Pii: s0140-6736(01)06413-3

Prevalence of adverse events associated with potent antiretroviraltreatment: Swiss HIV Cohort Study Jacques Fellay, Karim Boubaker, Bruno Ledergerber, Enos Bernasconi, Hansjakob Furrer, Manuel Battegay, Bernard Hirschel, Pietro Vernazza, Patrick Francioli, Gilbert Greub, Markus Flepp, Amalio Telenti, for the Swiss HIV Cohort Study* IntroductionBecause so many retroviral agents are available, clinicians need a precise understanding of the efficacy treatment have been recorded in clinical trials, post- and toxic effects of the various drug combinations. When marketing analyses, and anecdotal reports. Such data efficacy is similar, the choice of combination will be might not be an up-to-date or comprehensive assessment of affected by the toxic effects of the drugs. Adverse all possible treatment combinations defined as potent reactions have been recorded anecdotally and in randomised clinical trials,1–3 but, little information isavailable about prevalence and severity of adverse events Methods Using a standard clinical and laboratory method, in routine clinical practice. To describe the pattern of we assessed prevalence of adverse events in 1160 clinical and laboratory abnormalities potentially patients who were receiving antiretroviral treatment. We associated with antiretroviral treatment, and to compare measured the toxic effects associated with the drug the prevalence of adverse events between drug regimens regimen (protease inhibitor [PI], non-nucleoside and and for various antiretroviral agents, we have done a nucleoside analogue reverse transcriptase inhibitor) and cross-sectional, observational study of 1160 patients who specific compounds using multivariate analyses. were receiving potent antiretroviral treatment. We did two types of analyses. First, we did a Findings 47% (545 of 1160) of patients presented with structured interview and laboratory analysis to identify clinical and 27% (194 of 712) with laboratory adverse and describe all potential adverse events attributed to events probably or definitely attributed to antiretroviral treatment according to standard definitions. Second, we treatment. Among these, 9% (47 of 545) and 16% (30 of identified independent associations using logistic 194), respectively, were graded as serious or severe.
regression analysis that excluded the investigator’s Single-PI and PI-sparing-antiretroviral treatment were assessment. This approach could be a useful strategy in associated with a comparable prevalence of adverse postmarketing analysis of the toxic effects of drugs used events. Compared with single-PI treatment, use of dual-PI- antiretroviral treatment and three-class-antiretroviraltreatment was associated with higher prevalence of adverse events (odds ratio [OR] 2·0 [95% CI 1·0–4·0], and 3·9 [1·2–12·9], respectively). Compound specific associations The Swiss HIV Cohort Study is a prospective cohort were identified for zidovudine, lamivudine, stavudine, study of individuals with HIV-1 who are aged 16 years or didanosine, abacavir, ritonavir, saquinavir, indinavir, older.4 Patients were followed up in one of seven nelfinavir, efavirenz, and nevirapine.
outpatient clinics (Basel, Bern, Geneva, Lausanne,Lugano, St-Gallen, Zürich). Potent antiretroviral Interpretation We recorded a high prevalence of toxic treatment is defined as a combination that includes at effects attributed to antiretroviral treatment for HIV-1. Such least three agents—a protease inhibitor (PI), a non- data provides a reference for regimen-specific and nucleoside reverse transcriptase inhibitor, or a nucleoside compound-specific adverse events and could be useful in analogue reverse transcriptase inhibitor. Drug regimens postmarketing analyses of toxic effects.
