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Biomedical subjects

Sharon L Walmsley

Publications and source records attributed to Sharon L Walmsley.

17 recordsLinked to original sources
PubMed2006

Efficacy of the protease inhibitors tipranavir plus ritonavir in treatment-experienced patients: 24-week analysis from the RESIST-1 trial.

BACKGROUND: Improved treatment options are needed for patients infected with multidrug-resistant human immunodeficiency virus type 1 (HIV-1). The nonpeptidic protease inhibitor tipranavir has demonstrated antiviral activity against many protease inhibitor-resistant HIV-1 isolates. The Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST-1) trial is an ongoing, open-label study comparing the efficacy and safety of ritonavir-boosted tipranavir (TPV/r) with an investigator-selected ritonavir-boosted comparator protease inhibitor (CPI/r) in treatment-experienced, HIV-1-infected patients. METHODS: Six hundred twenty antiretroviral-experienced patients were treated at 125 sites in North America and Australia. Before randomization, all patients underwent genotypic resistance testing, which investigators used to select a CPI/r and an optimized background regimen. Patients were randomized to receive TPV/r or CPI/r and were stratified on the basis of preselected protease inhibitor and enfuvirtide use. Treatment response was defined as a confirmed reduction in the HIV-1 load of > or = 1 log10 less than the baseline level without treatment change at week 24. RESULTS: Mean baseline HIV-1 loads and CD4+ cell counts were 4.74 log10 copies/mL and 164 cells/mm3, respectively. At week 24, a total of 41.5% of patients in the TPV/r arm and 22.3% in the CPI/r arm had a > or = 1-log10 reduction in the HIV-1 load (intent-to-treat population; P<.0001). Mean increases in the CD4+ cell count of 54 and 24 cells/mm3 occurred in the TPV/r and CPI/r groups, respectively. Adverse events were slightly more common in the TPV/r group and included diarrhea, nausea, and vomiting. Elevations in alanine and aspartate aminotransferase levels and in cholesterol/triglyceride levels were more frequent in the TPV/r group. CONCLUSIONS: TPV/r demonstrated superior antiviral activity, compared with investigator-selected, ritonavir-boosted protease inhibitors, at week 24 in treatment-experienced patients with multidrug-resistant HIV-1 infection.

Adult↗
PubMed2006

Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials.

BACKGROUND: Treatment options for HIV-1 infected individuals who have received extensive previous antiretroviral therapy are limited. We compared efficacy and safety of the novel non-peptidic protease inhibitor tipranavir co-administered with ritonavir plus an optimised background regimen with that of an investigator-selected ritonavir-boosted comparator protease inhibitor (CPI-ritonavir) in such patients. METHODS: We did a combined analysis of 48-week data from two ongoing, randomised, open-label, multinational, phase III, RESIST studies. HIV-1-infected adults with 3 months or longer previous triple antiretroviral class experience, two or more previous protease inhibitor regimens, HIV-1 RNA 1000 copies per mL or greater, and genotypically demonstrated primary resistance to protease inhibitor, were eligible. Primary endpoints were proportion of treatment responders (with reduction in viral load of 1 log(10) copies per mL or greater below baseline without treatment change) at 48 weeks and time to treatment failure through 48 weeks (intention-to-treat analysis). The RESIST studies are registered with ClinicalTrials.gov, numbers NCT00054717 (RESIST-1) and NCT00144170 (RESIST-2). FINDINGS: 3324 patients were screened; 746 received tipranavir-ritonavir and 737 CPI-ritonavir. 486 (65.1%) patients on tipranavir-ritonavir and 192 (26.1%) on CPI-ritonavir remained on assigned treatment until week 48. At week 48, more patients achieved and maintained treatment response in the tipranavir-ritonavir group than in the CPI-ritonavir group (251 [33.6%] vs 113 [15.3%]; p<0.0001). Median time to treatment failure was significantly longer in the tipranavir-ritonavir group than in the CPI-ritonavir group (113 days vs 0 days; p<0.0001). Gastrointestinal system disorders and raised transaminase, cholesterol, and triglycerides were more frequent in the tipranavir-ritonavir group than in the CPI-ritonavir group. INTERPRETATION: Compared with CPI-ritonavir, tipranavir-ritonavir with an optimised background regimen provides better virological and immunological responses over 48 weeks in patients who have received extensive previous antiretroviral treatment.

