The abacavir hypersensitivity reaction and interruptions in therapy.
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Anti-HIV Agents↗
Biomedical subjects
H Steel
Publications and source records attributed to H Steel.
Abacavir-lamivudine-zidovudine vs indinavir-lamivudine-zidovudine in antiretroviral-naive HIV-infected adults: A randomized equivalence trial.
CONTEXT: Abacavir, a nucleoside analogue, has demonstrated suppression of human immunodeficiency virus (HIV) replication alone and in combination therapy. However, the role of abacavir in a triple nucleoside combination regimen has not been evaluated against a standard protease inhibitor-containing regimen for initial antiretroviral treatment. OBJECTIVE: To evaluate antiretroviral equivalence and safety of an abacavir-lamivudine-zidovudine regimen compared with an indinavir-lamivudine-zidovudine regimen. DESIGN AND SETTING: A multicenter, phase 3, randomized, double-blind trial with an enrollment period from August 1997 to June 1998, with follow-up through 48 weeks at 73 clinical research units in the United States, Canada, Australia, and Europe. PATIENTS: Five hundred sixty-two antiretroviral-naive, HIV-infected adults with a plasma HIV RNA level of at least 10 000 copies/mL and a CD4 cell count of at least 100 x 10(6)/L. INTERVENTIONS: Patients were stratified by baseline HIV RNA level and randomly assigned to receive a combination tablet containing 150 mg of lamivudine and 300 mg of zidovudine twice daily plus either 300 mg of abacavir twice daily and indinavir placebo or 800 mg of indinavir every 8 hours daily plus abacavir placebo. After 16 weeks, patients with confirmed HIV RNA levels greater than 400 copies/mL were eligible to continue receiving randomized treatment or receive open-label therapy. MAIN OUTCOME MEASURE: Virologic suppression, defined as HIV RNA concentration of 400 copies/mL or less at week 48. RESULTS: The proportion of patients who met the end point of having an HIV RNA level of 400 copies/mL or less at week 48 was equivalent in the abacavir group (51% [133/262]) and in the indinavir group (51% [136/265]) with a treatment difference of -0.6% (95% confidence interval [CI], -9% to 8%). In patients with baseline HIV RNA levels greater than 100 000 copies/mL, the proportion of patients achieving less than 50 copies/mL was greater in the indinavir group than in the abacavir group with 45% (45/100) vs 31% (30/96) and a treatment diference of -14% (95% CI, -27% to 0%). The 2 treatments were comparable with respect to their effects on CD4 cell count. There was no difference between groups in the frequency of treatment-limiting adverse events or laboratory abnormalities. One death in the abacavir group was attributed to hypersensitivity reaction, which occurred following rechallenge with abacavir, approximately 3 weeks after initiating study treatment. CONCLUSIONS: In this study of antiretroviral-naive HIV-infected adults, the triple nucleoside regimen of abacavir-lamivudine-zidovudine was equivalent to the regimen of indinavir-lamivudine-zidovudine in achieving a plasma HIV RNA level of less than 400 copies/mL at 48 weeks.
Adult↗
Hypersensitivity reactions during therapy with the nucleoside reverse transcriptase inhibitor abacavir.
BACKGROUND: Hypersensitivity reactions consist of a variable group of clinical findings and have been described for a wide variety of chemical compounds. OBJECTIVE: This review characterizes the clinical profile of hypersensitivity to the nucleoside reverse transcriptase inhibitor abacavir sulfate. METHODS: We performed a retrospective medical review of pooled adverse events data from approximately 200,000 patients who received abacavir in clinical trials, through expanded-access programs, or by prescription from 1996 through 2000. Screened cases of hypersensitivity were classified as either definitive or probable. Definitive cases were identified when initial symptoms resolved on interruption of abacavir therapy and returned on reintroduction of abacavir therapy. RESULTS: A total of 1803 cases were identified, 1302 in the 30,595 patients participating in clinical trials or the expanded-access program and 501 in patients from the post-marketing experience. On review, 176 (9.8%) of these cases were considered definitive and the remainder probable. Based on the 1302 cases identified in clinical trials or the expanded-access program, the calculated incidence of hypersensitivity was 4.3%. Symptoms reported in > or = 20% of cases of this multiorgan reaction included fever, rash, malaise/fatigue, and gastrointestinal symptoms such as nausea, vomiting, and diarrhea, among others. Respiratory symptoms occurred in 30% of cases and included dyspnea (12%), cough (10%), and pharyngitis (6%). In 90% of cases, hypersensitivity reactions occurred within the first 6 weeks after initiation of abacavir (median time, 11 days); after an initial reaction, rechallenge with abacavir resulted in the reappearance of symptoms within hours of reexposure. Hypotension was present in 25% of these rechallenge reactions. Among patients who received abacavir in clinical trials, the mortality rate was 0.03% (3 per 10,000 patients). CONCLUSIONS: Hypersensitivity to abacavir is an idiosyncratic reaction and a distinct clinical syndrome characterized predominantly by systemic involvement. It can be expected to appear as a treatment-limiting event in approximately 5% of patients. The appearance of clinical symptoms consistent with this syndrome mandates immediate discontinuation of abacavir. Hypersensitivity to abacavir is an absolute contraindication to subsequent treatment with any formulation that includes this agent.
Clinical Trials, Phase II as Topic↗
A dose-ranging study to evaluate the safety and efficacy of abacavir alone or in combination with zidovudine and lamivudine in antiretroviral treatment-naive subjects.
