Young adults with vertical transmission (VT) of human immunodeficiency virus (HIV) represent a fragile population. This study evaluates factors associated with viro‐immunological outcome of these patients.3, and CD4+/CD8+ ratio ≥ 1.We performed a multicenter study including HIV‐infected subjects with VT ≥ 18 years old from six Italian clinics. Subjects were observed from birth to death, lost to follow‐up, or last visit until December 31, 2019. Condition of “optimal viro‐immunological status” (OS) was defined as the simultaneous presence of HIV ribonucleic acid (RNA) < 50 copies/mL, CD4+ > 500 cells/mm3, and 78/126 (67.2%) had CD4+/CD8+ < 1; 28 subjects (23.7%) presented in the condition of OS. Having a CD4+/CD8+ ratio ≥ 1 at 18 years of age was related with an increased probability of shift from suboptimal viro‐immunological status (SOS) to OS , and a reduced risk of shift from the OS to the SOS . Acquired immunodeficiency syndrome (AIDS) diagnosis significantly reduced the probability of shift from a viro‐immunological SOS to OS . Subjects who had not achieved an OS at 18 years of age had an increased risk of discontinuation of combination antiretroviral therapy .A total of 126 subjects were enrolled. At 18 years of age, 52/126 (44.4%) had HIV‐RNA > 50 copies/mL, 47/126 (38.2%) had CD4+ < 500/mmOnly a small proportion of subjects with VT of HIV reached the adult age with “OS”. Transition to the adult care with a compromised viro‐immunological condition represents a negative driver for future optimal infection control, with a higher risk of discontinuation of cART and a reduced probability to improve the immunological status later in the years.  Today, vertical infection is a very rare event in high‐income countries and occurs in particular clinical situations. However, there is still a proportion of patients, especially in resource‐limited settings, who become infected through vertical transmission.Compared to peers with adult‐acquired HIV infection, adults with VT HIV represent a different population: more immunologically fragile, with an increased incidence of comorbidities, a lower adherence to antiretroviral therapy, a reduced development of intellectual abilities, and a tendency to underestimate the severity of the disease. Several studies showed how these individuals are characterized by a worse course of HIV infection, with a higher incidence of acquired immunodeficiency syndrome (AIDS) events, higher AIDS‐related mortality, as well as a higher incidence of comorbidities linked to the systemic effects of HIV infection along with a prolonged proinflammatory state, and long‐term toxicities of antiretrovirals.≥ 1.The main driver of AIDS‐related mortality and AIDS occurrence reduction are, on one hand, the effectiveness of antiretroviral therapy and, on the other hand, the achievement of a full immunological recovery with values of CD4+ T‐cell count > 500 cells/mm³ and a CD4+/CD8+ ratio The primary objective of this study was to analyze the long‐term viro‐immunologic efficacy of cART in patients with VT HIV infection. The analysis was done on patients aged ≥ 18 years on December 31, 2020 by (1) evaluating virological suppression during the follow‐up; (2) evaluating the immunologic status of subjects during the follow‐up, comparing subjects who achieve full viro‐immunologic recovery and those who fail to achieve an optimal infection control.22.1Retrospective longitudinal multicenter observational study involving six infectious diseases centers devoted to HIV care in Italy.1)virological suppression, defined as HIV ribonucleic acid (RNA) < 50 copies/mL;2)3, 200–500 CD4+/mm3, >500 CD4+/mm3, and of the CD4+/CD8+ ratio, defined as normal if ≥ 1 and not normal if < 1;immunological performance, assessed by measurement of CD4+ T cell‐count divided into three categories: <200 CD4+/mm3)3, and CD4+/CD8+ ratio ≥ 1. Any other combination (HIV RNA ≥ 50 copies/mL and/or CD4+ T‐cell count ≤ 500 cells/mm3 and/or CD4+/CD8+ ratio < 1) as a suboptimal viro‐immunological status (SOS).condition of “optimal viro‐immunological status” (OS), defined as the simultaneous presence of HIV RNA < 50 copies/mL, CD4+ T‐cell count > 500 cells/mmDemographic, clinical and viro‐immunological data, information about history of antiretroviral therapy, AIDS diagnosis, presence of co‐infections and comorbidities, and data about the virus resistance profile were collected during routine clinical practice. An anonymized electronic database has been created, including data available during follow‐up at Pediatrics (where subjects were in care until 18 years of age) and those during follow‐up at Adult Infectious diseases care unit. Study end‐points were evaluation of:2.2Inclusion criteria were (1) evidence of vertical transmission of HIV infection  and (2) age ≥ 18 years. There were no exclusion criteria.All subjects meeting the inclusion criteria and who had been referred to adult infectious diseases in the six centers considered were enrolled. Patients were observed from birth (or the earliest date of follow‐up available) until the date of death (if it occurred after 18 years of age), loss to follow‐up, last available follow‐up by December 31, 2019. Patients with >365 days of missing information who were not subsequently follow‐up were considered lost to follow‐up. The data collection was med between January 2018 and September 2019.2.3A preliminary descriptive analysis of the sample was performed using common indexes according to the type of variables: mean ± standard deviation, median and interquartile range for quantitative, percentages for qualitative variables. The OS event was modeled using a multistate Markovian model assuming that a subject could repeatedly transit over time from a stage of optimal infection control to a suboptimal one and vice‐versa. The therapeutic “switch” was modeled using a Cox model for recurrent events. Time‐dependent variables were associated with each time interval (between start and end of treatment regimen) considering the known value before the date of “switch” (discontinuation). Results are reported as hazard ratio (HR) and associated 95% confidence interval (CI). All analyses were two‐tailed at a 5% significance level.2.4The present study was approved by Ethics Committee of Brescia and acknowledged by the Ethics Committees of the participating centers, in accordance with current regulations , conducted in full respect of human dignity and fundamental rights as dictated by the “Declaration of Helsinki,” by the standards of “Good Clinical Practice” issued by the European Community , in implementation of what is also provided for by the Council of Europe Convention for the Protection of Human Rights and Dignity of the Human Beings in the application of biology and medicine made in Oviedo on April 4, 1997.Patient data have been made anonymous  in observance of the rights provided for by privacy legislation (Legislative Decree no. 196/2003 Art. 7). Since this study was retrospective and nonpharmacological, informed consent has not been provided because in Italy, ethical clearance for these studies is not needed . In addition, we used the general authorization of the Italian Guarantor for the use of anonymized demographical and clinical data.33.13, 38/126  had a CD4+/CD8+ ratio ≥ 1. Overall, at the considered time point, only 28 subjects (23.7%) presented in the status of OS as previously defined.A total of 126 patients from the 6 participating centers were enrolled. Sociodemographic