The East Central (EC) region of Uganda has the least viral suppression rate despite having a relatively low prevalence of human immunodeficiency virus (HIV). Although the viral suppression rate in Kamuli district is higher than that observed in some of the districts in the region, the district has one of the largest populations of people living with HIV (PLHIV). We sought to examine the factors associated with viral suppression after the provision of intensive adherence counselling (IAC) among PLHIV in the district.We reviewed records of PLHIV and used them to construct a retrospective cohort of patients that started and completed IAC during January – December 2019 at three high volume HIV treatment facilities in Kamuli district. We also conducted key informant interviews of focal persons at the study sites. We summarized the data descriptively, tested differences in the outcome  using chi-square and t-tests, and established independently associated factors using log-binomial regression analysis with robust standard errors at 5% statistical significance level using STATA version 15.We reviewed 283 records of PLHIV. The mean age of the participants was 35.06 (SD 18.36) years. The majority of the participants were female . The viral suppression rate after IAC was 74.20% (210/283). The most frequent barriers to ART adherence reported were forgetfulness 166 (58.66%) and changes in the daily routine 130 (45.94). At multivariable analysis, participants that had a pre-IAC viral load that was greater than 2000 copies/ml  and those that had a previous history of viral load un-suppression  were less likely to achieve a suppressed viral load after IAC. ART drug shortages were rare, ART clinic working hours were convenient for clients and ART clinic staff received training in IAC.Despite the consistency in drug availability, counselling training, flexible and frequent ART clinic days, the viral suppression rate after IAC did not meet recommended targets. A high viral load before IAC and a viral rebound were independently associated with having an unsuppressed viral load after IAC. IAC alone may not be enough to achieve viral suppression among PLHIV. To improve viral suppression rates after IAC, other complementary services should be paired with IAC. Over 38 million people globally are living with the human immunodeficiency virus (HIV) , and morIAC is a continual and repeated process initiated by health providers to support patients to identify possible barriers and resolutions to ART adherence. IAC is provided through various individualized processes including education sessions, counselling, and assessments , 13. By In 2016, the Ministry of Health Uganda (MoH) adopted the WHO guidelines requiring all PLHIV with a viral load above 1000 copies to receive IAC , 18–20. We conducted both a retrospective and a cross-sectional study but used complementary discussed the findings. For the retrospective aspect, we reviewed health facility records of a cohort of patients that started and completed on IAC between the periods of January 2019 – December 2019. This cohort was chosen because it was the most recent cohort for which all patients had completed IAC by the study period time. We collected data on IAC, viral suppression, socio-demographic, personal and other clinical characteristics through data triangulation from MoH client files, ART Registers, Counselling forms, and the Non-suppressed viral load register. The data were collected using a pretested quantitative questionnaire.For the cross-sectional aspect, ART clinic focal persons for the three sites were chosen as key informants for interviews. These were chosen because they provided the most holistic information about viral suppression and IAC at the study sites. The ART clinic focal persons supported responses to questions on the health-related factors during the period under study for the clients. These data were used to provide narratives and explanations related to practices and experiences at the health facilities during the study period. The data were collected using a key informant interview guide.The primary study population was all available records of PLHIV that were virally unsuppressed who started, and completed IAC between January 2019 – December 2019 at Kamuli General Hospital, Namwendwa Heath Centre (HC) IV, and Nankandulo HC IV in Kamuli district. These facilities were chosen because they attend to the highest proportion of HIV patients in the district. Only records of PLHIV who had started and completed IAC were included because they had a viral load test result available at the end of IAC. PLHIV that didn’t complete IAC did not have a viral load test after IAC, albeit, the MoH guidelines stipulate that the assessment of viral suppression after IAC should be done after successful completion of IAC [All records of PLHIV who were unsuppressed started and completed IAC between January 2019 – December 2019 and all ART Clinic In-charges working at Kamuli Hospital, Namwendwa HC IV, and Nankandulo HC IV were included in the study.The study excluded the records of the following participants, virally unsuppressed PLHIV that were not started on IAC, started but not during the period January 2019 – December 2019, started on but didn’t complete IAC during January 2019 – December 2019, health workers not working at the ART clinic at Kamuli General Hospital, Namwedwa HC IV, and Nankandulo HC IV and all PLHIV referred from any other health centres in the region.The outcome of the study was viral suppression after IAC. It was categorized into suppressed (Yes/ less than 1000 copies/ml of blood) and unsuppressed (No / more than 1000 copies /ml of blood). Viral suppression for this study was defined as the suppression of viral load to less than 1000 copies/ml of blood after a repeat viral load at the end of 3 consecutive IACs that are one month apart with good adherence. The independent variables included the patient’s socio-demographic, personal and clinical characteristics.The study was a retrospective review of 283 records of the non-suppressed viral load register ART registers, MOH client files and counselling forms using a census of all records of HIV+ of unsuppressed clients who started and completed IAC between January 2019 – December 2019 at Kamuli General Hospital, Namwendwa HC IV and Nankandulo HC IV. A census was conducted because the virally unsuppressed population in Kamuli district is relatively small and well-defined. This eliminated potential bias that occurred through using a sampling technique and it was the best use of the limited time and resources available for this study. The study site facilities hosted the majority of PLHIV who are unsuppressed within the districts offering a more than fair chance of representation of the findings. The study period offered the best chance of gathering the most recent and complete information available for the study objectives, and all patients within the chosen period had completed IAC period by the time of the study. Key informant interviews were conducted among ART Clinic In-Charges who were purposely chosen because of their unique experience and understanding of aspects regarding HIV care and IAC at their health facilities. They were HIV Focal Persons of the clinics so their selection for the study was strategic and supported explanatory aspects of the findings.A complete enumeration of records of all HIV+ unsuppressed clients who started and completed IAC between January 2019 – December 2019 at Kamuli hospital, Nankadulo HC IV, and Namwedwa HC IV was be made. For each of the records listed, data was collected on the objectives from MOH Client files, ART Registers, Counselling forms, and the Non-Suppressed viral load register into a pre-designed questionnaire. Each ART In-Charges at this health was purposively selected for a key informant interview. One key informant interview per health facility was conducted.The study primarily involved the collection of quantitative data from MOH client files, ART registers, counselling forms, and the non-suppressed viral load register using a pre-designed questionnaire. The collection of qualitative data for the study was done by conducting a one-on-one in-depth interview with an ART Clinic In-Charge of the selected health facilities in the district using a predesigned questionnaire.The data was double-blind captured in KoBo Collect and exported into Microsoft Excel, cleaned, and analyzed using STATA 15, for analysis. Depiction of the discoveries was made utilizing relevant measurements. Summary data were aggregated and presented using frequencies and rates for variables that are grouped , however, for continuous variables such as age, averages were presented with standard deviations (SD). Pearson’s chi-squared and Fisher’s tests were used to confirm or nullify the existence of a relationship between the outcome variable (dependent) and the independent variables for the study. A log-binomial regression analysis with robust standard errors at a 5% statistical significance level was used to assess the association, risk ratios and corresponding confidence intervals (CI) were reported. Recorded interviews were transcribed verbatim transcriptionists, coded, harmonized, themed, and verified. The researcher themed transcriptions into major and common discussion areas for summative narrative. Under the broad theme Influencers of viral suppression, three subthemes were established, (1) Drug availability, (2) Staffing adequacy and (3) Patient follow up procedures. Some highlights/excerpts from the analysis were quoted verbatim.Between January – December 2019, a total of 354 PLHIV were reported to be virally unsuppressed at the three health facilities of whom 316 were enrolled on IAC. We excluded 71 records for reasons: 38 were not enrolled on IAC, 24 did not complete IAC and 9 were incomplete. Overall, 283 records were included in the study.Figure The mean age of the participants was 35.06 (SD 18.36) years. The youngest participant was 1 year old while the oldest participant was aged 79 years old. The highest proportion  of the participants were aged between 45-54 years. Children (<15 years) made up 20.49% (58/283) of the participants while 13.07% (37/283) were more than 55 years old. Females made up a higher proportion  compared to males. Slightly more than half of the participants  were married and the majority  had children. Most of the participants  lived in rural areas and more than half of the participants had completed primary education .Less than a quarter  were substance abusers , less than half  had ever missed an ART clinic appointment, 30.04% (95/283) had ever been represented during an ART clinic appointment, 17.31 (49/283) had ever had an ART appointment representation during IAC, 16.25% (46/237) had been on ART for more than 5 years and the majority 96.11% (272/283) received ART adherence support from a caregiver. Most of the participants  had a suppressed viral load 6 months after the start of ART. Slightly more than half  had a viral load greater than 2000 copies/ml before initiation of ART, less than half  had a previous history of viral un-suppression before the study period, 15.55% (44/283) were underweight at the start of IAC. Most of the participants  had a disease stage 1 at the beginning of ART and the majority  had never been bedridden during ART. 27.21% (77/283) had experienced at least one ART side effect while 1.14% (4/283) had experienced at least one adverse event. 