Going beyond undetectable: a review of the unmet long-term health needs of people living with HIV Back

Introduction: unmet needs resulting from HIV as a chronic disease

Overall prevalence of HIV in Europe

 

Since surveillance of the HIV epidemic began, more than half a million (504,455) HIV diagnoses have been reported in EU/EEA countries (Austria, Belgium, Bulgaria, Croatia, Republic of Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, the Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden and the UK; EEA countries include EU countries plus Iceland, Liechtenstein and Norway).1,2 Despite relatively stable prevalence since 2004, HIV in these countries remains a major public health issue,3 with 29,157 new diagnoses reported by EU/EEA countries in 2013.

In some European countries, increasing rates of HIV transmission are being observed, particularly among men who have sex with men.4 The number of PLWHIV who are unaware of their status is high.5 Furthermore, there is a 54% rate of late diagnosis (CD4 count <350 cells/mL at presentation or presenting with an AIDS-defining event, regardless of CD4 cell count), which reduces the likelihood of successful treatment.6

 

HIV: a lifelong condition

Over the past 20 years, increases in median life expectancy for PLWHIV have been demonstrated in developed and developing countries.7,8 In North America and Europe, life expectancy for PLWHIV who are diagnosed early enough and are undergoing ART is close to that of the uninfected population (Figure 1).9,10 In addition, the proportion of people newly diagnosed with HIV at an older age is increasing.4

Together these phenomena have created an older population of PLWHIV. For example, in Europe and North America between 2000 and 2013, the number of PLWHIV aged 50 years and over is estimated to have almost quadrupled.11 In Europe in 2012, approximately one in three adults living with HIV was aged 50 or older,12 with this figure predicted to increase to 73% in 2030.13

The transformation of HIV into a chronic disease (Table 1) is one of the most notable successes of contemporary medicine. However the changing age demographic is accompanied by an increasing burden of inflammation, immunodeficiency and age-related comorbidities, polypharmacy and with it the potential for drug-drug interactions (DDIs).14 Furthermore, the accumulated toxic effects of long-term exposure to ART can cause significant metabolic disorders and end-organ damage.15,16

 

In 2011, the HPTN 052 study found that using ART to prevent HIV infection was 96% effective, with reduced risk of tuberculosis (TB) infection shown to be an additional advantage of early treatment.17 Four years later in 2015, final results from the START trial provided clear evidence that starting ART immediately upon diagnosis regardless of CD4+ T-cell count provided patients with a considerably lower risk of developing AIDS or some HANA comorbidities than if they waited to start treatment until their CD4+ T-cell count had fallen; for example, the WHO guideline levels of below 500 cells/mm3.18

 

The burden of age-related comorbidities

The burden of HANA comorbidities may be greater in developing countries due to higher prevalence of HIV infection, the presence of healthcare systems primarily designed to supply acute rather than chronic care, as well as the greater burden of infectious illnesses such as TB in these countries. The focus for this paper, however, is primarily on the challenges posed by HIV and ageing in developed countries.

The diverse range of HANA comorbidities associated with older age includes liver disease, CVD, various cancers, osteoporosis, renal disease and neuropsychiatric impairment.16 These tend to combine into complex patterns of multi-morbidity (MM) with associated increased costs of management.14 Resulting polypharmacy gives rise to increased risks of DDIs, prescription errors and adherence issues.14

Studies have shown that PLWHIV are more susceptible to developing such non-infectious comorbidities than uninfected individuals and may develop these conditions at an earlier age (Figure 2).19 

An ageing population of PLWHIV also presents challenges due to the link between increasing age and late presentation at first diagnosis;20 this has been attributed to older people’s relative lack of awareness of the risks of unsafe sexual practices, lack of knowledge about the importance of testing and treating early and importantly fear of being stigmatised.21 In addition, there is a link between late presentation and increased risk of HANA comorbidities.21

In terms of comorbidity prevalence, a 2012 European study of individuals aged ≥45 years both with and without HIV found that 74.4% of the HIV group reported one or more HANA comorbidities compared with 60.4% in the non-HIV group (see Figure 3).22 Notably, the HIV group also included a higher proportion of current, heavy smokers and alcohol abusers.

