Emerging drug toxicities of highly active antiretroviral therapy for human immunodeficiency virus (HIV) infection.

To provide an overview of the epidemiologic parameters of emerging adverse effects associated with antiretroviral therapy for human immunodeficiency virus (HIV) disease. All available antiretroviral agents are associated with significant adverse drug effects. Of particular interest are newly emerging suspected adverse drug effects which were not generally noted in pre-marketing trials nor captured under current standard clinical care practices. Suspected antiretroviral toxicities meeting these criteria include: HIV-associated lipodystrophy which can include peripheral lipoatrophy, lipohypertrophy and metabolic abnormalities; hyperlactatemia and lactic acidosis; and metabolic bone abnormalities such as decreased bone mineral density, osteoporosis and osteonecrosis. Results of prospective and observational studies reported to date suggest that these abnormalities, while aetiologically complex, are likely attributable to treatment factors and may be intricately interrelated. The medical management of these symptoms remains unsatisfactory given the unexplored efficacy of traditional approaches in the HIV positive population. While the pathogenic mechanism of these disorders remains obscure, a theory of tissue-specific mitochondrial toxicity has been proposed. With the continued introduction of novel therapies and standard treatment with combination therapy, new adverse events will continue to emerge among persons being treated for HIV disease. Beyond their immediate clinical implications, these events may contribute to changing patterns of antiretroviral utilisation including therapy initiation, adherence and cessation.

Lipodystrophy-associated morphological, cholesterol and triglyceride abnormalities in a population-based HIV/AIDS treatment database.

OBJECTIVE: To provide population-based estimates of the prevalence of lipodystrophy syndrome and constituent symptoms and to identify correlates of prevalent symptomology. METHODS: Participants in a province-wide HIV/AIDS treatment programme reported morphological and metabolic abnormalities. Probable lipodystrophy was defined as self-report of at least one morphological abnormality or both high cholesterol and triglyceride levels. Explanatory variables investigated included: age; sex; ethnicity; transmission risk group; CD4 cell count; plasma viral load; AIDS diagnosis; duration of infection; alternative therapy use; past, current and duration of use of antiretroviral therapy (ART) by class and specific drug; total duration of ART; and current adherence. Stepwise logistic regression identified possible determinates of lipodystrophy. RESULTS: Of 1035 participants, 50% appeared to have probable lipodystrophy, with 36% reporting peripheral wasting, 33% abdominal weight gain, 6% buffalo hump, and 10 and 12% increased triglyceride or cholesterol levels, respectively. In multivariate analysis, lipodystrophy was associated with older age (per year) (AOR 1.03; 95% CI 1.01, 1.04), the use of ingested alternative therapies (AOR 1.46; 95% CI 1.06, 2.01), having ever used protease inhibitors (PI) (AOR 2.63; 95% CI 1.89, 3.66), and duration of stavudine treatment (per year) (AOR 1.35; 95% CI 1.15, 1.58). In analysis limited to participants exposed to PI, after similar adjustment, the duration of lamivudine rather than stavudine treatment was associated with lipodystrophy (AOR 1.32; 95% CI 1.13, 1.53). CONCLUSION: Increased risk of abnormalities is associated with the use of PI, and the duration of stavudine and lamivudine treatment after adjustment for personal characteristics, clinical disease stage, duration of infection and detailed treatment history.

HIV-associated risk factors among young Canadian Aboriginal and non-Aboriginal men who have sex with men.

Young Aboriginal men face marginalization distinct in cause but similar in pattern to those seen among men who have sex with men (MSM) and may be at increased risk for HIV infection. We compared sociodemographic characteristics and risk taking behaviours associated with HIV infection among MSM of Aboriginal and non-Aboriginal descent. Data for this comparison were gathered from baseline questionnaires completed by participants in a cohort study of young MSM. Data collection included: demographic characteristics such as age, length of time residing in the Vancouver region, housing, employment, income and income sources; mental health and personal support; instances of forced sex and sex trade participation and; sexual practices with regular and casual male sex partners. Data were available for 57 Aboriginal and 624 non-Aboriginal MSM. Aboriginal MSM were significantly less likely to be employed, more likely to live in unstable housing, to have incomes of <$10,000 and to receive income assistance than non-Aboriginals (all P<0.01). Aboriginals also had higher depression scores (P<0.01), were more likely to report non-consensual sex (P=0.03), sexual abuse during childhood (P=0.04) and having been paid for sex (P<0.01). In the past year they were no more likely to have had sex with a male partner they knew to be HIV positive, to have had more than 50 male partners or to have unprotected anal insertive or receptive intercourse with their male partners (all P>0.05). Our data indicate that among MSM, Aboriginal men are at increased risk of antecedent risk factors for HIV infection including sexual abuse, poverty, poor mental health and involvement in the sex trade.

