pyrimidinones and Acquired-Immunodeficiency-Syndrome

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

Few randomized trials comparing antiretroviral therapy (ART) regimens have been conducted in resource-limited settings.. In the Republic of South Africa, antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals >14 years old with a CD4 cell count <200 cells/μL or a prior AIDS diagnosis were randomized to receive efavirenz (EFV) or lopinavir/ritonavir (LPV/r) with either zidovudine (ZDV) plus didanosine (ddI) or stavudine (d4T) plus lamivudine (3TC) in an open-label, 2-by-2 factorial study and followed up for the primary outcome of AIDS or death and prespecified secondary outcomes, including CD4 cell count and viral load changes, treatment discontinuation, and grade 4 events.. In total, 1771 persons were randomized and followed up for a median of 24.7 months. AIDS or death occurred in (1) 163 participants assigned EFV and 157 assigned LPV/r (hazard ratio [HR], 1.04 [95% confidence interval {CI}, 0.84-1.30]) and in (2) 170 participants assigned ZDV+ddI and 150 assigned d4T+3TC (HR, 1.15 [95% CI, 0.93-1.44]). HIV RNA levels were lower (P < .001) and CD4 cell counts were greater (P < .01) over follow-up for d4T+3TC versus ZDV+ddI. Rates of potentially life-threatening adverse events and overall treatment discontinuation were similar for d4T+3TC and ZDV+ddI; however, more participants discontinued d4T because of toxicity (12.6%) than other treatments (<5%).. EFV and LPV/r are effective components of first-line ART. The poorer viral and immune responses with ZDV+ddI and the greater toxicity-associated discontinuation rate with d4T+3TC suggest that these treatments be used cautiously as initial therapy.. ClinicalTrials.gov identifier: NCT00342355.

Topics: Acquired Immunodeficiency Syndrome; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Didanosine; Drug Therapy, Combination; Female; HIV; Humans; Lamivudine; Lopinavir; Male; Pyrimidinones; Ritonavir; RNA, Viral; South Africa; Stavudine; Treatment Outcome; Zidovudine

: Direct comparison of the efficacy and safety of different agents is needed to guide selection of optimal treatment regimens for therapy-naive HIV-1-infected patients.. : Gemini was a 48-week, multicenter, open-label, noninferiority trial in treatment-naive HIV-1-infected adults randomized to either saquinavir/ritonavir (SQV/r) 1000 mg/100 mg twice a day or lopinavir/ritonavir (LPV/r) 400 mg/100 mg twice a day, each with emtricitabine/tenofovir 200 mg/300 mg every day.. : A similar proportion of participants in the SQV/r (n = 167) and LPV/r (n = 170) arms had HIV-1 RNA levels <50 copies per milliliter at week 48: 64.7% vs 63.5% and estimated difference in proportion for noninferiority: 1.14%, 96% confidence interval: -9.6 to11.9 (P < 0.012), confirming that SQV/r was noninferior to LPV/r treatment. There were no significant differences in week 48 CD4 counts between arms. The rate and severity of adverse events were similar in both groups. There were no significant differences in the median change from baseline between arms in plasma lipids except for triglyceride levels, which were significantly higher in the LPV/r at week 48.. : In treatment-naive, HIV-1-infected patients, SQV/r treatment was noninferior in virologic suppression at 48 weeks to LPV/r treatment and offered a better triglyceride profile.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Aged; Anti-HIV Agents; Drug Therapy, Combination; Female; HIV-1; Humans; Lipids; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; RNA, Viral; Saquinavir

