Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 251–258
doi: 10.1111/jcpt.12253
Review Article
Pharmaceutical interventions in antiretroviral therapy: systematic review and meta-analysis of randomized clinical trials B. S. Rocha* M.Sc., M. P. T. Silveira† PhD, C. G. Moraes‡ M.Sc., R. S. Kuchenbecker‡ PhD and T. S. Dal-Pizzol‡ PhD *Secß~ao de Farmacia Clınica, Hospital de Clınicas de Porto Alegre, Porto Alegre, †Departamento de Fisiologia e Farmacologia, Universidade Federal de Pelotas, Pelotas, and ‡Programa de Pos-Graduacß~ao em Epidemiologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
Received 11 January 2015, Accepted 3 February 2015
Keywords: acquired immunodeficiency syndrome, adherence, antiretroviral therapy, human immunodeficiency virus, meta-analysis, pharmaceutical care, systematic review
antiretroviral medication; some studies indicate that adherence levels lower than 95% are associated with lower rates of viral suppression.4,5 The need to achieve an adherence >95% of the doses of the treatment regimens, which are often quite complex, requires individuals undergoing treatment to adjust their daily habits and make changes in their routines. A systematic review that assessed studies measuring ART adherence found that a significant fraction of patients did not attain a desirable level of adherence. The metaanalysis obtained a summary estimate indicating that only 62% of the patients took more than 90% of the prescribed doses.6 Pharmacists could play a relevant role in increasing patients’ adherence to ART. Because antiretroviral drugs must be taken on a continuous basis, patients need to visit pharmacies periodically, once per month in most cases, to pick the medication up; thus, they have frequent contact with pharmacists. Murphy et al. conducted a study that assessed the impact of HIV-specialized pharmacies on ART adherence and found that such pharmacies did help the patients achieve greater adherence to treatment compared with non-specialized community pharmacies.7 A retrospective cohort study conducted by Ma et al. to assess the impact of a pharmacist’s interventions on ART adherence found a reduced pill burden and improved adherence to treatment following interventions that aimed to adjust treatment, reduce its adverse effects and adapt the frequency of drug intake.8 A systematic review of studies published from 2000 to 2011 on the impact of clinical pharmacists on HIV treatment, including cohort studies, cross-sectional studies, before–after comparisons, quasi-experimental studies and clinical trials, found positive associations between pharmacists’ interventions and improved adherence to treatment and viral suppression. However, the results of that review were not clustered or described in quantitative terms as expected for meta-analyses, and the quality of the included studies was not assessed.9 The aim of this study was to assess the impact of pharmaceutical interventions on ART via a systematic review of randomized clinical trials.
SUMMARY What is known and objective: High levels of adherence to antiretroviral therapy (ART) are needed to achieve the desired results. Because pharmaceutical care might contribute to improved adherence to treatment, the aim of this study was to assess the impact of pharmaceutical interventions on ART via a systematic review of randomized clinical trials (RCT). Methods: Study selection, data extraction and risk-of-bias assessment were performed independently by two reviewers. Results and discussion: A total of 681 studies were located; only four of these met the inclusion criteria and were analysed. The summary measure corresponding to the outcome adherence to treatment was 147 (95% confidence interval [CI]: 081–265), and the measure corresponding to the outcome virologic suppression was 195 (95% CI: 061–625). What is new and conclusion: The results suggest that pharmaceutical interventions might contribute to improved adherence to ART and the achievement of virologic suppression, although the differences between the intervention and control groups were not statistically significant. Pharmaceutical interventions might be more efficacious in populations with low adherence to treatment and greater vulnerability.
WHAT IS KNOWN AND OBJECTIVE According to estimates, 353 million people lived with the human immunodeficiency virus (HIV) in 2012. Approximately 23 million new HIV infections occurred worldwide, representing a decline in the number of infections relative to 2001 (34 million). In 2012, the number of deaths related to HIV infection worldwide was 16 million, which is 33% lower than the estimate for 2005 (23 million).1 One of the main factors contributing to the improvement in indicators associated with HIV infection is antiretroviral therapy (ART). ART aims to reduce the morbidity and mortality of individuals infected with HIV, thus improving their life expectancy and quality of life.2,3 There is a direct relationship between sustained viral repression and an individual’s intake of more than 95% of his or her
METHODS
Correspondence: B. S. Rocha, Secß~ ao de Farm acia Clınica, Hospital de Clınicas de Porto Alegre, Av. Ramiro Barcellos 2350, sala 933, CEP 90035-903, Porto Alegre, RS, Brazil. Tel.: 55 51 33598016; fax: 55 51 33085281; e-mail: [email protected]
© 2015 John Wiley & Sons Ltd
Research protocol A research protocol was elaborated to standardize and guide all of the study steps; that protocol can be requested from the authors.
