Compiled by Rakesh Lodha, Tanu Singhal, SK Kabra
Department of Pediatrics, All India Institute of Medical Sciences, New Delhi
for Pediatric HIV/AIDS, First National Conference (Held on 3^rd & 4^th November, 2001 at Delhi)

Pediatric HIV Infection II: Management

The advent of potent antiretroviral drugs has enabled transformation of human immunodeficiency virus (HIV) infection from a fatal to a chronic disease in developed countries (1). However supportive care, appropriate prophylaxis and management of infections are equally important. They are, in fact, the mainstay of therapy in countries such as ours where antiretroviral therapy is ill affordable by most patients (2). This article attempts to provide an overview of the basic treatment principles of this increasingly common pediatric illness.

Initial evaluation

This includes detailed history to ascertain the mode of transmission, symptoms related to HIV and HIV status of the family members. The socioeconomic status and level of disease awareness in the caretakers should also be enquired into. A detailed physical examination including anthropometry, pulse oximetry, fundoscopy and neurodevelopment assessment should be carried out.

Subsequently if feasible, the immune status and viral burden should be determined by estimation of CD4 counts and HIV RNA levels. Other laboratory tests include a complete hemogram including platelet count, liver and renal function tests, X ray film of the chest, tuberculin test, stool examination, urine analysis and ECG. Immunoglobulin levels, echocardiogram, computerized tomography (CT) of the chest and plain head CT may be requested if indicated.

After clinical and immune categorization of the illness, treatment details are planned and discussed with the caretakers.

Antiretroviral therapy

Antiretrovirals can be classified as nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). As many as 13 antiretroviral agents are currently FDA approved for treatment of HIV infection (1). All drugs that have been approved for use in adults may be used in children even though specific pediatric studies on efficacy and long-term safety may not be available (3). NRTIs were the first drugs to be used and are the least expensive. NNRTIs are increasingly being evaluated in pediatric treatment protocols. They are not associated with significant interactions with food, need to be taken once or twice daily and freely cross the blood brain barrier. Protease inhibitors are very efficacious but expense and side effects are major limiting factors. Details of commonly used drugs are listed in Table 1 (3). Certain new drugs including NRTIs such as Abacavir, Adefovir and NNRTIs such as Efavirenz are also being evaluated in children (1).

Indications for anti retroviral therapy

Antiretroviral therapy provides significant clinical benefit in HIV infected children with immunologic or clinical symptoms of HIV infection with substantial improvements in neurodevelopment, growth, immunologic and/or virologic status (4). The efficacy of antiretroviral therapy in asymptomatic children has not been demonstrated. However given the pathophysiologic sequence of events in HIV infection, early aggressive therapy may help in preservation of the immune system and minimization of the risk of antiviral resistance. Moreover it has been found that infants and children have higher levels of plasma virus and more rapid disease progression as compared to adults (1). Therefore the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children has proposed the following indications for initiation of antiretroviral therapy (3).

• Clinical symptoms associated with HIV infection (Categories A, B, C)
• Evidence of immune suppression (Immune category 2 or 3)
• Age < 12 months-regardless of clinical, immunologic or virologic status.
• For asymptomatic children > 1 year with normal immune status the preferred approach is to offer therapy to all. Alternatively treatment may be deferred and the virologic, immunologic and clinical status monitored. Therapy is initiated in the following circumstances.
• High or increasing HIV RNA copy number.
• Rapidly declining CD4 count/percentage approaching immune category 2.
• Development of clinical symptoms.

To simplify, the recent consensus is to use antiretrovirals in all HIV infected children irrespective of clinical, immunologic and virologic status (5).

Regimen of anti retroviral drugs (Table 2)



As in adults, the combination of two NRTIs and one protease inhibitor is the preferred regime and comprises what is known as Highly Active Antiretroviral Therapy (HAART). Recommended NRTI combinations are zidovudine (ZDV) with dideoxyinosine (ddI) or ZDV and lamivudine (3TC). Limited data are available for combinations of stavudine (d4T) and ddI, d4T and 3TC, and ZDV and zalcitabine (ddC). Combinations of d4T with ZDV and ddC with ddI/d4T/3TC should be avoided. The protease inhibitors currently approved for infants and children are nelfinavir or ritonavir and indinavir for those who can swallow capsules (3).

Nevirapine with two NRTIs is an alternative and cheaper regime but its clinical benefit and durability is not well defined (3). The combination of only two NRTIs though of limited benefit can be offered when cost, non-availability or toxicity precludes the use of protease inhibitors (3). This combination results in significant clinical improvement, virologic and immunologic recovery and improves the quality of life although for a short time (4). The risk of resistance with such therapy in children is of a lesser concern, as they in usual circumstances do not pass on the resistant strains to others.

