Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Reverse Transcriptase Inhibitors”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,063 records · Page 59Linked to original sources
PubMed2004

Pharmacokinetics of antiretrovirals in pregnant women.

Antiretroviral treatment of HIV-infected pregnant women is widely used to prevent mother-to-child HIV transmission and as primary therapy of maternal HIV infection. The physiological changes associated with pregnancy have a large impact on drug disposition, and changes in antiretroviral pharmacokinetics during pregnancy must be understood for these drugs to be used safely and effectively in pregnant women. Zidovudine and didanosine, two of the nucleoside reverse transcriptase inhibitors, demonstrate an increase in clearance and decrease in area under the concentration-time curve during pregnancy. The clinical significance of these changes is unknown due to the lack of a clear relationship between plasma concentrations of nucleoside reverse transcriptase inhibitors and clinical effects. Pharmacokinetic parameters of lamivudine, stavudine and abacavir are not significantly changed during pregnancy. There are no data describing the effect of pregnancy on the pharmacokinetics of the other nucleoside/nucleotide analogues (zalcitabine, emtricitabine and tenofovir). Pregnancy does not appear to have a significant effect on the pharmacokinetics of the non-nucleoside reverse transcriptase inhibitor nevirapine and there are no data describing the pharmacokinetics of the other non-nucleoside reverse transcriptase inhibitors (efavirenz and delavirdine) during pregnancy. Reduced plasma concentrations during pregnancy have been described for several of the protease inhibitors, including nelfinavir (with administration of 750 mg three times daily), indinavir, saquinavir and Kaletra (a co-formulation of lopinavir and ritonavir). Plasma concentrations equivalent to those in nonpregnant adults have been reported in pregnant women receiving nelfinavir at doses of 1250 mg twice daily, and the addition of ritonavir to saquinavir greatly increases saquinavir exposure to therapeutic concentrations in pregnant women. No pregnancy pharmacokinetic data are available for the newer protease inhibitors atazanavir and fosamprenavir, or with other dual protease inhibitor combinations that include low dose ritonavir to boost concentrations of the coadministered protease inhibitor. Further investigations of antiretroviral pharmacology during pregnancy, including protein binding studies, are urgently needed.

Anti-HIV Agents↗
PubMed2000

Piperidinylethyl, phenoxyethyl and fluoroethyl bromopyridyl thiourea compounds with potent anti-HIV activity.

Derivatives of piperidinylethyl, phenoxyethyl and fluoroethyl bromopyridyl thioureas were designed and synthesized as non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1 reverse transcriptase (RT). The anti-HIV activity of these compounds was examined by determining their ability to inhibit the replication of the HIV-1 strain HTLV(IIIB) in human peripheral blood mononuclear cells. The unsubstituted parent pyridyl thiourea compound N-[2-(1-piperidine)ethyl]-N'-[2-(pyridyl)] thiourea (1) exhibited no anti-HIV activity, even at 100 microM. However, the thiourea derivatives that contain a bromo- or chloro-substituted pyridyl group, compounds 2 and 5, inhibited HIV-1 replication at nanomolar concentrations. The addition of a methyl group onto the piperidine ring significantly altered the potency of these compounds; while methyl substitution at the 3-position of the piperidine ring reduced the activity, methyl substitution at the 2-position enhanced the anti-HIV activity. The IC50 value of the lead piperidinyl compound, N-[2-(2-methylpiperidinylethyl)]-N'-[2-(5-bromopyridyl)] thiourea (4) was <0.001 microM. All three phenoxyethyl derivatives, including the unsubstituted parent phenoxyethyl pyridyl thiourea compound N-[2-(phenoxy)ethyl]-N'-[2-(pyridyl)]thiourea (8) and the bromo-/chloro-substituted phenoxyethyl halopyridyl thiourea compounds N-[2-(phenoxy)ethyl]-N'-[2-(5-chloropyridyl)]thiourea (9) and N-[2-(phenoxy)ethyl]-N'-[2-(5-bromopyridyl)]thiourea (10) exhibited potent anti-HIV activity with nanomolar IC values. The corresponding fluoroethyl halopyridyl thiourea compounds beta-fluoro[2-phenethyl]-N'[2-(5-chloropyridyl)]thiourea (11) and beta-fluoro[2-phenethyl]-N'[2-(5-bromopyridyl)]thiourea (12) inhibited HIV-1 replication in PBMC with subnanomolar IC50 values and selectivity indices >30000. Compared to the corresponding phenoxyethyl thiourea compounds 9 and 10, these compounds were >4-5-fold more active as anti-HIV agents. Notably, the lead fluorothiourea compounds 11 and 12 were both substantially more active against the NNRTI-resistant HIV strains RT-MDR (V106A) and A17 (Y181C) than nevirapine or delavirdine. Taken together, our results provide additional experimental evidence that the structural features of the 'linker unit' between the pyridyl and phenyl moieties and changes in the phenyl group of PETT-related thiourea compounds significantly affects their biological activity as NNRTIs of HIV-1 RT.

