abacavir--lamivudine-drug-combination and Drug-Hypersensitivity

Integrase inhibitors are the latest drug family to be added to the therapeutic arsenal against human immunodeficiency virus infection. Drugs in this family that do not require pharmacological boosting are characterized by a very good safety profile. The latest integrase inhibitor to be approved for use is dolutegravir. In clinical trials, dolutegravir has shown an excellent tolerability profile, both in antiretroviral-naïve and previously treated patients. Discontinuation rates due to adverse effects were 2% and 3%, respectively. The most frequent adverse effects were nausea, headache, diarrhea and sleep disturbance. A severe hypersensitivity reaction has been reported in only one patient. In patients coinfected with hepatropic viruses, the safety profile is similar to that in patients without coinfection. The lipid profile of dolutegravir is similar to that of raltegravir and superior to those of Atripla® and darunavir/ritonavir. Dolutegravir induces an early, predictable and non-progressive increase in serum creatinine of around 10% of baseline values in treatment-naïve patients and of 14% in treatment-experienced patients. This increase is due to inhibition of tubular creatinine secretion through the OCT2 receptor and does not lead to a real decrease in estimated glomerular filtration rate with algorithms that include serum creatinine. The effect of the combination of dolutegravir plus Kivexa(®) on biomarkers of bone remodeling is lower than that of Atripla(®). Dolutegravir has an excellent tolerability profile with no current evidence of long-term adverse effects. Its use is accompanied by an early and non-progressive increase in serum creatinine due to OCT2 receptor inhibition. In combination with abacavir/lamivudine, dolutegravir has a lower impact than enofovir/emtricitabine/efavirenz on bone remodelling markers.

Topics: Bone Remodeling; Clinical Trials as Topic; Creatinine; Dideoxynucleosides; Drug Combinations; Drug Hypersensitivity; Drug Therapy, Combination; Gastrointestinal Diseases; Headache; Hepatitis, Viral, Human; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Immune Reconstitution Inflammatory Syndrome; Kidney Tubules; Lamivudine; Lipid Metabolism; Mood Disorders; Organic Cation Transport Proteins; Organic Cation Transporter 2; Oxazines; Piperazines; Pyridones; Respiration Disorders; Sleep Initiation and Maintenance Disorders

Although efavirenz and lopinavir/ritonavir(r) are both recommended antiretroviral agents in antiretroviral-naïve HIV-infected patients, there are few randomized comparisons of their efficacy and tolerability.. A multicenter and randomized study was performed including 126 antiretroviral-naïve patients, randomly assigned to efavirenz+Kivexa (n=63) or lopinavir/r+Kivexa (n=63). Efficacy endpoints were the percentage of patients with HIV-RNA < or =50 copies/mL at week 48 and CD4 recovery. Safety was assessed by comparing toxicity and discontinuations. Statistical analyses were performed on an intention-to-treat (ITT) basis (Missing=Failure).. At week 48, 56.7% of patients in the efavirenz and 63.2% in the lopinavir/r groups showed HIV-1 RNA <50 copies/mL (P=0.770) (intention-to-treat analysis; Missing=Failure). Only 1 (1.53%) patient from each group experienced virological failure. CD4 values increased in both groups (298 cells in the efavirenz group, P=0.001; 249 cells in the lopinavir/r group, P=0.002; P=0.126 between groups). HDL-cholesterol only increased in the efavirenz group (from 39+/-12 mg/dL to 49+/-11; P=0.001). Discontinuations were more frequent in the lopinavir/r group (36.5% versus 28.5%; P=0.193), but more patients with efavirenz interrupted due to toxicity (11.1% versus 6.3%); most of them were attributed to hypersensitivity reaction.. Similar virological efficacy was observed for efavirenz and lopinavir/r, when administered with Kivexa in antiretroviral-naïve patients, while immunological improvement was slightly superior for efavirenz. The higher rate of discontinuation due to toxicity in the efavirenz group was related to a higher incidence of hypersensitivity reaction. Nowadays, the use of the new formulation of lopinavir/r and the HLA-B*5701 genotype test before starting abacavir should improve the safety profiles of these regimens.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Dideoxynucleosides; Drug Combinations; Drug Hypersensitivity; Female; HIV Infections; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; RNA, Viral; Treatment Outcome; Viral Load; Withholding Treatment

To obtain safety and effectiveness data on a combined anti-HIV drug, Epzicom (abacavir 600 mg/lamivudine 300 mg), a post-marketing surveillance on Epzicom that was required by the Japanese regulatory authority was conducted between January 2005 and December 2010.. A joint survey (HIV-related drug [HRD] survey) has been conducted involving manufacturers of drugs for treatment of HIV infection in Japan. Safety and effectiveness data from total 624 cases (1107.3 person-years) registered to the HRD surveys and received Epzicom were obtained. Adverse drug reactions (ADRs) were defined as adverse events (AE) of which association with Epzicom could not be 'ruled out'.. It was found that the incidence of ADR was 32.4% (202/624 cases) on the case basis. In addition, the frequently reported ADR included hyperlipidaemia (59 cases), hypertriglyceridaemia (21 cases), blood bilirubin increased (19 cases), gamma-glutamyltransferase increase (14 cases), blood triglyceride increase (14 cases) and rash (14 cases). Serious AEs were seen in 19 patients (30 events), including one death (no evident association with Epzicom). There were four cases (0.6%) of survey-defined 'hypersensitivity', and the incidence was 0.9% (4/445) among abacavir naïve patients; none of which was reported as serious. No case of myocardial infarction was reported. One pregnant case who delivered a normal baby by caesarean section was reported to have experienced aggravation of anaemia and nausea.. The post-marketing surveillance indicated that the incidence of both ischaemic heart disease and hypersensitivity associated with Epzicom was considerably low, suggesting that this drug can be safely used in the Japanese population.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Combinations; Drug Hypersensitivity; HIV Infections; Humans; Incidence; Japan; Lamivudine; Myocardial Ischemia; Product Surveillance, Postmarketing

Abacavir/lamivudine (Epzicom) and emtricitabine/tenofovir (Truvada), two new once-daily fixed-dose NRTI combinations, have been approved for use in antiretroviral regimens to treat HIV infection. Epzicom appears to be as effective as its components taken separately and, in one study, Truvada was at least as effective as zidovudine/lamivudine (Combivir). Use of once-daily fixed-dose combinations means less flexibility in dosing, and some patients with hepatic or renal impairment will not be able to take them.

Topics: Anti-HIV Agents; Deoxycytidine; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Combinations; Drug Hypersensitivity; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; HIV Infections; Humans; Lamivudine; Organophosphorus Compounds