Treatment of Pediatric HIV Infection
by Mark W. Kline, M.D.
1. Antiretroviral Agents Currently Available for Treatment of Pediatric HIV Infection
In the U.S., any drug that is approved by the Food and Drug Administration (FDA) for use in adults can be prescribed for children, as well. However, most pediatricians are careful to use only those drugs for which doses in children are known, and safety in children has been proven. In addition, pediatric formulations of some antiretroviral agents are unavailable, largely eliminating the use of these agents for children too young, or too immature, to swallow tablets or capsules.
Three main classes of antiretroviral agents are in use today. Within each class, there are various individual agents. These agents are used in various combinations with one another; monotherapy of any kind currently is not recommended.
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
The NRTIs are prodrugs that undergo activation intracellularly to an active 5’-triphosphate form. Viral RNA is used as a template for synthesis of proviral DNA. The active triphosphate derivatives of the NRTIs compete with endogenous deoxynucleotide triphosphates for incorporation into proviral DNA, a process regulated by viral reverse transcriptase. Once incorporated, there is premature termination of elongation of the proviral DNA chain. Generally in combination with one another, the NRTIs provide the backbone for most of the combination treatment regimens in use today.
Six NRTIs have been or are being used by prescription in children (zidovudine [ZDV,AZT], didanosine [ddI], stavudine [d4T], lamivudine [3TC], zalcitabine [ddC], and abacavir). The dosing and common side effects of these drugs are shown in Tables 1 and 2, respectively.
Table 1. Comparing NRTI Drugs for Children
|Capsule, strawberry flavored syrup
|90-180 mg/meter2 body surface area three or four times daily (maximum 200 mg four times daily)
|Chewable orange flavored tablet, pediatric powder for oral solution
|90-120 mg/meter2 body surface area twice daily (maximum 200-250 mg twice daily)
|Capsule, oral liquid solution
|1 mg/kg twice daily (maximum 40 mg twice daily)
|Tablet, strawberry-banana flavored liquid
|4 mg/kg twice daily (maximum 150 mg twice daily)
|0.005-0.01 mg/kg three times daily (maximum 0.75 mg three times daily)
|Tablet, strawberry-banana flavored liquid
|8 mg/kg twice daily (maximum 300 mg twice daily)
|*Not approved for use in children younger than 13 years of age.
Note: ddI should be administered on an empty stomach. The drug should be taken with water or apple juice only. Administration of the drug with other liquids or food reduces absorption of ddI from the stomach. The other approved NRTIs may be taken with or without food.
Table 2. Serious Side Effects of NRTIs in Children
|Side Effects/Adverse Events
|Bone marrow suppression with neutropenia (low white blood cell count) or anemia (low red blood cell count)
|Pancreatitis, peripheral neuropathy
|Peripheral neuropathy (rare in children)
|Pancreatitis, peripheral neuropathy
|Peripheral neuropathy, oral ulcers
|Note: AZT-associated bone marrow suppression usually is treated by temporarily stopping treatment with the drug, reducing the AZT dose, or giving another medicine to help boost bone marrow activity. Pancreatitis (inflammation of a digestive organ called the pancreas) is a potentially severe (even life-threatening) side effect of therapy with either ddI or 3TC. Symptoms of pancreatitis include abdominal pain and vomiting. Symptoms of peripheral neuropathy include numbness, pain, or tingling, usually of the arms, legs, hands, or feet. Peripheral neuropathy usually improves or goes away when the drug is stopped.
