Predictors of first-line antiretroviral therapy discontinuation due to drug-related adverse events in HIV-infected patients: a retrospective cohort study
© Prosperi et al.; licensee BioMed Central Ltd. 2012
Received: 20 April 2012
Accepted: 1 November 2012
Published: 12 November 2012
Drug-related toxicity has been one of the main causes of antiretroviral treatment discontinuation. However, its determinants are not fully understood. Aim of this study was to investigate predictors of first-line antiretroviral therapy discontinuation due to adverse events and their evolution in recent years.
Patients starting first-line antiretroviral therapy were retrospectively selected. Primary end-point was the time to discontinuation of therapy due to adverse events, estimating incidence, fitting Kaplan-Meier and multivariable Cox regression models upon clinical/demographic/chemical baseline patients’ markers.
1,096 patients were included: 302 discontinuations for adverse events were observed over 1,861 person years of follow-up between 1988 and 2010, corresponding to an incidence (95% CI) of 0.16 (0.14-0.18). By Kaplan-Meier estimation, the probabilities (95% CI) of being free from an adverse event at 90 days, 180 days, one year, two years, and five years were 0.88 (0.86-0.90), 0.85 (0.83-0.87), 0.79 (0.76-0.81), 0.70 (0.67-0.74), 0.55 (0.50-0.61), respectively. The most represented adverse events were gastrointestinal symptoms (28.5%), hematological (13.2%) or metabolic (lipid and glucose metabolism, lipodystrophy) (11.3%) toxicities and hypersensitivity reactions (9.3%). Factors associated with an increased hazard of adverse events were: older age, CDC stage C, female gender, homo/bisexual risk group (vs. heterosexual), HBsAg-positivity. Among drugs, zidovudine, stavudine, zalcitabine, didanosine, full-dose ritonavir, indinavir but also efavirenz (actually recommended for first-line regimens) were associated to an increased hazard of toxicity. Moreover, patients infected by HIV genotype F1 showed a trend for a higher risk of adverse events.
After starting antiretroviral therapy, the probability of remaining free from adverse events seems to decrease over time. Among drugs associated with increased toxicity, only one is currently recommended for first-line regimens but with improved drug formulation. Older age, CDC stage, MSM risk factor and gender are also associated with an increased hazard of toxicity and should be considered when designing a first-line regimen.
KeywordsHIV HAART Toxicity Side effects Therapy-naïve
Combination antiretroviral therapy (cART) has markedly changed the prognosis of HIV-infected patients, reducing AIDS-related morbidity and mortality . Rates of virological failure during first line regimens are decreasing both in clinical trials and in studies performed during routine clinical practice [2, 3]. However, drug-related adverse events and toxicities are increasingly recognized [4–7] and represent one of the most common reasons for treatment discontinuation or switch [2, 3, 8–11]. In recent years, the introduction of newer antiretroviral agents with improved efficacy and tolerability profiles has allowed for a decline of treatment-limiting toxic effects; however, drug-related adverse events still represent an issue of concern.
Treatment-limiting cART toxicity has been associated with several factors such as demographical characteristics, drug-drug interactions, co-morbidities and recently genetic factors . However, determinants of toxicity are not fully understood. In particular, the role of newer and apparently better tolerated antiretroviral drugs needs to be fully investigated. Moreover, the influence of baseline chemistry remains to be elucidated.
The aim of this study is to investigate predictors of first-line antiretroviral therapy discontinuation due to adverse events and their evolution in more recent years, characterized by an increased use of regimens with better tolerability profiles. In particular, the analysis is focused on the evaluation of baseline demographic and clinical characteristics, prescribed drugs and chemical parameters which could represent objective tools to tailor regimens on patients’ characteristics.
HIV-infected patients followed up at the Infectious Diseases Clinic of the Catholic University of the Sacred Heart (CUSH) in Rome, Italy, starting a first-line anti-HIV antiretroviral therapy, were screened retrospectively via the electronic CUSH data base, which includes data on more than 4,300 HIV-infected patients, with the first available anti-HIV therapy record dated 1988. All patients included in the data base had previously signed an informed consent to be included in observational studies. Access and data analyses of the CUSH data base are regulated by an institutional internal ethics committee and conform to Italian and European privacy legislations. The latest available updated version (up to January 2011) of the CUSH data base was used.
