SEARCH · PubMed Health
Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Cytotoxic and antiretroviral activity of cycloSal-d4TMP derivatives were tested in a new AZT-resistant H9 cell subline (H9rAZT250). The results showed, that cycloSal-d4TMP derivatives overcame resistance of HIV-1 to d4T in H9rAZT250 cells, which exert decreased thymidine kinase (TK) gene expression.
Changes in body fat in persons infected with the human immunodeficiency virus (HIV) have been associated with deleterious changes in blood lipids and insulin resistance, raising concern that these changes will increase the risk for accelerated atherosclerosis. Changes in body fat are often identified in advanced disease but may also occur early after HIV infection is detected. Conflicting evidence suggests that fat maldistribution may be related to use of protease inhibitors, nonnucleoside reverse transcriptase inhibitors, or a combination of these two classes of drugs, but the etiologies of the various changes in body fat remain uncertain. To date there have been no remedies for the loss of subcutaneous fat, but recent evidence has suggested that discontinuation of stavudine or zidovudine therapy may be associated with limited restoration of extremity fat. For fat accumulation, a number of strategies have been attempted, including treatment with human growth hormone, androgens, or metformin, and changes in diet and exercise. As in persons not infected with HIV, it is expected that the cornerstone of management, especially in the presence of central obesity, dyslipidemia, and insulin resistance, will include a diet low in saturated fat, with low-glycemic index carbohydrates, and high in fiber. Very limited evidence in persons infected with HIV has suggested that a supervised exercise program may be beneficial.
We report two separate, unrelated instances of the transmission of HIV-containing mutations associated with high levels of resistance to protease inhibitors or reverse transcriptase inhibitors. In the absence of antiretroviral drugs, these mutations persisted almost unchanged in the newly infected index cases, whereas most mutations reverted to wild type in the source patients upon discontinuation of therapy. Furthermore, a rapid loss of CD4 cells was observed in the newly infected individuals.
BACKGROUND: Genotypic diversity among HIV-1 subtypes and circulating recombinant forms (CRF) may lead to distinct pathways to drug resistance. This study evaluated subtype-related differences in the development of resistance in culture to tenofovir. METHODS: Genotyping determined nucleotide diversity among subtypes. Representative subtype B, C, CRF1_AE, CRF2_AG, G, and HIV-2 isolates were selected for resistance to tenofovir, lamivudine and didanosine in cell culture. Phenotypic assays determined the effects of the K65R substitution in reverse transcriptase (RT) on drug susceptibility. RESULTS: Subtype C isolates show unique polymorphisms in RT codons 64 (AAG-->AAA), 65 (AAA-->AAG), and 66 (AAA-->AAG), absent in other subtypes. The K65R mutation (AAG-->AGG) arose with tenofovir by week 12 in four subtype C selections. In contrast, no tenofovir resistance arose in four subtype B (> 34-74 weeks), one each of CRF2_AG and G (> 30-33 weeks), and three HIV-2 (> 27-28 weeks) selections. K65R appeared after 55 and 73 weeks in two CRF1_AE selections with tenofovir. In contrast, times to the appearance of M184V with lamivudine pressure (weeks 8-14) did not vary among subtypes. Selective didanosine pressure resulted in the appearance of M184V and L74V after 38 weeks in two of four subtype C selections. The K65R transitions in subtype C and other subtypes (AGG and AGA) conferred similar 6.5-10-fold resistance to tenofovir and five to 25-fold cross-resistance to each of abacavir, lamivudine, and didanosine, while not affecting zidovudine susceptibility. CONCLUSION: Tenofovir -based regimens will need to be carefully monitored in subtype C infections for the possible selection of K65R.
