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Date: 11/01/2022
To: "Lila Fairfax Hawkinson"
From: "The Green Journal" [email protected] Subject: Your Submission ONG-22-1710
RE: Manuscript Number ONG-22-1710
Universal Repeat Screening for HIV in the Third Trimester of Pregnancy: A Cost-Effectiveness Analysis Dear Dr. Hawkinson:
Thank you for sending us your work for consideration for publication in Obstetrics & Gynecology. Your manuscript has been reviewed by the Editorial Board and by special expert referees. The Editors would like to invite you to submit a revised version for further consideration.
If you wish to revise your manuscript, please read the following comments submitted by the reviewers and Editors. Each point raised requires a response, by either revising your manuscript or making a clear argument as to why no revision is needed in the cover letter.
To facilitate our review, we prefer that the cover letter you submit with your revised manuscript include each reviewer and Editor comment below, followed by your response. That is, a point-by-point response is required to each of the EDITOR COMMENTS (if applicable), REVIEWER COMMENTS, and STATISTICAL EDITOR COMMENTS (if applicable) below.
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Your submission will be maintained in active status for 21 days from the date of this letter. If we have not heard from you by 11/22/2022, we will assume you wish to withdraw the manuscript from further consideration.
EDITOR COMMENTS:
Please note the following:
* Help us reduce the number of queries we add to your manuscript after it is revised by reading the Revision Checklist at https://journals.lww.com/greenjournal/Documents/RevisionChecklist_Authors.pdf and making the applicable edits to your manuscript.
* Figures 1-3: Please be sure all figures are cited within the manuscript text and the figures are numbered for the original in which they first appear. Please upload as figure files on Editorial Manager.
REVIEWER COMMENTS:
Reviewer #1:
1. This is a detailed and laborious mathematic-modeling based study, which essentially (with considerable limitations, discussed by the authors late in the Discussion section), supports / confirms the obvious. Universal repeat screening for HIV infection in the third-trimester reduces the likelihood of vertical infection, enhances earlier appropriate maternal treatment, and due to the significantly low cost of (highly effective screening tools) is likely cost-effective.
2. I believe the authors should discuss and reference the CDC recommendation the prenatal providers routinely
recommend repeat HIV testing preferably at 34-36 weeks' gestation (see MMWR 2006; 55[RR-14}:1-17). The ideal timing for the second test is at least three (3 months after the initial test.
3. In our inner City teaching hospital serving a population of patients at increased risk of adverse perinatal outcome, we have long-practiced uniform (and State Department of Health-mandated) third-trimester screening. This practice has led to a considerable number of detections of patients who recently concerted to a HIV positive status, despite earlier first-
View Letter
1 of 3 11/28/2022, 11:54 AM
trimester HIV negative testing. In my assessment, detection of a potentially life-threatening disease to the mother and congenital infection of the fetus / neonate (the latter which may be treated if detected) cannot and should not, be a financial consideration.
4. The inherent drawbacks of mathematic modeling are clear and outlined by the authors. I am concerned specifically regarding the undetermined incidence of HIV in pregnancy, and in particular among patients considered at low-risk for adverse perinatal outcome.
5. Overall, the relative weaknesses of this submission are reflected in the final conclusion statement (lines # 216-219),
"clinicians should strongly consider offering repeat screening to patients regardless of their risk profile", and in the vague second sentence of the Abstract Conclusion statement (line # 29), "These results merit consideration of broader HIV screening in the third trimester".
6. I doubt these ill-defined conclusions will lead to implementation of significantly increased third-trimester screening for HIV by clinicians, without across the board / uniform requirements as directed by governing bodies.
7. Line # 201: Rather than "worse", I suggest the authors state "lower".
8.I find Figure 1, complex (despite being "collapsed for easier visualization").
Reviewer #2: The study analyzed the cost-effectiveness and anticipated outcomes of repeat third-trimester screening for asymptomatic HIV infection in women who were screened negative in the first trimester.