251
B. S. Rocha et al.
Pharmaceutical interventions in antiretroviral therapy
Eligibility criteria
681 Located studies - 367 MEDLINE - 155 EMBASE - 24 Web Of Science - 25 SCOPUS - 10 SCIELO - 12 LILACS - 5 IBEHCS - 69 IPA - 5 CINAHL - 8 COCHRANE - 1 Clinical trials
Randomized clinical trials conducted with HIV-seropositive patients of any age and gender that included pharmaceutical care were included. According to previous systemic reviews of pharmaceutical interventions for other chronic clinical conditions,10,11 pharmaceutical intervention was defined as present when a pharmacist provided direct care to patients or dealt with drugrelated issues to solve problems related to pharmacological therapy. The interventions considered could be performed by pharmacists alone or with other professionals; this criterion was also adopted in a previous systematic review.10
28 studies selected based on title/abstract for full-text analysis
Information sources The studies were located via searches of the following databases from their onset to July 2013, with no restriction on the language of articles: Medline, the Cochrane Central Register of Controlled Trials, Embase, IBECS, CINAHL, IPA, Scopus, Web of Science, LILACS, SciELO and Clinical Trials. A grey literature search was conducted in CAPES, ProQuest, OpenGrey and The British Library databases and also master and doctoral dissertations. The references quoted in the selected articles were also surveyed to find additional studies.
- 7 Repeated studies - 17 Studies did not meet the inclusion criteria following full-text analysis
4 studies included for systematic review
Fig. 1. Flow chart of study selection. immune failure; (iv) viral load; (v) virologic failure and/or virologic suppression; (vi) the development of viral resistance; (vii) mortality rate; and (viii) quality of life.
Search strategy The following combinations of keywords as mesh terms and text words were used: HIV; Acquired Immunodeficiency Syndrome; AIDS; Human Immunodeficiency Virus; Antiretroviral Therapy, Highly Active; HAART; Medication Adherence; Medication Compliance; Medication Non-Adherence; Medication Non-Compliance; Patient Compliance; Patient Adherence; CD4 Lymphocyte Count; Viral Load; Drug Resistance, Viral; Pharmaceutical Services; Pharmaceutical Care; Pharmacist; Pharmacy Services, Hospital; Pharmacies; Pharmaceutical Assistance; and Pharmacotherapy Follow-Up. A filter was included in the search strategy to restrict the search to randomized clinical trials, as indicated in Medline’s Clinical Queries.12 The search strategies used in the Medline and Embase databases can be requested from the authors.
Assessment of risk of bias The methodological quality of each study was established by assessing the risk of bias of the randomized clinical trials using the Cochrane Collaboration tool,13 which recommends assessing the following domains: random sequence generation, allocation sequence concealment, the blinding of participants and personnel, the blinding of outcome assessment, incomplete outcome data and selective outcome reporting. The risk of bias of each assessed domain was classified as low, high or unclear. Summary measure and synthesis of results
Study selection
The results were entered in a MICROSOFT OFFICE EXCEL 2007 spreadsheet. The data were summarized in a meta-analysis of the effect of pharmaceutical intervention on each selected outcome using REVIEW MANAGER 5.2 software. The random effects model was used to analyse the outcomes of the included studies. Heterogeneity was assessed graphically and statistically using Cochran’s Q test and the degree of inconsistency (I²).
Study selection was performed by two reviewers (BSR and MTS) working independently. The results were compared, and discrepancies were solved by a third reviewer (CGM). The examiners were not blinded to the authors, journals or results of studies. Data collection procedure The data were entered in extraction forms elaborated by the authors. The main extracted data were study population, sample and intervention, relevant outcomes, and assessment of the studies’ methodological quality based on their risk of bias. This step was also independently performed by two reviewers (BSR and MTS). The results were compared, and discrepancies were resolved by a third reviewer (CGM).
Sensitivity analysis A sensitivity analysis was performed to assess the robustness of the meta-analysis results by repeating the calculation of the summary odds ratios with the following modifications: (i) the use of the Peto method; (ii) following the exclusion of the study with the largest sample size; (iii) following the exclusion of the studies that applied different cut-off points to define adherence to treatment; (iv) following the exclusion of studies that used different methods to measure adherence to treatment; and (v) following the exclusion of studies in which intervention was performed by pharmacists working with other professionals.
Outcome measures The outcomes established a priori for inclusion in data collection were (i) adherence to treatment; (ii) CD4 lymphocyte count; (iii)
© 2015 John Wiley & Sons Ltd
Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 251–258 252
B. S. Rocha et al.
Pharmaceutical interventions in antiretroviral therapy
the studies.15–17 In most of the studies, the risk of masked assessment of clinical outcomes was unclear,14–16 and the risk of selective outcome reporting was low.15–17 In two of the studies, the risk of incomplete outcome data was low.15,17
RESULTS AND DISCUSSION The search located 681 studies, of which only four14–17 were included for analysis. The flow chart representing the article selection process is depicted in Fig. 1.
