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Biomedical subjects

B Yip

Publications and source records attributed to B Yip.

At least 19 recordsLinked to original sources
PubMed1999

Baseline HIV drug resistance profile predicts response to ritonavir-saquinavir protease inhibitor therapy in a community setting.

OBJECTIVE: To determine whether baseline drug resistance assays could help to predict treatment failure with the protease inhibitor combination ritonavir-saquinavir. METHODS: Baseline HIV-1 drug resistance was determined for 76 consecutive patients who started treatment with the dual protease inhibitor combination ritonavir-saquinavir between September 1996 and June 1997 either alone or in combination with other antiviral agents. Resistance to 10 different antiviral agents was assessed by both phenotype (Virco Antivirogram) and genotype (Vircogen). RESULTS: Resistance inferred from viral genotype was similar to measured phenotypic resistance for both ritonavir and saquinavir (P<0.01). Baseline drug resistance phenotype was predictive of poor virological response to this dual protease inhibitor combination, despite the confounding effects of other antivirals. Patients were at least four times less likely to achieve a 0.5 log10 decrease in plasma HIV RNA viral load if their viral isolates were resistant to ritonavir or saquinavir. Patients classified as resistant to either drug using either method had median decreases in plasma viral load of 0.05 log10 HIV RNA copies/ml or less, compared to >0.8 log10 for those with sensitive virus. Patients resistant to both drugs never achieved plasma viral loads <100000 copies/ml. As little as fourfold increases in baseline resistance appeared to be sufficient to compromise even dual protease inhibitor therapy. CONCLUSION: Baseline resistance to ritonavir or saquinavir or both was associated with a poor antiviral response. Our data suggest that the measurement of drug resistance may assist in optimizing antiretroviral therapy in the clinic.

Anti-HIV Agents↗
PubMed1999

Improved survival among HIV-infected patients after initiation of triple-drug antiretroviral regimens.

BACKGROUND: The efficacy of triple-drug antiretroviral regimens in the treatment of patients infected with HIV has been established in several randomized clinical trials. However, the effectiveness of these new regimens in patient populations outside clinical trials remain unproven. This study compared mortality and AIDS-free survival among HIV-infected patients in British Columbia who were treated with double- and triple-drug regimens. METHODS: The authors used a prospective, population-based cohort design to study a population of HIV-positive men and women 18 years or older for whom antiretroviral therapy was first prescribed between Oct. 1, 1994, and Dec. 31, 1996; all patients were from British Columbia. Rates of progression from the initiation of antiretroviral therapy to death or to diagnosis of primary AIDS were determined for patients who initially received an ERA-II regimen (2 nucleoside analogue reverse transcriptase inhibitors [NRTIs] including lamivudine or stavudine, or both) and for those who initially received an ERA-III regimen (triple-drug regimen consisting of 2 NRTIs and a protease inhibitor [indinavir, ritonavir or saquinavir] or a non-NRTI [nevirapine]). RESULTS: A total of 500 men and women (312 receiving an ERA-III regimen and 188 an ERA-III regimen) were eligible. Patients in the ERA-III group survived significantly longer than those in the ERA-II group. As of Dec. 31, 1997, 40 patients had died (35 in the ERA-II group and 5 in the ERA-III group), for a crude mortality rate of 8.0%. The cumulative mortality rates at 12 months were 7.4% (95% confidence interval [CI] 5.9% to 8.9%) for patients in the ERA-II group and 1.6% (95% CI 0.7% to 2.5%) for those in the ERA-III group (log rank p = 0.003). The likelihood of death was more than 3 times higher among patients in the ERA-II group (mortality risk ratio 3.82 [95% CI 1.48% to 9.84], p = 0.006). After adjustment for prophylaxis for Pneumocystis carinii pneumonia or Mycobacterium avium infection, AIDS diagnosis, CD4+ cell count, sex and age at initiation of therapy, the likelihood of death among patients in the ERA-II group was 3.21 times higher (95% CI 1.24 to 8.30, p = 0.016) than in the ERA-III group. Cumulative rates of progression to AIDS or death at 12 months were 9.6% (95% CI 7.7% to 11.5%) in the ERA-II group and 3.3% (95% CI 1.8% to 4.8%) in the ERA-III group (log rank p = 0.006). After adjustment for prognostic variables (prophylaxis for P. carinii pneumonia or M. avium infection, CD4+ cell count, sex and age at initiation of treatment), the likelihood of progression to AIDS or death at 12 months among patients in the ERA-II group was 2.37 times higher (95% CI 1.04 to 5.38, p = 0.040) than in the ERA-III group. INTERPRETATION: This population-based cohort study confirms that patients initially treated with a triple-drug antiretroviral regimen comprising 2 NRTIs plus protease inhibitor or a non-NRTI have a lower risk of morbidity and death than patients treated exclusively with 2 NRTIs.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Suppression of plasma virus load below the detection limit of a human immunodeficiency virus kit is associated with longer virologic response than suppression below the limit of quantitation.

