The prognosis of HIV infection has improved considerably after the introduction of highly active antiretroviral therapy (HAART) [1–5]. However, several observational studies on HIV patients starting HAART have shown an association between clinical progression to AIDS or death, and the CD4 cell count and plasma HIV-RNA levels at baseline [6,7]. Recently a large pooled analysis on 12 574 treatment-naive patients starting HAART in 13 different cohorts, found that the CD4 cell count at the time of the initiation of therapy was the dominant prognostic factor for disease progression .
Most information on mortality related to HIV infection has been derived from studies on risk factors for disease progression, or from comparisons with historical cohorts, not taking into account the mortality of the general population. The aim of the present study was to compare the mortality in HIV-infected patients starting HAART with the mortality of population controls, with focus on the impact of the CD4 cell count level at the time of starting treatment.
Subjects and methods
Demographics of HIV infection and health care in Denmark
The population of Denmark as of January 2002 was 5 368 000, of which 55% lived in Western Denmark defined as Funen and Jutland. HIV infection has a relatively low prevalence in Denmark: an estimated 3800 people were living with HIV infection in 2001, yielding an adult HIV prevalence of 0.15%.
Treatment for HIV infection in Denmark is restricted to specialized public centres, of which five are localised in Western Denmark. The Danish health care system provides free medical care and treatment for all residents, including antiretroviral treatment for HIV- infected individuals. Patient care and treatment strategies are similar throughout the country, with routine visits planned every 3 months for patients receiving antiretroviral therapy, and every 3 to 6 months during earlier stages of the disease. The main criteria for institution of antiretroviral therapy are: CD4 cell count < 300 × 106 cells/l, plasma HIV-RNA > 100 000 copies/ml, or HIV-related disease.
Population controls were retrieved by use of the Danish Civil Registration System, a nation-wide registry on all persons residing in Denmark after 1 April 1968. All residents in Denmark are assigned a unique 10-digit person identification number at birth (civil registration number, or CPR number), which is stored in the Danish Civil Registration System along with information on date of birth, residency, date of immigration or emigration, and date of death. The 10-digit CPR number is made up of the birth date, and a four-digit code that contains information on the gender of the individual.
A random sample from the Danish Civil Registration System in western Denmark was provided as population controls. For each HIV-infected patient (index-person), the data on 100 residents from this sample were retrieved. The aim with selecting 100 population controls per index-person was to give an approximation to the general population. The population controls were randomly chosen from the sample, and were matched on gender and age (month and year of birth). All population controls were alive at the date the index-person started HAART.
The HIV Cohort Study in Western Denmark is a prospective, population-based cohort study of all HIV-infected individuals treated by one of the HIV centres in Western Denmark. Study methods and baseline cohort characteristics have been described in detail . Briefly, all HIV-infected patients attending one of the centres after 1 January 1995 are included in the study. Up to January 2002, 971 patients were enrolled. The study is ongoing, with newly diagnosed HIV-infected individuals, and individuals with HIV infection who move to the region being continuously enrolled. Use of the CPR number, enables the centres to avoid multiple registrations on single patients, and to track whether the patients have died or moved outside the region when they are lost to follow-up.
Data on the patients were collected at baseline (i.e. the first visit to the centre), and every 12 months thereafter. Variables collected at baseline included date of birth, gender, mode of infection, race, ethnicity (if not Danish: country of origin and date of arrival to Denmark), date of first positive HIV-1 test, and diagnosis of AIDS-defining diseases (using the 1993 clinical definition of AIDS from the US Centers for Disease Control and Prevention ). Variables collected at follow-up visits included date and cause of death, date of initiation of HAART, date of starting and stopping an antiretroviral drug, indication for changing HAART regimen, prophylactic treatment against opportunistic infections, and laboratory values (CD4 cell count, plasma HIV-RNA, cholesterol (total) and triglycerides).
All HIV patients from the cohort who had started HAART before 1 January 2002 were eligible for this analysis. HAART was defined as a regimen consisting of at least three antiretroviral compounds. In the analysis of baseline factors, CD4 cell counts and HIV-RNA values were defined as the latest values measured within the 6 months prior to start of HAART. A previous AIDS-defining event was defined as having experienced an event prior to, or within 1 month of starting HAART. In the analyses of mortality, the outcome was death from any cause during the follow-up period. Causes of death were grouped into three categories: HIV-related, unknown, and other causes.
