pyrimidinones and AIDS-Related-Opportunistic-Infections

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Antiretroviral Therapy, Highly Active; Aryl Hydrocarbon Hydroxylases; Bundle-Branch Block; Cytochrome P-450 CYP3A; Drug Interactions; Enzyme Inhibitors; Heart; Heart Block; HIV Protease Inhibitors; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Oxidoreductases, N-Demethylating; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Syncope; Zidovudine

Adverse effects of combination antiretroviral therapy (CART) commonly result in treatment modification and poor adherence.. We investigated predictors of toxicity-related treatment modification during the first year of CART in 1318 antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals from the Swiss HIV Cohort Study who began treatment between January 1, 2005, and June 30, 2008.. The total rate of treatment modification was 41.5 (95% confidence interval [CI], 37.6-45.8) per 100 person-years. Of these, switches or discontinuations because of drug toxicity occurred at a rate of 22.4 (95% CI, 19.5-25.6) per 100 person-years. The most frequent toxic effects were gastrointestinal tract intolerance (28.9%), hypersensitivity (18.3%), central nervous system adverse events (17.3%), and hepatic events (11.5%). In the multivariate analysis, combined zidovudine and lamivudine (hazard ratio [HR], 2.71 [95% CI, 1.95-3.83]; P < .001), nevirapine (1.95 [1.01-3.81]; P = .050), comedication for an opportunistic infection (2.24 [1.19-4.21]; P = .01), advanced age (1.21 [1.03-1.40] per 10-year increase; P = .02), female sex (1.68 [1.14-2.48]; P = .009), nonwhite ethnicity (1.71 [1.18-2.47]; P = .005), higher baseline CD4 cell count (1.19 [1.10-1.28] per 100/microL increase; P < .001), and HIV-RNA of more than 5.0 log(10) copies/mL (1.47 [1.10-1.97]; P = .009) were associated with higher rates of treatment modification. Almost 90% of individuals with treatment-limiting toxic effects were switched to a new regimen, and 85% achieved virologic suppression to less than 50 copies/mL at 12 months compared with 87% of those continuing CART (P = .56).. Drug toxicity remains a frequent reason for treatment modification; however, it does not affect treatment success. Close monitoring and management of adverse effects and drug-drug interactions are crucial for the durability of CART.

Topics: Adenine; Adult; AIDS-Related Opportunistic Infections; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Deoxycytidine; Dideoxynucleosides; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Nevirapine; Oligopeptides; Organophosphonates; Proportional Hazards Models; Prospective Studies; Pyridines; Pyrimidinones; Risk Factors; Switzerland; Tenofovir; Zidovudine

The population pharmacokinetics (PK) of lopinavir in tuberculosis (TB)/human immunodeficiency virus (HIV) co-infected South African children taking super-boosted lopinavir (lopinavir/ritonavir ratio 1:1) as part of antiretroviral treatment in the presence of rifampicin were compared with the population PK of lopinavir in HIV-infected South African children taking standard doses of lopinavir/ritonavir (ratio 4:1).. Lopinavir concentrations were measured in 15 TB/HIV-co-infected paediatric patients who were sampled during and after rifampicin-based TB treatment and in 15 HIV-infected children without TB. During TB therapy, the dose of ritonavir was increased to lopinavir/ritonavir 1:1 in order to compensate for the induction of rifampicin. The children received median (interquartile range=IQR) doses of lopinavir 292 mg/m(2) (274, 309) and ritonavir 301 mg/m(2) (286, 309) twice daily. After TB treatment completion the children received standard doses of lopinavir/ritonavir 4:1 (median [IQR] lopinavir dose 289 mg/m(2) [286, 303] twice daily) as did those without TB (median [IQR] lopinavir dose 265 mg/m(2) [249, 289] twice daily).. Lopinavir oral clearance (CL/F) was about 30% lower in children without TB than in co-infected children treated with super-boosted lopinavir. However, the predicted lopinavir C(min) was above the recommended minimum therapeutic concentration during TB/HIV co-treatment in the 15 children. Lopinavir CL/F increased linearly during the dosing interval.. Increasing the ritonavir dose to achieve a lopinavir/ritonavir ratio of 1:1 when given in combination with rifampicin-based TB treatment did not completely compensate for the enhancement of lopinavir CL/F caused by rifampicin. The time-dependent lopinavir CL/F might be due to a time-dependent recovery from ritonavir inhibition of lopinavir metabolism during the dosing interval.

Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Infant; Lopinavir; Male; Pyrimidinones; Rifampin; Ritonavir; South Africa; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary

Leishmania is the etiologic agent of leishmanisais, a protozoan disease whose pathogenic events are not well understood. Current therapy is suboptimal due to toxicity of the available therapeutic agents and the emergence of drug resistance. Compounding these problems is the increase in the number of cases of Leishmania-HIV coinfection, due to the overlap between the AIDS epidemic and leishmaniasis.. In the present report, we have investigated the effect of HIV aspartyl peptidase inhibitors (PIs) on the Leishmania amazonensis proliferation, ultrastructure, interaction with macrophage cells and expression of classical peptidases which are directly involved in the Leishmania pathogenesis. All the HIV PIs impaired parasite growth in a dose-dependent fashion, especially nelfinavir and lopinavir. HIV PIs treatment caused profound changes in the leishmania ultrastructure as shown by transmission electron microscopy, including cytoplasm shrinking, increase in the number of lipid inclusions and some cells presenting the nucleus closely wrapped by endoplasmic reticulum resembling an autophagic process, as well as chromatin condensation which is suggestive of apoptotic death. The hydrolysis of HIV peptidase substrate by L. amazonensis extract was inhibited by pepstatin and HIV PIs, suggesting that an aspartyl peptidase may be the intracellular target of the inhibitors. The treatment with HIV PIs of either the promastigote forms preceding the interaction with macrophage cells or the amastigote forms inside macrophages drastically reduced the association indexes. Despite all these beneficial effects, the HIV PIs induced an increase in the expression of cysteine peptidase b (cpb) and the metallopeptidase gp63, two well-known virulence factors expressed by Leishmania spp.. In the face of leishmaniasis/HIV overlap, it is critical to further comprehend the sophisticated interplays among Leishmania, HIV and macrophages. In addition, there are many unresolved questions related to the management of Leishmania-HIV-coinfected patients. For instance, the efficacy of therapy aimed at controlling each pathogen in coinfected individuals remains largely undefined. The results presented herein add new in vitro insight into the wide spectrum efficacy of HIV PIs and suggest that additional studies about the synergistic effects of classical antileishmanial compounds and HIV PIs in macrophages coinfected with Leishmania and HIV-1 should be performed.

Topics: AIDS-Related Opportunistic Infections; Animals; HIV Protease Inhibitors; Humans; Leishmania mexicana; Lopinavir; Macrophages; Nelfinavir; Protease Inhibitors; Pyrimidinones

Topics: Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antiprotozoal Agents; Antiretroviral Therapy, Highly Active; CD4-Positive T-Lymphocytes; Hepatitis C, Chronic; Histiocytes; Humans; Lamivudine; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Lopinavir; Male; Meglumine; Meglumine Antimoniate; Organometallic Compounds; Patient Compliance; Pentamidine; Pyrimidinones; Recurrence; Ritonavir; Tattooing; Zidovudine

Topics: Adenine; AIDS-Related Opportunistic Infections; Algorithms; Anti-HIV Agents; Antiviral Agents; Comorbidity; DNA, Viral; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Function Tests; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Thymidine

Topics: Adult; AIDS-Related Opportunistic Infections; Amphotericin B; Anti-HIV Agents; Antifungal Agents; Biopsy; Female; Histoplasma; Histoplasmosis; HIV Infections; HIV Protease Inhibitors; Humans; Itraconazole; Lopinavir; Pyrimidinones; Skin; Treatment Outcome

Topics: Adult; AIDS-Related Opportunistic Infections; Amphotericin B; Anti-HIV Agents; Antifungal Agents; Antiretroviral Therapy, Highly Active; CD4-Positive T-Lymphocytes; Fluconazole; Flucytosine; HIV Infections; Humans; Immunologic Memory; Lamivudine; Lopinavir; Male; Meningitis, Cryptococcal; Pyrimidinones; Recurrence; Ritonavir; Syndrome; T-Lymphocyte Subsets; Zidovudine

Human immuno deficiency virus (HIV) weakens the immune system so that many opportunistic infections (OIs) like tuberculosis, hepatitis, bacterial infections etc can develop. In this paper, we designed aminopyrimidinimino isatin lead compound as a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with broad-spectrum chemotherapeutic properties for the effective treatment of AIDS and AIDS-related OIs. Compound 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[[N4-[3'-(4'-amino-5'-trimethoxybenzyl pyrimidin-2'-yl)imino-1'-(5-methylisatinyl)]methyl]-N1-piperazinyl]-3-quinoline carboxylic acid (10) emerged as the most potent broad-spectrum chemotherapeutic agent active against HIV, HCV, Mycobacterium tuberculosis and various pathogenic bacteria.