Suppression of human immunodeficiency virus type 1 plasma virus load (PVL) to <20 copies/mL is associated with a longer virologic response after initiation of antiretroviral therapy. The relationship between duration of virologic response and PVL nadir according to a less sensitive assay was explored. When compared with subjects with a PVL nadir >500 copies/mL, the relative risks of PVL rising above 1000 copies/mL for participants in the INCAS trial and the British Columbia Drug Treatment Program with a PVL nadir below the limit of detection (LOD) were 0.04 (95% confidence interval [CI], 0.02-0.09) and 0.06 (95% CI, 0.03-0.12), respectively. The corresponding relative risks for persons with a detectable but not quantifiable PVL nadir were 0.25 (95% CI, 0.13-0.50) and 0.54 (95% CI, 0.25-1.19). The relative risks of virologic failure associated with a PVL nadir detectable but not quantifiable and a PVL nadir below the LOD were statistically different (P<.0001) in both data sets.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Barriers to use of free antiretroviral therapy in injection drug users.

CONTEXT: In British Columbia, human immunodeficiency virus (HIV)-infected persons eligible for antiretroviral therapy may receive it free but the extent to which HIV-infected injection drug users access it is unknown. OBJECTIVE: To identify patient and physician characteristics associated with antiretroviral therapy utilization in HIV-infected injection drug users. DESIGN: Prospective cohort study with record linkage between survey data and data from a provincial HIV/AIDS (acquired immunodeficiency syndrome) drug treatment program. SETTING: British Columbia, where antiretroviral therapies are offered free to all persons with HIV infection with CD4 cell counts less than 0.50 x 10(9)/L (500/microL) and/or HIV-1 RNA levels higher than 5000 copies/mL. SUBJECTS: A total of 177 HIV-infected injection drug users eligible for antiretroviral therapy, recruited through the prospective cohort study since May 1996. MAIN OUTCOME MEASURES: Patient use of antiretroviral drugs through the provincial drug treatment program and physician experience treating HIV infection. RESULTS: After a median of 11 months after first eligibility, only 71 (40%) of 177 patients had received any antiretroviral drugs, primarily double combinations (47/71 [66%]). Both patient and physician characteristics were associated with use of antiretroviral drugs. After adjusting for CD4 cell count and HIV-1 RNA level at eligibility, odds of not receiving antiretrovirals were increased more than 2-fold for females (odds ratio [OR], 2.53; 95% confidence interval [CI], 1.08-5.93) and 3-fold for those not currently enrolled in drug or alcohol treatment programs (OR, 3.49; 95% CI, 1.45-8.40). Younger drug users were less likely to receive therapy (OR, 0.47/10-y increase; 95% CI, 0.28-0.80). Those with physicians having the least experience treating persons with HIV infection were more than 5 times less likely to receive therapy (OR, 5.55; 95% CI, 2.49-12.37). CONCLUSIONS: Despite free antiretroviral therapy, many HIV-infected injection drug users are not receiving it. Public health efforts should target younger and female drug users, and physicians with less experience treating HIV infection.

Adult↗
PubMed1998

The antiviral effect of ritonavir and saquinavir in combination amongst HIV-infected adults: results from a community-based study.

