Compiled by Dr.R.R.Gangakhedkar
Assistant Director, National AIDS Research Institute, Pune
for Pediatric HIV/AIDS, First National Conference (Held on 3^rd & 4^th November, 2001 at Delhi)

Introduction

In the initial phase of HIV epidemic, HIV infection in pediatric age group was observed mostly as a consequence of blood transfusions. It was more common among children who were suffering from diseases requiring repeated transfusion support. Subsequently, the transmission from HIV-infected mother-to-child become common as the heterosexual epidemic matured and women started moving into the centre-stage of HIV epidemic. The management of pediatric AIDS was difficult to begin with as clinical trials in pediatric population were not given due primacy. However, FDA US proposed in 1997 that every new drug should have data on pediatric population. This proposition provided impetus to clinical trials among pediatric populations.

According to the estimates made by UNAIDS, there were 33.6 million individuals infected by HIV by the end of 1999, of which, 1.2 million were children below the age of 15 years. It is estimated that a total of 3.6 million children below 15 years age have already died since the beginning of the epidemic. The HIV prevalence in antenatal clinics is reported to be more than 1% in six states of India - Maharashtra, Tamilnadu, Karnataka, Andhra Pradesh, Manipur and Nagaland.

The development of tests and protocols for early diagnosis of the HIV infected infant provided an impetus to initiating the highly active antiretroviral therapy (HAART) in pediatric age group. Moreover, development of plasma viral load test revolutionised management of AIDS, not only in adults, but in children as well. Hence, timely and optimal pediatric HIV management becomes important. However, the cost-related issues, lower availability of pediatric formulation, and low accessibility of these drugs reduce the feasibility of offer of HAART in developing countries. In resource-poor settings, appropriate management through prevention and early treatment of opportunistic infections remains as the cornerstone in clinical management.

Challenge Of Pediatric AIDS Management

Since transmission of pediatric HIV infection can be reduced significantly by interventions during pregnancy, identification of HIV infection among women during pregnancy is crucial. These women need to be offered anti-HIV drugs like zidovudine or nevirapine and counselled about the issues related to breast-feeding, medical termination of pregnancy and offer of prophylaxis against opportunistic infections especially PCP in infancy to all HIV-exposed infants. Various treatment regimens for HIV-infected pregnant women based on several combinations of antiretrovirals are currently being evaluated world over. The safety and efficacy of several of these agents is still to be determined, and treatment strategies are constantly evolving.

There certain differences between HIV- infected children and adults such as;

1. Children infected with HIV tend to have a lower survival span,
2. Their virological and immunological responses tend to be different than adults,
3. They tend to have a different morbidity profile than adults,
4. They are more likely to have growth retardation and generalised systemic manifestations such as hepatosplenomegaly etc.

The incidence of pneumocystis carinii pneumonia is higher among children, particularly in infancy (12%). The incidence of tuberculosis, especially that of tuberculous meningitis is lower than adults. Certain diseases involving central nervous system like cryptococcal meningitis, toxoplasma and lymphoma are infrequent in children. But, HIV encephalopathy is more common among them. Recurrent bacterial infections and recurrent pneumonia are more commonly observed than that among adults. Chronic Parotitis is peculiarly more common in children infected by HIV. Lymphoid interstitial pneumonitis (LIP) is one of the important common respiratory manifestations in children. Kaposi's sarcoma is rare in children. Nephropathy and cardiomyopathy is also observed frequently in children.

The pharmacokinetic profile of drugs is different in children. The bioavailability of any drug is especially a critical issue in management. Nutritional aspects especially the food-drug interaction is equally important in management of HIV infection among children. The non-availability of pediatric formulation of various antiretroviral preparations poses a major hurdle in management. Timely immunization of infants is critical in pediatric HIV management. All these issues make the pediatric HIV management a complicated task.

Prerequisites For Effective Management

Early management of pediatric HIV disease based on timely institution of chemoprophylaxis, immunization, management of opportunistic infection, nutritional support and antiretrovirals when required is found to be effective. However, early management using appropriate measures is possible only if these children are diagnosed early. Prior to the era of offering antiretroviral prophylaxis to reduce mother-to-child transmission in areas where HIV prevalence rate among pregnant women is more than 1%, most often the diagnosis of pediatric HIV infection in a child was made on the basis of clinical suspicion. However, nowadays, a pregnant woman is detected as HIV infected during pregnancy, which leads to testing of the baby and its diagnosis as being HIV infected. However, wherever HIV prevalence among pregnant women is less than 1% and antiretroviral prophylaxis is not offered, the first pattern of index case being a child will still predominate. In order to detect such HIV infected children at the earliest in low HIV prevalence areas, operational research to evolve indigenous clinical criteria, compare it with WHO classification of pediatric AIDS and assess its sensitivity and specificity should be given high priority.

Spectacular advancement has been made in strategies to reduce mother-to-child transmission in recent past. Offer of voluntary counselling and testing for HIV infection to identify pregnant women who need these drugs is a critical hurdle in our crowded antenatal settings in both public and private sector.

Issues For Pediatricians

It has been clearly shown that early effective medical interventions in the pediatric age group can improve the quality of life, morbidity and mortality. In order to provide effective management of pediatric HIV infection, a pediatrician should be able to offer appropriate care to HIV exposed infant and manage those who are found to be infected by HIV appropriately. However, this would need timely identification of the mother as being HIV infected and also early detection of HIV infection.

Transmission

The vertical transmission of HIV infection may occur in utero (about 30-50% cases), intrapartum (about 50-70% cases) or through breast-feeding (about 14-29% cases). The timing of transmission of HIV infection to the child is determined by a simple categorisation used as a definition by doing PCR at 48 hours, 2 months and 6 months.

1. An infant is considered to have in utero infection if virologic tests (HIV DNA or RNA PCR or culture) are positive within 48 hours after birth.
2. Infants are considered to have acquired HIV during intrapartum period, if diagnostic tests within the first 48 hours of life are negative but further virologic testing after one week of life is positive.
3. When an infant is found to be negative by PCR test between 2 to 6 months of age and later the infant is detected to have HIV infection, it is termed as late postnatal transmission, most often caused by the breast-feeding.

However, not much is known about the timing of transmission of HIV infection from India. This is important since majority of women are likely to breast feed their children in India. It is essential that the data that is collected in the ongoing feasibility study on zidovudine prophylaxis to HIV infected mothers and all subsequent studies be analysed to answer this research question. It has important implications on strategies to reduce mother-to-child transmission of HIV infection in India.