characteristics of the subjects are summarized in Table In total, 32/126 subjects (26.9%) were diagnosed with at least one AIDS‐related condition. The mean age at first diagnosis of an AIDS event was 14.22 years (±10), ranging from 0 to 30 years.Regarding co‐infections, 3/119 (2.5%) subjects had hepatitis B virus (HBV)‐related chronic liver disease , of which 2 (1.7%) had vertical HBV acquisition; 17/85 (20%) had chronic hepatitis C virus (HCV) infection , of which 13 had HCV maternal transmission; of these, 7 were exposed at least once to therapy with interferon, and 11 underwent eradicant therapy with direct‐acting antivirals (DAAs). Finally, 1/110 (0.9%) acquired syphilis in adulthood, and 1/121 (0.8%) was diagnosed with congenital syphilis.In 65/126 (51.6%) patients, at least one comorbidity was present, and 7/126 (5.6%) had three comorbidities involving different districts simultaneously  had been exposed to at least one non‐cART therapy regimen and 1/117 (0.9%) was still undergoing a non‐cART regimen at 18 years of age; 98/117 (83.8%) were taking a standard triple therapy regimen, 14/117 (12.0%) a regimen consisting of <3 molecules, and 5/117 (4.3%) a mega cART with >3 molecules on therapy. The ongoing regimens did not include a nucleoside/nucleotide reverse transcriptase inhibitor  in 15/117 (12.8%) cases; a nonnucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI), an integrase strand transfer inhibitor (InSTI), or an entry inhibitor were included in the ongoing antiretroviral regimen in 43 (36.8%), 65 (55.6%), 30 (25.6%), and 2 (1.7%) cases, respectively.The viral genotype for sequences involving reverse transcriptase inhibitors (NRTIs and NNRTIs) and PIs was available for 70 subjects. Among these, 31/70 (44.3%) had at least one major mutation for NRTIs, 24/70 (34.3%) had at least one for the NNRTIs, and 16/70 (22.9%) had at least one mutation for PIs. For 69 patients, the genotype for InSTI resistance was available, with only 1/69 (1.4%) having at least one mutation conferring resistance.3.2Based on the definition of OS and SOS, we assessed the probability of transition from one condition to another and the expected average time within each status.The mean predicted residence time in the OS was 2.59 years (95% CI: 1.94–3.47), whereas that in the SOS was 6.91 years (95% CI: 5.29–9.02). The viro‐immunological status was evaluated at the age of 18. The probability for those in the suboptimal condition to remain in that status was 89% (95% CI: 85.8%–91%), whereas that of transit to the optimal status was 11% (95% CI: 8.8%–14%); for those who were in the OS, the probability of remaining in that status was 70% (95% CI: 62.6%–77%), whereas the probability of migrating to SOS was 30% (95% CI: 23.3%–37%).These same parameters were assessed in the presence of some covariates. Sex has not been shown to have a significant impact on the risk of transit from both optimal to SOS and vice‐versa, with an HR of 0.86 (95% CI: 0.46–1.62) and 0.91 (95% CI: 0.52–1.59), respectively, as reported in Table Patients with a CD4+/CD8+ ratio ≥ 1 at 18 years of age had an increased probability of improve their viro‐immunological condition, transiting from SOS to OS , and a reduced risk of shift from the OS to SOS .On the other hand, having an HIV RNA value ≥ 50 copies/mL at 18 years of age did not impact the likelihood of transit from SOS to OS , but it increased the risk of shift from OS to SOS .The presence of a history of AIDS diagnosis significantly reduced the probability of transit from SOS to OS , whereas it had no significant impact on the risk of migration from the OS to SOS .Finally, patients who had at least one major mutation conferring resistance to any class of antiretrovirals  had no significant impact on the probability of transit from one viro‐immunological condition to another .The expected average time to remain in each status and the probability of maintaining or changing a viro‐immunological condition are shown in Table The presence of coinfections as well as the presence of comorbidities did not have a significant impact on the probability of either transit from the suboptimal condition to the optimal nor vice‐versa.p = .019), who started from CD4+/CD8+ ratio < 1 (p = .003), who had a level CD4+ T cells ≤ 500 (p = .003) and an HIV RNA value ≥ 50 (p < .001), as shown in Table Assessing the risk of cART discontinuation, Cox model regression showed an increased risk of cART interruption or modification throughout all the observation period of the study in subjects who had not achieved OS  had at least one comorbidity and 5.6% had three comorbidities affecting different body districts. A South African study  analyzed the prevalence of comorbidities compared to HIV‐negative adolescents and young adults of the same age.At the age of 18, all subjects for whom data were available were on cART, but only 44.4% had a confirmed HIV RNA < 50 copies/mL. This figure differs from the virological efficacy rate recorded in subjects with adult‐acquired HIV infection on therapy, which today in some settings reaches and exceeds 90%, and which in 2010 (the year closest to the mean age of 18 years in the sample studied) was described as ranging between approximately 60% and 70% in the industrialized countries.Regarding the achievement of the “optimal viro‐immunological condition,” this study has shown that only a low proportion (23.7%) of subjects with VT HIV infection reach that state at the age of 18. This finding is in‐line with the results of a recent Spanish study on a cohort of young people with VT HIV, whose immune system was found to have an increased activation and exhaustion profile, even after long‐term suppression under cART.From our data, we cannot say whether this result is due to the use, by subjects who had achieved OS, of more effective molecules or whether from being on therapy longer. What we do know is that overall in the patients included, although they were young, the average number of regimens of antiretroviral therapy taken was 5.6, with a maximum recorded number of 24 regimens; this finding is in‐line with that reported by a recent Italian study of the ARCA cohort on the prevalence of resistance‐associated genotypic mutations in adults with vertical HIV infection, which reported a mean number of regimens received of 5.In the dynamic modeling that analyzed the probability of transition from one state to another, we observed how the primary goal in the treatment of vertically acquired HIV infection is to immediately achieve full viro‐immunological recovery from the earliest stages of life and maintain it as long as possible.The reported proportion of subjects with at least one resistance is high when compared with that of the general HIV‐positive population.This study has some strengths that it is important to emphasize: first of all, the sample size is considerable if we think of the low prevalence of vertical transmission of HIV in Italy. In addition, the follow‐up time of the study is very high. Many variables were considered, providing a very broad framing of the study subjects. Finally, the multicenter design limits the influence that the prescribing habits of a single center might have had on the management of the infection in the enrolled subjects.However, the study has some limitations: the retrospective design limited the availability of clinical, viro‐immunological, and therapeutical information, especially related to the pediatric follow‐up years. The