In developed countries, HANA comorbidities are now the most frequent cause of death for PLWHIV. In another 2012 study for example, the proportion of deaths with AIDS-related causes among a French cohort of PLWHIV fell from 47% to 36% between 2000 and 2005, with CVD, non-AIDS-defining malignancies and diseases of the liver identified as the predominant causes of mortality.23

A 2015 European study predicts that in 2030, 84% of PLWHIV will have at least one age-associated non-communicable comorbidity, including CVD, diabetes, chronic kidney disease (CKD), osteoporosis and non-AIDS malignancies, with 28% of PLWHIV in 2030 having three or more HANA comorbidities.13

In addition, while some of these HANA comorbidities occur as a response to HIV itself, many routinely used ARTs continue to be associated with problems of long-term safety and tolerability, with a range of side-effects (see Table 2).15 In some cases, the precise aetiologies of these side-effects continue to elude researchers; for example, the role of specific ART regimens in raising the risk of bone fracture is yet to be fully understood.24

 

The impact of lifestyle factors

In developed countries, PLWHIV are between two- and three-times more likely to smoke than people in the general population.25 Smoking among PLWHIV is linked with many adverse health outcomes, as well as with lower QoL, increased pain and reduced cognitive functioning. It is reported that, with increasing age, PLWHIV undergoing ART who smoke may lose more life years through smoking than through HIV26 and it has been suggested that smoking may cause more atherosclerosis in HIV-positive patients than in uninfected individuals.27

Like smoking, alcohol consumption is more common among PLWHIV, with rates of heavy drinking almost twice those found among the general population.28 Studies have highlighted the role of alcohol as an underlying cause of liver-related mortality among PLWHIV,23 and improvements in mortality might be assisted through programmes designed to detect and treat alcohol abuse.29

Managing lifestyle factors

Interventions for smoking cessation, alcohol abuse and dietary management should be prioritised if PLWHIV are to maximise life expectancy and HRQoL as the treated HIV-infected population ages. However, where such interventions are in place (for example, smoking cessation programmes), studies have reported relatively low abstinence rates and suggested that this is due to the complexity of social, economic, psychiatric and medical needs of PLWHIV presenting serious obstacles.32

A lifetime of accumulating risks

With extended life expectancy, PLWHIV are now more likely to experience diseases of ageing that affect the general population. Moreover, these diseases are more prevalent with earlier onset in PLWHIV. This section provides a brief overview of recent research describing the implications of ageing with HIV on liver, CV, cancer, bone, renal and neuropsychiatric health.

Liver disease

Among PLWHIV, liver disease is a major non-AIDS-related cause of death and accounts for between 14% and 18% of all deaths among PLWHIV and almost half of deaths among hospitalised PLWHIV.33 Risk factors include viral hepatitis, alcohol abuse, obesity, abnormal lipid levels and diabetes. Hepatitis C (HCV) co-infection; affecting approximately 30% of PLWHIV in Europe, has historically been the most significant factor influencing disease progression, increasing cirrhosis risk.34

Around 90% of deaths in HIV-positive patients with end-stage liver disease are due to HCV infection, and HIV accelerates both hepatitis B (HBV) and HCV liver disease. HIV/HCV co-infection is associated with a reduced rate of spontaneous HCV RNA clearance and a more rapid rate of fibrosis progression.35 Co-infected patients have an approximately trebled risk of ART-associated hepatotoxicity than patients with HIV only.34 However, direct-acting antivirals (DAAs) are revolutionising the treatment of HCV and increasing evidence suggests that DAAs work just as effectively in HIV/HCV co-infection as in HCV mono-infection.36

HBV, which affects fewer than 10% of PLWHIV in Europe, is also responsible for increased liver-associated mortality in PLWHIV, causing faster fibrosis progression and leading to increased rates of hepatocellular carcinoma. However, most cases of chronic HBV can be controlled with ART regimens.37

Alongside an increasing median age for PLWHIV, there is also increasing evidence to suggest a higher prevalence of non-alcoholic fatty liver disease in PLWHIV, accounted for largely by insufficient exercise and poor diet, but also linked to long-term exposure to some ART regimens.38

A high mortality rate among PLWHIV, attributable to liver disease (related mainly to HCV infection) has made orthotopic liver transplantation (OLT) an increasingly necessary intervention in this population. Currently OLT takes place in selected PLWHIV with end-stage liver disease. In recent years, OLT in PLWHIV with liver diseases not related to HCV has resulted in excellent outcomes,39 although in patients with HIV/HCV co-infection, results are worse than in HCV mono-infected patients.40 However, with the wider use of current DAAs against HCV, outcomes of HIV/HCV co-infected patients undergoing an OLT may improve considerably.