OBJECTIVE: To characterize the antiviral effect and predictors of response to ritonavir and saquinavir-based antiretroviral combination therapy. DESIGN: Intent-to-treat analysis with suppression of plasma viral load to levels below 2.7 log10 copies/ml as the main outcome measure. PATIENTS: All adult HIV-positive individuals in the province of British Columbia who started taking ritonavir and saquinavir (each at 600 mg twice daily) in combination from 1 September 1996 to 28 February 1997, with a minimum of two plasma viral load measurements, one at baseline and one after the initiation of therapy. RESULTS: A total of 58 participants were prescribed ritonavir and saquinavir. The median plasma viral load at entry was 4.80 log10 copies/ml (interquartile range, 4.51-5.15 log10 copies/ml). A total of 29 (50%) subjects demonstrated a decrease in plasma viral load to levels below 2.7 log10 copies/ml. This level of suppression was associated with higher baseline CD4 cell counts (P=0.022) and no prior exposure to protease inhibitors (P=0.001). After controlling for baseline CD4 cell count and plasma viral load, participants naive to protease inhibitors were almost seven times (odds ratio, 6.99; 95% confidence interval, 1.85-26.39; P=0.004) more likely to suppress their plasma viral load to below 2.7 log10 copies/ml than those who had previously used protease inhibitors. CONCLUSION: Our analysis demonstrates that a ritonavir and saquinavir-based combination can produce a substantial decrease in plasma viral load with half of the participants decreasing their plasma viral load to below the limit of quantification of the assay. This response, however, is seriously compromised by prior exposure to protease inhibitors.

Adult↗
PubMed1998

Antiviral effect of double and triple drug combinations amongst HIV-infected adults: lessons from the implementation of viral load-driven antiretroviral therapy.

OBJECTIVE: To study the antiviral effect and predictors of response to two- and three-drug regimens amongst antiretroviral-naive individuals using an intent-to-treat analysis. MAIN OUTCOME MEASURE: Suppression of plasma viral load to < 500 copies/ml. PATIENTS: A total of 420 (264 double drug, 156 triple drug) individuals in a province-wide treatment programme were studied. RESULTS: A decrease in plasma viral load to < 500 copies/ml was documented in 197 (47%) subjects. This was independently associated with a lower baseline plasma viral load (odds ratio, 3.67; 95% confidence interval, 2.13-6.30) and initiation onto a three-drug regimen (odds ratio, 3.86; 95% confidence interval, 2.24-6.66). Median plasma viral load failed to reach < 500 copies/ml and in fact rebounded in the two-drug group. In contrast, 91 (58%) subjects receiving three drugs reached < 500 copies/ml during the study period. CONCLUSION: These results support the use of powerful triple drug regimens as initial therapy in HIV-infected individuals.

Adult↗
PubMed1998

Improved survival among HIV-infected individuals following initiation of antiretroviral therapy.

CONTEXT: Clinical trials have established the efficacy of antiretroviral therapy with double- and triple-drug regimens for individuals infected with the human immunodeficiency virus (HIV), but the effectiveness of these regimens in the population of patients not enrolled in clinical trials is unknown. OBJECTIVE: To characterize survival following the initiation of antiretroviral therapy among HIV-infected individuals in the province of British Columbia. DESIGN: Prospective, population-based cohort study of patients with antiretroviral therapy available free of charge (median follow-up, 21 months). SETTING: Province of British Columbia, Canada. PATIENTS: All HIV-positive men and women 18 years of age or older in the province who were first prescribed any antiretroviral therapy between October 1992 and June 1996 and whose CD4+ cell counts were less than 0.350 x 10(9)/L. MAIN OUTCOME MEASURES: Rates of progression from initiation of antiretroviral therapy to death or a primary acquired immunodeficiency syndrome (AIDS) diagnosis for subjects who initially received zidovudine-, didanosine-, or zalcitabine-based therapy (ERA-I) and for those who initially received therapy regimens including lamivudine or stavudine (ERA-II). RESULTS: A total of 1178 patients (951 ERA-I, 227 ERA-II) were eligible. A total of 390 patients died (367 ERA-I, 23 ERA-II), yielding a crude mortality rate of 33.1%. ERA-I group subjects were almost twice as likely to die as ERA-II group subjects, with a mortality risk ratio of 1.86 (95% confidence interval [CI], 1.21 -2.86; P=.005). After adjusting for Pneumocystis carinii and Mycobacterium avium prophylaxis use, AIDS diagnosis, CD4+ cell count, sex, and age, ERA-I participants were 1.93 times (95% CI, 1.25-2.97; P=.003) more likely to die than ERA-II participants. Among patients without AIDS when treatment was started, ERA-I participants were 2.50 times (95% CI, 1.59-3.93; P<.001) more likely to progress to AIDS or death than ERA-II participants. CONCLUSION: The HIV-infected individuals who received initial therapy with regimens including stavudine or lamivudine had significantly lower mortality and longer AIDS-free survival than those who received initial therapy with regimens limited to zidovudine, didanosine, and zalcitabine.

