Cancer and the other noncommunicable chronic diseases in older people living with HIV/AIDS in resource-limited settings: a challenge to success

Hirschhorn, Lisa R.a,b,c; Kaaya, Sylvia F.d; Garrity, Philip S.b; Chopyak, Elenaa; Fawzi, Mary C.S.a

doi: 10.1097/QAD.0b013e328355ab72
Supplement Articles

Objective: There is considerable research around the morbidity and mortality related to noncommunicable diseases (NCDs), particularly cardiovascular disease and diabetes, among people living with HIV/AIDS (PLWHA) in resource-richer settings. Less is known about the burden and appropriate management of NCDs, particularly ‘other’ NCDs including cancer, renal, pulmonary, neurocognitive and mental health conditions, among older PLWHA in resource-limited settings (RLSs). We undertook a literature review of these other NCDs to explore what is currently known about them and identify areas of further research.

Methods: Systematic literature review of published manuscripts and selected conference abstracts and reports.

Results: Although there is growing recognition of the importance of these NCDs among the aging population of PLWHA in RLSs, significant gaps remain in understanding the epidemiology and risk factors among older PLWHA in these settings. Even more concerning is the limited available evidence for effective and feasible approaches to prevention, screening and treatment of these conditions. The burden of these NCDs is related to both the aging of the population of PLWHA and an increased risk due to HIV infection, other comorbidities associated with HIV infection or transmission risk and underlying risk factors in the general community. Results from resource-richer settings and RLSs highlight malignancies, neurocognitive and mental health as well as renal disease as the most significant challenges currently and likely to increase in the future.

Conclusion: Although some lessons can be taken from the growing experience with NCDs in older PLWHA in resource-richer settings, additional research is needed to better understand their risk and impact and identify optimal models of care to effectively address this challenge in the areas where the majority of older PLWHA will be receiving care.

aDepartment of Global Health and Social Medicine, Harvard Medical School

bPartners in Health

cJSI Research and Training Institute, Boston, Massachusetts, USA

dDepartment of Psychiatry and Mental Health, Muhimbili University of Health and Allied Sciences, School of Medicine, Dar es Salaam, Tanzania.

Correspondence to Lisa R. Hirschhorn, MD, MPH, 888 Commonwealth Avenue, Boston, MA 02215, USA. Tel: +1 617 504 5794; fax: +1 617 482 0617; e-mail: lrh3@hms.harvard.edu

Received 3 January, 2012

Accepted 7 May, 2012

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Background and rationale

The success of effective combination antiretroviral therapy (ART) has resulted in decreased morbidity and mortality associated with HIV in resource-richer and resource-limited settings (RLSs) [1]. As a result of the decreased mortality and ongoing infections, there is an increasing proportion of people living with HIV/AIDS (PLWHA) who are now older than 50 years, with one study published in 2010 estimating that 14.3% of adults living with HIV in sub-Saharan Africa (SSA) are already over 50 years of age [2]. In rural South Africa, HIV prevalence was estimated at 9.4% among the population over 50 with an estimated incidence of 0.5 per 100 person-years among adults 50 years of age or older, similar to UNAIDS estimated incidence of 0.8 per 100 person-years among 18-year-olds [3,4]. Hontelez et al. [5] estimated that the ART rollout in South Africa will result in tripling of the proportion of PLWHA who are over 50 years of age in the next 30 years.

The care of older people living with HIV is complicated by a higher risk of comorbid noncommunicable chronic diseases (NCDs), which threatens the success of extending the lifespan of this population [6–11]. In the last few years, considerable attention has been focused on diabetes and cardiovascular disease as major NCDs associated with HIV, HIV-treatment and age [12,13]. However, there are a number of other NCDs which also pose a significant burden to older PLWHA and a challenge to their healthcare providers in resource-richer settings and RLSs [1,7,14–17]. Although this is a concern for all older individuals living in RLSs, some conditions are occurring at higher rates or at an earlier age in PLWHA. In addition, guidelines and tools for prevention, diagnosis and treatment are limited in these settings.

