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A comparative binding energy (COMBINE) analysis on a series of nonnucleosidic reverse transcriptase inhibitors yields a QSAR model with high predictive ability and correctly identifies the effect of mutations on relevant protein residues.
OBJECTIVES: To assess intracellular and plasma efavirenz concentrations in HIV-infected patients who switched to efavirenz-based highly active antiretroviral therapy (HAART) from successful protease inhibitor-based HAART. PATIENTS AND METHODS: A total of 49 patients were included in this observational cohort study. At inclusion, all patients had plasma HIV-RNA levels<50 copies/mL and switched to efavirenz combined with two nucleoside reverse transcriptase inhibitors. Intracellular and plasma concentrations were measured 12 h post-dose, 1 month (M1) and 6 months (M6) after starting efavirenz. Virological success (VS) was defined as plasma HIV-RNA level<50 copies/mL within the first 12 months and remaining undetectable at the end of the follow-up. RESULTS: VS was documented in 48 patients for at least 12 months (range 12-78 months). High inter-patient variabilities of intracellular and plasma efavirenz concentrations were observed (coefficients of variation>40%). At M1 and M6, respectively, median [Q1; Q3] intracellular efavirenz concentrations were 5300 [2830; 11 530] and 6790 [3870; 8790] ng/mL, median plasma efavirenz concentrations were 2050 [1600; 3100] and 2100 [1410; 2500] ng/mL. No correlation was found between intracellular and plasma concentrations. Plasma efavirenz levels exceeded the proposed threshold of 1000 ng/mL in 96% of patients from M1. CONCLUSIONS: For moderately pre-treated HIV-infected patients with few mutations who switched to efavirenz from previous successful HAART, the proposed plasma efficacy-threshold was reached without any dosage adaptation. VS was maintained beyond 12 months, despite high inter-patient and intra-patient variabilities of intracellular and plasma efavirenz concentrations.
OBJECTIVE: To assess the efficacy of combination therapy that includes ritonavir in HIV-1 infected children. DESIGN: A monocentric retrospective study. PATIENTS AND METHODS: Twenty-two children with a minimum follow-up of 6 months under triple therapy including ritonavir were analysed for treatment efficacy. At entry, all the patients were protease inhibitor naive and all but two had received previous antiretroviral therapy during a median period of 5 years. Their initial median CD4+ lymphocyte count and viral load were 121 x 10(6)/l and 5.08 log10 copies/ml, respectively. Clinical and biological evaluation included clinical assessment every 6 weeks and determination of CD4 cell count and HIV-RNA concentration every 3 months. RESULTS: Median length of follow-up on triple therapy was 15 months (range: 7-21 months). Neither progression in the CDC classification nor death occurred. No significant change in mean weight SD scores was noted when baseline values were compared with values obtained after 1 year of triple therapy. Median CD4 count increases were of 210 x 10(6)/l, 415 x 10(6)/l, and 472 x 10(6)/l cells at 6, 12, and 18 months, respectively. Among the patients baseline characteristics, neither age nor initial CD4 cells count influenced the magnitude of immunologic improvement. There were median decreases of 1.14, 0.95, and 1.5 log10 per ml of plasma in the concentration of viral RNA at 6, 12, and 18 months respectively. Seven patients maintained an undetectable viral load when under treatment. The introduction of at least one new reverse transcriptase inhibitor at the initiation of triple therapy correlated significantly with a greater viral suppression. CONCLUSION: Despite variable viral response, antiretroviral-experienced HIV-infected children demonstrated a substantial CD4 cell increase during a median period of 15 months of ritonavir containing combination therapy.
