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Journal of the International Association of Physicians in AIDS Care - Vol. 1, No. 1, January/March 2002
David A. Cooper, MD, DSc
Professor of Medicine and Director, National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia
Didanosine (ddI) has been a cornerstone of HIV management since it was made available in October 1991. Didanosine was originally introduced as an alternative to zidovudine (ZDV) for patients who were intolerant of ZDV or experienced disease progression during ZDV monotherapy. Didanosine is now used extensively as an integral component of multidrug combination regimens in both adults and children with HIV infection, and is now available for once-daily administration in the United States, Canada, and Europe.
The recently approved Videx®EC is an enteric-coated didanosine capsule dosed as one capsule, once daily. This paper provides an update of recently published studies on the use of ddI in combination anti-HIV therapy. In particular, these studies examine the rationale for the use of ddI as first-line anti-HIV therapy, and describe newer findings concerning its long-term efficacy, side effects, compliance, resistance, and once-daily use. The increased survival of HIV-infected patients is largely attributed to the introduction of the triple combination drug therapy but is probably also due to the long-term clinical efficacy of ddI.
Key words: didanosine, combination drug therapy, treatment outcome
Didanosine (ddI) is an antiviral agent that belongs to the nucleoside analog reverse transcriptase inhibitor (NRTI) class. The mechanismof action of ddI involves intracellular phosphorylation of the parent drug to its active metabolite, 2', 3'-dideoxyadenosine 5'-triphosphate (ddATP).1-3 ddATP prevents HIV (human immunodeficiency virus) replication by inhibiting the action of the viral reversetranscriptase through competition with the naturally occurring nucleoside deoxyadenosine triphosphate for incorporation into the growing viral DNA chain. Incorporation of ddATP into viral DNA stops viral DNA elongation, terminating HIV replication.
The antiviral activity of ddI in vitro is well established. Didanosine has been shown to effectively inhibit HIV replication in vitro in a concentration-dependent fashion and maintain activity in a variety of different cell types.4-6 Antiviral activity in vitro may be a useful marker of antiviral potency in vivo, but the relationship between in vitro antiviral activity of ddI and its clinical efficacy has not been established. The antiviral activity of ddI is additive or synergistic with that of other antiretroviral drugs, a property that increases the activity of combination antiretroviral therapy.
The pharmacokinetics of ddI is linear and dose-proportional 1following oral single- and multi-dose administration.7,8 Didanosine is able to cross the blood-brain barrier and improvement in the symptoms of acquired immunodeficiency syndrome (AIDS)-related dementia has been reported following ddI administration,9,10 however, current evidence does not show that ddI achieves therapeutic concentrations in the cerebrospinal fluid. The metabolism of ddI in humans is presumed to occur by the same pathways responsible for the elimination of endogenous purines, and its excretion is primarily renal.11
The antiviral activity and therapeutic efficacy of ddI has been demonstrated in numerous clinical trials both as monotherapy and in combination with other antiretroviral drugs.12-16 Most of the earlier studies of the efficacy of ddI were based on clinical endpoints, such as mortality and duration of disease-free survival. Later studies used validated surrogate markers, eg, CD4 T cell count and viral load, as reliable predictors of severity of HIV disease and, by extension, therapeutic efficacy of ddI in arresting HIV disease progression. The vast majority of clinical studies of ddI have been in patients receiving combination therapy with multiple drugs, and as for other therapeutic agents for HIV infection, few placebo-controlled studies with ddI have been conducted for ethical reasons.17 Studies have shown that early initiation of combination therapy achieves significant and durable virological and immunological responses, and that such treatment prolongs the duration of disease-free survival in HIV-infected patients.18-20 Findings from ongoing studies will help clarify the effects of early aggressive treatment on immune system reconstitution, body composition changes, and other aspects of long-term HIV management.