AIDS-Related Opportunistic Infections↗
PubMed1998

Hemophilia B in a female carrier due to skewed inactivation of the normal X-chromosome.

A novel missense mutation (codon 351, GCT (Ala) --> CCT (Pro)) of the FIX gene was characterised in a young female with mild hemophilia B. She is heterozygous for the FIX mutation inherited from her carrier mother. Analysis of the methyl-sensitive Hpa II sites at the 5' end of the hypoxanthine phosphoribosyltransferase gene showed that skewed inactivation of the X chromosome carrying her normal FIX gene accounted for the hemophilia phenotype.

Adult↗
PubMed1998

The incidence and spectrum of AIDS-defining illnesses in persons treated with antiretroviral drugs.

The incidence and spectrum of primary AIDS-defining illnesses in human immunodeficiency virus-positive patients receiving antiretroviral drugs may have changed since the introduction of newer antiretroviral agents. We performed a retrospective analysis of patients enrolled in the British Columbia Drug Treatment Program who were ever prescribed antiretroviral drugs between 1 January 1994 and 31 December 1996. Rates were calculated on a 6-month basis. There were 344 AIDS cases diagnosed among 2,533 participants between 1994 and 1996. The incidence of primary AIDS diseases decreased from 1994 to 1996, with a sharp decline in 1995 and 1996. There was no statistically significant change in the incidence of primary AIDS diagnoses relative to one another, and Pneumocystis carinii pneumonia and Kaposi's sarcoma remain the most common AIDS index diagnoses. In patients receiving antiretroviral therapy in the modern era, the incidence of AIDS-defining illnesses has decreased substantially, but the spectrum of AIDS-defining illnesses remains unchanged.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Do dual nucleoside regimens have a role in an era of plasma viral load-driven antiretroviral therapy?

This study was undertaken to characterize predictors of response to double nucleoside combinations among 245 human immunodeficiency virus-infected persons initiating antiretroviral therapy. The median time for receiving antiretroviral therapy in this group was 6 months, and the plasma virus load was 58,000 copies/mL. The most commonly prescribed regimens were zidovudine/lamivudine (154 subjects, 63%) and stavudine/lamivudine (46 subjects, 19%). A total of 96 (39%) subjects had their virus load decrease to < 500 copies/mL after the initiation of therapy. Of the 245 study subjects, 102 (41.6%) had > or = 5 months of follow-up and two or more consecutive virus load determinations performed after the start of antiretroviral therapy. Multivariate analysis demonstrated that baseline virus load was the only significant factor associated with obtaining two or more plasma virus loads of < 500 copies/mL. Overall, these data demonstrate that dual nucleoside therapy (using currently licensed agents) cannot reliably achieve a high level of suppression of plasma virus load.

Adult↗
PubMed1998

Average annual drug cost and its determinants in a population based cohort of HIV-positive adult men and women.

The purpose of this study is to determine drug costs and the sociodemographic and clinical determinants of drug costs in a large open cohort of HIV-positive adult men and women in British Columbia, Canada from 1993 to 1995. The study is descriptive and population-based using time-series data. Individuals included in the study were men and women enrolled in a province-wide HIV/AIDS drug treatment programme who had given consent to access their entire prescription records held by the provincial drug plan. The primary outcome measure was the average annual drug cost for treating HIV/AIDS among programme participants; results were stratified by sociodemographic status, drug category and disease severity. The analysis was restricted to 1271 consenting programme participants. The average annual drug cost per participant in 1996 Canadian dollars ($Can) was $Can3431 in 1993, $Can3892 in 1994 and $Can4377 in 1995. Between 1993 and 1995, the average annual cost of antiretroviral therapies increased by 6.6% ($Can2579 in 1995), anti-infectives increased by 61.4% ($Can2402 in 1995) and other drugs used in the management of patients with HIV disease increased by 35.7% ($Can1146 in 1995). The overall increase over this period was 27.6%. In 1995, the average annual drug cost was $Can4720 for those on social assistance, $Can4545 for seniors and $Can5937 for the general population (nonpoor and nonelderly). In 1995, the average annual drug cost was $Can6887 for those with AIDS and $Can3911 for those without. Multivariate modelling indicated that drug costs were significantly related with CD4+ cell count (p < 0.001), diagnoses of AIDS (p < 0.001), provincial drug plan type (p = 0.002), time participants had spent in the HIV/AIDS Drug Treatment Program (p = 0.003), number of hospitalisations (p = 0.003) and patient's age (p = 0.004). Our data demonstrate that the average annual drug costs for persons with HIV/AIDS in British Columbia have been increasing even though the cost of antiretrovirals has been relatively stable. This was due mainly to the increase in the cost of anti-infectives and other drugs. Important cost drivers were participant's age, socioeconomic status (by provincial drug insurance coverage level) and rate of disease progression as measured by CD4+ cell counts, hospitalisation events and duration of illness.

