Composition Vendor Newgen KnowledgeWorks (P) Ltd. PLoS ONE plos plosone PLOS ONE 1932-6203 Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0317223 PONE-D-23-40207 Research Article Biology and life sciencesMicrobiologyMedical microbiologyMicrobial pathogensViral pathogensImmunodeficiency virusesHIVHIV-2 Medicine and health sciencesPathology and laboratory medicinePathogensMicrobial pathogensViral pathogensImmunodeficiency virusesHIVHIV-2 Biology and life sciencesOrganismsVirusesViral pathogensImmunodeficiency virusesHIVHIV-2 Biology and life sciencesOrganismsVirusesImmunodeficiency virusesHIVHIV-2 Biology and life sciencesOrganismsVirusesRNA virusesRetrovirusesLentivirusHIVHIV-2 Biology and life sciencesMicrobiologyMedical microbiologyMicrobial pathogensViral pathogensRetrovirusesLentivirusHIVHIV-2 Medicine and health sciencesPathology and laboratory medicinePathogensMicrobial pathogensViral pathogensRetrovirusesLentivirusHIVHIV-2 Biology and life sciencesOrganismsVirusesViral pathogensRetrovirusesLentivirusHIVHIV-2 Biology and life sciencesMicrobiologyMedical microbiologyMicrobial pathogensViral pathogensImmunodeficiency virusesHIV Medicine and health sciencesPathology and laboratory medicinePathogensMicrobial pathogensViral pathogensImmunodeficiency virusesHIV Biology and life sciencesOrganismsVirusesViral pathogensImmunodeficiency virusesHIV Biology and life sciencesOrganismsVirusesImmunodeficiency virusesHIV Biology and life sciencesOrganismsVirusesRNA virusesRetrovirusesLentivirusHIV Biology and life sciencesMicrobiologyMedical microbiologyMicrobial pathogensViral pathogensRetrovirusesLentivirusHIV Medicine and health sciencesPathology and laboratory medicinePathogensMicrobial pathogensViral pathogensRetrovirusesLentivirusHIV Biology and life sciencesOrganismsVirusesViral pathogensRetrovirusesLentivirusHIV Biology and life sciencesMicrobiologyVirologyViral transmission and infectionViral load Biology and life sciencesImmunologyVaccination and immunizationAntiviral therapyAntiretroviral therapyProtease inhibitor therapy Medicine and health sciencesImmunologyVaccination and immunizationAntiviral therapyAntiretroviral therapyProtease inhibitor therapy Medicine and health sciencesPublic and occupational healthPreventive medicineVaccination and immunizationAntiviral therapyAntiretroviral therapyProtease inhibitor therapy Biology and life sciencesImmunologyVaccination and immunizationAntiviral therapyAntiretroviral therapy Medicine and health sciencesImmunologyVaccination and immunizationAntiviral therapyAntiretroviral therapy Medicine and health sciencesPublic and occupational healthPreventive medicineVaccination and immunizationAntiviral therapyAntiretroviral therapy Medicine and health sciencesDiagnostic medicineHIV diagnosis and management Medicine and health sciencesDiagnostic medicineTuberculosis diagnosis and management Biology and life sciencesPopulation biologyPopulation metricsDeath rates Mortality, loss to follow-up and advanced HIV disease following virologic success in West African HIV-2 patients Mortality, loss to follow-up, advanced HIV disease following virologic success in West African HIV-2 patients https://orcid.org/0009-0005-8972-8114 Koffi Jean J. Formal analysis Project administration Supervision Writing – original draft 1 2 * Boni Simon P. Formal analysis Writing – original draft 1 3 Mba Lionèle Investigation Resources 1 4 Bitty-Anderson Alexandra Writing – review & editing 1 5 Tchabert Annick G. Writing – review & editing 1 Toure Frank Y. Writing – review & editing 1 Coffie Patrick A. Writing – review & editing 1 2 6 Inwoley Andre Writing – review & editing 4 6 Eholie Serge Paul Writing – review & editing 1 2 6 Ekouevi Didier K. Conceptualization Validation Writing – review & editing 1 5 7 Tchounga Boris Conceptualization Formal analysis Methodology Validation Writing – original draft Writing – review & editing 1 8 Programme PACCI site ANRS de Côte d’Ivoire, Abidjan, Côte d’Ivoire Service des Maladies Infectieuses et Tropicales, CHU de Treichville, Abidjan, Côte d’Ivoire Programme de lutte contre le cancer, Abidjan, Côte d’Ivoire Research and Diagnosis Center for AIDS and other infectious diseases (CeDReS), CHU (University Hospital) of Treichville, Abidjan, Côte d’Ivoire Centre Inserm 1219 & Institut de Santé Publique d’épidémiologie et de développement, Université de Bordeaux, Bordeaux, France Université Félix Houphouët-Boigny, Abidjan, Côte d’Ivoire Département de santé Publique, Faculté des Sciences de la santé, Université de Lomé, Lomé, Togo Elizabeth Glazer Pediatric A.I.D.S. Foundation, Yaoundé, Cameroon Dememew Zewdu Gashu Editor Management Sciences for Health (MSH), ETHIOPIA * E-mail: jean-jacques.koffi@pac-ci.org

The authors have declared that no competing interests exist.

 242025 2025 20 4 e0317223 6122023 23122024 2025 Koffi et al This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background

People living with HIV-2 are mainly found in West Africa and their identification and treatment have been impaired by diagnostic challenges and availability of effective antiretroviral treatment (ART). With the roll out of first line dolutegravir (DTG)-based regimen, the situation may have improved, emphasizing the need for data on long-term treatment outcomes and advanced HIV disease among ART-experienced people living with HIV-2.

 Method

A prospective cohort was initiated in 2012 in Côte d’Ivoire and Burkina Faso. All adult patients from Côte d’Ivoire with an undetectable viral load, were included and followed up. HIV-2 viral load and CD4 counts were done during the routine follow-up visits and a detailed clinical assessment was done during the last follow up visit of the year 2018 corresponding to the censor date of the cohort. Outcomes were described as follow: in care (known alive and present during the last ART follow up visit), loss to follow-up (absent for more than 90 days and not reported dead), and dead (reported dead with a date of event). Advanced HIV disease followed WHO definition and virologic failure was define as viral load > 50 copies/mm3. The Kaplan-Meier curve was used to estimate mortality and Loss to follow-up probability.

 Results

Among the 108 HIV-2 patients in virologic success in 2012, 95 agreed to participate and were enrolled in the “success cohort”. Their median age was 53 [47–60] years and all of them were receiving boosted-lopinavir-based ART regimen. Of the 95 participants, 65 (68.4%) remained in care, 20 (21.1%) were loss to follow-up and 10 (10.5%) were reported dead. The survival analysis retrieved a decreasing probability of remaining alive and in care over the time, moving from 90% to 80.7% and to 73.0% after 24, 48 and 72 months respectively. Overall, 36 (37.9%) patients presented with advanced HIV disease at their last visit, higher among those dead/ loss to follow-up compared to those remaining in care (60.0% vs 27.7%; p-0.003).

