Objectives: The objective of this study was to estimate the retention rate of patients in an ART program and identify the predictors of attrition.Methods: This was a historical cohort study of HIV patients who started ART between September 2007 and April 2020, and were followed up on for at least 6 months in nine large-volume sites. Kaplan Meier techniques were used to estimate cumulative retention and attrition probabilities. Cox proportional hazards models were used to identify predictors of attrition.Results: The cumulative probability of retention at 12 and 24 months was 76.2% and 70.2%, respectively. The attrition rate after a median follow-up time of 3.1 years was 35.2%, or an incidence of 11.4 per 100 person-years. Having initiated ART between 2012 and 2015; unmarried status; having initiated ART with CD4 count <100 cells/μL; and having initiated ART at an advanced clinical stage were factors significantly associated with attrition.Conclusion: The retention rate in our study is much lower than the proposed national target (90%). Studies to understand the reasons for loss to follow-up are needed. The scale of the HIV epidemic has changed dramatically over the past 30 years. Once a fatal disease, HIV infection is now considered as a chronic and manageable disease . This trFor this reason, global initiatives promoted by UNAIDS (ending the HIV epidemic by 2030) and the World Health Organization (Test and Treat) , 5, haveHowever, patient retention in care remains a challenge, particularly in sub-Saharan African countries –8 and unWith a national HIV prevalence of 1.5%, Guinea has a generalized HIV epidemic. After the introduction of free ART in 2007, several changes were made to the HIV management protocol in Guinea. ART initiation with a CD4 count less than 200 cells/μL between 2007 and 2012; ART initiation with a CD4 count less than 350 cells/μL between 2012 and 2015; ART initiation with a CD4 count less than 500 cells/μL between 2015 and 2017; introduction of the “Treat All” strategy (putting HIV-positive people on ART regardless of their CD4 count) between 2017–2020 , 11. DesAlso, previous studies have shown that low retention of HIV-infected patients on treatment remains a serious problem in antiretroviral treatment programs in Guinea. Thus, according to a study, the rate of loss to follow-up among patients who initiated antiretroviral therapy between 1st May 2017 and 30th June 2019 was 26.0% . AnotherWe conducted a historical cohort study by using routine individual follow-up data of patients who initiated antiretroviral therapy in Guinea between September 2007 and April 2020.This study was conducted in high-volume care sites for people living with HIV (PLHIV) in Guinea. In the Guinean context, a site is considered high-volume when the number of people living with HIV it serves is 250 or more. In 2019, 29 out of 142 sites nationally met this definition, and covered more than 90% of all patients on ART in the country. The large-volume sites are present in each of the eight Guinean health regions . This stThe study population consisted of children under 15 years of age (9–14 years) and adults 15 years and older who were confirmed HIV-positive and started ART during the period of 1 September 2007 to 30 April 2020, with a minimum of 6 months of follow-up prior to the data extraction date. The data extraction date was 31 October 2020. The length of follow-up in this study was chosen to address the need for information in Guinea regarding long-term retention of patients on ART . Patients who had not started triple antiretroviral therapy during the study period and patients for whom data needed to calculate follow-up time were missing were excluded.Participants were selected from the registration database of patients who started on antiretroviral therapy at the study centers. We performed an exhaustive sampling of patients who met the inclusion criteria for this study. A total of 23,686 patients were obtained for the different analyses.Variables extracted for the analysis of retention and attrition included socio-demographic characteristics, clinical and therapeutic characteristics, biological markers (CD4), the ART initiation year, and patient monitoring status  .TIER.NET (managed by NGO Doctors Without Borders Belgium) and AVICEMA (managed by Mission PhilAfricaine), then exported to Excel for processing and cleaning. To ensure confidentiality, information on patients’ surnames, first names, affiliation, physical address, and contacts (telephone number and e-mail address) were excluded when extracting data from the different study sites. Only the patient code, also known as the unique identification number assigned by the sites following the instructions of the national aids and hepatitis program, was used to identify the patients included in this study.The data for this study were extracted from two databases: The data was analyzed using SPSS version 21 software. The primary outcome was attrition, defined as death and loss to follow-up. Kaplan Meier techniques (life tables and Kaplan Meier curves) were used to estimate the probabilities of retention and attrition of patients in the ART care program throughout the follow-up timeline. In the univariate analysis, Kaplan Meier curves were plotted to assess retention according to potential risk factors, and the Mantel Haenszel log-rank test was used to compare survival curves. The choice of variables included in the Kaplan Meier curves and in the Cox proportional regression model was guided by the results of the scientific literature relating to the factors associated with attrition or non-retention. We estimated the association between predictor variables and attrition among patients on ART using a univariate Cox proportional hazards regression model. The crude relative risk or hazard ratio (HR) and its 95% confidence interval was used as the measure of association.The identification of factors that predicted attrition was performed using a multivariable Cox proportional hazard model. This allowed us to calculate the adjusted hazard ratios and their 95% confidence intervals. The proportional hazards assumption was evaluated using Kaplan-Meier plots against Cox predictions and the results of these analyses suggested that the proportional hazards assumption is valid.p-value < 0.1). Due to their clinical and biological relevance in the retention of HIV patients in the ART program, we ensured that the variables “sex and level of care” were among the initial variables selected. Second, stepwise backward elimination was used until all remaining variables were significantly associated with attrition .To identify independent associated factors of attrition, first variables were selected into the multivariable model based using a stepwise forward strategy , or 3.1 years. The median age was 37 years (IQR: 30–46). The majority of patients were women (69.0%). Nearly half (47.7%) had initiated ART at an advanced clinical stage of HIV infection, or stages III and IV of the WHO classification. The majority (40.8%) of patients in this study had initiated ART during the 2017–2020 period, which corresponds to the implementation period of the “Treat All” approach in the ART program in Guinea. Patients who initiated ART between 2012 and 2015 (the peak period of the Ebola epidemic in Guinea) represented 17.0% of the sample .The 37.2 months or 3.1 years of follow-up time of the 23,686 patients who started ART between September 2007 and April 2020 represents 73,427 person-years of follow-up. At the end of the study period, 1,617 (6.8%) had died, and 6,720 (28.4%) were lost to follow-up; refer to The cumulative probability of retention was 64.8% (95% CI: 64.2%–65.4%). This cumulative probability at 12, 24, 48, 120, and 156 months was 76.2%; 70.2%; 64.0%; 53.6%, and 48.0%, respectively. The probability of retention for women at 12 months  was better than for men  .p-value < 0.001  was better than for adults 15 years and older . The Kaplan Meier retention curves for patients who started antiretroviral therapy with high CD4 counts were higher in trend than those for patients with low CD4 counts. Similarly, the Kaplan Meier curve for the probability of retention of patients who started antiretroviral therapy at an early clinical stage (I and II of the WHO classification) of HIV infection had a higher trend than that of patients who started therapy at an advanced clinical stage (III and IV). The differences observed between the Kaplan Meier curves on the probability of retention were significant, with a log-rank test  < 0.001 .Of the 23,686 patients included in the study, 8,337 were patients no longer retained in the antiretroviral therapy program, for a cumulative probability of attrition of 35.2% (95% CI: 32.2%–37.2%), representing a cumulative incidence of attrition of 11.4 cases per 100 person-years. Of the 8,337 who experienced attrition, 1,618 (19.4%) were deceased and 6,719 (80.5%) were lost to follow-up. If all patients included in the study are considered, loss to follow-up accounted for 28.4% and deaths accounted for 6.8% of the sample at the end of the study. At multivariate analysis, having initiated ART between 2012–2015 vs. between 2017–2020 (aHR 2.81: 2.172–3.643); initiated ART as an adult (15 years and older) vs. as a young person (younger than 15 years) (aHR 1.50: 1.102–2.002); unmarried status vs. married status (aHR 1.182: 1.013–1.347); initiated ART with CD4 count <100 cells/μL vs. with CD4 count > 350 cells/μL (aHR 5.92: 5.091–6.543); having initiated ART at an advanced clinical stage (stages III and IV WHO classification) vs. at an early stage (stage I and II WHO classification) (aHR 3.66: 3.045–3.975) were factors significantly associated with attrition in this study .In this study, we analyzed retention and attrition in the antiretroviral treatment program between September 2007 and April 2020 at nine large-volume care sites for people living with HIV in Guinea.After a median follow-up of 3.1 years, 35.2% were no longer retained in the program, for an overall retention rate of 64.8%. This probability was 86.0% at 6 months, 76.2% at 12 months and 