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Investigating the impact of HIV on patients with first episode psychosis: a study protocol for a longitudinal cohort study ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2020-046593

Article Type: Protocol

Date Submitted by the 04-Nov-2020 Author:

Complete List of Authors: Chhagan, Usha; University of KwaZulu-Natal, Ntlantsana, Vuyokazi; University of KwaZulu-Natal Tomita, Andrew; University of KwaZulu-Natal College of Health Sciences, Naidu, Thirusha; University of KwaZulu-Natal Chiliza, Bonginkosi; University of KwaZulu-Natal, School of Clinical Medicine Paruk, Saeeda; University of KwaZulu-Natal

Schizophrenia & psychotic disorders < PSYCHIATRY, HIV & AIDS < Keywords: INFECTIOUS DISEASES, MENTAL HEALTH

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4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 6 7 8 9 I, the Submitting Author has the right to grant and does grant on behalf of all authors of the Work (as defined 10 in the below author licence), an exclusive licence and/or a non-exclusive licence for contributions from authors 11 who are: i) UK Crown employees; ii) where BMJ has agreed a CC-BY licence shall apply, and/or iii) in accordance 12 with the terms applicable for US Federal Government officers or employees acting as part of their official 13 duties; on a worldwide, perpetual, irrevocable, royalty-free basis to BMJ Publishing Group Ltd (“BMJ”) its 14 licensees and where the relevant Journal is co-owned by BMJ to the co-owners of the Journal, to publish the 15 Work in this journal and any other BMJ products and to exploit all rights, as set out in our licence. 16 17 The Submitting Author accepts and understands that any supply made under these terms is made by BMJ to 18 the Submitting Author Forunless you peer are acting as review an employee on behalf only of your employer or a postgraduate 19 student of an affiliated institution which is paying any applicable article publishing charge (“APC”) for Open 20 Access articles. Where the Submitting Author wishes to make the Work available on an Open Access basis (and 21 intends to pay the relevant APC), the terms of reuse of such Open Access shall be governed by a Creative 22 Commons licence – details of these licences and which Creative Commons licence will apply to this Work are set 23 out in our licence referred to above. 24 25 Other than as permitted in any relevant BMJ Author’s Self Archiving Policies, I confirm this Work has not been 26 accepted for publication elsewhere, is not being considered for publication elsewhere and does not duplicate 27 material already published. I confirm all authors consent to publication of this Work and authorise the granting 28 of this licence. 29 30 31 32 33 34 35

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44 on September 30, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Investigating the impact of HIV on patients with first episode psychosis: a study 4 protocol for a longitudinal cohort study 5 6 1 1 2,3 4 7 Usha Chhagan , Vuyokazi Ntlantsana , Andrew Tomita , Thirusha Naidu , Bonga 8 Chiliza1, Saeeda Paruk1 9 10 1 Discipline of Psychiatry, Nelson R Mandela School of Medicine, University of 11 KwaZulu-Natal, Durban, South Africa. 12 13 2 14 KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), College of 15 Health Sciences, University of KwaZulu-Natal, Durban, South Africa 16 17 3 Centre for Rural Health, School of Nursing and Public Health, College of Health 18 Sciences, University of KwaZulu-Natal, Durban, South Africa BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 19 20 4 21 Department of Behavioural Medicine, University of KwaZulu-Natal, Durban, South 22 Africa 23 24 Corresponding authorFor peer review only 25 Dr Usha Chhagan 26 27 Author affiliations 28 29 Usha Chhagan, [email protected], Discipline of Psychiatry, Nelson R Mandela 30 School of Medicine, University of KwaZulu-Natal, Durban, South Africa. +27 031-260- 31 4321. 32 33 Vuyokazi Ntlantsana, [email protected], Discipline of Psychiatry, Nelson R 34 Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa. +27 35 031-260-4321. 36 37 38 Andrew Tomita, [email protected], KwaZulu-Natal Research Innovation and 39 Sequencing Platform (KRISP), College of Health Sciences, University of KwaZulu- 40 Natal, Durban, South Africa. Centre for Rural Health, School of Nursing and Public 41 Health, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa. 42 +27 031-260-4321. 43 44 45 Thirusha Naidu, [email protected], Department of Behavioural Medicine, University 46 of KwaZulu-Natal, Durban, South Africa. +27 031-260-4321. 47 48 Bonga Chiliza, [email protected], Discipline of Psychiatry, Nelson R Mandela 49 School of Medicine, University of KwaZulu-Natal, Durban, South Africa.

50 http://bmjopen.bmj.com/ 51 52 Saeeda Paruk, [email protected], Discipline of Psychiatry, Nelson R Mandela 53 School of Medicine, University of KwaZulu-Natal, Durban, South Africa. +27 031-260- 54 4321. 55 56 Authors’ contributions 57 UC, VN, TN and SP conceived the study. UC, VN will collect data. AT performed the 58 statistical analysis. SP and BC supervised the work undertaken. All authors have read and on September 30, 2021 by guest. Protected copyright. 59 60 approved the final manuscript.

Funding statement This study is funded by National Research Foundation of South Africa (Grant #: 117858) and the Society for Biological Psychiatry Research Fund. Funding (Grant #: N/A) was also received from University of KwaZulu-Natal College of Health Sciences PhD Scholarship (Grant #: N/A). The opinions and findings presented are those of the authors and not a reflection of the funders.

Competing interests None declared.

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1 2 3 Investigating the impact of HIV on patients with first episode psychosis: a study 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 protocol for a longitudinal cohort study 6 7 8 ABSTRACT 9 10 Introduction: South Africa has a high HIV prevalence and limited mental health care 11 12 resources. Neuropsychiatric complications such as psychosis onset in people living with HIV 13 14 (PLWHIV) remains poorly understood. The study aims to compare the socio-demographic, 15 clinical, substance use, cognitive and trauma profile of PLWHIV presenting with first episode 16 17 psychosis (FEP) to those with the condition but without HIV. 18 For peer review only 19 20 21 Methods and Analysis: This study will compare presentation, course, and outcome of a 22 cohort of PLWHIV and FEP with a control group recruited over a 3-year period. We will 23 24 prospectively test the hypothesis that the 2 groups are socio-demographically, clinically and 25 26 cognitively distinct at illness presentation, with higher trauma burden and poorer outcomes in 27 those with the dual burden of HIV and FEP. FEP participants, confirmed by a structured 28 29 neuropsychiatric interview, will have their socio-demographic, psychosis, mood, motor, 30 31 trauma, and substance use variables assessed. A neuropsychological battery will be 32 33 completed to assess cognition, while quality of life, psychotic symptoms and HIV markers 34 will be measured at 3, 6 and 12 months. 35

36 http://bmjopen.bmj.com/ 37 38 Ethics and dissemination: The study protocol has been reviewed and ethics approval 39 40 obtained from the Biomedical Research Ethics Committee (BC 571/18) of the University of 41 KwaZulu-Natal. The results from this investigation will be actively disseminated through 42 43 peer-reviewed journal publications and conference presentations.

44 on September 30, 2021 by guest. Protected copyright. 45 46 Keywords: Mental Health; HIV; Psychosis; Africa. 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2

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1 2 3 Strengths and limitations of this study 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5  The study may provide valuable insight into the long-term impact of HIV infection on 6 psychosis presentation which is poorly understood in low- and middle-income 7 8 countries. 9  Extensive neuropsychological assessments will be undertaken. 10 11  Randomized controlled trial (RCT) design is not possible given that study monitors 12 disease progression. 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35

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44 on September 30, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 3

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1 2 3 INTRODUCTION 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 Psychiatric illness in the presence of Human Immunodeficiency virus (HIV) and Acquired 6 7 Immunodeficiency Syndrome (AIDS) has been linked to negative health behaviours and 8 poorer clinical outcomes[1]. The prevalence of HIV among those with serious mental illness 9 10 (SMI) ranges from 1 to 24%[2] . Left untreated, mental disorders in people living with HIV 11 12 (PLWHIV) result in poorer quality of life, greater interpersonal difficulties, increased suicide 13 14 risk and poor adherence to antiretroviral therapy. 15 16 17 Psychotic disorders are associated with a significant burden of disease, with affected persons 18 For peer review only 19 often relying on limited public sector mental health resources in low- and middle-income 20 21 countries (LMICs)[3]. There is a lack of research on HIV and psychosis in LMICs, 22 particularly sub-Saharan Africa (SSA), despite this region accounting for more than two- 23 24 thirds of the world’s HIV-positive population[4]. While research from high-income countries 25 26 has demonstrated that there is a bi-directional relationship between HIV/AIDS and mental 27 illness, there may be differences in the way this relationship is expressed in SSA[5]. Studies 28 29 have also shown variations in the socio-demographic and clinical profile of those with dual 30 31 burden of HIV and first episode psychosis compared to those with psychosis only[6]. 32 33 34 Socio-demographic profile of PLWHIV and first episode psychosis 35

36 There is limited literature on the association of HIV and first episode psychosis (FEP), with http://bmjopen.bmj.com/ 37 38 previous studies mainly describing HIV prevalence rates or clinical profiles[7]. A Ugandan 39 40 study by Lundberg and colleagues[8] found that HIV positive patients with mental illness 41 were more likely to be females and older (40-49 years). A KwaZulu-Natal (KZN) Province, 42 43 SA, study of patients with FEP reported a higher HIV prevalence in less educated individuals,