 Conclusion

High advanced HIV disease rate was found in HIV-2 patients, six years after an initial virologic success. This emphasizes the need to enable the one-stop-shop model that allow an early management of opportunistic infections while integrating non-communicable diseases services in HIV-2 care.

 The author(s) received no specific funding for this work. Data Availability The data is available on figshare at the following address: https://figshare.com/s/a8b9fa7d5ba8a5968235 Introduction

HIV-2 is endemic in West Africa and in countries with historical ties to this part of the world [1]. Compared with HIV-1 infection, HIV-2 is characterized by a longer asymptomatic stage, lower plasma viral load, decreased mortality rate due to AIDS, lower rates of sexual transmission [2–5]. However, without appropriate care and treatment, a significant proportion of people living with HIV-2 (PLHIV-2) progress to AIDS disease [2,6], and experience AIDS-related morbidity and mortality [7].

HIV-2 is also characterized by an intrinsic resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) and the suboptimal treatment response to some protease inhibitors (PI), as mainly three PI have potent activity against HIV-2: lopinavir, saquinavir and darunavir [8–11]. Recent data indicate that integrase strand transfer inhibitor (INSTI) class is safe and effective against HIV-2 [12,13]. In addition, the 2019 WHO guidelines recommend dolutegravir (DTG) combined with a nucleoside reverse transcriptase inhibitor (NRTI) as first-line treatment for people starting antiretroviral therapy (ART), including those living with HIV-2. [14].

In addition to the long-term management of ART regimen, the monitoring of treatment response is also challenging for PLHIV-2. Data from the Natural history of HIV-2 infection in adult patients living in France Cohort Study (ANRS CO5 HIV-2) showed lower than expected CD4 cell recovery in HIV-2 treated patients, despite the high virologic suppression rate [15]. Viral load assay for HIV-2 was recently approved and is still on the process for routine utilization as per the national guidelines [16].

As the treatment options for the management of PLHIV-2 are improving with the roll out of DTG, limited data are available on the long-term treatment outcome among PLHIV-2 in West Africa. This study aimed at describing mortality, loss to follow-up (LTFU), advanced HIV disease and virologic suppression in PLHIV-2 in West Africa.

 Methods Study design, population and settings

A cohort of PLHIV-2 identified as monoinfected and followed up in HIV clinics was initiated in January 2012. These HIV clinics were all participating in the International Epidemiological Database to Evaluate AIDS (IeDEA) West Africa. Participants were enrolled based on the results of a cross-sectional survey assessing virologic failure among treatment experienced HIV-2 patients [17]. All adult patients from Côte d’Ivoire with an undetectable viral load in the 2012-virologic survey were enrolled in the “success cohort” and followed up as per the national PLHIV treatment guidelines [18].

 Follow-up procedures

As per the national guidelines for PLHIV, clinically and virologically stable patients should have a systematic quarterly visit at HIV clinic for ART drug refill and medical check. In case of missed appointment, a phone-base tracking procedure has been taken place to bring the patient back to care, and if not successful, home visits were organized for the patients who agreed and provided localization of their house at enrolment. Blood sample was collected every six months from each patient to perform CD4 count measurements. The last visit for all participants took place between October and December 2018. To ensure consistency in analysis, they were assessed by the same clinician who conducted a thorough clinical examination, updated the disease’s clinical stage (if applicable), and finally collected blood samples for viral load testing. Those who missed their last appointment or who were known LTFU in the facility were tracked by phone to ascertain their vital status (death, alive) and their treatment situation.

 Data collection

A structured questionnaire allowed data to be extracted from patients’ medical records, and additional data were obtained through face-to-face interviews with patients or abstracted from the facility’s database. Data collected included baseline socio-demographic (age, gender, education status, marital status), HIV follow-up characteristics (duration of infection, ART, WHO clinical stage), immunological and virological response (history of CD4 cells, viral load). Follow-up data included clinical response (history of clinical stage), immunological response (history of CD4 count), virological response (history of viral load measurement) and follow-up outcomes including LTFU, and death.

 Outcomes variables

The main outcome variables observed in this analysis were death, LTFU and advanced HIV disease. LTFU was defined as being absent for more than 90 days, not reported death and not transferred out and unable to reach after a completed tracking procedure. Death was defined as being reported dead in facility register or documented as dead with a death certificate. Advanced HIV disease was defined according to WHO guideline definition: CD4 count < 200 cell/mm3 or WHO clinical stage 3 or 4. Clinical stage was defined using WHO recommended staging process and was evaluated on a quarterly basis at each follow-up visit. Based on their follow up status, participants were categorized as in care (still in the follow-up and receiving ART, including being transferred out), dead and LTFU. The last two were subsequently combined in one category in the analyses, as they both constitute a negative outcome and it is always challenging to know the proportion of deaths among LTFU [19].

 Statistical analysis

Data analysis was performed using STATA® version 12.0, Stata Corp, College Station, Texas USA. Quantitative variables were described as medians with their interquartile range (IQR), and categorical variables were presented as proportions. Chi-square (X2) or Fisher’s exact tests were used to compare proportions. The Kaplan-Meier survival curve was used to estimate mortality and LTFU probability among the participants. Variables were statistically significant when the p value < 0.05.

 Ethical considerations

The protocol of this study was approved by the national Institutional Review Board of Côte d’Ivoire, the “Comité National d’Ethique des Sciences de la Vie et de la Santé” (approval number 144-18/MSHP/CNESVS-km). Prior to the enrolment in the cohort, detailed information about the study was given to each study participants and a signed informed consent was obtained. Data of the participants were anonymized during the abstraction and no identifiable data was collected or entered in the database. The database was password-protected, stored in the secured server of PACCI research center and accessible only to the research team.

 Results

Among the 108 HIV-2 clients in virologic success in 2012, 95 agreed to participate in the cohort. The median age at enrolment was 53 [47 – 60] years old, with gender parity and 56.8% of patients had secondary or higher education (Table 1). At enrolment, the median duration on ART was 9 [6 – 11] years, the median CD4 count was 319 [164 – 455] cells/mm3 and all patients were receiving a PI based ART regimen.

