MANAGEMENT OF PEDIATRIC HIV INFECTION
Dr. Nitin K. Shah*
  • Hon. Hematologist Oncologist, BJ Wadia Hospital for Children
  • President Indian Academy of Pediatrics, 2006
  • Chairperson, IAP National Task Force on Pediatric HIV
  • Editor, IAP Textbook on Pediatrics
  • Editor, IAP Book on Pediatric HIV
*
Introduction
World over 42 million people are estimated to be living with HIV infection. Though children represented only 6% of all these as of December 2005, they accounted for 18% of the 3.1 million AIDS deaths in 2005; and this is because only 40,000 or 4% of the one million people now on antiretroviral treatment are children. This is gross neglect of the fountain of life!

The estimated total number of people living with HIV in India was 5.134 million in 2004 of which children were 0.17-0.24 million (3.5-5%). Half of HIV positive children die undiagnosed before their 2nd birthday as they are not tested by nucleic acid tests which are expensive. Eight states (Maharashtra, Karnataka, Tamilnadu, Andhra Pradesh, Manipur and Nagaland) fall in to high prevalence zone with average prevalence in ANC mothers of 1.6%, 2 states (Gujarat and West Bengal) fall in the intermediate prevalence zone with average prevalence in ANC mothers of 0.5% and rest of the states fall in the low prevalence zone with average prevalence in ANC mothers of 0.2%. The national average of HIV prevalence in ANC mothers is 0.7%.(1, 2, 3)

In children, 95% of transmission occurs due to vertical transmission. Of the 27 million deliveries occurring in India annually, at the rate of 0.7% average HIV prevalence in ANC mothers, nearly 1.9 lakh deliveries occur in HIV infected mothers. In the absence of effective coverage of the PPTCT measures, 30% of these exposed babies get HIV infected at birth ie, nearly 60,000 babies every year. This is almost 10% of the 650,000 babies estimated to be born annually world over due to mother to child transmission. More than 90% of these babies can be prevented from getting infected from their mothers by implementing proper and country appropriate PPTCT (Prevention of Parent to Child Transmission) services. However less than 4% of the pregnancies actually avail the PPTCT services in India, less than 7% of such exposed babies are put on PPTCT protocol and less than 3.5% of the babies are actually prevented from getting infected from their mothers. This is far less than the UNGASS goals of reduction of PPTCT by 20% by 2005. Lastly, it is equally important to provide support to those who are infected in spite of the best efforts. This is a huge task for a country like India. Indian Academy of Pediatrics has done a lot in this field with the help from NACO, UNICEF and WHO.(1, 2, 3)
Management of HIV Infection
The main issues in the management of HIV infected children include early diagnosis of the exposed baby, clinical follow up and clinical classification as per WHO revised clinical staging, immunological classification whenever possible, counseling, immunization, breastfeeding and young infant feeding practices, growth and development monitoring, nutritional support, treatment of opportunistic infections and other complications, prophylaxis for PCP, anti-retroviral drug therapy, psychosocial support and last but not the least Prevention of parent to child transmission. It is obvious that it needs a multidisciplinary approach to treat an HIV infected child. It is better to take help of persons experienced in caring for and treating HIV infected children.
Counseling
Counseling is the most important aspect of total management strategy for HIV4. Professional help may be available in big centers, otherwise the treating physician should fulfill this role. One needs to counsel both the parents and even the child if he is old enough to understand about the disease. Pre and post-test counseling are very important while ordering a test for HIV diagnosis. Counseling also helps a mother decide about the infant feeding choice. It is equally important while treating a child with ART as adherence of >95% to the prescribed drugs including the schedule and timings is essential for the efficacy and prevention of development of drug resistance. This is even more important while managing infected adolescents who are always a challenge for the treating physicians.
Care of the Baby at the Time of Birth
Care of HIV exposed infants should follow standard neonatal care according to safe motherhood guidelines. The baby's mouth and nostrils should be wiped as soon the head is delivered. Infants should be handled with gloves until all blood and maternal secretions have been washed off. The cord should be clamped soon after birth, but milking should be avoided. Cover the cord with glove hand and gauze before cutting. Initiate feeding within the first hour of the birth according to the mother's preferred and informed choice.(3)
Care of the Baby at the Time of Birth
There are 2 important general issues related to immunization of HIV infected patients. First there could be suboptimal response to vaccination and second that certain live vaccines could be contraindicated in patient with significant immunodeficiency.
  1. Suboptimal response: One may need to give double the dose at each vaccination (e.g., with hepatitis B vaccine), and or use additional doses (eg 0, 1, 2, 12 schedule with hepatitis B or 2 dose instead of 1 dose with varicella vaccine even in children < 13 years of age) to induce maximum possible response. It may also be prudent to check for seroconversion and titers at the end of vaccination to check for efficacy whenever possible (e.g., following hepatitis B vaccine should follow the instruction of the vaccine manufacturer while giving vaccine to HIV infected children.
  2. Contraindications: As a rule, live vaccines are contraindicated in immunodeficient patients. All inactivated vaccines are safe in HIV patients. For those HIV patients who are asymptomatic and are not immunodeficient, even live vaccines are safe to be used. Hence practically speaking, BCG as it is given at birth, is safe in HIV patients as no newborn that is HIV-infected is immunodeficient at birth. Similarly, primary doses of OPV, which are given before 14 weeks of age, are also safe. Booster doses of OPV given later are also safe as they lead to only local gut infection and do not spread systemically. This has also been proved by the Pulse Polio Immunization experience where OPV is given to all the children below 5 years of age irrespective of their HIV status. Measles vaccine is an exception as it is recommended to be used even in symptomatic HIV patients, as wild measles can be fatal in them. Mumps and rubella vaccines are not recommended in immunodeficient HIV patients. Similarly oral typhoid vaccine is contraindicated especially when alternative Vi vaccine is available. Varicella vaccine is safe in HIV patients who are not immunodeficient.

