For people living with HIV (PLWH), sustained viral suppression is the primary goal of combination antiretroviral treatment (cART).[1,2] Sustained viral suppression dramatically decreases the likelihood of sexual (and perinatal) HIV transmission[3,4] and is important for maintaining good health through immune function reconstitution (reducing risk of illness and decreasing mortality).[5–8] PLWH can now expect life expectancy similar to that of people living without HIV, if they are able to achieve and maintain viral suppression, making HIV a chronic, manageable disease.[5–8]
Historically, subpopulations including younger adults (≤29 years of age) have experienced suboptimal clinical outcomes when compared to older adults living with HIV.[9,10] Considering the high rates of new HIV diagnoses that annually occur among people aged 29 and younger, this population is of interest for research and intervention. Young adults may face different challenges than older adults (e.g., access to developmentally appropriate care) resulting in cART nonadherence, putting younger adults at risk for unsustained viral suppression, and subsequent viral rebound.[9–15] Viral rebound increases vulnerability to illness, treatment failure, cART resistance, and the potential for HIV transmission.[3,6,15–19] With treatment resumption, individuals can usually regain viral suppression.[20,21]
Previous research indicates, that compared with older adults, young adults are less likely to achieve and maintain viral suppression.[10,22] Among those who do reach suppression, they are more likely than older adults to have suboptimal adherence, and poorer retention in care, risking viral rebound.[10,12,13,14] Viral rebound has been associated with younger age, poor adherence and various other behavioral and sociodemographic factors.[23–26] Suboptimal cART adherence is strongly associated with progression to AIDS and mortality.[27,28]
In Canada, young adults comprise nearly one-quarter of all HIV-positive tests annually. Using data from Canada's largest HIV treatment cohort, we measured and compared the prevalence and correlates of viral suppression and subsequent viral rebound among younger and older adults living with HIV in Canada.
2.1 Study methodology
The Canadian HIV Observational Cohort Collaboration (CANOC) is a retrospective cohort study of PLWH. The data used for this analysis was comprised of 8 population or clinic-based cohorts from 3 provinces (British Columbia, Ontario, and Quebec). CANOC eligibility criteria include: documented HIV infection; resident of Canada; aged 18 years and over; initiation of a first antiretroviral regimen comprised of at least 3 individual agents (i.e., antiretroviral-naive prior to initiating cART) on or after January 1, 2000; and at least 1 measurement of HIV-1 RNA viral load and CD4 cell count within 6 months of initiating cART.
Data extraction of a predefined set of demographic, laboratory, and clinical variables is performed bi-annually by the participating sites and submitted to the BC Centre for Excellence in HIV/AIDS (the Data Coordinating Site). All participating cohorts received research ethics board approval to contribute anonymous patient data to CANOC and for aggregate and de-identified results to be disseminated.
The last date of follow-up data for this analysis was December 31, 2014. Reporting was conducted in accordance with the international STROBE guidelines —a set of recommendations to promote complete reporting of cohort data in a systematic manner.
2.2 Study population
For this analysis, in addition to meeting the CANOC eligibility criteria, participants’ first antiretroviral treatment date must have been before December 31, 2013 (to ensure a minimum of 1 year follow-up time) and individuals had to have at least 2 viral load measurements after starting cART. There were 477 participants excluded from the analysis based on this criteria; number of people excluded did not vary significantly between younger and older adults (P value = 0.339). Loss to follow-up among patients included in this analysis was defined as no contact (e.g., clinical visits or laboratory tests) for at least 1 year during the study period (January 1, 2000–December 31, 2014).
2.3 Outcomes and covariates
The primary outcomes were viral suppression and viral rebound. Viral suppression was defined as the time to the first of at least 2 consecutive viral load measurements <50 HIV-1 RNA copies/mL, at least 30 days apart, in a one-year period. Viral rebound was defined as the first of at least 2 consecutive viral load measurements >50 HIV-1 RNA copies/mL, at least 30 days apart, after reaching viral suppression. Prevalence of viral suppression and viral rebound were considered as binary variables, did suppression or rebound ever occur (yes versus no). Viral suppression and subsequent rebound were also included as time-varying variables, beginning at baseline.