were defined as single-PI-antiretroviral treatment(contains one PI and no non-nucleoside reverse transcriptase inhibitors), PI-sparing-antiretroviraltreatment (contains no PIs and one non-nucleosidereverse transcriptase inhibitor, or triple nucleosideanalogue reverse transcriptase inhibitors includingabacavir), dual-PI-antiretroviral treatment (contains two PIs and no non-nucleoside reverse transcriptaseinhibitor), and three-class-antiretroviral treatment University Hospital of Lausanne, Lausanne, Switzerland (J Fellay MD, (contains nucleoside analogue reverse transcriptase, PI, K Boubaker MD, Prof P Francioli MD, G Greub MD, A Telenti MD); and non-nucleoside reverse transcriptase inhibitors ). In University Hospital of Zürich, Zürich, Switzerland(B Ledergerber PhD, M Flepp MD); University Hospital of Bern, Bern, patients receiving dual-PI-antiretroviral treatment, no Switzerland (H Furrer MD); University Hospital of Basel, Basel, pharmacokinetic boosting with low-dose ritonavir was Switzerland (M Battegay MD); University Hospital of Geneva, Geneva, Switzerland (Prof B Hirschel MD); Hospital of Lugano, We did a cross-sectional study over 4 weeks (August, Lugano, Switzerland (E Bernasconi MD); Hospital of St-Gallen, 1999, to September, 1999) that included all participants St-Gallen, Switzerland (P Vernazza MD); Swiss HIV Cohort Study in the Swiss HIV Cohort Study who were receiving Data Centre, Lausanne, Switzerland (P Francioli) potent antiretroviral treatment. We excluded patients Correspondence to: Dr Amalio Telenti, Division of Infectious who had started or changed regimens within the previous Diseases, University of Lausanne, CHUV-1011, Lausanne, 30 days. During an outpatient visit, physicians completed a questionnaire about adverse events. The questionnaire was based on classification used by the THE LANCET • Vol 358 • October 20, 2001 For personal use. Only reproduce with permission from The Lancet Publishing Group.
AIDS Clinical Trials Group (http://aactg.s-3.com).
zidovudine with lamivudine, didanosine with stavudine, Physicians explicitly asked patients if symptoms listed in indinavir with lamivudine), to improve the power of the the questionnaire had arisen within the 30 days logistic model to separate associations. For analysis of preceding the visit. Lipodystrophy was described long-term toxic effects (lipodystrophy, paraesthesia, and according to Carr and colleagues.5 Potential adverse neuromotor disorders), the model included type and events were scored according to severity (1=mild, duration of previous antiretroviral drug exposure as 2=moderate, 3=severe, 4=serious) and the likelihood of covariables. For analysis of liver-specific laboratory resulting from antiretroviral treatment (unlikely, abnormalities, the model included hepatitis C and B possible, probable, and certain), after the definition of serostatus. Analysis of regimen-specific toxic effects used the World Health Organisation (http://www.who- single-PI-antiroviral treatment as reference. We used STATA version 7.0 for statistical analysis. Blood concentrations of haemoglobin, creatinine, urate, Table 1 summarises demographic and HIV-related transaminases, alkaline phosphatase, bilirubin, amylase, characteristics of the 1160 participants. 60% of patients creatine phosphokinase, lactate, glucose, triglyceride, were receiving single PI-antiretroviral treatment, 15% and cholesterol were measured. We also recorded the each PI-sparing-antiretroviral treatment or dual-PI- number of blood neutrophils and platelets, and the antiretroviral treatment, and 10% three-class- concentration of protein in the urine. Blood lactate antiretroviral treatment (table 1). Patients on three-class- concentration was measured after the tourniquet was antiretroviral treatment tended to have a lower CD4 cell removed, in tubes containing sodium fluoride. Glucose count and more instances of suboptimum viral and triglyceride concentrations were assessed according suppression (and thus more advanced disease) than to whether or not the patient was fasting at the time of those in the other three treatment groups (p=0·0001, blood sampling. Normal limits were defined as the p=0·045, respectively). Intravenous drug users (23% of interval between the 2·5 and 97·5 percentiles of healthy participants) were less likely to be on PI-sparing- people. CD4 cell count was measured by flow cytometry, antiretroviral treatment than non-users (p=0·023).
and viral loads were ascertained with the Roche Agents for treatment or prophylaxis of opportunistic Amplicor Monitor assay (Roche Diagnostic, Basel, infections were used by 354 (30·5%) patients. 36 Switzerland), which could detect 400 or more copies patients (3%) were receiving lipid-lowering drugs and 12 RNA/mL. Laboratory analyses were done at or (1%) antidiabetic agents. We did not gather data on immediately before (<10 days) the outpatient visit.
other comedication. More men who have sex with men(42% vs 36%; p=0·0001), and fewer intravenous drug users (24% vs 28%; p=0·001) were recorded in our study We investigated associations between clinical and compared with 2225 Swiss HIV Cohort Study patients laboratory abnormalities and different antiretroviral on antiretroviral treatment examined in 1999, but not treatment regimens, and between such abnormalities and included in this study. Patients in our cohort had lower specific drugs using multiple logistic regression.