Adult↗
PubMed1998

Modelling the potential economic impact of viral load-driven triple drug combination antiretroviral therapy.

The purpose of this study is to model the potential economic impact of viral load-driven triple drug combination (including a protease inhibitor) antiretroviral therapy on incremental drug and hospitalisation costs among individuals with HIV disease. Individuals included in the study were HIV-positive men and women from the province of British Columbia, Canada, who were aged 18 years or older and had given consent to access their medical records. The study employed pharmacoeconomic modelling of drug- and hospital-utilisation patterns among a population-based cohort with free access to antiretroviral therapy. Protease inhibitor use and associated costs based on actual use in a subsequent period was modelled upon men and women who were able to maintain stable CD4+ cell counts (slope > or = 0) for at least 6 months (baseline period) with an average follow-up period of 30 months (protease-like group). A control was modelled upon individuals with declining CD4+ cell counts (slope < 0) during similar baseline and follow-up periods. The primary outcome measure was average annual incremental cost of triple drug therapy net of hospitalisation and testing costs in 1996 Canadian dollars ($Can). The utilisation pattern of drugs and hospitals was modelled from actual use among a total of 1271 individuals who were eligible for this analysis. Programme participants who gave consent to access their medical records were more likely to be men (p < 0.001), older (p < 0.020), and on antiretroviral therapy (p < 0.001) than programme participants who did not give consent. No differences were observed between the protease-like and comparison groups with respect to age (p = 0.65) and CD4+ cell count (p = 0.30) at study entry. Over a period of 1 year, the protease-like group was shown to spend less time in hospital (2.7 vs 6.6 days; p < 0.001). This difference in hospitalisation remained in multivariate models, adjusting for prior AIDS-defining illnesses and gender. The average annual incremental cost of adding a protease inhibitor to a 2-drug antiretroviral regimen was estimated to be $Can2318 per person. The cost implications of hospital stay while using a protease inhibitor drug and 2 nucleosides translated into an average annual incremental cost (savings if negative) of between -$Can4798 and -$Can2227 per person. The overall average annual incremental cost impact per person associated with triple drug therapy with a protease inhibitor varied between -$Can2288 to $Can283. Negative incremental costs imply overall savings from adopting triple combination therapy. This modelling exercise demonstrated that the cost of triple drug combination antiretroviral therapy with a protease inhibitor among HIV-positive men and women was considerably less than the expected acquisition cost of the drug alone due to hospitalisation savings in the province of British Columbia.

Adult↗
PubMed1997

Expression of stable human O-glycan core 2 beta-1,6-N-acetylglucosaminyltransferase in Sf9 insect cells.

UDP-GlcNAc:Galbeta1-3GalNAc-R (GlcNAc to GalNAc) beta-1, 6-N-acetylglucosaminyltransferase (C2GnT) catalyses the formation of O-glycan core 2. Purification and characterization of C2GnT from natural sources has been hampered by the instability of this enzyme. We have been able to prepare a stable partly purified recombinant human C2GnT by expression of a truncated form of the enzyme in the baculovirus/Spodoptera frugiperda 9 (Sf9) insect cell system. C2GnT activity was secreted into the Sf9 culture medium (15 pmol/min per microl; approx. 0.2 mg/l) and was stable at 4 degrees C either in solution or after lyophilization. Endoglycosidase H and N-glycanase F treatment of the radiolabelled C2GnT indicated the presence of N-glycans at both potential N-glycosylation sites. The elimination of one or both of the two potential N-glycosylation sites or treatment of the virus-infected insect cells with tunicamycin resulted in loss of enzyme activity due in part to protein degradation.

Animals↗