Clinical Effectiveness and Safety of Amphotericin B With Flucytosine-Fluconazole Therapy for Cryptococcal Meningitis in Patients With HIV Infection
Conditions: Cryptococcal Meningitis
Sponsor: University of Pharmacy, Yangon

i 
 
 
University of Pharmacy, Yangon 
 
 
CLINICAL EFFECTIVENESS AND SAFETY 
OF AMPHOTERICIN B WITH 
FLUCYTOSINE-FLUCONAZOLE THERAPY 
FOR CRYPTOCOCCAL MENINGITIS IN 
PATIENTS WITH HIV INFECTION 
 
 
 
A Protocol Submitted to Postgraduate Board of Studies of  
University of Pharmacy, Yangon 
for the Degree of Master of Pharmacy 
(Clinical Pharmacy) 
 
 
 
 
Zin Win May 
B.Pharm. 
2020 
 
 
 

ii 
 
CONTENTS 
Page No. 
CONTENTS  
 
 
 
 
 
 
 
 
     i 
LIST OF TABLES 
iv 
LIST OF FIGURES 
v 
LIST OF ABBREVIATIONS 
vi 
1. INTRODUCTION 
1 
1.1. Background Information 
1 
1.2. Justification 
3 
2. LITERATURE REVIEW 
5 
2.1. Cryptococcosis 
5 
2.1.1. History 
5 
2.1.2. Epidemiology 
5 
2.1.3. Morphology and identification 
7 
2.1.4. Pathogenesis 
7 
2.1.5. Clinical presentation 
8 
2.1.6. Diagnostic laboratory tests 
8 
2.1.7. Complications 
9 
2.1.8. Induction, consolidation and maintenance antifungal treatment regimens 10 
2.1.9. Adjunctive corticosteroids in treating HIV-associated cryptococcal 
meningitis 
12 
2.1.10. CSF fungal clearance 
12 
2.1.11.  Preventing, monitoring and managing antifungal toxicity 
12 
2.1.12.  Safety 
14 
2.1.13. Mortality 
16 
2.2.14. Timing of ART 
16 
3. AIM AND OBJECTIVES 
17 
3.1. Aim 
17 
3.2. Objectives 
17 
3.3. Research Question 
17 
4. METHODOLOGY 
18 
4.1. Study Design 
18 
4.2. Study Site 
18 

iii 
 
CONTENTS 
Page No. 
4.3. Study Period 
18 
4.4. Reference Population 
18 
4.5. Study Population 
18 
4.6. Selection Criteria 
18 
4.6.1. Inclusion criteria 
18 
4.6.2. Exclusion criteria 
18 
4.6.3 Withdrawal criteria 
19 
4.7. Sample Size Determination and Sampling Procedure 
19 
4.7.1. Sample Size Determination 
19 
4.7.2 Sampling Method 
20 
4.8. Materials and Methods 
20 
4.9. Data Management and Analysis 
20 
4.10. Operational Definitions 
21 
4.11. Ethical Considerations 
22 
5.  DUMMY TABLES 
25 
6.  REFERENCES 
30 
Annex 1.  Pro forma 
36 
Annex 2.  Informed Consent Form (Myanmar and English) 
39 
Annex 3.  Scale 
56 
Annex 4. G antt chart 
59 
Annex 5.   Budget estimation 
60 
 
 
 

iv 
 
LIST OF TABLES 
 
 
 
Page No. 
 
 
 
Table 1. 
WHO 2018 Induction, consolidation and maintenance 
antifungal treatment regimens 
 
9 
Table 2. 
Myanmar hospital guidelines for clinical management of 
Cryptococcosis in HIV  
 
11 
Table 3. 
Minimum package for preventing, monitoring and 
managing amphotericin B toxicity 
 
12 
Table 4. 
Number of cryptococcal meningitis in patients with HIV 
infection enrolled from individual specialist hospital 
 
25 
Table 5. 
Distribution of age among study group of cryptococcal 
meningitis in patients with HIV infection 
 
25 
Table 6. 
Distribution of gender among study group of cryptococcal 
meningitis in patients with HIV infection 
 
25 
Table 7. 
Frequency distribution of headache among study group by 
Numerical rating Scale at day-1, day-7 and day-14 
 
26 
Table 8. 
Clinical effectiveness of study group by assessing presence 
of headache, fever, convulsion, abnormal mental status and 
death at day-1, day-7 and day-14 
 
 
27 
Table 9. 
 
 
Laboratory-defined adverse events of amphotericin B, 
flucytosine and fluconazole at baseline and day- 7 and day- 
14 by DAIDS grading 
 
 
28 
Table 10. 
Proportion of patients with grade 3 and 4 adverse events of 
hematological parameters at baseline, day-7 and day-14 
 
29 
Table 11. 
 
Proportion of patients who has bone marrow suppression 
among study group at baseline, day-7 and day-14 
 
29 
 

v 
 
LIST OF FIGURES 
 
 
 
Page No. 
Figure 1.  
Natural history of cryptococcosis 
6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

vi 
 
LIST OF ABBREVIATIONS 
 
ABCD  
 
 
Amphotericin B colloidal dispersion 
ABLC  
 
 
Amphotericin B lipid complex 
AmBd  
 
 
Amphotericin B deoxycholate or conventional  
 
 
 
 
amphotericin 
AE 
 
 
 
Adverse event 
AIDS 
 
 
Acquired immunodeficiency syndrome 
ALT   
 
 
Alanine transaminase  
 
AST   
 
 
Aspartate transaminase 
ART  
 
 
Antiretroviral therapy 
C-AMB  
 
 
conventional amphotericin B 
CD4 count 
 
CD4+ T-lymphocyte count 
CD 
 
 
 
Cluster of Differentiation  
CNS   
  
 
Central Nervous System  
CM 
 
 
 
Cryptococcal meningitis 
CSF 
 
 
 
Cerebrospinal Fluid  
DAIDS 
 
 
Division of AIDS 
HGB  
 
 
Hemoglobin 
HIV                        
Human immunodeficiency virus 
ICP 
 
 
 
Intracranial Pressure 
IV 
 
 
 
Intravenous 
L-AMB 
 
 
Liposomal amphotericin B 
NAP  
 
 
National AIDS Programme 
NRS 
 
 
 
Numerical rating scale 
OD 
 
 
 
Once a day 
OI 
 
 
 
Opportunistic infection 
PLT 
 
 
 
Platelet 
PLHIV  
 
 
People living with HIV 
RCT   
 
 
Randomized control trial 
SD 
 
Standard deviation 
SGPT  
 
 
Serum Glutamic Pyruvic Transaminase 
SGOT  
 
 
Serum Glutamic Oxaloacetic Transaminase 

vii 
 
LIST OF ABBREVIATIONS 
 
UNAIDS                   
Joint United Nations Programme on HIV/AIDS 
WBC 
 
White blood cells 
WHO                         
World Health Organization 
 

1 
 
1. INTRODUCTION 
 
1.1. Background Information 
 
 
According to data of Joint United Nations Program on HIV/AIDS 
(UNAIDS, 2019), a population of 37.9 million of globally was living with HIV, and the 
annual number of deaths due to AIDS-related illnesses was 770,000 worldwide. Among 
them, 5.9 million people were from Asia and the Pacific region, with the estimated 
200,000 AIDS-related deaths. In 2018, Myanmar had 240,000 adults and children 
living with HIV and there were about 7800 AIDS-related deaths (UNAIDS, 2019a). 
Although UNAIDS figured Myanmar high on its list of priorities as one of the six 
countries in Asia for the Global Fast Track Strategy to end HIV in 2030, there were still 
11,000 adults and children newly infected with HIV in 2018 (UNAIDS, 2019b).  
 
 
AIDS stands for acquired immune deficiency syndrome that develops as 
a result of advanced HIV infection which has destroyed the immune system and thus 
the body loses the ability to fight the organisms that cause diseases. The organisms take 
advantage of a weakened immune system, causing severe life-threatening opportunistic 
infections (OIs) (AIDSinfo, 2019b) that include Pneumocystis pneumonia (PCP), 
toxoplasma encephalitis, cytomegalovirus (CMV) retinitis, cryptococcal meningitis, 
tuberculosis, disseminated Mycobacterium avium complex (MAC) disease, and 
pneumococcal respiratory disease (AIDSinfo, 2019a). 
 
 
Cryptococcal meningitis (CM) is the most common opportunistic fungal 
infection of the central nervous system (CNS) caused mostly by Cryptococcus 
neoformans. For people who have been exposed, the fungus remains largely latent in 
the body and most will never fall ill. But for those living with a compromised immune 
system, infection can spread from the lungs to the brain and spinal cord, causing 
meningitis (Rajasingham et al., 2017). It usually occurs in patients with advanced 
immunosuppression at CD4 count < 100/mm³ (National AIDS Programme, 2017) and 
a major cause of morbidity and mortality especially in the developing world (WHO, 
2019), with mortality within the first 3 months of diagnosis (Hevey et al., 2019). There 
were an estimated 220,000 cases of CM that occur among people with HIV/ AIDS 
worldwide each year, resulting in nearly 181,000 death (Rajasingham et al., 2017) and 
the disease account for 15% of AIDS-related deaths (Ponatshego et al., 2019).  

2 
 
 
 
Patients may present with headaches, fever, meningism, features of 
raised intracranial pressure, seizures (Heckmann & Bhigjee, 2014). In African and 
Vietnam trial, headache (100 %) was the most prominent clinical presentation which 
was followed by fever (77%), neck stiffness (73%), abnormal mental status (46.7%) 
and seizure (19.2%) (Day et al., 2013 & Molloy et al., 2018). 
 
 
In WHO guideline (2018) for the management of cryptococcal disease, 
the preferred regimen is a short-course (one-week) induction regimen with 
amphotericin B deoxycholate and flucytosine followed by 1 week of fluconazole. It has 
been estimated that inductive treatment of Cryptococcal meningitis with ﬂucytosine 
alone causes a prohibitive expense for low GDP nations (Shiri, 2019) and due to this 
reason, it is unavailable in all low and middle-income countries (Loyse et al., 2013). 
Thus, the treatment of cryptococcal meningitis in resource-limited settings is 
challenging (Molloy et al., 2018) and alternative options of two weeks amphotericin B 
deoxycholate plus fluconazole are used depending on drug availability (WHO, 2018). 
According to guidelines for clinical management of cryptococcosis in Myanmar, 
initiation of treatment is with Amphotericin plus Fluconazole for at least 2 weeks 
followed by consolidation with Fluconazole for 8 weeks followed by maintenance of 
Fluconazole until CD4 count rises to 200/mm³ with ART (National AIDS Programme, 
2017).   
 
 
As a partner drug with amphotericin B, flucytosine was superior to 
fluconazole in cryptococcal meningitis in patients with HIV infection as one week of 
amphotericin B plus flucytosine was associated with the lowest mortality of 24.2% in 
ACTA (Advancing cryptococcal meningitis treatment for Africa) trial (Molloy et al., 
2018). Moreover, clearance of cryptococci from the cerebrospinal fluid (CSF) was 
exponential and significantly faster with amphotericin B plus flucytosine than, 
amphotericin B plus fluconazole (Day et al., 2013).  
 
 
Even where ﬂucytosine (5FC) is available, it is often not administered 
because of overstated fears regarding toxicity (Loyse et al., 2013). The most serious 
drug-related adverse effect of 5FC is bone marrow suppression and hepatotoxicity 
(Vermes et al., 2000). In California’s study, 5FC had be discontinued in over half of 
the patients because of cytopenia (Chuck & Sande, 1989). One patient in South Africa 
study also was discontinued 5FC because of thrombocytopenia on day-4 and the 
regimen was switched early to fluconazole (Bicanic et al., 2008). And also grade-4 
neutropenia was recorded in 3.2% of the patients with 5FC (Molloy et al., 2018). But 

3 
 
in Thailand study, the treatment was well tolerated and there was no severe bone-
marrow depression with 5FC (Brouwer et al., 2004). 
 
 
Regarding amphotericin B Deoxycholate, its major drug-related adverse 
effects include nephrotoxicity and anemia (Bicanic et al., 2015). In Vietnam trial, Grade 
3 and 4 anaemia were most prominent between amphotericin B plus flucytosine (35%) 
and amphotericin B plus fluconazole group (29%) (Day et al., 2013). Renal impairment 
occurs in nearly all patients treated with clinically significant doses of amphotericin. 
Fluconazole is relatively nontoxic, but reported to cause abnormalities in liver enzymes 
and very rarely, clinical hepatitis (Lampiris & Maddox, 2018).  
 
 
Although WHO treatment guidelines recommend treatment regimen 
containing flucytosine as the preferred therapy, in clinical practice, treatment is highly 
variable due to drug costs, availability, and ability to monitor and manage drug-related 
toxicities (Perfect, 2010). A previous study was carried out in Mandalay for 
cryptococcal meningitis with fluconazole monotherapy by Than-Maung in 2006 and 
amphotericin B monotherapy by Myo-Thet-Naing in 2013 but the effectiveness and 
safety of amphotericin with flucytosine and fluconazole combination regime have not 
been studied in Myanmar. Thus, this study will provide information regarding the 
clinical effectiveness and safety of this treatment regimen for management of HIV-
associated cryptococcal meningitis in Myanmar. 
 
1.2. Justification 
Cryptococcal meningitis is an AIDS-defining illness mostly caused by 
the fungus, Cryptococcus neoformans. In high-income countries, the use of 
amphotericin B in combination with a more expensive drug, flucytosine, is most 
effective for the management of cryptococcal meningitis; but access to flucytosine is 
severely limited in middle and low-income countries. In Myanmar, currently 
recommended regimen for cryptococcal meningitis are combination of amphotericin B 
with fluconazole. Although amphotericin plus flucytosine followed by fluconazole 
therapy is the currently preferred regimen in WHO treatment guidelines, it is not still 
commonly used in Myanmar clinical practice because of its limited availability. 
Therefore, the data regarding tolerability and clinical effectiveness of flucytosine are 
unavailable for Myanmar patients.  
Although trials were carried out for investigating the effectiveness of 
flucytosine in the HIV population of Africa, the variability in drug response can occur 

4 
 
in Myanmar patients due to the racial and genetic differences and whether it is effective 
and safe for Myanmar people is a great curiosity question for clinicians and healthcare 
workers. In Myanmar, amphotericin plus flucytosine followed by fluconazole regimen 
will be supplied by National AIDS Program (NAP) and indicated in 2020. Thus, the 
documents for effectiveness and safety profile need to be established. This is the reason 
that the effectiveness and safety of amphotericin B with flucytosine and fluconazole 
combination therapy should be studied. From this study, it can provide information to 
physicians regarding the effectiveness as well as safety of those drugs in the 
management of cryptococcal meningitis in HIV patients.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

5 
 
2. LITERATURE REVIEW 
 
2.1. Cryptococcosis 
2.1.1. History     
 
 
Cryptococcosis is an important cosmopolitan, infectious, mycotic 
disease of man and animals caused by the yeast, Cryptococcus neoformans which exists 
as saprobe in the environment. The disease is also known as Busse Buschke’s disease, 
European blastomycosis or Torulosis. The disease was considered as sleeping disease 
in older days became an awakening giant in present era. Over a period of more than one 
hundred years ago, in 1894 Cryptococcus neoformans was discovered when this yeast 
was isolated independently from peach juice in Italy, by Sanfelice and from the tibial 
lesion of a patient in Germany by Busse (1894) and Buschke (1895), simultaneously. 
Sanfelice studied the pathogenicity of organisms in laboratory animals and gave name 
as Saccharomyces neoformans to the pathogen (cited by Nayak et al., 2010). In 1901, 
Jean-Paul Vuillemin, (Barnett, 2010) at Nancy University in France, named Busse’s 
yeast Cryptococcus hominis and renamed Sanfelice’s yeast Cryptococcus neoformans 
because neither yeast formed ascospores, as would be expected of a member of the 
genus Saccharomyces. 
 