10.1371/journal.pone.0317223.t001Follow-up characteristics of ART-experienced people living with HIV-2 five years following virologic success in West Africa (N = 95).
Characteristics Total N =  95 In care n =  65 LTFU/dead n = 30 p
Age (Median; IQR), years 53 [45– 60] 53 [47 – 59] 53 [43 – 60]
Age class, years 0.746
<50 36 (37.9) 23 (35.4) 13 (43.3)
≥50 59 (62.1) 42 (64.6) 17 (56.7)
Gender 0.944
Male 48 (50.5) 33 (50.8) 15 (50.0)
Female 47 (49.5) 32 (49.2) 15 (50.0)
Education level 0.174
No formal education/ Primary 41 (43.2) 25 (38.5) 16 (53.3)
Secondary/ High school 54 (56.8) 40 (61.5) 14 (46.7)
Duration on ART (Median; IQR), years, 9 [6 – 11] 10 [8–12] 6 [4 – 8]
Class duration on ART, years <0.001
0–10 67 (70.5) 41 (63.1) 26 (86.7)
≥10 28 (29.5) 24 (36.9) 4 (13.3)
Follow-up duration in the cohort in months (median, IQR) 76 [53 – 78] 77 [75 – 78] 40 [22 – 63] <0.001
CD4 count at enrolment in the cohort (median, IQR), cells/mm3 319 [164 – 455] 351 [199 – 479] 222 [102 – 350] 0.005
CD4 count at last visit (median, IQR), cells/mm3 518 [353 – 639] 534 [383 – 662] 431 [272 – 619] 0.090
Class CD4 count at last visit, cells/mm3 0.222
>500 50 (52.6) 38 (58.5) 12 (40.0)
[200–500] 34 (35.8) 21 (32.3) 13 (43.3)
<200 11 (11.6) 6 (9.2) 5 (16.7)
Last viral load <0.001
Detectable 8 (8.4) 8 (12.3) 0 (0.0)
Undetectable 46 (48.4) 46 (70.8) 0 (0.0)
Not available 41 (43.2) 11 (16.9) 30 (100.0)
WHO Clinical stage at last visit 0.012
1-2/A-B 43 (45.3) 36 (55.4) 7 (23.3)
3-4/C 34 (35.8) 18 (27.7) 16 (53.4)
Missing 18 (18.9) 11 (16.9) 7 (23.3)
Last ART regimen
2 NRTI +  PI/r 95 (100.0) 65 (100.0) 30 (100.0)
Advanced HIV Disease at last visit (Y/N) 0.003
Yes 36 (37.9) 18 (27.7) 18 (60.0)

After a median follow-up duration of 77 [75 – 78] months, 65 (68.4%) of the 95 participants remained in care, while 20 (21.1%) were LTFU and 10 (10.5%) were reported dead after a median follow-up duration of 40 [22 – 63] months. At the last follow-up visit 43 (45.3%) participants presented with WHO clinical stage 1-2/A-B, higher among patients remaining in care compared to those dead/LTFU (55.4% Vs 23.3%; p = 0.012). Advanced HIV disease was identified in 36 (37.9%) participants at their last follow-up visit, higher among those dead/LTFU compared to those remaining in care (60.0% vs 27.7%, p =  0.003) (Table 1). Of the 10 patients reported dead, four had a specified cause of death, including one heart attack, one heart failure, one renal failure and one cervical cancer.

The median CD4 count at enrollment in the cohort was 319 [164 – 455] cells/mm3, higher among those remaining in care compared to those dead/LTFU (351 Vs 222; p = 0.005). At the last follow-up visit, the median CD4 count was 518 [353 – 639] cells/mm3, and there is no statistically significant difference in those remaining in care compared to those dead/LTFU (534 Vs 431; p = 0.09). Among the 65 participants remaining in care, the viral load was undetectable in 46 (70.8%) and detectable in 8 (12.3%) and those dead/LTFU did not have viral load recorded by the time of death or LTFU (Table 1).

The survival analysis revealed decreasing probability of remaining alive and in care over the time. At 24 months the probability of remaining alive and in care was 90% and decreased to 80.7% at 48 months and to 73% at 72 months (Fig 1).

10.1371/journal.pone.0317223.g001Probability of remaining alive and in care among ART-experienced people living with HIV-2 five years following a virologic success. Discussion

The follow-up of treatment-experienced PLHIV-2 initially in virologic success, revealed that one-third of participants were dead or LTFU after 40 months, and almost two participants out of five presented with advanced HIV disease at their last follow-up visit. In addition, there was a decreasing probability of remaining alive and in care, around 73% after 72 months.

In our cohort, the proportion of patients who died or were LTFU was 30% five years following virologic success and enrollment in the cohort. This proportion was 27% in Burkina Faso in the same follow-up period and around 33% in a West African multi-country cohort of 1,825 PLHIV-2 after two years of follow-up [20,21]. In addition, a similar cohort of PLHIV-2 initially in virological failure, reported an attrition of 45%, after a median follow-up duration of five years. This result is higher than what we report here, but is concurring with the idea of important attrition among PLHIV-2 during the follow-up [22]. This important attrition rate among treatment experienced PLHIV-2 probably has the same drivers reported in PLHIV-1, such as male gender, advanced age and advanced HIV disease at treatment initiation, also, long distances to facility, transportation fees, long waiting time in the facility as well as stigma and discrimination [21,23,24]. Some of these were addressed by the implementation of differentiated service delivery model such as multi-month ART dispensation, community and family ART dispensation model, review of patients flow to enable the one-stop-shop model as well as training and sensitization of healthcare workers to reduce stigma and discrimination [25–28]. In addition, since 2019, national HIV treatment guidelines have recommended using the Tenofovir + Lamivudine + Dolutegravir (TLD) regimen as first-line treatment and switching to this treatment for patients already on antiretrovirals, with boosted protease inhibitors (PI/r) reserved as second-line. However, despite all these approaches and strategies, the long-term attrition among PLHIV-2 remained high, suggesting that additional efforts are needed to improve retention in this population. Improving holistic care to PLHIV-2 by integrating the systematic screening and management of non-communicable diseases such as hypertension, diabetes, obesity, renal failure, cancers and mental health assessment as well as giving specific support to vulnerable PLHIV-2 could be part of the solution as suggested for PLHIV-1 [29,30].

Our study also revealed that nearly 40% of PLHIV-2 had advanced HIV disease, similar to 39.3% reported in an HIV-2 cohort in Guinea-Bissau [31]. These similar or even higher proportions in PLWH-2 could be explained by the fact that, before the recommendation of integrase inhibitors, treatment options for PLWH-2 were very limited due to the resistance of HIV-2 to certain ARVs. This situation exposed these patients to a higher risk of death in the event of failure of first-line ART [32]. Thus, despite progress in HIV treatment and prevention, the rate of advanced HIV disease still remains high in sub-Sahara African countries and this high rate can be explained by various forms of treatment interruptions as suggested in Botswana [33,34]. It is well known that people with advanced HIV disease are at high risk of dying from tuberculosis, severe bacterial infections or cryptococcal meningitis, in absence of early diagnosis and appropriate treatment [35]. Our results emphasize the critical need to make diagnosis and treatment of advanced HIV disease more accessible to PLHIV [36–38]. Indeed, since 2017, WHO published a specific guideline for the management of advanced HIV disease involving screening, treatment and prophylaxis of major AIDS-defining illnesses, prompt initiation of ART and intensified adherence support [39]. These include cotrimoxazole prophylaxis, the use of Xpert MTB/RIF, lateral flow lipoarabinomannan (LF-LAM) and isoniazid for the diagnosis and prevention of tuberculosis disease, as well as cryptococcal antigen (CrAg) screening and liposomal amphotericin B/ fluconazole for diagnosis and treatment of cryptococcosis [40,41].

