Antiretroviral resistance among HIV-infected persons who have died in British Columbia, in the era of modern antiretroviral therapy.

BACKGROUND: The prevalence of antiretroviral resistance among persons enrolled in the centralized HIV/AIDS Drug Treatment Program in British Columbia, Canada, who had died between July 1997 and December 2001, was investigated, to determine the degree to which antiretroviral resistance contributed to mortality. METHODS: During this period, 637 deaths had occurred. The last plasma sample obtained during therapy was genotyped retrospectively for treated individuals who had died of a nonaccidental cause. Samples with plasma human immunodeficiency virus (HIV) loads <500 copies/mL were not genotyped. Drug resistance among 1220 living HIV-infected persons who had experienced virologic therapy failure during the study period also was examined. RESULTS: Of 554 individuals who had died of nonaccidental causes, 58 (10.4%) were antiretroviral naive, and 99 (17.9%) had very brief exposure to antiretroviral therapy (median, 2 months). The majority of isolates from the remaining 397 individuals harbored either no major resistance mutations or represented samples with plasma HIV suppression of <500 copies/mL. Resistance to >/=1, >/=2, or 3 drug classes was observed in 76%, 42%, and 11% of individuals, respectively, in the group of 1220 living individuals experiencing virologic therapy failure, compared with only 44%, 23%, and 5% of individuals, respectively, who had died (P<.001). CONCLUSION: Only a relatively low prevalence of multidrug resistance was observed in this cohort, indicating that the exhaustion of treatment options because of drug resistance was not a significant contributor to mortality.

Provider bias in the selection of non-nucleoside reverse transcriptase inhibitor and protease inhibitor-based highly active antiretroviral therapy and HIV treatment outcomes in observational studies.

OBJECTIVE: To compare the characteristics of patients prescribed non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI), and evaluate treatment outcomes in a setting in which nevirapine has been preferentially recommended since 1998. METHODS: A population-based analysis of antiretroviral-naive adults who started highly active antiretroviral therapy (HAART) between 1 August 1996 and 31 July 2000, and who were followed until 31 March 2002. We compared baseline characteristics, and evaluated virological responses and mortality. RESULTS: Overall, 439 patients (28.8%) started HAART with NNRTI (94.1% used nevirapine), 100 (6.6%) used a double PI, and 983 (64.6%) used a single PI-based regimen. Substantial differences were observed between the baseline clinical characteristics of these populations. In adjusted analyses, in comparison with single PI therapy, only the use of NNRTI was associated with more rapid HIV-RNA suppression [relative hazard (RH) 1.42; 95% confidence interval (CI) 1.22-1.65; P < 0.001]. A total of 204 deaths were identified in the study population [42 (9.6%) NNRTI; 11 (11%) double PI; 151 (15.4%) single PI, respectively]. In adjusted analysis, NNRTI (RH 1.01; 95% CI 0.71-1.45) and double PI-based HAART (RH 0.74; 95% CI 0.40-1.39) had similar mortality rates to the single PI reference category. CONCLUSION: NNRTI use was associated with more rapid virological suppression, whereas similar rates of rebound and mortality were found. Nevertheless, major baseline differences existed between patients prescribed the various initial regimens. As such, it is likely that similar selection factors may explain why our findings contrast with several non-randomized studies showing worse clinical outcomes of patients prescribed nevirapine.

Total lymphocyte count as a possible surrogate of CD4 cell count to prioritize eligibility for antiretroviral therapy among HIV-infected individuals in resource-limited settings.

