VF occurred in 26% of participants at least once during the study follow-up. The probability of experiencing VF decreased per calendar year (OR 0.78, 95%CI 0.72/0.85). VF was more probable in heterosexually infected patients (OR 5.20, 95% CI 1.39;19.38), patients originating from Latin America or the Caribbean (OR 6.59, 95% CI 2.08;20.92) and patients infected through a blood transfusion or a needle accident (OR 9.93, CI 1.34;73.84. Patients with a nadir CD4+ count >500 cells/μl were more likely to experience VF (OR 11.36, 95%CI 2.03;63.48). We found no associations between VF and gender, Sub-Saharan African origin, peak HIV VL, or cumulative duration of ART use (Table 2). Separate analyses of complete cases only (without imputation N = 711) showed an increased risk for VF in patients originating from Sub-Saharan Africa (OR 3.80, CI 1.08;13.41, P = .04), which was not observed in the imputed datasets. Contrary, no additional risk was observed in complete cases for patients infected through a blood transfusion or a needle accident (OR 7.95, CI 0.64; 98.05, P = .11). All other outcomes were similar (data not shown).
The percentages of cases experiencing VF sorted by calendar year are shown in Figure 2. Repeating the analysis taking into account the use of a triple NRTI regimen had no significant impact on the results (data not shown).
Our study assessed long-term virological outcomes in behaviorally young adults living with HIV on cART in the Netherlands. In our cohort, 26% of 816 participants were not sustained virological suppressed during the study follow-up after starting cART. Outcomes improved significantly over time, highlighting the importance of taking into account calendar year when assessing and interpreting HIV-related outcomes for young adults. During our study period, some important milestones in cART development occurred, in 2006 the first 1 pill regime was introduced, followed by the introduction of HIV integrase inhibitors in 2007 and the second-generation HIV integrase inhibitors in 2013. Our findings suggest that young adults greatly benefitted from improved cART regimens, that have shown to be more potent and forgiving with lesser side effects.
We report higher overall HIV suppression rates than results from cross-sectional studies in young adult populations in the United States (53–64%) and in adolescents and young adults in Europe (62%).[11,13] This could, in part, be explained by methodological factors, including the use of different measures of adherence, such as viral suppression, pill count, and self-report. However, we believe that longitudinal data provide a more thorough view on treatment outcomes by using multiple observations over time.
A 4-year study on trends of antiretroviral therapy prescription and viral suppression in young adults reporting HIV non-suppression rates of 20% to 30% approached our results more closely. In accordance with our results, this study reported on the increased proportion of sustained viral suppression in young adults over the years. A recent longitudinal study with a median follow-up period of 2.1 years from the United States described VF in 29% in those previously achieved viral suppression. In line with our data, young adults in this study who entered care after the year 2012 showed significantly better outcomes with only 3% experiencing VF after start cART.
Despite these similarities, our results indicate that young adults living with HIV in the Netherlands have generally better virological outcomes than their peers in other high-resource countries. This may be caused, in part, by differences in general access to health care and/or organization of HIV care in Western countries. Today, HIV suppression rates in young adults in our cohort are comparable to reported suppression rates of 95% in adults in the Netherlands in 2016. Previous studies in young adult and older adult populations living with HIV report older age as a contributing factor to treatment adherence.[26,27] In our cohort, development of young adults towards adulthood might be of influence on improved outcomes as well. However, taking into account the large effect of calendar year, we have to consider the possibility that in today's cART era, adherence rates in young adults further improved due to more potency, less side effects, and higher availability of current 1-pill regimens as compared to older treatments. Furthermore, with newer regimens, the necessary rate of adherence to achieve viral suppression may be lower than with older regimens.
We identified several subgroups and factors that are associated with VF in our cohort. Firstly, we found a strong association between VF and being heterosexually infected as compared to being infected though MSM contact. Poorer treatment outcomes in heterosexuals as compared to MSM were previously observed in studies in both adults and young adults.[29,30] Studies suggest that acceptance of same sex relationships within a society is likely of considerable influence on access to HIV care. Moreover, young MSM with less negative feelings towards homo- and bisexuality and HIV infection are more likely to be engaged in care.[31,32] In 2015, the Dutch Association of People living with HIV published a study on quality of life in 468 people living with HIV in the Netherlands, of whom 40% was heterosexual. Heterosexuals reported more HIV-related depressive symptoms and feelings of guilt and shame as compared to the MSM group. Further, heterosexual men were less likely to seek support from family or friends in coping with their HIV infection. Our results may thus (at least partly) be explained by these psychosocial components that have a negative effect on adherence. VF occurred more often in young adults infected though a blood transfusion or needle accident. This association reflects a small subgroup and we have to consider unmeasured factors influencing optimal HIV suppression in this group. As HIV infection through a blood transfusion in the Netherlands occurred mainly in the beginning of the epidemic, this group was most likely exposed to different (less potent) cART regimes and has a high chance of having developed multiple drug resistance. Further, for persons not originating from the Netherlands, HIV transmission routes cannot always be verified.
