0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Investigation |

Treatment Modification in Human Immunodeficiency Virus–Infected Individuals Starting Combination Antiretroviral Therapy Between 2005 and 2008 FREE

Luigia Elzi, MD, MSc; Catia Marzolini, PhD; Hansjakob Furrer, MD; Bruno Ledergerber, PhD; Matthias Cavassini, MD; Bernard Hirschel, MD; Pietro Vernazza, MD; Enos Bernasconi, MD; Rainer Weber, MD; Manuel Battegay, MD; Swiss HIV Cohort Study
[+] Author Affiliations

Author Affiliations: Divisions of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel (Drs Elzi, Marzolini, and Battegay), and University Hospital Zurich, Zurich (Drs Ledergerber and Weber); University Clinic for Infectious Diseases, University Hospital Bern and University of Bern, Bern (Dr Furrer); and Divisions of Infectious Diseases, University Hospital Lausanne, Lausanne (Dr Cavassini), University Hospital Geneva, Geneva (Dr Hirschel), Regional Hospital St Gallen, St Gallen (Dr Vernazza), and Cantonal Hospital Lugano, Lugano (Dr Bernasconi), Switzerland.


Arch Intern Med. 2010;170(1):57-65. doi:10.1001/archinternmed.2009.432.
Text Size: A A A
Published online

Background  Adverse effects of combination antiretroviral therapy (CART) commonly result in treatment modification and poor adherence.

Methods  We investigated predictors of toxicity-related treatment modification during the first year of CART in 1318 antiretroviral-naive human immunodeficiency virus (HIV)–infected individuals from the Swiss HIV Cohort Study who began treatment between January 1, 2005, and June 30, 2008.

Results  The total rate of treatment modification was 41.5 (95% confidence interval [CI], 37.6-45.8) per 100 person-years. Of these, switches or discontinuations because of drug toxicity occurred at a rate of 22.4 (95% CI, 19.5-25.6) per 100 person-years. The most frequent toxic effects were gastrointestinal tract intolerance (28.9%), hypersensitivity (18.3%), central nervous system adverse events (17.3%), and hepatic events (11.5%). In the multivariate analysis, combined zidovudine and lamivudine (hazard ratio [HR], 2.71 [95% CI, 1.95-3.83]; P < .001), nevirapine (1.95 [1.01-3.81]; P = .050), comedication for an opportunistic infection (2.24 [1.19-4.21]; P = .01), advanced age (1.21 [1.03-1.40] per 10-year increase; P = .02), female sex (1.68 [1.14-2.48]; P = .009), nonwhite ethnicity (1.71 [1.18-2.47]; P = .005), higher baseline CD4 cell count (1.19 [1.10-1.28] per 100/μL increase; P < .001), and HIV-RNA of more than 5.0 log10 copies/mL (1.47 [1.10-1.97]; P = .009) were associated with higher rates of treatment modification. Almost 90% of individuals with treatment-limiting toxic effects were switched to a new regimen, and 85% achieved virologic suppression to less than 50 copies/mL at 12 months compared with 87% of those continuing CART (P = .56).

Conclusions  Drug toxicity remains a frequent reason for treatment modification; however, it does not affect treatment success. Close monitoring and management of adverse effects and drug-drug interactions are crucial for the durability of CART.

Figures in this Article

Combination antiretroviral therapy (CART) has dramatically reduced human immunodeficiency virus (HIV)–related morbidity and mortality.13 Current guidelines recommend starting CART at earlier stages of HIV infection and continuing lifelong treatment.46 However, adverse drug reactions, drug-drug interactions, and comorbidities and socioeconomic barriers may influence the safety and efficacy of CART.

Adverse events have been reported with all antiretroviral drugs and are among the most common reasons for switching or discontinuing therapy and for poor adherence to the medication regimen.712 In the Swiss HIV Cohort Study (SHCS), the presence of laboratory adverse events was associated with increased mortality during 6 years of follow-up.13 Treatment-limiting toxic effects in randomized controlled trials appear to be declining with newer antiretroviral regimens, ranging from 3% for individuals treated with combined tenofovir disoproxil fumarate and emtricitabine with atazanavir sulfate14 to 4% for those receiving combined tenofovir and emtricitabine with efavirenz and 9% for combined zidovudine and lamivudine with efavirenz.15 However, Vo et al7 recently reported that up to 40% of patients in the SHCS changed their antiretroviral treatment within the first year after starting CART, half of them because of toxic effects. In that study, rates of treatment modification did not vary from 2000 to 2005, possibly reflecting the increased availability of alternative drugs.

Toxic effects of CART have been associated with demographic characteristics, drug-drug interactions, comorbidities, and, more recently, genetic factors. Patients coinfected with hepatitis B and/or C virus are at increased risk for hepatic events caused by several antiretroviral drugs, but this association remains controversial.7,12,1618 Moreover, the prevalence of adverse events affecting the central nervous system (CNS) during treatment with efavirenz, leading to treatment discontinuation in about 10% to 15% of patients,19 was related to higher plasma levels20 and black ethnicity.21 Knowledge about the genes implicated in pharmacokinetics, mode of action, efficacy, and toxicity of drugs provides relevant results for clinical practice. For example, the presence of the HLA-B*5701 allele predicts an abacavir sulfate hypersensitivity reaction with potentially severe consequences.22,23

This study investigates factors associated with early CART modification owing to drug toxicity in antiretroviral-naive HIV-infected individuals who recently started CART within the SHCS. Specific objectives were to assess the probability of a treatment switch or discontinuation according to the most often recommended and prescribed antiretroviral regimens (ie, nonnucleoside reverse transcriptase inhibitor [NNRTI] vs protease-inhibitor [PI] based, efavirenz vs nevirapine, boosted atazanavir [atazanavir/r], and boosted lopinavir [lopinavir/r]), to explore risk factors of the most common toxic effects (ie, gastrointestinal tract intolerance, hypersensitivity, CNS adverse effects, and hepatic events) leading to a switch or discontinuation of therapy within the first year after starting CART, and to explore the impact of treatment modification on virologic and immunologic outcomes.

STUDY DESIGN

We analyzed the SHCS database,24 a large prospective cohort study with continuous enrollment of HIV-infected individuals 16 years or older. Basic sociodemographic characteristics, data on the clinical course (occurrence of opportunistic infections or death), coinfection with hepatitis B and C viruses, antiretroviral therapy, comedication (prophylaxis and treatment of opportunistic infections, cardiovascular drugs, and treatment of hepatitis C virus and neoplasms), and immunologic and virologic variables are collected at enrollment into the study and every 6 months thereafter on standardized data collection forms. AIDS-defining diseases are recorded using the 1993 revised clinical definition of AIDS from the Centers for Disease Control and Prevention.25 The cause of death is reported using the International Statistical Classification of Diseases and Related Health Problems, 10th Revision.26

For the present analysis we used the SHCS database extract of January 2009.

