The Cedar Project: exploring determinants of psychological distress among young Indigenous people who use drugs in three Canadian cities.

BACKGROUND: Mental health and wellbeing, including addressing impacts of historical trauma and substance use among young people, has been identified as a key priority by Indigenous communities and leaders across Canada and globally. Yet, research to understand mental health among young Indigenous people who have used drugs is limited. AIMS: To examine longitudinal risk and strengths-based factors associated with psychological distress among young Indigenous people who use drugs. METHOD: The Cedar Project is an ongoing cohort study involving young Indigenous people who use drugs in Vancouver, Prince George, and Chase, British Columbia, Canada. This study included participants who completed the Symptom Checklist-90-Revised, returned for follow-up between 2010 and 2012, and completed the Childhood Trauma Questionnaire. Adjusted linear mixed-effects models estimated effects of study variables on changes in area T-scores of psychological distress. RESULTS: Of 202 eligible participants, 53% were women and the mean age was 28 years. Among men, childhood maltreatment (emotional abuse, physical abuse, sexual abuse, physical neglect), any drug use, blackouts from drinking, and sex work were associated with increased distress. Among women, childhood maltreatment (emotional abuse, physical abuse, physical neglect), blackouts from drinking, and sexual assault were associated with increased distress, while having attempted to quit using drugs was associated with reduced distress. Marginal associations were observed between speaking their traditional language and living by traditional culture with lower distress among men. CONCLUSION: Culturally safe mental wellness interventions are urgently needed to address childhood trauma and harmful coping strategies that exacerbate distress among young Indigenous people who use drugs.

Application of the World Health Organization system for HIV infection in a cohort of homosexual men in developing a prognostically meaningful staging system.

OBJECTIVE: Validation of a modified version of the recently proposed World Health Organization (WHO) staging system for HIV infection and disease in a cohort of homosexual men. METHODS: Five hundred and thirty HIV-positive men followed for a median of 51 months (range, 1-98 months) were eligible for analysis. Subjects were classified into stages at their first seropositive visit and at all subsequent visits. RESULTS: As of 1 April 1991, 136 subjects (26%) had progressed to stage IV of the modified WHO system on the basis of their CD4 lymphocyte counts, and 78 subjects (15%) had died. Kaplan-Meier estimates for progression to stage IV from stages I, II and III were 52.8 +/- 7.5% over 6.6 years, 58.1 +/- 7.1% over 5.9 years and 66.5 +/- 9.7% over 5.7 years (log-rank P = 0.0001). Estimated median times to stage IV were 6.4, 5.3 and 3.8 years from stages I, II and III, respectively. Estimated median times to death were 10.9, 8.2, 6.3 and 1.7 years from stages I to IV, respectively. Results remained unchanged when CD4 lymphocyte count was replaced with lymphocyte count in the laboratory axis of the staging system. CONCLUSIONS: The proposed staging scheme, based on the WHO system, provides a prognostically meaningful classification for HIV infection in a cohort of homosexual men. Furthermore, the use of absolute lymphocyte count as a valid alternative for CD4 lymphocyte count has implications for the applicability of this system in many parts of the world where diagnostic resources are limited.

Indirect costs of HIV/AIDS mortality in Canada.

OBJECTIVE: To estimate and compare the societal impact of HIV infection and AIDS with other selected causes of male mortality in terms of the indirect costs of future production lost. DESIGN: Descriptive, population-based economic evaluation study. PATIENTS: All men aged 25-64 years for whom HIV/AIDS or another selected disease was listed as the underlying cause of death in Canada from 1987 to 1991, as reported to Statistics Canada. SETTING: Canada. MAIN OUTCOME MEASURES: Present value of future earnings lost for men using a human capital approach based on potential years of life lost in men aged 25-64 years. RESULTS: Assuming a 2% annual growth in earnings and a 3% annual real discount rate, the present value of the total loss of future production for all men aged 25-64 years who died in Canada during 1987-1991 was estimated to be 39.74 billion 1990 US$. Deaths due to HIV/AIDS accounted for 5.3% of this total loss or 2.11 billion in 1990 US$. Future production loss due to HIV/AIDS more than doubled during the period from 1987 to 1991, from 0.27 to 0.60 billion 1990 US$. The loss in future earnings attributable to HIV/AIDS was exceeded only by that of ischaemic heart disease (15.2%), suicide (9.4%), motor vehicle accidents (6.6%), and lung cancer (6.6%). In total, these five causes of death accounted for 43.1% of the total indirect cost of production lost for men aged 25-64 years during the 5-year period. CONCLUSION: Our findings demonstrated HIV/AIDS mortality is already having a dramatic impact on future wealth production in Canada. If the past trend continues, the production lost in 1994 should exceed 0.86 billion 1990 US$ and will account for more than 10% of the total annual loss for men aged 25-64 years.

