The delivery of antiretroviral therapy (ART) to injection drug users (IDU) may be influenced by provider concerns regarding the potential for increased HIV-related risk behavior following the initiation of HIV treatment. We evaluated whether ART initiation was associated with changes in syringe lending patterns among a long-term prospective cohort of HIV-positive IDU in Vancouver, Canada. Among 380 ART-naïve individuals eligible for this analysis, the median age was 34.2 (interquartile range [IQR] 27.7 – 40.8), 171 (45.0%) were female, and the median follow-up duration was 60 months (IQR = 18 – 113). Between May 1996 and April 2008, 260 (68.4%) participants initiated ART. In a generalized linear mixed-effects model which compared each individual’s likelihood of sharing syringes prior to and following the initiation of ART, syringe lending was not significantly associated with ART initiation in unadjusted (odds ratio = 0.72, 95% CI: 0.38 – 1.36) or adjusted (odds ratio = 0.78, 95% CI: 0.42 – 1.45) analyses. Concerns regarding increased injection risk behaviors following the initiation of ART were not observed in this setting.
injection drug use; antiretroviral therapy; syringe lending; HIV
To model the effect of adherence and duration of viral suppression on the risk of viral rebound.
Viral rebound was defined as the first of at least 2 consecutive viral loads >400 copies/mL following initial viral suppression. The main exposures were adherence, presence of ARV class resistance before rebound or censoring date, and the percentage of follow-up time with viral suppression.
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 [CI] 0.32-0.42). Among individuals with moderate levels of adherence (80%-<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-value <0.01). Individuals with drug resistance were at a higher risk of viral rebound.
The risk of viral rebound decreased with longer duration of viral suppression within each of adherence strata studied. While 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.
Adherence; HAART; virologic failure; viral rebound; resistance; long-term suppression
Although antiretroviral therapy (ART) dramatically reduces viral load and improves survival among HIV-infected injection drug users (IDU), several short-term studies have raised concerns that ART initiation may result in increases in sexual risk behaviour among IDU.
We used data from a long-running cohort of HIV-positive IDU to examine whether ART initiation was associated with increases in several measures of sexual risk behaviour. The date of ART initiation was determined through a validated linkage to a centralized ART dispensation pharmacy.
We used generalized linear mixed-effects modeling to examine whether sexual activity, unprotected intercourse, and multiple sexual partnerships were more likely in the 12 month period following ART initiation.
Among 457 individuals who were ART naïve at baseline, the median age was 34 (interquartile range [IQR]: 28–41) and 202 (44.2%) were female. Between May 1996 and April 2008, 260 (56.7%) participants initiated ART. In multivariate analyses, ART initiation was not associated with sexual activity (adjusted Odds Ratio [AOR] = 0.87, 95%CI: 0.60–1.25), unprotected intercourse (AOR = 0.82, 95%CI: 0.51–1.31), or multiple sexual partnerships (AOR = 0.93, 95%CI: 0.61–1.40).
In this study of HIV-positive IDU, we failed to detect an increase in sexual risk behaviour during the period following ART initiation. In light of this evidence, and given the known positive effect of ART on survival and its potential role in reducing HIV transmission, concerns regarding potential increases in sexual risk-taking should not undermine the delivery of ART to IDU.
injection drug use; antiretroviral therapy; sexual risk; HIV; AIDS
Cohort studies and mathematical models have suggested that expanded coverage with highly active antiretroviral therapy (HAART) could decrease HIV transmission. This study focuses on the HIV epidemic, stratified by injection drug use, in the province of British Columbia, Canada, and seeks to estimate the association between plasma HIV-1-viral load, HAART coverage and number of new cases of HIV at the population-level.
HAART use, plasma HIV-1-viral level determinations, and rates of reportable sexually transmitted infections, including HIV, are all recorded in province-wide registries allowing for temporal comparisons of these parameters. Trends of new HIV positive tests and number of individuals on HAART were modeled using generalized additive models. Poisson log-linear regression models were used to estimate the association between the outcome new HIV positive tests (per 100 population) and the covariates viral load (log10 transformed), year, and number of individuals on HAART.
Our results demonstrate a strong association at the population-level between increasing levels of HAART coverage, decreased viral load and decreased new HIV diagnoses/year, against a background of increased HIV testing and increased rates of other STIs in the province. Our results support the proposed secondary benefit of HAART, used within current medical guidelines, on HIV transmission at a population level.