The study is very well-written with very few grammatical and/or syntax errors.
The first sentence in the study suggests that the standard of care in the United States requires HIV screening in the first trimester although 19 states and the District of Columbia have no statutory testing requirement for HIV testing at any time during pregnancy. Do the authors have an opinion on this apparent conflict between the law and the reported standard of care? (Lines 7-8)
The study states that "only select populations deemed at higher risk receiving repeat screening in the third trimester".
While this may be true in some states, 22 states have statutes requiring either HIV testing "in L&D", in the third trimester, or in the third trimester with subsequent neonatal screening. Discussion on this apparent discrepancy is warranted as it directly affects study applicability in certain jurisdictions (Lines 8-9)
"Receiving" should be "receive". (Line 9)
Why was the willingness-to-pay (WTP) threshold set at $100,000? (Lines 119-120)
The sentence beginning with "However" (Lines 184-185) is confusing and should be clarified.
The authors indicate that many patients in whom repeat testing is either medically warranted or statutorily required are currently not being retested (Lines 197-204). Do the authors have an opinion on why this is true? Given this finding, what additional impact is this study likely to make?
STATISTICAL EDITOR COMMENTS:
lines 122-123: The variability boundaries of 1 SD above or below the estimated standard probability is not wide enough, nor should 1 SD be the basis for determining the boundaries. Many of the probabilities, esp costs, would not be expected to conform to a normal or even symmetric distribution, but rather be extremely right skewed. Should run the model with more variability of the standard estimates. Should include the ranges for probabilities in Table 1 and either reference or otherwise justify the choice for distributions.
Need to include the tornado diagram.
Fig 3: Given the number of variables in Table 1, should increase the number of simulations to at least 50,000. Should also report in legend to ICE figure the proportion of simulations above the WTP= $100,000 demarcation line.
General: The model would perhaps be more informative if it did not assume uniformity of HIV risk for the entire birth cohort. If, rather, there were a high-risk subset (based on known risk factors) and lower risk subset, then how would the
View Letter
3 11/28/2022, 11:54 AM
cost-effectiveness of that scenario compare vs universal testing?
-- Sincerely,
Jason D. Wright, MD Editor-in-Chief
The Editors of Obstetrics & Gynecology
__________________________________________________
In compliance with data protection regulations, you may request that we remove your personal registration details at any time. (Use the following URL: https://www.editorialmanager.com/ong/login.asp?a=r). Please contact the publication office if you have any questions.
View Letter
3 11/28/2022, 11:54 AM
November 22
nd, 2022
Re: Resubmission of revised manuscript, “Universal Repeat Screening for HIV in the Third Tri- mester of Pregnancy: A Cost-Effectiveness Analysis”
The Editors
Obstetrics & Gynecology Dear Editors,
On behalf of my co-authors and myself, I am pleased to resubmit this revised manuscript, “Uni- versal Repeat Screening for HIV in the Third Trimester of Pregnancy: A Cost-Effectiveness Analysis” to be considered for publication as an original research piece in Obstetrics &
Gynecology. Each author participated in the data analyses, writing and editing of the manuscript, and approving this submitted version. The authors report no conflicts of interest. This manuscript has not been previously published by another journal nor is it under consideration elsewhere. The comments offered by reviewers of the original manuscript have been reviewed and responded to in the comments attached to this cover letter, as well as in the text of the revised manuscript. This manuscript will not be submitted elsewhere unless a final decision is made by the Editors of Obstetrics & Gynecology.
As this study was a theoretical cohort that involved no human subjects, no institutional review board approval was required.
I will be serving as the corresponding author if you have any questions about the manuscript.
Thank you for your consideration.
Sincerely,
Lila F. Hawkinson M.D. Candidate
Oregon Health & Science University
The lead author, Lila Hawkinson, affirms that this manuscript is an honest, accurate, and trans- parent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.