Current India National ART Guidelines have recommended use of Hib vaccine in each and every HIV infected child and the same is likely to be made available free through the ART centers.3,5 Similarly pneumococcal vaccines, influenza vaccine, typhoid vaccine, hepatitis A vaccine and varicella vaccine (when not contraindicated) are recommended to be used routinely in HIV infected children whenever possible.3 Rabies immunoglobulin is always indicated in patients with HIV as they may not adequately respond to vaccine. Similarly Hepatitis B immunoglobulin and varicella immunoglobulin should be used liberally as indicated clinically.
Nutritional Support
Malnutrition would further impair the immunity of an HIV infected child. Nutritional deficiencies are known to occur early in HIV infected baby. Malnutrition in HIV infected child occurs due to various factors like poor intake (stomatitis, oral thrush), malabsorption (chronic and recurrent diarrhea), and increased requirements due to catabolic state (recurrent OIs) and most important due to emotional deprivation (orphan and vulnerable child). Management should stress on treatment and prophylaxis for oral and esophageal candidiasis with anti-fungals, prevention and treatment of opportunistic infections, improved diet with high calories and proteins from the available and customary home made food especially during recovery phase of associated opportunistic infections, energetic treatment of specific diseases like diarrhea, tuberculosis etc., psychosocial support, emotional support, economical support, immunization guidance and health education of whole family. Calories and proteins are calculated as per the weight of the child in an HIV infected child who is not sick or stunted and as 150% of the age criteria while treating stunted and sick HIV infected children. Routine supplements of vitamins and minerals is indicated in HIV infected children especially Vit. A and zinc, both of which are important for the immunity.
Infant Feeding Choice (Breast Feeds vs. Replacement Feeds)
Breast feeding can increase the risk of HIV transmission by 5-20% depending on the length of breast feeding and maternal health.(6, 7, 8) However top feeding, especially by bottle, is not at all safe in developing countries as the risk of the child dying of diarrhea is 4 times more and that with pneumonia is 2 times more in a top fed child than a breast fed child.(9) WHO recommend avoidance of all breast feeding if replacement feeding is acceptable, feasible, affordable, sustainable and safe.

Otherwise exclusive breast feeding in the first months of life is recommended by WHO. Accordingly one can exclusively breast feed the child for the first 6 months and than wean abruptly over next 15 days to home made food items and undiluted cow's milk with spoon. One thing must be kept in mind that it should be either exclusive breast feeding or exclusive replacement feeding and never mixed feeding as the chances of HIV transmission are most with mixed feeding than exclusive breast feeds or top feeds.(10)
PCP {Now known as Pneumocystis jiroveci (for the Human strain)}
Treatment: The treatment of choice for PCP infection is Cotrimoxazole in the dose of 20 mg/kg/day of Trimethoprim component preferably IV QID for the first 5 days followed by oral route in the same dose in 2 divided doses for a period of total 21 days. If IV preparation is not available, total therapy is given by oral route. If patient is sensitive to sulpha, the alternative is pentamidine, which is given in the dose of 4 mg/kg/day as IV drip for 21 days. Other agents used include, dapsone either singly or in combination with sulpha drugs. If the patient has severe respiratory distress oral prednisolone is given in the dose of 2 mg/kg/day for 5 days, 1 mg/kg/day for next 5 days and 0.5 mg/kg/day for next 11 days.(3) ART is obviously indicated in all patients who develop PCP as per the recent national guidelines.