Using multivariate logistic regression, we examined the prevalence and correlates of homelessness among youth enrolled in a community-recruited prospective cohort known as the At-Risk Youth Study (ARYS), between September 2005 and October 2006. Of 478 individuals included in this analysis, 132 (27.6%) were female and 120 (25.1%) self-identified as Aboriginal. The median age was 22 (IQR: 20–24). In total, 284 (56.9%) participants reported baseline homelessness, with most living either at no fixed address, on the street, or in a hostel or shelter. Factors associated with homelessness included public injecting, frequent crack use, experienced violence, having less than a high-school education, and not having been in any addiction treatment. Homeless individuals were at-risk for various adverse health outcomes. These findings indicate the need for additional interventions, including residential addiction treatment, to address homelessness and drug use among youth.
Homelessness; youth; drug use; risk behavior
VprR77Q has been associated with long-term nonprogressive (LTNP) HIV infection. We wished to investigate the prevalence, clinical correlates, and effect on treatment response of VprR77Q in a cohort of antiretroviral-naïve individuals initiating Highly Active Antiretroviral Therapy (HAART). Baseline plasma samples from 728 subjects were genotyped using RT-PCR and direct DNA sequencing. Cox proportional hazards regression was used to model the effects of VprR77Q on virologic and immunologic responses, and survival following initiation of HAART, over a median 4.5 years follow-up. We found that 308 subjects (42.3%) harbored VprR77Q alone or in combination with another amino acid, while 420 (57.7%) harbored an amino acid other than Q. A cross-sectional analysis found no correlation between R77Q and baseline plasma viral load (pVL), CD4 count, diagnosis of AIDS, or sociodemographic characteristics including age, gender and history of injection drug use (p > 0.1). In multivariate analyses, no significant associations between VprR77Q and initial pVL and CD4 responses to HAART (p > 0.1) or survival following initiation of treatment were observed. The high prevalence and the lack of association with pre-therapy clinical parameters in this cohort argue against an association of R77Q with LTNP status. These results do not support an association between R77Q and HAART response.
HIV; Vpr; R77Q; antiretroviral therapy response; HOMER cohort
This paper examines the ethical probity of Health Canada’s Special Access Program (SAP). The SAP is designed for patients with life-threatening conditions who require “emergency” access to drugs that are not authorized for use in Canada when conventional therapies have failed. We argue that the SAP inappropriately uses the tenets of evidence-based decision-making in situations where evidence-based decision-making is unfeasible. The SAP should abandon its pretence of evidence-based decision-making and adopt a transparent process in which the values guiding decisions are explicit and corrigible. We recommend the ethical principles of autonomy, non-maleficence, beneficence and justice.
We examined the effect of hepatitis C virus (HCV) seropositivity on risk of death among people receiving their first antiretroviral treatment (ART) for HIV infection.
In British Columbia, the HIV/ AIDS Drug Treatment Program is the only source of free ART. Patients who initiated a triple-drug ART regimen between July 31, 1996, and July 31, 2000, were included if they were ART-naive and had baseline HCV serological data. Outcomes of interest for survival analysis were deaths from natural and HIV-related causes, with a data cutoff of June 30, 2003.
Of 1186 eligible subjects, 606 (51%) were HCV positive and 580, negative. Fewer HCV-positive people were male (78% v. 93%, p < 0.001) and had an AIDS diagnosis at baseline (11% v. 15%, p = 0.028). Their CD4 fraction was significantly higher at baseline (19% v. 16% of T lymphocytes, p < 0.001) but their absolute CD4 counts, log HIV viral load and the type of ART initiated were similar to those of HCV negative people. Of 163 deaths (from natural causes only) during the study period, 118 (19%) were in HCV positive and 45 (8%) in HCV negative patients (p < 0.001); of the 114 deaths attributed to HIV infection, these proportions were 79 (13%) versus 35 (6%; p < 0.001). After adjustment for potential confounders, HCV seropositivity remained predictive of death (adjusted hazard ratio [HR] 2.20, 95% confidence interval [CI] 1.50– 3.21, p < 0.001), especially HIV-related death (adjusted HR 1.75, 95% CI 1.13– 2.72, p = 0.012).
In this population-based HIV treatment program, we found HCV seropositivity to be an independent predictor of mortality, especially death related to HIV infection.