5.88% (16/283) had experienced at least and 37.1% (105/283) were on the first ART regimen. Table In Table p=0.040), had never been represented on ART compared to those that had ever been represented , received no ART clinic appointment representation during IAC compared to those that had , had a viral load 6 months after ART start that was less than 1000 copies/ml blood compared to higher , had a viral load at IAC start that was between 1000-2000 copies/ml of blood , had a normal body weight , had no document ART-adverse events , had no other infections during IAC compared to those that had  and participants that were on the first regimen compared to a second or higher regimen . See Table In Table p=0.62), changes in the daily routine , a high pill burden , illness , clinical depression , sleeping through dosing times , ART side effects , distance  versus to those that had reported . The proportion of participants that had achieved viral suppression after IAC was higher among those that reported forgetfulness as a barrier compared to those that did not . For 3.18% (8/283) of the participants, no barriers were established during IAC.In Table p=0.063), had a viral load 6 months after starting ART  that was less than 1000 copies per ml , had a normal body mass index  or if they were on the first ART regimen . Participants were less likely to have a suppressed viral load if they: had ever sent someone to pick medication refills on their behalf during an ART clinic appointment (represented) before IAC , represented during IAC , reported distance as a barrier to ART adherence , had a viral load at the start of IAC that was greater than 2000 copies per ml , had a previous history of having an unsuppressed viral load  or if participants had another infection during IAC . In the adjusted analysis, participants were less likely to achieve viral suppression after IAC if they had a viral load of more than 2000 copies/ml of blood  or if participants had a previous history of having an unsuppressed viral load . Having; a viral load 6 months after starting ART that was less than1000 copies per ml , ever had an ART clinic appointment representation , received any ART clinic representation during IAC  and Being on the first ART regimen  were not statistically significantly associated with viral suppression after IAC. Table In the multivariate analysis, only factors with a p-value <0.05 at bivariate analysis were considered for the unadjusted analysis and consequently for the adjusted analysis. In the multivariable analysis, we dropped variables that did not improve the fit of the model based on the log-likelihood. In the unadjusted analysis, participants were more likely to have a suppressed viral load after IAC if they; had children   and the The study also established that patients with higher load (>2000 copies/ml) at the start of IAC were less likely to achieve viral suppression after IAC compared to those that had a lower unsuppressed load (between 1000-2000 copies/ml). A high initial viral load is associated with a lesser likelihood of achieving viral suppression as observed by studies in Ethiopia , VietnamOur findings also showed that a previous history of a high viral load i.e. having a viral rebound was associated with a lower likelihood of achieving viral suppression after IAC. This finding may be attributed to multiple causes. A suboptimal regimen potency may result in an early warning of regimen failure , 33, unrThe health facilities were routinely fully stocked with all necessary ART regimens and implied that patients never missed drugs to ART drug shortages. This may have supported the achievement of the viral suppression rate observed. The availability of different regimens free-of-charge is also associated with viral suppression as observed by studies in the United States , CamerooAll health facilities had a trained counsellor to support patient counselling at ART start and during IAC and all staff in the ART clinic were trained in counselling particularly IAC counselling. This was a good approach that helped to support client counselling and may have influence the viral suppression rate observed by the study . FurtherWe used census data, this helped to avoid potential bias that could have occurred through using a sampling technique. The study was conducted over a short period offering the best use of the limited time and resources available for this study. The findings of this study have therefore been made available in a short period and can help IAC programming in the district and country. The study involved an examination of the most recent cohort of patients that started and completed on IAC (January 2019– December 2019). This encompassed the entire year which helps to account for any effects caused by season variations and provides the most recent information about the situation in the district. However, the retrospective nature of the study made it vulnerable to missing or incomplete information from the data sources, however, the researcher trained assistants on how to use the multiple available data sources to bridge gaps in data. Also, the researcher selected data collectors who had long-term experience in HIV-related work. The study was unable to assess the quality of IAC sessions neither was it able to collect and assess other factors that may have influenced viral suppression beyond those collected for its scope. However, the investigators reviewed various literature and included the most likely factors in the study to minimize this effect. Also, the study was conducted at only three health facilities with one district which may not be sufficient to represent the entire district or country.The viral suppression rate after IAC was lower than international and national targets threatening the achievement of the goal to end the HIV epidemic by 2030. The factors associated with viral suppression were a viral load of more than 2000 copies/ml of blood and a previous history of having an unsuppressed viral load. Virally unsuppressed patients with a viral load of more than 2000 copies/ml of blood need a closure examination during clinical practice and possibly an extended period of IAC. This may improve the viral suppression rate in this category. Further, health workers should use a previous history of an unsuppressed viral load as a marker for possible unsuccessful IAC and make more tailored follow-up interventions for patients in this category. On a positive note, there were good measures that addressed continued drug availability, adequate staffing levels and patient follow-up procedures. However, complementing the available staff cadres with the staff of higher cadres could help support improve viral suppression rates after IAC.Ethical approval was granted by the Clarke International University Ethical Review Board under CLARKE-2020-18. Additionally, permission and approval to conduct the study were sought and granted by the District Health Office and each of the health facility administration. Newly generated identifiers were used for the data collection, the codebook was available only to the Principal Investigator of the study to ensure the anonymity records. Additionally, the audio and transcript were anonymized not shared with any external parties to the research. To ensure confidentiality, all patient identifiers were excluded from the data and instead substituted with newly generated codes. Informed consent was obtained from all the participants before the interview. All procedures performed in the study that involved human participants were following the ethical standards of the Clarke International University Research Ethics Committee (CIUREC) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards . The fin


Methods: HIV-positive, ART-experienced patients have been enrolled in four semi-urban localities in the Republic of the Congo. Plasma samples were collected, and viral RNA was extracted. The viral load for each patient was evaluated by RT-qPCR, following the general diagnostic procedures of the University Hospital of Bordeaux. Finally, drug resistance genotyping and phylogenetic analysis were conducted following Sanger sequencing of the pol region. Results: A high diversity of HIV-1 strains was observed with many recombinant forms. Drug resistance mutations in RT and PR genes were determined and correlated to HAART. Because integrase inhibitors are rarely included in treatments in the Republic of the Congo, the prevalence of integrase drug resistance mutations before treatment was also determined. Interestingly, very few mutations were observed. Conclusions: We confirmed a high diversity of HIV-1 in the Republic of the Congo. Most patients presented an accumulation of mutations conferring resistance against NRTIs, NNRTIs and PIs. Nonetheless, the absence of integrase mutations associated with drug resistance suggests that the introduction of integrase inhibitors into therapy will be highly beneficial to patients in the Republic of the Congo.Background: HIV infects around one hundred thousand patients in the Republic of the Congo. Approximately 25% of them receive an antiretroviral treatment; current first-line regimens include two NRTIs and one NNRTI, reverse transcriptase inhibitors. Recently, protease inhibitors (PIs) were also introduced as second-line therapy upon clinical signs of treatment failure. Due to the limited number of molecular characterizations and amount of drug resistance data available in the Republic of the Congo, this study aims to evaluate the prevalence of circulating resistance mutations within the  In 2020, UNAIDS estimated that one hundred thousand people were living with HIV in the Republic of the Congo (RC), and only 25% of them received an antiretroviral treatment (ART). According to the 2016 WHO guidelines, a combination of two nucleoside reverse transcriptase inhibitors (NRTIs) and one non-nucleoside reverse transcriptase inhibitor (NNRTI) is recommended as a first-line regimen, and two NRTIs and one protease inhibitor (PI) as second-line therapy. Recently, Dolutegravir (DTG), an integrase strand transfer inhibitor (INSTI), was introduced as first-line therapy, according to the WHO guidelines. ART efficacy requires regular biological and clinical monitoring of ART-experienced patients in order to monitor the appearance of resistance. Despite the efficacy of these combination therapies, some patients still experience treatment failure. The monitoring of HIV-1-infected Congolese living in rural localities remains problematic and could affect ART efficacy. In these localities, HIV-infected populations face several challenges that impact adherence to treatment and facilitate emerging resistance mutations, such as distance to medical structures, lack of infrastructure for biological monitoring , treatment breaks, stigma and cultural beliefs. There are limited data available on the molecular characterization of HIV-1 in the RC. Studies performed in urban regions before the inclusion of DTG reported the predominance of specific circulating recombinant forms (CRFs), including CRF02_AG, and an important genetic variability with the accumulation of drug resistance mutations (DRM) [020. In 2n the RC .From 2019 to 2020, we conducted a cross-sectional study of HIV-1-infected patients, excluding newly diagnosed patients, from four care centres in four semi-rural localities of the RC . Viral RNA was extracted from plasma samples using the High Pure Viral RNA Kit , following the manufacturer’s protocol, and stored at −80 °C until further use. For the identification of HIV-1 subtype and drug-associated resistance mutations, reverse transcriptase (RT), protease (PR), and integrase (INT) coding regions were amplified according to the protocol of the French National Agency for AIDS Research ). PCR products were processed by Sanger sequencing on both strands using an Applied Biosystems 3500xl Dx Genetic Analyzer. Accordingly, minority variants could not be detected and only mutations present at minimum frequencies above 15% to 20% of the viral quasi-species were monitored. FASTA sequences of each region  were assembled using the Integrative Database Network System  Smartgene 2021) in order to determine the HIV-1 genotype and drug resistance mutations. PR, RT and INT sequences were analyzed for DRMs according to the ANRS algorithm ) and the WHO international working group for the surveillance of transmitted HIV-1 drug resistance [http://hiv.lanl.gov/ (2019), accessed on 1 March 2021). Phylogenetic trees were inferred using the neighbor-joining method from matrix distances calculated after gap stripping alignments, according to a Kimura two-parameter algorithm. Bootstrapping was performed with 100 replicates. The circular trees were obtained using ITOL  