OBJECTIVE: To compare antiretroviral efficacy, safety and tolerance of three dosing regimens of the novel nucleoside reverse transcriptase inhibitor, abacavir (1592U89) over 24 weeks and its efficacy in open-label combination with zidovudine and lamivudine. DESIGN: Sixty HIV-1-infected antiretroviral therapy naive subjects (entry criteria; CD4+ cell count > or = 100 cells/mm(3), plasma HIV-1 RNA > or = 30 000 copies/ml), randomized into 20 subjects per cohort received 100, 300 or 600 mg abacavir twice daily. Subjects successfully completing 24 weeks' randomized therapy could switch to open label therapy (abacavir, zidovudine, lamivudine at 300, 300 and 150 mg twice daily, respectively) for a further 24 weeks of studly, as could subjects meeting one or more switch criteria. METHODS: Subjects were assessed for antiretroviral activity by measuring changes in plasma HIV-1 RNA load and CD4+ cell counts. Evaluation of safety and tolerance was based on clinical adverse events and laboratory analyses. RESULTS: At week 4, subjects receiving 300 or 600 mg abacavir twice daily had greater reductions in plasma HIV-1 RNA (median changes -1.55 and -1.61 log10) copies/ml, respectively); differences (P = 0.007 and P < or = 0.001, respectively) than subjects receiving 100 mg abacavir twice daily (median change, -0.63 log10 copies/ml). Differences between the 300 and 600 mg twice daily groups were not clinically or statistically significant. At 24 weeks, analysis showed a median change in plasma HIV-1 RNA of -0.70 and -1.30 log10 copies/ml in the 300 and 600 mg twice daily groups, respectively. During the open label phase in which zidovudine/lamivudine was added to 300 mg abacavir twice daily, a further median reduction in plasma HIV-1 RNA of 1.74 log10 copies/ml was seen. At 48 weeks pooled data from all abacavir-treated subjects showed a sustained reduction in plasma HIV-1 RNA of 2.8 log10) copies/ml; 65% and 43% of subjects had < or = 400 and < or = 50 HIV-1 RNA copies/ml, respectively, and a further median increase of 111 CD4+ cells/mm3 were seen. Abacavir was generally well tolerated with few clinically significant adverse events. Two subjects (3.3%) developed hypersensitivity reactions to abacavir. There were no differences between the groups with regard to serious adverse events. CONCLUSIONS: In terms of antiretroviral therapy naive subjects, treatment with 300 or 600 mg abacavir twice daily was statistically superior to a 100 mg twice daily dose at 4 weeks. Combinations therapy containing abacavir-zidovudine-lamivudine was a highly effective antiretroviral regimen, resulting in substantial reductions in plasma HIV-1 RNA which may be comparable to combinations containing protease inhibitors. Abacavir was generally tolerated.
Acquired Immunodeficiency Syndrome↗
Virologic and immunologic benefits of initial combination therapy with zidovudine and zalcitabine or didanosine compared with zidovudine monotherapy. Wellcome Resistance Study Collaborative Group.
A randomized controlled study was done to determine whether initial combination therapy with zidovudine and zalcitabine or zidovudine and didanosine would delay the emergence of zidovudine-resistant virus. Human immunodeficiency virus (HIV)-1-infected patients with <300 CD4 cells/mm3 and <4 weeks of prior zidovudine therapy were randomized to zidovudine, zidovudine plus zalcitabine, or zidovudine plus didanosine. Combination therapy did not delay the emergence of zidovudine-resistant virus isolates. However, combination therapy resulted in a significant increase in CD4 cells through 72 weeks compared with zidovudine monotherapy and a greater and more sustained decline in serum HIV-1 RNA. Although this trial was not designed as a clinical end-point study, patients assigned to zidovudine plus didanosine combination therapy experienced a significant delay in time to first AIDS-defining event or death compared with those assigned to zidovudine monotherapy.
Adult↗
Association of cytomegalovirus infection with post-transplantation cardiac rejection as studied using the polymerase chain reaction.
The relationship between cytomegalovirus (CMV) infection and cardiac allograft rejection is controversial, some authors reporting a significant association, others not, on the basis of the results of conventional virological diagnosis by culture or serology. This problem was reinvestigated in 88 patients using a semi-quantitative nest polymerase chain reaction (PCR) procedure for detecting CMV DNA in endomyocardial biopsy specimens. Significantly more positive biopsies were obtained from patients with moderate (grade 2; P = 0.02) or severe (grade 3a-4; P = 0.03) rejection than with no or mild (grade 0-1b) rejection, whereas there was no significant association between rejection and CMV as diagnosed by virus isolation from urine, throat or blood, or by the detection of CMV-IgM. PCR-positive biopsies originated most frequently from CMV-antibody positive recipients (R+) of hearts from seropositive donors (D+), in association with moderate or severe rejection rather than with mild or no rejection The detection of CMV in the heart thus seemed to be related more to R+D+ serological status than to severity of rejection, that is, to circumstances that favoured co-infection with strains of CMV from both donor and recipient. Studies on sequential biopsy specimens from selected patients also provided evidence that CMV infection and rejection were not always related events. The PCR was able to differentiate latent from active CMV infection; moreover, some seronegative individuals gave repeatedly positive biopsies, thereby supporting the work of others that some patients undergo CMV infection without mounting a detectable antibody response.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Case report 108. Eosinophilic granuloma of right pedicle and posterior elements of T11.
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Child↗
Fibrodysplasia ossificans progressiva.
Three hundred fifty-three previously reported cases of fibrodysplasia ossificans progressiva were reviewed and six new cases were analyzed radiologically. Characteristic findings of fibrodysplasia ossificans progressiva were confirmed and radiographic signs of the disease were demonstrated, including medial cortical thickening of the proximal tibia, narrow lumbar spinal canal, accessory epiphysis of the second phalanx of the fifth finger, and decreased humeral/epicondylar angle.
Bone and Bones↗