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Biomedical subjects

D Pillay

Publications and source records attributed to D Pillay.

At least 37 records · Page 2Linked to original sources
PubMed2001

Failure of combination therapy with lamivudine and famciclovir following lamivudine monotherapy for hepatitis B virus infection in patients coinfected with human immunodeficiency virus-1.

Individuals coinfected with human immunodeficiency virus 1 (HIV-1) and hepatitis B virus (HBV) often receive treatment with an antiretroviral regimen including lamivudine. Lamivudine monotherapy for HBV may lead to drug-resistant mutations in a significant number of patients. The virological and biochemical responses of 8 patients coinfected with HBV/HIV-1 treated with both lamivudine and famciclovir were studied. Patients exhibiting HBV viral rebound at 1 year were analyzed for the emergence of HBV polymerase mutations. Only 1 patient had no prior exposure to lamivudine. Addition of famciclovir to the treatment regimen resulted in a median fall in HBV DNA level of 0.33 log(10) at 3 months and an overall rise in HBV DNA level of 3 log(10) at 12 months. The only patient in whom durable viral suppression and HBV e antigen seroconversion were noted began receiving lamivudine and famciclovir simultaneously. HBV polymerase gene sequencing identified resistance-associated mutations in 6 of 7 patients with viral rebound. Sequential nucleoside analogue therapy is unlikely to be successful in achieving long-term suppression of HBV replication, and combination therapy should be considered at treatment initiation.

2-Aminopurine↗
PubMed2001

Penetration of efavirenz into the male genital tract: drug concentrations and antiviral activity in semen and blood of HIV-1-infected men.

Efavirenz is a potent non-nucleoside reverse transcriptase inhibitor, licensed for the treatment of HIV-1. Data on sanctuary site penetration are limited. Therefore, we measured efavirenz concentrations in the blood and semen of 19 HIV-1-positive men and found concentrations in seminal plasma averaged 10% of those in blood plasma. Furthermore, seminal plasma viral loads were suppressed by 24 weeks of therapy in all patients. These data suggest that efavirenz-containing regimens have antiviral activity within the male genital tract.

Alkynes↗
PubMed2001

Recombinant strains of HIV type 1 in the United Kingdom.

Twenty-five recombinant (mosaic) HIV-1 genomes were detected among 151 samples comprising 118 non-B subtype sequences and 33 samples containing subtype B sequences. Seven of the 25 mosaic patterns were similar to characterized circulating recombinant forms (two A/E, four A/G, and one D/F) and one was a MAL-like A/D recombinant. Eighteen of the recombinants had evidence of subtype A sequences in at least one region of their genome. One sample was found to contain a novel recombinant form (pol F, env K). Two samples could not be characterized unambiguously as recombinant forms and a further one appeared to be a complex C/J/D/A genomic form. The majority of the mosaic genomes were recombinants between gag, pol, or env, whereas the C/J/D/A mosaic had cross-over breakpoints within pol. These findings suggest that almost 20% of non-B subtype isolates of HIV-1 circulating in the United Kingdom have mosaic genomes. This shows the diverse origin of HIV-1 strains circulating in the United Kingdom and may have implications for antiretroviral drug resistance.

Cluster Analysis↗
PubMed2001

Xylitol production by recombinant Saccharomyces cerevisiae expressing the Pichia stipitis and Candida shehatae XYL1 genes.

The xylose reductase gene (XYL1) was isolated from Pichia stipitis and Candida shehatae, cloned into YEp-based vectors under the control of ADH2 and PGK1 promoter/terminator cassettes and introduced into Saccharomyces cerevisiae Y294 by electroporation. Shake-flask fermentations were carried out with 5% xylose and 1% galactose, glucose or maltose as co-substrates. Xylose uptake was similar in both the recombinant strains when different co-substrates were used and slowed once the co-substrate was depleted. The recombinant strains converted xylose to xylitol with yields approaching the theoretical maxima. Xylitol production was most rapid when the co-substrate was still present. Approximately 50% of the xylose was not metabolized due to the depletion of the co-substrate.

Aldehyde Reductase↗
PubMed2001

Antiretroviral drug concentrations in semen of HIV-infected men: differential penetration of indinavir, ritonavir and saquinavir.

Variable drug penetration of antiretroviral drugs into the genital tract may contribute to the differential evolution of HIV and the emergence of drug resistance. This, in turn, may have an impact on the sexual transmission of resistant HIV in patients treated with antiretroviral drugs. We have measured concentrations of the HIV-1 protease inhibitors indinavir, ritonavir and saquinavir in the blood plasma (BP) and seminal plasma (SP) of 23 HIV-1-positive men. Forty-five time-matched blood and semen samples were obtained. SP concentrations of indinavir exceeded the EC95 of indinavir, corrected for protein binding, of 42 ng/mL at all time intervals. In contrast, the median ritonavir and saquinavir SP concentrations were below the relevant EC95 at all times post drug ingestion. The median SP:BP concentration ratios for indinavir were 0.6, 0.8 and 1.4, respectively, at 0-2, 2-6 and 6-8 h post-drug ingestion. In contrast, the median SP:BP concentration ratios at 0-3, 3-9 and 9-12 h post-drug ingestion were <0.02, <0.04 and <0.04, respectively, for both ritonavir and saquinavir. These differences justify further study of HIV-1 evolution and development of resistance in the genital tract of men taking these anti-HIV drugs.

Adult↗
PubMed2001

Resistance-associated mutations in the human immunodeficiency virus type 1 subtype c protease gene from treated and untreated patients in the United Kingdom.

This work reports the variability of human immunodeficiency virus type 1 (HIV-1) protease from treated and untreated patients infected with HIV-1 subtype C in the United Kingdom. The most common primary mutation observed in treated patients was L90M. D30N, M46I, V82A/F, and I84V were seen rarely. M36I and I93L mutations were observed in nearly all samples from both treated and untreated patients and so cannot be considered as resistance-associated mutations in this subtype.

Diseases in Twins↗
PubMed2001

Acute liver graft failure due to emergence of lamivudine resistant hepatitis B virus: rapid resolution during treatment with adefovir.

BACKGROUND: Strategies for prevention of liver graft reinfection by hepatitis B virus (HBV) have been developed during recent years. Initially, passive immunoprophylaxis with high titre HBV immunoglobulin (HBIg), followed by lamivudine prophylaxis, and then the combination of lamivudine and HBIg have been employed. However, suboptimal use of the combination may be associated with failure of prophylaxis reflected by the emergence of HBV species with genetic changes that confer resistance to lamivudine and HBIg. Reinfection of the graft by HBV can be associated with rapid development of liver failure. CASE REPORT: A 43 year old HBV infected man received lamivudine before transplantation, and lamivudine and HBIg after transplantation. Despite prophylaxis, graft reinfection and severe hepatitis were observed. The observed serological evolution and genetic sequencing of the emergent HBV species suggested selection of lamivudine resistant and surface antigen escape mutants consecutively. Adefovir treatment began after the development of graft failure. OUTCOME: A rapid exponential decline in serum HBV titre was observed. Liver function tests normalised and signs of liver failure resolved. CONCLUSION: The use of HBIg and lamivudine permits prevention of graft reinfection by HBV for the majority of patients. Adefovir, a potent inhibitor of lamivudine resistant HBV, should be used when failure of prophylaxis is associated with graft hepatitis.

Acute Disease↗
PubMed2001

Laboratory guidelines for the practical use of HIV drug resistance tests in patient follow-up.

HIV drug resistance is one of the major limitations in the successful treatment of HIV-infected patients using currently available antiretroviral combination therapies. When appropriate, drug susceptibility profiles should be taken into consideration in the choice of a specific combination therapy. Guidelines recommending resistance testing in certain circumstances have been issued. Many clinicians have access to resistance testing and will increasingly use these results in their treatment decisions. In this document, we comment on the different methods available, and the relevant issues relating to the clinical application of these tests. Specifically, the following recommendations can be made: (i) genotypic and phenotypic HIV-1 drug resistance analyses can yield complementary information for the clinician. However, insufficient information currently exists as to which approach is preferable in any particular clinical setting; (ii) when HIV-1 drug resistance testing is required, it is recommended that testing be performed on plasma samples obtained before starting, stopping or changing therapy, on samples that have a viral load above the detection limit of the resistance test; (iii) the panel recommends that genotypic and phenotypic HIV-1 drug resistance testing for clinical purposes be performed in a certified laboratory under strict quality control and quality assurance standards; and (iv) the panel recommends that resistance testing laboratories provide clinicians with resistance reports that include a list of drug-related resistance mutations (genotype) and/or a list of drug-related fold resistance values (phenotype), with interpretations of each by an experienced virologist. The interpretation of genotypic and phenotypic analysis is a complex and developing science, and in order to understand HIV-1 drug resistance reports, communication between the requesting clinician and the expert that interpreted the resistance report is recommended.

Acquired Immunodeficiency Syndrome↗
PubMed2001

The emergence and epidemiology of resistance in the nucleoside-experienced HIV-infected population.

HIV drug resistance remains one of the most important influences on long-term therapeutic prospects. Resistance and therapeutic failure arises out of the selection and preservation of randomly generated genomic mutations that confer a replicative advantage in the presence of one or more antiretrovirals. The primary correlate to the time to emergence of a drug-resistant HIV variant is the extent of residual replication under selecting drug pressure, emphasizing the importance of full virological suppression to long-term therapy. Further contributions to the time to emergence are the degree of selective pressure exerted by a given drug, whereby greater potency forces earlier selection of mutant strains in balance with the extent of residual replication, and the degree of reduced drug susceptibility afforded by a particular mutation. Once evolved, drug-resistant strains can persist indefinitely as minority viral populations or archived genomes in latently infected CD4 cells, despite long-term withdrawal of the selecting drugs, to reemerge rapidly on rechallenge with those or any cross-resistant drug. Variable adherence to medication in the routine clinical setting has given rise to resistance mutations being observed in some 50-60% of those with detectable viral loads on therapy in countries where antiretroviral therapy has been widely available. Nucleoside reverse transcriptase inhibitor-associated mutations form the majority of these, and the long and almost universal use of zidovudine and stavudine has led to mutations selected by these drugs being the most common observed, along with the primary lamivudine resistance mutation M184V. Transmission of drug-resistant HIV in cases of new infection has also been widely studied, and although the extent is considerably lower than that in the treated population (typically 4-10% outside certain geographic areas), early data suggest that it is rising over time as the infected source population becomes more therapy-experienced. Once again, mutations from zidovudine or, to a lesser extent, stavudine exposure form the majority of mutations observed in cases of primary transmission. These data are a cause for concern, and imply that, as things stand, the use of a drug resistance test may become as important to the design of an effective first-line highly active antiretroviral therapy regimen as they have become for selecting new drugs on therapeutic failure.

Anti-HIV Agents↗
PubMed2000

Concentrations of nevirapine, lamivudine and stavudine in semen of HIV-1-infected men.

OBJECTIVE: To determine the concentrations of nevirapine (NVP), lamivudine (3TC) and stavudine (D4T) in seminal and blood plasma in HIV-1-infected men. METHODS: Twelve HIV-1-infected men on NVP-containing regimens including 3TC (n = 8) or D4T (n = 11) provided 23 blood plasma and 22 seminal plasma samples for drug concentration and viral load quantitation. Concentrations of all drugs were assessed by sensitive validated high performance liquid chromatography (HPLC) assays. Blood plasma and seminal plasma viral loads were measured using nucleic acid sequence-based amplification (NASBA). Samples were grouped according to time after drug ingestion, 0-2, 2-4, 4-8 and 8-12 h. For matched seminal and blood plasma samples, obtained within 1 h of each other, a seminal:blood plasma ratio was calculated. RESULTS: The concentration of NVP in seminal plasma appeared to mirror the concentrations in blood plasma. Absolute median seminal plasma NVP concentrations at 0-2, 2-4, 4-8 and 8-12 h were 3.1 microg/ml (range 1.7-4.89), 2.68 microg/ml (2.5-3.9), 2.5 microg/ml (2.3-2.7) and 3.09 microg/ml (1.3-9.1). The median seminal:blood plasma ratios for the four time periods were 0.54 (range 0.34-0.85), 0.83 (range 0.43-1.08), 0.53 (0.48-0.59), and 0.61 (0.59-0.78). 3TC and D4T appeared to reach concentrations in seminal plasma of a similar magnitude or higher than concentrations in blood plasma. The median seminal plasma viral load for all patients was less than 800 copies/ml (range < 800-11000). The median blood plasma viral load was less than 400 copies/ml (< 400-1100). CONCLUSION: NVP reaches concentrations in the semen approximately 60% of those in the blood plasma throughout the 12 h dosing period. In a smaller dataset, 3TC and D4T concentrations in blood plasma and seminal plasma were similar. These data may well have implications for the evolution of drug-resistant virus within the genital tract.

Adult↗
PubMed2000

Relatedness of Thermomyces lanuginosus strains producing a thermostable xylanase.

Properties of an endo-beta-xylanase produced by a locally isolated Thermomyces lanuginosus strain SSBP was compared to seven other T. lanuginosus strains isolated from different geographical regions. Strain SSBP produced the highest xylanase activity of 59600 nkat ml(-1) when cultivated on corn cobs (maize) medium, whereas the seven other strains produced xylanase activities ranging from 6000 to 32000 nkat ml(-1). No cellulase activity was produced by the strains. Despite the variability in the production of xylanase, little difference in the other characteristics of the strains could be found. The optimal temperature and pH for xylanase production by the strains was either 40 or 50 degrees C and between pH 6 and 7, respectively. Optimal xylanase activity of the strains was observed at 70 degrees C and at pH 6 or 6.5. Culture supernatant analysis by SDS-PAGE and isoelectric focusing PAGE of all strains revealed the presence of a single 24.7 kDa and pI 3.9 xylanase. Phylogenetic analysis by PCR amplification and sequencing of the internal transcribed spacer of nuclear rRNA repeat units and 5.8S rDNA revealed no strain diversity. However, random amplified polymorphic DNA analysis pointed to greater diversity and with one primer (5'-GCCCGACGCG-3'), a relationship was established between xylanase levels and the RAPD pattern.

Ascomycota↗
PubMed2000

Evolution of lamivudine-resistant hepatitis B virus and HIV-1 in co-infected individuals: an analysis of the CAESAR study. CAESAR co-ordinating committee.

OBJECTIVES: Lamivudine has potent activity against HIV-1 and hepatitis B virus (HBV). Co-infection with these two viruses is common, and this may therefore influence the choice of antiretroviral therapies. A cohort of co-infected patients treated with lamivudine were studied in order to evaluate the differential effects of lamivudine on the two viral populations within the same individual after 44-52 weeks of therapy. DESIGN AND METHODS: Retrospective virological analysis of an HIV-1/HBV co-infected lamivudine cohort derived from a randomized, placebo-controlled study of lamivudine in HIV infection, the CAESAR study. RESULTS: Five of thirteen patients with HBV viral load > 10,000 copies/ml after 44-52 weeks of lamivudine therapy had genotypic drug resistance. Four of these five had a rebound of viral replication over the period of study and in one case this was associated with an alanine transaminase serum elevation. Ten of the thirteen patients had a 44-52 week HIV viral load > 1000 copies/ml, all of whom also had HIV reverse transcriptase M184V or M184I mutations. CONCLUSIONS: Extrapolating these results to the population yields an estimated 1-year incidence of drug-resistant HBV of at least 14% in lamivudine-treated HIV-1/HBV co-infected patients. The clinical and virological benefit of HBV lamivudine monotherapy in co-infected patients should be balanced against the potential for emergence of drug resistance. Further, these data suggest that the determinants of HIV and HBV drug resistance are different and that parallel evolution, rather than co-evolution of HBV and HIV-1 in co-infected individuals occurs.

CD4 Lymphocyte Count↗