Adult↗
PubMed2006

Lipodystrophy severity does not contribute to HAART nonadherence.

Lipodystrophy severity among 77 people living with HIV/AIDS (PHA) with body fat redistribution was not related to antiretroviral adherence including doses missed during the previous month, categorical rating of maximal adherence, and the PMAQ7 adherence behavior scale. Two thirds of the sample reported submaximal adherence, 19% missing more than two doses, but adherence behavior ratings reflected good overall adherence. Overall symptom burden, convenience of regimen schedule and remembering to organize and take antiretroviral doses, but not regimen adaptation or treatment support, were associated with adherence. Remembering was most strongly related to adherence indicators, retaining statistical significance in adjusted multivariate regression analyses.

Aged↗
PubMed2005

Durable efficacy of enfuvirtide over 48 weeks in heavily treatment-experienced HIV-1-infected patients in the T-20 versus optimized background regimen only 1 and 2 clinical trials.

BACKGROUND: The T-20 Versus Optimized Background Regimen Only (TORO) 1 and TORO 2 clinical trials are open-label, controlled, parallel-group, phase 3 studies comparing enfuvirtide plus an optimized background (OB) of antiretrovirals (n = 661) with OB alone (n = 334) in treatment-experienced HIV-1-infected patients. METHODS: The primary objective at week 48 was to investigate durability of efficacy, as measured by the percentage of patients maintaining their week 24 response or improving. Efficacy analyses used the intent-to-treat population. RESULTS: A total of 73.7% of patients randomized to the enfuvirtide group remained on treatment through week 48 versus 21.3% originally randomized to the control group. At week 48, a higher proportion of week 24 responders maintained their response or were new responders in the enfuvirtide group than in the control group in each responder category: HIV-1 RNA level > or =1.0 log(10) change from baseline, <400 copies/mL and <50 copies/mL (37.4%, 30.4%, and 18.3% in the enfuvirtide group vs. 17.1%, 12.0%, and 7.8% in the control group, respectively; P < 0.0001 for all comparisons). CD4 cell count increases from baseline were twice as great in the enfuvirtide group as in the control group. CONCLUSION: These data demonstrate durable efficacy of enfuvirtide plus OB over 48 weeks.

Adolescent↗
PubMed2005

CD4(+) cell count increase predicts clinical benefits in patients with advanced HIV disease and persistent viremia after 1 year of combination antiretroviral therapy.

The relationship between 12-month CD4(+) cell count response and clinical outcome (AIDS-defining event or death) in a subset of 228 patients with a human immunodeficiency virus load >400 copies/mL despite receiving combination antiretroviral therapy as part of a larger randomized trial was defined by use of Cox models. The 12-month CD4(+) cell count responses were divided into 5 categories, ranging from decrease or no change (29% of patients) to a > or =100-cell/mm(3) increase (27% of patients). There was a lower risk of clinical progression for each incremental increase in CD4(+) cell count response. A 25-cell/mm(3) increase in CD4(+) cell count was associated with a 21% reduction in the risk of an AIDS-defining event or death (P<.0001).

Antiretroviral Therapy, Highly Active↗
PubMed2004

Baseline HIV-1 RNA level and CD4 cell count predict time to loss of virologic response to nelfinavir, but not lopinavir/ritonavir, in antiretroviral therapy-naive patients.

Baseline CD4 cell counts and human immunodeficiency virus (HIV)-1 RNA levels have been shown to predict immunologic and virologic responses in HIV-infected patients receiving antiretroviral therapy. In our randomized, double-blind, comparative trial, 653 antiretroviral therapy-naive patients received lopinavir/ritonavir or nelfinavir, plus stavudine and lamivudine, for up to 96 weeks. The risk of loss of virologic response was significantly higher for nelfinavir-treated patients than for lopinavir/ritonavir-treated patients (Cox model hazard ratio, 2.2; 95% confidence interval, 1.7-3.0; P<.001). For nelfinavir-treated patients, but not for lopinavir/ritonavir-treated patients, higher baseline HIV-1 RNA levels and lower baseline CD4 cell counts were associated with a higher risk of loss of virologic response.

Anti-HIV Agents↗
PubMed2004

Treatment of HIV infection in pregnant women: antiretroviral management options.