The efficacy of all antiretroviral agents is limited to varying degrees by their toxicity and their propensity for the development of viral resistance. Improvement in the survival of HIV-infected patients creates the need for therapeutic interventions with not only sustained clinical efficacy but also long-term tolerability. Long-term clinical efficacy is now a major consideration in the selection of antiretroviral agents for the individual patient, but the sustained efficacy of most anti-HIV drugs, particularly those that have been recently approved, is uncertain. In a five-year follow-up study in 72 patients with advanced HIV infection, ddI was found effective and was well tolerated for over four years.21 Such findings underscore the need for antiretroviral agents with sustained efficacy and tolerability for patients at all stages of HIV infection.
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Multiple drug combination therapy is the cornerstone of HIV disease management. This strategy is supported by the findings of pivotal clinical trials that demonstrated improvements in surrogate markers of HIV disease progression, and also in clinical endpoints in patients receiving multiple combination antiretroviral therapy.12-16
Two of the primary studies to demonstrate benefit of combination antiretroviral therapy over monotherapy were the Delta trial and the ACTG 175 trial.12,13 The Delta trial was a randomized double-blind study comparing zidovudine (ZDV) alone with ZDV plus ddI or ZDV plus zalcitabine (ddC). It included both treatment-experienced and treatment-naïve patients who were followed for a mean of 2.5 years. The trial demonstrated a significant survival advantage for both combination regimens over ZDV alone, and this difference was greatest in the treatment-naïve group. Similarly, the ACTG 175 trial demonstrated a significant advantage of the ddI plus ZDV regimen over ZDV monotherapy, and also showed that ddI monotherapy was significantly better than ZDV alone. The association between clinical endpoints and changes in surrogate markers of HIV disease activity observed in the Delta trial has recently been analyzed.22,23 HIV RNA levels and CD4 T lymphocyte counts at baseline and after eight weeks of treatment were significantly associated with survival in all patient groups.22 Reductions in HIV RNA levels were consistent with clinical results, and the decrease in HIV RNA achieved at 16 weeks was highly predictive of the clinical response.
The INCAS trial was a randomized, controlled, double-blind study of the safety and efficacy of the three-drug combination of ZDV, ddI, and nevirapine (NVP) in 153 treatment-naïve patients with HIV infection.14 After 52 weeks of treatment, the proportion of patients with HIV RNA levels below 20 copies/ml was 51 percent in patients receiving triple combination therapy, 12 percent in patients receiving ZDV and ddI, and zero percent in those receiving ZDV and NVP. Rates of disease progression or death were significantly lower in the triple combination group (12 percent) than in the ZDV and NVP or ZDV and ddI groups (23 percent and 25 percent, respectively), corroborating the virologic responses.
The efficacy of the triple drug combination of ZDV, ddI, and NVP was examined in a randomized, double-blind trial by Floridia et al.15 In this study, 68 treatment-naïve patients with advanced HIV disease were randomized to receive ZDV and ddI, or the threedrug combination and were followed for 48 weeks. HIV RNA levels decreased and remained below baseline for the duration of the study in both treatment groups, and the decrease was significantly greater in the triple combination group than in the ZDV and ddI group. Body weight increased in all patients during treatment with a trend for greater increases in patients receiving ZDV and ddI. Such treatment of patients with less advanced immune deficiency might be expected to have greater effectiveness.
Triple combination therapy with ZDV, ddI, and NVP proved superior to ZDV alternating with ddI, ZDV and zalcitabine, and ZDV and ddI in a randomized study of 1,313 patients with advanced HIV infection.16 Although surrogate and clinical endpoints favored triple combination therapy, only CD4 T cell increases were statistically significant between the triple therapy and ZDV and ddI groups. The incidence and severity of treatment-related toxicities were similar in all four groups.
