pyrimidinones and abacavir

Previous work has demonstrated the existence of systemic interaction between tenofovir (TFV) disoproxil fumarate (TDF) and didanosine as well as between TDF and lopinavir-ritonavir (LPV/r). Here we investigated TDF interactions with the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine (3TC) and abacavir (ABC), comparing both the concentrations of nucleoside/nucleotide reverse transcriptase inhibitors in plasma and the intracellular concentrations of their triphosphate metabolites (NRTI-TP) for human immunodeficiency virus-infected patients receiving these NRTIs with TDF and after 4 weeks of TDF interruption. We also looked at interactions between TDF-ABC and LPV/r, comparing patients receiving or not receiving LPV/r. Blood samples were taken at baseline and at 1, 2, and 4 h after dosing. Liquid chromatography-tandem mass spectrometry was used to measure NRTIs and NRTI-TPs. Statistical analyses were performed on pharmacokinetic parameters: the area under the concentration-time curve from 0 to 4 h (AUC(0-4)), the maximum concentration of the drug (C(max)), and the residual concentration of the drug at the end of the dosing interval (C(trough)) for plasma and the AUC(0-4) and C(trough) for intracellular data. Among the groups of patient discontinuing TDF, the very long intracellular half-life of elimination (150 h) of TFV-DP (the diphosphorylated metabolite of TFV, corresponding to a triphosphorylated species) was confirmed. Comparison between groups as well as the longitudinal study showed no significant systemic or intracellular interaction between TDF and ABC or 3TC. Significant differences were observed between patients receiving LVP/r and those receiving nevirapine. For ABC, plasma exposure was decreased (40%) under LVP/r, while, in contrast, plasma exposure to TFV was increased by 50% and the intracellular TFV-DP AUC(0-4) was increased by 59%. A trend for a gender effect was observed for TFV-DP at the intracellular level, with higher and C(trough) values for women.

Topics: Adenine; Adult; Anti-HIV Agents; Area Under Curve; Cross-Sectional Studies; Dideoxynucleosides; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Longitudinal Studies; Lopinavir; Male; Middle Aged; Organophosphonates; Pilot Projects; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Tenofovir; Treatment Outcome

Switching a thymidine analogue to a non-thymidine analogue or changing to a nucleoside-sparing regimen has been shown to partially reverse peripheral lipoatrophy. The current study evaluated both approaches.. Subjects at 15 AIDS Clinical Trial Group sites receiving thymidine analogue stavudine- or zidovudine-containing regimens with plasma HIV RNA < or =500 copies/mL and lipoatrophy were prospectively randomized to: (i) switch the thymidine analogue to abacavir; (ii) discontinue all antiretrovirals and switch to lopinavir/ritonavir plus nevirapine (LPV/r+NVP); or (iii) delay switching for 24 weeks (ClinicalTrials.gov identifier: NCT00028314). Single-slice computer tomography of mid-thigh and abdominal fat and metabolic and virological/immunological parameters were measured at baseline and weeks 24 and 48.. Among the 101 patients enrolled, there were significant subcutaneous thigh fat and subcutaneous abdominal tissue (SAT) increases over time and decreases in visceral adipose tissue to total adipose tissue (VAT:TAT) ratios for both interventions, and a decrease in VAT for abacavir. CD4 increased in the LPV/r+NVP arm. LPV/r+NVP had a significantly shorter time to grade 3 or higher toxicity (P = 0.007), but discontinuation rates were similar. Glucose levels did not change, but insulin decreased in the LPV/r+NVP arm. Lipids tended to increase in the LPV/r+NVP arm.. Switching stavudine or zidovudine to a non-thymidine analogue or changing to a nucleoside reverse transcriptase inhibitor-sparing regimen is associated with qualitatively similar improvements in thigh fat, SAT and VAT:TAT ratio at 48 weeks. Abacavir also resulted in VAT reductions and LPV/r+NVP resulted in CD4 count increases.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Female; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Intra-Abdominal Fat; Lopinavir; Male; Middle Aged; Nevirapine; Pyrimidinones; Radiography, Abdominal; Stavudine; Thigh; Viral Load; Zidovudine

