Intentional- but not Unintentional Medication Non-adherence was Related with Beliefs about Medicines Among a Multi-Ethnic Sample of People with HIV.

Medication non-adherence can be intentional or unintentional. We investigated the prevalence of unintentional and intentional non-adherence to antiretroviral therapy (ART) and the relationship with beliefs about medicines, sociodemographic- and HIV-related variables among people with HIV (PWH) attending the HIV clinic of the Amsterdam University Medical Centers. Participants completed the Medication Adherence Rating Scale (MARS) and the Beliefs about Medicines (BMQ) questionnaire. About half of 80 participants reported unintentional non-adherence and 20% reported intentional non-adherence. Both unintentional and intentional non-adherence were associated with younger age. Additionally, intentional non-adherence was associated with being a migrant from Suriname /Netherlands Antilles, having more concerns about negative effects of ART and stronger beliefs that medicines in general are overused/ overprescribed. In conclusion, intentional but not unintentional non-adherence was associated with beliefs about medicines. Eliciting and discussing beliefs about medicines may be a promising avenue to address patients' concerns and perceptions thereby potentially enhancing medication adherence.

Reduced Forced Vital Capacity Among Human Immunodeficiency Virus-Infected Middle-Aged Individuals.

BACKGROUND: Pulmonary function impairments are more common among people living with HIV (PLWH), as are contributing risk behaviors. To understand the effects of human immunodeficiency virus (HIV) infection independent of risk behaviors, pulmonary function was evaluated in lifestyle-comparable HIV-infected and -uninfected AGEhIV cohort participants. METHODS: Prevalence of obstructive lung disease in 544 HIV-infected and 529 HIV-uninfected participants was determined using spirometry. Logistic regression was used to assess HIV as a determinant of obstructive lung disease. Additional explanatory models were constructed to explain observed differences. RESULTS: The unadjusted obstructive lung disease prevalence was similar in HIV-infected (23.0%) and -uninfected (23.4%) participants. Multivariable logistic regression analysis showed an effect modification whereby obstructive lung disease prevalence among persons with limited smoking experience was notably lower among HIV-infected compared with HIV-uninfected participants. This resulted from a lower forced vital capacity (FVC) in HIV-infected participants but similar 1-second forced expiratory volume (FEV1), especially in those with limited smoking experience. CONCLUSIONS: The lower FVC in HIV-infected participants could indicate HIV-related restrictive or fibrotic pulmonary changes. Factors that decrease the FVC could obscure emphysematous changes in the lungs of PLWH when using the FEV1/FVC ratio as single diagnostic measure. CLINICAL TRIALS REGISTRATION: NCT01466582.

Dolutegravir/Lamivudine Is Noninferior to Continuing Dolutegravir- and Non-Dolutegravir-Based Triple-Drug Antiretroviral Therapy in Virologically Suppressed People With Human Immunodeficiency Virus: DUALING Prospective Nationwide Matched Cohort Study.

Background: Confirming the efficacy of dolutegravir/lamivudine in clinical practice solidifies recommendations on its use. Methods: Prospective cohort study (DUALING) in 24 human immunodeficiency virus (HIV) treatment centers in the Netherlands. HIV RNA-suppressed cases were on triple-drug antiretroviral regimens without prior virological failure or resistance and started dolutegravir/lamivudine. Cases were 1:2 matched to controls on triple-drug antiretroviral regimens by the use of dolutegravir-based regimens, age, sex, transmission route, CD4+ T-cell nadir, and HIV RNA zenith. The primary endpoint was the treatment failure rate in cases versus controls at 1 year by intention-to-treat and on-treatment analyses with 5% noninferiority margin. Results: The 2040 participants were 680 cases and 1380 controls. Treatment failure in the 390 dolutegravir-based cases versus controls occurred in 8.72% and 12.50% (difference: -3.78% [95% confidence interval {CI}, -7.49% to .08%]) by intention-to-treat and 1.39% and 0.80% (difference: 0.59% [95% CI, -.80% to 1.98%]) by on-treatment analyses. The treatment failure risk in 290 non-dolutegravir-based cases was also noninferior to controls. Antiretroviral regimen modifications unrelated to virological failure explained the higher treatment failure rate by intention-to-treat. A shorter time on triple-drug antiretroviral therapy and being of non-Western origin was associated with treatment failure. Treatment failure, defined as 2 consecutive HIV RNA >50 copies/mL, occurred in 4 cases and 5 controls but without genotypic resistance detected. Viral blips occured comparable in cases and controls but cases gained more weight, especially when tenofovir-based regimens were discontinued. Conclusions: In routine care, dolutegravir/lamivudine was noninferior to continuing triple-drug antiretroviral regimens after 1 year, supporting the use of dolutegravir/lamivudine in clinical practice. Clinical Trials Registration: NCT04707326.