The efficacy of the combination of ZDV, ddI, and NVP may be compromised by drug-drug interactions between ZDV and NVP.24 Zidovudine bioavailability is decreased by about 30 percent in the presence of NVP, whereas NVP does not appear to interfere with ddI bioavailability. Although the decrease in ZDV bioavailability during combination treatment with NVP may be clinically insignificant, it is not known whether the effect of NVP on ZDV bioavailability influences the selection of resistant HIV mutants during combination therapy.
Didanosine has also been studied with the nonnucleoside reverse transcriptase inhibitor (RTI) efavirenz, although to a lesser extent. A once-daily protease inhibitor (PI)-sparing regimen of ddI plus efavirenz plus the investigational nucleoside RTI emtricitabine given to 40 treatment-naïve subjects showed that 98 percent and 93 percent achieved plasma HIV RNA levels less than 400 copies/ml and less than 50 copies/ml at 24 weeks.25
The effective treatment of early HIV infection may be associated with prolonged suppression of viral replication and the preservation of immune function. In a study of 10 patients with primary HIV infection who were treated with the triple combination of ZDV, ddI, and lamivudine (3TC) starting at five to 28 days after the onset of symptoms, all patients achieved undetectable viremia after a mean of 108 days of follow up.26 The plasma HIV RNA response was accompanied by a large viral decrease in multiple compartments and a waning of antibody response in some cases.
An alternative strategy for the treatment of early HIV infection consists of immunotherapy administered in combination with antiretroviral therapy. In a phase II study by Simonelli et al, 12 patients with early stage HIV infection received subcutaneous interleukin-2 with ZDV and ddI for 24 weeks followed by an additional 24 weeks of ZDV and ddI.27 In addition to improvements in CD4 T cell counts and HIV viremia, the combination treatment was associated with improvements in some immunologic functions as indicated by increased expression of CD4 T cell subsets CD25, CD45RO, and CD45RA, and significant decrease in proviral DNA in peripheral blood mononuclear cells. The majority of patients maintained undetectable HIV RNA levels during 24 weeks of follow-up.
The combination of ZDV and ddI with the nonnucleoside RTI delavirdine (DLV) demonstrates significant synergy and antiviral activity in vitro.28 A proven combination is that of ddI and stavudine (d4T), a thymidine nucleoside analog, which has been studied as dual NRTI therapy29-35 and as part of triple-drug therapy.36-43 In a study of 65 heavily pretreated patients with HIV infection who received only ddI/d4T, the CD4 T cell count increased by a mean of 70 x 106/L and the HIV RNA level decreased by a mean of 0.89 log10 copies/ml at week 24.29 Undetectable plasma viremia was achieved by 14 percent of the patients at week 24, and adverse effects were generally mild and observed in 32 percent of the patients.
The most recent evidence of the benefit of ddI in regimens also containing d4T was reported in the START II trial by Eron et al.39 In this 48-week open-label study, 205 HIV-positive patients received initial treatment with indinavir plus ddI/d4T or indinavir plus ZDV/3TC. In the ddI/d4T arm, the percentage of patients with HIV RNA levels below 50 copies/ml at week 48 was greater (41 percent) compared with that in the ZDV/3TC arm (35 percent), and the CD4 T cell count increase from baseline at 48 weeks was significantly greater (214 and 142 cells/µL, respectively; p = 0.026).
The results from these and other clinical studies of highly active antiretroviral therapy (HAART) regimens containing the ddI/d4T backbone have shown that ddI/d4T-containing regimens, including those with other protease inhibitors like nelfinavir and ritonavir (only reported as abstracts), were associated with good virologic and immunologic responses (table),36-42 though concerns for hepatotoxicity must temper such use.