Protease inhibitor (PI) therapy for patients infected with the human immunodeficiency virus has been associated with lipid disorders and insulin resistance. We compared the incidence of myocardial infarction (MI) among participants receiving treatment with PIs with or without nucleoside reverse transcriptase inhibitors (nRTIs) to nRTI therapy alone in 30 phase II/III double-blind, randomized studies conducted before 1999 for the first 4 PI drugs. In most trials included in this analysis, participants could receive combination therapy with a PI plus nRTIs in open-label extensions after the blinded phase concluded. Person-years (PY) of follow-up were calculated from treatment initiation to the diagnosis of MI, or to the end of the randomized phases for nRTI-only therapy or to the conclusion of the studies for PI-containing regimens. Separate analyses were conducted for the randomized and the randomized-plus-extension phases. Among 10,986 participants, 7951 (72%) received PI drugs at some point for an average duration of 12 months. There were 10 MIs (1.31/1000 PY) in the randomized phases and 19 MIs (1.63/1000 PY) in the randomized-plus-extension phases. The overall stratified relative risk of MI for PI-containing (1.82 MI/1000 PY) versus nRTI-only (1.05 MI/1000 PY) regimens of 1.69 was not significantly increased (95% confidence interval [CI], 0.54 to 7.48). The absolute difference in MI risk was +0.77 (95% CI, -0.71 to +2.26) MIs/1000 PY. Compared with NRTI-only therapy, patients receiving PI-containing regimens for an average of 1 year did not have significantly more MIs, but the upper bound of the 95% CI indicates there may be up to 2.3 additional MIs per 1000 PY. Although studies with a longer duration of PI therapy are in progress to assess whether a later increase in MI incidence occurs, our analysis did not demonstrate a dramatic increase in MI risk during the first year of PI therapy.
BACKGROUND: First results of Trilège demonstrated that the strategy of less intensive antiviral therapy is less effective than continuation of triple-drug therapy. OBJECTIVE: To compare the final number of failures at month 18 and to study viral dynamics in patients experiencing a virological failure. DESIGN: Longitudinal follow-up from a randomized controlled trial. SETTING: Forty-three AIDS clinical-trial units. PATIENTS: A total of 279 HIV-1 infected adults randomized in Trilège. MEASUREMENTS: Analysis of recurrent values of HIV RNA > 500 copies/ml beyond time to virologic failure. RESULTS: A total of 83 patients experienced virological failure by month 18; 10 in the zidovudine (ZDV) + lamivudine (3TC) + indinavir (IDV) arm, 46 in the ZDV + 3TC arm, and 27 in the ZDV + IDV arm, confirming previous results. Whatever the treatment ultimately received, 87% of patients had an HIV RNA < 500 copies/ml at month 18 with no statistical difference between randomized arms. Patients experiencing a failure in the triple-drug regimen had a greater tendency to maintain HIV RNA > 500 copies/ml beyond the time of virological failure than patients in both less intensive treatment groups who experienced failure. Lower levels of HIV RNA at failure and reinitiating of either the original triple-drug regimen or a new combination of nucleoside analogue reverse transcriptase inhibitors and protease inhibitors were associated with lower hazard ratios for developing recurrent HIV RNA > 500 copies/ml. CONCLUSION: Results confirmed the failure of a less intensive regimen to maintain patients with a viral suppression (HIV RNA < 500 copies/ml). Although there is a lower incidence of failure in the triple-drug regimen, randomization to a less intensive regimen of ZDV + 3TC or ZDV + IDV was not detrimental, as treatment modification, either to the original triple regimen, or a different regimen was successful.