2.1.2. Epidemiology 
 
 
Cryptococcus neoformans and Cryptococcus gattii are environmental, 
basidiomycetous yeasts. Unlike other pathogenic fungi, these yeast cells possess large 
polysaccharide capsules. Bird droppings (particularly pigeon droppings) enrich for the 
growth of Cryptococcus neoformans and serve as a reservoir of infection. The organism 
grows luxuriantly in pigeon excreta, but the birds are not infected. It is estimated that 
1g of dry pigeon excreta may contain up to 50 million viable cells of C. neoformans. 
 
 
It is isolated readily from dry pigeon feces, as well as trees, soil, and 
other sites. Cryptococcus gattii is less common and typically associated with trees in 
tropical areas. Both species cause cryptococcosis, which follows inhalation of 
desiccated yeast cells or possibly the smaller basidiospores (Brooks et al., 2013). It can 
infect any organ in the body organs (e.g. skin, eyes, prostate), but has a predilection for 
the lung and the CNS. The lung is the usual portal of entry and symptoms range from 

6 
 
asymptomatic colonization to severe pneumonia. Meningitis is the most frequent 
manifestation of cryptococcosis (AIDSinfo, 2019a). 
 
 
Figure (1) Natural history of cryptococcosis (Brooks et al., 2013) 
 
 
Cryptococcus neoformans occurs in immunocompetent persons but 
more often in patients with HIV/AIDS, hematogenous malignancies, and other 
immunosuppressive conditions. In HIV-infected patients, the disease is associated with 
profound immunosuppression, usually occurring at CD4 counts <100 cells/μl. There is 
a greater likelihood of involvement outside the CNS and relapse if antifungal therapy 
is discontinued prior to effective antiretroviral therapy (AIDSinfo, 2019a). 
 
 
Overall, approximately one million new cases of cryptococcosis occur 
annually, and the mortality approaches 50%. More than 90% of these infections are 
caused by C neoformans. In sub-Saharan Africa, the epicenter of HIV/AIDS, 
Cryptococcus neoformans is the leading cause of meningitis with an estimated one 
million new cases and 600,000 deaths per year (Brooks et al., 2013). 
 

7 
 
2.1.3. Morphology and identification 
 
 
In culture, Cryptococcus species produce whitish mucoid colonies 
within 2–3 days. Microscopically, in culture or clinical material, the spherical budding 
yeast cells (5–10 μm in diameter) are surrounded by a thick non-staining capsule. All 
species of Cryptococcus, including several nonpathogenic species, are encapsulated 
and possess urease. However, C neoformans and C gattii differ from nonpathogenic 
species by the abilities to grow at 37°C and the production of laccase, a phenol oxidase, 
which catalyzes the formation of melanin from appropriate phenolic substrates (eg, 
catecholamines). Both the capsule and laccase are well characterized virulence factors 
(Brooks et al., 2013). 
 
 
There are four serotypes based on the capsular polysaccharide, 
glucuronoxylomannan (GXM) (Klatt, 2019). Capsular types A through D correspond 
to the variants C. neoformans var. grubii (A), C. neoformans var. gattii (B and C) and 
C. neoformans var. neoformans (D) (Warkentien, T & Crum-Cianﬂone, NF., 2010). 
 
2.1.4. Pathogenesis 
 
 
Cryptococcus is a basidiomycetous yeast that exists in the environment 
in the sexual form and produces hyphae with terminal basidiospores (chains of 
unbudded yeast) (Klatt, 2019).  To enter the alveolar spaces of the lungs and establish 
pulmonary infection, an organism must produce viable forms smaller than 4 μm in 
diameter. The typical vegetative form of C. neoformans is the yeast form with a cell 
diameter of 2.5 to 10 μm (Nayak et al., 2010). When the 3μL basidiospores break off 
they become aerosolized and may be inhaled into the alveoli.  Less commonly, the 
portal of entry is the gastrointestinal tract or the skin (Klatt, 2019). The organism 
remains dormant in the lungs until the immune system weakens and then reactivates 
and disseminate to the central nervous system, other body sites such as the skin, bone, 
joint, eye, heart, adrenals and prostate gland. (Nayak et al., 2010, Brooks et al., 2013). 
The inflammatory reaction is usually minimal or granulomatous (Brooks et al., 2013) 
 
 
 Cryptococcus may survive within human because of a polysaccharide 
capsule that allows it to evade phagocytosis.  Capsular polysaccharides include 
galactoxylomannan as well as glucuronoxylomannan, and they impart resistance to 
phagocytosis. In addition, a phenol oxidase enzyme uses catecholamines as substrate to 
produce melanin, which accumulates in the cell wall, and synthesis of catecholamines 

8 
 
for neurotransmitters may predispose to involvement of the central nervous system 
(Klatt, 2019). 
 
2.1.5. Clinical presentation 
 
 
In HIV-infected patients, cryptococcosis commonly presents as a 
subacute meningitis or meningoencephalitis with fever, malaise, and headache. Classic 
meningeal symptoms and signs, such as neck stiffness and photophobia, occur in only 
one-quarter to one-third of patients. Some patients experience encephalopathic 
symptoms, such as lethargy, altered mentation, personality changes, and memory loss 
that are usually a result of increased intracranial pressure (AIDSinfo, 2019a). In African 
trial, headache (98.2 %) was the most prominent presentation which was followed by 
fever (52.9%), abnormal mental status (46.7%) and seizure (19.2%) (Molloy et al., 
2018). 
 
 
The findings in this study are comparable with those from studies from 
Myanmar. In the studies of Myo-Thet-Naing and Nyein-Chan-Win, headache was the 
most common presentation (100%). Other clinical parameters in order of decreasing 
frequency on admission were fever (58.70%), neck stiffness (45.65%) and impaired 
conscious level (13.04%) (Myo Thet Naing, 2013). In the study of Than-Maung, the 
most common clinical features are headache (97.87%), fever (85.11%), neck stiffness 
(63.83%), abnormal mental status (42.55%), convulsion (41.3%), focal neurological 
symptoms (14.89%) and papilledema (12.77%).  
 
 
2.1.6. Diagnostic laboratory tests  
A. Specimens, Microscopic Examination, and Culture 
 
 
Specimens include cerebrospinal fluid, tissue, exudates, sputum, blood, 
cutaneous scrapings, and urine. Spinal fluid is centrifuged before microscopic 
examination and culture. For direct microscopy, specimens are often examined in wet 
mounts, both directly and after mixing with India ink, which delineates the capsule.   
Colonies develop within a few days on most media at room temperature or 37°C. Media 
with cycloheximide inhibit Cryptococcus and should be avoided. Cultures can be 
identified by growth at 37°C and detection of urease. Alternatively, on an appropriate 
diphenolic substrate, the phenol oxidase (or laccase) of C neoformans and C gattii 
produces melanin in the cell walls and colonies develop a brown pigment. 
B. Serology  

9 
 
 
 
Tests for capsular antigen can be performed on cerebrospinal fluid, 
serum and urine. The latex slide agglutination test or enzyme immunoassay for 
cryptococcal antigen is positive in 90% of patients with cryptococcal meningitis. With 
effective treatment, the antigen titer drops—except in AIDS patients, who often 
maintain high antigen titers for long periods (Brooks et al., 2013). 
 
2.1.7. Complications 
 
 
Complications are common; raised intracranial pressure in the absence 
of ventricular dilatation may cause profound visual or hearing loss. Less commonly, 
patients may develop cognitive impairment and gait ataxia due to obstructive 
hydrocephalus with ventricular dilatation (Bicanic & Harrison, 2005). 
(a)  Raised intracranial pressure 
 
 
The pathophysiology of elevated ICP in patients with cryptococcal 
meningitis is poorly understood and it is likely caused by several convergent factors.  
It has been postulated that it may be due to the outflow obstruction precipitated by 
aggregation of fungal polysaccharide accumulating in arachnoid villi and subarachnoid 
spaces thus providing the blockage of the channels for CSF drainage (Lee et al., 1996). 
Moreover, another possible important factor is cerebral oedema resulting from 
cytokine-induced inflammation and possibly osmotic effect by fungus-derived 
mannitol (Denning et al., 1991). 
(b) Ophthalmologic Complications 
 
 
The most severe ophthalmologic complication of cryptococcal 
meningitis is optic atrophy with resultant marked diminution of vision. This atrophy 
appears, at least in some patients, to be the result of direct invasion and destruction of 
the optic nerve by the cryptococci. The patients with most severe visual loss either had 
optic atrophy when first seen, or presented with minimal papilledema in relationship to 
CSF pressure (Okun & Butler, 1964). 
 
 
 
 
 

10 
 
2.1.8. Induction, consolidation and maintenance antifungal treatment regimens 
Table 1. WHO 2018 Induction, consolidation and maintenance antifungal treatment 
regimens (WHO, 2018) 
 
 
Induction (adults, adolescents and children) 
Preferred 
regimen 
amphotericin B deoxycholate (1.0 mg/kg/day) 
and flucytosine (100 mg/kg/day, divided into 
four doses per day) (one week), followed by 1 
week of fluconazole (1200 mg/day for adults, 
12 mg/kg/day for children and adolescents, up 
to a maximum dose of 800mg daily) 
Strong 
recommendation, 
moderate certainty 
evidence for 
adults, low-
certainty evidence 
for children and 
adolescents 
Alternative  
Two weeks of fluconazole (1200 mg daily for 
adults, 12 mg/kg/day for children and 
adolescents) + flucytosine (100 mg/kg/day, 
divided into four doses per day) 
strong 
recommendation, 
moderate-certainty 
evidence 
Alternative  
Two weeks of amphotericin B deoxycholate 
(1.0 mg/kg/day) + fluconazole (1200 mg daily 
for adults, 12 mg/kg/day for children and 
adolescents up to a maximum of 800 mg daily 
strong 
recommendation, 
moderate-certainty 
evidence 
Consolidation 
Consolidation 
Fluconazole (800 mg daily for adults, 6–12 
mg/kg/day for children and adolescents up 
to a maximum of 800 mg daily) for eight 
weeks following the induction phase 
strong 
recommendation, 
low-certainty 
evidence 
Maintenance (or secondary prophylaxis) 
Maintenance 
(or 
secondary 
prophylaxis) 
 
Fluconazole (200 mg daily for adults, 6 
mg/kg/day for adolescents and children) 
strong 
recommendation, 
high-certainty 
evidence 
 
 
In March 2018, WHO published “Guidelines for the Diagnosis, 
Prevention and Management of Cryptococcal Disease in HIV-Infected Adults, 
Adolescents and Children”. This guideline recommends a short-course (one-week) 

11 
 
induction regimen with amphotericin B deoxycholate and flucytosine followed by 1 
week of fluconazole is the preferred regimen. In low- and middle-income countries, 
due to limited availability of flucytosine, alternative options of two weeks amphotericin 
B deoxycholate plus fluconazole are used depending on drug availability (WHO, 2018). 
Although guidelines exist for the antifungal management of cryptococcal meningitis, 
recommendations are based on limited data from RCTs, and in clinical practice 
treatment is highly variable due to drug costs, availability, and ability to monitor and 
manage drug-related toxicities (Perfect, 2010).  
Table 2. Myanmar Specialist hospital guidelines for clinical management of 
Cryptococcosis in patients with HIV (2019) 
Initiation 
IV Amphotericin 1 mg/kg plus Fluconazole 1200 mg IV/oral/ day 
for at least 2 weeks 
Consolidation 
Fluconazole 800 mg po od for 8 weeks 
Maintenance 
Fluconazole 200 mg OD until CD4 count rises to 200/mm³ with 
ART 
Treatment for localized non-meningeal disease 
 
 
Treatment with fluconazole 800 mg/day for two weeks followed by 400 
mg/day for eight weeks followed by fluconazole 200-mg/day maintenance therapy is 
suggested based on expert opinion. 
 
 
For optimal treatment of cryptococcoma, the following treatment 
regimen is suggested based on expert opinion: intravenous amphotericin B and oral 
flucytosine for at least six weeks, followed by consolidation and maintenance therapy 
with fluconazole (all doses similar to those used for cryptococcal meningitis). 
Corticosteroids or surgical intervention may be considered for intracranial lesions with 
evidence of mass effect (WHO, 2018). 
Treatment for pregnant women 
 
 
Amphotericin B therapy can be given to pregnant women with 
meningeal and non-meningeal disease. Exposure to flucytosine and fluconazole during 
pregnancy has been associated with an increased risk of birth defects in animal studies 
and some uncontrolled human studies. The use of flucytosine and fluconazole for 
treating cryptococcal disease in pregnant women should be evaluated on an individual 
basis, considering the benefits and potential harm (WHO, 2018). 
 

12 
 
2.1.9. Adjunctive corticosteroids in treating HIV-associated cryptococcal 
meningitis 
 
 
Routine use of adjunctive corticosteroid therapy during the induction 
phase is not recommended in treating HIV-associated cryptococcal meningitis among 
adults, adolescents and children (strong recommendation, high-certainty evidence for 
adults and adolescents, moderate-certainty evidence for children) (WHO, 2018). 
 
2.1.10. CSF fungal clearance 
 
 
Thailand study revealed that clearance of Cryptococci from the CSF was 
exponential and was significantly faster with amphotericin B plus flucytosine than with 
amphotericin B alone (p=0·0006), amphotericin B plus fluconazole (p=0·02) (Brouwer 
et al.,2004). In Vietnam study, amphotericin B plus flucytosine was associated with 
significantly increased rates of yeast clearance from cerebrospinal fluid (−0.42 log10 
colony-forming units [CFU] per milliliter per day vs. −0.31 and −0.32 log10 CFU per 
milliliter per day in groups 1 (amphotericin B) and 3 (Amphotericin B plus 
fluconazole), respectively; P<0.001 for both comparisons (Day et al., 2013). Largest 
ACTA trial confirmed that flucytosine as the partner drug given with amphotericin B 
was associated with more rapid clearance than fluconazole (Molloy et al., 2018). 
 
2.1.11.  Preventing, monitoring and managing antifungal toxicity 
Preventing, monitoring and managing antifungal amphotericin B toxicity 
 
 
Drug toxicity and side-effects from amphotericin B therapy, especially 
hypokalaemia, nephrotoxicity and anaemia, are barriers to optimal induction treatment, 
safe administration of amphotericin B should be given priority and may require referral 
to a centre with access to a minimum package of preventing, monitoring and managing 
toxicity (WHO, 2018). 
Table 3. Minimum package for preventing, monitoring and managing amphotericin B 
toxicity (WHO, 2018).  
Pre-emptive hydration and electrolyte supplementation 
Adults and 
adolescents 
One litre of normal saline solution with 20 mEq of potassium 
chloride (KCl) over two hours before each controlled infusion 
of amphotericin B and one to two 8-mEq KCl tablets orally 
twice daily. An additional 8-mEq KCl tablet twice daily may 

13 
 
be added during the second week. If available, magnesium 
supplementation should also be provided (two 250-mg tablets 
of magnesium trisilicate or glycerophosphate twice daily, or 
magnesium chloride 4 mEq twice daily). 
 
