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author:("Yip, benito")
1.  Limited Evolution of Inferred HIV-1 Tropism while Viremia Is Undetectable during Standard HAART Therapy 
PLoS ONE  2014;9(6):e99000.
HIV patients on suppressive antiretroviral therapy have undetectable viremia making it impossible to screen plasma HIV tropism if regimen change is required during suppression. We investigated the prevalence and predictors of tropism switch from CCR5-using (“R5”) to non-CCR5-using (“non-R5”) before and after viral suppression in the initially therapy-naïve HOMER cohort from British Columbia, Canada.
We compared pre-therapy and post-suppression viral genotypic tropism in patients who initiated on PI/NNRTI-based antiretroviral regimens between 1996-1999 (n = 462). Virologic suppression was defined as having two consecutive viral loads of <500 copies/mL, which was the sensitivity limit of most viral load assays at the time. Viral tropism was inferred by V3-loop-population-sequencing and geno2pheno[coreceptor] with cutoff at 5.75% false positive rate (FPR).
When virologic suppression was defined as two-consecutive viral loads <500 copies/mL, 34 (9%) of the 397 patients with pre-therapy R5-virus switched to non-R5 at viral load rebound after a median of 19 months (IQR 8–41 months) of undetectable viremia. Duration of viral load suppression was not a predictor of switch, but lower CD4 count during suppression (median 400 versus 250 cells/mL) and an increased prevalence of pre-therapy non-R5 HIV by “deep” sequencing (median 0.2% versus 3.2%) were independently associated with switch (p = 0.03 and p<0.0001, respectively).
R5-to-non-R5 tropism switches in plasma virus after undetectable viremia were relatively rare events especially among patients with higher CD4 counts during virologic suppression. Our study supports the use of pre-suppression tropism results if maraviroc is being considered during virologic suppression in this subgroup of patients.
PMCID: PMC4048224  PMID: 24905411
2.  The cascade of HIV care in British Columbia, Canada, 1996–2011: a population-based retrospective cohort study 
The Lancet infectious diseases  2013;14(1):40-49.
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.
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.
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.
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.
British Columbia Ministry of Health, US National Institute on Drug Abuse (National Institutes of Health).
PMCID: PMC4017913  PMID: 24076277
3.  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 
PLoS ONE  2014;9(2):e87872.
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.
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.
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%.
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.
PMCID: PMC3922718  PMID: 24533061
4.  The Combined Effect of Modern Highly Active Antiretroviral Therapy Regimens and Adherence on Mortality Over Time 
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.
PMCID: PMC3606956  PMID: 19223785
adherence; boosted PI; HAART; marginal structural models; mortality; NNRTI
5.  Application and Validation of Case-Finding Algorithms for Identifying Individuals with Human Immunodeficiency Virus from Administrative Data in British Columbia, Canada 
PLoS ONE  2013;8(1):e54416.
To define a population-level cohort of individuals infected with the human immunodeficiency virus (HIV) in the province of British Columbia from available registries and administrative datasets using a validated case-finding algorithm.
Individuals were identified for possible cohort inclusion from the BC Centre for Excellence in HIV/AIDS (CfE) drug treatment program (antiretroviral therapy) and laboratory testing datasets (plasma viral load (pVL) and CD4 diagnostic test results), the BC Centre for Disease Control (CDC) provincial HIV surveillance database (positive HIV tests), as well as databases held by the BC Ministry of Health (MoH); the Discharge Abstract Database (hospitalizations), the Medical Services Plan (physician billing) and PharmaNet databases (additional HIV-related medications). A validated case-finding algorithm was applied to distinguish true HIV cases from those likely to have been misclassified. The sensitivity of the algorithms was assessed as the proportion of confirmed cases (those with records in the CfE, CDC and MoH databases) positively identified by each algorithm. A priori hypotheses were generated and tested to verify excluded cases.
