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Virologic and Immunologic Response to Highly Active Antiretroviral Therapy in Indigenous and Nonindigenous HIV-1–Infected Patients in The Netherlands

Nellen, Jeannine F. MD*; Wit, Ferdinand W. MD, PhD*†; de Wolf, Frank MD, PhD‡§; Jurriaans, Suzanne PhD||; Lange, Joep M. MD, PhD*†; Prins, Jan M. MD, PhD*

JAIDS Journal of Acquired Immune Deficiency Syndromes: August 1st, 2004 - Volume 36 - Issue 4 - p 943-950
Epidemiology and Social Science

Objective: To compare the results of antiretroviral treatment (highly active antiretroviral therapy [HAART]) in indigenous Dutch (ID) and nonindigenous HIV-1–infected patients in Amsterdam, the Netherlands. We focused on the largest groups of nonindigenous people visiting our outpatient clinic: patients from other industrialized countries (western), from Surinam/Netherlands Antilles (SNA), and from sub-Saharan Africa (SSA).

Design: Retrospective cohort analysis of 692 therapy-naive HIV-1–positive individuals who visited our outpatient clinic for the first time between July 1, 1996 and December 31, 2001.

Methods: We compared the groups at the time of their first visit to our clinic; at the start of HAART; and according to the virological, immunologic, and clinical treatment response during the 96 weeks after the start of HAART.

Results: Of the patients starting antiretroviral therapy, 362 were ID, 84 were western, 72 were from SNA, and 110 were from SSA. SNA and SSA patients had a lower CD4 cell count at first visit (ID = 330 cells/mm3, western = 330 cells/mm3, SNA = 250 cells/mm3, and SSA = 170 cells/mm3; P = 0.0002). Treatment in SNA and SSA patients was also started at a lower CD4 cell count, but the plasma HIV-1 RNA level was comparable. After the start of HAART, a similar rise in CD4 cell count was seen in the 4 groups (P = 0.33), but the baseline difference in CD4 cell count remained present during the follow-up period of 96 weeks. After adjusting for variables potentially influencing treatment outcome, the proportion of patients not reaching a plasma HIV-1 RNA level <400 copies/mL was not different for the 4 groups in contrast to the percentage not reaching a plasma HIV-1 RNA level <50 copies/mL (at 48 weeks: ID = 4.8%, western = 27.5%, SNA = 23.1%, and SSA = 24.2%; P = 0.017 over the 96-week time period). After the start of HAART, nonindigenous patients also more often had progression to Centers for Disease Control and Prevention (CDC) stage C or died (P = 0.006).

Conclusions: In nonindigenous patients, treatment with HAART was equally successful in terms of the increase in CD4 cell count but was substantially less effective in achieving a plasma HIV-1 RNA level below 50 copies/mL. Further investigations should explore differences in adherence and pharmacokinetics in these patient groups.

From the *Department of Internal Medicine, Division of Infectious Diseases, Tropical Medicine and AIDS, and ||Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; †International Antiviral Therapy Evaluation Center, Amsterdam, the Netherlands; ‡HIV Monitoring Foundation, Amsterdam, the Netherlands; and §Department of Infectious Disease Epidemiology, Imperial College, Medical Faculty, London, United Kingdom.

Received for publication September 8, 2003; accepted November 24, 2003.

Supported by the AIDS Fonds, the Netherlands (grant 7004).

Reprints: Jan M. Prins, Academic Medical Center, Room F4-217, PO Box 22660, 1100 DD, Amsterdam, the Netherlands (e-mail:

Since the 1990s, highly active antiretroviral therapy (HAART) has been prescribed in the developed world for the treatment of HIV infection, resulting in a significant decline in HIV related morbidity and mortality. 1,2 In the Netherlands, the effect of HAART was monitored in a multicenter clinical cohort of HIV-1–infected patients, the ATHENA cohort, comprising more than 3000 patients. It showed a decrease in incidence of Centers for Disease Control and Prevention (CDC) stage C events in the time period between 1996 and 2000 from 2.63 to 0.04 per person-year, and mortality rates declined from 0.09 to 0.02 per person-year in the same period. 3

During the past years, the absolute and relative number of nonindigenous HIV-infected patients in the Netherlands is increasing. Of the new patients visiting the outpatient clinic of the Academic Medical Center, the percentage of nonindigenous patients increased from 36% in 1995 to 60% in 2001. Most of these new nonindigenous patients are immigrants from sub-Saharan Africa (SSA) and the former Dutch colonies in the Americas (Surinam and the Netherlands Antilles [SNA]). Whether or not the results obtained in the ATHENA cohort also apply to these nonindigenous patients is not known because they are underrepresented in this cohort for reasons of inability to read and understand or unwillingness to sign the informed consent.