STUDY POPULATION

Antiretroviral-naïve HIV-infected individuals participating in the SHCS who started CART between January 1, 2005, and June 30, 2008, and had a follow-up of at least 6 months were eligible for this study. Pregnant women were excluded from this analysis because drug-related adverse events may affect this population differently, and women initiating CART for prevention of mother-to-child transmission often discontinue treatment after delivery.

DEFINITIONS

We defined CART as an antiretroviral regimen containing at least 3 drugs, that is, 2 nucleoside/nucleotide reverse-transcriptase inhibitors (NRTIs) in combination with an NNRTI or a PI, or 3 NRTIs. Antiretroviral regimens and the NRTI backbone were classified according to the preferred recommended regimens,4,5 that is, boosted atazanavir/r, lopinavir/r, efavirenz, nevirapine, zidovudine/lamivudine, abacavir/lamivudine, tenofovir/emtricitabine, or tenofovir/lamivudine. We excluded individuals receiving investigational regimens containing CC-chemokine receptor 5 inhibitors or integrase inhibitors.

Treatment modification was defined as a switch or discontinuation of CART within the first year. A switch to another regimen was defined as changing 1 or more drugs within 4 weeks after stopping CART. Discontinuation was defined as stopping any antiretroviral drug for at least 4 weeks. A switch from tenofovir-lamivudine to tenofovir-emtricitabine was not considered a treatment modification because it reflects the delayed availability of the new fixed formulation of tenofovir-emtricitabine in Switzerland in 2007. The main reason for treatment modification was classified as treatment failure, intolerance and/or toxic effects, the patient's choice, the physician's decision, and other reasons. Information on drug concentration was used to investigate the occurrence of CNS adverse events in patients with available results.

Virologic suppression was defined as achieving HIV-RNA counts of less than 50 copies/mL at 12 months after starting CART.

STATISTICAL ANALYSIS

The primary end point was the time to the first treatment modification (ie, a switch to another antiretroviral regimen or discontinuation) during the first year after starting CART.

Basic sociodemographic characteristics, CD4 cell count, HIV viral load, and CART were compared using the χ2 test or Fisher exact test for categorical variables and the Mann-Whitney test for continuous variables. We used Kaplan-Meier curves to describe the cumulative incidence of treatment modification according to the most frequently recommended first-line antiretroviral regimens, and the curves were compared using log-rank tests. Risk factors of treatment switch or discontinuation within the first year after starting CART were investigated using Cox proportional hazards models. All patients were censored at 1 year after starting CART if no treatment modification or death had occurred.

All analyses were performed using commercially available software (Stata, version 9.2 for Windows; StataCorp, College Station, Texas).

STUDY POPULATION

Between January 1, 2005, and June 30, 2008, 1318 antiretroviral-naive HIV-infected individuals participating in the SHCS started CART. Baseline characteristics according to the calendar year of starting CART are shown in Table 1. The median CD4 cell count at the start of CART increased from 198/μL (interquartile range [IQR], 107/μL-281/μL) in 2005 to 273/μL (186/μL-338/μL) in 2008 (P < .001), reflecting recent treatment guidelines,4,5 whereas the proportion of patients with a prior AIDS-defining condition declined from 23.3% in 2005 to 10.7% in 2008 (P = .002). Although the proportion of patients starting a boosted PI-based regimen compared with an NNRTI-based regimen did not differ over time, once-daily regimens were increasingly used (37.9% in 2005 vs 62.0% in 2008; P < .001), reflecting the expanding availability of new drugs and particularly formulations with a fixed combination of antiretrovirals.

Table Graphic Jump LocationTable 1. General Characteristics of 1318 Study Patients According to the Calendar Year of Starting CARTa
TREATMENT MODIFICATION DURING THE FIRST YEAR AFTER STARTING CART

Of 1318 individuals starting CART, 391 (29.7%) modified their treatment (ie, switched or discontinued CART) during the first year, corresponding to 41.5 (95% confidence interval [CI], 37.6-45.8) treatment modifications per 100 person-years, half of them occurring within the first 3 months. The most frequent reasons for treatment modification were toxic effects (46.6%), followed by a physician's decision (22.8%), the patient's choice (16.9%), and treatment failure (5.9%). Overall, 297 individuals (76.0%) switched to a new antiretroviral regimen within 4 weeks after stopping CART, whereas 94 (24.0%) discontinued CART for at least 4 weeks. Among switchers, 48.8% modified the backbone and the third drug; 43.8%, the third drug only; and 6.4%, the backbone only. The outcome in terms of virologic suppression to less than 50 copies/mL at 12 months was similar in individuals switched to another regimen compared with those who did not modify their treatment (87.9% vs 89.2%; P = .90). Similarly, no difference in the median CD4 cell count increase at 12 months was noted among switchers and individuals who did not change their treatment (169/μL vs 170/μL; P = .79). In contrast, patients discontinuing CART for longer than 4 weeks were less likely to achieve virologic suppression to less than 50 copies/mL (47.1%; P < .001) and immunologic recovery (median CD4 cell count increase of 107/μL; P = .002).

Individuals treated with zidovudine-lamivudine combined with lopinavir/r showed the highest rate of treatment modification (70.7 [95% CI, 57.7-86.8] treatment changes per 100 person-years), followed by tenofovir-emtricitabine with nevirapine (44.2 [26.2-74.7]) or lopinavir/r (44.1 [34.9-55.7]), abacavir-lamivudine with efavirenz (38.5 [24.6-60.3]), zidovudine-lamivudine with efavirenz (36.7 [24.2-55.7]), and tenofovir-emtricitabine with efavirenz (27.1 [21.7-33.7]) or atazanavir/r (24.1 [16.6-35.2]) (Figure, A). The probability of treatment modification tended to decrease for efavirenz and lopinavir/r and to increase for atazanavir/r and nevirapine during the study period. In a multivariate analysis (Table 2), the use of lopinavir/r and zidovudine-lamivudine was associated with higher treatment modification rates, as were female sex, nonwhite ethnicity, a prior AIDS-defining condition, and increasing baseline CD4 cell count.

Place holder to copy figure label and caption
Figure.