Experience in treating persons with HIV/AIDS and the legalization of assisted suicide: the views of Canadian physicians.

The objective of this study is to determine the opinions of a random sample of Canadian family physicians and a population of non-specialist physicians known to provide care to persons with HIV/AIDS about the legalization of physician assisted suicide for persons with HIV disease. In addition, we have attempted to ascertain the physician characteristics that may be associated with a favourable or negative opinion. Self-administered, anonymous questionnaires were mailed to 2,890 family physicians across Canada. Logistic regression analysis was used to determine whether physician characteristics were predictive of agreement with the legalization of physician assisted suicide. Of the respondents who had an opinion, 60% agreed with the legalization of physician assisted suicide. Multivariate analyses indicated that physicians who were living in the provinces of British Columbia (BC), Ontario, or Québec (OR = 1.63, 95% CI: 1.10, 2.43) and who provided routine follow-up care (OR = 1.85, 95% CI: 1.30, 2.63) or palliative care (OR 1.66, 95% CI: 1.13, 2.44) to those with HIV disease were more likely to agree with legalization of physician assisted suicide. This analysis demonstrates a strong support for the legalization of physician assisted suicide for persons with HIV disease among physicians experienced in providing care to those affected.

Human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) mortality in industrialized nations, 1987-1991.

OBJECTIVE: To compare patterns of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) mortality in 11 selected industrialized countries with highly developed death registration systems and a broad range of cumulative AIDS incidence rates. METHODS: Data on HIV/AIDS mortality were obtained from the World Health Organization (WHO) and Statistics Canada for the years 1987-1991. We obtained data for Australia, Canada, Denmark, France, the former Federal Republic of Germany, Italy, the Netherlands, New Zealand, Spain, Switzerland, and the US, stratified by sex and 5-year age groups. Population figures were obtained from national censal, post-censal or interpolated annual estimates compiled by WHO and from Statistics Canada. RESULTS: A total of 141534 deaths were attributed to HIV/AIDS (126224 in men and 15310 in women) in the 11 countries from 1987 to 1991. The majority of deaths (73.7%) occurred in the US. Other countries contributing substantially to the number of deaths were France (7.1%), Italy (4.9%), Spain (4.9%), former West Germany (3.5%), and Canada (3.0%). Age-specific death rates for men aged 25-44 years in 1991 were highest in the USA at 47.1 per 100000 population and highest for women in Switzerland at 7.7 per 100000 population. Potential years of life lost (PYLL) before age 75 years were highest for males in the US (2388 per 100000 population) and for females in Switzerland (373 per 100000 population). The lowest rates were in New Zealand (339 per 100000 population in men and 6.5 per 100000 population in women). CONCLUSIONS: This historical demographic analysis indicates that mortality resulting from HIV infection and AIDS among men and women varies considerable by country. Rates of death were highest in the US and lowest in Australia, the Netherlands, and New Zealand.

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.

Adherence to clinical guidelines for the therapeutic management of HIV disease.

OBJECTIVE: To determine the knowledge of HIV-disease management and the adherence to contemporary guidelines among British Columbia physicians whose practices focused on HIV/AIDS. DESIGN: Self-administered mail survey. PARTICIPANTS: All 659 physicians registered in a province-wide HIV/AIDS drug treatment program. OUTCOME MEASURES: Data on demographic and personal characteristics of respondents, level of HIV-related experience, use of preventive vaccinations and tests, and preferred approaches to the prophylaxis and treatment of common opportunistic infections. Knowledge scores in 4 areas of patient care, as well as an overall score, were computed by comparing respondents' answers with the therapeutic strategies recommended at the time of the survey. Associations between physician characteristics and knowledge scores were identified by linear regression analysis. RESULTS: Of the 659 physicians surveyed, 65% returned responses: only 38% returned completed surveys while a further 27% returned a follow-up survey that asked nonrespondents about their demographic characteristics and HIV-related experience. Scores for specific areas of patient management ranged from 29% for the treatment of opportunistic infections to 62% for preventive measures, with a mean overall score of 47%. Physician knowledge in all areas of patient care was associated with the number of HIV-positive patients in the practice (p = 0.003 to p < 0.001). Physicians who were younger were more knowledgeable regarding preventive measures (p = 0.001); those whose practice location was in Vancouver had a greater knowledge of prophylaxis (p = 0.047); and those who had medical specialty training were more knowledgeable about the treatment of opportunistic infections (p = 0.009). CONCLUSIONS: There is substantial disparity in how physicians approach the management of HIV and related conditions. Deviations from therapeutic guidelines are common and may be associated with physician characteristics, particularly lack of experience in managing HIV.