44 on September 30, 2021 by guest. Protected copyright. 45 however, this was a small sample[7]. In a more recent chart review of patients with psychosis 46 admitted to a psychiatric hospital in SA, HIV-infected patients with psychotic disorders were 47 48 more likely to be female (74.0%), younger than 50 years (94.0%) and less likely to have 49 50 secondary education than HIV-negative patients with psychotic disorders (56.0% vs. 51 52 72.0%)[9]. 53 54 55 PLWHIV and psychosis symptomatology 56 57 In a review of the literature, grandiose, persecutory, and somatic delusions were the most 58 common psychotic symptoms, followed by hallucinations and mood symptoms in PLWHIV 59 60 4

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1 2 3 with FEP[10]. An Italian study found that HIV infection increased the severity of symptoms 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 (more frequently paranoid delusions), was associated with a greater impairment in attention 6 7 and concentration, and had decreased depressive symptoms[6]. In addition, PLWHIV and 8 psychosis are more likely to be diagnosed as having a psychosis secondary to another medical 9 10 condition than a primary psychotic disorder, have more comorbid medical disorders and 11 12 increased haematological test abnormalities[9]. However, there is extremely limited literature 13 14 on HIV and psychosis symptomatology, particularly from Africa[7,11]. This suggests a hiatus 15 in the current literature on understanding the nature and severity of psychotic symptoms in 16 17 PLWHIV, particularly in the African context. There is a need for systematic studies of larger 18 For peer review only 19 cohorts with standardised tools to better understand how HIV may potentially influence 20 21 psychosis presentation and course, as well as HIV disease outcomes. 22 23 24 PLWHIV and FEP and cognition 25 26 Cognitive impairment is well established in both psychotic disorders and HIV infection, 27 being exacerbated in psychotic patients with HIV[11]. Being HIV positive is traditionally 28 29 associated with a sub-cortical cognitive impairment, the prevalence of cognitive deficits 30 31 being reported to range from 4% - 99% in a systematic review of HIV research in SSA[5]. 32 33 34 De Ronchi[6] described cognitive screen deficits in a sample of 22 FEP patients living with 35

36 HIV in Italy. Participants had impaired attention and concentration on the Mini Mental State http://bmjopen.bmj.com/ 37 38 Examination (MMSE) but no other differences on cognitive impairment. A study of cognitive 39 40 dysfunction among 156 HIV infected and 322 HIV non-infected patients with psychosis in 41 Uganda assessed them with the MMSE and a neuropsychological battery. They found that 42 43 PLWHIV and psychosis were more cognitively impaired than HIV negative psychotic

44 on September 30, 2021 by guest. Protected copyright. 45 patients at baseline, and although there was some improvement with treatment, they remained 46 more impaired at six months, suggesting that HIV worsened cognitive dysfunction in 47 48 psychosis[11]. While earlier studies have suggested that psychosis and impairment in 49 50 cognition were later manifestations of HIV, the Ugandan study demonstrated that both these 51 52 conditions occur early, as shown by the average CD4 count of 305 cell/uL and the 53 intermediate World Health Organization (WHO) staging of disease presentation. In addition, 54 55 impairment in cognition also remained, despite an improvement in the psychotic 56 57 symptoms[11]. Further research is warranted to establish the impact of HIV and psychosis on 58 59 60 5

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1 2 3 cognition, and whether HIV related cognitive changes are associated with increased risk for 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 psychosis or modifies psychosis onset or course. 6 7 8 PLWHIV and FEP and substance use 9 10 Studies traditionally suggest an association between substance use in FEP patients and HIV 11 12 infection[1]. A study of patients with FEP in KwaZulu-Natal (KZN), SA reported lower rates 13 14 of self-reported substance use among HIV positive then HIV negative patients with mental 15 illness[7], which was further supported by a retrospective chart review of patients with 16 17 psychosis[9]. This may suggest that either substance use/misuse may not be a significant 18 For peer review only 19 factor in HIV transmission in the KZN context, or that the study results were limited by 20 21 under-reporting or the small sample size. Thus, while the international literature suggests 22 that PLWHIV and mental illness may be vulnerable to substance use, this has not been borne 23 24 out in the local KZN studies, and warrants further research. 25 26 27 PLWHIV and FEP and Trauma 28 29 30 Trauma, particularly early life trauma, is also recognised as an environmental risk factor for 31 psychosis[12]. A South African study investigated the association between a history of 32 33 traumatic experiences and the clinical features of FEP. Duration of untreated psychosis, age 34 35 of and symptoms at onset were assessed in 54 psychotic patients, while 22% were HIV

36 infected. Almost half of the study subjects had witnessed (49%) or directly experienced http://bmjopen.bmj.com/ 37 38 serious physical assault (45%), both events being associated with positive psychotic 39 40 symptoms[13]. 41 42 43 The trauma experienced may influence psychosis and HIV outcomes, as found in a

44 on September 30, 2021 by guest. Protected copyright. 45 systematic review, that hallucinations and delusions were more severe in people with a 46 47 history of childhood trauma[14]. In addition, Leserman[15] reported on the negative 48 49 association of HIV, stress, and depression on the course of HIV in terms of decreasing the 50 CD4 lymphocytes, increasing the viral load and having greater risk for premature mortality. 51 52 53 54 Course of comorbid HIV and psychosis 55 PLWHIV and psychosis are more likely to develop comorbid medical disorders, experience 56 57 side effects of antipsychotic medication, develop metabolic syndrome secondary to ART, 58 59 have longer length of hospital stay and readmission rates, and poorer quality of life[1,9]. 60 6

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1 2 3 However, this has not been tested prospectively in the FEP patients in the African context 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 with the recent wide availability of ART. 6 7 8 Aims 9 10 The aim of the study is to investigate trends in clinical, substance use, cognitive and trauma 11 12 presentations in individuals experiencing first episode psychosis (FEP) over time, and to 13 14 compare presentation, course and 12-month outcomes between those with and without HIV. 15 16 17 METHODS 18 For peer review only 19 Patients referred to the participating psychiatry units will be screened by the respective 20 21 treating doctors for eligibility for recruitment into the study. The patients with first episode of 22 psychosis must fulfil the inclusion criteria and will be referred to the designated investigator 23 24 at each unit. Once written informed consent has been obtained, the protocol for data capture 25 26 will be followed, as per the list outlined in Table 1 and Figure 1, the same protocol being 27 followed for out- and in-patients. The clinical examination and psychiatric tests, which take 28 29 approximately two hours, will be undertaken by the investigators who are all medical 30 31 practitioners. Patient baseline assessments will be undertaken within six weeks of treatment 32 33 during their outpatient visit or following admission to the respective units at baseline. A 34 physical examination, body mass index and waist circumference measure will also be 35

36 obtained by a medical practitioner. Where possible, collateral information from a next of kin, http://bmjopen.bmj.com/ 37 38 with the participant’s consent, will also be sought. The follow-up visits will be done at three, 39 40 six and 12 months as outpatients, and the participants will be reimbursed for travel costs. 41 Attempts will be made to coincide each of these with scheduled clinic follow-up visits and 42 43 will be performed by the same initial interviewer at each psychiatry outpatient department.

44 on September 30, 2021 by guest. Protected copyright. 45 46 The cognitive battery assessment, which takes approximately 2 hours, will be administered 47 48 by a clinical psychologist, at the three- and 12-month visits. Translation services will also be 49 50 available for patients who require isiZulu translation during the interviews. 51 52 53 Following collating the data for steps 1-13 in Figure 1 and Table 2, we will perform steps 14 54 55 and 15 after voluntary counselling and testing. The required HIV tests, CD4 count and viral 56 57 load if HIV positive, as per the protocol, will be taken by a medical practitioner at each site. 58 59 60 7

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1 2 3 Other investigations, such as lipid profile, which are part of routine care, will be captured 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 from the clinical records. 6 7 8 Study design and setting 9 10 The comparative cohort study will be in keeping with a quantitative, descriptive and 11 12 longitudinal 12-month design of adult patients presenting with FEP that are either HIV 13 14 infected or non-infected. The study will take place in the eThekwini District, one of 11 in 15 KZN Province, with an estimated population of 3,442,361 people. The district has a high HIV 16 17 burden, with an estimated 650 000 people living with the virus in 2018[16]. In addition, there 18 For peer review only 19 are only five hospitals in the municipality with psychiatric services managed by a 20 21 psychiatrist, at which the study will be conducted. The hospitals selected are the four general 22 hospitals with specialist psychiatric services situated in eThekwini: Addington, King Edward 23 24 VIII, Prince Mshiyeni and RK Khan Hospitals, and at King DinuZulu Hospital, which serves 25 26 as the psychiatric hospital for the area. All hospitals have in- and out-patient psychiatric 27 services and receive referrals from within the district as well as from urban and rural areas as 28 29 far south as the Eastern Cape Province and northern KZN. 30 31 32 33 Male and female patients will be included if they are in or out-patients, aged 18-45 years, 34 have a first presentation to mental health care services for FEP meeting Diagnostic and 35

36 Statistical Manual (DSM)-V criteria[17] (American Psychiatric Association (APA) 2013) for http://bmjopen.bmj.com/ 37 38 a psychotic disorder, are neuroleptic naïve or minimally treated (maximum 6 weeks of 39 40 psychotropic treatment in this first episode), and provide consent to participate. 41 42 43 Patients will be excluded if they have been prescribed antipsychotics in the past or have had

