Author's response to reviews Title: Mortality and loss-to-follow-up during the pre-treatment period in an antiretroviral therapy programme under normal health service conditions in Uganda. Authors: Barbara Amuron (barbara_amuron@mrcuganda.org) Geoffrey Namara (namsgfr@yahoo.com) Josephine Birungi (birungijophine@yahoo.com) Christine Nabiryo (Nabiryoc@tasouganda.org) Jonathan Levin (jonathan.levin@mrcuganda.org) Heiner Grosskurth (heiner.grosskurth@mrcuganda.org) Alex Coutinho (acoutinho@idi.co.ug) Shabbar Jaffar (shabbar.jaffar@lshtm.ac.uk) Version: 2 Date: 3 July 2009 Author's response to reviews: see over
London School of Hygiene & Tropical Medicine (University of London) Department of Epidemiology and Population Health Keppel Street, London WC1E 7HT Tel: 020 7927 2418, Mobile: 07900 924 473 email shabbar.jaffar@lshtm.ac.uk INFECTIOUS DISEASE EPIDEMIOLOGY UNIT 29 June 09 Dear Editor We thank you for the review of our paper. Our response is as follows: Reviewer 1. This referee has made positive comments about the paper and did not raise any questions which need addressing. Reviewer 2: Stephen Lawn. Our responses are below in bold Reviewer's report: A fairly extensive literature exists concerning rates of mortality and loss to follow-up among patients accessing antiretroviral therapy (ART) in sub-saharan Africa. However, few studies have addressed the issue of losses to care among patients eligible and preparing to start ART. This is a very nice study from Uganda which clearly documents these losses among a large number of patients accessing care in rural Uganda. This is methodologically sound, clearly written and the conclusions are appropriate. The study highlights the high pre-art mortality and high rates of loss to follow-up, with financial barriers to health care access being identified as a key contributing factor to the latter. The paper could be strengthened in a number of ways as follows: It is unclear in the methods section how the network of HIV clinics is linked to the broader health care infrastructure and how patients access these HIV / ART clinics. This is an important issue as I suspect health systems delays upstream of the ART services (eg delayed referrals of patients diagnosed within TB clinics) may also contribute to pre-art mortality. Response: TASO is an independent NGO which has registered patients who receive care and support. The organisation does not have formal referral systems with the government services. However, because of the size of TASO (it has large centres in all parts of the country), most HIV-infected subjects and health care providers in the country know about TASO services and that these can accessed easily. We have now clarified that TASO bagan providing information to its registered clients and that 1
subsequently all subjects, including newly qualified could acess ART. This paragraph now reads: TASO began providing information about ART to its registered clients around the end 2003, mostly through group meetings and drama shows. Patients were screened for eligibility from August 2004 and the first patients began treatment about 4 weeks later. Recruitment into the programme ended in December 2006 when the funds available at that time had been used up. TASO was by far the largest provider of ART in the region. Patients who had been with the organisation the longest were given priority during the first year of the programme and thereafter ART was made available to all, including newly registered clients, on a first come first served basis. Referee comment: Methods, paragraph 3. TB (WHO stage 3 or 4) is not mentioned here with regard to ART eligibility. Please clarify. Response: we have removed reference to the individual conditions and this now reads: Those at WHO stage III or stage IV, or with CD4 count less 200 x10 6 /l were considered eligible for ART. Referee comment: Methods. Loss to follow-up must be defined. It seems from the Results section that patients took up to 406 days between the first and third clinic visits without being defined as lost to follow-up. There needs to be some sort of definition with a cut-off (however arbitrary this may seem) otherwise there is no distinction between lost to follow-up and just taking a rather long time between appointments. Response: We have now clarified this as the referee suggested: In the methods, we say Patients who had had an intial screening visit at anytime between the beginning of the TASO ART programme in 2003 and December 2006 and who had not initiated ART by May 2007 were followed-up. Referee comment: Discussion: How representative of the ART clinics described of HIV / ART services in Uganda? ie please comment on the generalisability of the data and on other limitations of this study. 2