HIV/AIDS care giving physicians: their experience and practice patterns.

To identify associations between HIV-related experience and patterns of service provision, physicians across Canada were solicited by mail to register in a national network of HIV/AIDS care givers. Respondents provided data about: personal, demographic and practice characteristics; the number of HIV-positive patients ever seen; the nature of the HIV-positive client population; and services provided to HIV-positive patients. Univariate techniques provided a demographic and professional profile of participating physicians. Logistic regression was used to identify associations between level of HIV-related experience and the provision of patient services. The 566 registered physicians have provided care to 56,378 HIV-infected persons and represent every province and territory in Canada. Multivariate analysis revealed that highly experienced physicians were more likely to provide all 3 types of services considered, to practise in Montreal, Vancouver or Toronto, and to be medical specialists (all P < 0.001).

Determinants of complementary therapy use in HIV-infected individuals receiving antiretroviral or anti-opportunistic agents.

OBJECTIVE: To identify sociodemographic and clinical characteristics of persons using complementary therapy in an HIV/AIDS drug treatment program and to evaluate the associations between complementary therapy use and participant characteristics. METHODS: A cross-sectional study using program participants who completed an annual participant survey between 09/95 and 06/96. Surveys gathered data on use and motivations for use of complementary therapies. Complementary therapies included dietary, medicinal, tactile, and relaxation therapies. Statistical analyses were carried out using parametric and nonparametric measures and multivariate logistic analyses. Multivariate modeling considered age, income, education, time spent out of bed, and degree of pain as independent variables against complementary therapy use (Yes versus No). All reported p values are two-sided. RESULTS: A total of 657 participants completed an annual participant survey within the study period. Of these, 256 participants (39%) had ever used complementary therapies. Univariate analysis indicated that 195 patients (30%) had used dietary supplements, 141 (22%) had used herbal and other medicinal therapies, 145 (22%) had used tactile therapies, and 128 (20%) had used mental relaxation techniques. Multivariate analysis indicated that complementary use was independently associated with younger median age (p = .003), income >$7,300 U.S. (p = .014), having greater physical pain (p = .003), and a university education (p = .002). CONCLUSION: Use of complementary therapies in conjunction with HIV/AIDS medications appears to be most prevalent in young and highly educated individuals and to be associated with the debilitating and chronic nature of HIV disease.

Patterns of geographic mobility of persons with AIDS in Canada from time of AIDS index diagnosis to death.

OBJECTIVE: To characterize migration patterns of persons with AIDS in Canada during the period from AIDS diagnosis to death. DESIGN: Descriptive, population-based study. SETTING: Canada. PATIENTS: Canada's AIDS Case Reporting Surveillance System (ACRSS) was linked to deaths in the Canadian Mortality Data Base (CMDB). Probabilistic linkage was based on initials, date of birth, date of death, birthplace, and location at diagnosis and at death. Analysis was restricted to AIDS cases reported from Jan. 1, 1982, to Sept. 30, 1994, and to deaths reported from Jan. 1, 1982, to Dec. 31, 1992. MAIN OUTCOME MEASURES: Change in usual place of residence; migration rates by region and community size. RESULTS: A total of 5755 AIDS cases recorded in the ACRSS were linked to deaths in the CMDB. Of these linked cases, 5366 (93%) included information on province or territory of usual residence or community size. A total of 160 (3.0%) persons with AIDS changed their province or territory of residence between the time of their AIDS diagnosis and death. Multivariate analysis indicated that those who changed residences between AIDS index diagnosis and death were more likely than other persons with AIDS to live in provinces other than British Columbia, Ontario and Quebec (p < 0.001), to be diagnosed earlier (p = 0.004), to be younger (p < 0.001) and to be gay or bisexual (p = 0.042). CONCLUSIONS: Our analysis revealed that only a small proportion of persons changed their residence between AIDS diagnosis and death. Geographic mobility was the greatest among persons with AIDS residing outside of the regions where the overwhelming majority of persons with AIDS in this country reside.

