Introduction

Globally, the proportion of older adults is increasing [1]. In regard to HIV, persons 50 years and above are considered “older adults” [2–4]. In this fourth decade of the AIDS epidemic, the HIV–infected population is growing older primarily due to successful antiretroviral therapy (ART) but also among those newly diagnosed [5]. Reports from high-income countries show that adults over 50 years doubled from 10-15% of the HIV–infected population in 2005, to about 30% by 2010 [6,7]. This phenomenon has also been observed in sub–Saharan Africa [8].

Older adults with HIV present with different clinical, immunological and even social profiles which potentially influence outcomes [9–14]. For example, adults aging with HIV experience multiple co-morbidities with resultant poly-pharmacy, may respond differently to ART, and are commonly stigmatized or socially isolated. However, existing evidence on aging and HIV/AIDS is largely from high income countries. The few publications from sub–Saharan Africa do not provide as much information regarding some of the co-morbidities such as Hepatitis B and C co-infection, renal dysfunction, hypertension or viral loads [8,15–17]. In order to explore these issues of HIV patients initiating ART, we compared clinical and immunological differences between older (≥ 50 years) and younger (18-49 years) adults starting ART in Uganda and Zimbabwe which are low income countries in sub–Saharan Africa.

Methods

Results

Discussion

HIV and aging is an inevitable global health challenge today [21]. The world population is aging to the extent that chronic diseases are on the rise and stretching health care budgets, particularly in sub–Saharan Africa [22]. Still, in low income countries like Uganda and Zimbabwe, the existing high burden of infectious diseases including HIV/AIDS, tuberculosis and malaria, presents a dual challenge to the health systems [22]. Therefore, innovative strategies to integrate care for older adults are urgently needed and understanding the characteristics of such a population is a sound starting point [3,23].

Our study explored clinical and immunological differences associated with older adults with HIV and AIDS starting antiretroviral therapy. Whilst such data are largely from the high income settings, few studies from sub–Saharan Africa have reported laboratory biomarkers for adults with HIV and AIDS older than 50 years. In the DART cohort, older adults had significantly higher systolic blood pressure, lower creatinine clearance, higher CD4+ cell counts, and higher plasma HIV–1 RNA viral copies/mL, compared to younger adults in the multivariable regression models. Women were also proportionately less well represented, despite making up the majority of the trial population.

That older adult females were significantly fewer in Zimbabwe and Uganda raises concern of gender inequity in accessing HIV and AIDS care in low income countries. This finding is corroborated in a recent study by Negin and colleagues who reported that older adults in Malawi were more likely to be male [24]. Indeed, older adult females with HIV are probably widowed, neglected and lack resources or the social fabric to reach HIV care and treatment services [25]. Alternatively, this could be a cohort effect depicting earlier mortality among females with HIV and AIDS compared to males such that, only those who survived accessed care. However, given results from a recent systematic review that men have worse outcomes even on ART, and that majority of trial participants were women, this is quite unlikely [26]. Noteworthy, this could be a consequence of earlier sexual debut associated with riskier sexual behavior and probably HIV infection in females compared to males [27,28]. On the contrary, older men may be more sexually active and with multiple partners, thus increasing their risk of HIV than older women [29]. Possibly, the DART recruitment procedures and avenues could have systematically excluded older women. Regardless of the underlying reason, our findings highlight the importance of HIV treatment and care interventions in Africa mainstreaming gender issues to improve access, even for females older than 50 years who are naturally no longer reproductive. Notably, menopause leads to changes in immune response, vaginal or cervical epithelium and secretions that may influence HIV transmission or progression among those who remain sexually active [30–32]. Hence, such programmes could consider expanding their maternal and child health paradigm to include women’s health. In relation to this, older adult females had consistently higher hemoglobin levels compared to the younger reproductive age group (potentially due to child-bearing in the latter) which underscores the point that their clinical needs are indeed different.

It is certainly not surprising that older adults had higher systolic blood pressure and lower creatinine clearance. Older age is characterized by general decline in organ (renal) function, narrowing and hardening of blood vessels [33–35]. However, recent evidence from Europe and America suggests that there is an excess risk of morbidity and mortality due to cardiovascular and renal diseases among HIV–infected compared to the non–HIV infected population [36,37]. Thus, older adults infected with HIV may require even closer monitoring of their renal and cardiovascular function, bearing in mind resultant poly-pharmacy and excess burden to the organs in the event of co-administration of treatment.

Although older adults had statistically higher CD4+ cell counts and higher plasma HIV–1 RNA levels compared to younger adults, clinically this should be interpreted cautiously. Coupled with the finding of fewer older adults in the lower WHO stages 3 and 4 univariate analysis, the higher CD4 counts suggests either earlier presentation and access to HIV care by older adults, or that more older adults died before they could access care, leaving those survivors who joined the DART trial with better underlying prognosis. The higher viral loads in older persons would tend to support the latter explanation, although they could also reflect decreased ability of the older immune system to respond to HIV [38].