The risk of transmission of HIV infection depends on maternal factors such as advanced HIV disease, having primary HIV infection, chorioamnionitis, premature rupture of membranes, type of delivery, chemokine receptor expression and certain foetal; factors such as breastfeeding, prematurity, foetal lacerations and order of birth among twins. However, the risk determinants of transmission of HIV infection are not known in Indian setting. Additionally, placenta acts as an efficient barrier in HIV infection. It is till not clear whether certain quasi-species of HIV have the ability to pass through the placenta efficiently. Research needs to undertaken to find out whether such a phenomena exists. Similarly, HIV is present in breast milk and mammary tissue. The risk of transmission may be dependent on both- the concentration of HIV and certain specific quasi-species of HIV. Initial evidences suggest that concentration of HIV may be reduced in mammary compartment after providing antiretroviral prophylaxis to the mother before delivery. However, further research needs to be conducted on these issues.

The cellular content of breast milk tends to vary in colostrums and mature milk. Therefore, the concentration of HIV is reported to be higher than that in mature milk. Research on determinants of transmission related to the colostrums also needs to prioritized especially in view of the presence of various protective immune factors in it and reports of presence of certain components related to mucosal immunity. Additionally, recent publications related to transmission of HIV through breast milk have led to development of guidelines to offer a safer choice of exclusive breastfeeding for 4-6 months and rapid weaning to HIV infected women. However, a recent publication in Lancet has reported that the risk of death in HIV infected mothers who decide to breastfeed increases by three folds have complicated the dilemma of breastfeeding. A high priority needs to be accorded to undertake observational studies to assess the impact of various infant feeding practices on infant as well as the mother urgently. A study had reported that the presence of lipases in breast milk inactivate HIV in breast milk when it is left standing at room temperature. Since this is a comparatively easier option, basic research to study the impact of keeping the extracted breast milk on standing for variable duration needs to be undertaken urgently. This study has a good potential to change the public health policy in relation to breastfeeding. Operational research on various other strategies such as boiling breast milk and clinical trials of long-acting antiretroviral drugs which are also excreted well in breast milk, used as prophylaxis to prevent transmission are important. Most often, it is believed that the immune factors present in breast milk are important for reducing morbidity and mortality. It is important to remember that though HIV infected persons may have an adequate quantity of antibodies against various organisms to which the person may be exposed to in its lifetime, the quality of these antibodies such as avidity is low. Therefore, study of the quality of immune factors in the breast milk of a lactating mother infected by HIV is also important.

Natural History Of Pediatric HIV Infection

Most of the HIV natural history cohorts in children have shown that there is a bimodal distribution of clinical disease progression. These are classified as rapid progressors and slow progressors. Of the HIV infected children, about 20-30% are rapid progressors. The rapid progressors tend to develop advanced disease usually in the first year of life (mostly by 5-6 months of age) . About 50% of these children develop AIDS by 5 years of age. Generally such children present with PCP, failure to thrive, hepatitis, diarrhoea and neurocognitive dysfunction during infancy itself. Their rate of increase of head circumference is lower. Intrapartum transmission of HIV appears to be a dominant mode of acquisition of HIV in such children (rapid progressors). Though the virus may be undetectable in some case of infection acquired intra-partum, majority of infant not treated with antiretroviral drugs maintain a very high burden of viral load. Some studies have shown that this high viral load may persist for a longer time in an infant compared to an adult after primary HIV infection.

Majority of the pediatric HIV infection cases can be categorised as slow-progressors. These children are relatively asymptomatic during infancy and according to a study about 15% were asymptomatic even at 5 years age. The slow progressors generally tend to have a higher CD8 counts and reveal a lower rate of fall of absolute CD4 counts. About one fourth of these children may show mild symptoms such as lymphadenitis and parotitis.

A larger group of children among the slow progressors have a more intermediate progression of HIV disease and will tend to develop evidence of severe immunosuppression by 7 to 8 years of age, having a gradual loss in CD4 counts. Prior to the institution of antiretroviral treatment, about 60-75% of the children used to belong to a group of intermediate/slow-progressors. About 5-10% of the HIV infected children used to be long term asymptomatics with a minimal to none decrease in CD4 counts. The median survival time of vertically infected children by HIV is reported to be about 8-9 years. Clinical indicators for rapid disease progression are; progressive respiratory distress first six months of age (PCP), failure to thrive, developmental delay/ loss of milestones, recurrent bacterial infections (sinusitis, otitis media, pneumonia, meningitis), bruising/ epistaxis, HIV cardiomyopathy, HIV nephropathy, recurrent oral candidiasis, CMV retinopathy, absence of lymphadenopathy with very advanced disease, hepatosplenomegaly, aphthous ulcers, HIV encephalopathy, thrombocytopenia, brain atrophy on CT scan or MRI, Positive urine cultures for CMV.

Those children who belong to slow progressors category are likely to be asymptomatic with usual pattern of childhood morbidity. They may have lymphadenitis. Certain manifestations such as; hepatosplenomegaly, parotitis, and lymphoid interstitial pneumonitis (LIP) have been commonly observed amongst these children.

However, two recent studies on natural history of HIV infection among children infected by HIV-1 subtype C from Africa have shown that the risk of development of AIDS is as high as that reported from the developed countries where the predominant subtype is HIV-1 B. However, the background mortality rate was higher at each age group category than that for development of AIDS. Primacy must be accorded to development of natural history cohort of HIV infected children which will not only help in understanding the evolution of infection, conduct basic studies in immunological and virological determinants of disease progression, but will also be useful to develop chemoprophylaxis and management protocols and test their efficacy.

Diagnosis Of Pediatric HIV Infection

The diagnosis of pediatric HIV infection through detection of antibodies against HIV needs to be undertaken at 18 months age due to the passive transfer of maternal antibodies. The routine HIV ELISA cannot distinguish between passively transferred antibodies against HIV and those that are produced due to the infection itself. Hence early diagnosis needs to be undertaken using other methods to diagnose HIV infection in the pediatric age group.

The early diagnosis of the HIV infection can be undertaken using polymerase chain reaction (PCR) technique. The HIV DNA PCR can be performed in the first 48 hours of life. One can also undertake HIV culture. However, one needs to wait for almost a month to be sure of a negative HIV culture and it is an expensive test. Both these methods are highly sensitive and specific. HIV culture is done in research settings in a couple of centres in India. It is a costly, labour-intensive, time consuming test requiring well- trained laboratory personnel. It takes about four weeks to rule out HIV infection using virus culture. Sensitivity of virus culture is equivalent to that of PCR test.

