Introduction
In Europe, migrants from low-income countries, and particularly from sub-Saharan Africa, have a relatively high prevalence of HIV infection [1,2]. Foreign-born heterosexuals accounted for 39% of new diagnoses of HIV infection in France in 2014, and three-quarters of them were born in sub-Saharan Africa [3].
Various differences in the management of HIV infection between migrants and natives have been reported in European countries. Some studies suggest that sub-Saharan African (SSA) origin is associated with late diagnosis [1,4,5], delayed initiation of combined antiretroviral treatment (cART) after diagnosis [6], and a higher risk of AIDS [2,4], but with lower non-AIDS mortality (healthy migrant effect) [7].
A poorer immunologic response to cART has been observed among SSA migrants in some studies but not in others [4,8–12]. Poorer socioeconomic or living conditions have been frequently pointed out as responsible at least of part of these effects, but these factors are rarely recorded or analyzed [4,9]. Likewise, the contribution of factors such as vitamin D deficiency and levels of inflammatory markers, which might differ according to geographic origin [13], has not been explored, even though pretreatment levels of inflammatory markers have been found to influence clinical outcomes [14,15], and vitamin D deficiency has been linked both to low CD4+ cell counts and elevated inflammatory marker levels among ART-naive patients [13] and to poorer CD4+ cell recovery on cART [16–18].
The aims of this study were to compare CD4+ cell recovery during first-line cART between French natives and SSA migrants and to determine the role of socioeconomic status, living conditions, and inflammatory markers in any observed differences.
Patients and methods
Study design
The ANRS-C09-COPANA cohort is an ongoing prospective study conducted in 37 hospitals in France that enrolled between 2004 and 2008, 800 recently diagnosed (<1 year) HIV-1-infected adults [19]. They attended twice yearly follow-up visits, in which detailed clinical and biological data were collected. In addition, at enrollment and each year thereafter, the patients are asked to complete a self-administered questionnaire that includes detailed questions on various dimensions of their living conditions and depressive symptoms, as measured with the French version of the Center for Epidemiologic Studies-Depression Scale (CES-D) [20].
The Paris-Cochin Ethics Committee approved the study protocol, and all the participants gave their written informed consent to participate.
Variables of interest
As CD4+ cell counts at cART initiation, and also at HIV diagnosis [21], are a major determinant of the response to cART, the immunologic profile at cART initiation was categorized as follows: late presenters (<200 CD4+ cells/μl at diagnosis), late starters (>200 CD4+ cells/μl at diagnosis and <200 cells/μl at cART initiation), intermediate starters (CD4+ > 200 cells/μl at diagnosis and between 200 and 350 cells/μl at cART initiation), and early starters (CD4+ > 200 cells/μl at diagnosis and >350 cells/μl at cART initiation). Before 2008, French guidelines recommended ART initiation for asymptomatic patients with CD4+ cell counts below 200 cells/μl. The recommended cutoff was raised to 350 cells/μl in 2008 and to 500 cells/μl in 2010. Since 2013, ART initiation has been recommended for all HIV-infected patients, regardless of their CD4+ cell count.
Nationality, country of birth and age at arrival in France were documented in the baseline self-administered questionnaire. Participants born outside of France were considered to be migrants if they did not have French nationality or, for those with current French nationality, but of African ethnicity, if they arrived in France after 15 years of age, that is, after the minimum school-leaving age.
Sociodemographic characteristics, including age, sex, and educational level, were collected at enrollment through the physician questionnaire. Educational level was dichotomized, based on the UNESCO International Standard Classification of Education (ISCED), as Basic (ISCED 0–2) versus Secondary or Tertiary (ISCED 3–6).
At each follow-up visit, the following physician-reported information was also collected: BMI, alcohol consumption, and smoker status. Symptoms of depression in the preceding week were considered present if the CES-D score was above 17 for men and above 23 for women, according to the recommended cutoffs [20]. Indicators of living conditions, including employment status, income (above or below the French minimum monthly salary of 1070€), cohabiting partnership, and disclosure of HIV serostatus in the social network [sexual partner(s), family members, friends, and colleagues] were documented in the baseline and follow-up self-administered questionnaires. All these variables were analyzed as time-updated variables. The most recent values prior to the date of cART initiation were considered for this study.
Statistical analyses
We considered participants who were either French natives or SSA migrants, who initiated cART, had documented CD4+ cell count and HIV viral load values near the time of cART initiation (within a time window ranging from 3 months before to 10 days after), and had at least two available CD4+ cell counts during the 36 months after cART initiation.