Zidovudine usually is given 3 or 4 times daily, but twice daily dosing is being used in some studies. The drug can suppress the bone marrow, producing neutropenia or anemia. This side effect usually is easily managed by reducing the dose, or temporarily stopping treatment with, ZDV. Didanosine generally is given twice daily, but treatment of children with once daily ddI is being studied. Rare side effects of ddI therapy include pancreatitis and peripheral neuropathy. If one of these side effects occurs, permanent discontinuation of ddI treatment may be necessary. Stavudine is given twice daily. The drug is remarkably well-tolerated and safe for use in HIV-infected children. Although peripheral neuropathy occurs occasionally among HIV-infected adults treated with d4T, this side effect has been observed only rarely among HIV-infected children. Lamivudine is given twice daily. In combination with ZDV or d4T, 3TC is an important ingredient of several first-line therapies for HIV-infected children. The drug generally is well-tolerated and safe, but pancreatitis and peripheral neuropathy are reported side effects of 3TC therapy. Zalcitabine has not been studied extensively in children. Used alone, ddC appears to have less potent anti-HIV effects than some other anti-HIV medications. Reported side effects include peripheral neuropathy and oral ulcers. Abacavir is given twice daily. A small percentage of individuals treated with abacavir experience signs and symptoms of a hypersensitivity (allergic-type) reaction, which can include fever, nausea, vomiting, diarrhea, rash, and respiratory distress. If such a reaction occurs, abacavir must be discontinued permanently. Attempting to give abacavir to an individual who has experienced this reaction can be dangerous or life-threatening.
The HIV protease inhibitors are active at a late step in viral replication, preventing maturation of infectious virions. Their target is viral protease, which ordinarily is responsible for cleavage of large viral polyproteins into smaller, functional units. Taking protease inhibitors in the correct doses and on precise schedules is important. Missed doses can lead to viral resistance and drug failure, possibly limiting future HIV treatment options. In general, viral resistance to one protease inhibitor confers cross-resistance to other members of the class. This is an important limitation to the use of these agents.
All of the protease inhibitors interact pharmcologically with many other agents that are metabolized by the hepatic cytochrome P450 system. Extreme care should be exercised, and the drug package insert should be reviewed carefully, before the use of a protease inhibitor with any other drug.
The dosing and common side effects of the various HIV protease inhibitors are shown in Table 3. Four protease inhibitors, ritonavir, nelfinavir, amprenavir, and lopinavir/ritonavir, are available in pediatric formulations; two others, indinavir and saquinavir, only are available as adult capsules. Ritonavir is given twice daily. The drug is available as a liquid syrup that has a very bitter taste. Eating peanut butter or drinking chocolate milk before and after taking ritonavir can help mask the taste of the drug. The drug must be taken with food. In pediatric studies, nausea, vomiting, and hepatitis have caused some children to stop taking the drug. Giving gradually bigger doses of ritonavir over a period of about five days, until the total dose is reached, may help prevent nausea and vomiting. Nelfinavir generally is given twice or three times daily. The drug is available as a tablet and as a powder. Nelfinavir tablets can be crushed or pulverized for administration to children unable to swallow pills. The crushed tablets and powder dissolve poorly in liquids, so they should be given either suspended in a liquid (such as water, formula, or milk) or mixed with a soft food (such as pudding). Nelfinavir should not be given with citrus juices (such as orange juice) or in applesauce. Amprenavir is given twice or three times daily. It is not recommended for children less than four years of age. Amprenavir can be taken with or without food, but it should not be taken with a high-fat meal because of adverse effects on bioavailability. Lopinavir/ritonavir, recently approved by the FDA, is given twice daily with food.
Table 3. Comparing PI Drugs for Children
|400 mg/meter2 body surface area twice daily (maximum 600 mg twice daily)
|30 mg/kg three times daily (maximum 750 mg three times daily)
|22.5 mg/kg twice daily or 17 mg/kg three times daily (maximum daily dose, 2800 mg)
|12/3 mg/kg (7 to <15 kg) or 10/2.5 mg/kg (15 to 40 kg) twice daily (maximum 400/100 mg twice daily)
|Nausea, vomiting, hematuria, kidney stones
|500 mg/meter2 body surface area every 8 hours (maximum 800 mg every 8 hours)
|50 mg/kg three times daily (maximum 1200 mg three times daily)
|Note: Recommended doses are based on available information from pediatric studies. Dosing may change as additional information becomes available. Recommended doses are different when PI drugs are used in combination with one another. Always check with a knowledgeable health professional before giving any new medicine to a child who is receiving a PI drug.