Anti-HIV Agents↗
PubMed1978

Gliotoxin analogues as inhibitors of reverse transcriptase. 1. Effect of lipophilicity.

The reaction scheme, developed for the synthesis of the gliotoxin analogue 2, was found to be of general applicability for analogues with varying substituents at N(1) and C(2). Analogues 11b-g prepared by this method are inhibitors of reverse transcriptase (RNA-directed DNA polymerase). Their inhibitory activity seems to be related to the lipophilicity of the effector molecules: the most lipophilic compound is the most active inhibitor. The techniques of reversed-phase thin-layer chromatography with silylated, precoated plates as well as reversed-phase high-performance liquid chromatography were used to measure the relative lipophilicities; both techniques gave analogous results.

Anti-Bacterial Agents↗
PubMed2006

Genotypic drug resistance interpretation algorithms display high levels of discordance when applied to non-B strains from HIV-1 naive and treated patients.

Genotypic drug resistance interpretation algorithms have been developed on patients infected with HIV-1 subtype B to interpret complex patterns of mutations. As non-B strains are characterised by the natural presence of several resistance-related mutations, we examined to what extent this might result in interalgorithm discordances in naive and treated patients. We compared the prediction by three algorithms (ANRS, Stanford and Rega) of drug susceptibilities to diverse HIV-1 strains from 272 naive and 156 treated patients. In naive patients, higher levels of interalgorithm discordance were observed for predictions of protease inhibitor (0.60-39%) than for predictions of reverse transcriptase inhibitor susceptibility (0-4%). The main reason for discordant protease inhibitor interpretation was the presence of resistance mutations that were natural protease polymorphisms. In contrast, in the treated patients, more interalgorithm discordances were observed for predictions of reverse transcriptase inhibitor (5-48%) than protease inhibitor susceptibilities (10-31%). Discordances were related to disagreement between the intermediate and susceptible scores, the intermediate and resistant scores and the interpretations of complex mutation patterns, related to cross-resistance and antagonistic interactions.

Algorithms↗
PubMed2001

Quinoxalinylethylpyridylthioureas (QXPTs) as potent non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors. Further SAR studies and identification of a novel orally bioavailable hydrazine-based antiviral agent.

Quinoxalinylethylpyridylthioureas (QXPTs) represent a new class of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) whose prototype is 6-FQXPT (6). Docking studies based on the three-dimensional structure of RT prompted the synthesis of novel heteroarylethylpyridylthioureas which were tested as anti-HIV agents. Several compounds proved to be potent broad-spectrum enzyme inhibitors and significantly inhibited HIV-1 replication in vitro. Their potency depends on the substituents and the nature of the heterocyclic skeleton linked to the ethyl spacer, and structure-activity relationships are discussed in terms of the possible interaction with the RT binding site. Although the new QXPTs analogues show potent antiviral activity, none of the compounds tested overcome the pharmacokinetic disadvantages inherent to ethylpyridylthioureidic antiviral agents, which in general have very low oral bioavailability. Through an integrated effort involving synthesis, docking studies, and biological and pharmacokinetic evaluation, we investigated the structural dependence of the poor bioavailability and rapid clearance within the thioureidic series of antivirals. Replacing the ethylthioureidic moiety with a hydrazine linker led to a new antiviral lead, offering promising pharmacological and pharmacokinetic properties in terms of antiviral activity and oral bioavailability.

