Bruno Ledergerber, Matthias Egger, Véronique Erard, Rainer Weber, Bernard Hirschel, Hansjakob Furrer, Manuel Battegay, Pietro Vernazza, Enos Bernasconi, Milos Opravil, Daniel Kaufmann, Philippe Sudre, Patrick Francioli, Amalio Telenti, for the Swiss HIV Cohort Study. AIDS-Related Opportunistic Illnesses Occurring After Initiation of Potent Antiretroviral TherapyThe Swiss HIV Cohort Study. JAMA. 1999;282(23):2220–2226. doi:10.1001/jama.282.23.2220
Author Affiliations: Division of Infectious Diseases and Hospital Epidemiology, University Hospital, Zurich, Switzerland (Drs Ledergerber, Weber, and Opravil); Medical Research Council Health Services Research Collaboration, Department of Social Medicine, University of Bristol, Bristol, England (Dr Egger); Division of Infectious Diseases, University Hospital, Lausanne, Switzerland (Drs Erard, Kaufmann, Sudre, Francioli, and Telenti); Division of Infectious Diseases, University Hospital, Geneva, Switzerland (Dr Hirschel); University Medical Policlinic, Inselspital, Bern, Switzerland (Dr Furrer); University Medical Policlinic, Cantonal Hospital, Basel, Switzerland (Dr Battegay); Internal Medicine Clinic A, Cantonal Hospital, St Gall, Switzerland (Dr Vernazza); Infectious Diseases Ambulatorium, Regional Hospital, Lugano, Switzerland (Dr Bernasconi).
Context Acquired immunodeficiency syndrome–related opportunistic illnesses
(OIs) continue to occur after initiation of potent antiretroviral therapy
in patients with human immunodeficiency virus (HIV) infection. Risk factors
for clinical progression to OIs during potent therapy are not well defined.
Objective To examine the incidence of and risk factors for OIs among patients
treated with potent antiretroviral therapy in a population-based study.
Design The Swiss HIV Cohort Study, a prospective cohort study of adult HIV-infected
Setting Seven study centers throughout Switzerland.
Patients A total of 2410 cohort study participants with a potential follow-up
of at least 15 months after starting potent therapy between September 1995
and December 1997.
Main Outcome Measures Disease-specific incidence of OIs during the 6 months preceding potent
antiretroviral therapy and at 3 intervals after initiating therapy; risk factors
for development of OIs during therapy.
Results Of the 2410 participants, 143 developed 186 OIs after initiation of
potent antiretroviral therapy. Incidence of any OI decreased from 15.1 per
100 person-years in the 6 months before therapy to 7.7 in the first 3 months
after starting treatment, 2.6 in the following 6 months, and 2.2 per 100 person-years
between 9 and 15 months. Reductions in incidence ranged from 38% per month
for Kaposi sarcoma (P<.001) to 5% per month for
non-Hodgkin lymphoma (P = .31). Baseline CD4 cell
count continued to predict the risk of disease progression after initiating
potent therapy. Compared with CD4 cell counts above 200×106/L,
the hazard ratio for developing OIs was 2.5 (95% confidence interval [CI],
1.4-4.5) for counts between 51 and 200×106/L and 5.8 (95%
CI, 3.2-10.5) for counts below 51×106/L at baseline. Independent
of baseline CD4 cell count, a rise in CD4 cell count by 50×106/L or more and undetectable HIV-1 RNA in plasma (<400 copies/mL)
by 6 months reduced risk of subsequent events, with hazard ratios of 0.32
(95% CI, 0.20-0.52) and 0.39 (0.24-0.65), respectively.
Conclusions Our data indicate that the risk of developing an OI for a person receiving
potent antiretroviral therapy is highest during the initial months of therapy.
Baseline CD4 cell count and immunologic and virologic response to treatment
were strong predictors of disease progression in patients receiving potent
therapy. Individuals with CD4 cell counts of 50×106/L or
below may need close clinical surveillance after initiation of potent therapy.
Potent antiretroviral treatment has led to a dramatic decrease in human
immunodeficiency virus (HIV)-associated morbidity and mortality.1- 3
However, acquired immunodeficiency syndrome (AIDS)-related opportunistic illnesses
(OIs) continue to occur,4 and risk factors
for clinical progression during potent therapy are ill-defined at present.
Treatment is followed by progressive recovery of memory and naive CD4
T-lymphocyte subpopulations and of proliferative responses to various bacterial
and viral antigens; however, normalization may require years.5- 7
There is thus a period of uncertain immune function, particularly for persons
with advanced disease who are starting therapy. Also, initiation of potent
therapy may be accompanied by inflammatory reactions to opportunistic pathogens,8- 12
probably because of rapid immune response recovery, which may alter clinical
We examined the Swiss HIV Cohort Study database to identify incidence
patterns and risk factors for developing OIs among patients treated with potent
The Swiss HIV Cohort Study enrolls HIV-infected persons aged 16 years
or older.14 Patients are followed up in 1 of
7 study centers (Basel, Bern, Geneva, Lausanne, Lugano, St Gall, Zurich).
