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PubMed2004

Persistence of primary drug resistance among recently HIV-1 infected adults.

OBJECTIVES: Primary, or transmitted, drug resistance is common among treatment naive patients recently infected with HIV-1, and impairs response to anti-retroviral therapy. We previously observed that patients with secondary resistance (developed in response to anti-retroviral treatment) who chose to stop an anti-retroviral regimen experience rapid overgrowth of drug resistant viruses by wild-type virus of higher pol replication capacity. We sought to determine if primary drug resistance would be lost at a rapid rate, and viral pol replication capacity would increase, in the absence of treatment. METHODS: We tracked drug resistance phenotype, genotype, viral pol replication capacity (single cycle recombinant assay incorporating a segment of the patient pol gene [pol RC]), plasma HIV-1 RNA, and CD4 T cell counts in the absence of treatment among patients in early HIV-1 infection. RESULTS: Six of 22 patients had evidence of primary drug resistance to at least one class of drug; three resistant to protease inhibitors, three resistant to non-nucleoside reverse transcriptase inhibitors, and four resistant to nucleoside reverse transcriptase inhibitors. All six patients maintained evidence of drug resistance for the period of observation. Among patients with baseline primary drug resistance pol RC did not increase over time. CONCLUSION: The selection environment of early infection is determined by immune pressure, and stochastic events, not viral pol replication capacity. In contrast to secondary resistant infections that are rapidly overgrown when therapy is stopped, primary drug resistance persists over time. Surveillance and clinical detection of primary resistance is feasible in the first year of infection.

Adult↗

PubMed2002

New anti-HIV agents and targets.

Virtually all the compounds that are currently used or are subject of advanced clinical trials for the treatment of HIV infections, belong to one of the following classes: (i) nucleoside reverse transcriptase inhibitors (NRTIs): i.e., zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine and nucleotide reverse transcriptase inhibitors (NtRTIs) (i.e., tenofovir disoproxil fumarate); (ii) non-nucleoside reverse transcriptase inhibitors (NNRTIs): i.e., nevirapine, delavirdine, efavirenz, emivirine; and (iii) protease inhibitors (PIs): i.e., saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and lopinavir. In addition to the reverse transcriptase and protease reaction, various other events in the HIV replicative cycle can be considered as potential targets for chemotherapeutic intervention: (i) viral adsorption, through binding to the viral envelope glycoprotein gp120 (polysulfates, polysulfonates, polycarboxylates, polyoxometalates, polynucleotides, and negatively charged albumins); (ii) viral entry, through blockade of the viral coreceptors CXCR4 (i.e., bicyclam (AMD3100) derivatives) and CCR5 (i.e., TAK-779 derivatives); (iii) virus-cell fusion, through binding to the viral envelope glycoprotein gp41 (T-20, T-1249); (iv) viral assembly and disassembly, through NCp7 zinc finger-targeted agents [2,2'-dithiobisbenzamides (DIBAs), azadicarbonamide (ADA)]; (v) proviral DNA integration, through integrase inhibitors such as 4-aryl-2,4-dioxobutanoic acid derivatives; (vi) viral mRNA transcription, through inhibitors of the transcription (transactivation) process (flavopiridol, fluoroquinolones). Also, various new NRTIs, NNRTIs, and PIs have been developed that possess, respectively: (i) improved metabolic characteristics (i.e., phosphoramidate and cyclosaligenyl pronucleotides by-passing the first phosphorylation step of the NRTIs), (ii) increased activity ["second" or "third" generation NNRTIs ( i.e., TMC-125, DPC-083)] against those HIV strains that are resistant to the "first" generation NNRTIs, or (iii), as in the case of PIs, a different, modified peptidic (i.e., azapeptidic (atazanavir)) or non-peptidic scaffold (i.e., cyclic urea (mozenavir), 4-hydroxy-2-pyrone (tipranavir)). Non-peptidic PIs may be expected to inhibit HIV mutant strains that have become resistant to peptidomimetic PIs.

