Antiretroviral Therapy in Pediatric Acquired Immunodeficiency Syndrome



Antiretroviral Therapy in Pediatric Acquired Immunodeficiency Syndrome


Ross E. McKinney Jr.



The ultimate goal of antiretroviral therapy for human immunodeficiency virus (HIV) is to cure the patient of infection. Because this objective is not yet achievable, the second target is to provide a simple, inexpensive, well-tolerated regimen that is able to control the infection for a long period, even indefinitely. Unfortunately, even this objective is elusive, and current treatment strategies generally are complex, rigid, and burdened by toxicities. Their efficacy is time-limited, and their effectiveness is marginal. Nonetheless, progress has been made, and newer, more potent antiretroviral agents have allowed HIV-infected people to live longer, healthier lives. Much of this progress has been attributable to a better understanding of HIV and its biologic behavior, thus rendering drug selection and use a more rational process. This chapter describes the antiretroviral drugs currently available and outlines some basic strategies for their use.


BIOLOGY OF HUMAN IMMUNODEFICIENCY VIRUS AND ANTIRETROVIRAL THERAPY

The antiretroviral drugs in current clinical use target critical steps in the life cycle of the virus. Fusion inhibitors block the movement of the virus from its attachment point on the cell surface to the cytoplasm. Reverse transcriptase inhibitors act on the genetic replication of the virus by inhibiting the virus protein that makes a cDNA copy of the viral genomic RNA. Protease inhibitors (PIs) act at a later stage in the virus life cycle by blocking the step when the viral protease cleaves the viral gag-pol polyprotein into the subunits required to make a fully mature, infectious virion. Additional viral targets such as the virus attachment protein (gp120) and the coreceptors (CXCR4 and CCR5) are the subject of drug development efforts, and potentially useful antiviral drugs directed at these other targets currently are in clinical trials.

Two classes of reverse transcriptase inhibitors exist: nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). NRTIs are modified nucleosides designed lacking a 3′OH group. They are phosphorylated by host cell kinases and then are incorporated into the elongating viral polynucleotide chain. Their incorporation produces a prematurely terminated cDNA molecule because another nucleotide cannot add to the chain given the absent 3′OH bonding site. Because the viral reverse transcriptase has a greater relative affinity for the modified nucleosides than does the human DNA polymerase (which generally rejects them), NRTIs have a tolerable therapeutic index. The NNRTIs act through a different mechanism than do the NRTIs. The NNRTIs interfere with nucleotide binding at the active site of the reverse transcriptase, blocking the inititiation of reverse transcription, and have no effect on cellular DNA polymerases because they are very enzyme specific. In fact, they are so specific that the NNRTIs have no effect on the reverse transcriptase of HIV-2. NNRTIs and NRTIs also have very different side effect profiles. NNRTIs can be used in combination with NRTIs, often with synergistic activity. Box 140.1 lists the different categories of drugs used in the treatment of HIV, including the NRTIs and NNRTIs.

HIV’s gag virion structural proteins and the pol proteins are synthesized as a long polyprotein. The polyprotein must be cleaved into many smaller proteins by the viral protease to produce a fully mature and infectious virion. The HIV protease is an aspartyl protease with some similarities to cellular aspartyl proteases, but several relatively specific inhibitors of the HIV protease have been developed, with excellent antiviral activity.

Suboptimal antiretroviral dosing or noncompliance can permit continued viral replication in the presence of low concentrations of drug, thus promoting the development of resistance
to the agents. The development of resistant viruses can have important implications for the long-term efficacy of antiretroviral therapeutic regimens.


The recommended doses of antiretroviral agents are summarized in Table 140.1. The table includes doses both for drugs approved by the Food and Drug Administration (FDA) and, so readers may have some appreciation of drugs currently undergoing development, for antiretroviral drugs in advanced stages of clinical development. Dosing and indications may change, and new side effects and drug interactions may become known. The physician should consult a current version of the package insert when prescribing antiretroviral agents, particularly newer agents, or federal guidelines. Many antiretroviral drugs have serious side effects and potentially harmful interactions with other drugs. Patients must be monitored carefully for these potential problems. Antiretroviral therapy should be managed by or in close consultation with an expert in the care of pediatric HIV infection.