We undertook a review of the literature to describe what is known about more common other NCDs including neurocognitive and neuropsychiatric conditions including substance use, non-HIV-associated malignancies and renal, bone and pulmonary diseases. Chronic liver disease was not included as a separate category because the major cause is infection with hepatitis B or C virus and so reflects morbidity associated with communicable disease. This review also describes the current knowledge of the potential impact of these other NCDs on the care and outcomes for older PLWHA in care in RLSs and identifies areas where further research to improve prevention and treatment is needed.

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Methods

The aim of this article was to review the current knowledge on the burden and relative contribution of age and HIV for selected NCDs other than cardiovascular and diabetes in PLWHA in resource-limited countries. The main focus of the review was on Africa, but we also included articles from Asia and Central and South America when identified. For each condition, we provided a brief overview of the burden in RLSs in general; a review of identified information for each selected NCD among PLWHA in resource-richer and in more limited settings; the impact of HIV and of age among PLWHA on disease incidence, progression and management, and the impact of these comorbidities on effective treatment of HIV focusing on older PLWHA in RLSs.

PubMed and Cochrane databases were searched using MESH terms including age, older, Africa, Asia, Latin America, resource-limited settings, HIV and AIDS, as well as specific conditions (renal, pulmonary, bone, neurocognitive, substance use, mental illness and malignancies). Because limited information was obtained on older PLWHA with specific NCDs in RLSs, an additional search was made excluding MESH terms for RLSs and specific countries. Titles and abstracts were reviewed and promising articles pulled for further review. Articles earlier than 2000 in RLSs and earlier than 1995 in resource-richer settings, which largely reflected care in the pre-ART era, were generally excluded. Bibliographies from relevant articles were also reviewed to identify additional resources. In addition, abstracts from the International AIDS Society meetings from 2009 onward and selected Web sites (UNAIDS, WHO) were searched using terms related to specific comorbidities and aging. A total of 495 titles were reviewed, with 265 papers and reports reviewed in full, and 102 included in the final review (Fig. 1).

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Results

Malignancies

Malignancies in resource-limited settings

Malignancies are becoming an increasing burden on healthcare systems in resource-richer and more-limited settings. Primary causes of cancer-related deaths in RLSs include breast, cervical, lung, stomach and liver cancers [18]. The higher frequency of these malignancies is related to a number of causes: chronic infection with oncogenic viruses, environmental exposures, lifestyle (tobacco use) and relatively limited capacity for prevention and early diagnosis [19,20]. There has been a growing recognition of the need to increase capacity for screening and treatment of these cancers, with models building on lessons learned from chronic care in HIV [21,22].

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HIV, age and malignancies

Although rates of some of AIDS-defining cancers (ADCs) such as cervical cancer, Kaposi's sarcoma and non-Hodgkin's lymphoma have declined in settings where ART use is high, these remain a major challenge in many RLSs where access to ART remains limited. The burden of malignancy is now compounded by increasing numbers of non-AIDS-defining cancers (NADCs) seen among PLWHA in RLSs and resource-richer settings [1,11,23,24]. The most commonly reported NADCs (Table 1) regardless of setting include Hodgkin's lymphoma, lung, hepatocellular and breast cancer [24,25]. In populations in RLSs with high rates of hepatitis B or C virus (HBV or HCV, respectively) co-infection, hepatocellular carcinoma (HCC) is particularly common, representing 19% of malignancies in the TreatAsia cohort [25].

There is evidence of an increased risk in selected malignancies related to HIV infection, potentially due in part to premature aging in PLWHA caused by HIV-related inflammation and immunosenescence [26]. Studies from resource-richer settings found that HIV posed an increased risk over age alone in renal and lung cancer and cancers associated with oncogenic viruses (such as cervical and anal cancers), with no increase seen in breast, prostate and common epithelial malignancies (Table 2) [27–33]. In these settings, lung cancer has also been found to occur at an earlier age and high rate among PLWHA compared with the general population, even after adjusting for tobacco use [34]. In a Belgian cohort in which 47% of patients were from Africa, an increase in age standardized incidence rate (SIR) in PLWHA was found for Hodgkin's lymphoma [SIR 17.78, 95% confidence interval (CI) 6.49–38.71], liver (SIR 8.73, 95% CI 2.35–22.34), anal (SIR 22.67, 95% CI 8.28–49.34) and bladder cancers (SIR 3.79, 95% CI 1.02–9.70) [23]. Data from the USA found an elevated incidence risk ratio of 2.8 for hepatocellular carcinoma (95% CI 2.2–3.5) in HIV-positive compared with HIV-negative individuals, in part related to increased risk of chronic HBV and HCV co-infections [23].