Prophylaxis: The dose of CTX used for prophylaxis is 5 mg/kg/day of trimethoprim compound as single dose given orally daily. Primary prophylaxis is indicated in all HIV exposed newborns from 4 weeks of age and is continued till patient is proved to be HIV uninfected by nucleic acid testing and baby being not breastfed or in absence of availability of nucleic acid testing till 1 year of age irrespective their CD4 counts, HIV viral load or clinical condition. After 1 year, it is indicted for patients in clinical Stage 2 onwards as per the revised WHO clinical stage or in presence of severe and advanced immune suppression as per WHO classification of immune deficiency based on CD4+ counts. All patients who develop PCP and recover after treatment are put on secondary prophylaxis. In patient on ART, CTX prophylaxis can be stopped when the patient has shown immune recovery with CD4+ counts showing no or mild immune deficiency confirmed by 2 separate readings done at least 3 months apart. If patient is intolerant to sulpha, he can be put on aerosolized pentamidine in the dose of 4 mg/kg once a month, or lower doses once a week. Other drugs used include dapsone alone.(11)
Clinical and Immunological Classification
WHO has recently revised the clinical classification and immunological classification based on CD4+ counts.(3) Clinical classification helps us suspect a case and order for the appropriate test, define severity of disease and label a case as a presumptive diagnosis in child < 18 months. Where PCR based early diagnosis is not available, follow up a case clinically for disease progress, prognosticate a case, ascertain need to start ART, follow up response to ART, and ascertain need of PCP prophylaxis. Similarly CD4+ counts help us define immune deficiency with confidence and help us decide severity of disease, follow up the disease progression, ascertain need to start PCP and ART, follow up response to ART and prognosticate a case.
Anti-retroviral Drug Therapy (ART)
Combination ART therapy using triple drug combination has changed the quantity and quality of life for HIV infected children. Once a hopelessly fatal disease, HIV is now converted in to a chronic therapy dependant disease which can be controlled for years with proper and timely treatment. Availability of various groups of ART, drastic reduction of their costs, gain in clinical experience in their use, better outcome in long term studies combined with national guidelines, availability of free ART and changed political and social scene has helped the cause of HIV management. Correct management can lead to better physical and even better neurodevelopment in HIV infected babies.

Various anti-retroviral drugs act on one of the steps in HIV replication. None of them are true virucidal in the sense that none of them acts on resting virus. They act only when the virus and the host cell replicate. Hence none of them can act on the virus present in the infected dormant host cells. HIV is also hyper mutable and hence develops resistance to these drugs especially if used haphazardly, hence the need of proper therapy and near 100% compliance from patient to adhere to the treatment plan.(12,13)

Nucleoside Reverse Transcriptase Inhibitors (NRTI): Reverse transcriptase is an enzyme unique to HIV and not present in human cells. This enzyme is required to convert HIV RNA to proviral DNA. This enzyme can be blocked by drugs, which mimic the natural nucleotides substrate for the enzyme. These are called Nucleoside Reverse Transcriptase Inhibitor (NRTI). This group includes Zidovudine (ZDV), Stavudine (d4T), Lamivudine (3TC), ddC, ddI and Abacavir (ABC).

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI): Other drugs also block the reverse transcriptase enzyme by direct action. These are called as Non-Nucleoside Reverse Transcriptase Inhibitors or NNRTI. This group includes Nevirapine (NVP), efavirenz (EFV) and delaviridine.

Protease Inhibitors: Protease enzyme is again unique to HIV and not present in host cell. Protease enzyme helps cleavage of precursor molecule gp160 into envelope proteins gp120 & gp40. It also helps in viral assembly. Both these steps are required for the virus to complete its replication and emerge out of the host cell. There are various drugs, which inhibit protease enzyme and are very effective ARV drugs. This includes Nelfinavir, Ritonavir, Saquinavir, Indinavir, Amprenavir and Lopinavir. Most physicians prefer to use Ritonavir boosted lopinavir (LPV/r) or Saquinavir (SQV/r); or Nelfinavir alone as the PI of choice in pediatric patients3. These drugs though very effective are toxic, expensive and not easily available in India market in pediatric formulations.