In several Western cohorts, treatment outcomes were worse for people with a migrant background as compared to their native counterparts.[35,36] These differences occur also within the MSM population.[29,37] We could not confirm associations between VF and originating from Sub-Saharan Africa (SSA) with high confidence and observed differences between complete case and imputed case analyses. The weak effect that was found in the complete case analyses for people originating from SSA was attenuated in the imputed cases datasets losing statistical significance. Most likely, a substantial proportion of cases originating from SSA already started on (c)ART before immigration to the Netherlands. Imputing missing baseline values within the group originating from SSA might therefore have led to loss of significant association between VF and originating from SSA. Hence, longer survival on therapy can explain their generally better virological outcomes.
We did find that young adults originating from Latin America or the Caribbean were at higher risk for VF. People living with HIV in the Netherlands originating from non-Western regions were less likely to have disclosed their status and more likely to experience self-stigma as compared to people living with HIV originating from the Netherlands or other Western countries. Additionally, financial problems are most often reported in this subgroup. These psychosocial determinants as well as the presence of socio-economic inequality may contribute to the increased risk for VL in young adults originating from Latin America or the Caribbean. Details on socio-economic disadvantages, such as financial problems, unemployment, unstable housing, and low level of education, were not available to us, but were found previously to be strongly associated with adherence and viral suppression.[38,39]
Our study focused on clinical and socio-demographic characteristics, and future research is needed to gain better insight into the representation of identified risk factors for VF. Factors as self-efficacy, self-motivation, outcome expectation, social support, substance use, mental health problems, and perceived stigma may contribute to treatment adherence differently within specific YA subgroups at risk for VF.[14,34,40]
Starting cART at high nadir CD4 levels was identified as a risk factor for VF. Although this phenomenon is hard to explain, there is a possibility that it is driven by the lack of feeling for urgency and necessity for cART at this asymptomatic stage. Further analyses are needed to assess whether this effect holds in current times, in which it is more common to start treatment regardless of CD4 count.
Although we assessed long-term outcomes with robust statistical analyses of a large cohort of young adults in the Netherlands, our study has some limitations. Our study covers a long time- period in which the lower limit of detection of HIV VL in a sample of blood decreased. Therefore, determination of VF around the year 2000 was less accurate than in more recent years. As a result, the actual effect of age and calendar year is probably stronger, as the incidence of VF might be underestimated during the first time- period of the study.
Many potentially influencing social and personal factors were not available. Additionally, we included only those patients who were registered in the SHM database and prescribed cART (respectively 97.9 and 91.8% of all people living with HIV in the Netherlands). Since linkage to care and treatment use are relevant predictors of virological suppression, the actual number of young adults living with HIV that do not achieve viral suppression is probably higher than reported in our study.
In summary, in this longitudinal cohort study, we demonstrated that VF occurred in 26% of young adults living with HIV in the Netherlands. Heterosexual infection, Latin American or Caribbean origin, and nadir CD4 count >500 cells/μl at therapy initiation were additional factors that increased the risk of VF in young adults. Assessing group characteristics of those more vulnerable to suboptimal treatment to reveal what is driving adherence problems is crucial as well as identifying factors that promote treatment success.
Data curation: Ferdinand Wit.
Formal analysis: Annouschka Weijsenfeld.
Methodology: Annouschka Weijsenfeld, Martijn Stuiver, Ferdinand Wit.
Supervision: Martijn Stuiver, Dasja Pajkrt.
Validation: Charlotte Blokhuis.
Visualization: Charlotte Blokhuis.
Writing – original draft: Annouschka Weijsenfeld.
Writing – review & editing: Charlotte Blokhuis, Martijn Stuiver, Ferdinand Wit, Dasja Pajkrt.
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Keywords:Copyright © 2019 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
combination antiretroviral therapy; HIV; virological failure; young adults