Covariates of interest included: age; sex; province of residence; ethnicity; Indigenous ancestry; transmission risk category (men who have sex with men (MSM), injection drug use (IDU), and follow-up time (years). Clinical variables including hepatitis C (HCV) co-infection (ever); the presence of an AIDS-defining illness (ADI); era of cART initiation (2000–2003, 2004–2007, 2008–2011, 2012–2013); composition of initial cART regimen (nucleoside reverse transcriptase inhibitor (NRTI) backbone and third drug in the regimen); baseline CD4 cell count (cells/mm3); and HIV plasma viral load (log10). Baseline was defined as participant entrance into the CANOC cohort (date of cART initiation on or after the latter of January 1, 2000 or 18th birthday).
2.4 Statistical analysis
Sociodemographic and patient characteristics were compared by age (≤29 vs 30+ years old), viral suppression status (yes vs no), and viral rebound after suppression (yes vs no) in bivariate analyses using Chi-square tests for categorical variables and Wilcoxon's Rank Sum test for continuous variables. Viral load measurements were buffered to a minimum of 50 copies/mL and a maximum of 100,000 copies/mL to accommodate temporal changes in viral load assay sensitivities over the study period.
Kaplan–Meier methods and stratified life tables (using Log-rank tests and hazard ratios, respectively) were used to compare time to viral suppression and viral rebound stratified by age group (≤29 vs 30+ years old). Bivariate and unadjusted accelerated failure time (AFT) models with exponential distributions or Weibull distributions were explored before multivariable models were selected to determine the association between covariates and time to viral suppression and viral rebound. AFT models were fit using an exploratory model selection process based on Akaike Information Criterion (AIC) and Type III P-values. Goodness-of-fit was assessed by a log-survivor plot. Based on model diagnosis and the goodness-of-fit tests, we did not use a Cox Proportional Hazard model due to a violation of the proportional hazards assumption. As a sensitivity analysis, Cox Proportional Hazard models were constructed. A 2-sided P-value below 0.05 was considered statistically significant. All analyses were performed using SAS software version 9.3 (SAS Institute, Cary, NC).
3.1 Population characteristics
A total of 9031 individuals were included in this analysis, 1281 were aged 29 and under (14%). A higher proportion of younger adults were female (27% vs 16%), experienced an ADI after initiating cART (87% vs 79%), initiated cART in 2008–2011 (38% vs 36%) or 2012–2013 (21% vs 14%), and had higher baseline CD4 cell counts (Median 280 cells/mm3 vs 220 cells/mm3). Younger adults were less likely to be from the province of BC (43% vs 50%), be white (31% vs 37%), have a history of injecting drugs (18% vs 22%) or be HCV co-infected (18% vs 25%) (Table 1). Loss to follow-up at 12, 18, 24, and 36 months was not significantly different between younger and older adults (P-values: .213, .820, .906, .736, respectively).
Among the 8358 (93%) CANOC participants who achieved viral suppression, 2,231 (27%) experienced subsequent viral rebound. A lower proportion of young adults achieved viral suppression (90% vs 93%, P < .001) compared to older adults, though there were no significant differences in the probability of experiencing viral rebound (28% vs 26%) (Table 2).
3.2 Characteristics of those achieving viral suppression
Among young adults who achieved viral suppression (90%), a significantly higher proportion were: female (26% vs 16%); from Ontario (37% vs 30%) or Quebec (22% vs 21%); started cART with an unboosted PI (9% vs 6%); and initiated cART with a higher baseline CD4 count (cells/mm3) (median 280 vs 224) compared to older adults who achieved viral suppression. A lower proportion of young adults who achieved viral suppression: reported Caucasian ethnicity (32% vs 38%); had a history of IDU (16% vs 20%); were hepatitis C co-infected (17% vs 23%); and had ADI before or at cART initiation (9% vs 17%) compared to older adults who achieved viral suppression (Table 2).
Life table estimates of the probability of suppression were not significantly different between younger and older adults at 6, 12, 18, and 24 months (Table 2).
Kaplan–Meier curves indicated significant differences (P < .03) in viral suppression between younger and older adults (Fig. 1).