lack of this data may interfere with the evaluation of immunological damage in the study population. In addition, the lack of therapeutic characterization of the percentage of patients who achieved the OS endpoint does not allow us to dissertate on the reasons for that success: in particular, we cannot assess whether it is due to a long time on therapy or to the use of more effective molecules. Also, unfortunately, information on sociodemographic factors was very limited so the impact they might have on the history of these patients was not evaluated. The recorded proportion of deaths among the study population was low (2.4%); however, this finding certainly reflects the design of the study that aimed to observe precisely those subjects who survived to the pediatric age  and reached adulthood. Finally, the lack of comparison population, which is almost never available, except in subjects with documented seroconversion.5This study showed that reaching adult age with a compromised viro‐immunological status represents an obstacle to the subsequent achievement of an optimal one, despite the availability of a greater number of drugs with a better profile of both efficacy and tolerability. More efforts are needed to improve the adherence to cART of pediatric patients with HIV infection, and the retention in care of this particular group of people living with HIV.Franesca Pennati: Data curation; writing – original draft; writing – review and editing. Stefano Calza: Formal analysis; writing – review and editing. Antonio Di Biagio: Data curation; investigation; writing – review and editing. Cristina Mussini: Data curation; investigation; writing – review and editing. Stefano Rusconi: Data curation; investigation; writing – review and editing. Stefano Bonora: Data curation; investigation; writing – review and editing. Alberto Borghetti: Data curation; investigation; writing – review and editing. Eugenia Quiros Roldan: Data curation; investigation; writing – review and editing. Giovanni Sarteschi: Data curation; investigation; writing – review and editing. Marianna Menozzi: Data curation; investigation; writing – review and editing. Micol Ferrara: Data curation; investigation; writing – review and editing. Anna Celotti: Data curation; investigation; writing – review and editing. Arturo Ciccullo: Data curation; investigation; writing – review and editing. Vania Giacomet: Data curation; investigation; writing – review and editing. Ilaria Izzo: Data curation; investigation; writing – review and editing. Laura Dotta: Data curation; investigation; writing – review and editing. Raffaele Badolato: Data curation; investigation; writing – review and editing. Francesco Castelli: Data curation; investigation; writing – review and editing. Emanuele Focà: Conceptualization; supervision; writing – original draft; writing – review and editing.Emanuele Focà received speakers' honoraria, research grants, and advisory board fees from Viiv Healthcare, Janssen‐Cilag, Gilead Sciences, and Merck Sharp & Dohme. The remaining authors declare no conflict of interest.


The use of DTG-containing two-drug regimens is one of the most promising solutions to the need to ease the management of HIV treatment without harming its efficacy and safety. We report long- term results in patients switched, while virologically suppressed, to the combination of dolutegravir (DTG) plus lamivudine (3TC).This is a prospective, clinical, uncontrolled cohort enrolling ART-experienced people living with HIV (PLWH) with HIV-RNA < 50 copies/ml for 6 months or longer, negative hepatitis B virus surface antigen, and without known M184V/I mutations. Kaplan-Meiers curves are used to describe persistency of virological suppression on therapy and a Cox regression model to evaluate baseline characteristics and the risk of stopping therapy.218 individuals switched their regimen since 2015. The mean estimated follow-up was of 64.3 months (95% CI 61.3–67.3) for approximately 1000 patient/years. After 5 years of follow-up, 77.1% were still on the DTG-3TC combination. No virologic failure was detected throughout the whole study period, and only 15 subjects presented single isolated viral blips above 50 copies/ml. Most patients stopped therapy because of reasons unrelated to study drugs , but due to the unselected nature of the casuistry; 11 subjects died in the 5 years of follow-up mostly because of pre-existing co-morbidities (6 neoplastic diseases and 2 end-stage liver disease). The median baseline CD4 count was 669 cells/mcl (IQR 483–927). After 5 years it raised to 899 cells/mcl (IQR 646–1160) (P < 0.001) without a significant change of CD8 counts that lowered from 767 cells/mcl (IQR 532–1034) to 683 cells/mcl (IQR 538–988). Consequently, the CD4/CD8 ratio varied from 0.93 (IQR 0.60–1.30) to 1.15 (IQR 0.77–1.45) (P < 0.0001). A non-significant (P = 0.320) increment of mean creatinine, 0.06 mg/dl in magnitude, was observed over the whole follow-up.These long-term results over 5 years reinforce the durability and good tolerability of DTG-3TC. Our results continue to support the recommended switch use of this 2DR as a well-accepted treatment option for ART-experienced PLWH. Modern antiretroviral therapy (ART) allows for several treatment options with high efficacy and tolerability, available for both ART-naïve and -experienced people living with HIV (PLWH) , 2. The As most of these strategies were introduced in recent years, long-term durability studies are needed to definitively establish the future role of less-drug regimens. We report a prospective, clinical, uncontrolled experience on patients switched, while virologically suppressed, to the combination of dolutegravir plus lamivudine.The cohort started in 2015. In 2017, our study group published the short-term results of the cohort 24 weeks after the switch to DTG/3TC combination. The inclusion criteria to build the cohort and the methods applied were described in detail in the previous study . BrieflyResistance had to be determined by genotypic analysis before the start of ART or afterward in the occasion of viral blips before the current regimen was started. Patients were not included if they had a virological failure following their last genotypic test. Subjects were switched to a dual combination of dolutegravir (50 mg once daily) plus lamivudine (300 mg once daily).The possibility of the switch to DTG and 3TC was previously discussed individually with each patient, among other available drug regimens and according to available data , 15, 16;Since Italian guidelines considered DTG/3TC combination a well-established alternative option in ART management , no expeOnce included, patients were prospectively followed accordingly to current clinical practice as indicated from Italian guidelines with visits after 2, 4 months and thereafter every 3–6 months. Each visit included a physical examination and blood analysis (including HIV-RNA) performed using standard methods.For the only seek of this report, the primary endpoint was the virological response, defined as the proportion of patients with HIV viral load below 50 copies/ml 5 years after the switch, similarly patients with greater than > 50 copies/ml were asked to perform a new test within a months and in the case of confirmed positivity were considered virological failures.Several other commonly collected data were used to evaluate secondary endpoints. Safety and tolerability were studied by analyzing questioning of patients at each