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JAC Advance Access originally published online on November 6, 2008
Journal of Antimicrobial Chemotherapy 2009 63(1):189-196; doi:10.1093/jac/dkn450
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Effectiveness and safety of didanosine, lamivudine and efavirenz versus zidovudine, lamivudine and efavirenz for the initial treatment of HIV-infected patients from the Spanish VACH cohort

Manuel Crespo1, Esteban Ribera1,*, Ignacio Suárez-Lozano2, Pere Domingo3, Enric Pedrol4, José López-Aldeguer5, Agustín Muñoz6, Consuelo Viladés7, Trinitario Sánchez8, Pompeyo Viciana9, Ramón Teira10, María Luisa García-Alcalde11, Antonio Vergara12, Fernándo Lozano13, María José Galindo14, Jaime Cosin15, Bernardino Roca16, Alberto Terrón17, Paloma Geijo18, Francesc Vidal7, Myriam Garrido19 on behalf of the VACH Cohort Study Group

1 Hospital Universitari Vall d’Hebron, Barcelona, Spain 2 Hospital Infanta Elena, Huelva, Spain 3 Hospital de la Santa Creu i de Sant Pau, Barcelona, Spain 4 Hospital General de Granollers, Barcelona, Spain 5 Hospital la Fe, Valencia, Spain 6 Hospital Infanta Cristina, Badajoz, Spain 7 Hospital Joan XXIII, Universitat Rovira I Virgili, Tarragona, Spain 8 Hospital Virgen del Rosell, Cartagena, Murcia, Spain 9 Hospital Virgen del Rocío, Sevilla, Spain 10 Hospital de Basurto, Bilbao, Spain 11 Hospital de Cabueñes, Asturias, Spain 12 Hospital Clínico de Puerto Real, Cadiz, Spain 13 Hospital de Valme, Sevilla, Spain 14 Hospital Clínico, Valencia, Spain 15 Hospital Gregorio Marañon, Madrid, Spain 16 Hospital General de Castellón, Castellón de la Plana, Spain 17 Hospital SAS, Jerez de la Frontera, Cadiz, Spain 18 Hospital Virgen de la Luz, Cuenca, Spain 19 Data Management VACH Group, Huelva, Spain

* Correspondence address. Infectious Diseases Division, Hospital Universitari Vall d’Hebron, Paseo Vall d’Hebron 119-129, 08035 Barcelona, Spain. Tel: +34-934894497; E-mail: eribera{at}vhebron.net

Received 14 August 2008; returned 12 September 2008; revised 23 September 2008; accepted 2 October 2008


   Abstract
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Background: Preliminary data suggest that a once-daily combination of lamivudine, didanosine and efavirenz is an effective alternative regimen for antiretroviral-naive HIV-1-infected patients. However, data from randomized trials comparing this combination versus standard first-line regimens are not available yet. In an observational study, we analyse the efficacy and tolerability of didanosine plus lamivudine and efavirenz versus zidovudine plus lamivudine and efavirenz in a cohort of therapy naive patients.

Methods: We performed an observational study on prospectively collected data from patients participating in a multicentre Spanish treatment-naive cohort (VACH cohort). Efficacy was assessed comparing time to therapeutic failure and CD4 cell recovery. Safety was analysed comparing the proportion of patients who discontinued therapy for toxicity or any other reason.

Results: Overall, 219 patients treated with once-daily didanosine/lamivudine/efavirenz and 409 patients receiving twice-daily zidovudine/lamivudine (Combivir®) plus efavirenz were evaluated. By intent-to treat analysis (non-completers and therapeutic change = failure), time to treatment failure was similar in both groups of treatment: 40.0 months (95% CI 23.3–56.8 months) among patients on didanosine/lamivudine/efavirenz and 33.3 months (95% CI 25.6–41.1 months) in patients treated with zidovudine/lamivudine/efavirenz (P = 0.253). The risk of failure due to treatment change was almost double among patients treated with zidovudine/lamivudine/efavirenz compared with those who received didanosine/lamivudine/efavirenz.