Increasing age is associated with faster progression to neoplasms but not opportunistic infections in HIV-infected homosexual men.

OBJECTIVE: To characterize the associations of age and progression rates to AIDS-defining neoplasms and opportunistic infections (OI) in HIV-infected homosexual men. METHODS: Data from 407 homosexual men with documented dates of HIV seroconversion participating in cohort studies from four geographic locations were merged. Kaplan-Meier and Cox proportional hazards analyses were conducted with respect to the association of age with time from seroconversion to the first AIDS-defining neoplasm and OI. RESULTS: Among the 407 participants, 139 (34%) were diagnosed with AIDS; 45 (11%) with neoplasms and 90 (22%) with OI. Older age at seroconversion was significantly associated with faster progression to neoplasms, but not to OI. For each 10-year increase in age the risk for neoplasms increased 1.65-fold [95% confidence interval (CI), 1.12-2.43], after adjustment for clinical treatments. For OI this risk estimate was 0.98 (95% CI, 0.72-1.34). CONCLUSIONS: Increasing age is associated with faster progression to AIDS-defining neoplasms, but not with progression to OI. This has not been previously reported and may explain conflicting results in other studies among homosexual men that considered AIDS as a single entity. Our findings suggest that age and AIDS manifestations should be considered, particularly in the context of natural history studies, clinical trials and mathematical modelling.

The changing spectrum of AIDS index diseases in Canada.

OBJECTIVE: To describe the changing spectrum of AIDS index diseases in Canada over a 10-year period from 1981 to 1991. DESIGN: A descriptive, population-based study. SETTING: Canada. PATIENTS: All cases of AIDS in Canada reported by the Division of HIV/AIDS Epidemiology of the Department of National Health and Welfare. MAIN OUTCOME MEASURES: Age-standardized rates of initial AIDS manifestations (1987 Centers for Disease Control and Prevention case definition), by year of diagnosis among adults in Canada. RESULTS: A total of 6641 adult AIDS cases were examined. The rate of Pneumocystis carinii pneumonia (PCP) peaked in 1989 with a rate of 3.18 per 100,000, declining to 2.74 per 100,000 in 1991 (P = 0.894). Similarly, the rate of Kaposi's sarcoma (KS) stabilized during this interval from 1.06 per 100,000 in 1987 to 1.14 per 100,000 in 1991 (P = 0.189). In contrast, the rates of all other AIDS-defining illnesses increased from 1.48 per 100,000 in 1987 to 3.43 per 100,000 in 1991 (P = 0.001). For these other AIDS index diseases, significant rate increases were observed for esophageal candidiasis, cytomegalovirus (CMV) diseases, wasting syndrome, toxoplasmosis, and Mycobacterium avium complex (MAC) disease. CONCLUSIONS: Our study shows a leveling and decline in incidence of KS and PCP, respectively, and a concomitant increase of other diagnoses, especially esophageal candidiasis, CMV, wasting syndrome, toxoplasmosis, and MAC disease in Canada. These findings highlight the importance of developing specific strategies to prevent emerging AIDS index diseases and serve as a cautionary note to practicing clinicians, indicating the relative widening of the spectrum of HIV index diseases.

Needle exchange is not enough: lessons from the Vancouver injecting drug use study.