OBJECTIVE: To characterize the value of total lymphocyte counts in predicting risk of death among patients initiating triple combination antiretroviral therapy. METHODS: Study subjects included antiretroviral-naive persons aged 18 years or older who initiated treatment with triple combination therapy between August 1 1996 and September 30 1999 in a population-based observational cohort of HIV-infected individuals. Total lymphocyte counts as well as CD4 count and plasma viral load were assessed at baseline. Separate Cox proportional hazards models were devised to evaluate the effect on survival of total lymphocyte count in lieu of or with CD4 count after adjustment for other prognostic factors including plasma viral load. RESULTS: A total of 733 antiretroviral-naive persons initiated triple drug combination antiretroviral therapy over the study period with a median follow-up of 29.5 months. In the first analysis, only baseline CD4 cell counts of 50-199 cells/microl or less than 50 microl were associated with an increased risk of mortality [adjusted relative risk (ARR) 2.90; 95% CI: 1.40, 5.98] and (ARR 6.30; 95% CI: 2.93, 13.54), respectively. When CD4 counts were excluded from the analysis as if unavailable, total lymphocyte count of between 0.8 and 1.4 G/I, and less than 0.8 G/I were both significantly associated with an increased risk of mortality (ARR 2.36; 95% CI: 1.16, 4.78) and (ARR 6.17; 95% CI: 2.93, 13.01), respectively. CONCLUSION: Total lymphocyte count may provide a simple and cost-effective alternative for prioritizing therapy initiation in resource-limited settings. Our results suggest that, if appropriately validated, judicious application of total lymphocyte counts could overcome one of the practical obstacles to more widespread provision of antiretroviral therapy in resource-poor settings.

Highly active antiretroviral therapy: physician experience and enhanced adherence to prescription refill.

OBJECTIVE: To identify patient and physician characteristics that may act as determinants of adherence to prescription refill of triple combination antiretroviral therapy. METHODS: A population-based analysis of antiretroviral therapy-naive HIV-positive men and women in British Columbia, Canada, who initiated triple combination therapy between August 1 1996 and October 31 1998. Study participants were considered adherent if they were actually dispensed antiretrovirals > or = 95% over the first year of therapy. Log-binomial regression was used to identify patient and physician characteristics associated with adherence to prescription refill. RESULTS: Of the 886 individuals eligible for analysis, 495 (56%) were > or = 95% adherent to prescription refill. In multivariate analysis, adherence was positively associated with increased age [adjusted relative rate (ARR) 1.19; 95% CI: 1.07-1.32], having a diagnosis of AIDS (ARR 1.66; 95% CI: 1.29-2.15), being male (ARR 1.79; 95% CI: 1.27-2.53), and with greater experience of the treating physician (ARR 1.27; 95% CI: 1.13-1.42). History of injection drug use was negatively associated with adherence to prescription refill (ARR 0.65; 95% CI: 0.51-0.83), as was increased pill burden (per pill daily) (ARR 0.95; 95% CI: 0.92-0.99). A sub-analysis of 316 patients who provided additional data regarding psychosocial characteristics indicated that adherence was positively associated with physician experience (ARR: 1.28; 95% CI: 1.09-1.51) and being employed (ARR: 1.55; 95% CI: 1.14-2.21), and negatively associated with a history of injection drug use (ARR: 0.61; 95% CI: 0.43-0.85). CONCLUSION: While patient disease stage and personal characteristics may play an important role in patient adherence to prescription refill of complex therapeutic regimens, our findings indicate that HIV-experienced physicians may have greater success in maintaining patients on prescribed therapy.

Interventional cardiovascular procedures among HIV-infected individuals on antiretroviral therapy 1995-2000.

OBJECTIVE: To calculate the rate of interventional cardiac procedures (ICP) among HIV-infected individuals ever treated with antiretroviral therapy (ART) and to describe clinical and sociodemographic characteristics associated with ICP. METHODS: Since 1992, ART in British Columbia (BC) has been centrally distributed by the BC Centre for Excellence in HIV/AIDS. The BC Cardiac Registry maintains information regarding all cardiac procedures performed in BC. The two databases were linked to determine the number of HIV-positive individuals on ART who underwent ICP. Age-adjusted analyses were conducted using direct standardization, and linear regression to test for trend over time. Logistic regression was used to identify patient and treatment characteristics independently associated with having an interventional cardiac procedure. RESULTS: Of the 5082 individuals who have ever received ART, 63 (< 1%) were captured in the Cardiac Registry. There were 97 events: 70 (72%) since 1999. The age-adjusted event rate per 1000 HIV-positive individuals on ART increased significantly over time (P = 0.015) whereas that for the general BC population did not increase over time (P = 0.191). In multivariate analysis, age at baseline per 10 year increase [adjusted odds ratio (AOR) 2.5; 95% confidence interval (CI), 1.8-3.2), and months on ART (AOR 1.3; 95% CI, 1.1-1.4) remained significant. CONCLUSIONS: The rate of ICP among HIV-positive individuals on ART appears to be increasing; in addition, the duration of time on ART is independently associated with ICP after adjustment for patient demographic characteristics.