visit and on the basis of physical examination and laboratory analysis. We evaluated immunological changes in terms of CD4+, CD8+, cell/counts and CD4/CD8 ratio variations and we also collected changes in creatinine and blood lipid content as possible markers of drug toxicity.Data are presented as medians and interquartile range or percentages. Student’s t-test for paired samples was employed to identify significant changes in immunological, renal and metabolic functions. Kaplan-Meier curves were used to describe persistency on therapy; a Cox regression model was adopted to evaluate baseline characteristics and the risk of stopping therapy. We did all statistical analyses using SPSS version 17.Two-hundred eighteen individuals who switched their regimen (between January 2015 and July 2016) were enrolled and prospectively followed. Table Median age of the cohort was 52 (IQR 42–59); male individuals were 75.2% and most of individuals were of Italian origin (94%). Subjects had a long ART history (median 10 years [IQR 4.6–17.2]) and were on average on their 3rd line of therapy. Median time of viral suppression before switch was 75 months (IQR 33–122). Before switch, most of individuals (93.6%) were taking a triple-drug regimen, being the most common backbones tenofovir + emtricitabine (59.2%) or abacavir + lamivudine (27.5%). The most common anchor drugs were efavirenz (18.8%) and rilpivirine (16.5%) among NNRTIs, and either boosted darunavir (14.7%) or boosted atazanavir (14.2%) among PIs. A previous exposure to INSTI was documented in 22.5% of individuals.The main reasons for therapeutic switch were concomitant diseases and abnormality of laboratory tests followed by drug-related adverse events or possible adverse events or a potential drug-drug interaction. Several individuals had a mix of reasons. Each patient presented a median of 2 chronic non AIDS-related co-morbidities. The most frequent co-morbidities were: bone diseases (34.4%), hypertension (30.2%), liver diseases, including end-stage liver disease (24.3%), metabolic abnormalities (21.1%) and diabetes (12.4%), cardiovascular (12.3%), renal (11.0%) and neoplastic diseases (6.4%).Because of these pathologies, patients took a median of 2 (IQR 1–3) and up to 11 different drugs including, but not limited to, diuretics, beta-blockers, calcium-antagonists, aspirin, statins, benzodiazepines, vitamins, proton pump inhibitors, insulin, metformin.The mean estimated follow-up was of 64.3 months 95% CI 61.3–67.3) for approximately 1000 patient/years. After 5 years of follow-up, 77.1% were still on the DTG/3TC combination  but due to the unselected nature of the casuistry; 11 subjects died in the 5 years of follow-up mostly because of pre-existing co-morbidities (6 had neoplastic diseases and 2 had end-stage liver disease). No patient who dropped from the study for any reason had a viral load > 50 copies at the moment of withdrawal.At the enrollment, the median CD4 count was 669 cells/mcL (IQR 483–927); after 5 years it raised to 899 cells/mcL (IQR 646–1160) (P < 0.001), without a significant change of CD8 counts that lowered from 767 cells/mcL (IQR 532–1034) to 683 cells/mcL (IQR 538–988). Consequently, the CD4/CD8 ratio varied from 0.93 (IQR 0.60–1.30) to 1.15 (IQR 0.77–1.45) (P < 0.0001). A non-significant (P = 0.320) increment of mean creatinine, 0.06 mg/dl in magnitude, was observed over the whole follow-up and was more marked in the first two months raising the baseline value 0.94 mg/dl (IQR 0.78–1.11) to 0.97 mg/dl (IQR 0.84–1.13), but thereafter leveled on these values being the median after 5 years 1.01 mg/dl (IQR 0.84–1.20). The lipid profile was not influenced by switching to the dual regimen. Median total cholesterol variation was − 10 mg/dl (from 188 mg/dl [IQR 158–217] to 178 mg/dl [IQR 162–178]); median HDL-cholesterol change was − 1 mg/dl (from 47 mg/dl [IQR 38–56] to 46 mg/dl [IQR 39–60]) and triglycerides variation was − 4 mg/dl .With highly-effective antiretroviral drugs, the need of simpler, more manageable and less impactful regimens is becoming one of the priority in more and more patients in our clinics. From a physician’s perspective, the main consideration about whether to switch from a triple combination therapy to an equally effective dual regimen or not is the supposed possibility of reducing long-term side effects, making a pro-active switch. From the patients’ point of view, the success of 2DR in real-practice is driven also by the ease and the handling of these drugs, in particular if used as single-tablet regimens, with the least impact on their daily life , 18.The indication of DTG/3TC regimen in the switching strategy is the result of randomized clinical trials (RCTs) such as the recently updated TANGO study, which supports the effective virologic suppression at 144 weeks of DTG/3TC combination, non-inferior to tenofovir alafenamide (TAF)-based ART , in patiBesides RCTs, real-life studies have gathered lots of data about the use of DTG/3TC, with interesting aspects and considerations. In particular, these data come from evaluation on patient populations that, for different reasons, would have not be considered eligible for a clinical trial but that would mostly benefit from the switch in terms of less drug-drug interactions, less toxicities, ease of use, better tolerability and, as consequence, better adherence.A meta-analysis conducted by Patel et al. confirmed the effectiveness and safety of DTG/3TC in clinical practice, combining the data reported in several real-world studies and, therefore, supporting outcome from RCTs; in particular, virologic suppression ranged from 97 to 100% and 92–100% at 48-weeks and 96-weeks of DTG/3TC in the real-life studies considered and available so far . AlthougOur study reports data for a follow-up over 5 years and a total drug exposure of about 1000 patient/years. In our prospective cohort study, the main reasons for DTG/3TC discontinuation were related to the worsening of pre-existing comorbidities or to drug unrelated events, rather than virologic failures or DTG/3TC-related adverse events.These results support the hypothesis that DTG in dual-formulations has a well-known high genetic barrier to resistance development together with a high adherence rate, thus limiting the risk of virologic failure and development of resistance inducing mutations. With respect to this, to the best of our knowledge, in only one case, a new NRTI mutation (M41M/L) appeared at failure of the 2DR with DTG/3TC , yet witOur study has some limitations. First, in clinically unselected uncontrolled cohorts there is always the risk of bias due to unmeasured confounding, such as drug adherence levels or not reporting adverse effects. For this reason, we decided to report only adverse events leading to drug discontinuation or to clinically relevant decision (e.g. change in therapy). Another caveat was that we censored patients who were lost to follow-up. Such censoring could have led to bias in increasing rate of treatment failure. Finally, our study results could not be applied to those health care systems that do not have HIV case management programs and free ART available.Nevertheless, these long-term results over 5 years reinforce the durable efficacy, high barrier to treatment-emergent resistance, and good tolerability of DTG/3TC. Our results continue to support the recommended switch use of this 2DR as a well-accepted treatment option for virologically suppressed ART-experienced PLWH.


