Dr. Ira Shah
M.D, DNB, DCH(Gold Medalist), FCPS

Antiretrovirals are a group of drugs that are used in the treatment of HIV infected individuals to decrease the viral burden.
Before commencing on antiretroviral therapy, it is essential to understand that ART is not a curative therapy. It is a therapy, which keeps the HIV virus multiplications in check and thus prevents immune destruction, attacks of opportunistic infections and organ dysfunctions due to HIV. However, ART does not destroy the HIV virus completely and hence ART once started is a life-long therapy. Though there have been studies of giving intermittent ART, the results are still in the early phase to comment on the feasibility of such interrupted schedule. Thus, one needs to start ART in a child only when compliance for life-long therapy is assured. Infact with drug interruptions in between, mutations may occur in the HIV virus that may lead to resistance to antiretroviral drugs – a problem that is a serious reality in the developed countries in the present time. Hence, one needs to be really sure about compliance before starting ART.

Combination ART consisting of 3 or more antiretroviral drugs (ARV) has greatly improved health and survival rates of HIV infected children. ART helps in improving and restoring the immune system functioning and decreasing the mortality and morbidity associated with HIV infection. ART does not cure HIV infection and requires very close adherence in order to be effective and prevent emergence of resistance and thus patient has to be prepared for life long treatment in order to optimally control the virus replication. There are certain clinical and immunological guidelines with reasonably good recommendations for starting ART in children

However, prior to starting Antiretroviral therapy in HIV positive children, certain factors have to be considered:

• Children unlike adults usually acquire the infection through perinatal exposure.
• HIV infection in children progresses rapidly and most children affected die by 4-6 years. Some of them may remain asymptomatic for a prolonged period of time and are called the long-term non-progressors.
• Children may have already been exposed to antiretrovirals such as zidovudine and nevirapine as part of Parent to Child Transmission Prevention Programme.
• CD4 T cell count varies as per age in children and HIV viral load is higher in the 1st year of life.
• Pharmacokinetic parameters of the drugs change with the age. In adolescents with early puberty (Tanner Stage I & II), pediatric doses and schedules of ART are recommended whereas in those with late puberty, adult dosing schedule is recommended.
• Availability of appropriate, palatable drug formulations and adherence to antiretroviral treatment with their complexity of schedule and long term and short term side effects have to be considered.
• Presence of co-morbidity may affect drug choice such as TB, Hepatitis B or C, chronic renal disease or liver disease for e.g., co-administration of rifampicin can significantly reduce drug levels of nevirapine and most protease inhibitors.
• Minimum of triple drug therapy is recommended and drug interactions have to be kept in mind.

Although implementing ART is complex, a number of guidelines are available to help practitioners’ select effective regimens for particular patients. The decision to start ART depends on clinical, immunological and socio-economic conditions.

Clinical criteria:- The revised WHO Pediatric Clinical Classification (2006) gives recommendations for ART therapy in resource limited settings. In the Western countries, the 1994 revised CDC guidelines are used for classifying HIV disease in various clinical categories.

Center for Disease Control (CDC) has classified Pediatric HIV into 4 clinical categories:

• Category N = Not symptomatic
• Category A = Mildly symptomatic
• Category B = Moderately symptomatic
• Category C = Severely symptomatic (AIDS).

Patients in Category A usually have lymphadenopathy, parotid enlargement, hepatomegaly, splenomegaly and dermatitis. Patients in Category B have opportunistic infections by common pathogens, Pulmonary Tuberculosis, fever of more than 1-month duration and HIV related organ dysfunctions (except HIV encephalopathy). Patients in Category C have severe wasting, infections by uncommon organisms, HIV encephalopathy, Tuberculosis (Disseminated or Extrapulmonary) and malignancies.

Classification of HIV associatedclinical disease	WHO clinical stage
Asymptomatic	1
Mild	2
Advanced	3
Severe	4

Immunological criteria :- Since HIV virus predominantly affects the CD4 T cells, decrease in CD4 cell count would give an idea of the immune status of the body. However, one should remember that CD4 cell count in children varies according to the age. In order, to overcome this difficulty, CD4 percentage is taken into consideration rather than absolute CD4 count in children.