Monotherapy with any drug should be employed only for prevention of perinatal transmission and not for treatment purposes (3).

Monitoring and follow up

On follow up the child should be evaluated for clinical improvement, compliance, adverse drug reactions as well as for rise in the CD4 counts and suppression of HIV RNA levels (Table 3). CD4 counts are estimated every three months. Plasma RNA determinations 4 weeks after initiating therapy and then 3 monthly are advocated. With a combination of two NRTIs a five-fold reduction of HIV RNA levels by 8-12 weeks is expected (3). With the standard regime of 2 NRTIs and a protease inhibitor, a ten-fold reduction is expected by 8-12 weeks and levels should be undetectable by 4-6 months (3). However since perinatally infected children have high baseline RNA levels, complete suppression is often not achievable unlike adults (1). In case of lack of optimal response, compliance, dosing schedule and possible drug interactions should be reviewed. If these are satisfactory and the lack of response is persistent, antiretroviral resistance should be suspected. Molecular techniques to identify mutations for the confirmation of resistance to antiretroviral drugs are under evaluation.



Worsening of clinical symptoms (advancement from one CDC class to the next, growth failure and neurologic dysfunction), significant decline in CD4 counts, less than optimal decline/rise of RNA levels and unacceptable drug toxicity are indications for change in antiretroviral regime (3). If a change is indicated due to toxicity, decreasing the dose (as with reverse transcriptase inhibitors) or use of an agent with different side effect profile (as with protease inhibitors) are available options. If a change is warranted due to disease progression, two new drugs should be introduced (5). However when changing therapy treatment adherence issues and quality of life in a patient with advanced disease should also be considered.

Adjunct Therapy

Nutrition
This is of paramount importance and adequate calorie, protein and micronutrient intake should be ensured. Extra allowances should be made during fever, diarrhea, and sepsis and for malnourished children. Anorexic and severely malnourished children may require nasogastric feeding.

Immunization (Table 4)



The immunization schedule recommended by the WHO Expanded Programme on Immunization (EPI) for children in developing countries proposes only a few changes in the immunization schedule of HIV infected children as opposed to the United States guidelines (6,7). As per WHO recommendations OPV, DPT and measles should be administered as in normal children. BCG can be safely given to asymptomatic children. Hepatitis B, pneumococcal vaccines and H. influenzae vaccines are also recommended. Yearly influenza vaccines in children beyond 6 months of age may be administered if available.

Management of common infections

Serious bacterial infections occur with increased frequency in HIV-infected children. Approximately 25% of HIV-infected children will have at least one invasive bacterial 'infection' (8). Streptococcus pneumonia is the commonest pathogen responsible for invasive bacterial infection. The risk increases with immunosuppression (Category 2 or 3).

Acute infections are responsible for a large proportion of deaths in HIV-infected children. In a cohort study of HIV-infected children. In a cohort study of HIV-infected children from Uganda, it was observed that 45% were asymptomatic or mildly symptomatic (category N or A) 2 weeks before death (9). This suggests that acute infections can lead to rapid death in HIV-infected children.

Pneumonia
Common etiologic agents of pneumonia include the usual bacterial pathogens such as pneumococcus, H Influenzae, staphylococcus, common respiratory viruses such as respiratory syncytial virus, influenza and parainfluenza and Gram negative organisms such as Salmonella, E coli and Klebsiella (10). Pneumocystis carinii pneumonia (PCP) is an important cause in infants and children not on prophylaxis. Mixed infections are also common. Rare pathogens include fungi and CMV. Lymphoid interstitial pneumonia, tuberculosis and atypical mycobacteria should be considered when respiratory symptoms are of insidious onset.

Non-severe pneumonia can be treated on an ambulatory basis with drugs such as coamoxiclav, newer macrolides. Severe pneumonia requires hospitalization and investigation for cause. Pending results, empirical treatment with intravenous broad-spectrum antibiotics (IIIrd generation cephalosporins, aminoglycosides and antistaphylococcal antibiotics) should be instituted.

PCP is the most common serious opportunistic infection in HIV-infected children; infants are at the highest risk. Clinical features are variable and include life-threatening hypoxia and respiratory distress. A typical chest radiograph will show bilateral interstitial infiltrates without hilar adenopathy. However, other patterns, e.g. nodules, cystic or cavitating lesions, pneumothorax, and pleural effusion may also be seen. Diagnosis is confirmed by microbiologic analysis of bronchoalveolar lavage fluid, tracheal aspirate, transbronchial biopsy, or open lung biopsy.