Conclusions: Our data suggest that didanosine/lamivudine/efavirenz is a combination with an efficacy comparable to zidovudine/lamivudine/efavirenz as first-line therapy for HIV infection. The risk of treatment change was significantly higher among patients treated with zidovudine/lamivudine/efavirenz than in those starting therapy with didanosine/lamivudine/efavirenz.

Keywords: nucleoside reverse transcriptase inhibitors , naive patients , observational cohort study , once-a-day regimen


   Introduction
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 Introduction
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The introduction of antiretroviral therapy has markedly improved treatment outcome in HIV-1-infected individuals. Despite the improvement in virological response rates over time, more than 20% of antiretroviral-naive patients who start antiretroviral treatment (ART) fail to achieve plasma HIV-RNA levels <50 copies/mL at 48 weeks of treatment.1 Reasons for virological failure are complex, but suboptimal adherence is the most common cause in clinical settings.2 A simple and well tolerated regimen is thought to increase patient adherence and hence the chance to achieve a sustained virological suppression, which is the main goal of ART.3–6

Enteric-coated didanosine (EC-didanosine) plus lamivudine and efavirenz is an attractive low-pill burden, well tolerated and dosed once-daily regimen. Data from three previously reported uncontrolled studies7–9 and one controlled pilot study10 suggest that didanosine/lamivudine/efavirenz is a convenient, safe and effective combination as a first-line ART. This combination is considered as an alternative regimen for ART-naive patients.3–6

On the other hand, zidovudine in combination with lamivudine was until recently the preferred nucleoside reverse transcriptase inhibitor (NRTI) backbone for treatment-naive patients, and is still widely used when fixed-dosed once-daily combinations, such as tenofovir plus emtricitabine or abacavir plus lamivudine, are contraindicated or not available.

Recently released results from a Spanish randomized trial showed that once-daily didanosine plus lamivudine and efavirenz was not inferior to zidovudine/lamivudine/efavirenz in treatment-naive patients, but complete data from this study are still to be published.11

Here, we undertake an observational cohort analysis based on prospectively collected data to compare the long-term efficacy and tolerability of EC-didanosine/lamivudine/efavirenz dosed once daily with food with a standard combination of zidovudine plus lamivudine (dosed twice-a-day as Combivir®) and efavirenz in ART-naive patients from the multicentre Spanish VACH cohort.


   Patients and methods
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 Patients and methods
Results
 Discussion
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Data collection

The VACH cohort is a prospective-recruited Spanish cohort currently made of 10 800 HIV-infected adult patients from 19 hospitals across Spain. Enrolment started in 1997. Data are prospectively collected in an electronic case record form according to standardized criteria and are electronically stored in the Aplicación de Control Hospitalario (AC&HTM). This application was specifically developed for the management of the cohort data: demographic data, HIV risk factors, Centers of Disease Control and Prevention (CDC) stage according to 1993 definitions, HIV-1 treatment initiation date, the specific antiretroviral regimens used, the date of change of every single drug and the reasons for change, CD4 cell counts, plasma HIV-RNA levels, blood cell counts and blood chemistry tests. Data are periodically recorded at each patient visit, every 3–4 months. All collected information was transformed into a standardized format and merged into a central dataset. The data passed an internal duplicate control at the central data centre that identifies patients by a unique code. Internal validation controls and quality controls of the data were used.

Patient selection

Eligible patients were antiretroviral-naive HIV-1-infected patients from the VACH cohort who started treatment either with twice-daily Combivir® (co-formulated as zidovudine, 300 mg, plus lamivudine, 150 mg) plus efavirenz (600 mg/daily) or a once-a-day regimen composed of weight-based EC-didanosine (<60 kg: 250 mg/daily; ≥60 kg: 400 mg/daily) plus lamivudine (300 mg/daily) and efavirenz (600 mg/daily). For analysis, we included patients recruited from 1 June 1999 to 31 May 2006. Patients were instructed to take EC-didanosine/lamivudine/efavirenz at bedtime. The decision to start with a particular highly active antiretroviral treatment (HAART) regimen was based on the physician's discretion. All patients starting ART with one of these two regimens were included in the analysis.

