Multivariate analyses were performed to identify the determinants of higher risk of VF. Of 1,029 HIV-infected children and adolescents (393 children and 636 adolescents), 801 (77.8%) cumulatively presented with VL <1000 copies/mL within 12 months on ART. Adolescents were more likely to have VF than children . Patients followed-up in decentralized care units were significantly more likely to have VF compared to those attending the accredited treatment centers . Our findings show a high rate of VL suppression  among HIV-infected children and adolescents, albeit lower than the established target of 90%. Being adolescent and patients followed in the decentralized care units are high risk factors for VF, thereby necessitating routine therapeutic education of patients and guardians in resource limited countries to improve VLS.Virological response to antiretroviral therapy (ART) remains a challenge for HIV-infected children and adolescents due to non-optimization of pediatric ART for resource-limited settings. In this study, we aimed to investigate factors associated with virologic failure (VF) in HIV-infected-children and adolescents on ART in Cameroon. A prospective patient-based cohort study was conducted among HIV-infected children (0–9 years) and adolescents (10–19 years) followed-up between November 2018 and October 2019 in 38 healthcare centers located in the Littoral region of Cameroon. The 1 Although global incidence and mortality due to Human Immunodeficiency virus (HIV) have declined, HIV infection remains a major public health problem in several parts of the world. In 2018, approximately 37.9 million people were living with HIV worldwide, including 1.7 million children and adolescents aged 0 to 14 years, of whom 160,000 were new infections [Good adherence to ART is a key determinant of viral load suppression (VLS), but it is rarely observed in most patients with chronic disease, including in HIV-infected patients ,6. TreatUnfortunately, in Central Africa, there is limited data on VLS or virologic failure (VF) in the HIV-infected children and adolescents. Most studies do not provide information on VLS at specific time point, and VLS are highly variable in this population . PreviouCameroon is located in Central Africa and adheres to the three strategic objectives of the UNAIDSs: 90% of HIV-infected people will know their serological status, 90% of HIV-infected people knowing their status receive sustained ART, and 90% of patients on ART have VLS by 2020 ,16. Recetest and treat” strategy in Cameroon. This region is divided into four departments  and its capital is Douala an economic capital of the country. With an estimated average annual population growth rate of 5% the last 31 years and a current population of approximately 3,270,000 inhabitants, Douala is therefore the most populated city of Cameroon.A prospective population-based cohort study was conducted from November 2018 to October 2019 in the Littoral Region of Cameroon two years after the start of “The Littoral Region of Cameroun concentrates about 20%  of people living with HIV (PLHIV) on ART in Cameroon. During the study period, about 2,200 children (aged less than 10 years old) and adolescent (aged 10 years to 19 years) on ART were followed up in two Accredited HIV Care Centers (AHCC) and 36 Decentralized HIV Care Unit (DHCU) mainly in Douala. One AHCC  and six DHCU  which concentrated about 1,150 (52.3%) children and adolescents on ART were selected according to the health facilities level and the number of patients followed up.We used data sources from the previous studies  and assuThe survey’s target population was all HIV-infected children (0–9 years) and adolescents (10–19 years) on at least 6 months ART and regularly followed-up in the pediatric wards of the 7 seven selected health facilities.nd VL (VL2) was performed between 3 and 6 six months later according to national guidelines. VLS was defined as VL < 1000 RNA-copies/mL of blood plasma [At the inclusion, VL1 test was carried out and when VL1 was ≥ 1000 RNA copies/ml of blood plasma, an assessment of compliance was carried out by an educator and the 2d plasma ,33.This study was conducted in accordance with ethics directives related to research on humans in Cameroon. The study received an ethical clearance from the Institutional Health Research Ethics Committee of the University of Douala (N°2437/CEI-UD/08/2020) and, administrative authorization was obtained from all health facilities and the Regional delegation of public health for the Littoral. Before enrollment and the administration of questionnaire, patients/tutors were informed on the purpose and process of the investigation . Adolescents were allowed to give their own written assent to participate in the study if they were judged by the study nurses to be able to give consent, and signed informed consent was obtained from the parents/guardians of children and adolescents in accordance with the Helsinki declaration and national guidelines. Participation was voluntary, anonymous and unpaid. Participation was voluntary, anonymous and without compensation.They were closed-ended interview questions, including a single answer, and multiple choices questions. Data collection sheets were used to collect data on socio-demographic characteristics . The second part focused on i) clinical initiation status and, ii) therapeutic history (date on ART start and current ART regimen) were collected from registers and medical records. Administered questionnaire was conducted following a 1-week pre-test among 10 patients or parents/tutor per site to assess: i) understanding and acceptability of participants to the study and ii) to standardize and homogenize data collection in all sites. Interview questions were formulated so as not to influence participants in their answers.In the follow up health facilities, 1,000 microL of plasma were separated from venous blood samples (4 ml) collected into EDTA (Ethylene diamine tretracetic acid) vacutainer tubes after centrifugation (10.000 rotations per minute for 10 minutes). Plasma was then transferred in the cryobox and stored at -80°C to the molecular biology laboratory of the Douala Laquintinie Hospital until use for the HIV-1 plasmatic RNA quantification.HIV-1 RNA quantification was performed on plasma samples using the Abbott m2000 RealTime HIV-platform according to manufacturer recommendations . We used 50 μl of extracted RNA and 50 μl of Master Mix for a total volume of 100 μl. The tests were carried out at the molecular biology laboratory at DLH. After plasma centrifugation at 5000g for 5 minutes, a protocol using 600 microL of plasma was used for RNA extraction with the Abbott m2000sp automate. Individual eluated RNA extraction was diluted at 1/2  was then deposited in the microplates and amplified with the Abbott m2000rt thermal cycler. The lower limit of detection of the assay is < 40 copies/mL of HIV-1 RNA and the upper limit is 10.000.000 copies/mL.IQR; 25%–75%) and percentage in tables and/or charts. Multivariate logistic regression analysis was used to identify the determinants of VF. The odd ratios (OR) were computed to appraise the strength of association between dependent and independent variables, accounting for the potential confounding factors. Significance was set at p-values less than 5%. All statically analyses were performed using statistical package for social sciences (SPSS) version 20.0 for Windows (SPSS. Inc. Chicago. U.S.A) and Stata software version 11 for Windows.Data were presented as mean, median, interquartile range  were transferred to other health facilities during the study. Transfers were most often requested by parents/guardians after they have moved out of the city or to neighborhoods that are some distance away from the seven health facilities selected. Finally, a total of 1,029 patients were included in the seven health facilities, 427 (41.5%) in DLH, 62 (6.0%) in NRH, 167 (16.2%) in NDH, 89 (8.6%) in DDH, 130 (12.6%) in CDDH, 73 (7.1%) in SALCH and 81 (7.7%) in SMC . Most of25-75%: 7.6–15.4; min-max: 7.0–19.6 years). Patients were mostly girls (52.5%) and 38.0% were orphans.Children accounted for 393 (38.2%) of the patient population and 636 (61.8%) were adolescents . The medIn total, 77.8% (801/1.029) had a suppressed VL after the first and the second test and among them, 40.1% (321/801) were children and 59.9% (480/801) were adolescents .vs 18.3%, OR = 1.45, 95%CI: 1.06–1.98, p = 0.020). The number of patients with VF was significantly higher among maternal orphans , father orphans  or orphans of both parents  compared to those who had both parents. VF was higher in patients living with their mother  and with other family members .Adolescents were significantly more likely than children to have VF   . The numTo identify the demographic and therapeutic risk factors that associated independently with VLNS in the population, multivariate analyses was done using age group, heath facility, parents’ life status and residence family. As shown in Virological surveillance is the main method used to assess the effectiveness of ART in PLWH. VL monitoring can therefore help to detect treatment failure and determine whether the patient should be switched to another treatment regimen. This study describes the virological response and factors associated with VF on 1,029 HIV-infected children and adolescents (393 children and 636 adolescents) routinely followed in seven health facilities in the Littoral region of Cameroon. This is one of the limited studies assessing VLNS in a large cohort involving more than a thousand HIV-infected children and adolescents in Central Africa and particularly in Cameroun.Among HIV-infected children and adolescents on ART for at least 6 months, 70.2% had undetectable VL at their first VL assessment, whereas the remaining 29.8% had received adherence counselling sessions before the second VL test. The intervention with the therapeutic education increased the VLS from 70.2% to 77.8% in the entire pediatric population after the two VL measurements separated by 3 to 6 months, thus reducing the number of patients with VLNS at 22.7%. This approach used in our study in determining virological response to ART punctuated by therapeutic education could explain the difference observed with several other studies conducted in the same area  and in oChildren had a better virological response than adolescents. A similar result was reported in a study conducted in Cameroon among patients on ART recruited in the Center, South and East Regions of Cameroon . SimilarIn this study and in another among HIV-infected children in Senegal, the VF rate was higher among patients routinely followed up in the DHCU compared to those followed up in the AHCC . In CameVLS was lower among adolescent orphans and who did not live with their parents. A similar trend was observed in a previous study in Ethiopia where the death of both parents was a risk factor for VF among pediatric population . AnotherThe ART duration was not associated with VF in this study, whereas several other studies conducted in pediatric populations on ART showed that ART duration less than 48 months ,43 and AThis could be explained by the fact that the virological data of the participants in our study were not obtained from the time of ART initiation to determine the time of VF onset in children and adolescents on ART.The current study shows that VF remains a major challenge for HIV-infected children and adolescents on ART and particularly among adolescents. HIV-infected adolescents and patients followed-up in a DHCU are more at risk of VF and therapeutic education improves the virological response. A specific intervention targeting adolescents in particular, patients followed in the DHCUs and orphans because of their precarious social status, would be necessary.


