Corresponding Author Katharina Kranzer, Department of Clinical Research, Faculty of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK. Tel.: +44 20 7636 8636; E-mail: firstname.lastname@example.org
Objective To characterize the frequency, reasons, risk factors, and consequences of unstructured anti-retroviral treatment interruptions.
Method Systematic review.
Results Seventy studies were included. The median proportion of patients interrupting treatment was 23% for a median duration of 150 days. The most frequently reported reasons for interruptions were drug toxicity, adverse events, and side-effects; studies from developing countries additionally cited treatment costs and pharmacy stock-outs as concerns. Younger age and injecting drug use was a frequently reported risk factor. Other risk factors included CD4 count, socioeconomic variables, and pharmacy stock outs. Treatment interruptions increased the risk of death, opportunistic infections, virologic failure, resistance development, and poor immunological recovery. Proposed interventions to minimize interruptions included counseling, mental health services, services for women, men, and ethnic minorities. One intervention study found that the use of short message service reminders decrease the prevalence of treatment interruption from 19% to 10%. Finally, several studies from Africa stressed the importance of reliable and free access to medication.
Conclusion Treatment interruptions are common and contribute to worsening patient outcomes. HIV/AIDS programmes should consider assessing their causes and frequency as part of routine monitoring. Future research should focus on evaluating interventions to address the most frequently reported reasons for interruptions.
Objectif: Caractériser la fréquence, les raisons, les facteurs de risque et les conséquences des interruptions non structurées du traitement antirétroviral (ART).
Méthode: Revue systématique.
Résultats: 70 études ont été incluses. La proportion médiane des patients qui ont interrompu le traitement était de 23% pour une durée médiane de 150 jours. Les raisons d’interruption les plus fréquemment rapportées étaient la toxicité des médicaments, les effets indésirables et les effets secondaires. Les études dans les pays en développement ont en outre cité comme inquiétant, les coûts du traitement et les ruptures de stock de pharmacie. L’âge plus jeune et l’utilisation de drogues injectables étaient des facteurs de risque fréquemment rapportés. D’autres facteurs de risque comprennent le taux de CD4, les variables socio-économiques et les ruptures de stock de pharmacie. Les interruptions de traitement augmentaient le risque de décès, les infections opportunistes, l’échec virologique, le développement de la résistance et une pauvre récupération immunologique. Les interventions proposées pour minimiser les interruptions comprennent des conseils, des services de santé mentale, des services pour les femmes, pour les hommes et pour les minorités ethniques. Une étude d’intervention a constaté que l’utilisation d’un service de courts messages de rappel diminuait la prévalence des interruptions du traitement de 19%à 10%. Enfin, plusieurs études en Afrique ont souligné l’importance d’un accès fiable et gratuit aux médicaments.
Conclusion: Les interruptions de traitement sont courantes et contribuent à l’aggravation des résultats des patients. Les programmes VIH/SIDA devraient envisager d’évaluer les causes et la fréquence dans le cadre de la surveillance de routine. Les recherches futures devraient mettre l’accent sur l’évaluation des interventions pour s’attaquer aux causes les plus fréquemment rapportées pour les interruptions.
Objetivo: Caracterizar la frecuencia, las razones, los factores de riesgo y las consecuencias de las interrupciones no estructuradas del tratamiento antirretroviral (TAR).
Método: Revisión sistemática.
Resultados: Se incluyeron 70 estudios. La mediana de la proporción de pacientes que interrumpían el tratamiento era del 23% para una duración media de 150 días. Las razones más frecuentemente reportadas para las interrupciones eran la toxicidad de la droga, los eventos adversos y los efectos colaterales; los estudios en países en vías de desarrollo reportaban además los costes y la falta de existencias en las farmacias. La interrupción del tratamiento aumentaba el riesgo de muerte, las infecciones oportunistas, el fallo virológico, el desarrollo de resistencias y una mala recuperación inmunológica. Las intervenciones propuestas para minimizar las interrupciones incluían el aconsejamiento, servicios de salud mental, servicios para mujeres, hombres y minorías étnicas. Un estudio de intervención encontró que el uso de un servicio de avisos por SMS disminuyó la prevalencia de interrupción del tratamiento del 19% al 10%. Finalmente, varios estudios en África subrayaron la importancia de un acceso fiable y gratuito a la medicación.