Causes of anti-HIV first-line therapy discontinuation in the study population (n=1,096)
% Over strata
% Over total
Adverse events (toxicity/allergy)
302 (1 death)
Central nervous system
Metabolic (glucose or lipid metabolism, lipodystrophy)
End of pregnancy
Enrolment in a new prospective study
176 (6 deaths)
Baseline chemical markers (with cut-offs) of the study population (n=1,096)
High (>1.2 mg/dL)
High (≥200 mg/dL)
Low (<12 g/dL)
High (>60 IU/L)
High (>110 mg/dl)
Diabetes (>126 mg/dL)
High (>40 IU/L)
Low (<40 mg/dL)
High (≥130 mg/dL)
high (≥150 mg/dL)
Low (<60 mg/dL/1.73m2)
The antiretroviral therapy was encoded in different ways: (i) as a combination therapy of 2 nucleoside reverse transcriptase inhibitors (NRTI) + 1 non-nucleoside reverse transcriptase inhibitor (NNRTI), 2 NRTI + 1 protease inhibitor (PI), 2 NRTI + 1 PI boosted with ritonavir (PI/r), and other combinations; (ii) as single compounds, i.e. emtricitabine, lamivudine, abacavir, zidovudine, stavudine, zaltacibine, didanosine, tenofovir, nevirapine, efavirenz, atazanavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir full or boosting dose, and saquinavir; (iii) as a combination therapy of different brand names, including those combinations with a frequency of at least 10; (iv) as Truvada® + Sustiva®, Atripla®, Reyataz®, Kaletra®, any other NRTI+PI, any other NRTI+PI/r, any other NRTI+NNRTI, and other combinations. Other compounds including enfuvurtide, maraviroc, raltegravir, darunavir, and etravirine, were not included due to their low frequency.
Statistical methods included descriptive summaries, calculation of incidence ratios and confidence intervals, Kaplan-Meier estimation for the probability of surviving an adverse event, multivariable proportional-hazard hypothesis testing, and multivariable Cox model fitting in order to identify factors associated to an increased/reduced hazard of an adverse event happening. Effect of covariate interactions and nested model comparison via ANOVA were also carried out. All statistical analyses were carried out using R software (http://www.r-project.org).
Characteristics of the study population (n=1,096)
Non Italian nationality
First-line anti-HIV therapy (encoding i)
First-line anti-HIV therapy (encoding iv)
Truvada® + Sustiva®
Reyataz® ± ritonavir + backbone
Kaletra® + backbone
Any other NRTI+NNRTI
Any other NRTI+PI
Any other NRTI+PI/r
Non-anti-HIV therapies (concomitant)
Discontinuation/switch for adverse events
Discontinuation/switch for other causes
Non-discontinued first-line anti-HIV therapies
Discontinuation/switch for adverse events
Patients starting a first-line ART
Days on first-line anti-HIV therapy
Years from the first HIV positive test
HIV-RNA Log10 copies/mL
CD4+ T cells/mm3
Multivariable Cox model fit: relative hazards of adverse events, with two different antiretroviral therapy encodings (n=1,096)
calendar year (per more recent)
gender M vs. F
age per one year older
nationality non-Italian vs. Italian
nationality unknown vs. Italian
risk homo/bisexual vs. heterosexual
risk IDU vs heterosexual
risk other/unknown vs. heterosexual
years from first positive test
CDC stage B vs. A
CDC stage C vs. A
HBsAg positive vs. negative
HBsAg unknown vs. negative
HCVAb positive vs. negative
HCVAb unknown vs. negative
CD4+ per cell/mm3 higher
HIV-RNA per Log10 higher
subtype 17 BF vs. B
subtype 28 BF vs. B
subtype 29 BF vs. B
subtype C vs. B
subtype F1 vs. B
subtype other vs. B
subtype unknown vs. B
bilirubin high vs. normal
bilirubin unknown vs. normal
hemoglobin normal vs. low
hemoglobin unknown vs. low
gammaGT high vs. normal
gammaGT unknown vs. normal
