Michael V. O'Shaughnessy

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 drug 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 Vancouvers 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.

Intermittent use of triple-combination therapy is predictive of mortality at baseline and after 1 year of follow-up.

Objective To characterize the impact of intermittent use of triple drug antiretroviral therapy on survival. Design, setting and participants Population-based analysis of 1282 antiretroviral therapy naive HIV-positive individuals aged 18 years and older in British Columbia who started triple-combination therapy between August 1996 and December 1999. Therapy use was estimated by dividing the number of months of medications dispensed by the number of months of follow-up. Intermittent therapy was defined as the participant having obtained less than 75% of their medication in the first 12 months. Main outcome measure Cumulative all-cause mortality rates from the start of triple drug antiretroviral therapy to 30 September 2000. Results As of 30 September 2000, 106 subjects had died. Cumulative mortality was 3.9% (± 0.5%) at 12 months. In a multivariate model, after controlling for other variables that were significant in the univariate analyses each 100 cell decrement in baseline CD4 cell count and the intermittent use of antiretroviral drugs were associated with increased mortality with risk ratios of 1.31 [95% confidence interval (CI), 1.16–1.49;P < 0.001] and 2.90 (95% CI, 1.93–4.36;P < 0.001), respectively. In order to control for downward drift, intermittent use of therapy was measured over the first year whereas other factors were measured at the end of year 1. After adjusting for all other factors, those participants who used antiretroviral drugs intermittently were 2.97 times (95% CI, 1.33–6.62;P = 0.008) more likely to die. Conclusion Our study demonstrates that even after adjusting for other prognostic factors intermittent use of antiretroviral therapy was associated with increased mortality.

Decline in deaths from AIDS due to new antiretrovirals

We determined whether availability of new antiretroviral treatments has had any impact on the rate of death for people with HIV-1 infection. Distribution of antiretroviral drugs in British Columbia, Canada, is free of charge through the Centre for Excellence in HIV/AIDS Treatment Programme. For physicians to prescribe antiretrovirals, they must complete a participant enrolment form that serves as the drug prescription. Individuals infected with HIV-1 are eligible to receive antiretroviral therapy from this programme if they have at least one CD4 cell count less than 0·5 10/L. Until December, 1995, monotherapy was made available to participants with CD4 counts less than 0·5 10/L, while double combination therapy was made available to those with CD4 counts of less than 0·35 10/L. After December, 1995, double combination treatment was made available to everyone with CD4 counts less than 0·5 10/L. Viral-loaddriven antiretroviral treatment and triple combination therapy became available after June, 1996. Of the five new medications introduced in 1996, lamivudine became available in January, saquinavir in June, stavudine in July, and indinavir and ritonavir in September. Patterns of mortality were assessed by comparing changes in death rates for those individuals on antiretroviral therapy by quarter and CD4-count groupings (0·1 10/L, 0·1–0·34 10/L, and 0·35–0·49 10/L). Mortality data were obtained through regular surveillance and computerised record linkages with Division of Vital Statistics of the British Columbia Ministry of Health. Population figures were based on the number of programme participants actively on antiretroviral therapy. Rates were expressed as deaths per 1000 active participants and were calculated over a 3-year period from January, 1994 to December, 1996. There were 604 deaths during this period among individuals ever on antiretroviral therapy; of these, 475 deaths (79%) were attributed to participants with CD4 counts less than 0·1 10/L. There was a significant decline in programme mortality rates since the first quarter of 1994 (trend test p<0·001). On average, the rate of death for those on antiretroviral treatment declined at a rate of 1·7 deaths per 1000 participants per quarter or from 18·9 deaths per 1000 participants in the first quarter of 1994 to 5·7 deaths per 1000 participants in the last quarter of 1996. As shown in the figure, the greatest decline in mortality was experienced in those participants with CD4 counts less than 0·1 10/L (trend test p<0·001). On average, the death rate for participants with CD4 counts of less than 0·1 10/L declined at a rate of 3·5 deaths per 1000 participants per quarter—ie, from 62·0 to 19·8 deaths per 1000 participants from the first quarter of 1994 to the last quarter of 1996. Although there was a decline in the death rates for other two CD4-count groups, the rates were not statistically significant. Delayed reporting was not likely to affect our analysis. The vast majority of deaths were reported through active follow-up. In this analysis, data on 536 (89%) deaths were obtained through physician and hospital reports and data on 68 (11%) were obtained through linkages. Furthermore, in a subanalysis of 179 deaths obtained through physician and hospital reports over a 1-year period ending on June 30, 1996, we found that the median follow-up time between the actual date of death and the date of reporting was 7 days (interquartile range 5–11 days). Our data show a substantial decrease in AIDS-related mortality in the province of British Columbia. The decline in mortality coincides with the availability of lamivudine in the province through open access and with the expanded use of double combination antiretroviral therapy. We believe this mortality trend will likely continue as protease inhibitors and non-nucleoside reverse transcriptase inhibitors are used to greater extent within the treatment programme.