Comparison with the general population
In the analysis of relative mortality, we used a person-years analysis to estimate the rate of death during the follow-up period. Person-years at risk (PYR) were accrued from the time of starting HAART (or for population controls from the date the index-person started HAART) to the date of death, or last follow-up. Event-free subjects were right censored as of 1 January 2002, or at the date of moving outside the country. For both groups a mortality rate (MR) per 1000 PYR was estimated, and for comparisons between the groups we estimated the ratio between the two MRs, the mortality rate ratio (MRR). In all analyses, we used an approach, in which the patients continued to contribute to the PYR despite treatment interruptions or terminations.
To evaluate the influence of the baseline CD4 cell count on mortality, the cohort of HIV-infected patients and the respective population controls were grouped into four arbitrary baseline CD4 groups: CD4 cell count < 50, 50–99, 100–199, and ≥ 200 × 106 cells/l. The baseline CD4 cell count was defined as the latest CD4 cell count measured before start of HAART; however, individuals who had no CD4 cell count measured within 6 months of starting HAART were excluded from the analyses of the CD4 cell groups. For each CD4 cell group the MRR was estimated by comparing the MR of the HIV-infected patients, to the MR of the respective population controls. Similar, MRs were estimated for two arbitrary baseline plasma HIV-RNA levels (< 100 000 and ≥ 100 000 copies/ml). The baseline CD4 cell count and HIV-RNA groups used in this study, were chosen as they represent levels that have been demonstrated to be associated with survival in HIV patients starting HAART . In the analyses of the MRs in the various groups based on baseline CD4 cell count or plasma HIV-RNA, the HIV-infected patients and respective population controls, remained in the particular group, ignoring subsequent changes in CD4 cell count or plasma HIV-RNA during treatment.
In order to restrict the analysis to HIV-infected patients not reporting intravenous drug use (IDU) as primary mode of infection, we repeated the analysis after excluding these patients. In this analysis we accordingly excluded the respective population controls.
Risk factors within the HIV cohort
To summarize the risk of dying during follow-up in the cohort of HIV-infected patients, we used Kaplan–Meier analysis to construct survival curves. In these time-to-event analyses, the Cox proportional hazards model was used to study the association between patient baseline factors and mortality, estimating the relative risk of death, and associated 95% confidence intervals. The following potential confounders were considered for inclusion in the final model: gender, age (more than 40 years versus less than 40 years), history of IDU, year of HIV diagnosis, previous AIDS-defining event, CD4 cell count at the start of HAART (< 50, 50–99, 100–199, and ≥ 200 × 106 cells/l), viral load at the start of HAART (< 100 000 versus ≥ 100 000 copies/ml), previous antiretroviral treatment, and treatment with saquinavir (SQV) hard-gel capsule in the initial HAART regimen. A variable was included in the final model if it changed the estimated exposure effect by at least 10% when considered as the sole covariate . Data analysis was performed using SPSS version 10.0 (Norusis; SPSS Inc., Chicago, Illinois, USA) statistical software.
In total, 647 HIV-infected patients starting HAART before 1 January 2002, were included in the analyses, yielding 1970 PYR. The median follow up time was 3.5 years. Table 1 shows the demographic and baseline characteristics at the time of starting HAART in all patients, and in the patients in the four CD4 cell groups. Overall, males constituted 66.8% of the patients, and the median age at starting HAART was 37.3 years. More than half of the patients (52.6%) were infected through heterosexual contact. The median CD4 cell count was 198 × 106 cells/l, and median plasma HIV-RNA was 4.8 log10 copies/ml. Of all subjects, 44.4 % were antiretroviral treatment experienced prior to starting HAART. In the first-line HAART regimen, 64.9% received a single protease inhibitor (PI), 11.9% a dual PI, 11.6% an non-nucleoside reverse transcriptase inhibitor (NNRTI) (without a PI), 5.1% an NNRTI with a PI, and 6.5% a triple nucleoside reverse transcriptase inhibitor (NRTI) regimen. A total of 163 patients (25.2%) started a SQV hard gel-based regimen.