Antiretroviral-naive HIV-1-infected volunteers received zidovudine/lamivudine plus either lopinavir/ritonavir (n=104) or efavirenz (n=51). Lopinavir/ritonavir-treated subjects demonstrating 3 consecutive monthly HIV-1 RNA levels <50 copies/mL started lopinavir/ritonavir monotherapy. In previous-failure=failure analysis, 48% (lopinavir/ritonavir) and 61% (efavirenz) maintained HIV-1 RNA at <50 copies/mL through week 96, (P= .17; 95% confidence interval [CI] for the difference, -29% to 4%); in noncompletion=failure analysis, 60% (lopinavir/ritonavir) and 63% (efavirenz) maintained HIV-1 RNA at <50 copies/mL at week 96 (P= .73; 95% CI for the difference, -19% to 13%). Significant sparing of peripheral lipoatrophy was noted in the lopinavir/ritonavir simplification strategy. This study has provided important information for future studies using treatment simplified to lopinavir/ritonavir monotherapy.

Topics: Acquired Immunodeficiency Syndrome; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Diarrhea; Drug Therapy, Combination; Glucose Tolerance Test; HIV Protease Inhibitors; Humans; Lopinavir; Nausea; Pyrimidinones; Ritonavir; RNA, Viral; Time Factors; Treatment Outcome; Viral Load

The extent to which drug-resistant human immunodeficiency virus type 1 (HIV-1) acquired through mother-to-child transmission (MTCT) or failed chemoprophylaxis populates viral reservoirs and limits responses to antiretroviral treatment in infants is unknown.. We evaluated the presence, type, and persistence of drug-resistant HIV-1 in pretreatment plasma and resting CD4(+) T cells from US infants enrolled in a multicenter, open-label, phase 1/2 treatment trial of lopinavir/ritonavir (Pediatric AIDS Clinical Trials Group Protocol 1030) in young infants.. Twenty-two consecutively enrolled infants initiating highly active antiretroviral therapy at a median age of 9.7 weeks and treated for up to 96 weeks were studied. Drug-resistant HIV-1 was present in 5 (23.8%) of 21 infants analyzed; 4 (80.0%) had nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV-1, only 1 of whom had a history of receiving nevirapine chemoprophylaxis. All 4 infants had NNRTI-resistant variants other than the K103N mutation. The fifth infant had the M184V mutation. Drug-resistant virus was archived in the resting CD4(+) T cell latent reservoir in all 5 infants.. The high rate, types, and early archiving of drug-resistant HIV-1 suggests that resistance testing be considered for infants, especially when an NNRTI-based regimen is planned. Furthermore, drug-resistance outcomes in infants should be an important secondary end point in MTCT trials.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; DNA, Complementary; Drug Resistance, Viral; HIV-1; Humans; Infant; Lopinavir; Male; Pyrimidinones; Reverse Transcriptase Inhibitors; Reverse Transcriptase Polymerase Chain Reaction; Ritonavir; RNA, Viral; United States; Viral Load; Zidovudine

Nucleoside reverse transcriptase inhibitor-sparing regimens have not yet been systematically evaluated in children. The nonnucleoside reverse transcriptase inhibitors nevirapine and efavirenz lower plasma levels of protease inhibitors in adults and children. Therefore, coadministration of lopinavir/ritonavir with nevirapine and efavirenz necessitates a 30% increase in the dose of lopinavir/ritonavir in adults. In children, the extent of the pharmacokinetic interaction between efavirenz and lopinavir/ritonavir has not yet been studied.. To investigate the pharmacokinetics of increased-dose (300/75 mg/m2 twice-daily) lopinavir/ritonavir with normal-dose (14 mg/kg once-daily) efavirenz in HIV-1-infected children.. Steady-state pharmacokinetics of lopinavir and efavirenz were determined and compared with historical data.. Fifteen children of median age 11.8 (range, 5.7-16.3) years were included. Area under the plasma concentration-time curve (AUC0-12), peak levels (Cmax), and trough levels (Cmin) of lopinavir were similar to historical data in adults and children. Medians (interquartile range) were 92.3 (43.5-138.5) mg/L.h, 12.5 (6.9-16.7) mg/L, and 5.7 (1.3-8.0) mg/L, respectively. Efavirenz pharmacokinetics approximated previous data in adults and children.. The increased dose of 300/75 mg/m2 twice-daily lopinavir/ritonavir compensates for the enzyme-inducing effect of efavirenz in HIV-infected children.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Alkynes; Anti-HIV Agents; Area Under Curve; Benzoxazines; Child; Child, Preschool; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Female; HIV Protease Inhibitors; Humans; Lopinavir; Male; Oxazines; Pyrimidinones; Ritonavir; Safety