Signed by: Lila Hawkinson
Obstetrics & Gynecology, Response to Reviewers, 1st Revision
Universal Repeat Screening for HIV in the Third Trimester of Pregnancy: A Cost-Effectiveness Analysis EDITOR COMMENTS: Please note the following: * Help us reduce the number of queries we add to your manuscript after it is revised by reading the Revision Checklist at
https://urldefense.com/v3/ https://journals.lww.com/greenjournal/Documents/RevisionChecklist Authors.pdf ;!!
Mi0JBg!NuDYOk5KO8TUCMm2OK4RmmtHvTOBrGmXin2JuP8Yrp5de5l6Li7RBGEePtYGSFH0LhQ5nEAMz PMBXRDm9Q$ and making the applicable edits to your manuscript.
Thank you for this information. We have reviewed the Revision Checklist and included the required compo- nents in the revision submission. * Figures 1-3: Please be sure all figures are cited within the manuscript text and the figures are numbered for the original in which they first appear. Please upload as figure files on Editorial Manager.
Thank you. All figures have been cited within the text and have been uploaded on Editorial Manager.
REVIEWER COMMENTS Reviewer #1:
1. This is a detailed and laborious mathematic-modeling based study, which essentially (with considerable limita- tions, discussed by the authors late in the Discussion section), supports / confirms the obvious. Universal repeat screening for HIV infection in the third-trimester reduces the likelihood of vertical infection, enhances earlier ap- propriate maternal treatment, and due to the significantly low cost of (highly effective screening tools) is likely cost- effective.
Thank you for this supportive comment.
2. I believe the authors should discuss and reference the CDC recommendation the prenatal providers routinely rec- ommend repeat HIV testing preferably at 34-36 weeks' gestation (see MMWR 2006; 55[RR-14}:1-17). The ideal timing for the second test is at least three (3) months after the initial test.
Thank you for this suggestion. The recommendations outlined by the CDC in this 2006 document parallel those discussed in the Introduction and Discussion section of this paper; third trimester screening is recom- mended for pregnant individuals who meet “high risk” criteria, while it is also noted that repeat screening
“may be considered” for all pregnant patients. The paper cited in support of this recommendation is also cit- ed in our paper (Sansom et al, 2003).1 However, this study is limited by a perspective that incorporated only neonatal QALYs (rather than also considering maternal QALYs) and by publication prior to the current generation of HIV screening tests and combined antiretroviral therapies. We have enhanced this area of the manuscript - see below.
Original manuscript: “Current screening guidelines call for universal opt-out HIV testing at the initial prena- tal visit, with repeat screening in the third trimester for select populations deemed at higher risk.”
Lines 41-46, revised manuscript: “Current American College of Obstetricians and Gynecologists (ACOG) and CDC screening guidelines call for universal opt-out HIV testing at the initial prenatal visit, with repeat screening in the third trimester for select populations deemed at higher risk. CDC guidelines additionally state that third trimester screening may be considered as a cost effective measure for all pregnant individuals, but stop short of a stronger endorsement of this practice.”
3. In our inner City teaching hospital serving a population of patients at increased risk of adverse perinatal outcome, we have long-practiced uniform (and State Department of Health-mandated) third-trimester screening. This practice has led to a considerable number of detections of patients who recently converted to a HIV positive status, despite earlier first-trimester HIV negative testing. In my assessment, detection of a potentially life-threatening disease to
the mother and congenital infection of the fetus / neonate (the latter which may be treated if detected) cannot and should not, be a financial consideration.
Thank you for this important comment. This comment reflects the ways in which repeat screening guidelines are unevenly applied; as discussed in the manuscript, third trimester testing in high prevalence areas is not uniform, even in states where it is required by law. While some health systems (such as this reviewer’s) may require such screening, others may not have implemented such an institutional policy. Shortcomings in risk- based screening have been identified in high prevalence communities since the 1990s.2,3
While we agree that decisions regarding care practices should not be based on financial considerations, prov- ing cost-effectiveness can be a significant impetus to change in a US healthcare system that is, unfortunately, constructed around profit. Given this context, interventions should be assessed both by cost and burden on the healthcare system in identifying what should be prioritized in a system with limited resources. Ultimately, cost-effectiveness analyses have a role in guiding policy and in supporting insurance coverage for aspects of care.