Tuberculosis (TB) coinfection in human immunodeficiency virus- (HIV-) infected patients is considered a risk of antiretroviral therapy (ART) failure. Coadministration of antitubercular therapy (ATT) with ART is another challenge for TB management.  The study was aimed at investigating contributing factors affecting treatment outcomes in HIV-/TB-coinfected patients. Setting. Samples were collected from the Pakistan Institute of Medical Sciences Hospital Islamabad. Subject and Methods. Clinicodemographic and immunovirological factors between the two groups were compared. The Student t-test and chi-square test were applied to compare outcome variables, and logistic regression was applied to determine the effect of TB on virological failure (VF). Main Outcome Measures. TB coinfection did not increase VF even in univariate (p = 0.974) and multivariate analysis at 6 and 12 months of 2nd-line ART start. ARV switching was significant (p = 0.033) in TB-coinfected patients. VF was significantly high in ATT-coadministered patients along with a viral load of ≥1000 (p = 0.000). Sample Size and Characteristics. We recruited seventy-four HIV patients on 2nd-line ART; 33 coinfected with TB were followed for at least 12 months.  Cross-sectional.  In HIV-/TB-coinfected patients, CD4 count, CD4 gain, and VF remained comparable to HIV patients with no TB infection. ATT significantly affects the treatment outcome, suggesting drug-to-drug interactions. These factors are important to revisit the therapeutic guidelines to maximize the benefit of dual therapy in resource-limited settings. Human immunodeficiency virus (HIV) infection in patients and tuberculosis (TB) coinfection in resource-constrained settings are a major concern. A lethal combination of two diseases is an emerging threat for healthcare providers. The risk of opportunistic infections (OIs), like TB, increases in HIV-infected patients because of suppressed immunity . People Active TB (pulmonary or extra pulmonary) is also more challenging to detect in HIV patients. Tb progresses promptly in HIV patients. Coinfection of TB needs additional measures like antitubercular therapy (ATT). Coadministration of ART and ATT may decrease the effectiveness of each other and may result in premature discontinuation of therapy. On the one hand, HIV is acquiring drug resistance and a growing number of HIV patients on first line of ART require to shift on second line of ART. On the other hand, increasing prevalence of multidrug-resistant (MDR) and extremely drug-resistant (XDR) TB is an additional challenge for physicians to treat TB in general population and in HIV patients. Furthermore, therapeutic complications may arise due to human genetic factors involving ADME genes, adverse reactions (AR), drug-to-drug interactions, and a high number of pills leading to nonadherence to therapy . These fposTBpos, taking 2nd-line ART on initiation of treatment, and was TB coinfected (n = 33). The second group was designated as HIVposTBneg, taking 2nd-line ART on initiation of treatment, and was without TB coinfection (n = 41). Two patients, who were treated for TB before the start of 2nd-line ART, were excluded. Characteristics of the two groups are compared in posTBpos was further subdivided into two groups. The first group ARTyesATTyes is comprised of patients coadministered with ART and ATT. The second group ARTyesATTno is comprised of HIV-/TB-coinfected patients only on ART.The study was conducted at HIV/AIDS Care and Treatment Center, PIMS, Islamabad, Pakistan. It is the only focal and referral center in the capital of Pakistan, Islamabad. HIV patients were divided into two groups. The first group of patients was designated as HIVth May 2019. All Pakistani adult patients that shifted to 2nd-line ART for at least one year after 1st-line ART resistance, between December 2005 and June 2020, were enrolled. All patients with complete clinical data, CD4, and viral load (VL) data on follow-up were included. Females who were pregnant and transgender were excluded. Real-time PCR-based, HI-Virus-1 RG-RT-PCR Kit was used to determine the VLon Rotor-Gene Q-PCR system  according to the manufacturer's instructions. BD FACSCalibur flow cytometry  was used to determine CD4 count according to the manufacturer's instructions. Treatment failure is defined as advancement of disease even after initiation of 1st- or 2nd-line ART in terms of clinical, virological, or immunological failures which are defined as under. A definite diagnosis of treatment failure based on clinical and immunological failure criteria should be supported by virological failure. Clinical failure is defined as new or recurrent WHO stage IV event and also certain stage III conditions. A definite virological failure is when a single VL is >10,000 copies/ml at 12 months of follow-up. A probable virological failure is when either a single VL is >1000 copies/ml at 12 months or a VL at 12 months is ≥400 copies/ml, which is still elevated on second measurement taken after 30 days. Immunological failure is the decline of CD4 counts, less than the CD4 count before the start of treatment or <50% decrease of a peak value on 2nd-line ART or persistently lower than 100 cells/ml [Patients were requested to provide written consent for participation in the study. HEC Pakistan provided funding for the study. The ethical committee of CUI Islamabad approved the study (CIIT-BIO-Science/Office/215-2016) dated 10p < 0.05 was considered significant. Categorical outcome variables were compared using the chi-square (χ2) test. An independent-sample Student t-test was used for continuous variables. The effect of TB coinfection on virological failure was determined through binary logistic regression.SPSS version 26.0 was used for statistical analysis. Categorical variables were described as frequency (%) and continuous variables as mean ± standard error of the mean (std. error mean). Two-tailed tests were performed and nd-line ART were included in the analysis. A significant difference (p = 0.021) in mean age at the start of 2nd-line ART was recorded between HIVposTBpos and HIVposTBneg patients (nd-line ART start. Non-Tenofavir-based regimens (p = 0.941) were prescribed in 44.9% and 55.1% of patients in HIVposTBpos and HIVposTBneg patients, respectively . Relationship status, employment status, education level, weight, and 1st-line nonnucleoside reverse transcriptase inhibitor regimen at 2nd-line ART start in both groups were insignificant (Seventy-four patients contributing 209.33 person-years (p-y) of follow-up on 2patients . There wectively . HIVposTnificant .nd line of ART in both groups (p = 0.924) and multivariate (p = 0.081) analyses  and VL of ≥1000 copies/ml after 12 months of 2nd-line ART treatment (p = 0.000). Adherence of <95% (p = 0.000) was significantly associated with VF in ARTyesATTyes patients. Mortality rate was 3.17 (95% CI 0 to 5.94) per 100 p-y with 12.16% (n = 9) deaths in both groups. Mortality was not associated with adherence as 60% of dead patients were having ≥95% of adherence. No significant difference in mortality rate was observed between the two groups and even in patients on ATT along with ART  were coadministered with ATT along with 2nd-line ART.TB coinfection and simultaneous use of ATT are known global factors resulting in ART failure , and it ountries , 12. Theountries . In our p = 0.064). However, candidiasis and chronic diarrhea were experienced by most patients. The exact cause of diarrhea could not be determined due to a lack of experienced microbiological testing in routine laboratories as reported by other local studies in which cryptosporidium-related diarrhea was also underreported [During treatment, patients experience different OIs, which are tabulated in reported , 14.n = 9) in both groups. Rates of mortality varied substantially, ranging from 11% to 29% in different studies [n = 8) deaths were observed in association with age > 30. However, with better care, diagnosis, and therapeutic management, the mortality rate has declined significantly among HIV-/TB-coinfected patients in the Asia-Pacific region since 2004 [nd-line ART [The mortality rate was 13.51%  or in the multivariate model (p = 0.081) with VF. TB was included in the multivariate model due to its close association with HIV [nd-line ART is significantly associated with VF. This is the first study, analyzing the treatment outcome of coadministration of ATT and 2nd-line ART in Pakistan. Baqi et al. described the interaction of 1st-line ART and ATT, especially with rifampicin. Efavirenz has good therapeutic response than nevirapine in coadministration with ATT [st-line ART regimen with efavirenz was the preferred therapy and was predominantly prescribed in our study group. Protease inhibitors (PIs) with other ART combinations and ATT may have a role to interact with each other. Another factor could be the genetic variability effect of ADME  genes [nd-line ART needs more optimization in the country. Ineffective ATT in HIV-/TB-coinfected patients is leading to multidrug-resistant (MDR) TB which further complicates the therapeutic management [TB was not significantly associated either in the univariate analysis  genes . This inn) genes . Treatmenagement . Integranagement . Nationand-line ART [In our institution, we have been using WHO-recommended ritonavir boosting dose with lopinavir, concomitantly in combination with rifampicin. But this combination has resulted in hepatotoxicity and poor tolerability . On the line ART . Nationand line of ART. Drug-to-drug interactions and plasma levels were not determined. TB coinfection did not significantly increase the risk of virological failure. On the other hand, coadministration of ATT with ART significantly increases the virological failure. It is mandatory for our national AIDS and TB control program to scale up concurrent HIV/TB treatment under integrated care.In HIV-/TB-coinfected patients, CD4 count, CD4 gain, and VF remained comparable to HIV patients with no TB infection. ATT significantly affects the treatment outcome, suggesting drug-to-drug interactions. These factors are important to revisit the therapeutic guidelines to maximize the benefit of dual therapy in resource-limited settings. A small sample size is a limitation but important where low numbers of patients are on 2


