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PubMed2007

Frequent methamphetamine use is associated with primary non-nucleoside reverse transcriptase inhibitor resistance.

We determined whether methamphetamine use is associated with the increased prevalence of primary HIV drug resistance among a cohort of men who have sex with men recently infected with HIV. In multivariate analysis, we found that frequent methamphetamine use was strongly associated with primary non-nucleoside reverse transcriptase inhibitor resistance, but not with protease inhibitor or nucleoside reverse transcriptase inhibitor resistance. We postulate that this association may be caused by methamphetamine-associated treatment interruptions among source partners.

Adult↗
PubMed2005

Antiviral activity of GW678248, a novel benzophenone nonnucleoside reverse transcriptase inhibitor.

The compound GW678248 is a novel benzophenone nonnucleoside reverse transcriptase inhibitor (NNRTI). Preclinical assessment of GW678248 indicates that this compound potently inhibits wild-type (WT) and mutant human immunodeficiency virus type 1 (HIV-1) reverse transcriptase in biochemical assays, with 50% inhibitory concentrations (IC(50)s) between 0.8 and 6.8 nM. In HeLa CD4 MAGI cell culture virus replication assays, GW678248 has an IC(50) of < or =21 nM against HIV-1 isogenic strains with single or double mutations known to be associated with NNRTI resistance, including L100I, K101E, K103N, V106A/I/M, V108I, E138K, Y181C, Y188C, Y188L, G190A/E, P225H, and P236L and various combinations. An IC(50) of 86 nM was obtained with a mutant virus having V106I, E138K, and P236L mutations that resulted from serial passage of WT virus in the presence of GW678248. The presence of 45 mg/ml human serum albumin plus 1 mg/ml alpha-1 acid glycoprotein increased the IC(50) approximately sevenfold. Cytotoxicity studies with GW678248 indicate that the 50% cytotoxicity concentration is greater than the level of compound solubility and provides a selectivity index of >2,500-fold for WT, Y181C, or K103N HIV-1. This compound exhibits excellent preclinical antiviral properties and, as a prodrug designated GW695634, is being developed as a new generation of NNRTI for the treatment of HIV-1 in combination with other antiretroviral agents.

Anti-HIV Agents↗
PubMed2002

Tenofovir disoproxil fumarate: a nucleotide reverse transcriptase inhibitor for the treatment of HIV infection.

BACKGROUND: Tenofovir disoproxil fumarate (DF) is the first nucleotide reverse transcriptase inhibitor approved for use in combination with other antiretroviral agents in the treatment of HIV-1 infection in the United States. Unlike the nucleoside reverse transcriptase inhibitors, which must undergo 3 intracellular phosphorylation steps for activation. nucleotide analogues such as tenofovir require only 2 such steps. This reduction in the phosphorylation requirement has the potential to produce more rapid and complete conversion of the drug to its pharmacologically active metabolite. OBJECTIVE: This article describes the pharmacologic properties and potential clinical usefulness of tenofovir DF. METHODS: Relevant information was identified through searches of MEDLINE (1996-April 2002), Iowa Drug Information Service (1996-April 2002), and International Pharmaceutical Abstracts (1970-April 2002), as well as from meeting abstracts of major HIV/AIDS conferences (1996-2002), using the search terms tenofovir tenofovir disoproxil fumarate, PMPA, bis(POC)PMPA, GS-4331-05, acyclic nucleoside phosphonate, and nucleotide reverse transcriptase inhibitor. Additional information was obtained from material submitted to the US Food and Drug Administration by the manufacturer of tenofovir DF in support of its New Drug Application. RESULTS: In vitro, tenofovir DF has exhibited anti-HIV activity in various HIV-infected cell lines and has produced a synergistic or additive effect against HIV when combined with other antiretroviral agents. In adult humans, tenofovir has a volume of distribution of 0.813 L/kg, is minimally bound to plasma protein (7.2%), has a plasma elimination half-life of 12.0 to 14.4 hours, and is mainly excreted unchanged in urine (70%-80%). Dose adjustment based on sex or body weight does not appear to be necessary, although dose reduction may be necessary in the elderly; there are currently no data on tenofovir DF in renal or hepatic insufficiency. The results of clinical trials suggest the efficacy of tenofovir DF in reducing plasma levels of HIV-1 RNA when used as an add-on to a stable antiretroviral regimen. The most commonly (>3%) reported adverse events in clinical trials have included nausea, diarrhea, asthenia, headache, vomiting, flatulence, abdominal pain, and anorexia. The most commonly (>2%) reported laboratory abnormalities (grade III or IV) included increases in creatine kinase, triglycerides, amylase, aspartate aminotransferase, and alanine aminotransferase, as well as hyperglycemia and glucosuria. Serious adverse events leading to discontinuation of tenofovir DF were infrequent (5%), occurring with an incidence similar to that with placebo (8%). The recommended dosage of tenofovir DF in adults is 300 mg/d PO; pharmacokinetic and efficacy studies in children are ongoing. CONCLUSION: Although additional studies are needed, tenofovir DF appears to be a promising agent for the treatment of HIV infection.