Sensitivity analysis Characteristics of the selected studies
In the sensitivity analysis, which followed the shift to the Peto (fixed effects) model, the summary measure corresponding to the outcome adherence to treatment was 137 (093–201), with a heterogeneity of v² = 505 (P = 017). Following the exclusion of the study with the greatest weight in the meta-analysis,17 the summary measure increased to 207 (060–717), with a heterogeneity of v² = 489 (P = 009). When only the studies that used a 95% cut-off point to define adherence to treatment were analysed,15–17 the summary measure corresponding to that outcome decreased to 120 (079–181), with a heterogeneity of v² = 059 (P = 044). A sensitivity analysis of the studies that used MEMS only14,15 resulted in an increase of the summary measure to 420 (083–2128). The summary measure corresponding to the outcome adherence to treatment for interventions performed by pharmacists only15,17 was 146 (089–237), with a heterogeneity of v² = 054 (P = 046). When such interventions were jointly performed by pharmacists and other professionals,14,16 the summary measure was 278 (021– 3605), with a heterogeneity of v² = 407 (P = 004). Regarding the outcome virologic suppression, following calculation using the Peto method, the summary measure was 120 (080–180), with a heterogeneity of v² = 474 (P = 009). The summary measure corresponding to the studies in which intervention was performed by pharmacists only15,17 was 213 (030–1521), with a heterogeneity of v² = 320 (P = 007). Following the exclusion of the study with the greatest weight in the metaanalysis,17 the summary measure was 408 (107–1555), with a heterogeneity of v² = 057 (P = 045). Following the exclusion of the study that applied the highest cut-off point relative to the outcome virologic suppression,15 the summary measure was 121 (059–260), with a heterogeneity of v² = 135 (P = 025).
Table 1 describes the main characteristics of the selected studies. One of the selected studies was conducted in Brazil,17 and the remainder were conducted in the United States. Intervention was provided by pharmacists together with other professionals in two studies,14,16 and by pharmacists alone in the other two.15,17 The length of patient follow-up varied from three to 12 months. Interventions performed by pharmacists working with other professionals included an educational programme for medication self-management14 and collaborative care for depression, including counselling on pharmacological therapy.16 Interventions exclusively performed by pharmacists included pharmaceutical care using the Dader method17 and counselling provided by a clinical pharmacist.15 Outcome measures Regarding the outcomes included in the protocol for the present review, no data on virologic resistance, CD4 lymphocyte count, deaths or quality of life were found in the selected studies. All four studies assessed the outcome adherence to ART; the results are described in Table 2. Adherence was measured in two studies via electronic monitoring using the Medication Event Monitoring System (MEMS),14,15 one applied a semi-structured questionnaire,16 and one used patient self-reporting.17 The cut-off points selected to define patients as adherent were 80%,14 95%16,17 and 90 and 95%.15 The results corresponding to adherence to treatment and association measures were favourable to pharmaceutical intervention in all four studies; however, the between-groups difference in adherence was statistically significant in only one study.14 Figure 2 depicts the forest plot corresponding to the outcome adherence to treatment in the studies included in the metaanalysis, with a summary measure of 147 (95% confidence interval [CI]: 081–265). The result of Cochran’s Q test was 488 (P = 018), and the degree of inconsistency was 39%. Viral load was measured in three studies,14,15,17 and the corresponding data allowed the outcome virologic suppression to be established based on each study’s cut-off point for defining virologic failure or suppression and viral load detection limit. The results corresponding to the outcome virologic suppression in each individual study are described in Table 3. Figure 3 depicts the forest plot corresponding to the outcome virologic suppression for all of the studies included in the meta-analysis, with a summary measure of 195 (95% CI: 061–625). The result of Cochran’s Q test was 435 (P = 011), and the degree of inconsistency was 54%.
