Long-term effectiveness and safety of didanosine combined with lamivudine and efavirenz or nevirapine in antiretroviral-naive patients: a 9-year cohort study in Senegal

Authors


Corresponding Author Christian Laurent, Institut de Recherche pour le Développement (UMR 145), 911 avenue Agropolis, BP 64501, 34394 Montpellier Cedex 5, France. E-mail: Christian.Laurent@ird.fr

Summary

Objective  The use of didanosine (ddI) in first-line antiretroviral therapy has been recently promoted for resource-limited settings. We therefore compared the long-term effectiveness and safety of the regimen combining ddI, lamivudine, and efavirenz or nevirapine with that of the WHO-recommended regimen of zidovudine (ZDV), lamivudine, and efavirenz or nevirapine in antiretroviral-naïve patients in Senegal.

Methods  Observational cohort study of patients enrolled between January 2000 and April 2002 in the Senegalese antiretroviral drug access initiative. Multivariate analyses were performed to compare, between the ddI and ZDV groups, the proportion of patients with a viral load <500 copies/ml during follow-up; the increase in the CD4 cell count; survival; treatment changes and severe adverse events.

Results  Of 151 patients, 71 received the ddI-based treatment and 80 received the ZDV-based treatment. Throughout follow-up, 80–95% of patients had a viral load below 500 copies/ml in both the ddI and ZDV groups (= 0.5). The CD4 cell count increased after treatment initiation from 176 to 497 cells/mm3 in the ddI group and from 176 to 567 cells/mm3 in the ZDV group (> 0.3). The rate of death tended to be higher in the ddI group (= 0.06). ddI was less commonly discontinued than ZDV (= 0.03).

Conclusion  The combination of ddI, lamivudine, and efavirenz or nevirapine resulted in sustained viral suppression and immunological recovery.

Abstract

Objectif:  L’utilisation du didanosine (ddI) comme antirétroviral en première ligne a été récemment promue pour les pays à ressources limitées. Nous avons donc comparé l’efficacitéà long terme et la sécurité du schéma associant ddI, lamivudine et éfavirenz ou névirapine à celle du régime recommandé par l’OMS de zidovudine (ZDV), lamivudine et éfavirenz ou névirapine chez les patients naïfs au traitement antirétroviral au Sénégal.

Méthodes:  Etude de cohorte observationnelle de patients inscrits entre janvier 2000 et avril 2002 à l’Initiative Sénégalaise pour l’accès aux antirétroviraux. Des analyses multivariées ont été effectuées pour comparer dans les groupes au ddI et au ZDV, la proportion de patients ayant une charge virale <500 copies/mL au cours du suivi, l’augmentation du nombre de lymphocytes CD4, la survie, les changements de traitement et les évènements indésirables sévères.

Résultats:  Sur 151 patients, 71 ont reçu le traitement à base de ddI et 80 ont reçu celui à base de ZDV. Tout au long du suivi, 80–95% des patients avaient une charge virale inférieure à 500 copies/ml dans les deux groupes ddI et ZDV (P = 0,5). Le taux de CD4 a augmenté après l’initiation du traitement de 176 à 497 cellules/mm3 dans le groupe ddI et de 176 à 567 cellules/mm3 dans le groupe ZDV (P > 0,3). Le taux de mortalité semblait plus élevé dans le groupe ddI (P = 0,06). Le didanosine a été moins souvent abandonnée que le zidovudine (P = 0,03).

Conclusion:  La combinaison de didanosine, lamivudine et éfavirenz ou névirapine a entraîné la suppression virale durable et la récupération immunologique.

Abstract

Objetivo:  Recientemente se ha promovido el uso de la didanosina (ddI) como terapia antirretroviral de primera línea en emplazamientos con recursos limitados. Por lo tanto, hemos comparado la efectividad a largo plazo y la seguridad de un régimen que combina ddI, lamivudina, y efavirenz o nevirapina con el régimen recomendado por la OMS - zidovudina (ZDV), lamivudina, y efavirenz o nevirapina, en pacientes de Senegal que previamente no habían recibido ninguna terapia antirretroviral (naïve).