OBJECTIVES: To assess the effects of switching from HIV-1 protease inhibitors (PI) to nevirapine on metabolic abnormalities in patients with fat redistribution and on CD4 T lymphocytes and plasma HIV-1 RNA. DESIGN: Longitudinal data analysis of 23 consecutive patients treated with two nucleoside reverse transcriptase inhibitors and at least one PI who decided to stop PI despite sustained virological suppression (< 200 copies/ml) because of psychological repercussions caused by body changes. PI were replaced by nevirapine in all patients. METHODS: Physical examination [including measurements of body mass index (BMI) and waist: hip ratio (WHR)], fasting cholesterol, triglycerides, glucose, insulin, CD4 T lymphocytes and plasma HIV-1 RNA were performed at baseline and every 3 months. RESULTS: Awareness of body changes occurred after a median of 12 months (range, 6-26 months) from the commencement of PI. Seventeen patients complained of increased abdominal girth (in 15 also of peripheral fat wasting) and six of peripheral fat wasting only. Hypertriglyceridemia (> or = 200 mg/dl) was present in 23 (100%), hypercholesterolemia (> or = 200 mg/dl) in 18 (78%), and impaired fasting glucose (> or = 110 mg/dl) in seven (30%) patients. Baseline CD4 T lymphocytes were 514 x 10(6)/l (range, 83-994 x 10(6)/l). HIV-1 RNA had been < 200 copies/ml a median of 9 months (range, 3-14 months) prior to withdrawal of PI. Median follow-up from the replacement of PI by nevirapine was 8 months (range, 7-11 months). Six months after PI withdrawal there was a significant improvement in cholesterol (decrease of 22%; P = 0.0005), triglycerides (decrease of 57%; P = 0.0001), glucose (decrease of 15%; P = 0.008), and fasting insulin resistance index (decrease of 45%; P = 0.0001). CD4 T-lymphocyte counts remained unchanged (401 x 10(6)/l; range, 57-941 x 10(6)/l; P = 0.13) and in only one patient did the viral load become detectable at a low count (546 copies/ml; P = 0.32). BMI did not vary (23.30 versus 23.56 kg/m2; P = 0.73), but WHR decreased significantly from 0.91 to 0.85 (P = 0.048). Twenty-one patients (91%) subjectively reported a partial improvement in their body shape (particularly in peripheral fat wasting), although none admitted to have their body shaped as prior to body changes. CONCLUSIONS: Metabolic abnormalities associated with potent antiretroviral regimens including PI may revert at least partially, whereas the suppression achieved may be preserved at least at mid-term after replacing PI by nevirapine.
An aqueous extract from the marine red alga, Schizymenia pacifica has been tested in a cell free system for its effect on reverse transcriptase from avian retrovirus (avian myeloblastosis virus), and mammalian retrovirus (Rauscher murine leukemia virus). The extract inhibited reverse transcriptase from both these retroviruses but showed almost no effect, if any, on the activity of cellular DNA polymerase alpha and RNA polymerase II in vitro. Consequently it is unlikely to have an adverse effect on the growth of cultured cell. The inhibitory activity of the extract was stable over a relatively wide pH range (pH 1-11) and was not lost after pronase digestion. Inhibitory activity of the extract was lost after boiling at 100 degrees C in 0.67 N HCl, and after treatment with 100 mM NaIO4. The active principle in the extract has an apparent molecular weight in excess of 100,000 daltons. This new reverse transcriptase inhibitor is probably a polysaccharide.
The objective of antiretroviral therapy is to obtain an almost complete and durable suppression of viral replication in all compartments to facilitate recovery of the immune system. We assessed the virologic effect in plasma, tonsillar tissue, and cerebrospinal fluid (CSF) in 94 HIV-1-infected patients with CD4 counts >500 x 106 cells per liter and viral load >5000 copies/ml randomly assigned to triple antiretroviral therapy (two nucleoside reverse transcriptase inhibitors (NRTIs) plus one protease inhibitor) versus double therapy (two NRTIs). We also analyzed the immunologic recovery in this cohort of patients. Lymphoid tissue and cerebrospinal fluid viral load, development of genotypic resistance, proliferative responses to HIV-1 specific antigens, and other immunophenotypic markers were analyzed. The proportion of patients who achieved a decrease in HIV RNA levels to <200 copies/ml was significantly greater in the triple therapy group than in the two drug groups (p =.0002 for each pair-wise difference). At week 52, tonsillar tissue HIV RNA from 5 patients treated with triple therapy was lower than the limit of detection, whereas the mean +/- standard error in patients with double therapy (n = 5) was 5.03 +/- 0.34 copies/mg/tissue. In all 10 patients, CSF viral load (VL) was <20 HIV-1 RNA copies/ml at week 52. CSF cell counts and protein levels tended to decrease after 52 weeks of antiretroviral therapy. After 1 year of therapy, 13 of 21 patients (62%) in the double-therapy groups (zidovudine plus lamivudine [n = 9] and stavudine plus lamivudine [n = 12]) had evidence of M184V mutation. None of the 10 samples of patients receiving triple therapy could be amplified because of low HIV RNA levels. The mean increase in CD4 cells at week 52 was greater in the stavudine and lamivudine and indinavir group than in the double-treatment arms (186 versus 67 and 102, respectively; p =.03). In patients treated with triple therapy, the increase in naive T cells (CD4 and CD8) was greater than in patients treated with double therapy. Markers of activation decreased further in patients treated with the regimen that included protease inhibitors. Proliferative responses to HIV-1 p24 antigen were never recovered after double or triple therapy. Our study suggests that even in very early stages of HIV-1 disease only therapy with two NRTIs and one protease inhibitor reduces plasma, lymphoid tissue, and CSF VL to undetectable levels. HIV-1-related immune system abnormalities improved but were still defective after 1 year of antiretroviral therapy.