Conclusión: Las interrupciones en el tratamiento son comunes y contribuyen al empeoramiento de los resultados obtenidos por los pacientes. Los programas para el VIH/SIDA deberían considerar evaluar sus causas y frecuencia como parte de la monitorización rutinaria. Las investigaciones futuras deberían focalizarse en la evaluación de intervenciones con el fin de identificar las razones de interrupción del tratamiento más frecuentemente reportadas.
The potential for provider-directed, structured treatment interruptions as a way to limit antiretroviral exposure (and therefore both toxicities and costs) was abandoned after randomized trials and cohort studies found an increased risk of opportunistic infection and death (El-Sadr et al. 2006; Mugyenyi et al. 2008; Seminari et al. 2008). Nevertheless, patient-initiated unstructured treatment interruptions are a reality of routine clinical care and have been reported in both developed (Holkmann Olsen et al. 2007) and developing country settings (Kranzer et al. 2010).
To better characterize the frequency, reasons, risk factors, and consequences of unstructured treatment interruptions in routine clinical practice, we conducted a systematic review of available studies reporting on unstructured treatment interruptions.
Criteria for selection of studies
We aimed to identify studies reporting on unstructured ART treatment interruptions in clinical practice. Unstructured treatment interruption was defined as discontinuation of all ART drugs for any period of time, after which treatment was resumed. We considered that any interruption was undesirable, and thus did not limit our search to specific causes or durations. We excluded studies reporting on structured treatment interruptions, defined as physician-initiated, cyclical interruptions guided by CD4 count or viral load. We also excluded studies only reporting on patients experiencing virologic failure. We included both cross-sectional and cohort studies, but excluded editorials, case studies, case reports, and reviews.
We searched three electronic databases for primary studies: Medline, Embase, and Global Health using the compound search strategy summarized in Table S1 and searched the bibliographies of retrieved articles for additional studies. Our search was limited to studies published and conducted from 1996 (the time when highly active ART became available) until the end of the search period (March 2011). We also searched for conference abstracts from all conferences of the International AIDS Society (April, 1985–July, 2010), and all Conference on Retroviruses and Opportunitistic Infections (January, 1997–February, 2010) and the PEPFAR implementers meeting 2007–2009. No language restriction was applied.
Study selection and data extraction
Studies were entered into an electronic database (EndNote X1) to screen potentially eligible studies by title and abstract according to our pre-defined inclusion and exclusion criteria. Full-length articles of all studies considered eligible upon initial screening were obtained and reviewed for eligibility; conference abstracts were screened first by title, then by full abstract. All reviews were carried out independently, in duplicate. After agreeing on eligibility, we abstracted the following information using a standardized extraction form: definitions of treatment interruption, frequency and duration of interruption, reasons, risk factors, consequences of treatment interruption, and proposed interventions. Whenever required, we attempted to contact study authors for clarification by email.
Finally, we assessed full articles for determinants of methodological quality using a pre-defined assessment framework. The following factors were assessed: definition and objectivity of treatment interruption provided, appropriateness of the statistical analysis. Studies investigating consequences or treatment failure (e.g. mortality or viral rebound) were assessed for adjustment for potential confounding and use of objective outcome measures.
Characteristics of included studies
The study selection process is summarized in Figure 1. Our initial search yielded 813 potentially relevant publication and 577 potentially relevant conference abstracts, from which 47 publications and 23 abstracts were considered eligible for inclusion. Three studies considered potentially eligible were excluded because it was unclear whether patients restarted treatment (i.e. interruption) or not (i.e. discontinuation); authors were contacted but did not provide clarification (Berenguer et al. 2004; Braitstein et al. 2007; Ayuo et al. 2008). Sixteen studies were from Africa, 14 from North America, two from Australia, one from South America, two from Eastern Europe, three from Asia, and 32 from Europe. The majority of studies (63) reported results of treatment interruptions in adults from the general population; of the remainder, two studies were among children, one was among adolescents, one was among injecting drug users, one was among men who have sex with men, one was among recurrent prisoners, and one was among women. We judged the methodological quality of studies included as full-length articles to be moderate: a third of studies (15/47) provided a definition and objectivity of treatment interruption; almost all (46/47) used an appropriate statistical analysis approach, and where appropriate the majority (23/25) adjusted for confounders and used an objective outcome measure (29/30).