Adenine↗
PubMed1999

HIV reverse transcriptase inhibitors of natural origin.

Inhibitors of HIV reverse transcriptase (RT) are important drugs for the treatment of acquired immuno-deficiency syndrome (AIDS). One approach to identify novel inhibitors of HIV-1-RT is the screening of natural compounds. Many natural products have been shown to be active as RT inhibitors. These compounds belong to a wide range of different structural classes, e.g., coumarins, flavonoids, tannins, alkaloids, lignans, terpenes, naphtho- and anthraquinones, and polysaccharides. The life forms from which the bioactive compounds were isolated are as equally diverse and comprise terrestrial and marine plants, micro-organisms, and marine animals. From the most extensive screening effort, carried out by the NCl, calanolide A, isolated from the terrestrial plant Calophyllum lanigerum (Guttiferae), has been discovered as the most interesting natural RT inhibitor. The promise of this natural product probably relates to a novel mechanism of action. The current review describes natural products from various sources that are able to inhibit HIV-RT.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Resistance to dual nucleoside reverse-transcriptase inhibitors in children infected with HIV clade A/E.

The prevalence of nucleoside reverse-transcriptase inhibitor (NRTI) mutations was determined among 95 human immunodeficiency virus-infected Thai children who were treated with dual nucleoside reverse-transcriptase inhibitors. Almost all children had resistance to at least 1 NRTI, and approximately half of the children had resistance to multiple NRTIs. Cross-resistance to stavudine and azidothymidine was universal.

Child↗
PubMed2006

Virological and immunological outcomes at 3 years after starting antiretroviral therapy with regimens containing non-nucleoside reverse transcriptase inhibitor, protease inhibitor, or both in INITIO: open-label randomised trial.

BACKGROUND: Antiretroviral therapy has greatly reduced HIV mortality and morbidity. However, the best sequence of regimens and implications of initial regimen for long-term therapeutic success are not well defined. METHODS: In INITIO, a large international randomised trial, we compared antiretroviral therapy with two nucleoside analogue reverse transcriptase inhibitors (didanosine+stavudine) plus either a non-nucleoside reverse transcriptase inhibitor (efavirenz, EFV) or a protease inhibitor (nelfinavir, NFV), or both (EFV/NFV), in patients with HIV-1 infection who had not previously received antiretroviral drugs. Primary outcomes were proportion with undetectable HIV RNA in plasma, and change in CD4 count from baseline at 3 years. Analyses were by intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN44582462. FINDINGS: We followed up 911 participants (297 EFV, 311 NFV, 303 EFV/NFV). At 3 years, the proportion with HIV RNA less than 50 copies per mL was highest in the EFV group (188 [74%] EFV, 162 [62%] NFV, 155 [62%] EFV/NFV; p=0.004). Mean (95% CI) increases in CD4 count were 316x10(6) cells per L (288-343) for EFV, 289x10(6) cells per L (262-316) for NFV, and 274x10(6) cells per L (231-291) for EFV/NFV (p=0.1). Fewer participants in the EFV group than in the other groups stopped adequate antiretroviral therapy for more than 30 days (p=0.005). Participants in the EFV/NFV group had shorter time to stopping the initial regimen (p<0.0001) and to a treatment modifying adverse event (p=0.04) than those in the other groups. INTERPRETATION: Starting antiretroviral therapy with a three-drug/two-class regimen including efavirenz was better than starting with regimens including nelfinavir or efavirenz plus nelfinavir in terms of virological suppression and durability of the initial regimen. The shorter time on adequate antiretroviral therapy or to a treatment-modifying adverse event might explain the absence of additional benefit for the four-drug regimen.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Reverse transcriptase mutations 118I, 208Y, and 215Y cause HIV-1 hypersusceptibility to non-nucleoside reverse transcriptase inhibitors.

