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In the early years of the highly active antiretroviral therapy (HAART) era, HIV with resistance to two or more agents in different antiretroviral classes posed a significant clinical challenge. Multidrug-resistant (MDR) HIV was an important cause of treatment failure, morbidity, and mortality. Treatment options at the time were limited; multiple drug regimens with or without enfuvirtide were used with some success but proved to be difficult to sustain for reasons of tolerability, toxicity, and cost. Starting in 2006, data began to emerge supporting the use of new drugs from the original antiretroviral classes (tipranavir, darunavir, and etravirine) and drugs from new classes (raltegravir and maraviroc) for the treatment of MDR HIV. Their availability has enabled patients with MDR HIV to achieve full and durable viral suppression with more compact and cost-effective regimens including at least two and often three fully active agents. The emergence of drug-resistant HIV is expected to continue to become less frequent in the future, driven by improvements in the convenience, tolerability, efficacy, and durability of first-line HAART regimens. To continue this trend, the optimal rollout of HAART in both rich and resource-limited settings will require careful planning and strategic use of antiretroviral drugs and monitoring technologies.

Background We aimed to characterize changes in patterns of new HIV diagnoses, HIV-related mortality, and HAART use in Canada from 1995 to 2008. Methods Data on new HIV diagnoses were obtained from Health Canada, HIV-related mortality statistics were obtained from Statistics Canada, and information on the number of people on HAART was obtained from the single antiretroviral distribution site in British Columbia (BC), and the Intercontinental Marketing Services Health for Ontario and Quebec. Trends of new HIV-positive tests were assessed using Spearman rank correlations and the association between the number of individuals on HAART and new HIV diagnoses were estimated using generalized estimating equations (GEE). Results A total of 34,502 new HIV diagnoses were observed. Rates of death in BC are higher than those in Ontario and Quebec with the rate being 2.03 versus 1.06 and 1.21 per 100,000 population, respectively. The number of HIV infected individuals on HAART increased from 5,091 in 1996 to 20,481 in 2008 in the three provinces (4 fold increase). BC was the only province with a statistically significant decrease (trend test p

Objective To establish the reliability and validity of a shortened (10-item) depression scale used among HIV-positive patients enrolled in the Drug Treatment Program in British Columbia, Canada. Methods The 10-item CES-D (Center for Epidemiologic Studies Depression Scale) was examined among 563 participants who initiated antiretroviral therapy (ART) between August 1, 1996 and June 30, 2002. Internal consistency of the scale was measured by Cronbach’s alpha. Using the original CES-D 20 as primary criteria, comparisons were made using the Kappa statistic. Predictive accuracy of CES-D 10 was assessed by calculating sensitivity, specificity, positive predictive values and negative predictive values. Factor analysis was also performed to determine if the CES-D 10 contained the same factors of positive and negative affect found in the original development of the CES-D. Results The correlation between the original and the shortened scale is very high (Spearman correlation coefficient = 0.97 (P

The characteristics of HIV-associated ITP were documented prior to the HAART era, and the optimal treatment beyond HAART is unknown. We performed a review of patients with HIV-associated ITP and at least one platelet count 9/L since January 1996. Of 5290 patients in the BC Centre for Excellence in HIV/AIDS database, 31 (0.6%) had an ITP diagnosis and platelet count 9/L. Initial ITP treatment included IVIG,n=12; steroids,n=10; anti-RhD,n=8; HAART,n=3. Sixteen patients achieved response and nine patients achieved complete response according to the International Working Group criteria. Median time to response was 14 days. Platelet response was not significantly associated with treatment received, but complete response was lower in patients with a history of injection drug use. Complications of ITP treatment occurred in two patients and there were four unrelated deaths. At a median followup of 48 months, 22 patients (71%) required secondary ITP treatment. This is to our knowledge the largest series of severe HIV-associated ITP reported in the HAART era. Although most patients achieved a safe platelet count with primary ITP treatment, nearly all required retreatment for ITP recurrence. New approaches to the treatment of severe ITP in this population are needed.

Background We developed and validated a new and simple metric, the Programmatic Compliance Score (PCS), based on the IAS-USA antiretroviral therapy management guidelines for HIV-infected adults, as a predictor of all-cause mortality, at a program-wide level. We hypothesized that non-compliance would be associated with the highest probability of mortality. Methods and Findings 3543 antiretroviral-naive HIV-infected patients aged ≥19 years who initiated antiretroviral therapy between January 1, 2000 and August 31, 2009 in British Columbia (BC), Canada, were followed until August 31, 2010. The PCS is composed by six non-performance indicators based on the IAS-USA guidelines: (1) having

Background The lower limit of detection of the original Roche Amplicor HIV plasma viral load (pVL) assay (50 copies/mL) has defined HIV treatment success. The Amplicor assay, however, has been replaced by the Roche TaqMan assay(s). Changes to the limits of detection and calibration have not been validated for clinical utility. Sudden increases in the number of patients with detectable pVL have been reported following the introduction of the TaqMan version 1 assay. Methods Between October 2009 and April 2010 all routine pVL samples from British Columbia, Canada, with 40–250 copies/mL by TaqMan were re-tested by Amplicor (N = 1198). Subsequent short-term virological and resistance outcomes were followed in patients with unchanged therapy (N = 279; median 3.2 months follow-up). Results TaqMan and Amplicor values correlated poorly at low pVL values. Low-level pVL by TaqMan was not associated with impending short-term virological failure; only 17% of patients with 40–250 copies/mL by TaqMan had detectable pVL by Amplicor at follow-up. During the follow-up period only 20% of patients had an increase in pVL by TaqMan (median [IQR]: 80 [36–283] copies/mL). In addition, in ∼2.4% of samples pVL was dramatically underestimated by TaqMan due to poor binding of the proprietary TaqMan primers. Conclusions The replacement of Amplicor with the TaqMan assay has altered the previously accepted definition of HIV treatment failure without any evidence to support the clinical relevance of the new definition. Given the systematic differences in measurement in the low pVL range the British Columbia HIV treatment guidelines now use a threshold of >250 copies/mL by TaqMan to define treatment failure.

Background Recent studies have suggested that failing nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens may have greater potential to induce the development of resistance mutations, which may limit options for second-line therapy. Methods Antiretroviral therapy (ART)-naive individuals aged ≥18 years who initiated triple combination ART between January 2000 and June 2006 in British Columbia, Canada were enrolled in the study. We compared genotypic sensitivity scores (GSSs) derived from the development of resistance mutations between participants who initiated ART with ritonavir-boosted protease inhibitors (PIs) with those who initiated ART with NNRTIs, and determined the effects of these mutations on remaining active drugs. Results A total of 1666 participants initiated ART, 818 (49.1%) with NNRTI-based regimens and 848 (50.9%) with boosted PI-based regimens. Among participants who developed resistance mutations, those who initiated NNRTI-based regimens had a lower median GSS than those on boosted PI-based regimens (9.8 vs. 11.0, respectively; P 200 cells/μL (AOR 3.44; 95% CI 1.73, 6.84) were more likely to have the maximum number of drug options. Conclusion The use of NNRTI-based first-line ART regimens may limit the options for second-line treatment when the number of available drugs is limited.