Monitoring (adults, adolescents and children) 
Serum potassium 
Baseline and 2–3 times weekly (especially in the second week 
of amphotericin B administration) 
Serum creatinine 
Baseline and 2–3 times weekly (especially in the second week 
of amphotericin B administration) 
Haemoglobin 
Baseline and weekly 
Management (adults, adolescents and children) 
Hypokalaemia 
If hypokalaemia is significant (K <3.3 mol/l), increase 
potassium supplementation to 40 mEq KCl by intravenous 
infusion and/or one to two 8-mEq KCl tablets orally three times 
daily. Monitor potassium daily. 
Elevated creatinine If creatinine increases by ≥2 fold from the baseline value, 
increase pre-hydration to 1 L every eight hours and consider 
temporarily omitting a dose of amphotericin B. Once creatinine 
improves, restart amphotericin B at 0.7 mg/ kg/day and 
consider alternate-day amphotericin B. If creatinine continues 
to rise, consider discontinuing amphotericin B and continuing 
with fluconazole at 1200 mg/ day, especially if seven doses of 
amphotericin have been received. Consider fluconazole dose 
adjustment if significant renal impairment. Monitor creatinine 
daily. 
Severe anaemia  
Transfusion should be undertaken if possible for severe 
amphotericin B–related anaemia (anaemia may also be a reason 
to discontinue amphotericin B prematurely in the second week 
of a planned two-week induction course of amphotericin B with 
fluconazole) 
Additional notes:  

14 
 
 Potassium replacement should not be given to people with pre-existing renal 
impairment or hyperkalaemia.  
 Careful attention should be given to monitoring of intake and output of fluid 
and daily weight, especially among children.  
 Flucytosine – because of concerns about bone marrow suppression, regular 
monitoring of full blood counts should be considered. 
 The incidence of renal dysfunction and electrolyte disturbance is much less 
with liposomal amphotericin preparations, but renal function and electrolytes 
still need to be monitored 
 
Managing fluconazole toxicity 
-Renal insufficiency 
 
 
If renal function decreases to 20-50 ml/min then reduce the dose by 50% 
 
 
If renal function decreases to < 20 ml/min then reduce the dose by 25% 
-Liver function abnormality (Perfect et al., 1992) 
 
 
If during therapy, ALT (SGPT) from normal to 5x upper limit or form 
abnormal baseline increases by 150 then, if possible, stop fluconazole and switch to 
amphotericin. 
-Drug Interactions 
 
 
Fluconazole may increase levels of phenytoin, warfarin and 
sulfonylurea derivatives. If concomitant use of warfarin: check INR. If concomitant use 
of sulfonylurea derivatives there is risk of hypoglycemia, so check glucose levels more 
often. 
 
 
Rifampicin will reduce the levels of fluconazole if the patient has been 
on it for > 2 weeks. Increase the dose of fluconazole by 50 %, in consolidation and 
maintenance phases. 
 
 
Fluconazole is contraindicated in combination with cisapride and the 
new drug class of antihistamines such as terfenadine and astemizole (Molloy et al., 
2018). 
 
2.1.12.  Safety 
 
 
In ACTA trial, they randomly assigned HIV-infected adults with 
cryptococcal meningitis to receive an oral regimen (fluconazole [1200 mg per day] plus 

15 
 
flucytosine [100 mg per kilogram of body weight per day] for 2 weeks), 1 week of 
amphotericin B (1 mg per kilogram per day), or 2 weeks of amphotericin B (1 mg per 
kilogram per day). Each patient assigned to receive amphotericin B was also randomly 
assigned to receive fluconazole or flucytosine as a partner drug. Laboratory-defined 
side effects were less frequent in the oral-regimen group than in the 1-week or 2-week 
amphotericin B groups. Grade 4 anemia developed in 0.9% of patients in the oral-
regimen group, 4.9% of patients in 1-week amphotericin B groups, and 8.8% of patients 
in the 2-week amphotericin B group. And also Grade 3 anemia developed in 4% of 
patients in the oral-regimen group, 8.9% of patients in 1-week amphotericin B groups, 
and 17.5% of patients in the 2-week amphotericin B group.  A grade 3 or 4 increase in 
the serum creatinine level developed in 4.9% of patients in the oral-regimen group, 
6.2% of patients in the 1-week amphotericin B groups, and 8.8% of patients in the 2-
week amphotericin B groups. Grade 4 hypokalemia developed in only one patient, most 
likely because preemptive electrolyte replacement was provided for patients receiving 
amphotericin B.  
 
 
Grade 4 neutropenia was recorded in 3.2% of the patients who were 
taking a regimen that included 2 weeks of flucytosine, in 0.9% of those taking 1 week 
of flucytosine, and in 1.3% of those taking a flucytosine free regimen. A grade 4 
increase in the alanine aminotransferase level developed in only two patients, one of 
whom was taking fluconazole. Clinical adverse events were frequent with all regimens, 
which was reflective of the severe immunosuppression in this patient population. 
 
 
As a partner drug with amphotericin, 1week amphotericin and 
flucytosine group develop Grade 3 and 4 anaemia of 8.8% and 24.56 % in 2 weeks 
amphotericin and fluconazole group. (Molloy et al., 2018). 
 
 
In Vietnam trial, Grade 3 and 4 anaemia were most prominent between 
amphotericin B plus flucytosine (35%) and amphotericin B plus fluconazole group 
(29%). Grade 3 and 4 Neutropenia (9%) were similar between the two groups. 4% of 
amphotericin B plus flucytosine group develop Grade 3 and 4 thrombocytopenia with 
3% in the fluconazole group. Grades 3 and 4 increase in aminotransferase level was 6% 
in flucytosine group and 14 % in fluconazole group (Day et al., 2013). 
 
 
But in one cohort study of amphotericin B with fluconazole, none of the 
patients developed any serious Grade 3, 4 anaemia and elevated ALT level. Only 2 
patients developed grade III hypokalemia and thrombocytopenia. And 7 patients 

16 
 
develop grade 3,4 neutropenia and 4 patients develop grade III elevated creatinine level.  
(Muzoora et al., 2011). 
 
2.1.13. Mortality 
 
 
In Africa trial, as a partner drug with amphotericin B, flucytosine was 
superior to fluconazole (71 deaths [31.1%] vs. 101 deaths [45.0%]; hazard ratio for 
death at 10 weeks, 0.62; 95% confidence interval [CI], 0.45 to 0.84; P = 0.002). One 
week of amphotericin B plus flucytosine was associated with the lowest 10-week 
mortality (24.2%; 95% CI, 16.2 to 32.1) (Molloy et al., 2018). 
 
 
In Thailand study, the standard therapy for human immunodeﬁciency 
virus (HIV)–associated cryptococcal meningitis of amphotericin B (AmB; 0.7 mg/kg 
per day) plus ﬂucytosine frequently takes 12 weeks to sterilize the cerebral spinal ﬂuid, 
and acute mortality remains high. In this trial of AmB-based combination therapy, 
the10-week survival rate was 76%, the highest reported to date from Africa (Bicanic et 
al., 2008) At least two factors might explain high acute mortality: raised intracranial 
pressure and only moderately effective antifungal regimens, which frequently take 
more than 2 weeks to sterilize CSF. Mortality was 14% (nine/63) at 2 weeks and 22% 
(14/63) at 10 weeks. Elevated intracranial pressure was associated with death in 13 of 
14 patients during step one. For the initial treatment of AIDS associated cryptococcal 
meningitis, the use of higher-dose amphotericin B plus flucytosine is associated with 
an increased rate of cerebrospinal fluid sterilization and decreased mortality at two 
weeks, as compared with regimens used in previous studies (Van Der Horst et al., 
1997).In Vietnam study, combination therapy with flucytosine was associated with a 
reduced hazard of death, as compared with amphotericin B alone (hazard ratio, 0.56; 
95% CI, 0.36 to 0.87; P = 0.01) or with amphotericin B plus fluconazole (hazard ratio, 
0.55; 95% CI, 0.35 to 0.88; P = 0.01) (Day et al., 2013). 
 
2.2.14. Timing of ART  
 
 
Immediate ART initiation is not recommended for adults, adolescents 
and children living with HIV who have cryptococcal meningitis because of the risk of 
increased mortality and should be deferred by 4–6 weeks from the initiation of 
antifungal treatment (WHO, 2018). 
 
 

17 
 
3. AIM AND OBJECTIVES 
 
3.1. Aim 
 
 
To study the clinical effectiveness and safety of amphotericin B with 
flucytosine-fluconazole therapy for cryptococcal meningitis in patients with HIV 
infection. 
  
3.2. Objectives 
1. To find out the back-ground characteristics of patients with HIV-associated 
cryptococcal meningitis 
2. To describe the clinical effectiveness of amphotericin B with flucytosine-
fluconazole combination therapy by assessing clinical parameters at day 1, day 
7 and day 14 
3. To determine the severity of headache before and after treatment by numerical 
rating scale 
4. To describe the clinical safety of amphotericin B with flucytosine-fluconazole 
combination therapy by assessing hematological and biochemical parameters 
by DAIDS grading at baseline, day 7 and day 14 
 
3.3. Research Question 
 
 
What will be the clinical effectiveness and safety of Amphotericin B 
with Flucytosine -Fluconazole combination therapy for cryptococcal meningitis in 
patients with HIV infection? 
 
 
 
 
 
 
 

18 
 
4. METHODOLOGY 
 
4.1. Study Design 
 
 
Hospital-based descriptive study 
 
4.2. Study Site 
1. Inpatient Departments of Specialist Hospital Waibargi (SHW) 
2. Inpatient Departments of Specialist Hospital Mingalardon (SHM) 
3. Inpatient Departments of Specialist Hospital Thakeyta (SHT) 
 
4.3. Study Period 
 
 
This study period will be conducted from October 2020 to September 
2021. 
 
4.4. Reference Population 
 
 
Cryptococcal meningitis in patients with HIV infection 
 
4.5. Study Population 
 
 
Patients admitted to SHW, SHM and SHT with HIV-associated 
cryptococcal meningitis who will be treated with amphotericin + flucytosine + 
fluconazole induction regimen.  
 
4.6. Selection Criteria 
4.6.1. Inclusion criteria 
1. Patients with HIV-associated cryptococcal meningitis, admitted to inpatient 
department of SHW, SHM and SHT during the study period  
2. Patients of both sexes 
3. Age above 14 years 
4. Patients or caregivers who will give informed consent to participate in this study 
 
4.6.2. Exclusion criteria 
1. Pregnancy 

19 
 
4.6.3 Withdrawal criteria 
1. On patient’s request 
 
4.7. Sample Size Determination and Sampling Procedure  
4.7.1. Sample Size Determination 
 
 
The sample size was calculated by using the following formula  
 
  
    𝑧(1−𝛼
2)
2
 p (1-p) 
 
n =  
 
 
 
 
 
 
              d2 
 
Sample size for clinical safety, 
Where, 
p 
= Proportion of absence of grade III/IV anaemia in patients with HIV-
associated cryptococcal meningitis infection after being treated with 
Amphotericin B, Flucytosine plus Fluconazole  
 
 
= 0.83 (Molloy et al., 2018) 
z 
= Standard normal deviate = 1.96 (95% CI) 
d 
= Absolute precision = 0.14 
n 
= minimal required sample size = 27 
 Sample size for clinical effectiveness, 
   Where, 
p 
= Proportion of improvement of headache in patients with HIV-
associated cryptococcal meningitis infection after being treated with       
Amphotericin, Flucytosine plus Fluconazole  
 
= 0.8 
z 
= Standard normal deviate = 1.96 (95% CI) 
d 
= Absolute precision = 0.15 
n 
= minimal required sample size = 27 
So, the required sample size is 27. 
 
 

20 
 
4.7.2 Sampling Method 
 
 
All patients admitted to the inpatient departments of SHW, SHM and 
SHT during the study period will be included.  
 
4.8. Materials and Methods 
 
 
After getting approval from medical superintendent, patients with HIV-
associated cryptococcal meningitis admitted to inpatient departments of SHW, SHM 
and SHT will be studied. They will be given IV infusion of amphotericin B (1 
mg/kg/day) and oral flucytosine (100 mg/kg) for one week followed by oral fluconazole 
(1200 mg/day) for one week according to the hospital standard treatment guideline 
chosen by the physician depends on patient’s clinical condition. Before giving 
treatment, informed consent will be obtained. 
 
 
All patients meeting the inclusion criteria will be studied under the 
supervision of experienced physicians. Baseline data for accessing clinical 
effectiveness such as fever, convulsion and abnormal mental status and for safety such 
as hematological and biochemical parameters (hemoglobin, neutrophil, platelet, ALT, 
AST, serum creatinine and serum potassium level) will be noted from medical charts. 
Hematological and biochemical parameters will be graded according to DAIDS 
grading. Assessment of headache and its severity will be done by numerical rating scale 
under the supervision of physician.  
 
 
Seven days and fourteen days after treatment, clinical effectiveness 
parameters such as headache, fever, convulsion, abnormal mental status and death will 
be reassessed. Clinical safety concerning hematological and biochemical parameters 
like hemoglobin, neutrophil, platelet, ALT, AST, serum creatinine and serum 
potassium level will also be reassessed and graded according to DAIDS grading by 
reviewing from patient’s medical charts at seven and fourteen days. With regard to 
severity of headache, it will be documented by using numerical rating scale at weekly 
intervals for two weeks.  Clinical effectiveness parameters (headache, fever, 
convulsion, abnormal mental status and death) and hematological and biochemical 
parameters will be described. The results will be documented for data analysis.  
 
4.9. Data Management and Analysis 
 
 
Data will be collected by using pre-constructed pro forma. Following 
data collection and prior to data entry, all data will be carefully screened for accuracy. 

21 
 
Data entry will be done by using Microsoft Excel 2019. The data will be statistically   
analyzed by using computerized statistical software SPSS (Statistical Package for 
Social Science Version 21). 
 
 
Data summarization for description will be done by showing frequency 
distribution tables and appropriate graphs. The parameters for clinical effectiveness and 
laboratory-defined adverse event gradings will be described by number, percentage in 
treatment group.  
 
4.10. Operational Definitions  
(1)  HIV-seropositive patient  
 
 
Patients who have been diagnosed as HIV infected patients by 
laboratory diagnostics tests in Myanmar. HIV testing strategies for HIV confirmation 
include three HIV antibody tests namely Determine (HIV-1/2) ICT, Uni-Gold (HIV) 
ICT and STAT-PAK (HIV 1/2) ICT (National AIDS Programme, 2017).  
 
(2) Cryptococcal meningitis in patients with HIV infection 
 
 
HIV-seropositive patient with symptoms and signs consistent with the 
diagnosis of cryptococcal meningitis and one or more of positive India ink test, positive 
cryptococcal antigen test in CSF. 
 
(3) Clinical Effectiveness 
 
 
Clinical effectiveness will be assessed by using these parameters such 
as headache, fever, convulsion, abnormal mental status and death.  
(i) Severity of headache 
 
 
Severity of headache is assessed by using Numerical rating scale (NRS). 
The NRS score range from zero to 10. Headache severity will be categorized according 
to the number given by patients for their headache. Headache will be categorized as no 
pain, mild, moderate, severe, and intolerable when scores are 0, 1-3, 4-6, 7-9, and 10. 
Headache will be evaluated by administration of a headache questionnaire at day-1, 
day-7 and day-14. 
 
 (ii) Fever 

22 
 
 
 
It is defined as  rise in body temperature  above 37 C (98.6 F) in the 
morning. 
(iii) Convulsion 
 
 
It is defined as a medical condition where body muscles contract and 
relax rapidly and repeatedly, resulting in uncontrolled actions of the body. 
(iv) Abnormal mental status 
 
 
It is defined as patients is somnolent, lethargy, disoriented and 
disruptions in perception and behavior. 
 