glucose diabetes vs. normal
glucose high vs. normal
glucose unknown vs. normal
GPT high vs. normal
GPT unknown vs. normal
HDL normal vs. low
HDL unknown vs. low
LDL high vs. normal
LDL unknown vs. normal
TGL high vs. normal
TGL unknown vs. normal
MDRD normal vs. low
MDRD unknown vs. low
other antibiotic therapy
other concomitant drugs
Atripla® vs. Truvada®+Sustiva®
Reyataz® vs. Truvada®+Sustiva®
Kaletra® vs. Truvada®+Sustiva®
any other therapy vs. Truvada®+Sustiva®
any other NRTI+NNRTI vs. Truvada®+Sustiva®
any other NRTI+PI vs. Truvada®+Sustiva®
any other NRTI+PI/r vs. Truvada®+Sustiva®
Emtricitabine* (in the cART, yes vs. no)
Lamivudine* (in the cART, yes vs. no)
Abacavir* (in the cART, yes vs. no)
Zidovudine* (in the cART, yes vs. no)
Stavudine* (in the cART, yes vs. no)
Zalcitabine* (in the cART, yes vs. no)
Didanosine* (in the cART, yes vs. no)
Tenofovir* (in the cART, yes vs. no)
Nevirapine* (in the cART, yes vs. no)
Efavirenz* (in the cART, yes vs. no)
Atazanavir* (in the cART, yes vs. no)
Fosamprenavir* (in the cART, yes vs. no)
Indinavir* (in the cART, yes vs. no)
Lopinavir* (in the cART, yes vs. no)
Nelfinavir* (in the cART, yes vs. no)
Ritonavit full dose* (in the cART, yes vs. no)
Saquinavir* (in the cART, yes vs. no)
Ritonavir boosting dose* (in the cART, yes vs. no)
Also, in order to analyze the possible role of the introduction in Italy of tenofovir (November 2002), Truvada® (September 2005), and Atripla® (October 2008), the calendar year was stratified into: 1988–1996, 1997–1998, 1999–2002, 2003–2005, 2006–2008, and 2009–2010. However, this did not lead to any appreciable difference across time periods.
Of note, a trend toward an increased risk of adverse events was observed for HIV genotype F1 (when compared to genotype B). Moreover, unknown TGL showed a higher RH as compared to the corresponding “normal” (<150 mg/dL) category. We also formally tested for interactions between the calendar year and the efavirenz intake, using an ANOVA comparison on the nested models (i.e. with/without interaction), but the more complex model did not show a higher likelihood (p=0.5); the interaction term was not significant and the significant effect of efavirenz was canceled out.
In order to better assess the role of CD4+ T cell counts, different Cox regression models were fit with either the sole CD4+ or log(CD4+) cell/mm3 count or including the full covariate set with the exception of the CDC stage. Only for the univariable log(CD4+) regression there was a significant (p<0.05) decreased hazard of an adverse event per log(CD4+) higher (RH=0.88, 95% CI 0.79-0.99).
As a sensitivity analysis, we repeated the multivariable Cox regression using the subset of therapies posterior to 1998 (n=779, number of events=193, PYFU=1228.948, incidence of 0.16 with a 95% CI of 0.14-0.18), including only cART regimens (although 12/779, i.e. 1.5%, where not 2NRTI+1NNRTI or 2NRTI+1PI±r regimens). The described relative hazards did not change, and in addition there was a significant reduced hazard of an adverse event for any other/unknown risk group as compared to the heterosexual category (RH=0.62, 95% CI 0.40-0.95, p=0.03), and a trend of increased hazard for nevirapine (RH=4.42, 95% CI 0.92-21.12, p=0.06), fosamprenavir (RH=5.64, 95% CI 0.94-34.01, p=0.06), and nelfinavir (RH=4.42, 95% CI 0.97-20.22, p=0.05). Moreover, in this model a significant higher risk of discontinuation for adverse events was demonstrated for HIV genotype F1 (RH 2.63, 95% CI 1.22-5.67, p=0.013 when compared to genotype B), while a trend was observed for genotype C (RH 2.24, 95% CI 0.94-5.33, p=0.067).