Response: we have taken on board the referee s suggestion and have added the sentence below in the discussion. A strength of our study was that it was done under normal health service conditions in a typical predominantly rural setting with care provided according to national guidelines. However, our study population had high rates of disclosure of their HIV status and a good and sometimes long-standing relationship with the service provider. It is possible that in other parts of Africa, where stigma is greater and the health service is less personalised, that the rates of retention, early mortality and others outcomes might be even worse than observed in our study. Referee comment: Discussion, paragraph 2. The decrease over time in the proportion of patients completing screening could also reflect diminishing capacity within these clinics to cope with escalating patient load. This is an important issue with concerning sustainability of ART scale up. Our experience in South Africa is that rates of loss to follow-up have increased over time because of this. Response: in Uganda, we think it was mostly because earlier patients were more motivated and that more recently there has been a much greater choice of service providers and we think people are switching between programmes. Nonetheless, we cannot rule the possibility of escalting workload affecting retention and have added this to the sentence. This entire sentece now reads: The reasons for this increase over time in the number who did not complete screening are unclear but it is possible that earlier patients were more motivated, that more recently there was a greater choice of service providers available and TASO patients left to join other programmes or it may reflect diminishing capacity within the TASO clinic to cope with escalating patient load. Referee comment: Discsussion, para 3. The issue of financial / logistical barriers to accessing care is obviously an important one. If the data were available, it would have been nice to assessed distance to travel to the clinic from home. Response: we don t have these data in this population group. This a complex question since distance can be calculated in different ways. Referee comment: Discussion. The high mortality rate in the screening period provides a window into the possibility of a much greater cumulative mortality risk accruing upstream of ART services. This raises a whole raft of other issues health systems delays, 3
ART eligibility criteria, need for much earlier HIV diagnosis. Without inappropriately lengthening the paper too much, I think the discussion could be broadened a little with regard to these bigger picture issues. Response: we would prefer to keep the paper focussed on the issues relating to our data. However, we have taken on board the referee s suggestion and added an additional paragraph in the discussion. This reads: Our research indicates clearly of the priority to identify people earlier in the course of their HIV-infection and initiate ART sooner but how this should be done is unclear given the weak health systems in Africa, in particular the severe shortages of clinical staff and the difficulties of accessing care for patients. Whether HIV-infected patients who present to health services with advanced disease could be started on ART immediately, with limited pre-art counselling, is also unclear. Research is needed to inform health service strategy and to identify cost-effective and sustainable models of HIV care. Referee comment: Discussion. In light of the high mortality accruing during the pre-art preparation period, the authors should address the pros and cons of the 4-8 week duration of this period. Response: we have addressed in the paragraph above. We say: Whether HIV-infected patients who present to health services with advanced disease could be started on ART immediately, with limited pre-art counselling, is also unclear. Referee comment: Discussion. Did the authors consider any other potential causes of high loss to follow-up? For example, some published data have highlighted pregnant women as having high risk of loss to follow-up, possibly as a result of the challenges these women face in attending multiple fragmented components of the healthcare system..art services, TB clinics, ANCs, paediatric clinics etc. Response: This did not come up as a reason in our cohort (among subjects who were lost to follow-up after the initial screening visit) (very few of our sample of women will have been pregnant). All the reasons reported by the patients are shown in Table 3. Referee comment: Discussion / Introduction: The following study from South Africa has just been published and should be included : Bassett et al. Loss to care and death before antiretroviral therapy in Durban, South Africa. J Acquir Immune Defic Syndr. 2009 Jun 1;51(2):135-9. 4