With significant reductions in AIDS-related morbidity and mortality, HIV is increasingly viewed as a chronic condition. However, people on antiretroviral therapy (ART) are experiencing new challenges such as metabolic and morphological body changes, which may affect self-perceived body image. The concept of body image is complex and encompasses an individual's perception of their existential self, physical self and social interpretation of their body by others. The Longitudinal Investigations into Supportive and Ancillary Health Services (LISA) cohort is a prospective study of HIV-positive persons on ART. An interviewer-administered survey collects socio-demographic and health information including body image, stigma, depression, food insecurity, and quality of life (QoL). In bivariate analyses, Chi-squared or Wilcoxon rank sum tests were used to compare individuals reporting positive body image with those reporting negative body image. Multivariate logistic regression was used to examine associations between negative body image and covariates. Of 451 LISA participants, 47% reported negative body image. The adjusted multivariate analysis showed participants who reported high stigma in the presence of depressive symptoms were more likely to have negative body image compared to people reporting low stigma and no depressive symptoms (adjusted odds ratio [AOR]: 2.41, confidence interval [CI]: 1.24-4.68). The estimated probability of a person having positive body image without stigma or depression was 68%. When stigma alone was included, the probability dropped to 59%, and when depression was included alone the probability dropped to 34%. Depressive symptoms and high stigma combined resulted in a probability of reporting positive body image of 27%. Further efforts are needed to address body image among people living with HIV. In order to lessen the impacts of depression on body image, such issues must be addressed in health care settings. Community interventions are also needed to address stigma and negative body image to improve the lives of people living with HIV.

Sustained combination of HIV prevention strategies is essential to curb the spread of the HIV/AIDS epidemic. The use of highly active antiretroviral therapy (HAART) decreases morbidity and mortality, as well as HIV transmission, among treated individuals. The concept of ‘treatment as prevention’ is dependent on HAART’s ability to sustain HIV-1 RNA virological suppression at the individual and population levels, and has been demonstrated in studies evaluating transmission in mother-to-child, sero-discordant couples and large treated populations. The worldwide expansion of maximally effective antiretroviral drug regimens has been coupled with concerns regarding the magnitude of the financial investment required. However, HAART’s compounding effect on reduced morbidity, mortality and transmission makes the expansion of HAART coverage highly cost-averting. Building on a mathematical model that evaluated the impact of expanded HAART access on viral load in a Canadian setting, we demonstrate that an investment of CA$249 million over the lifetime of treated individuals would result in a net gain of CA$2.1 billion over 30 years. This provides a powerful economic incentive to rapidly scale up HAART access worldwide.

HIV drug resistance testing is recommended as routine part of clinical practice in HIV/AIDS treatment and care. Our objective is to assess the determinants of accessing HIV drug resistance testing and examine the factors associated with resistance testing prior to or after starting highly active antiretroviral therapy (HAART) in a setting where access to HIV care is free and universal. The Longitudinal Investigation into Supportive and Ancillary health services (LISA) study is an open prospective cohort of HIV-positive persons on HAART in British Columbia (BC), Canada. Non-clinical data were collected through an interviewer-administered survey and clinical data were obtained through the BC Centre for Excellence in HIV/AIDS Drug Treatment Program. Independent associations between key explanatory variables and resistance testing were analyzed using logistic regression. We restricted our post-HAART analyses to those patients who met the criteria for resistance testing after HAART initiation. Of 359 LISA participants who started HAART after 2000 and at a time when resistance testing was available free of charge, almost half did not receive a baseline resistance test. Post-HAART initiation, 165 of 359 study subjects met the criteria for resistance testing based on current therapeutic guidelines due to virological failure. About 37.6% of them remain untested for resistance. Multivariable analyses show that baseline testing was less likely performed for persons of Aboriginal ethnicity and more likely performed for patients initiating HAART in 2004 or after. Additionally, persons initiating HAART in 2004 or after were less likely to have received a resistance test after virologic failure. Our results show that despite existing clinical guidelines, resistance testing is underused, even in an environment where the service is available free of charge. Further, resistance testing is particularly underutilized among vulnerable populations. Urgent efforts are needed to ensure the optimal use of resistance testing at baseline and at the time of virologic failure as recommended by current guidelines.

Background We examined trends in AIDS-defining illnesses (ADIs) among individuals receiving highly active antiretroviral therapy (HAART) in British Columbia (BC), Canada to determine whether declines in ADIs could be contributing to previously observed improvements in life-expectancy among HAART patients in BC since 1996. Methods HAART-naïve individuals aged ≥ 18 years who initiated treatment in BC each of the following time-periods 1996 - 1998; 1999 - 2001; 2002 - 2004; 2005 - 2007 were included. The proportion of participants with reported ADIs were examined for each time period and trends were analyzed using the Cochran-Armitage Trend Test. Cox proportional hazards models were used to examine factors associated with ADIs. Results A total of 3721 individuals (81% male) initiated HAART during the study period. A total of 251 reports of ADIs were received from 214 unique patients. These occurred in a median of 4 months (IQR = 1-19 months) from HAART initiation. The proportion of individuals with a reported ADI did not change significantly from 4.6% in the earliest time period to 5.8% in the latest period (p = 0.181 for test of trend). There were no significant declines in any specific ADI over the study period. Multivariable Cox models found that individuals initiating HAART during 2002-04 were at an increased risk of ADIs (AHR = 1.55; 95% CI 1.04-2.32) in comparison to 1996 - 98, but there were no significant differences in other time periods. Conclusions Trends in reported ADIs among individuals receiving HAART since 1996 in BC do not appear to parallel improvements in life-expectancy over the same period.

Objective: To model the effect of adherence and duration of viral suppression on the risk of viral rebound. Methods: Viral rebound was defined as the first of at least two consecutive viral loads greater than 400 copies/mL after initial viral suppression. The main exposures were adherence, presence of antiretroviral class resistance before rebound or censoring date, and the percentage of follow-up time with viral suppression. Results: A total of 274 (N = 1305 [21%]) individuals experienced viral rebound. Median time of suppression before rebound was 2 years. Viral rebound was less likely to occur among those with longer duration of continuous viral suppression (odds ratio, 0.37; 95% confidence interval, 0.32 to 0.42). Among individuals with moderate levels of adherence (80% to less than 95%), the probability of virologic failure was 0.85 after being suppressed for 12 months and it was 0.08 after 72 months being suppressed (P < 0.01). Individuals with drug resistance were at a higher risk of viral rebound. Conclusions: The risk of viral rebound decreased with longer duration of viral suppression within each of adherence strata studied. Although perfect adherence remains an important goal of therapy to prevent disease progression, individuals with long-term viral suppression may be able to miss more doses without experiencing viral rebound.