Topics: Acquired Immunodeficiency Syndrome; Drug Combinations; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir

In light of the increasing worldwide AIDS pandemic, there is a continuing need to develop new prevention strategies to inhibit the transmission of HIV-1. In the absence of a successful vaccine, topical microbicides represent the best strategies to reduce the epidemic. Following the success of HIV therapeutic cocktail strategies, combinations of microbicides including nucleotide reverse transcriptase inhibitors (NtRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) may offer significant protection from infection over single agents. We have developed a combination microbicide gel formulation for the delivery of IQP-0528, a novel NNRTI, and tenofovir (TFV), a NtRTI. Gel formulations were evaluated based on quantitative viscoelastic and physiochemical evaluations defined by a target product profile (TPP). For the majority of the evaluations, the gel formulations behaved similarly; all showed shear thinning behavior, were stable, nontoxic, and active against HIV-1 infection. Gel formulation F2759 displayed increased drug release of 289 ± 100 µg/(cm(2) h(1/2) ) and a tissue permeability of 60 times the half maximal effective concentration (EC(50) ) of TFV and 800 times the EC(50) of IQP-0528. In addition, F2759 showed osmolality within TPP and the highest performance in gel spreading. We have identified a gel formulation to deliver a combination microbicide of IQP-0528 and TFV that has significant potential to prevent infection of HIV-1.

Topics: Acquired Immunodeficiency Syndrome; Adenine; Anti-HIV Agents; Anti-Infective Agents; Cell Line; Chemistry, Pharmaceutical; Excipients; Gels; HIV-1; Humans; Organophosphonates; Pyrimidinones; Reverse Transcriptase Inhibitors; Solubility; Tenofovir; Viscosity

HIV infected patients often take at least three anti-HIV drugs together in Highly Active Antiretroviral Therapy (HAART) and/or Ritonavir-Boosted Protease Inhibitor Therapy (PI/r) to suppress the viral replications. The potential drug-drug interactions affect efficacy of anti-HIV treatment and major source of such interaction is competition for the drug metabolizing enzyme, cytochrome P450 (CYP). CYP3A4 isoform is the enzyme responsible for metabolism of currently available HIV-1 protease drugs. Hence administration of these drugs in HARRT or PI/r leads to increased toxicity and reduced efficacy in HIV treatment. We used computational molecular docking method to predict such interactions by which to compare experimentally measured metabolism of each HIV-1 protease drug. AutoDock 4.0 was used to carry out molecular docking of 10 HIV-protease drugs into CYP3A4 to explore sites of reaction and interaction energies (i.e., binding affinity) of the complexes. Arg105, Arg106, Ser119, Arg212, Ala370, Arg372, and Glu374 are identified as major drug binding residues, and consistent with previous data of site-directed mutagenesis, crystallography structure, modeling, and docking studies. In addition, our docking results suggested that phenylalanine clusters and heme are also participated in the binding to mediate drug oxidative metabolism. We have shown that HIV-1 protease drugs such as tipranavir, nelfinavir, lopinavir, and atazanavir differ in their binding modes on each other for metabolic clearance in CYP3A4, whereas ritonavir, amprenavir, indinavir, saquinavir, fosamprenavir, and darunavir share the same binding mode.