A total of 25,673 individuals were identified as having at least one HIV-related health record. Among 9,454 unconfirmed cases, the selected case-finding algorithm identified 849 individuals believed to be HIV-positive. The sensitivity of this algorithm among confirmed cases was 88%. Those excluded from the cohort were more likely to be female (44.4% vs. 22.5%; p<0.01), had a lower mortality rate (2.18 per 100 person years (100PY) vs. 3.14/100PY; p<0.01), and had lower median rates of health service utilization (days of medications dispensed: 9745/100PY vs. 10266/100PY; p<0.01; days of inpatient care: 29/100PY vs. 98/100PY; p<0.01; physician billings: 602/100PY vs. 2,056/100PY; p<0.01).
The application of validated case-finding algorithms and subsequent hypothesis testing provided a strong framework for defining a population-level cohort of HIV infected people in BC using administrative databases.
PMCID: PMC3557280  PMID: 23382898
6.  Development and Validation of a Composite Programmatic Assessment Tool for HIV Therapy 
PLoS ONE  2012;7(11):e47859.
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).
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.
PMCID: PMC3501505  PMID: 23185244
7.  Technical and Regulatory Shortcomings of the TaqMan Version 1 HIV Viral Load Assay 
PLoS ONE  2012;7(8):e43882.
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.
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).
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.
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.
PMCID: PMC3427308  PMID: 22937116
8.  Risk of Viral Failure Declines with Duration of Suppression on HAART, Irrespective of Adherence Level 
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.
PMCID: PMC2974791  PMID: 20838225
Adherence; HAART; virologic failure; viral rebound; resistance; long-term suppression
9.  Trends in reported AIDS defining illnesses (ADIs) among participants in a universal antiretroviral therapy program: an observational study 
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.
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.
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.
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.
PMCID: PMC3180248  PMID: 21892955
10.  Expanded HAART Coverage is Associated with Decreased Population-level HIV-1-RNA and Annual New HIV Diagnoses in British Columbia, Canada 
Lancet  2010;376(9740):532-539.
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.
PMCID: PMC2996043  PMID: 20638713
11.  Physician's manual reporting underestimates mortality: evidence from a population-based HIV/AIDS treatment program 
BMC Public Health  2010;10:642.
In clinical and cohort research, mortality estimates are often derived from manual reports generated by physicians or electronic reports from vital event registries. We examined the rate of underreporting of deaths by manual methods as compared with electronic reports from a vital event registry.
The retrospective analyses included deaths among participants registered in an observational cohort who initiated highly-active antiretroviral therapy (HAART) between August 1, 1996 and June 30, 2006. Deaths were routinely reported manually by physicians and through annual electronic record linkages with a population-based vital event registry. Multivariate logistic regression was carried out to assess independent predictors of death reporting by manual methods.
Of the 3,116 individuals included in the analyses, 622 (20.0%) died during follow-up. Manual reporting by physicians only identified 377 (60.6%), while electronic linkages captured 598 (96.1%) of all deaths. Multivariate analysis indicated that deaths among individuals with lower CD4 cell count, higher HIV plasma viral load, a history of injection drug use, and under the care of an HIV-experienced physicians were more likely to be reported manually. Furthermore, non-accidental deaths were more likely to be reported manually, and manual reporting of deaths increased over time.
Relying only on manual reports to ascertain deaths significantly underestimates the total number of deaths in the population. This can generate important biases when evaluating the impact of therapeutic interventions in the populational setting.
PMCID: PMC2987398  PMID: 20973962
12.  Improved Virological Outcomes in British Columbia Concomitant with Decreasing Incidence of HIV Type 1 Drug Resistance Detection 
There have been limited studies evaluating temporal changes in the incidence of detection of drug resistance among human immunodeficiency virus type 1 (HIV-1) isolates and concomitant changes in plasma HIV load for treated individuals in a population-wide setting.
