PONE-D-19-31426

Prevalence and Predictors of Prescription Drug Diversion, Misuse and Abuse among People Living with HIV in eThekwini District, KwaZulu-Natal, South Africa

PLOS ONE

Dear Ms. Buyisile,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Overall, reviewers thought this was an important topic and study (“really important and shows another angle in abuse and misuse of prescription medication”) but requires major revisions.  These reviews suggest two issues that should be the primary focus of the revision: 

1. Contextualization in the literature, especially from South Africa
   1. Doing this will also requiring clarifying key points raised by the reviewers
   2. Make sure the terminology describing substance use is accurate and up to date for this field.
2. More clear and accurate presentation of the data, and in some places consider re-running statistics (see comments on logistic regression model)
   1. Please consider carefully the comments on presentations of data and interpretation.
   2. Mare sure that the narrative carefully reflects the results
   3. Please address sample size considerations

Generally, there are many small errors that need to be corrected.

There is a growing literature that examines the multiple challenges faced by people living with HIV which can meaningfully be used to inform policy and intervention, so I encourage the authors to use these thoughtful and specific reviews to improve this paper.

We would appreciate receiving your revised manuscript by Wednesday, March 25 2020. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Partly

Reviewer #4: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: No

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: No

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Data presented in the results section does not match the narrative (comments attached). It is also not clear if the authors are discussing diversion and misuse of ARVs, or opioids used for pain management.

Reviewer #2: I think the study is really important and shows another angle in abuse and misuse of prescription medication; but I have some concerns about it:

*I dont believe that most of the research on this topic is mostly conducted in the USA only

*Reference provided about studies done in other countries (China, Jordan) show findings of prescription drug misuse in the general population and not im PWLH; therefore not similar to this study's findings

*There are several studies conducted in SA that looked at use and abuse of prescription medications; but these studies are not mentioned; and the statement mentioned about the study on misuse of codeine containig medicines use is not correct

*Description of 'misuse and abuse' is not clearly stated and that is confusing

*I appreciate the acknowledgement of excluding mental health variable as a limitation; i think the authors should have looked at it as is almost impossible to talk about HIV and exclude mental health (depression, anxiety, etc)

*Looks like figue 2 and figure 3 is the same graph and the y-axis heading is the same, confusing

*There are spelling mistakes, so the authors need to re-read the manuscript to avoid this

*I would have liked to see the names of commonly misused/diverted/abused medications; to see if these medications are mostly associated with mental health illnesses (to self-medicate)

Data analysis was conducted rigourously and that is appreciated. So i think the authors should be given another chance to look at corrections and resubmit the manuscript

Reviewer #3: The reviewer feels that it would be extremely valuable for the authors to engage further with literature around prescription and over the counter medication in low and middle income countries, but in South Africa particularly to get a sense of what some of the concerns and issues are in this context. Examples are publications on codeine data (authors to look for are Parry, C., Dada, S. and Carney, T.) and the SACENDU data which is widely available. There are also definitely at least a few studies on opioid use and HIV, which is increasingly a problem in KZN. Definitions of misuse and abuse and diversion are also not clearly provided. Please look at the latest terminology used in substance use literature.

It would have been very interesting to look at the relationship between HIV outcomes and problem prescription use among PLWH-could these types of analyses be run? There are some studies conducted in South Africa (one qualitative one actually conducted in KZN) that mention people may be misusing ART as well. Was this included in the current study?'

The results section could be presented in a more succinct way and it is difficult to interpret Figure 3 and 4. A suggestion would be to present the univariate and multiple regression models in one table-perhaps look at other literature for examples.

A study limitation is that this is a small sample size to be representative of eThekweni PLWH and attending healthcare services. Are there any additional comments to make around this, such as do the authors think that this is a representative sample?

Reviewer #4: The authors present results of a cross-sectional study on the prevalence and predictors of prescription drug diversion, misuse and abuse among individuals with HIV in a district within South Africa. The authors find that there is more misuse than drug diversion among their sample, and very little prescription drug abuse. They also identify a few risk factors for drug diversion and misuse. The manuscript will be strengthened if the authors consider the following points.