A total of 25 patients had no CD4 cell count measured within 6 months of starting HAART, and were excluded from the analyses of the CD4 cell groups. Among the patients starting HAART, baseline CD4 cell count was: < 50 × 106 cells/l in 118 patients (19%), 50–99 × 106 cells/l in 69 (11%), 100–199 × 106 cells/l in 134 (22%), and ≥ 200 × 106 cells/l in 301 (48%). When considering the baseline characteristics of the patients in the four CD4 cell-based groups, it appeared that median plasma HIV-RNA was highest in the group with CD4 cell count < 50 × 106 cells/l, with 5.3 log10 copies/ml, declining through the groups to 4.5 log10 copies/ml in the group with CD4 cell count ≥ 200 × 106 cells/l. Similarly, the proportion having an AIDS-defining event prior to, or at the time of starting HAART, declined from 50.8% in the lowest CD4 cell group, to 8.6% in the highest CD4 cell group. The four CD4 cell groups did not differ substantially with regard to gender, age, mode of infection, or racial background.
A total of 64 700 subjects were included as controls and followed for a total of 215 580 person-years, starting observation time at the date the index person (i.e. the HIV-infected person) started HAART.
During follow-up there were 53 deaths in the HIV-infected patients and 815 in the population cohort. The MR was 26.9 deaths per 1000 PYR among HIV-infected patients, and 3.8 deaths per 1000 PYR in the population controls. Comparing HIV-infected patients with population controls, we found a MRR of 7.1 [95% confidence interval (CI), 5.4–9.4]. Figure 1 shows the Kaplan–Meier plots for death after starting HAART (for HIV-infected patients), or the index date (for population controls). Overall, 3.9% of HIV-infected patients died within 52 weeks (95% CI, 2.4–5.5) and 0.32% (95% CI, 0.28–0.36) among population controls. At 104 weeks the estimated proportions were 5.7% (95% CI, 3.8–7.6) and 0.67% (95% CI, 0.61–0.72), respectively.
The mortality in the HIV-infected patients varied according to CD4 cell counts. Figure 2 shows the cumulative risk of death in the HIV-infected patients and the respective population controls, when dividing the cohorts into four groups according to baseline CD4 cell count. The MRs in the CD4 cell groups of HIV-infected patients differed dramatically, being 70.0 per 1000 PYR in the lowest CD4 cell group (< 50 × 106 cells/l), 45.7 in the group 51–99 × 106 cells/l, 20.8 in the group 100–199 × 106 cells/l, and 3.2 for those with the highest CD4 cell counts (≥ 200 × 106 cells/l). The Kaplan–Meier estimates of the cumulative mortality proportions at 52 weeks for the four groups were: 9.7, 8.0, 4.0 and 0.7% (from CD4 cell count < 50 to ≥ 200 × 106 cells/l).
Table 2 presents the MRRs comparing the MRs between HIV-infected patients with population controls. There was an excess risk of death in the HIV-infected patients in all four CD4 groups. However, the MRRs declined with increasing CD4 cell counts, from 15.3 (95% CI, 9.8–23.8) among those with the lowest counts to 3.6 (95% CI, 2.0–6.5) among those with the highest.
To minimize the impact of excess mortality in HIV patients reporting IDU as mode of transmission, we repeated the analysis after excluding these patients, 36 in all (five deaths). Compared to the non-resticted analyses this analysis showed modestly lower MRs and MRRs. Hence, excess mortality expressed by the MRR were 14.9 (95% CI, 9.5–23.4), 7.7 (95% CI, 3.8–15.8), 5.4 (95% CI, 2.6–10.9), and 3.0 (95% CI, 1.5–5.8) in the four strata (from CD4 cell count < 50 to ≥ 200 × 106 cells/l).