North America's first medically supervised safer injecting facility for illicit injection drug users was opened in Vancouver on Sept. 22, 2003. Although similar facilities exist in a number of European cities and in Sydney, Australia, no standardized evaluations of their impact have been presented in the scientific literature.
Using a standardized prospective data collection protocol, we measured injection-related public order problems during the 6 weeks before and the 12 weeks after the opening of the safer injecting facility in Vancouver. We measured changes in the number of drug users injecting in public, publicly discarded syringes and injection-related litter. We used Poisson log-linear regression models to evaluate changes in these public order indicators while considering potential confounding variables such as police presence and rainfall.
In stratified linear regression models, the 12-week period after the facility's opening was independently associated with reductions in the number of drug users injecting in public (p < 0.001), publicly discarded syringes (p < 0.001) and injection-related litter (p < 0.001). The predicted mean daily number of drug users injecting in public was 4.3 (95% confidence interval [CI] 3.5–5.4) during the period before the facility's opening and 2.4 (95% CI 1.9–3.0) after the opening; the corresponding predicted mean daily numbers of publicly discarded syringes were 11.5 (95% CI 10.0–13.2) and 5.4 (95% CI 4.7–6.2). Externally compiled statistics from the city of Vancouver on the number of syringes discarded in outdoor safe disposal boxes were consistent with our findings.
The opening of the safer injecting facility was independently associated with improvements in several measures of public order, including reduced public injection drug use and public syringe disposal.
Law enforcement is often used in an effort to reduce the social, community and health-related harms of illicit drug use by injection drug users (IDUs). There are, however, few data on the benefits of such enforcement or on the potential harms. A large-scale police “crackdown” to control illicit drug use in Vancouver's Downtown Eastside provided us with an opportunity to evaluate the effect.
As part of our ongoing prospective cohort study of IDUs in Vancouver, we examined data collected from 244 IDUs in the 3 months before the police crackdown and from 142 IDUs in the 3 months after the start of the crackdown, on Apr. 7, 2003. All study subjects were active drug users. We also examined external data on needle exchanges and syringe disposal.
The 2 groups of IDUs were statistically similar: they were mainly young (mean age 39 years) and male (63%), and they had injected illicit drugs for 13 years on average. Ethnic background and the proportion homeless were also similar. There were no statistically significant reported differences (all p > 0.1) in the street price of heroin, cocaine or “crack” in the 2 periods. In the 3-month periods before and after the crackdown, respectively, the rates of daily heroin injection were 27.9% and 26.8%, daily cocaine injection 28.7% and 27.5%, and daily crack use 59.4% and 60.6% (all p > 0.1). The proportions of study subjects receiving methadone treatment, 41.0% and 44.4% (p = 0.516), did not differ. However, the proportions reporting a change in where drugs were used, 22.5% and 33.8% (p < 0.05), and the proportions reporting a change in the neighbourhood of use because of police presence, 18.1% and 26.8% (p < 0.05), increased significantly. Needle-exchange data confirmed that the community levels of drug use were unchanged. Disposal statistics demonstrated that the monthly average number of used syringes found on the streets outside the traditional area of drug use increased from 784 in the 3 months before Apr. 1 to 1253 in the subsequent 3 months (p = 0.002) and the monthly average number of used syringes found in public boxes for the safe disposal of syringes decreased from 865 to 502 (p = 0.018).
The effort to control illicit drug use did not alter the price of drugs or the frequency of use, nor did it encourage enrolment in methadone treatment programs. Several measures indicated displacement of injection drug use from the area of the crackdown into adjacent areas of the city, which has implications for both recruitment of new initiates into injection drug use and HIV prevention efforts.
LONG-TERM REMISSION OF HIV-1 DISEASE CAN BE READILY ACHIEVED by combinations of antiretroviral agents. The suppression of plasma viral loads to less than the limit of quantification of the most sensitive commercially available assays (i.e., less than 50 copies/mL) and the coincident improvement in CD4 T cell counts is associated with resolution of established opportunistic infections and a decrease in the risk of new opportunistic infections. However, prolonged treatment with combination regimens can be difficult to sustain because of problems with adherence and toxic effects. All antiretroviral drugs can have both short-term and long-term adverse events. The risk of specific side effects varies from drug to drug, from drug class to drug class, and from patient to patient. A better understanding of the adverse effects of antiretroviral agents is of interest not only for HIV specialists as they try to optimize therapy, but also for other physicians who care for HIV-positive patients.
