Rolando Barrios

Expansion of HAART coverage is associated with sustained decreases in HIV/AIDS morbidity, mortality and HIV transmission: the "HIV Treatment as Prevention" experience in a Canadian setting.

Background There has been renewed call for the global expansion of highly active antiretroviral therapy (HAART) under the framework of HIV treatment as prevention (TasP). However, population-level sustainability of this strategy has not been characterized. Methods We used population-level longitudinal data from province-wide registries including plasma viral load, CD4 count, drug resistance, HAART use, HIV diagnoses, AIDS incidence, and HIV-related mortality. We fitted two Poisson regression models over the study period, to relate estimated HIV incidence and the number of individuals on HAART and the percentage of virologically suppressed individuals. Results HAART coverage, median pre-HAART CD4 count, and HAART adherence increased over time and were associated with increasing virological suppression and decreasing drug resistance. AIDS incidence decreased from 6.9 to 1.4 per 100,000 population (80% decrease, p = 0.0330) and HIV-related mortality decreased from 6.5 to 1.3 per 100,000 population (80% decrease, p = 0.0115). New HIV diagnoses declined from 702 to 238 cases (66% decrease; p = 0.0004) with a consequent estimated decline in HIV incident cases from 632 to 368 cases per year (42% decrease; p = 0.0003). Finally, our models suggested that for each increase of 100 individuals on HAART, the estimated HIV incidence decreased 1.2% and for every 1% increase in the number of individuals suppressed on HAART, the estimated HIV incidence also decreased by 1%. Conclusions Our results show that HAART expansion between 1996 and 2012 in BC was associated with a sustained and profound population-level decrease in morbidity, mortality and HIV transmission. Our findings support the long-term effectiveness and sustainability of HIV treatment as prevention within an adequately resourced environment with no financial barriers to diagnosis, medical care or antiretroviral drugs. The 2013 Consolidated World Health Organization Antiretroviral Therapy Guidelines offer a unique opportunity to further evaluate TasP in other settings, particularly within generalized epidemics, and resource-limited setting, as advocated by UNAIDS.

The cascade of HIV care in British Columbia, Canada, 1996-2011: a population-based retrospective cohort study

BACKGROUND The cascade of HIV care has become a focal point for implementation efforts to maximise the individual and public health benefits of antiretroviral therapy. We aimed to characterise longitudinal changes in engagement with the cascade of HIV care in British Columbia, Canada, from 1996 to 2011. METHODS We used estimates of provincial HIV prevalence from the Public Health Agency of Canada and linked provincial population-level data to define, longitudinally, the numbers of individuals in each of the eight stages of the cascade of HIV care (HIV infected, diagnosed, linked to HIV care, retained in HIV care, highly active antiretroviral therapy (HAART) indicated, on HAART, adherent to HAART, and virologically suppressed) in British Columbia from 1996 to 2011. We used sensitivity analyses to determine the sensitivity of cascade-stage counts to variations in their definitions. FINDINGS 13,140 people were classified as diagnosed with HIV/AIDS in British Columbia during the study period. We noted substantial improvements over time in the proportions of individuals at each stage of the cascade of care. Based on prevalence estimates, the proportion of unidentified HIV-positive individuals decreased from 49·0% (estimated range 36·2-57·5%) in 1996 to 29·0% (11·6-40·7%) in 2011, and the proportion of HIV-positive people with viral suppression reached 34·6% (29·0-43·1%) in 2011. INTERPRETATION Careful mapping of the cascade of care is crucial to understanding what further efforts are needed to maximise the beneficial effects of available interventions and so inform efforts to contain the spread of HIV/AIDS. FUNDING British Columbia Ministry of Health, US National Institute on Drug Abuse (National Institutes of Health).