3.3 Characteristics of those achieving viral rebound
Among those who experienced viral rebound, a higher proportion of young adults were: female (45% vs 21%); from Ontario (35% vs 25%); Indigenous (12% vs 9%); started cART with an unboosted PI (16% vs 9%); and initiated cART with a higher baseline CD4 count (cells/mm3) (median 245 vs 180) compared to older adults who experienced viral rebound. Fewer young adults who experienced viral rebound were: Caucasian (33% vs 40%); identified as MSM (34% vs 40%); or had an ADI before or at cART initiation (13% vs 19%) compared to older adults (Table 2).
Life table estimates of the probability of experiencing viral rebound after viral suppression indicated that rebound was not significantly different between younger and older adults at 6, 12, 18, and 24 months (Table 2).
Kaplan–Meier curves indicated significant differences (P < .001) in viral rebound between younger and older adults (Fig. 1).
3.4 AFT models of younger and older adults
The overall adjusted AFT model, including older and younger adults, indicated that per 1-year increase in age, there was a 1% increase in the rate of viral suppression. Viral suppression was also positively associated with: being male (adjusted hazard ratios [aHR] 1.27 95% confidence intervals (CI): 1.19, 1.35); having a baseline CD4 cell count above 200 cells/mm3 (aHR 1.09, 95%CI: 1.04, 1.14); later era of cART initiation; and Quebec province of residence (aHR 1.08, 95% CI: 1.01–1.15) compared to British Columbia. Viral suppression was negatively associated with: having a history of IDU (aHR 0.58, 95%CI: 0.54, 0.61); initial cART regimen containing an unboosted PI (aHR 0.59, 95% CI: 0.48–0.72) or a boosted PI (aHR 0.78, 95%CI: 0.67–0.91) compared to (non-nucleoside reverse-transcriptase inhibitors) NNRTI; and higher viral load at baseline (aHR 0.73, 95%CI: 0.70, 0.76) (Table 3).
Adjusted AFT models indicated that per 1-year increase in age, there was a 1% decrease in the likelihood of viral rebound. Viral rebound was also less likely to occur among males (aHR 0.65, 95%CI: 0.59, 0.72), participants who experienced an ADI, either before (aHR 0.73, 95% CI: 0.56–0.94) or after initiating cART (aHR 0.72, 95% CI: 0.54–0.90) compared with never experiencing an ADI, later era of treatment initiation and province of residence. Overall, those with a history of IDU (aHR 1.64, 95%CI: 1.48, 1.82), and Indigenous heritage (aHR 1.44, 95%CI: 1.23, 1.68) were more likely to experience viral rebound (Table 3).
Results from the sensitivity analysis indicate that the associates and direction of association were the same for AFT models and for Cox Proportional Hazard models.
3.5 AFT models of younger adults
Among younger adults, adjusted AFT models indicated that, being male (aHR 1.45, 95%CI: 1.25, 1.67), and initiating cART in 2004 to 2013 (compared with 2000–2003) was associated with a higher probability of achieving viral suppression. A history of IDU (aHR 0.59, 95%CI: 0.50, 0.71), initiating cART with an unboosted PI (aHR 0.62, 95%CI: 0.50, 0.78) compared to an NNRTI and higher viral load (aHR 0.72, 95%CI: 0.65, 0.79) were associated with a decreased probability of experiencing viral suppression (Table 4).
Decreased probability of experiencing viral rebound was associated with being male (aHR 0.51, 95%CI: 0.41, 0.64), initiating cART between 2008 and 2011 (aHR 0.72, 95%CI: 0.53, 0.97) compared with 2000 to 2003 and having a higher viral load (aHR 0.80 95%CI: 0.67, 0.96). Increased probability of experiencing viral rebound was associated with having a history of IDU (aHR 2.21 95%CI: 1.68, 2.91), being Indigenous (aHR 1.60 CI: 1.11, 2.32), having a CD4 cell count ≥200 cells/mm3 (aHR 1.30 95%CI: 1.02, 1.66), and initiating cART with an unboosted PI (aHR 1.59 95%CI: 1.14, 2.22) or a boosted PI (aHR 1.48 95%CI: 1.15, 1.90) compared to an NNRTI (Table 4).