ObjectivesHighly active antiretroviral therapy (HAART) has decreased morbidity and mortality among HIV/AIDS-infected patients; however, many patients experience treatment failure. The present study aims to evaluate HIV-infected patients' clinical and immunological profiles with first-line antiretroviral treatment (ART) failure  at tertiary care hospitals in Northeast India and explore related treatment failure factors.MethodsThe hospital-based observational study was conducted among HIV-infected patients with first-line ART failure attending a tertiary care hospital from July 1, 2019, to June 30, 2020. The type of first-line ART failure was defined as a clinical, immunological, or virological failure as decided by the State AIDS Clinical Expert Panel (SACEP) meeting. Data were analyzed with Windows MS Excel  and Statistical Package for the Social Sciences (SPSS) version 21 .Results3, with 38 (42.2%) patients, and by patients on efavirenz (64.5%) and tenofovir-based regimens (56.6%). Failures occurred more for 24-30 months and were common among patients with adherence below 90%.Among the 90 HIV-infected patients experiencing first-line ART treatment failure, the majority, 38 (42.2%), were in the age group of 30-40 years, 64 (71.1%) were males, and 70 (77.8%) were of average weight. Tuberculosis was the most typical opportunistic infection, affecting 11 (12.2%) patients. Most patients (38.9%) were initially presented at clinical stage 3. Maximum failures were experienced by patients with baseline CD4 ranging from 100-200 cells/mmConclusionTreatment failure was more common among young male patients and those with normal body mass index (BMI). Low baseline CD4 count and poor adherence were influential in the occurrence of treatment failure. First-line ART failure was higher in tenofovir- and efavirenz-based regimens. With cases documented from almost every nation, HIV infection is a global pandemic. The HIV epidemic has spread worldwide, with each wave having distinct characteristics. HIV is primarily spread through sexual contact, blood and blood products, and by infected mothers to their infants.HIV infection can have various clinical effects. The clinical effects may be from a primary infection-related acute clinical illness through an extended asymptomatic period to advanced disease.With an HIV/AIDS prevalence rate of 0.3%, India ranks 80th globally. It has 2.1 million individuals living with the disease, according to the 2018 Joint United Nations Program on HIV/AIDS (UNAIDS) report [Treatment failure is an inadequate response to treatment or a lack of a sustained response based on clinical, immunological, or virological criteria . MonitorThe present study was undertaken to study the clinical and immunological profile of first-line ART failure patients and to explore any relationship of treatment failure with the type of ART, duration of first-line ART, and adherence among HIV-infected patients with treatment failure  to first-line ART attending tertiary care hospital of north-east India.The current hospital-based observational study was conducted among HIV-infected patients with treatment failure  to first-line ART attending ART plus center and outdoor patient department (OPD) and indoor patient department (IPD) of the Department of Medicine at the Gauhati Medical College and Hospital (GMCH) during the period July 1, 2019, to June 30, 2020.Inclusion and exclusion criteriaHIV/AIDS patients aged above 15 years with first-line ART treatment failure  willing to participate in the study after six months of treatment were included. HIV-infected patients under 15 years, those with first-line ART duration of less than six months, ART-naive patients, and patients on or failing second-line ART were excluded from the study. HIV-2 patients were also not included. Patients unwilling to participate in the study were also excluded.Sample sizeThe sample size was determined based on the following formula:where n is the minimum sample size, w is the estimated error (0.05), p is the estimated prevalence (6%), and z = 1.96 by assuming a 95% confidence interval, and the sample size estimated is 90.The type of first-line ART failure was defined as a clinical, immunological, or virological failure as decided by the State AIDS Clinical Expert Panel (SACEP) meeting based on the Guidelines of Treatment Failure of NACO (NACO-2018) as follows.Clinical FailureA new or recurrent WHO stage 4 condition after at least six months of ART is considered a clinical failure.Immunological Failureimmunological failure.A fall of CD4 count to pre-therapy baseline (or below), a 50% fall from on-treatment peak value if known, or persistent CD4 levels below 100 cells/microliter after six to 12 months of treatment is considered an Virological FailurePlasma viral load > 1000 copies/ml is considered a virological failure.Adherence calculationAdherence was calculated as per the formula mentioned below:which is also equal to:Data were collected on the patient's demographics, medical history, clinical examination, and laboratory parameters in a preformed and pretested proforma.Statistical analysisData were analyzed with Windows MS Excel  and Statistical Package for the Social Sciences (SPSS) version 21 . The distribution of categorical data was described as count and percentages, while continuous data were presented as mean and standard deviation (SD). Association between categorical variables was tested using a chi-square test, considering a p-value < 0.05 as significant.Ethical issuesEthical approval was obtained from the Ethics Committee of Gauhati Medical College, Guwahati, with Ref. #: MC/190/2007/Pt-II/MAR-2019/PG/54. Before collecting the data, informed consent was taken from the patients. Complete privacy was maintained for the patient’s data as per the NACO guideline.A total of 90 HIV-infected patients with treatment failure  to first-line ART attending ART Plus Center and OPD and IPD of medicine were included in this study.Among the first-line ART failure patients , the maximum failure rates were seen in the 30-40 age group in 38 (42.2) patients. The mean age of failure was 37.72 years. Out of the 90 patients, 64 71%) were males with a male-to-female ratio of 2.46:1. The median BMI was 21.94, with 70 (77.8%) out of 90 patients being of average weight (Table % were maThe data showed high mean serum transaminase levels among the patients. The details are shown in Table As shown in Table 3 in 38 (42.2%) patients, followed by those with baseline CD4 200 cells/mm3 and above  had presented with treatment failure initially at clinical stage 3 in the present study. The median baseline CD4 was 195.58. Maximum failures were experienced by patients with baseline CD4 ranging from 100-200 cells/mm1.1% had Among 90 treatment failure patients, all patients had an immunological failure. Virological failure was observed in 72 (80.0%) cases Table .The median viral load was 139646 copies/milliliter. Among the 90 ART failure patients, 44 (48.9%) had a viral load between 1,000-100,000 copies/milliliter, and 28(31.1%) had a viral load above 100,000 copies/milliliter , the maximum failure rates were observed with the TLE regimen in 49 (54.5%) patients, followed by the ZLN regimen in 30 (33.3%) patients. TLN regimen had the lowest failure rate (2.2%). Maximum failures were seen in the duration of 24-30 months. The median time of failure was 37 months. Almost 19% (17/90 patients) of failures occurred after 48 months of treatment. Maximum failure was seen in the patients (38/90 patients) with adherence below 90% Table .The factors significantly associated with time to treatment failure after ART initiation were age at ART initiation, plasma viral load, and adherence . A significant linear trend  was observed between age at ART initiation and time to treatment failure, indicating a delay in treatment failure (>24 months) among those aged more than 30 years. ART failure occurred significantly early (≤42 months) among those having plasma viral load >1000 copies/milliliter . Poor treatment adherence was also considerably associated with early treatment failure (≤42 months). The details are shown in Table Managing first-line ART failure is a primary concern for HIV programs. A higher risk of morbidity and mortality is linked to continuing a failing first-line treatment regimen. Additionally, the emergence of medication resistance restricts the future development of effective and tolerable regimens. The present study was undertaken to study the clinical and immunological profiles of first-line ART failure patients and to explore any relationship between treatment failure with the type of ART, duration of first-line ART, and adherence.The maximum number of patients with first-line ART failure  was found to be in the age group of 30-40 years (42.2%), with a mean failure age of 37.72 years. The finding suggests that older patients are less likely to fail the first-line regimen. Similar studies observed a lower incidence of treatment failure among the older age group after adherence adjustment for therapy . A signiIn contrast to our observations, a recent systematic review observed that female children were at higher risk of first-line ART failure than male children . However3 (42.2%). CD4 count is the strongest predictor of subsequent disease progression and survival. An inverse relationship between the CD4 count at baseline and the risk of disease progression and treatment failure was reported by various researchers [Most of the ART failure patients were presented initially at clinical stage 3. Several authors have reported a preponderance of ART failure patients with advanced baseline clinical stage ,18. A reearchers -22.Among 90 treatment failure patients, all patients had an immunological failure (100%), 72 had a virological failure (80.0%), and only eight had a clinical failure (8.9%). Previous studies on treatment failure were primarily prospective, including failure and responder cases. Hence, the present study could not draw a conclusive parallel comparison of failure type.However, in a study conducted among 54 patients with first-line treatment failure , 48 (88.9%) had immunological failure, six (11.1%) had clinical failure, and 37 (68.5%) had virological failure .In our study among nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) drug regimens, most (56.6%) of the first-line ART failure patients were on a tenofovir-based regimen. While among non-nucleoside reverse transcriptase inhibitor drugs (NNRTIs), first-line ART failure was mostly encountered among patients on an efavirenz-based regimen (64.5%). Previous studies have primarily compared the effectiveness between efavirenz-based HAART and protease inhibitor (PI)-based HAART, suggesting a consistent result of higher effectiveness of the efavirenz-based regimen . The higAmong the first-line ART failure patients , maximum failure was seen in the duration of 24-30 months, with a median time of failure of 37 months. With the early and prompt diagnosis per NACO operational guidelines, the median time of switching to the second line has been delayed as observed in the present study, which agrees with another Indian study . Also, wAdherence is the most significant patient-enabled predictor of treatment outcomes for the patients on HAART. WHO recommends at least 95% adherence to ART to avoid the emergence of resistant strains. In our study, among the first-line ART failure patients , maximum failure was seen in the patients with adherence of <90%. These findings were almost like another study. Previous research has identified inadequate adherence as an independent predictor of first-line ART treatment failure . A recenThe global HIV response, with coordinated political and financial commitment, has made substantial progress toward its goals of reaching critical populations and other marginalized groups, removing barriers to treatment caused by poverty, integrating communities in service delivery and decision-making processes, and placing the right to health at the forefront . EnhanceLimitationThe results of this observational study, which was limited to one ART center, may only apply to some. To draw a firm conclusion, further prospective research with a bigger sample size in a larger community and several ART centers is required.Younger male patients with normal BMIs had a higher propensity for treatment failure. Low baseline CD4 count and poor adherence were influential in the occurrence of treatment failure. Compared to other NRTIs and NNRTIs, the incidence of first-line ART failure was higher with tenofovir- and efavirenz-based regimens. The median time of first-line ART failure has been postponed due to the development of newer, more potent ARV medications.