Most estimates of HIV retention are derived at the clinic level through antiretroviral (ART) patient management systems, which capture ART clinic visit data, yet these cannot account for silent transfers across HIV treatment sites. Patient laboratory monitoring visits may also be observed in routinely collected laboratory data, which include ART monitoring tests such as CD4 count and HIV viral load, key to our work here.In this analysis, we utilized the NHLS National HIV Cohort (a system-wide viewpoint) to investigate the accuracy of facility-level estimates of retention in care for adult patients accessing care (defined using clinic visit data on patients under ART recorded in an electronic patient management system) at Themba Lethu Clinic (TLC). Furthermore, we describe patterns of facility switching among all patients and those patients classified as lost to follow-up (LTFU) at the facility level.Of the 43,538 unique patients in the TLC dataset, we included 20,093 of 25,514 possible patient records (78.8%) in our analysis that were linked with the NHLS National Cohort, and we restricted the analytic sample to patients initiating ART between 1 January 2007 and 31 December 2017. Most (60%) patients were female, and the median age (IQR) at ART initiation was 37 (31–45) years. We found the laboratory records augmented retention estimates by a median of 860 additional active records  from the facility viewpoint; this augmentation was more noticeable from the system-wide viewpoint, which added evidence of activity of about one-third of total active records in 2017. In 2017, we found 7.0% misclassification at the facility-level viewpoint, a gap which is potentially solvable through data integration/triangulation. We observed 1,134/20,093 (5.6%) silent transfers; these were noticeably more female and younger than the entire dataset. We also report the most common locations for clinic switching at a provincial level.Integration of multiple data sources has the potential to reduce the misclassification of patients as being lost to care and help understand situations where clinic switching is common. This may help in prioritizing interventions that would assist patients moving between clinics and hopefully contribute to services that normalize formal transfers and fewer silent transfers. Continuity in HIV care from antiretroviral treatment (ART) initiation to virologic suppression is essential for the overall health of HIV-infected patients and the prevention of HIV transmission at the population and individual levels , 2. MostHowever, patient laboratory monitoring visits may also be observed in routinely collected laboratory data, which include results of ART monitoring tests such as CD4 count and HIV viral load. We previously utilized laboratory test results from South African National Health Laboratory Service (NHLS) to create the NHLS National HIV Cohort—a longitudinal cohort of patients accessing HIV care in South Africa's public sector between 2004 and 2018 , 11. In We utilized two sets of routinely collected public sector data, which are as follows:1) Right to Care Clinical Cohort: facility-level dataRight to Care South Africa (RTC) is a South African NGO that has engaged in South African HIV program since the early 2000s. Through the electronic medical record (EMR) database TherapyEdge™ (TE), RTC has collected patient-level data on clinical visits, treatment, and laboratory monitoring of patients. These data have been developed into the RTC Clinical Cohort representing >100,000 patients at multiple facilities across Gauteng, Limpopo, and Mpumalanga . In this2) The NHLS National HIV Cohort: national-level laboratory dataThe NHLS conducts all routine laboratory monitoring for the public sector HIV program in South Africa and maintains these electronic records. As these data lack a unique patient identifier, a linkage algorithm was developed to identify unique patients (and their associated laboratory results) through the demographic data available using probabilistic and network-based linkage methodology, creating the NHLS National HIV Cohort . This coIn our analysis, we included records for adult patients aged >18 years with a documented ART start date at TLC during the study period of 2007–2017. Visit data were not available for the full year of 2018, so we limited the data to those who started ART before the end of 2017 to allow for a sufficient follow-up to monitor LTFU. Records for these patients were then linked to the NHLS National HIV Cohort using both deterministic and probabilistic matching approaches . Since lThe primary outcome of this study was the misclassification of patient retention in HIV care. We defined patient retention from a system-wide perspective as well as at the facility level shown in . SpecifiA) Visit record retention: Patients were considered active in care during each calendar year under study if a clinic visit at TLC was observed in the electronic medical record (EMR) of the site during the corresponding period.B) Laboratory record retention: A patient was considered active in care during each calendar year under study if a laboratory test was observed in the NHLS National HIV Cohort records for the originating facility during that corresponding period.C) Proxy gold standard of patient activity at TLC: An estimated total number of patients active in care by combining patients classified by either the facility-level visit record (A) or facility-level laboratory record (B) for each calendar year. This observed total number of patients was deduplicated to give a denominator of total unique patients active in care each year at TLC.D) Patient record retention: The classification of the patient status was recorded in the EMR at the facility . Patient record outcomes  were not included as part of this gold standard as these outcomes are manually entered, rather than directly observed data.However, in our definition of system-wide retention, a patient was considered retained if the patient was active in care by having a patient visit or laboratory test observed at any facility included in the NHLS National HIV Cohort data during the corresponding calendar year (column E).Our secondary outcome was clinic switching, which was defined by examining all records as well as records indicating a silent transfer. We defined a silent transfer to have occurred if a patient had a lost to follow-up (LTFU) outcome recorded for at least 6 months in the electronic patient record at TLC, and evidence of a laboratory test after the LTFU outcome date observed in any other facility besides TLC within the NHLS National HIV Cohort.We described the study population characteristics at ART initiation using descriptive statistics including proportions for categorical variables and medians with their corresponding interquartile ranges (IQRs) for continuous variables. Our analysis focused on reporting two main measures: (1) the proportion of people classified as active in care in the entire dataset and (2) the proportion of records accurately classified as active in care compared with the gold standard definition by either the visit record or the laboratory record. To do this, we report on the