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PubMed2001

Efavirenz: a pharmacoeconomic review of its use in HIV infection.

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used in the treatment of patients with HIV infection. Both US and British treatment guidelines for HIV infection recommend NNRTI- or protease inhibitor-based combinations [i.e. with nucleoside reverse transcriptase inhibitors (NRTIs)] as first-line treatmentoptions in the management of HIV disease. Results of a pivotal randomised study (DMP 266-006) comparing efavirenz- versus indinavir-based triple combination therapy in patients with HIV infection (the majority of whom were antiretroviral therapy-naive) showed the efavirenz-based regimen was better tolerated and had greater success in achieving reductions in viral load below the limit of detection. These and other clinical data were incorporated into economic models in 2 analyses, one conducted in the US and the other in Canada. The US analysis examined long term clinical and economic outcomes predicted on the basis of response (viral load and CD4+ cell counts), tolerability and willingness to adhere to therapy. The efavirenz-based regimen was the dominant treatment strategy as it was predicted to improve survival and reduce direct medical costs in the US healthcare system. Compared with the indinavir-containing regimen, survival was increased by 11% (absolute difference) and cumulative costs were reduced by $US10,326 per patient (1998 discounted costs) at 5 years after starting treatment with efavirenz-based therapy. The Canadian analysis was conducted from the perspective of the Ontario healthcare system. This study did not consider differences in clinical efficacy between treatment groups, costs of study medication or outcomes beyond 1 year--all factors that would have favoured the efavirenz-based regimen. Of the 2 treatment options, the efavirenz-based regimen was associated with 7.4% lower average annual medical care costs, primarily because of greater costs associated with adverse clinical events with the indinavir-based regimen. In conclusion, current treatment guidelines for HIV infection recognise efavirenz-based combination regimens as a first-line treatment option. A pivotal comparative clinical trial (DMP 266-006) showed a significantly greater virological response to efavirenz- than indinavir-based triple combination therapy, and the efavirenz-based regimen was better tolerated. These clinical data are supported by pharmacoeconomic analyses conducted in the US and Canada, both of which showed lower medical care costs with the efavirenz-based regimen. The US analysis also predicted long term health benefits, such as improved survival, with efavirenz- versus indinavir-based triple combination therapy. These results must be weighed against the inherent difficulties of predicting long term treatment failure rates from short term data, and the limited number of pharmacoeconomic analyses conducted with efavirenz to date.

Alkynes↗
PubMed2001

[Current antiretroviral therapy].

INTRODUCTION: Advances in HIV/AIDS therapy have been rapid and profound. CURRENT KNOWLEDGE AND KEY POINTS: In developed countries the epidemic infection has stabilized and there are dramatic decreases in morbidity and mortality resulting from the use of intensive but expensive therapies. HIV patients who have detectable viral loads and/or evidence of immunologic dysfunction should be treated with a potent combination antiretroviral regimen. Currently, this consists of two nucleoside reverse transcriptase inhibitors with at least one protease inhibitor, or a non-nucleoside reverse transcriptase inhibitor, or another combination with adequate potency. Current therapies do have limitations, including side effects, cross-resistance, adherence challenges, and drug interactions. FUTURE PROSPECTS AND PROJECTS: Drug resistance is a major factor contributing to the failure of antiretroviral therapy: the ability to predict clinical response to therapy on the basis of genotype and/or phenotype depends on knowledge of appropriate data for defining drug resistance. Moreover, careful selection and monitoring of combination drug therapy along with individualized rather than standard dosage regimens may minimize the pharmacological problems and help ensure optimum antiviral activity. Further developments include new drugs, vaccine, cytokine-, and gene therapy-based treatment strategies.

Anti-HIV Agents↗
PubMed2002

A search for optimal criteria in initiating antiretroviral therapy in chronic human immunodeficiency virus infection focusing on CD4 count and HIV RNA.