Animals↗
PubMed2003

Genotype and phenotype at baseline and at failure in human immunodeficiency virus-infected antiretroviral-naive patients in a randomized trial comparing zidovudine and lamivudine plus nelfinavir or nevirapine.

For the 127 Spanish patients enrolled in the Combine Study, a resistance substudy was performed with 100 (79%) plasma samples obtained at baseline and with 18 samples obtained from 19 patients at the time they experienced treatment failure. At baseline, primary mutations to nonnucleoside reverse-transcriptase inhibitors and protease inhibitors were not detected, whereas mutations to nucleoside reverse-transcriptase inhibitors were observed in 10% of patients. At failure, mutations were detected in 7 of 16 patients. An agreement in the results of virtual and real phenotypes was observed in the 93 samples in which both tests were performed.

Adult↗
PubMed1996

Determination of HIV-1 susceptibility to reverse transcriptase (RT) inhibitors by a quantitative cell-free RT assay.

BACKGROUND: Mutations in the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) gene confer resistance to antiviral drugs acting on RT. Current methods employed to detect such resistance require time-consuming culture techniques during which selective pressures may affect the outcome of the test. OBJECTIVES: We sought to determine whether drug-susceptible and drug-resistant HIV-1 derived from clinical specimens could be distinguished by the effects of the active form of the drug on the enzyme activity in a quantitative, cell-free RT assay. STUDY DESIGN: Polyethylene glycol (PEG)-precipitated virus was obtained from 7-day culture supernatants. RT activity in the lysed viral extracts was measured in the presence of increasing concentrations of the active form of the drug being tested. IC50 (50% inhibitory concentration) values were determined by application of the median effect equation. RESULTS: Assays from nine post-nevirapine therapy isolates gave IC50 values at least 2 logs greater than pre-nevirapine isolates. The method also correctly distinguished between isolates sensitive and resistant to 2',3'-dideoxyinosine (ddI), but not between the ZDV-sensitive and ZDV-resistant isolates tested. The results agreed with data obtained by sequencing and by culture-based susceptibility assays.

Cell-Free System↗
PubMed2003

Resistance of HIV-1 to multiple antiretroviral drugs in France: a 6-year survey (1997-2002) based on an analysis of over 7000 genotypes.

BACKGROUND: Evaluating the proportion of patients with mutated drug-resistant HIV-1 strains is a major issue of current AIDS research and therapy. According to a recent study in the United States, nearly 80% of HIV-1-infected patients have virus strains that are resistant to at least one antiretroviral drug. The aim of this study was to assess the extent of multiple drug resistance among individuals followed for HIV-1 infection in France. METHODS: We compiled data in a relational database for 3884 reverse transcriptase (2248 patients) and 3915 protease (2194 patients) sequences of plasma samples submitted for testing between January 1997 and March 2002 at the reference HIV AIDS hospitals located in Marseille (France). RESULTS: Genotypic resistance to at least one nucleoside reverse transcriptase inhibitor (NRTI) was present in 78.3%, resistance to at least one non-nucleoside reverse transcriptase inhibitor (NNRTI) was present in 38.9%, and resistance to at least one protease inhibitor (PI) was present in 47.0% of plasma samples. The proportion of patients carrying a virus with multiple resistance to three categories of drugs (at least one NRTI plus at least one NNRTI plus at least one PI) peaked at 25.9% in 2000 and stabilized at 25.5% in March 2002. CONCLUSION: This study demonstrates the high prevalence of drug-resistant virus in a European cohort of patients currently under treatment for HIV-1 infection. New therapeutic strategies based on a more rational use of genotypic data should be worked out to prevent the development of resistance.