proportion of patients correctly classified as active in care by each retention definition both at the facility and system-wide levels as compared to the proxy gold standard.We quantified misclassification for the single year of 2017 in two ways: misclassification at the facility level and misclassification at the system-wide level. We considered a patient misclassified at the facility level if either the (1) visit record or (2) the laboratory record did not concur with the facility-level gold standard retention classification. We defined system-wide misclassification to have occurred if either (1) a system-wide laboratory record or (2) a facility-level visit record did not agree with the system-level gold standard retention classification.Lastly, we described observed clinic switching as the proportion of patients with an observed laboratory record at any facility within the NHLS cohort other than TLC (observed clinic switch), and among those classified as LTFU at TLC each year between 2007 and 2017. Clinic switching (presumed mobility) was summarized at the facility and provincial levels using frequencies and simple proportions.Ethical approval for this analysis was granted by the Human Research Ethics  Committee of the University of the Witwatersrand Human Research Ethics Committee  M190981 and M1902105. Data were anonymized, and access was limited to the study team; our work also followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines  13)..13).3, with a median CD4 count at initiation of 136 cells/mm3 (52–230). Over 70% of the cohort-initiated treatment during the period 2007–2012, with a median time on ART (IQR) of 6.7 (4.3–8.6) years at the database censor date of 31 December 2017.Of the 43,538 unique patient records in the TLC dataset, we excluded 400 records (0.9%) of individuals younger than 18 years, 9,223 records (21.2%) without an ART start date, 7,746 records (17.8%) with ART start dates before 2007, 655 records (1.5%) with ART start dates after 2017, and 5,421 records (12.5%) that were not observed in the NHLS National HIV Cohort . In our By the end of the study period in 2017, 13,981 (70%) of the total study sample were considered active in care at the system-wide level. Estimates of correctly classifying patients as active in care increased over the study period across all definitions of retention . The proFrom the facility-level viewpoint, laboratory record estimates of retention classified the largest proportion of active patients correctly, outperforming visit record retention in nearly every year (reporting higher retention). Laboratory records added a median of 860  additional correctly classified active records  to retention estimates . The proFrom the system-wide retention viewpoint, visit record data correctly classified a maximum of 76.9% of patients who were identified as active in care at the health system level . PatientOver time, facility-level laboratory estimates appear to largely outperform the visit record data and patient record retention estimates for each year until 2012 . While i3 144 vs. 157).Of 10,802 patients reported as retained in 2017 from the facility-level viewpoint, we observed 756 (7.0%) records with misclassification errors ; of thesn = 20,093), we observed 5,414 (27%) patients with laboratory records at TLC only, while the remaining 14,679 (73%) records had evidence of laboratory monitoring from at least one facility other than TLC , clinic switch from another clinic to TLC , clinic switch from TLC to another facility , and dual clinic access  .Of the total study population (than TLC . There wn = 705) of silent transfer records and 64.4%  of all patient records with evidence of clinic switching were female. We found that silent transfers were also on ART for a shorter amount of time than all records with clinic switching as well as the entire dataset, with median years on ART (IQR) of 1.8 (0.7–3.3) for silent transfers, 3.1 (1.1–6.1) for all records with evidence of clinic switching, and 6.7 (4.3–8.6) for the entire dataset. The age at ART initiation was 34.4 (29.0–40.7) years for the silent transfer group, which was younger than that for all records with clinic switching, 36.8 (30.8–44.3), and the entire dataset, 37.3 (31.2–44.8). We also observed records with laboratory results from as many as 12 facilities in the dataset , and the median laboratory records were 2 (IQR: 1–3) facilities. Of all records with evidence of movement, 22.9%  had a switch outside of Gauteng compared with 31.0% (n = 351) of the silent transfers. The most common provinces for movement were KwaZulu-Natal , North West (6.6 vs. 5.4%), Eastern Cape (5.6 vs. 3.3%), and Limpopo (4.8 vs. 3.9%). About 75% of the silent transfers had their LTFU outcomes before 2015, but about a quarter had their LTFU outcome between 2015 and 2017.We describe two groups of patients with evidence of possible clinic switching: (1) patients with observed clinic switching of the entire dataset 14,679/20,093 (73.1%) and (2) likely “silent transfers” from the dataset . The silWe described the accuracy of record classification of 20,093 ART patient records at Themba Lethu Clinic (TLC) from 2007 to 2017 from three viewpoints: (1) visit record retention, (2) laboratory record retention, and (3) patient record retention. The second viewpoint derived from the NHLS National HIV Cohort , provideWe highlight four main findings: (1) The laboratory records augmented retention estimates by a median of 860 additional active records  from the facility viewpoint, and this augmentation was more noticeable from the system-wide viewpoint, which added evidence of activity of about one-third of total active records in 2017; (2) in 2017, we found 7.0% misclassification at the facility-level viewpoint, a gap which is potentially solvable through data integration/triangulation; (3) across our records, we observed 1,134 of 20,093 (5.6%) of the total records were silent transfers, which had noticeably more female and younger patients than the entire records; and (4) of all records with evidence of movement, 3,368 (22.9%) had a switch outside of Gauteng, while common clinic switching included the following provinces: KwaZulu-Natal , North West (6.6 vs. 5.4%), Eastern Cape (5.6 vs. 3.3%), and Limpopo (4.8 vs. 3.9%).National-level patient records, such as laboratory cohorts, have the potential to improve facility-based estimates of patient care status. Our findings support others who have chronicled the importance and possibility of data integration theoretically  and pracWe have highlighted that South African patients undergoing ART are highly mobile , 5, and Our findings align with Kaplan 2017) and others who have called for “interlinkage” of routine health information systems , 7, 14.  