PEER REVIEW HISTORY BMJ Open publishes all

PEER REVIEW HISTORY BMJ Open publishes all reviews undertaken for accepted manuscripts. Reviewers are asked to complete a checklist review form (http://bmjopen.bmj.com/site/about/resources/checklist.pdf) and are provided with free text boxes to elaborate on their assessment. These free text comments are reproduced below.

ARTICLE DETAILS TITLE (PROVISIONAL) AUTHORS

Hepatitis B virus contact disclosure and testing in Lusaka, Zambia: a mixed methods study Franklin, Sarah; Mouliom, Amina; Sinkala, Edford; Kanunga, Annie; Helova, Anna; Dionne-Odom, Jodie; Turan, Janet M.; Vinikoor, Michael

VERSION 1 – REVIEW REVIEWER REVIEW RETURNED GENERAL COMMENTS

Yusuke Shimakawa Institut Pasteur, France 29-Mar-2018 This is a well written manuscript, which estimated the frequency of disclosure to household members about HBV infection status, and described the barriers to contact disclosure. The study was conducted in Zambia where both HIV and HBV are highly prevalent, using the mixed methods. The study focused an important area of research (awareness and knowledge of hepatitis B in community and people diagnosed to carry HBV); this is particularly relevant topic when the WHO developed a global strategy to eliminate hepatitis B, and increasing treatment uptake has become one of the key interventions to achieve this goal. I have several comments that may improve the paper. 1. Focus of the paper After carefully reading the paper, I found that the main outcome of the study was “disclosure to contacts” rather than “contact testing”. For the quantitative analysis (Table 2), the authors investigated factors associated with disclosure to contact. But I do not see any analysis to assess factors associated with “contact testing”. The authors presented % contact tested (23.6% (77/326)) according to the index patient’s knowledge. But there is high risk of underascertainment, as the authors appropriately acknowledged in the discussion (Page 14, lines 47-52). Most of the qualitative part was about “disclosure” (page 9, lines 517; page 11, lines 9-19), “awareness & knowledge” or “stigma”. I found two descriptions on HBV testing (page 10, lines 25-42); however, the first one is about an experience of a person who has been diagnosed as hepatitis B, and the second one is perceived priority of HIV testing compared to HBV testing in a healthcare setting. I do not see any analysis that addressed the feasibility of contact testing, by assessing its acceptability. This study interviewed people diagnosed to be infected with HBV; but did not interview contacts themselves. Unless interviewing contacts, it is difficult to evaluate the feasibility or utility of “contact testing”.

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I think “disclosure of HBV status to contacts” and its obstacle has never been studied in sub-Saharan Africa (as far as I know). And without having high rate of contact disclosure, we cannot have high rate of contact testing. Therefore, I recommend the authors to focus on “contact disclosure” in this paper: Title should be about “contact disclosure” rather than “contact testing”. In the abstract, the objective of the study should be “to estimate the frequency of disclosure to contacts”, rather than “uptake and outcomes of contact testing”. The term “contact testing” can be replaced by “disclosure to contacts”, throughout the abstract. In the results (page 12, lines 16-19), the sub-title should be “summary of barriers to HBV status disclosure to contacts”. In the discussion (page 14, lines 5-8), I do not see any data collected from this study, that supported the utility and feasibility of contact testing approach.