(4) Clinical safety 
 
 
Clinical safety will be assessed by laboratory defined adverse events. 
Adverse event is defined as any untoward medical occurrence in a subject to whom a 
medicinal product has been administered including occurrences which are not 
necessarily caused by or related to that product (Division of AIDS, 2017). Laboratory 
parameters (hematological and biochemical parameters) such as HGB, NEUT, PLT, 
ALT, AST, serum creatinine, serum potassium level will be graded according to 
DAIDS grading in appendix 3. Bone marrow suppression is defined as Grade 3 and 4 
adverse events in one or more of anaemia, neutropenia and thrombocytopenia. 
 
4.11. Ethical Considerations 
 
 
The study will be hospital-based descriptive study regarding the clinical 
effectiveness and safety of amphotericin B with flucytosine-fluconazole combination 
therapy for treatment of HIV-associated cryptococcal meningitis. In this study, all 
patients according to selection criteria admitted to inpatient departments of SHW, SHM 
and SHT will be included. The participants eligible to the selection criteria will be 
invited to voluntary participation in the study and then explained in details about the 
study by the investigator with the information sheet of informed consent form (Part-I). 
 
 
Only after they have understood the nature of study, objectives, 
methodology, procedure and duration, they can voluntarily take part in the study or they 
have right to refuse or withdraw at any time from the study without penalty of loss of 
benefit to which he or she would otherwise be entitled. If they agree, the written 
informed consent will be obtained by using informed consent form (Part-II) from all 
participants or from parents/relatives/next of kin if the patient could not provide the 
consent. 

23 
 
 
 
The study will be done under the supervision of a physician. The study 
will collect data under routine management. No new drugs will be administered and no 
treatment will be restricted for the purpose of thesis. The participants will be closely 
monitored throughout the research process. If any adverse reactions occur, the 
researcher will immediately inform to the physician and urgent treatment will be given 
and the necessary actions will be taken according to the standard treatment procedure.
 
 
The investigator will strictly maintain the rules of privacy and 
confidentiality. The name of patients will not be mentioned in this study. Only coded 
system will be used and research information will be kept by a password-protected file 
in the investigator’s personal computer. All the personal information of the subject in 
Pro forma will be destroyed and the personal information in the investigator’s personal 
computer will be deleted after the study period. The presentation on research data will 
be used in medical workshop, seminars and conference and the data will also be 
published for the academic purposes- only in thesis, papers and medical journals if 
necessary. 
 
 
This study will follow the research guidelines of University of Pharmacy 
and laid out in the booklet - Manual for protocol and dissertation/ Thesis writing (2020). 
The research protocol will be summited and approved by the Ethic Review Committee 
(ERC) of University of Pharmacy.   
 
 
It is the duty of the investigator to perform the research study according 
to the objectives, methodology and procedures approved by ERC of University of 
Pharmacy. 
 
 
 
 
 
 
 
 
 
 
 
 

24 
 
4.12. Algorithm 
 
HIV-seropositive patients with 
diagnosis of cryptococcal 
meningitis
Select according to inclusion 
criteria
Patients who  will give informed 
consent
Baseline assessment for clinical effectiveness (headache, 
fever, convulsion , abnormal mental status, death) and  clinical 
safety  (hematological and biochemical parameters) 
Amphotericin B (1 mg/kg) plus Flucytosine (100 
mg/kg) for 1 week followed by Fluconazole 
(1200 mg/day) for 1 week
Reassess clinical effectiveness 
and clinical safety on Day-7 and 
Day-14
Data analysis
Exclude according 
to exclusion criteria  

25 
 
5. DUMMY TABLES 
 
Table 4. Number of Cryptococcal meningitis in patients with HIV infection enrolled 
from individual specialist hospital 
Hospital 
Number (N) 
Percentage (%) 
Specialist hospital Waibargi 
 
 
Specialist hospital Mingalardon 
 
 
Specialist hospital Thakeyta 
 
 
Total 
 
 
 
Table 5. Distribution of age among study group of Cryptococcal meningitis in patients 
with HIV infection 
 
Table 6. Distribution of gender among study group of Cryptococcal meningitis in 
patients with HIV infection 
 
Gender 
Amphotericin B, Flucytosine plus 
Fluconazole group  
Number 
Percentage 
Male 
 
 
Female 
 
 
Total 
 
 
 
Age (completed years) 
Amphotericin B, 
Flucytosine plus Fluconazole group 
Number 
Percentage 
≤ 20 
 
 
21-40 
 
 
>40 
 
 
Total 
 
 

26 
 
Table 7. Frequency distribution of headache among study group by Numerical rating 
Scale at day-1, day-7 and day-14 
Days 
Headache 
Amphotericin B, Flucytosine plus 
Fluconazole group  
Number 
Percentage 
day-1 
No pain 
 
 
Mild 
 
 
Moderate  
 
 
Severe  
 
 
Intolerable  
 
 
Day-7 
No pain 
 
 
Mild 
 
 
Moderate  
 
 
Severe  
 
 
Intolerable  
 
 
Day-14 
No pain 
 
 
Mild 
 
 
Moderate  
 
 
Severe  
 
 
Intolerable  
 
 
 
 
 
 
 

27 
 
Table 8. Clinical effectiveness of study group by assessing presence of headache, 
fever, convulsion, abnormal mental status and death at day-1, day-7 and  
 
day-14 
Clinical parameters 
Amphotericin B, Flucytosine plus Fluconazole 
group  
Day 1 
Day 7 
Day 14 
N 
% 
N 
% 
N 
% 
Headache 
 
 
 
 
 
 
Fever 
 
 
 
 
 
 
Convulsion 
 
 
 
 
 
 
Abnormal mental status 
 
 
 
 
 
 
Death 
 
 
 
 
 
 
 
 
 

28 
 
Table 9. Laboratory-defined adverse events of amphotericin B, flucytosine and 
fluconazole at baseline and day-7 and day-14 by DAIDS grading  
Days 
DAIDS 
Grading 
Hematological parameters & Biochemical parameters 
Total 
Anaemia 
Neutropenia 
Thrombocytopenia 
Elevated ALT 
level 
Elevated AST level 
Hypokalemia 
Hyper creatinemia 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N 
(%) 
N (%) 
 
Baseline 
Grade 1 
 
 
 
 
 
 
 
 
Grade 2 
 
 
 
 
 
 
 
 
Grade 3 
 
 
 
 
 
 
 
 
Grade 4 
 
 
 
 
 
 
 
 
Day-7 
Grade 1 
 
 
 
 
 
 
 
 
Grade 2 
 
 
 
 
 
 
 
 
Grade 3 
 
 
 
 
 
 
 
 
Grade 4 
 
 
 
 
 
 
 
 
Day-14 
Grade 1 
 
 
 
 
 
 
 
 
Grade 2 
 
 
 
 
 
 
 
 
Grade 3 
 
 
 
 
 
 
 
 
Grade 4 
 
 
 
 
 
 
 
 
 
 
 
 

29 
 
Table 10. Proportion of patients with grade 3 and 4 adverse events of hematological 
parameters at baseline, day-7 and day-14 
   
Grade 3 and 4 
adverse events 
Baseline 
Day -7 
Day -14 
N 
% 
N 
% 
N 
% 
Amphotericin B, 
Flucytosine plus 
Fluconazole group 
Anaemia 
 
 
 
 
 
 
Neutropenia 
 
 
 
 
 
 
Thrombocytopenia 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
Table 11. Proportion of patients who has bone marrow suppression at baseline, day-7 
and day-14 
Bone marrow suppression  
Baseline 
Day -7 
Day -14 
N 
% 
N 
% 
N 
% 
Amphotericin B, Flucytosine plus 
Fluconazole group 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

30 
 
6. REFERENCES 
 
AIDSinfo (2019a) Guidelines for the Prevention and Treatment of Opportunistic 
Infections in Adults and Adolescents with HIV [online]. Available from 
<https://aidsinfo.nih.gov/guidelines> [Assessed 4 November 2019]. 
AIDSinfo (2019b) Understanding the HIV/AIDS Fact sheet [online]. Available form 
<https://aidsinfo.nih.gov/understanding-hiv-aids/fact-sheets/19/46/the-stages-
of-hiv-infection> [Assessed 9 November 2019]. 
Barnett, J.A. (2010) A history of research on yeasts 14: medical yeasts part 2, 
Cryptococcus neoformans. Yeast: pp27; 875-904. 
Bicanic, T. & Harrison, T.S. (2005) Cryptococcal meningitis. British Medical Bulletin: 
72; 99-118. 
Bicanic, T., Bottomley, C., Loyse, A., Brouwer, A.E., Muzoora, C., Taseera, K., 
Jackson, A.,   Phulusa, J., Hosseinipour, M.C., van der Horst, C., 
Limmathurotsakul, D., White, N.J., Wilson, D., Wood, R., Meintjes, G., 
Harrison, T.S. & Jarvis, J.N. (2015) Toxicity of Amphotericin B Deoxycholate-
Based Induction Therapy in Patients with HIV-Associated Cryptococcal 
Meningitis. Antimicrobial Agents and Chemotherapy :59 (12); 7224-7231. 
Bicanic, T., Wood, R., Meintjes, G., Rebe, K., Brower, A., Loyse, A., Bekker, L-G., 
Jaffar, S. & Harrison, T. (2008) High-Dose Amphotericin B with Flucytosine 
for the Treatment of Cryptococcal Meningitis in HIV-Infected Patients: A 
Randomized Trial. Clinical Infectious Diseases: 47; 123–30. 
Brooks, G.F., Carroll, K.C., Butel, J.S., Morse, S.A. & Mietzner,T.A. (2013) Jawetz, 
Melnick, & Adelberg’s Medical Microbiology .26th ed. London : McGraw-Hill. 
Brouwer, A. E., Rajanuwong, A., Chierakul, W., Griffin, G.E., Larsen, R.A. & White, 
N.J. (2004) Combination antifungal therapies for HIV-associated cryptococcal 
meningitis: a randomised trial. The Lancet :363; 1764-1767. 
Centers for Disease Control and Prevention (2019) HIV Basics [online]. 
<https://www.cdc.gov/hiv/basics/whatishiv.html> [Assessed 26 November 
2019] 

31 
 
Chuck, S.L. & Sande, M.A. (1989) Infections with Cryptococcus neoformans in the 
acquired immunodeficiency syndrome. N Engl J Med :321 (12); p.794-799. 
Chow, S.C., Shao, J. & Wang, H., 2003. Sample Size Calculations in Clinical Research 
.2nd edition. Chapman & Hall/CRC; 88. 
Day, J.N., Mai, P.P., Dung, N.T., Mai, N.H., Phu, N.H., Nghia, H.D., Phong, N.D., 
Thai, C.Q., Thai, L.H., Chuong, L.V., Sinh, D.X., Duong, V.A., Hoang, T.N., 
Diep, P.T., Campbell, J.I., Sieu, T.P.M., Baker, S.G.,Chau, N.V.V., Hien, T.T., 
Lalloo, D.G. & Farrar, J.J.(2013) Combination Antifungal Therapy  for 
Cryptococcal Meningitis. The new england journal of medicine: 368(14); 1291-
1302. 
Denning, D. W., Armstrong, R. W., Lewis, B. H.  & Stevens, D. A. (1991) Elevated 
cerebrospinal fluid pressures in patients with cryptococcal meningitis and 
acquired immunodeficiency syndrome. American Journal of Medicine :91(3); 
267– 272. 
Hevey, M.A., Presti, R.M., O’Halloran, J.A., Larson, L., Raval, K., Powderly, W.G. & 
Spec, A.  (2019) Mortality After Cryptococcal Infection in the Modern 
Antiretroviral Therapy Era. J Acquir Immune Deﬁc Syndr:82 (1); 81-87. 
Heckmann, J.M. & Bhigjee, A.I. (2014) Tropical Neurology. In Manson's Tropical 
Infectious Diseases. 23th ed., ed. Farrar, J., Hotez, P.J., Junghanss, T., Kang, G., 
Lalloo, D., White, N.J.; p.1047-1060. Elsevier Saunders. 
Hoffmann, C. & Rockstroh, J.K. (eds.) (2015) HIV 2015/16.Hamburg: Medizin Fokus 
Verlag. 
Klatt, E.C. (ed) (2019) Pathology of HIV/AIDS. 30th ed. Mercer University. School of 
Medicine. Savannah. 
Kumar, V., Abbas, A. K. & Aster, J. C. (2015) Robbins and Cotran Pathologic Basis 
of Disease. 9th edition. Canada: Elsevier. 
Kyaw-Lun-Aung-Hmu (2006) A clinical profile of cryptococcal meningitis in HIV  
 
positive patients in Mandalay General Hospital. Master Thesis. University of 
Medicine, Mandalay. 

32 
 
Lampiris, H.W & Maddix, D.S. (2018) Antifungal Agents. In Basic & Clinical 
Pharmacology. 14th ed., ed. Katzung, B.G; p.853-858. USA: McGraw-Hill 
Education. 
Lee, S.C., Dickson, D.W. & Casadevall, A. (1996) Pathology of Cryptococcal 
Meningoencephalitis: Analysis of 27 Patients with Pathogenetic Implications. 
Human Pathology: 27(8); 839–847. 
Loyse, A., Dromer, F., Day, J., Lortholary, O. & Harrison, T.S. (2013) Flucytosine and 
cryptococcosis: time to urgently address the worldwide accessibility of a 50-
year-old antifungal. J Antimicrob Chemother: 68; 2435–2444. 
Loyse, A., Wilson, D., Meintjes, G., Jarvis, J.N., Bicanic, T., Bishop, L., Rebe, K., 
Williams, A., Jaffar, S., Bekker, L-G., Wood, R. & Harrison, T.S. (2011) 
Comparison of the Early Fungicidal Activity of High-Dose Fluconazole, 
Voriconazole, and Flucytosine as Second-Line Drugs Given in Combination 
with Amphotericin B for the Treatment of HIV-Associated Cryptococcal 
Meningitis. Clinical Infectious Diseases: 54(1); 121–128. 
Molloy, S.F., Kanyama, C., Heyderman, R.S., Loyse, A., Kouanfack, C.,Chanda, D., 
Mfinanga, S., Temfack, E., Lakhi, S.,  Lesikari, S., Chan, A.K., Stone, N., 
Kalata, N., Karunaharan, N., Gaskell, K.,  Peirse, M., Ellis, J.,  Chawinga, C., 
Lontsi, S., Ndong, J.-G., Bright, P., Lupiya, D., Chen, T., Bradley, J., Adams, 
J., van der Horst, C., van Oosterhout, J.J., Sini, V.,  Mapoure, Y.N., Mwaba, P., 
Bicanic, T., Lalloo, D.G., Wang, D., Hosseinipour, M.C., Lortholary, O., Jaffar, 
S. & Harrison, T.S. (2018) Antifungal Combinations for Treatment  of 
Cryptococcal Meningitis in Africa. The New England Journal of Medicine: 378 
(11); 1004-1017. 
Muzoora, C.K., Kabanda, T., Ortu, G., Ssentamu, J., Hearn, P., Mwesigye, J., Longley, 
N., Jarvis, J.N., Jaffar, S. & Harrison, T.S. (2011) Short course amphotericin B 
with high dose fluconazole for HIV-associated cryptococcal meningitis. 
Journal of Infection: 64; 76-81. 
Myo-Thet-Naing (2013) Efficacy of amphotericin B in human immunodeficiency virus 
associated cryptococcal meningitis. Master Thesis. University of Medicine, 
Mandalay. 