Protease genotype, as a variable in outcome to combination therapy for human immunodeficiency virus (HIV) type 1 infection, was evaluated among protease inhibitor-naive children and adolescents who had received extensive treatment with reverse-transcriptase inhibitors. After 24 weeks of combination therapy, 35% had viral and immune success (VSIS patients), 19% had viral and immune failure (VFIF patients), and 46% had viral failure but marked improvement in CD4 T cells (VFIS patients). Disease stage was the only pretherapy clinical variable associated with outcome (P=.02). Although reverse-transcriptase genotype was unrelated to outcome, pretherapy protease genotype was related significantly to therapy response (P=.005). Odds for immune or viral failure were 17.7 to 1 and 2.5 to 1, respectively, for protease genotype as a single variable. Protease genotype combined with disease stage and CD4 cell percentage predicted correct therapy response for 81% of patients (100% of VFIF, 78% of VSIS, and 75% of VFIS patiens). Naturally occurring amino acid polymorphisms in protease provide sensitive biomarkers for treatment response among inhibitor-naive patients with advanced HIV disease.
We investigated, in a prospective cohort follow-up study, whether substituting efavirenz (EFV) for protease inhibitors (PIs) could be safe in HIV-infected patients with optimal viral suppression achieved on PI-containing regimens. In patients with undetectable plasma viral load (pVL) <50 copies/ml who were naive to therapy with nonnucleoside reverse transcriptase inhibitors (NNRTIs), PIs were replaced by EFV whereas associated nucleoside analogs (NAs) were retained. 62 patients were enrolled. Median follow-up on EFV was 64 weeks (2-88 weeks). Side effects due to EFV occurred in 48 patients. Two patients experienced a high level viral rebound due to diminished compliance; 55 (88.7%) maintained a pVL <50 copies/ml; 3 showed one episode of viremia (52-89 copies/ml); 2 stopped EFV before any VL control. Mean CD4 cell count did not change significantly. One AIDS patient experienced a single cutaneous recurrence of Kaposi's sarcoma after 40 weeks on EFV. Replacing PI with EFV in patients with optimal pVL suppression appears to be safe both virologically and immunologically.
The bovine immunodeficiency virus (BIV) and human immunodeficiency virus types 1 and 2 (HIV-1 and -2) are members of the lentivirus genus of retroviruses. Although DNA sequences of these viruses have diverged considerably, the BIV genome organization, function of structural and regulatory genes, and replication cycle are very similar to that of HIV-1, making BIV a potentially useful model to study compounds with anti-HIV-1 activity. A cell culture-based antiviral assay was developed to test compounds for inhibition of BIV replication. The assay uses an embryonic rabbit epithelial (EREp) cell line that is highly sensitive to BIV infection and cytopathology. The 50% effective concentrations (EC50) at which the virus was inhibited in EREp cells were determined for 13 nucleoside analog, non-nucleoside, tumor-suppressive, or membrane-surface inhibitory compounds. The nucleoside analogs (3'-azido-2',3'-dideoxythymidine, 2',3'-dideoxyinosine and 2',3'-dideoxycytosine), surface-membrane inhibitors (dextran sulfate, hypericin, Chicago Sky Blue and quinobene), the nucleoside reductase inhibitor (hydroxyurea), and a tumor-suppressive phorbol ester (prostratin) inhibited BIV with EC50 values similar to those derived in HIV-1 lymphocyte (CD4+)-based assays. BIV was markedly more resistant to inhibition with HIV-1-specific non-nucleoside reverse transcriptase inhibitors (NNRTIs) (thiazolobenzimidazole, oxathiin carboxanilide and thiocarbamate) than was HIV-1, which parallels results with NNRTIs in HIV-2 assays.