2. Definition of contact In the methods (Page 6, line 26), it is important to define what are the contacts. How this was explained to the study participants? People who live in a same house? People who share the meal? People who had sexual contact before? 3. Major mode of HBV transmission in Zambia Historically, in many of African countries the prevalence of antiHBc steadily increased over childhood, and reached to >70-80% by adolescence (Kiire CF, Gut, 1996). This implies that the major mode of transmission was horizontal between children (and MTCT in a lesser extent), and the vast majority of people were exposed to HBV before they reach the age of sexual activity. Therefore, unlike HIV epidemiology, sexual transmission during adulthood is rare as there are only few susceptible adults. It is important to discuss whether HBV contact testing for a partner/spouse is relevant or not in Zambia, in considering HBV epidemiology in this context. 4. In the abstract (page 2, line 44) “According to the index patient’s knowledge” should be added to a sentence starting with “Of 776 contacts enumerated, …”. 5. Stigma score Page 10, line 46. What is the total score (i.e., the highest score possible)? 6. Table 2 In the analysis to identify factors associated with disclosure to contact, there were only 9 subjects who did not disclose to any contact. With this number of outcome, the study is not powered enough to do a multivariable analysis. I recommend to just present a univariable analysis. In this table, some variables were treated as continuous (age and stigma score) while some as categorical (HBV knowledge score). It is important to justify these in the methods section. Or present all these variables as continuous may be another option. REVIEWER REVIEW RETURNED

Barbara Castelnuovo Infectious Diseases Institute Kampala, Uganda 10-Apr-2018

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GENERAL COMMENTS

This is an interesting paper on the experience of the authors in scaling up Hepatitis B care in SSA. I don’t have major comments, however I have some minor suggestions. 1) Title: I would revise the title and make it more appealing , e.g. “Hepatitis B contact testing is feasible but could be undermined by HIV related stigma by association”- just an example 2) Methods line 27. Can the authors add 2 lines on HIV management according to the National policies? Most country in SSA don’t even have policies for Hep B treatment 3) Discussion: line 50-51 page 13. Using the same clinic for Hep B and HIV testing. The authors should expand on this. This approach can be also cost saving. The staff may need less training not only because the same drugs are used but also to deal with other patients such as counselling of stigma for example. On the other end using the same clinics could enhance the stigma by association. 4) Can the authors also comment on if the stigma is only by association to HIV or there is a specific hep B component stigma? 5) Conclusions. I do not entirely agree with the authors. I think some of their results can be generalized to many African contexts in SSA and not just in Zambia. It is likely that future countries implementing Hep B treatment will face similar challenges. 6) Conclusions. Can the author elaborate more about the need to understand more stigma? The sentence is very vague

REVIEWER

Jacqui Richmond Burnet Institute, Australia 11-Apr-2018

REVIEW RETURNED GENERAL COMMENTS

Thank you for the opportunity to review this very interesting manuscript. This is an important piece of work that explores numerous issues, including testing cascades, hepatitis B knowledge and the impact of stigma, using mixed method design. The FGD quotes have been used very effectively and really allow for an in-depth exploration of the issues. I have only minor comments for clarification: 1. How many HBsAg+ patients are cared for with the UTH Dept of Medicine? What is the sampling population? I note 140 patients were recruited. 2. p.5, line 33-34 - "... presence/absence of liver disease signs and symptoms and measure[d] baseline..." 3. p.5, line 36 - the follow up visits every 3-6 months - was this part of standard clinical monitoring? Participants' parking was paid for standard follow up? How long does this occur for. What is the fail to attend rate? p.6 - Patient involvement - I'm assuming this section is required by the journal? I don't think it adds anything to article - consider deleting. p.10, line 48-49 - "eduction" has been mis-spelt p.11, line 56 - I wonder if the quote is meant to refer to the brother having hepatitis B rather than HIV??? "Like last time .... take some drugs at the hospital there for HIV {should this be hepatitis B?] and he was in the same line with HIV patients".

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Table 3 - this is an unusual way to present data - it's not customary to compare quant and qual data like this? I'm not sure it adds anything to the manuscript. Consider deleting. Once again this is a very interesting study that provides a very useful insight into the impact of stigma, link between hep B and HIV and a novel, innovative approach to increasing hepatitis B testing and diagnosis. Well done!

VERSION 1 – AUTHOR RESPONSE Reviewer: 1 Reviewer Name: Yusuke Shimakawa Institution and Country: Institut Pasteur, France 1.

