Causes of hospitalisation among a cohort of people with HIV from a London centre followed from 2011 to 2018.

BACKGROUND: We describe the spectrum of ICD-10 classified causes for hospitalisations occurring between 2011 and 2018 in a cohort of people living with HIV (PLHIV). METHODS: This sub-study includes 798 PLHIV participating in the Antiretroviral, Sexual Transmission Risk and Attitudes (ASTRA) questionnaire study who were recruited from a large London centre. A medical record review identified the occurrence and causes of hospitalisation from the date of questionnaire completion (February-December 2011) until 1 June 2018. Up to five causes were classified by an HIV clinician using the ICD-10 system. RESULTS: There were 274 hospitalisations in 153 people (rate = 5.8/100 person-years; 95% CI: 5.1, 6.5). Causes were wide-ranging; the most common were circulatory (16.8%), digestive (13.1%), respiratory (11.7%), infectious diseases (11.0%), injury/poisoning (10.6%), genitourinary diseases (9.9%) and neoplasms (9.1%). A tenth (27/274) of hospitalisations were related to at least one AIDS-defining illness. Median duration of hospitalisation was 5 days (IQR 2-9). At the time of hospitalisation, median CD4 count was high (510 cells/µl; IQR: 315-739), while median CD4 nadir was relatively low (113 cells/µl; IQR: 40-239). At admission, half of individuals (51%) had a previous AIDS-defining illness and 21% had viral load > 50 copies/ml. Individuals admitted for infectious diseases were particularly likely to have unfavourable HIV-related clinical characteristics (low CD4, viral non-suppression, not on antiretroviral therapy (ART), previous AIDS). CONCLUSIONS: In the modern combination antiretroviral therapy era, the spectrum of causes of hospitalisation in PLHIV in the UK is wide-ranging, highlighting the importance of holistic care for PLHIV, including prevention, early detection and treatment of comorbidities.

Prospective association of social circumstance, socioeconomic, lifestyle and mental health factors with subsequent hospitalisation over 6-7 year follow up in people living with HIV.

BACKGROUND: Predictors of hospitalisation in people with HIV (PLHIV) in the contemporary treatment era are not well understood. METHODS: This ASTRA sub-study used clinic data linkage and record review to determine occurrence of hospitalisations among 798 PLHIV from baseline questionnaire (February to December 2011) until 1 June 2018. Associations of baseline social circumstance, socioeconomic, lifestyle, mental health, demographic and clinical factors with repeated all-cause hospitalisation from longitudinal data were investigated using Prentice-Williams-Peterson models. Associations were also assessed in 461 individuals on antiretroviral therapy (ART) with viral load ≤50 copies/ml and CD4 count ≥500 cells/ µl. FINDINGS: Rate of hospitalisation was 5.8/100 person-years (95% CI: 5.1-6.5). Adjusted for age, demographic group and time with diagnosed HIV, the following social circumstance, socioeconomic, lifestyle and mental health factors predicted hospitalisation: no stable partner (adjusted hazard ratio (aHR)=1.59; 95% CI=1.16-2.20 vs living with partner); having children (aHR=1.50; 1.08-2.10); non-employment (aHR=1.56; 1.07-2.27 for unemployment; aHR=2.39; 1.70-3.37 for sick/disabled vs employed); rented housing (aHR=1.72; 1.26-2.37 vs homeowner); not enough money for basic needs (aHR=1.82; 1.19-2.78 vs enough); current smoking (aHR=1.39; 1.02-1.91 vs never); recent injection-drug use (aHR=2.11; 1.30-3.43); anxiety symptoms (aHRs=1.39; 1.01-1.91, 2.06; 1.43-2.95 for mild and moderate vs none/minimal); depressive symptoms (aHRs=1.67; 1.17-2.38, 1.91; 1.30-2.78 for moderate and severe vs none/minimal); treated/untreated depression (aHRs=1.65; 1.03-2.64 for treated depression only, 1.87; 1.39-2.52 for depressive symptoms only; 1.53; 1.05-2.24; for treated depression and depressive symptoms, versus neither). Associations were broadly similar in those with controlled HIV and high CD4. INTERPRETATION: Social circumstance, socioeconomic disadvantage, adverse lifestyle factors and poorer mental health are strong predictors of hospitalisation in PLHIV, highlighting the need for targeted interventions and care. FUNDING: British HIV Association (BHIVA) Research Award (2017); SMR funded by a PhD fellowship from the Royal Free Charity.

Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration.

BACKGROUND: With the advent of effective antiretroviral treatment, the life expectancy for people with HIV is now approaching that seen in the general population. Consequently, the relative importance of other traditionally non-AIDS-related morbidities has increased. We investigated trends over time in all-cause mortality and for specific causes of death in people with HIV from 1999 to 2011. METHODS: Individuals from the Data collection on Adverse events of anti-HIV Drugs (D:A:D) study were followed up from March, 1999, until death, loss to follow-up, or Feb 1, 2011, whichever occurred first. The D:A:D study is a collaboration of 11 cohort studies following HIV-1-positive individuals receiving care at 212 clinics in Europe, USA, and Australia. All fatal events were centrally validated at the D:A:D coordinating centre using coding causes of death in HIV (CoDe) methodology. We calculated relative rates using Poisson regression. FINDINGS: 3909 of the 49,731 D:A:D study participants died during the 308,719 person-years of follow-up (crude incidence mortality rate, 12.7 per 1000 person-years [95% CI 12.3-13.1]). Leading underlying causes were: AIDS-related (1123 [29%] deaths), non-AIDS-defining cancers (590 [15%] deaths), liver disease (515 [13%] deaths), and cardiovascular disease (436 [11%] deaths). Rates of all-cause death per 1000 person-years decreased from 17.5 in 1999-2000 to 9.1 in 2009-11; we saw similar decreases in death rates per 1000 person-years over the same period for AIDS-related deaths (5.9 to 2.0), deaths from liver disease (2.7 to 0.9), and cardiovascular disease deaths (1.8 to 0.9). However, non-AIDS cancers increased slightly from 1.6 per 1000 person-years in 1999-2000 to 2.1 in 2009-11 (p=0.58). After adjustment for factors that changed over time, including CD4 cell count, we detected no decreases in AIDS-related death rates (relative rate for 2009-11 vs 1999-2000: 0.92 [0.70-1.22]). However, all-cause (0.72 [0.61-0.83]), liver disease (0.48 [0.32-0.74]), and cardiovascular disease (0.33 [0.20-0.53) death rates still decreased over time. The percentage of all deaths that were AIDS-related (87/256 [34%] in 1999-2000 and 141/627 [22%] in 2009-11) and liver-related (40/256 [16%] in 1999-2000 and 64/627 [10%] in 2009-11) decreased over time, whereas non-AIDS cancers increased (24/256 [9%] in 1999-2000 to 142/627 [23%] in 2009-11). INTERPRETATION: Recent reductions in rates of AIDS-related deaths are linked with continued improvement in CD4 cell count. We hypothesise that the substantially reduced rates of liver disease and cardiovascular disease deaths over time could be explained by improved use of non-HIV-specific preventive interventions. Non-AIDS cancer is now the leading non-AIDS cause and without any evidence of improvement. FUNDING: Oversight Committee for the Evaluation of Metabolic Complications of HAART, with representatives from academia, patient community, US Food and Drug Administration, European Medicines Agency and consortium of AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, ViiV Healthcare, Merck, Pfizer, F Hoffmann-La Roche, and Janssen Pharmaceuticals.

Systemic amyloidosis in England: an epidemiological study.

Epidemiological studies of systemic amyloidosis are scarce and the burden of disease in England has not previously been estimated. In 1999, the National Health Service commissioned the National Amyloidosis Centre (NAC) to provide a national clinical service for all patients with amyloidosis. Data for all individuals referred to the NAC is held on a comprehensive central database, and these were compared with English death certificate data for amyloidosis from 2000 to 2008, obtained from the Office of National Statistics. Amyloidosis was stated on death certificates of 2543 individuals, representing 0·58/1000 recorded deaths. During the same period, 1143 amyloidosis patients followed at the NAC died, 903 (79%) of whom had amyloidosis recorded on their death certificates. The estimated minimum incidence of systemic amyloidosis in the English population in 2008, based on new referrals to the NAC, was 0·4/100 000 population. The incidence peaked at age 60-79 years. Systemic AL amyloidosis was the most common type with an estimated minimum incidence of 0·3/100 000 population. Although there are various limitations to this study, the available data suggest the incidence of systemic amyloidosis in England exceeds 0·8/100 000 of the population.