In a large Canadian HIV treatment cohort, we found that younger adults were less likely to achieve viral suppression compared with older adults. We observed no differences in prevalence of viral rebound after suppression between the two groups. However, all measured differences between younger and older adults were moderate, and may not be clinically significant. Among younger and older adults, the rate of viral suppression was 93%, surpassing the United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 targets. Among younger adults, sex, era of cART initiation, history of IDU, composition of first cART regimen and viral load were independently associated with viral suppression, in addition to the aforementioned characteristics, being Indigenous and CD4 cell count at cART initiation were associated with viral rebound.
Youth in our study had better outcomes compared with other large cohort studies. The UK Collaborative HIV Cohort Study (UK-CHIC) found that for every 10-year increase in age, the rate of viral rebound decreased by 28%, compared to a 1% decrease per year in our analysis. A large adolescent and young adult cohort in the United States (REACH) found that only 51% of young people maintained a suppressed viral load for a year; in contrast our study indicated that only 11% of youth experienced viral rebound at 12 months post suppression. Though, differences may be explained by systematic differences between the health systems in the UK, USA, and Canada.
Our results align with previous research indicating that young women are at greater risk of viral rebound compared to young men, which may be partially explained by lower levels of adherence among women.[33,34] Many women with HIV contend with complex, competing priorities, such as childcare, employment, and housing as well as competing comorbidities such as depressive symptoms and substance use disorders, which create barriers and challenges to optimal cART adherence.[35–38] Access to women-centred HIV care, cART adherence support, transportation support, and onsite childcare may result in improved treatment outcomes.[39,40] In addition, gender sensitivity training is recommended for all health care workers to ensure that positive women receive comprehensive care in a holistic, comfortable and respectful clinic environment.[39,40]
We found that unboosted PIs were associated with a reduced likelihood of achieving viral suppression and increased risk for viral rebound. This may be due to unboosted PI regimens being more complex compared to NNRTI. Beyond adherence, women and youth have historically been excluded from clinical trials, minimizing knowledge about the effectiveness of cART on disease progression for young women living with HIV. Given that complex drug regimens are related to poor adherence the effects of regimen and era of cART initiation may be directly related to the increasing availability of once-daily regimens increasing adherence.[42,43] We found that initiating cART later was associated with increased suppression and reduced likelihood of viral rebound.
Young adults with a history of IDU often have significant difficulties in maintaining cART adherence.[37,44,45] Treating their HIV may not be their first priority in the face of other competing necessities such as food, housing, and addiction services.[37,44,45] Many young adults with a history of IDU have also tested positive for HCV co-infection. Those who are co-infected with HCV may stop cART due to toxicities or competing treatment priorities. Many young people who inject drugs report facing stigma when attending health clinics, making them reluctant to follow-up on their care.[47–49] Low-threshold support programs such as directly observed therapy (DOT) and maximally assisted therapy (MAT) programs have been shown to improve adherence for people on cART who use drugs. The development of such programs for young adults living with HIV could assist those who are in need of low-threshold health care and support to remain on treatment as well as access other services that may be linked. Treatment partnerships in which health providers work directly with the patient to tailor health care to the individual's needs can increase feelings of support and levels of comfort when communicating with health providers increasing the likelihood of the individuals being retained in care.[51,52]
Our finding that younger adults who identify as Indigenous are more likely than non-Indigenous people to experience viral rebound suggests the importance of retention in care and follow-up while on treatment. For many young Indigenous people in Canada, especially women, remaining in care can be a difficult, in part due to complex historical relationships relating to colonialism and trauma. The lack of culturally safe health services can hinder young peoples’ willingness to remain in care. Young people of Indigenous ancestry have voiced their frustration with the lack of youth friendly messaging and language, and services available to them.
