Introduction

Older people (50+years) are at risk of chronic morbidity such as heart diseases, arthritis, diabetes and hypertension, associated with physiological changes with age [1-4], but these conditions remain often undiagnosed particular in resource poor settings. The disease burden may be exacerbated by both HIV and antiretroviral therapy (ART) [3,5-8], suggesting worse health outcomes in HIV-infected, especially those on ART, than in HIV-uninfected adults. Generally, the earlier a disease is diagnosed, the more likely it is that it can be cured or successfully managed. However, the association between HIV status and chronic morbidity, and possible benefit of regular access to general medical services within HIV treatment and care, remains little explored. Evidence on differential morbidity by HIV status from two studies was conflicting [9,10] and neither study include specific age-related morbidities in their outcome measure.

Certain biomarkers are useful tools for predicting clinical events [11] and are increasingly employed in monitoring health, identifying individuals at risk and evaluating therapeutic interventions [12,13]. Cytokines are released in response to trauma, infection or inflammation and sustained elevation has been linked to age-associated conditions and increased mortality [13-16]. Cytokines of interest in chronic conditions of older age include Interleukin- 1 and 6 (IL1 and IL6), Tumor Necrosis Factor alpha (TNFα), and C-Reactive Protein (CRP)[14-17]. Little is known on the association of HIV and ART status with cytokine levels and age-related chronic morbidity.

Obesity is linked to chronic health problems such as cardiovascular diseases, diabetes and arthritis [12,17,18] and, similar to ageing, is characterised by chronic low-grade inflammation [17,19]. Cytokine levels, as inflammation, trauma or infection markers, are thus normally higher in obese [17,19] and HIV-infected individuals with advanced disease [20,21]. It is critical to understand the associations of obesity with cytokine levels increasingly used to measure health risks and explain individual health status, in both HIV-infected and HIV–uninfected older adults.

We use data from a cross-sectional cohort of older people in a high HIV prevalence area to examine levels of chronic morbidity in HIV-infected and uninfected older adults and subsequent association of HIV and ART status with selected cytokines and BMI.

Methods

Results

Of the 422 older WOPS participants, 161 (38%) were HIV-uninfected, 108 (26%) were HIV-infected with at least a year on ART, 109 (26%) were HIV-infected ART-naïve and 44 (10%) had unknown HIV status with characteristics similar to those HIV-uninfected. Men comprised 25% of the 422 individuals (n=106). Median age for HIV-uninfected individuals was 10 years higher than for HIV-infected hence all analyses were age adjusted. As would be expected in this population and setting, few individuals reported currently or ever smoking or drinking (Table 1).

Self-reported morbidity

Of the 422 participants, 124 (29.4%; 95% CI: 25.0-33.8) reported never having been diagnosed with any chronic condition (Table 1) whilst 169(40.1%; 95% CI: 35.4-44.7) and 100(23.7%; 95% CI: 19.6-27.8) reported diagnosis with one and two conditions, respectively; 29(6.9%) individuals had more than two conditions. Significantly more HIV-uninfected and HIV-infected ART-naïve participants than HIV-infected participants receiving ART reported current morbidity i.e. receiving therapy for either one of heart disease, arthritis, stroke, hypertension, asthma or diabetes (Figure 1) (p=0.033). Specific current morbidities are illustrated using Figure 1.

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Figure 1. Proportion with 95% confidence intervals of disease specific chronic morbidity in 422 older adults stratified by HIV status.

https://doi.org/10.1371/journal.pone.0077379.g001

HIV status, obesity and morbidity

Controlling for factors known to be associated with ill health (age, sex, smoking and wealth quintile), HIV-infected older adults on ART were significantly less likely (OR=0.49, p=0.027) to report current morbidity than HIV-uninfected adults (Figure 2a). Cytokine levels were not significantly associated with morbidity. In a model including obesity marker (BMI) but not ratio of good:bad (HDL) cholesterol, there was borderline association between being obese/morbidly-obese and current morbidity (aOR=1.75; 95%CI: 1.0-3.0). However, including cholesterol:HDL ratio in the model, BMI lost its significance whilst higher levels of this ratio significantly increased the odds of current morbidity(Figure 2a). Cholesterol:HDL ratio was associated with BMI, with normal BMI category having only 4.0% and those obese 11.7% with ratio4. Of the obese/morbidly-obese, only 10.8% had ratio 1 compared to 28.7% of those with normal BMI.