Definition of treatment interruption and measurement
We found substantial variation and uncertainty in the definition of treatment interruption applied by the individual studies. Twenty-eight did not define the duration of treatment interruption, while of the 42 studies that did specify a definition, duration ranged from 24 h to 1 year (Figure 2). Two cross-sectional studies investigating self-reported treatment interruptions defined interruption as discontinuation of all drugs for more than 24–48 h in the 4 weeks preceding the survey (Glass et al. 2006; Marcellin et al. 2008). Two studies investigating short interruptions defined a maximum duration of treatment discontinuation of 1 month (Oyugi et al. 2007) and 3 months (Taffe et al. 2002).
The methods used to determine treatment interruptions varied: self-report (21/70), electronic medication monitoring (4/70) data, prospectively collected by clinicians (7/70), information extracted from clinical records (7/70), pharmacy prescriptions in combination with clinical records (3/70), pharmacy prescriptions only (2/70), combination of data collected by clinicians and/or self-report and/or prescriptions (4/70). Twenty-two studies did not describe the method used to identify treatment interruptions.
Frequency and duration of treatment interruption
Forty-two studies reported frequencies of treatment interruptions, either as proportions (35), rates (1), or proportions and rates (3) of interruption, or as rates or proportions of discontinuation and resumption (3) (Table 1). The proportion of treatment interruptions ranged from 5.8% [adults in Switzerland (Glass et al. 2006)] to 83.1% [recurrent prisoners in the USA (Pai et al. 2009)]; the median proportion of patients interrupting treatment was 23.1% (IQR 15.0–48.0). Rates of treatment interruptions ranged from 2.0 per 100 person-years in the United Kingdom (Bansi et al. 2008), to 6.0 in the Euro-SIDA study (Holkmann Olsen et al. 2007). Eleven studies reported on the mean or median duration of treatment interruptions, with durations ranging from 11.5 days (Oyugi et al. 2007) to 18 months (Holkmann Olsen et al. 2007) (median 150 days). Treatment interruptions were frequently reported as recurrent events, with up to three interruptions per person reported in South Africa (Kranzer et al. 2010) and Senegal (Uhagaze et al. 2006), five in Switzerland (Taffe et al. 2002), six in the EuroSIDA study (Holkmann Olsen et al. 2007), and an average of two in Uganda (Oyugi et al. 2007).
Older age Injecting drug use Time lag between HIV diagnosis and treatment initiation Anxiety related to therapy Subjective antiretroviral therapy (ART) intolerance Experience of more than four regimens
Women Injecting drug use High baseline viral load High baseline CD4 count Low current CD4 count
Consequences of treatment interruption
Thirty-eight studies reported on various consequences of treatment interruption, comprising mortality, opportunistic infections, immunological and virologic changes, the development of resistance mutations, neurocognitive impairment, and decreased health-related quality of life.
Four studies investigated the development of resistance mutations (Parienti et al. 2004; Spacek et al. 2006; Oyugi et al. 2007; Sanchez et al. 2007). In a study from France, interrupting treatment more than once was significantly associated with the development of resistance to the non-nucleoside-reverse-transcriptase inhibitors (NNRTI) class (hazard ratio 22.5, 95% CI 2.8–180.3) (Parienti et al. 2004). Among 19 treatment interrupters in Spain, nine had mutations in the reverse transcriptase gene and 17 had polymorphism in the protease gene, with L63P being the most commonly found (Sanchez et al. 2007). In Uganda, none of the patients with continuous treatment had evidence of resistance mutations, but 13% of patients with a history of treatment interruption had resistance mutations: all of them had mutations conferring nevirapine resistance, five had mutations conferring lamivudine resistance, and three had mutations conferring stavudine resistance (Oyugi et al. 2007). Another study from Uganda showed resistance to NNRTI class in 26 of 36 patients with detectable viral load with the most common mutation being K103N. Twenty-three of the 36 patients had the M184V/I mutation and three had genotypic resistance to PIs (Spacek et al. 2006).
We only identified one intervention study. This randomized controlled trial from Kenya showed that short message service reminders either daily or weekly reduced the prevalence of treatment interruptions exceeding 48 h from 19% to 10% (P = 0.03) (Pop-Eleches et al. 2011).