OBJECTIVE: To describe prevalence and incidence of HIV-1, hepatitis C virus (HCV) and risk behaviours in a prospective cohort of injecting drugs users (IDU). SETTING: Vancouver, which introduced a needle exchange programme (NEP) in 1988, and currently exchanges over 2 million needles per year. DESIGN: IDU who had injected illicit drugs within the previous month were recruited through street outreach. At baseline and semi-annually, subjects underwent serology for HIV-1 and HCV, and questionnaires on demographics, behaviours and NEP attendance were completed. Logistic regression analysis was used to identify determinants of HIV prevalence. RESULTS: Of 1006 IDU, 65% were men, and either white (65%) or Native (27%). Prevalence rates of HIV-1 and HCV were 23 and 88%, respectively. The majority (92%) had attended Vancouver's NEP, which was the most important syringe source for 78%. Identical proportions of known HIV-positive and HIV-negative IDU reported lending used syringes (40%). Of HIV-negative IDU, 39% borrowed used needles within the previous 6 months. Relative to HIV-negative IDU, HIV-positive IDU were more likely to frequently inject cocaine (72 versus 62%; P < 0.001). Independent predictors of HIV-positive serostatus were low education, unstable housing, commercial sex, borrowing needles, being an established IDU, injecting with others, and frequent NEP attendance. Based on 24 seroconversions among 257 follow-up visits, estimated HIV incidence was 18.6 per 100 person-years (95% confidence interval, 11.1-26.0). CONCLUSIONS: Despite having the largest NEP in North America, Vancouver has been experiencing an ongoing HIV epidemic. Whereas NEP are crucial for sterile syringe provision, they should be considered one component of a comprehensive programme including counselling, support and education.

One world, one hope: the cost of providing antiretroviral therapy to all nations.

OBJECTIVE: To estimate the potential direct cost of making triple combination antiretroviral therapy widely available to HIV-positive adults and children living in countries throughout the world. METHODS: For each country, antiretroviral costs were obtained by multiplying the annual cost of triple antiretroviral therapy by the estimated number of HIV-positive persons accessing therapy. Per capita antiretroviral costs were computed by dividing the antiretroviral costs by the country's total population. The potential economic burden was calculated by dividing per capita antiretroviral costs by the gross national product (GNP) per capita. All values are expressed in 1997 US dollars. RESULTS: The potential cost of making triple combination antiretroviral therapy available to HIV-positive individuals throughout the world was estimated to be over US$ 65.8 billion. By far the greatest financial burden was on sub-Saharan Africa. The highest per capita drug cost in this region would be incurred in the subregions of Southern Africa (US$ 149) followed by East Africa (US$ 116), Middle Africa (US$ 44), and West Africa (US$ 42). In the Americas, subregional data indicated the highest per capita drug cost would be in the Latin Caribbean (US$ 22), followed by the Caribbean (US$ 17), Andean Area (US$ 7), the Southern Cone (US$ 6), North America (US$ 6), and Central American Isthmus (US$ 5). In Asia and Europe the percentage of the GNP necessary to finance drug therapy was less than 1% in most countries examined. CONCLUSION: Our results demonstrate that the cost of making combination antiretroviral therapy available worldwide would be exceedingly high, especially in countries with limited financial resources.

PIP: In 1997, an estimated 5.8 million people worldwide were infected with HIV, of whom 90% lived in developing countries, especially in sub-Saharan Africa. While antiretroviral therapy has been shown to prolong survival in people with HIV/AIDS, many of the countries with the highest rates of HIV infection have little or no access to antiretroviral therapy, for a number of reasons, including cost. Findings are presented from a study conducted to estimate the potential direct cost of making triple combination antiretroviral therapy widely available to all of the world's HIV-infected population. The potential cost of making such therapy available to HIV-positive people worldwide was estimated to be over US$65.8 billion, in 1997 US dollars, with the greatest expenditures needed in sub-Saharan Africa. The highest per capita drug cost in sub-Saharan Africa would be incurred in Southern Africa (US$149), followed by East Africa (US$116), Middle Africa (US$44), and West Africa (US$42). In the Americas, per capita drug costs would be US$22 in the Latin Caribbean, US$17 in the Caribbean, US$7 in the Andean Area, US$6 in the Southern Cone and North America, and US$5 in the Central American Isthmus. In Europe and Asia, the percentage of GNP needed to finance drug therapy was less than 1% in most countries examined. For each country, antiviral costs were determined by multiplying the annual cost of triple antiretroviral therapy by the estimated number of HIV-positive people accessing therapy. Per capita therapy costs were calculated by dividing the antiretroviral costs by the country's total population. The potential economic burden was calculated by dividing per capita antiretroviral costs by the gross national product (GNP) per capita.

Clinical correlates of in vitro HIV-1 resistance ot zidovudine. Results of the Multicentre Canadian AZT Trial.