The main aim of the present systematic review was to assess the impact of pharmaceutical interventions on ART. In this type of investigation, the risk of bias is minimized when studies that applied experimental designs, such as randomized clinical trials, are selected. The meta-analyses performed in the present study provide objective results regarding outcomes relevant to ART. Systematic reviews of the impact of pharmaceutical interventions on several diseases are available in the literature.11,18,19 As a function of the scarcity of studies in this field,20 most such reviews included fewer than 10 studies. We were not able to locate any systematic review of randomized clinical trials addressing the impact of pharmaceutical interventions on ART for HIV. In all of the studies analysed in the present review, the results relative to the outcomes adherence to treatment and virologic suppression were superior in the groups that underwent pharmaceutical intervention. Nevertheless, that difference was statistically significant in only one clinical trial.14 Although the percentage of patients who achieved virologic suppression was higher in the groups that received pharmaceutical intervention, that difference was not statistically significant in any of the analysed studies. The study by Smith et al. consisted of a multiprofessional intervention based on the use of medication self-management techniques, and it assessed the outcomes adherence to treatment
Assessment of risk of bias Figure 4 depicts the assessment of risk of bias, and Fig. 5 shows the risk-of-bias assessment for each individual study. Most of the studies exhibited a low risk of bias relative to random sequence generation15–17 and an unclear risk relative to allocation sequence concealment.14,16,17 The risk of bias relative to the blinding of participants and personnel was high in most of
© 2015 John Wiley & Sons Ltd
Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 251–258 253
© 2015 John Wiley & Sons Ltd
254
Control: 138 Intervention: 138
Control: 166 Intervention: 166
Silveira (2014)17
Control: 21 Intervention: 22
Rathburn (2005)15
Pyne (2011)16
Control: 21 Intervention: 22
Smith (2003)14
Author (year)
Randomized individuals (n)
Brazil
USA
USA
USA
Country
Specialized outpatient clinic
Specialized outpatient clinic
University specialized outpatient clinic
Clinical research center
Study setting
Table 1. Characteristics of the included studies (n = 4)
Adults
Adults undergoing treatment for depression
Indigent adults
Adults starting protease inhibitor treatment
Sample description
Pharmaceutical care using the Dader method. Exclusive pharmaceutical intervention
Standard care combined with medication self-management program: education about medication and skills training Multi-professional intervention Standard care combined with education provided by clinical pharmacist (proper ART administration, dietary restrictions, management of adverse reactions and monitoring of patient progress after onset of therapy) Exclusive pharmaceutical intervention PHQ (health questionnaire). Five-step depression treatment model, including counseling on pharmacological treatment. Multi-professional intervention
Intervention group
PHQ (health questionnaire). Standard treatment provided by general practitioners or doctors specialized in mental health who did not participate in the treatment of the patients in group intervention. Standard care (not including a pharmacist)
Standard care by health care staff (doctor and nurse)
Standard care: counseling and orientation to improve adherence to treatment.
Control group
12 months
12 months
7 months
3 months
Follow-up length
Adherence to treatment Viral load Virologic failure Depression scale
Adherence to treatment Depression scale
Adherence to treatment Viral load Virologic failure
Adherence to treatment Viral load Virologic failure
Outcomes
Pharmaceutical interventions in antiretroviral therapy B. S. Rocha et al.
Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 251–258
B. S. Rocha et al.
Pharmaceutical interventions in antiretroviral therapy Table 2. Measurement of adherence to treatment in the selected studies (n = 4)
Author (year)
Method to measure adherence
Individuals with outcome measure
Adherence intervention n/n total (%)
Adherence control n/n total (%)
Smith (2003)14 Rathburn (2005)15 Pyne (2011)16 Silveira (2014)17
MEMS, cut-off point 80% MEMS, cut-off point 90% and 95% Semi-structured questionnaire, cut-off point 95% Self-report, cut-off point 95%
43 33 178 319
7/8 (96) 10/16 (625) 68 (739) 128 (798)
3/9 (37) 7/17 (412) 64 (744) 117 (738)
Intervention Study or subgroup
Events
Control
Odds ratio
Total Events Total Weight
M-H, Random, 95% CI Year
7
8
3
9
5·1%
14·00 [1·14, 172·64] 2003
Rathbun 2005
10
16
7
17
14·1%
2·38 [0·59, 9·65] 2005
Pyne 2011
68
92
64
86
36·3%
0·97 [0·50, 1·91] 2011
128
161
117
158
44·5%
1·36 [0·81, 2·29] 2014
Smith 2003
Silveira 2014
Total events
213
1·47 [0·81, 2·65]
270 100·0%
277
Total (95% CI)
Odds ratio M-H, Random, 95% CI
191
Heterogeneity: τ² = 0·13; χ² = 4·88, d.f. = 3 (P = 0·18); I² = 39%
0·01
Test for overall effect: Z = 1·28 (P = 0·20)
0·1
1
10
100
Favours [control] Favours [experimental]
Fig. 2. Forest plot corresponding to the outcome adherence to treatment.