The study objective was to identify optimal starting criteria regarding levels of CD4 cells and human immunodeficiency virus (HIV) RNA at initiation of highly active antiretroviral therapy (HAART) in chronically HIV-infected people. All 162 treatment-naive patients in the centre who were treated for at least 180 d with 2 nucleoside reverse transcriptase inhibitors plus at least 1 protease inhibitor or 1 non-nucleoside reverse transcriptase inhibitor were included. The patients were stratified according to their levels of CD4 cells and HIV RNA at initiation of therapy. Baseline CD4 groups were: group 1: CD4 < 0.1 x 10(9)/l; group 2: CD4 > or = 0.1 and < 0.2 x 10(9)/l; group 3: CD4 > or = 0.2 and < 0.35 x 10(9)/l; and group 4: CD4 > or = 0.35 x 10(9)/l. Two patients died and 38 developed an HIV-related disease (Centers for Disease Control category B or C) during the study. The prevalence of HIV-related disease before HAART was significantly increased in groups 1 and 2 compared with groups 3 and 4. The level of HIV RNA was not associated with HIV-related disease either before or after treatment initiation. Subjects in group 1 had an increased risk of HIV-related disease after treatment initiation both in univariate Cox analysis and after adjustment for HIV RNA, gender, mode of transmission and age, compared with group 2 [adjusted risk ratio with 95% confidence interval: 3.76 (1.48-9.61)], group 3 [5.90 (2.07-16.95)] and group 4 [5.05 (1.96-12.90)]. The association between CD4 count and morbidity appeared to be particularly strong for older subjects. In conclusion, this study suggests that in chronically HIV-infected individuals, in most cases HAART can be withheld until the CD4 cell count falls towards 0.2 x 10(9)/l.

Adolescent↗
PubMed2003

Antiretroviral treatment of human immunodeficiency virus infection: Swedish recommendations.

The Swedish guidelines (SwG) for treatment of human immunodeficiency virus (HIV) infection have several important roles. A major task involves the promotion of a uniformly high standard of care in all HIV treatment clinics in Sweden and the identification of strengths, weaknesses and relevance of recent research findings. CD4+ T-cell counts < 200 cells/microl are clear indications for the initiation of treatment, whereas high viral loads serve as an indication for increased vigilance rather than a criterion for therapy. It is recommended that the first regimen consists of 2 nucleoside reverse transcriptase inhibitors in combination with 1 protease inhibitor or 1 non-nucleoside reverse transcriptase inhibitor. The definition of treatment failure is rigorous. Treatment change should be considered if the viral load has not fallen by at least 1.5 log in 4 weeks or is undetectable within 3-4 months. Resistance testing is endorsed at primary infection, in the event of treatment failure and in pregnant women. Interaction with experts in HIV resistance testing is emphasized. Therapeutic drug monitoring is advocated. Patients with treatment failure should be handled individually and the decision on therapeutic strategy should be based on treatment history, resistance testing and other clinical facts. The SwG do not give recommendations for some important issues such as prolonged drug holidays and preferences in initial treatment regimens. More scientific data are likely to be available soon and the SwG will be refined accordingly. The present guidelines are translated from Swedish; they are published on the Medical Products Agency (MPA) and Swedish Reference Group for Antiviral Therapy (RAV) websites (www.mpa.se and www.rav.nu.se), including 7 separate papers based on a thorough literature search. A complete reference list is available on request from the MPA.

Anti-HIV Agents↗
PubMed2003

Therapeutic drug monitoring: an aid to optimising response to antiretroviral drugs?

Therapeutic drug monitoring (TDM) has been proposed as a means to optimise response to highly active antiretroviral therapy (HAART) in HIV infection. Protease inhibitors (PIs) and the non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine satisfy many criteria for TDM. Nucleoside reverse transcriptase inhibitors (NRTIs) are not suitable candidates for TDM, since no clear plasma concentration-effect relationships have been established for these drugs. Several important limitations to the application of TDM for antiretroviral drugs should be recognised, including uncertainty about the best pharmacokinetic predictor of response and insufficient validation of target concentrations for individual PIs and NNRTIs. Data from two clinical trials support the use of TDM in treatment-naive HIV-infected patients who start with an indinavir- or nelfinavir-based regimen. TDM either prevented virological failures (presumably by preventing the development of resistance) or treatment discontinuations due to concentration-related toxicity. Application of routine TDM in other patient groups (treatment-experienced patients) or for drugs other than indinavir or nelfinavir (NNRTIs, other PIs, combination of PIs) is speculative at this moment. However, TDM can be used in selected patient groups (children, pregnant women, patients with renal or hepatic dysfunction) to confirm adequate drug concentrations, and for management of drug-drug interactions.TDM in treatment-experienced patients may be optimally used in conjunction with resistance testing. The integration of pharmacological and virological measures in the inhibitory quotient (IQ) needs to be standardised and elaborated further. TDM should be accompanied by careful assessment of adherence and can itself help identify non-adherence, although a drug concentration only reflects the last few drug doses taken by a patient. Additional clinical trials are needed before routine TDM can be adopted as standard of care in the treatment of HIV infection.