70.2% at 24 months. The authors of a systematic review from studies in sub-Saharan Africa showed weighted average retention rates of 79.1%, 75.0%, and 61.6% at 6, 12, and 24 months, respectively .The retention rate in our study is much lower than the proposed national goal (80% retention rate for children under 15 years of age after 12 months of follow-up and 90% retention rate for adults 15 years of age and older after 12 months of follow-up) [The cumulative probability of attrition was 35.2%, or a cumulative incidence of 11.4 per 100 person-years. Death and loss to follow-up were the two components for attrition. Cumulative mortality at the date of data extraction was 6.8%. This death rate increased very gradually over the years of follow-up on ART, which is comparable to the observations made by other authors of studies conducted in low- and middle-income countries –19.Although mortality is important, loss to follow-up was the main reason for attrition in our cohort. Of the 23,686 patients included in our cohort, 28.4% of patients were lost to follow-up by the end of the study. These results are comparable to those found elsewhere –24.Several hypotheses can be put forward to explain the high number of people lost to follow-up. Some patients may change treatment sites to obtain ART from other sites without their original sites being informed. These patients may be categorized as lost to follow-up at their home sites, despite continuing to take ART elsewhere. Twaya et al. found in a Malawian cohort that 21% of patients considered lost to follow-up in their home sites were obtaining supplies from other sites . BrinkofPoor quality of care may also be a reason for PLHIV to change treatment sites. Some services are not available in many sites  of HIV infection, who were 3.66 times more at risk of attrition than patients who initiated ART at an early stage (stage I and II of the WHO classification). Several previous studies have reported similar results –33. PatiIt is therefore essential to mobilize resources for the reinforcement of laboratory equipment, the training of health workers, and the provision of health facilities with the health products necessary for the care of patients with advanced HIV infection.This study also showed that patients who initiated ART during the period 2012–2015 were 2.81 times more at risk of attrition than patients who initiated ART between 2017 and 2020. This result could be explained by the impact of the Ebola virus disease epidemic on health systems in West Africa, including Guinea between 2014 and 2016. It should be recalled that the period 2014–2015, belonging to the period 2012–2015 was the period of high transmission of the Ebola virus in Guinea. This has led in Guinea, as in the affected countries of West Africa, to a drastic result in the use of health services, which can therefore lead to an increase in the rate of attrition among patients on ART. This hypothesis is supported by a study that has assessed the impact of the Ebola virus disease epidemic in Guinea and West Africa . AnotherOur study also found that patients who initiated ART as adults (15 years and older) were 1.50 times more at risk of attrition than patients who initiated ART young (less than 15 years). Our results are contrary to those of several studies conducted in Africa which found that young age was a risk factor for attrition , 36, 37.In our study, unmarried patients were 1.18 times more at risk for attrition than married patients. A study conducted in Kenya in 2020 showed that unmarried status was associated with both loss to follow-up and mortality in the cohort of patients in an ART program . For thiOur study assessed the retention of people living with HIV in a treatment program implemented in several large cohort sites in Guinea and identified risk factors associated with attrition. It covered a long follow-up period (13 years) and included a large sample of patients on ART . The cohort of patients followed in the sites involved in this study represented more than 45% of the national cohort of patients on ART in all 142 sites in the country.It is also important to recall that since the advent of free ART in 2007, this is the first large-scale study that has not only estimated retention, but also analyzed the factors that influence attrition  of patients living with HIV in an ART program in Guinea.Despite the strengths mentioned above, this study has some limitations. The data analyzed were collected retrospectively through longitudinal patient follow-up databases, which presents a risk of information bias due to under-reporting of some events of interest , and some key variables such as CD4.Mortality estimation was based on reported deaths only. Adjustment for mortality was not made due to lack of information on deaths among those lost to follow-up. Data on potential predictors such as education, socio-economic level, weight, height, and hemoglobin level were missing. Also, the study did not investigate the reasons why patients are lost to follow-up and go to other care sites. Finally, the sample for this study was drawn from large-cohort sites that had more or less a good electronic management system for patients on ART, so small-cohort sites were absent. It should also be noted that the inclusion of only one site outside of Conakry, and the fact that all sites in the study are supported by NGO partners, limits the representativeness of this study for the entire country, Guinea. Also, the use of the availability of electronic databases as an inclusion criterion for ART centers could be a bias in this study, as retention or attrition could be worse or better in centers without an electronic database archive. However, this study provides a solid evidence base for the Conakry sites and for the Ministry of Health and National AIDS and Hepatitis Control Program authorities in improving retention in the ART program in Guinea. It also provides a good evidence base for further studies on this topic at the national level.This study showed a high attrition rate of HIV patients on ART, making the retention rate in our study much lower than the proposed national target of 90%. This suggests that mechanisms to improve retention of patients on ART for life should be put in place or strengthened: implementation of online electronic patient data management platforms, strengthening of community-based psychosocial support mechanisms for patients, strengthening of the implementation of innovative approaches to HIV management , and strengthening of nutritional and dietary support. Another study (mixed-methods study) with direct questioning of patients could also complete this research through an analysis of a larger number of predictors of attrition.


In total, 59.9% received treatment at out-of-facility locations, with more males receiving treatment in this setting than females [65.7% vs. 54.8% p-value < 0.001]. Of those in whom blood pressure was assessed (65.9% of the treatment cohort), 9.6% were hypertensive, with males being less likely to be hypertensive [8.0% vs. 11.1% p-value < 0.001] than females. Overall, retention as of September 2022 was 96.4%, while VS was 99.0% and did not differ significantly by sex . VS was slightly but not significantly higher among females than males . Although older males and females living with HIV had similar treatment outcomes, hypertension screening was suboptimal and could impact long-term morbidity and mortality. Our study emphasizes the need to integrate noncommunicable disease screening and the management of hypertension in the care of older persons living with HIV.Studies show that treatment outcomes may vary among persons living with HIV. To fast-track the attainment of epidemic control across gender and age groups, the Accelerating Control of the HIV Epidemic (ACE-5) Project implemented in Akwa Ibom and Cross Rivers States, Nigeria, examined the hypertension rates and treatment outcomes of older adults living with HIV. The demographic and treatment characteristics of males and females ≥ 50 years living with HIV, who initiated antiretroviral therapy (ART) as of September 2021, were abstracted from medical records across 154 health facilities and community sites in Akwa Ibom and Cross River states, Nigeria. We compared these characteristics by sex using the chi-square test. The log-rank test was used to compare differences in their retention  and viral suppression (VS) rates [<1000 copies/Ml] in September 2022. Of the 16,420 older adults living with HIV (10.8% of the treatment cohort) at the time of the study, 53.8%, and 99.5% were on a first-line ART regimen. Among the 3585 with baseline CD4 documented (21.8% of the cohort), the median [IQR] CD4 count was 496 [286–699] cells/mm The global scale-up of antiretroviral therapy (ART) has led to improved survival of people living with the human immunodeficiency virus (HIV), leading to a growing number of older adults living with HIV ,2. The dHowever, aging increases the risk of non-infectious morbidity, and comorbidities have been associated with chronic inflammation from HIV infection and adverse effects from long-term ART ,10,11,12In Nigeria, ART coverage has significantly improved from 63% in 2019 to 89% in 2020, and over 25% of all adults living with HIV are categorized as older adults . While the sociodemographic features and clinical outcomes of PLHIV have been well described ,18,19, tWe conducted an analysis of program data to determine the burden of hypertension in males and females living with HIV in southern Nigeria who were older than 50 years, and we described the clinical characteristics, retention in care, and viral suppression. Our hypothesis was that there are differences between genders in the proportion with hypertension and that HIV treatment outcomes also differ among older female and male adults receiving ART.The ACE-5 project was implemented in 34 local government areas (LGAs) in Akwa Ibom and Cross River States, Nigeria. ART services were provided through 154 health facilities, 95 community pharmacies, and 68 community ART management (CAM) teams comprising community mobilizers (for