The DNA PCR testing is more rapid, less laborious, and relatively inexpensive when compared to HIV culture and hence is widely used. HIV RNA PCR is generally not used for early diagnosis. However, it may be more sensitive than HIV DNA PCR in making early diagnosis. In a prospective study of 271 HIV?infected infants using HIV DNA PCR, 38% of children were found to be positive within 48 hours of life, 93% were positive by 14 days of age, and 96% of the total number of infected children were positive by four weeks of age. Therefore, HIV DNA PCR is a good laboratory test for early detection of HIV infection in infancy.

One can also use a test to find out the presence of plasma p24 antigen (p24 Ag) only after completion of one month's age, preferably around three months age of the infant due to high false positivity. However, the presence of antibodies against p24 is likely to interfere in its detection. Hence, an acid dissociation approach has been used to conduct p24 test. But both these tests have lower sensitivity and hence are not considered as ideal for early diagnosis of HIV infection during infancy, when used alone.

The battery of HIV diagnostic tests should be repeated between one to two months of age and between four to six months of life among infants who were initially found to be negative. If one is using HIV ELISA for diagnosis before 18 months of age, two negative HIV tests at least one month apart, if performed after six months of age, may also be used to exclude HIV infection in children with no clinical evidence of disease.

When prophylactic antiretroviral treatment in pregnancy came in vogue, there were concerns that it might affect the virological HIV diagnostic tests. However, this concern does not seem to be correct. The sensitivity of these HIV diagnostic tests was not found to be different among infants whose mothers were receiving zidovudine prophylaxis. However, it is not yet clear whether instituting a combination regime like HAART may affect the sensitivity of these diagnostic tests. The diagnosis of HIV infection is delayed if ELISA test is the only available test. It is unlikely that PCR technology would be widely available in India. Different tests to diagnose HIV infection earlier than that by ELISA are available such as p24 test. A simple, cost-effective, feasible algorithm for early diagnosis of HIV infection during infancy for various levels of health care should be developed and tested for sensitivity and specificity.

Management Of The HIV? Exposed Infant

All infants born to HIV?infected women should receive prophylaxis for Pneumocystis carinii pneumonia (PCP), usually with trimethropim?sulfamethoxazole from six weeks age as the incidence of PCP is high during this period. This should be continued till the diagnosis of HIV infection is confirmed as mentioned above. The prophylaxis should be discontinued in infants, who sero-revert. In the event the infant is found to be HIV infected, PCP prophylaxis should continue until one year of age regardless of CD4 counts. However, it was found that use of TMP/SMX prophylaxis leads to development of community strains of resistant bacteria. Since TMP/SMX is also used in ARI programme, it is necessary that a study to assess the development of resistant strains should be undertaken urgently.

HIV?infected Infant

Prior to the effective screening of pregnant women for HIV, diagnosis of HIV infection was generally established only after the child develops symptoms of disease. In fact the diagnosis of HIV infection in a child was followed by its detection in a mother. These symptomatic children exhibited severe degree of immunosuppression and high viral load. With the advent of antiretroviral therapy, early detection of HIV infection and timely management of HIV disease came into vogue to change the set point of the HIV disease progression. Between 1990-92, pediatric advanced HIV disease cases were managed using zidovudine (ZDV) monotherapy. Later ddI monotherapy was also used for management of these symptomatic children. In order to avoid emergence of drug resistant HIV, sequential regimes came into practice. Later, it was realised that the combination anti-HIV drugs result in better clinical and immunological response, hence two drug combinations were widely used. With the advent of protease inhibitors, using three drugs (one of which is a protease inhibitor) became a standard of care for pediatric HIV management. Early institution of HAART in children to delay disease progression is currently practiced in the western countries.

Monitoring HIV Disease

Apart from periodic clinical assessment, certain tests like CD4/CD8 counts and plasma viral load estimations need to be done repeatedly. The CD4 counts are a surrogate marker for HIV disease progression. The plasma viral load estimation is crucial in assessing the impact of the antiretroviral drugs.

CD4 Counts

Normally, children have a much higher CD4 lymphocyte counts than those among healthy adults due to the characteristic lymphocytosis observed in that age group. Generally, these counts approach adult values by six years of age. Absolute CD4 count and percentage are surrogate markers of disease progression in HIV and should be obtained at baseline prior to initiation of any treatment. Rapid reduction in CD4+ cell subsets in the first year of life may be an indicator that the infant is a rapid progressor. Since, the CD4 counts are affected by diurnal variation, the period during which the blood shall be withdrawn must be fixed. The blood must be processed within 48 hours of collection, better still within 24 hours. As the CD4 counts can be altered in the presence of any other infection, as far as possible, it should be taken in otherwise normal child or a month after the infection. For interpretation of CD4 counts, age- adjusted CD4 values are used to avoid misleading conclusions due to higher counts in childhood. Compared to absolute CD4 counts, the percent CD4 is a robust indicator among children due to the childhood lymphocytosis. Percent CD4 gives a better indication of the disease stage. The therapy should not be modified on a single assessment but such as consideration can be given if the values remain same on repeat testing.

The estimation of CD4% at the baseline is also useful in assessing the risk of mortality. A study reported that the risk of death at about five years increases from 33% for children having more than 35% CD4 count to almost 97% for those having it below 5%. The CD4 counts should be done every three months especially while managing a patient with antiretrovirals.

It is now reported that in adults from certain parts of India, especially south India, tend to have lower CD4/CD8 counts, which complicates disease staging and medicinal interventions. It is necessary that a study should be undertaken to assess the baseline CD4/CD8 counts among normal health Indian children belonging to various age groups, urgently.

Plasma Viral Load Estimation

Quantification of free virus in plasma can be performed using HIV RNA assays. In adults the HIV RNA levels are high until 6-12 months after becoming HIV infected. The immune responses limit this virus to a set point at this time point. Generally, the HIV RNA levels seen during primary HIV infection, decline by more than 100 fold during by 6-12 months. However, this pattern is different in those children who acquire HIV infection through transplacental route. Certain studies have shown that there is a lag period of two months after birth when the viral load reaches the peak. Later a fall in these levels has been observed. The mean plasma HIV RNA levels are as high as 185,000 copies per ml at the age of one year. Generally, these levels keep on falling in the next few years of life. This peculiar phenomenon is attributed to the presence of a large quantity of HIV susceptible cells. Plasma HIV RNA levels of more than 299000 copies per ml in an infant has been correlated with rapid disease progression and death. In general, a plasma HIV RNA load of more than 100000 copies per ml and CD4 % of less than 15% is considered as a poor prognostic sign for survival. Most studies to date have indicated that the persistence of very high HIV RNA levels in children younger than one year of age correlates with a poor prognosis of HIV disease. However, one should be guarded in over-interpreting viral load values during infancy as the HIV RNA values are likely to fall by 4 fold every year between 12 to 24 months and 4 to 5 years. There is tremendous biological variation in the HIV RNA levels. These levels are known to vary by 3 fold during a day or on different days among adults. This variation may be higher in children. It is important to note that due to the considerable intra?patient biologic variability in HIV RNA levels and only changes greater than 5?fold in HIV RNA copy number for children under two years of age and those greater than 3?fold in children older than two years should be considered significant.