tube. The plasma samples (2 mL per patient) obtained after centrifugation were aliquoted in cryotubes, then stored at −80 °C before being transported by flight for molecular analysis to the UMR5234 Fundamental Microbiology and Pathogenicity Laboratory of Bordeaux University. HIV-1 plasma viral load was evaluated by RT-qPCR with the COBASp value of < 0.05 was considered statistically significant.Analyses were performed with R version 3.4.4 and GraphPad Prism 6  software. Quantitative variables were expressed as the median and interquartile range (IQR) and compared using the one-way ANOVA test. Categorical variables were presented as number of cases and percentages, and were compared using Pearson’s chi-squared test. A p = 0.02) was noticed in the localities of Dolisie and Owando, where more patients in stage 4 were classified. In addition, 35.3% of patients had a viral load above 100,000 copies/mL. The majority of patients (47.1%) were on first-line regimen AZT + 3TC + NVP or EFV, and only 17.6% of the patients received a DTG-containing regimen, an integrase strand transfer inhibitor (INSTI). Finally, 42.4% of patients were on ART for more than 48 months.We included 210 patients in this study. Only samples from 85 patients were successfully amplified, consisting of 29 samples from Dolisie, 33 from Ouesso, 13 from Owando, and 10 from Sibiti . Among tpol region showed that HIV-1 CRF02_AG was the predominant subtype with a prevalence of about 22%  were M184V/I with a prevalence of 37%, followed by T215Y/F/S/V at 18% a. AdditiRegarding resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs), observed frequent mutations included K103N (26%), A98G/S (13%), V179F/I/T (12%), and Y181C/V (10%). The additional mutations at lower frequencies were G190A/E/S (6%), K101E/P/R (6%), P225H (5%), V90I (5%), H221Y (5%), V106A/I/M (4%), Y188C/L (4%), E138A/Q (3%), and L100I (1%). b.Because protease inhibitors were not often used 4.7%, , the majInterestingly, even if 17.6% of the patients received DTG as part of their regimen, no major INSTI mutation was observed. Still, T97A (38%) and L74I (38%) were abundantly selected . Even thFor the calculation of the GSS, we classified different types of treatment into two lines. The first-line regimen included combinations based on two NRTIs and one NNRTI, and the second-line regimen included combinations based on PI or DTG according to national therapeutic guidelines. Based on the GSS estimates, 34 patients had a GSS = 1, meaning that they harboured genotypes that were not fully susceptible to all three drug components of the preferred first-line regimen . InteresLimited access to HIV drug resistance testing in the RC is a major barrier to monitoring the effectiveness of combination therapies, especially at a time when DTG is being introduced into treatment lines. It is therefore very important to know the resistance mutations circulating in the RC in order to better orientate therapeutic choices. This is the first study from the Republic of the Congo to characterize HIV-1 genetic subtypes and HIV drug resistance in ART-experienced patients from four semi-rural localities.pol region. It confirms the genetic diversity of HIV-1 in the RC, and shows that genetically diverse HIV-1 strains are observed in the RC. We noticed a decrease in the proportion of pure subtypes with an increase in the number of CRFs . Once more, this indicates that prolonged drug exposure without viral load monitoring, which is necessary for early detection of virological failure, is a major drawback in the fight against drug resistance. Unfortunately, biological monitoring is lacking in these semi-rural settings, and HIV patients are inadvertently maintained on their “failing” drug regimens with the consequence of the accumulation of drug resistance mutations. To avert the situation, assays need to be developed for biological patient monitoring, including CD4 counts, viral load and drug resistance testing, which are key parameters for global HIV care in semi-rural areas.The M184V mutation was the most frequent NRTI DRM. This coincided with the extensive use of 3TC (or FTC) as a backbone in all regimens in the RC and all over SSA. The presence of this mutation significantly reduces 3TC activity, while conferring low-level resistance to ABC, and reduces viral replicative fitness ,14,15. IThe observed high levels of DRMs to NRTI and NNRTIs in these semi-rural localities could be linked to several factors. Firstly, the availability of transportation to treatment centers is generally significantly reduced in rural areas compared to urban areas. Secondly, shortages of ART supplies are common occurrences in rural localities. Finally, cultural differences and stigma hinder patients from easily undertaking their treatment, alongside inadequate planning and poor follow-up  from health authorities. The majority of the NRTI and NNRTI resistance mutations found in this study are quite similar to ones previously described by Pircher et al. , who repDespite the high prevalence of DRMs to NRTIs and NNRTIs, the prevalence of DRMs to PI and INSTIs was relatively low or absent. However, many polymorphic mutations were observed. These results confirm the situation described in the WHO 2019 HIV drug resistance report ,22. DespAnother limitation arose from the lack of data on treatment adherence. Accordingly, it was not possible to associate the observed virological failure to poor adherence. Importantly, the lack of CD4 counts did not allow us to assess the immunological response of patients to different ART regimens. In addition, the sample size was small in some localities, and the rate of amplification and sequencing of the three target genes further reduced the numbers used in the statistical analysis. Even though 210 patients were included in this study, only 85 samples were successfully processed. The thawing and refreezing cycles of plasma during travel from the localities to Bordeaux could have favored the degradation of nucleic acids in certain samples, which could explain the low amplification rate of the samples. Caution should be taken not to overinterpret those data, and further characterization should be performed to evaluate the global HIV-infected population of the RC. Nonetheless, even if this study presented no evidence that a duration of drug exposure without viral load monitoring will lead to an accumulation of DRMs, our findings agree with the World Health Organization, which recommends routine viral load monitoring for the detection of treatment failure in patients on ART. Therefore, the true level of DRM might be underestimated, so epidemiological studies should be conducted in the general HIV-1-infected population each year in order to monitor the circulating subtypes of the HIV-1 strains, and to evaluate the emergence of new ARV DRMs.Our findings highlight the potential consequences for molecular follow-up of HIV-1-infected patients. Without proper biological monitoring, we observed that viruses replicated actively in many patients, with a selection of drug resistance mutations among viral strains present in the RC. It also highlights the tremendous benefits of the introduction of DTG in therapeutic lines, according to the absence of major INSTI DRMs. As mutation and recombination are the major forces driving HIV-1 genomic diversity, the continual emergence of new recombinant forms presents an enormous surveillance challenge. Thus, implementing a national HIV-1 DRM surveillance program is critical to help guide ART choice and improve interventional strategies.


Background: We aimed to describe the change in the incidence and causes of hospitalization between 2008 and 2018 among persons living with HIV (PLWHIV) who started antiretroviral therapy (ART) from 2008 onwards in Italy. Methods: We included participants in the ICONA  cohort who started ART in 2008. All the hospitalizations occurring during the first 30 days from the start of ART were excluded. Hospitalizations were classified as due to: AIDS-defining conditions (ADC), non-ADC infections and non-infections/non-ADC . Comparisons of rates across time were assessed using Poisson regression. The Poisson multivariable model evaluated risk factors for hospitalizations, including both demographic and clinical characteristics. Results: A total of 9524 PLWHIV were included; 6.8% were drug users, 48.9% men-who-have sex with men (MSM), 39.6% heterosexual contacts; 80.8% were males, 42.3% smokers, 16.6% coinfected with HCV and 6.8% with HBV (HBsAg-positive). During 36,157 person-years of follow-up (PYFU), there were 1058 hospitalizations in 747 (7.8%) persons; they had HIV-RNA >50 copies mL in 34.9% and CD4 < 200/mmc in 27%. Causes of hospitalization were 23% ADC, 22% non-ADC infections, 55% non-infections/non-ADC . Over the study period, the incidence rate (IR) decreased significantly (from 5.8 per 100 PYFU in 2008–2011 to 2.21 per 100 PYFU in 2016–2018). Age > 50 years, intravenous drug use (IDU), family history of cardiovascular disease, HIV-RNA > 50, CD4 < 200, were associated with a higher hospitalization risk. Conclusions: In our population of PLWHIV, the rate of hospitalization decreased over time.  Combination antiretroviral therapy (cART) is effective in reducing morbidity and mortality due to HIV infection for people living with HIV (PLWHIV) . Causes In Italy in 2018, the proportion of PLWHIV with CD4+ cells count < 200/µL at di-agnosis was 37.8% . Recent The observation of causes of hospitalization in PLWHIV is important in our clini-cal practice. The use of antiretroviral therapy decreased AIDS-related events; on the other hand, we observed an increase in median age in PLWHIV.Our hypothesis was that in the last 10 years, the use of cART with high immuno-virological success was associated with a decrease in hospitalization rates and with a change of causes, with an increase in non-infectious and non-AIDS-related comorbidi-ties, in particular related to age and metabolic parameters.This study describes incidence rate, causes of hospitalization, factors associated with the risk of hospitalization between 2008 and 2018 of people living with HIV starting ART after 2007.This is a retrospective analysis of prospectively collected data from the ICONA  Foundation cohort. ICONA is an observational cohort, set up in 1997, including HIV-1-infected subjects, naïve from ART at the time of enrollment. Demographic, viro-immunological and clinical data and information on antiretroviral regimens are collected and recorded using an electronic database.All patients signed consent forms to participate in the ICONA Foundation Study in their local participating clinical sites. The research study protocol has been approved by local institutional review boardsWe included HIV-infected persons who started first antiretroviral therapy in the period from 1 January 2008 to 31 December 2018, having at least one follow-up visit. For those patients, a hospitalization was considered if it occurred at least 30 days after the enrollment and was defined as admission to any Italian hospital for two or more days. Participants’ follow-up accrued from the date of enrollment (baseline) to their last visit or death or 31th December, 2018 (whichever was earlier). Participants could be included in multiple periods and could contribute more than one hospitalization per period. Socio-demographic factors were collected at baseline, such as sex, age group, nationality, HIV risk factor, family history of cardiovascular disease; HIV-related factors have been collected at baseline and during follow-up .The outcomes evaluated in this study were the rates of hospitalizations for any reason and hospitalizations for specific reasons grouped as follows: AIDS-defining conditions (ADC) see , infectiThe baseline for this analysis was the date of the start of the first antiretroviral therapy.Study period hospitalization rates were calculated as the number of hospitaliza-tions occurring during the period divided by the total of person-years of follow-up (PY). For each participant, the PY at risk were computed from the starting day of the first ART to the