44 on September 30, 2021 by guest. Protected copyright. 45 previous psychotic episode, an intellectual disability (assessed clinically or by chart review) 46 or other significant general medical conditions that maybe associated with FEP e.g. epilepsy 47 48 or syphilis, have less than seven years of formal schooling and refuse consent. 49 50 51 52 Participant selection and sampling strategy 53 All adult in-or out patients with FEP meeting the inclusion criteria will be recruited to the 54 55 study over a 3-year period. The sample size calculation was based on a log rank test group. In 56 57 order to achieve an 80% power to detect an odds ratio of 1.857 (to maximise variability) in a 58 design with three repeated measurements having a compound symmetry covariance structure 59 60 8

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1 2 3 when the proportion from group 2 is 0.500, the correlation between observations on the same 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 subject is 0.500, and the alpha (significance) level 0.05 or 5%. In addition, to allow for and 6 7 give an expected 36-month accrual, a minimum follow-up of 12 months, and a 10% dropout 8 rate, a sample of 130 PLWHIV and FEP and 130 HIV negative with FEP will be required. 9 10 11 12 Data collection 13 14 The study will utilize a clinical interview, physical examination, several psychiatric tools, and 15 HIV related haematological tests to measure variables. Baseline measures will be done within 16 17 six weeks of first presentation and as soon as the participant is able to consent. Participants 18 For peer review only 19 need to have responded to antipsychotic medication and will be assessed to have the capacity 20 21 to consent by a treating and research doctor. The study (HIV+) and control groups (HIV-) 22 will receive the same baseline assessments and follow-up at three, six and 12 months, which 23 24 are summarised in Table 1. The HIV negative group will have HIV testing at each visit to re- 25 26 confirm HIV status. The study procedures that will be followed are shown in the information 27 box 1. Data will be collected manually and captured electronically. 28 29 30 31 Clinical researchers with a medical background will administer the mental health diagnostic - 32 33 assessment, the MINI 7.02, Psychotic Disorders version, DSM-V[18] and diagnostic 34 interview face-to-face, and will be supported by a trained research assistant who will 35

36 facilitate the self-report questionnaires. A medical doctor will conduct the clinical http://bmjopen.bmj.com/ 37 38 assessments, collect the biological specimens (Table 1), and conduct the HIV counselling and 39 40 testing. We will use an HIV COBAS COMBI test to detect both HIV antibodies and p24 41 antigen. Standard pre-test and post-test counselling will be delivered in a culturally sensitive 42 43 manner, while the CD4 count and viral loads will be measured at every visit among

44 on September 30, 2021 by guest. Protected copyright. 45 PLWHIV. 46 47 48 Participants will be given a return research appointment date and telephonic contact will be 49 50 maintained between interviews. The study team (research assistant and clinician) will contact 51 52 participants to remind them of appointments to limit their withdrawing from the study. For 53 participants who do not arrive for their appointments, the research assistant will contact the 54 55 patient to reschedule an appointment in the same week. 56 57 58 59 60 9

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1 2 3 Data management and analysis 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 All participants will be allocated a participant identification number (PID) code at enrolment, 6 7 which will be used on samples and documents over the 12-month study period. Data will be 8 downloaded to a secure server and kept in a password-protected system. Laboratory results 9 10 will be merged into the main dataset using the unique PID. 11 12 13 14 Data was will be entered into SPSS version 24 and the analyses conducted using STATA 15. 15 The socio-demographic and clinical characteristics of participants will be summarized using 16 17 means (and standard deviation (SD) continuous variables. For categorical variables, 18 For peer review only 19 proportion (%) will be reported. Significant associations in contingency tables (cross 20 2 21 tabulations) will be assessed using the standard Pearson’s chi-square (χ ) test. An 22 independent samples t-test will be used for comparing differences in continuous variables 23 24 between two groups. If there are more than three groups, we will utilise ANOVA methods. A 25 26 p-value less than 0.05 will be regarded as statistically significant. 27 28 29 Patient and public involvement 30 31 No patients or members of the public were involved in the design, analysis or reporting of 32 33 this current investigation. 34 35

36 Ethics and dissemination http://bmjopen.bmj.com/ 37 38 Ethical approval to conduct the study was obtained from the Biomedical Research Ethics 39 40 Committee of the University of KwaZulu-Natal (UKZN). The study will be conducted in 41 accordance with South African Department of Health Research Ethics guidelines (2015) as 42 43 well as the UKZN policy on Research Ethics. Recruitment of study participants will

44 on September 30, 2021 by guest. Protected copyright. 45 commence as full ethics approval was received from Biomedical Research Ethics Committee. 46 No other independent ethics review was required. 47 48 49 50 All participants fulfilling the inclusion criteria will be selected for the study, from whom 51 52 written, informed consent will be obtained. All potential participants will have the 53 opportunity to participate, which will be made known to them in the information sheet. 54 55 Where participants are unable to consent independently, adequate steps will be taken to 56 57 ensure that legally acceptable proxy consent is obtained. All participants testing HIV positive 58 at any point in the study will be referred for ART and support. 59 60 10

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1 2 3

4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 The results from this investigation will be actively disseminated through peer-reviewed 6 7 journal publications and conference presentations. Upon completion of the peer-review 8 process, we will provide feedback to clinicians at Department of Health for further discussion 9 10 about enhanced treatment algorithm. 11 12 13 14 DISCUSSION 15 Potential risks 16 17 There will be minimal risk or discomfort to participants, with one test requiring bloods to be 18 For peer review only 19 taken. The only active involvement of the participants is for them to provide verbal responses 20 21 to assessment interviews and scales utilized for data collection. We acknowledge the 22 potential risk of psychological distress to patients, as they may be directly affected by 23 24 sensitive questions e.g. relating to trauma during the administration of the psychiatric scales. 25 26 The study has a distress plan to support such patients, which entails referral to treating team if 27 there is concern about relapse or danger to self or others. 28 29 30 31 Methodological challenges and study limitations 32 33 Several limitations may affect the study, including that it is hospital-based, which may 34 introduce sample bias and limit the generalizability to community samples. Another 35

36 limitation is the use of tools that have limited validity in the local South African context, as http://bmjopen.bmj.com/ 37 38 they have not been used previously. Language and cultural barriers in communication will be 39 40 addressed by an available isiZulu translator. A further limitation of the observational nature 41 of the study is the attendant lack of standardisation of treatment, for which will follow the 42 43 Essential Drug List (EDL) for hospital level adults (Department of Health, 2015). Although

44 on September 30, 2021 by guest. Protected copyright. 45 patients will follow the same algorithm, they may be maintained on different medication, 46 depending on the individual patient treatment response. The study will however provide an 47 48 adequate sample representing the clinical profile of patients with FEP and LWHIV in a 49 50 resource-constrained setting. 51 52 53 Study progress and challenges 54 55 A challenge we anticipate is the loss of participant follow-up, which is generally a common 56 57 failing in managing psychiatric patients, particularly in LMIC settings with challenging 58 psychosocial circumstances. The three-, six- and 12-month follow-up appointments may 59 60 11

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1 2 3 remain difficult to sustain, despite supporting participants with travel costs for visits. 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 Maintaining follow-up visits is a challenge we anticipated and for which we have a 6 7 contingency strategy, this being that a research assistant will have regular communication 8 with the recruited participants, confirming appointment dates, sending reminders, and 9 10 facilitating travel arrangements. Participants seroconverting to HIV positive status during the 11 12 study will be referred to antiretroviral services for care but continue follow-up assessments, 13 14 noting the change in their HIV status. 15 16 17 Study Significance 18 For peer review only 19 We postulate that the course and outcome of HIV psychosis differs from that in an HIV 20 21 negative individual, and that this study may provide valuable insight into the impact of HIV 22 infection on psychosis presentation and outcomes. Longitudinal comparative cohort studies 23 24 of this nature are limited and have not been conducted locally in one of the highest HIV 25 26 prevalence settings in Africa, hence the data will serve to introduce new knowledge on the 27 topic, as well as form the baseline for future research and treatment. A clearer understanding 28 29 of the association between HIV and psychosis may provide better insight into HIV as a 30 31 neurotropic virus. The findings of this study will contribute towards improving the care and 32 33 management of patients with FEP and HIV. 34 35

36 The World Health Organization reports that in 2020, psychiatric conditions are ranked the http://bmjopen.bmj.com/ 37 38 second leading cause of global disease burden after ischemic heart disease[19]. In the South 39 40 African context, this is even more pronounced by the additional burden of HIV infection and 41 AIDS. With an approximate overall HIV prevalence rate of 11.2% (6.19 million) and an 42 43 estimated 16.6% of the population (adults aged 15-49 years) being HIV positive, South

44 on September 30, 2021 by guest. Protected copyright. 45 Africa is in urgent need of interventions to address the related adverse consequences. 46 Psychotic disorders are associated with a significant burden of disease and often utilize the 47 48 limited mental health resources. Understanding the association between HIV and psychosis in 49 50 the era of antiretroviral treatment is thus an urgent priority. Utilizing the HIV psychosis as a 51 52 potential model for schizophrenia may also improve our understanding of its neurobiology. 53 The new knowledge, generated through this novel study, will enable an understanding of the 54 55 interplay between HIV and psychosis at a fundamental level, centred at the international 56 57 epicentre of the HIV pandemic. 58 59 60 12