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Figure 2. a. Logistic regression model of factors associated with current chronic morbidity in 422 older adults. b. Logistic regression of factors associated with IL1 levels in 422 older adults. c. Ordered logistic regression model for factors associated with #IL6 levels in 422 older adults.

https://doi.org/10.1371/journal.pone.0077379.g002

Discussion

Older HIV-infected adults face both chronic conditions of ageing and HIV [1,4,38,39], with data suggesting that HIV treatment may exacerbate chronic conditions associated with aging [2,3,6,40]. There is lack of reliable data in Africa regarding associations of HIV, obesity and age-related morbidity especially comparing morbidity by HIV and ART status. This study contributes to knowledge by being the first to demonstrate, in a rural African setting, the possibility of less current chronic morbidity in HIV-infected older adults receiving ART compared to HIV negatives. Could this be due to access to ART and/or health services?

We previously reported a higher WHO composite health score [a health measure collating an individual’s levels of difficulty in eight health domains (mobility, self-care, affect, vision, pain/discomfort, sleep/energy, interpersonal activities, and cognition)] amongst HIV-infected than in HIV-uninfected individuals, not accounting for ART status [9]. We now confirm this previous finding with more in-depth health measures and highlight differences by ART status. The fact that we previously report a higher composite health score using the same study population reduces the possibility that chronic morbidity in HIV-infected individuals remains undiagnosed or is misdiagnosed as HIV-related morbidity. It is likely that morbidity in HIV-infected older adults receiving ART is reduced through regular screening and treatment during frequent routine HIV clinic visits. In this setting, in accordance with the South African National HIV treatment guidelines, HIV positive individuals on ART visit the HIV clinics each month to consult with the HIV nurse and collect ART pills. Additionally patients receive adherence and health counseling during these monthly visits. Our findings here could suggest benefit of enhanced access to health care in HIV positive older adults through sustained frequent utilization of health care services for HIV treatment and care. In HIV positive individuals pre-ART, we did not observe morbidity differences from those HIV negative possibly due to the relatively infrequent clinic visits pre-ART since HIV positive individuals in routine HIV care and not yet eligible for ART are advised to visit the clinic once in six months.

Although elevated cytokine levels have been associated with increased cardiovascular and diabetes morbidity [17,19] it remains unknown whether the elevated cytokine levels result in morbidity or immune inflammatory response due to morbidity results in elevated cytokines. Our finding of lower morbidity in HIV-infected adults receiving ART and of the increased odds of elevated hsCRP and IL6 levels in this group may suggest that these cytokines may be associated more with chronic HIV rather than with other existing chronic morbidity. Compared to those HIV-uninfected, HIV-infected individuals on ART had nearly twice the odds of having elevated IL6 levels and more than twice the odds of elevated hsCRP levels, indicating immune inflammatory response. Similar elevated cytokine levels in HIV-infected adults have been reported from studies in resource-rich countries focused on HIV-infected people only, however these did not make comparisons with HIV-uninfected adults nor explored the association with ageing-morbidity [20,21]. Our study is the first to assess how in an African black population, controlling for age differences across HIV strata, cytokine levels differ by HIV and ART status and how these levels associate with chronic morbidity during ART. Although previous studies, not accounting for HIV status, report higher morbidity in individuals with elevated cytokine levels, they acknowledge that clinical mechanisms and significance of this phenomenon remains unclear [13-16].

