The HIV has received considerable attention as a causative agent of a global epidemic lasting nearly 40 years and remains a tough and intractable medical problem.1 According to the UNAIDS Fact Sheet, between 2000 and 2017, the number of people infected with HIV has risen from 27.4 million to 36.9 million (of these, 35.1 million are adults).2 Antiretroviral therapy (ART) has been used to treat HIV infection for nearly 30 years, since its development in 1990. The widespread use of ART has greatly improved the prognosis of HIV disease, reduced AIDS-related mortality, and extended the life span of HIV patients.3
The global population is aging. In 2009, 11% of the world's population were 60 years or older. This proportion continues to rise and is expected to reach 22% by 2050.4 The prevalence of HIV in older people can therefore not be neglected. It is reported that 17% of the world's adults older than 15 years living with HIV are aged 50 years and older, and the percentage of old people is still increasing. Moreover, UNAIDS estimates that 6.9 million people aged 50 years and older will be infected with HIV by 2020, rising by 47% from 4.7 million in 2010.5 Therefore, the prevention of HIV infection in and treatment of older people are of outmost importance. However, evidence relating to the efficiency of ART in older people and the differences between older and younger adults is still conflicting. For example, some researchers, such as Silverberg et al,6 Greenbaum et al,7 and Carriquiry et al,8 have demonstrated that good viral suppression was observed in older people, whereas work by Patterson9 has suggested that the rate of viral suppression has no difference between older and younger patients. Similarly, studies by Althoff et al10 and Dawood et al11 have suggested that the immunological response in young patients is superior to that in older individuals. Meanwhile, others have found that older patients had better immune outcomes than younger patients. No meta-analysis relating to the effectiveness of ART in older adults has been performed to date, and only one meta-analysis relating to the adherence of older people to ART exists. Given the importance of the age-related differences in ART outcomes, the effectiveness of ART in older adults needs to be comprehensively investigated.
Using the 40 articles included in this article, we focused on the immunological and virological responses in older HIV-infected adults on ART, by analyzing CD4 counts, viral load (VL), and mortality rates, to understand the characteristics of older patients receiving ART. We envisage that our work will provide advice on the treatment, prognosis, and the type of medical care required by older patients with HIV.
This systematic review was performed using the medical electronic databases PubMed/MEDLINE, the Cochrane Library, Chinese National Knowledge Infrastructure, and WanFang Data to retrieve articles published between the 1st of January 1998 and the 31st of November 2018. The articles selected were published in English and Chinese and reported immunological or virological responses in HIV-infected adults after ART initiation. Medical Subject Heading terms and a range of relevant keywords, including “HIV,” “ART,” “CD4,” “VL” and “age” or “old,” were included as the search strategy. We selected studies on HIV-infected adults. Retrospective, prospective cohorts and clinical cohorts were eligible for inclusion. There was no geographic restriction. The quality of the studies was evaluated using the Newcastle–Ottawa Scale. This systematic review was conducted in conformity to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.
The main inclusion criteria were as follows: (1) cross-sectional, prospective, or retrospective cohort studies comprising at least 100 HIV-infected patients, receiving either first-line or second-line ART; (2) patients older than13 years (adhering to the assumption that children enter puberty after 12 years of age); (3) original research papers that reported the immunological and virological outcomes or survival of HIV-infected patients for up to 5 years on ART.
We excluded studies in which subjects were not treated with ART or were children (aged <13 years). Studies exploring a follow-up duration ≥6 months and ≤5 years on ART were eligible for inclusion because we needed to extract and compare summary estimates of mean CD4 counts, the proportion of viral suppression, and mortality of HIV/AIDS patients at 6, 12, 24, 36, 48, and 60 months after ART initiation. When the same cohort was reported on by more than one article, we only take the publication that contained the most complete information into account. Two independent reviewers screened abstracts and titles to select eligible articles for inclusion in the analysis. If there was a dispute regarding the eligibility criteria, we resolved it through discussion with the help of a third reviewer.
In our study, subjects of age 50 years and older (defined as “older”) and younger than 50 years (defined as “younger”) were identified. However, 4 of the articles we included took 45 years of age as the cut-off to identify older and younger adults. An “increment” refers to the difference between CD4 counts after ART and the baseline CD4 counts before ART initiation. An individual on ART with a VL of less than 500 viral copies/mL was regarded as “virally suppressed.” The 2013 World Health Organization Consolidated ART guidelines set the CD4+ T-cell count threshold at 500 cell/mm3. AIDS-related mortality was defined as an AIDS-defining event or death.