There are several methods available to estimate HIV viral load. Since these assays exhibit different cutoff ranges, and sensitivity and specificity, one should try to use the same method for estimating viral load in a patient. Three methods are in vogue currently:

• RT (Reverse Transcriptase) PCR ? also known as Amplicor Monitor, Roche Diagnostic Systems,
• b (Branched) DNA ? also known as Quantiplex, Chiron Corporation
• NASBA (Nucleic acid sequence?based amplification) of plasma RNA ? Organon Technika,

Both RT PCR and NASBA assays tend to produce results two?fold higher than those obtained by the bDNA assay. The assays developed earlier were not sensitive to pickup C clade of HIV-1 and some other clades. However, this problem has now been rectified. The cost of tests to estimate plasma viral load is high which limits its affordability and usage while managing patients. Research to develop cheaper tests to monitor viral load or use of p24 antigen testing should be given a priority in India. Operational research to optimize the use of these tests while managing these patients should also be prioritized.

Other Evaluations And Support Activities

A baseline assessment should include complete blood counts, a blood chemistry panel- especially liver transaminases, amylase and lipase levels, lactic dehydrogenase (LD), and quantitative immunoglobulins. The HIV replication increases after primary CMV infection, which can occur in the first few months of life. Hence, wherever feasible urine culture for CMV is indicated. However, this recommendation may not be easy to practice in our country as the management of CMV is very costly. If there is a clinical indication or the head circumference is increasing at a lower rate, an MRI or CT scan may be done to identify whether it is caused by brain atrophy. In the developed countries measurement of antibodies following immunization is always undertaken after vaccinating symptomatic children. This is necessary since the "take" of vaccines in HIV becomes poor in symptomatic cases. However, it may not be feasible in our set ups. However, operational research to study the take and devise simple tests to assess it should be undertaken. Counselling facility must be extended to the family members and caregivers in the family. The counselling must also focus on issues related to drug adherence. Nutritional counselling is crucial in these children.

Antiretroviral Treatment In Pediatric HIV Infection

The management with antiretroviral drugs is important. These drugs act by inhibiting the replication of HIV. It is expected that this inhibition will also result in increased proportion of HIV unfit to survive due to decaying. These drugs belong to three different classes such as nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors. The cost is comparatively lower in children due to low dosage requirement. The following drugs are currently licensed in the USA for treatment of HIV infection:

Nucleoside reverse transcriptase inhibitors (NRTIs)

Non-nucleoside reverse transcriptase inhibitors (NRTIs)

Protease Inhibitors (PIs)

Note:Pediatric formulations of these drugs are currently available in USA. However, excepting syrup formulation of zidovudine and lamivudine, none of these formulations are available in India currently.

Which anti-HIV drugs to use?
Till 1992, use of a single drug to increase survival of late stage HIV disease patients was in vogue. However, this was found to be associated with a quick emergence of drug-resistant HIV. It became apparent however, that HIV variants rapidly developed specific mutations that rendered the virus resistant to the antiretroviral agent in use. In children the development of specific ZDV mutations coincided with subsequent HIV disease progression in selected studies. The advent of improved measures of virus load (specifically HIV RNA assays) allowed clinicians to discern that treatment failure led to increased virus replication and significant increases in virus plasma viremia, and that a persistently elevated virus load was a poor prognostic factor in children. In addition, virus replication kinetic studies in children indicated that over time there is a selection of a more biologically "fit" virus that is capable of replicating much faster and to much higher levels in PBMC cultures in vitro. Treatment with highly active antiretroviral agents modifies viral replication dynamics and slows viral replication significantly. Although by current assays virus load is undetectable in plasma, even patients with very successful treatment regimens might still have detectable virus when ultrasensitive RNA PCR or culture techniques are used. By standard techniques, HIV RNA PCR or culture may become negative following aggressive therapy, but proviral DNA persists in their PBMC. At present it is unclear whether this is exclusively due to long?lived cells or if low level replication contributes to the ongoing infection of cells.

Based on these findings, regimes using combination of two or three drugs belonging to different categories is now advocated in the west. The initial treatment could being with 2NRTIs + PI or 2NRTIs + NNRTI, or 2NRTIs. The most popular regime amongst these, is use of zidovudine, lamivudine with or without protease inhibitor such as indinavir/ ritonavir depending on the patient status. Pediatricians, who believe in aggressive management at initiation of the combination regimes, tend to use three drug regimes which include a protease inhibitor, and zidovudine / stavudine, and lamivudine or ddI. However, looking at the possibility of emergence of drug-resistance and subsequent utility of other potent drugs, one may chose two drug regimes to initiate such as zidovudine/stavudine with lamivudine/ ddI. Even a drug intake default of seven days can result in emergence of drug resistant HIV within few weeks time. Once a patient develops resistance, one may ideally need to change two antiretroviral drugs in most cases in salvage therapy, making the therapy more costlier and jeopardising the accessibility of drugs. Use of combination regimes have been shown to reduce the plasma viral load below undetectable level. The viral load in the lymphnodes is also reduces simultaneously. This reduction in viral load is also associated with reduction in symptoms, rate of disease progression, mortality as well as quality of life in late stage HIV disease.

When to initiate combination regime?
Though, recent retrospective studies indicate that survival of any patient is a function of a "set point" which is decided in the early phase of HIV infection. People having high plasma viral load, despite being in the early stage of HIV disease tend to die earlier. High plasma viral load is a proxy indicator of tilting balance between the HIV and immune system. The newly discovered, highly potent anti-HIV drugs belonging to protease inhibitors class reduce the plasma viral load very quickly within 2-4 weeks. However, the viral load returns back to baseline level within a couple of weeks of discontinuation or development of resistance to it. Some experts believe in "hit early, hit hard" principle using combination regime to lower the set point. Early treatment of all recently HIV diagnosed infants is recommended although there is only a limited amount of data available on the effectiveness of early combination antiretroviral therapy in this group of children. However, there is considerable data available on viral replication dynamics during primary viremia in adults. The rationale for early treatment is that prompt initiation of aggressive antiretroviral therapy during early viral replication might preserve the child's immune function, decrease viral seeding, lower the viral set point and result in improved clinical outcome. Therefore, it is recommended that antiretroviral therapy be initiated in all HIV infected infants as soon as the diagnosis is confirmed regardless of clinical status, immunologic status or virus load excepting children older than one year of age with normal immune status and a low risk of disease progression (low virus load).