Aims of ART: The main objectives of ART are to decrease the viral load which in turn will improve immunity, decrease opportunistic infections, slow the disease progression, prolong the survival, improve growth and development, improve neurological development and improve quality of life.

When to start ART: For revised WHO clinical stage 1 & 2, if CD4+ counts are not available, ART is not started and if CD4+ counts are available, ART is started for those with age appropriate severe or advanced immune suppression. For clinical stage 4, ART is always started irrespective of CD4+ counts or age of the child. Similarly for clinical stage 3, ART is started for all children irrespective of their age and CD4+ counts except when they are> 12 months of age and have CD4+ counts either normal or suggestive of mild immune suppression and have either of TB, oral hairy leucoplakia, LIP or thrombocytopenia.

Which drugs to Start: Only triple combination therapy is recommended. Monotherapy has role only for prophylaxis in PPTCT and dual therapy for post-exposure prophylaxis. Triple drug therapy is preferred as it is shown to best effective in suppressing viral load, with low chances of resistance development even when taken for long term. This would promote better disease control, lesser opportunistic infections, better physical and neuro-developmental growth with over all better quality of life.

1st line drugs: These protocols include 2 NRTI and 1 NNRTI or triple NRTI including Abacavir. The chances of development of resistance are low and these protocols are very effective clinically, immunologically and virologically. Of the NRTI, ZDV, 3TC and d4T are preferred and of the NNRTI, NVP or EF is preferred. D4T based combinations containing d4T, 3TC and NVP are easy to use as pediatric fixed drug combinations tablets and syrup are available in India and are cheaper than ZDV based combinations.(3) Besides they can be used in patients with significant anemia too. However Stavudine syrup needs refrigeration which is a practical problem for most HIV patients who are poor and do not have a refrigerator at home. ZDV based combination like ZDV plus 3TC plus NVP can be used if the patient does not have significant anemia, however pediatric fixed drug combinations are not available with this combination and hence may be difficult to use in children < 15 years unless one uses all the 3 drugs separately in syrup form. ZDV is never used with d4T due to drug interference. Efavirenz is expensive and dosing has not been worked out for children < 3 years of age or < 10 kg weight and hence is not preferred over NVP routinely. Always use the lead on dose of nevirapine for the 1st 14 days with half the daily dose recommended and switch to full dose after 14 days if there are no serious side effects especially skin reactions. Such corresponding lead on dual drug combinations without NVP are available in pediatric formulations containing d4T and 3TC. However, Nevirapine is known to interfere with rifampicin. Hence while treating a patient of HIV with tuberculosis, one has to use efavirenz-based combinations. If patient is not very sick, one can also defer the use of ART till rifampicin use is over after which one can continue to use NVP based Art or use Rifabutin in stead of rifampicin (not available in India), or at least use Efavirenz based ART till rifampicin is used and then switch back to NVP based combination to save costs. However EFV is expensive and is not easily available free through national ART centers. If a child < 3 years has HIV and TB and one needs to start ART and rifampicin based ATT together, one can use NVP and rifampicin together with caution.(3)

Evaluation and Monitoring: Patient must be counseled before starting the therapy especially on the benefits and risks of ART, goals of ART, need for life long medications, need for strict adherence to the treatment plan, costs involved, need for regular follow up and investigations and the potential toxicities, etc. One also needs to do a baseline CBC, LFT (when possible) and CD4+ counts and % (in children less than 5 years of age percentages are more reliable than absolute counts). After starting ART, one has to have regular follow of the patient which will help clinical, laboratory and immunological monitoring. One clinical follow up look for height, weigh, OIs, improvement in clinical picture, neurodevelopmental growth and toxicities of the drugs. Laboratory wise repeat CD4+ counts at least once in 6 months and in between as indicated if OIs develop and order for appropriate labs if toxicities are suspected. Counseling is continued at each visit for the adherence issues.(3)
2nd line ART drugs: These drugs are required when there is primary or secondary failure of 1st line drugs, non-compliance due to difficulty to adhere to the plan, frequent undesirable side-effects and availability of better drugs. Non response or relapse can be detected on the basis of clinical, immunological or virological status.( 3, 13) At least 24 weeks trial must be given before one can assess the response.