All patients included in this study provided informed consent to participate in the observational cohort. The study protocol was approved by the Institutional Review Board from every participant centre.

Study endpoints and statistical analysis

The primary endpoint was the time to treatment failure, using an intent-to treat (ITT) analysis that considered therapeutic failure as the following: virological failure, treatment change or discontinuation whatever the reason, loss of follow-up or clinical progression to AIDS or death. Virological failure was defined as never achieving a plasma viral load <50 copies/mL or having an increase above the limit of quantification in two consecutive determinations following virological suppression. For this analysis, time was 0 days for patients never achieving a plasma viral load <50 copies/mL. Additionally, we performed a modified ITT analysis considering non-completers as failure but ignoring changes of therapy. An on-treatment (OT) analysis was also conducted, which did not consider therapy change or interruptions of treatment as failures. For the primary efficacy endpoint, analyses were repeated separately according to pre-treatment CD4+ T cell count (<200 or ≥200 cells mm3) and pre-treatment HIV plasma viral load (<100 000 or ≥100 000 copies/mL). Secondary endpoints were: the percentage of patients with plasma undetectable viral load at treatment months 12, 24 and 36; change in CD4+ cell count from baseline at any timepoint; the occurrence of severe adverse effects, according to the definitions of the World Health Organization (WHO); and changes in plasma fasting glucose, creatinine, plasma lipid levels and haematological parameters. For patients whose data were missing at any individual timepoint, the last observation carried-forward imputation was applied.

Baseline characteristics were compared using {chi}2 or Fisher's exact test for categorical data and Mann–Whitney U-test for continuous data. Friedman test and Wilcoxon rank sum test were used to compare intra-group changes in CD4+ T cell count and in other continuous variables over time, and Mann–Whitney U-test was used to compare between-group median changes at different timepoints with respect to baseline values. Time-to-event analyses were conducted using Kaplan–Meier survival curves, comparing both groups by means of the log-rank test and the Cox proportional regression analysis. As potential confounders, the next variables were introduced in the Cox regression analysis: age, gender, nadir and baseline CD4 T cell count, pre-treatment HIV-RNA plasma level (log10), previous AIDS-defining event, year of starting treatment and hepatitis virus B and/or C co-infection. We used linear regression models to identify baseline predictors of CD4 gain at 6, 12 and 18 months of treatment. Data analyses were performed using the SPSS version 12.0 for Windows (SPSS Inc., Chicago, IL, USA).


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Comparison of study groups

The study group comprised 628 antiretroviral-naive patients who started treatment with zidovudine plus lamivudine and efavirenz (n = 409) or didanosine plus lamivudine and efavirenz (n = 219). Table 1 illustrates the characteristics of two treatment groups at baseline. Most patients started didanosine/lamivudine/efavirenz in more recent years compared with patients treated with zidovudine/lamivudine/efavirenz, consistent with the current trends to use regimens dosed less frequently.12 Both groups were comparable with respect to age, gender, CD4+ T cell count and the proportion of patients with CD4+ T cell count <200 cells/mm3, HIV-RNA plasma level and the percentage of patients with a pre-treatment plasma viral load >100000 copies/mL, HIV risk factor and the rate of hepatitis virus co-infection. A significantly higher number of patients who started zidovudine/lamivudine/efavirenz had pre-treatment AIDS-defining events compared with those who received didanosine/lamivudine/efavirenz (29.1% versus 20.5%, P = 0.020).


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  		Table 1. Baseline characteristics of study population according to treatment arm

