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.
to the agents. The development of resistant viruses can have important implications for the long-term efficacy of antiretroviral therapeutic regimens.
BOX 140.1 Classification of Antiretroviral Drugs
Nucleoside Reverse Transcriptase Inhibitors
Abacavir
Didanosine
Emtricitabine
Lamivudine
Stavudine
Tenofovir
Zalcitabine
Zidovudine
Nonnucleoside Reverse Transcriptase Inhibitors
Delavirdine
Efavirenz
Nevirapine
Protease Inhibitors
Amprenavir
Fosamprenavir
Lopinavir
Indinavir
Nelfinavir
Ritonavir
Saquinavir
Fusion Inhibitor
Enfuviritide
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 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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BOX 140.2 Clinical Trials of Antiretroviral Drugs
Nucleoside Reverse Transcriptase Inhibitors
Abacavir
The first pediatric study to use abacavir, Pediatric AIDS Clinical Trials Group (PACTG) Protocol 330, evaluated abacavir monotherapy in a cohort of children who had extensive experience with therapy. Unfortunately, in that setting, the drug had little virologic effect. The study included a phase in which a second nucleoside reverse transcriptase inhibitor (NRTI) was added to the abacavir monotherapy, but again little benefit was seen, probably because of already established antiviral resistance. Studies of abacavir in adults have demonstrated good antiviral activity, comparable with protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). Monotherapy in adults with limited antiretroviral exposure (up to 12 weeks of zidovudine [ZDV]) led to average decreases of 1.5 to 2.1 logs. Abacavir is synergistic with other nucleosides, so it generally is used in combination. A pediatric trial in Europe (PENTA 5) found that abacavir/lamivudine (3TC) or abacavir/ZDV was superior to ZDV/3TC when used in an initial treatment regimen.
Didanosine (ddI)
PACTG Protocol 152 demonstrated that monotherapy with ddI was more effective than was ZDV alone and perhaps as effective as was combination ZDV/ddI. However, PACTG Protocol 300 then found that both ZDV/3TC and ZDV/ddI were more effective than ddI monotherapy, both clinically and with regard to surrogate markers.
Emtricitabine (FTC)
The first study of FTC in children is PACTG 1021, which at 60 weeks has shown good safety and efficacy for a regimen of FTC, ddI, and efavirenz (EFV), each administered once daily.
Lamivudine (3TC)
PACTG Trial 300 compared ZDV/3TC with monotherapy ddI. The combination was superior with regard to clinical outcomes and surrogate markers. Recently, studies have explored the combination of 3TC with ddI and EFV, and the combination appears to have good efficacy.
Stavudine (d4T)
Trials of d4T in children have demonstrated a good safety profile. It has been studied as monotherapy and in combination with ddI and 3TC (Adult ACTG Trial 306). The clinical effects of combination therapy with ddI or 3TC are similar to those seen with ZDV. d4T also can be combined with PIs or NNRTIs. It should not be coadministered with ZDV.
Tenofovir (TDF)
Clinical information on use of TDF in children is still relatively limited. Concerns about bone mineralization effects have contributed to slowed pediatric development.
Zalcitabine (ddC)
Two large trials of ddC in children, PACTG studies 138 and 190, have been completed. The first was a phase II/III trial of two dosage regimens of ddC monotherapy for children whose infection had progressed on ZDV or were intolerant of that drug. In that study, ddC generally was well tolerated. More than one-half of the children had stabilization of growth and a decline in p24 antigen concentrations. Thirty percent of the children had an increase in CD4 counts and gained weight. In PACTG 190, ddC (0.03 mg/kg/day) or placebo was added to ZDV in patients who were clinically stable. Relatively few differences in the two study groups were found, although children who received ZDV/ddC had a slower decline in CD4 cell counts.
Zidovudine (ZDV)
The first comparative, placebo-controlled trial of ZDV in adults demonstrated the effectiveness of ZDV when the study was halted early in 1986. Two hundred eighty-two patients with acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related symptoms were treated with ZDV or placebo. Of the 145 ZDV-treated patients, only one died. In comparison, 16 of 137 patients in the placebo group died. The outcome was highly significant. Although this result unequivocally showed the short-term clinical benefit of ZDV, many questions were left unanswered.