Cardiovascular disease

Among the many comorbidities affecting PLWHIV, CVD is of particular concern due to the high prevalence of CVD lifestyle risk factors in PLWHIV and ART-induced changes in lipid metabolism, glucose metabolism, and endothelial and platelet functions.41

Even when traditional risk factors are adjusted for, PLWHIV have a significantly increased risk of serious CVD outcomes. For example, in a study of the extensive US-based Veterans Association medical system, PLWHIV exhibited an approximately 1.5-fold increased risk of myocardial infarction compared to adults without HIV; an effect that was present also in a cohort group with durable control of viral replication.42

Evidence increasingly indicates the role of HIV-related inflammatory and immunologic processes to additional risk for CVD in PLWHIV. In the SMART trial, for example, the group whose therapy was deferred until their CD4+ count fell to 250 cells/mL not only experienced a higher risk of AIDS illness or death than the group assigned to continuous ART but also more CVD events. Interrupting ART appears to have resulted in increases in blood levels of the inflammatory biomarkers interleukin-6 and D-dimer, end products of the dynamic process of thrombus formation and dissolution, and markers for the extent of fibrin turnover in the circulation, which reflects a prothrombotic status.43

A recent review of research into the links between HIV, inflammation and CVD has highlighted the ‘complex interplay of inflammatory cells with lymphocyte and macrophage activation, damage to the mucosal barrier, metabolic changes, and other factors directly or indirectly related to HIV replication’.44

Cancer

In addition to the high prevalence of cancer risk factors among PLWHIV (especially smoking, heavy alcohol use and viral infections such as human papillomavirus, HCV and HBV), damage to the immune system is also likely to be a contributor to earlier cancer diagnoses and greater risk of infection-related cancer in this population.

PLWHIV are at particular risk for cancers with a known infectious cause, although the raised risk has fallen in the ART era. One study has shown a more than nine-fold increased risk of infection-related, non-AIDS-defining cancer among PLWHIV compared to HIV-uninfected individuals, with significant differences in risk for anal squamous cell cancer and Hodgkin’s lymphoma.45 In this study, PLWHIV also experienced a 30% increased risk of non-AIDS-defining cancer unrelated to infection compared to those without HIV. This included a higher risk of lung, skin, other anal, and other head and neck cancers, but a decreased risk of prostate cancer. The study also noted the narrowing of difference in cancer risk between PLWHIV and uninfected individuals in recent years, concomitant with improvements in ART.45

Osteoporosis

The classic risk factors for osteoporosis within both the general population and PLWHIV are older age, female gender, hypogonadism, family history of hip fracture, low body mass index (≤19kg/m2), vitamin D deficiency, smoking, physical inactivity, history of low impact fracture, alcohol excess (>3 units/day) and glucocorticoid exposure (minimum oral prednisone 5mg/day or equivalent for >3 months).15

However, although a definitive causal link between HIV and bone loss has yet to be established, both men and women with HIV have also been found to have lower bone mineral density (BMD) and a modestly increased risk of fracture than the general population.24

Exposure to some ARTs is associated with short-term bone loss over 12–24 months when therapy is started, followed by partial recovery and then stabilisation of bone mass.46,47

Renal dysfunction

Renal function is estimated to be abnormal in up to 30% of PLWHIV and is considered an independent predictor of mortality in this population.48 Both HIV infection and ART are implicated in declining renal function in PLWHIV, and PLWHIV are more likely to develop both hypertension and diabetes compared with uninfected individuals;49 both common causes of end-stage renal disease and CVD.

