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Changing incidence of AIDS-defining illnesses in the era of antiretroviral combination therapy

Brodt, H Reinhard2; Kamps, Bernd S.; Gute, Peter; Knupp, Bernhard; Staszewski, Shlomo; Helm, Eilke B.1


Objective: To determine the incidence of AIDS-defining opportunistic infections and malignancies over a 5-year period from 1992 to 1996.

Study population: Subcohort of 1003 homosexual men with HIV infection and CD4 count less than 200 × 106cells/l from the Frankfurt AIDS Cohort Study.

Methods: Data including the earliest date that a CD4 T-lymphocyte count < 200 × 106/l was reached and the dates of AIDS-defining events were compiled from medical records. Incidence analyses for AIDS-defining events and death during the subsequent 5 years (1992–1996) were performed using rates per 100 person-years of exposure.

Results: During the observation period, the number of patients per year with CD4 T-lymphocyte counts < 200 × 106/l varied between 402 and 511. In 1992, 56.7% of patients experienced at least one AIDS-defining illness, and 20.7% in 1996. The annual number of AIDS-defining events per 100 patient-years of observation declined from 143.5 in 1992 to 38.3 in 1996, and the number of AIDS-related deaths fell from 25.7 to 12.9. Analysis of the number of events confirmed this trend for malignancies and single opportunistic infections, with the exception of mycobacterial diseases.

Conclusions: The incidence of AIDS-defining events in patients with advanced HIV infection at Frankfurt University Hospital has declined by more than 70% from 1992 to 1996.

1Department of Internal Medicine, Division of Infectious Diseases, Johann Wolfgang Goethe University, Frankfurt, Germany.

2Requests for reprints to: Dr H. Reinhard Brodt, Medizinische Klinik III/Infektiologie, Theodor-Stern Kai 7, D-60590 Frankfurt am Main, Germany.

Date of receipt: 13 May 1997; revised 3 July 1997; accepted 11 July 1997.

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Most AIDS-defining illnesses, especially opportunistic infections, occur when CD4 T-lymphocyte counts in HIV-infected patients are below 200 × 106/l [1–5]. The use of primary and secondary prophylaxis for opportunistic infections has reduced the number of infections such as Pneumocystis carinii pneumonia (PCP), toxoplasmosis, and herpes simplex virus infections [6–9]. The impact of antiretroviral therapy on the incidence of opportunistic infections has been well defined since the introduction of zidovudine monotherapy [10,11]. Despite these early advances in treatment, the fatal course of advanced HIV infection has remained substantially unchanged. Most patients eventually die of complications refractory to therapy, for example, disseminated cytomegalovirus (CMV) disease, disseminated Mycobacterium avium complex infection, Kaposi's sarcoma (KS) and non-Hodgkin's lymphoma (NHL) [12–15].

Since 1993, a series of new strategies has profoundly changed the approach to antiretroviral therapy. Combination therapy consisting of various active compounds is now administered [16–18]. Furthermore, the efficacy of the initial treatment regimen is monitored by measuring viral load. In case of treatment failure, the therapeutic regimen is changed to include drugs to which the patient has not been exposed [19,20]. Finally, inhibitors of HIV-1 protease, a completely new class of drugs with potent anti-HIV activity, have become widely available since 1995. For the first time since the AIDS epidemic began, it is now possible to suppress viral replication in an HIV-infected patient to very low levels [21]. Increases in CD4 T-lymphocyte counts, which were transient during previous antiretroviral monotherapy, now persist over long periods of time. In parallel, the number of AIDS-related events has declined in patients treated with potent antiretroviral combination regimens [22]. To assess the magnitude of this decline in incidence of opportunistic infections and AIDS-related malignancies, we examined the incidence of these illnesses in patients with CD4 counts less than 200 × 106/l over a 5-year period.

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The Frankfurt AIDS Cohort Study is an ongoing open, prospective cohort study of HIV-infected homosexual men from the Frankfurt Rhein/Main area. Since its inception in 1985 at Frankfurt University Hospital and up until December 1996, 1799 subjects were recruited. After an initial comprehensive medical evaluation, each subject has follow-up evaluations every 6 months (or at shorter intervals in case of acute disease). These evaluations consist of a physical examination and laboratory tests including a CD4 T-lymphocyte count. Data on clinical AIDS events, CD4 cell counts, antiretroviral therapy, and PCP prophylaxis are collected with standardized methods during each clinical visit and are confirmed by a physician.