BACKGROUND: HIV-1 hypersusceptibility to non-nucleoside reverse transcriptase inhibitors (NNRTI) improves the response to NNRTI-containing regimens. The genetic basis for NNRTI hypersusceptibility was partly defined in our earlier analyses of a paired genotype-phenotype dataset of viral isolates from treatment-experienced patients, in which we identified reverse transcriptase mutations V118I, H208Y, and T215Y as being strongly associated with NNRTI hypersusceptibility. OBJECTIVES: We evaluated the role of these mutations in NNRTI hypersusceptibility by site-directed mutagenesis and phenotypic analysis of HIV-1 recombinants. METHODS: Drug susceptibility and replication capacity were determined in single cycle assays. Hypersusceptibility was defined by a statistically significant (P < 0.01; Student's t-test) mean fold-change in 50% inhibitory concentration (IC50) of less than 0.4. RESULTS: The single mutations V118I, H208Y, and T215Y did not show hypersusceptibility to efavirenz with mean fold-change of 0.58, 0.55, and 0.70, respectively (P < 0.01 and P = 0.12). The H208Y/T215Y and V118I/H208Y/T215Y mutants showed marked hypersusceptibility to efavirenz, having mean fold-change values of 0.27 and 0.20, respectively (P < 0.001). In addition, H208Y/T215Y, V118I/T215Y, and V118I/H208Y/T215Y were hypersusceptible to delavirdine and nevirapine. The V118I/T215Y mutant was not replication impaired; whereas H208Y/T215Y and V118I/H208Y/T215Y had significantly (P < 0.01) reduced replication capacities of 40 and 35% of wild-type, respectively. CONCLUSION: Different combinations of V118I, H208Y, and T215Y produce NNRTI hypersusceptibility. The V118I/T215Y mutant is hypersusceptible to delavirdine and nevirapine without reduced replication capacity, whereas the H208Y/T215Y and V118I/H208Y/T215Y mutants are hypersusceptible to all NNRTI and show impaired replication. These findings suggest that more than one mechanism is involved in NNRTI hypersusceptibility.

Alkynes↗
PubMed2001

The emerging roles of non-nucleoside reverse transcriptase inhibitors in antiretroviral therapy.

The availability of potent non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens for antiretroviral therapy and concerns regarding protease inhibitor (PI)-related metabolic disturbances have led to significant shifts in treatment practices in HIV infection. NNRTI-based regimens may have several advantages over PI-based therapy for initial or prolonged therapy, including more convenient administration regimens, lower tablet volume, fewer drug interactions, and central nervous system penetration. No data from prospective clinical trials currently exist comparing the 3 approved agents (efavirenz, nevirapine or delavirdine). Both efavirenz and nevirapine have been compared to triple therapy with the PI indinavir over 48 weeks as initial therapy, with similar responses being observed with nevirapine regimens and superiority observed with efavirenz. A smaller 24-week study has suggested nevirapine may be superior to the PI nelfinavir. Limited comparative data in patients with high viral loads treated with nevirapine- or delavirdine-based regimens currently exist. However, cohort data and selected patient data from clinical trials suggest comparable activity to PI-based regimens in these patients. The superiority of efavirenz over indinavir-based regimens has been observed in comparative data in a subset of patients with high viral loads. In treatment-experienced patients, available uncontrolled data suggest these agents contribute to regimen efficacy in NNRTI-naïve, treatment-experienced patients. Efavirenz has demonstrated superiority over nelfinavir in nucleoside-experienced patients, although combining these 2 agents may represent the best approach in these circumstances. The tolerability of NNRTIs appears generally good with few individuals discontinuing in clinical studies as a result of adverse drug events. The majority of adverse events with NNRTIs occur within the first month, and are predictable and manageable without therapy interruption.