Discussion and conclusion
Since adverse events are the most frequent reason for first-line antiretroviral therapy discontinuation or switch, investigation of variables associated with their occurrence in a routine clinical practice setting is of increasing interest. Such an understanding is crucial to tailor antiretroviral regimens on patients’ characteristics in order to increase the probability of cART tolerability.
In this study several demographic, clinical, laboratory and cART-related variables were investigated, providing useful information for the management of antiretroviral therapy. The prescribed antiretroviral drugs are main determinants of treatment discontinuation for toxicity. As expected, the use of older drugs such as zidovudine, stavudine, zalcitabine, didanosine and full-dose ritonavir was associated with increased risk of adverse events. However, these drugs are no longer recommended for first-line therapy because of their greater potential for toxicity . When considering individual drugs currently recommended as preferred or alternative options in first-line regimens, an higher probability of treatment discontinuation for adverse events was observed for efavirenz (RH 2.4, 95% CI 1.2-5.1, p=0.02). Despite efavirenz has demonstrated high virologic efficacy, both neuropsychiatric and neurocognitive toxicity associated with this drug are not negligible [5, 18]. In a recent study, it was shown that nearly 20% of patients discontinue efavirenz due to central nervous system adverse events . Since similar rates of virological response have been observed for other recommended regimens, this observation should be taken into account at the time of prescription of fist-line cART and close clinical monitoring should be warranted in efavirenz-treated patients. However, our analysis includes mainly patients treated with non-co-formulated efavirenz, since the single tablet regimen including efavirenz/tenofovir/emtricitabine is available in Italy from October 2008, and its availability seems to improve treatment convenience and related quality of life .
In this study, female patients showed a higher risk of treatment discontinuation for drug-related side effects, in accordance with previous results [3, 21] . This might be due to peculiar gender-related pharmacokinetic characteristics which could influence drug exposure [21, 22].
An interesting finding is the increased risk of discontinuation for adverse events observed in men who have sex with men. This could be ascribed to a different perception of side effects eventually related to sociocultural barriers, as described among vulnerable populations .
Patients harboring HIV genotype F1 demonstrated an higher risk of treatment discontinuation for adverse events and a trend toward an association was observed for genotype C. F1 subtypes have been mostly detected in Latin America , where they were reported to be associated with faster HIV progression , and Central Africa . F1-carrying patients in our sample were generally immigrants from poor resources countries often with non-steady residence in Italy. This may explain the higher, though non-significant, frequency of interruptions related to F1 subtypes (vs. B).
In agreement with previous studies , we confirmed the increased predisposition of older patients to discontinue antiretroviral therapy for side effects. This could be related to several factors, as an altered drug pharmacokinetic (e.g. modification of absorption, protein binding or distribution, impaired drug metabolism) and a potential for drug interactions with co-medications. Since our database does not include detailed data on co-medications other than drugs used for the treatment of opportunistic infections and co-infections, the potential role of drug-drug interactions as a major determinant of treatment discontinuation could not be assessed adequately.
Previous studies suggested that prescription of concomitant medications used for the treatment of opportunistic infections could increase the risk of discontinuation owing to cumulative toxicities or drug interactions . In our population we did not observe an increased risk of discontinuation for adverse events in patients treated for PCP, TB or HCV co-infection. However, patients with AIDS-defining events were more likely to interrupt or switch cART for drug-related side effects.