OBJECTIVE: To describe the rate of development of in vitro HIV resistance to zidovudine (ZDV) and its prognostic implications within the Multicentre Canadian AZT Trial (MCAT). METHODS: HIV-infected subjects in Centers for Disease Control (CDC) stages IIB, III and IVC-2 with CD4 cell counts > 270 x 10(6)/l were treated with ZDV as part of a dose-range study. Participating volunteers underwent prospective clinical and laboratory evaluations at regular intervals. Viral cultures and sensitivity testing were performed every 12 weeks in a predefined subset of 50 volunteers. An isolate was designated ZDV-resistant if it had a median inhibitory concentration (IC50) for ZDV at least 50-fold higher than that of virus isolated from the same subject before initiation of antiviral chemotherapy. The relationship between resistance and subsequent disease progression was studied using the Mantel and Byar method, for which, at each instance of disease progression, 2 x 2 tables classifying progression versus resistance status were constructed. The observed number of progressions was compared with that expected under the null hypothesis using Mantel-Haenszel methods adjusted for baseline CD4:CD8 ratio. RESULTS: The Kaplan-Meier estimate for the cumulative development of in vitro resistance was 64% [95% confidence interval (CI), 41-78] at 180 weeks. Baseline CD4:CD8 ratio was negatively associated (P = 0.10) with the subsequent development of resistance (proportional hazard, 0.44; 95% CI, 0.17-1.10). After adjusting for baseline CD4:CD8 ratio, the numbers of observed and expected progressions following the development of resistance were 15 and 7.6, respectively (P = 0.008). A similar relative risk of progression between resistant and non-resistant states was found in the two CD4:CD8 strata; observed and expected progressions were 4 and 2.3 and 11 and 5.2 in the high and low CD4:CD8 strata, respectively. CONCLUSIONS: In vitro resistance to ZDV developed in 64% of subjects after 180 weeks of ZDV therapy. Lower CD4:CD8 ratio at baseline was associated with faster development of resistance. In addition, the development of resistance was found to be a marker of subsequent disease progression. This association persisted after adjustment for baseline CD4:CD8 ratio. Whether in vitro resistance to ZDV is merely a surrogate marker or a determinant of disease progression remains to be established.

Use of pooling and outpatient laboratory specimens in an anonymous seroprevalence survey of HIV infection in British Columbia, Canada.

OBJECTIVE: To conduct an anonymous HIV seroprevalence survey to establish a baseline estimate of HIV seroprevalence in a general population; to evaluate serum pooling and alternative testing strategies as cost-saving measures. DESIGN: Prospective anonymous HIV seroprevalence study using outpatient laboratory specimens. SETTING: Two large non-hospital-associated outpatient chemistry testing laboratories in the major population centers in British Columbia, Canada. PATIENTS AND SERA: Leftover sera received for chemistry screen testing in outpatient laboratories were provided to the study after chemistry testing was completed. Those from patients aged < 15 and > or = 55 years were excluded. METHODS: Patient identifiers were erased from samples. Sera were pooled 10:1 and tested by viral lysate enzyme-linked immunosorbent assay (ELISA). Sera from HIV-positive pools were tested individually. All individual HIV-positive specimens were retested for verification of positivity using a recombinant protein ELISA. MAIN OUTCOME MEASURES: HIV seroprevalence rates were stratified by sex, age group, and geographic area; and costs of pooling and alternative algorithm strategy were compared with those of conventional methods. RESULTS: A total of 80,238 sera were collected from 66,658 individuals (53% women, 47% men). Of these, 276 men (88.3 per 10,000) and 24 women (6.8 per 10,000) were HIV-seropositive. The highest rates were in those aged 30-34 years, for both men and women. Using pooling and non-Western blot verification saved US$2.07 per specimen, or 80% of the cost for conventional testing. CONCLUSIONS: The anonymous outpatient laboratory setting is practicable to obtain a reasonable estimate of HIV seroprevalence rates in a general population. Such studies can be made cost-effective by pooling sera and using alternative confirmatory strategies.

Lack of consistency between five definitions of nonprogression in cohorts of HIV-infected seroconverters.