Métodos:  Estudio observacional de cohortes con pacientes incluidos entre Enero del 2000 y Abril del 2002 en la iniciativa de Senegal para ampliar el acceso al tratamiento con antirretrovirales. Mediante un análisis multivariado se compararon los grupos de ddI y ZDV, la proporción de pacientes con una carga viral <500 copias/mL durante el seguimiento; el aumento en el recuento de CD4; supervivencia; cambio de tratamiento; y efectos adversos severos.

Resultados:  De 151 pacientes, 71 recibieron el tratamiento basado en ddI y 80 recibieron el tratamiento basado en ZDV. Durante el seguimiento, 80–95% de los pacientes tenían una carga viral de menos de 500 copias/mL en ambos grupos - ddI y ZDV (= 0.5). El recuento de células CD4 aumentó después del inicio del tratamiento de 176 a 497 células/mm3 en el grupo ddI, y de 176 a 567 células/mm3 en el grupo de ZDV (> 0.3). La tasa de mortalidad tendía a ser mayor en el grupo de ddI (= 0.06). Era menos común descontinuar la didanosina que la zidovudina (= 0.03).

Conclusión:  La combinación de didanosina, lamivudina, y efavirenz o nevirapina resultó en una supresión sostenida de la carga viral y en una recuperación inmunológica.

Introduction

First-line combination antiretroviral therapy (ART) recommended by WHO in resource-limited countries consists of one non-nucleoside reverse transcriptase inhibitor (NNRTI; efavirenz or nevirapine) and two nucleoside reverse transcriptase inhibitors (NRTI). The preferred NRTI backbones are now zidovudine (ZDV) plus lamivudine or tenofovir plus either lamivudine or emtricitabine (World Health Organization, 2010). But the use of ZDV, although common, is hindered by frequent haematological disorders (especially severe anaemia) of various origins, including the HIV infection itself, other infectious diseases and malnutrition (Colebunders et al. 2005; Moh et al. 2005). Tenofovir has only been adopted by few African programmes because of its high cost until recently and concerns about renal toxicity (Ford & Calmy 2010). Recently, the use of didanosine (ddI) in resource-limited settings has been promoted owing to higher efficacy of regimens including ddI plus either lamivudine or emtricitabine than regimes of ZDV plus lamivudine, and ddI’s low cost and wide availability (Carr & Amin 2009). However, the authors acknowledged as limitations of their study the ecological design, the short duration of follow-up (14 months) and the fact that only 12% of patients were from resources-limited settings. Here, we compared the long-term effectiveness and safety of the regimen combining ddI, lamivudine, and efavirenz or nevirapine with that of the WHO-recommended regimen of ZDV, lamivudine, and efavirenz or nevirapine in ART-naive patients treated in Senegal.

Methods

From August 1998 to April 2002, 404 HIV-1-infected patients (age >15 years) were enrolled in the Senegalese antiretroviral drug access initiative (ISAARV) in Dakar and included in an observational cohort study (Desclaux et al. 2003). The methods of the cohort study have been described extensively elsewhere (Etard et al. 2006). Of the 404 patients, 80 received ZDV, lamivudine, and efavirenz or nevirapine and 71 received enteric-coated ddI, lamivudine, and efavirenz or nevirapine. Of these latter, 40 patients participated for the first 18 months in a prospective, open-label, one-arm trial (Landman et al. 2003). Antiretroviral treatment was provided every month or 2 months free of charge for the 40 patients initially included in the clinical trial or commensurate with their incomes for the other patients, but became free for all patients as of December 2003. Patients attended clinical examinations at least every 2 months and biological examinations at least every 6 months including plasma HIV-1 viral load (Amplicor HIV-1 1.5 or 2.0 assay, Roche Molecular Systems or Bayer bDNA HIV-1 2.0 or 3.0 assay; Bayer Diagnostic) and CD4 cell count (FACSCount; Becton Dickinson). Phone calls and, if necessary, home visits were made to all patients who did not attend scheduled visits to discuss reasons for non-adherence or to identify deaths (Etard et al. 2006). The Senegalese national ethics committee approved the study, and the patients gave their informed consent.