Anti-HIV Agents↗
PubMed2005

Improved obstetric outcomes and few maternal toxicities are associated with antiretroviral therapy, including highly active antiretroviral therapy during pregnancy.

Data from 2543 HIV-infected women were analyzed to correlate antiretroviral therapy (ART) used during pregnancy with maternal and pregnancy outcomes. ART was analyzed according to class of agents used and according to monotherapy versus combination ART containing neither protease inhibitors (PIs) nor nonnucleoside reverse transcriptase inhibitors versus highly active ART. Timing of ART was classified according to early (recorded at or before 25-week gestation study visit) and late (recorded at 32-week gestation or delivery visit) use. Maternal outcomes assessed included hematologic, gastrointestinal, neurologic, renal, and dermatologic complications; gestational diabetes; lactic acidosis; and death. Adverse pregnancy outcomes assessed included hypertensive complications; pre-term labor or rupture of membranes; preterm delivery (PTD); low birth weight; and stillbirth. Logistic regression analyses controlling for multiple covariates revealed ART to be independently associated with few maternal complications: ART use was associated with anemia (odds ratio [OR] = 1.6, 95% confidence interval [CI]: 1.1-2.4), and late use of ART was associated with gestational diabetes (OR = 3.5, 95% CI: 1.2-10.1). Logistic regression analyses revealed an increase in PTD at <37 weeks for 10 women with late use of ART not containing zidovudine (ZDV; OR = 7.9, 95% CI: 1.4-44.6) and a decrease in adverse pregnancy outcomes as follows: late use of ART containing ZDV was associated with decreased risk for stillbirth and PTD at <37 weeks (OR = 0.06, 95% CI: 0.02-0.18; OR = 0.5, 95% CI: 0.3-0.8, respectively), and ART containing nucleoside reverse transcriptase inhibitors but not ZDV during early and late pregnancy was associated with decreased risk for PTD at <32 weeks (OR = 0.3, 95% CI: 0.2-0.7). Benefits of ART continue to outweigh observed risks.

Adult↗
PubMed1993

Comprehensive mutant enzyme and viral variant assessment of human immunodeficiency virus type 1 reverse transcriptase resistance to nonnucleoside inhibitors.

The nonnucleoside reverse transcriptase (RT) inhibitors comprise a class of structurally diverse compounds that are functionally related and specific for the human immunodeficiency virus type 1 RT. Viral variants resistant to these compounds arise readily in cell culture and in treated, infected human. Therefore, the eventual clinical usefulness of the nonnucleoside inhibitors will rely on a thorough understanding of the genetic and biochemical bases for resistance. A study was performed to assess the effects of substitutions at each RT amino acid residue that influences the enzyme's susceptibility to the various nonnucleoside compounds. Single substitutions were introduced into both purified enzyme and virus. The resulting patterns of resistance were markedly distinct for each of the tested inhibitors. For instance, a > 50-fold loss of enzyme susceptibility to BI-RG-587 was engendered by any of four individual substitutions, while the same level of relative resistance to the pyridinone derivatives was mediated only by substitution at residue 181. Similarly, substitution at residue 181. Similarly, substitution at residue 106 had a noted effect on virus resistance to BI-RG-587 but not to the pyridinones. The opposite effect was mediated by a substitution at residue 179. Such knowledge of nonucleoside inhibitor resistance profiles may help in understanding the basis for resistant virus selection during clinical studies of these compounds.

Acquired Immunodeficiency Syndrome↗
PubMed1999

[Evaluation of mutations that confer resistance to nucleoside analogs and protease inhibitors in HIV-1-infected patients]

Genotypes that confer drug resistance to reverse transcriptase inhibitors and protease inhibitors were evaluated in HIV-1 proviral DNA obtained from peripheral blood mononuclear cell samples. Fifty-three HIV-1-infected patients were studied, 19 of whom had not received antiretroviral treatment. In the other 34 patients, 9 had been treated with combinations of two reverse transcriptase inhibitors (AZT, ddI, d4T, 3TC) and 25 had been treated with triple antiretroviral therapy including a protease inhibitor (nelfinavir, indinavir, saquinavir, ritonavir). To determine the presence of mutations involved in the development of resistance to reverse transcriptase inhibitors a hybridization Microtiter assay was carried out. Mutations were detected in treated patients as well as in those without previous antiretroviral treatment, with the most frequent mutations being those that confer resistance to AZT, followed by those that develop cross-resistance to ddI/ddC and 3TC, which are the most commonly used drugs to date. No mutations were detected to any nucleoside analog in only 13 cases. To analyze the presence of mutations in the protease gene a dot-blot hybridization was carried out which included the mutations in codons 36, 82 and 90. Mutation 82 was detected in one case. Therefore, with the aim of determining the pattern of genotypic mutations in patients infected with HIV-1 and in order to make the best therapeutic choice, it would be recommended to consider carrying out genotypic resistance assays in clinical practice.