33 
 
Narayanan, M. (2012) Fungal infections. In Clinical Pharmacy and Therapeutics. 5th 
ed., ed. Walker, R. and Whittlesea, C; p.654-667. London: Churchill 
Livingstone Elsevier. 
National AIDS Programme. Department of Public Health. (2017) Guidelines for the 
clinical management of HIV infection in Myanmar.5th ed. Myanmar: Ministry 
of Health and Sports. 
Nayak, J.B., Brahmbahtt, C.V., Savalia, C.V., Pal, M. & Bhanderi, B.B. (2010) 
Cryptococcosis: A Garded Mycosis threat. Research Journal of Veterinary 
Sciences:3 (2); 101-112. 
Nyein-Chan-Win. (2014) Cryptococcal Meningitis in HIV seropositive patients with 
neurological symptoms. Master thesis. University of Medicine (2),  Yangon. 
Okun, E. & Butler, W.T. (1964) Ophthalmologic Complications of Cryptococcal 
Meningitis. Michigan State University: 71; 52-91. 
Perfect, J.R., Dismukes, W.E., Dromer, F., Goldman, D.L., Graybill, J.R., Hamill,R.J., 
Harrison, T.S., Larsen, R.A., Lortholary, O., Nguyen, M-H., Pappas, P.G., 
Powderly, W.G., Singh, N., Sobel, J.D & Sorrell, T.C. (2010) Clinical Practice 
Guidelines for the Management of Cryptococcal Disease: 2010 Update by the 
Infectious Diseases Society of America. Clinical Infectious Diseases: 50; 
p.291–322. 
Ponatshego, P.L., Lawrence, D.S., Youssouf, N., Molloy, S.F., Alufandika, M., Bango 
,F., Boulware, D.R., Chawinga, C., Dziwani, E., Gondwe, E., Hlupeni, A., 
Hosseinipour, M.C., Kanyama, C., Meya, D.B., Mosepele, M., Muthoga, C., 
Muzoora, C.K., Mwandumba, H., Ndhlovu, C.E., Rajasingham, R., Sayed, S., 
Shamu, S., Tsholo, K., Tugume, L., Williams, D., Maheswaran, H., Shiri, T., 
Boyer-Chammard, T., Loyse, A., Chen, T., Wang, D., Lortholary, O., Lalloo, 
D.G., Meintjes, G., Jaffar, S., Harrison, T.S., Jarvis, J.N & Niessen, L.W. (2019) 
AMBIsome Therapy Induction OptimisatioN (AMBITION): High dose 
AmBisome for cryptococcal meningitis ind uction therapy in sub-Saharan 
Africa: economic evaluation protocol for a randomised controlled trial-based 
equivalence study. BMJ :9; 1-8. 

34 
 
Rajasingham, R., Smith, R.M., Park, B.J., Jarvis, J.N., Govender, N.P., Chiller, T.M., 
Denning, D.W., Loyse, A & Boulware, D.R. (2017) Global burden of disease 
of HIV-associated cryptococcal meningitis: an updated analysis. The Lancet 
Infectious Diseases :17(8); 873-881. 
Ralston, S.H., Penman, I.D., Strachan, M.WJ. & Hobson, R.P. (eds.) (2018) Davidson’s 
Principles and Practice of Medicine.23rd ed. Edinburgh: Elsevier. 
Ritter, J.M., Lewis, L.D., Mant, T.GK. & Ferro, A. (2008) Antifungal Drug Therapy. 
In A Textbook of Clinical Pharmacology and Therapeutics. 5th ed. p.340-344. 
London: Hodder Arnold. 
Rogers, P.D & Krysan, D.J. (2018) Antifungal Agents. In Goodman & Gilman’s The 
Pharmacological Basis of Therapeutics. 13th ed., ed. Brunton, L.L., Hilal-
Dandan, R and Knollmann, B.C; p.1087-1095. USA: McGraw-Hill Education. 
Segal, B.H., Herbrecht, R., Stevens, D.A., Ostrosky-Zeichner, L., Sobel, J., Viscoli, C., 
Walsh, T.J., Maertens, J., Patterson, T.F., Perfect, J.R., Dupont, B.,  Wingard 
,J.R., Calandra, T., Kauffman, C.A., Graybill, J.R., Baden, L.R., Pappas, P.G., 
Bennett, J.E., Kontoyiannis, D.P., Cordonnier, C., Viviani, M.A., Bille, J., 
Almyroudis, N.G., Wheat, L.J., Graninger, W., Bow, E.J., Holland, S.M., 
Kullberg, B.J., Dismukes, W.E. & Pauw, B.E.D. (2008). Defining responses to 
therapy and study outcomes in clinical trials of invasive fungal diseases: 
Mycoses study group and European organization for research and treatment of 
cancer consensus criteria. Clinical Infectious Diseases 47: 674-683. 
Shiri, T., Loyse, A., Mwenge, L., Chen, T.,  Lakhi, S., Chanda, D., Mwaba, P., Molloy, 
S.F., Heyderman, R.S., Kanyama, C., Hosseinipour, M.C., Kouanfack, C., 
Temfack, E., Mfinanga, S., Kivuyo, S., Chan, A.K., Jarvis, J.N., Lortholary, O., 
Jaffar, S., Niessen, L.W. & Harrison, T.S. (2019) Addition of Flucytosine to 
Fluconazole for the Treatment of Cryptococcal Meningitis in Africa: 
A Multicountry Cost-effectiveness Analysis. Clinical infectious diseases:163.; 
1-4. 
Than-Maung (2006) The effectiveness of fluconazole therapy for cryptococcal 
meningitis in human immunodeficiency virus seropositive patients in Mandalay. 
PhD Thesis. University of Medicine, Mandalay. 

35 
 
UNAIDS (Joint United Nations Programme on HIV/AIDS) (2019). UNAIDS 
data[online]. 
Switzerland: 
UNAIDS. 
Available 
from 
<https://www.unaids.org/en/resources/documents/2019/2019-UNAIDS-data> 
[Assessed 25 October 2019]. 
UNAIDS (Joint United Nations Programme on HIV/AIDS) (2019). UNAIDS fact sheet 
–Global AIDS Update[online]. Switzerland: UNAIDS. Available from 
<https://www.unaids.org/en/resources/fact-sheet > [Assessed 25 October 
2019]. 
Van Der Horst, C.M., Saag, M.S., Cloud, G.A., Hamill, R.J., Graybill, J.R., Sobel, J.D., 
Johnson, P.C., Tuazon, C.U., Kerkering, T., Moskovitz, B.L., Powderly, W.G., 
Dismukes,W.E . & the National Institute of Allergy and Infectious Diseases 
Mycoses Study Group and AIDS Clinical Trials Group (1997) Treatment of 
cryptococcal meningitis associated with the acquired immunodeficiency 
syndrome. N Engl J Med: 337(1); 15-21. 
Vermes, A., Guchelaar, H-J. a Dankert, J. (2000) Flucytosine: a review of its 
pharmacology, clinical indications, pharmacokinetics, toxicity and drug 
interactions. Journal of antimicrobial chemotherapy: 46; 171-179. 
Warkentien, T. & Crum-Cianﬂone, N.F. (2010) An update on Cryptococcus among 
HIV-infected patients. International Journal of STD & AIDS :21; 679–684. 
World Health Organization (2018). Guidelines on the diagnosis, prevention and 
management of cryptococcal disease in HIV-infected adults, adolescents and 
children: supplement to the 2016 consolidated guidelines on the use of 
antiretroviral drugs for treating and preventing HIV infection. Geneva: World 
Health Organization; 2018. Licence: CC BY-NC SA 3.0 IGO. 
World Health Organization (2019). Cryptococcal disease: HIV/AIDS Cryptococcal 
disease 
what's 
new 
and 
important 
[online]. 
Available 
from 
<https://www.who.int/hiv/mediacentre/news/cryptococcal-disease-key-
messages/en/> [Assessed 10 October 2019]. 
 
 

36 
 
Annex 1.  Pro forma 
Title: Clinical effectiveness and safety of amphotericin B with flucytosine-fluconazole 
combination therapy for cryptococcal meningitis in patients with HIV infection. 
 
 
 
 
 
 
Date     
   ----------------------     
Study site           ----------------------  
 
 
 
 
 
 
Code No  
   ---------------------- 
I. Personal Identification 
 
 
 
 
IPD Registration No. 
---------------------- 
 
Name 
 
 
---------------------- 
Age 
 
 
--------------------- 
Gender  
 
    Male  
 Female 
 
 
 
 
Date of Admission 
--------------------- 
Occupation 
 
--------------------- 
Address  
 
--------------------- 
 
II. History taking and physical examination 
Time of diagnosis of HIV    ----------days ---------- months ---------- years 
ART status 
 
Yes  
  
 
 
 
 
 
No  
 
Defaulter   
CD4 count  at admission  
-------- cells/μL 
 
III. CSF Findings 
Macroscopic 
Colour 
  
---------------------- 
Microscopic 
Total cells count  
R.B.C. 
----------------------/cmm 
Neutrophil   ----------------------% 
W.B.C 
----------------------/cmm 
Lymphocyte ----------------------% 
CSF glucose ----------------------/mg/dL    CSF protein ---------------------- mg% 
India ink stain, Encapsulated yeast cell- seen              not seen      
CSF opening pressure, cm H2O  
 Therapeutic lumbar puncture 
 
mL    

37 
 
 CSF Crypto Ag  
 
Positive 
negative 
 
IV. Clinical diagnosis 
 
---------------------- 
 
V. Treatment 
Amphotericin B 
1 mg/kg 
1 week 
Flucytosine 
100 mg/kg 
Fluconazole 
1200 mg/day 
1 week 
 
VI. Assessment of Headache (Headache Severity by Numerical rating scale) 
Days 
Numerical rating Scale 
No pain 
0 
Mild 
1-3 
Moderate 
4-6 
Severe 
7-9 
Intolerable 
10 
Day 1 
 
 
 
 
 
Day 7 
 
 
 
 
 
Day 14 
 
 
 
 
 
 
VII.   Assessment of Fever  
Days 
Temperature (morning) 
Present 
Absent 
Day 1 
 
 
Day 7 
 
 
Day 14 
 
 
  
VIII. Assessment of Convulsion 
Days 
Convulsion 
Present 
Absent 
Day 1 
 
 
Day 7 
 
 
Day 14 
 
 
 
 
 

38 
 
IX. Assessment of Abnormal mental status 
Days 
Abnormal mental status 
Present 
Absent 
Day 1 
 
 
Day 7 
 
 
Day 14 
 
 
 
X. Laboratory (hematological and biochemical) parameters 
hematological and 
biochemical parameters 
Baseline 
Day-7 
Day-14 
HGB (g/dL) 
 
 
 
NEUT (10 3/µL) 
 
 
 
PLT (10 3/µL) 
 
 
 
ALT (U/L) 
 
 
 
AST (U/L) 
 
 
 
Serum creatinine (μmol/L) 
 
 
 
Potassium (mmol/L) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

39 
 
Annex 2.  Informed Consent Form (Myanmar and English) 
သုတေသနလုပ်ငန််းေွင်ပါဝင်ရန် သတ ောေူညီချက်တပ်းသည ်ပံုစံ (မြန်ြော) 
သုတေသနတခါင််းစဉ် 
- အိပ်(ချ်)အိုင်ဗွီ(HIV)တရောဂါပို်း ကူ်းစက်ခံရပပီ်း ခရစ်ေိုတကော ကေ်ြိှို 
တရောဂါပို်းေစ်ြျိ ်းတ ကောင ် 
ဉီ်းတ ှောက်အတမြ ်းတရောင်တရောဂါ 
ခံစော်းရသည ် 
လူနှောြျော်းေွင် 
အြ်ဖိုထတရစင် ီ (Amphotericin B)  င ်ေွဲ၍ သံု်းသည ် ဖလူဆိုက်ေိုစင််း (Flucytosine) + 
ဖလူကိုနှောတ ော (Fluconazole) တပါင််းစပ်ကုထံု်း၏ လက်တေွွေ့ေွင် တ ်းအ တရောယ်ကင််းရ င််းြှို 
 င ် အစွြ််းထက်ြှို ကို တလ လောမခင််း။ 
သုတေသနမပ လုပ်သူ 
- တ ေါ် င်ဝင််းတြ 
သုတေသနအဖွဲွေ့အစည််း - တဆ်းဝါ်းတဗ ဌောန၊ တဆ်းဝါ်းေကသိုလ်၊ ရန်ကုန်။ 
အပိုင််း (က) သုတေသန င ်ပေ်သက်၍ရ င််းလင််းေင် မပချက် 
 
(၁) နိ ါန််း 
 
 
ဤသုတေသနကို 
တဆ်းဝါ်းေကသိုလ်၊ရန်ကုန် 
တဆ်းဝါ်းတဗ ဌောနြ  
တဆ်းလက်တေွွေ့တဆ်းဝါ်းသိပံ 
 ွဲွေ့လွန်ပထြ စ်တကျောင််းသူ 
ကျွန်ြ 
တ ေါ် င်ဝင််းတြ 
ြ  
လုပ်တဆောင်ြည် 
မဖစ်ပါသည်။ 
ယခုသုတေသနကို 
တဆ်းလက်တေွွေ့ တဆ်းဝါ်းသိပံြဟော ွဲွေ့ 
အေွက် တဆောင်ရွက်မခင််း မဖစ်ပါသည်။ 
 
 
ယခုသုတေသနသည် အထူ်းကုတဆ်းရံု(တဝ ောဂီ)၊ အထူ်းကုတဆ်းရံု (ြဂလော ံု) 
 င ် 
အထူ်းကုတဆ်းရံု 
(သောတကေ) 
ေွင် 
အိပ်(ချ်)အိုင်ဗွီတရောဂါပို်း 
ကူ်းစက်ခံရပပီ်း 
ခရစ်ေိုတကော ကေ်ြိှိုတရောဂါပို်း 
ေစ်ြျိ ်းတ ကောင ် 
ဉီ်းတ ှောက်အတမြ ်းတရောင်တရောဂါ 
ခံစော်းရသည ်လူနှောြျော်းေွင် သံု်းြည ် တဆ်း ၃ြျိ ်း (Amphotericin B, Flucytosine  င ် 
Fluconazole) 
၏ 
လက်တေွွေ့ေွင် 
တ ်းအ တရောယ် 
ကင််းရ င််းြှို င ် 
အစွြ််းထက်ြှိုကို 
တလ လောမခင််းမဖစ်ပါသည်။ ကျွန်ြသည် ဤသုတေသန လုပ်ငန််းအတ ကောင််း ရ င််းမပအသိတပ်းပပီ်း 
သင ်အော်းပါဝင်ရန် ဖိေ်တခေါ်ပါသည်။ သုတေသန လုပ်ငန််းေွင် ပါဝင်မခင််း၊ ြပါဝင်မခင််းကို 

40 
 
ယခုဆံု်းမဖေ်တပ်းစရောြလိုပါ။ 
သင်ဆံု်းမဖေ်ချက်ြချခင် 
ဤသုတေသနလုပ်ငန််း င ် 
ပေ်သက်၍ 
သင်ခံစော်းရသြျှ 
ြည ်သူြဆို 
တမပောပိုင်ခွင ် 
ရ ိပါသည်။ 
ကျွန်ြတမပောတသော 
စကော်းြျော်းထွဲြ နှော်းြလည်တသောစကော်းလံု်းြျော်းရ ိပါကလည််းကျွန်ြအော်းချက်ချင််းတြ်း ိုင်ပါသ
ည်။ကျွန်ြအော်းလံု်းရ င််းမပပါြည်။အကယ်၍ 
တနှောက်ပိုင််းေွင် 
တြ်းစရောတြ်းခွန််းြျော်း 
တပေါ်လောပါက ကျွန်ြ (သိုို့ြဟုေ်) သင ်အော်းကုသတနတသော ဆရောဝန်ထံတြ်းမြန််း ိုင်ပါသည်။ 
ဤသုတေသနြ  လက်တေွွေ့ေွင် ပို၍  တ ်းအ တရောယ် ကင််းရ င််းပပီ်း အစွြ််းထက်သည ် 
တဆ်းဝါ်းြျော်း၏ အချက်အလက်ြျော်းကို ရရ ိ ိုင်သမဖင ် တနှောင်ေွင် ဆရောဝန်ြျော်းအတနမဖင ် 
ပိုြိုတကောင််းြွန်တသော ကုသြှိုကိုတပ်း ိုင်ရန် ရည်ရွယ်ပါသည်။ 
  