When focusing on the two groups based on plasma HIV-RNA at the time of starting HAART, the MRs differed considerably between the two groups: 34.5 and 13.7 deaths per 1000 PYR in the patients with ≥ 100 000 and < 100 000 copies/ml, respectively. Accordingly the MRRs also differed: 10.4 (95% CI, 6.8–15.9) and 3.6 (95% CI, 2.1–5.9) respectively (Table 2). Having a history of an AIDS-defining event at baseline also resulted in a high MR of 56.8 per 1000 PYR, as opposed to a MR of 19.2 per 1000 PYR in patients not having experienced an AIDS-defining event. The resulting MRRs were 14.1 (95% CI, 9.1–21.7) for patients with, and 5.2 (95% CI, 3.6–11.8) for patients without AIDS at baseline.
The crude and adjusted analyses of the baseline factors associated with the time to death in the cohort of HIV-infected patients, are presented in Table 3. In the multivariate analysis, only CD4 cell counts of less than 100 × 106 cells/l, and age ≥ 40 years at the time of starting HAART, were significantly associated with death. Patients with a CD4 cell count of less than 50 × 106 cells/l were 3.55 (95% CI, 1.46–8.65) times more likely to die during follow-up than patients with a CD4 cell count of 200 × 106 cells/l or more. Patients more than 40 years old were 3.59 (95% CI, 1.81–7.12) times more likely to die than patients younger than 40 years.
The causes of death for the HIV patients were HIV-related in 62.3% of the cases, other causes in 26.4%, and unknown in 11.3%. The distribution in causes of death did not change considerable between the CD4 strata; In the four strata (from CD4 cell count < 50 to ≥ 200), 59.1, 66.7%, 55.6, and 63.6 % of deaths were reported to be HIV-related, respectively.
As our analyses were restricted to patients starting HAART, some patients would have died before initiating therapy. In our cohort we found a total of 16 patients who died in the HAART-era after fulfilling positive criteria for treatment (CD4+ cell count < 300 × 106 cells/l, plasma HIV-RNA > 100 000 copies/ml, or HIV-related disease), but without having started HAART. Of these, the majority (nine patients) died before 1 January 1 1998, that is in the early HAART period.
In this population-based cohort study of HIV-infected patients, we found that those who started HAART had higher mortality rates than population controls, and that the excess mortality was highly dependent on the CD4 cell count at the time of starting HAART.
Our findings suggest that HIV-infected patients starting HAART have relatively low rates of mortality, especially when treatment was initiated with baseline CD4 cell counts of at least 200 × 106 cells/l. For these patients mortality was 3.6 times higher than for the population controls, decreasing to 3.0 times higher after restriction of the analysis to HIV patients not reporting intravenous drug use as the primary mode of transmission. Most interestingly, we found the excess mortality in patients with a baseline CD4 cell count of at least 200 × 106 cells/l to be similar to the excess mortality reported from various cohort studies on mortality in patients with insulin-treated diabetes [12–18]. These studies all find an excess mortality in the diabetic patients, but with large variations (standardized mortality ratio, (SMR) ranging from 1.9 to 7.4), probably because of considerable differences in design, location, study populations, gender and age. In a large British cohort study on more than 23 000 insulin-treated young diabetic patients (diagnosed under the age of 30 years), Laing et al. found an excess mortality with an SMR of 4.0 for females, and 2.7 for males overall, but reaching a peak of 5.7 in females aged 20–29 years, and of 4.0 in males aged 40–49 years .
In the interpretation of the results in our study, it is important to bear in mind that the excess mortality estimates will underestimate the efficacy of the HAART regimens. As we used an approach, in which the patients continued to contribute to the person-years at risk despite treatment interruptions or terminations, some of the patients starting HAART will contribute to the number of deaths even though they are no longer treated with antiretrovirals. A similar approach was used when defining the groups based on CD4 cell count at the start of HAART. Hence, of the patients dying in the highest CD4 cell group (≥ 200 × 106 cells/l), four patients (36%) had a CD4 cell count of less than 200 × 106 cells/l as the latest CD4 cell count measured (data not shown).