Anti-HIV Agents↗
PubMed2005

Accuracy, precision, and consistency of expert HIV type 1 genotype interpretation: an international comparison (The GUESS Study).

BACKGROUND: Resistance testing is considered standard of care in HIV medicine, but there is no standard interpretation system for genotype tests. We sought to determine how much agreement exists within a group of experts in the interpretation of complex genotypes. METHODS: Genotypes from clinical specimens were sent to an international panel of 12 resistance experts. Phenotypic susceptibility testing of these clinical isolates was performed with antivirogram. Experts predicted phenotype fold change category (<2.5-fold change, 2.5-4.0-fold change, >4.0- to 7.0-fold change, >7.0- to 10-fold change, >10- to 20-fold change, or >20-fold change) and predicted expected drug activity for each of 16 antiretroviral drugs. Experts were also asked to make treatment recommendations on the basis of the genotype. RESULTS: The experts predicted the exact phenotype fold change category correctly 44% of the time, but they varied widely by antiretroviral drug (range, 25%-74%). The highest accuracy was observed for lamivudine (74%) and the nonnucleoside reverse transcriptase inhibitors (66%-69%). Experts generally predicted higher levels of resistance to the remaining nucleoside reverse transcriptase inhibitors than what was found by phenotypic testing. Agreement among experts in predicting phenotype fold change category ranged widely depending on the drug (median agreement, 42% [range, 28%-74%]); the same pattern was observed in predicting expected drug activity (median agreement, 45% [range, 32%-87%]). Experts agreed on treatment recommendations in a median of 79% of instances, and recommendations were consistent over time, with blinded retesting. CONCLUSIONS: Although their ability to predict phenotype from a genotype varied for individual antiretroviral drugs, this expert panel had a high degree of agreement in deriving treatment recommendations from the genotype.

Anti-HIV Agents↗
PubMed2006

Therapeutic drug monitoring and human immunodeficiency virus (HIV) antiretroviral therapy.

Treatment with antiretroviral drugs such as the HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors have contributed to the improvement of life of many HIV-infected patients in recent years, but antiretroviral therapy is not without problems. In some patients, treatment is not effective and suppression of viral replication is not achieved. Other patients experience toxicity and have to stop treatment or change to a less effective treatment. Several studies have demonstrated a relationship between plasma concentrations of the protease inhibitors and non-nucleoside reverse transcriptase inhibitors and viral suppression and toxicity. Therapeutic drug monitoring uses drug concentrations to individualize and optimise therapy by dosage adjustments and many clinicians have advocated for the use of therapeutic drug monitoring in HIV antiretroviral therapy. Evidence from a number of randomized clinical trials supports the use of therapeutic drug monitoring, but the studies have limitations and might not apply to all the antiretroviral drugs. However, the consensus is that certain patients are very likely to benefit from therapeutic drug monitoring. Additionally, the combination of therapeutic drug monitoring and genotypic or phenotypic resistance testing might further improve antiretroviral therapy.

Anti-HIV Agents↗
PubMed2003

Impact of the central polypurine tract on the kinetics of human immunodeficiency virus type 1 vector transduction.