Indinavir is available as a capsule only. The drug usually is given every eight hours on an empty stomach. Attempts to develop a form of the drug for young children so far have failed. The contents of the capsules have a very bitter taste that most children will not tolerate. Giving the capsule contents in applesauce can help mask the taste, permitting some young children to take indinavir. In pediatric studies of indinavir, some children experienced nausea and vomiting or hematuria. Crystallization of indinavir in the renal tubules can produce nephrolithiasis. The risk of hematuria and kidney stones can be reduced by encouraging children to drink fluids copiously throughout the day. Saquinavir was available initially only as a hard gel capsule, but this form of the drug had very poor oral bioavailability. More recently, a soft gel capsule form of saquinavir has been developed that significantly improves the drug’s bioavailability. Even so, saquinavir generally is used only in combination with another protease inhibitor (e.g., ritonavir or nelfinavir) to boost its concentration in the blood. Saquinavir must be given with food.
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have a similar target, but work in a slightly different way, than NRTIs. These drugs have been used in combination with NRTIs and protease inhibitors and have been found to be generally well-tolerated and safe, although they share a propensity for causing skin rashes (including, occasionally, Stevens-Johnson syndrome). When it occurs, rash usually develops in the first several weeks after NNRTI therapy is started. In most cases, the rash disappears uneventfully within a few days, but serious (even life-threatening) rashes can occur. Similar to the protease inhibitors, viral resistance to one NNRTI generally confers cross-resistance to other members of the class.
Dosing guidelines for the NNRTIs are given in Table 4.
Table 4. Comparing NNRTI Drugs
|7 mg/kg (age 2 months to 8 years) or 4 mg/kg (age 8 years or older) twice daily (maximum 200 mg twice daily)
|200-600 mg once daily (maximum 600 mg once daily)
|Pediatric dosing guidelines are unavailable.
|Note: Recommended doses are based on available information from pediatric studies. Dosing may change as additional information becomes available. All of the NNRTIs can cause serious (or even life-threatening) rashes. Nevirapine often is given at reduced dose (4 mg/kg/day) for the first 14 days of treatment to help reduce the risk of rash.
Hydroxyurea is an anti-cancer drug in widespread use since the 1960’s. It first was proposed for the treatment of HIV infection because of its ability to inhibit a cellular protein, ribonucleotide reductase, which represents the rate-limiting step in synthesis of deoxynucleotide triphosphates. These compounds are intracellular competitors of the NRTIs. By reducing their concentrations, hydroxyurea promotes incorporation of nucleoside analogs into viral DNA by reverse transcriptase, thereby blocking DNA synthesis. This effect appears to be particularly powerful when hydroxyurea is combined with ddI, probably because of the competition of ddI with deoxyadenosine triphosphate, which hydroxyurea depletes more completely than other deoxynucleotides. However, hydroxyurea also enhances the in vitro anti-HIV activity of thymidine or cytidine nucleoside analogs by increasing their intracellular phosphorylation (activation), providing a possible rationale for combination therapy with hydroxyurea and drugs like d4T or 3TC.
Hydroxyurea has several potential advantages over existing antiretroviral agents. First, because it targets a cellular rather than viral protein, mutational resistance to the drug is unlikely to occur. Second, there is evidence that hydroxyurea can compensate for ddI resistance, possibly restoring the drug’s activity. This could be a particularly important consideration in the child with extensive antiretroviral experience and few or no remaining therapeutic options. Finally, hydroxyurea is remarkably inexpensive, which could make the drug particularly valuable in the developing world, where highly active antiretroviral therapy currently is prohibitively expensive.
Controlled studies have demonstrated superior reduction in plasma HIV RNA concentrations for HIV-infected adults treated with hydroxyurea in combination with ddI or d4T/ddI, as compared to those treated with ddI or d4T/ddI alone. Neutropenia or thrombocytopenia, pancreatitis, and peripheral neuropathy have been observed in some adults treated with hydroxyurea in combination with NRTIs. No controlled pediatric data are available, but several pediatric trials are ongoing.