 
Virological response

The median time of follow-up was 12.6 months [interquartile range (IQR) 6.7, 21.6] for patients who started didanosine/lamivudine/efavirenz and 18.4 months (IQR 7.4, 42.6) for those treated with zidovudine/lamivudine/efavirenz (P < 0.001; Mann–Whitney U-test). By ITT analysis (non-completer or treatment switch = failure), the Kaplan–Meier survival curves showed that the median time to treatment failure was 40.0 months (95% CI 23.3–56.8 months) and 33.3 months (95% CI 25.6–41.1 months) in patients treated with didanosine/lamivudine/efavirenz and zidovudine/lamivudine/efavirenz, respectively (P = 0.253, by log-range test) (Figure 1a). The percentage of patients without therapeutic failure (cumulative survival rate) at months 12, 24 and 36 of treatment was 79.1% [standard error (SE) 3.0], 62.6% (SE 4.3) and 56.6% (SE 5.1), respectively, among patients treated with didanosine/lamivudine/efavirenz and 75.2% (SE 2.2), 58.6 (SE 2.7) and 47.5% (SE 2.9), respectively, among patients treated with zidovudine/lamivudine/efavirenz, with no between-groups significant differences. Additional sensitivity-modified ITT analysis (non-completer = failure; ignoring treatment change) and OT approach (ignoring therapy switches or interruptions of treatment) showed no significant differences in median time to time to treatment failure between both groups of treatment (P = 0.610 and 0.908, respectively) (Figure 1b).


Figure 1
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  		Figure 1. Time to therapeutic failure in both groups of treatment. Representation of Kaplan–Meier time-to-event curves either by intention-to-treat analysis (a: non-completer or change = failure) or OT analysis (b: ignoring interruption and therapy switch). ZDV, zidovudine; 3TC, lamivudine; ddI, didanosine; EFV, efavirenz.

 
In a stratified analysis regarding CD4 T cell count at baseline (<200 or ≥200 cells/mm3) or pre-treatment plasma viral load (<100 000 or ≥100 000 copies/mL), no differences in cumulative survival rate (ITT analysis) were observed either intra-group or between both groups of treatment.

Table 2 summarizes the reasons for treatment failure. Rates of therapeutic failure driven by virological failure, drop-out, adverse events or clinical progression were similar in both groups of treatment. However, the risk of treatment change-driven failure was almost 2-fold higher among patients who received zidovudine/lamivudine/efavirenz in comparison with those treated with didanosine/lamivudine/efavirenz [hazard ratio (HR) 1.86; 95% CI 1.01–3.37]. Table 3 shows the independent baseline predictors for treatment failure. According to the ITT approach, therapeutic failure was associated with age (per 10 years older: HR 0.982; 95% CI 0.968–0.997; P = 0.015), HCV co-infection (HR 1.413; 95% CI 1.085–1.839; P = 0.010) and HCV/HBV co-infection (HR 2.183; 95% CI 1.137–4.194; P = 0.019). By OT approach, the only independent predictor for therapeutic failure was patient age (per 10 years older: HR 0.679; 95% CI 0.479–0.961; P = 0.029).


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  		Table 2. Reason accounting for treatment failure in both groups of treatment

 


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  		Table 3. Relative hazards of treatment failure from fitting a traditional Cox proportional hazards model and a weighted Cox regression

 
Immunological outcome and predictors of CD4+ T cell gain

A significant CD4+ T cell gain was observed in both groups of treatment. At month 12 of treatment, CD4+ T cell median increase was 187 cells/mm3 (IQR 104, 312) and 173 cells/mm3 (IQR 93, 306) among patients treated with didanosine/lamivudine/efavirenz and zidovudine/lamivudine/efavirenz, respectively (P < 0.001 for both comparisons). A trend for a faster CD4+ T cell increase was observed during the first 6 months of treatment among patients treated with didanosine/lamivudine/efavirenz, 153 cells/mm3 (IQR 83, 262) versus 133 cells/mm3 (IQR 62, 225) in those who received zidovudine/lamivudine/efavirenz (P = 0.060), but no differences were observed in median CD4+ T cell count between both groups over time (Figure 2). Independent predictors of CD4+ T cell gain at month 12 of treatment were age (P < 0.001), pre-treatment HIV plasma viral load (P = 0.042) and HCV infection (P = 0.001), whereas ART, gender, previous AIDS-defining event or HIV risk group had no influence on quantitative immune recovery.


Figure 2
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  		Figure 2. Between-group comparison of median CD4 cell count variation at months 12, 24 and 36 of treatment. Grey bars, ddI/3TC/EFV; white bars, ZDV/3TC/EFV. ZDV, zidovudine; 3TC, lamivudine; ddI, didanosine; EFV, efavirenz.

