Migrants from Sub-Saharan Africa in the Swiss HIV Cohort Study: access to antiretroviral therapy, disease progression and survival

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1 Migrants from Sub-Saharan Africa in the Swiss HIV Cohort Study: access to antiretroviral therapy, disease progression and survival Cornelia Staehelin a, Martin Rickenbach b, Nicola Low j, Martin Egger a, Bruno Ledergerber c, Bernard Hirschel d, Valérie D Acremont e, Manuel Battegay f, Thomas Wagels g, Enos Bernasconi h, Christine Kopp i, Hansjakob Furrer a and the Swiss HIV Cohort Study Objective: To examine the proportion of migrants from Sub-Saharan Africa entering the Swiss HIV Cohort Study (SHCS) and to compare these participants with participants from Northwestern Europe for access to antiretroviral therapy, progression to AIDS and survival. Design: Prospective national cohort study of HIV-1-infected adults from seven HIV centres in Switzerland. Methods: Trends in the proportion of participants from Sub-Saharan Africa were followed in HIV-infected adults entering the SHCS from 1984 to Survival methods were used to compare uptake of antiretroviral therapy, survival and progression to AIDS in the 2684 participants from Sub-Saharan Africa and Northwest Europe enrolled from Results: There was a steady increase in the proportion of Sub-Saharan African participants over time, reaching 11.9% in These participants were more likely to be younger, female, to have been infected by heterosexual intercourse and had lower CD4 cell counts at presentation. There were no differences between Sub- Saharan Africans and Northwest Europeans in uptake of triple antiretroviral therapy, progression to AIDS or survival up to 48 months after starting treatment. Tuberculosis was the most frequent AIDS-defining event in Sub-Saharan African patients. Conclusions: There is no evidence that access to potent antiretroviral therapy is influenced by geographic origin of participants. The prognosis of Sub-Saharan African patients on triple therapy is equivalent to that of Northwest European patients. Future research should address wider issues about access to specialist health services for HIVinfected people from Sub-Saharan Africa. & 2003 Lippincott Williams & Wilkins AIDS 2003, 17: Keywords: AIDS, Africa; CD4 cell count, cohort studies, disease progression, HIV, migration, proportional hazards models, survival, Switzerland, tuberculosis See also p From the a Division of Infectious Diseases, University Hospital Berne, b Data Center of the Swiss HIV Cohort Study Study, Lausanne, c Division of Infectious Diseases, University Hospital Zurich, d Division of Infectious Diseases, University Hospital Geneva, e Division of Infectious Diseases, University Hospital Lausanne, f Division of Infectious Diseases, University Hospital Basle, g Division of Infectious Diseases, Cantonal Hospital St. Gall, h Division of Infectious Diseases, Cantonal Hospital Lugano, i Swiss Federal Office of Public Health, Berne, Switzerland and the j Department of Social Medicine, University Bristol, UK. Requests for reprints to: Dr H. Furrer, Division of Infectious Diseases, University Hospital Berne, CH-3010 Bern, Switzerland. Received: 11 October 2002; revised: 27 February 2003; accepted: 15 April DOI: /01.aids ISSN & 2003 Lippincott Williams & Wilkins 2237

2 2238 AIDS 2003, Vol 17 No 15 Introduction The course of the HIV epidemics in Western Europe and Sub-Saharan Africa differ. While the numbers of newly detected HIV infections was declining in Switzerland in the late 1990s, the epidemic increased dramatically in most parts of Sub-Saharan Africa. The high prevalence of HIV infection in these countries of origin may be partly reflected in migrants to Western Europe. HIV prevalence could be lower in migrants because of a healthy migrant effect, since migrants need to be healthy enough to travel and have sufficient resources, but it could also be higher if they come predominantly from vulnerable and marginalized groups. No data, however, are currently available in Switzerland. In 2000, the Swiss Federal Office of Public Health reported that the number of newly detected HIV infections in Swiss nationals declined steadily from 1992 to 1998 but increased in patients of Sub-Saharan African origin in the same period [1]. Migration from Sub- Saharan Africa into Switzerland also rose, from 4398 per year in to 6495 per year in in people changing residency to Switzerland (Swiss Federal Office of Statistics, personal communication) and from 848 per year in to 4785 per year in in asylum seekers (Swiss Federal Office of Refugees, personal communication). The natural