CD4 concentrations (20% vs 16% had <200 cells/mL; Variables included in the basic model were age, sex, body p=0·004), and a greater number of visits (4 vs 3, mass index, intravenous drug use, last CD4 cell count, p<0·0001) than those in the 1999 cohort. No differences last viral load, and concomitant medication in the type of antiretroviral treatment were recorded (trimethoprim-sulfamethoxazol, antimycobacterial, between patients who were included and those who were antitoxoplasmosis, and anticytomegalovirus treatment).
We also did a subgroup analysis of drugs that are The figure shows the severity of adverse events and the commonly coprescribed (>80% coadministration; likelihood that they would be caused by antiretroviral ART=antiretroviral treatment. *NRTI=nucleoside analogue reverse transcriptase inhibitor. †PI =protease inhibitor, ‡NNRTI=non-nucleoside analogue reversetranscriptase inhibitor. THE LANCET • Vol 358 • October 20, 2001 For personal use. Only reproduce with permission from The Lancet Publishing Group.
definitely attributed to antiretroviral treatment (nephrolithiasis, severe thrombopaenia, renal dysfunction with grade 4 creatinine increase, or grade 4 Table 2 shows the adverse events attributed to different antiretroviral treatment combinations. In a
multivariate analysis that accounted for stage of diseaseas measured by CD4 cell count, viraemia concentration, and use of comedication for opportunistic illnesses, single-PI-antiretroviral treatment and PI-sparing- antiretroviral treatment had closely similar prevalence of adverse events. Compared with single-PI-antiretroviral treatment, use of dual-PI-antiretroviral treatment and three-class-antiretroviral treatment were associated with higher prevalence of adverse events (OR 2·0 [95% CI 1·0–4·0] and 3·9 [1·2–12·9], respectively).
Table 2 lists all associations identified in the logistic analysis. Compared with single-PI-antiretroviral treatment, use of three-class-antiretroviral treatment was associated with greater risk of diarrhoea, and increased concentrations of cholesterol, triglyceride, alkaline phosphatase, and lactate. Use of dual-PI- antiretroviral treatment was associated with greater risk of fever and diarrhoea, and increased concentrations of cholesterol, triglyceride, and alkaline phosphatase. Use of PI-sparing-antiretroviral treatment was associated with greater risk of vomiting, mood and sleep disorders, and increased concentrations of amylase; but reduced risk of diarrhoea, and increased concentrations of Table 3 lists all adverse events attributed to specific antiretroviral treatment by logistic analysis. In patients taking nucleoside reverse transcriptase inhibitors, lamivudine was independently associated with mood disorders and lipodystrophy; stavudine with headache, lipodystrophy, and rise in serum concentrations of urate, creatine phosphokinase, lactate, cholesterol, and triglyceride; didanosine with increase in urate and lactate concentrations; and abacavir with vomiting and increasein creatine phosphokinase concentrations. There was atrend towards an association between zidovudine and anaemia. Use of zidovudine and lamivudine in combination was associated with neutropenia. In patients on PI, ritonavir was independently associated with diarrhoea, hyperbilirubinaemia, and increases in cholesterol and triglyceride concentrations; saquinavir with diarrhoea and thrombocytopenia; indinavir with nephrolithiasis, rash, and hyperbilirubinaemia; and nelfinavir with diarrhoea. Since only 13 patients received amprenavir, we were unable to analyse this group. In patients on non-nucleoside reverse transcriptase inhibitors, efavirenz was associated with mood and sleep Prevalence, severity, and likelihood of adverse events resulting disorders, and nevirapine with rise in serum (Top) Clinical adverse events. (Bottom) Laboratory adverse events.