Abacavir sulfate/lamivudine (ABC/3TC) and tenofovir DF/emtricitabine (TDF/FTC) are widely used nucleoside reverse transcriptase inhibitors for initial HIV-1 treatment. This is the first completed, randomized clinical trial to directly compare the efficacy, safety, and tolerability of these agents, each in combination with lopinavir/ritonavir in antiretroviral-naive patients.. Six hundred and eighty-eight antiretroviral-naive, HIV-1-infected patients were randomized in this double-blind, placebo-matched, multicenter, noninferiority study to receive a once-daily regimen of either ABC/3TC 600 mg/300 mg or TDF/FTC 300 mg/200 mg, both with lopinavir/ritonavir 800 mg/200 mg. Primary endpoints were the proportion of patients with HIV-1 RNA below 50 copies/ml at week 48 (missing = failure, switch included analysis) and the proportion of patients experiencing adverse events over 96 weeks.. At week 48, 68% in the ABC/3TC group vs. 67% in the TDF/FTC group achieved an HIV-1 RNA below 50 copies/ml (intent-to-treat exposed missing = failure, 95% confidence interval on the difference -6.63 to 7.40, P = 0.913), demonstrating the noninferiority of ABC/3TC to TDF/FTC at week 48. Noninferiority of the two regimens was sustained at week 96 (60% vs. 58%, respectively, 95% confidence interval -5.41 to 9.32, P = 0.603). In addition, efficacy of both regimens was similar in patients with baseline HIV-1 RNA >or= 100 000 copies/ml or CD4 cell counts below 50 cells/microl. Median CD4 recovery (ABC/3TC vs. TDF/FTC, cells/microl) was +250 vs. +247 by week 96. Premature study discontinuation due to adverse events occurred in 6% of patients in both groups. Protocol-defined virologic failure occurred in 14% of patients in both groups.. Both ABC/3TC and TDF/FTC provided comparable antiviral efficacy, safety, and tolerability when each was combined with lopinavir/ritonavir in treatment-naive patients.

Topics: Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cardiovascular Diseases; CD4 Lymphocyte Count; Deoxycytidine; Dideoxynucleosides; Double-Blind Method; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Lamivudine; Lopinavir; Male; Organophosphonates; Pyrimidinones; Ritonavir; RNA, Viral; Tenofovir; Treatment Outcome

Significant interactions between abacavir and other antiretrovirals have not been reported. This study investigated the steady-state plasma pharmacokinetics of abacavir when co-administered with atazanavir/ritonavir or lopinavir/ritonavir in HIV-infected individuals.. HIV-infected subjects on abacavir (600 mg once daily) plus two nucleoside reverse transcriptase inhibitors (NRTIs) (excluding tenofovir) underwent a 24 h pharmacokinetic assessment for plasma abacavir concentrations. Atazanavir/ritonavir (300/100 mg once daily; arm (1) or lopinavir/ritonavir (400/100 mg twice daily; arm (2) were then added and the 24 h pharmacokinetic assessment repeated. Arm 3 included subjects stable on atazanavir/ritonavir or lopinavir/ritonavir and two NRTIs (excluding tenofovir or abacavir). These patients underwent a pharmacokinetic assessment for atazanavir/ritonavir or lopinavir/ritonavir concentrations on day 1, abacavir (600 mg once daily) was then added to the regimen and the pharmacokinetic assessment repeated. Within-subject changes in drug exposure were evaluated by geometric mean (GM) ratios and 95% confidence intervals (CI).. Twenty-four patients completed the study. GM (95% CI) abacavir area under the curve (AUC) was 18,621 (15,900-21,807) and 15,136 (13,339-17,174) ng.h/ml without and with atazanavir/ritonavir and 15,136 (12,298-18,628) and 10,471 (9,270-11,828) ng.h/ml without and with lopinavir/ritonavir. GM (95% CI) atazanavir AUC without and with abacavir was 26,915 (13,252-54,666) and 28,840 (19,213-43,291) ng.h/ml; lopinavir AUC without and with abacavir was 60,253 (48,084-75,509) and 63,096 (48,128-82,718) ng.h/ml.. No changes in atazanavir or lopinavir exposures were observed following the addition of abacavir; however, decreases in abacavir plasma exposure of 17% and 32% were observed following the addition of atazanavir/ritonavir or lopinavir/ritonavir, respectively.