history of HIV-1 infection in Africa shows some similarities to that in industrialized countries before the introduction of potent antiretroviral therapy [2,3]. Overall survival from seroconversion is estimated to be around 10 years [2], which is comparable to that of HIV-infected individuals in developed countries up to 1996 [4]. However, progression to symptomatic disease [5] and from AIDS to death [2] in Africa are rapid. This may be because non-specific signs and symptoms associated with HIV are also common in the general population and because secondary prophylaxis for AIDSdefining conditions may not be available [5]. In industrialized countries before the era of potent antiretroviral therapy, disease progression amongst black Africans did not differ from that of the white population [6]. The present study uses data from the Swiss HIV Cohort Study (SHCS) [7] to describe trends in presentation and characteristics of migrants from Sub-Saharan Africa and to compare their access to antiretroviral treatment and clinical course with those of participants of Northwestern European origin during the period when highly active antiretroviral therapy has been available. Methods The Swiss HIV Cohort Study Since 1988 the SHCS ( has continuously enrolled HIV-infected persons aged 16 years or older independent of disease stage or degree of immunodeficiency [8,9]. Patients are followed in one of seven study centres. All HIV-infected adults presenting at any of the study centres are asked to participate in the study and participation does not influence access to specialized health care. Refusal is uncommon, being 5.4% (73 out of 1331 patients) in one centre and has not changed over time. Data are collected according to standardized criteria on structured forms at registration and at follow-up visits scheduled at 6-month intervals. AIDS is defined according to category C clinical conditions of the Centers for Disease Control and Prevention (CDC) classification system for HIV infection revised in 1993 [10]. CD4 cell counts were measured by flow cytometry and HIV plasma RNA levels by the Roche Amplicor Monitor assay (Roche Diagnostics, Basel, Switzerland). Ethics committees in the seven centres approved the study, and informed consent was obtained from all participants. The SHCS is representative of the epidemiology of advanced HIV infection in Switzerland including approximately 70% of the patients diagnosed with AIDS in the country [7]. The patient s nationality is recorded and grouped according to geographical regions, using a similar classification to the UNAIDS report on the global HIV epidemic [11] and the Swiss Federal Office of Public Health [1]. In these classifications Western Europe is divided into two geographical regions; Northwestern Europe includes Switzerland and Southern Europe consists of Spain, Portugal, Italy, Greece, Malta and San Marino. The other geographic regions are Eastern Europe and Central Asia, USA and Canada, Caribbean, Latin America, Australia and New Zealand, South and East Asia, North Africa and the Middle East, and Sub- Saharan Africa. Analysis Using the SHCS database updated in April 2002, changes in the proportion of participants of Sub-Saharan African and Northwest European origin in the SHCS were analysed over four time periods: before 1989, , and Pertinent data such as sex, presumed mode of HIV transmission, age, CD4 cell count, plasma HIV RNA levels and CDC stage at enrolment of HIV-infected persons of Sub- Saharan African origin were compared with those of participants of Northwest European origin. CDC stage at enrolment included events related to HIV infection within 30 days of enrolment, thus taking into account events that prompted clinical presentation. Access to antiretroviral therapy was compared in the two groups of SHCS participants for the period , which represents the time when triple antiretroviral drug regimens had become the standard of care for patients with an indication for antiretroviral therapy, although guidelines for starting therapy changed during