Enrollment is independent of disease stage or degree of immunosuppression
and data are collected according to standardized criteria on structured forms
at registration and at follow-up visits scheduled at 6-month intervals. Medications
are registered by month of initiation and discontinuation. We measured CD4
cell counts with flow cytometry and viral load with the Roche Amplicor Monitor
assay (Roche Diagnostics, Basel, Switzerland, level of detection, 400 copies/mL).
AIDS was defined according to category C clinical conditions of the Centers
for Disease Control and Prevention classification system for HIV infection
revised in 1993.15 Ethics committees in the
7 centers approved the study, and informed consent was obtained from all participants.
We included all participants of the Swiss HIV Cohort Study who started
potent antiretroviral therapy between September 1, 1995, and December 31,
1997; had a CD4 cell count and viral load measurement during the 3 months
before starting; and made at least 1 follow-up visit more than 1 month after
starting potent therapy. The database included data up to March 1999. All
patients had a potential follow-up of at least 15 months after starting potent
therapy. Potent antiretroviral therapy was defined as combination treatment
with at least 3 drugs, including at least 1 protease inhibitor.
We excluded patients receiving regimens for which saquinavir hard gel
capsules were the only form of protease inhibitor used because of reduced
probability of reaching undetectable viremia2
(probably explained by inferior bioavailability of saquinavir in hard gel
We calculated disease-specific incidence for the 6 months preceding
potent antiretroviral therapy, and months 1 to 3, 4 to 9, and 10 to 15 after
initiating potent therapy. These intervals were chosen a priori. Incidences
were calculated by dividing the number of patients developing an event by
the number of person-years at risk. In patients developing the event of interest,
follow-up was censored at the date the diagnosis was made, but subjects were
followed up for all possible OIs as long as they survived. We used the Poisson
distribution to calculate confidence intervals (CIs). We used Poisson regression
to estimate slopes of incidence trends, coding time points as 0 for the period
preceding start of potent therapy; 1.5, covering the first 3 months; 6, months
4 to 9, and 12, months 10 to 15.
We analyzed the risk of progression to an OI at any time during follow-up,
including events occurring more than 15 months after initiating potent therapy,
by means of Kaplan-Meier life-table methods and Cox proportional hazards regression.
We measured time from initiating potent therapy either to the OI diagnosis
date or the date of the most recent follow-up visit. We considered the importance
of treatment response in analyses excluding the first 6 months (to allow adequate
assessment of treatment outcome) after starting potent therapy; however, all
patients were included in the analysis.
Proportional hazards assumptions were based on Schoenfeld residuals.17 Results are presented as odds ratios or hazard ratios,
with 95% CIs. Analyses were conducted using SAS (version 6.12; SAS Institute,
Cary, NC) and Stata software (version 6.0; Stata Corporation, College Station,
Between September 1995 and December 1997, 2867 (66.2%) of 4328 patients
seen in the Swiss HIV Cohort Study started protease inhibitor–containing
regimens with at least 3 antiretroviral drugs. We excluded 61 patients (2.1%)
having saquinavir (hard gel capsule formulation) as the only protease inhibitor,
98 patients (3.4%) who were not seen since initiating treatment, and 298 patients
(10.4%) with missing baseline viral load or CD4 cell count. The analysis was
thus based on 2410 patients (84.1%) contributing 3974 person-years of follow-up.
The mean number of visits per patient was 7.9 (range, 1-29); 642 patients
(26.6%) were female. Categories of HIV transmission included men having sex
with men (n = 925, 38.4%), injectable drug use (n = 701, 29.1%), heterosexual
intercourse (n = 689, 28.6%), and transmission via blood products or an unclear
route (n = 95, 3.9%). Indinavir was used in 1284 patients (53.3%), ritonavir
in 619 (25.7%), nelfinavir in 305 (12.7%), a saquinavir-ritonavir combination
in 167 (6.9%), and other combinations in 35 (1.4%). A total of 919 patients
(38.1%) were treatment-naive prior to initiation of potent antiretroviral
therapy. In comparing the 6-month period before starting potent therapy with
the subsequent 6 months, no significant (P>.25) changes
were noted for primary and secondary prophylaxis of Pneumocystis
carinii pneumonia and cerebral toxoplasmosis, antifungal or antimycobacterial
drugs, therapy for cytomegalovirus disease, or anticancer treatment.