Background: HIV-related mortality has been declining in Canada; however, little is known about regional differences in HIV-related mortality. The objective of this study was to characterize regional changes in HIV-related mortality from 1987-2006 in British Columbia (BC). Methods: BC Vital Statistics provided death certificate data for individuals ³18 years who died of an HIV-related cause in BC between 1987 and 2006. Annual mortality rates were calculated for all BC, five regional health authorities, and two areas within Vancouver. Joinpoint regression analyses measured changes in mortality rates. Results: There were 3,899 HIV-related deaths in BC from 1987-2006. Over time, HIV-related mortality rates were highest in the densely populated, southern regions, and lowest in the north. In BC, mortality significantly increased from 1987-1994 (annual percent change [APC] 16.3%). In 1994, the trend changed to a significant decrease in mortality from 1994-1998 (APC -20.0%), followed by a sustained reduction from 1998-2006. Four of the five health authorities showed mortality trends similar to the province; however, the north showed significantly increasing mortality from 1987-2006 (APC 6.7%). In Vancouver, the City Centre showed a mortality pattern similar to the province, but the Downtown Eastside had rising mortality rates until 1997, followed by a modest decline. Conclusion: In most areas of BC, HIV-related mortality declined after the introduction of effective antiretroviral therapy; however, this decline was delayed or absent in some regions. These regional variations may reflect differential access to health care, even in a setting where antiretroviral therapy is provided at no cost to patients. Key words: Mortality; mortality decline; death rate; HIV; Canada; British Columbia

Given the recent evolution of therapeutic trends, the frequency and determinants of multiclass-resistant HIV infection in the modern combination highly active antiretroviral therapy (HAART) era are less well understood. In this study, the authors characterize the epidemiology of antiretroviral multiclass resistance among HAART-naive patients enrolled in a province-wide HAART distribution program in British Columbia, Canada. HAART and resistance testing are free to eligible individuals in British Columbia. This study was based on patients who initiated naive on HAART and were followed during January 1, 2000-June 30, 2007. Explanatory logistic and survival models were built to identify those factors most influential in the emergence of multiclass resistance. Among the 1,820 individuals in our study, 833 (46%) were tested for antiretroviral resistance at least once during their follow-up. Multiclass resistance was observed in 142 individuals (n = 833; 17%) during a median follow-up of 14 months (interquartile range, 3-34 months) (incidence rate, 0.8 cases/1,000 person-months). The authors found that initial nonnucleoside reverse transcriptase inhibitor-based HAART was the main determinant of multiclass resistance. Given that these inhibitors are still widely used, priority should be given to make resistance testing and viral load monitoring a standard part of human immunodeficiency virus care to maximize the long-term efficacy and efficiency of HAART.

Background In 2008, the IAS-USA published the revised guidelines for the use of HAART in adults substantially increasing the number of individuals eligible for HAART. The epidemic in British Columbia (BC) is mainly among men who have sex with men and those with injection drug use. Here, we explored the potential impact of different HAART coverage scenarios, based on the new guidelines, on the HIV-related incidence, morbidity and mortality in BC, Canada. Methodology We built a mathematical transmission model to investigate different HAART coverage scenarios (50%, 60%, 75% and 100%) of those medically eligible to receive HAART under the 2008 IAS guidelines. All new scenarios were compared to the current coverage in BC under the 2006 IAS guidelines (i.e. baseline scenario). In BC, it is estimated that 25–30% of individuals are unaware of their status. Costs were drug-related and reported in Canadian dollars. HIV-related morbidity and mortality were estimated based on the disability-adjusted life years (DALY) methodology. Principal Findings Currently, there are 4379 individuals on HAART under the IAS 2006 guidelines and 6781 individuals who qualify for treatment based on the new guidelines. Within 5 years, increasing HAART coverage decreased yearly new infections by at least 44.8%. In the 50% scenario, in 5 years, DALY decreased by 53% corresponding to 4155 averted DALYs, and in 25 years it decreased by 66% corresponding to 5837 averted DALYs. The effect was even stronger if the 75% scenario was chosen instead. Compared to the 100% expansion scenario, we observed an excess in annual direct treatment expenditures at the end of 5 years of approximately 1 million dollars in the 75% scenario, and of approximately 2 million dollars in the 50% scenario. Conclusions/Significance The individual and public health benefits of these new guidelines are immense. The results show that by increasing the number of individuals on HAART save lives, it is cost averting, and it positively impacts society by decreasing the number of new HIV infections. Thus, public health community should consider incremental gains when considering guidelines and policy.

This letter to the editor discusses the report on PEPFAR and its positive effects on HIV-related prevalence and AIDS mortality in certain sub-Saharan African countries. It describes a study they conducted by obtaining raw prevalence data and AIDS and non-AIDS mortality data for adults and children to estimate HIV incidence in each of the 41 countries.

Objectives: To examine regional and temporal trends in migration among patients receiving HIV treatment in British Columbia (BC). Methods: Patients initiating antiretroviral therapy in BC between January 1993 and November 2004 were followed until November 2005. Migration was calculated as the cumulative number of times a patient’s residential address changed during their course of treatment. Analyses were performed at the provincial and at the regional health authority (HA) and local health area levels. Demographic methods were used to estimate the in- and out-migration rates, indices of dissimilarity and concentration across regions over time. Results: A total of 3,588 participants were followed during the study period. Individuals who migrated most often migrated to the Vancouver Coastal HA (from the Interior: 30%, Fraser: 41%, Vancouver Island: 28%, and Northern: 19%), specifically the city of Vancouver, which has been treating the most patients with HIV since the early stages of the epidemic. We also showed that this movement intensified as more contemporary HAART regimens became available (p-value for trend Discussion: Our results demonstrate that migration among people with HIV in BC is not homogeneous, with areas around large urban centres having the highest influx of patients. It is thus important that health authorities in BC work in partnership to monitor and evaluate accessibility of HIV-related health care services to ensure universal access for all patients. Furthermore, enhanced HIV care and support services need to be developed, on a province-wide basis, and funding allocation needs to be adjusted to reflect patient migration in BC. Key words: HIV/AIDS; migration; regional analysis; trend; British Columbia; Canada

Background We examined clinical outcomes, patient characteristics and trends over time of non-medically supervised treatment interruptions (TIs) from a free-of-charge antiretroviral therapy (ART) programme in British Columbia (BC), Canada. Methods Data from ART-naive individuals ≥18 years old who initiated triple combination highly active antiretroviral therapy (HAART) between January 2000 and June 2006 were analysed. Participants having ≥3 month gap in HAART coverage were defined as having a TI. Cox proportional hazards modelling was used to examine factors associated with TIs and to examine factors associated with resumption of treatment. Results A total of 1707 participants were study eligible and 643 (37.7%) experienced TIs. TIs within 1 year of ART initiation decreased from 29% of individuals in 2000 to 19% in 2006 (P