(၂) ရည်ရွယ်ချက် 
 
 
ယခုသုတေသနလုပ်ငန််း၏ ရည်ရွယ်ချက်ြ ော  အထူ်းကုတဆ်းရံု(တဝ ောဂီ)၊ 
အထူ်းကုတဆ်းရံု (ြဂလော ံု)  င ် အထူ်းကုတဆ်းရံု (သောတကေ) ေွင် အိပ်(ချ်)အိုင်ဗွီတရောဂါပို်း 
ကူ်းစက်ခံရပပီ်း ခရစ်ေိုတကော ကေ်ြိှို တရောဂါပို်းေစ်ြျိ ်းတ ကောင ် ဉီ်းတ ှောက်အတမြ ်းတရောင်တရောဂါ 
ခံစော်းရသည ် လူနှောြျော်းေွင် အြ်ဖိုထတရစင် ီ (Amphotericin B)  င ်ေွဲ၍ သံု်းသည ် 
ဖလူဆိုက်ေိုစင််း (Flucytosine) + ဖလူကိုနှောတ ော (Fluconazole)တပါင််းစပ်ကုထံု်း ၏ 
လက်တေွွေ့ေွင် တ ်းအ တရောယ်ကင််းရ င််းြှို  င ် အစွြ််းထက်ြှို ကို တလ လောရန် မဖစ်ပါသည်။ 
ယခု 
အသံု်းမပ ြည ် 
တဆ်းဝါ်းြျော်းကို 
၂၀၁၈ 
ခု စ်ေွင် 
ကြ္ော ကျန််းြောတရ်းဌောန၏ 
အိပ်(ချ်)အိုင်ဗွီတရောဂါပို်း 
ကူ်းစက်ခံရတသော 
လူကကီ်း၊လူငယ် 
 င ် 
ကတလ်းြျော်း၏ 
ခရစ်ေိုတကော ကေ်ြိှိုတရောဂါကို တရောဂါရ ောတဖွမခင််း၊ ကောကွယ်မခင််း၊ ကုသမခင််းလြ််းညွှန်ေွင် 
အေည်မပ ပပီ်း မဖစ်ပါသည်။ 
 
(၃) သုတေသန မပ လုပ်ြည ်လုပ်တဆောင်ချက် 
 
 
ဤသုတေသနသည်တဆ်းရံုအတမခမပ တလ လောတသောသုတေသန မဖစ်ပါသည်။ 

41 
 
(၄) သုတေသနေွင်ပါဝင်ြည ်သူတရွ်းချယ်မခင််း 
 
 
အထူ်းကုတဆ်းရံု(တဝ ောဂီ)၊ အထူ်းကုတဆ်းရံု (ြဂလော ံု)  င ် အထူ်းကုတဆ်းရံု 
(သောတကေ)ေိုို့ေွင် အိပ်(ချ်)အိုင်ဗွီတရောဂါပို်း ကူ်းစက်ခံရပပီ်း ခရစ်ေိုတကော ကေ်ြိှိုတရောဂါပို်း 
ေစ်ြျိ ်းတ ကောင ် ဦ်းတ ှောက်အတမြ ်းတရောင်တရောဂါ ခံစော်းရသည ် လူနှောြျော်းြ  သုတေသနဆိုင်ရော 
တရွ်းချယ်ြှို သေ်ြ ေ်စံ ှိုန််းမဖင ် ကိုက်ညီသူြျော်း ပါဝင်ြည်မဖစ်ပါသည်။ 
 
(၅) ဆ ဒအတလျောက်ပါဝင်မခင််း 
 
 
ဤသုတေသနေွင် ပါဝင်ရန်ြ ော ပါဝင်သူ၏ သတ ောဆ ဒ အတလျောက် 
မဖစ်ပါသည်။ ဤသုတေသန လုပ်ငန််း ေွင် ပါဝင်ပပီ်းသည ် တနှောက်ပိုင််း  ှိုေ်ထွက်လိုပါကလည််း 
ဆ ဒအတလျောက် 
အချိန်ြတရွ်း 
 ှိုေ်ထွက် ိုင်ပါသည်။ 
ဤသိုို့ 
 ှိုေ်ထွက်ပါကလည််း 
တရောဂါကုသြှိုေွင် တမပောင််းလွဲသွော်းမခင််း ရ ိြည်ြဟုေ်ပါ။ ြရ င််းလင််းသည ် အချက်အလက် 
ြျော်း င ် အမခော်းသိရ ိလိုသည်ြျော်းကို သုတေသနမပ လုပ်သူ (သိုို့ြဟုေ်)  ောသောရပ်ဆိုင်ရော 
ကျွြ််းကျင်သူ ေစ်ဦ်းဦ်းထံ တြ်းမြန််း ိုင်ပါသည်။ 
 
(၆)သုတေသနမပ လုပ်ြည ်အစီအစဉ် 
 
 
သုတေသနေွင်ပါဝင်သူ၏ ခွင ်မပ ချက် ရရ ိပပီ်းြ  ဤလုပ်ငန််းကို စေင်ပါြည်။ 
သုတေသနမပ လုပ်ြည ်သူသည် ယခုသုတေသနအြျိ ်းအစော်း၊ ပါဝင်ြည ် လုပ်တဆောင်ချက်ြျော်း၊ 
အကျိ ်းတကျ်း ူ်း င ် 
အ တရောယ်ေိုို့ကိုသုတေမပ သူြ  
သုတေသနမပ ရောေွင် 
ပါဝင်သူအော်း 
သ ောေူညီချက်ရရ ိ ိုင်ရန် ရ င််းလင််းတမပောမပပါြည်။ တရောဂါမဖစ်စဉ် ရော ဝင်တကောက်ယူမခင််း၊ 
စြ််းသပ်စစ်တဆ်းမခင််း င ် 
ဓောေ်ခွဲရလော ်အတမဖြျော်းကို 
အထူ်းကုတဆ်းရံု(တဝ ောဂီ)၊ 
အထူ်းကုတဆ်းရံု (ြဂလော ံု)  င ် အထူ်းကုတဆ်းရံု (သောတကေ) ၏အေွင််းလူနှောဌောနရ ိလူနှော၏ 
တဆ်း က်ဆိုင်ရော အချက်အလက်ကေ်မပော်း ြ တကောက်ယူြည်မဖစ်ပပီ်း  လူနှော၏ တခါင််းကိုက်ြှို 
အတမခအတန အကွဲမဖေ်ြှိုြ ေ်ေြ််းကို သြော်းတေော်၏ ကကီ်း ကပ်ြှိုတအောက်ေွင် လုပ်တဆောင် 

42 
 
ြည်  မဖစ်ပါသည်။ သုတေသနကောလ(၂)ပါေ်အေွင််းေွင် သုတေသနမပ သူသည် ပါဝင်သူ၏ 
ကျန််းြောတရ်းအတမခအတန အကွဲမဖေ်ြှိုြ ေ်ေြ််း  င ် ဓောေ်ခွဲရလော ်အတမဖြျော်း တကောက်ယူြှို၊ 
လူနှော၏တခါင််းကိုက်ြှိုအတမခအတန 
အကွဲမဖေ်ြှိုကို 
သြော်းတေော်၏ကကီ်း ကပ်ြှိုတအောက်ေွင် 
ေစ်ပါေ်ေစ်ကကိြ် တဆောင်ရွက်ြည် မဖစ်ပါသည်။ 
 
(၇) ကောမြင ်ချိန် 
 
 
သုတေသနမပ လုပ်ြည ်သူ င ် သုတေသနေွင်ပါဝင်ြည ်သူသည်စုစုတပါင််း (၃) 
ကကိြ်တေွွေ့ဆံုရပါြည်။ 
ပထြအကကိြ်အတနမဖင ် 
သုတေသနဆိုင်ရော 
အချက်အလက် 
တကောက်ယူမခင််း၊ တခါင််းကိုက်ြှိုအတမခအတန ြ ေ်ေြ််းတကောက်ယူမခင််း  အေွက် ခနို့်ြ န််းချိန် ၁၅ 
ြိနစ်ြ ြိနစ် ၃၀  ကောမြင ်ြည်မဖစ်ပါသည်။ ကျန်တသော (၂)ကကိြ်ေွင်သုတေသနမပ သူသည် 
သြော်းတေော်၏ လြ််းညွှန်ြှိုတအောက်ေွင် လူနှော၏ တခါင််းကိုက်ြှိုအတမခအတန ြ ေ်ေြ််းကို  
တကောက်ယူြည် မဖစ်ပါသည်။ ၎င််းေစ်ခုချင််းစီ အေွက် ခနို့်ြ န််းတမခ ၅ ြိနစ်ြ  ၁၀ ြိနစ်အထိ 
 ကောမြင ်ြည် မဖစ်ပါသည်။ သုတေသနမပ သူ င ်၃ ကကိြ်တေွွေ့ဆံုပပီ်းချိန်ေွင် သုတေသနေွင် 
ပါဝင်မခင််း ပပီ်းဆံု်းပါြည်။ သုတေသနအေွက် စုစုတပါင််း  ကောချိန်ြ ော ြိနစ် ၅၀ မဖစ်ပါသည်။ 
 
(၈) ကကံ တေွွေ့ ိုင်သည ်တ ်းထွက်ဆို်းကျိ ်း 
 
 
ဤသုတေသနသည် လူနှော၏ တဆ်း က်ဆိုင်ရောအချက်အလက် ကေ်မပော်းြ  
အချက်အလက်ြျော်းကိုသောတကောက်ယူြည်မဖစ်ပါသမဖင ် 
ဤသုတေသနတ ကောင ် 
လူနှောအ 
တပေါ်ေွင် တ ်းထွက်ဆို်းကျိ ်း မဖစ်တပေါ်တစြည်ြဟုေ်ပါ။ အကယ်၍ သုတေသနမပ လုပ်တနစဉ် 
ပံုြ န်ြဟုေ်တသော တ ်းထွက်ဆို်းကျိ ်းြျော်းမဖစ်တပေါ်ပါကသုတေသနမပ သူသည်သြော်းတေော်သိုို့ 
ချက်ချင််း အတ ကောင််း ကော်းပပီ်း လိုအပ်တသောကုသြှို ခံယူ ိုင်ရန် တဆောင်ရွက်တပ်းပါြည်။ 
 
 

43 
 
(၉) ကကံ တေွွေ့ ိုင်သည ် အ တရောယ် 
 
 
ဤသုတေသနသည်ပံုြ န်ကုသြှိုတပ်းတနတသောကုသြှိုလုပ်ငန််း ေွင် ဝင်တရောက် 
တဆောင်ရွက်ြည်မဖစ်တသောတ ကောင ် တ ်းအ တရောယ်ြ ော အလွန်နည််းပါ်းပါသည်။  
 
(၁၀) ကကံ တေွွေ့ ိုင်သည ်အဆင်ြတမပြှို 
 
 
သုတေသနလုပ်ငန််းတဆောင်ရွက်ချိန်ေွင် 
တြ်းခွန််းြျော်းတမဖဆိုရမခင််းတ ကောင ် 
စိေ်ြသက်သောြှိုအနည််းငယ်ကကံ တေွွေ့ရ ိုင်ပါသည်။ 
 
(၁၁) အကျိ ်းတကျ်း ူ်းြျော်း 
 
 
ဤသုတေသနရလော ်ြျော်းသည်  အိပ်(ချ်)အိုင်ဗွီတရောဂါပို်း ကူ်းစက်ခံရပပီ်း 
ခရစ်ေိုတကော ကေ်ြိှိုတရောဂါပို်းေစ်ြျိ ်းတ ကောင ် 
ဦ်းတ ှောက်အတမြ ်းတရောင်တရောဂါ 
ခံစော်းရသည ် 
လူနှောြျော်း တရောဂါတပျောက်ကင််း ိုင်မခင််း အမပင် ဆရောဝန်ြျော်း၊ ကျန််းြောတရ်းဝန်ထြ််းြျော်း 
အေွက်ြျော်းစွော အကျိ ်းရ ိတစြည် မဖစ်ပါသည်။ 
 
(၁၂) အကျိ ်းခံစော်းခွင ် 
 
 
ဤသုတေသနေွင်ပါဝင်သည ်အေွက် 
ပါဝင်သူြျော်းအတနမဖင ် 
တငွတ က်း 
(သိုို့ြဟုေ်) လက်တဆောင်ြျော်း ခံစော်းခွင ် ြရ ိပါ။သိုို့တသော် သုတေသနေွင် ပါဝင်သည ်အေွက် 
ပိုြိုထိတရောက်တသော ကုသြှိုရရ ိြည်မဖစ်ပါသည်။ 
 
(၁၃) သုတေသနရလော ်ြျော်း လျှိ ွေ့ဝ က်ထိန််းသိြ််းထော်းရ ိြှို 
 
 
သုတေသနမပ လုပ်သူက သုတေသနေွင် ပါဝင်သူ ေစ်ဉီ်းချင််းစီ၏ ကိုယ်တရ်း 
အချက်အလက်ြျော်းကို ြည်သည ် ပုဂ္ိ လ်၊ အုပ်စု၊ အဖွဲွေ့အစည််း ထံသိုို့ြ  ခွင ်မပ ချက်ြရ ွဲ 
တပါက် ကော်းြှို 
ြရ ိတအောင် 
ထိန််းသိြ််းရန် 
ေောဝန် 
ယူပါသည်။ 
သုတေသနဆိုင်ရော 
အချက်အလက်ြျော်း  င ် လူနှော၏တရောဂါစစ်တဆ်းြှို အတမဖေိုို့ကို စနစ်ေကျလျိ ွေ့ဝ က်ထိန််းသိြ််း 

44 
 
ထော်းြည်မဖစ်ပါသည်။ သုတေသန ေွင် ပါဝင်သူ ၏ ကိုယ်တရ်းအချက်အလက်ြျော်း ကို အြည် 
တဖော်မပမခင််း ြမပ  ွဲ ကု ်နံပါေ်စနစ် မဖင ် ြိြိ၏ ကိုယ်ပိုင် ကွန်မပြူေောေွင် တသချောစွော 
သိြ််းဆည််းထော်းြည် မဖစ်ပါသည်။စောရွက်စောေြ််းြျော်း၊ ကွန်ပျြူေောြ ေ်ေြ််းဖိုင် ြျော်းကိုလည််း 
သုတေသနမပ သူ င ် သုတေသန ကကီ်း ကပ်သူေိုို့ြ အပ အမခော်း ြသက်ဆိုင်သည ်သူြျော်း 
 ကည ်ရှိုွေ့မခင််း၊ ထုေ်ယူမခင််း ြမပ  ိုင်တအောင် လံုခခံ သည ်နည််း မဖင ် သိြ််းဆည််းြည် မဖစ်ပါသည်။ 
 