Amino Acid Sequence↗

PubMed2003

Impact of different HIV resistance interpretation by distinct systems on clinical utility of resistance testing.

PURPOSE OF REVIEW: Genotypic assays are widely used tools for determining HIV-1 drug resistance and for guiding treatment. Several systems have been developed to interpret the complex influence of amino acid substitutions in HIV reverse transcriptase or protease on the phenotypic susceptibility or clinical response to the 18 available antiretroviral agents. In this review we analyse both studies comparing interpretations by different systems and studies showing correlation of interpretations with clinical outcome, in order to identify discordance and how this may affect prediction of subsequent therapy outcomes. RECENT FINDINGS: During the last year, several studies analysing interpretation systems, individually or comparatively, have shown substantial variability of the predicted drug activities and therapeutic outcomes. Discrepant interpretation was detected mostly for nucleoside reverse transcriptase inhibitors and rarely for non-nucleoside reverse transcriptase inhibitors. Better correlation with treatment outcome was found with most recently updated systems, while a weaker prediction was found with systems interpreting activity of nucleoside reverse transcriptase inhibitors solely on the basis of phenotypic susceptibility. Virological, patient-related and treatment-related factors can all affect the results of systems' clinical validations. Refinement of resistance interpretation is possible by introducing rules derived from genotype-outcomes correlation or, at least for protease inhibitors, genotype-phenotype correlation. SUMMARY: Papers showing clinical validation of the available interpretation systems are presented with a critical view to help the readers' evaluation of their possible use. There is a need for developing a consensus towards common interpretations. Large clinical and virological databases with quality data will be useful for future improvements.

Acquired Immunodeficiency Syndrome↗

PubMed2004

Increasing number of anti-HIV drugs but no definite cure. Review of anti-HIV drugs.

AIM: This review surveys the different classes of drugs. METHOD: We searched electronic databases and selected articles about pharmacotherapy with anti-retroviral drugs. RESULTS: We discuss anti-retroviral drugs: the nucleotide reverse transcriptase inhibitors (NRTIs), the non-nucleoside reverse transcriptase inhibitors (NNRTIs), and the protease inhibitors (PIs). The combination of a PI and two NRTIs is very effective and lowers the viral load to below the limit of detection. However, it is not yet possible to eliminate the virus completely. Recently, the first member of a brand new class of drugs has become available, the fusion inhibitor enfuvirtide. We also discuss the problems associated with combining anti-retroviral drugs, such as compliance, resistance and serious side effects. DISCUSSION: It is important to investigate new combinations with new classes of drugs, like the fusion inhibitors, for better effectiveness and fewer side effects.

Anti-HIV Agents↗

PubMed2005

Eosinophilic folliculitis: before and after the introduction of antiretroviral therapy.