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1 2 3 In addition, in South Africa, substance use and trauma remain critical public health 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 challenges that need to be further explored. Thus, the study of the bidirectional associations 6 7 between HIV, substance use and traumatic experiences, psychosis onset and presentation in a 8 low- and middle-income setting is essential to better guide the strategic use of their limited 9 10 resources. Early insights into the role of substance use and trauma in HIV infection and 11 12 psychosis onset could be used to delay, modify, or even prevent the onset of HIV psychosis. 13 14 Furthermore, the interplay of these extraneous factors in genetically predisposed individuals 15 has not been explored. This study will allow us to begin to understand the contribution of 16 17 HIV to psychosis onset, increase awareness of the need for screening and care in a highly 18 For peer review only 19 vulnerable group, while building research capacity. 20 21 22 The results of this study will contribute to the development of management (investigation and 23 24 treatment) algorithms in the South African resource constrained health departments. 25 26 Reference will be made to the differences identified between the HIV positive and HIV 27 negative groups, facilitating appropriate tailored approaches to each sub-group. The benefits 28 29 of these would include policy changes and streamlined cost-effective treatment plans that will 30 31 be equally beneficial to patient and the health department. 32 33 34 Legend for Figure 1 35

36 List of all study procedures utilised in the patient assessment http://bmjopen.bmj.com/ 37 38 39 40 41 42 43

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1 2 3 REFERENCES 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 6 1. Subedi S, Chalise P, Aich T, Thapa D. Psychiatric co-morbidity in HIV/AIDS: A 7 neglected issue. Journal of Psychiatrists' Association of Nepal. 2013;2(2):6-10. 8 9 10 2. De Hert M, Cohen D, Bobes J, Cetkovich-Bakmas M, Leucht S, Ndetei DM, et al. 11 Physical illness in patients with severe mental disorders. II. Barriers to care, monitoring 12 13 and treatment guidelines, plus recommendations at the system and individual level. World 14 Psychiatry. 2011;10(2):138-51. 15 16 17 3. Wainberg ML, Scorza P, Shultz JM, Helpman L, Mootz JJ, Johnson KA, et al. Challenges 18 and OpportunitiesFor in Global peer Mental Health: review A Research-to-Practice only Perspective. Curr 19 Psychiatry Rep. 2017;19(5):28-. 20 21 22 4. Shao Y, Williamson C. The HIV-1 epidemic: low-to middle-income countries. Cold 23 Spring Harbor perspectives in medicine. 2012;2(3):a007187. 24 25 26 5. Breuer E, Myer L, Struthers H, Joska JA. HIV/AIDS and mental health research in sub- 27 Saharan Africa: a systematic review. African Journal of AIDS Research. 2011;10(2):101- 28 22. 29 30 31 6. De Ronchi D, Bellini F, Cremante G, Ujkaj M, Tarricone I, Selleri R, et al. 32 Psychopathology of first-episode psychosis in HIV-positive persons in comparison to first- 33 34 episode schizophrenia: A neglected issue. AIDS Care. 2006;18(8):872-8. 35

36 7. Mashaphu S, Mkize D. HIV seropositivity in patients with first-episode psychosis. South http://bmjopen.bmj.com/ 37 38 African Journal of Psychiatry. 2007;13(3):90-4. 39 40 8. Lundberg P, Nakasujja N, Musisi S, Thorson AE, Cantor-Graae E, Allebeck P. HIV 41 42 prevalence in persons with severe mental illness in Uganda: a cross-sectional hospital- 43 based study. International journal of mental health systems. 2013;7(1):20.

44 on September 30, 2021 by guest. Protected copyright. 45 46 9. Mere SM, Paruk S. Chart review of human immunodeficiency virus status in patients 47 admitted with psychosis in Durban, South Africa. South African Journal of Psychiatry. 48 2018;24. doi: 10.4102/sajpsychiatry.v24i0.1129 49 50 51 10. Dolder CR, Patterson TL, Jeste DV. HIV, psychosis and aging: past, present and future. 52 AIDS. 2004;18:35-42. 53 54 55 11. Nakasujja N, Allebeck P, Agren H, Musisi S, Katabira E. Cognitive dysfunction among 56 HIV positive and HIV negative patients with psychosis in Uganda. PLoS One. 2012;7(9): 57 58 e44415. 59 60 14

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1 2 3

4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 12. Bendall S, Jackson HJ, Hulbert CA, McGorry PD. Childhood Trauma and Psychotic 6 Disorders: a Systematic, Critical Review of the Evidence. Schizophrenia Bulletin. 7 2007;34(3):568-79. 8 9 10 13. Burns JK, Jhazbhay K, Esterhuizen T, Emsley R. Exposure to trauma and the clinical 11 presentation of first-episode psychosis in South Africa. Journal of Psychiatric Research. 12 13 2011;45(2):179-84. 14 15 14. Bailey T, Alvarez-Jimenez M, Garcia-Sanchez AM, Hulbert C, Barlow E, Bendall S. 16 17 Childhood Trauma Is Associated with Severity of Hallucinations and Delusions in 18 Psychotic Disorders:For A Systematicpeer Reviewreview and Meta-Analysis. only Schizophrenia Bulletin. 19 2018;44(5):1111-22. 20 21 22 15. Leserman J. Role of Depression, Stress, and Trauma in HIV Disease Progression. 23 Psychosomatic Medicine. 2008;70(5):539-45. 24 25 26 16. Ethekwini district AIDS council quarter 1, 2017/2018 report 27 28 17. American Psychiatric Association. Diagnostic and Statistical Manual of Mental 29 Disorders. Fifth Edition American Psychiatric Association; Washington, DC: 2013. 30 31 32 18. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The Mini- 33 International Neuropsychiatric Interview (M.I.N.I): The development and validation of a 34 structured diagnostic psychiatric interview for DSM-IV and ICD-10. The Journal of 35 Clinical Psychiatry. 1998;59(Suppl 20):22-33.

36 http://bmjopen.bmj.com/ 37 38 19. Murray CJ, Lopez AD, Organization WH. The global burden of disease: a 39 40 comprehensive assessment of mortality and disability from diseases, injuries, and risk 41 factors in 1990 and projected to 2020: summary: World Health Organization; 1996. 42 43 20. Bernstein DP, Stein JA, Newcomb MD, Walker E, Pogge D, Ahluvalia T, et al.

44 Development and validation of a brief screening version of the Childhood Trauma on September 30, 2021 by guest. Protected copyright. 45 46 Questionnaire. Child abuse & neglect. 2003;27(2):169-90. 47 48 21. Chouinard G, Margolese HC. Manual for the Extrapyramidal Symptom Rating Scale 49 50 (ESRS). Schizophrenia Research. 2005;76(2):247-65. 51 52 22. WHOQOL Group. Development of the World Health Organization WHOQOL- quality 53 54 of life assessment. Psychological medicine. 1998;28(3):551-8. 55 56 23. WHO ASSIST Working Group. The alcohol, smoking and substance involvement 57 58 screening test (ASSIST): development, reliability and feasibility. Addiction. 59 2002;97(9):1183-94. 60 15

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1 2 3 24. Joska JA, Witten J, Thomas KG, Robertson C, Casson-Crook M, Roosa H, et al. A 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 Comparison of Five Brief Screening Tools for HIV-Associated Neurocognitive 6 Disorders in the USA and South Africa. AIDS Behav. 2016;20(8):1621-31. 7 8 9 25. Kay SR, Fiszbein A, Opler LA. The Positive and Negative Syndrome Scale (PANSS) for 10 Schizophrenia. Schizophrenia Bulletin. 1987;13(2):261-76. 11 12 13 26. Kroenke K, Spitzer RL, Williams JB. The PHQ‐9: validity of a brief depression severity 14 measure. Journal of general internal medicine. 2001;16(9):606-13. 15 16 17 27. Sacktor NC, Wong M, Nakasujja N, Skolasky RL, Selnes OA, Musisi S, et al. The 18 International HIVFor Dementia peer Scale: areview new rapid screening only test for HIV dementia. AIDS. 19 2005;19(13):1367-74. 20 21 22 28. Weathers FW, Litz BT, Keane TM, Palmieri PA, Marx BP, Schnurr PP. The ptsd 23 checklist for DSM-V-5 (pcl-5). Scale available from the National Center for PTSD at 24 www ptsd va gov. 2013;10. 25 26 27 29. World Health Organization. Pathways of patients with mental disorders: A multi-centre 28 collaborative project. World Health Organization; 1987. 29 30 31 32 33 34 35

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1 2 3 Authors’ Contributions 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 UC, VN, TN and SP conceived the study. UC, VN will collect data. AT performed the 6 7 statistical analysis. SP and BC supervised the work undertaken. UC wrote the first draft. All 8 authors have read and approved the final manuscript. 9 10 11 12 Funding 13 14 This study is funded by National Research Foundation of South Africa (Grant #: 117858) and 15 the Society for Biological Psychiatry Research Fund. Funding (Grant #: N/A) was also 16 17 received from University of KwaZulu-Natal College of Health Sciences PhD Scholarship 18 For peer review only 19 (Grant #: N/A). The opinions and findings presented are those of the authors and not a 20 21 reflection of the funders 22 23 24 Competing interests 25 26 None declared. 27 28 29 30 31 32 33 34 35

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44 on September 30, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 17