last follow-up or death or 31 December, 2018 (whichever was earli-er). Participants could be included in multiple time periods and could contribute more than one hospitalization per time period.The number of hospitalizations, PY at risk and incidence rate (IR) of hospitaliza-tion (per 100 PY) were calculated overall and for three study periods (every four years and the last period has three years): 2008–2011, 2012–2015 and 2016–2018.Crude and adjusted incidence rate ratios (IRR) and 95% confidence intervals were calculated using Poisson regression models, and the overdispersion of data was as-sessed with deviance and Pearson goodness-of-fit tests.3) , HIV viral load (copies/mL) , hepatitis C coinfection  and time from HIV diagnosis to first ART (months) , na-tionality , HIV risk factor , cardiovascular familiarity , CD4  were updated at each time visit.p-value < 0.2 at univariate analysis and then backward selection with a log-likelihood ratio test p-value < 0.2 at each step). However, we decided to report the model with all covariates, given that the results were similar when using this approach (data not shown).All factors included in this analysis were also evaluated using a more parsimoni-ous model-building strategy .We included 9524 naïve participants in the ICONA cohort who started cART between 2008 and 2018: of whom 2166 (22.7%) between 2008 and 2011, 4322 (45.4%) between 2012–2015 and 3036 (31.9%) between 2016 and 2018.n = 7414) reported to be Italian. MSM represented 48.9% (n = 4571) of the study population, IDU 6.8% (n = 647) and heterosexual contact 38.6% (n = 3675). Coinfected with hepatitis C were 9.8% (n = 937) and 4.5% (n = 430) with hepatitis B. Family history of cardiovascular diseases was reported for 14.6% (n = 1393) of participants. Median time since the first positive HIV test was 2.3 months (IQR: 0.8–21.2). The median age at enrollment was 39 years (IQR: 32–48), 27% had CD4 count <200 and the vast majority (75.5%) had HIV VL >10,000 : 1.5–5.7). Men were 7695 (80.8%), 77.9%  compared with non-hospitalized (n = 8777) patients had a longer follow-up in years , were older , were more frequently women (25.4% vs. 18.7%), heterosexual and IDU  and HCV coinfected (16.6% vs. 9.3%); they had higher zenith HIV viral load , lower nadir CD4  and higher proportion of patients with CD4 ≤ 200 cells/mmc (41.6% vs. 25.8%).The hospitalized  were hospitalized at least once during 2008–2018, with 1058 separate hospital admissions. Of those 68% had one admission, 18% had two, 6% had three and 8% had four or more admissions. The median length of stay (LOS) was 10 days (IQR: 5–21).c.At hospitalization 34.9% had HIV-RNA > 50 copies mL and 27% CD4 < 200/mmThe highest number of hospitalization was due to non-infection/non-ADC (55%), 23% of hospitalizations were due to ADC and 22% to non-AIDS-defining infections.Non-infection/non-ADC included oncologic disease (11%), gastrointestinal/liver disease (9%), cardiovascular (6%), renal/genitourinary and psychiatric (5% both), pulmonary (4%) and all other causes not classified in the previously specified categories (15%). Observed non-AIDS-defining infections included pneumonia (33%), sexually transmitted infections (26%), sepsis (9%), viral infections (14%), gastrointestinal infections (6%), cutaneous infections (8%) and urinary infections (3%).The distribution of all the causes making up the definitions of ADC, infections non-AIDS-defining, and non-infections/non-ADC, over time are reported in 3 , time from HIV diagnosis and starting first ART between 2 and 20 months vs. <2 months (IRR 0.76) and period of hospitalization 2012–2015 and 2016–2018 vs. 2008–2011  were associated with lower risk of hospitalization , being IDU vs. heterosexual (IRR 1.56), family history of cardiovascular disease (IRR 1.30), HIV VL between 51 and 10,000 or >10,000 vs. <50 copies/mL  were associated with a higher risk of hospitalization. On the contrary male sex (RR 0.78), CD4 > 200  vs. ≤200 cells/mmlization .Further when we performed models with interaction terms between each factor and study period, we found significant interactions only for CD4, viral load and mode of infection. However, the effects did not change the direction of the association but the magnitude was increasing as the study period was more recent.When we performed the same analysis using hospitalization or death as the outcome, we obtained consistent results with those using as the outcome of hospitalizations see .The hospitalizations due to ADC were associated with higher levels of viral load, particularly 51–10,000 and >10,000 copies/mL ; the non-infection/non-ADC were most associated with other nationality than Italian (IRR 1.45), IDU and MSM  and high viral load, 51–10,000 and >10,000 copies/mL ; be over 52 years old, IDU, have a family history of cardiovascular disease and viral load between 51 and 10,000 copies/mL appeared to be associate with a higher risk of hospitalization for infection non-AIDS-defining . Higher CD4 levels (≥200 cells/mmc) were protective for all reasons . The current study showed a temporal decrease in the overall hospitalization rate and a decrease in the risk of hospitalization in people living with HIV in care from 2008 to 2018 in the ICONA cohort in care from 2008 to 2018 in the ICONA cohort. After the introduction of cART, the hospitalizations rate declined in PLWHIV, and this decline −61.8%) was greater than the decline in age-standardized hospitalization rates observed for the general population in the same time period (−26.4%), according to the official register of Italian Health Departement. Non-AIDS-related hospitalizations were more frequent than those related to AIDS 1.8% was ,8,9.A recent editorial underlines the importance of reaching zero hospitalizations to reach zero deaths attributable to HIV  and consWhen considering different reasons for hospitalization, major declines were detected for AIDS-defining events. This is comparable to other cohorts, and it is due to ART efficacy.Hospitalizations due to non-infection/non-ADC were stable over time. Published data of the ICONA cohort showed an increase in the prevalence of some non-communicable diseases from 2004 to 2014; in particular, the prevalence of dyslipidemia, hypertension and cardiovascular disease increased . In our The percentage of hospitalizations due to non-AIDS-defining infections increased during the observation time. The most common condition associated was pneumonia; this observation is consistent with another cohort  data; inThe higher risk of hospitalization was associated with older age, use of injecting drugs and detectable viral load. The overall prevalence of multimorbidity in the geriatric Italian GEPPO cohort amounted to 64%, and it is related to longer duration of HIV infection rather than older age per se ; the preThe use of injecting drugs could be related to sepsis; the likelihood of bacteremia was found to have increased in a consortium of sites in the USA in the HAART era . In our Detectable viral load is associated with a higher risk of hospitalization and, in particular, to non-AIDS-defining events due to inflammation-related events .Focus on social factors, low educational grades and unemployed are associated with a higher risk of hospitalization. Several studies have identified limited literacy as a risk factor for poor HIV medication adherence, despite evidence that questions this association ,23. ThesThis study has some limitations: first, ICONA is not representative of all Italian centers, and some of them are the reference for many clinical and surgical specialties; this could overestimate the hospitalization rate. Another limitation is the classification of hospitalization, with some diseases that could be misunderstood . Moreover, it is of note that we estimated some IRR with very large 95% confidence intervals. This reflects the lack of statistical power for some of the potential determinants.Our study is useful to understand the changing of hospitalization causes and rates in the era of antiretroviral therapy; we analyzed data of patients treated in the last 10 years considering the high rate of immunovirological success of recent cART, and in this setting, we conclude that prevention strategies against non-communicable diseases and non-AIDS-defining infections are crucial to decrease hospitalization rate. These strategies could include stop smoking, starting a low-calorie diet and use of specific drugs .


Viral load (VL) is a strong predictor of human immunodeficiency virus (HIV) disease progression. The aim of this study was to evaluate the effect of high baseline VL on antiretroviral therapy (ART) outcomes among HIV-infected patients.This retrospective study observed HIV-infected patients who had baseline VL test at ART initiation between 2015 and 2019 in Chongqing, China. Cox proportional hazards regression and logistic regression models were used to evaluate the effects of baseline VL on Acquired immunodeficiency syndrome (AIDS)-related mortality and virologic failure, respectively.The cohort included 7,176 HIV-infected patients, of whom 38.7% had a baseline VL ≥ 100,000 copies/mL. Of the patients who died during follow-up, 58.9% had a baseline VL ≥ 100,000 copies/mL. Compared with a baseline VL < 10,000 copies/mL, ART initiation at VL ≥ 100,000 copies/mL was significantly associated with the AIDS-related death  and virologic failure . Compared with patients with a baseline VL < 10,000 copies/mL, patients on the recommended first-line regimen with a VL ≥ 100,000 copies/mL at ART initiaition had higher mortality rate (5.1 vs. 1.7 per 100 person-years), but there was no significant difference in the mortality accoding to the initial VL level among patients on second-line ART (2.8 vs. 2.7 per 100 person-years). ART initiation ≤ 30 days after HIV diagnosis was associated with a lower risk of AIDS-related death (AHR = 0.6).ART initiation with VL ≥ 100,000 copies/mL was associated with a significantly greater risk of mortality and virologic failure. Optimizing the ART regimen and initiating ART early may help to reduce mortality effectively among patients with a high baseline VL. VL testing for all HIV patients is recommended at HIV diagnosis or on ART initiation. Currently, antiretroviral therapy (ART) is the most effective intervention to prevent new human immunodeficiency virus (HIV) infections and reduce the risk of Acquired immunodeficiency syndrome (AIDS)-associated mortality , 2. The HIV viral load (VL) is significantly associated with the degree of active HIV replication, and a high VL predicts faster disease progression to AIDS and death . MonitorIt generally takes longer for HIV-infected patients to control viral replication and restore their immune system after ART initiation if they have a high VL. Patients with a high VL at the time of ART initiation are more likely to fail treatment or to develop low-level viremia (LLV) –17. In CHowever, there is no guidance on managing patients with a high baseline VL in China. Southwest China is the region with the highest burden of the HIV infection . ChongqiThis retrospective observational cohort study of HIV patients initiatied on ART was conducted in Chongqing, China. Baseline VL was used to predict the treatment effects on patients' outcomes, including death and virologic failure. Data for individuals who were initiated ART between 2015 and 2019 were extracted from the NFATP database, which contained data on 35,056 individuals. All patients who had baseline VL test were selected. The eligibility criteria for inclusion in the analysis were; age ≥ 15 years when ART initiated, being newly initiated on treatment during the study period, and having follow-up records. A total of 7,176 (20.6%) individuals were included in the analysis. The cohort observations started on the date of ART initiation, with follow-up at 1, 2, and 3 months after ART initiation, and every 3 months thereafter, and terminated on December 31, 2020. All patients were followed up until death, loss to follow-up, or observation termination.ART data were extracted from the Chinese NFATP information system, a