Topics: Adult; Area Under Curve; Atazanavir Sulfate; Dideoxynucleosides; Drug Administration Schedule; Drug Combinations; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Oligopeptides; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir

Lopinavir-ritonavir is a preferred protease inhibitor co-formulation for initial HIV-1 treatment. Fosamprenavir-ritonavir has shown similar efficacy and safety to lopinavir-ritonavir when each is combined with two nucleoside reverse transcriptase inhibitors. We compared the two treatments directly in antiretroviral-naive patients.. This open-label, non-inferiority study included 878 antiretroviral-naive, HIV-1-infected patients randomised to receive either fosamprenavir-ritonavir 700 mg/100 mg twice daily or lopinavir-ritonavir 400 mg/100 mg twice daily, each with the co-formulation of abacavir-lamivudine 600 mg/300 mg once daily. Primary endpoints were proportion of patients achieving HIV-1 RNA less than 400 copies per mL at week 48 and treatment discontinuations because of an adverse event. The intent-to-treat analysis included all patients exposed to at least one dose of randomised study medication. This study is registered with ClinicalTrials.gov, number NCT00085943.. At week 48, non-inferiority of fosamprenavir-ritonavir to lopinavir-ritonavir (95% CI around the treatment difference -4.84 to 7.05) was shown, with 315 of 434 (73%) patients in the fosamprenavir-ritonavir group and 317 of 444 (71%) in the lopinavir-ritonavir group achieving HIV-1 RNA less than 400 copies per mL. Treatment discontinuations due to an adverse event were few and occurred with similar frequency in the two treatment groups (fosamprenavir-ritonavir 53, 12%; lopinavir-ritonavir 43, 10%). Diarrhoea, nausea, and abacavir hypersensitivity were the most frequent drug-related grade 2-4 adverse events. Treatment-emergent drug resistance was rare; no patient had virus that developed reduced susceptibility to fosamprenavir-ritonavir or lopinavir-ritonavir.. Fosamprenavir-ritonavir twice daily in treatment-naive patients provides similar antiviral efficacy, safety, tolerability, and emergence of resistance as lopinavir-ritonavir, each in combination with abacavir-lamivudine.

Topics: Carbamates; Dideoxynucleosides; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Lopinavir; Organophosphates; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides

Over the last decade, increased funding to support HIV treatment programs has enabled millions of new patients in developing countries to access the medications they need. Today, although demand for antiretrovirals continues to grow, the financial crisis has severely constrained funding leaving countries with difficult choices on program prioritization. Product optimization is one solution countries can pursue to continue to improve patient care while also uncovering savings that can be used for further scale up or other health system needs. Program managers can make procurement decisions that actually reduce program costs by considering additional factors beyond World Health Organization guidelines when making procurement decisions. These include in-country product availability, convenience, price, and logistics such as supply chain implications and laboratory testing requirements. Three immediate product selection opportunities in the HIV space include using boosted atazanavir in place of lopinovir for second-line therapy, lamivudine instead of emtricitabine in both first-line and second-line therapy, and tenofovir + lamivudine over abacavir + didanosine in second-line therapy. If these 3 opportunities were broadly implemented in sub-Saharan Africa and India today, approximately $300 million of savings would be realized over the next 5 years, enabling hundreds of thousands of additional patients to be treated. Although the discussion herein is specific to antriretrovirals, the principles of product selection are generalizable to diseases with multiple treatment options and fungible commodity procurement. Identifying and implementing approaches to overcome health system inefficiencies will help sustain and may expand quality care in resource-limited settings.

Topics: Anti-Retroviral Agents; Atazanavir Sulfate; Developing Countries; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Health Planning; Health Services; HIV Infections; Humans; Lamivudine; Lopinavir; Oligopeptides; Pyridines; Pyrimidinones; Treatment Outcome

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

To compare plasma antiretroviral concentrations in HIV-HCV co-infected and in matched HIV mono-infected patients.. This was a cross-sectional, observational study. Antiretroviral trough concentrations (C(min)) in plasma were measured in HIV-HCV co-infected patients with liver disease documented by liver biopsy, matched with HIV mono-infected patients according to gender and antiretroviral treatment. C(min) values in serum were measured using an HPLC method. Statistical analysis was performed using the Wilcoxon test.. Seventy-three HIV-HCV co-infected patients and 66 HIV-infected patients were enrolled; 70% of patients were receiving a protease inhibitor (PI)- and 30% a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen. Among the 73 co-infected patients, 27 had a fibrosis score (Fibrotest(®)) of F4. Abacavir was the only nucleoside reverse transcriptase inhibitor whose trough concentrations differed between the co-infected and mono-infected groups. PI median plasma C(min) values were not different in the two groups, except for lopinavir, with a lower C(min) in the co-infected group than in the HIV-infected group (median 3673 versus 5990 ng/mL, P=0.04), and nelfinavir, with significantly higher concentrations in the co-infected group. Seventy-five percent of co-infected patients scoring F4, 33% of those scoring F0-F3 and 12% of HIV-infected patients were underdosed (P=0.02). Co-infected patients receiving an NNRTI had a higher plasma C(min) than HIV-infected patients; median C(min) was 3583 versus 1494 ng/mL (P=0.025) and 5331 versus 3954 ng/mL (P=0.10) for efavirenz and nevirapine, respectively. Overall, there was a greater proportion of co-infected patients with high concentrations of both NNRTIs (15/23) compared with HIV mono-infected patients (5/21) (P=0.008), especially in co-infected patients with an advanced liver fibrosis stage.. Median plasma C(min) values differed significantly between HIV and HIV-HCV co-infected patients for abacavir, lopinavir and efavirenz. NNRTIs were strongly overdosed in HIV-HCV co-infected patients.

