The Impact of Pharmacists' Interventions on the Quality of Life of HIV-TB Co-infection Outpatients in Indonesia
The Impact of Pharmacists' Interventions on the Quality of Life of HIV-TB Co-infection Outpatients in Indonesia
Rationale:

 The co-infection of human immunodeficiency virus (HIV) and tuberculosis (TB) diseases
 presents further problems to patient's adherence due to high pill burden and adverse effects
 in the drug combination therapy. This situation is also a risk of the increase of multi-drug
 resistant TB and may affect the quality of life of patients. However, the prevalence of
 non-adherence has not been studied much in these patients in Indonesia, especially in West
 Java with several HIV patients who are still struggling with TB as their opportunistic
 infection. Pharmacist interventions in several studies have resulted in a better outcome of
 patients' therapy, especially in patients who need long-term adherence and compliance with
 drug treatment. It is hypothesized that patients' quality of life of HIV-TB co-infection
 patients will be improved with the intervention conducted by the pharmacist.

 Objective:

 In general, the study aimed to evaluate the utility of study participants with specific aims
 to describe the number of DRP and interventions applied, to describe drug concentration in
 selected participants (TB drugs: Rifampicin and Pyrazinamide), to compare changes of CD4+
 cell counts and plasma HIV RNA (viral load) between baseline and after of intervention, to
 assess participants compliance and persistence to medication therapy, and descriptive
 analysis on the direct and indirect costs.

 Study design:

 This is a prospective, cluster-randomized study with a stepped-wedge design. Clusters
 correspond to participating centers. A randomly selected center is crossed-over into the
 intervention with calculation after the start of inclusions within 6-months follow-up in 3
 different clinics in Indonesia (Bekasi City Public Hospital, Persahabatan Public Hospital
 Jakarta and Cipto Mangunkusumo general hospital).

 Intervention:

 Interventions are given by a pharmacist as a drug consultant is an intervention concerning
 the drug treatment of HAART and anti-TB. Monthly, patients will have a discussion regarding
 their medication and drug-related problems they experience. The pharmacist will identify
 drug-related problems before and during treatment and solve the problems.

 Main study parameters/endpoints: change from baseline utility (quality of life) at 6 months
 Secondary endpoints: changes from baseline in CD4+, VL, adherence, persistence at 6 months
 and total costs.
1. STUDY BACKGROUND

 1.1 HIV and TB Diseases Human Immunodeficiency Virus (HIV) is a global health concern
 which the World Health Organization (WHO) estimates that 36.7 million people are living
 with HIV (PLHIV) with 1.1 million deaths of PLHIV in 2015, worldwide. Among them, there
 were 2.1 [1.8-2.4] million new HIV infections. Because of its immunosuppressive action,
 people living with HIV (PLHIV) are prone to be infected with opportunistic infections,
 such as tuberculosis (TB), pneumonia, and toxoplasmosis. TB itself is known as one of
 the main risks of death in PLHIV as it considerably accelerates the progression of HIV
 to AIDS by not only activating viral replication but also accentuating the decline in
 CD4 cell counts. It is also estimated that TB would affect one-third of the world's
 population and 9 million new cases of TB are discovered worldwide each year, with more
 than 1 million cases occurring in patients with HIV or AIDS. The incidence of TB
 globally has risen enormously since 1990, particularly in certain countries where there
 is a significant overlap between HIV and TB epidemics. The risk of developing TB is 29
 (26-31) times higher in PLHIV than people without HIV as Mycobacterium tuberculosis and
 HIV are potentiating one another in accelerating the decrease of the immunological
 function and causing early death.

 HIV treatments have been implemented since the first production of antiretroviral drugs
 and have been developing fast since because of the increasing number of HIV cases
 worldwide. The introduction of ARV reduces the development of TB, but this disease
 continues to occur among PLHIV. Antiretroviral and anti-TB drugs have their complex
 regimens, and the combination of these drugs in HIV-TB co-infection patients has caused
 increasingly even more complex regimens, potential toxicities, and issues of adherence
 due to potential interaction between antiretroviral and anti-TB medications. In HIV
 patients receiving regular antiretroviral drugs and becoming infected with TB,
 considerations on the alteration or discontinuation of antiretroviral drugs and
 selection of TB agents are based upon the efficacy of each selected drug, drug
 interactions, drug resistance, prevention of treatment failure, and patient adherence.