OBJECTIVES: To use a viral dynamics model to compare the effectiveness of in vivo viral inhibition of several doses of maraviroc (MVC;UK-427,857) and to use a modeling approach to support design decisions for a monotherapy study using various dosing regimens of maraviroc given with and without food. DESIGN: The pharmacokinetic-pharmacodynamic model was developed using clinical data from a first monotherapy study (study A4001007). This was a randomized, double-blind, placebo-controlled, multicenter study of maraviroc in 44 asymptomatic HIV-1-infected patients. Patients received maraviroc under food restrictions at 25 mg once daily or 50, 100, or 300 mg twice daily, or placebo for 10 days. METHODS: Antiviral responses were assessed by measuring plasma HIV-1 RNA levels during screening, during randomization, at baseline, and daily during the 10 days of treatment and at days 11 to 15, 19, 22, 25, and 40. An integrated pharmacokinetic-pharmacodynamic model was developed using the mixed effects modeling approach with patients' pharmacokinetic profiles on the last day of treatment, HIV-1 RNA levels over time, and the individual viral susceptibility. The parameters derived from the viral dynamic model were used to calculate average viral inhibition fraction, decay rate of actively infected cells, and basic reproductive ratio for each treatment group. Monte Carlo simulation was then used to determine the distribution of viral load change across simulated patients over time for each regimen to be studied in another monotherapy study, A4001015. RESULTS: The decline rate in the 300 mg twice daily group was comparable to that induced by potent protease inhibitor monotherapy, but was significantly slower than that in patients receiving combination therapy including both protease inhibitor and reverse transcriptase inhibitors. The efficacy of inhibition in vivo was estimated to range from 0.15 to 0.38 for the 25 mg once daily dose group and from 0.88 to 0.96 for the 300 mg twice daily dose group. CONCLUSIONS: The model has aided the analysis and interpretation of the clinical data. The use of a model-based approach for selecting doses can accelerate drug development by replacing some arms or trials with simulations.
The frequencies of multidrug resistance-associated mutations at codons 145, 151, and 69 of the human immunodeficiency virus (HIV) reverse transcriptase (RT) gene in strains from a group of 3,595 highly active antiretroviral therapy (HAART)-experienced patients were 0.22, 2.36, and 0.86%, respectively. Several amino acid substitutions different from the recently reported Gln145Met change (S. Paolucci, F. Baldanti, M. Tinelli, G. Maga, and G. Gerna, AIDS 17:924-927, 2003) were detected at position 145. Thus, amino acid substitutions selected at position 145 were introduced into the wild-type HIV type 1 (HIV-1) RT gene by site-directed mutagenesis, and recombinant HIV strains were assayed for their drug susceptibilities. Only Met and Leu substitutions at position 145 of the HIV-1 RT conferred multidrug resistance, while other amino acid changes did not. Lower levels of replication of the Gln145Met recombinant strain compared with those of both Gln151Met and wild-type recombinant strains were observed. In in vitro inhibition assays, expression and purification of the recombinant Gln145Met HIV-1 RT revealed a strong loss of catalytic efficiency of the mutated enzyme, as well as significant resistance to both zidovudine and efavirenz. Specific amino acid substitutions in the HIV RT nucleotide-binding pocket might affect both antiretroviral drug recognition and binding and decrease the level of virus replication, possibly by interfering with the enzyme activity. This finding may explain the lower frequency of Gln145Met/Leu mutations observed compared with the frequencies of Gln151Met/Leu mutations and the insertion at position 69 in HAART-experienced patients.
We have compared nucleotide substitutions and polymorphisms at codons known to confer drug resistance in subtype B strains of human immunodeficiency virus type 1 (HIV-1) with similar substitutions in viruses of other subtypes. Genotypic analysis was performed on viruses from untreated individuals. Nucleotide and amino acid diversity at resistance sites was compared with a consensus subtype B reference virus. Among patients with non-subtype B infections, polymorphisms relative to subtype B were observed at codon 10 in protease (PR). These included silent substitutions (CTC-->CTT, CTA, TTA) and an amino acid mutation, L10I. Subtype A viruses possessed a V179I substitution in reverse transcriptase (RT). Subtype G viruses were identified by silent substitutions at codon 181 in RT (TAT-->TAC). Similarly, subtype A/G viruses were identified by a substitution at position 67 in RT (GAC-->GAT). Subtype C was distinguished by silent substitutions at codons 106 (GTA-->GTG) and 219 (AAA-->AAG) in RT and codon 48 (GGG-->GGA) in PR. Variations relative to subtype B were seen at RT position 215 (ACC-->ACT) for subtypes A and A/E. These substitutions and polymorphisms reflect different patterns of codon usage among viruses of different subtypes. However, the existence of different subtypes may only rarely affect patterns of drug resistance-associated mutations.
The majority of HIV isolated from infected patients uses CCR5 as a coreceptor (R5-HIV). Although R5-HIV fails to replicate efficiently in human transformed T-cell lines, HIV using CXCR4 (X4-HIV) can replicate well in such cell lines. Therefore, most of screening systems using the T-cell lines detect only X4-HIV replication. Here we report a new assay to monitor the replication of R5- as well as X4-HIV. An MTT assay using CD4-, CXCR4-, and CCR5-transduced human glioma NP-2 cells (NCK45 cells) was established and then compared with the representative assays including multinuclear activation of a galactosidase indicator assay (MAGI assay). The antiviral activities of not only an adsorption inhibitor and reverse transcriptase inhibitors but also a Tat antagonist in the NCK45 cells, were comparable to those obtained from the MTT assay using MT-4 cells or the MAGI assay. However, the activity of protease inhibitors (PIs) was underestimated, even though expressions of major multidrug resistant genes involved in efflux of PIs were comparable in MT-2, NP-2, and NCK45 cells. After cultivation of more than 6 months, NCK45 cells remained susceptible to HIV infection since NCK45 cells consistently expressed CD4, CXCR4, and CCR5. On the other hand, MAGI cells lost the CD4 expression during culture. Thus, this assay system can stably detect the replication of both X4- and R5-HIV, indicating that it should be useful for the evaluation of HIV replication and drug susceptibility.