We first compared the migrants and natives with respect to the time to the first viral load less than 50 copies/ml after cART initiation, using Kaplan–Meier survival analysis and the log-rank test.
CD4+ cell count (square-root-transformed) kinetics during the 36 months after cART initiation was modeled using a two-slope linear mixed-effects model, with random effects for the intercept and the slopes.
Data were analyzed from cART initiation to the last available measurement at the end-point date (12 October 2015), the first treatment interruption lasting more than 15 days, or 3 years after cART initiation, whichever came first. The best model minimizing Akaike's information criterion was a model with a slope change 4 months after cART initiation. The effect of different variables on the early and long-term immunologic response to cART was assessed by introducing interaction terms between the variable and each slope in univariate analyses. A first multivariate analysis was used to adjust for known determinants of CD4+ recovery on cART, such as age, sex, the pre-cART immunologic profile and plasma viral load, and the type of first cART regimen (model 1). Additional adjustments were made for risk factors of comorbidities, such as BMI, alcohol, and tobacco consumption, and depressive symptoms (model 2). Lastly, each of the following socioeconomic characteristics was successively taken into account: educational level, employment status, monthly income, and cohabiting partnership. HIV status disclosure was considered as potential intermediate factor. Finally, we checked that similar conclusions were reached when introducing all these variables together (model 3).
To take into account possible differences in the level of vitamin D or of inflammatory markers between the migrants and natives, which could potentially affect the immunologic response, the analysis was adjusted for these factors in the subset of patients for whom values were available [13]. The studied inflammatory markers were high-sensitivity C-reactive protein, monocyte chemoattractant protein-1 (MCP), tumor necrosis factor (TNF)-α, soluble tumor necrosis factor receptor 1 (sTNFR1), soluble tumor necrosis factor receptor 2, interleukin (IL)-6, and IL-8.
We performed several sensitivity analyses. First, we explored whether the results were affected when we restricted the analysis to patients who achieved a first viral load less than 50 copies/ml within the first 6 months after cART initiation and who subsequently remained virologically suppressed. As comorbidities may also affect CD4+ recovery, further analyses were performed after excluding patients coinfected by hepatitis virus B and/or C (HBV/HCV), after excluding patients diagnosed with symptomatic tuberculosis (TB) from 6 months before to 6 months after cART initiation [22], and after excluding patients diagnosed with clinical AIDS before cART initiation.
Data were analyzed with SAS software version 9.3 (SAS Institute Inc., Cary, North Carolina, USA).
Results
Characteristics of the study population
A total of 494 participants (319 French natives and 175 SSA migrants) were included in the study (refer to flowchart in Supplementary Fig. 1, https://links.lww.com/QAD/B73). A total of 49.7% of SSA migrants (n = 87) were from Central Africa (Cameroon, Central Africa, Congo, Gabon, and Chad) and 46.3% (n = 81) were from West Africa (Burkina Faso, Cape Verde, Ivory Coast, Ghana, Guinea, Mali, Mauritania, Niger, Senegal, and Togo). Only 4% (n = 7) came from East Africa (Burundi, Ethiopia, Kenya, and Rwanda). Length of time in France was 3 years in median [interquartile range (IQR)= 1; 6].
The median year of cART initiation was 2007 [French natives: 2007 (IQR: 2006; 2009); SSA migrants: 2006 (IQR: 2005; 2007)], and cART was initiated a median of 13.2 months after HIV diagnosis (18.8 and 7.5 months, respectively; P < 0.0001). Median follow-up after cART initiation was 67.5 months. During the first 36 months after cART initiation, 26 patients (13 natives and 13 migrants) interrupted their treatment for at least 15 days, and three patients died (all natives; including one patient who had discontinued treatment). Median time between consecutive CD4+ or viral load measurements did not differ significantly between French natives and SSA migrants (Table 1).
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Table 1: Patients characteristics at combined antiretroviral treatment initiation, according to their geographic origin: the ANRS COPANA cohort.