Time to treatment modification during the first year after starting combination antiretroviral therapy (CART) according to the first-line antiretroviral regimen. A, Modifications for all reasons. B, Modifications because of toxic effects. ABC indicates abacavir sulfate; FTC, emtricitabine; 3TC, lamivudine; /r, boosted; TDF, tenofovir disoproxil fumarate; and ZDV, zidovudine.

Graphic Jump Location
Table Graphic Jump LocationTable 2. Treatment Modification During the First Year of CART for All Reasons
TREATMENT MODIFICATION ATTRIBUTED TO DRUG INTOLERANCE AND/OR TOXICITY

During the first year of CART, 208 individuals (15.8%) modified their treatment because of drug intolerance and/or drug toxicity, corresponding to 22.4 (95% CI, 19.5-25.6) treatment modifications per 100 person-years, mostly (64.2%) during the first 3 months. No differences in the rate of treatment-limiting adverse events were observed during the study period (P = .26). Gastrointestinal tract intolerance was the most frequent toxic effect (28.9%), followed by hypersensitivity (18.3%), CNS adverse events (17.3%), and hepatic events (11.5%). The median time to treatment modification varied according to different toxic effects, ranging from 14 (IQR, 10-21) days for hypersensitivity to 66 (28-154) days for gastrointestinal tract intolerance, 72 (28-120) days for hepatic events, and 105 (50-228) days for CNS adverse events. Overall, 182 individuals (87.5%) switched to a new antiretroviral regimen, whereas 26 (12.5%) discontinued CART for at least 4 weeks. A large proportion of individuals achieved virologic suppression to less than 50 copies/mL at 12 months after starting CART regardless of treatment modification (85% vs 87%; P = .56) and the median increase in CD4 cell count was similar in both groups (166/μL vs 171/μL; P = .94). In contrast, only 58.2% of patients discontinuing CART for longer than 4 weeks achieved HIV-RNA suppression to less than 50 copies/mL at 12 months (P < .001) and showed a median CD4 cell count increase of 133/μL (P = .02).

In general, individuals starting an NNRTI-based regimen were less likely to modify their treatment compared with those treated with a PI (P = .052). The highest rate of treatment modification was noted among individuals starting zidovudine-lamivudine with lopinavir/r therapy (46.5 [95% CI, 36.0-60.0] treatment changes per 100 person-years), followed by tenofovir-emtricitabine with nevirapine therapy (32.1 [17.3-59.6]), zidovudine-lamivudine with efavirenz therapy (30.1 [18.7-48.5]), abacavir-lamivudine with efavirenz therapy (25.9 [15.1-44.7]), and tenofovir-emtricitabine with lopinavir/r therapy (15.1 [10.1-48.5]), efavirenz therapy (13.0 [9.5-17.9]), or atazanavir/r therapy (11.7 [6.8-20.2]) (Figure, B).

Efavirenz therapy was switched or discontinued mainly because of CNS adverse events (44.4%); lopinavir/r therapy, because of gastrointestinal tract intolerance (52.7%); and nevirapine therapy, after a hypersensitivity reaction (40.7%). The most frequent toxic effects related to the use of atazanavir/r were hepatic events (29.3%) and hypersensitivity (24.6%). In a multivariate analysis (Table 3), zidovudine-lamivudine (hazard ratio [HR], 2.71 [95% CI, 1.95-3.83]; P < .001), nevirapine (1.95 [1.01-3.81]; P = .05), concomitant treatment of opportunistic infections (2.24 [1.19-4.21]; P = .01), advanced age (1.21 [1.03-1.40] per 10-year increase; P = .02), female sex (1.68 [1.14-2.48]; P = .009), nonwhite ethnicity (1.71 [1.18-2.47]; P = .005), higher baseline CD4 cell count (1.19 [1.10-1.28] per 100/μL increase; P < .001), and an HIV viral load of more than 5.0 log10 copies/mL (1.47 [1.10-1.97]; P = .009) were associated with higher rates of treatment modification. Individuals with hepatitis B and C virus infection and intravenous drug users were not at higher risk of treatment-limiting toxic effects.

Table Graphic Jump LocationTable 3. Treatment Modification During the First Year of CART Owing to Drug Intolerance and/or Toxic Effects
SPECIFIC DRUG INTOLERANCES AND TOXIC EFFECTS
Gastrointestinal Tract Intolerance

Gastrointestinal tract intolerance was the most frequent toxic effect, with 6.3 (95% CI, 4.9-8.1) treatment modifications per 100 person-years, mostly associated with the use of lopinavir/r and zidovudine-lamivudine. In a multivariate analysis, risk factors of gastrointestinal tract intolerance were lopinavir/r and zidovudine-lamivudine, nonwhite ethnicity, and baseline CD4 cell count of more than 350/μL (Table 4).

Table Graphic Jump LocationTable 4. Treatment Modification During the First Year of CART According to Specific Toxic Effects
Hypersensitivity

Hypersensitivity was the main reason for 4.0 (95% CI, 2.9-5.5) treatment modifications per 100 person-years, mainly associated with the use of nevirapine. An increased risk of abacavir-related hypersensitivity was only observed for the year 2005 (HR, 6.67 [95% CI, 1.34-33.01]; P = .02) but not thereafter, reflecting the introduction of the screening test for HLA-B*5701 in clinical practice. Hypersensitivity was more likely in women, in individuals with a baseline CD4 cell count of more than 350/μL, and in those receiving nevirapine (Table 4).

CNS Adverse Events

The rate of treatment-limiting CNS adverse events was 3.8 (95% CI 2.7-5.2) per 100 person-years, clearly related to the use of efavirenz. In a multivariate analysis, treatment with efavirenz and female sex were independently associated with the occurrence of CNS adverse events (Table 4). In 196 patients with an available plasma drug concentration, higher efavirenz plasma levels were linked to higher treatment modification rates (P = .002). After adjustment for age, sex, ethnicity, and body mass index, efavirenz plasma level was the only factor associated with increased rates of treatment switch or discontinuation (P = .008).

Hepatic Events

The rate of treatment modification owing to hepatic events was 2.5 (95% CI 1.7-3.7) per 100 person-years, mainly associated with the use of atazanavir, which is known to cause elevation of indirect bilirubin levels. Treatment with atazanavir/r and comedication for opportunistic infection were independently associated with treatment modification coded as liver-related toxic effects (Table 4). Coinfection with hepatitis B or C virus did not increase the risk of treatment-related liver injury in this study.