Topics: Adult; Aged; Alkynes; Anti-Retroviral Agents; Benzoxazines; Case-Control Studies; Chromatography, High Pressure Liquid; Cross-Sectional Studies; Cyclopropanes; Dideoxynucleosides; Female; Hepatitis C, Chronic; HIV Infections; Humans; Liver Cirrhosis; Lopinavir; Male; Middle Aged; Plasma; Pyrimidinones

Topics: Adenine; Adult; Alkynes; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Hepatitis B, Chronic; Hepatitis C, Chronic; Hepatitis D, Chronic; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Lopinavir; Male; Nephrolithiasis; Oligopeptides; Organophosphonates; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine; Tenofovir

The aim of the study was to determine the factors that may contribute to decreases in bone mineral density (BMD) in patients with AIDS.. This was a prospective, non-randomized study. Dual X-ray absorptiometry (DXA) was used to determine the BMD of the lumbar spine, femoral neck and distal radius in treatment-naïve HIV-infected male patients with AIDS before and after 1 year of treatment with zidovudine (ZDV)/lamivudine (3TC) plus abacavir (ABC) or lopinavir/ritonavir (LPV/r).. Basal DXA was performed in 50 patients with CD4 counts <200 cells/microL and/or any AIDS-defining condition. Thirty-two patients completed 1 year with full adherence (17 on ABC and 15 on LPV/r) and a second DXA was then performed. At baseline, 19% had osteopenia at the lumbar spine and 19% at the femoral neck. Low body weight was related to low BMD. After 48 weeks, BMD loss was significant at the three locations. The percentage of BMD loss at the femoral neck tended to be greater in the lopinavir group (5.3 vs. 3.2%, P=0.058). The differences became significant at the lumbar spine (5.7 vs. 2.7%, P=0.044). In the multivariate analysis, the treatment with LPV/r remained associated with bone loss at the lumbar spine.. Osteopenia is frequent in treatment-naïve HIV-infected men with AIDS. Bone loss is higher with LPV/r-based regimens compared with triple nucleoside reverse transcriptase inhibitors.

Topics: Absorptiometry, Photon; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Bone Density; Case-Control Studies; Dideoxynucleosides; Femur Neck; HIV Infections; Humans; Lamivudine; Lopinavir; Lumbar Vertebrae; Male; Middle Aged; Prospective Studies; Pyrimidinones; Ritonavir; Zidovudine

HPV infections have become a major problem in immunocompromised patients, particularly in HIV-positive subjects. HPV lesions are observed more frequently in the ano-genital area and rarely in different body areas, such as the skin and oral cavity. However, in HIV-positive subjects there is an increased risk of oral condylomas. We describe the case of an HIV-positive Nigerian young woman, who came to our notice due to the appearance of small labial and mouth mucous membrane lesions, related to HPV infection, as shown by a biopsy. These lesions were not evident in the genital area. After two years in which the patient no longer received therapy, there was a progressive reduction in CD4 count, associated with the development of the oral condylomas. Hence the patient began a new HAART combination, but after seven months, although a slight improvement emerged in the CD4 count with the disappearance of HIV-RNA, there has been no regression of oral condylomas.