community entry and mapping), counsellor testers for testing, clinicians , and case managers (for case management and follow-up). To provide person-centered care to older PLHIV, alongside the standard care provided within the health facilities, the ACE 5 project also maintained the three community-based models (community pharmacy ART refill program (CPARP), community ART refill groups (CARGs), community ART refill clubs (CARCs)) and other decentralized drug distribution models, as previously described by Sanwo O. et al. .This retrospective cohort study analyzed program data for PLHIV (≥50 years) who initiated ART prior to September 2021 in 154 health facilities in Akwa Ibom and Cross River States in southern Nigeria.For this study, de-identified data were extracted from Lafiya Management Information System (LAMIS), an electronic medical record database—described previously—housing routine programmatic data collected from PLHIV who access services at supported health facilities . These sFor this analysis, data were abstracted for each patient record at baseline, including sociodemographic  characteristics, residence , ART regimen , the presence of hypertension (documented systolic blood pressure (BP) >  140 mmHg or diastolic BP > 90 mmHg), and the use of antihypertensive medication. Also extracted were ART status at the end line in September 2022 and recent viral load results. The extracted data contained no patient names or other personal information that could be used to identify individual patients, and they were subjected to internal consistency checks and assessed for outliers and wrong entries, which were removed prior to analysis.Time-based cohorts of eligible individuals were created based on the year of ART initiation, which also aligned with the PEPFAR program year that starts on October 1 and runs until September 30th of the subsequent year. This yielded seven cohorts: before October 2015, October 2015–September 2016, October 2016–September 2017, October 2017–September 2018, October 2018–September 2019, October 2019–September 2020, and October 2020–September 2021. We excluded individuals transferred in during the study follow-up period.Documentation of high blood pressure and retention for the 12-, 24-, 36-, 48-, 60-, 72-, and >72-months-on-ART cohorts was determined in September 2022. PLHIV having no clinic visit within >28 days from the last expected drug refill were considered lost-to-follow-up. Other outcomes were “stopped” , “dead” (if a death was reported by relatives or certified by a clinician), or “transferred-out” ; otherwise, the patients were considered “active”.® AmpliPrep, Abbott, and Hologic Panther ® are the platforms used for VL analysis and have a low detection limit of <40 copies/mL, which informed the various classifications.Viral suppression status was determined based on the client’s last viral load in September 2022 and categorized as “suppressed (HIV RNA threshold less than 1000 copies/mL)” or “unsuppressed ” following national and WHO guidelines . Viral sp-value of <0.05.Descriptive statistics (frequencies) were used to summarize categorical variables. Kaplan–Meier was used to assess retention rate , with an apriori expectation of a 95% PEPFAR retention threshold . The logPermission to analyze these program data was obtained from the Health Research Ethics Committee (HREC) in Akwa Ibom state. Patient informed consent was not required because only routine, anonymous, operational monitoring data were collected and analyzed.A total of 16,420 older adults living with HIV (10.8% of the treatment cohort) initiated ART as of September 2021. The majority, 53.8%, were females. The percentages of older males who started on ART in each cohort year increased by 14.0 percentage points from 39.1 percentage points in 2015 to 53.1 percentage points in 2021 .p < 0.001). Other comorbid conditions were not consistently documented and are not reported. CD4 testing was also either not consistently conducted or reported, with only 3585 or 21.8% of the cohort having files with a CD4 result. Of those with documentation, the median [interquartile range] CD4 count was reported to be 496 cells/mm3 [286–699], and, of those with a CD4, 11.4% [13.4 among males and 10.2% among females] had CD4 less than 200 cells/mm3. When compared by sex, there was a significantly higher number of males identified and commenced on ART in the community than females . More males had secondary education (61.5%) when compared to females (47.6%) (Most of the enrolled cohort (91.4%) were 50–65 years, 59.9% were identified in the community, and 60.6% resided in rural areas. Above half (54.1%) had secondary education, and the majority (69.7%) were married. A greater proportion of the older adults living with HIV (99.5%) were on first-line ART regimens. Blood pressure (BP), although a vital sign expected to be recorded at each encounter, was not consistently recorded, with only 10,828 (65.9%) of all files having a measurement. Of those with BP documentation, 9.6% were reported to be hypertensive. Of 1041 with hypertension, 627 (60.2%) were women. A significantly higher proportion of females (11.1%) than males (8.0%) had hypertension ( (47.6%) .p = 0.17)  . In addiViral suppression was slightly lower among those who received ART in the facility (98.4%) compared to those who received ART in the community (99.5%), lower in urban dwellers (98.5%) than in rural dwellers (99.4%), and lower among those separated from a spouse (98.7%) than those married (99.1%) or single (99.2%). By comparing regimen type, viral suppression was lower among those on a fixed-dose combination of Tenofovir + Lamivudine + Dolutegravir (99.1%) than among those on the Abacavir + Lamivudine + Dolutegravir (98.4%), and among those with hypertension (99.4%) than among those without hypertension (99.2%). All differences were not significant.p = 0.01); similarly, females on first-line ARVs had higher suppression than males . In the subgroup with low CD4 (<200 cells/mm3), females achieved higher viral suppression than males . However, there was no sex difference in viral suppression among those with hypertension .Overall, the retention rate was 96.4% . Retentip-value = 0.008]. Similarly, females residing in rural areas were more likely than males to be retained on ART . There was no difference in retention between males and females based on age category, educational level, regimen line and type, hypertension status, or baseline CD4 status (Females who received ART in the health facility were more likely than males to be retained on treatment [female: 95.4% vs. male: 93.9%; 4 status .Our study determined the burden of hypertension and compared characteristics and HIV treatment outcomes among males and females older than 50 years living with HIV in southern Nigeria. In this cohort, 96.4% were retained on antiretroviral therapy, and up to 99.0% achieved viral load suppression. These important program and clinical outcomes were similar for both males and females. However, we found poor rates of screening or documentation of hypertension, with only 65.9% having been assessed for this important comorbidity.Overall, we found more older females on treatment than men, consistent with the Nigerian epidemic ,25. HoweIn this study, the prevalence of hypertension among older adults living with HIV was 9.6%, lower than the 21% reported in a different Nigerian geriatric HIV cohort , the 32%Retention and viral load suppression were high in this cohort of older PLHIV and were similar among males and females, unlike in other studies that have highlighted challenges in keeping males engaged in HIV treatment programs . Our finOur finding of higher rates of viral suppression in females than in males in a small subpopulation of individuals with low baseline CD4 was surprising and warrants further inquiry. The low viral suppression in men in in the proportion with more advanced HIV is likely due to other concurrent comorbidities—beyond the data that we analyzed—that are probably more prevalent among men.Our study, like all retrospective studies, had some limitations. Firstly, variations exist among older adults living with HIV beyond the sociodemographic characteristics that we had access to for use in this analysis. For example, a review of retrospective data did not allow us to determine the reasons for the lower prevalence of hypertension in this setting, thus needing further research. Secondly, we used routine program data that have inherent weaknesses, including missingness and inconsistency in their recording.However, this study has some notable strengths and contributions to service delivery design. We used routine program data from a large PEPFAR-funded program that provided care to a wide variety of patients from different localities. While not generalizable, some lessons can be applied to similar resource settings like ours.In this large cohort of older adults living with HIV receiving ART, assessment and/or documentation of hypertension screening was poor, but hypertension rates were lower than in similar settings. However, retention in the HIV program and viral suppression rates were above the PEPFAR retention benchmark and UNAIDS target of 95% of PLHIV on ART having viral suppression. There were no differences in viral suppression between males and females, except for among those with advanced HIV, highlighting the successful engagement of older PLHIV in our HIV program. However, the low access to hypertension screening and access to CD4 testing at ART initiation are of concern. To address this, policymakers should explore an integrated approach that merges elements of geriatric medicine principles with HIV programs. This holistic strategy would ensure comprehensive care for older individuals living with HIV, with a particular emphasis on routine screening, early detection, and ongoing care, even at the primary healthcare level. The elevated prevalence of hypertension in older females warrants further investigation into causes and control measures. Our study findings can inform the design and implementation of a package of care for older persons living with HIV.