Table 3. Measurement of viral load and virologic suppression in the included studies (n = 3)
Author (year)
Viral load detection limit
Individuals with outcome measure
Virologic suppression intervention n/n total (%)
Virologic suppression control n/n total (%)
Smith (2003)14 Rathburn (2005)15 Silveira (2013)17
doi: 10.1111/jcpt.12253
Review Article
Pharmaceutical interventions in antiretroviral therapy: systematic review and meta-analysis of randomized clinical trials B. S. Rocha* M.Sc., M. P. T. Silveira† PhD, C. G. Moraes‡ M.Sc., R. S. Kuchenbecker‡ PhD and T. S. Dal-Pizzol‡ PhD *Secß~ao de Farmacia Clınica, Hospital de Clınicas de Porto Alegre, Porto Alegre, †Departamento de Fisiologia e Farmacologia, Universidade Federal de Pelotas, Pelotas, and ‡Programa de Pos-Graduacß~ao em Epidemiologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
Received 11 January 2015, Accepted 3 February 2015
Keywords: acquired immunodeficiency syndrome, adherence, antiretroviral therapy, human immunodeficiency virus, meta-analysis, pharmaceutical care, systematic review
antiretroviral medication; some studies indicate that adherence levels lower than 95% are associated with lower rates of viral suppression.4,5 The need to achieve an adherence >95% of the doses of the treatment regimens, which are often quite complex, requires individuals undergoing treatment to adjust their daily habits and make changes in their routines. A systematic review that assessed studies measuring ART adherence found that a significant fraction of patients did not attain a desirable level of adherence. The metaanalysis obtained a summary estimate indicating that only 62% of the patients took more than 90% of the prescribed doses.6 Pharmacists could play a relevant role in increasing patients’ adherence to ART. Because antiretroviral drugs must be taken on a continuous basis, patients need to visit pharmacies periodically, once per month in most cases, to pick the medication up; thus, they have frequent contact with pharmacists. Murphy et al. conducted a study that assessed the impact of HIV-specialized pharmacies on ART adherence and found that such pharmacies did help the patients achieve greater adherence to treatment compared with non-specialized community pharmacies.7 A retrospective cohort study conducted by Ma et al. to assess the impact of a pharmacist’s interventions on ART adherence found a reduced pill burden and improved adherence to treatment following interventions that aimed to adjust treatment, reduce its adverse effects and adapt the frequency of drug intake.8 A systematic review of studies published from 2000 to 2011 on the impact of clinical pharmacists on HIV treatment, including cohort studies, cross-sectional studies, before–after comparisons, quasi-experimental studies and clinical trials, found positive associations between pharmacists’ interventions and improved adherence to treatment and viral suppression. However, the results of that review were not clustered or described in quantitative terms as expected for meta-analyses, and the quality of the included studies was not assessed.9 The aim of this study was to assess the impact of pharmaceutical interventions on ART via a systematic review of randomized clinical trials.
SUMMARY What is known and objective: High levels of adherence to antiretroviral therapy (ART) are needed to achieve the desired results. Because pharmaceutical care might contribute to improved adherence to treatment, the aim of this study was to assess the impact of pharmaceutical interventions on ART via a systematic review of randomized clinical trials (RCT). Methods: Study selection, data extraction and risk-of-bias assessment were performed independently by two reviewers. Results and discussion: A total of 681 studies were located; only four of these met the inclusion criteria and were analysed. The summary measure corresponding to the outcome adherence to treatment was 147 (95% confidence interval [CI]: 081–265), and the measure corresponding to the outcome virologic suppression was 195 (95% CI: 061–625). What is new and conclusion: The results suggest that pharmaceutical interventions might contribute to improved adherence to ART and the achievement of virologic suppression, although the differences between the intervention and control groups were not statistically significant. Pharmaceutical interventions might be more efficacious in populations with low adherence to treatment and greater vulnerability.
WHAT IS KNOWN AND OBJECTIVE According to estimates, 353 million people lived with the human immunodeficiency virus (HIV) in 2012. Approximately 23 million new HIV infections occurred worldwide, representing a decline in the number of infections relative to 2001 (34 million). In 2012, the number of deaths related to HIV infection worldwide was 16 million, which is 33% lower than the estimate for 2005 (23 million).1 One of the main factors contributing to the improvement in indicators associated with HIV infection is antiretroviral therapy (ART). ART aims to reduce the morbidity and mortality of individuals infected with HIV, thus improving their life expectancy and quality of life.2,3 There is a direct relationship between sustained viral repression and an individual’s intake of more than 95% of his or her
METHODS
Correspondence: B. S. Rocha, Secß~ ao de Farm acia Clınica, Hospital de Clınicas de Porto Alegre, Av. Ramiro Barcellos 2350, sala 933, CEP 90035-903, Porto Alegre, RS, Brazil. Tel.: 55 51 33598016; fax: 55 51 33085281; e-mail: [email protected]
© 2015 John Wiley & Sons Ltd
Research protocol A research protocol was elaborated to standardize and guide all of the study steps; that protocol can be requested from the authors.