Expanded Highly Active Antiretroviral Therapy Coverage Among HIV-Positive Drug Users to Improve Individual and Public Health Outcomes

Highly active antiretroviral therapy (HAART) represents the single most significant advance in the fight against HIV/AIDS. The vast majority of patients treated with HAART will experience long-term remission of HIV disease. HAART does not cure HIV of course, but it changes the disease into a chronic and manageable condition. Use of HAART is associated with decreased HIV/AIDS-related morbidity, fewer opportunistic infections, and reduced mortality. Evidence has also shown that HAART can reduce HIV transmission. This is most clearly illustrated in studies of vertical or mother-to-child HIV transmission, in which use of HAART by the infected mother has virtually eliminated HIV transmission to her infant. Research has further shown that HAART use among heterosexual discordant couples in Africa was associated with a 92% reduction in HIV transmission. Until recently, the use of HAART among drug-using populations has remained controversial. However, HAART has now been shown to produce similar survival benefit when individuals with and without history of drug use were compared. This article discusses the need for an expansion in the provision of HAART to those in medical need, including drug users, to curb the devastating toll of the HIV pandemic. Such an effort should be done with the full promotion of human rights, including the need to respect each patients privacy and autonomy. Public health programs to intensify HAART use should be carried out within a comprehensive “combination prevention” framework. Such an approach for drug users would emphasize drug addiction treatment, HIV prevention including HIV testing and counseling and behavioral risk reduction interventions, and the removal of structural barriers to treat HIV-infected drug users and retain them in care.

Emergent drug resistance with integrase strand transfer inhibitor-based regimens

Objectives: To estimate the incidence of and risk factors for emergent resistance to integrase strand transfer inhibitor (INSTI) and nucleoside(-tide) reverse transcriptase inhibitors (NRTI) in HIV-1-infected adults receiving an INSTI and two NRTIs. Design: Retrospective cohort study. Methods: Persons aged at least 19 years were included if they received their first prescription for raltegravir, elvitegravir or dolutegravir in British Columbia, Canada in 2012–2014 and were followed to 31 December 2015. Emergent resistance was defined as new mutations conferring intermediate-high level NRTI or INSTI resistance (score ≥30, Stanford HIV Drug Resistance Algorithm v.7.0.1). First-year resistance rates and 95% confidence intervals (95% CI) were estimated for ‘any’ (INSTI or NRTI) resistance using Poisson regression. The relationship between any emergent resistance and explanatory variables was modeled by Cox proportional hazards. Results: There were 270 raltegravir, 323 elvitegravir and 392 dolutegravir-treated persons who were predominantly male (77%), antiretroviral therapy (ART)-experienced (81%), with low prevalence of preexisting drug resistance (16%). INSTI and NRTI resistance emerged in both ART-experienced and ART-naive persons (including dolutegravir-treated ART-naive), with no statistically significant differences in ‘any’ resistance rates (95% CI) between INSTIs: raltegravir 3.80 (1.90, 7.60), elvitegravir 2.37 (1.06, 5.27) and dolutegravir 1.48 (0.62, 3.55)/100 person-years. The strongest factors associated with emergent resistance were CD4+ less than 200 cells/&mgr;l, adjusted hazard ratio (95% CI) 10.46 (4.67, 23.41) and less than 80% adherence to the INSTI regimen hazard ratio 2.52 (1.11, 5.71). Conclusion: Incident drug resistance rates were low with ‘real-world’ use of INSTI-based regimens. However, incomplete ART adherence and low CD4+ cell count were associated with increased resistance rates regardless of which INSTI was prescribed. Provide adherence support and monitor for drug resistance.

Development and validation of a composite programmatic assessment tool for HIV therapy.

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 <3 CD4 count tests in the first year after starting antiretroviral therapy; (2) having <3 plasma viral load tests in the first year after starting antiretroviral therapy; (3) not having drug resistance testing done prior to starting antiretroviral therapy; (4) starting on a non-recommended antiretroviral therapy regimen; (5) starting therapy with CD4 <200 cells/mm3; and (6) not achieving viral suppression within 6 months since antiretroviral therapy initiation. The sum of these six indicators was used to develop the PCS score - higher score indicates poorer performance. The main outcome was all-cause mortality. Each PCS component was independently associated with mortality. In the mortality analysis, the odds ratio (OR) for PCS ≥4 versus 0 was 22.37 (95% CI 10.46–47.84). Conclusions PCS was strongly associated with all-cause mortality. These results lend independent validation to the IAS-USA treatment guidelines for HIV-infected adults. Further efforts are warranted to enhance the PCS as a means to further improve clinical outcomes. These should be specifically evaluated and targeted at healthcare providers and patients.