The development of novel drugs active against multi-drug resistant (MDR) HIV-1 strains is urgently required. HIV protease inhibitors and reverse transcriptase inhibitors constitute two categories of important drugs, which have greatly improved the clinical treatment of HIV-infected patients by their cocktail use designated as highly active anti-retroviral therapy (HAART). By combinatorial chemistry involving substructure units contained in known HIV protease inhibitors, we found effective protease inhibitors, TYA5 and TYB5, which showed potent anti-HIV activity even against MDR strains. Selection of drug-resistant viruses is also decreased when these new agents are tested in vitro. Subsequently, introduction of an (E)-alkene dipeptide isostere into TYB5 led to the development of a pure non-peptide protease inhibitor, TYB1. We have also studied the development of effective inhibitors for blocking HIV-entry into host cells based on recent discovery of an HIV entry mechanism involving the viral usage of chemokine receptors as coreceptors, CXCR4 and CCR5. We developed highly selective CXCR4 antagonists, T22 and T140 (18-mer and 14-mer peptides, respectively), which strongly suppress T-cell line-tropic HIV-1 (X4-HIV-1) entry through their specific binding to CXCR4. Recently, molecular-size reduction of T140 yielded low molecular weight CXCR4 antagonists, which might be more useful leads to drug-like structures. In this review, we discuss the development of two types of anti-HIV agents, protease inhibitors and CXCR4 antagonists, which would improve clinical AIDS chemotherapy.
Explore the source record for details and available documents.
OBJECTIVE: To assess the cost-effectiveness of highly active antiretroviral therapy (HAART) compared with two nucleoside reverse transcriptase inhibitors (NRTIs) for HIV infected individuals. DESIGN: Different data sources on the clinical effects and costs of treatments were combined using a Markov model. SETTING: English HIV treatment centres. Perspective UK public finance. INTERVENTIONS: HAART - dual NRTI therapy plus a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor - vs. dual NRTI therapy. PARTICIPANTS: Hypothetical cohorts of 1000 individuals infected with HIV. Outcome measures Projected life expectancy, cost-effectiveness in UK pound per life-year saved and per quality-adjusted life-years (QALYs) saved. RESULTS: Assuming a 2-year additional treatment effect of therapy with HAART produced incremental cost-effectiveness ratios of pound14 602 per life-year saved and pound17 698 per QALY saved. CONCLUSIONS: The results were sensitive to a number of assumptions including the cost of HAART and the discount rate, but they suggest that the use of HAART in England is at least moderately cost-effective compared with treatment with two NRTIs alone.
OBJECTIVE: To collect background information on drug-resistant HIV-1 strains in various regions before the start of nation-wide antiretroviral therapy in China. METHODS: Twenty percent of the 2,000 blood samples from antiretroviral therapy naive patients collected for the 2nd national HIV molecular epidemiology survey (NHMES) in 2002 were randomly sampled for this study. The entire protease gene and 20-230 amino acids of the reverse transcriptase gene were amplified by PCR from provirus DNA and sequenced. The results were analyzed with HIV db-Drug Resistance Algorithm and genotypic resistance mutations were determined to particular anti-HIV drugs. RESULTS: Totally 164 protease gene sequences and 138 reverse transcriptase gene sequences were obtained from patients; 0.61% of 164 sequences displayed primary resistance mutations in the protease gene, whereas 99.39% carried 1 or more secondary mutations. Genotypic resistance to at least one nucleoside reverse transcriptase inhibitors (NRTI) was present in 5.80%,and resistance to at least one non-nucleo side reverse transcriptase inhibitors (NNRTI) was present in 1.45% of samples. CONCLUSION: The prevalence of genotypic drug resistance is very low in drug-naive HIV infected patients from 21 provinces of China tested in this study. Laboratories participated in the NHMES have organized a network to provide drug resistance monitoring service in the current nation-wide antiviral treatment program in China.