HIV itself can infect kidney cells, causing HIV-associated nephropathy (HIVAN), which is found almost exclusively among people of Black African descent. The condition usually improves after starting ART and HIVAN-induced kidney damage can be reduced by early HIV diagnosis and treatment.49 However, where the treatment of HIV is delayed by late diagnosis and chronic damage to the renal interstitium has occurred, patients are at high risk of severe renal failure requiring dialysis.50

Several classes of drugs can impair renal function51 and some ARTs exhibit nephrotoxicity, contributing to renal dysfunction; some widely used boosted protease inhibitors have small but measurable effects on kidney function, mainly when they are used together in the same combination.52 Cumulative exposure to certain nucleoside reverse transcriptase inhibitors has been associated with a small increase in the risk of development of CKD.53 However, severe toxicity is infrequent providing PLWHIV are carefully monitored and managed. Discontinuing the drug responsible is often sufficient to alleviate the undesirable effects.15 In Caucasians living with HIV, diabetes and hypertension are major causes of renal dysfunction. Those over 50 and with borderline renal function at baseline (estimated glomerular filtration rate [eGFR] 60–75mL/minute/1.73m2) are at risk of ART-related further loss of renal function.54 This problem is set to increase as PLWHIV become older and carry a greater burden of HANA comorbidity. One 2015 European study predicts that in 2030, 17% of PLWHIV will have been diagnosed with diabetes (from 4% in 2010).13 Therefore, this will increase renal risks in these individuals.

Renal transplantation is safe and effective in HIV patients, and multiple studies have reported promising outcomes at 3–5 years after kidney transplantation in patients treated successfully with highly active ART.55

Neuropsychiatric disorders

Neuropsychiatric dysfunction is an important source of ongoing morbidity in PLWHIV taking ART, with a corresponding unmet need among a high proportion of the patient population, even with longstanding suppression of viraemia.56

HIV replication and immune activation can result in HIV-associated neurocognitive disorder (HAND), a range of problems caused by nerve damage.57 The prevalence of HAND disorders ranges from 52% to 59%, with the likelihood of prevalence and severity increasing with age.58 

Older PLWHIV exhibit better treatment adherence than younger adults,58 which might explain why many older adults are more likely to have suppressed viral load, but it is hypothesised that this advantage may disappear with neuropsychiatric dysfunction.58 In the long term, such neuropsychiatric damage can also reduce ability in various everyday tasks, which will increase the need for both informal and formal care among affected individuals, which will significantly reduce the QoL for affected PLWHIV.

One recent study highlighted the fact that data for neuropsychiatric impairment are poorly collected in cohort studies but have important consequences for treatment outcome, suggesting that collection of these data should be a priority in the context of the ageing HIV-infected population.13

As well as the physical effects of HIV infection on neuropsychiatric function, there are many other reasons why PLWHIV might experience cognitive, anxiety or mood disorders. Like physical forms of neuropsychiatric degeneration, depression has been reported to reduce drug adherence and QoL, while increasing polypharmacy, DDIs and mortality.59 Studies indicate that diagnosable depression is found in 20–37% of PLWHIV in Europe, with symptoms of major depressive disorder in around a quarter of patients.60 This compares to a lifetime prevalence of approximately 7% for major depressive disorder among the European general population.61 Other studies have found anxiety disorders in nearly half (47%) of PLWHIV, with an association found between anxiety symptoms and therapeutic failures.62

Assessing comorbidity risk

By simply living longer, PLWHIV are increasingly exposed to the long-term effects of ART and are at increased risk of HANA comorbidities. These HANA comorbidities affect treatment choices and mortality of PLWHIV. The likelihood of polypharmacy and possible DDIs may restrict an individual’s choice of HIV therapy, as well as influencing treatment adherence, therefore compromising the benefits of ART.

In order to assist clinicians with decision making, the EACS guidelines 7.115 provide detailed guidance on screening for comorbidities, although typical tools used to predict the risk of comorbidities in the general population (Framingham Risk Score, American College of Cardiology/American Heart Association [ACC/AHA] algorithm, eGFR, the Fracture Risk Assessment Tool [FRAX]) may be suboptimal in PLWHIV and underestimate the extent of the actual risk.63

In addition, an index has been designed to help characterise the effect of MM among PLWHIV who are treated with ART. The Veterans Aging Cohort Study Index has been found to be a more accurate means of predicting all-cause mortality among multi-drug-resistant, treatment-experienced PLWHIV, and is more responsive to changes in risk associated with treatment than an index using age and HIV biomarkers alone.64

Screening for cancer risk

Cancer screening is an important part of HIV care in clinical practice, as PLWHIV are at increased risk of several cancers compared to the general population.