Between-group comparisons (ddI group vs. ZDV group) were performed using the chi-square test, Fisher’s exact test and the non-parametric Mann–Whitney two-sample test as appropriate for baseline patients’ characteristics; Cox models for treatment changes and deaths; generalised estimating equations models for the proportion of patients with plasma HIV-1 viral load below 500 copies/ml; mixed-effect linear regression models for the evolution of the CD4 cell count and negative binomial models for grade 3 or 4 adverse events (classification of the French National Agency for Research on AIDS and Viral Hepatitis; http://www.anrs.fr/content/download/2242/12805/file/ANRS-GradeEI-V1-En-2008.pdf). We allowed the slope of the CD4 cell count to change after 6 months and included quadratic and cubic effects in the second phase. The multivariate analyses were adjusted on baseline variables associated with either the outcome (< 0.25 in univariate analysis) or the treatment group. Multiple imputations based on both baseline and outcomes data were used to fill out incomplete baseline variables assuming that data were missing at random (Rubin 1987). Data were censored at the time of ddI or ZDV change for the analyses of treatment responses.

Results

Of the patients enrolled between January 2000 and April 2002, 71 received ddI and 80 received ZDV (in addition to lamivudine and a NNRTI). Most patient characteristics were comparable between the ddI and ZDV groups (Table 1). However, compared to patients in the ZDV group, those in the ddI group had a higher Karnofsky score (51%vs. 31% had a score of 100%), viral load (median 5.4 vs. 4.9 log10 copies/ml) and neutrophil count (median 2385 vs. 1845 cells/mm3). In contrast, they had a lower haemoglobin level (median 10.3 vs. 11.1 g/dl) and were less likely to receive a cotrimoxazole prophylaxis (61%vs. 85%). Study follow-up was 470 person-years for the ddI group [median follow-up time of 7.7 years, interquartile range (IQR) 5.1–9.0] and 473 person-years for the ZDV group (median follow-up time of 7.0 years, IQR 5.9–7.4).

Table 1.   Baseline characteristics of the 151 patients by treatment group
 Didanosine (n = 71)Zidovudine (n = 80)P
  1. Numbers of missing data were: *4, †11, ‡39, 2§, ¶5, **12, ††14 and ‡‡15.

Women, no. (%)41 (58)40 (50)0.3
Age (years), median (IQR)37.1 (31.7–45.5)38.3 (31.5–44.1)0.7
Body weight (kg), median (IQR)58 (49–66)57 (50–68)0.8
Body mass index (kg/m2), median (IQR)*19.6 (17.7–22.3)19.8 (17.9–22.3)0.9
Karnofsky score 100%, no. (%)36 (51)25 (31)0.02
CDC clinical stage, no. (%)
 A6 (8)6 (8)0.9
 B26 (37)32 (40)
 C39 (55)42 (52)
CD4 cell count (/mm3), median (IQR)†176 (98–233)182 (88–261)0.9
HIV-1 viral load (log10 copies/ml)‡
 Median (IQR)5.4 (5.0–5.7)4.9 (4.5–5.3)<0.001
 <4.0, no. (%)2 (4)5 (9)<0.001
 4.0–4.9, no. (%)10 (18)27 (48) 
 ≥5.0, no. (%)44 (78)24 (43) 
Haemoglobin (g/dl), median (IQR)§10.3 (9.5–11.5)11.1 (9.8–12.5)0.04
Neutrophil count (/mm3), median (IQR)¶2385 (1716–3053)1845 (1417–2725)0.01
Alanine aminotransferase (UI/l), median (IQR)†20 (11–29)21 (13–31)0.3
Aspartate aminotransferase (UI/l), median (IQR)**29 (19–42)23 (17–32)0.06
HBsAg, no.†† (%)7 (11)13 (17)0.3
Anti-HCV, no.‡‡ (%)3 (5)5 (7)0.5
Non-nucleoside reverse transcriptase inhibitor, no. (%)
 Efavirenz63 (89)52 (65)0.001
 Nevirapine8 (11)28 (35)
Cotrimoxazole prophylaxis, no. (%)43 (61)68 (85)0.001