As shown in Table 1, although the French natives were mostly men (87.8%), who were generally infected through homo/bisexual contact (77.7%), most SSA migrants were women (62.9%). The migrants were more likely to have a CD4+ cell count less than 200 cells/μl at HIV diagnosis (33.7 versus 18.8%, P = 0.0002). At cART initiation, the migrants were younger than the natives (median 35.0 versus 37.5 years; P = 0.003) and had lower CD4+ cell counts (median: 231 versus 288 cells/μl; P < 0.0001). The proportions of patients with viral load at least 5 log/ml at cART initiation did not differ between the groups. The majority of patients in each group were prescribed a combination of two nucleoside reverse transcriptase inhibitors + one protease inhibitor boosted with ritonavir. Marked differences in socioeconomic characteristics were observed. SSA migrants were less educated (basic education only: 51.4 versus 34.5%), more frequently unemployed (54.3 versus 20.1%), and had lower incomes (low income: 37.7 versus 10.7%). In addition, cohabiting partnerships (40.0 versus 51.7%) and disclosure of HIV status (52.0 versus 88.1%) were less frequent among the migrants.
Virologic and immunologic responses to combined antiretroviral treatment
The time required to reach a first viral load below 50 copies/ml was not significantly different between the natives and migrants (median 4.1 months overall; log-rank test, P = 0.46, Fig. 1).
Fig. 1: Time to reach a first viral load less than 50 copies/ml, according to geographic origin.
During the first 4 months after cART initiation, the rate of unadjusted CD4+ cell recovery, on the square root scale, was 0.85√CD4+ cells/month overall. By comparison with French natives, SSA migrants had lower CD4+ cell counts at cART initiation (estimated mean 251 versus 308 cells/μl, P = 0.002) and also a significantly slower increase during the first 4 months [mean values: +0.69 versus +0.93√CD4+ cells/month; difference: −0.24√CD4+ cells/month, 95% confidence interval (CI) = (−0.43; −0.05), P = 0.01] (Table 2, Fig. 2a). The mean CD4+ cell count 4 months after cART initiation was 346 cells/μl among the migrants and 452 cells/μl among the natives (P < 0.0001).
Table 2: Immunologic response to combined antiretroviral treatment according to geographic origin: the ANRS COPANA cohort.
Fig. 2: Estimated mean CD4+ cell count (square root transformed) over time (a) among French natives (solid line) and sub-Saharan African migrants (dashed line) (univariate analysis), (b) according to baseline immunologic profile among male French natives (solid line) and male sub-Saharan African migrants (dashed line) aged 30–39 years with baseline viral load less than 5 log copies/ml and initiating combined antiretroviral treatment with two nucleoside reverse transcriptase inhibitor + one protease inhibitor boosted with ritonavir (multivariate analysis, model 1).
Between month 5 and month 36 of cART, the CD4+ cell count rose by +0.12√CD4+ cells/month overall. There was no significant difference between the migrants and natives [0.008√CD4+ cells/month, 95% CI = (−0.015; 0.031), P = 0.5].
After 36 months of cART, the mean CD4+ cell count was 508 cells/μl in the migrants and 623 cells/μl in the natives (P < 0.0001). The mean increase in the CD4+ cell count 36 months after cART initiation exceeded 250 cells/μl in both groups, but, on average, the natives gained 58 more CD4+ cells/μl than SSA migrants.
CD4+ cell recovery after 4 months of combined antiretroviral treatment, with adjustment for other determinants
After adjustment for sex, age, pre-cART viral load, the immunologic profile at cART initiation, and the first cART regimen (model 1), initial CD4+ recovery was still slower in the SSA migrants than in the French natives (difference in the mean rates of increase: −0.33√CD4+ cells/month, P = 0.002) (Table 3, Fig. 2b). This was observed both in men and women: no significant interaction was found between geographic origin and sex on the early CD4+ cell slope (P value for the interaction, P = 0.67). Additional adjustments for risk factors of comorbidities (model 2), including BMI, alcohol consumption, smoking, and depression, did not modify the results (difference of −0.30√CD4+ cells/month, P = 0.02), and neither did adjustment for socioeconomic characteristics (model 3: −0.40√CD4+ cells/month, P = 0.01).
Table 3: Multivariate analysisa of characteristics influencing the CD4+ cell gain during the first 4 months of cART: the ANRS COPANA cohort.
Other factors known to influence the response to cART, such as age, plasma viral load, and the immunologic profile at cART initiation, were independently associated with the rate of CD4+ recovery during the first 4 months of cART. Patients aged at least 50 years (versus <30 years) and patients with baseline viral load less than 5 log copies/ml (versus ≥5 log copies/ml) had slower CD4+ recovery. In contrast, no significant association was found with sex, BMI, alcohol consumption, smoking status, or depressive symptoms nor, surprisingly, with any of the considered socioeconomical characteristics.