Initiation of antiretroviral therapy at high CD4+ cell counts is associated with positive treatment outcomes.

Objective:There is limited research investigating the possible mechanisms of how starting combination antiretroviral therapy (cART) at a higher CD4+ cell count decreases mortality. This study investigated the association between initiating cART with short-term and long-term achievement of viral suppression; emergence of any drug resistance and of an AIDS-defining illness (ADI); long-term treatment adherence; and all-cause mortality. Methods:This retrospective cohort study included 4120 naive patients who initiated cART between 2000 and 2012. Patients were followed until 2013, death or until the last contact date (varied by outcome). The main exposure was the interaction between period of cART initiation (2000–2006 and 2007–2012) and CD4+ cell count at cART initiation (<500 versus ≥500 cells/&mgr;l). We considered both baseline and longitudinal covariates. We fitted different multivariable models using cross-sectional and longitudinal statistical methods, depending on the outcome. Results:Patients who initiated cART with a CD4+ cell count at least 500 cells/&mgr;l in 2007–2012 had an increased likelihood of achieving viral suppression at 9 months and of maintaining an adherence level of at least 95% over time, and the lowest probability of developing any resistance and an ADI during follow-up. These patients were not the ones with the highest likelihood of maintaining viral suppression over time, most likely due to viral load blips experienced during the follow-up. Conclusion:The outcomes in this study likely play an important role in explaining the positive impact of early cART initiation on mortality. These results should alleviate some of the concerns clinicians may have when initiating cART in patients with high CD4+s as recommended by current treatment guidelines.

HIV antiviral drug resistance: patient comprehension

Abstract A patients understanding and use of healthcare information can affect their decisions regarding treatment. Better patient understanding about HIV resistance may improve adherence to therapy, decrease population viral load and extend the use of first-line HIV therapies. We examined knowledge of developing HIV resistance and explored treatment outcomes in a cohort of HIV+ persons on highly active antiretroviral therapy (HAART). The longitudinal investigations into supportive and ancillary health services (LISA) cohort is a prospective study of HIV+ persons on HAART. A comprehensive interviewer-administrated survey collected socio-demographic variables. Drug resistance knowledge was determined using a three-part definition. Clinical markers were collected through linkage with the Drug Treatment Program (DTP) at the British Columbia Centre for Excellence in HIV/AIDS. Categorical variables were compared using Fishers Exact Test and continuous variables using the Wilcoxon rank-sum test. Proportional odds logistic regression was performed for the adjusted multivariable analysis. Of 457 LISA participants, less than 4% completely defined HIV resistance and 20% reported that they had not discussed resistance with their physician. Overall, 61% of the cohort is ≥95% adherent based on prescription refills. Owing to small numbers pooling was preformed for analyses. The model showed that being younger (OR=0.97, 95% CI: 0.95–0.99), having greater than high school education (OR=1.64, 95% CI: 1.07–2.51), discussing medication with physicians (OR=3.67, 95% CI: 1.76–7.64), having high provider trust (OR=1.02, 95% CI: 1.01–1.03), and receiving one-to-one counseling by a pharmacist (OR=2.14, 95% CI: 1.41–3.24) are predictive of a complete or partial definition of HIV resistance. The probability of completely defining HIV resistance increased from 15.8 to 63.9% if respondents had discussed HIV medication with both a physician and a pharmacist. Although the understanding of HIV resistance showed no differences in treatment outcomes in this cohort, overall adherence and complete understanding of HIV resistance were low. If patient understanding could be improved through discussions with physicians and pharmacists, potential exists to enhance overall adherence and treatment outcomes.

Process monitoring of an HIV treatment as prevention program in British Columbia, Canada.

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.