Uganda adopted and implemented the Universal Test and Treat (UTT) guidelines in 2017, which require HIV-infected persons to be initiated on antiretroviral therapy (ART) at any CD4 + cell count, and to be routinely monitored for viral load to assess response to ART. However, there is paucity of data on viral load suppression (VLS) among people living with HIV (PLHIV) with mental disorders. We conducted a parallel convergent mixed methods study to determine HIV VLS among people with a mental disorder and explored the socio-cultural determinants of VLS at Butabika hospital and Mulago (ISS) HIV Clinics in Uganda.We conducted a retrospective medical records review; seven key informant interviews (KII) among purposively selected healthcare providers and 12 in-depth interviews (IDI) among clinically stable PLHIV with a mental disorder. Data was collected on demographics, mental disorder, ART, viral load status, social support, stigma, and disclosure of HIV status. Quantitative data was analysed using descriptive statistics and modified Poisson regression, while Inductive thematic analysis was used for the qualitative data.Of the 240 PLHIV with a mental disorder who were enrolled, 161 (67.1%) were female with mean age 38.9 (± 11.2) years. Overall, 88.8% (95% Cl: 84.0 – 92.2%) achieved VLS. Age , male gender , divorced , widowed , baseline CD4 count < 200 , psychotic mental disorders  and fair (85–94%) ART adherence level  and TDF/3TC/DTG  were associated with HIV VLS. Social support from family members, knowledge of impact of negative thoughts on VLS, fear of breaking up with partners and compassionate healthcare providers positively influenced VLS. Stigma and discrimination from the community, self-perceived stigma hindering social relations, socio-economic challenges and psychiatric drug stock-outs negatively affected VLS.HIV VLS among PLHIV with mental disorders at institutions that provide integrated HIV and mental health care is still below the UNAIDS 95% target. Health promotion messaging focusing on benefits of VLS and countering stigma to create a safe environment; and active involvement of family members in care could improve HIV treatment outcomes for PLHIV with mental disorders. The prevalence of HIV among people with a mental disorder is higher compared to the general population –3. In UgEarlier research reported viral non-suppression among PLHIV with major depressive disorder at 12.2–13.5% . Mental Different factors are associated with VLS including age, marital status, treatment adherence, WHO clinical stage –19, and This was a parallel convergent mixed methods study where quantitative and qualitative data were collected and analysed simultaneously. The findings were interpreted together. The quantitative section used a cross sectional design while the qualitative section employed an exploratory design. The qualitative study was conducted and the results presented following the Social Ecological Model (SEM). The model takes into consideration the individual, and their relations to people, organizations, and community where they reside. It therefore depicts five levels – Individual, Interpersonal, Organizational, Community, and Public Policy . The quaThe study was conducted at Butabika National Referral Mental Hospital and Mulago ISS Clinics. Butabika is a national mental health referral and teaching hospital that offers general and specialized mental health treatment. The hospital runs a busy outpatient department which includes the HIV Clinic. The HIV clinic serves about 350 active patients who include PLHIV with and without mental disorders. An estimated 5–15 PLHIV diagnosed with mental disorders attend the clinic every week. Mulago ISS Clinic is also teaching facility located within Mulago National Referral Hospital complex. The clinic provides care to over 17,000 active PLHIV. An estimated 15–20 PLHIV diagnosed with mental disorders attend the clinic every week. Both HIV clinics  are supported by the Makerere University Joint AIDS Program (MJAP), a President’s Emergency Plan for AIDS Relief (PEPFAR) implementing partner in Uganda.PLHIV and mental disorders were eligible if they had: (a) been initiated on ART at Butabika hospital ART clinic or Mulago ISS Clinic between 2017 and 2021; (b) been on ART for at least 6 months; (c) a record of HIV diagnosis; (d) a record of any of the psychiatric diagnoses as per the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM V)  or a cliData was collected through document review using a structured data abstraction tool developed from literature. The tool was pilot tested on 10 randomly selected records of PLHIV with a mental disorder who were initiated on ART at Butabika ART clinic in 2016 and revised to address study objectives. Data was abstracted in duplicate by two research assistants, from patients’ medical records. Data was collected on demographics, mental disorder, ART regimen, most recent VL, CD4 cell count, adherence level, WHO Clinical stage, history of TB and psychiatric treatment. We retrieved the adherence level at ART initiation which had been previously determined by self-report or pill count and sub-categorised into poor (< 85), Average (85–94%) and Good (>/= 95) . DiscrepData were analysed using STATA 14 . Means (and standard deviations) were used to summarize normally distributed numerical variables; and medians (and interquartile ranges) reported for non-normally distributed data. Frequencies and percentages were used to summarize categorical variables. Viral load (VL) < 1000copies/ml was used as the cut off for VLS, the outcome of the study . We usedHealthcare providers were eligible for KII if they worked at the study sites for at least 12 months and gave written informed consent. Participants for the KII included medical doctors, psychiatric nurses, peer educators, HIV/ART counsellors, and general nurses. The IDI included only clinically stable PLHIV and any mental disorder who fulfilled the criteria for the quantitative survey and were able to give written informed consent. For this study, participants were considered as clinically stable if they were on mental health treatment, not currently admitted at the hospital and were able to bring themselves for their clinic visit. Participants were selected purposively. The adequate sample size was based on data saturation.Data was collected through KII and IDI using semi-structured interview guides. Participants for in-depth interviews were identified from records and contacted to participate in the study. They were a subset of the quantitative survey. The interviews were conducted through one-time face-to-face meetings in either English or Luganda depending on the preference of the participants. The interviews were audiotaped and short notes taken by the research assistant during interviews.Data was analysed following an inductive thematic approach. The qualitative section was designed, conducted and findings reported as per the consolidated criteria for reporting qualitative research (COREQ) guidelines . Analysi3 . 40% of participants were in WHO stage III. Nearly three quarters 171 (71.3%) of all participants were on tenofovir/lamivudine/efavirenz (TDF/3TC/EFV) as the initial ART regimen. Majority 98 (47.3%) of the participants had depression while 75 (36.2%) had psychosis as showed in Table Between November 2021 and January 2022, medical records of 240 PLHIV who had a mental disorder 67.1% of whom were female, mean age of 38.9 (± 11.2) years were reviewed and enrolled into the study . Ninety percent, (95%Cl: 81.8–94.8) in Butabika and 88% (95%Cl: 81.7–92.3) in Mulago. Among PLHIV and mental disorders, male participants were less likely to achieve VLS . Age had no effect on VLS . PLHIV with a mental disorder who were divorced  or widowed  were less likely to achieve VLS than the married. Similarly, viral suppression was uncommon among participants with a baseline CD4 count < 200 . Participants who had fair (85–94%) adherence level to ART were less likely to be suppressed compared to those with good (≥ 95%) adherence . Participants on TDF/3TC/DTG  as baseline ART regimen were less likely to be suppressed compared to those on TDF/3TC/EFV. Participants with psychotic mental disorders  were more likely to achieve VLS than those with non-psychotic disorders. The results are summarized in Table PLHIV who had a mental disorder (n = 12) and healthcare providers (n = 7) participated in the study for IDI and KII respectively. The summary of characteristics of the participants included for the IDI is presented in Table In the qualitative findings below, we describe the socio-cultural factors that influence HIV VLS according to patients and healthcare providers. We present these factors in relation to the domains of the social ecological model (SEM)  which inBoth of my parents died but I told my brother [about my HIV status] and he counselled me and escorted me to hospital.” .““I told him [Husband] when I went back home with the [HIV positive] results … he also tested positive. When am busy, he comes [for the drugs] or vice-versa.” .“My mother knows [about HIV and mental disorder] she brings me to hospital sometimes… sometimes she gives me transport or buys the mental health drugs” .Social support systems played a crucial role in enabling VLS. Participants reported that disclosing their HIV status to their immediate and close family members including partners helped them in achieving VLS because of the support that families rendered to them. And for most of the participants, families were aware of their mental health conditions.I have not yet told my boyfriend about my status …but we don’t stay together so am able to swallow my drugs without his knowledge…we have not engaged in sexual activity.” .“However, a participant in a new relationship expressed fear to disclose her status to her boyfriend because she was afraid of losing him. She, however, indicated that they do not stay together. Although it did not affect the way she takes her medication, non-disclosure makes partners vulnerable to HIV.They [healthcare providers] came in a vehicle to our home and also went to another man’s home who had disclosed his [HIV] status to the community and he does community peer education. So now people also suspect me to have HIV…they keep avoiding me.” .“Community-based models of health care delivery may put PLHIV and mental disorders at risk of stigma from the community, which consequently affects their viral load.“…my sister keeps laughing at me and abusing me…but I take my medicines but of course it tortures me. I have no peace of mind at home.”.She [Wife] left me, went with the children and stopped them from visiting me…she used to help me with cooking, washing…but I also miss my children…It’s hard to concentrate. The counsellors say you can’t fight the virus if you have negative thoughts but I can’t help it. ” .“Participants reported experiencing stigma or discrimination from the community due to either HIV or mental disorder. They noted that although it didn’t stop them from taking their medication, it affected them psychologically. Participants however expressed understanding of the impact that their mental health state could have on their viral load as evidenced by their explanations that negative thoughts were associated with high viral loads.Am afraid they will discriminate me …but I also fear making new friends because once they know [the HIV status] they will reject me.” .