Journal Article↗
PubMedDate not supplied

Pharmacokinetics of antiretrovirals administered to HIV-infected children via gastrostomy tube.

BACKGROUND: Surgical placement of a gastrostomy tube (g-tube) directly into a patient's gastrointestinal system to support antiretroviral administration is occasionally used to increase adherence in HIV-infected children. Absorption and distribution characteristics of antiretrovirals after g-tube administration, however, are unknown. The goal of this pilot study was to describe the pharmacokinetic characteristics of protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) when administered to HIV-infected children via g-tube. METHOD: Nine HIV-infected children who were receiving a PI- or NNRTI-containing regimen via g-tube were enrolled. All antiretrovirals (excluding efavirenz) were administered under direct observation for the pharmacokinetic evaluation. Blood samples were collected at predose and at 1, 2, 4, 8, and 12 hours postdose. Antiretroviral concentrations were measured in plasma using high performance liquid chromatography with ultraviolet detection. RESULTS: Systemic exposure of PIs and NNRTIs in our 9 patients was similar to data from historical oral administration controls. Due to likely drug interactions, LPV exposure was decreased and one patient had low exposure of all antiretrovirals. When doses were increased, adequate exposure was attained. CONCLUSION: This pilot study suggests that administration of most PIs and NNRTIs by a g-tube to HIV-infected children provides systemic exposure comparable with that achieved after oral administration.

Area Under Curve↗
PubMed2003

An open-label, prospective, observational study of the incidence of coronary artery disease in patients with HIV infection receiving highly active antiretroviral therapy.

BACKGROUND: The association of highly active antiretroviral therapy (HAART) regimens that include protease inhibitors (PIs) with metabolic and somatic disorders has raised concerns about the possibility of an increased risk of coronary artery disease (CAD) in patients with HIV infection. OBJECTIVE: The aim of this study was to assess the incidence of CAD in previously untreated HIV infected outpatients who received reverse transcriptase inhibitors with or without PIs. METHODS: In this open-label, multicenter, prospective, observational trial, previously untreated and asymptomatic HIV-infected Italian patients were followed to assess the incidence of CAD (primary end point) according to the HAART regimen they received: 2 nucleoside analogue reverse transcriptase inhibitors (NRTIs) in combination with PIs (group PI+) or 1 non-nucleoside reverse transcriptase inhibitor in combination with 2 NRTIs (group PI-). Patients underwent clinical examination and laboratory testing every 4 months. RESULTS: A total of 1551 HIV-infected patients (994 [64%] men; median age, 35 years; range, 22-50 years) were followed for a median 36 months (range, 34-42 months). The cumulative annual incidence of CAD-related events was 9.8/1000 in group PI+ and 0.8/1000 in group PI- (P < 0.001). The annual incidence of myocardial infarction was 5.1/1000 in group PI+ and 0.4/1000 in group PI- (P < 0.001). Independent of patient age, the incidence of CAD was greater among men (P < 0.001) and patients who smoked >20 cigarettes per day (P < 0.001). Lipodystrophy and metabolic alterations were observed in 62% of patients in group PI+ and in 4% of patients in group PI- (P < 0.001). Of 23 patients receiving PIs who developed CAD, 17 (73.9%) had lipodystrophy and all 23 had hypertriglyceridemia and hypercholesterolemia. CONCLUSIONS: According to our findings, HAART that includes PIs may accelerate the onset of CAD-related events in young, male, heavy smokers who develop metabolic disorders and lipodystrophy during therapy. Patients with increased coronary risk should receive careful cardiac monitoring if treated with PIs.

Adult↗
PubMed1999

[Recent advances in the treatment of HIV infection/AIDS].

