As treatment for HIV infection needs to be used continuously and lifelong, issues concerning long‐term outcomes, including those involving tolerability and safety of treatment, are gaining increasing importance. Although current combination antiretroviral therapy (cART) regimens are generally better tolerated than those in the early days of cART, treatment toxicity remains an important cause for discontinuation of (components) of treatment. Moreover, several of the potential toxicities of cART (including cardiovascular, metabolic, renal and bone toxicity) overlap with known ageing‐associated co‐morbidities. Given that our patient population with HIV is increasingly getting older as a result of the success of cART in reducing traditional HIV‐associated morbidity and mortality, these co‐morbidities are increasingly being seen and importantly influence patient management. Moreover, persons with HIV, in spite of having suppressed viraemia on cART seem to be at increased risk of the premature development of age‐associated non‐communicable co‐morbidities, including cardiovascular, chronic kidney, liver and pulmonary disease, diabetes mellitus, osteoporosis, non‐AIDS associated malignancies, and neurocognitive impairment. It has therefore been hypothesised that such individuals, despite effective cART, may be prone to accelerated ageing. The underlying pathogenesis is likely to be multifactorial and, apart from include sustained immune activation, both systemically and within the central nervous system. The presentation will review the current state of knowledge and investigation in this area.
Persistent immunosuppression despite viral suppression (immunovirological discordance, ID) has been associated with higher risk of AIDS and death, although the risk for AIDS seems to decrease with longer time of suppressed viral load (sVL). The impact of ID on a composite endpoint of AIDS/serious non‐AIDS/death has not been thoroughly investigated. Patients in EuroSIDA starting ≥1 new antiretroviral drugs after January 2001, when CD4 was <200 cells/mm3 and VL >500 copies/mL, and who achieved a sVL ≤50 copies/mL within 1 year were included. Person‐years of follow‐up (PYFU) accrued from the date of sVL until the first of a new AIDS or severe non‐AIDS (SNA) event or death, viral rebound >50 copies/mL (first of 2 consecutive values) or last visit. Rate ratios (RR) were calculated using Poisson regression according to whether or not patient's current CD4 count was still below 200 cells/mm3 (ID). Models were stratified according to whether or not persons were ART‐naïve at baseline. Multivariable models included age, HBV/HCV status, mode of HIV transmission, race, cohort, anemia, diabetes, hypertension or current eGFR, current cART, number of previous antiretrovirals, and time to viral suppression. 994 patients satisfied the inclusion criteria and contributed 4520 PYFU. Median age was 41 (IQR 34–47) years and 72.8% were male. 36.5% of patients were ART‐naïve and started a median of 3 (IQR 2–3) new drugs. 31 AIDS and 58 non‐AIDS events occurred, and 31 patients died (7 due to AIDS, 24 due to SNA). The rate of the combined endpoint in patients with ID (50.3 per 1000 PYFU [95% CI 35.2–69.9]) was higher than in patients recovered from ID (22.1 [17.6–27.3], adjusted RR 2.08 [1.32–3.28]; table). This was similar regardless of whether or not people were ART‐naïve before starting a new drug (interaction test p=0.47). In ID, rate was highest in the first 6 months of sVL (63.1 [33.6–107.9]) and declined thereafter (month 6–12: 60.5 [26.1–119.2],>12 months: 39.8 [22.2–65.6], adjusted RR compared to month 0–6 0.52 [0.24–1.13]). In analyses with endpoints AIDS/death due to AIDS and SNA/death due to SNA separately, the adjusted RR of ID vs. non ID was 4.11 ([1.76–9.60]; p=0.001) and 1.46 ([0.81–2.61]; p=0.207), respectively.
before starting a new antiretroviral drug according to the inclusion criteria, p(test for interaction):0.47 adjusted for smoking, HBV/HCV coinfection, transmission risk, race, cohort, current cART, change of ART before viral suppression, time to viral suppression, presence of diabetes, hypertension, anemia, current eGFR <90, CD4 nadir, CD4 count and viral load at baseline.
ID is a risk factor for clinical disease progression particularly related to AIDS events. In patients with ID, we found a trend for a declining incidence of events with longer periods of sVL, suggesting that sustained viral suppression might be of benefit.
