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

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.