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Drug-related toxicities and the development of resistance limit the beneficial effects of ZDV treatment. Alternating therapy with ZDV and other antiretroviral agents may be a useful strategy for reducing the toxicity of ZDV treatment while maintaining antiviral activity, but the clinical consequences of this approach have not been fully explored. Although no longer appropriate therapy for HIV infection, early monotherapy trials of ddI and ZDV allowed a comparative evaluation of these two drugs without possible confounding influences from the actions of other antiretroviral therapy. These trials showed that switching ZDV for ddI, or alternating treatment with ZDV and ddI on a monthly basis, is associated with greater beneficial effects compared to ZDV monotherapy.43 Significantly greater improvement in survival of patients with CD4 T cell counts less than 100/mL occurred, particularly among those who are ZDV-naïve.44 Alternating therapy with ZDV and ddI has no advantage in survival over monotherapy with either drug in patients with higher CD4 T cell counts, but the safety profile of alternating therapy is significantly better than that of ZDV or ddI monotherapy in all patient groups.
The survival of 2,367 HIV-infected patients treated with ZDV was significantly influenced by the use of other nucleoside analog drugs—ddI, ddC, d4T, and 3TC45. As compared with ZDV monotherapy, the relative mortality hazard, with the relative risk of death with ZDV monotherapy considered to be 1.0 in this case, was reduced to 0.41 in patients who added 3TC, 0.79 in those who added ddI, 0.74 for ddC, and 0.67 for d4T. This observational study has limited comparative justification, but consistency of added effectiveness is reassuring.
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To improve compliance, simple and well-tolerated antiretroviral regimens are needed. Treatment adherence is a major determinant of the clinical and virologic efficacy of antiretroviral drugs, and lack of compliance is a primary contributing factor to the development of drug resistance. The current emphasis on simplifying treatment regimens and improved compliance has shifted attention to oncedaily treatments.
The pharmacologic profile of ddI is characterized by sufficient bioavailability and prolonged intracellular half-life to support once-daily dosing.46 In vitro study has shown the intracellular half-life of the active drug (ddA-TP) is greater than 25 hours.47 Using the sametotal daily dose, the overall plasma exposure with once-daily dosing, as measured by the area under the concentration time curve (AUC) over 24 hours, was similar to twice-daily dosing.48 Although peak concentrations were about 50 percent lower with twice-daily regimen because of the lower dose, the AUC parameters were similar, suggesting once-daily dosing of ddI is appropriate. Early clinical studies of once-daily ddI have suggested that the total daily dosage of ddI rather than the dosage schedule may be a more important determinant of therapeutic response.46 Changes in surrogate markers appeared similar whether ddI was administered once or twice daily.
A number of recent studies of the safety and efficacy of once-daily ddI versus twice-daily ddI have been reported.30-34,49 All these studies showed once-daily ddI to be as effective as twice-daily ddI, and there was little difference in severity or frequency of adverse events with the two regimens. In a well-controlled, double-blind study of 87 treatment-naïve patients given either d4T plus ddI once daily or d4T plus ddI twice daily, Mobley et al found similar results with nearly a 2 log drop (-1.8 log10 copies/ml) over 2 to 24 weeks of treatment in both groups with similar side-effect profiles.34 The researchers found that gastrointestinal-related side effects occurred more frequently in the twice daily dose group and concluded that ddI once daily may be better tolerated. Further, the results of an open-label study by Monno et al, who also found the same difference between ddI once daily and twice daily dose groups for gastrointestinal side effects, suggested improved adherence with ddI once daily based on time on therapy.33
Of relevance to current treatment recommendations, once-daily ddI has been shown to be effective as part of various triple-drug therapies containing a protease inhibitor or a nonnucleoside RTI , such as in the VIRGO and Atlantic trials,36-38,50,51 (and R. Murphy, unpublished data). Other recent reports, including that by Gathe et al,51 comparing once-daily ddI with stavudine and nelfinavir to a standard triple PI regimen, have so far only been reported as abstracts.