During follow-up, ddI was discontinued in 10 patients (14%) and ZDV in 15 patients (19%). Treatment changes occurred after a median of 7.5 years (IQR 7.0–8.8) and 5.7 years (IQR 5.3–6.4), respectively (= 0.01). The incidence rates of treatment changes were 2.2 per 100 person-years [95% confidence interval (CI) 1.2–4.1] in the ddI group and 3.4 per 100 person-years (CI 2.0–5.6) in the ZDV group. The rate of change was significantly lower in the ddI group [hazard ratio (HR) 0.35, CI 0.13–0.91, = 0.03]. Treatment changes were owing to adverse effects (n = 5; digestive intolerance in one patient and unspecified intolerance in the others), treatment failure (n = 4) and 5-year loss to follow-up (n = 1) for ddI, and to treatment failure (n = 10), adverse effects (n = 4; anaemia in 3 patients and unspecified intolerance in the other) and loss to follow-up (n = 1) for ZDV. ddI was replaced by ZDV (n = 5) or tenofovir (n = 5), and ZDV was replaced by tenofovir (n = 11), ddI (n = 2) or stavudine (n = 2). Lamivudine and the NNRTI in the antiretroviral treatment were also switched in case of therapeutic failure.

Throughout follow-up, 80–95% of patients had a viral load below 500 copies/ml in both the ddI and ZDV groups (Figure 1). There was no significant difference between the treatment groups (ddI vs. ZDV group; adjusted odds ratio 1.27, CI 0.64–2.51, = 0.5). As shown in Figure 1, the CD4 cell count increased after treatment initiation from 176 to 497 cells/mm3 in the ddI group and from 176 to 567 cells/mm3 in the ZDV group. The increase was not significantly different between the two groups (> 0.3).

Figure 1.

 Outcomes in the 151 patients by treatment group: percentage of patients with plasma HIV-1 viral load below 500 copies/ml, mean CD4 cell count and survival. Bars indicate 95% confidence intervals.

There were 16 deaths (23%) in the ddI group and 11 (14%) in the ZDV group. The incidence rates of death were 3.5 (CI 2.2–5.7) and 2.5 (CI 1.4–4.4) per 100 person-years, respectively. The rate of death tended to be higher in the ddI group (Figure 1; adjusted HR 2.09, 0.96–4.54, = 0.06). In the ddI group, the deaths were related to meningitis (n = 3), tuberculosis (n = 3), HIV encephalopathy (n = 1), isosporiasis (n = 1), septicaemia (n = 1), unspecified infectious disease (n = 1), non-infectious liver disease (n = 1), non-infectious respiratory insufficiency (n = 1) or unknown cause (n = 4; three patients were lost to follow-up). In the ZDV group, the deaths were related to tuberculosis (n = 2), unspecified infectious disease (n = 2), HIV encephalopathy (n = 1), central nervous system toxoplasmosis (n = 1), pneumopathy (n = 1), cardiac failure (n = 1), anaemia (n = 1) or unknown cause (n = 2; one patient was lost to follow-up).

In the ddI group, 22 patients (31%) experienced at least one episode of grade 3 or 4 biological adverse event: once (n = 15), twice (n = 6) or eight times (n = 1). In the ZDV group, 19 patients (24%) did once (n = 15) or twice (n = 4). The rate tended to be higher in the ddI group but the difference was not significant (adjusted incidence rate ratio 1.79, CI 0.91–3.52, = 0.09). The predominant events were anaemia (n = 19), neutropenia (n = 5) and thrombopenia (n = 5) in the ddI group, and leucopenia (n = 5), anaemia (n = 4) and neutropenia (n = 3) in the ZDV group.

Discussion

This cohort study in Senegal showed comparable long-term virological and immunological effectiveness of a regime consisting of ddI, lamivudine, and efavirenz or nevirapine as a regime consisting of ZDV, lamivudine, and the same NNRTIs in ART-naive patients. ddI was less commonly discontinued than ZDV.