“I can’t do drugs [abuse drugs] again, she [partner] doesn’t like it and always warns me against relapsing…We swallow the drugs [ARVs] at the same time.” .““They are afraid of getting partners because of fear of rejection …and worry if they will have children…it stresses them and this is not good for them. But partners would support them in taking their medication and be able to control not only HIV but also the mental illness. ” (KII 4).Self-perceived stigma and fear of rejection limited social relations which would otherwise be beneficial. Participants were afraid of building their social networks and this was affirmed by healthcare providers. For some participants, the fear to separate with their partners motivated them to adhere to treatment so as to control their viral load and mental health relapses.“…sometimes I’m unable to come [to hospital] because of transport. At times I have to buy drugs because they run out of stock at the clinic….especially psychiatric drugs. And yet I don’t have money.” .I was laid off work because of regular absence due to sickness or hospital visits…my mother has to give me transport to hospital and other personal effects. Yet she can’t afford….” .“Participants noted to experience some socio-economic challenges that hindered their access to treatment. Majority did not have jobs. They reported to miss hospital visits and treatment because they have no money to buy the drugs that are out of stock at the facility. This negatively impacted VLS.The counsellors are good. They thank you for swallowing drugs well when the virus reduces. It’s encouraging…sometimes they are harsh like when the virus is not reducing… ”.“The clinic works on specific days but for these patients [PLHIV with mental disorders] we work on them any day they come.” (KII 1).“Supportive patient-provider relationship also positively influenced suppression. Participants reported healthcare providers to be very compassionate during the course of treatment which they believe was key in helping them suppress. However, they also noted some negative experiences with healthcare providers especially due to non-adherence.“…it would be good if the HIV clinic also had mental health drugs. Patients get tired lining up…the drugs run out stock and you have to tell the patient to buy. Most can’t afford and so they miss doses.”(KII 4).Stocking HIV Clinics with mental health drugs and minimising stock-outs would reduce on the waiting time and improve suppression. Participants reported inability to afford to buy mental health drugs that are out-of-stock. This interferes with adherence and may affect viral suppression.It is almost like a requirement to have a treatment supporter. Those that don’t have we encourage them to get treatment buddies. Because they are beneficial; they remind them to take their medication, hospital appointments, and offer physical and psychological support …they leave their [treatment supporter] contacts with the facility.” (KII 6).“Healthcare providers reported that they emphasise the need for patients to have treatment supporters to help them during the course of treatment which enables them to achieve VLS. Similarly, three quarters of participants in the quantitative survey had a treatment supporter. Treatment supporters included a relative, spouses, friend or fellow patient.the nurses on duty help them [in-patients] take their medication. They prioritise PLHIV and mental disorders.” (KII 4) “…the nurses alone are not enough to provide all the necessary care. Caretakers are encouraged to visit but some [caretakers] dump patients and never visit them. …those patients keep relapsing… and remain unsuppressed.” (KII 5).“…More at the institutional level, health care providers reported caring for in-patients but emphasised the need for family involvement in the treatment process. They argued that regular visits from family members motivates patients to adhere to treatment, which improves their viral load.This study aimed to determine HIV VLS among PLHIV with a mental disorder and to explore the socio-cultural factors associated with HIV VLS using the social ecological model. We found viral suppression at 88.8% with divorced people, those with a low CD4 cell count and people with poor adherence and those on TDF/3TC/DTG regimen being less likely have VLS. People with psychotic mental disorders were more likely to achieve VLS. Social support from family members, knowledge of impact of negative thoughts on VLS, fear of breaking up with partners and compassionate healthcare providers positively influenced VLS. Stigma and discrimination from the community, self-perceived stigma hindering social relations, socio-economic challenges and psychiatric drug stock-outs negatively influenced VLS.The overall HIV VLS was 88.8% which is lower than the UNAIDS target of 95% . It is aAmong PLHIV and mental disorders, male gender, low baseline CD4 cell count, being divorced or widowed, and poor adherence were associated with low viral suppression. These findings are consistent with findings from studies in sub-Saharan Africa , 36, 37.At the interpersonal level of the socio-ecological model, participants reported disclosing their HIV status to immediate family as encouraged by healthcare providers but were reluctant to disclose to community members. This earned them social support which they say helped them suppress the virus. Healthcare providers noted that relatives supported patients in treatment if they knew about their conditions which helped in achieving viral suppression. The support rendered included doing their laundry, preparing and providing meals and housing, support in activities of daily living, financial provision, picking for them drugs, escorting them on hospital visits among other. This nature of social support network helped patients to adhere to treatment and achieve suppression as seen in previous studies findings . This isHowever, stigma and segregation was a common problem among PLHIV and mental disorders. Participants reported experiencing double stigma due to HIV and mental disorders. The commonest reported forms of stigma were public stigma and self-perceived stigma. Self-perceived stigma hindered participants from engaging in meaningful relations due to fear of rejection. The stigma could be due to disclosure since majority had disclosed and could also be the reason why some participants (11.2%) in quantitative analysis were unsuppressed. The findings are consistent with literature , 44.Notably, participants expressed knowledge of the importance of having a positive attitude in achieving good treatment outcomes. They noted that negative thoughts hindered viral suppression as is stated in literature . This coThe other hindrance to suppression at individual level that was reported were socio-economic constraints. Most participants did not have a source of income and hence were unable to fend for themselves. Many depended on their family members for survival. This affected their adherence to psychiatric drugs especially when they were out of stock essentially affecting their viral suppression. Some participants even missed hospital appointments due to lack of transport to facilities. This is consistent with previous research where low relative wealth was associated with lack of viral suppression . AdditioLimitations of this study included information bias as patients who received psychiatric medications for indications not related to mental disorders might have been misclassified. Similarly, those who had mental disorders but remained untreated were left out in this study. To prevent this, the study employed a standardised definition of a mental disorder adopted from previous similar studies –29 that The findings from this study demonstrate the need for health promotion messaging focusing on the benefits of VLS. This could be drawn from findings at the individual and interpersonal level of the SEM, where PLHIV and mental disorders expressed the desire to have partners, and start families. Messaging that counters stigma in communities would also create a safe environment to improve their viral loads. At the individual level, programs need to incorporate income generating activities since finances were a common challenge among PLHIV and mental disorders. The other lesson from the interpersonal domain points to the role of active involvement of family members in the care for PLHIV and mental disorders in improving viral suppression. Additionally, at the institutional level, there’s need to minimise patient waiting time and provision of adequate mental health drugs for PLHIV and mental disorders. Further research could explore changes in viral suppression over time among PLHIV and mental disorders.In conclusion, HIV VLS among PLHIV and mental disorders at institutions that provide integrated HIV and mental health care is still below the UNAIDS 95% target. Adherence to ART and low CD4 at ART initiation are associated with viral suppression among PLHIV and mental disorders. Social support from family members, knowledge of impact of negative thoughts on VLS, fear of separation with partners and compassionate health care providers positively influenced VLS. Stigma and discrimination from the community, self-perceived stigma hindering social relations, socio-economic challenges and psychiatric drug stock outs at facilities negatively influenced viral suppression. The qualitative findings offer insights that institutions offering integrated HIV and mental health care can look into to improve treatment outcomes among PLHIV and mental disorders.


The evaluation of dolutegravir based on available preclinical and clinical studies reveals a risk of central nervous system (CNS) disorders associated with long-term use of the drug. The available literature on the pharmacokinetics of the drug, including its penetration of the blood–brain barrier, was reviewed, as well as clinical trials assessing the incidence of adverse effects in the CNS and the frequency of its discontinuation. This paper also summarizes the impact of factors affecting the occurrence of CNS disorders and indicates the key role of pharmacovigilance in the process of supplementing knowledge on the safety of drugs, especially those that are newly registered. As a result of damage to the blood–brain barrier (BBB) in human immunodeficiency virus (HIV)-infected patients, the virus invades the central nervous system (CNS) in the first few days, causing the development of a long-term inflammatory process and damage to the nerve cells. This leads to a variety of CNS disorders. Before the era of combined antiretroviral therapy (cART), HIV-associated dementia (HAD) and distal sensory polyneuropathy were experienced by as many as 35% of patients . HAD nowDrugs that penetrate well into the CNS are used to reduce the risk of central symptoms in HIV patients, leading to a reduction in HIV RNA in the cerebrospinal fluid (CSF). However, the use of increasingly effective antiretroviral drugs (ATRs) may also affect the CNS and cause adverse effects; the occurrence of neuropsychiatric disorders may lead to discontinuation of treatment .The problem of neurotoxicity may be linked to many groups of ATRs. Such reports have appeared in the case of dolutegravir (DTG), one of the most commonly used drugs