In summary, innovative strategies such as tests that can qualitatively classified PLHIV regarding their immunological status (CD4 counts less than 200 cells/mm3 or CD4 counts equal or over 200 cells/mm3), the implementation of differentiated service delivery models, optimal management of opportunistic diseases where appropriate, and increased access to integrase inhibitor-based ARV regimens will help to effectively address attrition and highly advanced HIV disease among PLWH-2. Urging national AIDS control program and global health stakeholder to integrate advanced HIV disease package in the HIV program free of charge could help reducing mortality among all PLHIV including those living with HIV-2.

Some limitations should be acknowledged in our study, especially the small sample size that may limit the extrapolation of our results to the entire population of HIV-2 patients worldwide. Furthermore, viral load measurement was not introduced into treatment guidelines at the time of data collection. Consequently, viral load analyses only include those supported by the study at the start of the cohort and at the time of the 6-year analyses. In addition, our observation period was limited to December 2018, while WHO recommendation to use dolutegravir as preferred first line for all patients was implemented on a large scale in Côte d’Ivoire starting 2019. Since then, all HIV-2 patients on NRTI/PI have been switched to dolutegravir, including those on virologic failure needing to be switched to INSTI. This transition has probably improved the management of PLWH-2 in virological failure by offering an alternative second-line treatment that was previously limited. Despite these limitations, this study is among the few ones to describe long-term outcomes among PLHIV-2 in a context where data on follow-up of PLHIV-2 is very limited.

 Conclusion

Our study indicates that six years after being reported stable, one-third of PLHIV-2 were reported dead or LTFU. A high advanced HIV disease rate also reported among them call for the need to improve holistic care (enabling one-stop-shop model that allows early management of opportunistic infections and integrating non-communicable diseases services) for HIV-2 patients and fast-track the transition to DTG-based regimen.

We would like to thank Jean Claude Azani for his assistance in managing and monitoring the data.

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Curr HIV/AIDS Rep. 2019;16(4):324–34. doi: 10.1007/s11904-019-00454-5 31230342 Tukei B, Fatti G, Tiam A, Ngorima-Mabhena N, Tukei V, Tshabalala I, et al. Twelve-month outcomes of community-based differentiated models of multimonth dispensing of ART among stable HIV-infected adults in Lesotho: A cluster-randomized noninferiority trial. JAIDS. 2020;85(3):280. Fatti G, Ngorima-Mabhena N, Mothibi E, Muzenda T, Choto R, Kasu T, et al. Outcomes of Three- Versus Six-Monthly Dispensing of Antiretroviral Treatment (ART) for Stable HIV Patients in Community ART Refill Groups: A Cluster-Randomized Trial in Zimbabwe. J Acquir Immune Defic Syndr. 2020;84(2):162–72. doi: 10.1097/QAI.0000000000002333 32097252 Shayo EH, Kivuyo S, Seeley J, Bukenya D, Karoli P, Mfinanga SG, et al. The acceptability of integrated healthcare services for HIV and non-communicable diseases: experiences from patients and healthcare workers in Tanzania. BMC Health Serv Res. 2022;22(1):655. doi: 10.1186/s12913-022-08065-4 35578274 Haregu T, Setswe G, Elliott J, Oldenburg B. Integration of HIV/AIDS and noncommunicable diseases in developing countries: rationale, policies and models. Int J Healthcare. 2015;1(1):21–7. Hønge BL, Jespersen S, Aunsborg J, Mendes DV, Medina C, da Silva Té D, et al. High prevalence and excess mortality of late presenters among HIV-1, HIV-2 and HIV-1/2 dually infected patients in guinea-bissau - a cohort study from west africa. Pan Afr Med J. 2016 [cited 2019 Mar 20];25. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5268749/ Ba S, Badiane NMD, Hawes S, Deguenonvo LF, Sall F, Ndour CT, et al. Infection à vih-2 au sénégal: échecs virologiques et résistances aux antirétroviraux (ARV). Pan Afr Med J. 2019 [cited 2024 Nov 11];33(222). Available from: https://www.panafrican-med-journal.com//content/article/33/222/full Organisation mondiale de la santé. Recommendations to reduce mortality and morbidity among people presenting with advanced HIV disease. In: Guidelines for managing advanced HIV disease and rapid initiation of antiretroviral therapy [Internet]. World Health Organization; 2017 [cited 2023 Aug 22]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK475970/ Lebelonyane R, Mills LA, Mogorosi C, Ussery F, Marukutira T, Theu J, et al. Advanced HIV disease in the botswana combination prevention project: Prevalence, risk factors, and outcomes. AIDS. 2020;34(15):2223. Organisation mondiale de la Santé. Traitement antirétroviral: lignes directrices pour la prise en charge du stade avancé de la maladie à VIH et l’initiation rapide du traitement antirétroviral: note d’information [Internet]. Organisation mondiale de la Santé; 2017 [cited 2023 Aug 22]. Report No.: WHO/HIV/2017.18. Available from: https://apps.who.int/iris/handle/10665/255886 Organisation mondiale de la santé. Prévention de la tuberculose: de nouvelles recommandations pour sauver des millions de vies [Internet]. 2020 [cited 2023 Aug 22]. Available from: https://www.who.int/fr/news/item/24-03-2020-new-who-recommendations-to-prevent-tuberculosis-aim-to-save-millions-of-lives Maokola W, Ngowi B, Lawson L, Robert M, Mahande M, Todd J, et al. Coverage of isoniazid preventive therapy among people living with HIV; a retrospective cohort study in tanzania (2012-2016). Int J Infect Dis. 2021;103(2):562–7. Ibe C, Okoye CA. Integrated healthcare approach can curb the increasing cases of cryptococcosis in Africa. PLoS Negl Trop Dis. 2022;16(8):e0010625. doi: 10.1371/journal.pntd.0010625 36006867 Directives de l’OMS pour la prise en charge de l’infection à VIH avancée et l’initiation rapide du traitement antirétroviral - OMS [Internet]. [cited 2023 Feb 24]. Available from: https://apps.who.int/iris/bitstream/handle/10665/255886/WHO-HIV-2017.18-fre.pdf;sequence=1 Hakim J, Musiime V, Szubert AJ, Mallewa J, Siika A, Agutu C, et al. Enhanced prophylaxis plus antiretroviral therapy for advanced HIV infection in Africa. N Engl J Med. 2017;377(3):233–45. doi: 10.1056/NEJMoa1615822 28723333 Mfinanga S, Chanda D, Kivuyo SL, Guinness L, Bottomley C, Simms V, et al. Cryptococcal meningitis screening and community-based early adherence support in people with advanced HIV infection starting antiretroviral therapy in tanzania and zambia: An open-label, randomised controlled trial. Lancet. 2015;385(9983):2173–82. doi: 10.1016/S0140-6736(15)60164-7 25765698 10.1371/journal.pone.0317223.r001 Author response to Decision Letter 0 Submission Version 0