251
B. S. Rocha et al.
Pharmaceutical interventions in antiretroviral therapy
Eligibility criteria
681 Located studies - 367 MEDLINE - 155 EMBASE - 24 Web Of Science - 25 SCOPUS - 10 SCIELO - 12 LILACS - 5 IBEHCS - 69 IPA - 5 CINAHL - 8 COCHRANE - 1 Clinical trials
Randomized clinical trials conducted with HIV-seropositive patients of any age and gender that included pharmaceutical care were included. According to previous systemic reviews of pharmaceutical interventions for other chronic clinical conditions,10,11 pharmaceutical intervention was defined as present when a pharmacist provided direct care to patients or dealt with drugrelated issues to solve problems related to pharmacological therapy. The interventions considered could be performed by pharmacists alone or with other professionals; this criterion was also adopted in a previous systematic review.10
28 studies selected based on title/abstract for full-text analysis
Information sources The studies were located via searches of the following databases from their onset to July 2013, with no restriction on the language of articles: Medline, the Cochrane Central Register of Controlled Trials, Embase, IBECS, CINAHL, IPA, Scopus, Web of Science, LILACS, SciELO and Clinical Trials. A grey literature search was conducted in CAPES, ProQuest, OpenGrey and The British Library databases and also master and doctoral dissertations. The references quoted in the selected articles were also surveyed to find additional studies.
- 7 Repeated studies - 17 Studies did not meet the inclusion criteria following full-text analysis
4 studies included for systematic review
Fig. 1. Flow chart of study selection. immune failure; (iv) viral load; (v) virologic failure and/or virologic suppression; (vi) the development of viral resistance; (vii) mortality rate; and (viii) quality of life.
Search strategy The following combinations of keywords as mesh terms and text words were used: HIV; Acquired Immunodeficiency Syndrome; AIDS; Human Immunodeficiency Virus; Antiretroviral Therapy, Highly Active; HAART; Medication Adherence; Medication Compliance; Medication Non-Adherence; Medication Non-Compliance; Patient Compliance; Patient Adherence; CD4 Lymphocyte Count; Viral Load; Drug Resistance, Viral; Pharmaceutical Services; Pharmaceutical Care; Pharmacist; Pharmacy Services, Hospital; Pharmacies; Pharmaceutical Assistance; and Pharmacotherapy Follow-Up. A filter was included in the search strategy to restrict the search to randomized clinical trials, as indicated in Medline’s Clinical Queries.12 The search strategies used in the Medline and Embase databases can be requested from the authors.
Assessment of risk of bias The methodological quality of each study was established by assessing the risk of bias of the randomized clinical trials using the Cochrane Collaboration tool,13 which recommends assessing the following domains: random sequence generation, allocation sequence concealment, the blinding of participants and personnel, the blinding of outcome assessment, incomplete outcome data and selective outcome reporting. The risk of bias of each assessed domain was classified as low, high or unclear. Summary measure and synthesis of results
Study selection
The results were entered in a MICROSOFT OFFICE EXCEL 2007 spreadsheet. The data were summarized in a meta-analysis of the effect of pharmaceutical intervention on each selected outcome using REVIEW MANAGER 5.2 software. The random effects model was used to analyse the outcomes of the included studies. Heterogeneity was assessed graphically and statistically using Cochran’s Q test and the degree of inconsistency (I²).
Study selection was performed by two reviewers (BSR and MTS) working independently. The results were compared, and discrepancies were solved by a third reviewer (CGM). The examiners were not blinded to the authors, journals or results of studies. Data collection procedure The data were entered in extraction forms elaborated by the authors. The main extracted data were study population, sample and intervention, relevant outcomes, and assessment of the studies’ methodological quality based on their risk of bias. This step was also independently performed by two reviewers (BSR and MTS). The results were compared, and discrepancies were resolved by a third reviewer (CGM).
Sensitivity analysis A sensitivity analysis was performed to assess the robustness of the meta-analysis results by repeating the calculation of the summary odds ratios with the following modifications: (i) the use of the Peto method; (ii) following the exclusion of the study with the largest sample size; (iii) following the exclusion of the studies that applied different cut-off points to define adherence to treatment; (iv) following the exclusion of studies that used different methods to measure adherence to treatment; and (v) following the exclusion of studies in which intervention was performed by pharmacists working with other professionals.
Outcome measures The outcomes established a priori for inclusion in data collection were (i) adherence to treatment; (ii) CD4 lymphocyte count; (iii)
© 2015 John Wiley & Sons Ltd
Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 251–258 252
B. S. Rocha et al.
Pharmaceutical interventions in antiretroviral therapy
the studies.15–17 In most of the studies, the risk of masked assessment of clinical outcomes was unclear,14–16 and the risk of selective outcome reporting was low.15–17 In two of the studies, the risk of incomplete outcome data was low.15,17
RESULTS AND DISCUSSION The search located 681 studies, of which only four14–17 were included for analysis. The flow chart representing the article selection process is depicted in Fig. 1.