OBJECTIVE: To characterize the relationship of new eosinophilic folliculitis (EF) cases between June 30, 1994, and January 5, 2000, and antiretroviral therapy (ART) status and immune reconstitution. DESIGN: Retrospective cohort analysis. SETTING: Dermatology clinics at a county hospital. SUBJECTS: Fifty-seven consecutive subjects with biopsy-proved EF from the pathology database. Subject groups were as follows: naïve to ART, receiving ART without protease inhibitors/nonnucleoside reverse transcriptase inhibitors, and receiving ART containing protease inhibitors/nonnucleoside reverse transcriptase inhibitors. MAIN OUTCOME MEASURES: Onset of EF, CD4 cell count and nadir at EF onset, and time of ART initiation. RESULTS: Among the 3 groups previously described, mean CD4 cell counts (86.26/microL vs 113.82/microL vs 145.65/microL, respectively [Kruskal-Wallis rank sum test, P = .15]) and nadir (68.43/microL vs 66.18/microL vs 64.17/microL, respectively [Kruskal-Wallis rank sum test, P = .41]) at EF diagnosis were not statistically different. Fifty-two subjects (91%), regardless of treatment group, had a nadir below 200/microL. Of the subjects undergoing ART, 28 (82%) developed EF within 6 months of initiating ART; their average CD4 cell count increase was 108/microL. Of the 23 subjects receiving protease inhibitor/nonnucleoside reverse transcriptase inhibitor-containing ART regimens, 17 (74%) were diagnosed as having EF within 3 months, with 4 additional subjects diagnosed as having EF within 6 months (a total of 21 [91%] of the 23 subjects). This is not significantly different from the 7 (64%) of 11 subjects diagnosed as having EF at 3 and 6 months of starting ART without protease inhibitors/nonnucleoside reverse transcriptase inhibitors (P = .07) (odds ratio, 0.18; 95% confidence interval, 0.01-1.54). CONCLUSIONS: Our study shows an association between low nadir (66.28/microL) and low CD4 cell count (115.54/microL) and the development of EF, regardless of subjects' ART status. However, most subjects receiving ART were diagnosed as having EF within 3 to 6 months of ART initiation, regardless of the regimen.

Acquired Immunodeficiency Syndrome↗

PubMed2000

In vitro evaluation of the effect of temporary removal of HIV drug pressure.

We tried to establish whether MT-4 cells that were infected with HIV-1(HTLV-III(B)) at a high multiplicity of infection (m.o.i.=1), and subsequently treated with high concentrations of anti-HIV drugs for several days, would be able to resume virus production after the antivirals are washed away. The HIV inhibitors studied were the nucleoside reverse transcriptase inhibitors (NRTIs) zidovudine and lamivudine, the non-nucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine, delavirdine and loviride, the acyclic nucleoside phosphonate RT inhibitor (R)-9-(2-phosphonylmethoxypropyl)adenine (tenofovir) and the protease inhibitors (PIs) saquinavir, indinavir and ritonavir. The compounds, at 50 and 500 times their 50% inhibitory concentration (IC(50), determined at a m.o.i.=0.01), were added immediately after virus adsorption and removed after an incubation period of 0 (wash control), 24, 48 or 72 h. Virus breakthrough was monitored by microscopical examination of cytopathicity, viral infectivity (yield) and p24 levels in the supernatant. The presence of HIV-1(HTLV-III(B)) proviral DNA was determined after a 72-h incubation period. None of the antiviral drugs studied was able to prevent resumption of viral growth after removal of the compound. Tenofovir, lamivudine and the NNRTIs nevirapine, delavirdine and loviride, at 500 times their respective IC(50), were able to delay viral breakthrough for approximately 2-3 days. The NRTI zidovudine and the PIs saquinavir, indinavir and ritonavir, under the same conditions, were not able to delay viral breakthrough at all. Virus recovered upon treatment proved as sensitive to the anti-HIV drugs as wild-type virus. Our results suggest that viral replication at the cellular level was not completely inhibited by drug monotherapy. Consequently, virus rebounded when drug therapy stopped. In conclusion, our findings suggest that drug holidays would result in viral breakthrough, even after virus replication has been previously suppressed by adequate drug levels.

Anti-HIV Agents↗

PubMed2001

Delavirdine: clinical pharmacokinetics and drug interactions.