6 Dec 2023

 10.1371/journal.pone.0317223.r002 Decision Letter 0 Fokam Joseph Academic Editor 2025 Joseph Fokam This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 0

29 Feb 2024

PONE-D-23-40207Mortality, loss to follow-up and advanced HIV disease following virologic success in West African HIV-2 patientsPLOS ONE

Dear Dr. Koffi,

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.

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We look forward to receiving your revised manuscript.

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Joseph Fokam, Ph.D

Academic Editor

PLOS ONE

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https://doi.org/10.1371/journal.pone.0236642

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed.

3. Please provide a complete Data Availability Statement in the submission form, ensuring you include all necessary access information or a reason for why you are unable to make your data freely accessible. If your research concerns only data provided within your submission, please write "All data are in the manuscript and/or supporting information files" as your Data Availability Statement.

4. One of the noted authors is a group [the EDIIMark-2 study group]. In addition to naming the author group, please list the individual authors and affiliations within this group in the acknowledgments section of your manuscript. Please also indicate clearly a lead author for this group along with a contact email address.

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

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: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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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

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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: No

Reviewer #2: Yes

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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: This is a single-center observational study on HIV-2 in West Africa. While the disease is important, the information presented is not novel although as the authors mentioned, that this study joins the few studies to describe long-term outcomes (~5-¬¬6 years) among PLHIV-2. For e.g. it is not surprising that the patients remaining in care are more likely to have better outcomes with higher CD4 and a higher proportion in WHO clinical stage 1-2/A-B. Nevertheless, this study adds on to the sparse literature available. The manuscript will benefit with further English language editing if publishing in English.

Comments:

Abstract / Methods

It would be better to state that comparison categories included lost to follow up and dead. The current abstract appears to define loss to follow up = absent for more than 90 days and dead which is confusing.

Main manuscript / Under introduction

•Awkward language: “In addition, the 2019 WHO guidelines recommended Dolutegravir (DTG) in combination with a nucleoside reverse-transcriptase inhibitor (NRTI) backbone as the preferred first-line regimen for people initiating antiretroviral treatment (ART), thus without any difference between those living with HIV-1 and HIV-2 [14].” The reference to HIV-1 here is not required as well, as the authors are not comparing the treatment outcomes across HIV-1 and HIV-2.

Main manuscript / Under outcomes and variables

•While it would be fair for the authors to collapse mortality cases with lost to follow up if the numbers are small, I am concerned about the scientific basis stated that loss to follow up is a proxy of death.

•The preceding sentence mentioned that the authors categorized the participants into “3 modalities” and the next they collapsed 2 of them into 1. Modalities would not be the correct word to use here, but rather categories.

•It is not necessary to comment on the creation of a new variable. It would suffice to say that participants were categorized into 2 or 3 categories based on whether they are still on follow up or not.

Main manuscript / Data collection

•Awkward word use: Instead of abstraction, extraction would be a better word to use e.g. “A standardized questionnaire allowed extraction of data…”

Main manuscript / Results

•Was there any documented reason for the 13 HIV-2 clients to not participate in the survey? It would be interesting if yes, and this could be detailed.

•The median follow-up period for the last visit for the LTFU and dead group should be stated.

•The time point of HIV-2 viral load check should be mentioned and what the median and IQR are for those who are not considered controlled.

Main manuscript / Discussion

•The discussion does not really discuss about the findings of the research. For e.g. the research findings do not talk about opportunistic infections, but the discussion went into a paragraph of what would be helpful with opportunistic infections. In a cohort study wherein participants were initially all well-controlled, retainment in care would be more relevant rather than OI treatment.

•The finding that all participants are on boosted PI/NRTI regimen could have also been commented on or discussed. Depending on the HIV-2 viral load on those who are not controlled, there is a consideration wherein II based regimens would be more helpful.

Reviewer #2: The work is of great public health importance in the context of HIV-2 management in West Africa. The manuscript is well written in standard English, considering sound statistical methods.

For comments for the authors:

-Page 4, the spelling of house should be corrected. wrong "hose"; correct "house"

-On Data collection section, a standard data extraction form should have been used not a standardised questionnaire. Correct accordingly.

-Page 6, third paragraph and sentences 3 and 4 are confusing. I suggest you delete the 3rd sentence.

-Page 7, Table 1. Varaibles Age(median, IQR) years and Duration of ART (years) have 3 entries for only 2 categories. This needs to be reviewed.

Question: It was mentioned that all the PLHIV-2 at enrolment were of PI. During the follow-up period following the WHO recommendation to transition all patients to DTG, was this transition done? If yes, when and do you think it could affect the survival of PLHIV-2 or rate progress to advanced HIV disease? Consider addressing these elements in your work. Thanks

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Reviewer #1: No

Reviewer #2: No

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 10.1371/journal.pone.0317223.r003 Author response to Decision Letter 1 Submission Version 1

29 Apr 2024

Journal requirements:

1. When submitting your revision, we need you to address these additional requirements.

Authors: We would like to thank the editor for his comments. We have taken the additional requirements into account in the new version of the revised manuscript.

2. We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed: https://doi.org/10.1371/journal.pone.0236642

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed.

Authors: We thank the editor for this comment, we reviewed the manuscript and removed all the overlaps with the above-mentioned paper.

3. Please provide a complete Data Availability Statement in the submission form, ensuring you include all necessary access information or a reason for why you are unable to make your data freely accessible. If your research concerns only data provided within your submission, please write "All data are in the manuscript and/or supporting information files" as your Data Availability Statement.

Authors: We thank the reviewer for this comment, we provided a complete statement about data availability, we were able to make the data available on a repository and provided the link: https://figshare.com/s/a8b9fa7d5ba8a5968235

4. One of the noted authors is a group [the EDIIMark-2 study group]. In addition to naming the author group, please list the individual authors and affiliations within this group in the acknowledgments section of your manuscript. Please also indicate clearly a lead author for this group along with a contact email address.

Authors: We thank the reviewer for this comment, the Study group has been removed from the author list, since the list is very long and we could not join all the members to sign the related consent as per our organization policy.