HIV and tuberculosis (TB) are leading global causes of mortality and morbidity, and yet effective treatment exists for both conditions. Rifamycin-based antituberculosis therapy can cure HIV-related TB and, where available, the introduction of highly active antiretroviral therapy (HAART) has markedly reduced the incidence of AIDS and death. Optimal treatment regimens for HIV/TB co-infection are not yet clearly defined. Combinations are limited by alterations in the activity of the hepatic cytochrome P450 (CYP) enzyme system, which in particular may produce subtherapeutic plasma concentrations of antiretroviral drugs. For example, protease inhibitors often must be avoided if the potent CYP inducer rifampicin is co-administered. However, an alternative rifamycin, rifabutin, which has similar efficacy to rifampicin, can be used with appropriate dose reduction. Available clinical data suggest that, for the majority of individuals, rifampicin-based regimens can be successfully combined with the non-nucleoside reverse transcriptase inhibitors nevirapine and efavirenz. Most available HAART regimens in areas that have a high burden of TB contain one or the other of these drugs as a backbone. However, significant questions remain as to the optimal dose of either agent required to ensure therapeutic plasma concentrations, especially in relation to particular ethnic groups. The timing of HAART initiation after starting antituberculosis therapy continues to be controversial. Debate centres upon whether early initiation of HAART increases the risk of paradoxical reactions (immune reconstitution-related events) and other adverse events, or whether delay greatly elevates the risk of disease progression. Further prospective clinical data are needed to help inform practice in this area.
OBJECTIVES: To assess the impact of HIV-1 protease mutations and intracellular and plasma lopinavir minimum concentrations (Cmin) on virological success or failure on lopinavir/ritonavir-containing highly active antiretroviral therapy (HAART). DESIGN: HIV-1-infected HAART-experienced patients included in an observational study, received lopinavir/ritonavir (400/100 mg twice a day) plus two to three nucleoside reverse transcriptase inhibitors (NRTI) or one NRTI plus one non-NRTI. A viral load less than 50 copies/ml at month 6 defined virological success. METHODS: Intracellular and plasma lopinavir concentrations were determined by high-pressure liquid chromatography with mass-spectrometry detection. Reverse transcriptase and protease genes were sequenced at baseline and the time of virological failure. RESULTS: When the 38 patients started the lopinavir/ritonavir-based regimen, baseline median (25-75th percentile) values were: CD4 cell count 218 cells/microl (133-477); plasma HIV-1-RNA load 5.3 log10 copies/ml (3.8-5.1); number of lopinavir mutations four per protease gene (two to six). Univariate analysis associated virological success or failure at month 6 (21/38 patients) with the number of baseline lopinavir mutations, intracellular and plasma lopinavir Cmin, and the genotype inhibitory quotient (GIQ) at months 1 and 6. Multivariate analysis showed that the number of baseline lopinavir mutations and intracellular and plasma lopinavir Cmin were independently associated with virological success or failure. We defined the most discriminating intracellular and plasma lopinavir Cmin efficacy thresholds (8 and 4 microg/ml, respectively) and GIQ thresholds (1 and 3, respectively). CONCLUSION: The monitoring of lopinavir/rironavir-based HAART efficacy should include the number of baseline lopinavir/ritonavir mutations, intracellular and plasma lopinavir Cmin and GIQ calculation.