Effect of Medication Adherence on Survival of HIV-Infected Adults Who Start Highly Active Antiretroviral Therapy When the CD4+ Cell Count Is 0.200 to 0.350 × 109 cells/L

Context Highly active antiretroviral therapy (HAART) improves outcomes in HIV-infected patients. When is the best time to start this therapy? Contribution 1422 HIV-infected adults were followed for 2 to 6 years after starting HAART. Adherent patients who started treatment with lower (0.200 to 0.349 109 cells/L) and higher ( 0.350 109 cells/L) CD4+ cell counts had statistically similar mortality rates. Nonadherent patients had higher mortality rates than adherent patients, regardless of baseline CD4+ cell count of 0.200 to 0.349 109 cells/L or 0.350 109 cells/L or greater. Implications In HIV-infected patients, adherence, rather than when therapy is initiated before a CD4+ cell count of 0.200 109 cells/L, may be the most important determinant of survival. The Editors The benefits of highly active antiretroviral therapy (HAART) in the management of HIV disease are well established. By suppressing plasma HIV-1 RNA, HAART decreases morbidity and mortality in HIV-infected patients (1, 2). However, the optimal time to initiate HAART is uncertain. As a result, expert recommendations on the optimal time to initiate antiretroviral therapy widely differ (3-6). Several studies have suggested that only patients who initiated therapy when the CD4+ cell count had declined below 0.200 109 cells/L were at increased risk for disease progression, regardless of the baseline HIV RNA level (7-9). In 1 of these studies, further examination with additional duration of follow-up suggested that mortality may be elevated in patients who initiated therapy after the CD4+ cell count declined below 0.350 109 cells/L (10). In fact, a growing number of studies have suggested that delaying HAART after the CD4+ cell count declines below 0.350 109 cells/L may be unsafe (11-14). However, previous studies (7, 9, 11-14) did not adjust for patient adherence. This limitation is critically important because incomplete adherence is associated with increased mortality (15-17). Therefore, we sought to evaluate the effect of baseline CD4+ cell count and adherence on survival rates after the initiation of HAART. Methods The HAART Observational Medical Evaluation and Research (HOMER) study, conducted through the British Columbia Centre for Excellence in HIV/AIDS Drug Treatment Program, has been described in detail elsewhere (7, 17). Briefly, the Centre is the only free source of antiretroviral medications in British Columbia, Canada; pharmaceutical sales suggest that less than 1% of HIV-infected patients in this province obtain antiretroviral agents outside the program (18). For all participants, the program maintains a complete prospective profile of antiretroviral therapy. In the present study, we restricted analyses to HIV-infected men and women who had been antiretroviral naive until triple-drug antiretroviral therapy was prescribed between 1 August 1996 and 31 July 2000 and were followed through 31 March 2002. Study participants were initially prescribed HAART regimens that included 2 nucleoside reverse transcriptase inhibitors and either a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor (the enrolling physician, in consultation with the patient, chose the regimen). End Points The primary end point in this analysis was time to death. Deaths occurring during the follow-up period were continuously identified from physician reports and through record linkages with the British Columbia Division of Vital Statistics. In the primary analysis, we evaluated all-cause mortality; in subanalyses, we censored deaths from accidental causes at the time of death and classified them as nonevents (7). Statistical Analysis KaplanMeier Analyses For the KaplanMeier analyses, we stratified patients into 5 baseline CD4+ cell count strata on the basis of previous studies and the recommendations of therapeutic guidelines: less than 0.200, 0.200 to 0.249, 0.250 to 0.299, 0.300 to 0.349, and greater than or equal to 0.350 109 cells/L (3-5, 7-9). We further stratified patients into adherent and nonadherent categories according to adherence to prescription refills (19). The definition of adherence was based on the ratio of time that medication dispensed would last as a proportion of follow-up time. This calculation was restricted to each patients first year of therapy in order to limit the potential for reverse causation in patients who ceased antiretroviral therapy after they became too sick to take medication (15, 20). We have previously demonstrated that adherence defined in this way strongly predicts virologic response and mortality and that it can be used to adjust for the potentially confounding effect of treatment interruption (15, 17, 21, 22). In the primary analysis, we wanted to evaluate how moderate adherence to HAART affected survival. Therefore, to estimate the effect of moderate adherence, a priori we categorized patients as nonadherent only if they received