Our results of lower morbidity in HIV-infected on ART, but not HIV-infected ART-naïve, than in HIV-uninfected older adults irrespective of high HIV-associated cytokine levels, may highlight the likelihood that even in the absence of co-morbid conditions, cytokine levels in HIV-infected adults do not return to pre-HIV infection levels despite ART and cytokine levels may not be ideal markers for chronic morbidity in such populations. Some studies have suggested that soluble cytokine receptors released in response to elevated cytokine levels, are more stable in circulation over time and hence might be more reliable markers of chronic inflammation than cytokines [13]. Longitudinal studies are needed to elucidate associations between HIV status and cytokine levels and how these relate to incident chronic morbidity and to explain mechanisms leading to morbidity decline in HIV-infected older adults on ART and to explain mortality differentials from chronic morbidity by HIV status. Within lifelong exposure to ART, vigilant monitoring of liver and kidney toxicities is required as these would negate the realized benefits.

Our results show that in this population with high obesity levels, it is the ratio of bad:good fat (cholesterol) ratio, a marker of cardiovascular disease risk, that is associated with high morbidity rather than BMI per se. In an analysis adjusted for this ratio, BMI ceased being an independent factor of morbidity, with the odds of morbidity nearly quadrupling in individuals within the highest ratio quartile possibly suggesting that total cholesterol:HDL ratio may be a stronger indicator of morbidity than BMI. Although BMI was not associated with morbidity when accounting for the ratio of bad:good fat, being obese/morbidly obese was associated with high hsCRP levels suggestive of increased inflammation and cardiovascular disease risk. Studies from developed countries have also shown increased inflammatory response in obese people [17,19] but literature from African populations is scarce.

Our results underscore the need of extending health care services to HIV-uninfected older adults, which need to go beyond mere provision at fixed clinics. Bringing health services to older adults through regular community chronic disease screening would ensure health care reaches all older adults in need, and could translate to considerable health benefits.

Our cross-sectional study has limitations, and we cannot assume causality in our associations but highlight possible associations which could be further elucidated in longitudinal cohort studies. Due to the complexities surrounding data collection of self-reported non-HIV medications for non-communicable chronic diseases, we did not collect information on the type of drugs that participants were taking for other age-related chronic conditions. Hence we could not assess the association of these medications with cytokine levels and morbidity by HIV and ART status. Although we cannot rule out the role of survivor bias, if the observed reduced reported morbidity in HIV-infected receiving ART was purely due to survivor bias we would also expect even larger morbidity decreases amongst the HIV-infected ART naïve group, which is not the case. Although our data was self-reported, we assumed that any unreliability of self-reports occurred equally across groups resulting in non-differential bias which does not affect validity of our results. This assumption was based on the fact that there is no evidence supporting the likelihood of over-reporting current morbidity amongst HIV-uninfected, but not infected, individuals. It is likely that HIV-infected individuals may over-report morbidity due to their knowledge of the underlying HIV infection. Furthermore both HIV-infected and HIV-uninfected participants were identified from the community via the longitudinal demographic surveillance system rather than from health care facilities, and thus would have reduced selection bias. Although our sample size is small, limiting the extent to which we could detect differences between groups, the fact that despite this we were able to detect significant differences between HIV-infected participants receiving ART and those HIV-uninfected possibly points towards an even larger morbidity difference had we used a larger sample size with tighter confidence intervals. As such the sample size issue does not nullify our results but rather confirms the strength of existing associations between morbidity prevalence and HIV-infection and ART.

Acknowledgments

We sincerely acknowledge the immense contribution of the research participants, without whom this study would not have been possible. Gratitude also goes to all WOPS staff for the Sterling work in data collection and capturing. Special mention should also be made of Colin Newell for the tremendous help in developing the database for data entry and archiving. Thank you to Dr Lorna Madurai and her laboratory team for running the assays.