 
Haematological profile

The haemoglobin level increased in both groups of treatment, but this gain was significantly higher in the didanosine/lamivudine/efavirenz subset. At treatment month 12, the median haemoglobin increase, by ITT analysis, was 1.3 g/dL (IQR 0.25, 2.90) in patients on the didanosine-based regimen versus 0.4 g/dL (IQR –0.40, 1.50) among those treated with zidovudine/lamivudine/efavirenz (P = 0.001). The median white blood cell count increase at month 6 of treatment was significantly higher in patients treated with the didanosine-based regimen [1.50 x 109 cells/mm3 (IQR –0.08, 3.76)] than in those who received zidovudine/lamivudine/efavirenz [0.20 x 109 cells/mm3 (IQR –1.58, 2.09)] (P = 0.043). With respect to the platelet count, the median increase at month 12 of treatment was significantly higher in patients treated with the zidovudine-based regimen, 53 x 109 cells/mm3 (IQR 8, 100) versus 19 x 109 cells/mm3 (IQR –37, 53) in those on the didanosine-based regimen (P < 0.005).

Metabolic profile

Fasting total cholesterol, low-density lipoprotein-cholesterol and high-density lipoprotein (HDL)-cholesterol levels modestly increased in both groups of treatment, with no between-group significant differences. This increase mainly occurred during the first 12 months of treatment, the parameters remaining stable thereafter. At month 12 of treatment, the median total cholesterol increase was 44 mg/dL (IQR 18, 72) among patients treated with didanosine-based ART and 32 mg/dL (IQR 13, 54) in those who received the zidovudine-based regimen (P < 0.001, for both groups of treatment). Regarding the total cholesterol to HDL-cholesterol ratio, no significant changes were observed over time in both groups of treatment. At treatment month 12, triglyceride levels increased to a median of 8 mg/dL (IQR –25, 60; P = 0.207) and 10 mg/dL (IQR –14, 55; P = 0.019) in patients treated with didanosine/lamivudine/efavirenz and Combivir®/efavirenz, respectively.

Fasting glucose levels increased during the first 6 months of treatment to a median of 4 mg/dL (IQR –4, 15) in patients treated with didanosine/lamivudine/efavirenz (P = 0.003) and 5 mg/dL (IQR –2, 10) among those who received zidovudine/lamivudine/efavirenz (P < 0.001) with no between-group differences and remained stable thereafter.


   Discussion
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 Patients and methods
 Results
 Discussion
Funding
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In this clinically based cohort study, time to treatment failure among patients treated with didanosine/lamivudine/efavirenz was similar to that observed among patients treated with zidovudine/lamivudine/efavirenz. Furthermore, immune recovery was similar in both groups of treatment. Indeed, a faster CD4+ T cell gain was observed during the first 6 months of treatment in patients treated with didanosine/lamivudine/efavirenz. Recently released data from D:A:D study raised concern about the increased risk of myocardial infarction among patients treated with didanosine or abacavir.13 In our study, metabolic effects were modest and similar in both treatment groups. However, data on the incidence of cardiovascular events were not collected.

In keeping with reported data from other studies that evaluated didanosine/lamivudine/efavirenz in a small number of patients,7–10 and with recently released data from a large randomized trial (GESIDA 3903),11 our results confirm the efficacy, safety and tolerability of this combination as an initial treatment for HIV-infected patients. Furthermore, in contrast to previously reported data,8 our study indicated that time to treatment failure in patients who received didanosine/lamivudine/efavirenz was similar irrespective of baseline CD4+ T cell count.