antiretroviral medications less than 75% of the time during the first year of therapy (15, 17). In a subanalysis, we estimated the risk for death from HIV disease among patients who were highly adherent to HAART. We defined adherence more rigorously for this analysis; patients were considered nonadherent only if they received antiretroviral medications less than 95% of the time during the first year of therapy (21, 23). We also censored deaths from accidental causes at the time of death and classified them as nonevents (7). For both analyses, we evaluated the cumulative mortality rates among the predefined baseline CD4+ cell count strata using KaplanMeier methods. Survival curves were compared by using the log-rank test. Cox Regression Analyses We were aware that additional confounding may persist if the distribution of baseline AIDS diagnoses or baseline HIV RNA levels differed between patients with various baseline CD4+ cell counts (9). Therefore, we performed Cox proportional-hazards regression analyses to calculate the adjusted relative hazards of mortality (24). In these analyses, we stratified patients into combined low (<0.200 109 cells/L), medium (0.200 to 0.349 109 cells/L), and high ( 0.350 109 cells/L) CD4+ cell count strata (3-5, 7-9). To derive adjusted relative hazards of mortality among adherent and nonadherent patients in the various CD4+ cell count strata, we built fixed models with indicator variables for each adherence and CD4+ cell count strata while adjusting for baseline HIV RNA level and other relevant covariates. Variables examined in these analyses included protease inhibitor use in the initial regimen (yes or no), a previous clinical diagnosis of AIDS (yes or no), age, sex, physician experience ( 6 patients previously enrolled in the program) (17), date of therapy initiation (before or after July 1997) (25), and baseline HIV RNA levels (log10-transformed). The assumption of proportional hazards was validated by inspection of log (log [survival function]) estimates against log time plots. We fit all multivariate models by adjusting for all variables that were statistically significant (P < 0.05) in univariate analyses. Role of the Funding Sources The funding sources had no role in the design, conduct, or reporting of the study or the decision to submit the manuscript for publication. Results Between 1 August 1996 and 31 July 2000, 1583 antiretroviral-naive participants 18 years of age and older began triple-drug therapy. Of these, 161 (10%) were excluded from this analysis because baseline CD4+ cell count and plasma HIV-1 RNA levels were not available within 6 months before the start of antiretroviral therapy. Therefore, the study sample was based on 1422 (90%) participants (1198 men [84%] and 224 women [15%]). Sex, presence of AIDS at baseline, and subsequent mortality did not differ between the study sample and the persons excluded. However, excluded persons were more likely to be younger (P = 0.04) and to be taking protease inhibitors (P = 0.02). The overall median follow-up time was 40.1 months (interquartile range, 27.7 to 52.9 months). At baseline, the median patient age was 37 years (interquartile range, 32 to 44 years), the median CD4+ cell count was 0.270 109 cells/L (interquartile range, 0.130 to 0.420 109 cells/L), and the median plasma HIV RNA level was 120 000 copies/mL (interquartile range, 38 000 to 300 000 copies/mL). Initial therapy was a protease inhibitor in 983 (69.1%) patients and a nonnucleoside reverse transcriptase inhibitor in 439 (31%) patients. During the study period, 193 patients died: 25 (13%) as a result of an accident or suicide and 14 (7%) as a result of an illicit drug overdose. Compared with patients who were less than 75% adherent, patients who were at least 75% adherent were more likely to be male (78.0% vs. 59.4%) and older (37.9 years vs. 35.4 years) and were less likely to have a history of injection drug use (78.3% vs. 65.5%) (P < 0.05 for all comparisons). In the primary analysis that considered all-cause mortality and 75% adherence, 45 of the 632 patients with at least 75% adherence who initiated HAART before the CD4+ cell count reached 0.200 109 cells/L had died by 31 March 2002; the crude mortality rate was 7.1% (Figure 1, left). Conversely, among the 264 patients who started HAART when the CD4+ cell count was 0.200 109 cells/L or greater and who were less than 75% adherent, 40 had died (crude mortality rate, 15.2%) (Figure 1, right). The absolute difference in crude mortality between adherent and nonadherent patients with a baseline CD4+ cell count of 0.200 109 cells/L or greater was 8.1 percentage points (Table 1). In KaplanMeier analyses, when patients were considered according to the CD4+ cell count strata (<0.200, 0.200 to 0.249, 0.250 to 0.299, 0.300 to 0.349, and 0.350 109 cells/L), starting HAART at a CD4+ count of 0.200 109 cells/L or greater had no survival benefit in the 632 patients who were at least 75% adherent (Figure 1, left). Table 2 shows the log-rank P values and estimated CIs comparing patients with