This study had limitations, which can be addressed by future research. Relatively few older adults were recruited in the DART trial meaning power to detect differences between older and younger adults was low. In addition viral load results were available for only a third of the participants, thus limiting power of the findings in the second model. Certain data were not collected including substance abuse, mental health as well as specific biomarkers such as cholesterol, D–dimer, cystatin C and IL–6 all of which have been found to predict HIV treatment outcomes among older adults in western cohorts [39,40]. Lastly, a control group of non–HIV infected individuals would have provided vital information on the effect of HIV infection itself. Nonetheless, this is among the first studies on HIV and aging to explore clinical and immunological differences in a sub–Saharan African cohort.

Conclusions

Our study explored and identified some bio-markers which may be useful in optimizing monitoring of care for older adults with HIV and AIDS. We also exposed information gaps for future research in cohorts of older adult Africans with HIV. These include establishing non–HIV infected cohorts to compare whether indeed in this setting, there is an interaction between aging and HIV in the clinical, immunological differences identified in our study; and which of these are optimal for reliably predicting outcomes of HIV treatment.

Acknowledgments

This paper is dedicated to Sujal M. Parikh (RIP) who initiated this research project, but did not live to see its fruition.

Members of the DART Trial Team include:

From the MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda: H Grosskurth, P Munderi, G Kabuye, D Nsibambi, R Kasirye, E Zalwango, M Nakazibwe, B Kikaire, G Nassuna, R Massa, K Fadhiru, M Namyalo, A Zalwango, L Generous, P Khauka, N Rutikarayo, W Nakahima, A Mugisha, J Todd, J Levin, S Muyingo, A Ruberantwari, P Kaleebu, D Yirrell, N Ndembi, F Lyagoba, P Hughes, M Aber, A Medina Lara, S Foster, J Amurwon, B Nyanzi Wakholi, K Wangati, B Amuron, D Kajungu, J Nakiyingi, W Omony, K Fadhiru, D Nsibambi, P Khauka.

From the Joint Clinical Research Centre, Kampala, Uganda: P Mugyenyi, C Kityo, F Ssali, D Tumukunde, T Otim, J Kabanda, H Musana, J Akao, H Kyomugisha, A Byamukama, J Sabiiti, J Komugyena, P Wavamunno, S Mukiibi, A Drasiku, R Byaruhanga, O Labeja, P Katundu, S Tugume, P Awio, A Namazzi, GT Bakeinyaga, H Katabira, D Abaine, J Tukamushaba, W Anywar, W Ojiambo, E Angweng, S Murungi, W Haguma, S Atwiine, J Kigozi, L Namale. A Mukose, G Mulindwa, D Atwiine, A Muhwezi, E Nimwesiga, G Barungi, J Takubwa, S Murungi, D Mwebesa, G Kagina, M Mulindwa, F Ahimbisibwe, P Mwesigwa, S Akuma, C Zawedde, D. Nyiraguhirwa, C. Tumusiime, L. Wnamara Bagaya, J. Kigozi, J. Karungi, R. Kankunda, R. Enzama

From the University of Zimbabwe, Harare, Zimbabwe: A Latif, J Hakim, V Robertson, A Reid, E Chidziva, R Bulaya-Tembo, G Musoro, F Taziwa, C Chimbetete, L Chakonza, A Mawora, C Muvirimi, G Tinago, P Svovanapasis, M Simango, O Chirema, J Machingura, S Mutsai, M Phiri, T Bafana, M Chirara, L Muchabaiwa, M Muzambi, E Chigwedere, M Pascoe, C Warambwa, E Zengeza, F Mapinge, S Makota, A Jamu, N Ngorima, H Chirairo, S Chitsungo, J Chimanzi, C Maweni, R Warara, M Matongo, S Mudzingwa, M Jangano, K Moyo, L Vere, I Machingura

From theInfectious Diseases Institute (formerly the Academic Alliance): Makerere University, Mulago, Uganda: E Katabira, A Ronald, A Kambungu, F Lutwama, I Mambule, A Nanfuka, J Walusimbi, E Nabankema, R Nalumenya, T Namuli, R Kulume, I Namata, L Nyachwo, A Florence, A Kusiima, E Lubwama, R Nairuba, F Oketta, E Buluma, R Waita, H Ojiambo, F Sadik, J Wanyama, P Nabongo, J Oyugi, F Sematala, A Muganzi, C Twijukye, H Byakwaga.

From The AIDS Support Organisation (TASO), Uganda: R Ochai, D Muhweezi, A Coutinho, B Etukoit.

From Imperial College, London, UK: C Gilks, K Boocock, C Puddephatt, C Grundy, J Bohannon, D Winogron.

From the MRC Clinical Trials Unit, London, UK: J Darbyshire, DM Gibb, A Burke, D Bray, A Babiker, AS Walker, H Wilkes, M Rauchenberger, S Sheehan, C Spencer-Drake, K Taylor, M Spyer, A Ferrier, B Naidoo, D Dunn, R Goodall.