Increasing rates of HIV infection in women worldwide, especially among those of childbearing age, reinforce the importance of understanding the management of HIV in pregnancy. Over the past decade, significant advances have been made in the prevention of vertical HIV transmission, including the use of single and combination antiretroviral therapy, elective caesarean section as the preferred mode of delivery and the elimination of breast feeding. Multiple clinical trials assessing antiretroviral therapy in pregnancy have been carried out worldwide. The first pivotal clinical trial, the AIDS Clinical Trials Group (ACTG) 076 study, was conducted in 1994 using a three-part zidovudine regimen. Despite the success of this regimen at decreasing rates of vertical transmission, it is not affordable in many developing countries. Consequently, many international clinical trials have concentrated on short-course antiretroviral regimens including zidovudine alone, zidovudine and lamivudine, and nevirapine alone. In the developed world, the management of nonpregnant HIV-infected individuals has also undergone significant advances and has implications for the management of HIV in pregnancy. A number of countries have participated in the development of guidelines for the management of HIV in pregnancy, which recommend that HIV-infected pregnant women should be offered combination antiretroviral therapy based on viral load and CD4+ cell count cut-offs used for individuals who are not pregnant, preferably with the inclusion of zidovudine. However, to maximise the benefits to their offspring, therapy is recommended at lower viral load thresholds than for nonpregnant adults. For antiretroviral-naive women, therapy is deferred until the second trimester because of the potential and uncertain risk of teratogenesis and the low risk of transmission during this period. Research has also found that maternal factors including viral load, immune status, chorioamnionitis, prematurely ruptured membranes and, to a lesser extent, intravenous drug use and smoking are associated with increased vertical transmission. These represent potentially modifiable risk factors that should be addressed before and throughout pregnancy. Despite the benefits of antiretroviral therapy to reduce HIV vertical transmission, its use can be complicated by known and unknown risks of toxicity to the mother, fetus or both as well as carrying the risk of developing drug-resistant virus. The latter can potentially compromise future treatment options for both the mother and child. Other important challenges include the use of antiretroviral drugs during pregnancy when the mother does not meet criteria for them for her own health, and balancing the relative risks and benefits of elective caesarean section at various degrees of viral load suppression. Clinicians managing HIV in pregnancy need to keep up to date with all the literature to provide optimal care, including counselling to allow mothers to balance the risks and benefits while deciding on treatment for both themselves and their children.

Anti-HIV Agents↗
PubMed2004

Predictive value of HIV-1 protease genotype and virtual phenotype on the virological response to lopinavir/ritonavir-containing salvage regimens.

The predictive values of HIV-1 protease genotype and virtual phenotype (vPhenotype) results on the HIV-1 RNA response to lopinavir/ritonavir (LPV/r)-containing salvage regimens were assessed. Data were evaluated from patients with antiretroviral (ARV) resistance testing prior to initiating an LPV/r-containing salvage ARV regimen, from two independent cohorts from Toronto, Ontario and British Columbia, Canada. Multivariate logistic regression models controlling for previous non-nucleoside reverse transcriptase inhibitor use, baseline viral load and AIDS-defining illness were used to assess the impact of different protease genotypic mutations (individual and in combination) and lopinavir vPhenotyping on virological suppression to <50 copies/ml by 12 months. We confirmed that the 11-mutation 'lopinavir mutation score' (LMS) was significantly inversely associated with the probability of virological suppression within 12 months [odds ratio (OR)=0.91; P=0.02]. The only single specific protease mutation found to predict virological response in multivariate analyses was 461 (OR=0.55; P=0.02). The most predictive three-mutation combination was 10F/I/R/V, 461, 82A/F/T (OR=0.18; P=0.0004). We confirmed that a 10-fold increase of lopinavir IC50 is an appropriate clinical cut-off for lopinavir vPhenotype. In univariate analyses, a cut-off of the LMS as low as 3 was significantly associated with a lack of virological suppression (P=0.04). This finding, which is in contrast to those of other studies, may be due to the high degree of ARV experience of our population and lack of active agents in the salvage regimen. Selecting the 11 specific mutations to make the LMS is potentially arbitrary; we determined that when different combinations of 11 protease mutations were chosen randomly from a set of 30, similar associations with virological response were found, probably due to the co-linearity of these mutations.

Adult↗
PubMed2003

Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area.