nationwide, real-time, reporting system, which is managed by the National Center for AIDS/STD Control and Prevention (NCAIDS) of the Chinese Center for Disease Control and Prevention (China CDC) . In ChinP-values ≤ 0.05 were regarded as statistically significant. All statistical analyses were performed using IBM SPSS Statistics, Version 19.0 .Death was treated as a time-dependent variable in the data analysis. The observed time was expressed in person-years (PYs). Chi-square tests were used to compare characteristics of HIV patients among baseline groups. Cox proportional hazards regression was used to assess the association between baseline VL and mortality. Logistic regression was used to evaluate the effect of baseline VL on virologic failure. In order to control for potential confounding, all baseline covariates were further entered the adjusted model based on univariate analyses. Based on baseline VL, all participants were categorized into three groups . Other potential confounders of the model included age, sex, marital status, transmission route, baseline CD4 counts, last ART regimen, duration from HIV diagnosis to ART, TB coinfection, and hepatitis B virus coinfection. The adjusted hazard ratio (AHR) and adjusted odds ratio (AOR) were calculated using multivariable regression analysis. Two-sided A sensitivity analysis was conducted to assess the potential bias for individuals with missing VL data at initiation and at 12 months using Chi-square tests. We compared the baseline characteristics of HIV patients according to whether they received a baseline VL test and a VL test at 12 months , 2. The 3 at ART initiation, and most individuals (62.9%) started ART within 30 days after diagnosis. A total of 9.4% of individuals had TB coinfection, and 9.0% had hepatitis B virus coinfection. The percentage of patients with baseline VL results < 10,000 copies/mL, 10,000–99,999 copies/mL, and ≥100,000 copies/mL was 21.0% , 40.3%  and 38.7% , respectively. Among patients with a baseline VL < 10,000 copies/mL, 28.5% had a baseline CD4 count < 200 cells/mm3, while among patients with a baseline VL ≥ 100,000 copies/mL, 72.7% had a baseline CD4 count <200 cells/mm3.A total of 7,176 HIV-infected patients met the inclusion criteria. The patient characteristics are shown in n = 83), 26.2% (n = 146) and 58.9% (n = 328), respectively. ART initiation at VL ≥ 100,000 copies/mL was associated with a significantly higher mortality . Other factors associated with a significantly increased risk of death after initiating ART included age ≥50 years old , use of alternative first-line regimens , TB coinfection , hepatitis B virus coinfection . Factors associated with a significantly decreased risk of death included use of second-line regimens , female sex , homosexual contact , ART initiation ≤ 30 days after HIV diagnosis , and a baseline CD4 count of 200–499 cells/mm3  or ≥500 cells/mm3 .A total of 557 patients experienced an AIDS-related death after initiating ART, accounting for 7.8% of the cohort. The overall AIDS-related mortality rate was 2.9 per 100 PYs . The pron = 172) had a baseline VL ≥ 100,000 copies/mL. The virologic failure rate of patients with a baseline VL < 10,000 copies/mL, 10,000–99,999 copies/mL, and ≥100,000 copies/mL was 2.8, 3.5, and 8.5%, respectively. The adjusted logistic regression model showed that a baseline VL ≥ 100,000 copies/mL was associated with an increased risk of virologic failure, compared with a baseline VL < 10,000 copies/mL .Of the 5,440 patients who had VL tested at 12 months after treatment initiation, 284 patients (5.2%) exhibited virologic failure . Among tA further analysis of mortality according to baseline VL, stratified by the last ART regimen is shown in In this study, a considerable proportion (38.7%) of HIV-infected patients had a high VL  on starting ART. This result is similar to that of an international cohort of European and Australian patients (36.8%) . The oveOur study showed that high baseline VL was one of the factors associated with ART mortality. Approximately 40% of HIV-infected individuals had a baseline VL ≥ 100,000 copies/mL, while ~60% of AIDS-related deaths after starting ART occurred among patients with a baseline VL ≥ 100,000 copies/mL. The adjusted Cox proportional hazards regression model showed that a baseline VL ≥ 100,000 copies/mL increased the hazard of mortality by 40% compared with a baseline VL < 10,000 copies/mL. We suggest strengthening baseline VL measurement among all HIV patients. Currently routine baseline VL testing is not recommended for all HIV patients in China. Most county-level ART clinics have the resources needed to measure VL. Efforts should be made to increase the availability of low-cost equipment for measuring HIV viral load.3, and 17% had TB coinfection. Therefore, HIV patients with high baseline VL are more likely to have poorer treatment outcomes and more disease progression.Virologic failure and low baseline CD4 counts may have accounted for the increased risk of death among patients with a high baseline VL. It generally takes several months after initiation of ART to achieve VL suppression . HoweverThese results suggest that optimizing the ART regimen and initiating ART early may help to limit mortality among patients with high baseline VL. A study in Henan region of China showed that long-term second-line ART was effective . AnotherOur study has some limitations. First, a notable proportion of individuals were excluded from the study because they did not have a baseline VL, which may have biased the results. Many patients did not have a baseline VL result because baseline VL testing is not recommended for all patients in China. Second, records of virologic failure only included individuals tested for VL during the 6–18 months following ART initiation; therefore, some patients without VL results during this time window were excluded from the analysis. Third, the number of deaths might have been underestimated due to unascertained deaths being reported as dropouts.Our study indicated that a considerable proportion of patients had high baseline VL, and that ART initiation with high VL was significantly associated with a greater risk of mortality and virologic failure. Optimizing the ART regimen and initiating ART early may help to reduce mortality among patients with a high baseline VL. All HIV patients should have a baseline VL test at ART initiation. In order to reduce HIV transmission, ideally a VL test should be provided at the time of HIV diagnosis.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Institutional Review Board of Chongqing CDC. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.CZ, GW, and YR drafted the manuscript. WZ, RL, and LO collected data. HX and YS guided the article design. All authors read and approved the final manuscript.This work was supported by the Research Project of Chongqing Municipal Science and Technology Bureau (cstc2019jscx-msxmX0225), Chongqing medical scientific research project of Chongqing Health Commission and Science and Technology Bureau (2022GDRC017), National Natural Science Foundation of China (11971479), and Chinese State Key Laboratory of Infectious Disease Prevention and Control.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Globally Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS) is an ongoing public health issue associated with high morbidity and mortality. Efforts have been made to reduce HIV/AIDS-related morbidity and mortality by delivering antiretroviral therapy. However, the incidence and predictors of mortality in border areas like Metema were not investigated. This study aimed to assess predictors of mortality rate among adult HIV-positive patients on antiretroviral therapy at Metema Hospital.Retrospective follow-up study was employed among ART patients from January 1, 2013, to December 30, 2018. Data were entered in Epi-data 3.1 and exported to STATA 14 for analysis. Kaplan–Meier and Log-Rank test was used to compare survival differences among categories of different variables. In bi-variable analysis p-values < 0.20 were entered into a multivariable analysis. Multivariate Weibull model was used to measure the risk of death and identify the significant predictors of death. Variables that were statistically significant at p-value < 0.05 were concluded as predictors of mortality.2  and viral load > 1000 copy/ml  were found to be a significant predictor for mortality among HIV patients on ART treatment.A total of 542 study participants were included. The overall incidence rate was 6.7 (95% CI: 5.4–8.4) deaths per 100 person-years of observation. Being male , STAGE IV , stage III , TB-coinfection , low hemoglobin , BMI ≤ 15.4 kg/mThe incidence of death was high. Being male, viral load, those with advanced STAGE (III & IV), TB co-infected, low BMI, and low hemoglobin were at a higher risk of mortality. Special attention should be given to male patients and high public interventions needed among HIV patients on ART to reduce the mortality rate.The online version contains supplementary material available at 10.1186/s12981-021-00353-z. Globally Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS) is an ongoing public health issue associated with high morbidity and mortality , 2. An eAccessing antiretroviral therapy (ART) has been increased since 2005, globally an estimated 21.7 million people were accessing antiretroviral therapy (ART) and 940,000 people died from AIDS-related illnesses at the end of 2017 , 5, 6. EInstitutional based retrospective follow-up study was conducted from January 1, 2013, to December 30, 2018, in Metema Hospital, which is located in west Gondar province of the Amhara National Regional State. It is 158 km away from Gondar town, 338 km from Bahir Dar , and 908 km from the country’s capital Addis Ababa.The town has a total population of 119,054  . There a2 = 0.93. Based on this, the calculated sample size by using STATA 14 software is 542. Regarding the sampling technique, a record of study participants have been filtered first from the ART database according to their entry time to follow up, next patients have been filtered using age and eligibility criteria, then we give a unique number for the remaining records and select each record for our study using systematic random sampling.All adult HIV-positive individuals who were on ART at Metema Hospital and who enrolled from January 1, 2013, to December 30, 2018, were included. However, transferred in-patients with incomplete baseline data and unknown initiation date of treatment and status of patients were excluded. The sample size was estimated using Log-Rank and Cox proportional hazard model in STATA version 14. The calculation was done based on the assumption that type I error of 5%, power of 80% and the exposure is body mass index (BMI) the most significant variable . SurvivaThe outcome variable was the time event (death) of patients on ART. The independent variables considered in the study were socio-demographic characteristics such as age, sex, level of education, occupation, marital status, clinical factors like WHO clinical stage, CD4 count, functional status, TB/HIV co-infection, opportunistic infection other than TB, drug adherence, viral load, hemoglobin level, body mass index (BMI) and substance use which is a behavioral factor.In this study was based on records as Good , Fair (85–94% or 4–8 doses missed per month) or Poor (less than 85% or ≥ 9 doses missed per month), health workers used reports by the patient or by directly counting the pills to classify adherence. Those patients who adhere greater than or equal to 95% was considered as good adherence; 85–94% fair adherence and Less than 85% was considered as poor adherence . PatientThe hemoglobin level > 10 gm/dl was categorized as normal hemoglobin and hemoglobin ≤ 10 gm/dl was categorized as low hemoglobin level . In thisTo assure the data quality, high emphasis was given in designing a data collection instrument. The training was given for data collectors and supervisors to have a common understanding of the purpose of research and the techniques of data collection. A