The data we eventually selected for inclusion in the literature related to the following: (1) The immunological response: baseline CD4 counts at ART initiation, mean CD4 counts at different time points (6, 12, 24, 36, 48, and 60 months), and a restoration of CD4 counts; (2) The virological response: baseline VL, failure to achieve VL and suppression; and (3) Mortality: AIDS-related mortality and non-AIDS-related mortality. All data were independently extracted by 2 researchers following the PICOS (population, intervention, comparator, outcome, and setting) process. The disputed data or indicators were discussed and processed by third parties. Eligible studies were examined to extract the mean (SD), median (interquartile range), crude risk ratio (RR), and 95% confidence intervals (95% CIs), as well as information on participant characteristics (eg, the age and geographical region of the patients as well as their treatment period) and study characteristics (eg, the authors, type of study, year of publication, and the number of patients in the cohort). For the articles with the same source, we discussed and retained the better-quality article containing the most complete data set, according to the Newcastle–Ottawa Scale quality evaluation scale.
We assessed heterogeneity between studies using the I2 statistic. Meta-analyses were conducted using the fixed effects model, based on the inverse-variance heterogeneity method to estimate weighted summary outcome measures and 95% CI for each of the outcomes. If substantial heterogeneity was observed with an I2 ≥ 50%,12 we would estimate outcomes using a random effects model based on inverse-variance.13,14 A P value < 0.05 (2-tailed) was considered statistically significant. Meta-regression analyses were performed to examine associations between ART efficiency and geographical region, the mean age of the patient group, type of study, and the year of publication. For the median and interquartile range data, we converted the values into the mean and SD.15
Most of the mortality studies included in the review, that used Kaplan–Meier methods, did not summarize the number of deaths and the number in the risk set at each time point. We therefore estimated mortality based on the proportion of deaths at each time point identified using the Kaplan–Meier curve, multiplied by the total number of study subjects.
Subgroup and Sensitivity Analyses
Meta-regression was performed for indicators with greater heterogeneity (baseline mean CD4 counts, baseline VL etc) according to the study source, study design, ART status, and age group. The heterogeneity in a subsection was obtained using the χ2 test. We also conducted a publication bias analysis (Egger's test). All of the aforementioned analyses were performed using the Review Manager 5.3 and STATA 14.0 software. ArcGIS 10.2 software was used to analyze the geographical distribution of the study cohorts.
We selected studies relating to immunological outcome, virological outcome, or survival analysis. We combined this information with search terms that specify length of time on ART to select outcomes obtained from individuals who comply with the inclusion criteria for treatment time. Finally, we excluded studies involving children who did not satisfy the inclusion criteria for age and single-arm studies from the search. Publications were examined for eligibility to include prospective, retrospective, and clinical cohort studies (Fig. 1).
The 40 selected studies were published between 2001 and 2018, and the chosen study cohorts were collected between 1986 and 2016 (Table 1). The study subjects selected were not limited by their geographical locations (Fig. 2). We screened 26 articles documenting the immunological outcome, 22 articles documenting the virological outcome, and 21 articles documenting mortality. Nineteen of these articles provided information on both the immunological and the virological outcomes. Nine articles contained immunological outcome and mortality data.
The Immunological Response of Older HIV-Infected Adults After ART Initiation
We included a total of 26 articles documenting immune reconstitution in older HIV-infected people. We subsequently used baseline CD4 counts, CD4 counts at different time point after ART initiation, and the recovery of CD4 counts as indicators of the immunological characteristics of older HIV-infected adults before and after ART.
Baseline CD4 Counts Before ART Initiation
A total of 23 articles were included, and among them, 21 articles defined older adults as 50 years older and 2 articles draw a distinction between older and younger by age 45 ears. Totally, 51,794 older patients from the 23 articles were studied. Overall, the baseline CD4 counts were lower in older than in younger adults (heterogeneity = 98.3%, P = 0.000) before the treatment. On performing regression, publication bias, and sensitivity analyses, we have not been able to identify the factors that led to this heterogeneity. We then conducted a further subgroup analysis based on the study region and showed that mean CD4 counts of older adults were significantly lower than those of younger adults in the European region (Weighted Mean Difference, WMD = −37.87, 95% CI −54.94 to −20.81, P = 0.000). There were no differences in the CD4 levels between the 2 groups originating from other regions or countries (see Figure 1, Supplemental Digital Content, http://links.lww.com/QAI/B414).