Topics: Acquired Immunodeficiency Syndrome; Antiretroviral Therapy, Highly Active; Computational Biology; Cytochrome P-450 CYP3A; Darunavir; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Nelfinavir; Pyridines; Pyrimidinones; Pyrones; Ritonavir; Sulfonamides

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Darunavir; Drug Resistance, Multiple, Viral; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Mutation; Pyridines; Pyrimidinones; Pyrones; Sulfonamides

The Antiretroviral Pregnancy Registry was established in 1989 to collect data on birth defects after pregnancy exposures to antiretroviral therapy. Using Registry data, this study estimates the birth defect risk after pregnancy exposures to lopinavir/ritonavir.. The analysis population includes all prospective lopinavir/ritonavir-exposed pregnancies enrolled in the Registry from September 2000 through July 2007. Birth defect prevalence after pregnancy exposure is compared with rates from a population-based surveillance system, and first-trimester exposures are compared with combined second/third-trimester exposures.. Among 955 live births prenatally exposed to lopinavir/ritonavir, 23 cases with birth defects were reported [2.4%, 95% confidence interval (CI) = 1.5 to 3.6). Among 267 live births with first-trimester exposures, 5 had birth defects (1.9%, 95% CI = 0.6 to 4.3). These rates are similar to the population-based comparator rate of 2.67% and the rate in infants with second/third-trimester exposures (2.6%, 95% CI = 1.6 to 4.1). No pattern of birth defects suggestive of a common etiology was seen.. The prevalence of birth defects among infants prenatally exposed to lopinavir/ritonavir is not significantly different from internal or external comparison groups. These data provide reassuring information to patients and clinicians about the safety of lopinavir/ritonavir in the treatment of HIV-positive pregnant women.

Topics: Abnormalities, Drug-Induced; Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Female; Humans; Lopinavir; Pregnancy; Pregnancy Complications, Infectious; Pyrimidinones; Registries; Ritonavir

Topics: Acquired Immunodeficiency Syndrome; CD4 Lymphocyte Count; Clinical Trials as Topic; Darunavir; Drug Resistance, Multiple; Drug Resistance, Viral; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Pyrimidinones; Sulfonamides; Viral Load

Topics: Acquired Immunodeficiency Syndrome; Anticoagulants; Drug Overdose; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; Warfarin

A patient with human immunodeficiency virus-related posterior fossa progressive multifocal leukoencephalopathy had serial diffusion-weighted imaging using b-values of 1000 and 3000 before and during highly active antiretroviral therapy (HAART). High-b-value images provided a superior definition of the leading edge of the lesion and additional information about the integrity of white matter tracts. Following HAART, there was a marked reduction of lesional apparent diffusion coefficient and reconstitution of anisotropy in the affected middle cerebellar peduncle.

Topics: Acquired Immunodeficiency Syndrome; Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Brain; Diffusion; Diffusion Magnetic Resonance Imaging; HIV Protease Inhibitors; Humans; Leukoencephalopathy, Progressive Multifocal; Lopinavir; Male; Organophosphonates; Pyrimidinones; Ritonavir; Tenofovir; Zidovudine

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Drug Industry; Global Health; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir

Hyperthyroidism has been described after highly active antiretroviral therapy for AIDS and has been attributed to late onset immune reconstitution. The team reports a young Polynesian man with AIDS who responded to highly active antiretroviraltherapy. However, 15 months after initiation of antiretroviral therapy, he was hospitalized for hypokalemic thyrotoxic periodic paralysis, an unusual manifestation of hyperthyroidism which typically occurs in young Asian males.

Topics: Acquired Immunodeficiency Syndrome; Adult; Antiretroviral Therapy, Highly Active; Autoimmunity; Diarrhea; Drug Combinations; Genetic Predisposition to Disease; Graves Disease; Hawaii; Humans; Hypokalemic Periodic Paralysis; Iodine Radioisotopes; Lamivudine; Lopinavir; Male; Native Hawaiian or Other Pacific Islander; Polynesia; Pyrimidinones; Thyrotoxicosis; Zidovudine