Delavirdine, a non-nucleoside reverse transcriptase inhibitor (NNRTI), is a potent and specific inhibitor of HIV-1 reverse transcriptase. The approved therapeutic regimen for delavirdine is 400mg 3 times daily in combination with appropriate antiretroviral agents; however, a dose of 600mg twice daily appears to provide similar systemic exposure. The steady-state pharmacokinetics of delavirdine are not appreciably affected by food. Delavirdine undergoes extensive metabolism by cytochrome P450 (CYP) with little urinary excretion of unchanged drug. Metabolic drug interactions between delavirdine and nucleoside reverse transcriptase inhibitors are unlikely as their metabolic pathways differ; delavirdine has no effect on the pharmacokinetics of zidovudine. Concomitant use of CYP inducers, such as rifampicin (rifampin), rifabutin, phenytoin, phenobarbital or carbamazepine, should be avoided since delavirdine plasma concentrations are significantly lowered. Reduction in gastric acidity (pH > 3) decreases the extent of delavirdine absorption, so administration of antacids and the buffered formulations of didanosine should be separated from that of delavirdine by at least 1 hour. Delavirdine, unlike other currently available NNRTI agents, is an inhibitor rather than an inducer of CYP isozymes. Consequently, the drug interaction profile and rationale for combining delavirdine with other antiretroviral agents is unique among the current NNRTI agents. Delavirdine inhibits the CYP3A4-mediated metabolism of HIV protease inhibitors and thereby increases systemic exposure to protease inhibitors. The ability of delavirdine to enhance the pharmacokinetic profiles of protease inhibitors may permit the use of simplified administration regimens. Combining delavirdine and indinavir removes the food restrictions during indinavir administration. Furthermore, the superior virological response observed in antiretroviral regimens containing delavirdine and protease inhibitors has been attributed to the favourable pharmacokinetic interactions and the introduction of a new drug class in NNRTI-naïve therapy-experienced patients. Pharmacokinetic drug interactions are an important consideration in selecting an HIV treatment regimen, due to the multiplicity of drugs that are coadministered and the varying direction and magnitude of interaction that can occur. Considerations for utilising delavirdine in a treatment regimen are different than for other NNRTI agents due to the unique drug interaction profile of delavirdine.

Delavirdine↗

PubMed1999

Resistance to non-nucleoside inhibitors of HIV-1 reverse transcriptase.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a structurally diverse group of compounds which function as inhibitors of HIV-1 replication in vitro and in vivo. Viral resistance is mediated through alterations in the amino acids which form the allosteric site on the HIV-1 reverse transcriptase to which NNRTIs bind. The rapid emergence of resistant viruses has limited the utility of NNRTI monotherapy; however, recent clinical studies have shown that potent NNRTIs can contribute to profound suppression of HIV replication when used in combination therapy. An understanding of the development of resistance to NNRTIs is critical to the effective use of this class of antiretroviral agents. Copyright 1999 Harcourt Publishers Ltd.

Journal Article↗

PubMed2005

No benefit of a structured treatment interruption based on genotypic resistance in heavily pretreated HIV-infected patients.

OBJECTIVE: To evaluate the potential benefits of a tailored antiretroviral treatment interruption with duration based on the observed reversion of resistance mutations. METHODS: In this open single-arm pilot study, 23 patients with multiple treatment failure interrupted therapy and underwent longitudinal genotypic resistance testing. Salvage gigatherapy was started when resistance mutations to at least two antiretroviral drug classes reverted. The primary endpoint was a fall in viral load by > 1 log10 copies/ml after 12 weeks of salvage therapy. RESULTS: Baseline median viral load was 5.14 log copies/ml and CD4 cell count 43 x 10 cells/l. Genotypic resistance testing showed a median of six, two and nine resistance mutations to nucleoside analogue reverse transcriptase inhibitors, non-nucleoside analogue reverse transcriptase inhibitors and protease inhibitors, respectively; viral strains were susceptible to no more than one drug in 17/23 patients. The median duration of treatment interruption was 24 weeks (range, 12-37), leading to median changes from baseline of + 0.54 log10 copies/ml and -30 x 10(6) cells/l. At the end of treatment interruption, plasma HIV was susceptible to at least three drugs in 16/23 patients. After 12 weeks of salvage multitherapy, only one patient had a decrease in viral load > 1 log copies/ml. All baseline resistance mutations recurred after treatment resumption. AIDS-defining events occurred in two-thirds of patients during the study period. CONCLUSION: In HIV-infected patients with multiple failures and no therapeutic options at baseline, significant reversion of resistance mutations after prolonged treatment interruption failed to restore antiviral efficacy of a salvage regimen and was clinically deleterious.