1. Figure 2: it is unclear why the confidence intervals presented in Figure 2 are not symmetric, since typical confidence intervals for proportions are symmetric. Authors should clarify how confidence intervals were computed and verify that what is presented in Figure 2 is correct.

2. lines 212-216 (also in the Abstract lines 36-40) and lines 248-250: The authors are reporting percentages out of all 392 participants, which isn't necessarily wrong, but the start of the sentences ("Majority" or "More than one-third") suggest that the reader should be focused on just those with drug diversion or with drug misuse. The authors are encouraged to think about what point they really want to make and whether it is most appropriate to report percentages out of the entire sample or out of just those that had the action of interest.

3. The authors have a tendency to overstate the findings, even when qualifying a statement by saying something wasn't statistically significant. In most of the situations, findings are not even close to being significant. Examples include lines 233-239, 241-244, 263-266, 272-275). Authors already include the ORs and 95% confidence intervals for the terms in the model in supplemental table 3, so readers can see these results. Some of these end up being discussed in the discussion (age and aware of the black market) and highlighted in the Abstract (homeless and awareness of the black market) as findings, which is inappropriate. In the discussion, they further highlight differences between males and females, but this finding does not hold up in the adjusted model.

4. In the adjusted models for drug diversion (model B), the authors include more variables than are generally recommended given the number of people who had the action of interest.Standard rules of thumb for logistic regression would suggest that no more than 5 predictors should be included in a model, yet the authors include 7.

Minor points:

1. line 27: "as mostly" should be "as most"

2. line 42: "diversion and misuse" should be "diversion or misuses" since not all factors were associated with both outcomes.

3. line 62: "South Africa account" should be "South Africa accounts" and consider changing "owning the" to "having the"

4. line 63: "has been" should be "have been"

5. line 70: "that correlates" should be "that correlate"

6. line 71: "suggest" should be "suggests"

7. line 73: "and abuse has been" should be "and abuse have been"

8. line 83: what do the authors mean by saying trends are close to non-existence (or non-existent) - do they mean there is little information?

9. lines 86-87: the sentence starting with "Furthermore" is an incomplete sentence

10. line 106: remove "until"

11: line 130: "Data was" should be "Data were"

12. line 144: "development the" should be "development of the"

13.lines 145-146: the sentence "The emphasises the importance..." is unclear and authors are encouraged to reword it for clarity.

14. line 148: "diversion stem" should be "diversion which stems"

15. line 150: "is prescription drug misuse was" should be " is prescription drug misuse and was"

16. line 151: "drug misuse stem" should be "drug misuse stems"

17. line 185: "rigour strategy" should be "rigorous strategy"

18. line 193: "Analysis were" should be "Analyses were"

19: line 203: the authors report a response rate of 102%, but it is unclear how a response rate can be larger than 100%.

20. Figure 2 and 4 appear to be identical, so authors should verify that the correct figure was uploaded for Figure 4.

21. lines 287-291: these lines should be reworded given that the percentages are so similar.

22. lines 298-299 - authors should be clear this result is from the adjusted model

23. line 328: "with an increase rates" should be "with increased rates"

24: line 349: "This strongly support" should be "This strongly supports"

25. line 361: "metal" should be "mental"

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

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Attachments

Attachment

Submitted filename: PONE-D-19-31426_reviewer.pdf

PONE-D-19-31426R1

Prevalence and Predictors of Prescription Drug Diversion, Misuse and Abuse among People Living with HIV in eThekwini District, KwaZulu-Natal, South Africa

PLOS ONE

Dear Dr. Chibi,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Aug 23 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Becky L. Genberg

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

While some of the concerns from the previous review have been addressed, there remain concerns by one reviewer.