Alkynes↗
PubMed2005

Anti-human immunodeficiency virus type 1 activity of the nonnucleoside reverse transcriptase inhibitor GW678248 in combination with other antiretrovirals against clinical isolate viruses and in vitro selection for resistance.

GW678248, a novel nonnucleoside reverse transcriptase inhibitor, has been evaluated for anti-human immunodeficiency virus activity in a variety of in vitro assays against laboratory strains and clinical isolates. When GW678248 was tested in combination with approved drugs in the nucleoside and nucleotide reverse transcriptase inhibitor classes or the protease inhibitor class, the antiviral activities were either synergistic or additive. When GW678248 was tested in combination with approved drugs in the nonnucleoside reverse transcriptase inhibitor class, the antiviral activities were either additive or slightly antagonistic. Clinical isolates from antiretroviral drug-experienced patients were selected for evaluation of sensitivity to GW678248 in a recombinant virus assay. Efavirenz (EFV) and nevirapine (NVP) had > or = 10-fold increases in their 50% inhibitory concentrations (IC50s) for 85% and 98% of the 55 selected isolates, respectively, whereas GW678248 had a > or = 10-fold increase in the IC50 for only 17% of these isolates. Thus, 81 to 83% of the EFV- and/or NVP-resistant viruses from this data set were susceptible to GW678248. Virus populations resistant to GW678248 were selected by in vitro dose-escalating serial passage. Resistant progeny viruses recovered after eight passages had amino acid substitutions V106I, E138K, and P236L in the reverse transcriptase-coding region in one passage series and amino acid substitutions K102E, V106A, and P236L in a second passage series.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Mutations in HIV-1 reverse transcriptase potentially associated with hypersusceptibility to nonnucleoside reverse-transcriptase inhibitors: effect on response to efavirenz-based therapy in an urban observational cohort.

BACKGROUND: Hypersusceptibility to nonnucleoside reverse-transcriptase inhibitors (NNRTIs) was described in association with reverse-transcriptase (RT) mutations conferring resistance to nucleoside reverse-transcriptase inhibitors (NRTIs). We evaluated the effect of RT mutations associated with hypersusceptibility to NNRTIs on the response to efavirenz-based therapy. METHODS: We analyzed an observational database of patients for whom highly active antiretroviral therapy failed and who received genotypic resistance testing-guided therapy, either efavirenz or protease inhibitor (PI) based. Study end points were achievement of virus load <80 copies/mL, achievement of virus load <80 copies/mL without rebound to >500 copies/mL, and changes in CD4 cell counts. RESULTS: The baseline RT mutations M41L, M184V, L210W, and T215Y and the M41L/T215Y and M41L/T215Y/M184V combinations were associated with virological suppression for efavirenz-treated patients, whereas, for PI-treated patients, only the M184V mutation was associated with virological suppression, and the L210W mutation showed a negative correlation; no correlation was found between any mutation and virological response without rebound. CONCLUSIONS: The M41L, M184V, L210W, and T215Y mutations were associated with a better, although transient, virological outcome in patients treated with efavirenz-based regimens.

Adult↗
PubMed2004

Therapeutic drug monitoring of lopinavir/ritonavir given alone or with a non-nucleoside reverse transcriptase inhibitor.