4. The inherent drawbacks of mathematic modeling are clear and outlined by the authors. I am concerned specifical- ly regarding the undetermined incidence of HIV in pregnancy, and in particular among patients considered at low- risk for adverse perinatal outcome.
This is an important note, and thus is discussed at several points throughout the manuscript (including Mate- rial and Methods and Discussion). One of the advantages of cost-effectiveness modeling is the ability to exam- ine a range of assumptions to obtain additional information. To better understand how the baseline incidence of HIV impacts the model, we performed univariable sensitivity analysis on the probability of HIV in preg- nancy, which showed that third trimester is screening is cost-effective if the incidence rate is above 0.0052%.
Additionally, on our multivariable Monte Carlo simulation we found that third-trimester HIV screening is cost-effective in the vast majority of simulations (85%).
5. Overall, the relative weaknesses of this submission are reflected in the final conclusion statement (lines # 216- 219), "clinicians should strongly consider offering repeat screening to patients regardless of their risk profile", and in the vague second sentence of the Abstract Conclusion statement (line # 29), "These results merit consideration of broader HIV screening in the third trimester".
Thank you for this comment. We agree that our results have limitations and that the uncertainty in our re- sults must be noted in our conclusions.
6. I doubt these ill-defined conclusions will lead to implementation of significantly increased third-trimester screen- ing for HIV by clinicians, without across the board / uniform requirements as directed by governing bodies.
Thank you for this note. We agree that this paper is unlikely to impact broad change in practice, but hope that our study might be used by governing bodies such as ACOG to make stronger recommendations regard- ing HIV screening in pregnancy.
7. Line # 201: Rather than "worse", I suggest the authors state "lower".
Thank you for this suggestion. The manuscript has been revised accordingly.
Original manuscript: “Screening rates are considerably worse in regions without legislation in place...”
Lines 236-239, revised manuscript: “Notably, Florida is one of only 17 states with statutes requiring third trimester screening, and screening rates are considerably lower in high incidence regions without legislation in place.”
8.I find Figure 1, complex (despite being "collapsed for easier visualization").
Thank you for this feedback. The figure has been further simplified; see Figure 1 in the revised manuscript for these changes.
Reviewer #2: The study analyzed the cost-effectiveness and anticipated outcomes of repeat third-trimester screening for asymptomatic HIV infection in women who were screened negative in the first trimester. The study is very well- written with very few grammatical and/or syntax errors.
Thank you for this supportive comment.
The first sentence in the study suggests that the standard of care in the United States requires HIV screening in the first trimester although 19 states and the District of Columbia have no statutory testing requirement for HIV testing at any time during pregnancy. Do the authors have an opinion on this apparent conflict between the law and the re- ported standard of care? (Lines 7-8)
Thank you for this clarifying point. This sentence has been updated to reflect that the “standard of care” de- fined here is as per ACOG guidelines, rather than testing statutes. See below.
Original manuscript: “Current screening guidelines call for universal opt-out HIV testing at the initial prena- tal visit, with repeat screening in the third trimester for select populations deemed at higher risk.”
Lines 41-44, revised: “Current American College of Obstetricians and Gynecologists (ACOG) and CDC screening guidelines call for universal opt-out HIV testing at the initial prenatal visit, with repeat screening in the third trimester for select populations deemed at higher risk.”