The logistic regression model identified several associations with clinical symptoms or laboratory treatment. Clinical and laboratory abnormalities were abnormalities that were not from antiretroviral recorded in 78% (306 of 1160) and 85% (620 of 725 for treatment. Fatigue was associated with higher viral which all data were available) of patients respectively, load; paraesthesiae and neuromotor disorders but, most laboratory abnormalities were only possibly (polyneuropathy) with older age and higher viral load; attributed to treatment (figure). Overall, most adverse lipodystrophy with older age; and nausea and vomiting events were mild or moderate (grade 1 or 2). However, with intravenous drug use. Pancytopenia was associated for patients with probable or certain adverse events, 9% with lower CD4 cell count; hyperlipidaemia and (46 of 535) presented clinical and 16% (31 of 194) with hyperglycaemia with higher body mass index and older laboratory adverse events that were defined as severe or age. High concentrations of creatine phosphokinase were serious (grade 3 or 4). 6% of outpatient visits were not associated with use of statins. Drugs used for specifically triggered by an adverse event. Eight (0·6%) treatment or prophylaxis of opportunistic illnesses were patients were admitted to hospital during the study associated with neutropenia and raised lactate and period, four of whom had an adverse event probably or creatine phosphokinase concentrations.
THE LANCET • Vol 358 • October 20, 2001 For personal use. Only reproduce with permission from The Lancet Publishing Group.
Odds ratios (ORs) were estimated from the basic model using single-protease inhibitor-antiretroviral treatment as reference. PI=protease inhibitor. ART=antiretroviraltreatment. NS=not significant. *Significant (p<0·05) independent positive association. †Significant independent negative association.
Table 2: Logistic regression analysis of clinical and laboratory adverse events attributed to antiretroviral treatment regimens 37% and headache by 22% of patients, irrespective of the We have investigated the complex issue of attributing treatment taken. Lipodystrophy was strongly associated toxic effects to drug regimens, or to agents used in multi- with use of stavudine but not with use of PIs. Such an drug combinations. In view of the high prevalence of association has been recorded in three other adverse events associated with antiretroviral treatment, investigations.7–9 Some of the unexpected toxic effects, such information is essential for management of patients such as thrombocytopenia with saquinavir or mood with HIV-1. In the outpatient population included in this disorders with lamivudine, could have been missed by analysis, more than two thirds of patients presented one previous studies (saquinavir being almost always used in or more clinical or laboratory adverse events which could dual PI combination, which generates higher plasma have been due to antiretroviral treatment. A significant drug concentrations) or be spurious. By contrast with proportion of adverse events was classified as severe earlier reports,10 there was only a trend towards more (grade 3) or serious (grade 4). Four of eight admissions anaemia with use of zidovudine as compared with other of patients followed up during the study were attributed agents, and high creatine phosphokinase concentration to severe toxic effects. However, since patients included was more frequently seen in association with stavudine in the study were more frequently examined during 1999 and abacavir. The improved tolerability of zidovudine in outpatient clinics, and 6% of visits were specifically could be accounted for by the decrease in the due to an adverse event, our data could overestimate the recommended dose from 1500 mg/day to 500–600 mg/day in the early 1990s.10 In our study, as in others,8,11 Patients were asked point by point which symptoms of both didanosine and stavudine were associated with a potential toxic effects described in the standard AIDS high frequency of hyperlactataemia. Symptomless Clinical Trials Group questionnaire they had had. In a increase in urate concentrations has also been described first assessment, the likelihood of association was defined in patients on didanosine,12,13 but not, as we recorded, by the investigator, and thereafter, analysis was completed in those taking stavudine. Unconjugated hyper- with a logistic regression model that disregarded the bilirubinaemia has been associated with use of investigator’s assessment. Thus, bias incurred through indinavir,14 and was also associated with use of ritonavir attributing specific toxic effects to a particular drug or in our study. One-fifth of all patients had high drug regimen from pre-existing knowledge of particular concentrations of transaminases. But, after including toxic effect profiles was kept to a minimum. Prevalence of infection with hepatitis B and hepatitis C in the model, attributed adverse events was highest in three-class- only nevirapine was associated with a rise in antiretroviral treatment and in dual-PI-antiretroviral transaminase concentrations. This correlates with treatment than in single-PI-antiretroviral treatment or PI- reports about severe toxic effects in the liver as a result of We have described clinical and laboratory disorders headache were reported by 10–20% of patients taking associated with a wide variety of treatment placebo,6 but in our population, fatigue was reported by combinations. As in all cohort analyses, patients were THE LANCET • Vol 358 • October 20, 2001 For personal use. Only reproduce with permission from The Lancet Publishing Group.