Topics: Adenine; Adult; Alphapapillomavirus; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Deoxycytidine; Dideoxynucleosides; Emtricitabine; Female; HIV Infections; Humans; Italy; Lamivudine; Lopinavir; Mouth Mucosa; Nigeria; Organophosphonates; Papillomavirus Infections; Pyrimidinones; Ritonavir; Sex Work; Stomatitis; Tenofovir; Treatment Refusal; Zidovudine

Topics: Administration, Oral; Didanosine; Dideoxynucleosides; Drugs, Generic; HIV Infections; Humans; Lopinavir; Pyrimidinones; Reverse Transcriptase Inhibitors; Stavudine; United States; United States Food and Drug Administration

A 38-year-old Caucasian woman with uncontrolled human immunodeficiency virus (HIV) infection was treated with highly active antiretroviral therapy (HAART) consisting of zidovudine, lamivudine, and nevirapine. Because her therapeutic response was inadequate, the HAART regimen was changed to abacavir, lamivudine, and lopinavir-ritonavir. Three months after this therapy was started, the patient developed progressive and notable hair loss. Her hair became fair and thin, and her appearance deteriorated considerably. Hair loss due to HAART was diagnosed. Lopinavir-ritonavir was stopped, and efavirenz was substituted; abacavir and lamivudine were continued. After 4 weeks, her hair growth substantially improved, as evidenced by rapid growth of new hair. Her general condition also improved. No relapse was observed with the new HAART regimen, and the patient's hair loss completely reversed in 8 weeks. Alopecia is a possible adverse event in HIV-infected patients treated with protease inhibitors, particularly indinavir. Our patient's severe and generalized alopecia was temporally related to the initiation and discontinuation of lopinavir-ritonavir. On the basis of the Naranjo adverse drug reaction probability scale, the adverse reaction was considered probable. Although generalized hair loss due to lopinavir-ritonavir is rare, clinicians should be aware of this potential adverse reaction of this widely used drug. If alopecia is severe or particularly distressing to the patient, the offending drug should be discontinued, and therapy with another HIV drug should be started.

Topics: Adult; Alkynes; Alopecia; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Lopinavir; Probability; Pyrimidinones; Ritonavir

Chronic viral hepatitis is common among persons with HIV-1 infection, because of shared modes of transmission, and coinfection results in accelerated liver damage, compared with persons with chronic viral hepatitis alone. The use of highly active antiretroviral therapy (HAART) has led to a significant decrease in the morbidity and mortality associated with HIV-1 infection. A number of the medications that are commonly used in HAART regimens are metabolized by the hepatic CYP enzymes, which raises the possibility of significant interactions between antiretroviral medications and hepatic impairment induced by chronic viral hepatitis. Although the data are still very scant, the pharmacokinetics of several antiretroviral medications have been shown to be significantly altered in the presence of liver disease. In the present report, we review the available data and consider potential options, such as dose adjustment and therapeutic drug monitoring, for the administration of antiretroviral therapy to patients with significant hepatic impairment.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Hepatitis; HIV Infections; Humans; Indinavir; Liver Function Tests; Lopinavir; Nelfinavir; Nevirapine; Oxazines; Protease Inhibitors; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Zidovudine

The human immunodeficiency virus type 1 (HIV-1) resistance profile, K65R, K70E and M184V, on reverse transcriptase gene was associated with the virologic rebound consecutively to the switch of lopinavir/r to tenofovir DF in a stable regimen with nucleoside backbone of abacavir, lamivudine and didanosine. The high selective pressure on the same resistance pathway was probably associated with the loss of antiviral potency, even in well-controlled patient.

Topics: Adenine; Adult; Anti-HIV Agents; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; Female; Gabon; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Lopinavir; Microbial Sensitivity Tests; Mutation; Organophosphonates; Pyrimidinones; Tenofovir; Viral Load

Identify the determinants and consequences of interrupting and discontinuing highly active antiretroviral therapy (HAART) among a population-based cohort of HIV-infected men.. Longitudinal analyses were applied to 2916 person-visit pairs (589 men) of continuous HAART use, 243 person-visit pairs (154 men) during which HAART was interrupted, and 151 person-visit pairs (130 men) in which HAART was discontinued by the second visit. HIV RNA increase was defined as > or =1 log10 copies/mL across the visit pairs.. : Younger age, black race, geographic location, higher HIV RNA level, depression, shorter time on HAART, lower medication adherence, and not taking a lamivudine-containing regimen predicted interrupting HAART use. Younger age, higher HIV RNA level, depression, and taking an abacavir- or lopinavir-containing regimen predicted discontinuing HAART. Among men with < or =1000 HIV RNA copies/mL, approximately 5% of those who interrupted HAART for < or =7 days and those who continued HAART had an HIV RNA increase. Men with longer interruptions and HAART discontinuers had significantly higher rates of HIV RNA increases (35.7% and 70.5%, respectively). Discontinuation and long interruptions resulted in lower CD4 cell counts.. Host characteristics play a role in short interruptions, whereas longer interruptions may be clinically indicated. These longer stoppages had further virologic and immunologic consequences, however.