Since the introduction of combination drug regimens to treat human immunodeficiency virus (HIV) infection, known as highly active antiretroviral therapy (HAART), the rates of HIV-related morbidity and mortality have been markedly reduced [1, 2]. Over time, there has been an increased variety and availability of antiretroviral drugs. However, suboptimal therapy response can lead to the development of antiretroviral drug resistance, which is a significant barrier to the future success of therapy. Virological failure while receiving HAART is dependent on several factors, including drug toxicity, insufficient adherence to therapy, and problems with drug pharmacokinetics. The prevalence of drug resistance can be defined as the amount of drug resistance present in an investigated population in a given period of time. Several cross-sectional studies have investigated the prevalence of HIV drug resistance in relatively small populations [3–5], as well as in larger populations [6–8]. Some of these studies have investigated the prevalence of transmitted resistance, whereas others have addressed the prevalence of acquired drug resistance among patients receiving treatment. Although studies that determine prevalence are important for assessing the current impact of HIV drug resistance, a critical indicator of the future success of HAART is the incidence of resistance over time while patients receive therapy, which remains relatively poorly defined. The incidence of drug resistance is defined as the number of new cases of drug resistance that develop in a population at risk for developing drug resistance during a given period of time. Thus far, one of the few studies that has investigated HIV drug resistance incidence on the scale of a large treatment population was done in Portugal and showed that the crude incidence of both multidrug resistance and full-drug-class resistance has decreased over time [9]. We undertook this study to evaluate the incidence rate of HIV drug resistance after initiation of therapy, reflecting the entire population of individuals being treated for HIV-1 infection in British Columbia from July 1996 through December 2008.

Bone mineral density (BMD) abnormalities are observed frequently among human immunodeficiency virus (HIV)-infected patients. Risk factors for reduced BMD in the setting of HIV have been previously studied, but detailed antiretroviral treatment history is often not available. A cross-sectional observational study was conducted between 2005 and 2007 among unselected HIV-infected adults attending an ambulatory urban HIV clinic. Dual-energy X-ray absorptiometry (DXA) scans of lumbar spine and femoral neck, full laboratory profile, detailed questionnaire, and antiretroviral history were obtained. Univariate and multivariate logistic regression analyses were performed to investigate factors associated with BMD below the expected range for age. Two hundred ninety patients completed the study: 80% Caucasians, 89% males, with median age of 49 yr. Low BMD as assessed by Z-score was present in 19.7% of the patients. By multivariate analysis, only lower body mass index (BMI) was an independent risk factor for low BMD. Cumulative exposure to protease inhibitors, non-nucleosides, and individual nucleoside and nucleotide analogs were not independently associated with low BMD. In conclusion, a 19.7% prevalence of abnormal BMD by DXA scan was identified in an unselected group of HIV-infected adults. Lower BMI was independently associated with low BMD. No correlation was found between abnormal BMD and cumulative exposure to any antiretroviral agents.

Antiretroviral-therapy rollout in resource-poor countries is often associated with limited, if any, HIV-RNA monitoring. The effect of variable monitoring on the emergence of resistance after therapy with commonly used drug combinations was assessed by systematic review of studies reporting resistance in patients infected with HIV with a CD4 count of fewer than 200 cells per muL treated with two nucleoside analogues (including a thymidine analogue) and a non-nucleoside reverse transcriptase inhibitor. 8376 patients from eight cohorts and two prospective studies were analysed. Resistance at virological failure to non-nucleoside reverse transcriptase inhibitors at 48 weeks was 88.3% (95% CI 82.2-92.9) in infrequently monitored patients, compared with 61.0% (48.9-72.2) in frequently monitored patients (p

To investigate the application of the new COBAS Ampliprep Taqman HIV-1 assay in comparison with the COBAS HIV-1 Ampliprep AMPLICOR MONITOR ultrasensitive assay version 1.5, with a particular focus on the most clinically relevant region near the lower limit of quantification.Scatterplots and the Bland-Altman plot were used to inspect the degree of agreement between the 2 assays when tested on samples from the British Columbia Centre for Excellence in HIV/AIDS monitoring and evaluation system. Consistency of clinically applicable values at low HIV-1 RNA copy number was assessed from samples from individuals with previously undetectable Amplicor results.Despite general agreement of these assays over a wide dynamic range, the Taqman assay resulted in a nearly 2-fold increase (from 3.6% to 6.9%) in the number of patients experiencing a plasma HIV-1 RNA level50 copies per milliliter after being suppressed to levels50 copies per milliliter consistently during the previous year (P0.01). In addition, rare discrepancies between the 2 assays were observed to be as high as 0.7 log10 copies per milliliter. The kappa statistic was 0.19, indicating only slight agreement at the critical threshold of 50 HIV RNA copies per milliliter, with 43% of undetectable samples in the Amplicor assay testing detectable in the Taqman assay (median 70 copies/mL; interquartile range 60-83 copies/mL).The increased frequency of detectable plasma HIV-1 RNA levels at the threshold of 50 copies per milliliter with the new Taqman assay has important implications for highly active antiretroviral therapy monitoring. Until there is clinical evidence that patients with detectable HIV by the Taqman assay (but undetectable HIV with Amplicor) have differential outcomes, it is unclear whether the Taqman assay is appropriate for routine management of HIV-1 therapy, and caution is required in the interpretation of low-level viremia by the Taqman assay until a clinical validation of a new cutoff is performed.

Achieving virologic suppression is a clear therapeutic goal for patients receiving combination antiretroviral therapy (cART). However, the effects of immunologic responses, whether measured as CD4 count changes from baseline or CD4 counts at follow-up, in patients with virologic suppression, have not been clearly established. Treatment-naive individuals aged > or =16 years, who initiated cART between 1998 and 2005 in participating cohorts of the ART Cohort Collaboration and achieved viral load < or =400 copies per milliliter 6 months after cART initiation, were included. We used Cox models to examine associations of CD4 change from baseline to 6 months, and absolute CD4 counts at 6 months, with subsequent rates of mortality and AIDS. Analyses were stratified by baseline CD4 count. Among 23,679 eligible participants, the median increase in CD4 count at 6 months, and the implications of these increases for subsequent mortality and AIDS, varied with baseline CD4 count. Mortality hazard ratios for increases of 0-50 cells per microliter, compared with >100 cells per microliter, were 1.87 (95% confidence interval: 1.28 to 2.73), 1.60 (1.13 to 2.28), 0.98 (0.58 to 1.65) and 1.24 (0.70 to 2.18) in participants with baseline CD4 cell count or =350 cells per microliter, respectively. In contrast, hazard ratios for mortality or AIDS associated with absolute CD4 cell counts at 6 months were similar across all but the highest baseline CD4 cell count strata. It is not possible to derive thresholds for change in CD4 count that define an adequate immunologic response in individuals receiving cART. Absolute CD4 counts at 6 months are a more useful measure of immunologic response and subsequent prognosis

The prevalence of HIV in Vancouver, British Columbia was subject to two distinct periods of rapid increase. The first occurred in the 1980s due to high incidence among men who have sex with men (MSM), and the second occurred in the 1990s due to high incidence among injection drug users (IDU). The purpose of this study was to estimate and model the trends in HIV prevalence in Vancouver from 1980 to 2006. HIV prevalence data were entered into the UNAIDS/WHO Estimation and Projection Package (EPP) where prevalence trends were estimated by fitting an epidemiological model to the data. Epidemic curves were fit for IDU, MSM, street-based female sex trade workers (FSW), and the general population. Using EPP, these curves were then aggregated to produce a model of Vancouver's overall HIV prevalence. Of the 505 000 people over the age of 15 that reside in Vancouver, 6108 (ranging from 4979 to 7237) were living with HIV in the year 2006, giving an overall prevalence of 1.21 percent (ranging from 0.99 to 1.43 percent). The subgroups of IDU and MSM account for the greatest proportion of HIV infections. Our model estimates that the prevalence of HIV in Vancouver is greater than one percent, roughly 6 times higher than Canada's national prevalence. These results suggest that HIV infection is having a relatively large impact in Vancouver and that evidence-based prevention and harm reduction strategies should be expanded.