Most previous studies on mortality in HIV-infected patients have focused on the decline in mortality rates after introduction of HAART in comparison with mortality rates in historical cohorts of untreated patients [1,3–5,19–21], or on identifying risk factors for clinical progression with death as endpoint [6,7,22–24]. To our knowledge, only one previous study has focused on the mortality in comparison with the general population, but this investigation did not take into account baseline CD4 counts. Among 1157 HIV-1 infected patients starting HAART, Lewden et al. found that mortality was 7.8 times higher in HIV patients starting HAART than in the general population . Our study was performed using a population-based cohort of HIV-infected patients and a general population under good general medical surveillance. Through linkage with the personal identification number to the well-maintained Danish mortality files, we were able to follow a large number of population controls over time, greatly enhancing the comparisons under study . The opportunity of selecting a large number of well-described population controls from the region covered by the HIV cohort, led us to estimate mortality by calculating a MRR in stead of using standardizated rates based on the indirect method. Along with the population-based design of the cohort of HIV-infected patients, the strength of our study is the setting: a uniformly organized health care system with free access to medical care, and similar patient care and treatment strategies throughout the region. Furthermore the patients had a long follow-up period of 3.5 years (median).
Nonetheless, our study has several potential weaknesses. Above all, our analyses comparing mortality rates between HIV-infected patients and population controls are crude analyses apart from the matching on gender and age. The population controls are derived from a central register, which does not leave us any information on a number of potential confounding factors. Apart from the HIV-related morbidity, the HIV-infected individuals are likely to have a higher co-morbidity than the general population, ultimately leading to a higher mortality from diseases that are not related directly to the HIV infection. Hence, it is well-known that the prevalence of tobacco smoking and alcohol intake is higher among HIV-infected individuals than in the general population [27–29]. Other confounding factors that most likely are unevenly distributed between the two groups are: intravenous drug use, chronic hepatitis C infection, depression, and low socio-economic status [30,31]. In an attempt to minimize this bias, we performed additional analyses restricted to patients not being infected through intravenous drug use. The use of HAART has also been documented to induce several long-term toxicities, including metabolic changes with hyperlipidemia, and insulin resistance with impaired glucose tolerance and diabetes [32–34]. Whether these toxicities will evolve into a higher incidence of death from cardiovascular disease, for example, remains to be clarified.
When focusing on the causes of death, most were related to the HIV infection, even in the patients starting HAART with a CD4 cell count ≥ 200 × 106 cells/l. However, several of these deaths occurred at lower CD4 cell counts as a result of treatment failure or non-adherence to therapy. Mocroft et al. found that the proportion of deaths due to HIV-related causes decreased during the later years . Our study was too small to observe a similar effect.
Our study furthermore suggests the importance of being diagnosed, and starting HAART before reaching the level of severe immunosuppression. Various cohort studies have consistently shown the CD4 cell count to be the most important prognostic factor for clinical disease progression in patients starting HAART, regardless of whether the CD4 count used in the analysis was measured at baseline [7,8,24], at a certain time after starting treatment , or was the most recent CD4 cell count measured . In accordance with these findings, we found a low CD4 cell count (< 50 × 106 cells/l) at the time of starting HAART to be associated with a high mortality, 15.3 times higher than the population controls, and an increased risk of death in the Cox regression analysis with an adjusted relative risk of 3.55 compared to the group of patients with a high baseline CD4 cell count (at least 200 × 106 cells/l).
As the present study is limited to HIV patients starting HAART, it is a conservative estimate of the mortality in HIV-infected patients in the HAART-era, as some patients might die before starting HAART. However, this number was small in our setting with free access to antiretroviral therapy, with the majority dying in the early HAART-era (before 1 January 1998).
In summary, the mortality in HIV-infected patients starting HAART compared with the general population, is highly dependent on the CD4 cell count at the time of starting therapy. Mortality rate ratios declined from 15.3 in patients with CD4 cell count of less than 50 × 106 cells/l, to 3.6 in patients with CD4 cell count of at least 200 × 106 cells/l, the latter being similar to the excess mortality reported in young insulin-treated diabetic patients. These findings suggest the importance of starting HAART before attaining the level of severe impairment of the immune system, as measured by the CD4 cell count.
Sponsorship: This study received financial support from The Danish AIDS Foundation, Aarhus University, and the Western Danish Research Forum for Health Sciences. The funding sources had no involvement in the study design, in the collection, analysis, and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication.
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