The benefits of highly active antiretroviral therapy (HAART) for the treatment of HIV infection are well documented, but concerns regarding access and adherence to HAART are growing. We evaluated virological responses to HAART among HIV-1 infected patients who were injection drug users (IDUs) in a population-based setting where HIV/AIDS care is delivered free of charge.
We evaluated previously untreated HIV-1 infected men and women who initiated HAART between Aug. 1, 1996, and July 31, 2000, and who were followed until Mar. 31, 2002, in a province-wide HIV treatment program. We used Kaplan–Meier methods and Cox proportional hazards regression in our evaluation of time to suppression (i.e., less than 500 copies/mL) and rebound (i.e., 500 copies/mL or more) of plasma HIV-1 RNA, with patients stratified according to whether or not they had a history of injection drug use.
Overall, 1422 patients initiated HAART during the study period, of whom 359 (25.2%) were IDUs. In Kaplan–Meier analyses, the cumulative suppression rate at 12 months after initiation of HAART was 70.8% for non-IDUs and 51.4% for IDUs (p < 0.001) (these values include people who achieved suppression before 12 months but who might not have been followed for the full 12-month period). Among patients who achieved suppression of plasma HIV-1 RNA, the cumulative rebound rate at 12 months after initial suppression was 23.8% for non-IDUs and 34.7% for IDUs (p < 0.001). However, after adjustment for adherence and other covariates, the rates of HIV-1 RNA suppression (adjusted relative hazard 0.9, 95% confidence interval [CI] 0.7–1.0) and HIV-1 RNA rebound (adjusted relative hazard 1.3, 95% CI 1.0–1.6) were similar between non-IDUs and IDUs. Differences between non-IDUs and IDUs were even less pronounced in subanalyses that considered only therapy-adherent patients (p > 0.1).
Non-IDUs and IDUs had similar rates of HIV-1 RNA suppression and rebound after the initiation of HAART, once lower levels of adherence were taken into account. Nevertheless, the lower virological response rates among IDUs suggest that, unless interventions are undertaken to improve adherence, these patients may experience elevated rates of disease progression and use of medical services in our setting.
More than 93% of the nearly $500 million spent annually on Canada's drug strategy goes toward efforts to reduce the illicit drug supply. However, little is known about the effectiveness of this strategy. On Sept. 2, 2000, Canadian police seized approximately 100 kg of heroin in one of the nation's largest-ever seizures of this drug. An ongoing prospective cohort study of injection drug users afforded an opportunity to evaluate the impact of this seizure.
The Vancouver Injection Drug User Study is a prospective cohort study of injection drug users that began in 1996. The present study relied primarily on data acquired from participants who were seen during the 30-day periods immediately before and after the seizure. We compared drug use and behavioural characteristics, heroin and cocaine prices, and participants' reports of whether law enforcement had affected their source of drugs or the types of drugs available on the street, as well as overdoses, in these 2 periods.
The 138 participants seen before the seizure were similar to the 123 participants seen after the seizure with respect to age, sex, ethnic background, education, HIV serostatus, neighbourhood residence, instability of housing, employment status, use of methadone maintenance therapy and all other measured potential confounders (all p > 0.10). We found no difference in the extent to which participants in the 2 groups reported daily use of heroin, frequency of nonfatal overdoses, or whether law enforcement had affected their source of drugs or the types of drugs available on the street (all p > 0.10). Although we detected no difference in the price of cocaine, the median reported price of heroin went down after the seizure (p = 0.034), which suggests that other shipments compensated for the seizure. External evaluations of deaths from overdoses and heroin purity indicated that the seizure had no impact, nor was any impact seen when the periods of analysis were extended.
The massive heroin seizure appeared to have no measurable public health benefit. Closer scrutiny of enforcement efforts is warranted to ensure that resources are delivered to the most efficient and cost-effective public health programs.
In several European countries safer injecting rooms have reduced the public disorder and health-related problems of injection drug use. We explored factors associated with needle-sharing practices that could potentially be alleviated by the availability of safer injecting rooms in Canada.
The Vancouver Injection Drug User Study is a prospective cohort study of injection drug users (IDUs) that began in 1996. The analyses reported here were restricted to the 776 participants who reported actively injecting drugs in the 6 months before the most recent follow-up visit, during the period January 1999 to October 2000. Needle sharing was defined as either borrowing or lending a used needle in the 6-month period before the interview.