OBJECTIVE: To identify appropriate criteria for characterizing HIV-infected nonprogressors. DESIGN: Five definitions were compared as follows: (1) last CD4 count > 500 x 10(6)/l; (2) two most recent CD4 counts > 500 x 10(6)/l; (3) calculated CD4 count based on linear regression > 500 x 10(6)/l; (4) CD4 slope > or = 0 with no antiretroviral use; (5) all CD4 counts > 500 x 10(6)/l, decline in CD4 slope < 5 cells per year, no antiretroviral use. PARTICIPANTS: Five prospective cohorts of homosexual men with documented dates of HIV-1 seroconversion. MAIN OUTCOME MEASURES: Proportions of nonprogressors were calculated 7, 8, 9 and 10 years following seroconversion (n = 285). Definitions were evaluated with respect to consistency over time and across sites. Subjects lacking CD4 counts within 3 years preceding end of follow-up were excluded. RESULTS: Across sites, proportions of nonprogressors ranged from 1% (definition 5) to 17.5% (definition 1) 10 years after seroconversion. Definitions based on absolute CD4 counts (definitions 1-3) had higher proportions and were less consistent than those based on stable slopes (definitions 4 and 5). For each definition, proportions decreased as follow-up increased, but were most stable for definition 4 (3%). Site differences decreased as follow-up increased, but remained nearly threefold for definitions 1-3. None of the definitions classified the same subjects as nonprogressors at any timepoint. CONCLUSIONS: Observations regarding nonprogression are highly dependent on the definition and the duration of follow-up. Our findings highlight methodological challenges which will need to be overcome in natural history studies of nonprogression.

Low HIV-1 proviral DNA burden detected by negative polymerase chain reaction in seropositive individuals correlates with slower disease progression.

During 1989, 316 members of a cohort of homosexual men were tested for HIV-specific DNA by the polymerase chain reaction (PCR) using a pair of gag-region primers. Of 125 HIV-seronegative subjects, 123 (98.4%) were PCR-negative while 158 (82.7%) of 191 HIV-seropositive subjects were PCR-positive. Fewer of the 33 subjects who were seropositive and PCR-negative were at Centers for Disease Control (CDC) stage IV than the seropositive, PCR-positive subjects (6 versus 25%; P = 0.030). The seropositive, PCR-negative group had higher mean CD4 counts (640 versus 490 x 10(6) cells/l; P = 0.006), higher CD4: CD8 ratios (0.92 versus 0.64; P = 0.004), lower immunoglobulin (Ig) G levels (1290 versus 1645 mg/dl; P = 0.002), lower IgA levels (168 versus 251 mg/dl; P less than 0.001), and lower C1q binding activity (8 versus 14%; P = 0.010) than the seropositive, PCR-positive subjects. The median rate of CD4 cell decline in the 3 years preceding the PCR sample was less marked in the seropositive, PCR-negative group than the seropositive, PCR-positive group (-58 versus -77 x 10(6) cells/l per year; P = 0.028). To control for duration of infection, we restricted the analysis to the subgroups of 11 seropositive, PCR-negative subjects and 34 seropositive, PCR-positive subjects who had seroconverted earlier in the cohort study. Both subgroups had similar durations of infection, yet the same pattern of differences persisted.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

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.

Do needle exchange programmes increase the spread of HIV among injection drug users?: an investigation of the Vancouver outbreak.

OBJECTIVE: An association between needle exchange attendance and higher HIV prevalence rates among injecting drug users (IDU) in Vancouver has been interpreted by some to suggest that needle exchange programmes (NEP) may exacerbate HIV spread. We investigated this observed association to determine whether needle exchange was causally associated with the spread of HIV. DESIGN AND METHOD: Prospective cohort study of 694 IDU recruited in the downtown eastside of Vancouver. Subjects were HIV-negative at the time of recruitment and had injected illicit drugs within the previous month. RESULTS: Of 694 subjects, the 15-month cumulative HIV incidence was significantly elevated in frequent NEP attendees (11.8+/-1.7 versus 6.2+/-1.5%; log-rank P = 0.012). Frequent attendees (one or more visits per week) were younger and were more likely to report: unstable housing and hotel living, the downtown eastside as their primary injecting site, frequent cocaine injection, sex trade involvement, injecting in 'shooting galleries', and incarceration within the previous 6 months. The Cox regression model predicted 48 seroconversions among frequent attendees; 47 were observed. Although significant proportions of subjects reported obtaining needles, swabs, water and bleach from the NEP, only five (0.7%) reported meeting new friends or people there. When asked where subjects had met their new sharing partners, only one out of 498 respondents cited the needle exchange. Paired analysis of risk variables at baseline and the first follow-up visit did not reveal any increase in risk behaviours among frequent attendees, regardless of whether they had initiated drug injection after establishment of the NEP. CONCLUSIONS: We found no evidence that this NEP is causally associated with HIV transmission. The observed association should not be cited as evidence that NEP may promote the spread of HIV. By attracting higher risk users, NEP may furnish a valuable opportunity to provide additional preventive/support services to these difficult-to-reach individuals.