Optimising HIV care using information obtained from PROMs: protocol for an observational study.

INTRODUCTION: Successful antiviral therapy has transformed HIV infection into a chronic condition, where optimising quality of life (QoL) has become essential for successful lifelong treatment. Patient-reported outcome measures (PROMs) can signal potential physical and mental health problems related to QoL. This study aims to determine whether PROMs in routine clinical care improve quality of care as experienced by people with HIV (PWH). METHODS AND ANALYSIS: We report the protocol of a multicentre longitudinal cohort studying PWH at Amsterdam University Medical Centres in the Netherlands. PROMs are offered annually to patients via the patient portal of the electronic health record. Domains include anxiety, depression, fatigue, sleep disturbances, social isolation, physical functioning, stigma, post-traumatic stress disorder, adherence, drug and alcohol use and screening questions for sexual health and issues related to finances, housing and migration status. Our intervention comprises (1) patients' completion of PROMs, (2) discussion of PROMs scores during annual consultations and (3) documentation of follow-up actions in an individualised care plan, if indicated. The primary endpoint will be patient-experienced quality of care, measured by the Patient Assessment of Chronic Illness Care, Short Form (PACIC-S). Patients will provide measurements at baseline, year 1 and year 2. We will explore change over time in PACIC-S and PROMs scores and examine the sociodemographical and HIV-specific characteristics of subgroups of patients who participated in all or only part of the intervention to ascertain whether benefit has been achieved from our intervention in all subgroups. ETHICS AND DISSEMINATION: Patients provide consent for the analysis of data collected as part of routine clinical care to the AIDS Therapy Evaluation in the Netherlands study (ATHENA) cohort through mechanisms described in Boender et al. Additional ethical approval for the analysis of these data is not required under the ATHENA cohort protocol. The results will be presented at national and international academic meetings and submitted to peer-reviewed journals for publication.

Exploring the Breastfeeding Desires and Decision-Making of Women Living with HIV in the Netherlands: Implications for Perinatal HIV Management in Developed Countries.

Introduction: Guidelines in high-income countries recommend women living with human immunodeficiency virus (HIV) to formula feed their newborns, because the possibility of mother-to-child-transmission of HIV during breastfeeding cannot be ruled out. It is an ongoing debate if the possible transmission risk outweighs the medical, cultural, psychological, and social importance of breastfeeding in women stable on current first-line suppressive antiretroviral regimens. The study aim was to explore breastfeeding desires and decision-making of immigrant and nonimmigrant women living with HIV in the Netherlands. Method: A questionnaire was administered orally or online to 82 women living with HIV in the Netherlands. The breastfeeding desires of the participants were collected as categorical data, and breastfeeding decision-making and willingness to adhere to additional monitoring were collected on a 5-point Likert scale. Categorical data were presented as proportions, and Likert scale data were presented in Likert scale bar plots. Results: Seventy-one percent of the participants expressed a desire to breastfeed in the future. The most important factors influencing decision-making to breastfeed were the chance of transmission of HIV to the infant and the advice by the doctor or nurse practitioner. Of the participants, 42% expressed their interest in breastfeeding with a <1/100 transmission risk. More than half of the participants expressed their interest to breastfeed with additional monitoring. Conclusions: A substantial proportion of the women living with HIV in the Netherlands has a desire to breastfeed, of which the majority are willing to adhere to additional monitoring to do so.