belonging to a new class of ATRs prescribed to patients infected with HIV-1. DTG is a second-generation integrase chain transfer inhibitor (INSTI), interrupting an enzyme involved in the reproduction of HIV. DTG works by blocking the transport and incorporation of proviral DNA into the host T-cell genome, inhibiting further steps in the replication process. This slows the multiplication and spread of the virus . DTG wasThe INSTI group also includes raltegravir (RAL), elvitegravir (EVG), bictegravir (BIC), and cabotegravir (CAB). Clinical trials in which oral INSTIs were used showed high efficiency with a rapid decrease in HIV RNA already in the fourth week from the start of treatment. In a study that compared the effectiveness of DTG with BIC, 76–80% of ATR-naïve HIV-positive patients presented with virological suppression as early as 4 weeks after starting . The INS14C] DTG to male rats. However, DTG radioactivity was low (< 2% of blood radioactivity). A recent mouse pharmacokinetics study of tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and DTG showed that each of the drugs had low brain exposure, with only TDF achieving concentrations above the 90% inhibitory concentration (IC90) DTG, which also suggested a low penetration of DTG into the CNS. PGP acts as a biological barrier; therefore, its substrates (toxins and xenobiotics) are excreted from cells, and inhibitors imply specific adverse effects. The presented analysis  assessed in vitro  .It should be emphasized that DTG is characterized by high antiviral efficacy. One of the factors limiting its use is the occurrence of neuropsychiatric adverse events (NPSAEs), which is associated with a reduction in the effectiveness of treatment and, in extreme cases, discontinuation of therapy .In 2017, Hoffman et al.  estimateSince then, many reports have been published on the safety of DTG. They showed that DTG has a favorable profile, but neurological and mental disorders may occur in patients a few months after the start of therapy, leading to discontinuation of DTG treatment. In the vast majority of cases, the severity of an NPSAE did not pose a threat to the patient’s life and did not require hospitalization. The NPSAEs resolved rapidly after discontinuation of DTG . The disIn 2017, Fettiplace et al. conducted a large-scale study assessing the incidence of NPSAEs in HIV-infected patients during treatment with DTG or other classes of antiretrovirals, including protease inhibitors (PIs) atazanavir (ATV) and darunavir (DRV), non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (EFV), and INSTI raltegravir. The analysis was based on data from five randomized phase III clinical trials  in which patients received DTG at a dose of at least 50 mg daily, the Observational Pharmaco-Epidemiology Research & Analysis (OPERA) cohort, and among cases spontaneously reported to the drug manufacturer. The assessed psychiatric disorders included different types of insomnia , anxiety , depression , and suicidal behavior . A low incidence of NPSAEs was observed in all five clinical trials but were most frequently reported by SINGLE (DTG: 17%), followed by SPRING-2 (DTG: 6%), SAILING (DTG: 3%), FLAMINGO (DTG: 8%), and ARIA (DTG: 4%). The severity of most symptoms was rated as mild or moderate .N = 3353; DTG, n = 1672; comparator therapies, n = 1681) in terms of estimated patient-years exposure time and not significantly different from clinical trial data . However, 834 (16.9%) had not received prior ART, whereas the remaining 4,105 had previously used ART, 2289 (55.8%) of which had < 50 copies HIV RNA/mL at the time of initiating the study drug. There was no significant difference in the incidence of neuropsychiatric disorders between the two cohorts at baseline, with 66 NPSAEs reported to lead to ART discontinuation, 39  in the DTG cohort and 27  in the non-DTG. HIV-infected, ART-naïve individuals with higher CD4 + T-cell counts and psychiatric disorders were more likely to develop CNS adverse events; non-NPSAEs were reported in 35/39 patients on DTG and 23/24 on non-DTG therapy. However, most NPSAEs were reversible and resolved when the ART was switched to a drug of the same or different class. At the same time, a lower event resolution rate was found in HIV-infected patients older than 50 years of age (p = 0.017). Thus, NPSAEs leading to discontinuation of ART occurred more frequently in patients treated with DTG than in those not treated with DTG. Most NPSAEs resolved after switching drugs, for both the DTG and non-DTG cohorts [In 2022, Taramasso et al. published the results of the prospective, observational SCOLTA cohort, which assessed the incidence of CNS adverse events after the administration of DTG and DTG-free ARTs. A total of 4939 HIV-infected subjects were enrolled in the study, of which 1179 were in the DTG group and 3760 in the non-DTG group [lopinavir/ritonavir , had neuropsychiatric symptoms. The effect of the SLC22A2 808C > A genetic variant in patients receiving DTG was evaluated and analyzed by real-time PCR. Among the 627 participants in the study, CA/AA carriers had a higher frequency of comorbid psychiatric illness and antidepressant use. Following 27.9 months of therapy, 108 participants discontinued DTG, with 64 having done so due to neuropsychiatric symptoms. Patients with a history of psychiatric comorbidities were more likely to discontinue DTG, whereas patients with the SLC22A2 CA/AA genotype were not. Within 30 days, most participants were completely symptom-free (61.8%). Discontinuation of DTG due to NPSAEs was not uncommon, and it was more common in participants with pre-existing psychiatric disorders. An interaction was observed between the SLC22A2 genetic variant and psychiatric comorbidities. Complete recovery from neuropsychiatric symptoms was not observed in 38.2% of patients after discontinuation of DTG, suggesting the involvement of additional factors [In 2022, Cusato et al. revealed that patients receiving DTG, which inhibits the renally and neuronally expressed organic anion transporter 2  in 107 HIV-infected Japanese patients receiving DTG. Patients with one or two UGT1A1*6 and UGT1A1*28 alleles had a higher incidence of adverse events than those with normal alleles. Patients with abnormal alleles who were over 40 years of age had higher serum concentrations of DTG [Some researchers have looked for risk factors for the occurrence of central adverse events. DTG is metabolized by uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1), and to a lesser extent by cytochrome P450 3A (CYP3A). Yagura et al. studied the relationship between a UGT1A1 gene polymorphism and the risk of neuropsychiatric adverse effects -B*5701 test result. These factors have not been confirmed by all authors, and their relationship with the occurrence of treatment complications requires further observation .A recent meta-analysis showed that there may be an increased risk of depression when DTG is co-administered with rilpivirine (RLP) compared to a single administration of either drug. The neurotoxic effect of DTG is explained by the ability of the drug to penetrate the BBB by passive diffusion, the possibility of changing the tight connections in the BBB, and secondary neuritis . The autNeurotoxicity may also occur when DTG is co-administered with sertraline. Ma et al. showed that the interaction of these two drugs increases the permeability of the BBB and risk of NPSAEs .®  has been updated several times as new information has become available. Initial results from animal studies show that single oral doses of DTG up to 500 mg/kg body weight in rats and 1000 mg/kg body weight in monkeys have minor effects on the nervous, respiratory, and cardiovascular systems. Already in the first characterization of the Tivicay® medicinal product (13 November 2013) based on the SPRING-2, SAILING, and SINLGE studies, NPSAEs included headache, insomnia, fatigue, depression, and abnormal dreams [The Summary of Product Characteristics (SmPC) for Tivicayl dreams . The curl dreams .The publications cited above indicate that DTG is associated with CNS disorders that may lead to a discontinuation or change of treatment. In most cases, the factors predisposing to their occurrence and affecting their severity are unknown. Prospective studies that will enable the identification of a larger group of patients with neuropsychiatric disorders are justified and could identify factors predisposing to their occurrence. There are no data in the literature on the therapeutic interventions used, assessment of their effectiveness, impact on the frequency and severity of neuropsychiatric disorders, and the risk of treatment discontinuation. Such studies are necessary to precisely determine the need for treatment of neuropsychiatric disorders and indicate the optimal treatment. At the same time, new information on the safety of a drug, in this case, DTG, is a natural element associated with the presence of a new drug on the market. Clinical trials, although conducted very meticulously according to restrictive rules, are not able to provide full and exhaustive knowledge about the drug, especially in the context of its safety. One should keep in mind the limitations related to the number of patients participating in clinical trials, limitations of their duration, and strictly defined groups of patients who qualify for the trials in accordance with the inclusion and exclusion criteria. All this means that rare, distant adverse effects not directly related to the mechanism of action can be identified only at the post-registration stage. Therefore, the role of pharmacovigilance is essential in this matter. Importantly, the central adverse events identified for DTG do not preclude its use in clinical practice. The drug belongs to a basic group of antiretroviral compounds currently used in the treatment regimens of patients with HIV. The effectiveness of DTG has been proven in pre- and post-registration studies. The research is only to draw attention to the mechanism of selected adverse effects, explain their causes and possible risks, indicate the need to monitor patients for selected symptoms, and allow practitioners to use the drug safely and effectively.DTG is a first-line drug in HIV-positive patients used as part of combination therapy with other ATRs. It is recommended in two-drug regimens of similar efficacy and tolerability to three-drug regimens. The choice of DTG as a first-line drug is due to its rapid and effective reduction of viral titers in the blood. DTG has been shown to be a more effective drug, easier to take, and to have fewer adverse effects than current alternative drugs. DTG also has a high genetic barrier to the development of drug resistance, which is particularly important in patients who have developed resistance to other types of ARTs. The benefit of DTG therapy is the relatively good tolerability of the drug and the low risk of drug interactions, and it can be used in patients with tuberculosis which might be concomitant to HIV infection. DTG is used once daily, and such drug regimens improve patient compliance.Undoubtedly, a limitation of treatment is the possibility of neuropsychiatric disorders, which may even lead to treatment withdrawal. The risk of adverse CNS effects is slightly higher for DTG than other INSTIs, but the intensity is generally mild to moderate.