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The combination of ZDV and ddI has proven superior to monotherapy with either agent alone in children with HIV infection.52-54 Englund et al randomized 839 children with symptomatic HIV infection to receive ZDV, ddI, or ZDV and ddI, and the primary study endpoint was length of time to death or progression of HIV disease.52 After a median follow-up of 23 months, the relative risk of HIV disease progression or death was 0.61 in the dual therapy group as compared with those in the monotherapy groups (p =0.007). At the end of the study (median, 32 months), however, the efficacy of ddI monotherapy was similar to that of the combination of ZDV and ddI. Children receiving ddI alone had a significantly lower risk of anemia or neutropenia as compared with those receiving ZDV. Palumbo et al reported similar findings in a review of data from 566 infants and children who participated in a Pediatric AIDS Clinical Trials Group clinical trial (PACTG 152).53 They found no significant difference in mean plasma HIV RNA reductions between children treated with ZDV and ddI and those treated with ddI alone.
Another PACTG study (PACTG 300) assessed the safety and clinical efficacy of the combination of ZDV and ddI, ZDV and 3TC, and ddI alone as first-line therapy in 615 children with symptomatic HIV infection.54 However, enrollment in the ZDV/ddI study arm was halted early when the results of the PACTG 152 study became known, and suggested that equal benefit could be obtained with ddI alone. The 152 study did show that, during a median follow-up of 9.4 months, both ZDV/3TC and ZDV/ddI recipients had a lower risk of both disease progression and death than those receiving ddI alone. The adverse event rates for ZDV/3TC and ZDV/ddI were comparable. In HIV-infected children in stable condition who were previously treated with ZDV alone and with ZDV resistance mutations, switching to ddI monotherapy is associated with a better short-term outcome than is continued ZDV monotherapy or combination therapy with ZDV and ddI.55 Among 94 children infected with HIV who had ZDV resistance-associated proviral mutations, clinical deterioration at six months occurred in significantly fewer children who switched to ddI monotherapy (15 percent) than in those who switched to ddI and ZDV (57 percent) or those who received continuous ZDV alone (55 percent). Differences between the groups at one year were not statistically significant.
The combination of ddI and d4T proved to be more effective than treatment with d4T alone in a study of 108 children with HIV infection.56 Mean declines in plasma HIV RNA levels at week 12 were 0.49 and 0.18 log10 copies/ml in the ddI/d4T and d4T monotherapy groups, respectively. These differences were maintained during 48 weeks of treatment.
Triple combination therapy is emerging as an important therapeutic strategy for the treatment of HIV infection in infants and children as well as in adults.57,58 The safety and efficacy of the combination of ZDV, ddI, and NVP were determined in eight infants with HIV infection who were asymptomatic or only mildly symptomatic at baseline.5 Within four weeks, reductions in plasma HIV RNA levels of at least 96 percent were achieved in seven of the eight infants. Over the six-month study period, viral replication was controlled in two infants who began therapy at 2.5 months of age, and viral load was reduced by 0.5 to 1.5 log10/ml in five of the other six infants. The three-drug regimen was well tolerated without clinically important adverse events.
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Resistance to antiretroviral drugs is a complex issue involving behavioral, pharmacologic, and biological factors. Both genotypic and phenotypic assays for determining antiviral drug susceptibility are available, but the clinical role of these tests is not yet clearly defined, as questions regarding the timing, methodology, and interpretation of drug resistance assays remain unanswered.59 The routine incorporation of susceptibility testing into antiretroviral drug trials may be a useful means of increasing the available data on antiviral drug resistance, and refining the clinical usefulness of the test.
Drug-resistant HIV has been detected in patients on all currently available antiretroviral drug regimens.60 High-level drug resistance, which is usually defined as greater than 100-fold increase in the 50 percent inhibitory concentration (IC50) of the drug, has been observed in patients treated with ZDV, 3TC, and NVP, whereas treatment with ddI, ddC, and d4T has only produced HIV strains with low-level resistance. However, a number of trials suggest that this low-level resistance may be associated with therapeutic failure of regimens including these drugs. Combination drug regimens can usually delay the emergence of drug-resistant HIV strains, but resistance eventually emerges unless complete suppression of viral replication is achieved.