The study states that "only select populations deemed at higher risk receiving repeat screening in the third tri- mester". While this may be true in some states, 22 states have statutes requiring either HIV testing "in L&D", in the third trimester, or in the third trimester with subsequent neonatal screening. Discussion on this apparent discrepancy is warranted as it directly affects study applicability in certain jurisdictions (Lines 8-9)
We thank the reviewer for this comment. While there are states, such as Florida, that have statutes requiring third trimester testing, they have relatively poor rates of repeat testing. Further, one important difference between third trimester screening and L&D screening is that the effectiveness of antiretroviral therapy in reducing viral loads <1000 can only happen with earlier third trimester screening, not simply with intrapar- tum zidovudine. Additional discussion to address this point has been incorporated in the Discussion section as outlined in the passages below. Original manuscript: “Our model was also constructed in comparison to a testing strategy incorporating first trimester screening only, while current guidelines advise repeat screening in the third trimester for individuals considered at high risk.However, this comparison was appropriate, giv- en the limited degree of third trimester screening even among communities and individuals at elevated risk.” Lines 230-234, revised manuscript: “Our model was also constructed in comparison to a testing strategy incorporating first trimester screening only, while current national guidelines advise repeat screen- ing in the third trimester for individuals considered at high risk.However, this comparison was appropriate, given the limited degree of third trimester screening even for those at elevated risk and in states with third trimester screening requirements.” Original manuscript: “Screening rates are considerably lower in high incidence regions without legislation in place, with only 28.4% of pregnant women receiving repeat screening in the high incidence setting of Baltimore. Repeat screening has not been well-studied in lower incidence set- tings, but only 82.4% of pregnant individuals nationally receive any prenatal screen for HIV, and as low as 68.3% of patients on a state-by-state basis.”
Lines 237-246, revised manuscript: “Notably, Florida is one of only 17 states with statutes requiring third trimester screening, and screening rates are considerably lower in high incidence regions without legislation in place. In Baltimore, which has the third highest rate of HIV diagnoses across metropolitan areas nation- wide, only 28.4% of pregnant individuals received repeat screening.Several factors may contribute to this picture, including poor patient access to consistent prenatal care, unanticipated delivery prior to term, and
lack of adherence to guidelines by physicians – possibly due to inadequate understanding of HIV prevalence in their communities. Repeat screening has not been well-studied in lower incidence settings, but only 82.4%
of pregnant individuals nationally receive any prenatal screen for HIV, and as low as 68.3% of patients on a state-by-state basis.”
"Receiving" should be "receive". (Line 9)
Thank you for identifying this error. This line has been updated (lines 9-10 of the revised manuscript).
Original manuscript: “However, only select populations deemed at higher risk receiving repeat screening in the third trimester.”
Lines 9-10, revised manuscript: “However, only select populations deemed at higher risk receive repeat screening in the third trimester.”
Why was the willingness-to-pay (WTP) threshold set at $100,000? (Lines 119-120)
Thank you for this question. In the United States, the most common WTP threshold is $100,000, although this may vary by country and healthcare system. We have added a citation at line 140 to support that this is standard for these analyses in the United States.4
The sentence beginning with "However" (Lines 184-185) is confusing and should be clarified.
Thank you for this comment. This sentence is lines 200-204 in the revised manuscript; it has been edited for clarity:
Lines 200-204, original manuscript: “However, considering the costs associated with repeat testing for 3.8 million individuals, this is a relatively low cost per QALY, demonstrating the significant decrease in HIV treatment costs when diagnosed at an earlier stage of infection as well as the clinical benefits of preventing vertical transmission. ”
Lines 200-204, revised manuscript: “However, the ICER still falls far below the WTP threshold of $100,000, likely due to the decrease in need for and the costs of HIV treatment both when HIV is diagnosed at an earli- er stage of infection as well as due to decreased vertical transmission. ”
The authors indicate that many patients in whom repeat testing is either medically warranted or statutorily required are currently not being retested (Lines 197-204). Do the authors have an opinion on why this is true? Given this finding, what additional impact is this study likely to make?
Thank you for this thoughtful comment. This may be the case due to the fragmented nature of current testing regulations, with significant state-by-state differences, including relatively recent adoption of universal test- ing statutes by states such as Maryland. There may be significant differences among practice settings as well, with some centers providing additional institutional support ensuring third trimester testing. Patient access to care is likely another factor in these discrepancies.