Sensitivity analysis Characteristics of the selected studies
In the sensitivity analysis, which followed the shift to the Peto (fixed effects) model, the summary measure corresponding to the outcome adherence to treatment was 137 (093–201), with a heterogeneity of v² = 505 (P = 017). Following the exclusion of the study with the greatest weight in the meta-analysis,17 the summary measure increased to 207 (060–717), with a heterogeneity of v² = 489 (P = 009). When only the studies that used a 95% cut-off point to define adherence to treatment were analysed,15–17 the summary measure corresponding to that outcome decreased to 120 (079–181), with a heterogeneity of v² = 059 (P = 044). A sensitivity analysis of the studies that used MEMS only14,15 resulted in an increase of the summary measure to 420 (083–2128). The summary measure corresponding to the outcome adherence to treatment for interventions performed by pharmacists only15,17 was 146 (089–237), with a heterogeneity of v² = 054 (P = 046). When such interventions were jointly performed by pharmacists and other professionals,14,16 the summary measure was 278 (021– 3605), with a heterogeneity of v² = 407 (P = 004). Regarding the outcome virologic suppression, following calculation using the Peto method, the summary measure was 120 (080–180), with a heterogeneity of v² = 474 (P = 009). The summary measure corresponding to the studies in which intervention was performed by pharmacists only15,17 was 213 (030–1521), with a heterogeneity of v² = 320 (P = 007). Following the exclusion of the study with the greatest weight in the metaanalysis,17 the summary measure was 408 (107–1555), with a heterogeneity of v² = 057 (P = 045). Following the exclusion of the study that applied the highest cut-off point relative to the outcome virologic suppression,15 the summary measure was 121 (059–260), with a heterogeneity of v² = 135 (P = 025).
Table 1 describes the main characteristics of the selected studies. One of the selected studies was conducted in Brazil,17 and the remainder were conducted in the United States. Intervention was provided by pharmacists together with other professionals in two studies,14,16 and by pharmacists alone in the other two.15,17 The length of patient follow-up varied from three to 12 months. Interventions performed by pharmacists working with other professionals included an educational programme for medication self-management14 and collaborative care for depression, including counselling on pharmacological therapy.16 Interventions exclusively performed by pharmacists included pharmaceutical care using the Dader method17 and counselling provided by a clinical pharmacist.15 Outcome measures Regarding the outcomes included in the protocol for the present review, no data on virologic resistance, CD4 lymphocyte count, deaths or quality of life were found in the selected studies. All four studies assessed the outcome adherence to ART; the results are described in Table 2. Adherence was measured in two studies via electronic monitoring using the Medication Event Monitoring System (MEMS),14,15 one applied a semi-structured questionnaire,16 and one used patient self-reporting.17 The cut-off points selected to define patients as adherent were 80%,14 95%16,17 and 90 and 95%.15 The results corresponding to adherence to treatment and association measures were favourable to pharmaceutical intervention in all four studies; however, the between-groups difference in adherence was statistically significant in only one study.14 Figure 2 depicts the forest plot corresponding to the outcome adherence to treatment in the studies included in the metaanalysis, with a summary measure of 147 (95% confidence interval [CI]: 081–265). The result of Cochran’s Q test was 488 (P = 018), and the degree of inconsistency was 39%. Viral load was measured in three studies,14,15,17 and the corresponding data allowed the outcome virologic suppression to be established based on each study’s cut-off point for defining virologic failure or suppression and viral load detection limit. The results corresponding to the outcome virologic suppression in each individual study are described in Table 3. Figure 3 depicts the forest plot corresponding to the outcome virologic suppression for all of the studies included in the meta-analysis, with a summary measure of 195 (95% CI: 061–625). The result of Cochran’s Q test was 435 (P = 011), and the degree of inconsistency was 54%.