Longitudinal plasma viral load and genotypic resistance data were obtained from patients receiving antiretroviral therapy from the British Columbia Drug Treatment Program from July 1996 through December 2008. A total of 24,652 resistance tests were available from 5422 individuals. The incidence of successful plasma viral load suppression and of resistance to each of 3 antiretroviral categories (nucleoside/nucleotide reverse-transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors) was calculated for the population receiving therapy.
There has been a drastic decrease in the incidence of new cases of HIV-1 drug resistance in individuals followed during 1996–2008. In 1997, the incidence rate of any newly detected resistance was 1.73 cases per 100 person-months of therapy, and by 2008, the incidence rate had decreased >12-fold, to 0.13 cases per 100 person-months of therapy. This decrease in the incidence of resistance has occurred at an exponential rate, with half-times on the order of 2–3 years. Concomitantly, the proportion of individuals with plasma viral load suppression has increased linearly over time (from 64.7% with HIV RNA levels <50 copies/mL in 2000 to 87.0% in 2008; R2 = 0.97; P <.001).
Our results suggest an increasing effectiveness of highly active antiretroviral therapy at the populational level. The vast majority of treated patients in British Columbia now have either suppressed plasma viral load or drug-susceptible HIV-1, according to their most recent test results.
PMCID: PMC2922860  PMID: 19951169
13.  Emergence of Drug Resistance Is Associated with an Increased Risk of Death among Patients First Starting HAART 
PLoS Medicine  2006;3(9):e356.
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.
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
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
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
PMCID: PMC1569883  PMID: 16984218
14.  Effect of serostatus for hepatitis C virus on mortality among antiretrovirally naive HIV-positive patients 
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.
PMCID: PMC1174855  PMID: 16027432
15.  Alcohol use and incarceration adversely affect HIV-1 RNA suppression among injection drug users starting antiretroviral therapy 
We conducted this study among HIV-infected injection drug users to determine the effect of self-reported alcohol use and prior incarceration at the time of initiating antiretroviral therapy on subsequent HIV-1 RNA suppression. We examined the demographics, recent incarceration history, and drug and alcohol use history from the Vancouver Injection Drug User Study (VIDUS) questionnaire closest to the date of initiating antiretroviral therapy. We linked these data to the HIV/AIDS Drug Treatment Program. There were 234 VIDUS participants who accessed antiretroviral therapy through the Drug Treatment Program from August 1, 1996, to July 31, 2001. In terms of illicit drug use, 196 (84%) reported injecting heroin and cocaine at the time of initiating antiretroviral therapy. Multiple logistic regression revealed that in the 6 months prior to initiating antiretroviral therapy, alcohol use (adjusted odds ratio [AOR] 0.32; 95% CI 0.13–0.81) and incarceration (AOR 0.22; 95% CI 0.09–0.58) were independently associated with lower odds of HIV-1 RNA suppression. Factors positively associated with HIV-1 RNA suppression included: adherence (AOR 1.27; 95% CI 1.06–1.51); lower baseline HIV-1 RNA (AOR 1.30: 95% CI 1.01–1.66); highly active antiretroviral therapy (AOR 4.10; 95% CI 1.56–10.6); months on therapy (AOR 1.1; 95% CI 1.06–1.14). Among HIV-infected injection drug users who were on antiretroviral therapy, any alcohol use and incarceration in the 6 months prior to initiating antiretroviral therapy were negatively associated with achieving HIV-1 RNA suppression. In addition to addition treatment for active heroin and cocaine use, the identification and treatment of alcohol problems should be supported in this setting. As well, increased outreach to HIV-infected drug users recently released from prison to ensure continuity of care needs to be further developed.
PMCID: PMC3456224  PMID: 14709714
Anti-HIV agents; HIV infections; Human; Logistic regression models; Substance abuse; Intravenous; Alcohol; Prison
16.  Adherence and plasma HIV RNA responses to highly active antiretroviral therapy among HIV-1 infected injection drug users 
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.
PMCID: PMC202281  PMID: 14517122

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