Long-Term Virological Treatment Outcomes in Adolescents and Young Adults With Perinatally and Non-Perinatally Acquired Human Immunodeficiency Virus.

Background: Long-term viral suppression on antiretroviral therapy (ART) is not established among all people with human immunodeficiency virus (PWH). Young adults (18-24 years) are recognized as a group vulnerable for suboptimal virological treatment outcomes. The aim of this study is to evaluate longitudinal virological treatment outcomes and to identify risk factors for virological failure (VF) among young adults with non-perinatally and perinatally acquired human immunodeficiency virus (HIV) in the Netherlands. Methods: We included individuals registered in the national ATHENA observational cohort from 2000 until 2020 who had entered care before the age of 25 years, who had received ART for at least 6 months with at least 2 available HIV ribonucleic acid measurements between the age of 18 and 24 years. We compared VF between age groups 12-17, 18-24, and 25-30 years. A multivariable generalized linear mixed model was used to evaluate risk factors for VF. Analyses were stratified by HIV acquisition mode. Results: In total, 1174 non-perinatally PWH and 157 perinatally PWH were included. In 2020, VF rate was 7% in non-perinatally PWH young adults and 19% in perinatally PWH young adults. The adjusted risk for VF was significantly higher in those aged 18-24 compared to 25-30 years in both non-perinatally PWH (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.07-1.50) and perinatally PWH (OR, 2.34; 95% CI, 1.48-3.71). Conclusions: Young adulthood is a vulnerable period, with increased risk for VF, especially for perinatally PWH. The probability of VF decreased over time, but less for perinatally PWH compared to non-perinatally PWH.

HIV status disclosure among HIV-positive African and Afro-Caribbean people in the Netherlands.

HIV status disclosure is often characterized as a dilemma. On the one hand, disclosure can promote health, social support, and psychological well-being. On the other, disclosure can lead to stigmatization, rejection, and other negative social interactions. Previous research has shown that HIV status disclosure is a reasoned process whereby the costs and benefits to oneself and to others are weighed. As such, understanding disclosure requires understanding the reasons for and against disclosure employed by people living with HIV (PLWH). In this study, disclosure among a population disproportionately affected by HIV in the Netherlands, namely African and Afro-Caribbean diaspora, was investigated. Reasons for nondisclosure were fear of stigmatization, previous negative experiences with disclosure, having observed the stigmatization of other PLWH, shame, the desire to protect others - particularly one's children and family - from stigmatization by association and/or worrying, and the belief that one's HIV status is a private matter. Participants reported disclosing because they were in a close and supportive relationship, disclosure led to emotional release, disclosure could lead to emotional or financial support, they felt a perceived duty to inform, and they had a desire to educate others about sexual risk-taking. The findings suggest that stigma plays an important role in disclosure decisions among these populations. They further point to a need for HIV-related stigma reduction interventions in African and Afro-Caribbean communities and culturally sensitive counseling for PLWH whereby caregivers do not automatically assume that disclosure is best but rather provide a safe environment in which the costs and benefits of disclosure can be weighed and strategies for disclosure can be developed, if perceived as beneficial by PLWH.

Frequency, Risk Factors, and Mediators of Frailty Transitions During Long-Term Follow-Up Among People With HIV and HIV-Negative AGEhIV Cohort Participants.