In a review of NADCs among PLWHA in SSA, Sasco et al. [28] reported HIV-related increased risks for a number of malignancies from a range of studies (and methodologies) including Hodgkin's lymphoma [odds ratio (OR) 5.7, 95% CI 1.7–12], non-cervical human papilloma virus (HPV)-related malignancies (OR ranging from 2.2 to 4.8) and squamous cell skin cancers. One study from Uganda found higher SIRs in PLWHA for a number of other malignancies including renal (SIR 16, 95% CI 1.8–58), thyroid (SIR 5.7, 95% CI 1.1–16) and uterine (SIR 5.5, 95% CI 1.5–14) [29]. In contrast, a number of studies in RLSs have described no increased (or even decreased) risk of breast cancer in PLWHA compared with age-matched HIV-negative women [28,29].

Similar to HIV-negative individuals, advanced age among cohorts of PLWHA has been associated with increased risk of selected malignancies in resource-richer settings [24,27,35]. Although the TreatAsia cohort reported a 1.39-fold increase in risk for NADCs for every 5-year increase in age among the cohort of PLWHA [25], only limited additional data on age among PLWHA in RLSs were found. While this limits the ability to understand the relative contribution of aging to the burden of NADCs in PLWHA in RLSs, it is reasonable to expect at least similar age-related risks among older PLWHA in RLSs as seen among HIV-positive populations in resource-richer settings as well as older populations in general.

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Implications for prevention, screening and treatment of cancer among older people living with HIV/AIDS in resource-limited settings

One of the major barriers to decreasing the risk of ADCs remains limited access to effective ART in many RLSs. In a review of AIDS-related malignancies in SSA, Sasco et al. [28] reported continued increased risk for ADCs among PLWHA compared with HIV-negative populations including Kaposi's sarcoma (21.9–47-fold increase), non-Hodgkin's lymphoma (5–12.6-fold increase) and cervical cancer, in part related to limited access to timely ART. Although expanding access to timely ART will decrease the risk of selected ADCs and HBV-related HCC, increased research is needed to identify and replicate effective and feasible approaches for prevention, screening and treatment of other cancers among PLWHA in RLSs. For example, the implementation of a simplified and effective screen-and-treat strategy for cervical cancer in women with (and without) HIV from Zambia highlights the potential for appropriate technology, task shifting and systems strengthening to expand access [36]. Applying lessons learned from this and other experiences to address other malignancies is needed to speed up the translation from clinical trials and standards of care in resource-richer settings into effective systems of care for older PLWHA in RLSs. One example is the need to develop appropriate screening and delivery to ensure that recent advances in the treatment for HCV infection are accessible to decrease the risk of HCC for HCV co-infected PLWHA [37].

More research is also needed to better understand the relative interaction of age, HIV and malignancies as a growing number of PLWHA survive into older age in RLSs. This information will be critical for programs to implement age-appropriate and effective interventions for cancer screening and prevention. This work needs to be integrated into the wider efforts in RLSs to increase overall capacity in health systems for cancer prevention (such as tobacco cessation, HBV and HPV vaccination, treatment for alcohol abuse) and screening (such as mammograms, cervical cancer screening). Although there is currently no evidence for increased frequency or earlier initiation of screening for most cancers (exceptions include HPV-related ano-genital malignancies), more research is needed to understand how to effectively increase access. For example, development and testing of screening approaches for breast, lung and anal cancers which are inexpensive and require limited technology and expertise are urgently needed for both older people with and without HIV.