(၁၄) သုတေသနရလ ်အချက်အလက်ြျော်းကိုမဖနို့်တဝမခင််း 
 
 
သုတေသနြ  
ရရ ိတသော 
အတမဖရလော ်ြျော်းကို 
တဆ်းပညောဆိုင်ရော 
အလုပ်ရံုတဆွ်းတ ွ်းပွဲြျော်း၊ ကျန််းြောတရ်းအသိပညော  ီ်းတ ှောဖလ ယ်ပွဲြျော်း၊ တဆ်းပညောဆိုင်ရော 
ညီလောခံြျော်း င ် 
အချက်အလက်ြျော်းကို 
တဆ်းပညောဆိုင်ရော 
သုတေသနစောေြ််း င ် 
ဂျောနယ်ြျော်းေွင် 
အသံု်းမပ ရန်လိုအပ်ြ သော 
အသံု်းမပ ပါြည်။ 
ပါဝင်သူြျော်း၏ 
ကိုယ်ပိုင် 
အချက်အလက်ြျော်းကို တဖော်မပြည်ြဟုေ်ပါ။ 
 
(၁၅) သုတေသနေွင် ပါဝင်ရန်မငင််းဆိုခွင ် (သိုို့ြဟုေ်) သုတေသနြ   ှိုေ်ထွက်ခွင ် 
 
 
သုတေသနလုပ်ငန််းေွင် သင်၏ ပါဝင်ြှိုသည်  ြိြိသတ ောဆ ဒအရသောမဖစ်ပပီ်း  
သုတေသနေွင်ြပါဝင်လိုလျှင် 
အစပိုင််းေွင် 
မငင််းပယ် ိုင်သည ်အမပင် 
သုတေသနေွင် 
ပါဝင်တနစဉ် 
အချိန်ြတရွ်း 
မငင််းပယ် ိုင် 
(သိုို့ြဟုေ်) 
 ှိုေ်ထွက် ိုင်ပါသည်။ 
ထိုသိုို့ 
မပ လုပ်မခင််းတ ကောင ် ပံုြ န်တရောဂါ ဆက်လက်ကုသြှိုကိုထိခိုက်တစြည်ြဟုေ်ပါ။ 
 
(၁၆) ဆက်သွယ်စံုစြ််းရန် 
 
 
ဤသုတေသန င ် 
ပက်သေ်၍ 
သင ်အတနမဖင ် 
တြ်းမြန််းစရောြျော်း 
ြရ င််းလင််းသည်ြျော်းရ ိပါက ယခုတြ်း ိုင်ပါသည်။ 
တနှောက်ြ တြ်းလိုလျှင်လည််း တအောက်ပါ 
လိပ်စောအေိုင််း စံုစြ််းတြ်းမြန််း ိုင်ပါသည်။ 

45 
 
တ ေါ် င်ဝင််းတြ  
ပထြ စ်၊ တဆ်းလက်တေွွေ့တဆ်းဝါ်းြဟောသိပံသင်ေန််း  
တဆ်း က်ကျွြ််းကျင် (၂) (တဆ်းဝါ်း)၊ အထူ်းကုတဆ်းရံု (သောတကေ)၊ ရန်ကုန်ပြိ ွေ့ ။ 
ဖုန််းနံပါေ် - ၀၉၉၇၅၅၀၆၉၈၄ 
 
အပ ိုင််း (ခ) သ ဘောတူညီချက်  
(၁) 
ကျွန်တေော်/ကျွန်ြသည် 
အိပ်(ချ်)အိုင်ဗွီတရောဂါပို်း 
ကူ်းစက်ခံရပပီ်း 
ခရစ်ေိုတကော ကေ်ြိှိုတရောဂါပို်းေစ်ြျိ ်း 
တ ကောင ်မဖစ်တသော 
ဉီ်းတ ှောက်အတမြ ်းတရောင်တရောဂါ 
ေွင်သံု်းတသော တဆ်းြျော်း၏ သုတေသနအေွက် ပါဝင်ရန် ဖိေ် ကော်းမခင််း ခံရပါသည်။ 
၎င််းသုတေသနေွင် လူနှော၏ တခါင််းကိုက်ြှိုအတမခအတန ြ ေ်ေြ််းကို  တကောက်ယူရန် 
သုတေသနမပ လုပ်သူ င ်(၃)ကကိြ်တေွွေ့ဆံုရြည်မဖစ်တ ကောင််းသိရ ိပါသည်။ ဤသုတေသနသည် 
ပံုြ န်လုပ်ရို်းလုပ်စဉ်ကုသြှိုလုပ်ငန််းအေွင််းေွင်ဝင်တရောက်တဆောင်ရွက်ြည်မဖစ်ပပီ်းဤသုတေ
သနတ ကောင ် တ ်းအ တရောယ် ြမဖစ်တ ကောင််း တမပောမပထော်းပပီ်းမဖစ်ပါသည်။ 
(၂) 
သုတေသန င ်ဆိုင်တသော လိုအပ်တသော  ကျန််းြောတရ်းတစောင ်တရ ောက်ြှို  ြ အပ အမခော်း 
ြည်သည ်ခံစော်းခွင ်ြ  
ြရ ိတ ကောင််းကို 
သိရ ိပပီ်းမဖစ်သည်။ 
ကျွန်တေော်/ကျွန်ြသည် 
သုတေသနမပ သူအြည် ၊ ဆက်သွယ်ရန် ဖုန််းနံပါေ် င ်လိပ်စော ေိုို့ကိုလည််းသိရ ိပပီ်း မဖစ်သည်။         
(၃) အထက်တဖော်မပပါ စောပို ်ြျော်းြ  အတ ကောင််းအရောြျော်းအော်းလံု်းကို တကောင််းစွော အတသ်းစိေ် 
ဖေ်ရှိုွေ့ပပီ်း (သိုို့) ဖေ် ကော်းမပသည်ကို နှော်းတထောင်ပပီ်းမဖစ်ပါသည်။ နှော်းြလည်ပါက မပန်လည် 
တြ်းမြန််းခွင ်ရရ ိပပီ်း ြည်သည ်တြ်းခွန််းြဆို တကျနပ်သည်အထိ သုတေသနမပ ြ  မပန်လည် 
တမဖဆိုပပီ်းမဖစ်ပါသည်။ တကောင််းစွောနှော်းလည် သတ ောတပါက်ပါသည်။  
(၄) 
ြိြိကိုယ်ေိုင် 
သတ ောဆ ဒအရ 
သုတေသနေွင် 
ပါဝင်ြည်မဖစ်ပပီ်း 
အချိန်ြတရွ်း 
သုတေသနြ  
ြိြိဆ ဒအတလျောက် 
 ုေ်ထွက် ိုင်တ ကောင််း 
နှော်းလည်ပါသည်။ 

46 
 
တဆ်းပညောအကျိ ်းအလိုို့င ော 
သုတေသန၏ 
တေွွေ့ရ ိချက်အတမဖြျော်းကိုလည််း 
ကိုယ်တရ်းကိုယ်ေောတဖော်မပချက်ြပါ ွဲ ထုေ်တဖော်ေင်မပရန်အေွက် သတ ောေူခွင ်မပ ပါသည်။ 
သုတေသနေွင်ပါဝင်ြည ်သူ၏ လက်ြ ေ် 
------------------------------------- 
သုတေသနေွင်ပါဝင်ြည ်သူ၏ အြည်  
------------------------------------- 
သုတေသနေွင်ပါဝင်ြည ်သူ၏ လိပ်စော  
------------------------------------- 
 င ် ဖုန််းနံပါေ် (ရ ိလျှင်)  
 
 
------------------------------------- 
ရက်စွဲ (လ၊ ရက်၊  စ်)  
 
 
------------------------------------- 
 
အကယ်၍စောမတတ်ပါက 
 
ယခုသုတေသနေွင် 
ပါဝင်ြည ်သူ 
(လူနှော)အော်း 
ကျွ ်ုပ်၏ 
တရ ွေ့တြ ောက်ေွင် 
သတ ောေူညီချက် ြျော်းကို ေိေိကျကျ ရ င််းလင််းဖေ်မပပပီ်း မဖစ်ပါသည်။ ပါဝင်သူက 
ြရ င််းလင််းသည်ြျော်းကိုလည််း 
တြ်းမြန််းခွင ် 
ရရ ိပါသည်။ 
ထိုသူသည် 
ဆ ဒအတလျောက် 
သတ ောေူညီချက်ကို လွေ်လပ်စွော တပ်းမခင််းမဖစ်တ ကောင််း အေည်မပ ပါသည်။ 
ပါဝင်သူ လက်ဝွဲလက်ြလက်တဗွပံုစံ 
 
 
 
အသိသက်တသလက်ြ ေ် 
------------------------------- 
 
 
 
အသိသက်တသအြည်  
------------------------------- 
 
 
 
ရက်စွဲ (လ၊ ရက်၊  စ်)  
------------------------------- 
 
 
 
အသိသက်တသတနရပ်လိပ်စော 
------------------------------- 
 
 
ကျွ ်ုပ်သည် ဤသုတေသနေွင် ပါဝင်ြည ်သူအော်း သတ ောေူညီချက်ြျော်းကို 
ေိေိကျကျ 
ရ င််းလင််းဖေ်မပပပီ်းမဖစ်ပါသည်။ 
ပါဝင်သူကြရ င််းလင််းသည်ြျော်းကိုလည််း 
တြ်းမြန််းခွင ် ရရ ိပါသည်။ ထိုသူသည် ြိြိဆ ဒအတလျောက် သတ ောေူညီချက်ကို လွေ်လပ်စွော 
တပ်းမခင််းမဖစ်တ ကောင််း အေည်မပ ပါသည်။ 

47 
 
သုတေသနမပ သူ၏ လက်ြ ေ် --------------------------------------------------- 
သုတေသနမပ သူ၏အြည် 
--------------------------------------------------- 
ရက်စွဲ (လ၊ ရက်၊  စ်)  
--------------------------------------------------- 
သတ ောေူညီချက် ြိေတြူေစ်တစောင်ကို သုတေသနေွင် ပါဝင်သူြည ်သူအော်း တပ်းအပ်ပပီ်း 
မဖစ်ပါသည်။ ------------------ 
 
အပ ိုင််း(ခ) သ ဘောတူညီချက် (က ိုယ်တ ိုင်သ ဘောတူညီချက်မ ပ်းန ိုင်သူမျော်းအတွက်) 
(၁) 
ကျွန်တေော်/ 
ကျွန်ြသည် 
သုတေသနေွင်ပါဝင်သူ၏----------------------------
တေော်စပ်သူမဖစ်ပါသည်။ 
(၂) ကျွန်တေော်/ကျွန်ြ ၏ တဆွြျိ ်း/သော်းသြီ်း သည် အိပ်(ချ်)အိုင်ဗွီတရောဂါပို်း ကူ်းစက်ခံရပပီ်း 
ခရစ်ေိုတကော ကေ်ြိှိုတရောဂါပို်းေစ်ြျိ ်း 
တ ကောင ်မဖစ်တသော 
ဉီ်းတ ှောက်အတမြ ်းတရောင်တရောဂါ 
ေွင်သံု်းတသော တဆ်းြျော်း၏ သုတေသနအေွက် ပါဝင်ရန် ဖိေ် ကော်းမခင််း ခံရပါသည်။ 
၎င််းသုတေသနေွင် 
လူနှော၏ 
တခါင််းကိုက်ြှိုအတမခအတနြ ေ်ေြ််းကို 
 
တကောက်ယူရန် 
သုတေသနမပ လုပ်သူ င ်(၃)ကကိြ်တေွွေ့ဆံုရြည်မဖစ်တ ကောင််းသိရ ိပါသည်။ ဤသုတေသနသည် 
ပံုြ န်လုပ်ရို်းလုပ်စဉ်ကုသြှိုလုပ်ငန််းအေွင််းေွင်ဝင်တရောက်တဆောင်ရွက်ြည်မဖစ်ပပီ်းသုတေသန 
တ ကောင ် တ ်းအ တရောယ် ြမဖစ်တ ကောင််း တမပောမပထော်းပပီ်းမဖစ်ပါသည်။ 
(၃) 
ကျွန်တေော်/ကျွန်ြအပါအဝင် 
ကျွန်တေော်/ကျွန်ြ၏ 
တဆွြျိ ်း/သော်းသြီ်းအေွက် 
သုတေသန င ်ဆိုင်တသော လိုအပ်တသော  ကျန််းြောတရ်းတစောင ်တရ ောက်ြှိုြ အပ အမခော်းြည်သည ် 
ခံစော်းခွင ်ြ  ြရ ိတ ကောင််းကို သိရ ိပပီ်းမဖစ်သည်။ ကျွန်တေော်/ကျွန်ြသည် သုတေသနမပ သူအြည်၊ 
ဆက်သွယ်ရန် ဖုန််းနံပါေ်  င ်လိပ်စောေိုို့ကိုလည််း သိရ ိပပီ်း မဖစ်သည်။         
(၄) 
အထက်တဖော်မပပါစောပို ်ြျော်းြ အတ ကောင််းအရောြျော်းအော်းလံု်းကိုတကောင််းစွော အတသ်းစိေ် 
ဖေ်ရှိုွေ့ပပီ်း 
(သိုို့) 
ဖေ် ကော်းမပသည်ကို 
နှော်းတထောင်ပပီ်းမဖစ်ပါသည်။ 
နှော်းြလည်ပါက 

48 
 
မပန်လည်တြ်းမြန််း ခွင ်ရရ ိပပီ်း ြည်သည ်တြ်းခွန််းြဆို တကျနပ်သည် အထိ  သုတေသနမပ သူြ  
မပန်လည်တမဖဆိုပပီ်း မဖစ်ပါသည်။ တကောင််းစွော နှော်းလည် သတ ောတပါက်ပါသည်။ 
(၅) 
ကျွန်တေော်/ကျွန်ြ၏ တဆွြျိ ်း/သော်းသြီ်း အော်း သုတေသနေွင် ပါဝင်ရန် ၎င််းကိုယ်စော်း 
ြိြိသတ ော ဆ ဒအတလျောက် သတ ောေူညီချက်ကို လွေ်လွေ်လပ်လပ်တပ်းမခင််းမဖစ်တ ကောင််း 
အေည်မပ ပါသည်။ ဤသုတေသနြ   
ြိြိသတ ောဆ ဒအတလျောက် အချိန်ြတရွ်း  ှိုေ်ထွက် 
 ိုင်တ ကောင််း နှော်းလည်ပါသည်။ 
ပါဝင်သူ၏အြည် 
 
 
-------------------------------------------- 
ပါဝင်သူ၏တဆွြျိ ်း/ြိ လက်ြ ေ် 
-------------------------------------------- 
ပါဝင်သူ၏တဆွြျိ ်း/ြိ အြည်  
-------------------------------------------- 
ရက်စွဲ (လ၊ ရက်၊  စ်)  
 
-------------------------------------------- 
 
အကယ်၍စောမတတ်ပါက 
 
 
ယခုသုတေသနေွင် ပါဝင်ြည ်သူ (လူနှော)အော်း ကျွ ်ုပ်၏ တရ ွေ့တြ ောက်ေွင် 
သတ ောေူညီချက် ြျော်းကို ေိေိကျကျ ရ င််းလင််းဖေ်မပပပီ်း မဖစ်ပါသည်။ ပါဝင်သူက 
ြရ င််းလင််းသည်ြျော်းကိုလည််း 
တြ်းမြန််းခွင ် 
ရရ ိပါသည်။ 
ထိုသူသည် 
ဆ ဒအတလျောက် 
သတ ောေူညီချက်ကို လွေ်လပ်စွော တပ်းမခင််းမဖစ်တ ကောင််း အေည်မပ ပါသည်။ 
 
 
 