The first pediatric trial of ZDV was performed from 1986 through 1987. It demonstrated that ZDV could be used in children in a manner similar to that for adults, although children may have had fewer adverse events. Benefits of ZDV treatment included weight gain faster than anticipated, decreased hepatosplenomegaly, and lowering of immunoglobulin G (IgG) and IgM concentrations toward more normal values. The first large phase II trial of ZDV in children had very similar results, confirming the positive effects of ZDV treatment on growth.
PACTG Trial 152 demonstrated that both ZDV/ddI and ddI alone were clinically superior to ZDV monotherapy. Similarly, PACTG Trial 300 demonstrated that both combination ZDV/ddI and ZDV/3TC were superior to ddI monotherapy. ACTG Trial 338 demonstrated that combination regimens containing ritonavir (RTV) and ZDV/3TC or d4T produced better short-term virus suppression than did ZDV/3TC alone. As a result of such studies, ZDV virtually is never used as a monotherapy but instead is used in combinations.
ACTG Protocol 076 established that ZDV monotherapy had a role in the prevention of vertical HIV transmission (mother to infant). In that study, ZDV (200 mg) was administered to the mother five times each day, intravenous ZDV was infused after the onset of labor (a 2-mg/kg bolus, then 1 mg/kg/hour), and the baby was given oral ZDV for 6 weeks (2 mg/kg/dose every 6 hours). This regimen decreased the transmission rate from 26% to 8%. Subsequently, through the use of combination therapy, rates for vertical transmission of HIV have decreased to less than 2% and to less than 1% in mothers whose virus is able to be fully suppressed. However, the therapies required for transmission rates this low are expensive and generally are not available in the developing world.
Case-control studies have suggested that ZDV is beneficial in the prevention of transmission of HIV in other contexts, particularly after needlestick accidents. As a result, the Centers for Disease Control and Prevention issued guidelines for preventing needlestick-related transmission of HIV that include ZDV in the treatment regimens. For individuals with high-risk needlestick accidents (hollow-bore needles, deep penetration, blood from a highly viremic patient), combination therapy with ZDV and 3TC, with or without a third drug, which should be chosen after consultation with an HIV care specialist, is suggested. A reasonable theoretic rationale exists for the prophylactic use of an NRTI because it blocks the initial steps in virus replication. If the virus RNA is not transcribed fairly quickly into DNA, it will biodegrade and become noninfectious.
Nonnucleoside Reverse Transcriptase Inhibitors
Efavirenz (EFV)
EFV appears to be approximately as effective as is a PI, provided the other agents in the combination regimen are active in the particular patient. A once-daily regimen of FTC, ddI, and EFV in children has been studied in PACTG Protocol 1021 and preliminarily appears to be active and well tolerated.
Nevirapine (NVP)
NVP has been used in a number of pediatric studies in combination with NRTIs. It shows consistent efficacy, although combination regimens including other active drugs for the specific patient are important. As perinatal prophylaxis, PACTG 316 evaluated the addition of NVP to the mother’s standard regimen. No effect could be seen, but the transmission rate in the placebo group was lower than expected, so demonstrating a therapeutic benefit was difficult, while at the same time showing the potency of the prophylactic effect of the other components of the regimens. HIVNet 012 demonstrated a role for two-dose NVP prophylaxis in vertical transmission. Mothers were given a single dose of NVP (200 mg) during labor, and the infants received 2 mg/kg of NVP at 48 to 72 hours old. The transmission rate dropped by almost 50%, from 21% for infants whose mothers received short-course ZDV (the control group) to 12% in mother-infant pairs given NVP.
Protease Inhibitors
Amprenavir (APV)
Clinical experience with APV remains relatively limited, especially in children. It has good virologic effect when used in combination with NRTIs, producing undetectable viral loads in most treatment-naive patients.
Lopinavir (LPV; LPV/r)
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