Review Comments to the Author:

Reviewer #1: This is a single-center observational study on HIV-2 in West Africa. While the disease is important, the information presented is not novel although as the authors mentioned, that this study joins the few studies to describe long-term outcomes (~5-¬¬6 years) among PLHIV-2. For e.g. it is not surprising that the patients remaining in care are more likely to have better outcomes with higher CD4 and a higher proportion in WHO clinical stage 1-2/A-B. Nevertheless, this study adds on to the sparse literature available. The manuscript will benefit with further English language editing if publishing in English.

Authors: We thank the reviewer for this comment, we reviewed the manuscript to improve English and editing.

Comments:

Abstract / Methods

1• It would be better to state that comparison categories included lost to follow up and dead. The current abstract appears to define loss to follow up = absent for more than 90 days and dead which is confusing.

Authors: We would like to thank the reviewer for this comment. We clarified this confusion in the revised manuscript as follow: “Outcomes were described as follow: in care (known alive and present during the last ART follow up visit), loss to follow-up (absent for more than 90 days and not reported dead), and dead (reported dead with a date of event)".

Main manuscript / Under introduction

2• Awkward language: “In addition, the 2019 WHO guidelines recommended Dolutegravir (DTG) in combination with a nucleoside reverse-transcriptase inhibitor (NRTI) backbone as the preferred first-line regimen for people initiating antiretroviral treatment (ART), thus without any difference between those living with HIV-1 and HIV-2 [14].” The reference to HIV-1 here is not required as well, as the authors are not comparing the treatment outcomes across HIV-1 and HIV-2.

Authors: We thank the reviewer for this comment. We agree that there was no comparison between HIV-1 and HIV-2 planned in this analysis. Therefore, we removed the phrase “thus without any difference between those living with HIV-1 and HIV-2” in the revised version of the manuscript.

Main manuscript / Under outcomes and variables

3•While it would be fair for the authors to collapse mortality cases with lost to follow up if the numbers are small, I am concerned about the scientific basis stated that loss to follow up is a proxy of death.

Authors: We thank the reviewer for this comment. We decided to combine LTFU and death because there are papers in the literature that suggest that lost to follow-up is a proxy of death ("Loss to Follow-up: A Major Challenge to Successful Implementation of Prevention of Mother-to-Child Transmission of HIV-1 Programs in Sub-Saharan Africa). We included this paper as reference in the revised manuscript.

4• The preceding sentence mentioned that the authors categorized the participants into “3 modalities” and the next they collapsed 2 of them into 1. Modalities would not be the correct word to use here, but rather categories.

Authors: We thank the reviewer for this suggestion that has been taken into consideration by replacing “modalities” by “categories” in the revised version of the manuscript.

5• It is not necessary to comment on the creation of a new variable. It would suffice to say that participants were categorized into 2 or 3 categories based on whether they are still on follow up or not.

Authors: We thank the reviewer for this comment. We adjusted the sentence accordingly in the revised version of the manuscript.

Main manuscript / Data collection

6• Awkward word use: Instead of abstraction, extraction would be a better word to use e.g. “A standardized questionnaire allowed extraction of data…”

Authors: We thank the reviewer for this suggestion, we adjusted the text accordingly in the revised version of the manuscript.

Main manuscript / Results

7• Was there any documented reason for the 13 HIV-2 clients to not participate in the survey? It would be interesting if yes, and this could be detailed.

Authors: We thank the reviewer for this comment. Among this 13 people living with HIV-2 who did not participate to the cohort, height did not consent to participate and the remaining 5 have been transferred to facilities out of the town and not part of the study sites, making them not eligible.

8• The median follow-up period for the last visit for the LTFU and dead group should be stated.

Authors: We thank the reviewer for this comment. The median follow-up period for the last visit for the LTFU and dead group is (40 [22 - 63] months) and can be found in the results section of the manuscript, at the third line of paragraph 2.

9• The time point of HIV-2 viral load check should be mentioned and what the median and IQR are for those who are not considered controlled.

Authors: We thank the reviewer for giving an opportunity to update and improve the quality of our manuscript. In Cote d’Ivoire, HIV-2 Viral load was not routinely prescribed like CD4 count, because it was not supported by the HIV program. Thus, HIV-2 Viral load reported in our study was sponsored by the research project and done only at two-time point in 2012 and in 2018.

We recognized that median and IQR of viral load could be more informative. However, the lab results were not always given with the number of copies making it difficult to estimate the median number of copies for all the participants. We therefore made the choice to present the conclusion of the lab set as detectable or undetectable.

Main manuscript / Discussion

10• The discussion does not really discuss about the findings of the research. For e.g. the research findings do not talk about opportunistic infections, but the discussion went into a paragraph of what would be helpful with opportunistic infections. In a cohort study wherein participants were initially all well-controlled, retainment in care would be more relevant rather than OI treatment.

Authors: We thank the reviewer for this comment. We apologize for the confusion brought in the discussion when mentioning opportunistic infection. Our study did not focus on opportunistic infections as the reviewer rightly said, but rather explored attrition (LTFU and Death) and advanced HIV disease.

In the first graph we comment on the high attrition rate, giving the causes of this high rate and extrapolate on potential strategies to improve retention to care. In the second paragraph, we comment on the high rate of advanced HIV disease, and extrapolate on solutions that increase survival of patients. we adjusted the discussion section and tried to clarify that.

11• The finding that all participants are on boosted PI/NRTI regimen could have also been commented on or discussed. Depending on the HIV-2 viral load on those who are not controlled, there is a consideration wherein II based regimens would be more helpful.

Authors: We thank the reviewer for this comment. We added a comment in the discussion section reflecting the situation of participants receiving the recommended ART regiment for HIV-2 and experiencing an uncontrolled Viral load. Indeed, these patients should be switched on II. It is true that by 2018 the II were recommended only for the third lines, but with the roll out of DTG in 2019, all these patients were systematically switched to a DTG-based regimen. 

Reviewer #2:

1• Page 4, the spelling of house should be corrected. wrong "hose"; correct "house"

Authors: We would like to thank the reviewer for spotting this typing error. We corrected this misspelling in the update version of the manuscript.

2• On Data collection section, a standard data extraction form should have been used not a standardised questionnaire. Correct accordingly.

Authors: We thank the reviewer for this comment. The correct term is data extraction sheet. We have made a correction in the revised version of the manuscript.

3• Page 6, third paragraph and sentences 3 and 4 are confusing. I suggest you delete the 3rd sentence

Authors: We thank the reviewer for this comment. In the third sentence, we would like to show the proportions of the latest viral loads in our entire study population. However, we agree with the reviewer that it could be confused with the sentence that follows. In this revised version, we deleted this sentence as suggested by the reviewer.