The objective of this study was to develop a reliable HAART optimism scale among HIV-positive women in Uganda and to test the scale's validity against measures of fertility intentions, sexual activity, and unprotected sexual intercourse. We used cross-sectional survey data of 540 women (18-50 years) attending Mbarara University's HIV clinic in Uganda. Women were asked how much they agreed or disagreed with 23 statements about HAART. Data were subjected to a principal components and factor analyses. Subsequently, we tested the association between the scale and fertility intentions and sexual behaviour using Wilcoxon rank sum test. Factor analysis yielded three factors, one of which was an eight-item HAART optimism scale with moderately high internal consistency (alpha = 0.70). Women who reported that they intended to have (more) children had significantly higher HAART optimism scores (median = 13.5 [IQR: 12-16]) than women who did not intend to have (more) children (median = 10.5 [IQR: 8-12]; P0.0001). Similarly, women who were sexually active and who reported practicing unprotected sexual intercourse had significantly higher HAART optimism scores than women who were sexually abstinent or who practiced protected sexual intercourse. Our reliable and valid scale, termed the Women's HAART Optimism Monitoring and EvaluatioN scale (WHOMEN's scale), may be valuable to broader studies investigating the role of HAART optimism on reproductive intentions and sexual behaviours of HIV-positive women in high HIV prevalence settings.

We developed a mathematical model using a multiple source of infection framework to assess the potential effect of the expansion of highly active antiretroviral therapy (HAART) coverage among those in medical need on the number of individuals testing newly positive for human immunodeficiency virus (HIV) and on related costs in British Columbia, Canada, over the next 25 years. The model was calibrated using retrospective data describing antiretroviral therapy utilization and individuals testing newly positive for HIV in the province. Different scenarios were investigated on the basis of varying assumptions regarding drug resistance, adherence to HAART, therapeutic guidelines, degree of HAART coverage, and the timing of HAART uptake. Expansion of HAART lead to substantial reductions in the growth of the HIV epidemic and related costs. These results provide powerful additional motivation to accelerate the roll out of HAART programs aggressively targeting those in medical need, both for their own benefit and as a means of decreasing new HIV infections.

Background. We explore the temporal and regimen-specific changes of HIV-1 drug resistance in a large cohort of antiretroviral-naive individuals starting highly active antiretroviral therapy (HAART).Methods. Individuals (n = 2350) initiating first HAART between August 1996 and November 2004 were followed until November 2005 (median follow-up, 4.8 years; n = 6066 tests). A logistic regression model was used to predict the probability of the emergence of resistance, adjusting for baseline predictors.Results. The cohort included 991 individuals initiating nonboosted protease inhibitor (PI)-based regimens, 475 initiating ritonavir-boosted PI-based regimens, and 884 initiating nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based regimens. There was no difference in the development of resistance between nonboosted PI-based regimens (reference group) and NNRTI-based HAART regimens (odds ratio [OR], 1.09 [95% confidence interval {CI}, 0.84–1.42]), but there were greatly reduced odds for boosted PI- based regimens (OR, 0.42 [95% CI, 0.28 – 0.62]). Individuals initiating HAART more recently (2002–2004) were at a reduced risk of resistance, compared with those who started HAART between 1996 and 1998 (OR, 0.43 [95% CI, 0.30 – 0.61]).Conclusions. Individuals initiating first HAART with a boosted PI-based regimen had a 2.4-fold lower OR for developing HIV drug resistance than did those starting nonboosted PI-based or NNRTI-based HAART, at all adherence levels. The data demonstrate marked temporal improvement in the likelihood of the development of drug resistance for those initiating more recent HAART regimens.

Migration among persons with HIV/AIDS is common; however, it is not clear how migration relates to antiretroviral adherence, a key determinant of treatment efficacy. Therefore, our objective was to determine the scale of regional migration and its association with adherence patterns over time among HIV-infected individuals in British Columbia (BC), Canada. Participants initiated HAART in August 1996-November 2004, and were followed until November 2005. Adherence was defined as the number of days worth of antiretrovirals dispensed divided by the number of days of follow-up (expressed as a percentage), and considered a binary time-dependent outcome: 'non-adherence' (less than 95%) versus 'adherence' (95% or more). Migration was calculated as the cumulative number of times a patient's residential address changed during the course of treatment, and treated as a time-dependent variable. Non-linear mixed-effects models were used to estimate the association between migration and adherence over time. All analyses were adjusted for relevant fixed and time-dependent variables. A total of 2421 participants were followed during the study period. Descriptive analysis demonstrated high stability in adherence over time, with more than 55% of patients moving at least once during the course of their treatment. We observed that those individuals migrating at least 3 times were 1.79 times more likely to be in the 'non-adherence' group than individuals who did not migrate. Our results demonstrate that migration in BC is not homogeneous across subpopulations. These results suggest that proactive strategies are needed to ensure that antiretroviral therapy remains available on a continued basis to highly migrant populations.

Objectives: The objectives of this study were to examine neighborhood measures of socioeconomic status and their effect on the risk of mortality among HIV-positive persons accessing and not accessing treatment, the effects of late access to treatment by CD4 cell count, and survival among those who accessed treatment. Methods: We limited our analysis to the era of highly active antiretroviral therapy (HAART). We used individual-level patient and clinical characteristics and neighborhood-level socioeconomic data to address our objectives. The Pearson X 2 and Wilcoxon sign rank tests were used to compare mortality among HIV-positive persons accessing and not accessing treatment, logistic regression models were used to compare persons who accessed treatment with low CD4 cell counts (

Objective: To determine the impact of depressive symptoms on mortality among HIV/ AIDS patients first initiating HAART and the potential role of patient adherence as a confounder and effect modifier in this association. Methods: The study comprised HIV-positive individuals who were first prescribed HAART between August 1996 and June 2002. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale. Cox proportional hazards models were used to determine the association between depressive symptoms, adherence and all-cause mortality while controlling for several baseline confounding factors. Results: A total of 563 participants met the study inclusion criteria. Of these subjects, 51% had depressive symptoms at baseline and 23% of participants were less than 95% adherent in the first year of follow-up. The overall all-cause mortality rate was 10%. Multivariate analysis showed that individuals with depressive symptoms and adherence < 95% were 5.90 times (95% confidence interval, 2.55-13.68) more likely to die than adherent patients with no depressive symptoms. The estimated median model-based survival probabilities stratified by adherence and depressive symptoms levels ranged from 81 % (interquartile range, 72-89%) for depressive symptoms and adherence < 95% to 97% (interquartile range, 94-98%) for no depressive symptoms and adherence ≥ 95%. Conclusion: The results indicate that both depressive symptoms and adherence were associated with shorter survival among individuals with HIV accessing HAART. Given the high prevalence of depressive symptoms in HIV-positive patients and a strong association with adherence, the findings support improvement in the diagnosis and treatment of depression as well as adherence in order to maximize the effectiveness of HAART.