AIMS: To evaluate the interindividual variability in the plasma concentrations of lopinavir in the context of routine monitoring with or without treatment with a non-nucleoside reverse transcriptase inhibitor and to assess the interaction between the coformulation of lopinavir/ritonavir and efavirenz or nevirapine. METHODS: Plasma trough and peak concentrations (C(trough), C(max)) of lopinavir from 182 HIV-1-infected patients were analysed by high-performace liquid chromatography. Three lopinavir/ritonavir regimens were assessed, namely (A) 400 mg lopinavir/100 mg ritonavir twice daily given alone (n = 125), (B) 400/100 mg twice daily together with a non-nucleoside reverse transcriptase inhibitor (n = 25), and (C) 533/133 mg twice daily together with a non-nucleoside reverse transcriptase inhibitor (n = 32). RESULTS: Median (ng ml(-1)) C(trough) and C(max) lopinavir (interquartile range, CV) were: (A) 4852 (3198-6891, 56%) and 8501 (6333-11 584, 41%), (B) 2979 (1704-5186, 74%) and 5612 (3362-11 704, 76%) and (C) 5082 (2696-7226, 74%) and 9757 (4883-12 963, 60%). Median C(trough) of lopinavir was lower in patients taking both efavirenz [P = 0.01, 95% confidence interval (CI) for difference between medians 343, 2713] and nevirapine (P = 0.019, 95% CI for difference between medians 354, 3681) compared with those taking lopinavir/ritonavir alone. A higher interindividual variability was observed when lopinavir/ritonavir was given with a non-nucleoside reverse transcriptase inhibitor. The risk of achieving a 'suboptimal'C(trough) of lopinavir (below a threshold of 3000 ng ml(-1)) was statistically higher in patients treated with a non-nucleoside reverse transcriptase inhibitor (P < 0.001, 95% CI for difference between percentages 8.8, 43.1%) compared with those receiving lopinavir/ritonavir alone. CONCLUSIONS: Our results confirmed the interaction between lopinavir and efavirenz, and also demonstrated a significant interaction between the former drug and nevirapine, resulting in lower C(trough) of lopinavir. The wide interpatient variability in this interaction suggests that therapeutic drug monitoring may be useful in optimizing the dose of lopinavir.

Adolescent↗
PubMed2003

HIV-1 resistance profile of the novel nucleoside reverse transcriptase inhibitor beta-D-2',3'-dideoxy-2',3'-didehydro-5-fluorocytidine (Reverset).

Nucleoside reverse transcriptase inhibitors (NRTIs) represent the cornerstone of highly active antiretroviral therapy when combined with non-nucleoside reverse transcriptase inhibitors (NNRTIs) or HIV-1 protease inhibitors (PIs). Unlike the NNRTIs and PIs, NRTIs must be successively phosphorylated by cellular kinases to a triphosphate form, which represents the active metabolite possessing antiviral activity. Emergence of viral resistance to NRTIs has severely hampered treatment options for persons infected with HIV-1. As such, there is an urgent need to develop NRTIs capable of suppressing NRTI-resistant strains of HIV-1. We have recently reported that the cytidine analogue D-d4FC (DPC817, Reverset) effectively inhibits clinically prevalent resistant strains of HIV-1. In this report, we have extended these findings and now describe a detailed resistance profile for this novel NRTI. By examining a panel of 50 viruses carrying RTs derived from HIV-1 clinical isolates displaying a wide range of NRTI resistance mutations, we report that the median fold increase in effective antiviral concentration for such a panel of viruses is 3.2, which is comparable to tenofovir (2.8-fold) and didanosine (2.4-fold). D-d4FC is highly effective at inhibiting subsets of lamivudine- and zidovudine-resistant variants but, like other NRTIs, seems less potent against multi-NRTI-resistant viruses, particularly those carrying the Q151M complex of mutations. Finally, in vitro selections for HIV-1 mutants capable of replicating in the presence of D-d4FC yielded a mutant carrying the RT K65R mutation. This mutation confers 5.3- to 8.7-fold resistance to D-d4FC in vitro. These findings suggest that D-d4FC may represent an alternative NRTI for the treatment of individuals infected with lamivudine- and zidovudine-resistant strains of HIV-1.

Adenine↗
PubMed2000

Salvage therapy with abacavir plus a non-nucleoside reverse transcriptase inhibitor and a protease inhibitor in heavily pre-treated HIV-1 infected patients. Swiss HIV Cohort Study.