BACKGROUND: We previously demonstrated a higher prevalence of frailty among AGEhIV-cohort participants with HIV (PWH) than among age- and lifestyle-comparable HIV-negative participants. Furthermore, frailty was associated with the development of comorbidities and mortality. As frailty may be a dynamic state, we evaluated the frequency of transitions between frailty states, and explored which factors were associated with transition toward frailty in this cohort. METHODS: The study enrolled 598 PWH and 550 HIV-negative participants aged ≥45 years. Of those, 497 and 479 participants, respectively, participated in ≥2 consecutive biennial study-visits between October 2010 and October 2016, contributing 918 and 915 visit-pairs, respectively. We describe the frequency, direction, and risk factors of frailty transitions. Logistic regression models with generalized estimating equations were used to evaluate determinants for transition to frailty, including HIV-status, socio-demographic, behavioral, HIV-related factors, and various inflammatory and related biomarkers. RESULTS: Transitioning between frailty states in any direction occurred in 36% of a total of 1833 visit-pairs. The odds of nonfrail participants transitioning toward frailty were significantly higher for PWH, occurring in 35 PWH (7.3%) and 25 (5.2%) HIV-negative nonfrail participants, respectively (odd ratioHIV 2.19, 95% confidence interval 1.28 to 3.75). The increased risk among PWH was attenuated when sequentially adjusting for waist-hip ratio, number of pre-existent comorbidities, and the presence of depressive symptoms. CONCLUSION: PWH are at increased risk of transitioning to frailty, and thereby at increased risk of adverse health outcomes. Whether optimizing the management of obesity, comorbidity, or depressive symptoms may modify the risk of becoming frail requires further investigation.

Which method of adherence measurement is most suitable for daily use to predict virological failure among immigrant and non-immigrant HIV-1 infected patients?

In industrialized countries, virological failure occurs more often among HIV-infected immigrant patients. Non-adherence is the most credible explanation. We compared adherence of immigrant patients with that of non-immigrant patients in the Netherlands, and investigated which method of adherence measurement is most suitable for daily use to predict virological treatment failure: testing knowledge of the current regimen, a quantitative adherence interview, pharmacy prescription refill ratio (dispensed medication divided by prescribed medication, DM/PM), and plasma drug levels. Included were 61 immigrants and 81 non-immigrants. Virological failure did occur more often in immigrants than in non-immigrants (19.7% (12/61) versus 8.6% (7/81), p=0.056), especially among previously naive patients (19.6% (11/56) versus 0% (0/54), p<0.01). There were no differences between both groups on any of the four adherence measures. Virological failure was associated with reporting stopping medication when not feeling well (OR=12, 95%CI=1.9-77.7, p=0.02), and, among naive patients, also with a DM/PM < 0.85 (Odds Ratio=5.1, 95%Confidence Interval=1.2-22.3, p=0.03). Although our study confirmed a much higher virological failure rate among immigrants, we were unable to identify clear differences in adherence between immigrants and non-immigrant patient, although virological failure was associated with stopping medication when not feeling well and a low DM/PM. Unstructured treatment interruptions are a likely explanation of the findings. Interventions should be aimed at preventing patients to stop medication. A DM/PM below 0.85 can be indicative for patients who did stop medication and are at risk for virological failure.

Preconception use of cART by HIV-positive pregnant women increases the risk of infants being born small for gestational age.

BACKGROUND: The benefits of combination anti-retroviral therapy (cART) in HIV-positive pregnant women (improved maternal health and prevention of mother to child transmission [pMTCT]) currently outweigh the adverse effects due to cART. As the variety of cART increases, however, the question arises as to which type of cART is safest for pregnant women and women of childbearing age. We studied the effect of timing and exposure to different classes of cART on adverse birth outcomes in a large HIV cohort in the Netherlands. MATERIALS AND METHODS: We included singleton HEU infants registered in the ATHENA cohort from 1997 to 2015. Multivariate logistic regression analysis for single and multiple pregnancies was used to evaluate predictors of small for gestational age (SGA, birth weight <10th percentile for gestational age), low birth weight and preterm delivery. RESULTS: A total of 1392 children born to 1022 mothers were included. Of these, 331 (23.8%) children were SGA. Women starting cART before conception had an increased risk of having a SGA infant compared to women starting cART after conception (OR 1.35, 95% CI 1.03-1.77, p = 0.03). The risk for SGA was highest in women who started a protease inhibitor-(PI) based regimen prior to pregnancy, compared with women who initiated PI-based cART during pregnancy. While the association of preterm delivery and preconception cART was significant in univariate analysis, on multivariate analysis only a non-significant trend was observed (OR 1.39, 95% CI 0.94-1.92, p = 0.06) in women who had started cART before compared to after conception. In multivariate analysis, the risk of low birth weight (OR 1.34, 95% CI 0.94-1.92, p = 0.11) was not significantly increased in women who had started cART prior to conception compared to after conception. CONCLUSION: In our cohort of pregnant HIV-positive women, the use of cART prior to conception, most notably a PI-based regimen, was associated with intrauterine growth restriction resulting in SGA. Data showed a non-significant trend in the risk of PTD associated with preconception use of cART compared to its use after conception. More studies are needed with regard to the mechanisms taking place in the placenta during fetal growth in pregnant HIV-positive women using cART. It will only be with this knowledge that we can begin to understand the potential impact of HIV and cART on the fetus, in order to be able to determine the optimal individualised drug regimen for HIV-infected women of childbearing age.