Incidence of morphological and lipid abnormalities: gender and treatment differentials after initiation of first antiretroviral therapy.

OBJECTIVE: To provide population-based incidence estimates for constituent symptoms of human immundeficiency virus (HIV)-related lipodystrophy syndrome and to identify possible independent predictors of accrued cases. DESIGN: Prospective population-based cohort. Methods Study subjects were antiretroviral-naïve individuals who initiated treatment between October 1998 and May 2001 and provided completed self-reported data regarding the occurrence of lipoatrophy, lipohypertrophy and increased triglyceride and cholesterol levels. Possible predictors of incident lipoatrophy, lipohypertrophy, dyslipidaemia and mixed lipodystrophy (symptoms of both lipoatrophy and lipohypertrophy) were identified using logistic regression modelling. A sub-analysis restricted to subjects retaining original treatment at study completion was conducted using similar methods. RESULTS: Among the 366 study subjects, cumulative incidence was 29% for lipoatrophy, 23% for lipohypertrophy, 9% for dyslipidaemia, and 13% for mixed lipodystrophy after a median duration of 12 months of antiretroviral therapy. In an intentto-treat analysis incident lipoatrophy and lipohypertrophy were independently associated with initiation of protease inhibitor (PI)-containing regimens, (adjusted odds ratio [AOR] = 1.94; 95% CI: 1.25-3.03 and AOR = 1.76; 95% CI: 1.09-2.85, respectively) and female gender (AOR = 2.06; 95% CI: 1.03-4.12 and AOR = 2.36; 95% CI: 1.17-4.74, respectively). Both mixed lipodystrophy and reported dyslipidaemia were associated only with PI inclusion in the initial regimen (AOR = 2.27; 95% CI: 1.14-4.53 and AOR = 2.14; 95% CI: 1.26-3.65, respectively). Similar results were obtained in analysis of individuals retained in initial treatment groups throughout follow-up. CONCLUSION: Incident morphological and lipid abnormalities are common among individuals initiating first-time antiretroviral therapy. Use of PI was consistently associated with all lipodystrophy-related abnormalities after adjustment for a broad range of patient personal, clinical and treatment characteristics.

Intentional nonadherence due to adverse symptoms associated with antiretroviral therapy.