BACKGROUND: Highly active antiretroviral therapy (HAART) may fail, especially in pre-treated patients. OBJECTIVE: To examine retrospectively whether heavily pre-treated patients not responding to HAART at least once respond to a salvage therapy with abacavir, a nucleoside reverse transcriptase inhibitor (NRTI) plus a non-nucleoside analogue reverse transcriptase inhibitor (NNRTI) and one or two protease inhibitors (PI). PATIENTS: We retrospectively identified and analysed patients followed in the Swiss HIV Cohort Study with > 1000 HIV RNA copies/ml on HAART, naive to abacavir who were switched to abacavir plus one NNRTI (efavirenz or nevirapine) and one or two PI which had not been used in the previous HAART. RESULTS: Of 23 identified HIV-infected patients with four (median) therapy changes before salvage, 10 patients (43%) achieved a decrease of plasma HIV RNA > 0.5 log10 at 6 months of therapy. After 6 months only two patients had an HIV-1 RNA < 500 copies/ml, one of them < 50 copies/ml. Seven patients increased their CD4 cell counts by > 30% above baseline. Three patients, all with CD4 cell counts < 100 x 10(6)/l before salvage therapy had a > 30% decline in CD4 cell count. An extended number of resistance-associated mutations was found in almost all patients at baseline. One patient had two new AIDS-defining events. Five patients (22%) discontinued treatment because of side-effects, mainly occurrence of a rash. CONCLUSION: Salvage therapy in intensively pre-treated patients has a low virological success rate despite usage of abacavir and NNRTI. Nevertheless, this did not correlate with immunological and clinical course. This study emphasizes the difficulty of second-line treatment in HIV-1 infection and stresses the need for new compounds.

Adult↗
PubMed2002

Sustained high proportion of zidovudine-resistant HIV variants despite prolonged substitution of zidovudine by other nucleoside reverse transcriptase inhibitors.

The consequences of zidovudine (ZDV) replacement by other nucleoside reverse transcriptase inhibitors on the expression of resistance mutations at codons 215 and 41 of the reverse transcriptase (RT) gene was investigated prospectively in 66 patients harboring mutant genotypes who were changed to an effective two- or three-drug combination antiretroviral regimen. Quantitation of mutant (MUT) viral populations at codon 215 by means of RT-PCR with differential hybridization of amplicons specific for MUT and wild (WT) variants revealed no difference in the proportion of 215 MUT variants prior to (93.5 +/- 2.4%) and 12 to 20 months after (96.9 +/- 1.9%) ZDV replacement, independently of a therapeutic change for stavudine. The fitness of the variants harboring the ZDV-resistant MUT 215 genotype following drug withdrawal was calculated to be 96 to 99% of that of the variants harboring the WT 215 genotype. The apparent stability of ZDV-resistant variants in the study population may have two main complementary explanations: persistent selective pressure secondary to partial cross-resistance due to the new regimens given after the therapeutic alteration and suppression of viral replication after the therapeutic alteration that could have hampered the replacement of less fit variants by fitter variants. These findings indicate that, at least within 15 months following discontinuation of ZDV, an effective antiretroviral therapy is insufficient to allow for ZDV-resistant strains to disappear, and thus to allow for the safe re-introduction of the drug.

Adaptation, Physiological↗
PubMed2003

Simultaneous determination of six HIV nucleoside analogue reverse transcriptase inhibitors and nevirapine by liquid chromatography with ultraviolet absorbance detection.

An accurate, sensitive and specific reversed-phase high-performance liquid chromatography assay for the simultaneous quantitative determination of the nucleoside reverse transcriptase inhibitors zalcitabine, lamivudine, didanosine, stavudine, zidovudine, and abacavir with the non-nucleoside reverse transcriptase inhibitor nevirapine in human blood plasma is described. The new Polarity dC C(18) silica column used in this method provides better resolution and peak shape than all other columns tested. Also, four different ultraviolet wavelengths were used for accurate and specific quantitation of the analytes. The method was validated over the range of 10-10000 ng/ml for all analytes except zalcitabine (10-5000 ng/ml). This method is accurate (average accuracies of three different concentrations ranged from 97.2 to 105%), and precise (within- and between-day precision measures ranged from 0.5 to 5.1% and 0.5 to 5.6%, respectively), and is currently being used for determination of plasma drug concentrations in our laboratory.

Chromatography, High Pressure Liquid↗
PubMed2005

High virological failure rate in HIV patients after switching to a regimen with two nucleoside reverse transcriptase inhibitors plus tenofovir.