Sensitivity analyses
SSA migrants were more likely to have HBV/HCV coinfection (56 migrants and 25 natives) and to be diagnosed with TB around the time of cART initiation (11 migrants and two natives). SSA migrants still had poorer early CD4+ cell recovery when we excluded patients diagnosed with HBV (hepatitis B surface antigen-positive or anti-hepatitis B core antigen-positive alone) or HCV coinfection [difference of −0.47√CD4+ cells/month (−0.95 to 0.02), P = 0.06 in the fully adjusted model 3] or TB [difference of −0.39√CD4+ cells/month (−0.78 to 0.01), P = 0.05]. A difference of similar magnitude was observed when we excluded patients (20 migrants and 28 natives) diagnosed with clinical AIDS before cART initiation.
The difference in CD4+ recovery during the first 4 months of cART was of similar magnitude when the analysis was restricted to early virologic responders (first viral load <50 copies/ml within 6 months on cART) who remained virologically suppressed throughout follow-up.
25-Hydroxyvitamin D and inflammatory marker levels were available for a subgroup of patients. Vitamin D levels were significantly lower in migrants than in natives [median (IQR): 13 (9; 19) versus 17 ng/ml (10; 24), P = 0.002]. Migrants also had lower levels of MCP-1 [176.9 (122.9; 224.7) versus 310.8 pg/ml (235.1; 403.0), P < 0.0001] and sTNFR1 [1150.0 (944.1; 1407.1) versus 1400.1 ng/ml (1182.5; 1650.4), P = 0.0002]. The difference in early CD4+ recovery between the migrants and natives persisted after adjustment of model 3 for the 25-hydroxyvitamin D level [difference of −0.43√CD4+ cells/month (−0.79 to −0.07), P = 0.02] or for the MCP-1 level [difference of −0.60√CD4+ cells/month (−1.18 to −0.03), P = 0.04]. Only adjustment for sTNFR1 levels attenuated the difference in CD4+ recovery [−0.26√CD4+ cells/month (−0.67 to 0.15)], which was no longer statistically significant (P = 0.21).
Discussion
HIV-infected SSA migrants living in France had slower CD4+ cell recovery than French natives during the first 4 months of first-line cART, despite similar virologic responses. This slower response was not explained by socioeconomic and living conditions, 25-hydroxyvitamin D status, or levels of inflammatory cytokines, with the exception of sTNFR1, which attenuated the difference in the rate of early CD4+ cell recovery. Beyond 4 months of cART, there was no difference in CD4+ recovery between SSA migrants and natives, the gap therefore persisting throughout time. The estimated mean CD4+ cell count after 36 months of cART exceeded 500 cells/μl in both groups, with the persistence of an additional mean gain of 58 CD4+ cells/μl in natives.
This slower initial immunologic response to cART among migrants living in an industrialized country is consistent with the results from some [4,9,12,23,24] but not all observational studies conducted in Europe [8,10,11]. The reasons for these discrepancies may include differences in sample size or a lack of information on treatment interruptions; in addition, contrary to our study, CD4+ cell count trajectories were not always modeled. CD4+ cell recovery after cART initiation is due initially to a redistribution of memory CD4+ T cells from lymphoid tissue, followed by repopulation with newly produced naive CD4+ T cells from the thymus, as well as memory CD4+ T lymphocytes [25,26]. The difference we observed in CD4+ cell recovery between migrants and natives occurred only during the first, rapid phase of recovery corresponding to the first 4 months of cART. Similar results were obtained in another study [27], in which White ethnicity (versus Black African/other) was associated with better CD4+ recovery during the first 3 months of treatment but not thereafter.
The difference in early CD4+ recovery was not explained by factors known to influence the immunologic response to cART, such as age, the pre-cART CD4+ cell count, or viral load [27–29]. Importantly, our study was sufficiently powered to detect a role of such factors. The results were also unaffected when we excluded patients with HBV/HCV coinfection or symptomatic TB.
Contrary to some observational studies [10,30] but consistent with a recent one in France [31], we did not observe a weaker early virologic response among SSA migrants. The difference in early CD4+ recovery persisted when we restricted our analysis to patients with sustained viral suppression from 6 months after cART initiation, suggesting that a difference in adherence was not responsible.