Overall, 214 (27.6%) of the participants reported sharing needles during the 6 months before follow-up; 106 (13.7%) injected drugs in public, and 581 (74.9%) reported injecting alone at least once. Variables independently associated with needle sharing in a multivariate analysis included difficulty getting sterile needles (adjusted odds ratio [OR] 2.7, 95% confidence interval [CI] 1.8–4.1), requiring help to inject drugs (adjusted OR 2.0, 95% CI 1.4–2.8), needle reuse (adjusted OR 1.8, 95% CI 1.3–2.6), frequent cocaine injection (adjusted OR 1.6, 95% CI 1.1–2.3) and frequent heroin injection (adjusted OR 1.5, 95% CI 1.04–2.1). Conversely, HIV-positive participants were less likely to share needles (adjusted OR 0.5, 95% CI 0.4–0.8), although 20.2% of the HIV-positive IDUs still reported sharing needles.
Despite the availability of a large needle-exchange program and targeted law enforcement efforts in Vancouver, needle sharing remains an alarmingly common practice in our cohort. We identified a number of risk behaviours — difficulty getting sterile needles, needle sharing and reuse, injection of drugs in public and injecting alone (one of the main contributing causes of overdose) — that may be alleviated by the establishment of supervised safer injecting rooms.
Although HIV treatment as prevention (TasP) via early antiretroviral therapy (ART) has proven to reduce transmissions among HIV-serodiscordant couples, its full implementation in developing countries remains a challenge. In this study, we determine whether China's current HIV treatment program prevents new HIV infections among discordant couples in rural China.
A prospective, longitudinal cohort study was conducted from June 2009 to March 2011, in rural Yunnan. A total of 1,618 HIV-discordant couples were eligible, 1,101 were enrolled, and 813 were followed for an average of 1.4 person-years (PY). Routine ART was prescribed to HIV-positive spouses according to eligibility (CD4<350 cells/µl). Seroconversion was used to determine HIV incidence.
A total of 17 seroconversions were documented within 1,127 PY of follow-up, for an overall incidence of 1.5 per 100 PY. Epidemiological and genetic evidence confirmed that all 17 seroconverters were infected via marital secondary sexual transmission. Having an ART-experienced HIV-positive partner was associated with a lower rate of seroconvertion compared with having an ART-naïve HIV-positive partner (0.8 per 100 PY vs. 2.4 per 100 PY, HR = 0.34, 95%CI = 0.12–0.97, p = 0.0436). While we found that ART successfully suppressed plasma viral load to <400 copies/ml in the majority of cases (85.0% vs. 19.5%, p<0.0001 at baseline), we did document five seroconversions among ART-experienced subgroup.
ART is associated with a 66% reduction in HIV incidence among discordant couples in our sample, demonstrating the effectiveness of China's HIV treatment program at preventing new infections, and providing support for earlier ART initiation and TasP implementation in this region.
HIV leads to CD4:CD8 ratio inversion as immune dysregulation progresses. We examined the predictors of CD4:CD8 normalization after combination antiretroviral therapy (cART) and determined whether normalization is associated with reduced progression to AIDS-defining illnesses (ADI) and death.
A Canadian cohort of HIV-positive adults with CD4:CD8<1.2 prior to starting cART from 2000–2010 were analyzed. Predictors of (1) reaching a CD4:CD8 ≥1.2 on two separate follow-up visits >30 days apart, and (2) ADI and death from all causes were assessed using adjusted proportional hazards models.
4206 patients were studied for a median of 2.77 years and 306 (7.2%) normalized their CD4:CD8 ratio. Factors associated with achieving a normal CD4:CD8 ratio were: baseline CD4+ T-cells >350 cells/mm3, baseline CD8+ T-cells <500 cells/mm3, time-updated HIV RNA suppression, and not reporting sex with other men as a risk factor. There were 213 ADIs and 214 deaths in 13476 person-years of follow-up. Achieving a normal CD4:CD8 ratio was not associated with time to ADI/death.
In our study, few individuals normalized their CD4:CD8 ratios within the first few years of initiating modern cART. This large study showed no additional short-term predictive value of the CD4:CD8 ratio for clinical outcomes after accounting for other risk factors including age and HIV RNA.