3 Sub-Saharan migrants in the Swiss HIV Cohort Study Staehelin et al this period [12 14]. The uptake of antiretroviral therapy was measured as the proportion of participants with CD4 cell counts, cells/l who started an antiretroviral regimen with at least three drugs during follow-up regardless of their CDC stage of infection. Pearson s chi square and Wilcoxon rank sum tests were used as appropriate for group comparisons. Kaplan Meier survival analysis was used to measure the time from enrolment to the start of therapy and the clinical response to antiretroviral therapy for two well-defined clinical endpoints [15]: the time from enrolment in the SHCS to a first AIDS-defining event and overall survival. The analysis of the uptake of therapy included patients starting antiretroviral drugs up to 30 days before the date of enrolment because this takes into account delays between the initial consultation and the formal start of follow-up when written consent had been obtained. Cox proportional hazards models were used to control for differences between the two patient groups. Transmission category was dichotomized into acquisition by injection drug use and all other routes because a recent publication showed that the former was associated with worse outcomes in patients starting potent antiretroviral therapy [16]. Statistical analyses were conducted using Stata software (version 7.0; Stata Corporation, College Station, Texas, USA). Results Trends in proportions of migrants from Sub- Saharan Africa and clinical characteristics Up to 30 April 2002, HIV-infected adults had been enrolled in the SHCS; 9420 (79%) were of Northwestern European origin, 671 (6%) of Sub- Saharan African origin and 1781 (15%) from other geographic regions. The proportion of migrants from Sub-Saharan Africa among SHCS participants (Fig. 1) rose steadily over time from 0.9% before 1989 to % % % 77.6% % 2.8% 5.9% 11.9% Before N-W-Europe Sub-Sah Africa Fig. 1. Registrations within the Swiss HIV Cohort Study during the four time periods for enrolees from Northwestern Europe (grey bars) and Sub-Saharan Africa (black bars). 11.9% in (linear trend P, 0.001). The relative increase was more pronounced in women, who constituted a greater proportion of this patient group. Sub-Saharan African women accounted for 23% (247/1072) of all women enrolled from 1997 to 2001 and 34% (57/170) of those enrolled in During that period, a greater proportion of women from Sub- Saharan Africa (18%, 44/247) were pregnant at entry into the study, had given birth to a child or had experienced abortion during the 6 months before entering the SHCS, compared with 6% (38/641) of women of Northwest European origin (P, 0.001). The main presumed transmission mode amongst the Sub-Saharan African patients was heterosexual (Table 1). From 1997 to 2001, participants of Sub-Saharan African origin were younger and had lower median CD4 cell counts at registration than participants from North- Western Europe. However, the proportion of enrolees with CD4 cell counts, cells/l in the two patient groups was similar: 35% in Sub-Saharan Africans and 31% in Northwestern Europeans (P ¼ 0.13). There was no difference in plasma HIV load between participants from the two regions (Table 1). Within men, 28% of Sub-Saharan origin presented with AIDS compared with 18% of their European counterparts. This difference could be explained by the increased numbers of tuberculosis in the former. Women from Sub-Saharan Africa were less likely than Northwest European women to present with AIDS at enrolment. Access to antiretroviral therapy Of the 2684 participants entering the SHCS in , 570 had started triple antiretroviral therapy more than 30 days before enrolment, 23% (88/390) of those from Sub-Saharan Africa and 21% (482/2,294) of those from Northwest Europe. By comparison, 51% (199/ 390) of Sub-Saharan African and 43% (989/2,294) of Northwest Europeans had CD4 cell counts, cells/l and had not started antiretroviral therapy before entering the SHCS. Of those, 83% (165/199) of Sub-Saharan African and 85% (844/989) of Northwest European participants started any antiretroviral treatment during follow-up, including 16 (10%) of the participants from Sub-Saharan Africa and 85 (10%) participants from Northwest Europe whose first regimen consisted of fewer than three drugs. Amongst patients starting triple antiretroviral therapy, there was a trend towards starting treatment at a lower CD4 cell count in patients of Sub-Saharan African origin [median cells/l; interquartile range (IQR) ] than in patients of Northwest European origin (median cells/l; IQR ) (P ¼ 0.07), reflecting the lower baseline CD4 cell