BACKGROUND: Regimens with two nucleoside analogue reverse transcriptase inhibitors (NRTI) plus tenofovir DF have been associated with a high failure rate when administered as first line therapy. Little is known about patients with undetectable viral loads who are switched to these regimens. METHODS: A post-hoc review of the virological outcomes at 24 weeks of patients who switched from a successful (< 50 copies/ml) highly active antiretroviral therapy regimen to a tenofovir plus two NRTI combination. RESULTS: Fifty-five patients started a two NRTI plus tenofovir regimen mostly because of previous toxicity/intolerance of the original drugs (74%). After 24 weeks, only 17 patients (31%) remained virologically suppressed. Patients with a regimen including a didanosine plus tenofovir-based regimen had significantly poorer outcomes than those on other combinations (success rate 5 versus 47.1%, P = 0.001). In contrast, patients on a regimen including zidovudine plus tenofovir showed a trend towards a better outcome (75 versus 27%, P = 0.083). Multivariate analysis confirmed the combination of didanosine plus tenofovir as the only variable associated with a higher rate of failure (odds ratio 17.7; 95% confidence interval 2.1-147; P = 0.007). Patients with previous reverse transcriptase mutations presented virological failure in all cases. At failure a new pattern, including the K65R mutation with M184V or thymidine analogue mutations, was observed. CONCLUSIONS: Even in patients with suppressed viraemia, a two NRTI plus tenofovir regimen is associated with a high virological failure rate, but significant variations are found depending on the nucleosides included.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Mitochondrial dysfunction and nucleoside reverse transcriptase inhibitor therapy: experimental clarifications and persistent clinical questions.

Nucleoside reverse transcriptase inhibitors (NRTIs) in combination with other antiretrovirals (HAART) are critical in current AIDS therapy, but mitochondrial side effects have come to light with the increased use of these compounds. Clinical experience, pharmacological, cell and molecular biological evidence links altered mitochondrial (mt-) DNA replication to the toxicity of NRTIs in many tissues, and conversely, mtDNA replication defects and mtDNA depletion in specific target tissues are observed. The shared features of mtDNA depletion and energy depletion became key observations and related the clinical and in vivo experimental findings to inhibition of mtDNA replication by NRTI triphosphates in vitro. Subsequent to those findings, other observations suggested that mitochondrial energy deprivation is concomitant with or the result of mitochondrial oxidative stress in AIDS (from HIV, for example) or from NRTI therapy itself. With increased use of NRTIs, mtDNA mutations may become increasingly important pathophysiologically. One important future goal is to prevent or attenuate the side effects so that improved efficacy is achieved.

Anti-HIV Agents↗
PubMed2004

Design, synthesis, anti-HIV activities, and metabolic stabilities of alkenyldiarylmethane (ADAM) non-nucleoside reverse transcriptase inhibitors.

The alkenyldiarylmethane (ADAM) HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) are effective anti-HIV agents in cell culture. However, the potential clinical utility of the ADAMs is expected to be limited by the presence of methyl ester moieties that are likely to be metabolized by nonspecific esterases in blood plasma to biologically inactive carboxylic acid derivatives. The present investigation was therefore undertaken to investigate the anti-HIV activities of the ADAMs versus HIV-1(IIIB) and HIV-2(ROD) in MT-4 cells and the stabilities of the biologically active ADAMs in rat plasma. The ADAMs displayed a wide range of metabolic stabilities in rat plasma, with half-lives ranging from 0.9 to 76.6 min. A wide assortment of structural modifications was tolerated, with 18 of the 32 compounds tested displaying EC(50) values between 0.3 and 3.7 microM versus HIV-1(IIIB) in MT-4 cells, 3 compounds in the EC(50) = 13.2-35.4 microM range, and the remaining compounds inactive. Consistent with the mechanism of action of the ADAMs as NNRTIs, they were inactive or displayed comparatively low activity versus HIV-2(ROD). The replacement of the two aromatic methyl ester substituents in one of the most active ADAMs (EC(50) = 0.6 microM) with two methyl thioester groups resulted in an increase in plasma half-life from 5.8 to 55.3 min, while maintaining the antiviral potency at the EC(50) = 1.8 microM level. At the same time, the bis(thioester) modification was less cytotoxic to uninfected MT-4 cells, with a CC(50) of >224 microM versus 160 microM for the parent compound.

Alkenes↗