As efforts to expand cancer treatment in RLSs continue, more research into the optimal management of older PLWHA with cancer is also clearly needed. Data from resource-richer settings have been mixed regarding the tolerability of cancer treatment depending on the malignancy and regimen, with some antiretrovirals associated with increased toxicity of chemotherapy [38]. Given the limited treatment resources and options, prospective evaluations of the tolerability and outcomes of cancer treatment in this population are also needed.

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Renal

Renal disease in resource-limited settings

Acute and chronic kidney disease (CKD) are increasingly common in both resource-richer settings and RLSs [39]. Data on the full spectrum of renal disease in RLSs are largely lacking, so most rates focus on end-stage renal disease (ESRD). Prevalence rates of ESRD in SSA, India and Latin America range from 100 to 400 per million population [40], which only represents a small percentage of the overall burden of renal disease [40,41]. In SSA and other RLSs, hypertension, diabetes and chronic glomerulonephritis and obstructive uropathy related to infectious diseases are the most common causes of CKD [40,41]. Other risk factors for CKD may include low birth weight and genetic predisposition in SSA [40]. Increased risk of renal disease including HIV-associated nephropathy (HIVAN) has been associated with single-nucleotide polymorphisms on chromosome 22q, which are found more commonly among individuals of African ancestry. A high prevalence of this genetic risk factor among Africans, similar to that found in blacks of African ancestry, may also significantly contribute to the risk of renal disease among Africans in general and PLWHA in particular [42]. There has been some early implementation of programs focused on primary prevention through screening for underlying diseases such as diabetes and hypertension, urine analysis for early detection of proteinuria and management of early renal disease to decrease rates of progression, but access to renal replacement therapy remains very limited [41]. The rates of ESRD in RLSs are likely underestimated because of high rates of mortality among these patients due to this lack of access to dialysis in most of these settings.

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HIV, age and renal disease

Understanding the burden of renal insufficiency among PLWHA is critical, as it represents a significant risk factor for morbidity and mortality. In a cohort of patients in Zambia, Mulenga et al. [43] found a high rate of renal insufficiency at the time of ART initiation (33%), although the rate of severe disease (creatinine clearance <30 ml/min) was low (3.1%). In a cohort of PLWHA in Botswana, Wester et al. [1] found a decreased glomerular filtration rate (GRF) of 2.4 per 1000 person-years, comparable to rates found in an HIV cohort in the USA (Table 3) [44–46].

HIV infection has been clearly associated with increased risk of renal insufficiency, with HIVAN representing the most common cause of CKD and acute kidney disease in PLWHA [47]. HIVAN, characterized by high-grade proteinuria and progression to ESRD, is more common among individuals with high viral load and low CD4 cell count, both common conditions in RLSs where universal access to ART has not been achieved. If started early enough, ART is effective in reducing the risk of ESRD among patients with HIVAN by up to 60% [15]. However, some antiretroviral medications may also contribute to renal dysfunction, including indinavir and more recently tenofovir [47,48]. Nephrotoxic medications used in the treatment of opportunistic and other infections also pose a risk for PLWHA. In the aging population of PLWHA, other comorbidities associated with renal dysfunction in the general population such as diabetes and hypertension are likely to become more common causes as increased access to ART results in decreased rates of HIVAN [46,49,50]. Independent of these causes, increased age among PLWHA is also an independent risk factor for renal disease, with studies finding an association between renal dysfunction and older age among PLWHA in Zambia [43], Nigeria [44], Botswana [1] and Kenya (Table 3) [51].

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Implications for care and treatment of older people living with HIV/AIDS with renal disease in resource-limited settings

The significant impact of renal disease on both morbidity and mortality for PLWHA in RLSs emphasizes a need for resource-appropriate screening algorithms to strengthen screening for early detection and management of CKD and acute kidney disease and reversible risk factors [43,46,52]. This is particularly urgent in RLSs where access to renal-replacement therapies remains severely limited [47].