Co-infection with HBV or HCV have been claimed as a predisposing factor for treatment discontinuation due to hepatic adverse events ; however, this association remain controversial [2, 3]. In our population we did not observe a significant role of HCV co-infection, but HBsAg-positive patients showed an increased hazard of adverse events. The importance of co-infection with hepatitis viruses could be strictly related to the frequency of prescription of specific antiretroviral drugs, with older drugs bearing a higher risk of hepatotoxicity.
The calendar year was not showing an impact on the hazard of toxicity/allergy events. A similar observation has been previously described in other cohorts [2, 27]. This could seem paradoxical since in recent years several drugs with better tolerability profile have been introduced in routine clinical practice. A possible explanation of this finding can rely on the increased number of alternative regimens that have become available in recent years; for this reason clinicians can be more prone to switch drugs also for less severe adverse events. Unfortunately, we could not verify this hypothesis since grading of clinical adverse events was not available in our database.
The potential association of treatment discontinuation for side effects and baseline chemical parameters has not been investigated in previous studies. Chemistry characteristic can represent important tools on the basis of which clinicians can choose the appropriate antiretroviral regimens in order to limit the occurrence of toxicities. In our population, we did not observe any association with the explored parameters; however, the relevant proportion of missing data could have influenced such finding masking the real effects in terms of increased/reduced hazard of adverse events occurrence. Moreover, only baseline markers were analyzed, while the effect of current markers may be crucial, for instance the raise levels of bilirubin during atazanavir-containing antiretroviral therapy . We decided not to perform a time-dependent analysis given the high rate of missing information in the baseline variables. A few multi-centric HIV study cohorts in Italy, specifically the MASTER (http://www.mastercohort.it) and Icona (http://www.fondazioneicona.org) foundations, and in Europe, including the Copenhagen HIV Programme and EuroSIDA (http://www.cphiv.dk) record such detailed information for all patients, besides the standard HIV serologic markers [15, 16].
Some limitations should be recognized when interpreting the results of our study. First, cART toxicity was analyzed considering only treatment modification, but clinical events or alterations in laboratory parameters not leading to treatment discontinuation were not investigated, thus leading to an underestimation of overall drug-related side effects. There might be a population bias, since the first-line anti-HIV therapies could have been tuned appositely on the patients’ background, basing on the guidelines available at that time. This can be truer for drug combinations circulating for a longer time, whose adverse effect have been deeply disclosed. Since this study is retrospective, the bias cannot be ruled out even using strong selection criteria and a patient cohort with a high level of detail and follow up.
Another possible limitation of this study is that we conducted a cause-specific analysis, ignoring the potential effects of competing events in the survival analysis; such events may drive the happening of adverse effects, and surely a design of a competing-risk analysis after this study is warranted.
Given the current, fair, rate of virologic and immunologic successes of first-line anti-HIV antiretroviral therapies in the European Union and other developed countries [29–32], along with the decrease of drug-resistance prevalence [33–39], the objective is now the prolongation of the therapy duration with the minimization of adverse events. Intolerance/toxicity still remains the major cause of drug discontinuation in Italy . Therefore, an effort in gathering data from all available sources to assess more precisely prognostic factors and relative hazards of adverse events is warranted. Eventually, a personalized scoring system might be inferred, as it has been done with the prediction of virologic responses and time to virologic failure [41–44].
In conclusion, several predictors of treatment discontinuation for drug-related adverse events were investigated. These findings could help clinicians to identify individuals at higher risk of developing toxicity, thus allowing an improved prescription of antiretroviral regimens tailored on patients’ characteristics. Moreover, these results suggest the importance of anticipating the probability of occurrence of adverse events in order to ensure close clinical and laboratory monitoring and adequate management of side effects which could improve the durability of cART.
Combination antiretroviral therapy
Catholic University of the Sacred Heart
Glutamate pyruvate transaminases
Glomerular filtration rate
Modification of diet in renal disease formula
Non-nucleoside reverse transcriptase inhibitor
Nucleoside reverse transcriptase inhibitors
Pneumocystis jirovecii pneumonia
PI boosted with ritonavir
Person years of follow up
- 95% CI:
95% Confidence Interval.
No specific funding was received for this work.
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