ANTIRETROVIRAL DRUGS


Nucleoside Reverse Transcriptase Inhibitors

The NRTIs were the first class of antiretroviral drugs to be used in HIV infection. They can be divided into two categories: thymidine derivatives and nonthymidine NRTIs. The thymidine derivatives are zidovudine (ZDV) and stavudine (d4T), and because of its resistance pattern, tenofovir (TDF). ZDV and d4T do not work well together, probably because ZDV inhibits the phosphorylation of d4T to d4T-triphosphate; the latter is the active form of d4T. In general, most combination regimens include at least two NRTIs.

The effective pharmacokinetic properties of the NRTIs are determined by the pharmacokinetic properties of the active, intracellular triphosphate form of the drug. The serum half-life of the unphosphorylated native drugs is relatively short, and most are excreted rapidly, some after hepatic glucuronidation. However, within the cell, the phosphorylated forms of the drugs may have a prolonged half-life, which allows for less frequent dosing intervals than the serum half-life would suggest.

The NRTIs as a class can produce mitochondrial toxicity. Although it can be tolerated in most patients for years of therapy, in some patients a syndrome of lactic acidosis and hepatic steatosis can develop. The usual symptoms are nausea, vomiting, abdominal pain, and weakness in a patient who has been receiving nucleosides for 6 months or longer. This syndrome occurs more commonly in adults, female patients, and overweight individuals, and it is a particular concern in pregnant women. The incidence is probably approximately 1% of people receiving long-term NRTI therapy. Information regarding clinical trials in NRTIs is presented in Box 140.2.


Abacavir

Abacavir (Ziagen) is a relatively potent carbocyclic guanosine analogue nucleoside that has excellent activity when used as first-line antiviral therapy. If used in first-line therapy, it appears to be one of, if not the most, potent NRTIs. Its use has been somewhat limited by the relatively severe hypersensitivity syndrome seen in roughly 5% of patients who use it. Both tablet and liquid preparations are available. Abacavir is also available in a fixed ratio combination tablet (Trizivir) with ZDV and 3TC.


Pharmacokinetics

Abacavir is administered on a schedule of one dose every 12 hours. The serum half-life is approximately 1 hour. Food has no effect on absorption. Abacavir crosses the blood brain barrier in a manner similar to that of ZDV, with a ratio of cerebrospinal fluid to plasma of approximately 0.2.


Antiviral Effects

Abacavir is an effective nucleoside, perhaps the most potent of current compounds as initial therapy, but resistance occurs frequently in patients who have been treated previously with other NRTIs. Most studies of abacavir have involved combinations with other antiretroviral agents. When used with PIs in therapy-naive adults, abacavir produced 2 log decreases in RNA copy number. Substantial cross-resistance exists between abacavir and other nucleosides. The key resistance sites appear to be at reverse transcriptase codons 65, 74, 115, 184, and the standard thymidine resistance mutations (41, 67, 70, 210, 215, 219).


Adverse Effects

The main concern with using abacavir is an idiosyncratic hypersensitivity reaction that occurs most often in the first weeks of therapy and is manifested by rash, fever, nausea, and vomiting. If it occurs, abacavir rechallenge should not be considered; patients have progressed to shock and even death as a result of rechallenge after an episode of hypersensitivity. This reaction can be difficult to distinguish from the rash syndrome of nevirapine (NVP) and even from some infectious conditions (adenovirus, scarlet fever).


Didanosine

Didanosine (ddI; Videx) is an NRTI metabolized from dideoxyinosine to its active form, dideoxyadenosine (ddA). It has a good side effect profile for children, but its use is limited by inconvenient dosage regimens in young children. These problems are caused principally by ddI’s chemical instability in acid conditions such as those found in the stomach and the consequent requirement for oral coadministration of a buffering agent. ddI is available as a liquid mixed in antacid (usually Maalox), as a chewable and dissolvable tablet, or in its most convenient preparation, an enteric-coated, delayed-release capsule.