Further research to understand the optimal management of older PLWHA with preexisting CKD or high risk of development of renal dysfunction is also needed. The most effective treatment for HIVAN patients is initiation of ART as soon as possible regardless of CD4 cell count [53]. In addition to ART, interventions that decrease the level of proteinuria and improve control of hypertension and diabetes are also effective in improving renal outcomes among PLWHA in RLSs [39]. However, a better understanding of the relative contributions of HIV, antiretroviral regimen, age and comorbidities to the risk and progression of CKD and their impact on management strategies is clearly needed. For example, in the DART study based in RLSs, the 4-year cumulative incidence of CKD was 5%, with 2.8% developing severe renal impairment (estimated glomerular filtration rate <30 ml/min per 1.73 m2), with no difference seen between tenofovir-containing and nontenofovir-containng regimens [54]. In contrast, a study in Japan found a two-fold increased risk of renal dysfunction in patients on tenofovir and low body weight [55].

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Mental health and neurocognitive dysfunction

Mental health and neurocognitive dysfunction in resource-limited settings

There has been an increasing recognition of the often undiagnosed and untreated mental health issues in RLSs. The estimate of the burden of disease due to mental health disorders in the age group 15–44 years in these settings is 14% of the disease burden worldwide, with depression being a leading cause of disability, contributing 8.6% to this burden [56–58]. Other common disorders in low-income and middle-income countries include somatization and anxiety disorders (including posttraumatic stress disorder). These common mental disorders, when either assessed using symptom screening measures for more general ‘psychological distress’ such as the General Health Questionnaire (GHQ) or with specific diagnostic measures like the Revised Clinical Interview Schedule (CIS-R), are in part due to significant political and/or economic instability in more RLSs [59]. Although in recent years better approaches to diagnose, treat and manage mental illness have been developed, addressing mental health problems remains a significant challenge for health systems in developing countries [60].

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HIV, age and mental health

There is a growing literature on the burden and morbidity of mental health disorders in PLWHA regardless of setting. Some of this burden is related to the increased risk of HIV infection among individuals with certain mental health disorders including substance use and depression [60,61]. In particular, there is significant literature on the presence and role of depression among individuals with HIV infection [62], with evidence of a negative impact on medication adherence and quality of life [63]. Although most of this literature is from resource-richer settings, an analysis of studies on PLWHA from SSA reported pooled prevalence estimates of depressive symptoms and major depression at 31.2 and 18%, respectively [64]. In an outpatient setting in Tanzania, assessment of PLWHA using the CIS-R identified depression or mixed anxiety and depression in 15.5% of the participants, with other anxiety disorders in an additional 4.5% [65]. Wright et al. [66] reported that 36% of HIV-positive outpatients screened for neurological complications in 10 sentinel sites in the Asia Pacific region were clinically depressed; defined as a score of more than 16 on the Center for Epidemiologic Studies-Depression Scale.

At present, we have limited information on the impact of depression specifically on older PLWHA in RLSs. However, symptoms equivalent to DSM-IV depression were associated with increased mortality in HIV-positive pregnant women in Tanzania [67] and depressive disorder in progression of HIV in other groups [68]. The impact of depression on HIV disease may be related to challenges in ART adherence [69], although some authors postulate a role of depression-related decrease in cell-mediated immunity as well [60,70]. In addition, a socially driven mechanism for increased depression among HIV-positive individuals is the role of HIV-related stigma; this association has been demonstrated in a number of contexts [61,62,71,72].

Substance use disorders (SUDs) including alcohol use is common mental health comorbidity in certain populations of PLWHA. Injection drug use (IDU) is associated with high prevalence of HIV infection; 99 of 147 low-income and middle-income countries reported such drug use patterns by 2008, and an estimated 11.8 million IDUs (range from 8 to 16 million) [73]. SUDs can also serve as a barrier to adherence and/or uptake of HIV treatment [61], as well as increase the risk of other comorbidities including HCV co-infection among IDUs. In resource-richer settings, studies have found that HIV-positive drug users are at a higher risk of comorbidities as they age, including problems related to hormonal, cardiovascular, liver, renal, mental health and cognitive function, further raising the risk of poor outcomes among older PLWHA [74,75].