Previous studies suggest that active drug use may compromise HIV treatment among HIV-positive injection drug users (IDU). However, little is known about the differential impacts of cocaine injection, heroin injection, and combined cocaine and heroin injection on plasma HIV-1 RNA suppression.
Data were derived from a longstanding open prospective cohort of HIV-positive IDU in Vancouver, Canada. Kaplan-Meier methods and Cox proportional hazards regression were used to examine the impacts of different drug use patterns on rates of plasma HIV-1 RNA suppression.
Between May 1996 and April 2008, 267 antiretroviral (ART) naïve participants were seen for a median follow-up duration of 50.6 months after initiating ART. The incidence density of HIV-1 RNA suppression was 65.2 (95%CI: 57.0–74.2) per 100 person-years. In Kaplan-Meier analyses, compared to those who abstained from injecting, individuals injecting heroin, cocaine, or combined heroin/cocaine at baseline were significantly less likely to achieve viral suppression (all p < 0.01). However, none of the drug use categories remained associated with a reduced rate of viral suppression when considered as time-updated variables (all p > 0.05).
Active injecting at the time of ART initiation was associated with lower plasma HIV-1 RNA suppression rates; however, there was no difference in suppression rates when drug use patterns were examined over time. These findings imply that adherence interventions for active injectors should optimally be applied at the time of ART initiation.
injection drug use; antiretroviral therapy; viral suppression
Little is known about the potential impact of food insecurity on mortality among people living with HIV/AIDS. We examined the potential relationship between food insecurity and all-cause mortality among HIV-positive injection drug users (IDU) initiating antiretroviral therapy (ART) across British Columbia (BC).
Cross-sectional measurement of food security status was taken at participant ART initiation. Participants were prospectively followed from June 1998 to September 2011 within the fully subsidized ART program. Cox proportional hazard models were used to ascertain the association between food insecurity and mortality, controlling for potential confounders.
Among 254 IDU, 181 (71.3%) were food insecure and 108 (42.5%) were hungry. After 13.3 years of median follow-up, 105 (41.3%) participants died. In multivariate analyses, food insecurity remained significantly associated with mortality (adjusted hazard ratio [AHR] = 1.95, 95% CI: 1.07–3.53), after adjusting for potential confounders.
HIV-positive IDU reporting food insecurity were almost twice as likely to die, compared to food secure IDU. Further research is required to understand how and why food insecurity is associated with excess mortality in this population. Public health organizations should evaluate the possible role of food supplementation and socio-structural supports for IDU within harm reduction and HIV treatment programs.
Expanding access to highly active antiretroviral therapy (HAART) has become an important approach to HIV prevention in recent years. Previous studies suggest that concomitant changes in risk behaviours may either help or hinder programs that use a Treatment as Prevention strategy.
We consider HIV-related risk behaviour as a social contagion in a deterministic compartmental model, which treats risk behaviour and HIV infection as linked processes, where acquiring risk behaviour is a prerequisite for contracting HIV. The equilibrium behaviour of the model is analysed to determine epidemic outcomes under conditions of expanding HAART coverage along with risk behaviours that change with HAART coverage. We determined the potential impact of changes in risk behaviour on the outcomes of Treatment as Prevention strategies. Model results show that HIV incidence and prevalence decline only above threshold levels of HAART coverage, which depends strongly on risk behaviour parameter values. Expanding HAART coverage with simultaneous reduction in risk behaviour act synergistically to accelerate the drop in HIV incidence and prevalence. Above the thresholds, additional HAART coverage is always sufficient to reverse the impact of HAART optimism on incidence and prevalence. Applying the model to an HIV epidemic in Vancouver, Canada, showed no evidence of HAART optimism in that setting.
Our results suggest that Treatment as Prevention has significant potential for controlling the HIV epidemic once HAART coverage reaches a threshold. Furthermore, expanding HAART coverage combined with interventions targeting risk behaviours amplify the preventive impact, potentially driving the HIV epidemic to elimination.
(See the editorial commentary by Taiwo and Bosch, on pages 1189–91.)
Background. The importance of human immunodeficiency virus (HIV) blip magnitude on virologic rebound has been raised in clinical guidelines relating to viral load assays.