4 2240 AIDS 2003, Vol 17 No 15 Table 1. Comparison of participants from Sub-Saharan Africa and Northwestern Europe during the last registration period ( ). Female Male All Northwest European P value Sub-Saharan African Northwest European P value Sub-Saharan African Northwest European P value Sub-Saharan African No Median age [years (IQR)] 30 (26 35) 34 (30 40), (28 41) 38 (33 45), (26 37) 37 (32 43), Transmission category (%), 0.001, Heterosexual Sex between men 1 50 Injection drug use Other or unknown CDC stage (%) 0.5, A B C Median CD4 cell count [ cells/l (IQR)] 286 ( ) 330 ( ) ( ) 320 ( ) ( ) 324 ( ) Median plasma HIV RNA log10 HIV [copies/ml (IQR)] 4.1 ( ) 4.2 ( ) ( ) 4.3 ( ) ( ) 4.3 ( ) 0.27 IQR, interquartile range; CDC, Centers for Disease Control and Prevention [10]. counts of Sub-Saharan African participants. The time between enrolment and start of triple antiretroviral therapy in participants from both groups entering the SHCS with CD4 cell counts, cells/l was similar (Fig. 2). In a multivariable Cox regression model, higher plasma HIV RNA and a lower CD4 cell count were independently associated with starting antiretroviral therapy, while participants with intravenous drug use as transmission route started triple antiretroviral therapy later (Table 2). The results were materially unchanged when the analysis was restricted Proportion without triple antiretroviral therapy Proportion remaining AIDS free Proportion remaining alive (a) (b) (c) SSA NWE Follow-up time in months SSA Logrank p 0.59 Logrank p 0.14 NWE Follow-up time in months Logrank p 0.02 SSA NWE Follow-up time in months Fig. 2. Kaplan Meier graphs comparing uptake of antiretroviral therapy and disease progression in HIV-infected patients who are Sub-Saharan African and Northwest European in origin in the Swiss HIV Cohort Study. (a) Time to start triple antiretroviral therapy in participants entering with CD4 cell counts < cells/l. (b) Patients remaining AIDS free after entering the study. (c) Survival analysis after entering the study. SSA, participants of Sub-Saharan origin (bold line), NWE, participants from Northwestern Europe.

5 Sub-Saharan migrants in the Swiss HIV Cohort Study Staehelin et al Table 2. Cox regression models for time to start of triple antiretroviral therapy in patients with CD4 cell counts < progression to AIDS and death. cells/l, Start of triple antiretroviral therapy Progression to AIDS Progression to death Adjusted HR (95% CI) a P value Adjusted HR (95% CI) a P value Adjusted HR (95% CI) a P value Sub-Saharan versus North West European origin 1.0 ( ) ( ) ( ) 0.16 Female versus male sex 0.97 ( ) ( ) ( ) 0.2 Intravenous drug use versus other transmission 0.60 ( ), ( ) ( ) categories Age (per quartile increase) 1.02 ( ) ( ) ( ),0.001 Plasma HIV RNA at registration (per log 10 increase) 1.12 ( ) ( ), ( ) 0.06 CD4 count at registration (per cells/l 0.71 ( ), ( ), ( ) increase) CDC stage A 1 (reference) 1 (reference) 1 (reference) CDC stage B 1.08 ( ) ( ) ( ) 0.4 CDC stage C 1.02 ( ) 0.9 Not applicable 2.37 ( ),0.001 HR, hazard ratio; CI, confidence interval; CDC, Centers for Disease Control and Prevention [10]. a Hazard ratio adjusted for all the variables shown in the table. to participants with CD4 cell counts, cells/l at enrolment or those who acquired their infection heterosexually. Progression to a first AIDS-defining event There were 118 first AIDS-defining events after enrolment in the SHCS: 20 in participants from Sub- Saharan Africa and 98 in those from Northwest Europe. The most frequent AIDS-defining events were tuberculosis (7/20, 35%) and Kaposi s sarcoma (4/20, 20%) in the Sub-Saharan Africa group and Pneumocystis carinii pneumonia, candidal oesophagitis (17/98, 17% each) and Kaposi s sarcoma (11/98, 11%) in the Northwest European group. There were no significant differences in progression to AIDS between the two groups (P ¼ 0.14; Fig. 2b and Table 2). In the Cox regression model, only lower CD4 cell counts and higher plasma HIV RNA at enrolment were predictive of more rapid progression to AIDS. Including only participants with heterosexual transmission in the model did not change the results. If tuberculosis as an AIDS-defining event was excluded in the model, the adjusted hazard ratio (HR) for progression to AIDS in participants from Sub-Saharan Africa was 1.2 (95% confidence interval ) compared with the Northwest European group. Survival There were seven deaths in the Sub-Saharan African group and 129 deaths in Northwest Europeans in patients enrolled from 1997 to 2001 (Fig. 2c). The risk of death was significantly increased in patients of Northwest European origin (P ¼ 0.02) but was similar to that amongst Sub-Saharan African patients when only those presumed to have acquired their infection heterosexually were compared (P ¼ 0.09). In a multivariable Cox regression analysis, older age, CDC stage C, a lower CD4 cell count at registration and intravenous drug use as mode of transmission were independently associated with an increased hazard of death. Survival was not associated with country of origin (Table 2). Discussion The proportion of patients of Sub-Saharan African origin participating in the SHCS is increasing. This