This study evaluates clinical, virological and immunological responses to antiretroviral (ARV) therapy based on Lopinavir/ritonovir (LPV/r) in previously protease -inhibitor-experienced children. The study included 29 Brazilian children (median age = 5.91 years) who had failed previous ARV therapy and had begun a regimen based on LPV/r. At 12 months follow-up, a good virological response to LPV/r therapy was defined as achieving an undetectable viral load or as a decrease in plasma HIV RNA levels to > 1 log. A good immunological response was defined as an increase in CD4+ cell count from baseline sufficient to attain a better CDC immune stage classification. The number of infectious episodes 12 months before and 12 months after beginning LPV/r was assessed. Sixteen (55.2%) and 19 (65.5%) of 29 patients exhibited good virological and immunological responses, respectively. Baseline CD4+ values (>500) predicted both virological and immunological responses (p<0.05). Older children were less likely to develop an immunological response (p<0.001) than younger children. Nine children receiving 3 ARV drugs plus LPV/r showed an immunological response (100%) compared to 10/20 (50%) children receiving 2 drugs plus LPV/r (p=0.01). A lower number (n<5) of infectious episodes was noted after 12 months follow-up in children using the LPV/r regimen (p=0.006). There was a positive correlation between children whose baseline CD4+ values were greater than 500 cells/mm(3) and virological responses. Although virological responses to therapy were seen in about half the children (55.2%), the use of HAART containing LPV/r provided clinical and immmunological benefits.

Topics: Acquired Immunodeficiency Syndrome; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Child; Child, Preschool; Follow-Up Studies; HIV Protease Inhibitors; Humans; Longitudinal Studies; Lopinavir; Pyrimidinones; Ritonavir; RNA, Viral; Treatment Outcome; Viral Load

Consensus on the interpretation of mutations in the human immunodeficiency virus (HIV)-1 reverse transcriptase (RT) gene that predict the response to didanosine treatment is needed.. Baseline HIV-1 RT genotypes and 12-week virological outcomes for patients undergoing didanosine-containing salvage regimens were extracted from prospective studies. Existing didanosine genotypic-resistance interpretation rules were validated in the entire-patient data set. Mutations were given weighted positive or negative scores according to their coefficient of correlation with virological response in a derivation set. The score resulting from the algebraic sum of the mutations was then validated in an independent data set.. A total of 485 patients were analyzed. The didanosine-resistance scores derived from the Jaguar and Gesca studies predicted virological outcome. The best correlation with response was found with the derived score (M41L x 2) + E44D/A/G + T69D/S/N/A + (L210W x 2) + T215Y or revertants + L228H/R - D123E/N/G/S, by use of which viruses were categorized as being susceptible (score < or =0), as having intermediate resistance (1-3), and as being resistant (> or =4) to didanosine. In the validation set, the adjusted mean difference in 12-week virological response was +0.34 log(10) copies/mL (95% confidence interval, +0.11 to +0.57; P=.004) per higher resistance category. Correlation with virological response constantly outperformed that obtained with the previous interpretation.. The improved genotypic-resistance interpretation score can be applied to better guide the use of didanosine in treatment-experienced individuals.

Topics: Acquired Immunodeficiency Syndrome; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Didanosine; Female; Genotype; HIV Reverse Transcriptase; HIV-1; Humans; Lopinavir; Male; Middle Aged; Mutation; Nelfinavir; Nevirapine; Pyrimidinones; Reverse Transcriptase Inhibitors; RNA, Viral; Salvage Therapy

Topics: Acquired Immunodeficiency Syndrome; Drug Combinations; Drug Resistance, Viral; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir

Topics: Acquired Immunodeficiency Syndrome; Developing Countries; Drug Combinations; Drug Industry; HIV Protease Inhibitors; Humans; International Agencies; Lopinavir; Pyrimidinones; Ritonavir

Topics: Acquired Immunodeficiency Syndrome; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir; Urologic Diseases