4• Page 7, Table 1. Variables Age (median, IQR) years and Duration of ART (years) have 3 entries for only 2 categories. This needs to be reviewed.

Authors: We thank the reviewer for this valuable comment. The medians and categories of these variables overlapped and created confusion. We have distinguished them better in the new revised version of the manuscript.

5• Question: It was mentioned that all the PLHIV-2 at enrolment were of PI. During the follow-up period following the WHO recommendation to transition all patients to DTG, was this transition done? If yes, when and do you think it could affect the survival of PLHIV-2 or rate progress to advanced HIV disease? Consider addressing these elements in your work. Thanks

Authors: The WHO recommendation was implemented on a large scale in Côte d'Ivoire in 2019, after this study was carried out. Since then, all HIV-2 patients on NRTI/PI have been switched to dolutegravir. This transition has improved the management of PLWH-2 in virological failure by offering an alternative second-line treatment that was previously limited. We added a paragraph addressing the DTG transition in the discussion.

Submitted filename: Response to reviewers.docx

 10.1371/journal.pone.0317223.r004 Decision Letter 1 Dememew Zewdu Academic Editor 2025 Zewdu Dememew This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 1

8 Oct 2024

PONE-D-23-40207R1Mortality, loss to follow-up and advanced HIV disease following virologic success in West African HIV-2 patientsPLOS ONE

Dear Dr. Koffi,

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 ensure that your decision is justified on PLOS ONE’s publication criteria and not, for example, on novelty or perceived impact.

Please submit your revised manuscript by Nov 22 2024 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: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Zewdu Gashu Dememew, M.D, PhD

Academic Editor

PLOS ONE

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Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

Dear Authors,

Thank you very much for responding for comments from editor and reviewers.

There is a progress in this important article yet there are remaining issues to deal with.

Hope you will try your best to go through this important paper and come back with addressed suggestions and comments.

Good luck!

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 #1: All comments have been addressed

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Reviewer #1: Partly

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Reviewer #1: Yes

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Reviewer #1: Yes

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Reviewer #1: Yes

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Major

Discussion: Given that this cohort was only studied until 2018 and the national guidelines aligning with WHO guidelines occurred in 2019 – this alignment occurred post study. As such, the alignment of the national guidelines should not be included in “all these approaches and strategies, the long-term attrition” which the writing currently suggests. This is acknowledged as a limitation and I agree with the authors that a longer observation period would be useful to assess the effect of DTG transition.

Minor

Table 1 CD4 – brackets [200-500[ should be 200-500 ?

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Submitted filename: Academic Edit comm_HIV2 West Africa.docx

 10.1371/journal.pone.0317223.r005 Author response to Decision Letter 2 Submission Version 2

22 Nov 2024

’This emphasizes the need to improve holistic care for HIV-2 patients.” The term holistic care is quite comprehensive for recommendation. Could the authors specify discrete recommendations that need to be done to reduce the advanced HIV diseases?

Authors: We would like to thank the reviewer for this comment. We agree that “holistic care” is definitely quite comprehensive to be part of a conclusion. We have updated the abstract by rewording it and adding practical take home messages. The conclusion has been updated accordingly by summarizing the key messages regarding to “holistic” care, discussed in the discussion section. Page 2, lines 52-54.

Introduction

The last paragraph should make sure that there is no published article in this regard- scarcity of evidence should strongly and boldly be described.

Examples:

Raugi DN, Ba S, Cisse O, Diallo K, Tamba IT, Ndour C, Badiane NM, Fortes L, Diallo MB, Faye D, Smith RA. Long-term experience and outcomes of programmatic antiretroviral therapy for human immunodeficiency virus type 2 infection in Senegal, West Africa. Clinical Infectious Diseases. 2021 Feb 1;72(3):369-78.

Also check why the term mortality started with capital letter here,” … Mortality, loss to follow-up (LTFU), advanced HIV disease…’’ Please check similar issues throughout the document.

Authors: We thank the reviewer for this comment. We have corrected this capitalization in the revised version of the manuscript. Page 3, line 81.

Methods

The following sentence is too long, and it is not clear. Please revise. Do the same throughout the document.

“A cohort of people living with HIV-2, identified as mono-infected and followed-up in HIV clinics participating in the International Epidemiological Database to Evaluate AIDS (IeDEA) West Africa, was initiated in January 2012.”

Authors: We thank the reviewer for this comment. In the revised version of the manuscript, we have split this long sentence into two sentences to make it easier to understand. Page 4, lines 85-87.

Follow up

Mix of tenses used, future and past. You may revise,” In case of missed appointment, a phone-base tracking procedure will take place to bring the patient back to care, and if not successful, home visits can be organized for the patients who agreed and provided localization of their house at enrolment. Blood sample was collected every six months from each patient to perform CD4 count measurements. For the purpose of this analysis, all the participants were…”

Authors: We thank the reviewer for this comment. We have standardized the (past) tense in the revised version of the manuscript. Page 4, line 96.

This is a vague sentence as well, “For the purpose of this analysis, all the participants were seen from October to December 2018 during their last appointment by the same clinician who conducted clinical examination and updated the disease clinical stage before collecting blood sample for viral load testing”

Authors: We recognize that this sentence is not very precise. We have reworded it in the revised manuscript to make it more understandable. Page 4, lines 99-103.

Data collections

Again, mix of tenses,” A structured questionnaire allows extraction of data from patient’s medical files, and additional data were obtained during face-to-face interview with patients or abstracted in the facility databased.” Also check whether the word ‘abstracted’ is the right term to use here.

Authors: We've changed the sentence by harmonizing the tenses. The reviewer will find these changes in the revised version of the manuscript. Page 4, lines 108-110.

Check if the heading is “Outcomes and variables” or “Outcomes variables”. It seems only the outcome variables were operationalized. I strongly suggest to re-visit the PLOS ONE guidelines (https://journals.plos.org/plosone/s/submission-guidelines.#:~:text=The%20PLOS%20ONE%20article%20component%20must%20comply%20with%20the%20general)

Authors: The appropriate topic is 'Outcome variables', not 'Outcomes and variables'. We have made a correction in the revised version of the manuscript. Page 5, line 116.

Check why ‘Characteristic” started with capital letter here;” Table 1: Follow-up Characteristics of ART-experienced people living with HIV-2 five years following virologic success in West Africa (N=95)”

Authors: We have removed this major feature in the revised version of the manuscript. Page 7, line 172.

Gender parity-Table 1: how was the proportion of male and female became equal? Was it intentional? Please justify or check the data.

Authors: All patients with an undetectable viral load in 2012 were included in this study, regardless of gender. The equal proportion of men and women included in the analysis was by sheer coincidence. This result has already caught our attention during the data analysis phase, and even during the review by co-authors. After a second review, we confirmed it.

Now we are in 2024, and why could the authors not extend beyond 2018? Don’t you think the data is outdated?