Lentiviral vectors derived from human immunodeficiency virus type 1 (HIV-1) show great promise as gene carriers for future gene therapy. Insertion of a fragment containing the central polypurine tract (cPPT) in HIV-1 vector constructs is known to enhance transduction efficiency drastically, reportedly by facilitating the nuclear import of HIV-1 cDNA through a central DNA flap. We have studied the impact of the cPPT on the kinetics of HIV-1 vector transduction by real-time PCR. The kinetics of total HIV-1 DNA, two-long-terminal-repeat (2-LTR) circles, and, by an Alu-PCR, integrated proviral DNA were monitored. About 6 to 12 h after transduction, the total HIV-1 DNA reached a maximum level, followed by a steep decrease. The 2-LTR circles peaked after 24 to 48 h and were diluted upon cell division. Integration of HIV-1 DNA was first detected at 12 h postinfection. When HIV-1 vectors that contained the cPPT were used, DNA synthesis was similar but a threefold higher amount of 2-LTR circles was detected, confirming the impact on nuclear import. Moreover, a 10-fold increase in the amount of integrated DNA was observed in the presence of the cPPT. Only in the absence of the cPPT was a saturation in 2-LTR circle formation seen at a high multiplicity of infection, suggesting a role for the cPPT in overcoming a barrier to the nuclear import of HIV-1 DNA. A major effect of the central DNA flap on the juxtaposition of both LTRs is unlikely, since transduction with HIV-1 vectors containing ectopic cPPT fragments resulted in increased amounts of 2-LTR circles as well as integrated DNA. Inhibitors of transduction by cPPT-containing HIV vectors were also studied by real-time PCR. The reverse transcriptase inhibitor azidothymidine (AZT) and the nonnucleoside reverse transcriptase inhibitor alpha-APA clearly inhibited viral DNA synthesis, whereas integrase inhibitors such as the diketo acid L-708,906 and the pyranodipyrimidine V-165 specifically inhibited integration.

Animals↗
PubMed2006

Marked intraindividual variability in antiretroviral concentrations may limit the utility of therapeutic drug monitoring.

BACKGROUND: Effective therapeutic drug monitoring for antiretrovirals requires a better understanding of intraindividual variability in pharmacokinetics. METHODS: We determined concentrations of human immunodeficiency virus (HIV) protease and nonnucleoside reverse-transcriptase inhibitors for 10 patients with undetectable plasma HIV RNA levels who had been receiving stable regimens for > or = 11 months. Plasma samples were collected at the same time of day 3 times per week for up to 4 months. Patients were instructed to take their antiretrovirals at the same time every day. Plasma protease and nonnucleoside reverse-transcriptase inhibitor concentrations were determined using high-performance liquid chromatographic methods. Pharmacokinetic variability was expressed as intraindividual percentage coefficient of variation (ICV), which was calculated as the patient's standard deviation divided by the mean drug concentration for that patient. RESULTS: ICV was determined for 6 drugs for 10 patients, for a total of 17 different patient-drug combinations, using 600 total samples. ICV was unexpectedly high for most patients who were receiving protease inhibitors (ICVs for individual patients taking lopinavir/ritonavir were 24%, 33%, 51%, and 92%; for patients taking nelfinavir/M8 metabolite, they were 30%/44% and 39%/54%; for patients taking ritonavir, they were 34% and 43%; for patients taking saquinavir, they were 52% and 55%). ICVs for patients receiving nonnucleoside reverse-transcriptase inhibitors were lower (for patients receiving efavirenz, they were 7%, 13%, 29%, and 51%; for a patient receiving nevirapine, it was 25%). The median ICV for all patients receiving protease inhibitors (n = 12) was 43.5%, and for all patients receiving nonnucleoside reverse-transcriptase inhibitors (n = 5), the median ICV was 25%. CONCLUSIONS: Intraindividual variability in concentrations of antiretrovirals was surprisingly high in virologically suppressed patients. Possible contributors include food effects, concomitant use of prescription and herbal medications, assay variability, or medication timing, which was assessed by self-report. High intraindividual pharmacokinetic variability may limit the utility of single measurements in therapeutic drug monitoring for some antiretroviral agents.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Partial treatment interruption of protease inhibitors augments HIV-specific immune responses in vertically infected pediatric patients.