The main aim of the present systematic review was to assess the impact of pharmaceutical interventions on ART. In this type of investigation, the risk of bias is minimized when studies that applied experimental designs, such as randomized clinical trials, are selected. The meta-analyses performed in the present study provide objective results regarding outcomes relevant to ART. Systematic reviews of the impact of pharmaceutical interventions on several diseases are available in the literature.11,18,19 As a function of the scarcity of studies in this field,20 most such reviews included fewer than 10 studies. We were not able to locate any systematic review of randomized clinical trials addressing the impact of pharmaceutical interventions on ART for HIV. In all of the studies analysed in the present review, the results relative to the outcomes adherence to treatment and virologic suppression were superior in the groups that underwent pharmaceutical intervention. Nevertheless, that difference was statistically significant in only one clinical trial.14 Although the percentage of patients who achieved virologic suppression was higher in the groups that received pharmaceutical intervention, that difference was not statistically significant in any of the analysed studies. The study by Smith et al. consisted of a multiprofessional intervention based on the use of medication self-management techniques, and it assessed the outcomes adherence to treatment
Assessment of risk of bias Figure 4 depicts the assessment of risk of bias, and Fig. 5 shows the risk-of-bias assessment for each individual study. Most of the studies exhibited a low risk of bias relative to random sequence generation15–17 and an unclear risk relative to allocation sequence concealment.14,16,17 The risk of bias relative to the blinding of participants and personnel was high in most of
© 2015 John Wiley & Sons Ltd
Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 251–258 253
© 2015 John Wiley & Sons Ltd
254
Control: 138 Intervention: 138
Control: 166 Intervention: 166
Silveira (2014)17
Control: 21 Intervention: 22
Rathburn (2005)15
Pyne (2011)16
Control: 21 Intervention: 22
Smith (2003)14
Author (year)
Randomized individuals (n)
Brazil
USA
USA
USA
Country
Specialized outpatient clinic
Specialized outpatient clinic
University specialized outpatient clinic
Clinical research center
Study setting
Table 1. Characteristics of the included studies (n = 4)
Adults
Adults undergoing treatment for depression
Indigent adults
Adults starting protease inhibitor treatment
Sample description
Pharmaceutical care using the Dader method. Exclusive pharmaceutical intervention
Standard care combined with medication self-management program: education about medication and skills training Multi-professional intervention Standard care combined with education provided by clinical pharmacist (proper ART administration, dietary restrictions, management of adverse reactions and monitoring of patient progress after onset of therapy) Exclusive pharmaceutical intervention PHQ (health questionnaire). Five-step depression treatment model, including counseling on pharmacological treatment. Multi-professional intervention
Intervention group
PHQ (health questionnaire). Standard treatment provided by general practitioners or doctors specialized in mental health who did not participate in the treatment of the patients in group intervention. Standard care (not including a pharmacist)
Standard care by health care staff (doctor and nurse)
Standard care: counseling and orientation to improve adherence to treatment.
Control group
12 months
12 months
7 months
3 months
Follow-up length
Adherence to treatment Viral load Virologic failure Depression scale
Adherence to treatment Depression scale
Adherence to treatment Viral load Virologic failure
Adherence to treatment Viral load Virologic failure
Outcomes
Pharmaceutical interventions in antiretroviral therapy B. S. Rocha et al.
Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 251–258
B. S. Rocha et al.
Pharmaceutical interventions in antiretroviral therapy Table 2. Measurement of adherence to treatment in the selected studies (n = 4)
Author (year)
Method to measure adherence
Individuals with outcome measure
Adherence intervention n/n total (%)
Adherence control n/n total (%)
Smith (2003)14 Rathburn (2005)15 Pyne (2011)16 Silveira (2014)17
MEMS, cut-off point 80% MEMS, cut-off point 90% and 95% Semi-structured questionnaire, cut-off point 95% Self-report, cut-off point 95%
43 33 178 319
7/8 (96) 10/16 (625) 68 (739) 128 (798)
3/9 (37) 7/17 (412) 64 (744) 117 (738)
Intervention Study or subgroup
Events
Control
Odds ratio
Total Events Total Weight
M-H, Random, 95% CI Year
7
8
3
9
5·1%
14·00 [1·14, 172·64] 2003
Rathbun 2005
10
16
7
17
14·1%
2·38 [0·59, 9·65] 2005
Pyne 2011
68
92
64
86
36·3%
0·97 [0·50, 1·91] 2011
128
161
117
158
44·5%
1·36 [0·81, 2·29] 2014
Smith 2003
Silveira 2014
Total events
213
1·47 [0·81, 2·65]
270 100·0%
277
Total (95% CI)
Odds ratio M-H, Random, 95% CI
191
Heterogeneity: τ² = 0·13; χ² = 4·88, d.f. = 3 (P = 0·18); I² = 39%
0·01
Test for overall effect: Z = 1·28 (P = 0·20)
0·1
1
10
100
Favours [control] Favours [experimental]
Fig. 2. Forest plot corresponding to the outcome adherence to treatment.
Table 3. Measurement of viral load and virologic suppression in the included studies (n = 3)
Author (year)
Viral load detection limit
Individuals with outcome measure
Virologic suppression intervention n/n total (%)
Virologic suppression control n/n total (%)
Smith (2003)14 Rathburn (2005)15 Silveira (2013)17