 1.1.2 Pharmaceutical Care Interventions Such concerning and life-threatening diseases
 treatments have been massively conducted with a significant success worldwide, marked
 with the lower incidence of new cases of HIV and TB. However, the major diagnostic and
 therapeutic deficiencies remain. Health professionals, such as physicians, nurses,
 pharmacists, and other health professionals are required to ensure the success of HIV TB
 co-infection therapy based on the guidelines made by international organizations and
 local governments.

 In the past few decades, there has been a shifting perspective of the pharmacist's role
 from the traditional role of dispensing medication to the patient-oriented perspective
 in collaboration with or without other health providers to achieve improvement of
 patient outcomes as well as the improvement of quality of life. The Pharmaceutical Care
 (PC) program which involves the specific role of a pharmacist has been implemented
 mostly in high-income countries to hospitalized- and out-patients. Several systematic
 reviews and meta-analysis are conducted to evaluate the impact of the patients-oriented
 intervention in any disease states;8-12 thus the thoroughly and rigorous reviews enable
 other researchers or health providers to assess and implement the most valid processes
 of pharmacist intervention in their setting.

 1.1.3 Therapeutic Drug Monitoring in TB Drugs TDM is a multi-disciplinary clinical
 approach of evaluating and monitoring drug concentration in the blood, defined as the
 clinical laboratory measurement with proper medical interpretation. It is generally
 aimed to improve the quality of patient care by adjusting a patient's drug dosage
 individually within a therapeutic range. A combination of pharmaceutical,
 pharmacokinetics, pharmacodynamics knowledge and skills are needed to assess the
 efficacy and safety of particular drugs to achieve a maximum benefit of the patient's
 drug therapy.

 By far, TDM has been used in many indications, such as to evaluate drug-drug
 interactions, to assess drug efficacy and safety (toxicity level), and adherence or
 compliance. However, TDM is not necessarily carried out for all medications. There are
 several patients' criteria that may have the advantage of TDM, such as: patients with
 low response of drug treatment that may lead to treatment failure, patients with poor
 compliance to the treatment, and patients who get treated with narrow therapeutic range
 drugs (theophylline, aminoglycoside antibiotic, cyclosporine, and lithium). It is
 believed that TDM has a role in improving TB treatment, especially in TB patients with a
 low response to the treatment and in HIV/TB co-infection patients. Several studies have
 conducted TDM and revealed that it could be used as a useful strategy to identify the
 cause of slow response in TB treatment; thus, it may shorten the time to respond and
 achieve treatment completion and also optimize ARV dosage when combined with TB drugs.

 1.1.4 Pharmacoeconomics of the pharmacists' interventions There has been an increase in
 the number of diseases burden worldwide during the past few years which inevitably
 adding the burden of healthcare expenditures. Many strategies in healthcare settings
 intended to constrain the expenses, especially to restrict the expenses on drugs.
 Several studies try to assess the further impact of the intervention from the economic
 perspective point of view whereas pharmacists as the focus or in a multidisciplinary
 team. From a public health point of view, pharmacists may actively be involved in health
 promotion, such as smoking cessation, prevention and treatment of chronic and infectious
 diseases (e.g., diabetes, hypertension, HIV/AIDS and tuberculosis (TB).

 2. STUDY OBJECTIVES

 This study aims to evaluate the change in utility (quality of life) of study participants.
 The specific aims of this study are:

 1. To compare the changes of CD4+ cell-counts between baseline and after the study;

 2. To compare the difference of plasma HIV RNA (viral load) between baseline and after the
 study;

 3. To assess participants' adherence or compliance to medication therapy (antiretroviral
 and anti-TB drugs);

 4. To assess the direct costs and indirect costs of the pharmacists' interventions.

 3. STUDY DESIGN AND SETTING

 3.1 STUDY DESIGN

 The HIV-TB IND02017 study is a prospective, stepped wedge cluster randomized trial where
 stepwise randomization occurs at a clinic level. Clinics will be randomized to one of three
 roll-out schedules, each contributing at least one-month control period and one-month
 intervention period to the analysis. Data will be collected at the level of the individual,
 even though the randomization will be implemented at a clinic level. A stepped wedge design
 (SWD) is a type of crossover design in which different clusters will receive both control and
 intervention activities with varying points of time. It usually starts with all clusters in
 the control period, and at subsequent time points, each cluster will receive the intervention
 period with different duration of the intervention period. This design is being acknowledged
 in recent years for pragmatic reasons, such as in the HIV disease where there is a strong
 belief that adding new intervention will give good results than harms for patients with a
 higher risk of ethical issues if they are randomized into control and intervention groups.
 SWD has advantages compared to a parallel and crossover design, whereas SWD only needs fewer
 clusters and samples, useful in trial with resources and cost constraints and ethically
 acceptable since all the participants in clusters will receive the interventions.