In the absence of virologic failure: For adverse effects or intolerance substitute the individual drug. In case of NNRTI-induced rash, substitution with other NNRTIs must be monitored because of risk of shared toxicity. In case of Abacavir-induced hypersensitivity, the drug should be discontinued and re-challenge deferred due to severe toxicity and fatal reactions.

Due to virologic failure: Elaborate guidelines are available from WHO to decide when to change therapy in a given case of non-response or relapse.3 Essentially it needs referral to a center of excellence in HIV care for such decision to be taken. One takes decision based on the current clinical stage (labeled as T1, T2, T3 and T4 corresponding to clinical stages 1-4 only to indicate staging while on therapy) CD4+ status and the 1st line drugs used. In any case always treat the even that has occurred, ensure adherence to prescribed drugs, offer nutritional support, and ensure correct formulations before decision to change the drugs is taken. If the patient is in T1 or T2 one can continue to use the same drugs especially if there is no severe immune deficiency. For T3 stage, one must change drugs if there is severe immune deficiency or consider changing drugs if CD4+ counts are not available and for
T4 stage always change the drugs irrespective of CD4+ counts.

Ideally 2nd line drugs should include all 3 new drugs as we do not known to which primary drugs has the resistance developed unless we do in vitro sensitivity, which is almost impossible in our set up. NNRTIs are the most implicated rugs for resistance and as there is cross resistance amongst the group, one has to drop NNRTI and use a PI in stead. As there is cross resistance between ZDV, d4T and 3TC one has to drop all these drugs and in stead use ddI and ABC as the other 2 drugs. Hence the 2nd line will include ddI, ABC and PI. If ABD was used initially one can use ddI and ZDV along with a PI. In case ddI is not available, one can continue 3TC and add ABC plus a PI. The PI of choice is nelfinavir alone or ritonavir boosted lopinavir (LPV/r) or ritonavir boosted saquinavir (SQV/r) 3.

Schooling
Children with HIV infection should not be excluded from school for the protection of other children or personnel since HIV does not spread through social contacts. The family of an affected child has the right, and is not obliged to inform the school about the HIV infection status of the child. All schools should adopt the standard procedures for handling blood or contaminated fluids regardless of the HIV status of the injured child.
Prevention of HIV Infections
Prevention is always better than cure, especially for infection like HIV where the cure is still eluding all of us. If we look at the major routes of transmission of HIV, we will realize the areas where to concentrate to prevent pediatric HIV infection.

Sexual route: Prevention of this route includes education and counseling regarding avoiding unsafe and unprotected sex all together. Use of condom should be encouraged, though may be prevent HIV infection 100%. Family life education should begin early in life. At school exit time and stress should be given on learning to say no to peer pressure. Message of avoidance of premarital and extra-marital sex as well as multiple sex partners and special counseling to man who have sex with man as to how to protect themselves should be spread through appropriate tools.

Blood products: HIV can be transmitted by blood products if the blood product is not tested properly. Even though this is now mandatory for 2 decades, there could be some unscrupulous blood bank which may blatantly flout this rule. The other reason is window period which is a nightmare for the blood bank as the blood collected from a HIV infected person during the window period will test HIV negative and yet will be highly infective. Hence blood products should NOT be used un-indicated or where there is a substitute available. Avoiding paid donors and using blood only from voluntary donor will bring down the incidence of blood related HIV infection. Lastly, use of nucleic acid testing as practiced in West can shorten the window period to a large extent and can virtually eradicate transfusion transmitted infections including HIV. Of course, this is very expensive and not feasible in our set up.

Parent to Child Transmission: As discussed before, 95% of pediatric HIV infection now occurs due to parent to child transmission which accounts to nearly 60,000, new infections every year in India.(4) It is best to prevent HIV in would be mother by imparting life skills & education as discussed before. If the woman is already HIV infected, one must encourage her to avoid pregnancy by family planning measures, and if detected in time to be pregnant, one should discuss the option of therapeutic termination of pregnancy. If the woman wishes to continue the pregnancy, there are 3 main ways of preventing transmission to her child; safe delivery practices, avoidance of breast feeding after one to one discussion and anti-retroviral drugs to the mother and baby. Safe delivery includes avoidance of episiotomy as a routine, and if possible LSCS which decreases the transmission by 20%.(14)