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

ObjectiveTo provide population-based estimates of the prevalence of lipodystrophy syndrome and constituent symptoms and to identify correlates of prevalent symptomology. MethodsParticipants 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. ResultsOf 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). ConclusionIncreased 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.

Determinants of sexual risk-taking among young HIV-negative gay and bisexual men.

Data from a cohort of young HIV-negative gay and bisexual men were analyzed to identify determinants of sexual risk-taking at baseline. Gay/bisexual men aged between 18 and 30 completed a self-administered questionnaire including demographics, depression, social support, substance use, and consensual versus nonconsensual sex. Risk-takers were defined as those who had unprotected anal sex with casual male sex partners in the previous year; non-risk-takers were defined as those who reported consistent condom use during anal sex with all male partners in the previous year. Logistic regression was used to identify independent predictors of sexual risk-taking. Of 439 men studied, risk-takers had less education, a higher depression score, less social support, and were more likely to report nonconsensual sex and recreational drug use relative to non-risk-takers. Independent predictors of sexual risk-taking were low education, nitrite use, low social support (adjusted odds ratio [AOR]=1.65; 95% CI, 1.04-2.59), and nonconsensual sex experienced as a youth or adult (AOR=1.85; 95% CI, 1.15-2.96). Young gay/bisexual men reporting nonconsensual sex, low social support, or nitrite use were significantly more likely to have recently had unprotected anal sex with casual partners. HIV prevention programs aimed at young gay/bisexual men should include sexual abuse counselling and foster community norms supporting safer sex practices.

Nontuberculous Mycobacterial Immune Reconstitution Syndrome in HIV-Infected Patients: Spectrum of Disease and Long-Term Follow-Up

BACKGROUND The long-term outcome and spectrum of disease of nontuberculous mycobacterial immune reconstitution syndrome have not been described. METHODS We report the findings of an observational study. RESULTS Among 51 patients (43 with Mycobacterium avium complex [MAC] infection, 2 with Mycobacterium genavense infection, and 6 whose samples were smear positive but culture negative) from 1993-2004, the median follow-up period was 29 months. The incidence of nontuberculous mycobacterial immune reconstitution syndrome was 3.5% among patients initiating highly active antiretroviral therapy (HAART) with a baseline CD4+ cell count of <100 cells/microL. Three main clinical presentations were peripheral lymphadenitis (in 17 patients), pulmonary-thoracic disease (in 15 patients), and intra-abdominal disease (in 13 patients). Six other patients had cases that involved joint, spine, prostate, skin, soft tissue, and spontaneously resolving MAC bacteremia. Disease was usually localized. Median CD4+ cell counts before initiation of HAART and at diagnosis were 20 and 120 cells/microL, respectively, and the median reduction in human immunodeficiency virus (HIV) RNA load was 2.5 log10 copies/mL. Intra-abdominal disease was frequently preceded by disseminated MAC infection (in 62% of cases, compared with 6%-33% of cases for other groups; P=.003) and accounted for 16 (43%) of 36 hospitalizations (compared with 5%-35% for other groups; P=.008). The relapse rate was not higher among 10 patients who received no MAC therapy or received MAC therapy for < or =2 weeks. Prednisone was associated with clinical responses in 8 (89%) of 9 patients with evaluable cases. In total, 7 patients (14%) had 13 subsequent culture-positive MAC events (6 of which were cases of immune reconstitution syndrome, and 7 of which were cases of disseminated MAC infection). Ten patients (20%) died (2 of disseminated MAC infection, 5 of other opportunistic infections, and 3 of HIV-unrelated causes). CONCLUSIONS Nontuberculous mycobacterial immune reconstitution syndrome has a wide range of clinical presentations and severity. The long-term prognosis is favorable for HAART-adherent patients. Intra-abdominal disease is associated with greater morbidity than is peripheral lymphadenitis. The role of antimycobacterial therapy is uncertain, given the self-limited course of most nonabdominal cases.