Additional recommendations for treatment of HIV?infected children include;

• Treat all HIV infected children with clinical symptoms of HIV infection (Clinical categories A, B or C)
• Evidence of immune suppression (Immune categories 2 or 3) regardless of age or virus load.
• Age less than one year regardless of clinical, immunologic, virologic status

If the pediatrician decides to defer antiretroviral therapy at the baseline evaluation, it should be initiated promptly in such a HIV?infected child when:

• HIV RNA levels are found elevated or increasing (> 5?fold increase for children < two years and > 3?fold for those >/= two years of age)
• CD4+ absolute number or percentage is found to be declining rapidly to Immunologic category 2.
• Development of clinical symptoms
• All children with HIV RNA levels > 100,000 copies/ml
• Children older than 30 months who have HIV RNA levels consistent with treatment recommendations for HIV?infected adults (> 10,000 copies/ml)

Which antiretroviral regime to use?
The recommended, first choice regimen includes two nucleoside analogue RT inhibitors and one protease inhibitor. The rationale for this choice is to attain maximal suppression of virus replication. This approach has proven successful in selected studies where reduction to undetectable levels of HIV RNA was achieved in children. If there are concerns about toxicity and adherence to a protease inhibitor regimen, then one may initiate therapy with two nucleoside analogue inhibitors in combination with a non-nucleoside analogue (nevirapine). If the use of more potent therapy is to be deferred to a later time point because of concerns with drug adherence, dual combination regimens of two NRTIs. However, this regime tends to have lower potency.

Some of the favoured and popular combination regimes are;

• ZDV + 3TC + nelfinavir or ritonavir or nevirapine
• d4T + ddI + nelfinavir or nevirapine or ritonavir
• d4T + 3TC + nelfinavir or nevirapine or ritonavir

When one defers use protease inhibitors for various reasons, the commonly used regimes are; ZDV + 3TC ZDV + ddI d4T + ddI d4T + 3TC ZDV + ddC

However, one should never use following combinations:

1. ZDV + d4T ( antagonistic action)
2. d4T + ddC ( Toxicity concerns)
3. ddI + ddC ( Toxicity concerns)
4. ddC + 3TC (Toxicity concerns)
5. Monotherapy ( Resistance concerns)

Efavirenz, a recently approved anti-HIV drug, can be given in once a day dose. It is under trial in pediatric HIV disease

How to monitor the patients ?
Estimations of CD4 counts and plasma viral load ideally need to be done twice, 2-4 weeks apart before initiating the therapy, and at 2-4 weeks and 12 weeks following the therapy. CD4 counts and plasma viral load estimations should be done every 3-4 months subsequently. If a 10-fold (1 log 10) decrease in viral load is not observed at 12 weeks, the therapy needs to be reviewed for drug-resistance and changing / adding another anti-HIV drug to it.

Changing Antiretroviral Therapy
Treatment failure in HIV infection is characterized by disease progression that can translate clinically into growth failure, development of new infections indicative of immunodeficiency, or development or worsening of neurologic HIV disease. Virologic and immunologic failures also warrant change in therapy. A decline in CD4+ count values or an increase in virus load, as previously described, indicate increased virus replication. Given the complexity of combination therapy dosing it is not uncommon for problems with drug delivery and drug adherence to arise. Clinicians should verify that disease progression is in fact occurring because of drug failure and not due to failure to take the drug.

One can assess the treatment failure based on following criteria in HIV infected children:

• Less than a 10?fold decrease from baseline HIV RNA levels in children receiving two NRTIs and one PI, or less than a 5?fold decrease from baseline HIV RNA levels in children receiving less potent therapy after 8 to 12 weeks of therapy;
• Detectable HIV RNA levels after four to six months of therapy (may be longer when ultrasensitive assay is used).
• Repeated detection of HIV RNA in children who had undetectable levels following initiation of therapy;
• Persistent increase in HIV RNA levels after initiation of treatment > than 3?fold in children >/= 2 years, and > than 5?fold in children under two years of age

Indications of immunologic treatment failure in children include:

• Change in immunologic classification at follow up;
• For children with Immunologic category 3 (CD4+ percentage < 15%), a persistent decline of five or more percentiles; and,
• Rapid and significant decrease in absolute CD4+ cell number

In addition, a change in the antiretroviral regimen might be warranted if toxicity or intolerance ensues or if superior treatment regimens become available in the future.

What are the caveats for prescribing the combination regime?
Once these drugs are started, they need to be continued till the patient survives or gets cured. Statistical models in adults suggest that these regimes need to be continued for years (up to sixty years!) for a hypothetical "cure". There are no studies documenting cure of HIV infection with any of these regimes. These drugs have major drug-drug interactions and side-effects. Skillful changes in drug dosages are required when the patients suffer from loose motions that reduce the bio-available drugs. Drug compliance is an important issue as drug resistant HIV have been observed within 2-17 days of discontinuation of combination drugs. Therefore half- hearted attempts to initiate antiretroviral drug therapy should, at best be avoided. Studies to improve drug adherence using various interventions must be given priority. Necessary evaluation of future drug compliance must be made before prescribing the drugs in HAART. The cost of these drugs is tremendously high. Only zidovudine, saquinavir (hard gel preparation), ritonavir, stavudine (d4T) and lamivudine have been licensed for marketing in India by the Drug Controller of India. Other anti-HIV drugs can be procured on import licenses on individual basis, where regular supply needs careful planning. Therefore, prescribing these combination regimes requires due consideration of not only the medical aspects, but others such as; economic, psychological and drug-compliance related issues as well in India.

Antiretroviral Drugs and Toxicity

Apart from the well known toxicities certain newer toxic effects are also being reported of recent such as severe hepatotoxicity with use of Nevirapine for a short period; avascular necrosis of femur, ostopenia, mitochondrial dysfunction, and lipodystrophy. A registry of adverse events should be initiated for patients receiving antiretroviral drugs. It would be important to initiate a study to assess the impact of antiretroviral drugs on mineral metabolism.

Management of Opportunistic Infections

Prior to wide use of HAART, the gains in survival of HIV infected children were mainly due to chemoprophylaxis of opportunistic infections (OIs). Management of some important opportunistic infections is described in the following sections.