Anti-retroviral Protocols: Mothers who merit ART based on clinical and CD4+ criteria must form a priority in the society where limited patients can be treated with free ART, as is the case in India 1. Triple drug combination ART started well in time will reduce the risk of transmission to less than 2%.(3) If the mother does not merit ART due to early clinical/immunological staging, one can offer ART prophylaxis which will reduce transmission by as much as 50-65%. Various protocols have been used in this regards including the famous 076 protocol of using longterm single drug AZT for mother (20-35 weeks onwards) as well as baby (6 weeks) (efficacy 65%), Thai protocol of using AZT for a shorter duration for the mother (36 weeks onwards) alone without any baby component (efficacy 50%) and the Uganda protocol of using single dose nevirapine for the mother at the onset of labour and for baby as soon as possible after birth (short term efficacy 50%).(15, 16, 17) Many of these protocols have now used 2 drugs for mother as well as baby in various combinations and for various durations. Combination of AZT and 3TC used from 28-36 weeks of gestation for the mother and for 4 week for the baby seems to be very effective. Some of these protocols have also allowed breast feeding to continue as per the choice by the mother. Over all the long term efficacy of these protocols have been 50-65% if the breast feeding is not allowed (076 protocol - 65%, Thai protocol - 50%), but drops if breast feeding is allowed due to breast milk induced transmission (Uganda Protocol and Cote d ivory protocol - short term efficacy 50% dropped to 35% at 18 months). India at present uses single dose nevirapine protocol at national level as part of the PPTCT services.(1)

However there is the issue of nevirapine resistance using only a single dose in mother and baby making them unsuitable for free ART in future which are all based on nevirapine. Hence, there is a need to cover the so called 'tail' of nevirapine by using appropriate course of AZT/AZT + 3TC in mother and baby. If the mother has received NVP based ART, infant should be covered by 4 weeks of AZT + 3TC. If the mother has only received AZT + 3TC as prophylaxis, the infant is covered by 4 weeks of AZT alone. If the mother has received only the single dose nevirapine as prophylaxis, she should be covered using AZT and 3TC for 4 weeks post partum and the newborn with single dose nevirapine followed by 4 weeks of AZT. This will prevent the problem of nevirapine resistance.(3)
References :
  1. Joint Technical Mission to Support PPTCT Scale up and Pediatric Care Implementation in India, January 2006, Background material.
  2. Shah NK. Editorial: Indian perspective of HIV infection in children. IJPP 2003;5:275-277.
  3. Draft Treatment Guidelines for Pediatricians on HIV care and treatment including ART, NACO, March 2006.
  4. Bhave SY. Counseling in pediatric HIV/AIDA. IJPP 2003;5:306-314.
  5. Parthasarathy A, Dutta AK, Bhave SY. IAP Guide Book on Immunization, Committee on Immunization, Indian Academy of Pediatrics, 2001, pp 48.
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  8. Miotti PG, Taha TE, Kumwenda NI et al. HIV transmission through breastfeeding: a study in Malawi. JAMA 1999;282:744-749.
  9. Nduati R, John G, Mbori-Ngacha D, et al. Effect of Breastfeeding and Formula Feeding on Transmission of HIV - A Randomized Clinical Trial. JAMA 2000;283:1167-1174.
  10. Coutsoudius A, Pillay K, Spooner E, Kuhn L, Coovadia HM. Influence of infant - feeding patterns on early mother-to-child transmission of HIV-1 in Durban, South Africa: a prospective cohort study. South Africa Vitamin A study Group. Lancet 1999;354:471-476.
  11. PCP Prophylaxis CDC. 1995 revised guidelines for prophylaxis against Pneumocystis carinii pneumonia for children infected with or perinatally exposed to human immunodeficiency virus. MMWR 1995;44(RR-4):1-11.
  12. Kher A. Antiretroviral therapy. IJPP 2003;5:325-337.
  13. http://www.aidsinfo.nih.gov/guidelines/pediatric/
    html_pediatric.
  14. Kind C, Rudin C, Seigrist C et al. Prevention of vertical HIV transmission: additive protective effect of elective cesarean section and zidovudine prophylaxis. AIDS 1998;12-205-210.
  15. Connor EM, Sperling RS, Gelbeer R et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 1994;331:1173-1180.
  16. Schaffer N. Short course zidovudine for perinatal HIV-1 transmission in Bangkok, Thailand: a randomized controlled trial. Lancet 1999;353:773-780.
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