The HIV RT mutation L74V develops during ddI therapy and confers decreased susceptibility to ddI.61 This mutation, in conjunction with the ZDV-related mutation Thr215Tyr, also decreases ZDV resistance. In viruses with the L74V mutation, an 11 percent loss of replication ability compared with that of wild-type virus has been demonstrated.62 This decreased replication ability provides an explanation for the lower HIV RNA levels observed with ddI therapy compared with ZDV therapy in clinical trials.
Antiretroviral drug resistance may develop in multiple body compartments. Mayers et al evaluated drug resistance mutations in peripheral blood mononuclear cells (PBMC) and lymphoid tissue obtained from 22 HIV-infected patients treated with ZDV alone or in combination with ddI.63 During the eight-week study, 27 percent of the participants showed evidence of ZDV resistance at codon 215 and none of the patients developed the codon 74 mutation associated with ddI resistance. When HIV proviral DNA from PBMC was compared with that from lymphoid tissue, 95 percent of the samples were concordant for the 215 mutation at baseline whereas 86 percent were concordant after eight weeks.
The emergence of multiple drug resistance may occur in patients who are extensively pretreated with anti-HIV drugs. In a European study, multidrug NRTI-resistant HIV-1 strains were detected in four percent of patients treated with multiple dideoxynucleoside analogs for six months or more.64 The emergence of HIV-1 strains with unusual combinations of amino acid changes has been reported in extensively pretreated patients not responding to their current antiretroviral combination therapy.65 These changes include insertions of amino acids between codons 68 and 69, in the absence of previously known amino acid changes associated with resistance to ddI, ddC, 3TC, and d4T. Inserts, like point mutations, are selected in vivo during antiretroviral therapy and may provide resistance to multiple NRTI drugs.66 HIV-1 isolated from a patient receiving combination therapy with ddI and hydroxyurea (HU) was found to have RT amino acid substitutions T69S and K70R flanking a two amino acid insertion.67 The amino acid insertions conferred low-level nucleoside analog resistance while the substitutions appeared to represent a compensatory mechanism for the deleterious effects of the insertions on RT activity. Serial passages of HIV-1 in increasing concentrations of the combination of ddI and d4T resulted in mutations at RT codons 57 and 9868. These mutations were associated only with an 11.5-fold increase in the IC50 of ddI and a 4.5-fold increase in the IC50 of d4T. Neither of these mutations was associated with multidrug resistance. The underlying mechanism of NRTI multidrug resistance remains poorly understood.
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Hydroxyurea (HU) induces the activity of cellular kinases that phosphorylates nucleoside RTIs and preferentially depletes intracellular purines, which may enhance the antiviral activity of ddI; however, hydroxyurea also increases the toxicity of ddI, and the combination may not be helpful. The role for HU in the treatment of HIV infection remains uncertain.
HU has favorable pharmacokinetic properties and has demonstrated good tolerability when used in combination with ddI in patients with HIV infection.69,70 In a pilot study of 26 patients with advanced HIV infection treated with ddI who were randomized to receive 500 or 1000 mg/day of HU, median decreases in viral load of 0.02 and 0.63 log10 HIV-1 RNA copies/ml were achieved in the 500 and 1000 mg groups, respectively.71 HU has been used to intensify regimens and as part of PI-containing regimens. HU improved the efficacy of the combination of ddI and d4T72 and was shown to be effective when combined with ddI plus indinavir.73 However, patients treated with ddI in combination with d4T, with or without HU, may be at increased risk for pancreatitis, which may be fatal,11,74 and the risk may be too high for use in a clinical setting without further study.