CONTEXT: Severe acute respiratory syndrome (SARS) is an emerging infectious disease that first manifested in humans in China in November 2002 and has subsequently spread worldwide. OBJECTIVES: To describe the clinical characteristics and short-term outcomes of SARS in the first large group of patients in North America; to describe how these patients were treated and the variables associated with poor outcome. DESIGN, SETTING, AND PATIENTS: Retrospective case series involving 144 adult patients admitted to 10 academic and community hospitals in the greater Toronto, Ontario, area between March 7 and April 10, 2003, with a diagnosis of suspected or probable SARS. Patients were included if they had fever, a known exposure to SARS, and respiratory symptoms or infiltrates observed on chest radiograph. Patients were excluded if an alternative diagnosis was determined. MAIN OUTCOME MEASURES: Location of exposure to SARS; features of the history, physical examination, and laboratory tests at admission to the hospital; and 21-day outcomes such as death or intensive care unit (ICU) admission with or without mechanical ventilation. RESULTS: Of the 144 patients, 111 (77%) were exposed to SARS in the hospital setting. Features of the clinical examination most commonly found in these patients at admission were self-reported fever (99%), documented elevated temperature (85%), nonproductive cough (69%), myalgia (49%), and dyspnea (42%). Common laboratory features included elevated lactate dehydrogenase (87%), hypocalcemia (60%), and lymphopenia (54%). Only 2% of patients had rhinorrhea. A total of 126 patients (88%) were treated with ribavirin, although its use was associated with significant toxicity, including hemolysis (in 76%) and decrease in hemoglobin of 2 g/dL (in 49%). Twenty-nine patients (20%) were admitted to the ICU with or without mechanical ventilation, and 8 patients died (21-day mortality, 6.5%; 95% confidence interval [CI], 1.9%-11.8%). Multivariable analysis showed that the presence of diabetes (relative risk [RR], 3.1; 95% CI, 1.4-7.2; P =.01) or other comorbid conditions (RR, 2.5; 95% CI, 1.1-5.8; P =.03) were independently associated with poor outcome (death, ICU admission, or mechanical ventilation). CONCLUSIONS: The majority of cases in the SARS outbreak in the greater Toronto area were related to hospital exposure. In the event that contact history becomes unreliable, several features of the clinical presentation will be useful in raising the suspicion of SARS. Although SARS is associated with significant morbidity and mortality, especially in patients with diabetes or other comorbid conditions, the vast majority (93.5%) of patients in our cohort survived.

Adult↗
PubMed2002

Successful discontinuation of therapy for disseminated Mycobacterium avium complex infection after effective antiretroviral therapy.

BACKGROUND: Highly active antiretroviral therapy (HAART) is associated with improvement or resolution of several HIV-associated opportunistic infections. Although prophylaxis against disseminated Mycobacterium avium complex infection may be successfully discontinued after a favorable response to HAART, the 1999 guidelines from the U.S. Public Health Service/Infectious Diseases Society of America recommend continuing therapy for disseminated M. avium complex infection, regardless of the response to HAART. OBJECTIVE: To examine the outcome among patients with disseminated M. avium complex infection whose antimycobacterial therapy was discontinued after a favorable response to HAART. DESIGN: Retrospective chart review between May 2000 and May 2001. SETTING: 13 Canadian HIV clinics. PATIENTS: 52 HIV-infected adults (43 men; mean age, 37.3 years) in whom successful antimycobacterial therapy for disseminated M. avium complex infection was discontinued after a favorable virologic response to HAART. MEASUREMENTS: Survival, survival free of disseminated M. avium complex infection, and CD4(+) cell count responses. RESULTS: At the time of diagnosis of disseminated M. avium complex infection, the median CD4(+) cell count was 0.016 x 10(9) cells/L, and the median plasma HIV RNA level was 90 000 copies/mL (plasma HIV RNA levels were available for only 21 patients). The patients received a median of 32 months of antimycobacterial therapy that included ethambutol plus either clarithromycin or azithromycin. When antimycobacterial therapy was discontinued, the median CD4(+) cell count was 0.23 x 10(9) cells/L and the median plasma HIV RNA level was less than 50 copies/mL. A median of 20 months after discontinuation of antimycobacterial therapy, only 1 patient had developed recurrent M. avium complex disease (37 months after stopping antimycobacterial therapy). This patient had stopped HAART 2 months earlier because of uncontrolled HIV viremia. Twenty months after stopping antimycobacterial therapy, the other 51 patients had a median CD4(+) cell count of 0.288 x 10(9) cells/L; 34 (67%) had undetectable plasma HIV RNA levels, and 8 (15%) had plasma HIV RNA levels of 50 to 1000 copies/mL. CONCLUSIONS: Discontinuation of successful disseminated M. avium complex therapy after a successful response to HAART is safe and reduces patients' pill burdens, potential drug adverse effects, drug interactions, and costs of therapy.