Following the introduction of highly active anti-retroviral therapy (HAART), which uses a combination of chemotherapeutic agents including protease inhibitors a striking reduction in overall HIV mortality and morbidity has been observed. In Japan ten anti-retroviral agents (five nucleoside reverse-transcriptase inhibitors, one non-nucleoside reverse-transcriptase inhibitor and four protease inhibitors) have been approved and tentative guidelines for the use of these agents were proposed by some groups of investigators. After the introduction of HAART, however, new problems such as the emergence of mutants that are resistant to any available drugs and the long-term adverse effects of some antivirals have appeared. Further investigation into the new therapeutic strategies including immunotherapy, as well as the efforts to develop antiretroviral agents that overcome resistance, are urgently needed.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

Simplification of antiretroviral treatment--how to sustain success, reduce toxicity and ensure adherence avoiding PI use.

Shortly after protease inhibitors (PI) began to be widely prescribed for the treatment of HIV infection in 1996, we learned that the virological efficacy of highly active antiretroviral therapy (HAART) was frequently associated with severe quality of life impairment. In fact, failure of PI-based regimens is often due to poor adherence resulting from high pill burden, complex dosing schedules, adverse events, or long-term toxicity. The metabolic and morphologic abnormalities associated with prolonged PI use are of particular concern: fat accumulation and abnormalities of lipid and glucose metabolism may increase the risk of cardiovascular disease, and body-shape changes (lipodystrophy) may also have a psychological impact or decrease patients' willingness to adhere to therapy. The efficacy of PI-sparing regimens in drug-naïve subjects, which typically consist of nucleoside reverse transcriptase inhibitors (NRTIs) with or without non-nucleoside reverse transcriptase inhibitors (NNRTIs), gives support to simplification strategies. In patients who have maintained durable virologic suppression on a PI-based regimen, the replacement of a PI by an NRTI, usually abacavir (ABC), or an NNRTI, has been shown to be associated with maintenance of virologic suppression, while leading to improvements in adherence and in some PI-related toxicities. The replacement of a PI by an NNRTI or ABC is usually followed by reductions in total cholesterol and triglycerides, though this is less true with efavirenz (EFV) than with nevirapine (NVP) or ABC. While there may be some improvement in fat accumulation after switching from a PI-based regimen, no improvement in lipoatrophy has been demonstrated after PI switches, possibly because this toxicity is due to NRTIs rather than PIs. However, NVP should be used with caution in patients co-infected patients with hepatitis B or C, and EFV may be poorly tolerated in individuals with psychiatric morbidity. Patients taking methadone may require dosage increases with switches to either NVP or EFV.

HIV Infections↗
PubMed2000

Quantitative detection of RT activity by PERT assay: feasibility and limits to a standardized screening assay for human vaccines.

The detection of adventitious retroviruses has always been critical for assessing the safety concerns associated with viral vaccines. Assays for the enzymatic activity of reverse transcriptase (RT) are used as general methods for the detection of both known and unknown retroviruses. Several studies using newly-developed ultrasensitive PCR-based RT assays reported RT activity in viral vaccines grown in chicken cells. Here, we have assessed the performances of such a PCR-based RT assay--PERT assay--for the quantitative detection of RT activity in vaccines. Sensitivity, linearity and reproducibility of the method were studied on purified RT and viral vaccines treated to release RT from potentially contaminant retroviruses. The level of RT activity detected in chicken cell-derived vaccines was higher for live attenuated vaccines compared to inactivated ones. Contrary to other studies, RT activity was found in some mammalian cell-derived vaccines. AZT-TP sensitivity of RT activities detected in these vaccines and discrimination between retroviral and RT-like activities was further investigated. Feasibility and limits of PERT assay as a broad-spectrum retroviruses detection method in vaccines are discussed.

Animals↗
PubMed2005

Model of inhibition of Thermus aquaticus polymerase and Moloney murine leukemia virus reverse transcriptase by tea polyphenols (+)-catechin and (-)-epigallocatechin-3-gallate.

Non-nutritional polyphenolic compounds such as (+)-catechin and (-)-epigallocatechin-3-gallate (EGCG) are known as anticancer chemopreventive agents and have been utilised for medical purposes in form of tea drinking. Documented anticancer properties of these compounds result from their antioxidant effects. However, also direct alteration of an enzyme performance has been reported and deserves more attention. In this paper, a direct effect of catechin and EGCG on the performance of reverse transcription (RT) and/or polymerase chain reaction (PCR) was studied. Both tea polyphenolic compounds were added into real-time RT-PCR reactions and the fluorescence data obtained were fitted with a mathematical model. Several parameters of PCR performance were compared, obtained from the mathematical model for reactions with and without addition of (+)-catechin and EGCG. Addition of EGCG to enzyme reaction seems to inhibit the RT reaction (p < 0.05) and to slow down the DNA polymerase reaction (p < 0.001). Similarly, (+)-catechin inhibited the DNA amplification (p < 0.01) but had no effect on the RT reaction. The effects could be observed in physiological flavanol concentrations ranging from 10(-5) to 10(-8)M.