Authors: The reviewer points out an interesting issue about this paper. First, after the success of the DLT transition into most of HIV programs, learning through knowledge building and sharing is still needed. Even our data seems outdated exclusively based on the data collection period, we think that they should contribute to more learning about the improving of PLHIV care and could serve programs managers as the outcomes of their efforts and progresses. In addition, as documenting in the limitation paragraph, at the discussion section, lessons learnt through this study suggest the potential benefic effect of Protease inhibitors (PI) - Dolutegravir transition on improving the management of PLWH-2 in virological failure by offering an alternative second-line treatment.

Based on these reasons, we would like to submit again the manuscript and call for its publication to nourish the science and contribute to the experience learned on the long-term outcomes of PLHIV under PI-based ART.

Is there any difference in terms of the outcome variables between the two countries? Is it possible to include this in the result and discuss the difference?

Authors: We thank the reviewer for this comment. For logistical reasons, the PLHIV-2 from Burkina Faso included in the 2012 cohort did not contribute to this analysis. This study only included the Côte d'Ivoire cohort. We have added this specificity to the method section to make it clearer. The revised version of the manuscript was also updated. Page 4, line 89.

It is expected to have a better outcome from treating HIV2 as compared to HIV1. Why was the advanced HIV diseases, LTFU and death all same or more than those patients infected with HIV1? Please try to justifying this issue further.

Authors: These similar or even higher proportions in PLWH-2 could be explained by the fact that prior to the recommendation of integrase inhibitors based ART, the therapeutic options for PLWH-2 were very limited. The PI-based ART regimen were indicated for first-line regimen, so ARVs resistances to this first-line made challenging the PLHIV-2 management. This situation exposed these patients to a higher risk of death if first-line ART failed. In addition, as with HIV-1, PLWH-2 presented at a late stage with severe immunosuppression, most commonly associated with opportunistic infections. In the revised version of the manuscript, we have modified the discussion to include this rationale. Page 9, lines 206-210.

In conclusion (abstract and at end of the discussion) please try to suggest specified interventions for the alarmingly high LTFU/death/Advanced HIV diseases:

-Management of comorbidities, counseling for adherence and retention, addressing adherence issue, considering a better regimens etc…

Authors: We thank the reviewer for this comment. Strategies to improve the management of PLWH-2 and to prevent advanced HIV disease according to WHO recommendations were expanded in the discussion. We have summarized some strategies in the revised version of the manuscript (including abstract). Page 10, lines 224-229.

Discussion

It is shallow and may be expanded a bit.

Potential point of discussion could be the difference in the outcomes between the two countries (Cote d’Ivoire and Burkin faso) or outcome similarity between HIV1 and HIV2.

Please try to trim/consolidate the limitation.

Authors: The data collected in this study only covered HIV clinics in Côte d'Ivoire, as reported earlier in the method section. We were therefore unable to make a comparison with data from Burkina Faso, which was not collected during the 2018 monitoring visit.

We have reduced the limitations section as suggested by the reviewer.

Submitted filename: Response_to_Reviewers_auresp_2.docx

 10.1371/journal.pone.0317223.r006 Decision Letter 2 Dememew Zewdu Academic Editor 2025 Zewdu Dememew This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 2

23 Dec 2024

Mortality, loss to follow-up and advanced HIV disease following virologic success in West African HIV-2 patients

PONE-D-23-40207R2

Dear Dr. Jean Jacques Koffi

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,

Zewdu Gashu Dememew, M.D

Academic Editor

PLOS ONE

Dear Dr. Jean Jacques Koffi,

Thank you for coming up with the revised article. Major comments/suggestion well addressed.

Just consider the attached editorial suggestion prior to publication.

Best regards

Zewdu

Final comments to be fixed before consideration for publication

Abstract

Replace DTG with dolutegravir. Please look again in the manuscript—all abbreviations should be defined during their first instance if they are to be used again.

Introduction

“Data from the ANRS CO5 HIV-2 Cohort Study”. Same comment as above-- what is ANRS CO5 in, “ Data from the ANRS CO5 HIV-2 Cohort Study”? Also why capital letters?

Methods

‘’A cohort of people living with HIV-2 (PLHIV-2)…’’ only PLHIV-2 is enough. You have already defined.

Check again if it is important to start these phrases with capital letters, “ As per the National Guidelines for PLHIV, clinically…”

Check if the following long sentence could be revised to two sentences.

’’ Based on their follow up status, participants were categorized as in care (still in the follow-up and receiving ART, including being transferred out), dead and LTFU, and the last two were subsequently

combined in one category in the analyses as they both constitute a negative outcome and it is always challenging to know among the LTFU the proportion of death (19).”

May be replaced with;

‘’ Based on their follow up status, participants were categorized as in care (still in the follow-up and receiving ART, including being transferred out), dead and LTFU. The last two were subsequently

combined in one category in the analyses as they both constitute a negative outcome, and it is

always challenging to the proportion of death know among the LTFU (19).’’

Replace “Chi2-square or Fisher’s exact tests ..” with “Chi-square (X2) or Fisher’s exact tests ….”

Replace “Prior to the enrolment in the cohort, each participant received detailed information about the study and signed an informed consent form.”

With

“Prior to the enrolment in the cohort, detailed information about the study was given to each study participants and a signed informed consent was obtained .”

What is “PACCI”? Please define.

Check if “PI based ART regimen…” Could be written as, “ Protease inhibitors (PI) based ART regimen…”

Check if the sentence, “At the last follow-up visit, the median CD4 count was 518 [353 – 639] cells/mm3 not different in those remaining in care compared to those dead/LTFU (534 Vs 431; p=0.09).”

could better be written as,

“At the last follow-up visit, the median CD4 count was 518 [353 – 639] cells/mm3, and there is no statistically significant difference in those remaining in care compared to those dead/LTFU (534 Vs 431; p=0.09).”

Discussion

“Moreover, since 2019, national HIV treatment guidelines aligned on WHO guidelines

recommended Tenofovir plus Lamivudine plus dolutegravir (TLD) regimen as first-line and the

transition of all ART-experienced clients, while the use of boosted protease inhibitors (PI/r) as

second-line.” This is not easy to understand. Please simplify or written in a simple sentence for easy understanding.

Conclusions

Which one is right?

“..five years after an initial virologic success…” in the abstract conclusion

or

“Our study indicates that six years after being reported stable,…” in the final conclusion?

Submitted filename: Final comments_ZGD_Ac edit_Dec 23_2024.docx

 10.1371/journal.pone.0317223.r007 Acceptance letter Dememew Zewdu Academic Editor 2025 Zewdu Dememew This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PONE-D-23-40207R2

PLOS ONE

Dear Dr. Koffi,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

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Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

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on behalf of

Dr. Zewdu Gashu Dememew

Academic Editor

PLOS ONE