Bohdan Nosyk1,4,3, Jeong Eun Min1, Elizabeth Evans2, Libo Li3, Lei Liu5, Viviane D. Lima1, Evan Wood1, Julio Montaner1 1 BC Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada 2 UCLA, Los Angeles, CA, United States 3 UCLA Integrated Substance Abuse Programs, Los Angeles, CA, United States 4 Faculty of Health Sciences, Simon Fraser University, Vancouver, BC, Canada 5 Northwestern University, Chicago, IL, United States

Background Annually, 10 million adults transition through prisons or jails in the United States (US) and the prevalence of HIV among entrants is three times higher than that for the country as a whole. We assessed the potential impact of increasing HIV Testing/Treatment/Retention (HIV-TTR) in the community and within the criminal justice system (CJS) facilities, coupled with sexual risk behavior change, focusing on black men-who-have-sex-with-men, 15–54 years, in Atlanta, USA. Methods We modeled the effect of a HIV-TTR strategy on the estimated cumulative number of new (acquired) infections and mortality, and on the HIV prevalence at the end of ten years. We additionally assessed the effect of increasing condom use in all settings. Results In the Status Quo scenario, at the end of 10 years, the cumulative number of new infections in the community, jail and prison was, respectively, 9246, 77 and 154 cases; HIV prevalence was 10815, 69 and 152 cases, respectively; and the cumulative number of deaths was 2585, 18 and 34 cases, respectively. By increasing HIV-TTR coverage, the cumulative number of new infections could decrease by 15% in the community, 19% in jail, and 8% in prison; HIV prevalence could decrease by 8%, 9% and 7%, respectively; mortality could decrease by 20%, 39% and 18%, respectively. Based on the model results, we have shown that limited use and access to condoms have contributed to the HIV incidence and prevalence in all settings. Conclusions Aggressive implementation of a CJS-focused HIV-TTR strategy has the potential to interrupt HIV transmission and reduce mortality, with benefit to the community at large. To maximize the impact of these interventions, retention in treatment, including during the period after jail and prison release, and increased condom use was vital for decreasing the burden of the HIV epidemic in all settings.

Introduction : Despite the tremendous improvements in survival, some groups of people living with HIV (PLHIV) continue to have lower survival rates than the overall HIV-positive population. Here, we characterize the evolving pattern of mortality among PLHIV in British Columbia since the beginning of the expansion of antiretroviral treatment in 2003. Methods : This retrospective cohort study included 3653 individuals ≥20 years old, who enrolled on treatment between January 1, 2003, and December 31, 2012, and were followed until December 31, 2013. All-cause mortality rates and standardized mortality ratios (SMRs) were calculated to compare mortality outcomes of PLHIV to the general population. Abridged life tables were constructed to estimate the life expectancy at age 20 years for PLHIV. Results : The overall crude mortality rate was 28.57 per 1000 person-years, the SMR was 3.22 and the life expectancy was 34.53 years. Interestingly, if we considered only individuals alive after the first year, the life expectancy increased to 48.70 years (41% increase). The SMRs for males and females decreased over time. Although females had higher SMRs in 2003 to 2008, this difference no longer existed in 2009 to 2011. There were also important differences in mortality outcomes for different clinical and demographical characteristics. Conclusions : Mortality outcomes of PLHIV who initiated antiretroviral treatment have dramatically improved over the last decade. However, there is still room for improvement and multilateral efforts should continue to promote early, sustained engagement of PLHIV on treatment so that the impact of treatment can be fully realized. Keywords: PLHIV; mortality rate; life expectancy; standardized mortality ratios; clinical outcomes; treatment as prevention; British Columbia; Canada. To access the supplementary material to this article please see Supplementary Files in the column to the right (under Article Tools). (Published: 7 October 2015) Citation: Lima VD et al. Journal of the International AIDS Society 2015, 18 :20261 http://www.jiasociety.org/index.php/jias/article/view/20261 | http://dx.doi.org/10.7448/IAS.18.1.20261

BACKGROUND:Although the impact of Aboriginal status on HIV incidence, HIV disease progression, and access to treatment has been investigated previously, little is known about the relationship between Aboriginal ethnicity and outcomes associated with highly active antiretroviral therapy (HAART). We undertook the present analysis to determine if Aboriginal and non-Aboriginal persons respond differently to HAART by measuring HIV plasma viral load response, CD4 cell response and time to all-cause mortality.METHODS:A population-based analysis of a cohort of antiretroviral therapy naïve HIV-positive Aboriginal men and women 18 years or older in British Columbia, Canada. Participants were antiretroviral therapy naïve, initiated triple combination therapy between August 1, 1996 and September 30, 1999. Participants had to complete a baseline questionnaire as well as have at least two follow-up CD4 and HIV plasma viral load measures. The primary endpoints were CD4 and HIV plasma viral load response and all cause mortality. Cox proportional hazards models were used to determine the association between Aboriginal status and CD4 cell response, HIV plasma viral load response and all-cause mortality while controlling for several confounder variables.RESULTS:A total of 622 participants met the study criteria. Aboriginal status was significantly associated with no AIDS diagnosis at baseline (p = 0.0296), having protease inhibitor in the first therapy (p = 0.0209), lower baseline HIV plasma viral load (p < 0.001), less experienced HIV physicians (P = 0.0133), history of IDU (p < 0.001), not completing high school (p = 0.0046), and an income of less than $10,000 per year (p = 0.0115). Cox proportional hazards models controlling for clinical characteristics found that Aboriginal status had an increased hazard of mortality (HR = 3.12, 95% CI: 1.77–5.48) but did not with HIV plasma viral load response (HR = 1.15, 95% CI: 0.89–1.48) or CD4 cell response (HR = 0.95, 95% CI: 0.73–1.23).CONCLUSION:Our study demonstrates that HIV-infected Aboriginal persons accessing HAART had similar HIV treatment response as non-Aboriginal persons but have a shorter survival. This study highlights the need for continued research on medical interventions and behavioural changes among HIV-infected Aboriginal and other marginalized populations., Affiliation: Mark Daniel: Département de médecine sociale et préventive, Faculté de médecine, Université de Montréal et Centre de recherche du Centre hospitalier de l'Université de Montréal