This study, involving 1318 antiretroviral-naive HIV-infected individuals who started CART between January 1, 2005, and June 30, 2008, in a large cohort study, illustrates that drug toxicity remains a frequent problem in clinical practice, accounting for approximately half of all reasons for treatment switch or discontinuation during the first year of CART. Virologic and immunologic outcomes at 12 months were not impaired in individuals with treatment modification regardless of their reasons for change, suggesting that most people can achieve successful suppression using alternative antiretroviral regimens. Further findings of this study describe the toxicity-dependent time for treatment modification being the shortest for hypersensitivity and the longest for CNS adverse events. Also, a comparison of regimen-related toxic effects showed that the rate of therapy switch or discontinuation was lowest for patients treated with tenofovir-emtricitabine combined with atazanavir/r.

These findings are consistent with those from previous SHCS studies7,27 and other cohort studies,8,1012,17,2830 underlining the importance of close monitoring and adequate management of adverse effects and drug-drug interactions for the durability of CART in clinical practice. The discrepancy with lower treatment discontinuation rates (<10%) for new antiretroviral drugs reported in randomized clinical trials14,15 probably reflects a selection bias because individuals with severe comorbidities are often excluded from clinical trials. On the other hand, the broad availability of new drugs with the possibility of once-daily regimens may have triggered treatment modification,7,10,31 as suggested by the high proportion of patients switched to another antiretroviral regimen in our study. Among antiretroviral drugs, boosted lopinavir and zidovudine-lamivudine therapies were most frequently switched or discontinued during the first year of CART. No differences were observed between newer regimens, that is, tenofovir-emtricitabine combined with efavirenz or atazanavir/r, or abacavir-lamivudine combined with efavirenz, suggesting that these first-line regimens are suitable for long-term use.

In our study, women and individuals of nonwhite ethnicity were more likely to modify their antiretroviral treatment because of drug toxicity or intolerance. This may be explained by biological differences between the sexes20 and genetic factors influencing the pharmacokinetics of specific drugs and thus their plasma levels.18,21,32 Also, sociocultural barriers leading to a different perception of drug-related adverse events, as described among vulnerable populations, may play a role.21,28,29,33,34 Specific genetic tests can promptly influence treatment modification, as demonstrated in our study by the decreasing discontinuation rates of abacavir therapy after the introduction of screening for HLA-B*5701.23

As previously reported,7 higher baseline CD4 cell counts were associated with increased rates of treatment discontinuation, frequently without switching to alternative drugs, suggesting a lower motivation to continue an antiretroviral regimen causing adverse effects in patients with less urgent indication for CART. On the other hand, patients who were treated for a concomitant opportunistic infection (cytomegalovirus, toxoplasmosis, Pneumocystis jiroveci pneumonia, tuberculosis, or atypical mycobacteria) were more likely to modify their treatment as a result of drug-drug interactions and cumulative drug toxicity. In older individuals, a higher incidence of toxic effects may reflect altered pharmacokinetics, impaired drug metabolism, and frequent comedication with a potential for drug-drug interactions. Detailed data on comedication, particularly the use of psychotropic and over-the-counter drugs, were not available for the present analysis; therefore, the confounding role of drug-drug interactions in treatment modification could not be fully assessed. Nevertheless, a recent study of the SHCS on the prevalence and clinical relevance of drug-drug interactions in HIV-infected individuals reported no significant influence on treatment change rates in patients with drug-drug interactions.35 Coinfection with hepatitis B or C virus was not associated with a higher risk of toxic effects from CART in our study. This is in contrast to data from earlier studies,12,17 possibly because of different antiretroviral drugs being used more recently; for example, in our study a very low proportion of patients were treated with didanosine or stavudine, which have been linked to liver injury.

Individuals starting lopinavir/r combined with zidovudine-lamivudine therapy and those with higher CD4 cell counts and therefore less symptomatic HIV disease were at highest risk of gastrointestinal tract intolerance that may compromise quality of life and lead to poor treatment adherence. This is in contrast to other cohort studies,8,36 in which gastrointestinal tract adverse events tended to be more common in people with lower CD4 cell counts. This difference may be explained by the higher proportion of patients with advanced HIV disease in earlier studies, where misclassification of gastrointestinal tract intolerance might have occurred because diarrhea, dysphagia, and weight loss are frequently associated with opportunistic infections.37 A hypersensitivity reaction was most likely in women with a higher baseline CD4 cell count who were treated with nevirapine. Severe hepatic events ranging from skin rash to Stevens-Johnson syndrome have been observed during the first weeks of treatment when nevirapine therapy was initiated in antiretroviral-naive women with a CD4 cell count of more than 250/μL.18,38,39 For these patients, alternative regimens should be chosen.6 Treatment-limiting hepatic events were mainly noted in individuals receiving atazanavir/r and a comedication. Atazanavir is known to cause reversible elevation of unconjugated bilirubin levels by competitive inhibition of the uridine diphosphate glucuronosyltransferase UGT1A1 in up to 50% of patients. Jaundice is more likely to develop in individuals homozygous for the UGT1A1*28 allele.40 In this context, treatment modification was probably related to the occurrence of jaundice and not to liver injury. However, the need of comedication, particularly concomitant treatment of opportunistic infections, may cause drug-drug interactions, leading to an increase in transaminase levels and thus treatment modification.41,42 Finally, CNS adverse events were linked to an efavirenz-containing regimen and were more frequently reported by women. However, in 196 individuals with available efavirenz plasma concentrations, after adjustment for age, sex, ethnicity, and body mass index, the efavirenz plasma level was the only factor associated with higher modification rates, suggesting that sex differences result from different drug concentrations and that women may benefit from closer monitoring and dose adjustment of efavirenz.20

The strengths of this study were the high number of patients treated with newer antiretroviral regimens according to recent guidelines and the availability of comedication data that included treatment of opportunistic infection and use of cardiovascular drugs. We acknowledge some limitations. Misclassification of the reason for treatment modification may have occurred because many factors may play a role in decision making. In particular, no code for treatment simplification exists in the SHCS as a reason for stopping a specific drug therapy, although these individuals have probably received codes indicating the reason as being the patient's choice or the physician's decision. Toxic effects of CART were investigated by the occurrence of treatment modification, but alterations in laboratory variables (renal and liver function and bilirubin level) were not checked. Moreover, some adverse events may be difficult for patients to understand and report. It is therefore possible that the overall occurrence of drug-related adverse effects has been underestimated. As stated, information on comedications was not complete because information on psychotropic and over-the-counter drugs was not collected in the SHCS database. In addition, data on treatment adherence were not considered for the present analysis. Also, therapeutic drug monitoring was not performed routinely, except for special indications, mainly if treatment toxicity or treatment nonadherence was clinically suspected.

