1999. 353 (9155): 773-80.
  7. Guay LA, Musoke P,Fleming T ,et al.Intrapartum and neonatal single dose NVP compared with ZDV for prevention of mother to child transmission of HIV-1 in Kampala, Uganda : HIV NET 012.Randimized trial .Lancet 1999, 354 (9181) : 795-807.
  8. Moodley D, Moodley J, Coovadia H, et al. A multicentric trial of NVP verses a combination of ZDV+3TC to reduce intrapartum and early postpartum MTCT of HIV-1. J.Inf Dis, 2003.187 (5) : 725-35.
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