BackgroundAdherence to treatment is the key to the success of combination antiretroviral therapy (cART) for HIV infection. It is generally assumed that simplification of cART will lead to better adherence, higher treatment satisfaction, and quality of life (QoL), but randomized studies demonstrating such advantages of simplified regimens are scarce.MethodsAntiretroviral‐naïve patients who achieved viral load <50 c/ml in two consecutive samples between 12–24 weeks after commencing induction therapy with bid lopinavir/ritonavir (LPV/r) and fixed‐dose combination AZT/3TC (Combivir®) were randomly assigned to either continue LPV/r/Combivir® or switch to simplified therapy with bid fixed‐dose AZT/3TC/abacavir (Trizivir®). Both arms yielded similar antiviral efficacy after 48 weeks as reported previously [1]. Patients completed standardized questionnaires on adherence (Simplified Medication Adherence Questionnaire (SMAQ)), treatment satisfaction (HIVTSQ) and QoL (MOS‐HIV) at randomization and at weeks 48, 72 and 96. Adherence data were analyzed using generalized estimating equations, and satisfaction and QoL using mixed linear models.ResultsPatients in the Trizivir®‐group (n=30) tended to skip fewer doses both during the preceding 7 days (p=0.055) and during the preceding weekend (p=0.09) than patients in the LPV/r‐group (n=20). Moreover, patients in the Trizivir®‐group found their regimen significantly more convenient (p=0.022) than patients in the LPV/r‐group. However, patients in the LPV/r‐group reported a better QoL than patients in the Trizivir®‐group in the domains measuring cognitive functioning (p=0.003), energy/fatigue (p=0.046) and social functioning (p=0.074).ConclusionsIn this randomized trial simplification of therapy to fixed‐dose Trizivir® was perceived to be more convenient, and tended to result in improved adherence, but at the expense of a lower level of QoL. Our findings suggest that the choice for simplified regimens should be individualized and may involve a trade‐off between convenience and QoL.
Purpose of the studyPeople living with HIV (PLWH) appear to be at increased risk for earlier onset of age‐associated non‐communicable co‐morbidity (AANCC) and declines in physical and mental capacities, compared to the general population [1]. This earlier onset of AANCC in the setting of HIV infection is likely to negatively affect work participation and quality of life. Present study investigates prevalence and determinants of unemployment among older HIV‐1‐infected and HIV‐uninfected participants of the AGEhIV Cohort Study.MethodsData were collected (Oct. 2010–Jan. 2012) within the ongoing prospective AGEhIV Cohort Study, recruiting HIV‐1‐infected patients >45 years from a tertiary care HIV outpatient clinic, and HIV‐uninfected Public Health Service attendants, comparable regarding age, gender and ethnicity. Data on socio‐demographics, lifestyle, quality of life, AANCC and unemployment were collected, using a self‐administered questionnaire and through medical examination. Current analysis was restricted to participants in the working age (45–65 years). Logistic regression analysis was used to study determinants of unemployment.Summary of resultsThe majority from the first enrolled 277 HIV‐1‐infected and 251 HIV‐uninfected subjects was male (88%), Dutch (76%) and homosexual (74%). About 50% was highly educated and the median age was 52 [IQR: 48–57]. Almost all (94%) HIV‐1‐infected individuals were on cART, median time since first ART was 11 years [IQR: 4–15], median time since HIV‐diagnosis was 12 years [IQR: 7–18] and they had been diagnosed with more AANCC than HIV‐uninfected individuals (p<0.01). Unemployment was higher among HIV‐1‐infected (36.5%) compared to HIV‐uninfected participants (21.9%) (p<0.01). In multivariate analysis, being HIV‐infected (ORadj 2.0 [95% CI: 1.3–3.3]), experiencing >2 AANCC (ORadj 3.1 [95% CI: 1.4–6.8]), lower physical health status (ORadj 2.0 [95% CI: 1.6–2.6]), being unmarried (ORadj 2.1 [95% CI: 1.3–3.2]) and older age (ORadj 60‐65 yrs: 9.1 [95% CI: 4.5–18]) were independently associated with higher levels of unemployment.ConclusionsUnemployment among HIV‐1‐infected individuals is higher compared to HIV‐uninfected individuals, independent of socio‐demographic characteristics, lifestyle, quality of life or number of concomitantly diagnosed AANCC. This suggests that, apart from these factors, specific HIV‐related determinants, such as stage of HIV disease, but also experienced stigma, work related conditions, influence unemployment.
Purpose of the studyTo investigate the impact of ART, HIV viremia and immunosuppression on triglyceride (TG), total cholesterol (TC) and high density lipoprotein cholesterol (HDL‐C) levels.MethodsWe considered the cross‐sectional associations between TG, TC and HDL‐C (mmol/l; first available measurement on/after enrolment in the D:A:D study) and use of ART, HIV viral load (VL; copies/ml), and CD4 count (cells/mm3) measured at the same time. TG was log10 transformed to ensure normality. Analyses were performed using linear regression and adjusted for other factors known to impact lipid levels (table footnote). ART and VL status were combined (off ART&VL >100,000, off ART&VL <100,000, on ART&VL <500, on ART&VL >500), current and nadir CD4 count were categorised as <200, 200–349, 350–499 and >500.Summary of results44,322/49,734 participants in the D:A:D Study (89.1%) contributed a TG measurement (median; IQR 1.52; 1.00–2.45), 45,169 (90.8%) a TC measurement (4.80; 4.00–5.70) and 38,604 (77.6%) a HDL‐C measurement (1.12; 0.90–1.40). Most participants were male (74%), of white ethnicity (51%), without AIDS (78%), were not receiving lipid‐lowering drugs (4%) and were ART experienced (61%) with 47% previously exposed to PIs, 61% previously exposed to NRTIs and 29% previously exposed to NNRTIs. The median (IQR) age, current CD4 count and CD4 nadir were 38 (36–45) years, 400 (242–590) cells/µl and 240 (100–410) cells/µl respectively. Compared to those on ART with a suppressed VL, all lipids were lower for those off ART (Table); non‐suppressive ART was also associated with lower TC and HDL‐C levels (no impact on TG). A low current CD4 count was associated with lower lipid levels, whereas a low nadir CD4 count was associated with higher TC and TG levels. Prior AIDS diagnosis was associated with higher TG and TC, but lower HDL‐C levels.