TABLE 140.1. DOSING OF ANTIRETROVIRAL DRUGS





























































































Drug Pediatric Dose Adult Dose Comments
Nucleoside Reverse Transcriptase Inhibitors
Zidovudine (Retrovir) Prematures: 1.5 mg/kg q12h to age 2 weeks, then 2 mg/kg q8h; infants: 2 mg/kg/dose q6h or 1.5 mg/kg q6h intravenously; pediatric: 180 mg/m2/dose q8h or 240 mg/m2/dose q12h 300 mg bid or 200 mg tid Child perinatal prophylaxis: dose, 2 mg/kg q6h for 6 weeks. Maternal perinatal prophylaxis: dose, ACIG 076 trial established 100 mg five times per day, although 200 mg tid or 300 mg bid is probably acceptable.
Stavudine (Zerit) Neonates: not known; pediatric: 1 mg/kg bid to 30 kg >60 kg: 40 mg q12h; ≤60 kg: 30 mg q12h  
Lamivudine (Epivir) Neonates (<30 days): 2 mg/kg bid; pediatric: 4 mg/kg bid >50 kg: 150 mg bid; ≤50 kg: 2 mg/kg bid  
Didanosine (Videx) Neonates (<90 days): 50 mg/m2/dose q12h; pediatric: 90 mg/m2/dose q12h >60 kg: 200 mg bid; ≤60 kg: 125 mg bid If tablets are used, at least two must be used with each dose to achieve adequate antacid dose. Available as a powder for pediatric oral solution, which is mixed with an antacid during reconstitution and is poorly stable.
Zalcitabine (HIVID) Neonates: unknown; pediatric: 0.01 mg/kg q8h 0.75 mg tid  
Abacavir (Ziagen) 8 mg/kg dose bid 300 mg bid Dosing information tentative.
Tenofovir disfumerate (Viread) Unknown 300 mg qd Pediatric dosing under evaluation.
Nonnucleoside Reverse Transcriptase Inhibitors
Nevirapine (Viramune) Neonates: 5 mg/kg qd for 14 days, then 120 mg/m2 q12h for 14 days, then 200 mg/m2 dose q12h; pediatric: 120–200 mg/m2/dose q12h; for the first 14 days, dose is 120 mg/m2 qd, then escalate as tolerated 200 mg q12h. For first 14 days, use one-half of dose, then increase  
Delavirdine (Rescriptor) Unknown 400 mg tid  
Efavirenz (Sustiva) 10–15 kg: 200 mg qd; 16–20 kg: 250 mg qd; 21–25 kg: 300 mg qd; 26.0–32.5 kg: 350 mg qd; 32.6–40.0 kg: 400 mg qd; >40 kg: 600 mg qd 600 mg qd Capsules only: 50, 100, and 200 mg. Efavirenz is probably not useful in patients in whom prior nonnucleoside reverse transcriptase inhibitor therapy failed because of cross-resistance.
Protease Inhibitors
Nelfinavir (Viracept) Neonate: 10 mg/kg tid; pediatric: 20–30 mg/kg tid 750 mg tid Neonatal dose is an unproved estimate. Some people believe q8h is more appropriate than tid schedule.
Ritonavir (Norvir) Neonate: unknown; pediatric: 400 mg/m2 q12h; begin dosing at 250 mg/m2 q12h, then increase over 5 days to full dose 600 mg bid. Initiate at 300 mg bid, then escalate as tolerated over 5 days  
Indinavir (Crixivan) 500 mg/m2/dose q8h 800 mg q8h Pediatric dose is still unproved.
Saquinavir (Invirase) Unknown 1,000 mg bid  
Amprenavir (Agenerase) Capsule: 20 mg/kg bid; liquid: 1.5 mL/kg bid (liquid is 15 mg/mL) >50 kg: 1,200 mg bid; ≤50 kg: 20 mg/kg bid Dosages tentative; clinical trials in progress. Capsules are 150 mg each.
Lopinavir (Kaletra) Liquid: 7–14 kg: 12 mg/kg bid; 15–40 kg: 10 mg/kg bid; >40 kg: 400 mg Pobid 400 mg LPV bid Combined with RTV at a 4:1 ratio in liquid and capsules.




Jul 24, 2016 | Posted by in PEDIATRICS | Comments Off on Antiretroviral Therapy in Pediatric Acquired Immunodeficiency Syndrome

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