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| ANTIRETROVIRAL THERAPY IN HIV POSITIVE CHILDREN |
Dr
Ira Shah
MD, DNB, DCH, FCPS
Pediatrician & Pediatric HIV Specialist
Antiretrovirals are a group of drugs that are used in the treatment of HIV infected individuals to decrease the viral burden. They are potent inhibitors of viral replication. However, prior to starting Antiretroviral therapy in HIV positive children, certain factors have to be considered:
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- 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.
- CD 4 T cell count varies as per age in children and HIV viral load is higher in the 1 st 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.
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When to initiate Antiretroviral Therapy |
Antiretroviral therapy is a double edged sword with very few drugs in the amour of the Pediatric HIV specialist. Drug resistance is a rapidly progressing issue that may create problems in the future therapy options as well in drug regime failure. Antiretroviral therapy also has its own side effects that may add to the morbidity of the disease. Also HIV in children is usually “an acquired familial disease” whereby both parents and often siblings of the patient may also be infected. The cost of the therapy though has reduced over the years is still way beyond reach of most affected individuals and when entire family is affected, whom to start ART first is a very tricky financial and emotional situation.
One must also realize that antiretroviral therapy is not curative but definitely keeps the disease process under control by inhibiting further viral replication. However, mutant viruses are constantly being produced that may cause drug resistance and finally very few therapeutic options.
Compliance of the therapy has to be ensured prior to starting ART for multiple interruptions in the treatment schedule may increase further the chances of drug resistance. One may need to stress to the patients that ART in children presently is recommended as life long therapy. Though there are trials of interrupted HAART (Highly active antiretroviral therapy) schedule in children, there is still a long way before one can determine whether interrupted HAART can be recommended in children.
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Indications for starting Antiretroviral therapy: |
Absolute indications
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Any child with AIDS or clinical category C
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Any child with CD 4% <15% or in immune category 3.
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A child less than 12 months of age in clinical category B or C or immune category 2 or 3 (CD 4% <25%).
Relative Indications
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HIV RNA PCR (viral load) > 100,000 copies/ml in a child > 1 year of age ^.
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A child more than 1 year of age in clinical category A or B or immune category 2 (CD 4% = 15-25%)*.
^ Plasma HIV RNA levels are higher in HIV infected infants than older infected children and may be difficult to interpret in infants <12 months of age
* Most experts would initiate therapy if CD 4 cell percentage is between 15 to 20% and defer therapy with increased monitoring frequency in children with CD 4 cell percentage 21% to 25%.
Table 1- 1994 Revised Pediatric Classification System: Clinical Categories for HIV infection
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| Category N: Not Symptomatic
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Children who have no signs or symptoms considered to be the result of HIV infection or who have only one of the conditions listed in category A.
Category A: Mildly SymptomaticChildren with two or more of the following conditions but none of the conditions listed in categories B and C:
- Lymphadenopathy (>0.5 cm at more than two sites; bilateral = one site)
- Hepatomegaly
- Splenomegaly
- Dermatitis
- Parotitis
- Recurrent or persistent upper respiratory infection, sinusitis, or otitis media
Category B: Moderately Symptomatic
Children who have symptomatic conditions, other than those listed for category A or category C, that are attributed to HIV infection. Examples of conditions in clinical category B include but are not limited to the following:
- Anemia (< 8 gm/dL), neutropenia (<1,000/mm3), or thrombocytopenia (<100,000/mm3) persisting >30 days
- Bacterial meningitis, pneumonia, or sepsis (single episode)
- Candidiasis, oropharyngeal (i.e., thrush) persisting for >2 months in children aged >6 months
- Cardiomyopathy
- Cytomegalovirus infection with onset before age one month
- Diarrhea, recurrent or chronic
- Hepatitis
- Herpes simplex virus (HSV) stomatitis, recurrent (i.e., more than two episodes within one year)
- HSV bronchitis, pneumonitis, or esophagitis with onset before age one month
- Herpes zoster (i.e., shingles) involving at least two distinct episodes or more than one dermatome
- Leiomyosarcoma
- Lymphoid interstitial pneumonia (LIP) or pulmonary lymphoid hyperplasia complex
- Nephropathy
- Nocardiosis
- Fever lasting >1 month
- Toxoplasmosis with onset before age one month
- Varicella, disseminated (i.e., complicated chickenpox)
Category C: Severely Symptomatic
Children who have any condition listed in the 1987 surveillance case definition for acquired immunodeficiency syndrome, with the exception of LIP (which is a category B condition).
∗ Centers for Disease Control and Prevention. 1994 revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR, 1994. 43 (No. RR-12): p. 1-10.
Table 2 – Immune Categories Based on Age – Specific CD 4 T cell and Percentage
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< 12 mos |
1- 5 yrs |
6-12 yrs |
Immune category |
No./mm3 |
(%) |
No./mm3 |
(%) |
No./mm3 |
(%) |
Category 1:
No suppression |
> 1,500 |
(>25%) |
> 1,000 |
(>25%) |
>500 |
(>25%) |
Category 2 :
Moderate suppression |
750-1,499 |
(15%-24%) |
500-999 |
(15%-24%) |
200-499 |
(15%-24%) |
Category 3:
Severe suppression |
<750 |
(<15%) |
<500 |
(<15%) |
<200 |
(<15%) |
∗Modified from: CDC. 1994 Revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR 1994; 43 (No. RR-12): p. 1-10.
Note: Sometimes absolute CD 4 cell count adjusted for age and CD 4 percentage may not fall in the same immune category. Thus, of the 2 parameters, whichever is in the lower category is taken into consideration before starting ART.
Which are the Anti-Retroviral Drugs?