BACKGROUND: Although highly active antiretroviral therapy has significantly reduced morbidity and mortality in HIV-infected children, it often fails to completely suppress viral replication, thereby allowing the emergence of drug-resistant variants. Protease inhibitor (PI) based therapy has been hypothesized to depress cell-mediated immune responses by reducing antigen presentation. OBJECTIVES: To determine the effects of partial treatment interruption (PTI) of PI on HIV-specific cellular immune responses in children. METHODS: We conducted a retrospective longitudinal study of HIV-specific cellular immune responses in 13 children who were vertically infected with HIV. All had detectable plasma viremia and had undergone PTI for a median of 1.0 year (range, 0.41-3.35 years) while continuing nucleoside reverse transcriptase inhibitor and non-nucleoside reverse transcriptase inhibitor therapy. RESULTS: No significant changes in viral load were observed in the immediate time-point before and during PTI (P = 0.84) as well as in the overall period before and during PTI (P = 0.17). CD4 T-cell levels declined slowly immediately before and during PTI (P = 0.07) as well as during the overall PTI period (P = 0.0002), but the rate of CD4 T-cell decline was not significantly increased during PTI. Immediate to PTI, HIV-specific CD4 and CD8 T-cell responses increased by 70% (P < 0.0001) and 92% (P < 0.0001), respectively, and CD4 and CD8 T-cell activation levels (P = 0.6834 and P = 0.6081, respectively) remained unchanged. CONCLUSION: HIV-specific cellular immune responses are boosted in children who have interrupted PI-based therapy.

Adolescent↗
PubMed1998

Line probe assay for detection of human immunodeficiency virus type 1 mutations conferring resistance to nucleoside inhibitors of reverse transcriptase: comparison with sequence analysis.

We compared the line probe assay (LiPA) to sequence analysis for the detection of mutations conferring resistance to nucleoside inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). Plasma samples from 40 patients who had received zidovudine, dideoxyinosine, and dideoxycytosine, alone or in combination, and who were enrolled in the ALTIS 2 clinical trial (lamivudine [3TC] plus stavudine) were tested at enrollment and at week 24. RT PCR products from plasma were used for LiPA, and DNA was used for sequence analysis. LiPA gave uninterpretable results for 8.5% of the analyzed codons corresponding to 63 samples, mainly for codons 41, 69, and 70. Several minor discrepancies between the two methods occurred, mainly due to the ability of LiPA to detect mixed populations while sequence analyses detect a single homogeneous population. LiPA is suitable for detecting mixed populations and easy to implement in clinical laboratories and might be useful for epidemiological surveys of primary HIV-1 resistance.

Anti-HIV Agents↗
PubMed2006

Genotypic resistance and immunologic outcomes among HIV-1-infected women with viral failure.

OBJECTIVES: To describe the prevalence of specific protease inhibitor (PI) and nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations and the relationship between the presence of these mutations and immunologic outcomes following PI/NNRTI initiation among a cohort of HIV-1-infected women. METHODS: Viral genotypic resistance testing was done for 366 women enrolled in the Women's Interagency HIV Study at the visit immediately prior to 1st reported use of PI or NNRTI (baseline) and at the visit approximately 1 year after PI/NNRTI initiation. We modeled the changes in CD4+ T-cell counts and HIV RNA levels approximately 1 year after therapy initiation as a function of baseline and follow-up markers, type of antiretroviral therapy used, and resistance mutations. RESULTS: At baseline, 52% of women showed only nucleoside reverse transcriptase inhibitor (NRTI) mutations, 38% showed no mutations, and 10% showed PI or NNRTI mutations. Only 40% of women showed viral response (HIV-1 RNA < or = 80 copies/mL) 1 year after initiating a PI or NNRTI. Among those without a viral response, 54% developed PI or NNRTI mutations. NNRTI (among those with baseline NRTI mutations) and PI resistance mutations were associated with better CD4+ cell count changes (mean increase of 118 cells/mm3 and 64 cells/mm3, respectively, as compared with viral nonresponders with no PI or NNRTI mutations). CONCLUSIONS: In this population-based cohort, virologic failure with PI or NNRTI resistance was common. Viremia with these resistance mutations was associated with preserved CD4+ T-cell count responses, providing evidence of reduced virulence or viral fitness.