AIDS-Related Opportunistic Infections↗
PubMed2002

Field evaluation of the Merlin immediate HIV-1 and -2 test for point-of-care detection of human immunodeficiency virus antibodies.

The Merlin Immediate HIV-1 and -2 Test (Merlin point-of-care [POC] test; Merlin Biomedical & Pharmaceutical) is a nitrocellulose membrane flow immunoassay performed at the POC with the use of blood obtained from a fingerprick. The results of this test were compared with those of enzyme immunoassay (EIA) performed on venous blood samples in the laboratory. Positive results of both tests were confirmed by a Western blot (WB). The study included 553 adults with known HIV (human immunodeficiency virus) seropositivity (all of whom had positive Merlin POC test results) and 2659 adults with unknown HIV serostatus (20 of whom had positive EIA/WB results; 19 of the 20 also had positive Merlin-POC test results). The sensitivity of the Merlin POC test was 95.0% for patients with an unknown HIV serostatus and 99.83% for those with a positive serostatus. For previously untested subjects, the test's specificity and positive predictive value were 100%, its negative predictive value was 99.96%, and its overall accuracy was 99.96%. The Merlin POC test is highly accurate for the detection of HIV antibodies.

AIDS Serodiagnosis↗
PubMed2002

Salvage antiretroviral therapy in HIV infection.

Highly-active antiretroviral (ARV) therapy (HAART) has lead to a sharp decline in AIDS-related morbidity and mortality. Treatment failure is a common, significant problem and as many as 50% of patients have detectable plasma HIV RNA despite being on combination ARV therapy. Clinicians must be knowledgeable about the reasons for treatment failure and the best options available for management. Treatment failure can occur because of non-compliance, drug discontinuation, lack of drug potency, inadequate drug plasma concentration and drug resistance. Strategies used when selecting salvage therapy include the use of resistance testing to choose a regimen, the exploitation of pharmacokinetic interactions by boosting protease inhibitor (PI) trough levels and counselling the patient on compliance. When selecting the agents to use in salvage therapy, the new regimen should ideally include as many new agents to which no or minimal resistance is anticipated and at least one new class of drugs if possible. Data on salvage therapy mostly comes from anecdotal reports and retrospective cohort studies. With a paucity of clinical trial data, clinicians are often forced to prescribe unproven regimens based on what is anticipated about cross-resistance and drug interactions. It is important that new agents and new targets continue to be developed as an increasing number of patients in practice have exhausted all treatment options.

Anti-HIV Agents↗
PubMedDate not supplied

Long-term follow-up of a cohort of HIV-infected patients who discontinued maintenance therapy for cytomegalovirus retinitis.

PURPOSE: To determine the long-term safety of discontinuation of maintenance therapy for cytomegalovirus retinitis (CMVR) and to identify predictors for relapse. METHOD: This was a prospective cohort study. Patients with treated CMVR who responded to HAART were followed by ophthalmologic assessment, markers for CMV replication (blood and urine cultures, CMV antigenemia, CMV DNA by PCR), and in vitro lymphoproliferative responses to CMV and other antigens after discontinuation of CMVR maintenance therapy. RESULTS: 23 patients were followed a median of 34 (range, 5-61) months. Median CD4 count was 321/mm3 at enrollment and 395/mm3 at last follow-up. HIV RNA was <50 copies/mL in 78% of patients at enrollment and 65% at last follow-up. One CMVR reactivation occurred at 12 months at a CD4 count of 395/mm3 (21%) and HIV RNA <50 copies/mL. Urine cultures were a poor predictive marker for reactivation. Other CMV replication markers had good negative predictive value. 96% of patients had a good lymphoproliferative response to CMV antigen in vitro. CONCLUSION: Maintenance therapy for CMVR can safely be discontinued in patients who have responded to HAART. Combining our results with the published literature, the risk of reactivation is estimated at 0.016 per person year of follow-up. Markers to predict relapse and the need for re-initiation of maintenance therapy are not yet identified.

AIDS-Related Opportunistic Infections↗