Methods. Antiretroviral-naive individuals initiating combination antiretroviral therapy (cART) after 1 January 2000 and achieving virologic suppression were studied. Negative binomial models were used to identify blip correlates. Recurrent event models were used to determine the association between blips and rebound by incorporating multiple periods of virologic suppression per individual.
Results. 3550 participants (82% male; median age, 40 years) were included. In a multivariable negative binomial regression model, the Amplicor assay was associated with a lower blip rate than branched DNA (rate ratio, 0.69; P < .01), controlling for age, sex, region, baseline HIV-1 RNA and CD4 count, AIDS-defining illnesses, year of cART initiation, cART type, and HIV-1 RNA testing frequency. In a multivariable recurrent event model controlling for age, sex, intravenous drug use, cART start year, cART type, assay type, and HIV-1 RNA testing frequency, blips of 500–999 copies/mL were associated with virologic rebound (hazard ratio, 2.70; P = .002), whereas blips of 50–499 were not.
Conclusions. HIV-1 RNA assay was an important determinant of blip rates and should be considered in clinical guidelines. Blips ≥500 copies/mL were associated with increased rebound risk.
To characterize the impact of longitudinal adherence on survival in drug-naive individuals starting currently recommended highly active antiretroviral therapy (HAART) regimens.
Eligible study participants initiated HAART between January 2000 and November 2004 and were followed until November 2005 (N = 903). HAART regimens contained efavirenz, nevirapine, or ritonavir-boosted atazanavir or lopinavir. Marginal structural modeling was used to address our objective.
The all-cause mortality was 11%. Individual adherence decreased significantly over time, with the mean adherence shifting from 79% within the first 6 months of starting HAART to 72% within the 24- to 30-month period (P value < 0.01). Nonadherence over time (<95%) was strongly associated with higher risk of mortality (hazard ratio: 3.13; 95% confidence interval (CI): 1.95 to 5.05). Nonadherent (<95%) patients on nonnucleoside reverse transcriptase inhibitor (NNRTI)–based and boosted protease inhibitor–based regimens were, respectively, 3.61 times (95% CI: 2.15 to 6.06) and 3.25 times (95% CI: 1.63 to 6.49) more likely to die than adherent patients. Within the NNRTI-based regimens, nonadherent individuals on efavirenz were at a higher risk of mortality.
Incomplete adherence to modern HAART over time was strongly associated with increased mortality, and patients on efavirenz-based NNRTI therapies were particularly at a higher risk if nonadherent. These results highlight the need to develop further strategies to help sustain high levels of adherence on a long-term basis.
adherence; boosted PI; HAART; marginal structural models; mortality; NNRTI
To investigate the relationship between HIV-1 drug resistance and adherence and the accumulation rate of resistance mutations in 1191 HIV-infected, antiretroviral-naive adults initiating highly active antiretroviral therapy in British Columbia, Canada.
Plasma samples with plasma viral load >1000 copies per milliliter collected within 30 months of follow-up were genotyped for drug resistance. Adherence was estimated using prescription refills and plasma drug levels. The primary outcome measure was time to detection of drug resistance. Cox proportional hazard regression was used to calculate hazard ratios (HRs) associated with baseline variables.
The accumulation rates of multiple primary and secondary mutations were similar in patients initiating highly active antiretroviral therapy with protease inhibitor versus nonnucleoside reverse transcriptase inhibitor (NNRTI). Rates decreased approximately 50% per additional mutation. At 80%–90% adherence based on refills, there was greater risk of detecting lamivudine (3TC) [HR 3.0, 95% confidence interval (CI): 1.9 to 4.7; P < 0.0001] and NNRTI mutations (HR 6.0, 95% CI: 3.3 to 10.9; P < 0.0001) compared with the ≥95% refill reference group. In a multivariate model, individuals with <95% refills and consistently detectable plasma drug levels were at increased risk for 3TC (HR 4.5, 95% CI: 2.6 to 7.9; P = 0.0001) and NNRTI resistance (HR 7.0, 95% CI: 3.4 to 14.5; P = 0.0001) compared with the reference group of ≥95% refills with consistently detectable drug levels. Adherence–resistance relationships were much weaker for protease inhibitors and nucleoside reverse transcriptase inhibitors as there was little variance in HRs among the different adherence strata compared with 3TC and NNRTIs.
The relationships between resistance, adherence, and mutation accumulation differ between HIV drug classes.
adherence; HAART; HIV-1 drug resistance; mutations