Antiretroviral drugs consist of 3 main groups:-
- NRTI (Nucleoside Reverse Transcriptase Inhibitors & Nucleotide Reverse Transcriptase Inhibitors)
Nucleoside Reverse Transcriptase Inhibitors consists of:
- Zidovudine (AZT) ( Can be given in children from birth)
- Lamivudine (3TC) (Can be given in children > 3 months of age)
- Stavudine (d4T) (Can be given in children > 6 months of age)
- Didinosine (ddI) (Can be given in children > 3 months of age)
- Abacavir (ABC) (Can be given in children > 3 months of age).
Nucleotide Reverse Transcriptase Inhibitors consists of Tenofovir which is not recommended in children.
- NNRTI (Non-nucleoside Reverse Transcriptase Inhibitors).They consist of:
- Nevirapine (NVP) (In children > 3 months of age)
- Efavirenz (EFV) (In children > 3 years of age)
- Delaviridine (In children >13 years of age).
- Protease Inhibitors (PIs). They consists of:
- Indinavir (IDV) (In children > 13 years of age)
- Nelfinavir (NFV) (In children > 3 months of age)
- Amprenavir (In children > 4 years of age)
- Lopinavir/Ritonavir
- Saquinavir (SQV) (In children > 16 years of age)
The NRTIs and NNRTIs competitively and non-competitively respectively inhibit the reverse transcriptase enzyme thus preventing translation of HIV RNA into HIV DNA in the host cell. The PIs inhibit the protease enzyme and thus cleavage of multiple HIV virions in the cell. Thus, the antiretroviral decrease the HIV viral load in the body. However, all the antiretrovirals to first act requires the HIV virus to first infect the human cell. There are a new class of antiretroviral drugs now available called “FUSION INHIBITORS” that inhibit the entry of HIV virus into the host cell. Thus, they act extracellularly. However, at present they are recommended only in adults who have failed their primary regimes and not recommended in children as they need to be given as subcutaneous injections at least twice a day and compliance is a major problem.
What are the Antiretroviral drug schedules?
The ideal combination of antiretroviral therapy consists of 3 drugs minimum of which 2 NRTIs form the backbone. The 3 rd drug may either be a protease inhibitor or an NNRTI. Prior to initiation of antiretroviral therapy and on ART, one may need to monitor the child for disease progression (clinically, immunologically and virologically), monitor for potential side effects of antiretroviral therapy and watch for drug resistance.
Table 3 – Recommended Antiretroviral Regimens for Initial Therapy
Strongly Recommended
- One highly active protease inhibitors (Nelfinavir or ritonavir) plus two nucleoside analogue reverse transcriptase inhibitors.
- For children who can swallow capsules: the non-nucleoside reverse transcriptase inhibitor (NNRTI) Efavirenz ** plus two NRTIs, or Efavirenz plus Nelfinavir and one NRTI.
Recommended as an Alternative
- NVP and two NRTIs.
- ABC in combination with ZDV and 3TC.
- Lopinavir/ritonavir with two NRTIs or one NRTI and NNRTI.
- IDV or SQVsoft gel capsule with two NRTIs for children who can swallow capsules.
Offered only in Special Circumstances
- Two NRTIs.
- APV in combination with two NRTIs or ABC.
Not Recommended
- Any monotherapy.
- d4T and ZDV
- ddC and ddI
- ddC and d4T
- ddC and 3TC
** There are currently no data on appropriate dosage of EFV in children under age three years.
Except for ZDV chemoprophylaxis administered to HIV-exposed infants during the first 6 weeks of life to prevent perinatal HIV transmission; if an infant is confirmed as HIV-infected while receiving ZDV prophylaxis, therapy should be changed to a combination antiretroviral drug regimen.
Table 4 - Side Effects of Antiretroviral Therapy
NRTI |
Hepatitis, fatty liver, Lactic acidosis, pancreatitis, myopathy, peripheral neuropathy, cardiomyopathy, bone marrow suppression. |
NNRTI |
Rash, Granulocytopenia, Hepatotoxicity |
PI |
Hyperglycemia, lipodystrophy, hyperlipidemia, osteoporosis, diabetes, increased bleeding tendencies. |
Specific side effects
NRTI
- Bone marrow suppression
 ZDV
- Pancreatitis, neurotoxicityddI
- Lactic acidosis, lipoatrophy, peripheral neuropathy, hyperlipidemiad4T
- Single mutation confers resistance3TC
- Hypersensitivity reactionABC
NNRTI
- Stevens Johnson syndrome, hepatic failureNVP
- Neuropsychiatric side effectsEFV
- Teratogenic in pregnancyEFV
PI
- Lopinavir/RitonavirBitter taste
- DiarrheaNelfinavir
- NephrotoxicityIndinavir
Changing Antiretroviral Therapy
There are certain virologic, immunologic and clinical guidelines to determine whether a child requires a change in the antiretroviral therapy. However, one may consider changing the schedule if there is progression of the disease, failure to thrive (without any cause), progressive neurodevelopment deterioration, or fall in immunologic classification. At least 2 measurements should be performed before considering a change in therapy. Ideally a drug resistance testing should be done to determine what would be the best alternative therapy to be started.
Conclusion
Antiretroviral therapy in children requires special precautions, monitoring for drug interactions, adverse effects of ART and drug resistance. An ideal, individualized rational regime may go a long way in managing an HIV infected child and ensure a normal life style for such a patient.
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Last updated on 01-06-2004
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How to cite this url |
Shah I .Antiretroviral Therapy In HIV Positive Children.Pediatric Oncall [serial online] 2004 [cited 2004 June 1];1. Available from:
http://www.pediatriconcall.com/fordoctor/diseasesandcondition/infectious_diseases/
antiretroviral_therapy.asp
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