Health-adjusted life expectancy in HIV-positive and HIV-negative men and women in British Columbia, Canada: a population-based observational cohort study

BACKGROUND We sought to understand whether people living with HIV (PLHIV) ever on highly active antiretroviral therapy (ART) follow a pattern where morbidity is compressed into the last years of life or lessened as people age. We aimed to estimate health-adjusted life expectancy (HALE) among adults living with and without HIV, and examine dependency between causes of comorbidities. METHODS The Comparative Outcomes and Service Utilization Trends (COAST) study is a retrospective cohort of adults (≥20 years) including all known PLHIV and a 10% random sample of the general population of British Columbia, and with longitudinal data spanning from April 1, 1996, to Dec 31, 2012. We determined the prevalence of select comorbidities (cardiovascular, respiratory, liver, and renal diseases, and non-AIDS defining cancers because of their high prevalence among PLHIV) by age and sex by use of case-finding algorithms. Deaths were obtained from a vital event registry from British Columbia, Canada. Comorbid-specific HALE was estimated from 20 years of age by HIV status and sex. For each comorbidity, a healthy state was defined as the proportion of life expectancy comorbid-free, and was adjusted on the probability of occurrence of other different comorbidities. The sensitivity of HALE estimates was assessed to the sequencing of select comorbidities for the dependent comorbidity adjustments. FINDINGS Our sample consisted of electronic health records from 9310 HIV-infected and 510 313 uninfected adults over the period April 1, 1996, to Dec 31, 2012. These individuals contributed 49 605 deaths and 5 576 841 person-years over the study period. At exactly age 20 years, HALE was about 31 years (SD 0·16) among men living with HIV and 27 years (0·16) among women living with HIV. In the HIV-negative population, HALE was around 58 years (SD 0·02) for men and 63 years (0·02) for women. These results seem independent of ordering. However, PLHIV, particularly women living with HIV, had much shorter overall life expectancies than did their HIV-negative counterparts in the general population [29·1 years (SD 0·1) vs 65·4 years (0·1)], and thus spent less time in a healthy state. INTERPRETATION Although we noted little differences in the levels of morbidity compression by HIV status, PLHIV-especially women living with HIV-spent less time in a healthy state. Expanded service delivery interventions to address complex care needs of ageing PLHIV are crucial to address shorter life expectancies, and improve their healthy states. FUNDING Canadian Institutes of Health Research.

Relative effects of antiretroviral therapy and harm reduction initiatives on HIV incidence in British Columbia, Canada, 1996–2013: a modelling study

BACKGROUND Antiretroviral therapy (ART) and harm reduction services have been cited as key contributors to control of HIV epidemics; however, the specific contribution of ART has been questioned due to uncertainty of its true efficacy on HIV transmission through needle sharing. We aimed to isolate the independent effects of harm reduction services (opioid agonist treatment uptake and needle distribution volumes) and ART on HIV transmission via needle sharing in British Columbia, Canada, from 1996 to 2013. METHODS We used comprehensive linked individual health administrative and registry data for the population of diagnosed people living with HIV in British Columbia to populate a dynamic, compartmental transmission model to simulate the HIV/AIDS epidemic in British Columbia from 1996 to 2013. We estimated HIV incidence, mortality, and quality-adjusted life-years (QALYs). We also estimated scenarios designed to isolate the independent effects of harm reduction services and ART, assuming 50% (10-90%) efficacy, in reducing HIV incidence through needle sharing, and we investigated structural and parameter uncertainty. FINDINGS We estimate that 3204 (upper bound-lower bound 2402-4589) incident HIV cases were averted between 1996 and 2013 as a result of the combined effect of the expansion of harm reduction services and ART coverage on HIV transmission via needle sharing. In a hypothetical scenario assuming ART had zero effect on transmission through needle sharing, we estimated harm reduction services alone would have accounted for 77% (upper bound-lower bound 62-95%) of averted HIV incidence. In a separate hypothetical scenario where harm reduction services remained at 1996 levels, we estimated ART alone would have accounted for 44% (10-67%) of averted HIV incidence. As a result of high distribution volumes, needle distribution predominantly accounted for incidence reductions attributable to harm reduction but opioid agonist treatment provided substantially greater QALY gains. INTERPRETATION If the true efficacy of ART in preventing HIV transmission through needle sharing is closer to its efficacy in sexual transmission, ARTs effect on incident cases averted could be greater than that of harm reduction. Nonetheless, harm reduction services had a vital role in reducing HIV incidence in British Columbia, and should be viewed as essential and cost-effective tools in combination implementation strategies to reduce the public health and economic burden of HIV/AIDS. FUNDING BC Ministry of Health; National Institutes of Health (R01DA041747); Genome Canada (142HIV).