Despite gains made from improved antiretroviral therapy coverage in resource limited countries, the occurrence of first line drug resistance remains a priority agenda. To reduce the emergence of resistant viruses, HIV viral load monitoring plays a critical role. However, many resource limited countries have difficulty of monitoring viral load due to economic constraints.There is also limited study regarding viral failure in developing countries. Therefore, this study aimed to assess the incidence and predictors of virological failure among HIV-infected children and adolescents on first-line ART Ethiopia, 2021.Institution based retrospective follow-up study was employed on 492 children and adolescents. Data were collected by trained nurses who have experience working in ART clinics. Data were entered using Epi-data version 4.6 and exported to Stata version 14 for analysis. The proportional hazard assumption was checked, and the Weibull regression was fitted. Cox-Snell residual was used to test the goodness of fit, and the appropriate model was selected by AIC. Finally, an AHR with a 95% CI was computed, and variables with a P-value < 0.05 in the multivariable analysis were taken as significant predictors of virological failure.The overall incidence rate of virological failure was 4.2,  per 1000 person-months of observation with 20,169 person-months follow-up time. In multivariable analysis living in rural area , poor adherence , lower CD4 Count <200 cells/mm3  and 201–350 cells/mm3  respectively, and recent OI  are significantly associated with virological failure.The incidence rate of virological failure was high. Living in a rural, poor adherence, lower CD4 count, and recent opportunistic infection were independent risk factors associated with virological failure. Hence, it is better to give priority to strengthening the focused evaluation of important variables and managing accordingly. Virological failure is defined as a viral load above 1000 copies/ml based on two consecutive viral loads (VL) measurements, after 6 months of Antiretroviral Therapy (ART) initiation and with 3 months of enhanced adherence support following the first viral load test .Globally 38 million people are living with Human Immunodeficiency Virus (HIV), of which 25.8 million reside in Africa , and 83%Although there are limited studies conducted on VF among children and adolescents in sub-Saharan Africa, in a study conducted in South Africa, the incidence of virological failure 3 years following initiation of ART was 19.2%.19.2% . In addiMaintaining long-term viral suppression among children and adolescents on ART is very challenging . Their dDifferent studies conducted have indicated that various factors were associated with virological failures such as being male , poor adDespite gains made from improved antiretroviral therapy coverage in resource limited countries, the occurrence of first line drug resistance remains a priority agenda . HoweverDifferent stakeholders are working collaboratively intending to create an HIV-free generation in 2030 . The GloThe majority of the studies conducted in resource-limited countries were based on a combination of immunological, clinical and virological failure. This would underestimate the incidence of treatment failure (TF) and leads to improper management of patients on ART. Therefore, this study aimed to determine the incidence and predictors of VF among children and adolescents on first-line ART in East Shewa, Oromia region Ethiopia, 2021.An institutionally based retrospective follow-up study was carried out. Data were collected from April 1–30, 2021 among HIV infected children and adolescents on ART between January 1, 2015, to December 31, 2019, in East Shewa, Oromia region, Ethiopia. The study was conducted in five Oromia regional public hospitals namely Adama college referral hospital, Bishoftu general hospital, Olenchity hospital, Batu hospital and Mojo hospital. HIV care and treatment clinic is one of the core parts of outpatient activities, all hospitals provide service to Adult and Pediatric ART. The ART case team in the hospital is composed of ART-trained physicians, ART-trained nurses, pharmacists, laboratory technicians, data clerks, and drug adherence counselors. Currently, the hospital serves more than 10thousand patients.The source population was all HIV-infected children and adolescents aged ≤ 19 years old on the first-line ART ever enrolled in ART clinics in East Shewa public hospitals and the study population was all HIV-infected children and adolescents aged ≤ 19 years old who had been on first-line ART for at least 9 months in East Shewa public hospitals from January 2015 to December 2019.465. By considering incomplete patient records, 10% of the initial sample size was added and the final sample size was 511 , tFurthermore, the difference in study population reflects the inclusion in Jimma of children less than 15 years may also be a factors.In this study children and adolescents living in rural areas had HR of 1.97 times higher than those living in urban. This result is consistent with a study conducted in South Africa and Southern Ethiopia , 40. ThiRegarding adherence, the present study showed that the AHR of children and adolescents who had poor/fair adherence to ART regimens were 2.20 times higher hazard of experiencing first-line virological failure compared to their counterparts. This result is consistent with studies conducted in Uganda , 38, KenAccording to this study, baseline CD4 counts of (<200 cells/mm3) and (200–350 cells/mm3) are 2.5 and 2.4 times a higher hazard of developing virological failure compared to patients with more than 500 cells/mm3 CD4 count, respectively. This result is in line with a study conducted in Cameroon , TanzaniOther predictors of virological failure in this study were recent opportunistic infection, those children and adolescents with recent opportunistic infection were 4.6 times more hazard of failure than those who had no recent opportunistic infection. This is consistent with a study conducted Bihar Dar . This caSince the design was retrospective, the study was unable to exhaustively explore all predictor variables that may have an effect on the incidence of virological failures such as socioeconomic status of the caregiver, educational status, and some laboratory assessments.The incidence of virological failure among children and adolescents on first-line ART at East Shewa public hospitals was found to be high. Living in a rural, lower CD4 count (< = 200 cells/mm3 and 201–350 cells/mm3), poor adherence, and recent opportunistic infection at baseline were found to be predictors of first-line ART virological failure. Therefore, it is better to give priority to strengthening the focused evaluation on important variables and managing accordingly.


Adverse effects linked to antiretroviral therapy (ART) may contribute to poor adherence on the patient’s side. Consequently, human immunodeficiency virus (HIV) drug resistance mutations could emerge, negatively impacting the body’s immune system. Meanwhile, severe immunosuppression can lead to several conditions, including anemia. The cause of anemia in HIV infection is multifactorial, and can be mainly explained by deleterious direct effects of the virus on the bone marrow, and opportunistic infections such as Parvovirus B19. Other causes include blood loss resulting from neoplasms and gastrointestinal lesions. Moreover, anemia can also be caused by antiretroviral drugs. We report a case of persistent anemia after ART initiation, kidney injury and treatment failure following a lengthy period of non-adherence to ART. The anemia was classified as Pure Red Cell Aplasia (PRCA). With treatment modification, the anemia resolved and the patient attained virologic suppression. Lamivudine (3TC) was pointed out as the cause of PRCA, which resolved after its withdrawal from the ART regimen. This rare side effect should be investigated in patients on 3TC who present with recurrent anemia. Anemia in people living with human immunodeficiency virus (PLHIV) has been associated with poor HIV treatment responses, high viral loads (VL), low CD4 counts and increased risk of death , 2. SeveBesides, Nucleoside Reverse Transcriptase Inhibitors (NRTIs) such as zidovudine (AZT) and lamivudine (3TC) have the propensity to cause hematologic toxicity, including anemia .We present a patient assessed with severe persistent anemia, multiple treatment interruptions, HIV drug resistance and treatment failure months after ART initiation.3; hemoglobin (Hb): 10.8 g/dl; creatinine clearance: 63 ml/min and hepatitis B surface antigen (HBsAg): non-reactive. She neither had a history of alcohol intake nor cigarette smoking. She interrupted her ART 1 month after ART initiation. All efforts to retain her in care were unsuccessful.This is a 44-year-old single and self-employed female who was initiated on tenofovir disoproxil fumarate (TDF), 3TC and efavirenz (EFV) as an outpatient in July 2012. Her baseline laboratory test results were as follows: CD4 count: 190 cells/mm3, and her Hb was 9.6 g/dl. A gradual decline in her Hb level—from 9.6 g/dl to 6.3 g/dl—was observed over 19 months (February 2018 to September 2019). She neither had leucopenia nor thrombocytopenia; her CD4 count had dropped to 11 cells/mm3, and blood loss was excluded during this period. From February 2019 to January 2020, the HIV plasma viral loads were persistent at >1000 copies/ml despite sessions of enhanced adherence counseling. Her creatinine clearance dropped to 30 ml/min and TDF doses were adjusted accordingly.Six years later, when she returned to care, she was not taking ART. She complained of chronic fatigue and was assessed with advanced HIV disease and kidney dysfunction. She was reinitiated on the same ART regimen (TDF + 3TC + EFV). At re-initiation of ART, her CD4 count was 33 cells/mmIn July 2019, a full blood count showed normocytic, normochromic anemia and reticulocytes <1%. Additionally, bone marrow aspirate analysis revealed histologic features suggestive of Pure Red Cell Aplasia (PRCA), whereas, polymerase chain reactions (PCR) on the bone marrow biopsy were negative for Parvovirus B19, Cytomegalovirus, Epstein Bar Virus and mycobacterium avium complex. The protein electrophoresis and immunofixation were negative for multiple myeloma. The HBsAg remained non-reactive, as well as the cryptococcal serum antigen and tuberculosis screenings, and the creatinine clearance was estimated at 36 ml/min.The patient was initiated empirically on steroids in the oncology department for 7 months to control possible immunologic disorders commonly associated with anemia in PLHIV. During the course of the treatment, her Hb slightly improved to 8.5 g/dl. However, during the same period, she suffered from esophageal candidiasis, an acquired immunodeficiency syndrome (AIDS)-defining condition treated successfully with fluconazole.In January 2020, she was referred to an HIV specialist who diagnosed her with HIV treatment failure and PRCA. Hence, 3TC was suspected to be the cause of PRCA. The steroids were discontinued, and the Sanger genotyping resistance testing (GRT) exposed these mutations: K70KE, M184V, V106VA, E138G, V179D, G190GA and P225H in the reverse transcriptase enzyme, but no mutations in the viral protease enzyme . The HIV3, her plasma VL was maintained at <40 copies/ml of plasma  + atazanavir/ritonavir (ATV/r) + dolutegravir (DTG). Over a period of 9 months, the patient’s  creatinif plasma  and the f plasma .3. Her low baseline Hb was expected to be corrected after ART initiation and good adherence [Although anemia is frequently seen in PLHIV, rare side effects of ARVs should be investigated and managed accordingly. HIV disease severity is one of the predisposing factors to anemia , and anedherence . Howeveret al. reported that fear of ART-related side effects was associated with non-adherence and treatment failure [Bukenya  failure . A decliet al. [ART was re-started with the initial regimen namely—TDF, 3TC and EFV. A combination of AZT and 3TC can potentially cause PRCA, a rare hematologic adverse event . This liet al.  argued tOnly 7 months after treatment with steroids, an HIV-experienced clinician, guided by the patient’s medical history, suspected 3TC as the culprit. The PRCA could have resulted from HIV, multiple myeloma or opportunistic infections such as parvovirus B19 , 11. HowRegarding renal function, a decline in creatinine clearance was observed in the same period—following ART re-initiation. TDF causes proximal tubular cell injury, which aggravates pre-existent kidney diseases, such as HIV-associated Nephropathy, a condition frequently observed in patients of African descent . As suchOverall, 3TC remained this patient’s sole cause of anemia, and its withdrawal from the ART regimen was corroborated by improved patient’s general condition and raised Hb levels. However, symptomatic anemia associated with 3TC was responsible for non-adherence, resulting in extensive HIV-1 reverse transcriptase mutations and treatment failure, which was addressed with a treatment switch.Delayed work-up of the persistent symptomatic anemia negatively impacted the patient’s adherence to ART, and treatment failure ensued. We want to draw the reader’s attention to the rare and reversible drug toxicity profile of 3TC since earlier detection could have prevented non-adherence and the selection of mutations in the HIV-1 reverse transcriptase.3TC_Anemia_HIV_DR_cover_letter_omad022Click here for additional data file.