For the present analysis, a retrospective cohort was established based on homosexual men with CD4 counts of < 200 × 106cells/l, for whom at least one follow-up examination (at least 6 months apart) or death at some time was documented. Patients were recruited from January 1992 to December 1996 and were followed until March 1997.

For each patient, clinical AIDS diagnoses were retrieved from the cohort study database according to the 1993 Centers for Disease Control and Prevention criteria [23]. Further compiled data included age and the first known CD4 T-lymphocyte count for every year between 1992 and 1996, a history of AIDS-defining events at the first presentation each year, use of PCP prophylaxis with co-trimoxazole or aerosolized pentamidine during the year, and the type of antiretroviral regimen used at the last visit during that year. The antiretroviral regimens were classified as follows: (i) no therapy, (ii) monotherapy with zidovudine, (iii) two-drug therapy with reverse transcriptase inhibitors, and (iv) any combination therapy including at least one protease inhibitor. A treatment (or prophylaxis) regimen was allocated to an observation period (calendar year) only if patients had been treated for at least 90 days during that year, or if during the year they had stopped a treatment that had lasted for at least 90 days. If patients received more than one treatment regimen per year, only the upgraded regimen was included in the analysis of any given year.

The incidence of AIDS-related illnesses and deaths was calculated per 100 person-years (PY) of observation for each calendar year between 1992 and 1996. The observation period for any given year and for each patient began on 1 January if the patient had CD4 counts < 200 × 106/l during previous years, or if the patient had CD4 counts below 200 × 106/l for the first time during the given year on the day of the first known CD4 count < 200 × 106/l.

The observation period for any given year and for each patient ended on 31 December if the patient had follow-up examinations during subsequent years (until 31 March 1997 for the observation period 1996), on the date of the last presentation if the patient was lost to follow-up, or at the patient's death if the patient died during that year.

Differences in the frequency of each condition according to the year of observation were tested for significance using Pearson's χ2 test. Differences according to first CD4 cell count and age at the first visit per year were calculated using the Kruskal–Wallis test.

To assess changes in the occurrence of AIDS-related diseases and deaths, the proportion of patients with CD4 count less than 200 × 106/l who developed specific illnesses was calculated by year and the trend in this proportion examined using the χ2 test for trend [24]. The final analysis was based on 1003 homosexual men.

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Patient data are shown in Table 1. The annual number of patients with CD4 T-lymphocyte counts < 200 × 106/l varied between 402 and 511 over the 5-year observation period. The median patient age varied between 37 and 38 years. The median CD4+ count varied between 68 and 74 × 106/l during 1992–1995, and was 114 × 106/l in 1996. The percentage of patients receiving PCP prophylaxis was stable throughout 1992–1995 (74.1% in 1992, 77.6% in 1993, 78.2% in 1994, and 73.6% in 1995); however, this number declined in 1996 (62.6%). Comparison of the 1996 group with the previous groups revealed a statistically significant difference. There were no statistically significant differences between the groups with respect to patient history of AIDS.

Table 1

Table 1

The use of antiretroviral therapy changed continuously over the observation period, reflecting both the trend toward combination therapy, and, more recently, the availability of protease inhibitors (Fig. 1). In 1996, 87.3% of patients received one of the current antiretro-viral combination regimens, and 44.4% received at least one protease inhibitor.

Fig. 1

Fig. 1

The absolute number of patients with AIDS-defining events and AIDS-related deaths is shown in Table 2. Eleven patients died of causes such as non-AIDS-related malignancies (n = 4), myocardial infarction (n = 2), suicide (n = 4), and Staphylococcus aureus septicemia (n = 1); five patients died in 1992, three in 1993, one in 1994, two in 1995, and none in 1996. Changes in incidence rates reflecting the trend over time (expressed as events per 100 PY of observation) are shown in Fig. 2. Incidence rates in 1992 ranged from a low of 2.1 per 100 PY for Mycobacterium tuberculosis disease to a high of 19.2 per 100 PY for bacterial pneumonia. Over the subsequent years, the incidence of nearly all AIDS-defining events decreased. Major opportunistic infections such as PCP decreased from 17.8 per 100 PY in 1992 to 6.4 per 100 PY in 1996, disseminated CMV disease decreased from 14.7 per 100 PY in 1992 to 3.6 per 100 PY in 1996, and AIDS-related malignancies such as KS decreased from 17.5 per 100 PY in 1992 to 4.4 per 100 PY in 1996, and NHL decreased from 5.8 per 100 PY to 1.5 per 100 PY in 1996.