Pneumocystis carinii Pneumonia (PCP)
In about a third of the pediatric HIV infection cases, PCP is the AIDS-indicator disease. PCP may occur in infancy even when absolute CD4+ cell counts are more than 1500 cells/µl. The diagnosis of PCP can be made by staining specimen from bronchoalevolar lavage, tracheal aspirate or induced sputum with silver methanamine or Giemsa staining. In places where the tests are not available, one may give a therapeutic trial on clinical suspicion and watch for clinical response within 48 hours. Intravenous trimethoprim?sulfamethoxazole (TMP/SMX) in the dose of 20 mg/kg per day of trimethoprim divided in four daily doses for 21 days is the primary line of management. Alternatively intravenous pentamidine (single daily infusion of 4 mg/kg) can also be given. However, use of pentamidine should be avoided, if the patient is already receiving ddI due to the risk of pancreatitis. Oral atovaquone can be tried in the dose of 40 mg/kg per day, in two divided doses. Prednisolone (2 mg/kg/day in four divided doses) can be used when the child shows evidence of hypoxia (PaO2 of < 70 mm Hg).

Pneumocystis carinii pneumonia (PCP) was the most frequent opportunistic infection in children especially around three months age, prior to the current recommendation to initiate PCP prophylaxis at six weeks of age in infants born to HIV infected women. The incidence of PCP in HIV infected children has declined significantly with this prophylaxis. A high incidence is also evident with advanced HIV disease. Hence, PCP prophylaxis is administered from six to eight weeks gestational age till the confirmation of the diagnosis of HIV infection. Later, the decision to administer PCP prophylaxis to continue it for lifelong, is based on age-specific CD4 counts and percentages, such as;

TABLE TO BE INSERTED

Interestingly, a recent study from Thailand used an innovative algorithm for early discontinuation of TMP/SMX prophylaxis based on absence of certain clinical conditions. It is important that such innovative approaches should be studied in India as well.

The secondary prophylaxis needs to be life-long. Oral TMP/SMX (150 mg/m2/day of TMP or 750 mg/m2/day of SMX] in two daily doses 3 times a week on consecutive days [in HIV-exposed, indeterminate infection status] or everyday, when child is having advanced disease or pediatric AIDS. Daily TMP/SMX regimen also protects against toxoplasma, recurrent bacterial infection, and isospora diarrhoea. Among patients who are hypersensitive to sulfa drugs, one may undertake desensitisation or may select alternative regimen of oral Dapsone, 2 mg/ kg OD, or Aerosolized pentamidine (in children > 5 years age ), 300 mg administered via Respirgard II inhaler once a month.

Candidiasis
Fungal infections like oral candidiasis are common in HIV-infected children, which may recur. About 11-20% of the asymptomatic children present with oral candidiasis. Generally oesophageal candidiasis occurs in advanced HIV disease. It results in dysphagia and extensive oral thrush. Candidimia is rare in HIV disease as neutrophils are relatively less affected in HIV infection. In the initial episodes of oral candidiasis, one may use topical antifungal agents like clotrimazole or miconazole. However, the utility of these topical agents reduces with recurrent candidiasis. If there is no response to topical antifungal agents, one should use fluconazole (3-6 mg/kg/day in one or two divided doses) or ketoconazole (5-10 mg/kg/day in one to two divided doses) and if situation demands one may use itraconazole ( 2-5 mg/kg/day in one or two divided doses) for 5-7 days. Since the bioavailability of ketoconazole is lower, use of other remaining two agents is a safer alternative. However, the inadequate dosages and poor drug adherence may contribute to quick emergence of drug-resistant candida. Therefore, treatment using adequate dosages for reasonable duration is crucial in candidal management. Intravenous amphotericin B (0.5-1.0 mg/kg/day) may be required to manage candidimia or refractory candida oesophagitis. Candidal skin infections respond well to topical agents or a short course of systemic antifungals. Onychomycoses caused by Candida or Trichophyton can be treated with fluconazole, itraconazole or griseofulvin, but usually a prolonged treatment course is necessary. Primary chemoprophylaxis against candida is not indicated. However, good oral hygiene is vital. Lifelong secondary chemoprophylaxis against candida can be done with fluconazole, 3-6 mg/kg/day OD or one may use ketoconazole 5-10 mg/kg/day in one or two divided doses in children presenting with severe recurrent mucocutaneous candidiasis and oesophageal candidiasis. However, the drug-drug interaction and issues related to emergence of drug-resistant fungi should be considered and decision should be taken on case-to-case basis.

Cryptococcal meningitis
Cryptococcal meningitis is uncommon in children contrary to that in adults. The diagnosis of cryptococcal meningitis can be made using tests to detect the presence of cryptococcal antigen in the CSF or identification of the organism by India ink. The prognosis in cryptococcal meningitis is poor. One may use amphotericin B with or without flucytosine (5FC, 50-150 mg/kg/day in four divided doses ) to initiate therapy for 14 days and follow it up by maintenance therapy with fluconazole (6-12 mg/kg/day) for 8 to 10 weeks. Lifelong secondary prophylaxis with fluconazole is necessary. Avoiding areas where pigeon droppings are found can reduce the exposure to cryptococci.

Cytomegalovirus infection
Cytomegalovirus infection (CMV) is a fairly common infection in children. However, it is infrequently found in late stage HIV disease. This may be mainly due to lower survival of HIV-infected children compared to adults. In the initial period, children remain asymptomatic. Hence periodic fundoscopy is necessary, every six months. It may cause blindness due to retinitis. It can also cause encephalitis, colitis, esophagitis or pneumonitis. The diagnosis can be best established by doing tissue biopsy. Urine cultures may be negative due to intermittent shedding. And a positive urine culture may not necessarily mean an active infection. One can use intravenous ganciclovir ( 10 mg/kg/day in two divided doses administered over 1-2 hours) for 21 days and followed by lifelong maintenance therapy with 5 mg/kg/day, 5 days/week. Alternatively, one can use intravenous foscarnet ( 180 mg/kg/day in three divided doses administered over 1-2 hours each time) and followed by maintenance dose lifelong (90-120 mg/kg/day OD) for managing CMV disease. Oral ganciclovir has poor bioavailability and is being evaluated in children.The cost of management of CMV disease is very high as it needs a prolonged maintenance therapy. One can use gancyclovir or cidofovir implants to delay progression of CMV retinitis in ipsilaterally. Most of these drugs are nephrotoxic and hence their dosages may differ in children with impaired renal function. Use of blood tested for CMV antibodies for transfusional purposes among vulnerable children and adherence to good hand washing practices in pediatric hospitals as well as out-patient department may prevent the exposure to CMV.