In the present study, virological efficacy in patients who received zidovudine/lamivudine/efavirenz was similar to that observed in randomized clinical trials that used this combination of drugs.14–17 The combination of zidovudine with lamivudine has been the gold standard backbone for a long time, and there is extensive clinical data supporting its safety and efficacy. However, recently published data suggest that patients starting ART with zidovudine/lamivudine/efavirenz may be more likely to change therapy due to toxicity (mainly anaemia and gastrointestinal disturbances) than those starting with tenofovir/emtricitabine/efavirenz.16,18 The latter regimen has also been shown to be superior in terms of virological suppression and CD4+ T cell response.16,18 In keeping with this data, and with data from the GESIDA 3903 trial,11 our study shows that the number of patients who changed therapy was significantly higher among those treated with the zidovudine-based regimen in comparison with those treated with didanosine/lamivudine/efavirenz. Furthermore, zidovudine use has been associated with a greater risk of long-term development of lipoatrophy compared with tenofovir16,18 or abacavir.19 Consequently, zidovudine/lamivudine is losing popularity among clinicians and patients in favour of tenofovir/emtricitabine or abacavir/lamivudine, which are more convenient, better tolerated and safer combinations, and it has been changed from a preferred to an alternative backbone in recently updated treatment guidelines.3 Notwithstanding, the use of those preferred combinations might be precluded in some particular patients, mainly driven by tenofovir-associated nephrotoxicity20,21 or hypersensitivity reaction to abacavir,17,22 and alternative once-daily combinations might be useful to individually tailored ART, specially in poor-resource settings.

It is noteworthy that, in the present study, patients treated with didanosine/lamivudine/efavirenz took the three pills together with food at night. Since food can reduce EC-didanosine bioavailability by up to 25%, it has been recommended that EC-didanosine be administered on an empty stomach.23 Even though we did not perform a pharmacokinetic analysis, our data, in keeping with recently reported results,24 suggest that the effect of food on EC-didanosine might be clinically irrelevant, and support the efficacy of didanosine/lamivudine/efavirenz administered with food as a compact once-daily regimen.

When considering first-line therapy, it is important to bear in mind the impact on subsequent therapy options in the event of treatment failure. Zidovudine and stavudine may select for thymidine analogue mutations (TAMs), which in turn might induce cross resistance to other NRTIs,25 limiting long-term HAART efficacy.26,27 This concern is especially relevant in limited-resource countries, where virological failure is not usually monitored, allowing the gradual emergence of TAMs on a thymidine analogue-based failing regimen. In our study, virological failure was uncommon in both treatment arms. Unfortunately, since data on genotypic analysis were not available, we could not evaluate the impact of hypothetically selected mutations on subsequent regimens. In the case of failure with didanosine/lamivudine/efavirenz, M184V and efavirenz-associated mutations are the first mutations expected to occur followed by didanosine-specific mutations, mainly L74V or K65R,9 even though no patient treated with didanosine/lamivudine/efavirenz developed a didanosine-associated mutation in any other study.10 In either mutational scenario, the construction of highly active NRTI-based second-line regimens for patients who experience a virological failure on didanosine/lamivudine/efavirenz is virtually unimpaired.

The main limitation of our study is the lack of random allocation of patients to each treatment group. Consequently, we cannot exclude a confounding-by-indication bias.28,29 In addition, patients treated with didanosine/lamivudine/efavirenz had suffered a higher number of AIDS-defining events and were included in the study later than those starting treatment with zidovudine/lamivudine/efavirenz. However, the use of Cox proportional hazard models allowed us to control for multiple measured confounding factors, and both the two mentioned variables were not associated with treatment outcome. Furthermore, the difference in follow-up could be relevant in the Cox regression analysis if the rate of therapeutic failure changed over time. However, the Kaplan–Meier curves suggest that the rate of therapeutic failure was linear.

Nevertheless, unmeasured confounders could still have some impact on the results. For instance, patients' adherence to HAART was not collected through a standardized questionnaire, and we could not adjust the analysis according to this variable. Also the lack of blinding allocation could affect treatment outcome. Accordingly, although the difference observed in the proportion of patients who changed therapy could be due to zidovudine toxicity, it could also be driven by a clinician or patient preference to switch the zidovudine-based therapy to a compact once-daily regimen.