In conclusion, high rates of CART switch remain a major issue in clinical practice. The availability of different treatment options may trigger CART modification within the first weeks and months. If treatment is modified, this is done early and, as shown in our study, does not compromise CART outcome. Further research should address whether, with wider testing of toxicity-related factors (eg, genes associated with toxicity), first-line treatment regimens will be more robust in terms of durability.

Correspondence: Manuel Battegay, MD, Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland (mbattegay@uhbs.ch).

Accepted for Publication: August 31, 2009.

Author Contributions: Dr Battegay had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Elzi, Furrer, Ledergerber, and Battegay. Acquisition of data: Elzi, Marzolini, Furrer, Cavassini, Hirschel, Vernazza, Bernasconi, Weber, and Battegay. Analysis and interpretation of data: Elzi, Marzolini, Furrer, Ledergerber, Weber, and Battegay. Drafting of the manuscript: Elzi and Battegay. Critical revision of the manuscript for important intellectual content: Elzi, Marzolini, Furrer, Ledergerber, Cavassini, Hirschel, Vernazza, Weber, and Battegay. Statistical analysis: Elzi and Ledergerber. Obtained funding: Elzi and Battegay. Administrative, technical, and material support: Elzi, Cavassini, Hirschel, Vernazza, Bernasconi, and Battegay. Study supervision: Elzi and Battegay.

SHCS Group Members: Manuel Battegay, MD, University Hospital Basel, Basel; Enos Bernasconi, MD, Regional Hospital Lugano, Lugano; Jürg Böni, MD, Institute of Medical Virology, Zurich; Heiner C. Bucher, MD, MPH, Basel Institute for Clinical Epidemiology, Basel; Philippe Bürgisser, MD, University Hospital Lausanne, Lausanne; Alexandra Calmy, MD, University Hospital Geneva, Geneva; Sandro Cattacin, MD, University of Geneva, Geneva; Matthias Cavassini, MD, University Hospital Lausanne; Rolf Dubs, MD, University Hospital Zurich, Zurich; Matthias Egger, MD, PhD, University of Bern, Bern; Luigia Elzi, MD, MSc, University Hospital Basel; Marek Fischer, MD, University Hospital Zurich; Markus Flepp, MD, Klinik im Park, Zurich; Adriano Fontana, MD, University Hospital Zurich; Patrick Francioli, MD (President of the SHCS), University Hospital Lausanne; Hansjakob Furrer, MD (Chairman of the Clinical and Laboratory Committee), University Hospital Bern and University of Bern; Christoph A. Fux, MD, University Hospital Bern and University of Bern; Meri Gorgievski, MD, University of Bern; Huldrych Günthard, MD (Chairman of the Scientific Board), University Hospital Zurich; Hans H. Hirsch, MD, MSc, University Hospital Basel and University of Basel; Bernard Hirschel, MD, University Hospital Geneva; Irene Hösli, MD, University Hospital Basel; Christian Kahlert, MD, Regional Hospital St Gallen, St Gallen; Laurent Kaiser, MD, University Hospital Geneva; Urs Karrer, MD, University Hospital Zurich; Christian Kind, MD, University Children's Hospital, St Gallen; Thomas Klimkait, PhD, University of Basel; Bruno Ledergerber, PhD, University Hospital Zurich; Gladys Martinetti, MD, Institute of Microbiology, Bellinzona; Begona Martinez de Tejada, MD, University Hospital Geneva; Nicolas Müller, MD, University Hospital Zurich; David Nadal, MD, University Children's Hospital, Zurich; Milos Opravil, MD, Hirslanden Clinic Schachen, Aarau; Fred Paccaud, MD, University Hospital Lausanne; Giuseppe Pantaleo, MD, University Hospital Lausanne; Andri Rauch, MD, University Hospital Bern and University of Bern; Stephan Regenass, MD, University Hospital Zurich; Martin Rickenbach, MD (Head of Data Center), University Hospital Lausanne; Christoph Rudin, MD (Chairman of the Mother and Child Substudy), University Children's Hospital, Basel; Patrick Schmid, MD, Regional Hospital St Gallen; Detlev Schultze, MD; Institute of Microbiology, St Gallen; Jörg Schüpbach, MD, Swiss National Center for Retroviruses, Zurich; Roberto Speck, MD, University Hospital Zurich; Patrick Taffé, PhD, University Hospital Lausanne; Philip Tarr, MD, University Hospital Bruderholz, Bruderholz; Amalio Telenti, MD, PhD, University Hospital Lausanne; Alexandra Trkola, PhD, University of Zurich, Zurich; Pietro Vernazza, MD, Regional Hospital St Gallen; Rainer Weber, MD, University Hospital Zurich; and Sabine Yerly, MD, University Hospital Geneva.

Financial Disclosure: Dr Furrer has received grants from GlaxoSmithKline, Bristol-Myers Squibb, Gilead, Merck & Co Inc, and Boehringer-Ingelheim. Dr Cavassini has received travel grants from Abbott Laboratories, Gilead, Roche, and Boehringer-Ingelheim. Dr Hirschel has received travel grants and speakers' honoraria from Abbott Laboratories, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck & Co Inc, and Roche. Dr Vernazza has received travel grants or honoraria from Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Tibotec Pharmaceuticals, Abbott Laboratories, Pfizer Inc, and Roche. Dr Bernasconi has received travel grants or honoraria from Gilead, Roche, GlaxoSmithKline, Pfizer Inc, Boehringer-Ingelheim, and Tibotec Pharmaceuticals. Dr Weber has received travel grants or honoraria from Abbott Laboratories, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck & Co Inc, Pfizer Inc, Roche, TRB Chemedica, and Tibotec Pharmaceuticals. Dr Battegay has received research grants or speakers' honoraria from Abbott Laboratories, Bristol-Myers Squibb, Boehringer-Ingelheim, GlaxoSmithKline, Roche, Merck & Co Inc, TRB Chemedica, and Tibotec Pharmaceuticals.

Funding/Support: This study was supported within the framework of the SHCS by the Swiss National Science Foundation (SHCS project 597) and by an unrestricted grant from the Department of Internal Medicine, University Hospital Basel (Dr Elzi).