Herpes Simplex Virus Infection
Recurrent herpes simplex virus infections (HSV) is frequently seen in pediatric HIV infection. About 5% children present with HSV infection as an AIDS-defining condition. Oral acyclovir ( Acyclovir 80 mg/kg/day in four divided doses) can be used to manage HSV infection. Intravenous acyclovir 45-60 mg/kg/day divided in three doses can be used for 2-3 weeks in infants <1 months age. Acyclovir-resistance is difficult to manage.

Varicella Zoster Virus
Varicella zoster virus (VZV) infection can be more severe in HIV infected children than in immunocompetent patients. Recurrent varicella is unique to pediatric HIV infection with pain and severity of skin lesions decreasing with each episode. Additionally, they may have classical herpes zoster manifestation involving multiple dermatomes as seen in adults. This manifestation can be seen in children who already had varicella. Oral acyclovir (80 mg/kg/day in four divided doses for 10 days) can be used for accelerating healing process of the lesions and also in recurrent infections. Varicella zoster immunoglobulin (VZIG should be administered if the contact case is a child who is HIV-infected , within 96 hours of exposure. However, varicella vaccine should not be administered to an HIV-infected child, it being a contact of the index case.

Measles
Measles is associated with high morbidity and mortality in HIV infected children. Hence, all asymptomatic children should be immunised at the earliest. MMR vaccine should not be given to symptomatic children (Immune category 3) especially in view of a report of fatal vaccine -associated pneumonia. Immunoglobulins should be administered within six days of exposure (0.5 ml/kg, intramuscularly) irrespective of immunisation status to all the HIV infected children on definite exposure. Vitamin A, 100,000 IU for children between 6-12 months age and 200,000 IU for > 1 year old children, should be given orally for all the HIV infected children when they have measles.

Recurrent bacterial infections
Serious recurrent bacterial infections are a major cause of morbidity in symptomatic children with HIV. Almost a fifth of the HIV infected infants present with recurrent bacterial infections as an AIDS-defining condition. Generally, these infections are caused by S. pneumoniae (almost 50% of these infections), S. aureus, H. influenzae etc. Recurrent pneumonitis is also common in these children. These recurrent infections should be treated with appropriate antibiotics. However, if the frequency bacterial infections is high, child has hypogammaglobulinimia, or thrombocytopenia, Intravenous immunoglobulin (IVIG, 400 mg/kg every month) can be administered as a prophylaxis. The cost of IVIG therapy is very high. Hence one may use, TMP/ SMX prophylaxis in two divided doses in such children. Since this drug is used for prophylaxis against the PCP, it can also be useful in these circumstances and without an increase in the cost. There is no additional benefit of IVIG in a child receiving TMP/SMX. Use of conjugated H. Influenzae type b and polyvalent pneumococcal vaccine is recommended. Repeat vaccination should be done within 3 to 5 years of receipt of the vaccine.

Mycobacterial Infections
Children infected with HIV are more likely to develop infections by the mycobacteria. Both affect and thrive on suppression of cell-mediated immunity. Tuberculosis, per se is uncommon in western developed countries especially so in children. Tuberculosis being endemic in India, a cross-protection may be responsible for reduced incidence of MAC in India.

The likelihood of one of the parents having active tuberculosis may be higher in children acquiring HIV due to perinatal transmission. Therefore, this infection may become a common manifestation of pediatric HIV infection in India. In HIV positive children, a PPD >/= 5mm is considered positive. Children in contact with individuals with active tuberculosis are likely to acquire TB and hence chemoprophylaxis is necessary. In the absence of active disease (no symptoms and normal chest roentgenogram), children with a positive PPD should receive nine months of isoniazid therapy. Children with active TB should be administered four-drug regimen; INH (10-20 mg/kg/day ), Rifampicin ( 10-20 mg/kg/day ), pyrizinamide ( 30 mg/kg/day in one to two divided doses) and streptomycin (20-30 mg/kg/day) or ethambutol (15 mg/kg/day) for a minimum duration of 6-12 months. Contact of an HIV-infected child with an open, active TB case in the family should be avoided during the first two weeks of initiating anti-TB drugs or sputum negativity, whichever is later. Additionally, chemoprophylaxis should be administered to the child.

Disseminated Mycobacterium avium intracellulare complex (MAI or MAC) is not uncommon in advanced HIV disease. Generally, the prognosis is poor and most of the children may succumb to this illness. One may have to use a combination regimen of three to five drugs including; a macrolide (clarithromycin or azithromycin), rifabutin, amikacin, ethambutol, clofazimine or ciprofloxacin. However, institution of HAART in such patients have improved the survival rates with MAC. The infections due to these atypical mycobacteria are lower in India probably due to the higher likelihood of death due to other causes which occur at an earlier stage and also to some extent due to protective cross-immunity due to endemic TB.

Cryptosporidiosis
Diarrhoea is common in advanced HIV disease. Cryptosporidium is a commonly isolated organism in cases of chronic diarrhoea. It cause watery diarrhea. The infection is very difficult to manage in advanced HIV disease patients. The diagnosis is made using modified acid fast staining on concentrated stool samples. The management is mostly symptomatic. One has to use antimotility agents in these children to improve the quality of life. In some cases, use of azithromycin and paramomycin ( 30-40 mg/kg/day in three to four divided doses) have been reported to be effective. Bovine colostrum has not been found to be effective in controlling this diarrhoea. One may use octreotide (a somatostatin analogue) to control severe diarrhea. However, it may be used with caution in patients already receiving ddI, ddC or pentamidine for prophylaxis of PCP. HIV-infected children should avoid contact with human and animal faeces, newborn and young pets, calves and lambs, drinking water from lakes, rivers or water storage tanks. Use of submicron water filters may reduce the risk of exposure. Though boiling water for one minute is known to eliminate the risk of cryptosporidiasis, there is no data to show that boiling is efficacious. However, one may advise use of boiled water for drinking along with good hygiene to reduce the risk of enteric infections including cryptosporidiasis.

Toxoplasmosis
Toxoplasmosis, a common CNS manifestation in adults, is uncommon in children (0.3% cases of newly diagnosed AIDS cases). As this infection is generally due to reactivation, children with congenital toxoplasmosis form an important risk group amongst children for development of Toxoplasmosis. It can be managed using sulfadiazine ( 85-120 mg/kg/day in two to four divided doses), pyrimethamine (1 mg/kg/day, maximum dose 25 mg), and folinic acid (5-10 mg every three days). One may use clindamycin (20-30 mg/kg/day in four divided doses) along with pyrimethamine and folinic acid in cases having hypersensitivity reaction to sulpha drugs. Maintenance regime needs to be continued subsequently. Consumption of raw meat or undercooked meat and contact with soil should be avoided. The litter box of a cat, if reared as a pet animal in the house should be changed everyday and hands should be washed thoroughly. These precautions can prevent the risk of exposure.