Nelfinavir plasma concentrations are low during pregnancy.

Plasma nelfinavir concentration ratios (CRs) were calculated for all pregnant (n=27) and nonpregnant (n=48) human immunodeficiency virus type 1-infected women receiving the drug who visited our outpatient clinic. In pregnant women, mean and median nelfinavir CRs were significantly lower (P=.02 and P=.04, respectively), and 51% of the CRs were below the clinically relevant threshold of 0.90, compared with 35% of the CRs in nonpregnant women. After we adjusted for confounders, we found that the mean nelfinavir CR was 34% lower in pregnant women (P=.02). With targeted interventions, subsequent CRs in pregnant women showed a significant increase (median increase, 0.31; P=.01).

The Effect on Treatment Adherence of Administering Drugs as Fixed-Dose Combinations versus as Separate Pills: Systematic Review and Meta-Analysis.

Administering drugs as fixed-dose combinations (FDCs) versus the same active drugs administered as separate pills is assumed to enhance treatment adherence. We synthesized evidence from randomized controlled trials (RCTs) about the effect of FDCs versus separate pills on adherence. We searched PubMed for RCTs comparing a FDC with the same active drugs administered as separate pills, including a quantitative estimate of treatment adherence, without restriction to medical condition. The odds ratio (OR) of optimal adherence with FDCs versus separate pills was used as common effect size and aggregated into a pooled effect estimate using a random effect model with inverse variance weights. Out of 1258 articles screened, only six studies fulfilled inclusion criteria. Across medical conditions, administering drugs as FDC significantly increased the likelihood of optimal adherence (OR 1.33 (95% CI, 1.03-1.71)). Within subgroups of specific medical conditions, the favourable effect of FDCs on adherence was of borderline statistical significance for HIV infection only (OR 1.46 (95% CI, 1.00-2.13)). We observed a remarkable paucity of RCTs comparing the effect on adherence of administering drugs as FDC versus as separate pills. Administering drugs as FDC improved medication adherence. However, this conclusion is based on a limited number of RCTs only.

Hcv coinfection, an important risk factor for hepatotoxicity in pregnant women starting antiretroviral therapy.

OBJECTIVES: This retrospective cohort study evaluated the risk of hepatotoxicity in HIV-1 positive pregnant and non-pregnant women starting combined ART. METHODS: Data were used from the ATHENA observational cohort. The study population consisted of HIV-1 infected, therapy naïve, pregnant and non-pregnant women, followed between January 1997 and February 2008. Demographic, treatment and pregnancy related data were collected. Risk of hepatotoxicity was determined using univariate and multivariate logistic regression. Analyses were adjusted for age, region of origin, baseline HIV-RNA levels and CD4 cell counts, cART regimen and hepatitis B and C coinfection. ALT and AST values of more than 5 times ULN were considered as hepatotoxicity. RESULTS: Four-hundred and twenty-five pregnant and 1121 non-pregnant women were included. Independent risk factors of hepatotoxicity in all women were the presence of detectable HCV RNA (OR 5.48, 95% CI 2.25-13.38, p<0.001) and NVP use (OR 2.63, 95% CI 1.54-4.55, p<0.001). Stratified for pregnancy, the adjusted risk of hepatotoxicity was significantly associated with HCV coinfection only during pregnancy (OR 23.53, 95% CI 4.69-118.01, p<0.001). NVP use is related to hepatotoxicity in pregnant (OR 5.26, 95% CI 1.61-16.67, p<0.005) as well as in non-pregnant women (OR 2.13, 95% CI 1.11-4.00, p=0.02). CONCLUSION: HCV coinfection and NVP use are associated with a higher risk of cART induced hepatotoxicity in pregnant women.