OBJECTIVE: To estimate the frequency and possible predictors of patient-mediated intentional alterations in antiretroviral medication regimens in direct response to symptoms associated with antiretroviral therapy use. DESIGN: Cross-sectional survey of a population-based dynamic cohort of antiretroviral recipients in a province-wide HIV drug treatment program, the only source of free-of-charge antiretroviral medications in the province of British Columbia. METHODS: Program participants voluntarily complete program surveys on an annual basis. Study subjects were those who responded to the annual treatment program survey between January 1 and November 1, 2001. Patients reported on the occurrence and severity of symptoms of 42 side effects of antiretroviral agents. Symptoms were classified into four subgroups based on whether they were considered subjective or objective and whether they would or would not prompt clinical action. For each of the four symptom categories, patients reported what their physician recommended in response to symptoms in that group and what the patient actually did in response to these same symptoms. Intentional nonadherence was defined as reporting either skipping or altering dosages of selective regimen components or temporary cessation of therapy that was not recommended by the physician in response to adverse drug effects in the past year. RESULTS: Of 638 study subjects, 70 (11%) reported intentional nonadherence with between 4% and 7.4% reporting this activity over the preceding year depending on the symptom group. Multivariate analysis revealed that a plasma viral load of <400 copies/mL (adjusted odds ratio [AOR], 0.35; 95% CI, 0.21-0.61) and completion of high school (AOR, 0.43; 95% CI, 0.24-0.78) were both inversely associated with intentional nonadherence. Those subjects reporting at least one severe symptom were more than twice as likely to report intentional nonadherence (AOR, 2.24; 95% CI, 1.16-4.33). Similarly, each additional symptom considered to be objective and to require clinical action was associated with a 25% increase in the risk of intentional nonadherence (AOR, 1.25; 95% CI, 1.10-1.43). CONCLUSION: Intentional nonadherence to antiretroviral therapy is common among persons experiencing therapy-related side effects. Although the type and severity of adverse effects impact intentional nonadherence, this activity occurs in relation to symptoms regardless of their strict clinical relevance.

Antiretroviral treatment patterns and incident HIV-associated morphologic and lipid abnormalities in a population-based chort.

This study provides population-based estimates of the incidence of constituent symptoms associated with HIV-related lipodystrophy syndrome. Possible predictors of symptomatology based on analysis of accrued cases are provided after adjustment for a broad range of personal, clinical, and treatment characteristics. Patients enrolled in a province-wide HIV/AIDS treatment program reported annually on the occurrence of lipoatrophy, lipohypertrophy, and elevated triglyceride and cholesterol levels. Of 1261 individuals who provided baseline data, 745 were available at follow-up, among whom incidence was 27% for lipoatrophy, 21% for lipohypertrophy, and 10% and 16% for increased triglyceride and cholesterol levels, respectively. In logistic multivariate modeling, incident lipoatrophy was associated with duration of stavudine (per quarter) (adjusted odds ratio [AOR] 1.18; 95% confidence interval [CI] 1.09-1.27) and having been diagnosed with AIDS (AOR 2.07; 95% CI 1.20-3.56). Lipohypertrophy risk increased with use of protease inhibitor (AOR 3.53; 95% CI 1.81-6.86) and stavudine (AOR 3.67; 95% CI 1.61-8.38). Incident cholesterol or triglyceride abnormalities were associated with protease inhibitor use (AOR 7.17; 95% CI 2.46-20.96) and duration of ritonavir (per quarter) (AOR 1.12; 95% CI 1.04-1.21). Our findings suggest high annual rates of incidence and a role of first line antiretroviral therapies in symptom development. These outcomes, in conjunction with the findings of others have important implications for evolving treatment patterns.

Correlates of suicide attempts in an open cohort of young men who have sex with men.

OBJECTIVE: To investigate baseline correlates of attempted suicide in a large cohort of young gay and bisexual men. METHODS: Participants completed annual questionnaires asking demographic information, sexual behaviours, history of forced and paid sex, comfort with sexual orientation, use of illicit drugs, and validated measures of depression, social support, alcohol dependency, self-esteem and suicide ideation and attempts. Contingency table analysis and step-wise logistic regression were used to identify potential predictors of self-reported suicide attempts. RESULTS: Of 345 gay and bisexual men eligible for this cross-sectional analysis, 150 (43.5%) reported that they had ever considered suicide and 67 (19.4%) that they had attempted suicide at least once. After adjustment for multiple explanatory variables, the use of nitrite inhalants (poppers) (AOR = 2.37; 95% CI 1.30, 4.33), social support scores below the 75th percentile of all scores (AOR = 2.19; 95% CI 1.18, 4.09) and low or moderate self-esteem (AOR = 3.73; 95% CI 2.03, 6.86) were independently associated with elevated risk of attempted suicide. CONCLUSION: Our data indicate that men in this analysis who ideate or attempt suicide earlier in life are more likely to report lower social support and self-esteem, and high popper use.