If PCP is suspected cotrimoxazole should be started (20 mg/kg of TMP 6-8 hrly for 21 days preferably given intravenously in the initial stages). In the presence of hypoxemia, prednisone or its equivalent in a dose of 2-4 mg/kg can be administered for 5 to 14 days and then tapered for one additional week (11).

Tuberculosis
HIV infection greatly increases the risk of active tuberculosis in children infected with M tuberculosis (10 - 30 times increased risk). The clinical features are similar to those seen in immunocompetent children. However, extra pulmonary and disseminated TB are seen more frequently due to decreased immunity in HIV infection. The diagnosis poses problems as it does in immunocompetent individuals. The differential diagnoses to be considered include PCP and LIP. There are no typical radiographic appearance of pulmonary TB in a HIV - infected child. Tuberculosis skin test is usually negative. Because of paucibacillary nature of the disease, microbiological tests are also usually not helpful; however all attempts should be made to demonstrate the organism. In such a situation, the diagnosis is often based on clinical features and history of contact an adult tuberculosis patient.

The therapy of drug susceptible tuberculosis in HIV infected children consists of an initial intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol/ streptomycin (for 2 months) followed by continuation therapy with isoniazid and rifampicin. Total duration of treatment as recommended by the CDC is 6 months (10). However treatment should be extended upto 12 months in case of delayed clinical response or disseminated disease (12, 13). Treatment should preferably be directly observed and the child carefully monitored for adverse drug reactions that are more common in HIV infected children (14).

Rifampicin significantly lowers the drug levels of protease inhibitors/ NNRTIs and therefore should not be used with these drugs (12). In such instances rifampicin may be substituted by rifabutin. However the use of rifabutin with antiretrovirals such as ritonavir and nevirapine should also be avoided. In such a case the drug regime may be modified to one comprising isoniazid, streptomycin and pyrazinamide daily for 2 months and then 2-3 weekly for another 7 months (12). Interruption of antiretroviral therapy to allow use of rifampicin is no longer recommended (12).

Sub optimal response to antituberculosis drugs may be due wrong diagnosis (as symptoms of HIV and other opportunistic infections resemble those of tuberculosis) and drug resistance (15). Worsening symptoms termed as paradoxical reactions may occur due to restored immune function after initiation of antiretroviral therapy (12).

Diarrhea
Diarrhea - acute, recurrent and persistent - is a common disorder in HIV infected children. In a HIV child, infection with any enteropathogen can result in prolonged diarrhea and malabsorption with subsequent malnutrition. The etiologic agents for diarrhea in HIV infected children include the common enteropathogens, C. jejuni, Helicobacter cinaedi, Shigella and cryptosporidium (16). Cryptosporidium in associated with voluminous profuse watery diarrhea, anorexia, weight loss and even death in HIV- infected individuals. Stool contains mucus but no blood or leukocytes. Diarrhea may also be due to systemic infection with atypical mycobacteria, CMV, HIV enteropathy, drugs or bacterial overgrowth. The risk of persistant diarrhea is increased especially with cryptosporidium (17). Management is conservative with adequate attention to fluid, electrolytes and nutrition. Specific therapy includes oral quinolones for invasive gastroenteritis (blood in stools), parenteral quinolones/ IIIrd generation cephalosporins for salmonella bacteremia, cotrimoxazole (10 mg/kg/day of TMP) for isospora. Cryptosporidium infections may respond partially to azithromycin (18).

Use of boiled water prevents cryptosporidium infections, cotrimoxazole against isospora and recurrent salmonella bacteremia (19).

Fungal infections
Fungal infections especially invasive infections are also seen more frequently. These include candidiasis, cryptococcosis, histoplasmosis and aspergillosis. Superficial fungal infections like oral thrush may be treated with local cotrimazole applications. However, extensive superficial infections and non serious invasive infections need to be treated with systemic antifungals like fluconazole, ketoconazole, or itraconazole. Serious invasive fungal infections should be treated with parenteral antifungals, i.e. fluconazole or amphotericin B.

Prophylaxis

Pneumocystis carinii pneumonia (PCP)
PCP is an important cause of morbidity and mortality particularly in infancy where it may occur despite normal CD4 counts. The revised guidelines recommend prophylaxis in (20).

• All HIV-infected and indeterminate children from 4-6 weeks to 12 months of life (prophylaxis can be stopped if HIV infection has been excluded after 4 mo of age)
• HIV-infected children aged
  • 1 to 5 years; CD4 count less than 500/µl, CD4 percentage less than 15%.
  • 6 to 12 years; CD4 count less than 200/µl, CD4 percentage less than 15%.
• All HIV-infected children previously treated for PCP.

Trimethoprim-sulfamethoxazole (TMP-SMX) in a dose of 150 mg/m2 /day 12 hrly orally for three consecutive days a week is the therapy of choice. It may however also be given daily, or on three alternating days a week.