Withdrawal of HU and ddI in patients also treated with both drugs has not been associated with rebound of plasma viremia for at least one year after drug discontinuation.75 A possible explanation for the absence of viral rebound following withdrawal of this combination may be that the combination of ddI and HU exerts its antiviral effects in resting cells, as well as in those that are actively replicating. This observation has possible implications for the role of combination treatment with ddI and HU in persons with early HIV infection with the goals of prolonged suppression of viral replication, delay or avoidance of resistance, and possible viral eradication.76,77
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The labeling and prescribing recommendations for the use of ddI (Videx®, Bristol-Myers Squibb) in the United States were extensively revised in April 1998 and again in October 1999, including changes in sections relating to clinical pharmacology, indications and usage, precautions, and dosage and administration of ddI.11 Important changes to US labeling for Videx® related to the approval of ddI for once-daily administration and to the potential for increased risk of pancreatitis in patients receiving ddI in combination with d4T, with or without HU. Physicians should be aware of the clinical presentation of pancreatitis in light of the recent labeling changes (see below).
The revised pharmacokinetic information specifies that ddI is rapidly absorbed, with peak plasma concentrations generally observed from a quarter hour to one and a half hours after oral dosing. Increases in plasma ddI concentrations are dose-proportional over the range of oral doses administered in clinical practice, and steady-state pharmacokinetic parameters do not differ significantly from values obtained after a single dose. Binding of ddI to plasma proteins is less than five percent.
Peak plasma concentrations of ddI and the area under the plasma concentration time curve are decreased by about 55 percent when ddI tablets are administered up to two hours after a meal. It is recommended that ddI be taken on an empty stomach at least 30 minutes before or two hours after eating.
The dose of ddI should be reduced in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis. The pharmacokinetics of ddI in children older than 36 weeks of age is similar to that in adults, and ddI plasma concentrations increase in children in proportion to oral doses ranging from 80 to 180 mg/m2.
Drug interactions between ddI and various antiviral, antibacterial, and antifungal drugs have been reported,17 but an enteric-coated formulation has now eliminated or diminished unwanted interactions that were due to the presence of buffering agents in the tablet formulation (see section on Videx® EC below). No clinically significant drug interactions have been demonstrated between ddI and dapsone, loperamide, metoclopramide, ranitidine, rifabutin, stavudine, sulfamethoxazole, trimethoprim, and ZDV. The warnings accompanying the ddI prescribing recommendations have been revised to note that fatal pancreatitis has occurred during treatment with ddI. The frequency of pancreatitis is dose-related, and the incidence ranged from 1 percent to 7 percent in patients treated with recommended doses. Lactic acidosis and severe hepatomegaly with steatosis have been reported as rare, but potentially life-threatening, adverse effects with the use didanosine and other NRTIs alone or in combination. Fatal lactic acidosis has occurred in pregnant women receiving the combination of didanosine and stavudine.11 This effect is believed to be peculiar to this class of drugs, and the occurrence of lactic acidosis may be more related to the use of stavudine when didanosine and stavudine are given together. Retinal and visual changes have also been observed in patients treated with ddI.
Didanosine is currently indicated as once- or twice-daily dosing in the United States and Europe for the treatment of HIV infection in adults and twice-daily dosing in children. The recommended dosage of ddI tablets is 400 mg once daily or 200 mg twice daily in adults weighing 60 kg or more, and 250 mg once daily or 125 mg twice daily in adults weighing less than 60 kg. The dose should be administered at least 30 minutes before a meal, and the dosing interval should be 12 hours when used twice daily. The recommended dose of ddI monotherapy in children is 120 mg/m2 twice daily. There are no data on once-daily dosing in children.
Didanosine is supplied as chewable buffered tablets, buffered powder for oral solution, and pediatric powder for oral solution. The tablets and powder preparations of ddI are stored at room temperature. Because of the need for adequate buffering, the 200 mg strength tablet should only be used as a component of the 400-mg once-daily regimen. For either dosing regimen, two of the appropriate strength tablets at each dose should be administered to provide adequate buffering and prevent degradation by gastric acid.