and otheBisnauth et al.  have repAn examination of the latest available migration dynamics report from StatsSA triangulates with our descriptions of patient movement. Of the seven major inter-provincial migration corridors, our findings were in concordance with the six that included Gauteng . The onlLastly, our findings also align in some respect with misclassification research by others in South Africa, notably to the study by Etoori et al. , who shaOur primary strength was our access to relatively high-quality historical patient-based data  and the Our primary limitation is that these findings lacked verification from paper-based records. Second, the nature of our analysis did not allow for measuring switches that happened within the same year, except for the identification of silent transfers where precise dates were known and could be accounted for. Similarly, we counted the number of facilities at which a patient had a laboratory record within the same year; however, we could not count the total number of switches. Of note, TLC has integrated laboratory records into their TherapyEdge database since 2012 and is therefore not representative of typical public sector service points. Despite this, it is possible that there were still instances of misclassification in our analysis, which could have been due to laboratory results that occurred at the transition from 1 year to the next and thus were not classified in the correct year alongside the clinical visits. Lastly, we did not have data to assess movement during the COVID-19 pandemic, which is of critical importance , 29.We document the potential positive augmentation of using a National HIV Cohort (based on NHLS laboratory data) to create potentially more accurate estimates of retention. Integration of multiple data sources has the potential to reduce misclassification of patients as being lost to care and help to understand situations where clinic switching is common. This would help in prioritizing interventions that would assist patients moving between clinics and hopefully contribute to services that normalize formal transfers and fewer silent transfers.https://pubmed.ncbi.nlm.nih.gov/22434860/ and https://www.biorxiv.org/content/10.1101/450304v1. South Africa's Protection of Personal Information as well as conditions of the University of the Witwatersrand Human Research Ethics Committee and HE2RO's internal data handling policies will limit access to underlying data. Data accessibility is documented in this paper: Bor et al.  Committee of the University of the Witwatersrand Human Research Ethics Committee  M190981 and M1902105. Data were anonymized and access was limited to the study team; our work also followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.The study was conceived by JPM and MM. Data curation was conducted by JPM, KS, and CN. Analyses were conducted by JPM with input from KS, LJ, CN, and MM. The manuscript was drafted by JPM with input from KS, LJ, SP, MF, JM, and MM. All authors contributed to the interpretation of the findings and read and approved the final manuscript.


People living with HIV need to use antiretroviral therapy throughout their lives.Studies on the efficacy and safety of dual therapy are limited in Turkey. We sought to evaluate the treatment efficacy and side effects among patients who were given a combination of dolutegravir (DTG) and lamivudine (3TC) as a maintenance therapy.This retrospective, single-centre study included individuals with viral suppression who were older than 18 years of age, living with HIV, switched from a combination antiretroviral therapy regimen to DTG-3TC dual therapy, and followed up for at least 6 months.The study included 63 patients living with HIV. The median age was 42 years (interquartile range (IQR): 36–51 years). The median follow-up under the DTG-3TC regimen was 10.4 months (7.1–16.0 months). In the course of dual therapy, no patients developed any serious adverse effects that would necessitate a therapy switch, but virological blips were seen in two patients. Two patients lost their lives, with one dying from suicide and one dying from respiratory failure associated with the underlying chronic obstructive pulmonary disease.The DTG-3TC dual-therapy regimen is a promising and effective therapy that can be used as a treatment of choice for eligible patients. The treatment of HIV has undergone substantial changes and improvements since the first introduction of zidovudine (ZDV) monotherapy in 1987, followed by combination antiretroviral therapy (cART)/high-activity antiretroviral therapy (HAART) in 1996. Combination therapy is still a current treatment of choice and is based on the use of 3 drugs, of which at least 2 are from different groups. One example involves two nucleos(t)ide analogue reverse transcriptase inhibitors (N(t)RTIs) and one of the following: a non-nucleoside reverse transcriptase inhibitor (NNRTI), amplified protease inhibitor (PI), integrase inhibitor, fusion inhibitor, or attachment inhibitor. Although a complete cure cannot be achieved with current ART regimens, the aim is to reduce HIV-associated morbidity and mortality, to lengthen the life span of people living with HIV (PLWH), and to prevent HIV transmissionAttempts to achieve treatment goals have often been complicated by adverse drug effects, drug-drug interactions, and costs. This issue, motivated the development of different drug regimens, particularly dual therapies. Many different studies have been conducted in different countries regarding dual treatment regimens based on PI such as atazanavir (ATV), lopinavir (LOP), darunavir (DRV) and Integrase inhibitors such as Dolutegravir (DTG), raltegravir (RAL)We retrospectively evaluated patients who had been under outpatient follow-up with a diagnosis of HIV infection at the Infectious Disease and Clinical Microbiology Clinic of Istanbul Medeniyet University from January 2016 and April 2021. The study protocol was approved by the Ethics Committee of Istanbul Medeniyet University, Goztepe Training Hospital and the study was conducted in accordance with the principles of the Helsinki Declaration (2020/0123).The study included non-naive patients who had no viral failure, for whom the triple ART regimen had been switched to a DTG-3TC maintenance dual regimen due to drug side effects , outdated current treatment, drug-drug interaction, or simplification. Of the 1006 patients who presented to the outpatient clinic of infectious diseases, 74 were identified as receiving dual treatment, but 11 patients were excluded from the study because 8 of them had received a dual treatment for less than 6 months, and 3 of them had missing data. The inclusion criteria were as follows: living with HIV, age 18 years or older, absence of pregnancy, receipt of any triple ART regimen prior to the dual regimen, an HIV RNA level of less than 100 IU/ml or an undetectable level for at least 6 months, and receipt of the DTG-3TC dual regimen for at least 6 months. All patients had a CD4+T lymphocyte count of more than 200 cells/mm3 at the time of switching. The cARTs that were administered before the dual treatment were recorded.Viral suppression refers to a decrease in the plasma HIVRNA level to below the detection threshold of the test used, remaining constant at that level, being less than 50 copies/ml, or being at an undetectable level. The test-dependent limit used in the current study was accepted as less than 100 IU/mL.Viral failure refers to a level of HIV-RNA of more than 200 copies/ml at week 24 and the inability to maintain the suppression of viral replication.Virological blip