In accordance with other studies, our clinical impression is that nonindigenous patients present with more advanced HIV disease. 4–6 Moreover, the impression of many HIV physicians is that antiretroviral therapy is less successful in these patients compared with that in indigenous (ID) Dutch patients. Biologic factors that might contribute to this lower success rate are differences in viral subtypes, 7–11 age at seroconversion, 12 disease stage at presentation, 13,14 pharmacokinetics, 15 and genetic factors. 16–18 Other factors that might contribute to a lower success rate are lower adherence because of problems with the Dutch language, other perceptions of illness and treatment, and differences in socioeconomic status.

If treatment results in this group are indeed less favorable, this should have consequences for the care that is offered. We therefore compared the nonindigenous patients visiting our outpatient clinic since 1996 with the ID patients with respect to disease stage at first presentation, transmission route, disease stage at HAART initiation, HAART regimen, and the virologic and immunologic success of therapy.

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Included in the study population were all patients who visited the HIV/AIDS outpatient clinic of the Academic Medical Center, Amsterdam, the Netherlands, between January 1996 and December 2001. The HIV-1 status of all patients was confirmed by a positive Western blot test.

Data on country of origin of all patients were provided by their treating physicians. Patients were defined as nonindigenous when they were not born in the Netherlands or when 1 or both parents were not born in the Netherlands.

Data of all nonindigenous patients were retrospectively collected on standardized forms from clinical case notes and computer-based medical records up to the time at which the patient entered the cohort, and prospectively thereafter, by trained data collectors or clerks experienced in HIV/AIDS care. The resulting database was updated approximately every 3 to 6 months and contains information on each patient’s country of origin, sex, age, transmission route, and start and stop dates as well as the dose frequency of every antiretroviral medication and prophylactic treatment administered against opportunistic infections, the primary reason why such treatments were stopped as classified by the treating physician, the dates of onset and resolution of HIV-related diseases, CD4 cell count, and plasma HIV-1 RNA level. Abnormal laboratory values are recorded, as are adverse events (all events that lead to a change in antiretroviral treatment and a number of pre-specified adverse events, such as neuropathy, lipodystrophy, and hepatitis). 19

Data of these nonindigenous patients were compared with data of the ID patients of our outpatient clinic who are monitored in the ATHENA cohort. Data in this cohort are collected in a similar way and by the same data managers.

During the study period, plasma HIV-1 RNA was quantified with 1 of 3 different quantitative assays: NASBA (Biomerieux) with a lower limit of detection (LLD) of 1000 copies/mL (from July 1996 until July 1997), NucliSens (Biomerieux) with an LLD of 400 copies/mL (from July 1997 until August 1, 1999) and later an LLD of 40 copies/mL because of a higher plasma input (from April 1, 1999 until June 2000), or Versant bDNA (Bayer) with an LLD of 50 copies/mL (from June 2000 onward).

At the time of analysis in September 2002, data were available for 1668 patients. The patients who were naive to therapy as of July 1, 1996 (date of the introduction of HAART in the Netherlands) or had a first visit after July 1, 1996 were included in the present analyses. Women who tested seropositive for HIV during pregnancy are described separately, because the decision to start and stop HAART and the choice of regimen are different in this group.

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Statistical Analysis

Data were analyzed with SAS version 8.02 (SAS Institute, Cary, NC). Differences between groups were considered significant at P < 0.05. All reported probability values are 2-sided.

Group comparisons were made using the Kruskal-Wallis test for continuous data. Categoric data were compared using the χ2 or Fisher exact test where appropriate. The increases from baseline in CD4 count were analyzed by a repeated measurement procedure using a generalized linear model (PROC MIXED of SAS software). Such an analysis takes into account that serial measurements of the outcome variable in a single patient are correlated and provides a valid statistical estimate of the main effect. The proportion of patients with an undetectable plasma HIV-1 RNA level while using HAART was compared between groups using the GENMOD procedure of SAS software. This procedure performs categoric data modeling by fitting linear models and incorporates repeated measurements. Differences in the incidence of disease progression and mortality were analyzed by Kaplan-Meier estimates and tested by the log-rank test. All analyses were carried out until 96 weeks of follow-up after the start of HAART.