Context Highly active antiretroviral therapy (HAART) is often withheld from injection drug users (IDUs) infected with the human immunodeficiency virus (HIV) based on the belief that their unstable lifestyles may predetermine a markedly inferior outcome with HAART. However, long-term evaluations of HIV treatment outcomes among IDUs in comparison with other risk groups are not available. Objective To compare survival rates among HIV-infected patients initiating HAART with and without a history of injection drug use. Design, Setting, and Patients Population-based, prospective cohort study (HAART Observational Medical Evaluation and Research [HOMER]) of 3116 antiretroviral-naive HIV-infected patients in a province-wide HIV/AIDS treatment program in British Columbia, Canada. Of the 3116 patients, 915 were IDUs (29.4%), 579 were female (18.6%), and the median age was 39.4 years (interquartile range, 33.3-46.4 years). Treatment with HAART was initiated between August 1, 1996, and June 30, 2006. The median duration of follow-up was 5.3 years (interquartile range, 2.8-8.3 years) for IDUs and 4.3 years (interquartile range, 2.0-7.6 years) for non-IDUs. Patients were followed up until June 30, 2007. Data were analyzed between November 1, 2007, and May 26, 2008. Main Outcome Measure All-cause mortality. Results Overall, 622 individuals died (20.0%) during the study period (232 IDUs and 390 non-IDUs), for a crude mortality rate of 20.0% (95% confidence interval [CI], 18.4%-21.5%). At 84 months after the initiation of HAART, the product limit estimate of the cumulative all-cause mortality rate was similar between the 915 IDUs (26.5%; 95% CI, 23.2%-29.8%) and 2201 non-IDUs (21.6%; 95% CI, 16.9%-26.2%) (Wilcoxon P = .47). In multivariate time-updated Cox regression, the hazard ratio of mortality was similar between IDUs and non-IDUs (1.09; 95% CI, 0.92-1.29). Conclusion In this study population, injection drug use was not associated with decreased survival among HIV-infected patients initiating HAART.

The catalytically active 66-kDa subunit of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) consists of DNA polymerase, connection, and ribonuclease H (RNase H) domains. Almost all known RT inhibitor resistance mutations identified to date map to the polymerase domain of the enzyme. However, the connection and RNase H domains are not routinely analysed in clinical samples and none of the genotyping assays available for patient management sequence the entire RT coding region. The British Columbia Centre for Excellence in HIV/AIDS (the Centre) genotypes clinical isolates up to codon 400 in RT, and our retrospective statistical analyses of the Centre's database have identified an N348I mutation in the RT connection domain in treatment-experienced individuals. The objective of this multidisciplinary study was to establish the in vivo relevance of this mutation and its role in drug resistance.The prevalence of N348I in clinical isolates, the time taken for it to emerge under selective drug pressure, and its association with changes in viral load, specific drug treatment, and known drug resistance mutations was analysed from genotypes, viral loads, and treatment histories from the Centre's database. N348I increased in prevalence from below 1% in 368 treatment-naïve individuals to 12.1% in 1,009 treatment-experienced patients (p = 7.7 x 10(-12)). N348I appeared early in therapy and was highly associated with thymidine analogue mutations (TAMs) M41L and T215Y/F (p < 0.001), the lamivudine resistance mutations M184V/I (p < 0.001), and non-nucleoside RTI (NNRTI) resistance mutations K103N and Y181C/I (p < 0.001). The association with TAMs and NNRTI resistance mutations was consistent with the selection of N348I in patients treated with regimens that included both zidovudine and nevirapine (odds ratio 2.62, 95% confidence interval 1.43-4.81). The appearance of N348I was associated with a significant increase in viral load (p < 0.001), which was as large as the viral load increases observed for any of the TAMs. However, this analysis did not account for the simultaneous selection of other RT or protease inhibitor resistance mutations on viral load. To delineate the role of this mutation in RT inhibitor resistance, N348I was introduced into HIV-1 molecular clones containing different genetic backbones. N348I decreased zidovudine susceptibility 2- to 4-fold in the context of wild-type HIV-1 or when combined with TAMs. N348I also decreased susceptibility to nevirapine (7.4-fold) and efavirenz (2.5-fold) and significantly potentiated resistance to these drugs when combined with K103N. Biochemical analyses of recombinant RT containing N348I provide supporting evidence for the role of this mutation in zidovudine and NNRTI resistance and give some insight into the molecular mechanism of resistance.This study provides the first in vivo evidence that treatment with RT inhibitors can select a mutation (i.e., N348I) outside the polymerase domain of the HIV-1 RT that confers dual-class resistance. Its emergence, which can happen early during therapy, may significantly impact on a patient's response to antiretroviral therapies containing zidovudine and nevirapine. This study also provides compelling evidence for investigating the role of other mutations in the connection and RNase H domains in virological failure.