standard checklist was used to record information extracted from electronic and patient cards. Before the actual data collection pretest was done on 25 patient charts, those charts were not included in the study. A standard checklist was used for recording information from the database and patient cards. This form was developed using the standardized ART entry and follow-up form employed by the ART clinic. Three experienced ART Nurses who were trained on comprehensive HIV care were involved in data collection. Throughout the data collection process, completeness, consistency, and accuracy were checked by supervisors and the principal investigator daily.The data was entered in Epi-data 3.1 and exported to STATA 14 for analysis. Descriptive statistics including proportions, median, tables, and charts was done to describe the characteristics of study participants. Nonparametric estimations of Kaplan–Meier was done graphically and Log-rank test was used to compare the survival probabilities of categorical variables. After fitting the survival model, the proportional hazard assumption was checked using a graphical and global test (goodness test). The model goodness of fit was checked by using the Cox-Snell residual. Cox proportional and parametric models were compared using Akaike Information Criteria (AIC) or Bayesian Information Criteria (BIC). Weibull model was selected since they have low value of AIC and had a good fitness of the Cox Snell residual. Those covariates with a p-value < 0.2 in the bi-variable analysis were again fitted to the multivariable Weibull regression analysis. Both crud and adjusted hazard ratio with the corresponding 95% Confidence Interval (CI) was calculated to show the strength of association. In multivariable analysis, covariates with a p-value of < 0.05 were considered statistically significant.3, and the baseline WHO staging 2470 (45.6%) of patients were at stage I followed by stage III and stage IV 115 (21.2%). Most of the 413 (76.2%) of the study participants had working functional status and three-fourths of the study subjects had good treatment adherence  study participants were females. The median age of study participants was 32 (IQR = 26–39) years. Nearly two-thirds of the study participants were not educated. Almost half of the 278 51.3%) study participants disclosed their HIV status and nearly half of the 274 (50.5%) study subjects are co-infected with tuberculosis (TB) ) per 100-person year of observation. Over the 72 months follow-up period; 4.9 per 100 adult-months (95% CI 3.7–6.3) died during the first 12 months and 0.7 per 100 adult-months (95% CI 0.4–1.1) died during the second year of follow-up. The cumulative survival probability of patients on ART was 77.44% at the end of the study period  survivor curves versus ln  over different categories of variables. The graph of the two categories of tuberculosis and hemoglobin level hazards does not cross each other, which means that the proportional hazard assumption was satisfied Fig. . An addiThe Cox-Snell residuals  were done to check the goodness of fit for all models. The figure shows that the plot of the Nelson Aalen cumulative hazard function with Cox-Snell follows the 45° line closely. Hence, the output shows Cox–Snell residuals of the Weibull model were satisfied the overall model fitness compared with other models. Among all models, the Weibull model was appropriately fitted data compared with others ) times higher than females. Patients with low hemoglobin patients were 4.14 ) times higher risk of death than those with normal hemoglobin. The hazard of death among patients who had a high viral load was 6.7 ) times higher than that of low viral load. Patients at baseline on ART advanced CLINICAL stage IV had 5.64 ) times increased risk of mortality compared to those presenting with WHO clinical Stage I at the initiation of ART ) per 100-person year of observation, consistent with other studies conducted in different areas of Ethiopia , 27. ThiIn this study, the hazards of death among male patients were 2.4 times higher than females in line with other studies , 35, 36,In this study, those ART clients with higher viral load had an increased hazard of death in agreement with the study conducted in seven teaching Hospitals of Ethiopia . This coSimilarly, patients who had advanced WHO clinical stages (stage III and IV) were a higher hazard of death than those in the WHO clinical stage I consistency with studies conducted in Sub-Saharan Africa , 38–41. Patients who had low hemoglobin levels have an increased hazard of death than those who had normal hemoglobin levels. This finding is comparable with the studies conducted in Sub-Saharan Africa , 42–44. Patients with TB-co infected with increased the hazard of death compared to clients not developing TB. This finding is consistent with studies conducted in rural Uganda  and in E2 was 2.4 times higher than those with a BMI ≥ 18.5 kg/m2. This study is similar to studies conducted in Tanzania [In this study, the hazard of death among patients with BMI ≤ 15.4 kg/mTanzania , CamerooTanzania , Uganda Tanzania , and MalTanzania . PatientTanzania .The potential limitation of this study was because of the retrospective nature of the study which lacks completeness of patient records like substance use, provision of opportunistic infection, prophylaxis status, and hospitalization of patients. We could not ascertain that all recorders of mortality were AIDS-related, so all mortality was considered as HIV/ AIDS-related because of the lack of records on the cause of mortality.2, and being male sex had a higher risk of mortality. Special attention should be given to male patients and high public interventions needed among HIV patients on ART to reduce the mortality rate. Nutritional support and close monitoring of patients in the early period of ART treatment initiation is very vital to improve patient survival.In this study, the incidence of mortality was high. Patients on ART who have Advanced WHO patients (stage III and IV), viral load > 1000 copy /ml, hemoglobin ≤ 10 mg/dl, TB co-infection, BMI ≤ 15.4 kg/mAdditional file 1. AIC and BIC value for model comparison of Cox and parametric model


Contemporary antiretroviral agents afford enhanced potency and safety for patients living with HIV. Newer antiretroviral drugs are often better tolerated than those initially approved in the early stages of the HIV epidemic. While the safety profile has improved, adverse drug reactions still occur. We have segregated the antiretroviral agents used in contemporary practice into class groupings based on their mechanism of antiviral activity  while providing a review and discussion of the hepatoxicity seen in the most relevant clinical literature published to date. Clinical literature for individual agents is discussed and agent comparisons afforded within each group in tabular format. Our review will provide a summative overview of the incidence and medications associated with hepatic adverse reactions linked to the use of contemporary antiretroviral drugs. Since the introduction into practice of the first antiretroviral drug zidovudine in 1987, the development of new antiretroviral drugs has evolved at a rapid pace. The Food and Drug Administration (FDA) has approved 34 antiretroviral drugs  and 24 fixed-dose combinations for the treatment of the HIV infection . In. In44]. Raltegravir was the first INSTI available on the market. Phase III clinical trials “Blocking integrase in treatment experienced patients with a novel compound against HIV: Merck” (BENCHMRK-1 and BENCHMRK-2) and “Long-term treatment with raltegravir or efavirenz combined with tenofovir/emtricitabine for treatment-naive human immunodeficiency virus-1-infected patients” (STARTMRK) describe an evaluation of hepatic events. BENCHMRK-1 and BENCHMRK-2 were randomized, placebo-controlled, phase 3 trials that investigated the efficacy and safety of raltegravir plus an optimized background regimen in previously treated patients with multidrug-resistant HIV-1. STARTMRK was a phase 3 study of antiretroviral treatment-naive patients that compared the efficacy of raltegravir to efavirenz, each used in combination with tenofovir/emtricitabine. All three studies excluded individuals with cirrhosis given raltegravir’s primary hepatic metabolism. In BENCHMRK I and II, hepatic adverse events were similar between both groups ,59. One An evaluation of elvitegravir’s implications on hepatotoxicity is difficult given the required co-administration with cobicistat. However, a single, phase IIa study evaluated 10 days of elvitegravir monotherapy in 40 patients; none developed hepatic adverse events . In two Primary data on dolutegravir monotherapy notes no hepatic adverse effects in a 10-day trial . In the As a newer integrase inhibitor, data on hepatic complications associated with bictegravir are limited. Primary insights come from Phase II and III data. In a Phase II trial comparing the safety and efficacy of bictegravir/emtricitabine/tenofovir alafenamide versus dolutegravir/emtricitabine/tenofovir alafenamide, 6/64 patients (9%) in the bictegravir arm developed grade 2–4 elevations in AST versus 1/32 patient (3%) in the dolutegravir arm; 4/64 patients (6%) in the bictegravir arm versus no patients in the dolutegravir arm developed ALT elevations. One of the patients in the bictegravir arm was diagnosed with hepatitis C coinfection with active alcohol use. All other elevations were transient and resolved even when therapy was continued . Week 14Cabotegravir is the newest antiretroviral in the INSTI class. Cabotegravir oral tablets, to be taken with oral rilpivirine, are used for lead-in therapy prior to initiating cabotegravir/rilpivirine long-acting intramuscular injections ,72. GiveProtease inhibitors (PIs) are an integral part of HIV treatment, particularly for those who are treatment-experienced. PIs in contemporary use  are paired with low-dose ritonavir or cobicistat as pharmacologic boosters . As a drp = 0.997). Hyperbilirubinemia associated with atazanavir/ritonavir was considered to be common and not a cause of significant hepatotoxicity [Atazanavir is well known to cause a reversible increase in serum unconjugated bilirubin without inducing liver injury; this is secondary to UGT1A1 enzyme inhibition, analogous to a chemical induction of Gilbert’s Syndrome . The pretoxicity . The fintoxicity .The impact of hyperbilirubinemia on atazanavir/ritonavir discontinuation rates, quality of life, and drug adherence was examined in the “Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naïve HIV-1-infected patients” (CASTLE) study, a randomized study that compared atazanavir/ritonavir to lopinavir/ritonavir in treatment-naïve HIV-infected patients. Forty-four percent of patients receiving atazanavir/ritonavir experienced hyperbilirubinemia, 5% experienced jaundice (11% of those with hyperbilirubinemia), and 7% of all patients had grade 3–4 LFT elevations (4% of those with hyperbilirubinemia). Less than 1% of patients discontinued treatment due to hyperbilirubinemia. Quality of life and adherence were the same in those with and without hyperbilirubinemia. The investigators concluded that hyperbilirubinemia did not negatively impact clinical outcomes in HIV-infected patients taking atazanavir/ritonavir .Atazanavir co-formulated with cobicistat also carries a warning for hyperbilirubinemia . In a phAtazanavir-induced hyperbilirubinemia occurring during pregnancy requires special consideration. An observational study of 22 HIV-infected women receiving atazanavir/ritonavir during pregnancy and their 23 infants revealed median cord blood atazanavir concentration was 130 ng/mL (range < 30–758) with a cord/maternal ratio of 21%. Bilirubin concentrations at birth were significantly higher than maternal concentrations, with a median of 44 μm/L (range 24–129); values on days 2–3 were 63 μm/L (range 8–212). Three neonates had mildly elevated AST levels. Five neonates had jaundice requiring phototherapy but did not experience liver damage .While alIn clinical trials, lopinavir/ritonavir was associated with