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1 2 3 Table 1. 4 5 Objectives and measures used at each visit in HIV infected and non-infected participants 6 7 Visit 1 Visit 2 & 3 Visit 4 Domain Measures Source of measures/tool 8 Within first 6 weeks At 3 and 6 months At 12 months 9 10 Demographic factors Socio-demographic data Socio-demographic questionnaire X

11 Psychosis Psychiatric history andhttp://bmjopen.bmj.com/ MINI X 12 DUP & pathways to care WHO Encounter X 13 For peer review only 14 Severity and nature of psychosis symptoms PANSS X X X 15 Depression PHQ9 X X X 16 Trauma CTQ X 17 18 PCL X

19 on September 30, 2021 by guest. Protected copyright. Mental health outcome (Objective #1) PTSD Clinician administered PTSD scale for DSM-V (CAPS 5) X 20 Motor symptoms ESRS X X X 21 22 HIV associated cognitive deficit screen CAT-Rapid and IHDS X X X 23 Social cognition Neuropsychological battery X (at 3 months only) X 24 Substance use WHO ASSIST X X X 25 26 Quality of life WHO-QOL BREF X X X 27 From Hospital Records: Full blood count, liver Function test, syphilis and Biochemical haematological and radiological tests 28 Hepatitis test. Cerebrospinal fluid biochemistry and neuroimaging if available. 29 30 HIV status Confirmatory HIV ELISA 31 HIV marker VL if HIV positive If applicable If applicable If applicable 32 Clinical markers of HIV (Objective #2) 33 HIV marker CD4 if HIV positive X 34 35 18 36 37 38 39 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 20 of 20

1 2 3 Table 2. 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 Cognitive test battery and domains to be tested 6 7 Domains Test 8 Motor skills Pegboard, Grip strength 9 Visuospatial functioning WAIS R Block Design, Digit symbol, and 10 Rey-Osterrieth Rey Complex Figure (RCF) - Copy 11 12 Verbal Memory Rey Auditory Verbal Learning Test (RAVLT) 13 Non-Verbal Memory Rey-Osterrieth Rey Complex Figure (RCF) - Recall 14 Problem solving/Reasoning WAIS R Language test 15 Language Rey Auditory Verbal Learning Test (RAVLT) 16 Word generation Controlled Word Association Test (COWAT) 17 Animal Naming (Letter and category Cues) 18 For peer review only 19 Attention WAIS R Digit Span 20 Executive functioning Trail making, 21 Rey-Osterrieth Rey Complex Figure (RCF) 22 Wisconsin Card Sorting 23 Social cognition Emotion perception (Faces Test), 24 Theory of mind (Eyes Test), 25 26 Social knowledge (Situational Features Recognition Test) (SFRT) 27 28 29 30 31 32 33 34 35

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40 on September 30, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 215x368mm (200 x 200 DPI) 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from

Investigating the impact of HIV on patients with first episode psychosis: a study protocol for a longitudinal cohort study ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2020-046593.R1

Article Type: Protocol

Date Submitted by the 29-Mar-2021 Author:

Primary Subject Mental health Heading:

Secondary Subject Heading: HIV/AIDS http://bmjopen.bmj.com/

Schizophrenia & psychotic disorders < PSYCHIATRY, HIV & AIDS < Keywords: INFECTIOUS DISEASES, MENTAL HEALTH

on September 30, 2021 by guest. Protected copyright.

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1 2 3 Investigating the impact of HIV on patients with first episode psychosis: a study 4 protocol for a longitudinal cohort study BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 6 1 1 2,3 4 7 Usha Chhagan , Vuyokazi Ntlantsana , Andrew Tomita , Thirusha Naidu , Bonginkosi 8 Chiliza1, Saeeda Paruk1 9 10 1 Discipline of Psychiatry, Nelson R Mandela School of Medicine, University of KwaZulu- 11 Natal, Durban, South Africa 12 13 2 14 KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), College of Health 15 Sciences, University of KwaZulu-Natal, Durban, South Africa 16 17 3 Centre for Rural Health, School of Nursing and Public Health, College of Health Sciences, 18 University of KwaZulu-Natal,For peer Durban, South review Africa only 19 20 4 21 Department of Behavioural Medicine, University of KwaZulu-Natal, Durban, South Africa 22 23 Corresponding author 24 Dr Usha Chhagan 25 26 Author affiliations 27 Usha Chhagan, [email protected], Discipline of Psychiatry, Nelson R Mandela School 28 29 of Medicine, University of KwaZulu-Natal, Durban, South Africa. +27 031-260-4321. 30 31 Vuyokazi Ntlantsana, [email protected], Discipline of Psychiatry, Nelson R Mandela 32 School of Medicine, University of KwaZulu-Natal, Durban, South Africa. +27 031-260-4321. 33 34 Andrew Tomita, [email protected], KwaZulu-Natal Research Innovation and Sequencing 35 Platform (KRISP), College of Health Sciences, University of KwaZulu-Natal, Durban, South

36 http://bmjopen.bmj.com/ 37 Africa. Centre for Rural Health, School of Nursing and Public Health, College of Health 38 Sciences, University of KwaZulu-Natal, Durban, South Africa. +27 031-260-4321. 39 40 Thirusha Naidu, [email protected], Department of Behavioural Medicine, University of 41 KwaZulu-Natal, Durban, South Africa. +27 031-260-4321. 42 43 Bonginkosi Chiliza, [email protected], Discipline of Psychiatry, Nelson R Mandela

44 on September 30, 2021 by guest. Protected copyright. 45 School of Medicine, University of KwaZulu-Natal, Durban, South Africa. 46 47 Saeeda Paruk, [email protected], Discipline of Psychiatry, Nelson R Mandela School 48 of Medicine, University of KwaZulu-Natal, Durban, South Africa. +27 031-260-4321. 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Investigating the impact of HIV on patients with first episode psychosis: a study 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 protocol for a longitudinal cohort study 6 7 8 ABSTRACT 9 10 Introduction: South Africa (SA) has a high HIV prevalence and limited mental health care 11 12 resources. Neuropsychiatric complications such as psychosis onset in people living with HIV 13 14 (PLWHIV) remains poorly understood. The study aims to compare the socio-demographic, 15 clinical, substance use, cognitive and trauma profile of PLWHIV presenting with first episode 16 17 psychosis (FEP) to those with the condition but without HIV. 18 For peer review only 19 20 21 Methods and Analysis: This study will compare presentation, course, and outcome of a 22 cohort of PLWHIV and FEP with a control group recruited over a 3-year period. We will 23 24 prospectively test the hypothesis that the 2 groups are socio-demographically, clinically and 25 26 cognitively distinct at illness presentation, with higher trauma burden and poorer outcomes in 27 those with the dual burden of HIV and FEP. FEP participants, confirmed by a structured 28 29 neuropsychiatric interview, will have their socio-demographic, psychosis, mood, motor, 30 31 trauma, and substance use variables assessed. A neuropsychological battery will be 32 33 completed to assess cognition, while quality of life, psychotic symptoms and HIV markers 34 will be measured at 3, 6 and 12 months. 35

44 on September 30, 2021 by guest. Protected copyright. 45 46 Keywords: Mental Health; HIV; Psychosis; Africa. 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Strengths and limitations of this study 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5  This study will be among the first to examine the interacting roles of HIV, substance 6 7 use and trauma in a FEP study in Africa. 8 9  The study may provide valuable insight into the long-term impact of HIV infection on 10 psychosis presentation which is poorly understood in low- and middle-income 11 12 countries (LMIC). 13 14  Findings from this study will contribute towards baseline data to guide future studies 15 16 of patients with FEP. 17  The study is hospitals-based, and this may introduce sample bias and limit 18 For peer review only 19 generalizability to community samples. 20 21  Randomized controlled trial (RCT) design is not possible given that study monitors 22 23 disease progression. 24 25 26 27 28 29 30 31 32 33 34 35

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1 2 3 INTRODUCTION 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 Psychiatric illness in the presence of Human Immunodeficiency virus (HIV) and Acquired 6 7 Immunodeficiency Syndrome (AIDS) has been linked to negative health behaviours and 8 poorer clinical outcomes[1]. The prevalence of HIV among those with serious mental illness 9 10 (SMI) ranges from 1 to 24%[2]. Left untreated, mental disorders in people living with HIV 11 12 (PLWHIV) result in poorer quality of life, greater interpersonal difficulties, increased suicide 13 14 risk and poor adherence to antiretroviral therapy. 15 16 17 Psychotic disorders are associated with a significant burden of disease, with affected persons 18 For peer review only 19 often relying on limited public sector mental health resources in LMICs[3]. There is a lack of 20 21 research on HIV and psychosis in LMICs, particularly sub-Saharan Africa (SSA), despite this 22 region accounting for more than two-thirds of the world’s HIV-positive population[4]. While 23 24 research from high-income countries has demonstrated that there is a bi-directional 25 26 relationship between HIV/AIDS and mental illness, there may be differences in the way this 27 relationship is expressed in SSA[5]. There is much needed cross-cultural insight into the 28 29 relationship between HIV/AIDS and psychosis. Culture may influence the patients’ 30 31 perception and experience of psychosis as well as the clinical presentation. This highlights 32 33 the need to explore the impact of culture on psychosis[6]. Studies have also shown variations 34 in the socio-demographic and clinical profile of those with dual burden of HIV and first 35

36 episode psychosis compared to those with psychosis only[7]. http://bmjopen.bmj.com/ 37 38 39 40 41 Socio-demographic profile of PLWHIV and first episode psychosis 42 43 There is limited literature on the association of HIV and FEP, with previous studies mainly