Background The impact of the emergence of drug-resistance mutations on mortality is not well characterized in antiretroviral-naïve patients first starting highly active antiretroviral therapy (HAART). Patients may be able to sustain immunologic function with resistant virus, and there is limited evidence that reduced sensitivity to antiretrovirals leads to rapid disease progression or death. We undertook the present analysis to characterize the determinants of mortality in a prospective cohort study with a median of nearly 5 y of follow-up. The objective of this study was to determine the impact of the emergence of drug-resistance mutations on survival among persons initiating HAART. Methods and Findings Participants were antiretroviral therapy naïve at entry and initiated triple combination antiretroviral therapy between August 1, 1996, and September 30, 1999. Marginal structural modeling was used to address potential confounding between time-dependent variables in the Cox proportional hazard regression models. In this analysis resistance to any class of drug was considered as a binary time-dependent exposure to the risk of death, controlling for the effect of other time-dependent confounders. We also considered each separate class of mutation as a binary time-dependent exposure, while controlling for the presence/absence of other mutations. A total of 207 deaths were identified among 1,138 participants over the follow-up period, with an all cause mortality rate of 18.2%. Among the 679 patients with HIV-drug-resistance genotyping done before initiating HAART, HIV-drug resistance to any class was observed in 53 (7.8%) of the patients. During follow-up, HIV-drug resistance to any class was observed in 302 (26.5%) participants. Emergence of any resistance was associated with mortality (hazard ratio: 1.75 [95% confidence interval: 1.27, 2.43]). When we considered each class of resistance separately, persons who exhibited resistance to non-nucleoside reverse transcriptase inhibitors had the highest risk: mortality rates were 3.02 times higher (95% confidence interval: 1.99, 4.57) for these patients than for those who did not exhibit this type of resistance. Conclusions We demonstrated that emergence of resistance to non-nucleoside reverse transcriptase inhibitors was associated with a greater risk of subsequent death than was emergence of protease inhibitor resistance. Future research is needed to identify the particular subpopulations of men and women at greatest risk and to elucidate the impact of resistance over a longer follow-up period., Emergence of resistance to both non-nucleoside reverse transcriptase inhibitors and protease inhibitors was associated with a higher risk of subsequent death, but the risk was greater in patients with NNRTI-resistant HIV., Editors' Summary Background. In the 1980s, infection with the human immunodeficiency virus (HIV) was effectively a death sentence. HIV causes AIDS (acquired immunodeficiency syndrome) by replicating inside immune system cells and destroying them, which leaves infected individuals unable to fight off other viruses and bacteria. The first antiretroviral drugs were developed quickly, but it soon became clear that single antiretrovirals only transiently suppress HIV infection. HIV mutates (accumulates random changes to its genetic material) very rapidly and, although most of these changes (or mutations) are bad for the virus, by chance some make it drug resistant. Highly active antiretroviral therapy (HAART), which was introduced in the mid-1990s, combines three or four antiretroviral drugs that act at different stages of the viral life cycle. For example, they inhibit the reverse transcriptase that the virus uses to replicate its genetic material, or the protease that is necessary to assemble new viruses. With HAART, the replication of any virus that develops resistance to one drug is inhibited by the other drugs in the mix. As a consequence, for many individuals with access to HAART, AIDS has become a chronic rather than a fatal disease. However, being on HAART requires patients to take several pills a day at specific times. In addition, the drugs in the HAART regimens often have side effects. Why Was This Study Done? Drug resistance still develops even with HAART, often because patients don't stick to the complicated regimens. The detection of resistance to one drug is usually the prompt to change a patient's drug regimen to head off possible treatment failure. Although most patients treated with HAART live for many years, some still die from AIDS. We don't know much about how the emergence of drug-resistance mutations affects mortality in patients who are starting antiretroviral therapy for the first time. In this study, the researchers looked at how the emergence of drug resistance affected survival in a group of HIV/AIDS patients in British Columbia, Canada. Here, everyone with HIV/AIDS has access to free medical attention, HAART, and laboratory monitoring, and full details of all HAART recipients are entered into a central reporting system. What Did the Researchers Do and Find? The researchers enrolled people who started antiretroviral therapy for the first time between August 1996 and September 1999 into the HAART Observational Medical Evaluation and Research (HOMER) cohort. They then excluded anyone who was infected with already drug-resistant HIV strains (based on the presence of drug-resistance mutations in viruses isolated from the patients) at the start of therapy. The remaining 1,138 patients were followed for an average of five years. All the patients received either two nucleoside reverse transcriptase inhibitors and a protease inhibitor, or two nucleoside and one non-nucleoside reverse transcriptase inhibitor (NNRTI). Nearly a fifth of the study participants died during the follow-up period. Most of these patients actually had drug-sensitive viruses, possibly because they had neglected taking their drugs to such an extent that there had been insufficient drug exposure to select for drug-resistant viruses. In a quarter of the patients, however, HIV strains resistant to one or more antiretroviral drugs emerged during the study (again judged by looking for mutations). Detailed statistical analyses indicated that the emergence of any drug resistance nearly doubled the risk of patients dying, and that people carrying viruses resistant to NNRTIs were three times as likely to die as those without resistance to this class of antiretroviral drug. What Do These Findings Mean? These results provide new information about the emergence of drug-resistant HIV during HAART and possible effects on the long-term survival of patients. In particular, they suggest that clinicians should watch carefully for the emergence of resistance to NNRTIs in their patients. Because this type of resistance is often due to poor adherence to drug regimens, these results also suggest that increased efforts should be made to ensure that patients comply with the prescribed HAART regimens, especially those whose antiretroviral therapy includes NNRTIs. As with all studies in which a group of individuals who share a common characteristic are studied over time, it is possible that some other, unmeasured difference between the patients who died and those who didn't—rather than emerging drug resistance—is responsible for the observed differences in survival. Additional studies are needed to confirm the findings here, and to investigate whether specific subpopulations of patients are at particular risk of developing drug resistance and/or dying during HAART. Additional Information. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030356. US National Institute of Allergy and Infectious Diseases fact sheet on HIV infection and AIDS US Department of Health and Human Services information on AIDS, including details of approved drugs for the treatment of HIV infection US Centers for Disease Control and Prevention information on HIV/AIDS Aidsmap, information on HIV and AIDS provided by the charity NAM, which includes details on antiretroviral drugs

Background Non-HIV/AIDS-related diseases are gaining prominence as important causes of morbidity and mortality among people living with HIV. The purpose of this study was to characterize and compare changes over time in mortality rates and causes of death among a population-based cohort of persons living with and without HIV in British Columbia (BC), Canada. Methods We analysed data from the Comparative Outcomes And Service Utilization Trends (COAST) study; a retrospective population-based study created via linkage between the BC Centre for Excellence in HIV/AIDS and Population Data BC, and containing data for HIV-infected individuals and the general population of BC, respectively. Our analysis included all known HIV-infected adults (≥ 20 years) in BC and a random 10% sample of uninfected BC adults followed from 1996 to 2012. Deaths were identified through Population Data BC – which contains information on all registered deaths in BC (BC Vital Statistics Agency dataset) and classified into cause of death categories using International Classification of Diseases (ICD) 9/10 codes. Age-standardized mortality rates (ASMR) and mortality rate ratios were calculated. Trend test were performed. Results 3401 (25%), and 47,647 (9%) individuals died during the 5,620,150 person-years of follow-up among 13,729 HIV-infected and 510,313 uninfected individuals, respectively. All-cause and cause-specific mortality rates were consistently higher among HIV-infected compared to HIV-negative individuals, except for neurological disorders. All-cause ASMR decreased from 126.75 (95% CI: 84.92-168.57) per 1000 population in 1996 to 21.29 (95% CI: 17.79-24.79) in 2011-2012 (83% decline; p < 0.001 for trend), compared to a change from 7.97 (95% CI: 7.61-8.33) to 6.87 (95% CI: 6.70-7.04) among uninfected individuals (14% decline; p&thinsp

BACKGROUND In light of accumulated scientific evidence of the secondary preventive benefits of antiretroviral therapy, a growing number of jurisdictions worldwide have formally started to implement HIV Treatment as Prevention (TasP) programs. To date, no gold standard for TasP program monitoring has been described. Here, we describe the design and methods applied to TasP program process monitoring in British Columbia (BC), Canada. METHODS Monitoring indicators were selected through a collaborative and iterative process by an interdisciplinary team including representatives from all 5 regional health authorities, the BC Centre for Disease Control (BCCDC), and the BC Centre for Excellence in HIV/AIDS (BC-CfE). An initial set of 36 proposed indicators were considered for inclusion. These were ranked on the basis of 8 criteria: data quality, validity, scientific evidence, informative power of the indicator, feasibility, confidentiality, accuracy, and administrative requirement. The consolidated list of indicators was included in the final monitoring report, which was executed using linked population-level data. RESULTS A total of 13 monitoring indicators were included in the BC TasP Monitoring Report. Where appropriate, indicators were stratified by subgroups of interest, including HIV risk group and demographic characteristics. Six Monitoring Reports are generated quarterly: 1 for each of the regional health authorities and a consolidated provincial report. CONCLUSIONS We have developed a comprehensive TasP process monitoring strategy using evidence-based HIV indicators derived from linked population-level data. Standardized longitudinal monitoring of TasP program initiatives is essential to optimize individual and public health outcomes and to enhance program efficiencies.