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Patient Groups

Between July 1996 and December 31, 2001, 692 therapy-naive patients visited our outpatient clinic for the first time. Half (n = 343 [49.6%]) of the patients were ID, and 10.0% were from other industrialized countries in Europe (n = 54), the United States (n = 14), or Australia (n = 1) (western). Of the remaining 40.4%, the largest subgroups in our hospital were patients from SNA (n = 82 [11.8%]) and SSA (n = 121 [17.5%]). Of the patients from SSA, the largest proportion was from Ghana (n = 32). Given these numbers, we compared baseline and treatment results for ID, western, SNA, and SSA patients.

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Baseline Characteristics

Baseline characteristics are described in Table 1. Age, gender, and route of transmission differed significantly for the 4 groups. Patients from SSA were younger than ID patients and more likely to be female. The route of transmission was predominantly heterosexual in the patients from SSA and homosexual in ID patients.



The CD4 cell counts at presentation were 330 cells/mm3, 330 cells/mm3, 250 cells/mm3, and 170 cells/mm3 for ID, western, SNA, and SSA patients, respectively (P = 0.0002). The percentages of patients with a CD4 cell count below 200 cells/mm3 were 36.4%, 26.1%, 45.1%, and 55.4%, respectively (P = 0.0002). We found a statistically significant difference in plasma HIV-1 RNA; it was lower in the SNA and SSA patients in spite of a lower CD4 cell count (P = 0.038). The difference could not be attributed only to the higher percentage of women in the SNA and SSA patients. Linear regression analysis showed that CD4 cell count, race, and gender were independent predictors of viral load.

Disease stage according to the CDC classification did not differ between groups. The most frequent AIDS-defining conditions in ID patients were Pneumocystis carinii pneumonia (n = 28 [35.8% of C events in ID patients]) and esophageal candidiasis (n = 16 [20.5%]), whereas in SNA and SSA patients, tuberculosis (SNA: n = 2 [10%], SSA: n = 9 [36%]) and cerebral toxoplasmosis (SNA: n = 3 [14.3%], SSA: n = 4 [16%]) prevailed. The percentage of Kaposi sarcoma as an AIDS-defining condition did not differ between groups (ID = 14%, western = 9%, SNA = 10%, and SSA = 8%).

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Pregnant Patients

An additional 61 pregnant women visited our outpatient department for the first time between January 1996 and December 2001. The majority of these women came from SSA (n = 38), 13 came from SNA, 9 were ID, and 1 came from a western country. There were no significant differences between these groups with respect to age, CD4 cell count, and plasma HIV-1 RNA level at presentation (P > 0.1 in all cases). The CD4 cell count at presentation was significantly higher than in the nonpregnant women (ID = 360 cells/mm3, western = 1240 cells/mm3, SNA = 440 cells/mm3, and SSA = 290 cells/mm3). These 61 women were excluded from all further analyses.

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Characteristics of Patients Starting HAART

A total of 628 therapy-naive patients started HAART after July 1, 1996 (Table 2). At the start of treatment, the CD4 cell count (cells/mm3) differed significantly for the 4 groups: in SNA and SSA patients, the numbers of CD4+ T cells were 110 cells/mm3 and 130 cells/mm3 as compared with 220 cells/mm3 in ID patients and 250 cells/mm3 in western patients (P < 0.0001). There was no significant difference in plasma HIV-1 RNA level or CDC classification at the start of HAART. The time between the first positive HIV test and the start of HAART was significantly shorter in the SNA and SSA groups as compared with ID and western patients. The prescribed regimens seem to differ between groups, because there were more single and double protease inhibitor (PI)–based regimens prescribed in the ID group (P = 0.003). The explanation for this difference is that in 1996 and the beginning of 1997, no nonnucleoside reverse transcriptase inhibitors (NNRTIs) were available yet. In these years, the cohort contained more ID patients who got PIs prescribed as their first drug regimen. In later years, the proportion of nonindigenous patients in the cohort increased and NNRTIs also became available. Therefore, more PIs are prescribed in the ID group. At the time of the analysis, there was no significant difference between groups in NNRTI use (P = 0.26).