Focus of the paper

After carefully reading the paper, I found that the main outcome of the study was “disclosure to contacts” rather than “contact testing”. o

Response: We agree with the reviewer that although contact testing is the ultimate goal, disclosure was what we primarily measured in the study. However, as disclosure and testing are closely linked and underlying barriers are often similar and intertwined (e.g. stigma, lack of knowledge), we would prefer to discuss both in the paper. For example, we propose to revise the title of the paper to “Hepatitis B virus contact disclosure and testing in Lusaka, Zambia: a mixed methods study”.

For the quantitative analysis (Table 2), the authors investigated factors associated with disclosure to contact. But I do not see any analysis to assess factors associated with “contact testing”. The authors presented % contact tested (23.6% (77/326)) according to the index patient’s knowledge. But there is high risk of under-ascertainment, as the authors appropriately acknowledged in the discussion (Page 14, lines 47-52). Most of the qualitative part was about “disclosure” (page 9, lines 5-17; page 11, lines 9-19), “awareness & knowledge” or “stigma”. I found two descriptions on HBV testing (page 10, lines 25-42); however, the first one is about an experience of a person who has been diagnosed as hepatitis B, and the second one is perceived priority of HIV testing compared to HBV testing in a healthcare setting. I do not see any analysis that addressed the feasibility of contact testing, by assessing its acceptability. o

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Response: We agree with the reviewer that the data presented in this manuscript, quantitative and qualitative, are more related to disclosure than the testing. This is primarily because we did not enroll or directly interact with the contacts, just the index patients. Notably we only ascertained contact age, sex, and relationship to index patient (to maintain confidentiality) and we did perform (however, chose not to show it in the paper) an analysis of factors associated with contact testing among those who were disclosed to. Compared to contacts who were 40 years had lower odds of being tested (AOR, 0.24; 95% CI,

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0.08-0.75) compared to contacts 70-80% by adolescence (Kiire CF, Gut, 1996). This implies that the major mode of transmission was horizontal between children (and MTCT in a lesser extent), and the vast majority of people were exposed to HBV before they reach the age of sexual activity. Therefore, unlike HIV epidemiology, sexual transmission during adulthood is rare as there are only few susceptible adults. It is important to discuss whether HBV contact testing for a partner/spouse is relevant or not in Zambia, in considering HBV epidemiology in this context. o

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Response: In general, we agree that the majority of HBV-infected individuals in Africa acquired the infection during early childhood. However, sexual transmission of HBV is also important for a few reasons. First, data from East Africa (Uganda and Kenya) have documented the association of sexual risk factors with HBV infection, including one incidence study among men who have sex with men. Secondly, unlike HIV, a vaccine is available to prevent HBV; therefore, identifying at risk partners/contacts who are naïve to the infection can have a significant public health impact (as 5-10% of infected adults will develop chronic infection). Third, Africa is experiencing a shift from vertical/early childhood horizontal transmission to adult horizontal transmission (sex, drug use) and full control of HBV on the continent will require efforts to reduce all forms of transmission. Finally, we do anecdotally see acute HBV infections among young sexually active adults at University Teaching Hospital in Zambia. These cases likely represent the tip of the iceberg (the most symptomatic cases) and make us believe that sexual transmission is highly relevant in our setting. In the revised discussion section (Page 15, Paragraph 3), we added the following: “While the majority of HBV-positive individuals in Africa may have acquired the infection in early childhood, horizontal transmission in adulthood, through drug use or sexual contact, also contributes to the overall prevalence. HBV contact disclosure and testing can both identify undiagnosed chronic HBV infections and provide opportunities for prevention using the vaccine.”

In the abstract (page 2, line 44)

“According to the index patient’s knowledge” should be added to a sentence starting with “Of 776 contacts enumerated, …”. o 5.

Response: Thank you for your comment. The suggested wording has been added to the revised abstract.