During the same period, 1522 patients seen in a study clinic did not
start potent therapy. Compared with patients starting potent therapy, median
CD4 cell counts were higher (303 vs 188 × 106/L, P<.0001) and median viral load lower (3.94 vs 4.49 log RNA copies/mL, P<.001) among those not starting therapy.
Incidence trends across the 4 time periods before and after initiating
potent antiretroviral therapy are shown in Figure 1 for all OIs combined and for individual diseases diagnosed
in 10 or more patients. The incidence of 15.1 new OIs per 100 person-years
during the 6 months preceding potent therapy was similar to that of 15.7 per
100 person-years observed in the entire cohort from 1992 to 1994, before potent
therapies were available.18 Incidence of any
OI decreased to 7.7 per 100 person-years in the first 3 months after starting
treatment, 2.6 in the following 6 months, and to 2.2 per 100 person-years
between 9 and 15 months. Incidences of individual diseases generally followed
a similar pattern, although the decline appeared to be more pronounced for
some diseases than others. This was further examined in regression analyses.
The decline was described by a log linear relationship. Incidence of all OIs
combined decreased by an estimated 18% per month (P<.001).
The reduction in incidence ranged from 38% per month for Kaposi sarcoma (P<.001)
to 5% per month for non-Hodgkin lymphoma (P = .31).
A formal test for heterogeneity indicated that this variation in slopes was
unlikely to be due to chance (χ27 = 15.9; P = .03).
Incidence rates and selected characteristics of events are shown in Table 1 for 6 months before and 15 months
after initiating potent therapy. No significant difference was observed between
the 2 periods for CD4 cell count at diagnosis. Prior to initiation of potent
therapy, 9.2% of events (10/109) occurred at CD4 cell counts greater than
200×106/L vs 12.6% (13/103) during the 15 months after start
of therapy (P = .42 by χ2 test). With
potent therapy, significantly more events (P<.001)
occurred at undetectable viral load levels: 28.4% (29/102) vs 7.1% (7/98).
Overall, 143 participants developed 186 OIs at any time after starting
potent antiretroviral therapy. Esophageal candidiasis was the most frequent
OI (n = 49), followed by nontuberculous mycobacterial infections (n = 29),
cytomegalovirus disease (n = 27), non-Hodgkin lymphoma (n = 15), toxoplasmosis
(n = 13), P carinii pneumonia (n = 11), tuberculosis
(n = 9), progressive multifocal leukoencephalopathy (n = 8), Kaposi sarcoma
(n = 6), and other (n = 19). A new event occurred in 125 patients and 18 patients
suffered a relapse of a previous condition. At baseline, there were no differences
between subjects developing and not developing OIs in age and sex distribution,
HIV transmission group, history of antiretroviral therapy, or type of potent
In multivariate Cox regression analyses, baseline CD4 cell count was
the best predictor of disease progression risk in the setting of potent therapy.
Compared with CD4 cell counts above 200 ×106/L, the hazard
ratio for developing OIs was 2.5 (95% CI, 1.4-4.5) for counts of 51 to 200×106/L, and 5.8 (3.2-10.5) for counts of 50×106/L or below.
Baseline viral load, clinical stage, and age were also independent predictors
of progression risk (Table 2).
Kaplan-Meier estimates, stratified by baseline CD4 cell count, are shown in Figure 2. At 30 months of follow-up, the
estimated cumulative risk of developing an OI was 18.8% (95% CI, 14.8%-22.8%)
in patients with a baseline CD4 cell count below 50 × 106/L,
vs 7.3% (95% CI, 5.1%-9.5%) in patients at 50 to 200 × 106/L,
and 2.1% (95% CI, 1.1%-3.2%) in patients with a CD4 cell count above 200 ×
We analyzed the risk factors for developing OIs after the initial 6
months of potent antiretroviral therapy (Table 3). In Cox regression, baseline CD4 cell count, but not baseline
viral load, continued to predict the ongoing risk of clinical progression.
In addition, both a rise in CD4 cell count by 50 × 106/L
or more and reaching undetectable viremia by 6 months reduced risk of subsequent
events. This protective effect was also present for subjects with advanced
disease (CD4 cell count ≤50 × 106/L) since there was no
evidence of an interaction between effects associated with values at baseline
and at 6 months. Kaplan-Meier estimates of OIs stratified by CD4 cell count
and viral load at 6 months are shown in Figure
3. The cumulative incidence of OIs at 30 months was 16.6% (95% CI,
11.3%-21.8%) among participants with 200 × 106/L or fewer
CD4 cells and detectable viremia at 6 months, whereas rates of 5% or less
were observed among patients with CD4 cell counts above 200 × 106/L or with viremia below level of detection at 6 months.