The primary endpoint was toxicity through day 30 while the secondary and exploratory endpoints were quantitation of IL-12, IFNγ, CXCL10 and peripheral blood mononuclear cells (PBMC). The study maximum tolerated dose (MTD) was not reached indicating 1012 viral particles was safe. Total 115 adverse events were observed, most of which (92%) were grade 1/2 that did not require any treatment. Adenoviral DNA was detected only in two patients. Increase in IL-12, IFNγ, and CXCL10 was observed in 57%, 93%, and 79% patients, respectively. Serum cytokines demonstrated viral dose dependency, especially apparent in the highest-dose cohorts. PBMC analysis revealed immune system activation after gene therapy in cohort 5. The PSA doubling time (PSADT) pre and post treatment has a median of 1.55 years vs 1.18 years. This trial confirmed that replication-competent Ad5-IL-12 adenovirus (Ad5-yCD/mutTKSR39rep-hIL-12) was well tolerated when administered locally to prostate tumors.In a phase I dose escalation and safety study (NCT02555397), a replication-competent oncolytic adenovirus expressing yCD, TK and hIL-12 (Ad5-yCD/ Approximately 268,000 men are expected to be diagnosed with prostate cancer in USA in 2022 resulting in 34,500 deaths . Nearly Men with locally recurrent prostate cancer after definitive radiotherapy have few therapeutic options that can potentially eliminate the tumor with acceptable safety. Other than expectant management and systemic therapy , there are few local therapeutic options for locally recurrent prostate cancer such as salvage radical prostatectomy, salvage cryoablation, salvage brachytherapy, and salvage high-intensity focused ultrasound. Although some have demonstrated encouraging 5-year disease-free survival rates in single institution studies, most are associated with some morbidity and there are no prospective randomized studies demonstrating their long-term effectiveness.E. coli and HSV thymidine kinase (TK), which convert non-toxic pro-drugs  into potent agents that interfere with normal DNA synthesis [Several oncolytic adenovirus-based cytotoxic gene therapy vectors are currently being evaluated in clinical trials. Delivery of a conditionally cytotoxic gene, termed a “suicide gene” to the tumor is usually accomplished by direct intratumoral or systemic injection of a viral vector containing the suicide gene. Two suicide genes that have been evaluated in preclinical models and in the clinic are cytosine deaminase (CD) from yeast or ynthesis ,4. The tynthesis .Phagocytes and dendritic cells secrete interleukin-12 (IL-12) in response to pathogens. Subsequently, IL-12 activates innate  and adaptive (CD4+ Th and CD8+ Tc cells) immune system, causes IFN-γ secretion, enhances antigen presentation, and inhibits tumor angiogenesis.IL-12 has demonstrated significant anti-tumor activity in preclinical models including in prostate cancer . SystemiConsequently, we conducted an investigator-initiated phase I dose-escalation clinical trial to evaluate the maximum tolerated dose and safety of Ad5-IL-12 in men with recurrent localized prostate cancer. These men were administered Ad5-IL-12 directly into the prostate tumor at one of five escalating doses. Ad5-IL-12 viral replication, shedding and persistence was measured in patient blood (over time) by PCR. We also assessed the effect of the gene therapy on innate and adaptive immune system by quantitating peripheral blood mononuclear cells (PBMCs) before and after treatment with Ad5-IL-12 by flow cytometry. Additionally, IL-12, INFγ, and CXCL10 levels were measured in patient serum. Finally, the efficacy of the Ad5-IL-12 cytotoxic gene therapy in patients with recurrent prostate cancer was accessed by measuring patient survival.10 vp to 1 × 1012 vp . The adenovirus dose distribution was skewed toward sextants with higher-grade (Gleason ≥7) cancer.All patients had recurrent prostate cancer following at least one cycle of radiation therapy. Patients received an intraprostatic injection of the Ad5-IL-12 adenovirus on day 1 at doses ranging from 1 × 10By the study endpoint (day 30), a total of 115 adverse events (AEs) were documented. Ninety-two percent of the AEs were grade 1 (mild) and grade 2 (moderate). Several of treatment-related AEs could be either attributed to Ad5-IL-12 adenovirus  or the prodrugs such as diarrhea, anemia, nausea, lymphopenia, leukopenia; 10-1x1011 vp). Adenoviral DNA was detected only in one patient each in cohort 4 (3x1011 vp) and cohort 5 (1x1012 vp). Viral DNA in patient #12 (cohort 4) was detected for up to 24 days while it was observed for only 21 days in patient #13 . The viral load was measured by PCR for a target sequence that is common for all our adenoviral vector constructs. We evaluated Ad5-IL-12 adenoviral DNA in all the patients as described in methods. Genomic DNA extracted from the blood donated by a healthy volunteer and spiked with the adenovirus was used as a positive control for the PCR. Viral DNA was not detected in cohorts where patients were injected with low viral dose . Peak serum IL-12 was observed on Day 2 post injection in most patients. IFNγ was detected in all the patients except one patient  of 0.437, 0.367 and 0.502 and p = 0.01, 0.02 and 0.004 for IL12, IFNγ and CXCL10 further supporting that cytokine increase correlated with the viral dose administered. The IFNγ serum levels were unexpectedly high for patients in cohort 5; the correlation coefficient between IFNγ serum level and viral dose improved to 0.985 when IFNγ serum levels from cohorts 1 through 4 alone were considered. CXCL10 was detected in only one patient in cohort 1, and two patients each in cohorts 2 and 3. The highest increase in serum CXCL10 was observed in patient #12 (8533.5 pg/mL) and patient #13 (9928.6 pg/mL), both of which did show detectable levels of the Ad5-IL-12 adenoviral DNA in the blood  in patient 12  and on follow-up days as described in the clinical protocol. Blood was processed on the day of draw and collected PBMC’s were frozen at -80C until all the samples were collected from a patient. Subsequently, frozen PBMCs were thawed, processed and quantitated by multi-color flow cytometry as described in Materials and Methods. Antibodies against CD3, CD56, CD4, and CD8 served to measure NK, Th and Tc cells while activation of the immune system was monitored by staining for CD45RO, CD69, and proliferation by Ki67. Antibodies against Tim3 were used to detect suppression of the immune system following treatment ,22. The tient 12  and 10-ftient 12  on day 7w 5-fold  while itw 5-fold  on day 7w 5-fold  while inw 5-fold  which rew 5-fold . This da+CD4+ T helper (Th) cells was day 21 in cohort 1 . Patient 13 received just one dose of AST (Eligard) in October 2019 and restarted in March 2022 (PSA levels were measured from the patients before and after the virus injection. Eight of 15 (53.3%) subjects exhibited ≥20% reduction in PSA just after the initiation of gene therapy . The redrch 2022 .There was no significant effect of adenovirus injection on the PSA doubling time (PSADT) in individual patients . The med10 to 1 × 1012 viral particles. Starting on day 3 after adenovirus injection, subjects received 7 days of 5-FC and vGCV prodrugs. Similar to previous studies conducted with equivalent oncolytic adenoviral vectors, majority (>90%) of the AEs in this study were mild to moderate (grade 1/2) that did not involve any medical intervention. No serious adverse events (SAEs) were encountered in the present study indicating that the maximum tolerated dose was not attained. This trial establishes that intra-prostatic injection of Ad5-IL-12 followed by 5-FC and vGCV prodrug therapy is safe.The goal of this phase-1 clinical study was to estimate the maximum tolerated dose of oncolytic, cytotoxic Ad5-IL-12 gene therapy in men with recurrent prostate adenocarcinoma. Patients were administered increasing doses of Ad5-IL-12, ranging from 1 × 10SR39rep-ADP virus with gemcitabine and described that it was safe, well tolerated with a median PFS of 11.4 months [Investigators from our institution have successfully carried out five phase-I and a phase I/II clinical study utilizing ‘in-house’ developed replication competent, oncolytic adenoviruses in newly diagnosed and locally recurrent prostate cancer ,9,11,14.4 months . We have4 months . This tr4 months . Also, a4 months , althougAkin to the findings in the pancreatic cancer trial that was conducted with the same adenoviral vector , in this+, CD8+ T-cells). Since IL-12 plays multiple roles including priming and increasing T cell survival, promoting differentiation of Th1 cells, and enhancing T, NK, and NKT functions, we quantified the changes in different repertoire of immune cells by quantitating PBMC in blood drawn from patients before and after Ad5-IL-12 adenoviral injection. We observed a trend in NK cell populations  and adenoviral dose  are key markers of prostate cancer. We followed PSA in patients before and after gene therapy and estimated PSADT. Although, we observed an initial decrease in PSA in 8 out of 14 patients  of the Ad5-yCD/mutTKSR39rep-hIL-12 (Ad5-IL-12) adenovirus followed by one week (7 days) of 5-fluorocytosine and valganciclovir prodrug therapy. All subjects were treated in the Department of Radiation Oncology and the Department of Urology in the Henry Ford Cancer Institute, Henry Ford Health.The study was designed as a single site, prospective, non-randomized, phase I, classical 3+3 dose escalation trial of viral particles (vp). This trial was designed to enroll 15–30 men with locally recurrent prostate cancer after definitive radiotherapy under 5 cohorts with increasing