Stigma score

Page 10, line 46. What is the total score (i.e., the highest score possible)? o

Response: Thank you for this comment. We have included the following sentence in the Methods section: “The summed score range for this scale was 0-32.” To add, The Stigma Scale for Chronic Illnesses Short Form (SSCI-8) utilized and adapted for the use in this survey, included 8 items, all weighted equally. The scale utilized a 5-level Likert responses coded numerically 0-4 (0 = never, 1 = rarely, 2 = sometimes, 3 = often, 4 = always). Higher summed score was indicative of greater stigma.

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Table 2

In the analysis to identify factors associated with disclosure to contact, there were only 9 subjects who did not disclose to any contact. With this number of outcome, the study is not powered enough to do a multivariable analysis. I recommend to just present a univariable analysis. o

Response: We agree and have only displayed the univariable analysis in the revised manuscript (see revised Table 2).

In this table, some variables were treated as continuous (age and stigma score) while some as categorical (HBV knowledge score). It is important to justify these in the methods section. Or present all these variables as continuous may be another option. o

Response: Thank you for pointing this out. In the revised manuscript we now have indicated that we combined those with none to 8th grade education for analysis. We wrote, “Median educational attainment was grade 9-12 and those with 0 to 8th grade education were collapsed into one category for analysis.” We have used knowledge score as a continuous variable in the revised Table 2.

Reviewer: 2 Reviewer Name: Barbara Castelnuovo Institution and Country: Infectious Diseases Institute, Kampala, Uganda 1) Title: I would revise the title and make it more appealing , e.g. “Hepatitis B contact testing is feasible but could be undermined by HIV related stigma by association”- just an example o

Response: Thank you for your suggestion; however, as per the editor’s comment, the journal does not accept manuscripts with declarative titles. The title will therefore follow editor’s suggestions.

2) Methods line 27. Can the authors add 2 lines on HIV management according to the National policies? Most country in SSA don’t even have policies for Hep B treatment o

Response: In the revised methods we now mention that Zambia has guidelines on the use of antiviral therapy for HBV. On Page 5, Paragraph 3, we write, “the Ministry of Health has established national guidelines on the use of antiviral therapy for HBV,22 which were largely adapted from the WHO recommendations.”

3) Discussion: line 50-51 page 13. Using the same clinic for Hep B and HIV testing. The authors should expand on this. This approach can be also cost saving. The staff may need less training not only because the same drugs are used but also to deal with other patients such as counselling of stigma for example. On the other end using the same clinics could enhance the stigma by association. o

Response: Thank you for this comment. We agree with reviewer and have expanded by also writing (Page 14, Paragraph 1), “Although data are lacking, integration of HBV testing and care within an HIV care context may be cost saving and efficient.”

4) Can the authors also comment on if the stigma is only by association to HIV or there is a specific hep B component stigma? o

Response: Thank you for this comment. As indicated in the Discussion section of the manuscript, HBV-positive patients experience internalized and enacted stigma related to HBV alone, as well as stigma by association with HIV.

5) Conclusions. I do not entirely agree with the authors. I think some of their results can be generalized to many African contexts in SSA and not just in Zambia. It is likely that future countries implementing Hep B treatment will face similar challenges.

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Response: Thank you for this comment and we do agree the data will be useful broadly in Africa.

6) Conclusions. Can the author elaborate more about the need to understand more stigma? The sentence is very vague o

Response: In response to this comment, the following sentence has been moved from the preceding paragraph to expand on this statement (Page 15, Paragraph 2): “Future studies in this area should explore impact of different types of stigma, as well as pathways and effect of stigma on disclosure and testing among HBV index patients and their contacts.”