Topics: AIDS-Related Opportunistic Infections; Drug Design; HIV Reverse Transcriptase; Humans; Isatin; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pyrimidinones; Virus Replication

We describe a drug-drug interaction between coformulated lopinavir/ritonavir and itraconazole in a patient infected with human immunodeficiency virus type 1 who had disseminated histoplasmosis. Coadministration of these agents led to a strong increase in itraconazole concentrations and a decrease in concentrations of its metabolite, hydroxyitraconazole, which is equally active pharmacologically. The dosage of itraconazole was reduced when it was used in combination with lopinavir/ritonavir.

Topics: AIDS-Related Opportunistic Infections; Antifungal Agents; Antiretroviral Therapy, Highly Active; Drug Interactions; Drug Therapy, Combination; Histoplasmosis; HIV Infections; HIV Protease Inhibitors; Humans; Itraconazole; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir

To determine the incidence of significant liver enzyme elevations following the initiation of protease inhibitor (PI)-based antiretroviral therapy (ART) with or without pharmacokinetic boosting with ritonavir (RTV), and to define the role of chronic viral hepatitis in its development.. Prospective, cohort analysis of 1161 PI-naive, HIV-infected patients receiving RTV-boosted (lopinavir, indinavir and saquinavir) and unboosted PI-based ART (indinavir, nelfinavir) that had at least one liver enzyme measurement before and during therapy.. The incidence of grade 3 and 4 liver enzyme elevations among persons with and without hepatitis B and/or C co-infection treated with PI-based ART were compared. Severe hepatotoxicity was defined as an increase in serum liver enzyme >/= 5-times the upper limit of the normal range or 3.5-times an elevated baseline level.. The incidence of grade 3 or 4 elevations among PI-naive patients was: nelfinavir, 11%; lopinavir/RTV (200 mg/day), 9%; indinavir, 13%; indinavir/RTV (200-400 mg/day), 12.8%; and saquinavir/RTV (800 mg/day), 17.2%. The risk was significantly greater among persons with chronic viral hepatitis (63% of cases); however, the majority of hepatitis C virus (HCV)-infected patients treated with nelfinavir (84%), saquinavir/RTV (74%), indinavir, 86%, indinavir/RTV (90%) or lopinavir/RTV (87%) did not develop hepatotoxicity.. Our data suggest that the lopinavir/RTV is not associated with a significantly increased risk of hepatotoxity among HCV-infected and uninfected patients compared with an alternative PI-based regimen, nelfinavir. Accordingly, other medication-related factors (e.g, efficacy and non-hepatic toxicity) should guide individual treatment decisions.

Topics: Adult; AIDS-Related Opportunistic Infections; Antiretroviral Therapy, Highly Active; Chronic Disease; Drug Therapy, Combination; Female; Hepatitis; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Liver; Lopinavir; Male; Nelfinavir; Prospective Studies; Pyrimidinones; Reverse Transcriptase Inhibitors; Risk Factors; Ritonavir; Saquinavir; Treatment Outcome

Topics: AIDS-Related Opportunistic Infections; Anti-Bacterial Agents; Anti-HIV Agents; Clarithromycin; Drug Combinations; HIV Protease Inhibitors; HIV Seropositivity; Humans; Lopinavir; Nutrition Disorders; Patient Care Management; Physician-Patient Relations; Pyrimidinones; Quality of Life; Ritonavir

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Antiprotozoal Agents; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Leishmaniasis; Lopinavir; Male; Pyrimidinones; Renal Dialysis; Renal Insufficiency; Ritonavir

The 12th World AIDS Conference in Geneva brought together AIDS researchers, medical care providers, advocates, and people living with HIV to discuss implications related to providing global access to care. New drugs have decreased deaths and opportunistic infections in developed countries, but developing countries are becoming overwhelmed by the number of new patients. The World Health Organization estimates that the majority of the 30.6 million people infected with HIV/AIDS worldwide will die within a decade unless a cure is found or treatments are made accessible to them. Researchers are no longer optimistic about the feasibility of viral eradication, and instead are looking for strategies to overcome the virus that continues to live in latent reservoirs in the body. Descriptions are given of several new drugs currently being studied, including abacavir, amprenavir, efavirenz, ABT 378, and Hydroxyurea. Progress is also highlighted about dosing regimens, antiretroviral resistance, and reconstitution of the immune system.

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; CD4-Positive T-Lymphocytes; Clinical Trials as Topic; Congresses as Topic; Cyclopropanes; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Enzyme Inhibitors; Furans; Health Services Accessibility; HIV Protease Inhibitors; Humans; Hydroxyurea; Lopinavir; Oxazines; Patient Care Planning; Pyrimidinones; Remission Induction; Reverse Transcriptase Inhibitors; Sulfonamides; Switzerland; Virus Replication