We analyzed AIDS-related OIs before and after initiation of potent antiretroviral
therapy in a large HIV cohort. Our results indicate that decline in the incidence
of OIs takes place soon after starting potent therapy and is not explained
by concomitant changes in the use of drugs for OI prevention. The risk of
developing an OI while receiving potent therapy is highest during the initial
months of therapy and thus patients should be followed up closely during this
critical period. However, the decline varies between diseases. Early reductions
in incidence were less pronounced for cytomegalovirus disease, nontuberculous
mycobacterial disease, and esophageal candidiasis. Continued immunodeficiency
as well as inflammatory reactions accompanying the restoration of immune function10- 12 may have contributed
to this trend.9
Clinical manifestations that were suggestive of immune restoration disease
included uveitis and vitritis in 2 patients with cytomegalovirus retinitis,
diffuse adenopathy and cutaneous bullous reaction in a patient with disseminated Mycobacterium bovis infection, and necrotizing intra-abdominal
adenopathies in 2 patients with M avium who were
treated with antimycobacterial drugs. In the latter cases, mycobacteria were
observed microscopically but could not be cultured. We also observed 1 patient
with rapid development of multiple cerebral lesions compatible with progressive
multifocal leukoencephalopathy followed by spontaneous improvement and 2 patients
with Kaposi sarcoma having a rapid worsening of skin lesions. The incidence
of herpes zoster infection may also increase following initiation of potent
therapy.19 The occurrence of some OIs at higher
CD4 cell counts further supports the notion that a number of early events
may have been triggered by potent therapy. Adjuvant treatment with corticosteroids
has been shown to be useful in controlling some of these manifestations such
as tuberculosis20 and ocular cystoid macular
edema.13 Such treatment was successful in our
patients with Kaposi sarcoma and symptomatic intra-abdominal adenopathies
due to M avium disease. Controlled trials are required
to define the role of corticosteroids in management of immune restoration
disease after initiation of potent therapy.
Patients ceased to be at risk of developing Kaposi sarcoma once immune
function had been improved, whereas they appeared to continue to be at risk
for non-Hodgkin lymphoma, despite potent therapy. Numbers were small and results
should therefore be interpreted with caution. However, the discrepant trends
in the incidence of the 2 HIV-related malignancies were also evident in analyses
comparing the years when potent antiretroviral therapy was introduced with
previous periods.18 One could speculate that
the causal link with an infectious agent (human herpesvirus 8) makes Kaposi
sarcoma more amenable to control through recovery of specific immunity than
the process of malignant transformation in non-Hodgkin lymphoma.
The CD4 cell count at the time of initiation of potent therapy was a
strong predictor for development of OIs in ensuing months. Similar findings
were reported for the EuroSIDA study.21 Furthermore,
in our study, risk beyond the first 6 months was reduced substantially if
the CD4 cell count increased by at least 50×106/L and undetectable
viremia was reached. A therapy-induced CD4 cell count of 200×106/L at 6 months continued to distinguish more profound from moderate
immunodeficiency, as only a small percentage of all observed events occurred
above that threshold. This observation is relevant to the current discussion
about the pace of immune recovery for patients receiving potent therapy and
to the question of whether primary or secondary OI prophylaxis can be stopped.22 A number of studies suggest that it is safe to stop
primary prophylaxis against P carinii pneumonia in
patients who experience a sustained rise of their CD4 cell count to 200×106/L or above.23- 25
Low rates of disease progression were seen among patients reaching a
CD4 cell count of 200×106/L or more even in the presence
of virological failure, which confirmed the results of an earlier analysis
of the database.2 However, it is unclear how
long these CD4 cell counts can be maintained in the presence of uncontrolled
viremia.26,27 In a minority of
patients, OIs developed despite satisfactory control of viremia. In some patients,
the recovery of immune reactivity triggering clinical symptoms can be invoked
as a plausible explanation. Other patients have a slow CD4 cell recovery despite
optimal control of viremia.28 These patients
remain at risk, and would likely benefit from continuation of prophylactic
interventions and possibly additional treatments aimed at accelerating immune
recovery, for example, with interleukin 2.29
The pattern of OIs seen in the present study reflects the impact of
potent therapy in a population of HIV-infected persons living in a country
with nearly universal health insurance coverage. The reasons for initiating
or not initiating potent therapy in the Swiss HIV Cohort Study have been analyzed.30 Patients were treated with regimens that conform
to current guidelines regarding use of potent antiretroviral therapies.31 Unfortunately, adherence to treatment was not recorded
in this study. A measure of adherence has only recently been introduced.
In conclusion, our results should contribute to clinical decision making
in the era of potent antiretroviral therapy.32
Clearly, a thorough understanding of the natural history of AIDS-related OIs
and a comprehensive analysis of the pace and quality of immune recovery in
each patient is required for optimal clinical management.