Egger  MMay  MChêne  G  et alART Cohort Collaboration Prognosis of HIV-1–infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies [published correction appears in Lancet. 2002;360(9340):1178]. Lancet20023609327119129
PubMed
May  MSterne  JASabin  C  et al. Antiretroviral Therapy (ART) Cohort Collaboration, Prognosis of HIV-1-infected patients up to 5 years after initiation of HAART: collaborative analysis of prospective studies. AIDS 2007;21 (9) 1185- 1197
PubMed Link to Article
Antiretroviral Therapy Cohort Collaboration, Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet 2008;372 (9635) 293- 299
PubMed Link to Article
Clumeck  NPozniak  ARaffi  FEACS Executive Committee, European AIDS Clinical Society (EACS) guidelines for the clinical management and treatment of HIV-infected adults. HIV Med 2008;9 (2) 65- 71
PubMed Link to Article
Hammer  SMEron  JJ  JrReiss  P  et al. International AIDS Society-USA, Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. JAMA 2008;300 (5) 555- 570
PubMed Link to Article
DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents: a Working Group of the Office of AIDS Research Advisory Council (OARAC) Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents: November 3, 2008. http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf. Accessed January 30, 2009
Vo  TTLedergerber  BKeiser  O  et al. Swiss HIV Cohort Study, Durability and outcome of initial antiretroviral treatments received during 2000–2005 by patients in the Swiss HIV Cohort Study. J Infect Dis 2008;197 (12) 1685- 1694
PubMed Link to Article
O’Brien  MEClark  RABesch  CLMyers  LKissinger  P Patterns and correlates of discontinuation of the initial HAART regimen in an urban outpatient cohort. J Acquir Immune Defic Syndr 2003;34 (4) 407- 414
PubMed Link to Article
Glass  TRDe Geest  SWeber  R  et al.  Correlates of self-reported nonadherence to antiretroviral therapy in HIV-infected patients: the Swiss HIV Cohort Study. J Acquir Immune Defic Syndr 2006;41 (3) 385- 392
PubMed Link to Article
Lodwick  RKSmith  CJYoule  M  et al.  Stability of antiretroviral regimens in patients with viral suppression. AIDS 2008;22 (9) 1039- 1046
PubMed Link to Article
Li  XMargolick  JBConover  CS  et al.  Interruption and discontinuation of highly active antiretroviral therapy in the multicenter AIDS cohort study. J Acquir Immune Defic Syndr 2005;38 (3) 320- 328
PubMed
Mocroft  APhillips  ANSoriano  V  et al. EuroSIDA Study Group, Reasons for stopping antiretrovirals used in an initial highly active antiretroviral regimen: increased incidence of stopping due to toxicity or patient/physician choice in patients with hepatitis C coinfection. AIDS Res Hum Retroviruses 2005;21 (9) 743- 752
PubMed Link to Article
Keiser  OFellay  JOpravil  M  et al. Swiss HIV Cohort Study, Adverse events to antiretrovirals in the Swiss HIV Cohort Study: effect on mortality and treatment modification. Antivir Ther 2007;12 (8) 1157- 1164
PubMed
Molina  JMAndrade-Villanueva  JEchevarria  J  et al. CASTLE Study Team, Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1–infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet 2008;372 (9639) 646- 655
PubMed Link to Article
Gallant  JEDeJesus  EArribas  JR  et al. Study 934 Group, Tenofovir DF, emtricitabine, and efavirenz vs zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 2006;354 (3) 251- 260
PubMed Link to Article
Hooshyar  DNapravnik  SMiller  WCEron  JJ  Jr Effect of hepatitis C coinfection on discontinuation and modification of initial HAART in primary HIV care. AIDS 2006;20 (4) 575- 583
PubMed Link to Article
Mocroft  ARockstroh  JSoriano  V  et al. EuroSIDA Study Group, Are specific antiretrovirals associated with an increased risk of discontinuation due to toxicities or patient/physician choice in patients with hepatitis C virus coinfection? Antivir Ther 2005;10 (7) 779- 790
PubMed
Baylor  MSJohann-Liang  R Hepatotoxicity associated with nevirapine use. J Acquir Immune Defic Syndr 2004;35 (5) 538- 539
PubMed Link to Article
Blanch  JMartínez  ERousaud  A  et al.  Preliminary data of a prospective study on neuropsychiatric side effects after initiation of efavirenz. J Acquir Immune Defic Syndr 2001;27 (4) 336- 343
PubMed Link to Article
Marzolini  CTelenti  ADecosterd  LAGreub  GBiollaz  JBuclin  T Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1–infected patients. AIDS 2001;15 (1) 71- 75
PubMed Link to Article
Stöhr  WBack  DDunn  D  et al. Liverpool TDM Database; UK CHIC Study, Factors influencing efavirenz and nevirapine plasma concentration: effect of ethnicity, weight and co-medication. Antivir Ther 2008;13 (5) 675- 685
PubMed
Rauch  ANolan  DMartin  A McKinnon  EAlmeida  CMallal  S Prospective genetic screening decreases the incidence of abacavir hypersensitivity reactions in the Western Australian HIV Cohort Study. Clin Infect Dis 2006;43 (1) 99- 102
PubMed Link to Article
Mallal  SPhillips  ECarosi  G  et al. PREDICT-1 Study Team, HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 2008;358 (6) 568- 579
PubMed Link to Article
 The Swiss HIV Cohort Study and the Mother and Child HIV Cohort Study. http://www.shcs.ch. Accessed January 30, 2009
Centers for Disease Control and Prevention, 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep 1992;41 (RR-17) 1- 19
PubMed
World Health Organization International Classification of Diseases and Related Health Problems: 10th Revision (ICD-10). http://www.who.int/classifications/apps/icd/icd10online/. Accessed January 30, 2009
Kaufmann  GRKhanna  NWeber  R  et al. Swiss HIV Cohort Study, Long-term virological response to multiple sequential regimens of highly active antiretroviral therapy for HIV infection. Antivir Ther 2004;9 (2) 263- 274
PubMed
Robison  LSWestfall  AOMugavero  MJ  et al.  Short-term discontinuation of HAART regimens more common in vulnerable patient populations. AIDS Res Hum Retroviruses 2008;24 (11) 1347- 1355
PubMed Link to Article
Yuan  YL’italien  GMukherjee  JIloeje  UH Determinants of discontinuation of initial highly active antiretroviral therapy regimens in a US HIV-infected patient cohort. HIV Med 2006;7 (3) 156- 162
PubMed Link to Article
Park  WBChoe  PGKim  SH  et al.  Early modification of initial HAART regimen associated with poor clinical outcome in HIV patients. AIDS Res Hum Retroviruses 2007;23 (6) 794- 800
PubMed Link to Article
Keiser  OOrrell  CEgger  M  et alSwiss HIV Cohort Study (SHCS) and the International Epidemiologic Databases to Evaluate AIDS in Southern Africa (IeDEA-SA) Public-health and individual approaches to antiretroviral therapy: township South Africa and Switzerland compared [published correction appears in PLoS Med. 2008;5(9):e195]. PLoS Med200857e148http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2443185&blobtype=pdf. Accessed January 30, 2009
PubMed
 HIV-pharmacogenomics Web site. http://www.hiv-pharmacogenomics.org. Accessed January 30, 2009
Pence  BWOstermann  JKumar  VWhetten  KThielman  NMugavero  MJ The influence of psychosocial characteristics and race/ethnicity on the use, duration, and success of antiretroviral therapy. J Acquir Immune Defic Syndr 2008;47 (2) 194- 201
PubMed Link to Article
Tedaldi  EMAbsalon  JThomas  AJShlay  JCvan den Berg-Wolf  M Ethnicity, race, and gender: differences in serious adverse events among participants in an antiretroviral initiation trial: results of CPCRA 058 (FIRST Study). J Acquir Immune Defic Syndr 2008;47 (4) 441- 448
PubMed Link to Article
Marzolini  CGibbons  SElzi  L  et al.  Prevalence of potential drug-drug interactions in the Swiss HIV Cohort Study [abstract P141]. HIV Med 2009;10(suppl 1)52
Bongiovanni  MCicconi  PLandonio  S  et al.  Predictive factors of lopinavir/ritonavir discontinuation for drug-related toxicity: results from a cohort of 416 multi-experienced HIV-infected individuals. Int J Antimicrob Agents 2005;26 (1) 88- 91
PubMed Link to Article
Hill  ABalkin  A Risk factors for gastrointestinal adverse events in HIV treated and untreated patients. AIDS Rev 2009;11 (1) 30- 38
PubMed
 Dear Health Care Professional Letter: “clarification of risk factors for severe, life-threatening and fatal hepatotoxicity with VIRAMUNE (nevirapine)”, Boehringer Ingelheim.  February2004. http://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/UCM166534.pdf. Accessed January 30, 2009
Sanne  IMommeja-Marin  HHinkle  J  et al.  Severe hepatotoxicity associated with nevirapine use in HIV-infected subjects. J Infect Dis 2005;191 (6) 825- 829
PubMed Link to Article
Rotger  MTaffe  PBleiber  G  et al. Swiss HIV Cohort Study, Gilbert syndrome and the development of antiretroviral therapy-associated hyperbilirubinemia. J Infect Dis 2005;192 (8) 1381- 1386
PubMed Link to Article
University of Liverpool Drug interaction charts. http://www.hiv-druginteractions.org/drug/drg_main.asp. Accessed January 30, 2009
Boffito  MAcosta  EBurger  D  et al.  Therapeutic drug monitoring and drug-drug interactions involving antiretroviral drugs. Antivir Ther 2005;10 (4) 469- 477
PubMed