A 2011 review of the data regarding harms and benefits of cancer screening interventions in PLWHIV found little primary data, but suggested that ways of screening for common cancers among PLWHIV (anal, liver and lung) may require adaptation for this population due to increased risk with HIV, as well as lifestyle factors associated with PLWHIV.65 It concluded that the decision to screen any individual with HIV for cancer should always include an assessment of risk for the specific cancer as well as an appraisal of the potential benefits and harms associated with any test and its result.

The most recent EACS guidelines provide a comprehensive overview of at-risk populations, procedures, evidence of benefit and screening interval.15

Screening for cardiovascular disease risk

For adults, the EACS recommends assessment of CVD risk factors among PLWHIV with a standard heart risk calculator at specific points along the treatment cascade: upon entering care, when starting ART, when switching ART regimens and at regular intervals based on risk. The EACS also recommends annual electrocardiograms in men >40 years and women >50 years.

To calculate CVD risk, EACS guidelines recommend the Framingham equation or ‘whatever system local National Guidance recommends’ and also direct clinicians to a risk equation (DAD 5 Year Estimated Risk) developed for HIV populations available at: www.hivpv.org15

This is in recognition of the fact that tools developed to predict CVD risk among the general population may not be accurate for PLWHIV. For example, one 2015 study comparing predicted CVD risk versus observed outcomes among HIV patients using a variety of methods, including the Framingham Risk Score and the ACC/AHA algorithm, found underestimation of CVD risk was between 15% and 25%.63

The HIV-specific DAD 5 Year Estimated Risk calculator factors in several variables linked to ART including duration of treatment with, and current exposure to, certain drugs or current/past exposure to various drugs, as well as smoking, diabetes and family history of CVD.

Screening for renal impairment

Given the negative consequences of CKD for PLWHIV, including the implications of kidney function on ART, early detection of CKD is crucial. Guidelines from the EACS recommend a three-step screening process including an annual urine dipstick analysis for proteinuria, an annual blood pressure check and monitoring of eGFR every 3–6 months if the patient is on ART, or every 6–12 months if not on ART. The guidelines also recommend referral to a nephrologist for PLWHIV at high risk of kidney disease.15

Risk assessment tools for kidney disease and lipid abnormalities have been developed by the Copenhagen HIV Programme (CHIP) and can be found at: www.hivpv.org15

Screening for bone disease/fracture risk

EACS guidelines recommend undertaking a FRAX assessment in patients aged over 40 years (www.shef.ac.uk/FRAX/) to provide a 10-year probability risk of major osteoporotic fractures. However, the guidelines note that the FRAX tool does not account for the impact of HIV infection on BMD.15 As an illustration, a 2015 study designed to assess the accuracy of FRAX in estimating fracture risk among 24,400 HIV-positive and HIV-negative men aged 50–70 found observed fracture rates significantly higher than FRAX estimates in both HIV-positive and HIV-negative men, with both the estimated and observed fracture rates higher among HIV-positive than among HIV-negative men.66

According to the EACS guidelines, PLWHIV who have a history of previous fracture or who exhibit any or all of the following risk factors should be screened for loss of BMD using dual energy X-ray absorptiometry (DXA):

  • Postmenopausal women
  • Men ≥50 years
  • High risk for falls (Falls Risk Assessment Tool [FRAT]; www.health.vic.gov.au/agedcare/maintaining/falls_dev/downloads/b2b_1a_frat.pdf)
  • Clinical hypogonadism
  • Oral glucocorticoid use (minimum 5mg/day prednisone equivalent for >3 months).

The results of the DXA measurement should be included in a FRAX risk assessment.15

Screening for depression risk

With a substantially higher prevalence of depression reported in PLWHIV than in the general population, and the significant disability and poorer treatment outcomes associated with depression,67 it is essential that depression is identified among PLWHIV so that it can be diagnosed and managed effectively. Current EACS guidelines outline a range of possible symptoms and propose a question-based screening approach every 1–2 years for PLWHIV with one or more of the following risk factors:15

  • Positive history of depression in family
  • Depressive episode in personal history
  • Older age
  • Adolescence
  • Persons with history of drug addiction, psychiatric, neurologic or severe somatic comorbidity
  • Use of efavirenz and other neurotropics, including recreational drugs.15

Conclusion and discussion

‘Going beyond undetectable’

Therapeutic innovations have converted HIV infection into a chronic condition and ageing PLWHIV now suffer a range of comorbidities at higher rates and earlier in life than those observed among the uninfected population. This is due to cumulative risks of HIV infection, ageing itself, lifestyle and long-term treatment.