Pharmacological responses to issues with adherence to combat viral rebound are extremely valuable; however, the best clinical practice must incorporate comprehensive, multidisciplinary approaches to promote retention and adherence. A recent study from a large North American HIV cohort (NA-ACCORD) showed that young people retained in care were more likely to maintain viral suppression. The most promising strategies for improving retention among young people use holistic approaches involving patient and caregiver education, self-monitoring, peer support, and follow-up.[55–58] Given that health literacy is often a barrier to adherence, education sessions and mentorship programs can provide a safe environment to discuss HIV treatment with young people and to answer any questions they may have.[59,60] Young people may not completely understand the gravity of staying on treatment and remaining adherent. It is up to the health care and social service providers to meet young people where they are at, in a respectful, culturally appropriate, gender-sensitive and compassionate manner, in order to improve retention in care.
Readers should be cautious when interpreting these data. We did not consider antiretroviral adherence, an important predictor of viral suppression and rebound, as adherence data were not available from all cohorts. The data were obtained from only 3 provinces and thus the findings cannot be generalized to all PLWH in Canada. However, the majority of PLWH in Canada receive care in these 3 provinces. In fact, CANOC contains over one-third of all patients on therapy and a much larger proportion of those who initiated treatment since 2000. It is possible that some women in the study may have experienced viral rebound after halting therapy that was initiated solely for purposes of prevention of perinatal HIV transmission; however, pregnancy data are not available in the CANOC database. Perinatal versus behavioral infection was not documented in CANOC; however, the inclusion criteria of being cART naïve on or after 18 years of age may reduce the number of PLWH who were perinatally infected. Additionally, the differences between provinces in viral suppression may be due to the fact that the sample of participants in British Columbia is population based, while the sample from Ontario and Quebec is based on a selection of clinics. Variances may also reflect differences in access to cART between provinces. Some variables had a high proportion of missing or unknown data included, which may introduce bias. Despite these limitations, important information regarding factors associated with viral suppression and viral rebound for young adults were identified. This information is of value in identifying young people at risk for suboptimal therapeutic outcomes.
In conclusion, our results indicate that difference in the likelihood, as well as time to viral suppression and subsequent rebound are modestly different between younger and older adults living with HIV in Canada. The independent associates of viral suppression and rebound for younger adults are similar to those known to affect older adults (e.g., history of IDU), highlighting at-risk populations for future research and intervention. Tailored approaches to engage young people including, women, people who use drugs and Indigenous people, should be developed to assist these populations to reach their optimal health. Antiretroviral therapy adherence and retention in care are important issues for all people living with HIV and should be considered in the context of Treatment as Prevention and reaching the UNAIDS 90-90-90 targets. Reducing barriers to care for important key populations will assist in reaching these targets by 2030.
5 Authors’ information
The CANOC Collaborative Research Centre includes: CANOC Principal Investigator: Robert Hogg (British Columbia Centre for Excellence in HIV/AIDS, Simon Fraser University), site Principal Investigators: Ann N. Burchell (Ontario HIV Treatment Network, University of Toronto, OHTN Cohort Study [OCS]), Curtis Cooper (University of Ottawa, OCS), Deborah Kelly (Memorial University of Newfoundland), Marina Klein (Montreal Chest Institute Immunodeficiency Service Cohort, McGill University), Mona Loutfy (University of Toronto, Maple Leaf Medical Clinic, OCS), Nima Machouf (Clinique Medicale l’Actuel, Université de Montréal), Julio Montaner (British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia), Janet Raboud (University of Toronto, University Health Network, OCS), Chris Tsoukas (McGill University), Stephen Sanche (University of