refers to the detection of a transient increase in HIV RNA (50 to 400 copies/ml) after viral suppression is achieved.Due to its retrospective design, decisions to switch the ART were derived from patients' records with clinicians' decisions. HIV RNA levels  were tested with a real-time PCR method (ARTUS QIAGEN HI Virus-1 RG RT-PCR), and the CD4 T lymphocyte count was tested with a standard flow cytometry method . Total cholesterol and triglyceride levels were evaluated after a 12-hour fast. Levels of total cholesterol (upper limit 200 mg/dL) and triglyceride (upper limit 150 mg/dL) were assessed as normal or high, and co-morbidities were taken into account. Renal functions were evaluated with the estimated glomerular filtration rate (e-GFR), and GFR ≥60 was considered normal.The distribution characteristics of the data as well as distribution characteristics of the differences between the dependent variables were analyzed with both normality tests and graphs . For descriptive statistics, mean standard deviation, median (interquartile range-IQR), or number and frequency values were used, when appropriate.For continuous data, the Wilcoxon test or paired-sample T-test was used for dependent variables and the Mann-Whitney U-test or student's T-test was used for independent variables. Data were processed using IBM SPSS statistics  and a p-value of less than 0.05 was considered significant.The current study included 63 patients  with a median age of 42 years (interquartile range (IQR): 36 to 51 years). The youngest patient was 23 years old, and the oldest was 77 years old. 51.61% (n=32) of men had sex with other men (MSM). The earliest diagnosis was made in 2003, and the most recent was made in 2020. The average time of diagnosis was 5 years (4 to 7 years). There were 15 patients (23.8%) who had co-morbidities (64.3% of them were 50 years of age or older), of which the most common was hypertension. The median treatment durations of patients with viral suppression on triple therapy was 41.4 months (IQR: 30.4–59.1 months). The duration of the treatment was 10.4 months (7.1–16.0 months) after the switch, and the duration of total ART was 55.8 months (43.5–78.3 months). The main reason for switching to dual therapy was the detection of decreased bone mineral density (56.7%), which led clinicians to switch to dual therapy from triple therapy. Three patients were switched to dual therapy due to the development of hyperlipidemia during the treatment, and 13 patients were switched due to the development of renal dysfunction. There was no significant difference in CD4+T lymphocyte counts during the triple therapy and dual therapy (p = 0.154), and there was no significant difference in HIV RNAs. Two patients were found to have virological blips during dual therapy (215 IU/mL and 153 IU/mL). There were no significant differences in total cholesterol, triglyceride, and e-GFR levels between both treatments  with a potent dual-NRTI backboneThere are many studies on DTG-3TC dual therapy in different countries around the world, which cover both naive and patients who were switched from another therapy. In a study on naive patients, Cahn et al.Among patients who received a switched regimen, Maggiolo et al. 8 reported that a virological success of 100% was maintained at week 24, and Jolly et al.Lamivudine inhibits reverse transcriptase, thus terminating proviral DNA chain extension and preventing HIV replication competitively. It is a well-tolerated drug with high absorption after oral administration, as well as enhanced bioavailability. It can be taken with or without food, has a favorable safety profile, has no significant drug-drug interactions, and is less expensive.The present study demonstrated that as of 2019, dual therapy has become a preferred regimen more often than in previous years. The reason for this may be that the guidelines were updated in 2019 and encouraged physicians to switch to dual therapyThroughout the study period, the need for switching therapy was independent of age and was mostly due to decreased bone mineral density (osteopenia-osteoporosis). In PLWH, the balance between osteoblastic and osteoclastic activity is impaired, and some ARTs are known to contribute to this condition. In a meta-analysis, Goh et al. reported that there was a 2-fold increased risk of osteopenia/osteoporosis in PLWH undergoing an ART regimen as compared with the control groupPLWH also have a risk of nephropathy, which may be caused by both the direct effects of the virus and the antivirals on the kidneysHyperlipidemia is also an unfavourable condition that is noted in the follow-up of HIV and needs to be managed. Tenorio et alThe treatment of one of our patients was changed due to drug hypersensitivity. The patient presented with dyspnoea in the 4th week of ABC-DTG-3TC treatment. Consolidated areas of the lungs were detected in thorax CT, and infectious processes were ruled out. The complaints regressed after discontinuation of the patient's antiviral treatment. The patient had been receiving DTG-3TC therapy since June 27, 2017, and reported no complaints. ABC-dependent drug hypersensitivity has been reported in individuals who are positive for HLA 5701, and it can rarely be seen in negative patients. Stainsby et al. reported a rate of 1.3% or less for ABC-related hypersensitivity in their study on HLA 5701-negative patientsTwo patients switched ARTs due to persistent gastrointestinal adverse events, such as diarrhoea and indigestion, which improved after switching. Both patients were receiving PI , for which adverse events of the gastrointestinal system have been reportedA patient with a history of frequent hospitalizations for chronic obstructive pulmonary disease died from respiratory failure caused by exacerbation of the underlying disease while having a negative viral load. Another patient died from suicide. The patient had received a diagnosis of depression and had been receiving treatment for 4 years. Before switching to DTG-3TC therapy, the patient had been using cART containing DTG for 21 months and was HIV RNA negative until the last follow-up visit. Mental health problems are known to be frequent in PWLH, with depression being the most common psychiatric co-morbidity after substance misuseDuring the follow-up period, no side effects that would necessitate a change in treatment were encountered in patients who received dual therapy. DTG-3TC treatment was found to be an effective alternative with fewer side effects, it was easy to use, and it might be cost effective. However, since the study lacked a control group and had a retrospective design, there are missing data. Disruptions in routine outpatient services due to the COVID-19 pandemic and patients not seeking care were also limitations of the study.The choice of ART in the treatment of PLWH needs to be specific to the individual. Factors such as co-morbidities, drug toxicities, patient adherence to medications, and drug-drug interactions should be taken into consideration. DTG-3TC dual treatment seems to be an effective and reliable option in the long run with increased adherence to therapy, making it an appropriate alternative for eligible patients.