Mean CD4 Counts After the Initiation of ART, Reported by Age Group
We calculated the mean CD4+ T-cell counts and SD at each time point after ART initiation to show the patients' immune status after treatment. The differences in the mean CD4 counts between older and younger adults increased gradually over time (measured at 6, 12, 24, 36, and 48 months) after ART initiation. A significant difference in the mean of CD4 counts between older and younger in 6 months (350 vs 369, P < 0.001), 12 months (337.3968 vs 359.82, P < 0.001), 24 months (390.4169 vs 422.563, P < 0.001), 36 months (425.1956 vs 462.8522, P < 0.001), and 48 months (482.4449 vs 515.5153, P < 0.001) after ART (Fig. 3).
Restoration of CD4 Counts After ART Initiation
It has been reported that the increment in CD4 counts after ART initiation (An “increment” refers to the difference between CD4 counts after ART and the baseline CD4 counts before ART initiation) is an indicator of the immune response compared with baseline CD4 counts. We further analyzed the restoration of CD4 T-cell numbers after ART initiation. The observed increase in CD4 counts was lower in older individuals compared with the young group. The WMDs were −13.70 (95% CI −20.28 to −7.12, P < 0.0001) at 6 months (Fig. 4A) and −24.52 (95% CI −32.85 to −16.18, P < 0.00001) at 12 months (Fig. 4B), which was statistically significant (P < 0.05). And the WMD was −23.97 (95% CI −47.77 to −0.17, P = 0.05) at 24 months, which means the increment of CD4 counts was lower in older than the younger group, but it is not statistically significant.
Considering the high heterogeneity (I2 = 84%) of the results at 24 months, we performed a subgroup analysis taking into account the year of publication (considering publications before or after 2009, see Figure 2, Supplemental Digital Content, http://links.lww.com/QAI/B414) and found no significant differences among subgroup studies published before 2009 (P = 0.401, heterogeneity = 0%). However, in the subgroup using data from articles published after 2009, the expansion of CD4+ T-cells was significantly lower (P = 0.000, heterogeneity = 84.7%) in the older than in the younger group.
The Virological Response of Older HIV-Infected Adults After ART Initiation
Successful treatment requires a prolonged and profound virological response. The viral suppression rate is therefore an important indicator of the effectiveness of treatment in older patients. We included 22 articles and analyzed them for both aspects of the baseline VL and the viral suppression rate.
The Baseline Viral Load Before ART Initiation
Of the 22 articles included, 16 provided baseline VL data for a total of 94,655 patients, 12.8% of whom were aged 50 years and older. The initial VL in older adults was higher than that in the younger group (WMD = 0.14, 95% CI: 0.08 to 0.19, P = 0.000, total heterogeneity = 91.0%). Furthermore, we conducted a subgroup analysis based on the location of these 16 studies (Fig. 5). There was no significant difference between the results of subgroup analyses involving data from America and Africa. The initial VL was significantly higher in the older than in the younger European patients; WMD = 0.19 (95% CI: 0.07 to 0.31, P = 0.002, heterogeneity = 77.8%), with statistically significant effects.
The Viral Suppression Rate After ART Initiation
To analyze the differences in the virological response among different age groups after the initiation of ART, we determined viral inhibition rates at 6, 12, 24, and 36 months after ART initiation (Fig. 6). At 6, 12, and 24 months, there was no difference in the viral suppression rate between the older and younger groups. The RR values were 1.03 (95% CI: 0.97 to 1.10, P = 0.263) at 6 months, 1.04 (95% CI: 0.96 to 1.13, P = 0.299) at 12 months, and 1.03 (95% CI: 0.98 to 1.09, P = 0.197) at 24 months. However, the older adults exhibited a significantly higher rate of viral suppression compared with the younger adults at 36 months after ART initiation, with an RR value of 1.04 (95% CI: 1.01 to 1.08, P = 0.013).
The Mortality of Older HIV-Infected Adults After ART Initiation
We analyzed 21 articles documenting the mortality of HIV-infected individuals, assessing the risk of both AIDS-related (see Figure 3, Supplemental Digital Content, http://links.lww.com/QAI/B414) and non–AIDS-related mortality (see Figure 4, Supplemental Digital Content, http://links.lww.com/QAI/B414) and compared the total mortality to age-related risk of death for all of the articles included in this study.
The Total Mortality of HIV-Infected Adults, Reported by Age Group
We analyzed the total mortality rates for both old and young adult groups using the 17 articles included. The combined RR for age-related total mortality was significantly higher for older than younger patients (data not show). We then proceeded to compare AIDS-related and non–AIDS-related mortality.