MOTIVATION: Genotype-phenotype modeling problems are often overcomplete, or ill-posed, since the number of potential predictors-genes, proteins, mutations and their interactions-is large relative to the number of measured outcomes. Such datasets can still be used to train sparse parameter models that generalize accurately, by exerting a principle similar to Occam's Razor: When many possible theories can explain the observations, the most simple is most likely to be correct. We apply this philosophy to modeling the drug response of Type-1 Human Immunodeficiency Virus (HIV-1). Owing to the decreasing expense of genetic sequencing relative to in vitro phenotype testing, a statistical model that reliably predicts viral drug response from genetic data is an important tool in the selection of antiretroviral therapy (ART). The optimization techniques described will have application to many genotype-phenotype modeling problems for the purpose of enhancing clinical decisions. RESULTS: We describe two regression techniques for predicting viral phenotype in response to ART from genetic sequence data. Both techniques employ convex optimization for the continuous subset selection of a sparse set of model parameters. The first technique, the least absolute shrinkage and selection operator, uses the l(1) norm loss function to create a sparse linear model; the second, the support vector machine with radial basis kernel functions, uses the epsilon-insensitive loss function to create a sparse non-linear model. The techniques are applied to predict the response of the HIV-1 virus to 10 reverse transcriptase inhibitor and 7 protease inhibitor drugs. The genetic data are derived from the HIV coding sequences for the reverse transcriptase and protease enzymes. When tested by cross-validation with actual laboratory measurements, these models predict drug response phenotype more accurately than models previously discussed in the literature, and other canonical techniques described here. Key features of the methods that enable this performance are the tendency to generate simple models where many of the parameters are zero, and the convexity of the cost function, which assures that we can find model parameters to globally minimize the cost function for a particular training dataset. AVAILABILITY: Results, tables and figures are available at ftp://ftp.genesecurity.net. SUPPLEMENTARY INFORMATION: An Appendix to accompany this article is available at Bioinformatics online.
RNA viruses provide prominent examples of measurably evolving populations. In human immunodeficiency virus (HIV) infection, the development of drug resistance is of particular interest because precise predictions of the outcome of this evolutionary process are a prerequisite for the rational design of antiretroviral treatment protocols. We present a mutagenetic tree hidden Markov model for the analysis of longitudinal clonal sequence data. Using HIV mutation data from clinical trials, we estimate the order and rate of occurrence of seven amino acid changes that are associated with resistance to the reverse transcriptase inhibitor efavirenz.
A new field-based similarity forcing procedure for matching conformationally-flexible molecules is presented. The method extends earlier work on similarity matching of molecules based upon the program MIMIC, by directly coupling a similarity function to a molecular mechanics force field. In this way conformational energetics are fully accounted for in the similarity matching process. Simultaneous similarity/conformational searches can then be undertaken within a Monte Carlo or molecular dynamics framework. Here, a Monte Carlo approach is used to provide a simple example of two HIV-1 reverse transcriptase inhibitors, nevirapine and alpha APA, that illustrates the basic characteristics of the method and suggests areas for further investigation.
The FDA approved FTC (emtricitabine, Emtriva) in July 2003 for use by adults in combination with other anti-HIV drugs. FTC is a nucleoside analog reverse transcriptase inhibitor (NRTI). Other drugs in this class include 3TC, abacavir, AZT, Combivir, d4T, d4T XR, ddC, ddI, ddI EC and Trizivir.
A rapid and simple high-performance liquid chromatography method has been developed for the determination of the HIV-1 reverse transcriptase inhibitor abacavir in human plasma. It included a single liquid-liquid extraction procedure with a mixture of ethyl acetate-diethyl ether prior to reversed-phase chromatography on a C18 column and C18 precolumn insert. Ultraviolet detection was set at 285 nm. The mobile phase consisted of water-acetonitrile (83:17, v/v) and the flow rate was kept at 1 mL/min. The total run time for a single analysis was 10 min. The method has been validated over the range 50-2500 ng/mL. The assay was linear over the entire concentration range (r2 = 0.9993). Intra- and inter-day precision and accuracy were less than 8.1 and -5.2%, respectively. The extraction recovery was greater than 94.3%. Abacavir was stable under the relevant storage conditions tested. After the validation, the analytical error function was established as standard deviation (SD; ng/mL) = -1.072 + 0.037C (C = theoretical concentration value). The method developed and its associated analytical error function will be suitable for pharmacokinetic studies and monitoring of HIV-1 patients.