Topics: Adult; Age Factors; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cohort Studies; Depression; Dideoxynucleosides; Ethnicity; HIV; HIV Infections; Humans; Logistic Models; Lopinavir; Male; Middle Aged; Pyrimidinones; Risk Factors; RNA, Viral; Treatment Refusal

To assess the antiviral response to optimized therapy following genotypic resistance testing and to identify factors associated with virological response in HIV-1-infected patients failing antiretroviral therapy.. A prospective cohort study was conducted in 344 HIV-1-infected patients who underwent genotypic resistance testing because of virological failure. Virological response was defined as a plasma HIV RNA level below 200 HIV-1 RNA copies/mL or a drop of plasma viral load from baseline of more than 1 log10. A multivariate logistic regression analysis was performed to identify factors associated with virological response.. The median age of the patients was 40 years, with a male to female ratio of 4:1. Fifty-one per cent of patients had received the three major classes of antiretrovirals and the median duration of previous antiretroviral therapy was 4.6 years. At baseline, the median plasma HIV RNA level was 4.4 log10 copies/mL and the median CD4 cell count was 274 cells/microL. At 3 months, 55% of patients (188 of 344) had a virological response, which was sustained at 6 months (53%). Predictors of virological response were exposure to two or fewer protease inhibitors [odds ratio (OR) 1.8; P=0.046], and use in optimized therapy of a new class of antiretrovirals (OR 2.9; P=0.006), of more than two new drugs (OR 3.0; P<0.0001), of abacavir (OR 1.9; P=0.03), or of lopinavir/ritonavir (OR 3.7; P=0.0002).. A high proportion of patients achieved a short-term virological response in this cohort study. Patients with the least experience of protease inhibitor treatment and in whom a new class of antiretroviral, more than two new drugs, abacavir or lopinavir/ritonavir was used in optimized therapy had the best virological outcome.

Topics: Adult; Antiretroviral Therapy, Highly Active; Antiviral Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Administration Schedule; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Prospective Studies; Pyrimidinones; Ritonavir; RNA, Viral; Treatment Failure

Topics: Aged; Carbamates; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Furans; HIV Infections; Humans; Lopinavir; Male; Patient Compliance; Pyrimidinones; Ritonavir; Stavudine; Sulfonamides; Viral Load

Clinical cohort studies suggest that as many as 60% of patients experience virologic failure of a first-line antiretroviral regimen. Second-line and rescue (or salvage) regimens have a poorer success record: Most studies presented to date show a short-term virologic response rate of only approximately 30% in treatment-experienced individuals. That rate will improve with better understanding of what causes initial virologic failure, continued development of new antiretroviral agents (including drugs with new mechanisms of action) and new treatment strategies (including dual-protease inhibitor regimens), and more widespread use of resistance testing. Further clinical research is needed to improve salvage options, and physicians should consider enrolling treatment-experienced patients in clinical trials.

Topics: Anti-HIV Agents; Carbamates; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Therapy, Combination; Furans; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Microbial Sensitivity Tests; Mutation; Nelfinavir; Practice Guidelines as Topic; Pyrimidinones; Retroviridae; Retroviridae Infections; Reverse Transcriptase Inhibitors; Sulfonamides; Time Factors; Treatment Failure; Viral Load

Current treatment strategies need to be planned carefully, because there is an inadequate supply of new types of drugs available to treat people who have failed previous therapies. It is important to fully use existing therapies so as not to limit future options. Drugs in development include: ABT-378, a protease inhibitor from Abbott Laboratories; tipranavir (PNU-140690), a protease inhibitor by Pharmacia & Upjohn; and S-1153, a non-nucleoside reverse transcriptase inhibitor from Agouron Pharmaceuticals. All were effective and well-tolerated in recent trials. A warning was issued for adefovir, a nucleoside reverse transcriptase inhibitor, regarding the development of kidney toxicity for people taking the drug more than 20 weeks. Information on expanded access programs for abacavir, adefovir, amprenavir, and efavirenz is provided.

Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; CD4 Lymphocyte Count; Clinical Trials as Topic; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Drugs, Investigational; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Imidazoles; Kidney Diseases; Lopinavir; Oxazines; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; Sulfonamides; Viral Load

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