With regard to impact, we hope that our study might be used by governing bodies such as ACOG to make stronger recommendations regarding HIV screening in pregnancy. We have expanded upon the issues raised by your questions in the Discussion section - see lines 237-246 of the revised manuscript.
Original manuscript: “Screening rates are considerably lower in high incidence regions without legislation in place, with only 28.4% of pregnant women receiving repeat screening in the high incidence setting of Balti- more. ”
Lines 237-246, revised manuscript: “Notably, Florida is one of only 17 states with statutes requiring third trimester screening, and screening rates are considerably lower in high incidence regions without legislation in place. In Baltimore, which has the third highest rate of HIV diagnoses across metropolitan areas nation- wide, only 28.4% of pregnant individuals received repeat screening prior to the 2018 adoption of a Maryland statute requiring universal third trimester screening. Several factors may contribute to this picture, including poor patient access to consistent prenatal care, unanticipated delivery prior to term, and lack of adherence to guidelines by physicians – possibly due to inadequate understanding of HIV prevalence in their communi- ties.”
STATISTICAL EDITOR COMMENTS: lines 122-123: The variability boundaries of 1 SD above or below the es- timated standard probability is not wide enough, nor should 1 SD be the basis for determining the boundaries. Many of the probabilities, esp costs, would not be expected to conform to a normal or even symmetric distribution, but rather be extremely right skewed. Should run the model with more variability of the standard estimates. Should include the ranges for probabilities in Table 1 and either reference or otherwise justify the choice for distributions.
Thank you for this helpful comment. Table 1 has been updated to reflect the ranges used in generation of the tornado diagram, which encompass 3 standard deviations above and below the estimated mean. The distribu- tions used are those discussed in the Materials and Methods section regarding the Monte Carlo simulation - see lines 146-149 of the revised manuscript. A beta distribution was used for probabilities and utilities, gam- ma distribution for costs, and triangular distribution for life expectancies.
Need to include the tornado diagram.
Thank you for this note. We have added our Tornado Diagram to the manuscript. Please see Figure 2.
Fig 4: Given the number of variables in Table 1, should increase the number of simulations to at least 50,000.
Should also report in legend to ICE figure the proportion of simulations above the WTP= $100,000 demarcation line.
Thank you for this feedback. The simulation has been rerun for 50,000 samples and the figure has been up- dated (Figure 4). This resulted in 85% of samples falling below the WTP threshold (compared to 84% previ- ously). The legend has been updated to reflect the proportion of samples above the WTP line.
General: The model would perhaps be more informative if it did not assume uniformity of HIV risk for the entire birth cohort. If, rather, there were a high-risk subset (based on known risk factors) and lower risk subset, then how would the cost-effectiveness of that scenario compare vs universal testing?
Thank you to the reviewer for this suggestion. We agree that this would be an interesting addition to our study. To better understand how the baseline incidence of HIV impacts the model, we performed univariable sensitivity analysis on the probability of HIV in pregnancy, which showed that third trimester is screening is cost-effective until the incidence rate is below 0.0052%. Additionally, part of the underlying hypothesis of this paper is that targeted/risk-based screening guidelines do not result in adequate clinical uptake when actual testing practices are reviewed.
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2. Barbacci MB, Dalabetta GA, Repke JT, et al. Human immunodeficiency virus infection in women attending an inner-city prenatal clinic: ineffectiveness of targeted screening. Sex Transm Dis 1990;17:122--6.
3. Fehrs LJ, Hill D, Kerndt PR, Rose TP, Henneman C. Targeted HIV screening at a Los Angeles prenatal/family planning health center. Am J Public Health 1991;81:619--22.
4. Ubel PA, Hirth RA, Chernew ME, Fendrick AM. What is the price of life and why doesn't it increase at the rate of inflation?. Arch Intern Med. 2003;163(14):1637-1641. doi:10.1001/archinte.163.14.1637