Figures

Place holder to copy figure label and caption
Figure.

Time to treatment modification during the first year after starting combination antiretroviral therapy (CART) according to the first-line antiretroviral regimen. A, Modifications for all reasons. B, Modifications because of toxic effects. ABC indicates abacavir sulfate; FTC, emtricitabine; 3TC, lamivudine; /r, boosted; TDF, tenofovir disoproxil fumarate; and ZDV, zidovudine.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. General Characteristics of 1318 Study Patients According to the Calendar Year of Starting CARTa
Table Graphic Jump LocationTable 2. Treatment Modification During the First Year of CART for All Reasons
Table Graphic Jump LocationTable 3. Treatment Modification During the First Year of CART Owing to Drug Intolerance and/or Toxic Effects
Table Graphic Jump LocationTable 4. Treatment Modification During the First Year of CART According to Specific Toxic Effects

References

Egger  MMay  MChêne  G  et alART Cohort Collaboration Prognosis of HIV-1–infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies [published correction appears in Lancet. 2002;360(9340):1178]. Lancet20023609327119129
PubMed
May  MSterne  JASabin  C  et al. Antiretroviral Therapy (ART) Cohort Collaboration, Prognosis of HIV-1-infected patients up to 5 years after initiation of HAART: collaborative analysis of prospective studies. AIDS 2007;21 (9) 1185- 1197
PubMed Link to Article
Antiretroviral Therapy Cohort Collaboration, Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet 2008;372 (9635) 293- 299
PubMed Link to Article
Clumeck  NPozniak  ARaffi  FEACS Executive Committee, European AIDS Clinical Society (EACS) guidelines for the clinical management and treatment of HIV-infected adults. HIV Med 2008;9 (2) 65- 71
PubMed Link to Article
Hammer  SMEron  JJ  JrReiss  P  et al. International AIDS Society-USA, Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. JAMA 2008;300 (5) 555- 570
PubMed Link to Article
DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents: a Working Group of the Office of AIDS Research Advisory Council (OARAC) Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents: November 3, 2008. http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf. Accessed January 30, 2009
Vo  TTLedergerber  BKeiser  O  et al. Swiss HIV Cohort Study, Durability and outcome of initial antiretroviral treatments received during 2000–2005 by patients in the Swiss HIV Cohort Study. J Infect Dis 2008;197 (12) 1685- 1694
PubMed Link to Article
O’Brien  MEClark  RABesch  CLMyers  LKissinger  P Patterns and correlates of discontinuation of the initial HAART regimen in an urban outpatient cohort. J Acquir Immune Defic Syndr 2003;34 (4) 407- 414
PubMed Link to Article
Glass  TRDe Geest  SWeber  R  et al.  Correlates of self-reported nonadherence to antiretroviral therapy in HIV-infected patients: the Swiss HIV Cohort Study. J Acquir Immune Defic Syndr 2006;41 (3) 385- 392
PubMed Link to Article
Lodwick  RKSmith  CJYoule  M  et al.  Stability of antiretroviral regimens in patients with viral suppression. AIDS 2008;22 (9) 1039- 1046
PubMed Link to Article
Li  XMargolick  JBConover  CS  et al.  Interruption and discontinuation of highly active antiretroviral therapy in the multicenter AIDS cohort study. J Acquir Immune Defic Syndr 2005;38 (3) 320- 328
PubMed
Mocroft  APhillips  ANSoriano  V  et al. EuroSIDA Study Group, Reasons for stopping antiretrovirals used in an initial highly active antiretroviral regimen: increased incidence of stopping due to toxicity or patient/physician choice in patients with hepatitis C coinfection. AIDS Res Hum Retroviruses 2005;21 (9) 743- 752
PubMed Link to Article
Keiser  OFellay  JOpravil  M  et al. Swiss HIV Cohort Study, Adverse events to antiretrovirals in the Swiss HIV Cohort Study: effect on mortality and treatment modification. Antivir Ther 2007;12 (8) 1157- 1164
PubMed
Molina  JMAndrade-Villanueva  JEchevarria  J  et al. CASTLE Study Team, Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1–infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet 2008;372 (9639) 646- 655
PubMed Link to Article
Gallant  JEDeJesus  EArribas  JR  et al. Study 934 Group, Tenofovir DF, emtricitabine, and efavirenz vs zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 2006;354 (3) 251- 260
PubMed Link to Article
Hooshyar  DNapravnik  SMiller  WCEron  JJ  Jr Effect of hepatitis C coinfection on discontinuation and modification of initial HAART in primary HIV care. AIDS 2006;20 (4) 575- 583
PubMed Link to Article
Mocroft  ARockstroh  JSoriano  V  et al. EuroSIDA Study Group, Are specific antiretrovirals associated with an increased risk of discontinuation due to toxicities or patient/physician choice in patients with hepatitis C virus coinfection? Antivir Ther 2005;10 (7) 779- 790
PubMed
Baylor  MSJohann-Liang  R Hepatotoxicity associated with nevirapine use. J Acquir Immune Defic Syndr 2004;35 (5) 538- 539
PubMed Link to Article