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HIV, age and neurocognitive dysfunction

With the expansion of ART, the incidence of HIV-associated dementia has fallen, but the overall prevalence has increased along with less severe HIV-related cognitive disorders, including HIV-associated neurocognitive disorder (HAND), particularly among older PLWHA and those with advanced immunosuppression [14,76–79]. In SSA, there is a growing recognition of HAND in patients in care and treatment [33% for neurocognitive impairment, 12% for mild neurocognitive disorder and 2% for HIV-associated dementia using the HIV Neurobehavioral Research Center (HNRC) International neuropsychological test battery [80]], with similar findings in the Asia Pacific region [12% of patients had moderate–severe HIV-related neurocognitive impairment; the neuropsychological test battery for this study included the timed gait, finger tapping (nondominant), grooved pegboard (dominant) and Semantic Fluency (animals)] [66,80,81]. Although ART clearly reduces the risk of this comorbidity, a persistence of impairments or progressive decline in neurocognitive function among some patients on chronic ART has been described [79,82].

Aging independently raises the risk of a range of neurocognitive disorders including memory impairment and mild-to-severe dementia. Less well understood is the relative impact of HIV infection independent of age in the setting of effective ART as well as the contribution of other conditions more common among some populations of PLWHA, such as depression [74]. Processes such as memory function, executive control over mental activities and information processing may be negatively impacted by either aging or HAND as well as by their combined impact on cognitive dysfunction [14]. In an HIV-positive cohort, a two-fold higher prevalence of cognitive impairment was seen among PLWHA over the age of 50 years compared with those under 35 years of age using a neuropsychological assessment including functioning in attention, working memory, speeded information processing, learning, recall, verbal fluency, abstraction, problem solving and motor ability [83,84].

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Implications for care and treatment of older people living with HIV/AIDS with mental health or neurocognitive problems in resource-limited settings

The importance of adherence to ART adds to the general importance of appropriate screening and treatment of mental health conditions and neurocognitive dysfunction among PLWHA. Some immediate needs include the ability to diagnose early and more advanced dementia, substance use and depression to provide the additional support and treatment of these comorbidities and ensure adherence to care and ART [85]. There is some evidence that choice of specific regimens may decrease this risk, with higher neurocognitive performance found among HIV-positive patients taking ART with higher penetration into the central nervous system [14,84]. Identification and management of other risk factors associated with neurologic decline is also important [14]. More importantly, there is a clear need to expand availability of well tolerated and effective medications for depression as well as effective approaches to address substance use particularly in populations of older PLWHA in RLSs. The presence of depression and substance abuse can also raise the risk of drug interactions between ART with prescribed [86,87] and recreational drugs [88,89], a risk which also increases with age as the number of medications needed to treat other age-related conditions increases [88].

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Noncommunicable chronic respiratory diseases

Noncommunicable chronic respiratory diseases in resource-limited settings

Noncommunicable chronic respiratory diseases represent a growing health burden in RLSs. In South Africa, the major nonneoplastic conditions include chronic obstructive pulmonary disease (COPD), asthma and lung diseases related to occupational exposure [19]. The WHO has projected that COPD will rank fifth in 2020 in the worldwide burden of disease [90]. Smoking represents a significant risk for chronic respiratory diseases, with rates predicted to increase by over 3% per year, although current data on the prevalence of smoking in RLSs remain limited. Other factors include indoor air pollution from cooking fires and growing pollution in urban centers.

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HIV, age and noncommunicable chronic respiratory diseases

Rates of a number of the noncommunicable chronic respiratory diseases increase with age, including COPD and pulmonary fibrosis [91], with an increase in rates described among older PLWHA in resource-richer settings compared with younger HIV-infected individuals [92]. There is also evidence that HIV adds an additional risk to age in the occurrence of some of these conditions. Findings from the Veterans Administration Aging cohort in the USA demonstrated an increased risk among PLWHA compared with age-matched HIV-negative patients for a number of chronic nonmalignant pulmonary diseases including COPD, pulmonary hypertension and pulmonary fibrosis, but not asthma [91]. In the USA, increased risk of chronic respiratory disease has also been reported among PLWHA who smoke compared with HIV-negative smokers [93], with a greater negative impact of chronic respiratory diseases on physical functioning in PLWHA compared with a matched cohort of HIV-negative individuals [92]. Significant information on rates and burden of noninfectious pulmonary disease in PLWHA in RLSs and the relative contribution of age was not found in our literature search.