a 2–9% incidence of hepatotoxicity with the concomitant presence of HCV infection, imparting a 4.7-fold increase in LFT abnormalities ,89. A reIn the “Performance of TMC114/r when evaluated in treatment-experienced patients with PI resistance” (POWER-1 and POWER-2) trials, randomized, phase IIB studies of the efficacy and safety of darunavir in combination with low-dose ritonavir in treatment-experienced HIV-1-infected patients, darunavir/ritonavir was associated with moderate-to-severe LFT elevations in 3–10% of patients. The liver injury occurred generally at one to eight weeks following initiation of treatment, usually in a hepatocellular pattern with the absence of chronic hepatitis . In an aMaraviroc selectively binds to the human chemokine CCR5 receptor, blocking the necessary interaction of GP120 and CCR5 for viral fusion and entry into CD4 cells. Maraviroc received FDA approval in August 2007 for use for treatment-experienced patients and carries a black box warning for hepatotoxicity. However, the combined clinical trial data and extended evaluation of maraviroc use over five years in close to 1000 patients do not justify the concern prompted by the black box warning .During early clinical development of maraviroc, a study patient experienced acute hepatocellular injury with rash, fever, and eosinophilia, which was attributed to maraviroc. This occurred shortly after clinical development of aplaviroc (another CCR5 inhibitor) was terminated in 2005 due to unacceptable hepatoxicity . The mecSafety data from 2350 patients during clinical development show maraviroc has a low incidence of associated liver toxicity through phase 1/2a trials and up to 96 weeks of phase 2b/3 evaluation in both treatment-naïve and treatment-experienced patients . HealthyThe “Maraviroc versus efavirenz in treatment-naive patients” (MERIT) study evaluated maraviroc twice daily versus efavirenz, each combined with co-formulated zidovudine/lamivudine, in treatment-naïve patients with CCR5-tropic (R5) HIV-1. Comparable drug exposure occurred between groups  through 96 weeks. No significant differences between grade 1/2, grade 3, or grade 4 elevations of ALT were seen, and equivalent proportions of patients (24.9% vs. 23.1%) had an increase of one grade from the baseline during the study . No bili“Maraviroc therapy in antiretroviral treatment-experienced HIV-1 infected patients” (MOTIVATE 1 and 2) evaluated maraviroc versus a placebo in combination with an optimized background regimen through 96 weeks in a pair of phase 3 studies of treatment-experienced patients . PatientEvent rates from MOTIVATE 1 and 2 are provided in Hepatitis B and C coinfection rates varied between approximately 4–8% in the MERIT and MOTIVATE study arms, but co-infection during the study timeframe did not appear to affect the hepatobiliary adverse effect incidence in the study populations, nor did it impact differences between groups.In summary, the initial concerns of hepatoxicity of maraviroc have not been supported. Extensive clinical data demonstrate safe and successful use of maraviroc through 2300 clinical trials participants, 96-week safety results from the MOTIVATE and MERIT study populations, a five-year planned safety analysis, and lack of a significant signal in post-marketing reports.Ibalizumab-uiyk is a recombinant humanized monoclonal antibody. It exerts an antiviral effect by binding to domain 2 of the CD4 receptor. When the HIV GP120 protein binds to the CD4 receptor, steric hindrance from ibalizumab prevents the conformational changes necessary for fusion and viral entry into the cell. Clearance of ibalizumab occurs via protein and cellular degradation . IbalizuIn the 40 evaluable patients who received at least one dose of study drug in TMB-301 through the 24 week study period, there were no reports of grade 3/4 transaminase elevations, and no evidence of hepatoxicity attributable to ibalizumab ,109. TheSafety analysis for trial extension through 96 weeks failed to identify any drug attributable hepatotoxicity or any liver safety issues ,111. FurFostemsavir is a prodrug that is hydrolyzed to the active agent, temsavir. Temsavir binds directly to GP120 and prevents attachment to CD4 receptors. Four dosing approaches for fostemsavir  were all well tolerated in 200 patients through 48 weeks in AI438011, a phase 2 clinical trial that compared the safety and efficacy of fostemsavir vs. ritonavir-boosted atazanavir  in treatment-experienced HIV-1-infected subjects. No discontinuations due to drug-related hepatic adverse effects occurred . At 48 wThe “Fostemsavir in adults with multidrug-resistant HIV-1 infection” (BRIGHTE) phase 3 study evaluated fostemsavir 600 mg twice daily in addition to an optimized background regimen in 371 treatment-experienced patients with HIV, stratified in two cohorts by the available number of fully active antiretroviral agents. Fostemsavir did not demonstrate significant hepatotoxic potential. The percentage of patients who increased to grade 3 or 4 laboratory abnormalities from baseline was low . Only thTwenty-five deaths (7%) occurred during the trial, mostly attributable to underlying disease and/or opportunistic illness . Two of the deaths were caused by hepatic failure (one resulting from a flare of hepatitis B and the other from progression of hepatitis C) and, again, not related to fostemsavir . Only onThe extended evaluation of current clinical trial results supports that fostemsavir has a low risk of contributing to hepatobiliary toxicity.The antiretroviral drugs used in the contemporary treatment of HIV infection are potent and well-tolerated. However, liver-related adverse drug reactions continue to be reported, albeit at lower rates than noted with earlier drugs. There is no established standard of care for hepatic injury secondary to ART. Elimination and/or minimization of other hepatotoxins  is a sensible first step. Screening for and treating viral hepatitis as indicated is also an important measure. A careful consideration of the risks and benefits of stopping or changing the suspected offending drug(s) in an ART regimen should be undertaken with the advisement of an HIV specialist. Monitoring patients on ART for the emergence of liver injury, in particular in those with conditions that pose a higher risk, such as viral hepatitis and alcohol use, should remain a key component of the management of HIV infection.


The DUALIS study showed that switching to boosted darunavir (bDRV) plus dolutegravir  was non-inferior to continuous bDRV plus 2 nucleoside/nucleotide reverse-transcriptase inhibitors  in treatment-experienced virologically suppressed people living with HIV (PLWH). We analyzed virologic outcomes with respect to treatment history and HIV drug resistance.Post hoc analysis of a randomized trial.Main inclusion criteria were an HIV RNA level < 50 copies/mL for ≥ 24 weeks and no resistance to integrase strand transfer inhibitors or bDRV. Resistance-associated mutations (RAMs) were interpreted using the Stanford HIVdb mutation list. Outcomes measures were 48-week virologic response  and HIV RNA ≥ 50 copies/mL .The analysis population included 263 patients : 90.1% males; median age, 48 years; CD4 + T-cell nadir < 200/µl, 47.0%; ≥ 2 treatment changes, 27.4%; NRTI, non-NRTI (NNRTI), and major protease inhibitor (PI) RAMs in 9.5%, 14.4%, and 3.4%, respectively. In patients with RAMs in the 2DR and 3DR groups, virologic response rates were 87.8% and 96.0%, respectively; the corresponding rates in those without RAMs were 85.7% and 81.8%. RAMs were unrelated to virologic non-response in either group. No treatment-emergent RAMs were observed.DTG + bDRV is an effective treatment option without the risk of treatment-emergent resistance for PLWH on suppressive first- or further-line treatment with or without evidence of pre-existing NRTI, NNRTI, or PI RAMs.Trial registration: EUDRA-CT Number 2015-000360-34; registered 07 April 2015; https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-000360-34/DE. Both ced PLWH –8. The Dced PLWH . In thisOR study/study drug discontinuation due to: (i) a lack of efficacy, or (ii) reasons other than adverse events or death, with the last HIV RNA level being ≥ 50 copies/mL; hereinafter referred to as snapshot virologic non-response). Since this is a post hoc analysis, only descriptive statistics have been applied .The study population and statistical methods of the DUALIS study have been previously described . The incThe ITTe analysis population of the DUALIS study included 263 patients : 90.1% were of male sex; median age, 48 years; Centers for Disease Control category C, 29.7% of patients; and CD4 + T-cell nadir < 200/μL, 47.0% of patients. The median duration of ART was 5.3 years; 27.4% of the patients had a history of at least two ART changes, including ≥ 2 NRTI and/or ≥ 2 PI changes in 20.9% and 11.0% of the patients, respectively. Prior INSTI use was documented in 8.4% of the patients .Former or current reports of genotypic resistance were available for 63.5% of the patients 167/263). NRTI, NNRTI, and/or (major or minor) PI RAMs were observed in 9.5%, 14.4%, and 30.0% of the ITTe set, respectively. Major PI RAMs were documented in 3.4% of the patients. ART-related history and the prevalence of RAMs stratified by the study arms are shown in Table 67/263. NPrimary endpoint analyses with respect to treatment history and the presence of RAMs are shown in Fig. nd-line or ≥ 3rd-line ART prior to baseline, snapshot virologic non-response rates were 1.3% (one out of 74), 6.9% (two out of 29), and 7.4% (two out of 27) in the 2DR group, and 5.3% (three out of 57), 10.0% (three out of 30), and 2.2% (one out of 45) in the 3DR group, respectively. Of the study participants with major or minor RAMs before baseline, virologic non-response was observed in 2.0% in each study arm . In the 2DR subgroup, virologic non-response was observed in a case with minor PI mutations/polymorphisms (M36I and L63P) and viral mutations associated with NRTI resistance  before baseline. In the 3DR subgroup, virologic non-response was observed in a patient with only a minor PI mutation (A71T) prior to baseline.For patients on first-line, 2Grouping patients without documented RAMs before baseline and patients without available historic resistance test data, virologic non-response rates were 4.9% in the 2DR group (four out of 82 patients) and 7.3% in the 3DR group (six out of 82). In patients without RAMs, virologic non-response was observed in 7.4% of study participants . In patients without resistance test, non-response was observed in 5.2% of study participants . During the follow-up, no emergence of RAMs was observed in either study arm. Of the nine patients with documented major PI RAMs, no patient in either group experienced virologic non-response. The same was true for the 12 patients with NRTI RAMs in the 3DR study arm.In the DUALIS study, dual therapy with DTG plus bDRV was an effective treatment option with no treatment-emergent resistance in PLWH on suppressive first- or further-line ART with or without evidence of pre-existing NRTI, NNRTI, or PI RAMs. Neither the presence of major or minor PI RAMs (not conferring phenotypic resistance to DRV based on the interpretation of resistance patterns) nor that of NRTI or NNRTI RAMs (assessed based on available historic genotypic resistance reports) affected the maintenance of virologic response after switching to DTG plus bDRV over 48 weeks. However, a limitation of this post hoc analysis of the DUALIS study is the only low to moderate prevalence of relevant RAMs. Prior to baseline, NRTI, NNRTI, or major PI RAMs were observed in 9.5%, 14.4%, and 3.4% of the analysis population, respectively. Moreover, the information on primary resistance and/or history of emerging resistance mutations pertaining to previous antiretroviral regimens was not available for approximately one-third of the study population. Of note, post hoc measurement of archived resistance mutations in proviral DNA was not foreseen in the study. The reason for missing historic resistance information could have been that primary resistance had not been evaluated before treatment initiation or resistance testing had not been available or feasible at the time of previous virologic failure in some cases (which was not an exclusion criterion of the study). However, these probably missed opportunities for resistance testing might indicate an underestimated prevalence of RAMs, namely that even more mutations may have been present in the study population than documented. Of note, transmitted HIV drug resistance in Germany has been reported to be relatively stable at approximately 10% .Real-word data are in line with the results of this study. Several cohort studies evaluating bDRV plus DTG in PLWH with extended treatment experience and an even higher prevalence of NRTI, NNRTI, and major PI RAMs than in the DUALIS study confirmed a high virologic effectiveness and a high resistance barrier of the dual regimen –15. In a