Prevalence of primary HIV drug resistance among seroconverters during an explosive outbreak of HIV infection among injecting drug users.

OBJECTIVES: This study examined the frequency of transmission of drug resistant HIV in the population of injecting drug users (IDU) in Vancouver, Canada during a period of particularly high virus transmission. DESIGN: All subjects enrolled in the Vancouver Injection Drug Users Study who seroconverted from HIV negative to positive status (n = 61) between December 1996 and February 1998 were eligible for analysis. The first seropositive sample from 57 individuals with plasma samples available was analyzed for resistance to antiretroviral agents by population based sequencing of the HIV protease and reverse transcriptase genes. METHODS: Plasma viral RNA was extracted and the viral reverse transcriptase and protease regions were amplified by nested reverse transcription-PCR. The presence of mutations associated with antiretroviral drug resistance was assessed by automated sequence analysis. RESULTS: Protease and reverse transcriptase sequences were successfully obtained from the 57 recent seroconverters. No cases of transmission of variants associated with significant resistance to protease inhibitors or nucleoside and non-nucleosides reverse transcriptase inhibitors were detected. CONCLUSION: The frequency of transmission of drug resistant HIV amongst these recently infected IDU is extremely low, with no protease or reverse transcriptase inhibitor resistant strains detected soon after seroconversion. The data provide no rationale for withholding treatment from this already marginalized population.

Effects of long-term seropositivity to human immunodeficiency virus in a cohort of homosexual men.

The long-term effects of HIV infection were evaluated by comparing data from two visits a mean of 18 months apart in groups of 148 persistently seropositive and 287 persistently seronegative homosexual men. At each visit, the seropositive men exhibited lower CD4 counts, CD4/CD8 ratios, hemoglobin concentrations and lymphocyte counts, and higher C1q binding, IgG and IgA levels. More important, the decline of the CD4/CD8 ratio and the rise of the C1q binding, IgG and IgA, progressed significantly in the seropositive group between visits. Seropositive men were at elevated risk of developing constitutional symptoms and generalized lymphadenopathy. An association was present between development of symptoms and inversion of the CD4/CD8 ratio. The 11 seropositive men who have progressed to AIDS had lower CD4 counts and CD4/CD8 ratios, and higher C1q binding, IgG and IgA, than 134 seropositive AIDS-free men a mean of 21.4 months prior to diagnosis. The AIDS group demonstrated greater decline between visits in the CD4 count, hemoglobin and white blood count (WBC) than the seropositive AIDS-free group. The present data document the long-term effects of HIV infection in a seropositive cohort and suggest the possibility of a subgroup particularly susceptible to the progressive effects of HIV that precede the development of the acquired immunodeficiency syndrome (AIDS).

Susceptibility to AIDS progression appears early in HIV infection.

To investigate whether predictors of AIDS progression are operative very early in the natural history of HIV infection, we conducted a nested case-control study within a cohort of 119 subjects who seroconverted while under observation in a prospective study of homosexual men. For each of the 18 cases who have progressed to AIDS, we randomly selected three controls who had seroconverted within 3 months of the case but who have remained AIDS-free. Cases and controls were compared with regard to laboratory and clinical parameters obtained at the time of the earliest HIV-positive result. The median duration between the estimated date of seroconversion and this first positive result was 4 months for cases and 6 months for controls. Cases exhibited lower CD4 counts (657 versus 774 x 10(6)/l; P = 0.037), lower CD4: CD8 ratios (0.98 versus 1.39; P = 0.003), higher immune complex levels (C1q binding: 25 versus 15%; P = 0.002), lower hemaglobin concentrations (14.8 versus 15.2 g/l; P = 0.011), higher immunoglobulin (Ig) A levels (272 versus 184 mg/dl; P = 0.003), and higher IgG levels (1530 versus 1300 mg/dl; P = 0.037) than controls. Cases exhibited higher CD8 counts of marginal statistical significance (732 versus 597 x 10(6)/l; P = 0.059). No differences were observed with respect to IgM levels, total lymphocyte or white blood cell counts, or the frequency of generalized lymphadenopathy. A total of 27.8% of cases but only 11.5% of controls reported one or more symptoms during the 6-month period preceding the first positive visit (P = 0.027). We conclude that laboratory and clinical abnormalities which are predictive of more rapid progression to AIDS may appear very early in HIV infection. This suggests that some of the factors responsible for more rapid disease progression are present in the host prior to or shortly after infection occurs.

Antiretroviral medication use among injection drug users: two potential futures.

OBJECTIVE: To model the potential impact of HIV infection rates and the use of antiretroviral medication on life expectancy and mortality in the Downtown Eastside of Vancouver, British Columbia, Canada, from 1999 to 2006. DESIGN: Population projections were made to estimate the population of the Downtown Eastside in the year 2006. METHODS: Two scenarios were modelled to predict the impact of HIV infection and antiretroviral use on mortality and life expectancy. The use of antiretroviral therapy was estimated to be 80% in the first scenario and 20% in the second. The prevalence of HIV by age and sex, and by year infected was estimated using data from the Vancouver Injection Drug User Study. RESULTS: If the level of antiretroviral therapy use among HIV-positive individuals was 80% at baseline, then we estimate that the life expectancy at birth in the year 2006 will be 60.8 years for men and 72.8 years for women, and 172 AIDS deaths will occur between 1999 and 2006. In contrast, if the present level of antiretroviral medication use persists, the life expectancy at birth in the year 2006 will be 56.9 years for men and 68.6 years for women, and 503 AIDS deaths will occur between 1999 and 2006. CONCLUSION: Our analysis suggests that if the low levels of antiretroviral therapy use persist, life expectancy in Vancouver's Downtown Eastside will soon be on a par with many of the world's least developed countries. Our findings highlight the large health status decline that can be expected in many inner city neighbourhoods if low levels of antiretroviral use persist. Although reasonable coverage targets for injection drug users (IDU) have not been established, the expanded use of antiretroviral medication is urgently needed to avert a drastic decline in health status.

Comparison of sexual behaviors, unprotected sex, and substance use between two independent cohorts of gay and bisexual men.

OBJECTIVE: To compare demographic characteristics, sexual practices, unprotected receptive and insertive anal intercourse, substance use and rates of HIV-1 seroconversion between two prospective cohorts of HIV-negative men who have sex with men. DESIGN: Comparative analysis of two independent cohorts. METHODS: Between May 1995 and April 1996, 235 HIV-negative Vanguard Project (VP) participants were enrolled and between January and December 1985, 263 HIV-negative participants in the Vancouver Lymphadenopathy AIDS Study (VLAS) completed a follow-up visit. The VP participants were compared with VLAS participants with respect to self-reported demographic variables, sexual behaviors, unprotected sex, substance use and rates of HIV-1 seroconversion during follow-up. RESULTS: In comparison with the VLAS participants the VP participants were younger (median age, 26 versus 34 years; P< 0.001), more likely to be non-Caucasian (75 versus 97%; P< 0.001), and were less likely to have attended university/college (35 versus 46%; P = 0.014). The VP participants reported a higher mean number of male sex partners in the previous year (15 versus 12; P= 0.026) and a higher mean number of regular partners (1.7 versus 0.6; P < 0.001). The VP participants were more likely to report engaging in receptive (92 versus 60%; P< 0.001) and insertive (90 versus 69%; P < 0.001) anal intercourse with regular partners and receptive anal intercourse with casual partners (62 versus 38%; P< 0.001). The VLAS participants were more likely to report never using condoms during insertive and receptive anal intercourse with both regular and casual partners. The VP participants were less likely to report using nitrite inhalants (34 versus 43%; P= 0.033), but more likely to report the use of cocaine (30 versus 8%; P< 0.001), LSD (21 versus 3%; P < 0.001), amphetamine (11 versus 1%; P< 0.001), heroin (3 versus 0%; P= 0.010) and methyldiamphetamine (17 versus 10%; P= 0.034). The VLAS participants were nine times more likely to report high-risk sexual behavior, after controlling for differences in age, ethnicity, substance use, and method of recruitment between cohort members. After adjustment for differences in demographics, sexual behaviors, and level of substance use, the risk ratio for seroconversion among VLAS participants remained significantly elevated compared with VP participants. CONCLUSION: These data provide evidence that men who have sex with men who were enrolled in the VP were more sexually active than their VLAS counterparts were 10 years ago as measured by self-reported numbers of regular and casual partners and frequency of anal intercourse with these partners. However, condom use appears to be significantly higher among VP participants, which has contributed to a lower rate of HIV-1 infection.