Classification of HIV associated immunodeficiency	Age-related CD4 values
	< 11 months(%)	12-35 months(%)	36-59 months(%)	> 5 years(Cells/cum)
Not significant	> 35	> 30	> 25	> 500
Mild	30-35	25-30	20-25	350-499
Advanced	25-30	20-25	15-20	200-349
Severe	< 25	< 20	< 15	< 200 or < 15%

Before antiretroviral therapy is started, it is essential that parents, care-givers and patients are counseled regarding the importance of adherence to the prescribed treatment regimen. The goal of therapy should ensure normal growth and development, avoiding opportunistic infections and organ dysfunctions due to HIV and maintaining as healthy and normal life style as possible. Antiretroviral therapy is never an emergency and potential problems should be identified and resolved prior to starting therapy.

Clinical symptoms associated with HIV infection (i.e. clinical categories A, B or C) Evidence of immune suppression indicated by CD4 T cell absolute number of percentage. Age < 12 months – regardless of clinical, immunologic or virologic status. For asymptomatic children aged > 1 year with normal immune status, two options can be considered: Option 1 : Initiate therapy – regardless of age or symptom status. Option 2 : Defer treatment in situations in which the risk for clinical disease progression is low and other factors (i.e. concern for the durability of response, safety and adherence) favor postponing treatment. In such cases, the health-care provider should regularly monitor virologic, immunologic and clinical status. Factors to be considered in deciding to initiate therapy include the following: High or increasing HIV RNA copy number Rapidly declining CD4 + T cell number or percentage to values approaching those indicative of moderate immune suppression Development of clinical symptoms.

WHO PediatricStage	Availability of CD4 cellmeasurements	Age specific treatment recommendation
		< 12 months	> 12 months
4a	CD4	Treat all
	No CD4
3a	CD4	Treat all	Treat all, CD4 guided in those children with TBb, LIP, OHL, thrombocytopenia
	No CD4		Treat all
2	CD4	CD4 – guided TLC – guided CD4 – guided Do not treat
	No CD4
1	CD4
	No CD4

Notes:LIP – Lymphocytic interstitial pneumonia; OHL – Oral Hairy Leukoplakia; TB – Tuberculosis.
a. Stabilize any opportunistic infection prior to initiation of ARV therapy.
b. In children with pulmonary tuberculosis, the CD4 level and clinical status should be used to determine the need for and timing of initiation of ART in relation to tuberculosis treatment.

Preferred Regimen 2 NRTI + NNRTI :- 2 NRTI + PI :-	AZT + 3TC / FTC + EFVABC + 3TC / FTC + EFV AZT + 3TC / FTC + LPVrABC + 3TC / FTC + LPVr
Alternative Regimens 2 NRTI + NNRTI :-	ddI or d4T      + 3TC or FTC      + Efavirenz or Nevirapine ddI or d4T      + 3TC or FTC      + LPVr or NFV or IDV
Special circumstances :- 3 NRTI :-	ABC + 3TC + AZT (use only when a NNRTI or PI based regimen cannot be used)

Data for use of TDF in children is lacking.

The following combinations should not be used:
  - d4T & AZT
  - 3TC & FTC
  - ddI & d4T
  - EFV & NVP

Efavirenz is not recommended in children < 3 years of age or < 10 kg and should not be given in girls who are in 1st trimester of pregnancy.

1. World Health Organization. Antiretroviral therapy of HIV infection in infants and children in resource-limited settings, towards universal access: Recommendations for a public health approach. February 2006.
2. Guidelines for use of antiretroviral Agents in Pediatric HIV infection. Working Group on Antiretroviral Therapy, NPHRC, HRSA and HIH. December 2001.
3. Antiretroviral Therapy. Clinical Manual for Management of the HIV infected adult 2006.
4. Shah I. Management of Pediatric HIV Pediatric Oncall. Mumbai. 2005.

Last Updated June 11,2007