Nucleoside analogue reverse transcriptase inhibitors 0·6 1·0 1·8 0·6 2·2 1·3 1·5 1·1 0·8 1·1 0·8 (0·3–1·2) 1·3 0·9 0·9 0·8 1·4 1·1 1·0 1·3 0·8 1·2 1·4 (0·9–1·7) 1·4 1·1 0·7 1·0 2·3 1·1 0·5 1·0 0·7 1·3 1·6 (0·9–2·1) 0·8 0·5 0·9 1·3 0·5 2·4 2·1 0·5 3·1 0·9 1·0 (0·6–1·1) 1·1 1·7 1·0 0·5 1·0 0·9 1·4 1·1 0·8 1·5 1·6 0·9 0·9 1·1 0·9 1·4 0·8 0·9 0·9 0·8 2·1 1·0 0·8 1·2 1·4 1·1 0·9 0·6 1·2 2·0 0·7 1·0 0·9 (0·5–1·2) 0·4 1·2 2·9 1·1 2·8 0·7 0·3 0·8 1·2 3·0 Paresthesia 1·1 0·9 0·9 0·7 1·4 1·2 1·0 1·0 1·1 0·8 1·2 Neuromotor 1·2 1·1 1·0 0·8 1·7 1·2 0·7 1·3 0·8 1·2 0·6 disorders 0·8 1·6 1·8 1·0 0·7 1·0 1·4 1·2 0·9 0·7 1·7 LaboratoryAnaemia 2·3 0·8 0·4 0·7 2·1 1·4 1·7 0·4 1·1 0·4 2·2 Neutropenia 2·4 2·4 0·4 0·5 0·7 0·4 2·8 0·3 1·5 1·4 0·8 0·6 1·1 1·8 0·6 1·0 0·5 4·9 0·9 0·9 1·0 1·7 Aspartate 0·6 0·5 1·2 1·5 0·5 1·0 1·3 0·4 1·3 1·6 1·4 aminotrans- (0·3–1·2) feraseAlanine 0·8 0·6 0·9 1·1 0·7 0·9 1·4 0·8 1·3 1·0 2·2 aminotrans- (0·6–1·2) 0·5 0·6 0·9 1·3 1·0 1·5 1·4 0·5 0·6 1·5 1·6 0·7 0·9 1·3 0·7 0·3 2·5 0·3 18·3 0·2 0·4 0·7 0·7 0·8 1·3 2·1 0·3 1·5 1·2 0·8 1·7 0·9 (0·4–1·4) 1·0 2·2 0·9 0·5 1·0 0·8 1·6 1·7 1·2 1·4 1·6 (0·5–2·1) Proteinuria 1·0 1·6 1·2 0·5 1·0 1·0 1·5 1·4 0·6 1·6 1·8 Urate 0·4 0·5 2·1 3·2 0·9 0·8 1·2 0·9 1·3 0·6 0·3 CPK 0·6 1·4 1·8 0·8 2·9 1·6 0·4 1·4 0·9 1·3 0·5 Lactate 0·5 0·8 1·7 1·8 0·8 0·9 0·7 0·8 1·0 1·6 2·0 Glucose 0·9 1·0 0·9 0·6 1·6 0·6 1·2 1·9 1·0 1·6 0·9 Cholesterol 0·6 1·0 1·8 1·0 1·0 2·0 0·7 1·0 1·0 1·3 0·8 Triglyceride 0·6 1·1 1·5 0·9 0·9 2·4 1·1 1·0 0·7 0·8 0·7 Odds ratios (OR) were estimated from the basic model including all drugs as covariables. Values in boxes are significant at p<0·05. CPK=creatine phosphokinase.