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Response to Treatment

The differences in CD4 cell count between ID and western patients versus SNA and SSA patients persisted during treatment (Fig. 1). This was attributable to differences at baseline, because the increase in CD4 cell count did not differ between patient groups (P = 0.33).



After adjusting for variables potentially influencing treatment outcome (baseline CD4 cell count, baseline plasma HIV-1 RNA level, age, gender, CDC stage of disease, and antiretroviral regimen), ethnicity was found to influence treatment outcome significantly. Kaplan-Meier estimates of the proportion of patients not reaching a plasma viral load (pVL) <400 copies/mL at any point over time were not different for the groups, but the percentage of patients not reaching a plasma HIV-1 RNA level <50 copies/mL at any point over time was significantly different over the 96-week period (P = 0.017); at t = 48 weeks, the percentages were: ID = 4.8 %, western = 27.5%, SNA = 23.1%, and SSA = 24.2% (Figs. 2A, B). To explore whether viral suppression was sustained during follow-up, overall percentages of patients with an undetectable viral load during follow-up are shown in Figures 2C and D. There was no difference in the overall percentage of patients during follow-up having an undetectable plasma HIV-1 RNA level when tested in the assays with an LLD of 400 copies/mL in contrast to the percentage tested in the assays with an LLD of 50 copies/mL (ID vs. western:P = 0.0012, ID vs. SNA:P = 0.049, and ID vs. SSA:P = 0.0006; see Figs. 2C, D).



The proportion of patients still using the original HAART regimen after 48 weeks was around 50% (Fig. 3), which was not different for the 4 groups (P = 0.45). Major reasons for changing therapy were toxicity (n = 201) and pharmacologic reasons (eg, interaction with comedication, simplification of regimen [n = 61];Table 3). Reasons for changing therapy did not differ between groups. There was a significant difference in patients who stopped therapy for more than 12 weeks during the follow-up period (ID = 8.6%, western = 21.8%, SNA = 27.9%, and SSA = 10%; P = 0.001).





After the start of HAART, 48 people progressed to CDC classification stage C (32 patients) or died (16 patients). Kaplan-Meier estimates of progression to these clinical end points at 96 weeks showed significant differences for the groups: ID = 3.45%, western = 10.2%, SNA = 16.4%, and SSA = 7.5% (P = 0.0006) The differences between the groups remained significant after adjustment for baseline CD4 cell count and age; nonindigenous patients reached end points more often (P = 0.006).

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On theoretic grounds, the course of HIV-1 infection and the response to therapy may be influenced by viral, environmental, and host factors. The population we treat for HIV-1 at our outpatient clinic has changed. In the past years, it has shifted to a population that contains many more nonindigenous, female, heterosexual patients with a different ethnicity and language, who are less informed about their HIV infection and treatment possibilities. Because our impression was that treatment results in these new groups were less favorable, we tried to confirm this impression by analyzing our own data.

Here, we focused on the 2 largest groups of nonwestern patients visiting our hospital. People from SSA are mainly refugees and first-generation inhabitants of the Netherlands. They rarely speak Dutch but mainly speak English and French. People from SNA are first- and second-generation inhabitants of the Netherlands. They mostly speak Dutch and have Dutch nationality, but there remains a cultural difference, although they are familiar with Dutch culture.

We classified people according to country of origin as a marker for ethnicity. Ethnicity stands for being part of a group with a shared origin, culture, and religious tradition. 20,21 Whatever classification system is used, it is a simplification of reality. 22 Classifying by country of origin has the limitations of ignoring ethnic and cultural differences within that country. The period of time people live in the Netherlands is also lost in the definition. Further, in some countries of origin, a single race is predominantly present, whereas in other countries, the population contains many races. Classification on the basis of race is even more complicated, however. 23–25