44 on September 30, 2021 by guest. Protected copyright. 45 describing HIV prevalence rates or clinical profiles[8]. A Ugandan study by Lundberg and 46 colleagues[9] found that HIV positive patients with mental illness were more likely to be 47 48 females and older (40-49 years). A KwaZulu-Natal (KZN) Province, SA, study of patients 49 50 with FEP reported a higher HIV prevalence in less educated individuals, however, this was a 51 52 small sample[8]. In a more recent chart review of patients with psychosis admitted to a 53 psychiatric hospital in SA, HIV-infected patients with psychotic disorders were more likely 54 55 to be female (74.0%), younger than 50 years (94.0%) and less likely to have secondary 56 57 education than HIV-negative patients with psychotic disorders (56.0% vs. 72.0%)[10]. 58 59 60

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1 2 3 PLWHIV and psychosis symptomatology 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 In a review of the literature, grandiose, persecutory, and somatic delusions were the most 6 7 common psychotic symptoms, followed by hallucinations and mood symptoms in PLWHIV 8 with FEP[11]. An Italian study found that HIV infection increased the severity of symptoms 9 10 (more frequently paranoid delusions), was associated with a greater impairment in attention 11 12 and concentration, and had decreased depressive symptoms[7]. In addition, PLWHIV and 13 14 psychosis are more likely to be diagnosed as having a psychosis secondary to another medical 15 condition than a primary psychotic disorder, have more comorbid medical disorders and 16 17 increased haematological test abnormalities[10]. A study in Gauteng province, SA, found that 18 For peer review only 19 amongst PLWHIV presenting to psychiatry services, 23 individuals were diagnosed with 20 21 psychosis due to another medical condition whilst only two were diagnosed with 22 schizophrenia[12]. However, there is extremely limited literature on HIV and psychosis 23 24 symptomatology, particularly from Africa[8,13]. This suggests a hiatus in the current 25 26 literature on understanding the nature and severity of psychotic symptoms in PLWHIV, 27 particularly in the African context. There is a need for systematic studies of larger cohorts 28 29 with standardised tools to better understand how HIV may potentially influence psychosis 30 31 presentation and course, as well as HIV disease outcomes. 32 33 34 PLWHIV and FEP and cognition 35

36 Cognitive impairment is well established in both psychotic disorders and HIV infection, http://bmjopen.bmj.com/ 37 38 being exacerbated in psychotic patients with HIV[13]. Being HIV positive is traditionally 39 40 associated with a sub-cortical cognitive impairment, the prevalence of cognitive deficits 41 being reported to range from 4% - 99% in a systematic review of HIV research in SSA[5]. 42 43

44 on September 30, 2021 by guest. Protected copyright. 45 De Ronchi[7] described cognitive screen deficits in a sample of 22 FEP patients living with 46 HIV in Italy. Participants had impaired attention and concentration on the Mini Mental State 47 48 Examination (MMSE) but no other differences on cognitive impairment. A study of cognitive 49 50 dysfunction among 156 HIV infected and 322 HIV non-infected patients with psychosis in 51 52 Uganda assessed them with the MMSE and a neuropsychological battery. They found that 53 PLWHIV and psychosis were more cognitively impaired than HIV negative psychotic 54 55 patients at baseline, and although there was some improvement with treatment, they remained 56 57 more impaired at six months, suggesting that HIV worsened cognitive dysfunction in 58 psychosis[13]. While earlier studies have suggested that psychosis and impairment in 59 60 cognition were later manifestations of HIV, the Ugandan study demonstrated that both these

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1 2 3 conditions occur early, as shown by the average CD4 count of 305 cell/uL and the 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 intermediate World Health Organization (WHO) staging of disease presentation. In addition, 6 7 impairment in cognition also remained, despite an improvement in the psychotic 8 symptoms[13]. Further research is warranted to establish the impact of HIV and psychosis on 9 10 cognition, and whether HIV related cognitive changes are associated with increased risk for 11 12 psychosis or modifies psychosis onset or course. 13 14 15 PLWHIV and FEP and substance use 16 17 Studies traditionally suggest an association between substance use in FEP patients and HIV 18 For peer review only 19 infection[1]. Substance use patterns vary across the different regions of SA. This may be 20 21 related to both ethnic and socio-economic differences[14]. Davis et al. confirmed both the 22 growing pattern of substance use as well as the trend of psychiatric comorbidity in KwaZulu- 23 24 Natal (KZN). The rates of substance use in this province were also significantly higher than 25 26 that reported in studies of the general population in SA[14]. Another study of patients with 27 FEP in KZN, SA, reported lower rates of self-reported substance use among HIV positive 28 29 then HIV negative patients with mental illness[8], which was further supported by a 30 31 retrospective chart review of patients with psychosis[10]. This may suggest that either 32 33 substance use/misuse may not be a significant factor in HIV transmission in the KZN context, 34 or that the study results were limited by under-reporting or the small sample size. Thus, 35

36 while the international literature suggests that PLWHIV and mental illness may be vulnerable http://bmjopen.bmj.com/ 37 38 to substance use, this has not been borne out in the local KZN studies, and warrants further 39 40 research. 41 42 43 PLWHIV and FEP and Trauma

44 on September 30, 2021 by guest. Protected copyright. 45 Trauma, particularly early life trauma, is also recognised as an environmental risk factor for 46 47 psychosis[15]. A South African study investigated the association between a history of 48 49 traumatic experiences and the clinical features of FEP. Duration of untreated psychosis, age 50 of and symptoms at onset were assessed in 54 psychotic patients, while 22% were HIV 51 52 infected. Almost half of the study subjects had witnessed (49%) or directly experienced 53 54 serious physical assault (45%), both events being associated with positive psychotic 55 symptoms[16]. 56 57 58 59 60

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1 2 3 The trauma experienced may influence psychosis and HIV outcomes, as found in a 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 systematic review, that hallucinations and delusions were more severe in people with a 6 7 history of childhood trauma[17]. In addition, Leserman[18] reported on the negative 8 association of HIV, stress, and depression on the course of HIV in terms of decreasing the 9 10 CD4 lymphocytes, increasing the viral load and having greater risk for premature mortality. 11 12 13 14 Exposure to violence and resultant trauma is of major public health concern. In SA, the 15 mortality rate secondary to violence was estimated at 73/100,000[19,20]. Whilst much 16 17 research on early trauma has been conducted in developed countries, there is a need to 18 For peer review only 19 examine the association of trauma and FEP in developing countries[19,20,21]. 20 21 22 Course of comorbid HIV and psychosis 23 24 PLWHIV and psychosis are more likely to develop comorbid medical disorders, experience 25 26 side effects of antipsychotic medication, develop metabolic syndrome secondary to ART, 27 have longer length of hospital stay and readmission rates, and poorer quality of life[1,10]. 28 29 However, this has not been tested prospectively in the FEP patients in the African context 30 31 with the recent wide availability of ART. 32 33 34 Aims 35

36 The aim of the study is to investigate trends in clinical, substance use, cognitive and trauma http://bmjopen.bmj.com/ 37 38 presentations in individuals experiencing first episode of psychosis over time, and to compare 39 40 presentation, course and 12-month outcomes between those with and without HIV. 41 42 43 METHODS

44 on September 30, 2021 by guest. Protected copyright. 45 Patients referred to the participating psychiatry units will be screened by the respective 46 treating doctors for eligibility for recruitment into the study. The patients with FEP must 47 48 fulfil the inclusion criteria and will be referred to the designated investigator at each unit. 49 50 Once written informed consent has been obtained, the protocol for data capture will be 51 52 followed, as per the list outlined in Table 1 and Figure 1, the same protocol being followed 53 for out- and in-patients. The clinical examination and psychiatric tests, which take 54 55 approximately two hours, will be undertaken by the investigators who are all medical 56 57 practitioners. Patient baseline assessments will be undertaken within six weeks of treatment 58 during their outpatient visit or following admission to the respective units at baseline. A 59 60 physical examination, body mass index and waist circumference measure will also be

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1 2 3 obtained by a medical practitioner. Where possible, collateral information from a next of kin, 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 with the participant’s consent, will also be sought. The follow-up visits will be done at three, 6 7 six and 12 months as outpatients, and the participants will be reimbursed for travel costs. 8 Attempts will be made to coincide each of these with scheduled clinic follow-up visits and 9 10 will be performed by the same initial interviewer at each psychiatry outpatient department. 11 12 13 14 The cognitive battery assessment, which takes approximately 2 hours, will be administered 15 by a clinical psychologist, at the three- and 12-month visits. Translation services will also be 16 17 available for patients who require isiZulu translation during the interviews. 18 For peer review only 19 20 21 Following collating the data for steps 1-13 in Figure 1 and Table 2 22 [22,23,24,25,26,27,28,29,30,31,32,33], we will perform steps 14 and 15 after voluntary 23 24 counselling and testing. The required HIV tests, CD4 count and viral load if HIV positive, as 25 26 per the protocol, will be taken by a medical practitioner at each site. HIV testing will be 27 carried out at baseline for all participants as well as at each visit for HIV negative 28 29 participants. A patient with a positive HIV test will be referred to the HIV clinic at the site for 30 31 further management. Other investigations, such as lipid profile, which are part of routine 32 33 care, will be captured from the clinical records. 34 35