Additionally, I have concerns regarding the definitions of prescription drug abuse, self-medication, and diversion. Firstly, what drugs specifically are you inquiring about? the potential for misuse or abuse and the implications for HIV prevention and treatment would apply only to specific classes of prescription drugs. Were these assessed? Secondly, the definition of abuse is not in line with the substance use literature and should be reconsidered. Please clarify that 100% response rate means that all persons approached to participate agreed and completed the survey. Finally I also share concerns of the reviewer about the need for careful editing, as some numbers appear incorrect and there are several typographical and grammatical errors throughout the manuscript that remain in this revision. In this revision I would recommend adhering to commonly accepted terms when referring to people who use drugs.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

Reviewer #4: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

Reviewer #4: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #4: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

Reviewer #4: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: (No Response)

Reviewer #4: The authors have addressed the majority of my earlier concerns. There are a few remaining issues that should be addressed.

1. line 103: "might unfolds" should be "might unfold"

2. lines 122-123: "areas with lack training" should possibly be "areas which lack tracking"

3. line 207: "would their participation affect their healthcare" should be "and participation would not affect their healthcare"

4. line 280: mention these are exact 95% confidence intervals

5. Table 1: authors should carefully check numbers and p-values as I found a number of incorrect calculations. Examples include the percentage for 18-24 years in the Total sample (which should be 10% not 7%), the percentage of completed high school and tertiary studies in the did not misuse prescription drugs group (which should be 10% not 26%), the numbers of homeless add to 18, not 17 when looking at the yes/no columns for both divert and misuse prescriptions, the p-value for ever used alcohol comparing those that diverted and those that did not seems wrong (based on the numbers provided), I get a much smaller p-value for ever used tobacco in those that diverted vs not, the numbers of ever used marijuana in the diverted and did not divert columns add to 56 not 55.

6. It is recommended that in the text (lines 339, 360, 390) and S2 and S3 tables, the authors remind the readers what model A and model B mean. At a minimum, there should be a note for S2 and S3 tables that defines these models.

7. lines 350-356 are all results that have extremely high p-values, so reporting a 20% or 50% increase in odds is misleading. There is no evidence in the data to suggest that there is any increased chance of diverting PM based on these characteristics. I am fine with keeping the marijuana and illegal drugs findings, since with the 95% confidence interval, the readers can see that the lower limit for the CI is just under 1.

8. lines 365 and 367, remove "among the participants who misused drugs", because the authors are reporting percentages out of the entire sample not just those who misused drugs.

9. lines 321-385: it is misleading to say that these have higher odds of misusing PM, since the results all have p-values >0.1.

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Reviewer #2: No

Reviewer #4: No

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PONE-D-19-31426R2

Prevalence and Predictors of Prescription Drug Diversion, Misuse and Abuse among People Living with HIV in eThekwini District, KwaZulu-Natal, South Africa

PLOS ONE

Dear Dr. Chibi,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

ACADEMIC EDITOR:

 Thank you for addressing most of the concerns from the previous review. There are some remaining concerns:

    1) The legends (or footnotes) for Figures 2 and 4 should specify the difference between Model A and Model B.

    2) In the analysis section, the statements about the selection of factors included in the model should be appropriately referenced. For example, where in lines 329-30 commenting on "known confounders" of the exposure-outcome relationship. Also, with respect to the language in this paragraph; these are associations, not effects, between the variables and the outcomes. These factors are also more appropriately termed correlates, not predictors.

    4) The assessment of "drug abuse" is not an accepted method of measurement, and the terminology is outdated. The idea that one could assess this type of use by directly asking about use to intentionally harm oneself lacks the understanding that addiction is a behavioral pattern in which one uses substances despite the negative consequences. I highly recommend removing this from the paper and focusing on diversion and misuse and the types of misuse examined.

==============================

Please submit your revised manuscript by Oct 31 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Becky L. Genberg

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

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Prevalence and correlates of prescription drug diversion and misuse among people living with HIV in the eThekwini district, KwaZulu-Natal, South Africa

PONE-D-19-31426R3

Dear Dr. Chibi,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Dawn K. Smith

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thank you for the revisions in response to reviewer comments.