In conclusion, we say that the follow-up of patients living with HIV in the community does not negatively affect the evolution of the disease as one might think.Community-based organizations (CBOs) are one of the initiatives implemented in Cameroon to improve access to antiretroviral treatment and influence retention in treatment centers. Despite its importance in the decongestion of patients in health facilities, we do not have data to evaluate the overall impact of these organizations. We conducted a two-part observational study. The first part was a descriptive cross-sectional study, where we included patients screened and initiated on anti-retroviral treatment (ART) either by the approved Treatment center (ATC) of Yaoundé Central Hospital (YCH) or by any of our CBOs in 2020. Then, the second part was a retrospective cohort-type study including patients from the 2015 cohort followed up from 2018 to 2020 in order to assess viral load suppression. As regards the first “90”, 7,234 screening tests were performed by CBOs in 2020 out of the 28,302 screening tests registered at the YCH, giving a contribution of 25.6%. From the 7,234 screening tests performed by CBOs, 314 people had an HIV-positive result and 230 (73.34%) were linked to ART through CBOs. From the 28,302 screening tests performed at YCH, 1,089 people had an HIV-positive test, and only 354 (32.50%) were linked to ART, giving a significant difference in the link to ART . Concerning the 3 In 2014 the Joint United Nations Program on HIV and AIDS (UNAIDS) set up a response plan to HIV infection under the name 90-90-90 with the objective that, by 2020, 90% of all people with HIV will be diagnosed, 90% of all people diagnosed will be on treatment, and 90% of people on treatment will achieve viral suppression . In CameStudy design: we carried out a two-part observational study in the various community-based organizations and in the approved treatment center (ATC) of the Yaoundé Central Hospital between July 2020 and July 2021. In the first part, it was a descriptive study including patients screened and put on ART thanks to the six CBOs of the Central Hospital of Yaoundé in 2020. In the second part, it was an analytical study retrospective cohort type.Setting: a community-based organization is an association of people within a community, united for the defense of common interests with common goals well-defined. In Cameroon, Community-based organizations of people living with HIV were recognized by the authorities in 2017, with the objectives of promoting HIV awareness, giving psychosocial support to newly diagnosed patients, providing antiretroviral (ARV) treatments to stable patients defined by the ATC, and preventing new infections through frequent screening in the community ) after 24 months and 70.2% vs 95.5% (RR = 0.52 [0.18-1.54]) after 36 months (6 months .The study we conducted aimed to determine the contribution of CBOs in improving the three UNAIDS “90s”. To do this, we conducted a two-part study for 12 months in the ATC of the Central Hospital of Yaoundé and the CBOs attached to this ATC. In the first part, we describe the patients screened in each of these entities during the year 2020. In the second part, we analyzed data from a cohort of 2017 in order to evaluate and compare the effectiveness of CBOs to the YCH ATC. This study has the merit of being one of the first in our context to assess the role of CBOs in HIV care in Cameroon. However, we note limitations in this study, in particular, the poor matching of patients in the CBO and ATC groups due to the plurality of therapeutic protocols for the same patient. We also highlight the difficulty of finding all the necessary information in the different registers and archives. Regarding HIV screening at the Yaoundé Central Hospital, the CBOs carried out a quarter of tests carried out during the year 2020, giving 25.6%, which is inferior to data from other studies in a rural district of Malawi who found a community counselor contribution of 41% or 21 358 out of 52 510 HIV tests performed at the district and counseling sites . These rAt the end of our study, whose objective was to determine the contribution of CBOs in the improvement of the three 90 of UNAIDS at Yaoundé Central Hospital, it appears that a quarter of patients screened at YCH were carried out thanks to CBOs in 2020. Community-based organizations have a better link to care with more than 2/3 of PLHIV on ART compared to ATC which only initiated less than a third. This study also shows that ART continuation in CBOs does not give poor viral load suppression results.


These findings suggest that a better therapeutic management of HIV infection might result in positive clinical and economic outcomes.This real-world analysis conducted on administrative databases of a sample of Italian healthcare entities was aimed at describing the role of therapeutic pathways and drug utilization in terms of adherence, persistence, and therapy discontinuation in HIV-infected patients under antiretroviral therapies (ART) and Tenofovir Alafenamide (TAF)-based regimens on healthcare resource consumption and related direct healthcare costs. Between 2015 and 2019, adults (≥18 years) prescribed with TAF-based therapies were identified and characterized in the year prior to the first prescription (index-date) for TAF-based therapies and followed-up until the end of data availability. Overall, 2658 ART-treated patients were included, 1198 of which were under a TAF-based regimen. TAF-based therapies were associated with elevated percentages of adherence  and persistence (78.5%). The discontinuation rate was low in TAF-treated patients, ranging from 3.3% in TAF-switchers to 5% in naïve. Persistent patients had lower overall mean annual healthcare expenditures (EUR 11,106 in persistent vs. EUR 12,380 in non-persistent,  The development and introduction of antiretroviral therapies (ART) and then the availability of combination ART in the clinical practice has dramatically changed the course of human immunodeficiency virus (HIV) infection from an acute to a chronic disease . NowadayAccording to the World Health Organization (WHO), adherence is defined as “the extent to which a person’s behaviour—taking medication, following a diet, and/or executing lifestyle changes, corresponds with agreed recommendations from a health care provider” . AdherenThis real-world analysis was aimed at describing the demographic and clinical characteristics of patients treated with ART and evaluating therapeutic pathways and drug utilization. A special focus was placed on adherence, persistence, and therapy discontinuation of Tenofovir Alafenamide (TAF)-based regimens either as multi-tablet regimens (MTR) or single-tablet regimens (STR) among naïve patients and those with previous ART who switched for the first time to TAF-based regimens and the resulting impact on healthcare resource consumptions and related direct costs for the Italian National Health Service (INHS).The present retrospective observational analysis was based on data collected from the administrative databases of a sample of Italian Local Health Units (LHUs), covering around 5.52 million health-assisted subjects belonging to Apulia, Abruzzo, Molise, Campania, Lazio, Umbria, Liguria, Piedmont, and Veneto regions. The following databases were used for the analysis: (1) demographic database to obtain data on age, gender, and mortality; (2) pharmaceutical database for information related to drug prescriptions, such as anatomical-therapeutic chemical (ATC) code, number of packages, number of units per package, costs, and prescription date; (3) hospitalization database, including all hospitalization data with discharge diagnosis codes classified according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), diagnosis-related group (DRG), and DRG-related charge; and (4) outpatient specialist services database, reporting data on prescriptions, type, description of diagnostic tests, and specialist visits. To guarantee patients’ privacy, an anonymous univocal numeric code (patient ID) was assigned to each health-assisted subject by the LHUs. The patient ID code allowed the electronic linkage between the databases. The anonymous code of the patient ensures the anonymity of the extracted data in full compliance with UE Data Privacy Regulation 2016/679 (“GDPR”) and Italian D.lgs. n. 196/2003, as amended by D.lgs. n. 101/2018. All the results of the analyses were produced as aggregated summaries, which could not be connected, either directly or indirectly, to individual patients. All adult (≥18 years old) patients prescribed with ART between January 2015 and December 2019 were screened. Among them, patients with TAF-based therapies were identified during all inclusion period by presence of the following drugs: TAF (ATC code J05AF13); emtricitabine and tenofovir alafenamide (ATC code J05AR17); emtricitabine, tenofovir alafenamide, elvitegravir, and cobicistat (ATC code J05AR18); emtricitabine, tenofovir alafenamide, and rilpivirine (ATC code J05AR19); emtricitabine, tenofovir alafenamide, and bictegravir (ATC code J05AR20); and emtricitabine, tenofovir alafenamide, darunavir, and cobicistat (ATC code J05AR22). Patients with TAF-based therapies were defined as naïve if they did not present any ART prescription in the 12 months before starting TAF-based therapies and as TAF-switchers if they had switched from a non-TAF-based to a TAF-based regimen.Patients who moved to another LHU during the period considered in the analysis or with just one ART prescription or with prescription gaps greater than 12 months between subsequent prescriptions were excluded from the analysis. The date of the first prescription for TAF detected within the inclusion period was defined as the index date. Patients’ clinical characteristics were evaluated during at least 12 months prior to the index date (characterization period), while patients were followed-up until the end of database availability, which was at least 12 months for each patient. At baseline, the following comorbidities were evaluated: depression, respiratory disease, renal failure, alcohol/drugs abuse, cardiovascular disease, neoplastic diseases, diabetes, dyslipidemia, HBV/HCV, and hypertension , namely the ratio between the number of days of medication supplied and days of therapy, multiplied by 100 . To defip < 0.05. All the analyses were performed using Stata SE version 12.0 .Continuous variables are reported as mean ± standard deviation and categorical variables as numbers and percentages. A generalized linear model (GLM) with gamma distribution and identity link function was developed to assess the relationship between adherence level and non-ART costs. Statistical significance was accepted at A total of 2658 adult patients treated with ART were included in the analysis, and their demographic and clinical characteristics in the overall population and by calendar year are shown in In the total inclusion period, the mean age was 48.6 years, with the majority of patients in the age range of 36–55 years (61.6%). Male gender was more represented (71.6%). Analyzing the demographic characteristics by each year of inclusion, the male gender remained more frequent (71–73%), and a slight increase in age was noticed over the years. In the overall inclusion period, the most frequent comorbidities were hypertension (19.5%), followed by respiratory disease (15.9%) and dyslipidemia (11.2%) and mild average CCI (0.2) with 87.2% of patients with CCI score 0. The pattern of comorbidity distribution analyzed by each calendar year mirrored that of the total inclusion period. The analysis focused on 1198 patients prescribed a TAF-based regimen during inclusion period. Adherence and persistence in the subgroups and in the total sample population were then investigated. In detail, the proportion of patients adherent to TAF-based regimens was 83.3% with a PDC threshold above >95%; specifically, it was higher among TAF-switchers (85.6%), followed by TAF-STR (84.4%), TAF-MTR (81.9%), and naïve (79.9%). The proportion of adherent patients with PDC > 85% was 90.6% . Data on persistence revealed that the proportion of patients persistent to TAF-based regimens was 78.5% and reached 96% when persistence to any ART was analyzed. Switch to another ART not TAF-based occurred in 18% of patients, and 4% discontinued