' s response to reviews Title : Clinical and Immunological outcomes according to adherence to first-line HAART in a urban and rural cohort of HIV-infected patients in Burkina Faso , West Africa

“Is known that in developing Countries adherence evaluation is a very challenging task.” Adherence is a challenge everywhere, in consequence of many different reasons, many times complementary and sometimes mutually reinforcing. There is no a priori reason patients from Burkina Faso should be more or less adherent than, for instance, uninsured Americans or drug dependent people anywhere. Optimal or less than optimal adherence is a function of a complex combination of individual and contextual variables. R: Thank you for this comment: we added the word “also” before the word “in”, accordingly (line 36) Developing countries is nowadays a very confusing category. “Low/Middle/High Income countries” should be used here. For instance, in the context of the current European crisis, Greece has a lower per capita GDP than most of the so-called “developing countries”. R: we thank for this comment but we do not agree. There is no established convention for the designation of “developed” and “developing” Countries or areas within the United Nation system. However, GDP per capita is not a measure of individual income. According to HDI we believe that life expectancy, education and income indicators must be considered in order to define a “low/middle/high income Country”. However, we changed all the “disputed” definition into “Low-income Countries” as suggested. “Literacy” is a key sociodemographic variable, which has been fully incorporated into key indicators such as HDI, and should be described as such! Thank you for this comment: unfortunately we are not able to calculate the education level as in HDI. We considered as “illiterates” those who were unable to read and write (analphabets). Besides, we considered as literates those who had gone to school for at least one year (then able to read and write). I have no idea what does a “custom” questionnaire mean. Please, use instead a regular concept people could easily understand when they read the abstract. R: we used the word “custom” to define a “home-made” and non-standardized questionnaire. According to the referee’s suggestion, we deleted the word “custom” from the manuscript. I must confess I could not follow such system of points that seems to refer to visits instead of measuring adherence to ARVs. Please, rephrase it, clarifying what does such original (?) process of ranking points (per visit?) actually mean. R: Thank you for this comment. However, as we mentioned in the background section: “WHO usually defines adherence to any treatment as “the extent to which a person’s behavior-taking medication, following a diet, and/or executing lifestyle changes, corresponds with agreed recommendations from a healthcare provider”. Since no measurement strategy can be considered optimal especially when used alone, an integrated multi-method approach is currently suggested. Therefore, not only punctuality to consultation but also “standard” adherence ARVs measurement such as pill count were considered CD4 absolute counts are quite inaccurate biomarkers of disease progress. I could not understand the reason the authors used it. Of course, they have results respecting overall lymphocyte counts, so proportions would be much more useful and accurate, and would not mean to spend a single extra cent. R: thank you for this comment: we agree that CD4 T-cell count alone is not an accurate marker of disease progression. However, in some settings (such as our setting in Burkina Faso) CD4+ T-cell count may be the ONLY immunological marker available. Therefore we analyzed it. Please, rephrase: “patients with higher adherence 51 (Group B p<0.001 and Group C p=0.014) and followed in a urban Center (p<0.001) were associated with lower”. Patients (i.e. concrete individuals) are NOT associated with something. Some of their characteristics may or may not be associated with a given outcome (such as optimal versus less than optimal adherence), so they be more or less likely to adhere to something. Variables and concrete individuals should not confused. Variables are amenable to statistical analysis, whereas individuals are something much more complex than what can be summarized by a small set of variables (in this specific case, a metrics defined by a ranking process, the place where patients have been followed, and a single biomarker!). R: thank you for this suggestion: we apologize for the mistake. We redrafted our conclusion accordingly Do the authors call absolute CD4 counts “Immunological outcomes” or do they include other data not mentioned before in their abstract? R: We thank for the referee’s comment: unfortunately, no immunological markers (other than absolute CD4+ T cell count) were available in our setting. Consequently, we used CD4+ T-cell count recovery as “immunological outcome”. “suggesting that our score might be a feasible 56 and suitable tool to easily and precisely monitoring HAART adherence.” This conclusion does not make sense. Something can NOT be based on a given criterion and then back-validates itself. Of course, statistical findings must be based on something, but cannot at the same time validate findings AND basic assumptions. This would be a circular way of defining ways to measure things and doing analysis. Actually, wrong assumptions may generate consistent findings, but cannot tell anything about their validity, so consistent associations between A and B may perfectly match, despite the fact both can be right (or totally wrong). So, in case I use dark green glasses to look at a horse, I may say he or she is green, what is perfectly consistent considering my glasses, but would means I would be finding green horses in nature! R: Thank you for this comment: following the editor’s comments as well, we redrafted our conclusion looking for a less strong and more appropriate results’ interpretation. Main Text: Background at the end of 2011 – Please update it! Were WHAT? Reported? “These dramatic data suggest that HIV infection in Africa is a major public health problem whose burden is very difficult to assess and control.” This has been repeated again and again by UNAIDS, the PEPFAR reports, the UNGASS sessions over three decades! Please, delete it or replace it with some concrete/innovative statement. R: we changed the text in the light of these suggestions by updating all the epidemiological data. “even in resource-limited settings” Why EVEN? Is there any intrinsic characteristic of people living in such countries that should make them “a priori” impervious to the benefits of medical science? R: In accordance with the referee’s comment we eliminated the word “even” (see text) “adherence monitoring represents a useful marker of HAART effectiveness” Monitoring is NOT a marker!, but rather an active process of tracking and evaluating things, providing feedback for policymakers and health professionals. R: thank you for this comment. We reformulated this sentence, as suggested (line 69) “Despite this, only few studies have been carried on to better assess adherence patterns in poor resource settings” This is by no means true. There are hundreds of papers assessing adherence in such settings. See, for instance, PEPFAR and/or CDC reports, available at: http://www.pepfar.gov/reports/progress/index.htm Or some peer-reviewed papers, available at: http://www.ncbi.nlm.nih.gov/pubmed/?term=lowincome+countries+and+ARVs R: We fully agree with this comment. Therefore, we better updated the state of art by adding some references. In particular this sentence was modified (line 72) “suitable methods should be implemented” They HAVE been implemented!, See, for instance, the creative papers by W. El-Sadr and her team as follows: http://www.ncbi.nlm.nih.gov/pubmed/?term=el-sadr+w R: thank you for this comment: we agree with the referee’s comment and we updated the cited references as suggested. “non absolute adherence is actually a normal behavior among HIV-infected individuals.” What does mean NORMAL here? R: thanks for your comment: we eliminated this sentence to avoid some conceptual misunderstandings that would need another paper to be adequately explicated,. “Aims of this study are: (1) to assess HAART adherence through a custom score” Whatever such “custom” score can mean, it is not an AIM, but rather a tool or means to achieve the actual aim, i.e. to accurately measure adherence in this concrete setting, among these concrete patients. R: thank you for this comment, we rephrased the sentence in order to better focalize the objectives’ presentation (lines 93).