Blanch  JMartínez  ERousaud  A  et al.  Preliminary data of a prospective study on neuropsychiatric side effects after initiation of efavirenz. J Acquir Immune Defic Syndr 2001;27 (4) 336- 343
PubMed Link to Article
Marzolini  CTelenti  ADecosterd  LAGreub  GBiollaz  JBuclin  T Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1–infected patients. AIDS 2001;15 (1) 71- 75
PubMed Link to Article
Stöhr  WBack  DDunn  D  et al. Liverpool TDM Database; UK CHIC Study, Factors influencing efavirenz and nevirapine plasma concentration: effect of ethnicity, weight and co-medication. Antivir Ther 2008;13 (5) 675- 685
PubMed
Rauch  ANolan  DMartin  A McKinnon  EAlmeida  CMallal  S Prospective genetic screening decreases the incidence of abacavir hypersensitivity reactions in the Western Australian HIV Cohort Study. Clin Infect Dis 2006;43 (1) 99- 102
PubMed Link to Article
Mallal  SPhillips  ECarosi  G  et al. PREDICT-1 Study Team, HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 2008;358 (6) 568- 579
PubMed Link to Article
 The Swiss HIV Cohort Study and the Mother and Child HIV Cohort Study. http://www.shcs.ch. Accessed January 30, 2009
Centers for Disease Control and Prevention, 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep 1992;41 (RR-17) 1- 19
PubMed
World Health Organization International Classification of Diseases and Related Health Problems: 10th Revision (ICD-10). http://www.who.int/classifications/apps/icd/icd10online/. Accessed January 30, 2009
Kaufmann  GRKhanna  NWeber  R  et al. Swiss HIV Cohort Study, Long-term virological response to multiple sequential regimens of highly active antiretroviral therapy for HIV infection. Antivir Ther 2004;9 (2) 263- 274
PubMed
Robison  LSWestfall  AOMugavero  MJ  et al.  Short-term discontinuation of HAART regimens more common in vulnerable patient populations. AIDS Res Hum Retroviruses 2008;24 (11) 1347- 1355
PubMed Link to Article
Yuan  YL’italien  GMukherjee  JIloeje  UH Determinants of discontinuation of initial highly active antiretroviral therapy regimens in a US HIV-infected patient cohort. HIV Med 2006;7 (3) 156- 162
PubMed Link to Article
Park  WBChoe  PGKim  SH  et al.  Early modification of initial HAART regimen associated with poor clinical outcome in HIV patients. AIDS Res Hum Retroviruses 2007;23 (6) 794- 800
PubMed Link to Article
Keiser  OOrrell  CEgger  M  et alSwiss HIV Cohort Study (SHCS) and the International Epidemiologic Databases to Evaluate AIDS in Southern Africa (IeDEA-SA) Public-health and individual approaches to antiretroviral therapy: township South Africa and Switzerland compared [published correction appears in PLoS Med. 2008;5(9):e195]. PLoS Med200857e148http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2443185&blobtype=pdf. Accessed January 30, 2009
PubMed
 HIV-pharmacogenomics Web site. http://www.hiv-pharmacogenomics.org. Accessed January 30, 2009
Pence  BWOstermann  JKumar  VWhetten  KThielman  NMugavero  MJ The influence of psychosocial characteristics and race/ethnicity on the use, duration, and success of antiretroviral therapy. J Acquir Immune Defic Syndr 2008;47 (2) 194- 201
PubMed Link to Article
Tedaldi  EMAbsalon  JThomas  AJShlay  JCvan den Berg-Wolf  M Ethnicity, race, and gender: differences in serious adverse events among participants in an antiretroviral initiation trial: results of CPCRA 058 (FIRST Study). J Acquir Immune Defic Syndr 2008;47 (4) 441- 448
PubMed Link to Article
Marzolini  CGibbons  SElzi  L  et al.  Prevalence of potential drug-drug interactions in the Swiss HIV Cohort Study [abstract P141]. HIV Med 2009;10(suppl 1)52
Bongiovanni  MCicconi  PLandonio  S  et al.  Predictive factors of lopinavir/ritonavir discontinuation for drug-related toxicity: results from a cohort of 416 multi-experienced HIV-infected individuals. Int J Antimicrob Agents 2005;26 (1) 88- 91
PubMed Link to Article
Hill  ABalkin  A Risk factors for gastrointestinal adverse events in HIV treated and untreated patients. AIDS Rev 2009;11 (1) 30- 38
PubMed
 Dear Health Care Professional Letter: “clarification of risk factors for severe, life-threatening and fatal hepatotoxicity with VIRAMUNE (nevirapine)”, Boehringer Ingelheim.  February2004. http://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/UCM166534.pdf. Accessed January 30, 2009
Sanne  IMommeja-Marin  HHinkle  J  et al.  Severe hepatotoxicity associated with nevirapine use in HIV-infected subjects. J Infect Dis 2005;191 (6) 825- 829
PubMed Link to Article
Rotger  MTaffe  PBleiber  G  et al. Swiss HIV Cohort Study, Gilbert syndrome and the development of antiretroviral therapy-associated hyperbilirubinemia. J Infect Dis 2005;192 (8) 1381- 1386
PubMed Link to Article
University of Liverpool Drug interaction charts. http://www.hiv-druginteractions.org/drug/drg_main.asp. Accessed January 30, 2009
Boffito  MAcosta  EBurger  D  et al.  Therapeutic drug monitoring and drug-drug interactions involving antiretroviral drugs. Antivir Ther 2005;10 (4) 469- 477
PubMed

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 59

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
Related Collections
PubMed Articles
JAMAevidence.com