study shows that the uptake of triple antiretroviral therapy and rates of HIV disease progression among Sub-Saharan Africans are similar to those of participants from Switzerland and other parts of Northwest Europe. The main strength of this study lies in the study design. The SHCS collects data on HIV-infected patients throughout Switzerland, who are enrolled continuously, and is representative of HIV-infected people, especially those with late-stage disease [7]. The prospective design and the use of standardized definitions of AIDS-defining diseases mean that ascertainment of outcomes is unbiased with respect to the geographical origin of participants. The large number of participants in the SHCS, particularly women, also increases the precision of our estimates of outcomes of interest and the generalizability of our findings. The study also has limitations. The SHCS is a large study that collects data on a wide range of clinical demographic and social variables. For some specific research questions, the data are not sufficiently detailed. For example, the SHCS routinely collects information about country of birth but recording of ethnic group is less complete, so it is not possible to distinguish between participants from, say South Africa, who were from white, black or other ethnic groups. Both variables are needed for a comprehensive analysis of factors influencing the uptake of treatment, because the key issue is determining

6 2242 AIDS 2003, Vol 17 No 15 whether there is evidence of discrimination in the prescription of antiretroviral therapy. If a substantial proportion of Sub-Saharan African patients were from white and other ethnic groups with better access to antiretroviral drugs, this could mask a difference in uptake of therapy or progression rates between black Africans and participants from other ethnic groups. We think this unlikely, however, since available information suggests that the vast majority of Sub-Saharan Africans in the SHCS are from black ethnic groups. Migration from Sub-Saharan Africa to Switzerland has increased in the past few years. The increase in the proportion of participants of Sub-Saharan African origin in the SHCS shows a similar but more pronounced trend, which has been found in other European HIV clinics [17,18]. People from Sub-Saharan Africa accounted for 22.5% of those with newly detected HIV infection in 2000 in Switzerland [1], although they make up only % of the Swiss population. This might reflect the rising HIV prevalence in their countries of origin in recent years, now often exceeding 10% of the population [11]; however, it could also result from increased HIV-testing activity amongst African populations, particularly in women. Women of Sub-Saharan African origin now account for more than 30% of all newly registered women. Nearly one fifth of these women were admitted to an HIV treatment centre during pregnancy or shortly after having given birth. These events may have prompted the first serological test for HIV infection and highlight the importance of antenatal HIV testing as an intervention to reduce vertical transmission of HIV infection. Our study measured access to antiretroviral therapy quantitatively as the initiation of a triple antiretroviral regimen after enrolment in the SHCS. Uptake of treatment has also been used in studies examining the effects of race and ethnicity, socioeconomic factors and injecting drug use on access to therapy. Our results show that both the proportion of Sub-Saharan African patients with CD4 cell counts, cells/l prescribed triple antiretroviral therapy and the time taken to starting treatment were the same as for patients from Switzerland and other Northwest European countries. While the exact level of immunosuppression at which antiretroviral drugs should be started has been questioned, it is agreed that therapy is indicated in patients with a CD4 count, cells/l [6,19]. An analysis of our data using this cut-off value showed no difference between uptake in participants of Northwest European and Sub-Saharan African origin (P ¼ 0.8). This study confirms an earlier analysis from the SHCS showing that nationality was not associated with the uptake of antiretroviral therapy [20]. This may be because in Switzerland antiretroviral treatment is fully paid by the basic health insurance package, which is mandatory. A universal health-care system does not, however, guarantee equitable access to treatment, since a study from Canada showed that HIV-infected people from lower socioeconomic groups, which are likely to include more people from minority ethnic groups, were less likely to be prescribed