Other factors that could have influenced CD4+ recovery were considered as adjustment variables, including the BMI [32,33], tobacco and alcohol consumption, and depression, which might have been associated with a proinflammatory state or with poorer adherence to cART. As these factors were collected at each yearly visit, we were able to analyze the patients’ status to the time of cART initiation.
Most importantly, the difference in early CD4+ recovery between SSA migrants and French natives also persisted after additional adjustment for socioeconomic and living conditions. Most studies having shown an effect of socioeconomic status on the response to ART were conducted in the United States [34], where universal free healthcare is not available. The effect of socioeconomic status in these studies was largely attenuated after adjustment for adherence [34]. In France, all HIV-infected patients have free access to care: this may explain why we found no evidence of influence of socioeconomic factors on the immunologic response to cART. Similarly, the recent COHERE paper showed similar rate of CD4+ cell count recovery by educational level in the 6 months after cART initiation [35].
Vitamin D deficiency has been linked to weaker CD4+ recovery during antiretroviral therapy [16–18]. As expected [13,36], we found that SSA migrants had lower vitamin D levels, but this did not explain their slower initial CD4+ recovery. Levels of some inflammatory markers, such as sTNFR1 and MCP-1, were also lower in the SSA migrants. This is consistent with a study that showed lower sTNFR1 levels among Black individuals [37], as well as a higher frequency of MCP-1 gene polymorphisms associated with low MCP-1 expression [38]. Adjustment for MCP-1 levels did not modify our results, however. In contrast, adjustment for sTNFR1 levels, lower in SSA migrants, contributed to attenuate the difference in CD4+ recovery between groups, which was no longer significant; of note, this adjusted analysis was performed among a smaller subset of patients, for whom the inflammatory marker was measured.
Among limitations of our study, we could not adjust for the HIV-1 subtype, as almost all SSA migrants were infected with a non-B subtype. However, many studies have shown that the immunologic response to cART is not weaker in patients infected with non-B subtypes [39–41]. In one study [42], the CD4+ cell increment was similar whatever the subtype, except that subtype A tended to be associated with slower initial but more rapid long-term recovery. Note that subtype A accounts for only 6% of non-B subtypes in France [41].
We also had only a crude measure of alcohol consumption (classified as two glasses a day), as data on units of alcohol or type of alcohol were not systematically recorded.
A major strength of this study is the simultaneous recording of clinical and biological characteristics, as well as regularly updated social and economic characteristics, collected through regular visits and repeated self-administered questionnaires during a long follow-up period. This allowed us to conclude, in a context in which HIV care is freely accessible and uniformly proposed to all HIV-infected individuals, that the slower initial CD4+ response to cART among SSA migrants could not be explained by differences in social or economic characteristics relative to French natives. This was also unlikely related to known clinical and biological determinants, factors already adjusted for. This points to the possible role of other mechanisms, including microbial translocation. Gut microbiota of migrants may not resemble that of French natives. Gut bacteria have been proposed to play a key role in HIV disease progression. Even after sustained ART, microbial translocation is not fully controlled by antiviral therapy and is associated with inefficient CD4+ cell reconstitution [43]. In our study, median length of time between arrival in France and diagnosis was 3 years.
SSA migrants were diagnosed at later stage, with a lower CD4+ level, and the initial CD4+ recovery on cART was slower than in French natives. This highlights the need for regular and close follow-up to prevent the occurrence of complications of opportunistic infections during this initial period. However, although initially slower than in their native French counterparts, the immunologic response among SSA migrants was good, with an average gain of more than 250 CD4+ cells/μl after 36 months of cART. This further justifies cART prescription to all HIV-infected patients, whatever their origin and administrative status. Strategies need to be developed to allow HIV screening at an early stage of HIV infection.
Acknowledgements
R.D.-S., L.M., and R.S. wrote the article; M.G. and R.S. analyzed data; S.A., L.C., C.G., P.-M.G., A.M., F.R., and Y.Y contributed to interpretation of data and critically revised the article for important intellectual content.
The authors are grateful to all participants of the ANRS COPANA cohort study, and the ANRS COPANA cohort study group. They also thank Abdellatif Essabbani and Tatiana Feitoza for data monitoring. They thank David Young for editing the article.
The COPANA cohort is supported by the ANRS (‘France Recherche Nord&Sud Sida-HIV Hépatites’)
Conflicts of interest
There are no conflicts of interest.
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* Rosemary Dray-Spira and Laurence Meyer contributed equally to this work.