Our results show that SNA and SSA patients in the Netherlands are more often women and heterosexually infected. This likely reflects the epidemic in those geographic areas. They present at the outpatient clinic with a lower CD4 cell count and a lower or comparable viral load. Although a substantial proportion of these patients are at risk for opportunistic infections because of a CD4 cell count below 200 cells/mm3, the number of CDC stage C events was not higher than in ID patients. The lower CD4 cell count at first visit can be explained by the fact that most nonindigenous patients seek medical care when they have complaints. Many ID homosexual patients ask for HIV testing on a regular basis or after risky sexual behavior, without health complaints. When pregnancy was the reason for HIV screening, we showed that there were no differences between ID and nonindigenous patients. Normal values for the CD4 cell count may differ in different populations. Absolute CD4 cell counts in healthy Ethiopians are significantly lower than in healthy Dutch. 26 This may be the result of an immune system persistently activated by helminth infections. There is evidence that this difference disappears when Ethiopians live long enough in a western country and helminthic infections are cured. 27

In the groups with a lower baseline CD4 count, a higher mean plasma HIV-1 RNA level would be expected. Saul et al 28 reported a lower plasma HIV-1 RNA level given a certain CD4 cell count in black Africans. Patients from SSA and SNA are mainly of the Negroid race. Women also tend to have a lower viral load at a given CD4 cell count above 200 cells/mm3.29

HIV-1–infected patients from Africa living in London presented with a lower CD4 cell count and with different AIDS indicator diseases compared with non-Africans. 30 Differences in progression to AIDS and death in the pre HAART era between Africans and non-Africans living in London could not be attributed to ethnicity or different viral subtypes. 4 Age and clinical and immunologic status were the major determinants of outcome.

The start of medication at a lower CD4 cell count in non-indigenous patients is likely a reflection of the late presentation. The much shorter period between the first positive HIV test and the start of HAART supports this. Another possible contributing factor is that physicians may postpone treatment longer, in terms of absolute CD4 cell count, perhaps because they are afraid of problems with adherence to treatment.

In contrast to the similar increase in CD4 cell count for the 4 groups, virologic efficacy differed. The percentage of western, SNA, and SSA patients with an undetectable viral load was significantly lower than that of ID patients. A substantial proportion of the nonindigenous patients must have a plasma HIV-1 RNA level between 50 and 400 copies/mL, given the difference in outcome when analyzing the data for these 2 LLDs. Jensen-Fangel et al 31 found no effect of race/ethnicity on virologic response in a cohort in Denmark using an LLD of 500 copies/mL. For a sustained virologic response, a plasma HIV-1 RNA level below 50 copies/mL is necessary. 32 This is also a likely explanation for the similar increase in CD4 cell count between the groups: even suboptimal viral suppression can initially result in a good immunologic response.

How should these differences in virologic response be explained? Viral subtypes differ per part of the world 7–11,33 and can affect the time to disease progression and response to HAART. 34,35 Subtypes A, C, and D prevail in SSA, whereas in the western world, subtype B is predominant. The lower virologic success rate in SSA patients has therefore been attributed to a higher proportion of non-B subtypes, although genetic polymorphisms or lower adherence can also cause an impaired response to therapy. 11,15–18,36–38 Frater et al 6 determined viral subtypes in a European cohort and an African cohort living in London and found no effect of the subtype on virologic response. 6 Similar to our results, a significant difference was found between the cohorts in virologic response, and it was suggested this was the result of lower adherence. Here, we show that switching therapy was not the reason for this poorer virologic outcome, because in all groups, only 50% of patients used their baseline antiretroviral regimen after 48 weeks of treatment. Also, side effects of therapy did not differ between groups. SNA patients (but not SSA patients) more often stopped their therapy for longer periods of time, however.

In western patients, surprisingly, the reaction to HAART was also less favorable than in ID patients. This is may be a result of the specific characteristics of this group: young people in an early stage of the disease who travel a lot and stop medication frequently; thus, adherence problems are most likely the explanation for the poorer results in this group.

In conclusion, attention should be paid to early diagnosis of HIV in SSA and SNA groups, because their late presentation makes them at risk for opportunistic infections not shown by differences in CDC stage C events but in progression to CDC stage C events or death after the start of therapy. Further investigations should explore possible differences in adherence and drug metabolism so as to explain the poorer virologic success of antiretroviral therapy in the same groups. For the care that is offered today, these results justify special attention to adherence and therapeutic drug monitoring in nonindigenous patient groups.

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The authors thank Y. M. Ruijs and E. van der Ven for data collection and entry.

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HIV-1 infection; ethnic groups; highly active antiretroviral therapy; cohort studies; viral load

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