Heterogeneity of physician agreement with recommended therapeutic guidelines for the management of HIV-associated disease.

The aims of this study were to assess the degree of heterogeneity in the knowledge of therapeutic management of HIV infection among HIV-experienced physicians in British Columbia, Canada, and to identify associations between physician characteristics and their agreement with contemporary therapeutic guidelines. A self-administered anonymous questionnaire was mailed to 6500 physician members of the British Columbia Medical Association. The questionnaire provided information about demographic and personal characteristics, including sex, age, medical specialization and practice location; level of experience in treating HIV-infected patients; use of HIV testing procedures; use of preventative vaccinations and tests; and preferred approaches to antiretroviral therapy and the prophylaxis and acute treatment of opportunistic infections. We compared physicians' patterns of knowledge with contemporary recommendations. Logistic regression identified associations between physician characteristics and their agreement with contemporary guidelines. A total of 463 HIV-experienced physicians (a high proportion of the HIV-experienced physicians in British Columbia, Canada) responded to the questionnaire. The agreement with contemporary guidelines about HIV testing and preventative vaccinations and tests among responders ranged from 27% to 71%. For antiretroviral therapy, agreement with the guidelines ranged from 12% to 35%. For the prophylaxis and treatment of opportunistic infections, agreement with the guidelines ranged from 11% to 89% (prophylaxis) and from 46% to 91% (treatment). Regression analysis revealed that physicians actively involved in the care of HIV-infected patients were more likely to agree with the guidelines in all areas of patient care. General practitioners were more likely to agree with the guidelines regarding preventative therapies, and male general practitioners under 45 years old were more likely to agree with the guidelines on antiretroviral therapy. Our data confirm that there is substantial heterogeneity in the management of HIV-associated disease, including some deviations from contemporary guidelines. Concordance with contemporary guidelines increased with the physician's level of HIV-related experience. Our results support the idea that adherence to state-of-the-art practices may be responsible, at least in part, for the recently described association between physician experience and improved survival of HIV-infected individuals.

HIV/AIDS mortality in Canada: evidence of gender, regional and local area differentials.

OBJECTIVE: To assess the impact of HIV infection and AIDS on mortality patterns in Canada with specific reference to gender and regional differentials and to other leading causes of death. DESIGN: Descriptive, population-based study. SETTING: Canada. PATIENTS: All persons for whom HIV/AIDS [ninth revision of the International Classification of Diseases (ICD-9) 042-044] was recorded as the underlying cause of death as reported to Statistics Canada between 1987 and 1992. For comparative purposes data was obtained on five other leading underlying causes of death including coronary heart disease (ICD-9 410-414), motor vehicle accidents (ICD-9 E810-E819), and suicides (ICD-9 E950-E959) in men and women, lung cancer (ICD-9 162) in men and breast cancer (ICD-9 174) in women. Population figures were obtained from Statistics Canada estimates. MAIN OUTCOME MEASURES: Age and cause-specific mortality rates, standardized mortality ratios (SMR), potential years of life lost (PYLL) before age 65 years, and life expectancy lost due to a select underlying cause of death. RESULTS: Over the period 1 January 1987 to 31 December 1992, 5546 deaths attributed to HIV/AIDS (5229 in men and 317 in women) were recorded in Canada. SMR for men were significantly higher than the national average in the cities of Vancouver, Toronto and Montreal, whereas those for women were significantly greater only in Montreal. Deaths from HIV/AIDS accounted for 3.6% of PYLL in men and 0.4% of PYLL in women. In 1992, HIV/AIDS was the third leading cause of male PYLL surpassing lung cancer. In the cities of Montreal, Toronto, and Vancouver HIV/AIDS was the leading cause of PYLL and was responsible for significant decrease in life expectancy at birth in men over the study period. CONCLUSIONS: HIV/AIDS has had considerable impact on mortality within Canada, principally among men and particularly in the cities of Toronto, Vancouver and Montreal.