Non–AIDS-related Mortality of HIV-Infected Adults, Reported by Age Group
We found that compared with the younger adults, older adults had a hazard ratio of 3.22 (95% CI: 2.81 to 3.69, P < 0.00001, see Figure 4, Supplemental Digital Content, http://links.lww.com/QAI/B414). This outcome was statistically significant.
The AIDS-Related Mortality of HIV-Infected Adults, Reported by Age Group
The AIDS-related mortality was slightly higher in older patients compared with younger patients, with an hazard ratio of 1.44 (95% CI: 1.30 to 1.60, P < 0.00001, see Figure 3, Supplemental Digital Content, http://links.lww.com/QAI/B414). This outcome was statistically significant.
The publication bias analyses were performed using a funnel plot and an Egger's linear regression test.16 There is no evidence suggesting publication bias for our results (Egger regression test; P > 0.1, data not shown) including mean CD4 count, restoration of CD4 counts, virological response, and mortality after ART. However, there is potential publication bias for baseline CD4 counts before ART initiation (Egger regression test; P = 0·001).
Studies from several countries have reported that the immune system declines with age,17 due to the dwindling immune repertoire and immune cell exhaustion, altering the immune response to infection and leading to the increased prevalence and incidence of chronic inflammatory diseases.18 In accordance, we believe that the difference in the CD4 counts observed in old and young individuals is age-related. This study indicates that the immunological response of older adults receiving ART is lower than that of younger adults. With the exception of European patients, the baseline CD4 counts were not significantly different between old and young individuals in any other region looked at. This result implies that due to the late diagnosis and treatment in some countries, HIV infection itself results in the exhaustion of the immune system and may mask the effects of the naturally aging immune response. Earlier diagnosis and treatment may reveal differences in the baseline CD4 counts between older and younger adults. We also found that the mean CD4 counts and restoration of these CD4 counts after ART initiation were lower in the older than the younger age group. ART reduces VL and allows the immune system to recover some level of function. Therefore, older patients living with HIV should receive more attention for early diagnosis and treatment. In addition, we should consider strengthening the immune function of older patients with adjuvant therapy.
In our study, the baseline VL was higher in the older than in the younger patients, which may possibly be caused by age. As the body ages, the size of the CD8+ T-cell repertoire gradually diminishes, meaning that older individuals exhibit a poorer resistance to the infection. For HIV patients undergoing ART therapy, there was a trend toward better viral suppression displayed by older compared with younger adults, as the treatment progressed. Although there was no significant difference during treatment (at 6, 12, and 24 months after ART initiation), by the 36th month on ART, the viral suppression rate was significantly higher in the older than in younger patients. These findings may be due to higher ART adherence by older adults with HIV than younger adults.19 Therefore, all HIV-infected individuals should follow medical advice to achieve good clinical outcomes.
We have shown that total mortality, non–AIDS-related mortality, and AIDS-related mortality for older patients are all higher than for younger patients. In the older group, the number of non–AIDS-related deaths was significantly higher. AIDS-related mortality was slightly higher in the older group than in the young group, which may be due to poorer immune function, leading to an increase in the incidence in opportunistic infections and other diseases. Older HIV-infected patients are at an increased risk of experiencing modifiable comorbidities and complications of long-term ART use, such as hypertension, diabetes, and renal impairment.20 Therefore, age is an important factor in mortality, and older people are more likely to suffer from hypertension, diabetes, and other associated diseases, despite having ART. However, we can still observe high AIDS-related mortality rates in older patients, possibly due to immune factors. All in all, this means that the care for older patients faces great challenges, not only in improving ART but also in preventing AIDS- and non–AIDS-associated diseases.
In this meta-analysis, some results showed obvious heterogeneity, such as the baseline CD4 counts and baseline VLs. We conducted several types of analysis to address this, including subgroup regression and sensitivity analyses, but found no significant positive factors. This heterogeneity may be due to the differences in the inclusion criteria, the study design among other factors.
Our study is with its limitations. First, we were limited by language, selecting only the English and Chinese literature. Second, all of the studies we included were cohort studies, introducing selection bias and obvious missing data bias due to the long follow-up times, which could greatly influence the heterogeneity of the results. Finally, there may have been some overlap in the geographic locations and timing of the population sampling. We tried to limit this by being as precise as possible when determining where patients come from and the period that the cohort was assembled, to avoid duplicating study populations.
This meta-analysis provides evidence that older HIV-infected individuals receiving ART exhibit poorer immunological responses, better viral suppression rates, and a higher risk of AIDS-related deaths compared with younger HIV-infected individuals. Further studies are required to define the biological mechanisms involved and to guide development of therapeutic interventions.
The authors thank Willa Dong for helping to revise the manuscript as an English native speaker.
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