Despite these limitations, our study provides relevant data in the interim until the results of randomized trials investigating didanosine/lamivudine/efavirenz are available. In addition, since inclusion criteria are much less restrictive than in randomized trials, data obtained from observational cohort studies may provide useful information regarding the treatment effectiveness on particular subpopulations that might not be well represented in clinical trials and are an important source of information regarding the effectiveness and safety of less studied antiretroviral regimens.29

In summary, in our cohort-based study, time to virological failure among patients treated with EC-didanosine plus lamivudine and efavirenz administered once daily with food was comparable to that observed in patients who received twice-daily zidovudine plus lamivudine and efavirenz. Therapy switch was significantly more frequent among patients treated with the latter regimen. EC-didanosine plus lamivudine and efavirenz is well tolerated and can be easily administered as a once-a-day regimen, without food restriction, which might enhance patient adherence. These results can help in making individual treatment decisions for patients starting antiretroviral therapy.


   Funding
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Funding
Transparency declarations
 References
 
This study was supported in part by grants from Red Temática Cooperativa de Investigación en SIDA (RIS G03/173-RETIC RD06/006).


   Transparency declarations
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None to declare.


   Acknowledgements
 
The authors thank Celine Cavallo for English language editing.


   References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Funding
 Transparency declarations
 References
 
1 Bartlett JA, Fath MJ, Demasi R, et al. An updated systematic overview of triple combination therapy in antiretroviral-naive HIV-infected adults. AIDS (2006) 20:2051–64.[Medline]

2 Lucas GM, Chaisson RE, Moore RD. Highly active antiretroviral therapy in a large urban clinic: risk factors for virologic failure and adverse drug reactions. Ann Intern Med (1999) 131:81–7.[Abstract/Free Full Text]

3 U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents—January 29, 2008. http://www.aidsinfo.nih.gov/Guidelines/ (12 February, date last accessed).

4 Hammer SM, Saag MS, Schechter M, et al. Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA panel. JAMA (2006) 296:827–43.[Abstract/Free Full Text]

5 Gazzard B. British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy. HIV Med (2005) 6(Suppl_2):1–61.[Web of Science][Medline]

6 Recommendations from the GESIDA/Spanish AIDS Plan regarding antiretroviral treatment in adults infected by the human immunodeficiency virus infection (updated January 2007). Enferm Infecc Microbiol Clin (2007) 25:32–53.[CrossRef][Web of Science][Medline]

7 Landman R, Schiemann R, Thiam S, et al. Once-a-day highly active antiretroviral therapy in treatment-naive HIV-1-infected adults in Senegal. AIDS (2003) 17:1017–22.[CrossRef][Web of Science][Medline]

8 Maggiolo F, Migliorino M, Maserati R, et al. Virological and immunological responses to a once-a-day antiretroviral regimen with didanosine, lamivudine and efavirenz. Antivir Ther (2001) 6:249–53.[Web of Science][Medline]

9 Santos J, Palacios R, Lopez M, et al. Simplicity and efficacy of a once-daily antiretroviral regimen with didanosine, lamivudine, and efavirenz in naive patients: the VESD study. HIV Clin Trials (2005) 6:320–8.[CrossRef][Web of Science][Medline]

10 Maggiolo F, Ripamonti D, Gregis G, et al. Once-a-day therapy for HIV infection: a controlled, randomized study in antiretroviral-naive HIV-1-infected patients. Antivir Ther (2003) 8:339–46.[Medline]

11 Berenguer J, González J, Ribera E, et al. Didanosine, lamivudine and efavirenz vs. zidovudine, lamivudine and efavirenz for initial treatment of HIV infection over 48 weeks: a randomized non-inferiority clinical trial, GESIDA 3903. Abstracts of the Forty-Seventh Interscience Conference on Antimicrobial Agents and Chemotherapy, 2007: Chicago, IL. Washington, DC, USA: Abstract H-363. American Society for Microbiology.

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13 Sabin C, Worm S, Weber R, et al. Do thymidine analogues, abacavir, didanosine and lamivudine contribute to the risk of myocardial infarction? The D:A:D study. Abstracts of the Fifteenth Conference on Retroviruses and Opportunistic Infections, 2008: Boston, MA. Alexandria, VA, USA: Abstract 957c. Foundation for Retrovirology and Human Health.

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