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Implications for care and treatment of older people living with HIV/AIDS with noncommunicable chronic respiratory conditions in resource-limited settings

The significant gaps in the knowledge of rates of chronic respiratory disease among older PLWHA in RLSs and the relative contribution of HIV, age and other factors highlight the need for epidemiologic research to define the burden and identify priority areas for prevention and treatment. Effective approaches to prevention of chronic respiratory disease through decreased exposure to known risk factors such as smoking and indoor air pollution, as well as increased health system capacity for effective treatment is needed for both older PLWHA and the general population in RLSs. Work is underway in a number of countries in RLSs to reduce disease through efforts such as the WHO Framework Convention on Tobacco Control [94]. The role of ART in reducing noninfectious respiratory morbidity remains unclear, with one study finding lower rates of COPD and asthma in PLWHA with lower HIV viral load and those on ART [91]. However, research to understand how to expand effective prevention interventions such as support for nicotine cessation and identify resource-appropriate management of older PLWHA with established respiratory diseases is clearly needed.

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Osteoporosis and osteopenia

Osteoporosis and osteopenia in resource-limited settings

Bone mineral density loss is a well described phenomenon associated with aging in the general population, presenting considerable burden to current and future morbidity due to fractures [16,95]. Although the rates of osteoporosis are not generally known in many RLSs, the rates of hip fractures (used as an outcome of osteoporosis) in SSA and Asia, though lower than those in resource-richer settings, are projected to increase with the aging of the population, particularly in postmenopausal women. An important additional risk factor for some in RLSs is a diet which contains low levels of vitamin D and calcium as well as growing rates of less-active lifestyles in populations living in urban settings [96].

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HIV, age and osteoporosis and osteopenia

A 10-fold increase in rates of osteoporosis and bone fractures ‘without adequate trauma’ have been described in older PLWHA (defined at age ≥65 years) compared with younger individuals in the Swiss HIV Cohort (adjusted hazard ratios of 10.5, 95% CI 3.58–30.5 and 9.13, 95% CI 4.10–20.3, respectively) [97]. Premature osteopenia and osteoporosis have also been described among PLWHA, regardless of age, with three-fold higher rates compared with HIV-negative individuals and higher rates of fractures compared with age-matched and sex-matched controls [98–100]. There is evidence that the increased risk of these conditions reflects both the impact of HIV infection, potentially related to chronic inflammation [26], as well as side effects of some antiretroviral drugs including certain protease inhibitors and nonnucleoside and nucleoside analogues as well as traditional osteoporosis risk factors [16,101]. The strongest evidence for antiretroviral-associated acceleration in bone loss has been in patients with prolonged tenofovir exposure [102]. In addition, some conditions which are associated with increased bone loss may also be more frequently diagnosed as PLWHA age regardless of setting, including chronic liver disease, malnutrition, low BMI, hypovitaminosis D and hypogonadism [16]. Data on rates of osteopenia, osteoporosis and nontraumatic fractures among older PLWHA in RLSs are not widely available, but given the rates of these risk factors for bone loss in these settings, it is likely that this condition is common and likely to increase in the future.

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Implications for care and treatment of older people living with HIV/AIDS with osteoporosis and osteopenia in resource-limited settings

More research is needed to define the burden, contributing risk factors and the appropriate frequency and approach for screening and effective prevention and treatment of osteopenia and osteoporosis among older PLWHA in RLSs. Some unanswered questions include what is the actual burden and what are the more common modifiable risk factors; what will be the impact of the increasing use of tenofovir in first-line regimens and the rise in other comorbidities associated with accelerated bone loss and overall aging of the population of PLWHA on overall burden of disease; what are lower cost and simpler technological alternatives to dual-energy X-ray absorptiometry for screening; is there a role of routine supplementation for vitamin D for prevention of osteoporosis and fractures; and what are affordable and effective strategies for treatment of patients with osteoporosis and nontraumatic fracture.