HIV encephalopathy
HIV encephalopathy is common manifestation of HIV disease in children. It is of two types - progressive and static encephalopathy. It results in cognitive and motor impairment. Most often, it is caused by HIV due to its tropism towards microglial cells. Additionally, HIV?associated opportunistic infections and neoplasms may cause neurological dysfunction. Increased viral load in CSF and brain tissue has been associated with cognitive dysfunction. HIV encephalopathy presents with developmental delay or regression in young children. Behavioral abnormalities such as loss of concentration and memory are common in older children. Progressive motor disease especially spastic diplegia is a peculiar feature of early onset encephalopathy. It may also manifest as microcephaly, which may be associated with cerebral atrophy or basal ganglia calcifications. Severe encephalopathy beginning in infancy is associated with poor prognosis. Neuro-radiologic and psychometric evaluation should be at baseline, every 3-4 months in infancy, every 6 months between 1-3 years, yearly till 10 years age and two-yearly assessment after ten years age. The management of encephalopathy can be frustrating. Not all antiretroviral drugs can cross the blood -brain barrier. Zidovudine , stavudine and to some extent ddI are known to cross it, but not the protease inhibitors. Dramatic, but transient benefits can be observed after initiating antiretroviral drugs in these children, particularly zidovudine and stavudine, which effectively cross the blood?brain barrier.

Lymphoid Interstitial Pneumonitis
Lymphoid interstitial pneumonitis (LIP) is a common pulmonary manifestation of HIV in children and is peculiarly seen in children. About 20-25% HIV infected children used to develop LIP prior to HAART era. Almost one in five children present with LIP as an AIDS-defining illness. LIP is related to primary exposure to Ebstein?Barr virus (EBV) and may also reflect a particular response to HIV from a developing immune system. Some children may remain asymptomatic for many years despite marked radiological changes. They do not require therapy. Others may develop secondary bacterial infections that need aggressive management. Chronic antibiotic therapy, nebulisation with selective brochodilators and physiotherapy can be of benefit. Steroids ( 1-2 mg/kg/day for 2-4 weeks) are indicated in patients having hypoxia. LIP is associated with good prognosis.

Other Clinical Manifestations of HIV Disease
Aphthous stomatitis is observed a significant proportion of HIV infected children. Topical application of steroid solution and local anaesthetic like viscous lignocaine are useful in its management. Children with HIV disease may reveal evidence of renal involvement such as proteinuria, nephrotic syndrome and renal failure. The physiopathology of HIV renal disease is not well understood. HIV cardiomyopathy is also a manifestation of advanced HIV disease in children. Many mild cardiac abnormalities may go undetected in the earlier period of infection.

Pancreatitis
This uncommon complication is most often associated with use of antiretroviral drugs such as ddI, or drugs like pentamidine, isoniazid. CMV infection can also lead to development of pancreatitis. However, serum amylase levels are likely to be found elevated in pediatric HIV disease. Unless they are associated with symptoms, one may not worry about it as it may be from the salivary glands as well. One needs to withdraw the offending anti-HIV drug in the management of this complication.

Hepatitis
Generally the hepatic transaminases are raised in pediatric HIV infection. Additionally, certain hepatotoxic drugs such as rifampicin, INH, fluconazole etc may increase these levels as well. The offending agent needs to be withdrawn. Hepatitis due to infections such as hepatitis B, hepatitis C, CMV etc is also common and needs to be treated accordingly.

Haematological abnormalities
Haematological complications such as thrombocytopenia are common especially in infancy and at times may be the first pointer towards HIV infection. Use of antiretroviral drugs, IVIG and steroid therapy (especially when the platelet count is less than 20000 cells/cumm) is useful in its management. Neutropenia is also a common laboratory finding in children receiving antiretroviral drugs especially zidovudine. The dose of zidovudine needs to be reduced in these circumstances. Sometimes one may have to use growth colony stimulating factor (G-CSF) for management of persistent severe neutropenia (less than 250 cells/cumm). Anemia associated with zidovudine use, may at times may require use of human erythropoietin (Epo). After infancy, the children do not require discontinuation of antiretroviral therapy for management of anaemia.

Supportive Care of the HIV?Infected Child

Nutrition
Children with HIV infection require a good nutritional support. HIV associated gastrointestinal disorders, oropharyngeal lesions such as candidiasis and dental caries may result in anorexia, nutritional deficiencies, weight loss and failure to thrive. Their nutritional requirement should be worked out and appropriate high calorie and high protein diet should be prescribed to them. Emphasis on food hygiene is crucial to prevent diarrhoeas due to certain organisms such as salmonella, giardia, campylobacter etc. The appetite stimulations using certain drugs may not be as much effective. Timely decision on initiating gastric feedings or total parenteral nutrition (TPN) is important.

Immunization
Routine immunization schedule should be followed excepting MMR to a symptomatic child with advanced HIV disease due to a concern of possible dissemination of live attenuated vaccine viruses. In fact administering vaccines strictly adhering to the national guidelines is crucial as the immunosuppression is less likely to be as profound during this period. Pneumococcal vaccine is recommended for children age two years or older. Yearly influenza immunization is recommended for children over six months of age and family members in the west.

Passive immunization
If HIV infected children are exposed to varicella, intramuscular varicella zoster immunoglobulin (VZIG) is indicated within 72 hours of exposure unless the child is known to have adequate antibodies against it or there is a reliable history of previous varicella.

Conclusion

The recent past has witnessed an explosive pace of research in mother-to-child transmission of HIV infection. It has also introduced a glimmer of hope of control of pediatric HIV infection especially so in developed countries like USA. There is a high morbidity in pediatric HIV disease. The mean survival is lower when compared to adults. The advances in HIV diagnostic tests have resulted in early diagnosis of pediatric HIV infection. The research on newer antiretroviral combination therapy, HAART has shown a dramatic change in quality of life and survival of HIV infected children. The development and use of newer disease staging tests such as plasma viral load and testing for anti-HIV drug resistant mutants have improved the approaches to management. Though the cost of standard-of-care as per the western guidelines is high, even effective management of opportunistic infections and a hope of reducing the cost of manufacturing gives us a hope that the management may improve in near future even in developing countries. The management of pediatric HIV disease, though a complicated and costly proposition, is a challenge, which pediatricians need to face to provide some solace to the hapless HIV infected parents.