Virologic and immunologic response to highly active antiretroviral therapy in indigenous and nonindigenous HIV-1-infected patients in the Netherlands.

OBJECTIVE: To compare the results of antiretroviral treatment (highly active antiretroviral therapy [HAART]) in indigenous Dutch (ID) and nonindigenous HIV-1-infected patients in Amsterdam, the Netherlands. We focused on the largest groups of nonindigenous people visiting our outpatient clinic: patients from other industrialized countries (western), from Surinam/Netherlands Antilles (SNA), and from sub-Saharan Africa (SSA). DESIGN: Retrospective cohort analysis of 692 therapy-naive HIV-1-positive individuals who visited our outpatient clinic for the first time between July 1, 1996 and December 31, 2001. METHODS: We compared the groups at the time of their first visit to our clinic; at the start of HAART; and according to the virological, immunologic, and clinical treatment response during the 96 weeks after the start of HAART. RESULTS: Of the patients starting antiretroviral therapy, 362 were ID, 84 were western, 72 were from SNA, and 110 were from SSA. SNA and SSA patients had a lower CD4 cell count at first visit (ID = 330 cells/mm(3), western = 330 cells/mm(3), SNA = 250 cells/mm(3), and SSA = 170 cells/mm(3); P = 0.0002). Treatment in SNA and SSA patients was also started at a lower CD4 cell count, but the plasma HIV-1 RNA level was comparable. After the start of HAART, a similar rise in CD4 cell count was seen in the 4 groups (P = 0.33), but the baseline difference in CD4 cell count remained present during the follow-up period of 96 weeks. After adjusting for variables potentially influencing treatment outcome, the proportion of patients not reaching a plasma HIV-1 RNA level <400 copies/mL was not different for the 4 groups in contrast to the percentage not reaching a plasma HIV-1 RNA level <50 copies/mL (at 48 weeks: ID = 4.8%, western = 27.5%, SNA = 23.1%, and SSA = 24.2%; P = 0.017 over the 96-week time period). After the start of HAART, nonindigenous patients also more often had progression to Centers for Disease Control and Prevention (CDC) stage C or died (P = 0.006). CONCLUSIONS: In nonindigenous patients, treatment with HAART was equally successful in terms of the increase in CD4 cell count but was substantially less effective in achieving a plasma HIV-1 RNA level below 50 copies/mL. Further investigations should explore differences in adherence and pharmacokinetics in these patient groups.

Race is not associated with nevirapine pharmacokinetics.

The effect of race on the pharmacokinetics of nevirapine was investigated in a nonselected population. Included patients were ambulatory HIV-1-infected patients from the outpatient clinics of the Academic Medical Center and the Slotervaart Hospital, Amsterdam, The Netherlands. All patients were using nevirapine as part of their antiretroviral regimen and had at least one plasma concentration available for analysis. From the included patients, gender, age, race, hepatitis C status, baseline ASAT value, and body weight were obtained. The nonlinear mixed-effect modeling program (NONMEM) version V 1.1 was used for all analyses. Population pharmacokinetic parameters [clearance (CL/F), volume of distribution (V/F), absorption rate constant (ka)] and interindividual (IIV) and interoccasion variability (IOV) were estimated. The influence of race on the CL/F of nevirapine was tested as Negroid race versus the other races, Asian race versus the other races, and the Negroid and the Asian races as separate variables versus the Caucasian race. A database of 1732 nevirapine plasma concentrations of 383 HIV-1-infected individuals collected during 1186 outpatient clinic visits was available for this analysis. The conclusion of this study is that race is not associated with the pharmacokinetics of nevirapine, and thus requires no dose adaptations.