The role of antiretroviral therapy in the incidence of pancreatitis in HIV-positive individuals in the EuroSIDA study.

AIM: This study investigated the incidence of pancreatitis and its association with antiretroviral therapy (ART), focussing on stavudine and didanosine. METHODS: EuroSIDA has collected information on pancreatitis since Summer 2001. All identified cases have been verified by the coordinating centre. Individuals were followed from June 2001 or the date of entry into EuroSIDA (whichever occurred later) until a diagnosis of pancreatitis or the last study visit. Factors associated with pancreatitis were investigated using Poisson regression. Cumulative lengths of exposure to didanosine without stavudine, stavudine without didanosine, stavudine with didanosine, and other ART were time-updated variables. Treatment variables were fitted with a 6-month time lag. RESULTS: There were 43 (nine presumptive) pancreatic events in 9678 individuals during 33 742 person-years (incidence 1.27/1000 person-years). The incidence among those with no, 2 or less and over 2 years' exposure to ART including stavudine and didanosine was 1.24, 1.73 and 0.78/1000 person-years, respectively. In multivariable analysis, higher baseline CD4 cell counts were associated with a decreased risk of pancreatitis. There was no evidence of an association of pancreatitis with cumulative exposure to didanosine and stavudine, didanosine without stavudine, stavudine without didanosine, or other ART. CONCLUSION: We observed a low overall rate of pancreatitis in the years 2001-2006, and did not find an association of an increased incidence of pancreatitis with cumulative exposure to antiretroviral agents generally, and to didanosine and stavudine in particular.

Role of N-terminal brain natriuretic peptide (N-TproBNP) in scleroderma-associated pulmonary arterial hypertension.

AIMS: The aims of this study were to evaluate the diagnostic value and to explore the prognostic value of N-terminal brain natriuretic peptide (N-TproBNP) in patients with systemic sclerosis (SSc) both with and without pulmonary arterial hypertension (PAH). METHODS AND RESULTS: N-TproBNP, six-minute walk distance (SMWD), haemodynamics (at right heart catheterization) or tricuspid gradient (by echocardiography), and survival were assessed in 109 patients with SSc. The study population included 68 individuals with PAH [mean pulmonary artery pressure (PAP) >25 mmHg and pulmonary capillary wedge pressure <15 mmHg] and 41 individuals without PAH. In patients with PAH, the prognostic value of baseline and change in WHO functional class, N-TproBNP levels, and SMWD were compared using Kaplan-Meier survival curves and Cox proportional hazard analysis. The mean duration of follow-up was 10 months (range 1-18 months). One year survival in patients with normal PAP was 100% when compared with 83.5% in those with SSc-PAH (P < 0.05). The patients without PAH had a mean N-TproBNP level of 139 pg/mL (SD 151); those with SSc-PAH had a significantly higher mean N-TproBNP level of 1474 pg/mL (SD 2642) (P = 0.0002). Among patients with PAH for every order of magnitude increase in N-TproBNP level there was a four-fold increased risk of death (P = 0.002 for baseline level and P = 0.006 for follow-up level). Baseline N-TproBNP levels were correlated positively with mean PAP (r = 0.62; P < 0.0001), pulmonary vascular resistance (PVR) (r = 0.81; P < 0.0001), and inversely with SMWD (r = -0.46; P < 0.0001). Among patients with SSc-PAH, 13 patients (19%) were in WHO functional classes II and had mean N-TproBNP levels of 325 pg/mL (SD 388). Fifty-three patients (78%) were in WHO classes III and IV and had significantly higher mean N-TproBNP levels of 1677 pg/mL (SD 2835) (P = 0.02). At an N-TproBNP level of 395 pg/mL, the sensitivity and specificity for predicting the presence of SSc-PAH were 56 and 95% respectively. CONCLUSION: Raised N-TproBNP levels are directly related to the severity of PAH. In screening programs, SSc patients with an N-TproBNP in excess of 395 pg/mL have a very high probability of having pulmonary hypertension. Baseline and serial changes in N-TproBNP levels are highly predictive of survival. A 10-fold increase in N-TproBNP level on therapy is associated with a greater than three-fold increase in mortality, and may indicate therapeutic failure.