Saskatchewan), Alexander Wong (University of Saskatchewan) Co-Principal Investigators: Tony Antoniou (St. Michael's Hospital, University of Toronto, Institute for Clinical Evaluative Sciences), Ahmed Bayoumi (St. Michael's Hospital, University of Toronto), Mark Hull (British Columbia Centre for Excellence in HIV/AIDS), Bohdan Nosyk (British Columbia Centre for Excellence in HIV/AIDS, Simon Fraser University) Co-Investigators: Angela Cescon (Northern Ontario School of Medicine), Michelle Cotterchio (Cancer Care Ontario, University of Toronto), Charlie Goldsmith (Simon Fraser University), Silvia Guillemi (British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia), P. Richard Harrigan (British Columbia Centre for Excellence in HIV/ AIDS, University of British Columbia), Marianne Harris (St. Paul's Hospital), Sean Hosein (CATIE), Sharon Johnston (Bruyère Research Institute, University of Ottawa), Claire Kendall (Bruyère Research Institute, University of Ottawa), Clare Liddy (Bruyère Research Institute, University of Ottawa), Viviane Lima (British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia), David Marsh (Northern Ontario School of Medicine), David Moore (British Columbia Centre for Excellence in HIV/ AIDS, University of British Columbia), Alexis Palmer (British Columbia Centre for Excellence in HIV/AIDS, Simon Fraser University), Sophie
Patterson (British Columbia Centre for Excellence in HIV/AIDS, Simon Fraser University), Peter Phillips (British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia), Anita Rachlis (University of Toronto, OCS), Sean B. Rourke (University of Toronto, OCS), Hasina Samji (British Columbia Centre for Excellence in HIV/AIDS), Marek Smieja (McMaster University), Benoit Trottier (Clinique Medicale l’Actuel, Université de Montréal), Mark Wainberg (McGillUniversity, Lady Davis Institute for Medical Research), Sharon Walmsley (University Health Network, University of Toronto) Collaborators: Chris Archibald (Public Health Agency of Canada Centre for Communicable Diseases and Infection Control), Ken Clement (Canadian Aboriginal AIDS Network), Fred
Crouzat (Maple Leaf Medical Clinic), Monique Doolittle-Romas (Canadian AIDS Society), Laurie Edmiston (Canadian Treatment Action Council), Sandra Gardner (OHTN, University of Toronto, OCS), Brian Huskins (Canadian Treatment Action Council), Jerry Lawless (University of Waterloo), Douglas Lee (University Health Network, University of Toronto, ICES), Renee Masching (Canadian Aboriginal AIDS Network), Stephen Tattle (Canadian Working Group on HIV & Rehabilitation), Alireza Zahirieh (Sunnybrook Health Sciences Centre) Analysts and Staff: Claire Allen (Regina General Hospital), Stryker Calvez (SHARE), Guillaume Colley (British Columbia Centre for Excellence in HIV/AIDS), Jason Chia (British Columbia Centre for Excellence in HIV/AIDS), Daniel Corsi (The Ottawa Hospital Immunodeficiency Clinic, Ottawa Hospital Research Institute), Louise Gilbert (Immune Deficiency Treatment Centre), Nada Gataric (British Columbia Centre for Excellence in HIV/AIDS), Alia Leslie (British Columbia Centre for Excellence in HIV/AIDS), Lucia Light (OHTN), David Mackie (The Ottawa Hospital), Costas Pexos (McGill University), Susan Shurgold (British Columbia Centre for Excellence in HIV/AIDS), Leah Szadkowski (University Health Network), Chrissi Galanakis (Clinique Médicale L’Actuel), Ina Sandler (Maple Leaf Medical Clinic), Benita Yip (British Columbia Centre for Excellence in HIV/AIDS), Jaime Younger (University Health Network), Julia Zhu (British Columbia Centre for Excellence in HIV/AIDS), and Karyn Gabler (British Columbia Centre for Excellence in HIV/AIDS).
We would like to thank all of the participants for allowing their information to be a part of the CANOC collaboration.
AP conceived of and designed the study. ED performed all statistical analyses. AP, ED, BR and KG contributed to the interpretation of the data. KG drafted the manuscript. All authors reviewed the manuscript critically for important intellectual content and approved the final version submitted for publication.
Conceptualization: Alexis Palmer, Beth Rachlis, Robert S Hogg.
Data curation: Jason Chia, Nic Bacani.
Formal analysis: Alexis Palmer, Erin Ding.
Funding acquisition: Robert S Hogg.
Methodology: Alexis Palmer.
Writing – original draft: Alexis Palmer, Karyn Gabler.
Writing – review & editing: Karyn Gabler, Beth Rachlis, Ahmed M. Bayoumi, Kalysha Closson, Marina Klein, Curtis Cooper, Ann Burchell, Sharon Walmsley, Angela Kaida, Robert S Hogg.
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