Reviewer: 3 Reviewer Name: Jacqui Richmond Institution and Country: Burnet Institute, Australia

1. How many HBsAg+ patients are cared for with the UTH Dept of Medicine? What is the sampling population? I note 140 patients were recruited. o

Response: In response to this comment, we have revised the following section of the Methods (Page 5, Paragraph 2) as follows: “UTH is the largest public-sector hospital in the country, with approximately 400,000 outpatient visits and 90,000 admissions per year. Within the Department of Medicine, care is provided for an estimated 300 HBV patients per year and the Ministry of Health has established national guidelines on the use of antiviral therapy for HBV,20 which were largely adapted from the WHO recommendations. During August 2016 to July 2017, consecutive outpatients within the Department of Medicine were recruited if they were HBsAg-positive, HIVnegative, and 18+ years old. Those who were unlikely to be retained in care in the opinion of the study team were excluded from participation.”

2. p.5, line 33-34 - "... presence/absence of liver disease signs and symptoms and measure[d] baseline..." o

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3. p.5, line 36 - the follow up visits every 3-6 months - was this part of standard clinical monitoring? Participants' parking was paid for standard follow up? How long does this occur for. What is the fail to attend rate? o

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Response: Thank you for noting this minor error. We have adjusted this sentence in the revised paper and reworded to: "We documented the presence/absence of liver disease signs and symptoms and measured baseline..."

Response: The study participants followed standard care protocol (follow-up visits every 3-6 months). As per study research protocol approved by the University of Zambia Biomedical Research Ethics Committee and the University of Alabama at Birmingham Institutional Review Board, study participants received compensation based on roundtrip bus ride from their home to UTH (typically 4-8 US dollars) at enrollment and at each 6 months follow-up visit up to 48 months after enrollment. In the few cases where patients used their own vehicle to park at UTH, the bus fare was used to cover fuel costs. However, in such cases, the parking is free for all patients. In response to this comment, we revised the following sentence in the Methods section: “Follow-up visits occurred every 3-6 months and transportation costs based on distance from home to clinic were reimbursed at each visit up to 48 months after enrollment to overcome reduce structural barriers to retention.” As indicated in the manuscript (page 6, paragraph 1), 85% of enrolled patients were retained in care over the first year of the cohort existence.

p.6 - Patient involvement - I'm assuming this section is required by the journal? I don't think it adds anything to article - consider deleting.

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p.10, line 48-49 - "eduction" has been mis-spelt o

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Response: Thank you for noting this minor error, which we have corrected in the revised paper.

p.11, line 56 - I wonder if the quote is meant to refer to the brother having hepatitis B rather than HIV??? "Like last time .... take some drugs at the hospital there for HIV {should this be hepatitis B?] and he was in the same line with HIV patients". o

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Response: Thank you for this comment. This section is now required by the journal and therefore cannot be removed.

Response: Thank you for noting this discrepancy, which we have corrected in the revised paper.

Table 3 - this is an unusual way to present data - it's not customary to compare quant and qual data like this? I'm not sure it adds anything to the manuscript. Consider deleting. o

Response: Thank you for this comment. After careful consideration, we believe that Table 3’s side-by-side comparison of qualitative and quantitative results provides additional level of data integration and visual joint display. The side-by-side comparison as presented in Table 3, is becoming one of the most recommended types of joint displays in mixed method research as per the below references: References: Guetterman TC, Fetters MD, Creswell JW. Integrating Quantitative and Qualitative Results in Health Science Mixed methods Through Joint Displays. Ann Fam Med. 2015 Nov;13(6):554-61. doi: 10.1370/afm.1865. Creswell, JW. A Concise Introduction to Mixed Methods Research. Thousand Oaks, CA: Sage Publications, 2015.

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Once again this is a very interesting study that provides a very useful insight into the impact of stigma, link between hep B and HIV and a novel, innovative approach to increasing hepatitis B testing and diagnosis. Well done! o

Response: Thank you for your positive feedback and insightful suggestions for improvements.

FORMATTING AMENDMENTS (if any) Required amendments will be listed here; please include these changes in your revised version: - Kindly remove all your Supplementary Table in your Main Document and upload it separately under file designation "Supplementary File" in PDF Format. o

Response: We have made the requested change. VERSION 2 – REVIEW

REVIEWER REVIEW RETURNED GENERAL COMMENTS

Yusuke Shimakawa Institut Pasteur, France 22-Jun-2018 The paper has substantially improved. This is an important first study that addressed disclosure to contacts about HBV infection. Congratulations!