The rate of viral rebound after attainment of an HIV load <50 copies/mL according to specific antiretroviral drugs in use: results from a multicenter cohort study.

BACKGROUND: Relatively few data are available on the association between the use of specific antiretroviral drugs and the rate of viral rebound in those attaining a viral load (VL) <50 copies/mL while receiving highly active antiretroviral therapy (HAART). METHODS: Patients achieving a VL <50 copies/mL for the first time while receiving HAART were followed until viral rebound (2 consecutive VLs >500 copies/mL). Pre-HAART antiretroviral-naive patients were analyzed separately from those with nucleoside reverse transcriptase inhibitor (NRTI) experience. RESULTS: Of 3565 suppressed antiretroviral-naive patients, 381 experienced viral rebound (rate, 6.26 events/100 person-years of follow-up [pyrs] [95% confidence interval {CI}, 5.63-6.89 events/100 pyrs]). For those receiving efavirenz, the rate was 4.08 (95% CI, 3.16-5.01) events/pyrs. Compared with this, the rebound rate for those receiving indinavir was 1.52 times higher (rate ratio [RR], 1.52 [95% CI, 0.82-2.84]). RRs (95% CIs) for other drugs were: soft-gel saquinavir, 0.54 (0.07-3.97); nelfinavir, 2.44 (1.68-3.54); indinavir/ritonavir, 1.96 (1.02-3.77); saquinavir/ritonavir, 1.12 (0.48-2.61); lopinavir/ritonavir, 1.23 (0.58-2.59); nevirapine, 1.53 (1.11-2.10); and abacavir, 2.03 (1.26-3.25). Of 810 NRTI-exposed patients, 145 experienced viral rebound (rate, 8.29 [95% CI, 6.94-9.64] events/pyrs). For those receiving efavirenz, the rate was 5.25 (95% CI, 3.11-8.30) events/pyrs. Compared with this, the RRs (95% CIs) were: indinavir, 1.75 (0.82-3.73); hard-gel saquinavir, 3.48 (0.36-33.37); nelfinavir, 2.64 (1.37-5.08); indinavir/ritonavir, 0.32 (0.04-2.49); saquinavir/ritonavir, 0.64 (0.23-1.80); nevirapine, 1.65 (0.90-3.02); and abacavir, 1.82 (0.73-4.52). CONCLUSIONS: We must make comparisons of antiretroviral outcomes in observational data with caution; however, our results suggest that, in those with VLs <50 copies/mL, certain drugs may be associated with higher rebound rates than others.

Factors influencing increases in CD4 cell counts of HIV-positive persons receiving long-term highly active antiretroviral therapy.

BACKGROUND: Highly active antiretroviral therapy (HAART) results in an improvement in immunologic function. We sought to investigate the factors associated with increases in CD4 cell count among human immunodeficiency virus (HIV)-positive antiretroviral-naive patients starting HAART. METHODS: Five hundred ninety-six subjects were followed for a median of 2.5 years (interquartile range, 1.0-4.0 years). Factors associated with changes in CD4 cell counts in the first 3 months of HAART and from 3 months onwards were analyzed. RESULTS: After 6, 12, and 24 months of HAART, the median increases in CD4 cell counts were 114, 181, and 248 cells/mm3, respectively; 84%, 84%, and 80% of subjects had a virus load of <400 copies/mL during the same periods. White ethnicity, higher pre-HAART virus load, and lower pre-HAART CD4 and CD8 cell counts were associated with greater increases in CD4 cell counts during the first 3 months of HAART. From 3 months onward, a greater cumulative proportion of time spent with virus load <400 copies/mL was associated with a more favorable change in CD4 cell count (an average increase of 5.2 cells/mm3/year [95% confidence interval [CI], 3.8-6.7 cells/mm3/year] for each extra 10% cumulative time spent with a virus load <400 copies/mL) (P<.0001). For every 100 cells/mm3 higher in baseline CD4 cell count, the increase was 6 cells/mm3/year less (95% CI, 2-11 cells/mm3/year) (P=.02). Sex, risk group, age, and HAART regimen were not associated with increases in CD4 cell counts. CONCLUSIONS: These findings emphasize the importance of maintaining virological suppression and suggest other factors that influence long-term CD4 cell response.