Animals↗
PubMed2004

Reverse transcriptase-based DNA vaccines against drug-resistant HIV-1 tested in a mouse model.

Drug resistance is becoming a problem in the treatment of the human immunodeficiency virus type one (HIV-1). To obtain therapeutic DNA vaccines that would target multiple drug-resistance (DR) mutations, we cloned genes for DR HIV-1 reverse transcriptase (RT) and codon-optimized synthetic genes encoding clusters of human CTL epitopes located at the sites of DR-mutations (RT minigenes) and antibody and CTL-epitope tags. Expression of RT genes/minigenes in eukaryotic cells was confirmed by Western blotting and immunofluoresence staining with RT- or tag-specific antibodies. Immunization of mice with DR-RT gene induced no RT-specific antibodies. Immunization of HLA-A(*)0201-transgenic mice with RT minigenes induced RT-specific cellular responses detected by interferon-gamma secretion. This documents first steps in creating therapeutic vaccine against drug-resistant HIV strains.

AIDS Vaccines↗
PubMed1999

Inhibition of beta-globin gene expression by 3'-azido-3'-deoxythymidine in human erythroid progenitor cells.

3'-Azido-3'-deoxythymidine (AZT) treatment in HIV-infected patients is limited by bone marrow suppression including neutropenia and anemia. Previous studies had shown a direct effect of high concentrations of this drug on globin gene expression in K-562 erythroleukemia cells. To better define the mechanism(s) of AZT-induced bone marrow toxicity, the present study evaluates these effects in more relevant human erythroid progenitor liquid cultures, because AZT is 100 times more toxic to human bone marrow cells than K-562 cells. At a clinically relevant concentration of 1 microM, AZT inhibited specifically erythroid cell growth by approximately 58% as compared with untreated cells. The percentage of cells synthesizing hemoglobin was decreased also by 47% in AZT-treated cells with beta-globin mRNA levels accounting for 0.27 pmol in treated cells as compared with 1.44 under control conditions while beta-actin levels remained unchanged. Under the same conditions, AZT inhibited the beta-globin chain synthesis by approximately 60% as compared with the control. Consistent with the data described above was the finding that a concentration as low as 0.1 microM of AZT decreased by almost 40% the binding level of the erythroid-specific transcription factor GATA-1. These findings demonstrate that AZT, at clinical relevant concentrations, specifically inhibits beta-globin gene expression in human erythroid progenitor liquid cell culture.

Actins↗
PubMed2002

The dynamics of mutations in the YMDD motif of the hepatitis B virus polymerase gene during and after lamivudine treatment as determined by reverse hybridisation.

We have analysed the dynamics of HBV variants related to Lamivudine resistance in 22 chronically infected patients during and after the end of Lamivudine therapy. Thirteen patients had a confirmed methionine mutation in the YMDD region of the reverse transcriptase domain determined by sequence analysis. They responded to therapy having a mean reduction of HBV DNA of 4.55 log (range 2.93-8.91). Nine patients partly responded to therapy, with a small decline of HBV DNA (mean reduction of 3.39 log, range 1.72-5.12) and no indication for an YMDD variant. Samples were re-analysed with a HBV Drug Resistance Line Probe assay (InnoLipa HBV-DR), which detected as low as 10% of a variant HBV population. With this assay, changes in the YMDD region were detected with a mean of 2 weeks (range -8 to 10) earlier than by an increase of HBV DNA levels. Increase of ALT was observed with a mean of 31 weeks (range 29-51) later than the methionine changes in the YMDD motif. Indications for a methionine into valine change could be determined in only one of the partial responders. An unexpected observation was the predominant presence of variant virus populations after end of therapy. In ten patients, we detected the wild type virus with a mean of 14 weeks after end of therapy (range 1-42 weeks). In three patients, no variant virus population could be detected at 25, 36 and 37 weeks, respectively, after cessation of treatment. This observation is important for the inclusion of the so-called naive patients in clinical trials.

Amino Acid Motifs↗