Topics: Acquired Immunodeficiency Syndrome; CCR5 Receptor Antagonists; Clinical Trials as Topic; Darunavir; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Organic Chemicals; Pyrimidinones; Pyrrolidinones; Raltegravir Potassium; Receptors, CCR5; Ritonavir; Salvage Therapy; Sulfonamides

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Bradycardia; Drug Combinations; Dyspnea; Electrocardiography; Female; HIV Protease Inhibitors; Humans; Lopinavir; Middle Aged; Pyrimidinones; Ritonavir; Syndrome; Tachycardia

Lopinavir/ritonavir has demonstrated antiviral activity in the HIV-infected patient.. To analyse virological response to lopinavir/ritonavir therapy in previously protease inhibitor (PI)-experienced HIV-1-infected children.. Sixty-seven HIV-1-children on lopinavir/ritonavir were studied in a multicentre prospective cohort observational study. The outcome variables were undetectable viral load (uVL; VL < or =400 copies/mL) and virological failure after uVL with a rebound of VL >400 copies/mL. VL and genotype of HIV-1-isolates were measured using standard assays.. 83.5% of children had a 1 log10 VL decrease including 65.6% who reached uVL. Children with >2 changes of antiretroviral therapy (ART) or >5 drugs needed a median time of 3-4 months higher than children with < or =2 changes of ART or < or =5 drugs previous to lopinavir/ritonavir, to reach those values, and the relative proportions (RP) were 2.2 (P =0.038) and 1.9 (P=0.050), respectively. Children with CD4+>15% (P=0.122), VL < or =30,000 (P < 0.001) copies/mL, and age >12 years (P=0.096) achieved an earlier control of VL during the follow-up. The children with virological failure or rebound of VL had higher baseline VL and lower CD4+ T-lymphocytes/mm3 and had taken a greater number of drugs previous to lopinavir/ritonavir. HIV-children with a new nucleoside reverse transcriptase inhibitor (NRTI), or protease inhibitor (PI) or PI plus non-nucleoside reverse transcriptase inhibitors (NNRTI) in the current regimen had a better virological response than children without these new drugs. Also, children with <6 protease mutations had an RP of 2.31 of achieving uVL.. Highly active antiretroviral therapy (HAART) including lopinavir/ritonavir induces beneficial effects in terms of virological outcome responses, and it is an effective option for salvage therapy in PI-experienced HIV-1-infected children.

Topics: Acquired Immunodeficiency Syndrome; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cohort Studies; Drug Therapy, Combination; HIV-1; Humans; Lopinavir; Prospective Studies; Pyrimidinones; Ritonavir; Salvage Therapy

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Clinical Trials as Topic; HIV Protease Inhibitors; Humans; Lopinavir; Patient Compliance; Pyrimidinones; Saquinavir; Treatment Outcome

Topics: Acquired Immunodeficiency Syndrome; Clinical Trials as Topic; Drug Administration Schedule; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Treatment Outcome

Tenofovir-related tubular damage, like all other recently reported cases, occurred in patients receiving the protease inhibitor (PI) ritonavir, often with lopinavir. Increased plasma concentrations of didanosine were also observed after the addition of tenofovir. It was suspected that tenofovir with PIs interacted with renal organic anion transporters, leading to nephrotoxic tubular concentrations of tenofovir and systemic accumulation of didanosine. Until there is a better understanding of these interactions, close monitoring is recommended for patients receiving tenofovir, PIs, and didanosine.