Response. We have included this study but have given it minimal mention since thid is a relatively small study, it was retrospective, done in an urban setting, had a high loss to follow-up, and used a cut-off for loss which was too narrow (3 months). Level of interest: An article of importance in its field Quality of written English: Acceptable Statistical review: Yes, and I have assessed the statistics in my report. Declaration of competing interests: 'I declare that I have no competing interests' Response to editor comments The following formatting revisions should also be made: 1) Please comment in the Methods section whether ethical approval was needed for this study. If yes, please document the details of the approval. Response: In fact ethical approval was not needed because this study was done as part of normal care. Much of the data come from TASO records. Patients were visited at home to ascertain their survival status but it is routine practice within TASO to do this for patients who are lost to follow-up. TASO conduct scientific and institutional ethics review of all research and this study was approved under that umbrella. Further, patients at TASO Jinja have given consent to use routinely collected programme data for purposes of operational research and publication and and a number of publications and abstracts have been prepared on this basis by TASO staff. We have added to the section below to the methods: The data presented here refer to the screening period before ART initiation and were collected to inform TASO services. They were collected as part of routine TASO service delivery. Patients at TASO Jinja have given consent for use of routinely collected programme data for purposes of operational research and publication. 2) Please include a 'Competing interests' section between the Conclusions and Authors' contributions. If there are none to declare, please write 'The authors declare that they have no competing interests'. The questions that are asked of authors are: Financial competing interests 5
- In the past five years have you received reimbursements, fees, funding, or salary from an organization that may in any way gain or lose financially from the publication of this manuscript, either now or in the future? Is such an organization financing this manuscript (including the article-processing charge)? If so, please specify. - Do you hold any stocks or shares in an organization that may in any way gain or lose financially from the publication of this manuscript, either now or in the future? If so, please specify. - Do you hold or are you currently applying for any patents relating to the content of the manuscript? Have you received reimbursements, fees, funding, or salary from an organization that holds or has applied for patents relating to the content of the manuscript? If so, please specify. - Do you have any other financial competing interests? If so, please specify. Non-financial competing interests Are there any non-financial competing interests (political, personal, religious, academic, ideological, intellectual, commercial or any other) to declare in relation to this manuscript? If so, please specify. Response: we have no conflict have interest and have now stated 'The authors declare that they have no competing interests'. 3) Please include an Authors' contributions section before the Acknowledgements and Reference list. For the Authors' contributions we suggest the following kind of format (please use initials to refer to each author's contribution): AB carried out the molecular genetic studies, participated in the sequence alignment and drafted the manuscript. JY carried out the immunoassays. MT participated in the sequence alignment. ES participated in the design of the study and performed the statistical analysis. FG conceived of the study, and participated in its design and coordination. All authors read and approved the final manuscript. An "author" is generally considered to be someone who has made substantive intellectual contributions to a published study. To qualify as an author one should 1) have made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; 2) have been involved in drafting the manuscript or revising it critically for important intellectual content; and 3) have given final approval of the version to be published. Each author should have participated sufficiently in the work to take public responsibility for appropriate portions of the content. Acquisition of funding, collection of data, or general supervision of the research group, alone, does not justify authorship. All contributors who do not meet the criteria for authorship should be listed in an acknowledgments section. Examples of those who might be acknowledged include a person who provided purely technical help, writing assistance, or a department chair who provided only general support. Thank you we have done this. Author contribution: BA, GN and JB co-ordinated the study. BA wrote the first draft of the paper. GN managed the data. JL did the statistical analysis. CN, HG, AC, SJ designed the study and monitored progress. SJ wrote second and subsequent drafts of the paper. All authors contributed to the drafts of the paper and have seen and agreed to the final version of the paper. Please also ensure that your revised manuscript conforms to the journal style (http://www.biomedcentral.com/info/ifora/medicine_journals ). It is important that your files are correctly formatted. 6
We look forward to receiving your revised manuscript by 17 July 2009. If you imagine that it will take longer to prepare please give us some estimate of when we can expect it. You should upload your cover letter and revised manuscript through http://www.biomedcentral.com/manuscript/login/man.asp?txt_nav=man&txt_man_id=1944392876278827. You will find more detailed instructions at the base of this email. Yours sincerely, Dr Shabbar Jaffar Reader in Epidemiology 7