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REVIEWER REVIEW RETURNED

Barbara Castelnuovo Infectious Diseaases Institute 18-Jun-2018

GENERAL COMMENTS

The reviewer completed the checklist but made no further comments.

REVIEWER

Jacqui Richmond Burnet Institute, Melbourne, Australia 12-Jun-2018

REVIEW RETURNED GENERAL COMMENTS

This is a very interesting and valuable piece of research that contributes significantly to our understanding of hepatitis B in Zambia. The study design and exploration of hep B-related stigma are highlights. Minor comments: 1. Chronic HBV - the usual acronym is Chronic Hepatitis B (CHB) 2." Hepatitis B patients" - this is not a very respectful term - I would prefer patients with hepatitis B. These participants should not be defined only by their hep B status. 3. What were the exclusion criteria for this study - you mentioned people were excluded if you assessed them to be "unlikely to be retained in care" - how did you determine this? 4. page 12, line 7 - need to define ARV 5. You list the 5 categories but have forgotten to label number 5 - page 13, line 2.

VERSION 2 – AUTHOR RESPONSE Reviewer: 1 Reviewer Name: Yusuke Shimakawa Institution and Country: Institut Pasteur, France The paper has substantially improved. This is an important first study that addressed disclosure to contacts about HBV infection. Congratulations! o Response: Thank you.

Reviewer: 2 Reviewer Name: Barbara Castelnuovo Institution and Country: Infectious Diseases Institute, Kampala, Uganda Comments: None o Response: Thank you. Reviewer: 3 Reviewer Name: Jacqui Richmond Institution and Country: Burnet Institute, Australia

1. Chronic HBV - the usual acronym is Chronic Hepatitis B (CHB) o Response: We have made the requested change. 2." Hepatitis B patients" - this is not a very respectful term - I would prefer patients with hepatitis B. These participants should not be defined only by their hep B status. o Response: We have made the requested change.

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3. What were the exclusion criteria for this study - you mentioned people were excluded if you assessed them to be "unlikely to be retained in care" - how did you determine this? o Response: This was mainly based on household location. Approximately 10% of patients seen for HBV treatment at University Teaching Hospital (UTH) reside outside Lusaka and without strong family and financial support they often have difficulty being in multi-year longitudinal studies. Secondly, patients with several medical illness and likely not to survive were also deemed unlikely to be retained in the cohort. In the revised paper we now state, “Those who were unlikely to be retained due to residence outside of Lusaka or severe medical illness were excluded from participation.” 4. Page 12, line 7 - need to define ARV o Response: This is the common term used in Zambia for antiretroviral drug for HIV treatment. In the revised paper we have stated, “For example, many stated that if others discovered a person with an ARV (antiretroviral therapy for HIV) medication bottle such as Truvada…”

5. You list the 5 categories but have forgotten to label number 5 - page 13, line 2. o

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Response: Thank you for noting this minor error. We have adjusted this sentence in the revised paper and reworded to: "Five thematic categories have been identified as barriers to HBV contact testing in Lusaka, Zambia based on converged data from HBV patient surveys and FGDs, including (1) low disclosure of HBV status, particularly to contacts other than primary partners, (2) low awareness of HBV in the community, (3) low knowledge about HBV both among patients with HBV and in the community, (4) enacted and internalized HBV stigma and HBV-HIV cross-sectional stigma, and (5) other barriers.”

Once again this is a very interesting study that provides a very useful insight into the impact of stigma, link between hep B and HIV and a novel, innovative approach to increasing hepatitis B testing and diagnosis. Well done! o

Response: Thank you for your positive feedback and insightful suggestions for improvements. We have made the requested changes.

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