The impact of adherence on CD4 cell count responses among HIV-infected patients.

BackgroundThere have been concerns that irreversible immune damage may result if highly active antiretroviral therapy (HAART) is initiated after the CD4 cell count declines to below 350 cells/&mgr;L; however, the role of antiretroviral adherence on CD4 cell count responses has not been well evaluated. MethodsWe evaluated CD4 cell count responses of 1522 antiretroviral-naive patients initiating HAART who were stratified by baseline CD4 cell count (<50, 50–199, and ≥200 cells/&mgr;L) and adherence. ResultsAmong patients starting HAART with <50 cells/&mgr;L, during the fifth 15-week period after the initiation of HAART, absolute CD4 cell counts were 200 cells/&mgr;L (interquartile range [IQR]: 130–290) for adherent patients versus 60 cells/&mgr;L (IQR: 10–130) for nonadherent patients. Similarly, among patients starting HAART with 50 to 199 cells/&mgr;L, during the fifth 15-week period after the initiation of HAART, absolute CD4 cell counts were 300 cells/&mgr;L (IQR: 180–390) versus 125 cells/&mgr;L (IQR: 40–210) for nonadherent patients. In Cox regression analyses, adherence was the strongest independent predictor of the time to a gain of ≥50 cells/&mgr;L from baseline (relative hazard [RH] = 2.88, 95% confidence interval [CI]: 2.46–3.37). Among patients with baseline CD4 cell counts <200 cells/&mgr;L, adherence was the strongest independent predictor of the time to a CD4 cell count >200 cells/&mgr;L (RH = 4.85, 95% CI: 3.15–7.47). ConclusionsThese data demonstrate that substantial CD4 gains are possible among highly advanced adherent patients and should contribute to the ongoing debate over the optimal time to initiate HAART.

Factors associated with persistent high-risk syringe sharing in the presence of an established needle exchange programme.

Vancouver has experienced an explosive HIV epidemic despite the presence of a needle exchange programme (NEP). We sought possible explanations for high-risk syringe sharing among Vancouver injection drug users over the period January 1999 to October 2000. Overall, 14% of participants reported high-risk sharing. Although acquiring needles exclusively from the NEP was independently associated with less sharing, we identified several risk factors for persistent sharing, including difficulty accessing sterile needles, bingeing, and frequent cocaine injection.

Impact of HIV infection on mortality in a cohort of injection drug users.

&NA; The prevalence of HIV has been rising among injection drug users (IDUs) and AIDS is now an important cause of death among that population. We tracked mortality and recorded detailed causes of death in the Vancouver Injection Drug Users Study (VIDUS). This is an open cohort of over 1,400 active IDUs that began in May 1996. At enrollment and at semiannual follow‐up visits, a trained interviewer administers a detailed semistructured questionnaire. Mortality was recorded during follow‐up and detailed causes of death were collected from coroners reports, hospital records, and the provincial (British Columbia) registry. Causes of death were obtained on 125 participants. Overall, the leading cause of death was overdose accounting for 25% of deaths among HIV‐positive participants and 42% among HIV‐negative participants. Of the 65 deaths among HIV‐positive individuals, 22 (34%) were HIV related. Mortality was associated with older age (adjusted hazards ratio [AHR], 1.03 per year), HIV positivity (AHR, 2.67), injection cocaine use (AHR, 2.23) and methadone treatment (AHR, 0.47). The high rate of HIV in this population has added significantly to the burden of illness and death in this marginalized population.