Six studies investigating risk factors associated with treatment interruptions discussed possible interventions. Studies from developed countries suggested appropriate counseling on the consequences of drug discontinuation, encouragement of optimal adherence, offering of mental health services, addressing addictions, and providing services specifically engaging women and ethnic minorities (Li et al. 2005; Moore et al. 2009; Murri et al. 2009). Studies from Uganda and Cameroon emphasized the importance of steady and reliable access to medication, as well as free access to ART and possibly food supply programs (Oyugi et al. 2007; Marcellin et al. 2008). A study from South Africa concluded that interventions should be targeted at men and during the first 6 months on ART (Kranzer et al. 2010).
When patients were asked to give at least one suggestion how to improve adherence and reduce treatment interruptions: 46% suggested reduction in daily doses, 28% more detailed information about therapy, 27% more attention to side effects, 20% more time dedicated to adherence-related issues, 19% supervised treatment interruptions, and 16% psychological help (Ammassari et al. 2004).
Medication-taking behavior is characterized by adherence which is defined as ‘extent to which a patient acts in accordance with the prescribed interval, and dose of a dosing regimen’ and persistence defined as ‘the duration of time from initiation to discontinuation of treatment’ (Cramer et al. 2008). Persistence emphasizes the concept of continuous therapy and is influenced by both defaulting from antiretroviral care and treatment interruption’ (Bae et al. 2011). Adherence and persistence are both important for optimal treatment outcomes, but their impact may vary dependent on the type of regimen prescribed and the duration and frequency of treatment interruptions.
We found that the characterization of treatment interruption in the literature to date is confused by heterogeneous definitions. A quarter of studies provided no definition, while for those that did definitions varied from more than 24 h to more than 1 year of discontinuation of treatment. Only half of studies reported on median duration of interruption. Similar problems with regard to uniformity of definitions have been encountered in studies investigating loss to follow-up where definitions ranged from 1 to 6 months late for a scheduled consultation or medication pick-up (Rosen et al. 2007). In addition, the method of determination of treatment interruption varied considerably: over a quarter of studies using self-report, while a similar number did not specify the method used to identify treatment interruptions.
The reported causes of treatment interruption are multi-dimensional and context-specific. However, research to date has largely assessed risk factors and reasons for treatment interruption, few in developing country settings. Studies from developing countries highlighted pharmacy stock outs and costs as important factors for treatment interruptions. While several interventions have been proposed, only one has been formally assessed.
Data synthesis is a desirable goal for systematic reviews. However, in view of the substantial degree of heterogeneity between studies with regard to definitions of treatment interruption and methods used to identify treatment interruptions, we decided against providing a data synthesis. In addition, because treatment interruptions depend on duration of ART, incidence would be a more informative measure, but few studies provided incidence estimates. Another limitation of our review, reflecting a limitation of the published evidence, is that only four studies investigated the association between treatment interruption and genotypic resistance. The sample size of these studies was small. One of these studies relied on self-report to identify treatment interruptions. Larger studies using objective measures of treatment interruptions are needed to confirm the association between treatment interruption and genotypic resistance. Finally, although our search strategy was extensive, yielding a high number of studies, we cannot exclude the possibility that our search strategy may not have captured all reports of treatment interruption.
Our study highlights several directions for future research and practice. First, reporting on treatment interruptions should be encouraged, both to improve the quality of program outcome reports, and support better characterization and quantification of the problem. Second, more uniform reporting of treatment interruption should be encouraged to support comparability across studies, as has been proposed for treatment defaulting. The range of proposed interventions in the literature does not reflect the range of causes reported, with a notable absence of attention on some of the most frequently reported drivers of treatment interruption, including drug toxicity, adverse events, and side effects. This suggests that a first step to minimizing treatment interruptions in many settings is simply to provide better care to patients. Finally, intervention studies should be planned to determine the effectiveness of approaches to minimize treatment interruption and encourage treatment resumption.
In conclusion, treatment interruptions are common both in developed and in developing countries and are associated with increased morbidity, mortality, and possibly genotypic resistance. Future research should focus on evaluating interventions to address the most frequently reported reasons for interruptions to support patients in a way that maximizes the chances of continuous and effective treatment.
KK is funded by the Welcome Trust, London, United Kingdom.