Table 3: Logistic regression analysis of adverse events attributed to specific antiretroviral treatment agents not randomly allocated to treatment. Allocation of suggest that patients taking methadone have significant treatment could have been biased since patients with rates of abandoning antiretroviral treatment if it contains more advanced disease would have been given three- efavirenz, probably because of pharmacological class antiretroviral treatment, and since intravenous drug interaction leading to reduced methadone concen- users were less likely to receive PI-sparing-antiretroviral treatment. Data from the Swiss HIV Cohort Study Furthermore, cross-sectional use of the AIDS Clinical THE LANCET • Vol 358 • October 20, 2001 For personal use. Only reproduce with permission from The Lancet Publishing Group.
Trial Group questionnaire excludes disorders that are being treated but were not bothersome during the study A Telenti and K Boubaker designed the study. J Fellay, G Greub, B visit (such as neuropathy controlled with analgesics, Ledergerber, and K Boubaker did the analysis. E Bernasconi, H Furrer,M Battegay, B Hirschel, P Vernazza, and M Flepp were responsible for diarrhoea or nausea controlled by medication). Another patient recruitment and clinical assessment. P Francioli directs the potential restriction of the study is that we did not Swiss HIV Cohort Study. J Fellay and A Telenti wrote the report, analyse early toxic effects such as hypersensitivity reactions that arose soon after initiation of antiretroviraltreatment, since patients had to be on stable treatment.
Swiss HIV Cohort Study membersR Amiet, M Battegay, E Bernasconi, H Bucher, P H Bürgisser, M Egger, We also did not include data on treatment interruption P Erb, W Fierz, M Flepp, P Francioli, H Furrer, M Gorgievski, and rechallenge, which would have provided stronger H Günthard, P Grob, B Hirschel, T H Klimkait, B Ledergerber, evidence for causality. An additional challenge is the M Opravil, F Paccaud, G Pantaleo, L Perrin, W Pichler, J-C Piffaretti, assessment of toxic effects that have persisted from M Rickenbach, C Rudin, P Sudre, V Schiffer, J Schupbach, A Telenti, P Vernazza, R Weber.
previous treatments. Patients were on the same regimenfor the 30 days preceding the study, which should have allowed recovery from most observed adverse events This study has been financed in the framework of the Swiss HIV CohortStudy, supported by the Swiss National Science Foundation. resulting from a previously used medication. For analysis of long-term toxic effects, we included previous drug usein the model, thereby avoiding attribution of cumulative toxic effects such as abnormal fat distribution or Max B, Sherer R. Management of the adverse effects of antiretroviral neurotoxicity to medications such as nevirapine or therapy and medication adherence. Clin Infect Dis 2000; 30 (suppl 2):
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would also be more complex in view of the treatment Henry K. The case for more cautious, patient-focused antiretroviral
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Saint-Marc T, Partisani M, Poizot-Martin I, et al. A syndrome of Thus, toxic effects attributed to a particular antiretroviral peripheral fat wasting (lipodystrophy) in patients receiving long-term
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treatment regimen (PI-antiretroviral treatment, PI- Carr A, Miller J, Law M, Cooper DA. A syndrome of lipoatrophy, sparing-antiretroviral treatment) will reflect actual use of lactic acidaemia and liver dysfunction associated with HIV nucleoside particular agents as components of the various regimens.
analogue therapy: contribution to protease inhibitor-related Change in relative use of a particular agent will modify lipodystrophy syndrome. AIDS 2000; 14: F25–F32
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of anti-HIV-1 treatment needs to be improved.
Further data available from author or from The Lancet
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