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In October 2000, a new once-daily, enteric-coated formulation of didanosine (Videx®EC) was approved in the United States. The enteric-coated formulation permits the use of didanosine without the buffers necessary with previous formulations to prevent degradation of didanosine by stomach acid.
The available efficacy data indicate that the enteric-coated formulation has good antiviral activity. In an open-label trial, 511 treatment- naïve HIV-infected patients received either a triple regimen of nelfinavir plus stavudine and enteric-coated didanosine, or a reference triple regimen of nelfinavir plus zidovudine and lamivudine for 48 weeks.78 Both treatments were found to have similar antiviral activity. The results of the primary efficacy analysis showed that a similar proportion of patients in the enteric-coated ddI regimen and the reference regimen had viral load suppression less than 400 copies/mL (56 percent and 53 percent, respectively). The two treatment groups were also comparable at 48 weeks for suppression below 50 copies/ml (37 percent and 35 percent, respectively) and for median decrease from baseline in viral load (HIV RNA –2.59 and –2.61 log10 copies/ml, respectively) and CD4 T cell count (120 and 162 cells/µL, respectively).
The pharmacokinetic data from healthy volunteers and HIV-infected subjects show that peak plasma concentration is reduced (approximately 40 percent) and time to maximum concentration is increased (from 0.67 to 2.0 hours) with the enteric-coated formulation.79 However, AUC is equivalent for didanosine when administered as the enteric-coated formulation or the buffered tablet formulation. This indicates equivalent bioavailability of the enteric-coated formulation and the ddI buffered formulation.
The absence of buffering agents has reduced the possible drug interactions with didanosine. In studies of the effects of coadministration of the enteric-coated formulation on the AUC and peak drug concentrations of antimicrobial agents from different classes— ciprofloxacin, indinavir, and ketoconazole, no clinically significant pharmacokinetic interactions were observed.79 The use of this oncedaily, enteric-coated didanosine formulation, which does not need buffering agents, will probably be associated with fewer gastrointestinal adverse events and fewer drug interactions than previous didanosine formulations. In a six-week open-label, crossover study, tolerability of the enteric-coated formulation of ddI was assessed in 42 HIV-infected patients currently receiving antiretroviral regimens containing the tablet formulation and who had gastrointestinal symptoms, eg, nausea, bloating, diarrhea, gas, cramps, of at least moderate severity.80 After switching to enteric-coated ddI, severity of gastrointestinal symptoms and negative impact of side effects on daily activities were significantly reduced (p<0.01) after four weeks. The overall safety profile of enteric-coated ddI is expected to improve the side effect profile of ddI as well as enhance tolerability and promote treatment adherence compared with the current buffered tablet formulation.
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The current goal of anti-HIV therapy is to reduce viral replication as low as possible for as long as possible. Numerous clinical trials have demonstrated that prolonged suppression of viral replication is associated with dramatic improvements in long-term survival of HIV-infected persons. Combination antiretroviral therapy represents the optimal means of achieving long-term suppression of HIV replication.
Didanosine is firmly established as a cornerstone of combination antiretroviral therapy. The safety and efficacy of ddI used alone and in combination with other antiretroviral agents has been demonstrated in both adults and children with either early or advanced HIV infection, and the efficacy of ddI is sustained during long-term therapy. Didanosine has consistent effects on viral load, a favorable pharmacokinetic profile, acceptable toxicity, and low propensity for drug interactions. The introduction of the one capsule, once-daily enteric-coated formulation of didanosine in 2000 provided a means of significantly enhancing the patient adherence and clinical efficacy of ddI, while improving its tolerability and reducing drug to drug interactions as compared with the buffered formulation.
The increasing survival of HIV-infected patients treated with ddI-containing regimens continues to support the major role ddI has in the anti-HIV therapeutic armamentarium. Ongoing studies of the dynamics of HIV replication and the clinical efficacy of newer antiretroviral agents will help further clarify the place of ddI in the management of persons with HIV infection.
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