Topics: Acquired Immunodeficiency Syndrome; Adenine; Adult; Anti-HIV Agents; Diabetes Insipidus, Nephrogenic; Didanosine; Drug Therapy, Combination; Fanconi Syndrome; Humans; Lopinavir; Male; Organophosphonates; Organophosphorus Compounds; Pyrimidinones; Ritonavir; Tenofovir

Topics: Acquired Immunodeficiency Syndrome; Clinical Trials, Phase II as Topic; Drug Combinations; Drug Resistance, Viral; Follow-Up Studies; HIV Protease Inhibitors; HIV-1; Humans; Long-Term Care; Lopinavir; Pyrimidinones; Ritonavir

Topics: Acquired Immunodeficiency Syndrome; Drug Combinations; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Quality of Life; Randomized Controlled Trials as Topic; Ritonavir

Topics: Acquired Immunodeficiency Syndrome; Clinical Trials as Topic; Cohort Studies; Drug Resistance, Multiple, Viral; Drug Synergism; Germany; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir; Salvage Therapy; Saquinavir

We describe 2 patients with acquired immunodeficiency syndrome who had potentially fatal bradyarrhythmia that occurred shortly after commencement of antiretroviral therapy. Lopinavir-ritonavir was the only drug that both patients were using.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Bradycardia; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Carbamates; Drug Interactions; Female; Furans; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Retrospective Studies; Salvage Therapy; Sulfonamides

Topics: Acquired Immunodeficiency Syndrome; Clinical Trials as Topic; Drug Resistance, Viral; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir

Topics: Acquired Immunodeficiency Syndrome; Drug Combinations; HIV Protease Inhibitors; Humans; Lopinavir; Pyrimidinones; Ritonavir; United States; United States Food and Drug Administration

Sexually active women represent the fastest growing HIV/AIDS (human immunodeficiency virus/acquired immunodeficiency syndrome) risk group. In an effort to develop a vaginal microbicidal contraceptive potentially capable of preventing HIV transmission as well as providing fertility control, we have synthesized novel non-nucleoside inhibitors (NNIs) of HIV-1 reverse transcriptase (RT) and examined them for dual-function anti-HIV and spermicidal activity. Structure-based drug design by use of a computer docking procedure for the NNI binding pocket generated from nine RT-NNI crystal structures led to the synthesis of three novel NNIs: N-[2-(2, 5-dimethoxyphenethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (D-PBT); N-[2-(2-fluorophenethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (F-PBT); and 5-isopropyl-2-[(methylthiomethyl)thio]-6-(benzyl)-pyrimidin-4-(1H)-on e (S-DABO). The anti-HIV activity of these NNIs was compared with that of trovirdine and virucidal/spermicide, nonoxynol-9 (N-9), by measuring viral RT activity and p24 antigen production as markers of viral replication using HTLVIIIB-infected human peripheral blood mononuclear cells (PBMCs). The effects on sperm motion kinematics and sperm membrane integrity were examined by computer-assisted sperm analysis and by confocal laser scanning microscopy (CLSM), respectively. The growth-inhibitory effects of NNI versus N-9 against normal human ectocervical and endocervical epithelial cells were tested using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay. All three NNIs were potent inhibitors of purified recombinant HIV RT and abrogated HIV replication in PBMCs at nanomolar concentrations (IC50 < 1 nM) when compared with N-9 or trovirdine (IC50 values of 2.2 microM and 0.007 microM, respectively). Two NNIs, F-PBT and S-DABO, also exhibited concentration- and time-dependent spermicidal activity. The drug concentration required to inhibit sperm motility by 50% (EC50 values) for the lead compound F-PBT versus N-9 was 147 microM and 81 microM, respectively. Sperm-immobilizing activity induced by F-PBT and S-DABO was rapid (t1/2 = 7-13 min) and irreversible. Unlike that of N-9, spermicidal activity of F-PBT and S-DABO was not accompanied by loss of acrosomal membrane as detected by fluorescent-lectin binding assay and CLSM. Whereas N-9 was cytotoxic to normal human ectocervical and endocervical cells at spermicidal doses, both F-PBT and S-DABO were selectively spermicidal. We conclude that as pote

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Cell Membrane; Computers; Detergents; Drug Design; Female; HIV-1; Humans; Male; Microscopy, Confocal; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; Sexually Transmitted Diseases; Sperm Motility; Spermatocidal Agents; Spermatozoa; Sulfides; Thiourea; Virus Replication

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