Mortality rates in the HIV-infected patient population have decreased with the advent of highly active antiretroviral therapy (HAART) for the treatment of AIDS. Due to the chronic nature of HAART, long-term metabolic complications are associated with therapy, such as hyperlipidemia, fat redistribution and diabetes mellitus. Currently, all of these symptoms are classified as the lipodystrophy (LD) syndrome(s). However, hyperlipidemia and fat redistribution occur independently, indicating there may be multiple syndromes associated with HAART. Although fat gain/loss and dyslipidemia occur in protease inhibitor (PI) naïve patients treated with nucleoside reverse transcriptase inhibitors (NRTIs), combination therapies (PI and NRTI) accelerate the syndrome. Recent clinical trials, cell culture and animal studies indicate that these effects are not drug class specific and select PIs, NRTIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs) can be associated with metabolic complications. Moreover, the effects can vary between various members of the same class of antiretroviral agents (i.e. not all PIs cause the same adverse reactions) and may be influenced by duration of infection, genetics and environmental factors. Although HAART increases the risk of metabolic complications, this does not outweigh the benefits of survival. In this review, we summarize the latest clinical and scientific information on these metabolic complications, examine current hypotheses explaining the syndromes and comment on the existing methods available to manage these metabolic side effects.
OBJECTIVE: To determine the prevalence of risk factors for cardiovascular disease (CVD) among HIV-infected persons, and to investigate any association between such risk factors, stage of HIV disease, and use of antiretroviral therapies. DESIGN: Baseline data from 17,852 subjects enrolled in DAD, a prospective multinational cohort study initiated in 1999. METHODS: Cross-sectional analyses of CVD risk factors at baseline. The data collected includes data on demographic variables, cigarette smoking, diabetes mellitus, hypertension, dyslipidaemia, body mass index, stage of HIV infection, antiretroviral therapy. RESULTS: Almost 25% of the study population were at an age where there is an appreciable risk of CVD, with those receiving a protease inhibitor (PI) and/or non-nucleoside reverse transcriptase inhibitor (NNRTI) tending to be older. 1.4% had a previous history of CVD and 51.5% were cigarette smokers. Increased prevalence of elevated total cholesterol (> or = 6.2 mmol/l) was observed among subjects receiving an NNRTI but no PI [odds ratio (OR), 1.79; 95% confidence interval (CI), 1.45-2.22], PI but no NNRTI (OR, 2.35; 95% CI, 1.92-2.87), or NNRTI + PI (OR, 5.48; 95% CI, 4.34-6.91) compared to the prevalence among antiretroviral therapy (ART)-naive subjects. Subjects who have discontinued ART as well as subjects receiving nucleoside reverse transcriptase inhibitors had similar cholesterol levels to treatment-naive subjects. Higher CD4 cell count, lower plasma HIV RNA levels, clinical signs of lipodystrophy, longer exposure times to NNRTI and PI, and older age were all also associated with elevated total cholesterol level. CONCLUSION: HIV-infected persons exhibit multiple known risk factors for CVD. Of specific concern is the fact that use of the NNRTI and PI drug classes (alone and especially in combination), particularly among older subjects with normalized CD4 cell counts and suppressed HIV replication, was associated with a lipid profile known to increase the risk of coronary heart disease.
Six novel enzyme inhibitors of RNA-directed DNA-polymerases of human immunodeficiency-, avian myeloblastosis and murine leukemia viruses were isolated from fermentations of a canadian Mniopetalum species. They were named mniopetals A, B, C, D, E and F. Their structures were elucidated by spectroscopic methods. The compounds, in addition to their inhibitory activities on reverse transcriptases, exhibit antimicrobial and cytotoxic properties.
Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that was first reported in the scientific literature in 1990. Varying doses of nevirapine (NVP) and a number of regimens containing this NNRTI have been studied in antiretroviral (ARV) näive patients. Four key studies have compared the efficacy and safety of triple drug regimens containing NVP in ARV näive, HIV-1 infected patients. The INCAS study was the first demonstration of how to use NVP in an effective and durable manner: as a component of a triple drug regimen. The COMBINE Study was a comparison of protease inhibitor (PI)-based and NVP-based triple regimens. The Atlantic Study is comparing the safety and efficacy of three triple drug regimens in ARV näive patients. In this study, treatment consists of a divergent drug regimen (PI and nucleoside reverse transcriptase inhibitors, NRTIs) targeting both HIV-1 protease and reverse transcriptase or a convergent regimen targeting reverse transcriptase alone (three NRTIs or two NRTIs plus a NNRTI). A clinical endpoint study (BI 1090) compared the efficacy and durability of multi-drug regimens in ARV näive patients with high baseline plasma HIV-1 RNA levels (pVLs) and low peripheral blood CD4+ lymphocyte counts. Data from these studies confirm that triple regimens containing NVP suppressed viral replication for up to one year, even when the ARV näive patients had low CD4+ cell counts at baseline. Nevirapine-containing regimens suppressed pVLs to < 50 copies/ mL in approximately 50% of patients in the studies discussed (Intent to Treat analyses). Data from 96 weeks of follow up in the Atlantic Study demonstrates that the regimens containing didanosine and stavudine plus indinavir or NVP were significantly more successful in suppressing pVLs to < 50 copies/mL during this period than a regimen composed of these NRTIs and lamivudine (p < or = 0.001). As with other ARV drugs, NVP should always be used as part of a fully suppressive ARV regimen. When used in this way, it is an effective ARV drug, which contributes to durable virological and immunological responses in approximately half of all treated patients. Nevirapine-containing regimens are effective in patients with advanced HIV-1 infection, i.e., low CD4+ cell counts. Data will soon be available from the 2NN Study that compares the efficacy and safety of four different regimens using NVP once daily, NVP twice daily, efavirenz once daily or a combination of NVP and efavirenz. All four arms of the study include a backbone of stavudine and lamivudine.
Phosphonated carbocyclic 2'-oxa-3'-aza-nucleosides have been synthesized in good yields by 1,3-dipolar cycloaddition methodology. The cytotoxicity and the reverse transcriptase inhibitory activity of the obtained compounds have been investigated. Phosphonated carbocyclic 2'-oxa-3'-aza-nucleosides, while showing low levels of cytotoxicity, exert a specific inhibitor activity on two different reverse transcriptases, which is comparable with that of AZT, opening new perspectives on their possible use as therapeutic agents, in anti-retroviral and anti-HBV chemotherapy.
CONTEXT: The effectiveness of different protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors outside the setting of clinical trials has not been well described. OBJECTIVES: To compare five different PI-and nevirapine (NVP)-containing regimens on virologic, immunologic, and clinical outcomes and treatment discontinuation. DESIGN AND SETTING: Observational cohort study based on an HIV clinic in London. PATIENTS: A total of 690 patients who received either saquinavir hard gel (SQV HG) (n = 183), indinavir (IDV) (n = 189), nelfinavir (NFV) (n = 109), ritonavir (RTV) (n = 42), ritonavir with saquinavir hard gel (RTV/SQV HG) (n = 45), or NVP (n = 122) as part of an initial PI-or NVP-containing treatment regimen between November 1994 and December 1998. A total of 351 (51%) patients had prior exposure to nucleoside reverse transcriptase inhibitors (NRTIs). MAIN OUTCOME MEASURES: The main outcome measures were virologic undetectability, subsequent virologic rebound, CD4 cell count rise, development of AIDS, and treatment discontinuation. All analyses were stratified for year of initiation of the PI-or NVP-containing regimen. RESULTS: Overall, 63% of patients attained an undetectable viral load (VL) within 6 months of starting their PI or NVP regimen. The adjusted relative hazard (95% confidence interval [CI]) for an undetectable VL relative to SQV HG was (in rank order): 2.77 (CI: 1.84-4.17) for NFV, 2.54 (CI: 1.81-3.57) for IDV, 2.43 (CI: 1.52-3.87) for RTV, 2.08 (CI: 1.28-3.37) for RTV/SQV HG, and 1.96 (CI: 1.35-2.85) for NVP. Forty-nine percent of patients experienced VL rebound within 12 months of initial attainment of undetectability, but relative to SQV HG, this did not differ significantly across the different PI and NVP regimens. The CD4 cell count response and rate of AIDS events were also similar across the different regimens. No independent predictors of VL undetectability were identified, but prior NRTI exposure was associated with VL rebound, and a lower baseline VL and CD4 cell count were associated with a reduced CD4 count response. The frequency (95% CI) of treatment discontinuation differed across the regimens; at 6 months, it was lowest for NFV (18% [CI: 13%-24%]), IDV (25% [CI: 22%-29%]), and NVP (28% [CI: 22%-34%]) and highest for RTV (41% [CI: 31%-52%]) and SQV HG (52% [CI: 48%-57%]). CONCLUSIONS: Although PI- and NVP-containing regimens were similar in their CD4 cell count response and rates of subsequent VL rebound, differences were observed in time to VL undetectability and discontinuation rates relative to SQV HG. SQV HG was consistently inferior to the other PIs and NVP. The use of NFV and IDV was associated with the highest rates of undetectability, and together with NVP, the lowest rates of discontinuation.