Anti-HIV Agents↗

PubMed2006

Fosamprenavir : clinical pharmacokinetics and drug interactions of the amprenavir prodrug.

Fosamprenavir is one of the most recently approved HIV-1 protease inhibitors (PIs) and offers reductions in pill number and pill size, and omits the need for food and fluid requirements associated with the earlier-approved HIV-1 PIs. Three fosamprenavir dosage regimens are approved by the US FDA for the treatment of HIV-1 PI-naive patients, including fosamprenavir 1,400 mg twice daily, fosamprenavir 1,400 mg once daily plus ritonavir 200mg once daily, and fosamprenavir 700 mg twice daily plus ritonavir 100mg twice daily. Coadministration of fosamprenavir with ritonavir significantly increases plasma amprenavir exposure. The fosamprenavir 700 mg twice daily plus ritonavir 100mg twice daily regimen maintains the highest plasma amprenavir concentrations throughout the dosing interval; this is the only approved regimen for the treatment of HIV-1 PI-experienced patients and is the only regimen approved in the European Union. Fosamprenavir is the phosphate ester prodrug of the HIV-1 PI amprenavir, and is rapidly and extensively converted to amprenavir after oral administration. Plasma amprenavir concentrations are quantifiable within 15 minutes of dosing and peak at 1.5-2 hours after fosamprenavir dosing. Food does not affect the absorption of amprenavir following administration of the fosamprenavir tablet formulation; therefore, fosamprenavir tablets may be administered without regard to food intake. Amprenavir has a large volume of distribution, is 90% bound to plasma proteins and is a substrate of P-glycoprotein. With <1% of a dose excreted in urine, the renal route is not an important elimination pathway, while the principal route of amprenavir elimination is hepatic metabolism by cytochrome P450 (CYP) 3A4. Amprenavir is also an inhibitor and inducer of CYP3A4. Furthermore, fosamprenavir is commonly administered in combination with low-dose ritonavir, which is also extensively metabolised by CYP3A4, and is a more potent CYP3A4 inhibitor than amprenavir. This potent CYP3A4 inhibition contraindicates the coadministration of certain CYP3A4 substrates and requires others to be co-administered with caution. However, fosamprenavir can be co-administered with many other antiretroviral agents, including drugs of the nucleoside/nucleotide reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor and HIV entry inhibitor classes. Coadministration with other HIV-1 PIs continues to be studied.The extensive fosamprenavir and amprenavir clinical drug interaction information provides guidance on how to co-administer fosamprenavir and fosamprenavir plus ritonavir with many other commonly co-prescribed medications, such as gastric acid suppressants, HMG-CoA reductase inhibitors, antibacterials and antifungal agents.

Adult↗

PubMedDate not supplied

Study of antiretroviral mutants in HIV patients with treatment failures and the effect of risk factors in the virological failures.

INTRODUCTION: Information about HIV phenotypes of resistant to available ART and the influence of different risk factors on virological failures (VF) in Costa Rican HIV positive patients prior or during HAART is unknown. MATERIALS AND METHODS: Eighty nine samples, 72 VF and 17 basal (before treatment) were analyzed by examining resistant mutants in reverse transcriptase (RT) and protease (PT) regions using Trugene or LIPA genotyping kits. Sixty eight control patients were selected and relevant information was collected in a questionnaire. RESULTS: Poor adherence, presence of resistant mutations and number of treatment's changes were the only significant factors found (p = 0.006, 0.04 and 0.01 respectively). From 66 sequenced samples, 78%, 50% and 50% showed resistance to NRTI (nucleoside reverse transcriptase inhibitors), NNRT (non-nucleoside reverse transcriptase inhibitors) and PI (protease inhibitors), respectively. The most frequent mutations were M41L, M184V, and T215FY in RT and L62PI, L10FIRV and M36I in PT. DISCUSSION: The most important factor related to treatment response in this study was adherence to treatment. Mutations in RT were related to the treatment failure while the ones found in PT were secondary mutations which have been previously described to influence the selection of primary resistance mutations in these regions. The study reveals the urgency to detect resistant mutations in VF to be considered by physicians for selection of treatment schedule, to analyze basal HIV patients for monitoring of the spread of resistant mutations and the importance to reinforce the adherence in the patients for overall treatment outcome.