ပါဝင်သူတဆွြျိ ်း၏လက်ဝွဲလက်ြလက်တဗွပံုစံ 
 
 
 
အသိသက်တသလက်ြ ေ် 
------------------------------- 
 
 
 
အသိသက်တသအြည်  
------------------------------- 
 
 
 
ရက်စွဲ (လ၊ ရက်၊  စ်)  
------------------------------- 

49 
 
 
 
 
အသိသက်တသတနရပ်လိပ်စော 
------------------------------- 
 
အပ ိုင််း(ခ) သ ဘောတူညီချက် (သို တသနပပြုသူအတွက်) 
 
 
ကျွ ်ုပ်သည် ဤသုတေသနေွင် ပါဝင်ြည ်သူအော်း သတ ောေူညီချက်ြျော်းကို 
ေိေိကျကျ 
ရ င််းလင််းဖေ်မပပပီ်းမဖစ်ပါသည်။ 
ပါဝင်သူက 
ြရ င််းလင််းသည်ြျော်းကိုလည််း 
တြ်းမြန််းခွင ် ရရ ိပါသည်။ ထိုသူသည် ြိြိဆ ဒအတလျောက် သတ ောေူညီချက်ကို လွေ်လပ်စွော 
တပ်းမခင််းမဖစ်တ ကောင််း အေည်မပ ပါသည်။ 
သုတေသနမပ သူ၏ လက်ြ ေ် --------------------------------------------------- 
သုတေသနမပ သူ၏အြည် 
--------------------------------------------------- 
ရက်စွဲ (လ၊ ရက်၊  စ်)  
--------------------------------------------------- 
သတ ောေူညီချက် ြိေတြူေစ်တစောင်ကို သုတေသနေွင် ပါဝင်သူြည ်သူ/ ပါဝင်ြည ်သူ၏ 
ြိ /အုပ်ထိန််းသူ/အနီ်းစပ်ဆံု်းတဆွြျိ ်း အော်း တပ်းအပ်ပပီ်းမဖစ်ပါသည်။------------------ 
 
 

50 
 
Informed Consent Form (English) 
Title 
- Clinical effectiveness and safety of amphotericin B with 
flucytosine-fluconazole combination therapy for cryptococcal 
meningitis in patients with HIV infection  
Principal investigator - Daw Zin Win May 
Organization 
- Department of pharmacology, University of Pharmacy,  
 
  Yangon. 
PART I.  Information sheet 
(1) Introduction 
 
 
 
The investigator is Daw Zin Win May, first year master student of 
clinical pharmacy, who will perform this study to fulfill the degree of M. Pharm. 
(Clinical Pharmacy), University of Pharmacy, Yangon. 
 
 
The present study will identify clinical effectiveness and safety of 
amphotericin B, flucytosine and fluconazole in HIV-associated cryptococcal meningitis 
patients at specialist hospital Waibargi, Mingalardon and Thakeyta, Yangon. I am going 
to give you information about this research and invite you to participate in it. You do 
not have to decide today whether or not you will participate in the research. Before you 
decide, you can talk to anyone you feel comfortable with about the research. There may 
be some words that you do not understand. Please ask me to stop as we go through the 
information and I will take time to explain. If you have questions later, you can ask me 
or any general practitioner who you are consulting. As it will provide information for 
better and safer drugs, clinicians will be able to give better treatments. 
 
(2) Purpose 
 
 
The aim of this research is to study the clinical effectiveness and safety 
of amphotericin B with flucytosine-fluconazole combination therapy for cryptococcal 
meningitis in patients with HIV infection at specialist hospital Waibarigi, Minglardon 
and Thakeyta, Yangon. The drugs used in this research are approved by WHO 2018 
guideline for the diagnosis, prevention and management of cryptococcal disease in 
HIV-infected adults, adolescents and children. 
 
(3) Type of research intervention 
 
 
 
This research is hospital based descriptive study. 
 

51 
 
(4) Participants selection 
 
 
All HIV patients with cryptococcal meningitis attending at specialist 
hospital Waibarigi, Minglardon and Thakeyta who would meet the eligibility criteria 
will be invited to participate in this study.  
 
(5) Voluntary participation 
 
 
The participation in this research is entirely voluntary. It is participant’s 
choice whether to participate or not, all the services received at these hospitals will 
continue and nothing will change. The participants can stop participating even if agreed 
earlier. The participant is free to refuse to take part or withdraw at any time without 
interfering management plan. 
 
(6) Protocol and Procedures 
 
  
After getting informed consent from those participants, the research will 
be done. Participants will be explained about the type and procedure of the research to 
get the informed consent from the participant. History taking and physical examination 
and laboratory results will be noted from medical charts of specialist hospital Waibargi 
and Mingalardon, and assessment of headache and its severity will be done under the 
supervision of physician. During the 2 weeks, researcher will access patient headache 
condition weekly for two weeks. 
 
(7) Duration 
 
 
Researcher and participants will encounter three times. For the first time, 
it will be taken about 15-30 minutes for the participants who give informed consent to 
fill pro forma. For the rest of the times, researcher will note down the patient’s condition 
and assess headache severity by numerical rating scale under the supervision of 
physician. Each of the time will takes approximately 5-10 minutes. After three times, 
the involvement of participants in this study will finish. The total duration of the study 
will be about 50 minutes. 
 
(8) Side effects 
 
 
There is no side effect at all in conducting this research because only the 
data recorded from patient’s medical chart will be collected and accessed. If any 
unusual side effects occur during the research, the researcher will immediately inform 

52 
 
to the physician and urgent treatment will be given and the necessary actions will be 
taken according to the standard treatment procedure. 
 
(9) Risks 
 
 
The risks will be minimal because it will be done under the routine 
treatment. 
 
(10) Discomforts 
  
 
There will be a little psychological discomfort in answering questions 
during the research process. 
 
(11) Benefits 
 
 
 By conducting this study, HIV patients with cryptococcal meningitis as 
well as clinicians and health care workers will get benefits  from the results of the study.
 
 
 
(12) Incentives 
 
 
There will be no financial or material incentives for the participants. But 
the patient will get more effective treatment by participating in this research. 
 
(13) Confidentiality 
 
 
The researcher will not reveal the patient’s identity and information to 
any person, group or institution without permission.  Strict confidentiality will be 
maintained upon research data and results concerning the patients All the information 
and confidential data of the subjects will be maintained and kept confidentially by using 
coding system in the investigator’s personal computer. Both documentaries and 
computerized information will be kept safely and no one apart from the researcher with 
the exception of research colleagues and supervisors will have authorized to assess 
them. 
 
(14) 
Sharing the result 
 
 
The results of the study will be shared only in medical workshop, 
seminars and conference and the data will only be published for the academic purposes- 

53 
 
only in thesis, papers and medical journals if necessary. The confidential information 
of the participants will not be shared. 
 
(15) 
Right to refuse or withdraw 
 
 
Your participation is completely voluntary and you can refuse or 
withdraw to participate in the study at any time. It has no effect on receiving optimal 
treatment for the participants. 
 
(16) 
Whom to contact 
 
 
If you have any questions you may ask me now or later, even after the 
study has been started. If you wish to ask questions later, you may contact any of the 
following:  
Daw Zin Win May 
First Year, M.Pharm. (Clinical Pharmacy) 
Pharmacist, Specialist Hospital (Thaketa), Yangon. 
Phone number: 09975506984 
 
PART II. Certificate of Consent  
(a) Certificate of Consent (Adult) 
1. I have been invited to participate in research of drugs used for treatment of 
cryptococcal meningitis. I understand that it will involve answering questions 
for headache condition and two follow-up visits. I have been informed that the 
study will be done under the routine management and the risks are minimal. 
2. I am aware that there may be no charges or incentives for participation in this 
research. I have been provided with the name, contact phone number and 
address of the researcher who I can easily contact to. 
3. I have read the foregoing information, or it has been read to me. I have been 
given opportunity to ask question about the study and have been answered to 
my satisfaction. I understand very well about the research. 
4. I consent voluntarily to participate as a participant in this research and 
understand that I have the right to withdraw from the research at any time 
without in anyway affecting my medical care. 
 
 

54 
 
Name of Participant  
---------------------------------- 
Signature of Participant 
---------------------------------- 
Date (day/ month / year) 
---------------------------------- 
 
If illiterate, 
 
 
A literate witness must sign (if possible, this person should be selected 
by the participant and should not have no connection to the research team). Participants 
who are illiterate should include their thumb print as well. 
 
 
I have witnessed the accurate reading of the consent form to the potential 
participant, and the individual has had the opportunity to ask questions. I confirm that 
the individual has given consent freely.  
 
Name of witness 
         _______________    and Thumb print of participant     
Signature of witness           _______________ 
Date (Day/month/ year)       _______________ 
 
 
 
I have accurately read or witnessed the accurate reading of the consent 
form to the potential participant, and the individual has had the opportunity to ask 
questions. I confirm that the individual has given consent freely.  
Name of Researcher  
__________________ 
Signature of Researcher  
__________________  
Date (Day/month/year)  
__________________ 
A copy of this Informed Consent Form has been provided to participant _____ 
 
 
 
 
 
 
        (initialed by the researcher) 
 
For children under 18 years of age and un-autonomous persons 
1. I have been invited to have my child/patient participate in research of drugs used 
for treatment of cryptococcal meningitis. I understand that it will involve my 
child/patient answering questions for headache condition and two follow-up 
visits. I have been informed that the study will be under the routine management 
and the risks are minimal. 
2. I am aware that there may be no charges or incentives to either myself or my 
child/patient personally for participation in this research. I have been provided 

55 
 
with the name, contact phone number and address of the researcher who I can 
easily contact to. 
3. I have read the foregoing information, or it has been read to me. I have had the 
opportunity to ask questions about it and any questions that I have asked have 
been answered to my satisfaction. I understand very well about the research. 
4. I consent voluntarily for my child/patient to participate as a participant in this 
study and understand that I have the right to withdraw my child/patient from the 
study at any time without in any way affecting either my patient’s or my own 
medical care. 
 
 
 
Name of Participant  
 
--------------------------------- 
Signature of parent or guardian 
---------------------------------- 
Name of parent or guardian  
---------------------------------- 
Date (day/ month / year) 
 
---------------------------------- 
If illiterate, 
 
 
A literate witness must sign (if possible, this person should be selected 
by the participant and should not have no connection to the research team). participant’s 
parent/guardian who are illiterate should include their thumb print as well. 
 
 
I have witnessed the accurate reading of the consent form to the potential 
participant’s parent/guardian, and the individual has had the opportunity to ask 
questions. I confirm that the individual has given consent freely.  
Name of witness 
         ____________and Thumb print of parent/guardian     
Signature of witness           ____________ 
Date (Day/month/year)       ____________ 
 
 
 
I have accurately read or witnessed the accurate reading of the consent 
form to the parent or guardian of the potential participant, and the individual has had 
the opportunity to ask questions. I confirm that the individual has given consent freely.  
Name of Researcher  
__________________ 
Signature of Researcher  
__________________  
Date (Day/month/year)  
__________________ 
A 
copy 
of 
this 
Informed 
Consent 
Form 
has 
been 
provided 
to 
the 
parents/guardian/relatives/next of kin of participant _____ 
 
 
 
 
 
 
(initialed by the researcher) 

56 
 
Annex 3.  Scale 
Headache severity assessment 
 
 
A numeric rating scale (NRS) is used to assess the severity of headache. 
The NRS score range from zero to 10. Headache severity will be categorized according 
to the number given by patients for their headache. Headache will be categorized as no 
pain, mild, moderate, severe, and intolerable when scores are 0, 1-3, 4-6, 7-9, and 10. 
Headache will be evaluated by administration of a headache questionnaire at the time 
of admission and during the follow up.  
 
 ခါင််းက ိုက်ရောတွင်နောကျင်မှုအဆင ်နှုန််းသတ်မှတ်ချက် မှတ်တမ််း 
သင်၏နှောကျင်ြှိုအဆင ်ကို သိသောတစရန် အသင ်တေော်ဆံု်း နံပါေ်ေစ်ခုကိုတရွ်းချယ်တပ်းပါ။ 
      ၀       ၁     ၂   
 ၃        ၄   
၅  
၆  
၇  
၈  
 ၉            ၁၀  
   
            
                 
       
 
 
   လံု်းဝ       
 
 
 
 
 
 
               အလွန်အြင််း                            
ြနှောကျင်ပါ 
                                                                             နှောကျင်ြှိုရ ိပါသ ည် 
 
 
 
 
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events 

57 
 
Parameter 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Potentially 
life-
threatening 
Hemoglobin, Low 
(g/dL)  
≥ 13 years of age 
(male only) 
10.0 - 10.9 
9.0 - 10.0 
7.0 - 9.0 
< 7.0 
≥ 13 years of age 
(female only) 
9.5 - 10.4 
8.5 - 9.5 
6.5 -8.5 
< 6.5 
Absolute 
Neutrophil Count 
(ANC), 
Low 
(cells/L) 
0.800-1.000 x 
109 
0.600-0.799 
x 109 
0.400-0.599 
x 109 
< 0.400 x 109 
Platelets, 
Decreased (cells/L)  
100-125 x 109 
50-100 x 
109 
25- 50 x 109 
< 25 x 109 
ALT 
or 
SGPT, 
High Report only 
one  
1.25-2.5 ULN 
 
2.5-5.0x 
ULN 
5.0 - 10.0 x 
ULN 
≥ 10.0 x ULN 
AST 
or 
SGOT, 
High Report only 
one  
1.25-2.5 x 
ULN 
 
2.5 - 5.0 x 
ULN 
5.0 -10.0 x 
ULN 
≥ 10.0 x ULN 
Creatinine, High  
1.1-1.3 x ULN 
> 1.3 -1.8 x 
ULN OR 
Increase to 
1.3 - 1.5 x 
participant’s 
baseline 
 
> 1.8 - 3.5 x 
ULN OR 
Increase to 
1.5 to < 2.0 
x 
participant’s 
baseline 
≥ 3.5 x ULN 
OR Increase of 
≥ 2.0 x 
participant’s 
baseline 
Potassium, 
Low 
(mEq/L; mmol/L)  
3.0 -3.4 
3.0 -3.4 
2.5 - 3.0 
2.5- 3.0 
2.0- 2.5 
2.0 -2.5 
< 2.0 
< 2.0 
Normal range of laboratory (hematological and biochemical) parameters in 
SHW, SHM and SHT 

58 
 
Hematological and biochemical 
parameters 
Normal Range 
HGB (g/dL) 
 
11-16 
NEUT (103/µL) 
2-7.5 
PLT (103/µL) 
150-400 
ALT (U/L) 
10-60 
AST (U/L) 
10-50 
Serum creatinine (μmol/L) 
53.0-114.9 
Potassium (mmol/L) 
3.5-5.5 

59 
 
Annex 4. Gantt chart 
 
 
 
 
 
Activities 
2019 
2020 
2021 
November 
December 
January 
October 
November 
December 
January 
February 
March 
April 
May 
June 
July 
August 
September 
October 
November 
December 
Protocol 
* 
* 
* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Preparation 
 
 
 
* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Main study 
 
 
 
* 
* 
* 
* 
* 
* 
* * * 
* 
* 
* 
 
 
 
Data analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* 
* 
 
 
Thesis writing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* 
* 
* 
 
Thesis defense 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* * 

60 
 
Annex 5.   Budget estimation 
Item 
Description 
Estimation (Kyats) 
1. 
Stationary (e.g. printing, copy, etc.) 
400,000 
2. 
Laboratory investigation fees 
2,000,000 
3. 
Thesis book 
300,000 
4. 
Miscellaneous 
300,000 
 
Total 
3,000,000 

61