The additional life-years provided by ART are of great significance, with major improvements in clinical care achieved to date in terms of mortality, better tolerability of ART, and immunological and virological recovery of patients. However, it is important that management of PLWHIV evolves to take account of their changing needs.

While clinicians are aware of a range of unmet needs among the ageing PLWHIV population, there is no simple, universal solution to the complexities of managing such a diverse range of HANA comorbidities. Reducing the risks of these comorbidities is an additional objective to preventing HIV transmission among individuals of all ages.

To optimise treatment success it seems likely that clinical care pathways must be developed around each individual living with HIV, with guidelines closely monitored and regularly updated to ensure that the right specialists are involved at appropriate junctures, co-ordinated and overseen by HIV physicians.

Determining where and when to involve specialists is likely to present one of the most challenging aspects of this new paradigm. Detection of many comorbidities and their risk factors can be problematic and deficiencies in risk assessment tools for PLWHIV in areas such as CVD and bone health are widely acknowledged.

However, it seems likely that any MDT approach will involve not only more referral to non-HIV physicians, more non-HIV physicians trained in the issues faced during treatment of PLWHIV and more interaction/communication between HIV and non-HIV physicians, but also more patient education on the benefits of a multidisciplinary approach; for example, the benefits of disclosing HIV infection to physicians beyond the immediate HIV specialist team.

Early treatment of comorbidities offers potentially significant benefits to PLWHIV as they grow older, so it is critical that they receive early and comprehensive medical evaluation to ensure prompt detection and treatment in order to reduce the comorbidity burden and improve overall HRQoL.

PLWHIV will need easier access to primary prevention services (eg smoking cessation clinics and lifestyle management on diet, exercise, mental health and the effects of recreational drug use) if they are to make the necessary alterations to lifestyle that they need to reduce the risks and impact of comorbidities.

Getting PLWHIV into the HIV treatment cascade earlier is vital if they are to gain full benefit from ART and provide clinicians with the best chance of managing HANA comorbidities.

It is also critical to recognise the important contribution of ARTs that can safely be given alongside co-medications, while maintaining high efficacy.

This situation calls for all those involved in research and clinical care to find effective ways of managing a changing patient population. PLWHIV should be encouraged to embrace lives that are worth living, rather than simply living longer lives. It requires a full understanding of the multiple unmet needs facing PLWHIV in this emerging landscape. Ultimately, it demands a refocused approach to HIV management in order to attain a standard of care that perceives undetectable viral load as the starting point of a lifelong care continuum.

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Declarations of interest

Dr Aguiar has received honoraria from Gilead Sciences for attendance at advisory boards and lectures. Professor Antela has received grants, funding or honoraria for clinical research, participation in advisory boards or talks in workshops or symposia from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen Cilag, Merck Sharpe & Dohme and ViiV Healthcare. Professor Compston has received funding from Gilead Sciences for advisory board attendance. Professor Gazzard has received support from Gilead Sciences, ViiV and AbbVie for lectures and/or advice. Professor Hendry has received funding for attending advisory boards and/or honoraria for lectures from Otsuka, AbbVie, Janssen, ViiV Pharmaceuticals, and Gilead Sciences. Dr Mallon has received support in the form of research grants awarded to the institution, attendance at advisory boards, honoraria, and/or travel to conferences from Janssen Cilag, Gilead Sciences, ViiV Healthcare, Bristol Myers Squibb and Merck Sharpe & Dohme. Dr Pourcher-Martinez has received funding from Gilead Sciences, BMS, MSD, AbbVie, ViiV and Janssen for attendance at advisory boards, honoraria and consultancy and to attend congress. Professor di Perri has received funding from AbbVie, BMS, MSD, Gilead Sciences, Janssen and ViiV for attendance at advisory boards, honoraria and consultancy.