Adult↗

PubMed2002

[Established and new drugs. Antiretroviral therapy 2002].

The nucleosidal reverse transcriptase inhibitors (NRTI), the protease inhibitors (PI) and the non-nucleosidal reverse transcriptase inhibitors remain the pillars of antiretroviral therapy (ART). In the spring of 2002, they were joined by a representative of a further class of substances, the nucleotidal reverse transcriptase inhibitors (NTRTI). The use of PI, but also of other substances, is associated with undesired effects, in particular on lipid and glucose metabolism. The aim of treatment is to achieve maximum reduction in the amount of virus in the blood. The question as to the timing of treatment--early or late--continues to arouse controversial discussion.

Acquired Immunodeficiency Syndrome↗

PubMed2004

Electronic transduction of HIV-1 drug resistance in AIDS patients.

A drug composition consisting of nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) is commonly used in AIDS therapy. A major difficulty encountered with the therapeutic composite involves the emergence of drug-resistant viruses, especially to the PIs, regarded as the most effective drugs in the composition. We present a novel bioelectronic means to detect the appearance of mutated HIV-1 exhibiting drug resistance to the PI saquinavir. The method is based on the translation of viral RNA, the association of cleaved or uncleaved Gag polyproteins at an electrode surface functionalized with the respective antibodies, and the bioelectronic detection of the Gag polyproteins associated with the surface. The bioelectronic process includes the association of anti-MA or anti-CA antibodies, the secondary binding of an antibody-horseradish peroxidase (HRP) conjugate, and the biocatalyzed precipitation of an insoluble product on the electronic transducers. Faradaic impedance measurements and quartz crystal microbalance analyses are employed to follow the autoprocessing of the Gag polyproteins. The method was applied to determine drug resistance in infected cultured cells and also in blood samples of consenting AIDS patients. The method described here is also applicable to the determination of drug effectiveness in AIDS patients and to screening of the efficiency of newly developed drugs.

Anti-HIV Agents↗

PubMed2004

[New therapeutic strategies in HIV infection-immune reconstitution and virus suppression].

BACKGROUND: In the last years, highly active antiretroviral therapy has decreased AIDS-associated mortality of patients dramatically. Due to this prolonged lifetime, the emergence of resistance against antiretroviral therapy has increased. Additionally, cross-resistance within the classes of nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), and protease inhibitors (PI) complicates HIV therapy. Development of new classes of therapeutic agents can help avoiding cross-resistance. Fuzeon, the first agent in the new class of fusion inhibitors, should be combined with as many effective antiretroviral agents as possible. CASE REPORT: The course of a 106-week therapy in a patient infected with a multiresistant virus is described. CONCLUSION: Fusion inhibitor Fuzeon represents a new option for patients having multiple resistance against HAART.

Acquired Immunodeficiency Syndrome↗

PubMed2005

HIV antiretroviral therapy in resource-limited settings: experiences from Haiti.

An unprecedented international effort to expand high activity antiretroviral therapy (HAART) to resource-poor nations has been launched. The World Health Organization (WHO) has created antiretroviral (ARV) treatment guidelines adapted to resource-poor settings. The first-line regimen is two nucleoside reverse transcriptase inhibitors (NsRTIs) and one nonnucleoside reverse transcriptase inhibitor (NNRTI). Therapy is initiated by clinical staging and CD4 T-cell counts when available. Adherence is the responsibility of health care workers. The use of ARV therapy in resource-poor settings faces several challenges, including the poverty of patients, political and social upheavals and violence, social stigma associated with HIV/AIDS, unreliable pharmacy systems, tuberculosis, and lack of trained health care workers. Using our experience in Haiti, we describe how we have addressed these challenges with the goal of increasing access to care for the poor with HIV/AIDS.