the therapy. The stratification in subgroups confirmed in general this overall trend, in particular for the rate of discontinuation that ranged between 3.3% (TAF-switchers) and 5% (naïve). Of note, patients under MRT regimen compared to those with STR showed a greater tendency to switch  and a lower persistence on TAF-based therapy . Overall persistence for TAF naïve patients was 74.3%.The healthcare resource consumption during first year of follow-up for TAF-based regimes patients evaluated in the last 3 years of inclusion (2017–2018–2019) showed the highest numbers for ART prescriptions and specialistic visits/diagnostic tests, followed by other drug prescriptions, with a decreasing trend over time . The relp = 0.005), and this difference was mostly appreciable in the cost item related to HIV hospitalization. Moreover, when the analysis was focused only on patients with HIV-related hospitalization, the mean costs were found to be higher for non-persistent patients (N = 25) compared to persistent ones (N = 79) .The evaluation of the role of persistence on healthcare resources consumptions during the first year of follow-up in patients with TAF-based regimen revealed that the most relevant consumptions were attributable to ART prescriptions and specialistic visits/diagnostic tests and, lastly, other drug prescriptions to a higher extent in non-persistent patients . RegardiThe healthcare resources consumption in TAF-treated patients stratified by adherence <80%, 81–95%, and >95% indicated ART prescriptions and specialistic visits/diagnostic tests as the most impactive items . ConsistHealthcare resources consumptions in non-adherent (PDC < 80%) patients treated with ART other than TAF and TAF-based regimens highlighted that even in non-adherent patients, the majority of consumptions were imputable to ART prescriptions and specialistic visits/diagnostic tests although less markedly in the patients receiving a TAF combination . p = 0.070, nearly significant), mostly driven by the expenses for other drugs  and specialistic visits and outpatient services .Cost analysis extended to the overall observation period in ART- and TAF-based regimens is shown in p < 0.001) and EUR 2265 in those over 65 . A worse comorbidity profile was also significantly predictive of higher non-ART costs   .The current awareness of the management of HIV patients chronically treated with ART and the subsequent rebounds on healthcare resource consumptions and expenditures is highly variable across the different countries ,21,22.The present analysis was conducted in a setting of real-life clinical practice in Italy to describe the state-of-art of HIV-infected patients treated with ART and more specifically with TAF-based regimens, evaluate therapeutic pathways and drug utilization, and give special attention to the impact of adherence, persistence, and therapy discontinuation of TAF-based regimens on HIV management and direct healthcare costs.The demographic characteristics of the overall ART population reported a male predominance and a mean age of around 49 years, which is in line with other Italian real-world studies on HIV ,23. HypeThere is large body of evidence from national and international studies that, despite the undeniable progression and growing availability of pharmacological options for HIV patients, the goal of maintaining an adequate therapy adherence in the long term is still far from being reached . This poPersistence to TAF-based regimens mirrored the trend observed for adherence, with a high proportion of persistent patients among those with STR or switchers. Sutton et al  found inTo the best of our knowledge, there are limited data on the actual economic burden for patients with TAF-based regimens in Italy, while the literature reports an estimation of cost-effectiveness or budget-impact analysis on such therapies ,34. The In all the scenarios depicted, cost analysis revealed that during the first year of follow-up, the weightiest item on the annual healthcare direct cost per patient was that for ART, which is consistent with previously published data for European countries ,36,37. The downward trend observed over the last 3 years of inclusion was mainly due to a halving in the costs of other drugs, hospitalizations, and outpatients’ services through the years, suggesting that the introduction of innovative ART on the market could influence the costs for the management of patients. Persistence to TAF-based therapies was associated with significantly lower mean annual costs, in particular for the cost item related to HIV hospitalization. Moreover, the comparison of mean annual healthcare direct costs by adherence (PDC > 85% vs. PDC < 85%) in TAF-based regimen revealed that increased costs not related to ART were observed in non-adherent patients; once again, this trend was evident for HIV hospitalizations. In this regard, Toh et al.  exploredConsidering the mean annual health care resource consumptions and costs during all available follow-up in TAF-treated patients with respect to adherence, we found tendentially increased consumptions and costs with growing adherence levels but this might be explained by the obviously higher burden of drug expenses in adherent patients, which is in line with the literature ,38. MultThese findings should be interpreted in the light of some limitations related to the observational retrospective design of the analysis, which was based on data extracted from administrative databases. Thus, there might be lacking or insufficient clinical information on a number of other potential confounders  that may have influenced the results. Secondly, data on the reasons for changing regimens (switch or discontinuation) are not reported within the database as well as the causes of non-adherence since not-measurable variables as patient attitudes towards medication or social status are not present; similarly, adherence and persistence were evaluated based on the drug dispensed; therefore, the actual use by the patient is unknown. Ultimately, indirect costs or out-of-pocket costs could not be evaluated, as administrative databases contain data on healthcare resources reimbursed by INHS. This real-world analysis provided an in-depth characterization of patients prescribed TAF-based regimens in terms of drug utilization and how this could have affected healthcare resource consumptions and costs. Higher levels of adherence and persistence to TAF-based regimens were detected among users of STR rather than MTR and among experienced patients that switched from an ART- to a TAF-based treatment compared to naïve patients.A declining trend over the years in healthcare resource consumption and the related direct costs could be suggestive of the changing of costs related to the management of HIV patients due to the advent of novel therapeutic options. The total healthcare costs were mainly driven by ART-related costs, which represent almost 70% of the total expenditure. Patients that showed a higher level of TAF persistence and adherence were reported to have a reduced healthcare cost related to HIV hospitalizations compared to those who were non-persistent or not adherent to TAF-based therapies, suggesting that the optimization of the drug utilization may have a positive impact not only from a clinical point of view but from the perspective of the sustainability of the INHS as well.


Dolutegravir(DTG)/lamivudine(3TC) is the first 2-drug regimen recommended as an initial treatment for people living with HIV (PLHIV).To assess the cost-effectiveness and potential budget impact of DTG/3TC in the US healthcare setting.A previously published hybrid decision-tree and Markov cohort state transition model was adapted to estimate the incremental costs and health outcome benefits over a patients’ lifetime. DTG/3TC was compared with current standard of care in treatment naive and treatment experienced virologically suppressed PLHIV. Health states included in the model were based upon virologic response and CD4 cell count, with death as an absorbing state. Clinical data was informed by the Phase III GEMINI 1 and 2 clinical trials, a published network meta-analysis (NMA) in treatment-naive patients and the Phase III TANGO clinical trial in treatment experienced patients. Costs and utilities were informed by published data and discounted annually at a rate of 3%. A separate 5-year budget impact analysis was conducted assuming 5%-15% uptake in eligible treatment naive and 10%-30% uptake in eligible treatment experienced patients.In the treatment naive analyses based on GEMINI 1 and 2, DTG/3TC dominated, i.e., was less costly and more effective, than all comparators. DTG/3TC resulted in 0.083 incremental quality-adjusted life-years (QALYs) at a cost saving of $199,166 compared with the DTG + tenofovir disoproxil(TDF)/emtricitabine(FTC) comparator arm. The incremental QALY and cost savings for DTG/3TC compared with DTG/abacavir(ABC)/3TC, cobicistat-boosted darunavir(DRV/c)/tenofovir alafenamide(TAF)/FTC, and bictegravir (BIC)/TAF/FTC, based on NMA results were 0.465, 0.142, and 0.698, and $42,948, $122,846, and $44,962, respectively. In the analyses of treatment-experienced virologically suppressed patients based on TANGO, DTG/3TC offered slightly lower QALYs (−0.037) with an estimated savings of $78,730 when compared with continuation of TAF-based regimen (TBR). Sensitivity analyses demonstrated that these conclusions were relatively insensitive to alternative parameter estimates. The budget impact analysis estimated that by 5th year a total of 70,240 treatment naive patients and 1,340,480 treatment experienced patients could be eligible to be prescribed DTG/3TC. The estimated budget savings over 5 years ranged from $1.12b to $3.35b  in the lowest and highest uptake scenarios, respectively.In conclusion, DTG/3TC with its comparable efficacy and lower drug acquisition costs, has the potential to offer significant cost savings to US healthcare payers for the initial treatment of treatment naive patients and as a treatment switching option for virologically suppressed patients. What is already known about this subjectCombination antiretroviral therapy (ART) has helped people living with HIV (PLHIV) achieve and sustain longterm viral suppression turning HIV into a manageable chronic condition.As PLWHIV live longer, the costs of HIV treatment and management are increasing.Simplified 2-drug ART regimens that provide equivalent efficacy while reducing ART exposure to standard of care 3-drug regimens are now endorsed by HIV clinical guidelines and have the potential for reduced costs.What this study addsThis analysis estimates the cost-effectiveness and potential economic impact of dolutegravir(DTG)/lamivudine(3TC), the first 2-drug regimen recommended as an initial treatment or stable-switch option for people living with HIV (PLHIV) in the United States.Results suggest that DTG/3TC, with its comparable efficacy, durability, and lower drug acquisition costs, is predicted to offer significant cost savings compared to other common standard of care HIV treatment regimens for both treatment naive PLWH and as a treatment switching option for virologically suppressed patients on existing treatment.1 As ART has improved, people living with HIV (PLHIV) are able to achieve and sustain long-term viral suppression, and HIV-1 has evolved into a manageable chronic condition.1 As a result, the mean estimated duration of lifetime exposure to ART is now approximately 40 years.2 PLHIV are surviving longer, requiring lifelong treatment, and have increased risks of chronic complications and comorbidities.3 The presence of these comorbidities in turn increases the potential for polypharmacy and drug-drug interactions (DDIs).4 Furthermore, the extended duration of ART exposure has heightened concerns about toxicities and long-term tolerability.5 All these factors have also led to increase in HIV management costs in the United States with an estimated increase of 34% in costs of HIV treatment and management of adverse events (AEs), and 176% increase in costs of managing HIV-related comorbidities.6 While the efficacy of currently available three-drug regimens (3DRs) is well established, all classes of ART have been associated with tolerability and toxicity concerns. Simplified ART regimens with fewer components that provide equivalent efficacy with reduced