doses. Each cohort of three patients with clinically localized recurrent prostate adenocarcinoma were intraprostatically injected with increasing doses (cohort-1 1x10The primary endpoint of this investigator-initiated phase-I study was to determine the dose-dependent toxicity and maximum tolerated dose (MTD) of oncolytic adenovirus-mediated cytotoxic and IL-12 gene therapy in men with locally recurrent prostate cancer after definitive radiotherapy. Secondarily we evaluated PSA response including PSA doubling time (PSADT) before and after administration of the study therapy. The exploratory aim was to determine a possible association between the primary and secondary outcomes and immunological endpoints including serum IL-12 and IFN-γ levels, and NK cell cytolytic activity. The protocol received all required regulatory approvals before initiation and was conducted under BB-IND 16536 . Good clinical practices were used throughout.Patients were required to have biopsy proven local recurrence of prostate cancer at least one year after the completion of definitive radiation therapy. The biopsy must have been performed within 180 days of study registration. Serum PSA < 100 ng/ or evidence of biologically active disease as demonstrated by an unequivocally rising serum PSA level that is ≥ 2 ng/mL above the nadir. Subjects were eligible if at least 18 years old with Karnofsky performance status ≥70. Patients were required to have negative lymph nodes as established by imaging (pelvic CT or pelvic MRI) within 90 days of registration. Men with lymph nodes equivocal or questionable by imaging were eligible if the nodes were ≤ 1.0 cm. Men with positive lymph nodes by capromab pendetide (ProstaScint) scans were eligible provided a corresponding lymph node identified by CT or MR imaging was ≤ 1.0 cm. Patients were required to demonstrate no evidence of metastatic disease, as evaluated by a bone scan and CT scan of the abdomen and pelvis within 90 days prior to registration. Equivocal bone scan findings were allowed if plain films were negative for metastasis. Patients were required to have adequate baseline organ function, as assessed by the following laboratory values, before initiating the protocol, including: (i) adequate renal function with serum creatinine ≤1.5 mg/dl or creatinine clearance ≥50 ml/min/m2; (ii) platelet count >100,000/μL; (iii) absolute neutrophil count >1,000/μL; (iv) hemoglobin >10.0 g/dL; and (v) bilirubin <1.5 mg/dL, and serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase <3 times the upper limit of normal. Patients had to have the ability to give informed consent and express a willingness to meet all of the expected requirements of the protocol for the duration of the study.Patients with any one of the following conditions were excluded from the study: (i) PSA ≥ 100 ng/mL, (ii) prostate volume > 100 cc, (iii) pathologically positive lymph nodes or nodes > 1.0 cm on imaging , (iv) evidence of M1 metastatic disease, (v) prior invasive malignancy except for non-melanoma skin cancer within 5 years of enrollment. Subjects were required to be disease-free for > 5 years, (vi) prior radical prostatectomy, cryosurgery for prostate cancer, or bilateral orchiectomy for any reason, (vii) biochemical failure while on AST if the subject had prior AST, (viii) prior systemic chemotherapy for prostate cancer. Prior chemotherapy for a different cancer was allowed given patients were >2 years post-completion of chemotherapy at the time of registration. Subjects on Proscar therapy were required to stop Proscar therapy to be eligible, (ix) severe active co-morbidity such as New York Heart Association Class II or greater congestive heart failure or active ventricular arrhythmia requiring medication, Chronic obstructive pulmonary disease (COPD) exacerbation or other respiratory illness requiring hospitalization within last 3 months or precluding study therapy at the time of registration, (x) acute infection, (xi) previous history of livery diseases including hepatitis, (xii) immunosuppressive therapy including systemic corticosteroids, and (xiii) impaired immunity or susceptibility to serious viral infections. All patients met the eligibility requirements of the protocol and signed the informed consent document. There were no protocol violations. All patients were recruited between October 2015 to March 2019.1.mutTKSR39rep-hIL-12 (Ad5-IL-12) adenovirus has been described previously [12 vp/ml. The vp-to-pfu ratio of the undiluted final product was 15. The potency of the clinical lot was re-evaluated every 6–12 months and there was no reduction in potency during the study.The design and construction of the replication-competent Ad5-yCD/eviously . ClinicaInformed consent was obtained from all patients before study-specific procedures were initiated. Pretreatment planning included transrectal ultrasound guided needle biopsy of the prostate and computerized tomography (CT) simulation. Transrectal ultrasound scan (TRUS)-guided biopsy cores (≥ 6 cores) were taken to map the location of the cancer within the prostate. Blood was collected for baseline detection of the Ad5-IL-12 adenovirus by polymerase chain reaction (PCR) and serum cytokines  by Enzyme-Linked Immunosorbent Assay (ELISA).Men received a single intraprostatic injection of Ad5-IL-12 adenovirus on day 1. The injection was performed on an outpatient basis as described previously ,8–10,34.Prodrugs were administered on an outpatient basis. 5-Fluorocytosine  was administered orally beginning on day 3 and continued for 1 week (7 days). A total of 150 mg/kg/day was given in four equally divided doses. Valganciclovir  was administered orally beginning on day 3 and continued for 1 week (7 days). A total of 1,800 mg/day was given in two equally divided doses every 12 h. The research nurse assigned to the trial counted the pills periodically to monitor patient compliance.Toxicity assessments were performed once a week prior to the start of chemotherapy (first 3 weeks) and then at scheduled follow-up visits at 3, 6, 9, 12, 18, and 24 months. Toxicities were graded using the National Cancer Institute’s Common Toxicity Criteria, CTCAE v.4.03. Case report forms (CRFs) specifically designed for this trial were used to document adverse events (AEs). The study was monitored by an internal Data and Safety Monitoring Board (DSMB). The primary end point, treatment toxicity, was monitored up to and including day 30. After treatment, patients received standard urologic care.The following evaluations were conducted once a week following the adenovirus injection through day 30: (i) physical examination, (ii) blood chemistries and complete blood counts including peripheral blood mononuclear cells (PBMC) (iii) serum PSA, (iv) presence of Ad5-IL-12 viral DNA and infectious adenovirus in blood, (v) cytokines including IL-12, CXCL10 and IFNγ, and (vi) performance status. The presence of Ad5-IL-12 viral DNA in blood, serum IL-12, IFNγ, and CXCL10 levels were monitored at every blood draw until not detected in two consecutive measurements.SR39 fusion gene contained in Ad5-IL-12. To generate a standard curve, 2.5 × 109 vp of Ad5-IL-12 was added to 0.5 ml of human volunteer blood making a concentration of 5.0 × 109 vp/ml. Serial 10-fold dilutions were prepared down to 50 vp/ml using human volunteer blood as the diluent. The sensitivity of the assay was 50 vp/mL.Blood was obtained before the adenovirus injection and at least once a week after for semi-quantitative determination of adenoviral DNA in blood. Total genomic DNA was isolated from 2.5–3 mL of blood using Qiagen columns following the protocols recommended by the manufacturer . 2–3 μL of eluted DNA was used as a template for the PCR reactions. The PCR primers have been previously described . The 5′ 2) values were >0.98 for all the analyses. Total cytokine levels were estimated for each patient for every blood draw. The highest increase in the cytokine levels (peak) after adenoviral injection and the day of “peak” serum cytokine was estimated for each patient  and then again on days +3, +7, +14, +21 and +28 (±3 days) to isolate serum and collect PBMCs. ELISA was performed following manufacturer’s protocol (BD Biosciences). For measuring CXCL10, serum samples were run after 10-fold and 100-fold dilution. Undiluted serum was used for IL-12 and IFNγ measurement. Log range dilution of purified cytokines were used for generating standard curve. Absorbance was measured at 450 nm from 96-well ELISA plates. The raw data was organized using MS Excel and analyzed on GraphPad Prism version 9. The data was interpolated using a standard curve with a second order polynomial (quadratic) equation and plotted with a 95% confidence interval (CI). The correlation coefficient . The effect of oncolytic adenovirus-mediated cytotoxic and IL-12 gene therapy on serum PSA levels was evaluated by estimating PSA doubling time (PSADT). PSADT was estimated for each patient pre-injection and post-injection. A single model of log (PSA) on time was built for each patient, and the PSA doubling time was calculated for each patient for pre-injection PSADT. For post-injection PSADT estimation, PSA doubling time from nadir was estimated using all PSA values. Minimum (MIN), Median and Mean values were estimated for pre- and post- injection PSADT. Additionally, post-injected PSADT for cohorts 1–3 and 4–5 were pooled.PSADT was calculated assuming first-order kinetics using the following equation:S1 Fig(DOCX)Click here for additional data file.S2 Fig(DOCX)Click here for additional data file.S1 File(PDF)Click here for additional data file.S2 File(PDF)Click here for additional data file.