36 We are keen to explore impact of pathways of care on sociodemographic and clinical http://bmjopen.bmj.com/ 37 38 variables. Rehabilitation programs are limited as many sites lack a multi- disciplinary team to 39 40 support this, however standard of care includes medication, supportive therapy, psycho- 41 education, referral to psychology if indicated, and management of comorbid substance use. 42 43

44 on September 30, 2021 by guest. Protected copyright. 45 Study design and setting 46 The comparative cohort study will be in keeping with a quantitative, descriptive and 47 48 longitudinal 12-month design of adult patients presenting with FEP that are either HIV 49 50 infected or non-infected. The study will take place in the eThekwini District, one of 11 in 51 52 KZN Province, with an estimated population of 3,442,361 people. The district has a high HIV 53 burden, with an estimated 650 000 people living with the virus in 2018[34]. In addition, there 54 55 are only five hospitals in the municipality with psychiatric services managed by a 56 57 psychiatrist, at which the study will be conducted. The hospitals selected are the four general 58 hospitals with specialist psychiatric services situated in eThekwini: Addington, King Edward 59 60 VIII, Prince Mshiyeni and RK Khan Hospitals, and at King Dinuzulu Hospital, which serves

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1 2 3 as the psychiatric hospital for the area. All hospitals have in- and out-patient psychiatric 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 services and receive referrals from within the district as well as from urban and rural areas as 6 7 far south as the Eastern Cape Province and northern KZN. 8 9 10 Eligibility criteria 11 12 Inclusion criteria 13 14 Male and female patients will be included if they are in or out-patients, aged 18-45 years, 15 have a first presentation to mental health care services for FEP meeting Diagnostic and 16 17 Statistical Manual (DSM)-V criteria[35] (American Psychiatric Association (APA) 2013) for 18 For peer review only 19 a psychotic disorder, are neuroleptic naïve or minimally treated (maximum 6 weeks of 20 21 psychotropic treatment in this first episode), and provide consent to participate. 22 23 24 Exclusion criteria 25 26 Patients will be excluded if they have been prescribed antipsychotics in the past or have had 27 previous psychotic episode, an intellectual disability (assessed clinically or by chart review) 28 29 or other significant general medical conditions that maybe associated with FEP e.g., epilepsy 30 31 or syphilis, have less than seven years of formal schooling and refuse consent. 32 33 34 Participant selection and sampling strategy 35

36 All adult in-or out patients with FEP meeting the inclusion criteria will be recruited to the http://bmjopen.bmj.com/ 37 38 study over a 3-year period. The sample size calculation was based on a log rank test group. In 39 40 order to achieve an 80% power to detect an odds ratio of 1.857 (to maximise variability), in a 41 design with three repeated measurements having a compound symmetry covariance structure 42 43 when the proportion from group 2 is 0.500, the correlation between observations on the same

44 on September 30, 2021 by guest. Protected copyright. 45 subject is 0.500, and the alpha (significance) level 0.05 or 5%, a sample of 130 PLWHIV and 46 FEP and 130 HIV negative with FEP will be required. In addition, this sample size accounts 47 48 for and permits a 10% dropout rate over an anticipated 36-month accrual with a minimum 49 50 follow-up of 12 months. 51 52 53 Data collection 54 55 The study will utilize a clinical interview, physical examination, several psychiatric tools, and 56 57 HIV related haematological tests to measure variables. Baseline measures will be done within 58 six weeks of first presentation and as soon as the participant is able to consent. Participants 59 60 need to have responded to antipsychotic medication and will be assessed to have the capacity

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1 2 3 to consent by a treating and research doctor. The study (HIV+) and control groups (HIV-) 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 will receive the same baseline assessments and follow-up at three, six and 12 months, which 6 7 are summarised in Table 1. The HIV negative group will have HIV testing at each visit to re- 8 confirm HIV status. The study procedures, with 9 10 instruments[36,37,38,39,40,41,42,43,44,45,46], that will be used are shown in the 11 12 information Figure 1. Data will be collected manually and captured electronically. 13 14 15 Clinical researchers with a medical background will administer the mental health diagnostic - 16 17 assessment, the MINI 7.02, Psychotic Disorders version, DSM-V[36] and diagnostic 18 For peer review only 19 interview face-to-face, and will be supported by a trained research assistant who will 20 21 facilitate the self-report questionnaires. All study personnel will be trained on initiation of the 22 study with an annual refresher training on the different tools by psychiatrists with research 23 24 and clinical experience. A medical doctor will conduct the clinical assessments, collect the 25 26 biological specimens (Table 1), and conduct the HIV counselling and testing. We will use an 27 HIV COBAS COMBI test to detect both HIV antibodies and p24 antigen. Standard pre-test 28 29 and post-test counselling will be delivered in a culturally sensitive manner, while the CD4 30 31 count and viral loads will be measured at every visit among PLWHIV. 32 33 34 Participants will be given a return research appointment date and telephonic contact will be 35

36 maintained between interviews. The study team (research assistant and clinician) will contact http://bmjopen.bmj.com/ 37 38 participants to remind them of appointments to limit their withdrawing from the study. For 39 40 participants who do not arrive for their appointments, the research assistant will contact the 41 patient to reschedule an appointment in the same week. 42 43

44 on September 30, 2021 by guest. Protected copyright. 45 Data management and analysis 46 All participants will be allocated a participant identification number (PID) code at enrolment, 47 48 which will be used on samples and documents over the 12-month study period. Data will be 49 50 downloaded to a secure server and kept in a password-protected system. Laboratory results 51 52 will be merged into the main dataset using the unique PID. 53 54 55 Data was will be entered into SPSS version 24 and the analyses conducted using STATA 15. 56 57 The socio-demographic and clinical characteristics of participants will be summarized using 58 means and standard deviation (SD) continuous variables. For categorical variables, 59 60 proportion (%) will be reported. Significant associations in contingency tables (cross

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1 2 3 tabulations) will be assessed using the standard Pearson’s chi-square (χ2) test. An 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 independent samples t-test will be used for comparing differences in continuous variables 6 7 between two groups. If there are more than three groups, we will utilise ANOVA methods. A 8 p-value less than 0.05 will be regarded as statistically significant. In addition, we may also 9 10 apply growth mixture modelling to observe whether subsets of individuals follow distinct 11 12 trajectories over time. 13 14 15 16 Patient and public involvement 17 No patients or members of the public were involved in the design, analysis or reporting of 18 For peer review only 19 this current investigation. 20 21 22 Ethics and dissemination 23 24 Ethical approval to conduct the study was obtained from the Biomedical Research Ethics 25 26 Committee of the University of KwaZulu-Natal (UKZN). The study will be conducted in 27 28 accordance with South African Department of Health Research Ethics guidelines (2015) as 29 well as the UKZN policy on Research Ethics. Recruitment of study participants will 30 31 commence as full ethics approval was received from Biomedical Research Ethics Committee. 32 33 No other independent ethics review was required. 34 35

36 All participants fulfilling the inclusion criteria will be selected for the study, from whom http://bmjopen.bmj.com/ 37 38 written, informed consent will be obtained. All potential participants will have the 39 40 opportunity to participate, which will be made known to them in the information sheet. 41 Where participants are unable to consent independently, adequate steps will be taken to 42 43 ensure that legally acceptable proxy consent is obtained. All participants testing HIV positive

44 on September 30, 2021 by guest. Protected copyright. 45 at any point in the study will be referred for ART and support. 46 47 48 The results from this investigation will be actively disseminated through peer-reviewed 49 50 journal publications and conference presentations. Upon completion of the peer-review 51 52 process, we will provide feedback to clinicians at Department of Health for further discussion 53 about enhanced treatment algorithm. 54 55 56 57 DISCUSSION 58 59 Potential risks 60

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1 2 3 There will be minimal risk or discomfort to participants, with one test requiring bloods to be 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 taken. The only active involvement of the participants is for them to provide verbal responses 6 7 to assessment interviews and scales utilized for data collection. We acknowledge the 8 potential risk of psychological distress to patients, as they may be directly affected by 9 10 sensitive questions e.g., relating to trauma during the administration of the psychiatric scales. 11 12 The study has a distress plan to support such patients, which entails referral to treating team if 13 14 there is concern about relapse or danger to self or others. The sites have specialist psychiatric 15 services, both inpatient and outpatient, with a team available to attend to any adverse event 16 17 that may arise during the interview process. 18 For peer review only 19 20 21 Methodological challenges and study limitations 22 Several limitations may affect the study, including that it is hospital-based, which may 23 24 introduce sample bias and limit the generalizability to community samples. Another 25 26 limitation is the use of tools that have limited validity in the local South African context, as 27 they have not been used previously. Language and cultural barriers in communication will be 28 29 addressed by an available isiZulu translator. A further limitation of the observational nature 30 31 of the study is the attendant lack of standardisation of treatment, for which will follow the 32 33 Essential Drug List (EDL) for hospital level adults (Department of Health, 2015). Although 34 patients will follow the same algorithm, they may be maintained on different medication, 35

36 depending on the individual patient treatment response. The study will however provide an http://bmjopen.bmj.com/ 37 38 adequate sample representing the clinical profile of patients with FEP and PLWHIV in a 39 40 resource-constrained setting. 41 42 43 Study progress and challenges

44 on September 30, 2021 by guest. Protected copyright. 45 A challenge we anticipate is the loss of participant follow-up, which is generally a common 46 failing in managing psychiatric patients, particularly in LMIC settings with challenging 47 48 psychosocial circumstances. The three-, six- and 12-month follow-up appointments may 49 50 remain difficult to sustain, despite supporting participants with travel costs for visits. 51 52 Maintaining follow-up visits is a challenge we anticipated and for which we have a 53 contingency strategy, this being that a research assistant will have regular communication 54 55 with the recruited participants, confirming appointment dates, sending reminders, and 56 57 facilitating travel arrangements. Participants seroconverting to HIV positive status during the 58 study will be referred to antiretroviral services for care but continue follow-up assessments, 59 60 noting the change in their HIV status.