Adolescent↗

PubMed2005

Pharmacokinetics of antiretroviral therapy in HIV-1-infected children.

The initiation of antiretroviral therapy has resulted in an impressive reduction in the rate of disease progression in AIDS and HIV-1-related deaths in children; however, there are still several major challenges to be faced in order to improve therapy. A major topic that needs to be dealt with is the establishment of the optimal dosage of antiretroviral therapy for children. This review presents the currently available peer-reviewed data on the pharmacokinetics of nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs) and fusion inhibitors (FIs) in children. In addition, the data are discussed in relation to the currently available European and US guidelines and the US FDA-approved drug labels. High intra- and interpatient variability in pharmacokinetics are often observed for all antiretroviral drugs. The number of children included in the pharmacokinetic studies is often small and children are often divided into divergent groups using different dosage levels and/or drug formulations. For a substantial number of antiretroviral drugs, dosage recommendations, especially for young children, are still absent in the European and US guidelines. The recommended drug dosages in the guidelines are often different from that in the officially approved drug product label. In addition, the recommended drug dosages may deviate between the European and US guidelines. Thus, while practioners aim to meet the recommendations in the official guidelines, patients may receive highly divergent dosages of medication. The high intra- and interpatient variability in pharmacokinetics of antiretroviral drugs in children hampers the application of fixed dosages of antiretroviral drugs. For PIs and NNRTIs, plasma drug levels correlate with viral suppression and drug toxicity. NRTIs are prodrugs that are intracellularly converted to their active triphosphate form and, therefore, plasma NRTI levels correlate poorly with viral suppression. Therapeutic drug monitoring of PIs and NNRTIs should be considered to optimise HIV therapy in children.

Anti-HIV Agents↗

PubMed2005

Hepatotoxicity of antiretroviral drugs.

The use of highly active antiretroviral therapy (HAART) has significantly slowed the HIV disease progression. However, adverse effects are now a limiting cause of HAART benefit in a substantial proportion of patients. Particularly hepatotoxicity which is a common complication occurring during every HAART regimen. All antiretroviral (ARV) drugs classes, Nucleoside/Nucleotide reverse transcriptase inhibitors (NRTI), non-Nucleoside reverse transcriptase inhibitors (nNRTI) and Protease Inhibitors (PI) may cause hepatotoxicity but in different pathways. Many risk factors have been identified for developing antiretroviral-related hepatotoxicity, however severe hepatitis remains very uncommon in patients receiving HAART, also if the incidence of hepatotoxicity is rather high. That being the case, means that every new available antiretroviral drug strongly necessities studies which can evaluate its hepatotoxicity and drug-drug interactions, to define the potential risk factors and the outcome of any side effects. This report will review the risk factors, the epidemiology and the pathogenic mechanisms of hepatotoxicity caused in every antiretroviral drug.

Animals↗

PubMed2002

Strategies for third line therapy.

One area of anti-HIV therapy research that has been inadequately addressed is strategies around third line therapy regimens. As a result, there is only a modest amount of data to guide physicians and patients in making treatment decisions in this setting. Third line therapy is usually defined as a regiment for an individual who has developed resistance to at least one drug in all three classes of anti-HIV therapies [nucleoside analogue reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors] or has failed two treatment regimens. In general, the nucleotide analogue drug, tenofovir (Viread) can be considered an NRTI as it shares some of the same resistance patterns. However, just because someone has developed resistance to some drug in all three classes of anti-HIV drugs does not mean that they have no further treatment options. This article will review some of the options available to people exploring third line regimen choices.

Anti-HIV Agents↗