CD4 Lymphocyte Count↗
PubMed1999

The choice of HIV protease inhibitor: indinavir is currently the best option.

(1) Recent consensus recommendations agree that first-line treatment of HIV infection should consist of a three-drug regimen combining a protease inhibitor and two nucleoside reverse transcriptase inhibitors. Some recommendations specifically advise against using the current formulation of saquinavir, but none express a preference for one of the other three protease inhibitors currently marketed in France (indinavir, nelfinavir and ritonavir). (2) These HIV protease inhibitors have established efficacy on viral load and the CD4+ lymphocyte count. Saquinavir may have lower virological efficacy. (3) The clinical efficacy of three-drug regimens containing indinavir or saquinavir is well demonstrated in patients at an advanced stage of HIV disease. (4) The risk of viral resistance is not currently a factor in choosing a HIV protease inhibitors. (5) Several epidemiological studies have compared the risk of adverse effects on three-drug regimens including indinavir, ritonavir or saquinavir. In these studies saquinavir was the best-tolerated drug and ritonavir the worst-tolerated. (6) Ritonavir interacts with many drugs. The poor bioavailability of the current saquinavir formulation also leads to risk of interactions. (7) Treatment constraints differ from one protease inhibitor to another, and these must be taken into account case by case. (8) The daily cost of treatment is not currently an important factor in choosing among the various preparations. (9) Taking into account efficacy, adverse effects, interactions and treatment constraints, the combination of indinavir with two nucleoside reverse transcriptase inhibitors currently seems to be the best choice for the largest number of patients. (10) If problems of compliance arise, nelfinavir can be an alternative to indinavir. (11) In patients at an advanced stage of HIV disease who comply well with their treatment, saquinavir can also be an alternative to indinavir.

Clinical Trials as Topic↗
PubMed1979

Rapid sequence determination of late simian virus 40 16S mRNA leader by using inhibitors of reverse transcriptase.

A method for the determination of the primary structure of spliced mRNA junction and leader sequences is described. By analogy to the DNA sequencing procedure of Sanger et al. [Sanger, F., Nicklen, S. & Coulson, A. R. (1977) Proc. Natl. Acad. Sci USA 74, 5463--5467], we use 2",3'-dideoxynucleoside triphosphates as chain-terminating inhibitors of the reverse transcriptase (RNA-dependent DNA polymerase) reaction. By using specific DNA restriction fragments as primers in combination with this technique, we have determined the sequence of the spliced junction between the body and the leader sequence of the 16S late mRNA of simian virus 40. The method described should be of general utility in mapping spliced mRNA regions for which the corresponding protein sequence (if any) is unknown.

Base Sequence↗
PubMed2004

Distinct effects of protease and reverse transcriptase inhibition in an immunological model of HIV-1 infection with impulsive drug effects.

We present an immunological model that considers the dynamics of CD4+ T cells interacting with free virions, reverse transcriptase inhibiting drugs and protease inhibiting drugs. We divide the T cells into multiple classes and use impulsive differential equations to describe the drug activity. As expected, we find that insufficient dosing of either drug corresponds to high viral load and a large population of infectious T cells. The model further predicts that, in the absence of physiological limits on tolerable drug concentrations, sufficiently frequent dosing with the reverse transcriptase inhibitor alone could theoretically maintain the CD4+ T cell count arbitrarily close to the T cell count in the uninfected immune system. However, for frequent dosing of the protease inhibitor alone, the limiting T cell populations may not be enough to maintain the immune system. Furthermore, frequent dosing of both drugs has the same net effect on the T cell population as frequent dosing of the reverse transcriptase inhibitor only. Thus, the two drug classes can have fundamentally different effects on the long-term dynamics and the reverse transcriptase inhibitor, in particular, plays a crucial role in maintaining the immune system. We also provide estimates for the dosing intervals of each drug that could theoretically sustain the T cell population at a desired level.

CD4 Lymphocyte Count↗