ART burden should be the focus of HIV management in the future.7Human immunodeficiency virus type 1 (HIV-1) is a retrovirus that can lead to acquired immunodeficiency syndrome (AIDS), an advanced stage of HIV infection wherein the immune system is severely damaged. Treatment for HIV infection, known as antiretroviral therapy (ART), has improved steadily since the advent of potent combination therapy in 1996.8 More recent evidence has shown that patients in these trials were able to maintain non-inferior viral suppression up to 96 weeks with no major tolerability concerns or risk of treatment emergent resistance.9 DTG/3TC has also demonstrated its noninferiority in maintaining virological suppression among patients switching to it from other guideline-recommended 3DRs in the TANGO study.10 Further, it is anticipated that DTG/3TC may reduce long term toxicities and serious DDIs by reducing ART exposure.11 DTG/3TC has also been recommended as a first line treatment for PLHIV in major guidelines.12 The objective of this analysis was to estimate the cost-effectiveness of DTG/3TC among naive and virologically suppressed patients initiating DTG/3TC treatment in the United States and to assess the budgetary impact of introducing DTG/3TC on payer formularies.Newer, more potent ARTs with higher barriers to resistance, namely dolutegravir (DTG), have now made it possible to achieve and maintain viral suppression with two antiretroviral (ARV) agents, often referred to as a 2-drug regimen. DTG/lamivudine (3TC) is one such 2-drug regimen which has been demonstrated to exhibit non-inferior efficacy and comparable safety to traditional, guideline-recommended, 3DRs among treatment naive HIV-1 infected patients in two Phase III randomized controlled trials (GEMINI 1 and GEMINI 2).13 was adapted to estimate the incremental costs and health outcome benefits associated with DTG/3TC compared with currently available HIV regimens among PLHIV in the United States.A previously published hybrid decision-tree and Markov cohort state transition modelHealth states included in the model are based upon treatment lines, virologic response and CD4 cell count, with death as an absorbing state . Whilst Upon model initiation, patients begin in the first ART line (first modelled line), consisting of a pairwise comparison between DTG/3TC and a comparator regimen. For each modelled arm, following discontinuation from first ART, patients are stratified amongst two possible second ART regimens, decided by their reason for discontinuation (“non-virologic” and “virologic”). Following discontinuation from the second ART, a similar stratification occurs. It is assumed that patients who discontinue due to “virologic” reasons are likely to develop resistance, and as such have poorer suppression rates in subsequent lines of therapy. To account for differing levels of resistance at entry to the “salvage” therapy line, patients may receive one of three “salvage” therapy efficacy profiles depending on the nature of their previous reasons for discontinuation.15 health states included are based on viral load , CD4 cell count  and death. During each cycle (one month), patients’ viral load status may improve, decline, or remain constant. For a given treatment, this is represented by transitions through the health states, the rate of which is determined by treatment-specific transition matrices. In general, patients within each health state are assumed to be homogenous, except those who experience virologic failure.Upon initiation into a given treatment line, patients enter the Markov process. Consistent with previous economic models,Discontinuation due to virologic failure is managed by the internal decision process:Virologic failure: to ensure that a cohort does not indefinitely remain on a failing treatment regimen, an internal memory process identifies those who have occupied the high viral load state (> 50 copies/mL) for 12 months. Patients who have failed to achieve virologic suppression within this period discontinue their current therapy. Patients discontinuing due to virologic failure remain in the same CD4 health state in the subsequent treatment arm, whilst also remaining in the high viral load state.Virologic rebound: patients who are achieving virologic suppression  face a monthly probability of experiencing virologic rebound. Patients experiencing virologic rebound are assigned to a higher  viral load state in a subsequent treatment line.Non-virologic reasons: patients in any CD4 or viral load health state face a monthly probability of discontinuing their current line of therapy due to other non-virologic reasons. Patients who discontinue through this process remain in their existing CD4 and viral load health state.16 Outcomes estimated were total costs, life-years (LYs) and quality-adjusted life-years (QALYs), with incremental cost-effectiveness ratios (ICERs) derived. The analysis was conducted from the perspective of health care payers in the United States.A lifetime perspective (up to 80 years from model initiation) was adopted for the model to adequately capture all outcomes over a patients’ lifetime. A cycle length of one month was set to make provision for timing of treatment switching, virologic response, CD4 cell count increases, and the prediction of ADEs, with the associated cost and quality of life implications. All costs and benefits were discounted at an annual rate of 3%.9 In the scenario analyses, DTG/3TC was compared with the most commonly used guideline recommended 3DRs in the United States, bictegravir (BIC)/TAF/FTC (Biktarvy), DTG/ABC/3TC (Triumeq) and DRV/c/TAF/FTC (Symtuza) via use of a published network meta-analysis (NMA) comparing these regimens to DTG/3TC.18 Second and third lines were represented by a pooled comparator where the cost was an average of 16 different ART regimens utilized in current US practice. Estimates of virologic suppression and CD4 cell counts for stable patients were taken from studies by Antinori and Baril, respectively, whilst those for failing population were estimated from Kanters study.21Two separate analyses were conducted in a treatment naive population. In the base case, DTG/3TC was compared with DTG + TDF/FTC using estimates obtained from the GEMINI trials.10 Second- and third-line treatments were represented by a pooled comparator, similar to treatment naive analyses.In treated patients who were virologically suppressed on a first-line regimen, DTG/3TC was compared with continuing a TAF-based 3 or 4 drug regimen (cTBR). Efficacy estimates were obtained from the TANGO trial which evaluated the efficacy and safety of switching to DTG/3TC compared with cTBR.Supplementary Table 1, available in online article).10 Model parameters not reported in clinical trials were obtained from published literature or expert consultation.Patient demographic and clinical data at baseline was obtained from GEMINI 1 and 2 in treatment naive analyses and from TANGO in treatment experienced, virologically suppressed patients .ART efficacy, estimated as virologic response, was defined as the achievement of a viral load (HIV-1 RNA) < 50 copies/mL, and immunological response, defined as the average increase in CD4 cell count. These measurements informed transition matrices that were used in the model to control patients’ movement between viral load and CD4 cell count based health states. Data from 0-48 weeks was used to inform this time period and data from 48-96 weeks was used to inform all subsequent 48-week periods (including post 96 weeks). The assumption therefore was that the pattern of observed movement from 48-96 weeks is consistent as long as a patient remains in the first line treatment. Efficacy parameters used in the model are displayed in 26 To reflect the additional mortality in the HIV-1 population, published estimates of relative risks comparing mortality in the HIV-1 population to that of the general population are included in the model.27 Patients experiencing ADEs also faced increased risks of mortality. This additional risk was estimated from the literature and applied additively to the all-cause mortality risk.28 The model did not include any adjustment for CVD-related mortality, assumed to be incorporated within the CD4 health state relative risks.Mortality in the model included all-cause and HIV-related death, and mortality due to ADEs and CVD. Rates of all-cause mortality were estimated using US gender-specific life tables.29 The incidence of ADEs in turn influences mortality, disease management costs, and quality of life. ADEs were modelled by the probability of occurrence within particular health states; if patients experienced them there were related mortality, utility and cost outcomes .The model included five categories of ADEs. Acute viral opportunistic infections (OI) included cytomegalovirus; acute bacterial OIs included mycobacterium avium infection and tuberculosis; acute fungal OIs included pneumocystis carinii pneumonia, cryptococcosis, and esophageal candidiasis; and acute protozoal infections included cerebral toxoplasmosis. Other ADEs included lymphoma, HIV-1 wasting syndrome, HIV-1 dementia, and Kaposi’s sarcoma. The probabilities of occurrence of specific ADEs were associated with CD4 cell count and time on treatment and were estimated from the literature.Supplementary Table 38, available in online article). An age dependent utility decrement was also applied additively to all patients.30Health related quality of life was estimated using CD4 + health state-based utilities calculated using patient level data from the GEMINI 1 and 2 trials for treatment naive analyses and from the TANGO study for treatment experienced analyses. In the TANGO trial, there were no patients with a CD4 cell count below 50 and therefore it was not possible to observe the utility value for these patients. It is conservatively assumed that these patients have the same utility as those who have a CD4 cell count under 200. As there are no patients starting in this health state, it is not assumed to affect results substantially. Utility decrements were applied for the presence of CVD and CKD, and the occurrence of fractures, AEs and ADEs. CVD events and fractures had an initial event-related utility decrement followed by chronic disutility whilst CKD, AEs and ADEs had an associated chronic utility decrement  and estimated glomerular filtration rate (eGFR) in line with observations in GEMINI trials.34 drug costs reflect wholesale acquisition costs (WAC). The monthly cost of DTG/3TC was estimated to be $2,408, whilst the costs of DTG + TDF/FTC, DTG/ABC/3TC, DRV/c/TAF/FTC, BIC/TAF/FTC, cTBR and a pooled comparator were estimated to be $3,669, $3,032, $3,722, $3,238, $3,103, and $3,254, respectively. The monthly cost for salvage therapy, assumed to be treatment with ritonavir-boosted darunavir (DRV/r)/TAF/FTC, was estimated to be $3,722.35Drug acquisition costs were obtained from MDDB US product price reporting system;36 and inflated costs were applied to AE rates derived from GEMINI and TANGO for treatment naive and treatment experienced analyses, respectively. The resultant costs included in the model were $277 (Standard Error [SE]: $28) for nausea and dizziness, and $214 (SE: $21) for diarrhea, soft feces, or flatulence. Other AEs were assumed to incur no additional costs.Costs associated with the management of AEs were applied as per event costs in the cycle of AE incidence. Costs associated with common drug-related AEs (incidence ≥ 1%) were estimated from literatureSupplementary Table 38, available in online article).37 The costs associated with ADEs, CVD, CKD, fractures, and end of life care were derived from published literature (Supplementary Table 38).55 The cost of CVD was assumed to incur an initial event cost followed by a monthly disease management cost. As the mean eGFR of the cohort changed over time, patients were assumed to transition through progressively worsening CKD categories. Each CKD category had an associated cost which was applied as a function of the time spent in that category. Costs of stage 1 CKD were assumed to be no more than the general population and were set to zero.Additional costs included in the model were those associated with outpatient care, ADEs, non-HIV medications, management of CVD, and end of life care. Resource use associated with all-cause health encounters was