Impact of ART, immunosuppression and viraemia, on TG, TC and HDL‐C (mmol/l)
Average impact on log10TG*†
Average inpact on TC* Average impact on HDL‐C*
ART and VL
Off ART … VL≥100000 −0.09 (−0.10,−0.08) <0.001 −0.55 (−0.60,−0.51) <0.001 −0.14 (−0.16,−0.13) <0.001
Off ART … VL<100000 −0.04 (−0.06,−0.03) <0.001 −0.85 (−0.91,−0.78) <0.001 −0.31 (−0.33,−0.29) <0.001
On ART … VL<500 Ref
Ref
Ref
On ART … VL≥500 0.00 (−0.01, 0.00) 0.38 −0.40 (−0.44,−0.36) <0.001 −0.16 (−0.17,−0.15) <0.001
estimates included are mutually adjusted for each other and for the following demographic variables: age; gender; mode of infection; ethnicity; body mass index; smoking; family history of CVD; diabetes; use of lipid lowering drugs; co‐infection with hepatitis C; participating cohort; and year of entry into study. TG is log10 transformed. Thus, the results presented for TG reflect relative rather than absolute effects. For example, lipid levels for those off ART … VL ≥100000 are 9% lower than those on ART … VL < 500.
ConclusionAlthough specific drug classes were not considered, lipid levels are considerably higher in those on a suppressive ART regimen. The higher TC/TG and lower HDL‐C levels seen among those with low nadir CD4 count and with a prior AIDS diagnosis suggests severe immunosuppression may be associated with dyslipidaemia over the long‐term.
Many studies have focused on chronic kidney disease in HIV‐positive individuals, but few have studied the less frequent events, advanced renal disease (ARD) and end‐stage renal disease (ESRD). The aim of this study was to investigate incidence, predictors and outcomes for ARD/ESRD and renal death in EuroSIDA. ARD was defined as confirmed eGFR < 30 ml/min per 1.73 m2 (>3 months apart) using Cockcroft‐Gault. ESRD was defined as hemo‐ or peritoneal dialysis>1 month/renal transplant. Renal deaths were defined as renal failure as the underlying cause of death, using CoDe methodology. Patients were followed from baseline (first eGFR after 1/1/2004) until last eGFR, ARD/ESRD/renal death; whichever occurred first. Poisson regression was used to identify predictors. 8817 persons were included, the majority were white (87.3%), males (73.9%) infected though homosexual contact (41.5%) and with a median age of 42 years (IQR 36–49). 45 persons (0.5%) developed the composite endpoint; ARD (24), ESRD (19) and renal death (2) during a median follow up (FU) of 4.5 years (IQR 2.7–5.8), incidence rate (IR) 1.21/1000 PYFU (95% CI 0.86–1.57). Of 312 persons (3.5%) with baseline eGFR<60 ml/min/1.73 m2, 13.3% (7.5–18.9) are estimated to develop ARD/ESRD/renal death within 6 years after baseline compared to 0.86% (0.58–1.1) of all patients, using Kaplan‐Meier methods. Predictors in multivariate analysis were older age (IRR 1.29 per 10 years [0.95–1.75]) any cardiovascular risk (IRR 2.34 [1.23–4.45]), CD4 count (IRR 0.76 per 2‐fold higher [0.60–0.97]) and eGFR (IRR 0.63 per 5 ml/min/1.73 m2 higher [0.58–0.69]).imageEthnicity, gender, nadir CD4, VL, HBV and using potential nephrotoxic antiretrovirals were insignificant in uni‐ and multivariate analysis. At 1 year after ARD/ESRD, 23.3% (CI 9.8–36.8) were estimated to have died using Kaplan‐Meier methods. The 11 deaths were from renal causes (2), non‐AIDS‐defining malignancies (2), hepatitis‐associated liver failure (1), respiratory failure (1), cardiovascular disease (1), pancreatitis (1) and unknown causes (3). The ARD/ESRD/renal death incidence was low in this population with the available FU, and was associated with traditional and HIV‐related risk factors. Most persons with ARD/ESRD/renal death had pre‐existing renal impairment, but some experienced a rapid progression from initial normal levels. Prognosis after ARD/ESRD was poor. Larger studies are required to address the possible contribution of specific antiretrovirals.