Table 2

Table 2

Fig. 2

Fig. 2

It is of interest that the incidence of tuberculosis remained stable throughout the observation period, and the incidence of disseminated M. avium complex infection declined less than that of other opportunistic infections.

In contrast to previous years, patients in 1996 had significantly fewer episodes (P < 0.05) of PCP, candida oesophagitis, bacterial pneumonia, CMV disease, progressive multifocal leukoencephalopathy, AIDS dementia, wasting syndrome, KS and NHL. Although the differences between 1996 and 1995 did not generally reach statistical significance, there was a trend toward fewer disease episodes. The overall incidence of all AIDS-defining events gradually but continuously declined from 143.5 events in 1992 to 38.3 events in 1996. Of the 1992 group, 56.7% of patients experienced at least one AIDS-defining illness during the same year in contrast to 20.7% in 1996. Deaths from AIDS-related causes declined in parallel from 25.7 cases in 1992 to 12.9 in 1996.

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These findings show a remarkable reduction of morbidity and mortality during the last 5 years of observation of a subcohort of homosexual patients with AIDS or high risk of AIDS (CD4 count < 200 × 106/l at least once). Compared with results in 1992–1995, overall morbidity and mortality due to AIDS-related diseases decreased significantly in 1996 (P < 0.001 and < 0.05, respectively). During the same period, antiretroviral combination regimens became established as the treatment of choice (5.7% in 1992; 87.3% in 1996). Consequently, the median CD4 T-lymphocyte count at the first clinical visit increased significantly by nearly one-third: from 68 × 106cells/l in 1992 to 114 × 106cells/l in 1996. The degree of immunodeficiency in patients who had CD4 T-lymphocyte counts less than 200 × 106/l thus seemed less pronounced during the last year of observation.

The incidence of each major opportunistic illness, with the exception of mycobacterial diseases, was significantly reduced in terms of absolute patient numbers and events per 100 PY from 1992 to 1996. Although the higher CD4 T-lymphocyte count in 1996 could in part explain the declining incidence of opportunistic infections, the reduction of KS and NHL found in our study was remarkable.

In contrast to previous studies, our data did not show an increase in the incidence of lymphoma in HIV-positive patients on prolonged antiretroviral treatment [15,25–28]. Indeed, the majority of NHL occur as late-stage AIDS diseases [29], are associated with low CD4 cell counts [30] and longer duration of HIV infection [31], and are known to be a consequence of long-lasting cellular immunodeficiency due to other diseases [4,32]. This suggests that the partial restitution of the immune system in our subcohort of patients may have caused the declining incidence of NHL.

The overall declining risk of KS in homosexual cohorts since 1993 is more intriguing. Although it has been discussed elsewhere to result from the lower transmission of KS-associated herpesvirus due to changes in sexual practices [33,34], no changes were observed in the incidence of KS as a consequence of antiretroviral therapy [14,35–38]. The reduction of newly acquired KS by one-half within 1 year (1996 compared with 1995) after the availability of protease inhibitors, however, is compatible with reports of KS regression under combination therapy with protease inhibitors. It remains unclear whether this is directly due to an antiviral effect or to improved immunosuppression [39]. Although the study was restricted to patients with CD4 counts less than 200 × 106 cells/l, our findings may also have consequences for patients with more than 200 × 106 CD4 cells/l. If the incidence of NHL and KS declined due to the more efficient antiretroviral combination therapy with protease inhibitors, this would theoretically justify administering this therapy to all HIV-infected persons, irrespective of the stage of disease. Further studies are required to confirm our results. Furthermore, it is necessary to determine whether the addition of anti-retroviral combination therapy (including protease inhibitors) to chemotherapy for NHL leads to a better outcome.