triple therapy [21] Tackling racism in the provision of health care [22,23] and improving access for people from minority ethnic groups also includes making services culturally sensitive and non-stigmatizing, in order to facilitate early presentation, and providing interpreters and patient advocates so that patients can participate fully in decisions about their management. The fact that Sub-Saharan African migrants presented in the SHCS with more advanced HIV disease, which is also the case in the UK [24], shows that barriers to access at the level of presentation to the health services may still exist, although those patients may already have had advanced HIV disease when they arrived in Switzerland. Further qualitative research with study participants and health professionals should be carried out to increase our understanding of these broader issues. Potent antiretroviral therapy has led to an impressive decline in morbidity and mortality in countries where these treatments are available [16,25 28]. While some reports have found faster disease progression of HIVinfected persons in Africa [5], del Amo and colleagues found similar rates of progression to AIDS and survival in patients of African and European origin followed up in London before potent antiretroviral therapy was available [6]. Our results show that disease progression is also comparable for patients in the era of potent antiretroviral therapy, despite lower baseline CD4 cell counts in Sub-Saharan African patients. This study provides evidence on clinical outcomes to complement virological and immunological studies in London, showing that the time taken for viral load to become undetectable and the CD4 cell count to respond to highly active antiretroviral therapy are also similar in Europeans with HIV-1 subtype B infections and Sub- Saharan African patients infected with non-b subtypes. There was, however, evidence of a reduction in virological response in African patients after 9 months of therapy, which may have been related to problems with adherence to therapy [29]. In our study, similar rates of disease progression and survival persisted for up to 48 months of follow-up, so the significance of changes in viral load over time should be further investigated. The most frequent AIDS-defining event in the Sub- Saharan African group in the SHCS was pulmonary or extrapulmonary tuberculosis. While there was weak evidence for more rapid progression to AIDS (HR 1.55; P ¼ 0.12) in Sub-Saharan Africans, the longer survival with AIDS in the Kaplan Maier analysis could be explained by the higher prevalence of tuberculosis, which has a good prognosis as an AIDS-defining event

7 Sub-Saharan migrants in the Swiss HIV Cohort Study Staehelin et al [6]. It is difficult to compare our results directly with studies conducted in Africa because the World Health Organization (WHO) clinical staging system for HIV infection, which is most frequently used in resourcepoor settings, does not include tuberculosis in stage 4, which is analogous with AIDS. Badri et al. [30] found that the incidence of tuberculosis in HIV-infected patients with advanced disease (WHO stage 3 or 4) not on antiretroviral therapy was 24.1/100 person-years but only 4.6/100 person-years amongst a cohort treated with triple therapy. Our data indicate that treatment and prophylaxis of tuberculosis infection in our cohort should be addressed more actively in patients from Sub-Saharan Africa. There is no evidence that the country of origin of participants in the SHCS affects uptake of potent antiretroviral therapy or rates of disease progression. Further quantitative and qualitative research should be done to explore barriers to accessing health services, adherence to therapy and longer-term outcomes of HIV disease in Sub-Saharan African patients. As the numbers of HIV-infected women increases, further work is needed to develop strategies for antenatal HIV testing, which will promote earlier access to antiretroviral treatment for women and reduce the risk of vertical transmission. Acknowledgments The members of the Swiss HIV Cohort Study are M. Battegay, E. Bernasconi, H. Bucher, Ph. Bürgisser, M. Egger, P. Erb, W. Fierz, M. Fischer, M. Flepp (Chairman of the Clinical and Laboratory Committee), P. Francioli (President of the SHCS, Centre Hospitalier Universitaire Vaudois, Lausanne), H. Furrer, M. Gorgievski, H. Günthard, P. Grob, B. Hirschel, L. Kaiser, C. Kind, Th. Klimkait, B. Ledergerber, U. Lauper, M. Opravil, F. Paccaud, G. Pantaleo, L. Perrin, J.-C. Piffaretti, M. Rickenbach (Head of Data Centre), C. 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