ritonavir and Drug-Hypersensitivity

HIV infection is a serious but treatable disease, yet current treatment is limited by development of resistance and high rates of adverse drug reactions. Antiretroviral therapy is especially suitable for pharmacogenomic investigation as both drug exposure and treatment response can be reliably measured. Increasing knowledge about genes implicated in pharmacokinetics, mode of action, efficacy, and toxicity of drugs has already provided relevant results for clinical practice, for example: The strong association of the abacavir hypersensitivity reaction with HLA-B*5701 permits testing patients for the allele, and if present avoiding the drug and therefore preventing the reaction. Persons with the allele CYP2B6*6 present higher efavirenz "area under the curve" and have increased risk of neuropsychological toxicity. Additional gene variants are being discovered that influence the action of antiretroviral drugs. And, moreover, it is expected that larger-scale comprehensive genome approaches will profoundly improve the landscape of knowledge of HIV therapy in the future. The present article shows some recent patents related to the treatment of viral infections.

Topics: Alkynes; Anti-Retroviral Agents; Aryl Hydrocarbon Hydroxylases; Atazanavir Sulfate; Benzoxazines; Central Nervous System Diseases; Cyclopropanes; Cytochrome P-450 CYP2B6; Dideoxynucleosides; Drug Hypersensitivity; Drug Resistance, Viral; Dyslipidemias; Genetic Predisposition to Disease; Genetic Testing; Glucuronosyltransferase; HLA Antigens; Humans; Hyperbilirubinemia; Nevirapine; Oligopeptides; Oxidoreductases, N-Demethylating; Patents as Topic; Patient Selection; Pharmacogenetics; Pyridines; Ritonavir

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

A HIV-infected patient treated since eight years with all antiretroviral classes save boosted protease inhibitors, at the time of changing therapy due to an emerging genotyping resistance to non-nucleoside reverse transcriptase inhibitors, experienced repeated episodes of hypersensitivity reactions to all available boosted protease inhibitors. After documenting a combined ritonavir and lopinavir hypersensitivity by means of a specific in vitro cellular antigen stimulation test (CAST), antiretroviral therapy was safely continued with unboosted atazanavir. According to our knowledge, we report the first case of application of the in vitro CAST assay to antiretroviral intolerance, and the subsequent, specific regimen selection in a HIV-infected subject who showed multiple allergy to all boosted protease inhibitors. Further, controlled investigation is strongly needed to implement in vitro allergometric testing in patients with HIV infection and related diseases, who are prone to show unpredictable drug intolerance reactions. In fact, HIV-infected patients may suffer from frequent allergic drug reactions which may be difficult to be systematically recognized (due to the frequent, multiple concurrent pharmacotherapy), while eventual drug rechallenges are expected to be potentially dangerous.

Topics: Adult; Anti-HIV Agents; Drug Hypersensitivity; HIV Infections; Humans; Immunoassay; Lopinavir; Male; Protease Inhibitors; Pyrimidinones; Ritonavir

We report on a Subsaharian patient with HIV infection and disseminated tuberculosis who developed acute, severe hypersensitivity reaction to efavirenz including acute renal failure in addition to liver and lung involvement, in the absence of skin changes or blood eosinophilia.

Topics: Acute Kidney Injury; Adenine; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Hypersensitivity; Ghana; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Male; Mycobacterium tuberculosis; Organophosphonates; Reverse Transcriptase Inhibitors; Ritonavir; Tenofovir; Tuberculosis