The decreasing incidence of opportunistic infections may be partly due to advances in prophylaxis and treatment. The only primary prophylaxis our patients received was inhaled pentamidine against PCP, and, beginning in 1993, co-trimoxazole against PCP and toxoplasmosis. Co-trimoxazole is effective against both conditions; however, the incidence of PCP and toxo-plasmosis continued to decrease throughout 1996, although compared with 1995, fewer patients received either inhaled pentamidine or co-trimoxazole in 1996. Bacterial pneumonia may also have been prevented by routine PCP prophylaxis with co-trimoxazole. As for necrotizing herpes simplex and candida oesophagitis, more early and easily administered treatment (including self-administered drugs) favours the prevention of clinically severe disease manifestions [11,40].

The specific mode of transmission and the pathogenesis of tuberculosis may explain why the incidence of this illness remained unchanged in our cohort; however, the number of events was small and further investigation is needed [41]. In contrast to other late-stage diseases such as CMV retinitis, leukoencephalopathy, and wasting syndrome, all of which had a substantially reduced incidence per year, the occurrence of disseminated M. avium infection did not significantly change as one would have expected. Whereas this finding agrees with other European reports, the incidence of M. avium disease in our study is nevertheless lower than in comparable populations in the United States [42–44].

Two major limitations of our study result from its design as a natural history study and the restricted inclusion of patients up to 1996. All patients were homosexually infected men who had been observed for a similar length of time. There were no differences with respect to age and the number of previous AIDS-defining illnesses. Nevertheless, the different numbers of patients who presented at our institution during subsequent years for the first time, as well as their initial health status before entering the study, could cause a selection bias in treatment and prophylaxis, because patients who seek medical care might be in a more advanced stage of disease. However, when disease events within the first 6 weeks of the first visit at our institution were excluded from the analysis, the results did not differ from the original analysis (data not shown). Furthermore, the percentage of patients with a history of AIDS-defining illnesses at first presentation did not change significantly during subsequent calendar years (34.8 to 40.2%). In addition, the percentage of patients who were known at our institution for at least 1 year was fairly constant over time and could not have influenced the decreasing incidence of AIDS-defining opportunistic diseases.

The increasing CD4 T-lymphocyte count of the patient populations in 1996 may not be solely a result of antiretroviral therapy, but may also be due to the selection bias caused by the decreasing numbers of new study patients when an increasing number of antiretro-viral drugs became generally available. Moreover, treatment effects and compliance have not been assessed individually, and data on the reasons for different treatment regimens were not collected. When we compared the incidence of AIDS-defining diseases in patients who received protease inhibitors and those who did not, we did not find a significant difference (data not shown). The reason for this was probably the fact that when protease inhibitors became available, they were prescribed to a substantial number of critically ill patients.

Despite these limitations, treatment and prophylaxis of all patients took place in the same department, and all patients received the best regimens available at the time. Information on antiretroviral medication was included in the analysis only if patients had had a full course of this medication and had been observed for more than 90 days in one of the four different treatment categories. Therefore, upgraded treatment changes in 1996 may not reflect the real situation in this population: at the end of 1996 up to 80% of all patients with CD4 counts less than 200 × 106cells/l were on protease inhibitors (data not shown). This study also shed light on the increasing difficulties of conducting time-dependent clinical endpoint studies, which were complicated by the natural history of the disease, rapid changes in HIV treatment, and the obligation to administer individually adjusted therapy. Clinical advantages and the efficacy of new drugs are thus usually demonstrated first only by virological and surrogate markers. However, despite these reservations, our findings clearly show the efficacy of combination therapy in an urban homosexual population outside a treatment protocol.

In summary, this study of the natural history of AIDS establishes that there has been an impressive reduction of AIDS-related mortality, opportunistic infections, and malignancies in homosexual patients with high risk of disease over the last 5 years. The extensive use of anti-retroviral combination therapy from 1992 to 1996 was accompanied by a substantial disease reduction of more than 70% in these patients. Above all, the remarkable decline of malignancies in our cohort raises hopes that these illnesses can be further reduced in the future.

An important aspect of the study is that it reflects the situation in the real world outside experimental protocols. Although the findings of our study can probably be applied to other groups with reasonably good access to comprehensive HIV care, generalizations must be made with caution. It is necessary to repeat our study in populations with other modes of HIV transmission, other highly endemic background infections such as mycobacterial diseases, and long-term combination therapy.

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Opportunistic infections; Kaposi's sarcoma; lymphoma; natural history; antiviral therapy

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