Serious bacterial infections
Daily prophylaxis with TMP-SMX, 150 mg/m2 TMP divided in two daily doses protects against recurrent bacterial infections (19). Administration of intravenous immunoglobulin (IVIG, 400mg/kg/month) for HIV infected children with hypogammaglobulinemia is recommended (19). The efficacy of IVIG in providing an added benefit in children (without hypogammaglobulinemia) who are already on antibiotic prophylaxis is controversial but it may still be considered for children with a history of two or more invasive bacterial infections in a 1-year period, especially for those who have failed or are intolerant to antibiotic prophylaxis (19, 21).

Tuberculosis
Prophylaxis with isoniazid (INH), 5mg/kg daily for 12 months is advocated in the following circumstances (12).

• All tuberculin positive children (Mantoux > 5 mm) who have previously not received treatment for tuberculosis.
• Children with recent contact with an infectious TB patient regardless of the results of tuberculin skin test or history of previous TB preventive treatment.
• Children with a history of prior untreated or inadequately treated past TB that healed regardless of the results of tuberculin skin test.
In all the above cases active tuberculosis should be ruled out by detailed history, clinical examination, chest radiography and other tests.

Disseminated Mycobacterium avium intracellulare infection
Children with advanced immunosuppression should receive prophylaxis against M. aviuminfection (19). Children younger than 12 months with CD4 counts less than 750 cells/µl, aged 1-2 years with counts less than 500 cells/µl, 2-6 years with counts less than 75 cells/µl and children older than 6 years with counts less than 50 cell/µl merit prophylaxis. Clarithromycin 15 mg/kg/day bid daily or azithromycin 20 mg/kg once a week or 5 mg/kg once a day may be used.

Management of other organ specific manifestations

Lymphoid interstitial pneumonitis is an AIDS defining illness classified under category B. The onset is usually insidious; cough and tachypnea precede symptoms of dyspnea, hypoxemia or clubbing. The course is usually benign. The diagnosis is essentially clinical, with supportive chest radiograph or CT findings of reticulonodular or interstitial infiltrates with or without areas of consolidation. It is important to exclude infectious etiology by suitable investigations.

Asymptomatic LIP with normal oxygen saturation does not require specific therapy. HAART is beneficial. In the presence of hypoxemia or clubbing steroids are indicated. Prednisone 2mg/kg/day for 4-12 weeks with subsequent tapering guided by the clinical and oxygenation status. Low dose daily/alternate dose of steroids may be required for many months (22).

HIV encephalopathy
Antiretrovirals with good CNS penetration i.e. zidovudine, stavudine or nevirapine should be used (5). CNS opportunistic infections should be excluded.

Cardiomyopathy
Symptomatic cardiac dysfunction should be managed with vasodilators (ACE inhibitors), diuretics and digoxin used in that order. Other measures include restriction of activity, fluid and salt restriction, correction of anemia. Some patients improve with HAART.

Anemia
Iron, Vitamin B12 and folic acid supplementation benefits nutritional anemia. Recombinant erythropoietin may benefit anemia with impaired reticulocyte response. Anemia may also result from use of antiretrovirals such as zidovudine and may improve with dose reduction.

Thrombocytopenia
Thrombocytopenia often improves after initiation of antiretroviral therapy. Platelet counts < 20,000/µl or active bleeding may require other interventions such as IVIG or corticosteroids (23).

Management of infants born to HIV positive mothers (24)

Appropriate management of a child born to an HIV infected mother can significantly reduce the risk of acquisition of infection. All infected pregnant women should receive antiretroviral drugs for reducing the probability of perinatal transmission. At birth, the child should be started on zidovudine. The child needs to be repeatedly tested for evidence of HIV infection (Figure 1). If there is evidence of HIV infection, HAART should be recommended. As the infected children are particularly susceptible to PCP, prophylaxis for the same should be started in all children born to HIV infected mothers at 6 weeks of age.

Feeding counseling: Since breast-feeding does increase the risk of perinatal transmission, formula feeding should be offered to those where literacy, awareness and socioeconomic status permit (25). In others exclusive breast-feeding should be advised and mixed feeding should be avoided. Mixed feeding has been shown to increase the risk of transmission more than that attributable to exclusive breast-feeding (26). The decision about feeding should be individualized after talking to the family and comparing the risks associated with top feeding with those of transmission of HIV infection by breastfeeding.

Conclusion

Most of the management strategies elucidated in this article have been borrowed from guidelines proposed by developed nations. There is a pressing need to systematically study the efficacy and feasibility of many clinical care strategies particularly the development of cheaper and simpler antiretroviral regimes.

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