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Discussion

The excitement resulting from the decreased mortality associated with effective ART in RLSs has been tempered by the growing challenges facing PLWHA and their healthcare providers to ensure that these benefits are not lost by the increase in a range of NCDs as the population in care ages. From resource-richer settings, we found evidence of increased risk associated with age, HIV or both for many of these NCDs as well as the potential role of other risk factors (Table 1). However, more limited data were identified on the burden of disease and risk factors among older PLWHA in RLSs for many of these conditions. Although aging is inevitable, we identified a number of modifiable risk factors for these other NCDs in RLSs as well as conditions which will complicate treatment. Integrating screening and management of these risks including diabetes and hypertension (renal), smoking (cancer) and substance use is clearly needed, with some models already described [21]. Although it is likely that these conditions already contribute to morbidity and mortality in older PLWHA either directly or by compromising the effectiveness of ART, this knowledge gap highlighted a number of areas where further research is critically needed. While some of the knowledge from resource-richer settings is likely to be relevant to RLSs, there are a number of areas where rates of underlying risk factors may differ (e.g. HBV and HPV co-infection, infectious causes of CKD, differences in lifestyle, genetics), limiting its direct usefulness. The limited relevance is also true when published reports of effective approaches to screening and treatment which rely on resources and technology not yet available in RLSs.

Measurement of the current burden of these NCDs among older PLWHA is needed to help programs develop strategies for building capacity to meet current needs for prevention, screening and treatment. This information, combined with a better understanding of the relative risks associated with age, HIV treatment status and other risk factors will allow managers and providers to develop systems to meet the growing needs and ensure that these services are accessible regardless of distance or ability to pay. Relatively resource-limited approach exist for screening and diagnosis for some of these NCDs and associated risk factors including renal disease, neurocognitive and mental health disorders, cervical cancer and diabetes, but work is needed to improve scale up of implementation. However, for a number of other NCDs, development of new and more affordable approaches are needed. These include screening and diagnosis for breast and anal cancer, osteoporosis and pulmonary disease. Understanding the magnitude of increased risk can also help inform guidelines on the approaches and timing of screening for these NCDs among an aging population of PLWHA. For example, what is the optimal frequency and methodology of screening for renal disease, what is cost-effective for osteoporosis detection, and when and how often screening for neurocognitive deficits should be done. Even more critical will be using this information to understand the effectiveness of prevention programs in this population, including nicotine cessation, osteoporosis prevention and control of diabetes, among many others.

Strengthening and integrating the treatment of these NCDs with HIV care can improve the chronic disease approach for PLWHA and enhance capacity in systems for HIV-negative individuals with these NCDs [21,22]. However, we also identified a considerable gap in the needed knowledge about the optimal approaches for treatment and on the impact of these NCDs on success of HIV treatment success and overall QOL for older PLWHA. For example, is there a need to change ART regimens and dosing to reduce risk of toxicities in older PLWHA, particularly those with other NCDs; what are the main drug interactions from medications available to treat concurrent NCDs; and what additional support is needed for older PLWHA with increased risk of age and HIV-related neurocognitive deficits. Equally important is the need to understand what will be the socioeconomic barriers to care among older PLWHA with one of these NCDs who may represent a particularly vulnerable population at risk for poor access and outcomes.

In conclusion, our review highlights the need to increase the research on the prevalence, presentations and appropriate management of these diseases in RLSs where the population of older PLWHA is expected to continue to increase. There has recently been a call for developing cohort studies focused on NCDs in RLSs to better understand the risks, progression and effective treatment. This approach would also be beneficial in helping providers, policy makers and researchers begin addressing the gaps in understanding of these other NCDs in older PLWHA in RLSs [103]. The challenge will be for health systems to build on the lessons learned and the infrastructure of longitudinal care and treatment of HIV to effectively provide the needed screening, prevention and management of these conditions in older PLWHA as well as the general aging populations in RLSs.

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Acknowledgements

No funding support was used for preparation of this manuscript.

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Conflicts of interest

There are no conflicts of interest.

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Keywords:

Africa; aging; cancer; HIV; neurocognitive dysfunction; noncommunicable chronic diseases; osteoporosis; renal disease

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