Didanosine has been used in first-line ART in Africa combined with other NRTIs, namely stavudine and ZDV (Laurent et al. 2002; Seyler et al. 2003). However, these combinations were abandoned owing to poor efficacy and/or tolerability (Canestri et al. 2007; Bussmann et al. 2009; Ratsela et al., 2009). To our knowledge, data on ddI–lamivudine–NNRTI in ART-naive patients in Africa are mainly limited to our Senegalese cohort. The clinical trial in 40 of our patients showed promising results for the first 15 months but there was no comparison regimen (Landman et al. 2003). Our present study therefore extends the knowledge in the long term and with comparison to one of the WHO-recommended regimens.

Overall effectiveness and tolerability with both ddI- and ZDV-based regimens were similar or even better to those seen initially in other African settings (Coetzee et al. 2004; Laurent et al. 2008) or western countries (Berenguer et al. 2008; Crespo et al. 2009). It is noteworthy that the good virological effectiveness was maintained in the long term and that the CD4 cell count continued to increase with both regimens. It was therefore surprising that the deaths tended to be more frequent in the ddI group. Unreported ddI toxicity was unlikely to explain the excess deaths because most deaths were related to infectious diseases or, to a lesser extent, loss to follow-up. Similarly to our study, one of the western studies reported a twofold higher risk of treatment change in patients who received a ZDV–lamivudine backbone as in those treated with ddI–lamivudine (Crespo et al. 2009).

The main limitation of our study is the lack of treatment randomisation. However, this observational cohort study in which all analyses were adjusted on baseline patients’ characteristics and which was performed over a 9-year period in Africa adds useful information to the current debate on the use of ddI in first-line ART in routine resource-limited settings (Benson & Hartz 2000; Concato et al. 2000; Concato & Horwitz 2004). The number of patients was also relatively small, potentially leading to fail demonstrating significant differences between the treatment groups (e.g. for death).

In conclusion, the combination of ddI, lamivudine, and efavirenz or nevirapine resulted in sustained viral suppression and immunological recovery. However, additional data on disease progression in these settings are needed.

Acknowledgements

We thank all the patients and staff who participated in the study. The study was funded by the French National Agency for Research on AIDS and Viral Hepatitis, IMEA, the European Union and the Institut de Recherche pour le Développement. Jules Brice Tchatchueng Mbougua was the recipient of a doctoral fellowship from IRD.

Appendix

ANRS 1215/1290 Study Group

I. Ndoye (Multisectorial AIDS Program, Dakar, Senegal), P. de Beaudrap, E. Delaporte, J. F. Etard, C. Laurent, B. Taverne (UMR 145, Institut de Recherche pour le Développement (IRD)/University Montpellier 1, Montpellier, France), M. M. Bitèye, A. B. Dieng, A. Diouf, A. Sarr, L. Zié (Regional Research and Training Center for HIV/AIDS, Fann University Teaching Hospital, Dakar, Senegal), V. Cilote, I. Lanièce (French Ministry of Foreign Affairs, Dakar, Senegal), I. Ndiaye, A. Ndir, C. T. Ndour, C. S. Senghor, P. S. Sow (Department of Infectious Diseases, Fann University Teaching Hospital, Dakar, Senegal), M. Basty Fall, N. M. Dia Badiane, N. Diakhaté, M. Diallo, L. M. Diouf, N. F. Ngom Guèye (Ambulatory Care Unit-Red-Cross, Fann University Teaching Hospital, Dakar, Senegal), K. Ba Fall, P. M. Guèye, C. Périno (Military Hospital of Dakar, Senegal), P. A. Diaw, H. Diop Ndiaye, S. Mboup, N. C. Touré Kane (Le Dantec University Teaching Hospital, Virology and Bacteriology Laboratory, Dakar, Senegal), K. Sow (AIDS Control Division, Ministry of Health, Dakar, Senagal), K. Diop, B. Ndiaye (Central Pharmacy, Fann University Teaching Hospital, Dakar, Senegal), M. Ciss (Ministry of Health, National Drug Laboratory, Dakar, Senegal), and A. Desclaux (Paul Cezanne University, CReCSS, Aix-en-Provence, France).

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