As cardiovascular diseases represent the main cause of non-AIDS related death in people living with HIV (PLWH) with undetectable viral load, we evaluated lipid profile, weight gain and calculated cardiovascular risk change after switching from tenofovir disoproxil fumarate (TDF)-based regimens to tenofovir alafenamide (TAF)-based regimens.+ count, weight, height, blood pressure, current/ex/non-smoker, diabetes mellitus, familial cardiovascular event, lipid profile, duration and nature of antiretroviral therapy. Lipid parameters, weight and calculated cardiovascular risk using 5-year reduced DAD score algorithm  were analyzed in each groups.For this retrospective study, we selected HIV-infected patients with suppressed viral load who fitted in one of the two groups below: First group (TDF/TDF): Patients treated continuously with TDF-based regimens. Second group (TDF/TAF): Patients treated with TDF-regimens during at least 6 months then switched to TAF-regimens while maintaining other drugs unchanged. Available data included date of birth, gender, ethnicity, lymphocyte T CD4Switching from TDF to TAF resulted in a significant increase in triglycerides levels, total cholesterol and HDL cholesterol. LDL cholesterol and total cholesterol/HDL ratio did not show significant changes. Calculated cardiovascular risk increased after switch from TDF- to TAF-based therapy.Together with favorable outcomes at the bone and kidney levels, potential negative impact of TAF on lipid profile should be included in the reflection to propose the most appropriate and tailored ARV treatment.The online version contains supplementary material available at 10.1186/s12879-021-06479-9. Since the advent of antiretroviral therapy (ART), HIV has changed from a fatal disease to a chronic disease, with people living with HIV (PLWH) attaining a normal life expectancy –4.However, despite efficient virological control, PLWH still experience excess morbidity and mortality compared to general population , 5. Age-Cardiovascular diseases (CVD) represent one of the main causes of non-AIDS related death , 7. It hPLWH with undetectable viral load under ART have an increased risk of CVD. It is thought to be due to several factors, including a persistent chronic atherogenic inflammatory state. The cause of this immune activation in treated HIV infection is unclear but may be related to various elements such as persistent low grade viral replication, direct effects of HIV proteins, viral co-infections , hepatitis C virus), regulatory lymphocytes T cell (Treg) deficiency, decreased thymic function and increased gut microbial translocation , 11, 12.Traditional risk factors for CVD are also common in PLWH: smoking, sedentary lifestyle, high blood pressure, high body mass index, hypercholesterolemia, diabetes, unhealthy diet and psychosocial stress are responsible for an increased CVD risk –15. AlsoUntreated PLWH with detectable viral load frequently develop dyslipidemia  due to HIV infection itself , 18. ARTThe Data collection on Adverse Effects of Anti-HIV Drugs Study (DAD) equation was specifically developed to evaluate cardiovascular risk of HIV-infected patients. DAD equation takes into account, in addition to the traditional CVD risk factors, ART exposure. It is based on the results of a large multicenter cohort study conducted mainly in Europe and North America .Studies demonstrated fat gain in ART-naïve PLWH due to restoration to health after initiation of ART. Otherwise, obesity and lipohypertrophy are over-represented in PLWH on ART. These fat storage alterations are of multifactorial origin: direct effect of HIV proteins and ARV on adipocytes, increased microbial translocation, tissue inflammation, genetic and other factors .As efficacy of the latest generations of ART is generally high, their specific adverse event profile may guide when choosing the initial regimen and switching therapies .Tenofovir alafenamide (TAF) has been introduced as a better prodrug of tenofovir. TAF achieves higher intracellular concentrations of tenofovir diphosphate (the active form of tenofovir) in mononuclear cells and hepatocytes but with lower plasma tenofovir concentration compare to its predecessor, the tenofovir disoproxil fumarate (TDF). These pharmacokinetic properties allow to reduce long term renal and bone toxicity compared to TDF , 27. ForHowever, as TDF has a favorable effect on dyslipidemia by reducing atherogenic lipids , switchiIn this study, we aimed at figuring out the impact of switching from TDF to TAF on lipid profile, calculated cardiovascular risk score and weight gain.First group (TDF/TDF): PLWH treated continuously with TDF-based regimens since 2016 or earlier with suppressed viral load for at least one year on 2016.Second group (TDF/TAF): PLWH treated with TDF-based regimens during at least six months then switched to TAF-regimens while maintaining other drugs unchanged (table S1.). TAF-regimens had to be continued during at least six months after switch. Viral load had to be suppressed for at least one year before switching.For this single center observational retrospective cohort study, we selected individuals from a database recording all HIV-infected outpatients attending CHU Liege hospital in Belgium on 18/01/19:Patients who modified their lipid lowering medications between available lipid measurements were excluded. Modification of other ARV drugs than TDF to TAF was also an exclusion criterion. Viral load had to be suppressed for at least one year before the first measurement of clinical and biological parameters in order to avoid modification of those parameters resulting from a 'return to health' effect.+ level, duration and type of previous and current ART and concomitant treatment related to comorbidities.Clinical and biological collected data included age, sex, weight, height, systolic blood pressure, current/ex/non-smoker, diabetes mellitus, total cholesterol (TC), HDL cholesterol, LDL cholesterol, TC/HDL cholesterol ratio, triglycerides, treated dyslipidemia, familial cardiovascular event, lymphocyte T CD4For lipid parameters in TDF/TDF group, we selected last lipid level values available in 2016 and 2018 with a minimum exposure of 6 months to TDF for the first value selected. For lipid parameters in TDF/TAF group, we selected lipid level values at baseline with a minimum exposure of 6 months to TDF and at 6 months minimum after switch.Cardiovascular risk score was calculated using reduced DAD (DAD-R) model equation from Friis-Møller et al. appendix . FurtherAll data were reviewed before being analyzed. Characteristics of the analyzed cohort are presented in Table The Ethical Committee (EC) of the University Hospital of Liège , Belgium, approved the study protocol. Patients were informed of data collection by their treating physician and patients could object to further collection of clinical data according to an opt-out procedure. All patients included were assigned unique identification numbers to anonymize the data and protect confidentiality. All methods were carried out in accordance with relevant guidelines and regulations. Informed consent was not required for this study, according to the EC  recommendations.Data were summarized as mean and standard deviation (SD) or median and interquartile range (P25–P75) for quantitative variables while frequency tables were used for the categorical findings. Evolution of lipid parameters and weight was investigated by Student t test for paired samples. Since the distribution of DAD-R and CD4 lymphocyte count is not symmetric, nonparametric tests were used to analyze those variables . Longitudinal mixed effect multiple regression modeling approach with a change point at TAF initiation and including potential confounding variables were used to assess TAF effect. Variables with univariate significant impact (at p < 0.10 level) or clinically identified as potential confounder were included in the multivariate models. A log-transformation was applied for DAD-R modelling, and since those variables were directly or indirectly part of the score calculation, covariates were not included in the model. Missing data were not replaced and data analysis was carried out using SAS (version 9.4 for Windows). Results were considered significant at the 5% critical level (p < 0.05).The TDF/TDF group included 31 patients with a TDF treatment duration ranging from 2 to 10 years  , evolution showed a non-significant decrease in the TDF/TDF group p = 0.38) (Table 8 (Table Cardiovascular (CV) risk did not change in TDF/TDF group between 2016 and 2018 (p = 0.32) Table A. but inOur study aimed at analyzing the impact of switching from TDF-based regimen to a TAF-based regimen on lipid profile, CV risk score and weight gain in virally suppressed individuals. As already demonstrated by other research groups , 29–31, These elements are significant as dyslipidemia is already particularly common in PLWH on ART of any kind. Interestingly, a recent study showed that changes in lipid profile are reversible after switching back to TDF . AccordiWe further showed the evidence of an increase in calculated CVD risk according to reduced DAD algorithm when switching from TDF to TAF due to increases in total cholesterol and triglycerides levels, although this effect was not confirmed in the linear mixed regression models. The impact of TAF on CVD risk should thus be investigated on larger cohort studies.This observation is important as PLWH are more susceptible to develop CVD even if viral load is undetectable under ART , making + T cell count and high baseline HIV RNA levels [Weight gain following the initiation of ART has been reported across multiple settings and study populations . Part ofA levels . A potenA levels –36. In tA levels .The main limitations of our study are its retrospective nature and the low number of patients included in the TDF/TDF group. However, this number is due strict inclusion/exclusion criteria needed to perform a relevant comparison of both groups. Indeed, the strengths of our study is that all included PLWH were effectively virally-suppressed to avoid a 'return to health' effect. All participants maintained their ARV regimens unchanged (except for TDF in TDF/TAF group) and did not modify their lipid-lowering therapy to avoid impact of other medications. Another quality of our study is its “real-world” setting and data with older patients compared to generally younger patients enrolled in clinical trials. Moreover, we used non-HDL cholesterol that is considered the best measure of the cholesterol carried by all proatherogenic lipoproteins.In conclusion, TAF is a new interesting drug with a security profile which is attractive as far as renal and bone complications are concerned, due to a much lower serum concentration and a higher intracellular concentration of tenofovir diphosphate (active form of tenofovir). Nevertheless, switching from TDF to TAF leads to a significant increase in atherogenic lipid levels and to a higher risk of requiring lipid-lowering medication . We furtAdditional file 1: Table S1. TAF-based regimens after switch from TDF-Based regimens. Table S2. Evolution of lipid parameters, weight and cardiovascular risk - Linear Mixed Regression Models.