expected to vary significantly between CD4 cell count health states and as such was estimated for each CD4 health state using data from publications of the HIV Research Network as reported in a study by Farnham and colleagues , mean absolute percentage error (MAPE) and the root mean square percentage error (RMSPE).The model was internally validated with independent double programming of the visual basic functions. It was also reviewed by a third researcher to ensure accuracy. External validation was undertaken using previously published cost-effectiveness studies that utilized similar models.In the deterministic analyses, DTG/3TC was compared with DTG + TDF/FTC, DTG/ABC/3TC, DRV/c/TAF/FTC and BIC/TAF/FTC using mean values as inputs for each of the model parameters. Univariate sensitivity analysis was undertaken by varying model parameters across pre-defined ranges. These ranges for patient baseline characteristics and model settings are displayed in Supplementary Materials). This analysis was designed as an update to an earlier study by Girouard et al 2015.43 This modelling exercise sought to evaluate the budget impact of the introduction of dual therapy (DTG and 3TC) but was conducted prior to the results of the clinical trials evaluating DTG/3TC. Here, we sought to provide an update to this analysis in light of the non-inferior trial results and details of the cost of the regimen.Further, a 5-year budget impact analysis was conducted of implementing DTG/3TC treatment strategy among treatment naive and treatment experienced, virologically suppressed PLHIV in the United States to estimate the potential cost savings (further details provided in the 44 Twenty percent of the Centers for Disease Control and Prevention estimated 1.2M people living with HIV (reflecting currently suppressed patients who have never experienced virologic failure) and 37% of the approximately 38,000 newly diagnosed each year were expected to be eligible to switch to DTG/3TC, consistent with the earlier study by Girouard et al.43 Of these eligible patients, three scenarios of DTG/3TC use were evaluated as follows: (1) 5% naive/10% experienced, (2) 10% naive/20% experienced, and (3) 15% naive/30% experienced. Uptake of DTG/3TC was assumed to be taken proportionally from existing HIV drug regimens based on their current market share in the United States. The current market shares for Integrase Strand Inhibitors (INSTIs), Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), Protease Inhibitors (PIs), and others were estimated to be 66%, 13%, 8%, and 12%; changing to 71%, 9%, 8%, and 12% over next 5 years, respectively, in the absence of DTG/3TC. The average cost for an INSTI core-agent-based treatment was calculated to be $3,265/month, estimated using the market shares of individual INSTI-based treatments. The corresponding monthly cost for NNRTIs-based, PI-based and other ARTs was $2,445, $3,676, and $2,513, respectively. The cost of DTG/3TC  is lower than the average regimen cost of the most widely used drug class, INSTI coreagent-based treatment, at $857 less per month . The total cost of the scenarios with and without the addition of DTG/3TC were compared to evaluate the budget impact of the introduction of DTG/3TC.Patients eligible to receive DTG/3TC were estimated from United States epidemiological data.Supplementary Figure 1, available in online article). The corresponding parameters in treatment experienced analysis were probability of non-virologic discontinuation for DTG/3TC and the comparators . Results of the PSA were consistent with DTG/3TC dominating DTG + TDF/FTC in 76% of iterations  versus expected (published results) results for costs, life years (LYs) and quality adjusted life years (QALYs) are presented in Supplementary Figure 3 (available in online article).The model exhibited a high degree of consistency with previously published cost-effectiveness analyses, with RMSPE and MAPE values of 14.7% and 17.7%, respectively. The overall RIn the budget impact analysis, the expected number of treatment naive patients initiating DTG/3TC ranged from 702 in scenario 1 to 2,107 in scenario 3. The corresponding number of treatment experienced patients switching to DTG/3TC by the end of 5 years ranged from 26,810 in scenario 1 to 80,429 in scenario 3. The resulting cost saving associated with introduction of DTG/3TC in year 1 ranged from $206M in scenario 1 to $618M in scenario 3 . Overall10 and has been recommended as an initial therapy in major clinical treatment guidelines.12 In this analysis, the cost-effectiveness of DTG/3TC as a maintenance treatment for PLHIV was evaluated. In the treatment naive PLHIV, DTG/3TC resulted in comparable QALYs with substantially lower costs to other standard of care (SoC) ART regimens. This is consistent with the non-inferiority results obtained in GEMINI 1 and 2 wherein participants treated with DTG/3TC achieved comparable viral suppression to those treated with a DTG + TDF/FTC based 3DR. Further, DTG/3TC was compared with guideline recommended, SoC fixed-dose combinations (FDC) such as DTG/ABC/3TC, DRV/c/TAF/FTC, and BIC/TAF/FTC. A published study has reported comparable efficacy and safety of DTG/3TC to these 3-drug FDCs in treatment naive PLHIV,17 and our analyses demonstrated its dominance in an economic context. The results in treatment experienced patients were similar, demonstrating treatment with DTG/3TC is likely to broadly maintain outcomes at lower costs among virologically suppressed patients switching to DTG/3TC. In this analysis, should TAF-based regimens be used instead of DTG/3TC, the estimated incremental cost-per-QALY is > $2M. This far exceeds willingness to pay thresholds widely considered to be cost-effective in the United States . Furthermore, building on the results from the cost-effectiveness analysis, the budget impact estimates demonstrated potential for substantial cost-savings, which were robust in all scenarios. DTG/3TC FDC may therefore present a valuable opportunity for obtaining significant budgetary savings without compromising treatment efficacy or safety.The fixed-dose 2-drug regimen DTG/3TC offers an alternative to traditional 3DRs, offering the potential to reduce lifelong drug exposure and costs without compromising clinical efficacy or safety for treatment naive and treatment experienced virologically suppressed PLHIV,44 The authors compared DTG + 3TC with DTG/ABC/3TC, the SoC at the time of the study, and reported DTG + 3TC to generate slightly fewer QALYs at significantly lower costs compared to SoC. They forecasted savings up to $3.4B if 50% of naive patients and 25% of eligible experienced patients switched to DTG/3TC over 5 years. As their analysis pre-dated the availability of head to head trial results, Girouard and colleagues made some simplifying assumptions in their model inputs compared to 3DRs. They assumed that DTG + 3TC would be slightly less effective at achieving virologic suppression and would be more likely to experience virologic failure over 96 weeks. As previously indicated, results from the two GEMINI studies and from the TANGO study demonstrated comparable and durable virologic suppression of DTG/3TC compared to SoC 3DRs.10 Additionally, Girouard and colleagues assumed no adherence benefits to co-formulated single tablet regimens (STRs) compared to multitablet regimens based on clinical trial experience but these assumptions have not borne out in real world settings where patients are not highly managed to strict protocol visits and procedures. The body of real-world observational evidence continues to grow suggesting adherence benefits to STR formulations in real world settings and that high adherence is associated with improved clinical outcomes and reduced costs.51 Using a similar approach to calculate the budgetary impact of DTG/3TC to Girouard and colleagues, but with model assumptions updated to reflect current clinical trials results and published WAC prices for DTG/3TC and other SoC STRs, our results were broadly consistent with their predictions with costs savings of $3.3B attributable to 15% eligible naive and 30% eligible experienced patients switching therapy. Whilst the precise proportions of naive and switch differ between the two studies, the overall patient numbers are comparable.A study by Girouard et al, conducted and published prior to data availability from the GEMINI studies, hypothesized significant cost savings with DTG + 3TC.6 Two-drug regimens such as DTG/3TC have the potential to alleviate the negative impact of long-term ARV therapy. Our analysis considered this benefit to the extent it was reported in the GEMINI trials, but further research is needed to estimate the true impact due to a relative paucity of long-term data. Further modelling, supplemented by real-life data, is needed to estimate the impact of DTG/3TC over a patients’ lifetime. Our analysis was based on 96-week data from GEMINI 1 and 2 and an NMA within naive PLHIV. Longterm outcomes in the model were based on observed trial results. Such extrapolation comes with its inherent uncertainty, further compounded by the non-inferior nature of the treatment comparison and, consequently, small differences in observed efficacy. To mitigate this uncertainty, the model was extensively validated internally and externally, and a scenario analysis with shorter time horizon was conducted, which showed consistent results.Certain considerations should be acknowledged when interpreting the findings of this analysis, perhaps warranting the need for further research. As the life expectancy of PLHIV increases, so does their exposure to ART therapy for long periods of time. This may increase the likelihood of DDIs alongside the incidence of ARV-related long-term toxicities, such as CVD, renal impairment, and bone fractures.Since the primary aim of economic evaluation of HIV technologies is to inform health care decision making, in this respect the time horizon for economic evaluations should be sufficiently long enough to capture all the potential costs and benefits associated with a new technology under consideration at the identified comparators. Guidelines for economic evaluations confirm this recommendation and also state that justification for the economic evaluation time horizon should be clearly stated. This distinguishes economic evaluation from clinical efficacy evaluation, which is based only on the follow-up period stated within the trial or group of trials which is similarly justified in the clinical trial protocol(s). The sequential nature of HIV technologies specifies that the introduction of a new technology to the sequence of treatment regiments clearly impacts on the subsequent treatment regimens that are included in the sequence. Hence, for this reason, the majority of HIV economic evaluations take a lifetime time horizon, which has been identified as the most common time horizon in SLRs of HIV treatment economic evaluations. Caution should be taken when considering shorter time horizons for HIV technologies, in that the entirety of the expected costs and benefits associated with the intervention and comparator would not be captured in the analysis and hence could lead to ill-informed decision-making inferences. Concerns about the evidence synthesis nature of model-based economic evaluation and extrapolation of single RCT data would not be address by considering shorter model time horizons. However, shorter model time horizons may help with model validation exercises to inform on how well the model performs with a view to the RCT outputs.We did not include adherence as a parameter in the model. Whilst adherence is important among PLHIV, the treatments being compared were oral daily ARTs, expected to have comparable adherence in real world clinical setting. Differences, if any, were likely to favor DTG/3TC which is a single tablet regimen compared to several multiple tablet regimen comparators.In conclusion, DTG/3TC is the first globally approved 2-drug ARV regimen (Food and Drug Administration (FDA)/European Medicines Agency (EMA)) for treatment-naive PLHIV. It has the potential to deliver benefits associated with reduced ART exposure, reduced long-term toxicity. With its comparable efficacy, durability, and lower drug acquisition costs, DTG/3TC has the potential to offer significant cost benefits to healthcare payers in the United States.