 3.2 STUDY SETTING

 The study of the impact of pharmacist intervention on improvement of quality of life of
 TB-infected HIV patients will be implemented in 3 hospital clinics in Jakarta and West Java
 (Bekasi public hospital, Persahabatan public hospital, and Cipto Mangunkusumo General
 Hospital Jakarta). The intervention program across each of these sites is 6-months in length
 or until treatment completion and will be operated in community clinics as this study has
 targeted HIV/TB outpatients. Pharmacists are the investigators in this study. Participants
 will be followed for their medication therapy and evaluated by the investigator during the
 study with the monthly intervention and counseling session at the time of medicine pick up.

 4. STUDY POPULATION

 4.1 POPULATION

 The study will include all HIV patients who develop TB disease at the time of the study at
 three participating hospital sites, and the follow-up patients will also be applied and
 maintained throughout the study. Identification of TB disease classification in HIV patients
 is based on the WHO standard guidelines for tuberculosis and Pedoman Nasional Pengendalian
 Tuberculosis 2014 (the 2014 Tuberculosis Control National Guidelines), which will include
 smear sputum results, chest X-ray, and geneXpert (if applicable).

 4.2 INCLUSION AND EXCLUSION CRITERIA Will be elaborated in the next section.

 4.3 SAMPLE SIZE CALCULATION

 The sample size calculation for the stepped wedge design is based on Hemming et al.48 We
 considered a small effect size of 0.30 with the statistical power of 80% and 5% significance
 in this study because no studies were investigating the effect of pharmacist intervention in
 HIV-TB co-infection patients. Based on the assumption and t-test calculation on individual
 randomization, such design would need 352 study participants (176 per arm). An intra-cluster
 correlation (ICC) of 0.05 is assumed with the meaning of little correlation between the
 clusters, which leads to a design effect of 2.12 in the stepped wedge model. With a fixed
 number of 3 clusters (k), time of observation (t) of 5, the number of observations (m) of 2,
 and 20% losses of follow-up patients, the sample size is calculated by N = 92 patients.

 Calculations of the sample size of stepped wedge model are as follows:

 Design effect (DE-SW) Formula:

 Total sample size per cluster : M = m x (t+1) = 2 x (5+1) = 12 participants Total study
 sample size : N = M x k = 12 x 3 = 36 participants Total required sample size : N = N x DE =
 36 x 2.12 = 76.32 participants Total sample size : N = 76.32 + 20% excess ≈ 92 participants
 (anticipated)

 Notations:

 m : the number of observations made in each cluster: 2 = quality of life and
 adherence/monitoring drug therapy; k : the number of clusters: 3 clusters (a fixed number of
 clusters) t : the number of steps: 5 (5 months) t+1 : the number of time points of study
 implementation (6 time points: before starting the study (time point 1), after month 1 (time
 point 2), after month 2 (time point 3), etc.)

 5. MEASUREMENTS

 Measurements included in the study are:

 1. Drug-Related Problem (DRP);

 2. The number of interventions;

 3. TB outcome;

 4. Adherence;

 5. Persistence;

 6. Quality of life;

 8) Direct costs; 9) Indirect costs.
Inclusion Criteria:

 1. patients aged 18 years or older;

 2. diagnosed with the HIV disease and co-infected with the definite TB disease (PTB or
 EPTB) during the study period, proven by geneXpert (if applicable), positive smear
 sputum, and chest X-ray;

 3. definite TB patients who are found infected with HIV;

 4. attending for outpatient care;

 5. can read and write in Indonesian language;

 6. not pregnant;

 7. taking ARV/HAART at the time of research and is just about to start TB treatment and
 receive first line of TB drugs;

 8. taking ARV/HAART at the time of research and in TB treatment until maximum 3 months
 from the first consumption of TB drugs and receive first line of TB drugs;

 9. HIV patients on TB therapy but have not received ARV/HAART yet;

 10. and patients who are willing to take part in this study (signing the informed
 consent).

 Exclusion Criteria:

 1. Patients who are diagnosed with only the HIV disease or with other non-TB diseases as
 reported in their medical records, such as hepatitis C;

 2. patients who have enrolled in another clinical trial that may change the nature of
 basic treatment;

 3. patients with limited clinical condition due to their severe condition and therefore
 are not able to attend outpatient visit, such as stroke.