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1 2 3 Study Significance 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 We postulate that the course and outcome of HIV psychosis differs from that in an HIV 6 7 negative individual, and that this study may provide valuable insight into the impact of HIV 8 infection on psychosis presentation and outcomes. Longitudinal comparative cohort studies 9 10 of this nature are limited and have not been conducted locally in one of the highest HIV 11 12 prevalence settings in Africa, hence the data will serve to introduce new knowledge on the 13 14 topic, as well as form the baseline for future research and treatment. A clearer understanding 15 of the association between HIV and psychosis may provide better insight into HIV as a 16 17 neurotropic virus. The findings of this study will contribute towards improving the care and 18 For peer review only 19 management of patients with FEP and HIV. 20 21 22 The World Health Organization reports that in 2020, psychiatric conditions are ranked the 23 24 second leading cause of global disease burden after ischemic heart disease[47]. In the South 25 26 African context, this is even more pronounced by the additional burden of HIV infection and 27 AIDS. With an approximate overall HIV prevalence rate of 11.2% (6.19 million) and an 28 29 estimated 16.6% of the population (adults aged 15-49 years) being HIV positive, SA is in 30 31 urgent need of interventions to address the related adverse consequences. Psychotic disorders 32 33 are associated with a significant burden of disease and often utilize the limited mental health 34 resources. Understanding the association between HIV and psychosis in the era of 35

36 antiretroviral treatment is thus an urgent priority. Utilizing the HIV psychosis as a potential http://bmjopen.bmj.com/ 37 38 model for schizophrenia may also improve our understanding of its neurobiology. The new 39 40 knowledge, generated through this novel study, will enable an understanding of the interplay 41 between HIV and psychosis at a fundamental level, centred at the international epicentre of 42 43 the HIV pandemic.

44 on September 30, 2021 by guest. Protected copyright. 45 46 In addition, in SA, substance use and trauma remain critical public health challenges that 47 48 need to be further explored. Thus, the study of the bidirectional associations between HIV, 49 50 substance use and traumatic experiences, psychosis onset and presentation in a low- and 51 52 middle-income setting is essential to better guide the strategic use of their limited resources. 53 Early insights into the role of substance use and trauma in HIV infection and psychosis onset 54 55 could be used to delay, modify, or even prevent the onset of HIV psychosis. Furthermore, the 56 57 interplay of these extraneous factors in genetically predisposed individuals has not been 58 explored. This study will allow us to begin to understand the contribution of HIV to 59 60

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1 2 3 psychosis onset, increase awareness of the need for screening and care in a highly vulnerable 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 group, while building research capacity. 6 7 8 In LMIC, 11.1% of the total burden of disease are attributable to mental disorders[21]. In 9 10 addition to the high prevalence and morbidity associated with mental disorders, it has been 11 12 shown that cultural influences impact significantly on and contribute to the risk for mental 13 14 and other health concerns in developing countries. The results of this study will contribute to 15 the development of management (investigation and treatment) algorithms in the South 16 17 African resource constrained health departments. Reference will be made to the differences 18 For peer review only 19 identified between the HIV positive and HIV negative groups, facilitating appropriate tailored 20 21 approaches to each sub-group. The benefits of these would include policy changes and 22 streamlined cost-effective treatment plans that will be equally beneficial to patient and the 23 24 health department. 25 26 27 Legend for Figure 1 28 29 List of all study procedures utilised in the patient assessment 30 31 32 33 Contributorship statement 34 UC, VN, TN and SP conceived the study. UC, VN will collect data. AT performed the 35

36 statistical analysis. SP and BC supervised the work undertaken. UC wrote the first draft. All http://bmjopen.bmj.com/ 37 38 authors have read and approved the final manuscript. 39 40 41 Competing interests 42 43 None declared.

44 on September 30, 2021 by guest. Protected copyright. 45 46 Funding 47 48 This study is funded by National Research Foundation of South Africa (Grant #: 117858), 49 50 South African Research Council SIR grant and a start-up grant from the Society for 51 52 Biological Psychiatry Research Fund. Funding (Grant #: N/A) was also received from 53 University of KwaZulu-Natal College of Health Sciences PhD Scholarship (Grant #: N/A). 54 55 Andrew Tomita was funded by UK Global Challenge Research Fund (MR/T029803/1). The 56 57 opinions and findings presented are those of the authors and not a reflection of the funders. 58 59 60

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19 on September 30, 2021 by guest. Protected copyright. Mental health outcome (Objective #1) PTSD Clinician administered PTSD scale for DSM-V (CAPS 5) X 20 Motor symptoms ESRS X X X 21 22 HIV associated cognitive deficit screen CAT-Rapid and IHDS X X X 23 Social cognition Neuropsychological battery X (at 3 months only) X 24 Substance use WHO ASSIST X X X 25 26 Quality of life WHO-QOL BREF X X X 27 From Hospital Records: Full blood count, liver Function test, syphilis and Biochemical haematological and radiological tests 28 Hepatitis test. Cerebrospinal fluid biochemistry and neuroimaging if available. 29 30 HIV status Confirmatory HIV ELISA 31 HIV marker VL if HIV positive If applicable If applicable If applicable 32 Clinical markers of HIV (Objective #2) 33 HIV marker CD4 if HIV positive X 34 35 36 37 38 21 39 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 23 of 23 BMJ Open

1 2 3 Table 2. 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 Cognitive test battery and domains to be tested 6 7 Domains Test 8 Motor skills Grip strength[22], Pegboard [23] 9 Visuospatial functioning WAIS-R Block Design, Digit symbol[24], and 10 Rey-Osterrieth Rey Complex Figure (RCF) – Copy[25] 11 12 Verbal Memory Rey Auditory Verbal Learning Test (RAVLT)[26] 13 Non-Verbal Memory RCF - Recall [25] 14 Problem solving/Reasoning WAIS-R Language test[24] 15 Language RAVLT[26] 16 Word generation Controlled Word Association Test (COWAT)[27] 17 Animal Naming (Letter and Category cues)[28] 18 For peer review only 19 Attention WAIS-R Digit Span[24] 20 Executive functioning Trail making[29], RCF[25], 21 Wisconsin Card Sorting Test (WCST)[30] 22 Social cognition Emotion perception (Faces Test)[31], 23 Theory of mind (Eyes Test)[32], 24 Social knowledge (Situational Feature Recognition Test) 25 26 (SFRT)[33] 27 28 29 30 31 32 33 34 35

36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43

44 on September 30, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

22 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24 of 23

1 2 3 Figure 1. 4 BMJ Open: first published as 10.1136/bmjopen-2020-046593 on 21 May 2021. Downloaded from 5 List of all study procedures utilised in the patient assessment. 6 7 8 Objective 1 9 To compare HIV infected and HIV non-infected patients with FEP at psychosis onset in 10 at baseline, 3-, 6- and 12-months regarding socio-demographic profile, clinical 11 12 features, substance use patterns, traumatic life events and quality of life. 13 14 15 1. A structured socio-demographic and clinical questionnaire: age; gender; marital status; 16 educational and employment levels; medical, psychiatric and trauma history. 17 18 2. Mini InternationalFor Neuro peer-psychiatric Interviewreview (MINI) version only 7.02: to confirm DSM V 19 diagnosis of psychotic disorder [36] 20 3. The Positive and Negative Syndrome Scale (PANSS) [37] 21 22 4. Physical examination: for weight, height and body mass index 23 5. Duration of Untreated Psychosis (DUP) and pathways: to care assessed with the WHO 24 Pathways to care questionnaire, WHO Encounter [38] 25 26 6. Patient Health Questionnaire (PHQ-9) [39] 27 7. Cognitive screening tools: Cognitive Assessment Tool (CAT) - rapid [40] and International 28 HIV Dementia Scale (IHDS) [41] 29 30 8. Cognitive battery (described in table 2) 31 9. Extrapyramidal Symptom Rating Scale (ESRS) [42] 32 10. Childhood trauma questionnaire Short Form (CTQ-SF) [43] 33 11. Posttraumatic Stress Disorder (PTSD) checklist for DSM-V (PCL-5) – Life Events Checklist 34 35 (LEC)-5 and extended criterion [44]

36 12. WHO Quality of Life Brief Version [45] http://bmjopen.bmj.com/ 37 13. WHO Alcohol, Smoking and Substance Involvement Screening Test [46] 38 39 40 Objective 2 41 To describe the association of HIV infection clinical markers (CD4 count and viral load) 42 43 and clinical variables of psychosis at illness presentation, 3, 6 and 12 months.

44 on September 30, 2021 by guest. Protected copyright. 45 46 14. HIV ELISA testing for all participants 47 15. HIV markers- CD4 count and viral load for PLWHIV at baseline, 3, 6- and 12-month visits. 48 49 50 51 52 53 54 55 56 57 58 59 60

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml