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A Pozniak

Publications and source records attributed to A Pozniak.

At least 19 recordsLinked to original sources
PubMed2005

Emergence and evolution of enfuvirtide resistance following long-term therapy involves heptad repeat 2 mutations within gp41.

The objective of this study was to track the evolution of sequence changes in both the heptad region 1 (HR1) and HR2 domains of gp41 associated with resistance to enfuvirtide (ENF) in a patient cohort receiving long-term ENF treatment. We studied 17 highly antiretroviral agent-experienced patients receiving long-term ENF treatment with virological rebound or a lack of suppression. Sixty-two samples obtained after between 5 and 107 weeks of ENF therapy were analyzed. Baseline samples from 15 of these 17 patients were available for analysis. Viruses from five samples from four patients were also sequenced after the cessation of ENF therapy. Drug susceptibilities were assessed by a pseudotype virus reporter assay. We identified HR1 and HR2 sequence changes over time in relation to the baseline sequences. Mutations in HR1 (amino acids 36 to 45) were noted in all cases, including previously unreported changes N42Q/H and N43Q. In addition to a range of HR2 sequence changes at polymorphic sites, isolates from 6 of 17 (35%) patients developed an S138A substitution in the HR2 domain at least 8 weeks after the start of ENF treatment and also subsequent to the first emergence of HR1 mutations. In most, but not all, cases the S138A mutation accompanied HR1 mutations at position 43. Molecular modeling demonstrates the close proximity of S138A with amino acids 40 and 45 in HR1. Of note, isolates in samples available from four patients demonstrated the loss of both the HR1 and the S138A HR2 mutations following the cessation of therapy. We show that the S138A HR2 mutation increased the level of resistance by approximately threefold over that conferred by the HR1 mutation N43D. Continual evolution of HR1 in the domain from amino acids 36 to 45 was observed during long-term ENF therapy. We have identified, for the first time, an ENF resistance-associated HR2 mutation, S138A, which appeared in isolates from 6 of 17 patients with virological failure and demonstrated its potential to contribute to drug resistance. We propose that this represents a possible secondary and/or compensatory mutation, particularly when it coexists with mutations at position 43 in HR-1.

Amino Acid Sequence↗
PubMed2002

The molecular epidemiology of tuberculosis in inner London.

The study used DNA fingerprint typing (spoligotyping and Heminested-lnverse-PCR) of Mycobacterium tuberculosis from all culture-confirmed inner London patients over a 12-month period to describe transmission. The methodology was evaluated by comparison with standard IS6110 typing and by examining its ability to identify known household clusters of cases. Isolates sharing indistinguishable typing patterns using both techniques were defined as clustered. Clusters were investigated to identify epidemiological links. The methodology showed good discriminatory power and identified known household clusters of cases. Of 694 culture-confirmed cases, 563 (81%) were typed. Eleven (2%) were due to laboratory cross-contamination and were excluded. Of the remaining 552 isolates 148 (27%) were clustered. Multivariate analysis indicated that clustering was more common in those with pulmonary smear positive disease (P < 0.02); those born in the United Kingdom (P < 0.0003) and in patients living in south London (P = 0.02). There was also a trend towards clustering being more common in those not known to have HIV infection (P = 0.051). The results suggest that in inner London, recent local transmission makes an important contribution to notification rates.

Adolescent↗
PubMed2002

Naively changing HAART.

BACKGROUND: Few UK studies have systematically investigated which antiretroviral therapy (ART) combinations HIV-infected people are commenced on, when they start and reasons for stopping or changing their regimens. OBJECTIVE: To describe when HIV-infected ART-naive patients started first-, second- or third-line triple ART, classes of drugs prescribed and whether stopping ART was associated with virological, immunological or clinical indicators of treatment failure. DESIGN: A multicentre prospective open cohort study, employing the National Prospective Monitoring System on the use, cost and outcome of HIV service provision in UK hospitals-HIV Health-economics Collaboration (NPMS-HHC). SETTING: Five hundred and eighty-five ART-naive patients seen in one London and two non-London HIV clinics between 1 January 1998 and 31 December 1999. RESULTS: Of 4,044 HIV-infected individuals seen, 585 (15%) were ART naive. Median time interval (interquartile range, IQR) between HIV diagnosis and starting triple ART was 800 (63-2,094) days. Median CD4 count when first diagnosed with HIV infection was 278 (IQR 127-481) cells/ micro L which dropped to 190 (IQR 86-297) cells/ micro L when starting triple ART. Of these 585 patients, 162 started second-line and 46 third-line ART during the study period. Of those patients who stopped ART, 51% did not have evidence of virological, immunological or clinical indicators of therapy failure. CONCLUSIONS: Reasons for the delay between diagnosis of HIV infection and starting ART are varied. The large proportion of individuals who stopped ART for reasons other than virological, immunological or clinical indicators of therapy failure, are most likely due to drug-associated toxicity. Both of these findings need to be elucidated in greater detail through prospective studies.

Adult↗
PubMed2001

Liver transplantation in adults coinfected with HIV.

OBJECTIVE: To report our experience of prospectively identifying and transplanting livers into HIV-positive patients. DESIGN: Liver transplantation in HIV-positive patients remains controversial. The finding of HIV is usually considered a contraindication to any form of transplantation. Previously reported cases are few and refer to patients who tested HIV positive after they had their liver transplantations or who seroconverted in the posttransplantation period. This is, to our knowledge, the only report of patients who were known to be HIV positive at the time of decision for listing for transplantation. METHODS: The medical records of five HIV-positive patients who received liver transplants in King's College Hospital, London, during a 5-year period (January 1995-December 1999) were reviewed. All five were known to be HIV positive at the time of listing for liver replacement. Three of them had end-stage liver disease due to hepatitis C (two of them had underlying Hemophilia A) while the other two had acute liver failure, one due to hepatitis B infection and one due to nonA-nonB-nonC hepatitis. In all but one patient the HIV infection had been asymptomatic. RESULTS: All patients survived the immediate posttransplantation period, but the three patients with hepatitis C died of complications of recurrent hepatitis C between 6 and 25 months posttransplantation. The other two patients are currently alive 4 and 34 months posttransplantation with good graft function and without complications from their HIV infection. CONCLUSION: The early outcome of liver transplantation in HIV seropositive patients can be good, and patients should not be excluded from transplantation if their liver disease determines their prognosis. More effective antiviral therapy for hepatitis C given posttransplantation, and for hepatitis B reinfection, should improve the longer-term outcome of HIV patients with end-stage liver disease due to hepatitis.

Adolescent↗
PubMed2001

Loss of blood CD11c(+) myeloid and CD11c(-) plasmacytoid dendritic cells in patients with HIV-1 infection correlates with HIV-1 RNA virus load.

Human blood contains at least 2 subpopulations of antigen-presenting dendritic cells (DCs) that can be differentiated by their expression of CD11c. Myeloid DCs (myDCs), which are CD11c(+), trap invading pathogens in the tissues and then migrate to lymphoid tissues where they stimulate pathogen-specific T-cell responses. Plasmacytoid DCs (pcDCs), which are CD11c(-), secrete interferon-alpha in response to viral infections. This study reports that in HIV-1 infection there is a progressive depletion of both these DC populations and that this correlates with an increasing HIV-1 plasma virus load. The median numbers of myDCs and pcDCs were 6978/mL and 9299/mL, respectively, in healthy male controls and 2298/mL and 1640/mL, respectively, in patients with more than 10(5) HIV-1 RNA copies/mL. Both DC populations expressed CD4, CCR5, and CXCR4. The findings suggest that loss of DCs in HIV infection may contribute to disease progression.

CD4 Antigens↗
PubMed2001

Continuing HIV therapy in the ICU.

The risks and benefits of stopping antiretroviral therapy in patients admitted to the ICU are largely unmeasured. In many cases therapy has to be stopped, as parenteral preparations are unavailable for all but one of the antiretroviral agents. Stopping treatment suddenly may be associated with increased risk of resistance because of the long half-life of some of the drugs, and also the risk of increased immunosuppression due to the viral load rebounding. Drugs given through the enteral route may be poorly absorbed, which again may lead to drug resistance. By inhibiting cytochrome P450 3A4 the drugs interfere with the metabolism of many other compounds routinely used in the ICU. Furthermore, the drugs themselves are occasionally associated with severe toxicity such as pancreatitis and lactic acidosis, which can have devastating consequences. Much active research in all of these areas is now needed.

Antiretroviral Therapy, Highly Active↗
PubMed2001

Long-term follow-up of antiretroviral-naive HIV-positive patients treated with nevirapine.

This article reports on the extended follow-up of 125 antiretroviral (ARV)-naive patients treated with nevirapine (NVP) in the United Kingdom. The patients have been observed for a median of 1.8 years after starting NVP (range, 4 days-2.7 years). Baseline CD4 counts and HIV RNA levels were 210 (interquartile range, 130 - 335) cells/mm3 and 4.86 (range, 4.52-5.26) log10 copies/ml, respectively. Eleven patients (9.0%) developed a rash thought to be related to NVP, of whom 4 permanently discontinued NVP. Twenty-four months after starting NVP, RNA levels had dropped by a median of 2.32 log10 copies/ml and CD4 counts increased by a median of 143 cells/mm3. In all, 96 patients had at least one viral load measured <500 copies/ml, a median of 2.8 months after starting NVP. RNA levels rebounded >500 copies/ml in 37 of these patients, on average 2 years after initial response. In conclusion, in ARV-naive patients, NVP is generally well tolerated and long-term response rates are good.

Adult↗
PubMed2001

Distribution of K103N and/or Y181C HIV-1 mutations by exposure to zidovudine and non-nucleoside reverse transcriptase inhibitors.

Our aim was to identify whether zidovudine has a role in the emergence of the K103N resistance mutation in the HIV-1 reverse transcriptase gene on non-nucleoside reverse transcriptase inhibitors (NNRTIs). No difference was found in the exposure to zidovudine or major zidovudine mutations between the resistance patterns K103N-/Y181C+, K103N+/Y181C- and K103N+/ Y181C+, either in group A (patients on nevirapine and previously NNRTI naive) or in group B (on any NNRTI and experience of two or more NNRTIs including nevirapine). Group B patients had the highest prevalence of K103N+/Y181C+. In conclusion, zidovudine seems not to determine the emergence of K103N; however, there appears to be an accumulation of NNRTI resistance mutations with sequential use of NNRTIs.

Anti-HIV Agents↗
PubMed2001

Multidrug-resistant tuberculosis and HIV infection.

In the 1990s, outbreaks of multidrug-resistant tuberculosis (MDR TB) among HIV-positive patients ultimately led to the establishment in the developed world of a comprehensive TB control strategy for these patients that is effective. The treatment regimen for HIV and MDR TB is complicated by the fact that most of the drugs used have not been studied for interactions with antivirals. Hence, overlapping toxicities require intensive management and monitoring of these patients. Good public health policy is essential to preventing MDR TB outbreaks among immunosuppressed patients.

AIDS-Related Opportunistic Infections↗
PubMed2001

HIV fusion inhibitors.

Explore the source record for details and available documents.

Acquired Immunodeficiency Syndrome↗
PubMed2000

The SPICE study: 48-week activity of combinations of saquinavir soft gelatin and nelfinavir with and without nucleoside analogues. Study of Protease Inhibitor Combinations in Europe.

OBJECTIVES: To compare the efficacy and safety of saquinavir soft gelatin capsules (SQV-SGC) and nelfinavir (NFV), with or without two concomitant nucleoside reverse transcriptase inhibitors (NRTIs), in an exploratory objective to identify populations most likely to benefit from quadruple therapy. DESIGN: Phase II/III, open-label, randomized, parallel-arm, multicenter trial. PARTICIPANTS: Enrollment included 157 protease inhibitor-naive adults (> or = 13 years) with HIV-1 RNA > or = 10,000 copies/ml; 132 participants completed 48 weeks of therapy. INTERVENTIONS: SQV-SGC 1200 mg, NFV 750 mg, SQV-SGC 800 mg plus NFV 750 mg, all with two NRTIs, and SQV-SGC 800 mg plus NFV 750 mg alone, all three times daily for 48 weeks. MAIN OUTCOME MEASURES: Proportion of participants with HIV-1 RNA <50 copies/ ml (16 and 48 weeks); time to virologic relapse (48 weeks). RESULTS: Proportions of patients with HIV RNA <50 copies/ml were not statistically significantly different between arms at 16 or 48 weeks, although trends favored the quadruple-therapy arm. In patients experiencing virologic relapse, time to relapse was statistically significantly longer in the quadruple-therapy arm than in the other three arms (p = .007). Quadruple therapy provided benefit in NRTI-experienced patients and those with viral loads above the median value at baseline. Adverse events were mainly mild gastrointestinal disorders in all treatment arms. CONCLUSIONS: Quadruple therapy, including SQV-SGC and NFV, gave a more durable response than triple therapy with either single protease inhibitor. Quadruple therapy might particularly benefit NRTI-experienced patients and those with high baseline viral loads.

Adult↗
PubMed1999

Decreased morbidity and use of hospital services in English HIV-infected individuals with increased uptake of anti-retroviral therapy 1996-1997. National Prospective Monitoring System Steering Group.

OBJECTIVE: To investigate the relationship between changing morbidity patterns, the use of hospital services by HIV-infected patients and the uptake of antiretroviral therapy (ART) in England. DESIGN: Prospective serial cross-sectional analyses based on data collected through the National Prospective Monitoring System (NPMS), a multi-centre prospective monitoring system. SETTING: HIV-infected patients seen in 10 clinics, five London and five non-London, during the three semesters, 1 January 1996 to 30 June 1997. MAIN OUTCOME MEASURES: The mean use of hospital services per patient-year, mean new HIV-related opportunistic illnesses per 1000 patient-years and percentage uptake of ART. RESULTS: The use of inpatient services changed particularly among AIDS patients. The mean number of inpatient days for AIDS patients decreased from 19.7 [95% confidence interval (CI) 13.7-25.7] in 1996 to 11.2 (95% CI 6.1-15.6) per patient-year in 1997. Concurrently the number of new AIDS-defining events decreased significantly from 567 (95% CI 529-607) to 203 (95% CI 183-225) per 1000 patient-years. The overall uptake of ART increased significantly from 33% (95% CI 31-35%) to 50% (95% CI 48-52%), and a switch from mono or dual to triple therapy or quadruple or more therapy was observed. However, by mid-1997 only 29% (95% CI 26-32%) of asymptomatic patients and 51% (95% CI 49-54%) of patients with symptomatic non-AIDS were on ART, compared with 69% (95% CI 66-71%) of AIDS patients. CONCLUSION: The observed reduction in new AIDS-defining events has led to a reduction in the need for inpatient hospital care and has been associated with an increased uptake of ART, including a switch to triple therapy. All of these factors are likely to have contributed to the observed reduction in mortality among English AIDS patients. As the overall uptake of ART remained relatively low in English centres further improvements can be anticipated. However, the medium to long-term effects of these treatment regimens will need to be closely monitored.

Anti-HIV Agents↗