To use SIV-mac239-infected Chinese rhesus monkeys to study white matter changes with and without regular combined antiretroviral therapy (cART) and the relationships between the changes and clinical results.Diffusion tensor imaging (DTI) data were collected at baseline and 10 days, 4 weeks, 12 weeks, 24 weeks, and 36 weeks after viral inoculation. Plasma CD4 T cell counts, CD4/CD8 ratio, plasma viral load, and cerebrospinal fluid (CSF) viral load were collected at baseline and 1 week, 5 weeks, 12 weeks, 24 weeks, and 36 weeks after viral inoculation. Microstructural characteristics were examined within 76 white matter areas defined by the DTI-white matter (WM) atlas for rhesus macaques. Corrections for multiple comparisons were performed using a false discovery rate . Correlation analyzes between imaging markers and clinical markers  were performed using Pearson correlations.White matter changes in SIV-infected macaques were detected in different brain regions as early as 4 weeks after inoculation. As time progressed, cART reversed, ameliorated, or even enhanced the effects. The CD4 T cell count was mainly associated with DTI metrics before cART, while the CD4/CD8 ratio was associated with white matter changes with and without cART. Viral load was positively associated with mean diffusivity in HIV patients without cART, and the opposite results were seen in HIV patients with cART.SIV-mac239 infection may be an ideal tool for studying HIV-induced changes in the brain. The first white matter changes appeared in a structure adjacent to the periventricular area as early as 4 weeks after inoculation. As time progressed, cART had different effects on different regions, reversing, attenuating, or even progressing the pathology. Moreover, these changes were closely related to the CD4/CD8 ratio and viral load, even after cART. These lead to marked inflammation, immune activation and suppression, and disruption of the blood-brain barrier –3 and reAn appropriate animal model whose pathological mechanisms are similar to those of HIV patients can be used to clarify this issue. Studies have shown that the pathology of simian immunodeficiency virus (SIV)-infected Chinese rhesus monkeys is very similar to that of HIV-infected patients, especially in terms of central nervous system (CNS) dysfunction, cognitive or behavioral deficits, and the development of AIDS –28. MoreIn the present study, we dynamically investigated white matter changes in SIV-mac239-infected Chinese rhesus monkeys with and without regular cART treatment and the relationship between DTI metrics and clinical tests  at different time points.22.1This study was approved by the Beijing Municipal Sciences & Technology Commission. Ten healthy male Chinese-origin rhesus monkeys  were applied in the study. Before conducting the longitudinal study, health screening and indirect immunoassay (IFA) were performed on all rhesus monkeys to confirm their healthy status and exclude possible infection with simian immunodeficiency virus (SIV), simian type D retrovirus (SRV), herpes B virus, or simian T cell lymphotropic virus-I (STLV-I).2.2Ten macaques were inoculated intravenously with a 50-fold half-tissue culture infective dose (TCID50) of SIVmac239 through the brachial vein and were all seroconverted to SIV within 7 days of inoculation. Five of them received cART 40 days after inoculation, while the other five macaques received no treatment. The treatment regimen included emtricitabine (50 mg/kg per day), tenofovir disoproxil fumarate (5.1 mg/kg per day), and dolutegravir (2.5 mg/kg per day). Baseline was determined 2 weeks before inoculation. Immunologic characteristics of peripheral blood, including plasma CD4 T cell counts, CD4/CD8 ratio, plasma viral load, and CSF viral load, were assessed at baseline and 1 week, 5 weeks, 12 weeks, 24 weeks, and 36 weeks after SIV-mac239 inoculation. The CD4/CD8 ratio was calculated based on T cell counts. MRI scans were performed at baseline and 10 days, 4 weeks, 12 weeks, 24 weeks, and 36 weeks after virus inoculation Figure 12.3All animals were housed at the Institute of Laboratory Animal Sciences, Peking Union Medical College, under the same housing conditions as in previous studies , 21, i.e2.42.4.13), and time points = 10 min 52 s.MRI scans were performed at Beijing YouAn Hospital, Capital Medical College, using a 3T Siemens Tim TRIO whole-body magnetic resonance imaging scanner  at each time point to assess the longitudinal effects of SIV infection on the brain. The monkeys were anesthetized and were in the supination position during the MRI scans. DTI images were acquired with gradient-echo single-shot echo planar imaging (EPI). The parameters were repeat time/echo time (TR/TE) = 5200/100 ms, FOV = 152 mm × 152 mm, data matrix = 76 × 76, flip angle = 90°, slice thickness = 2 mm (voxel size = 2 × 2 × 2 mm2.4.2https://fsl.fmrib.ox.ac.uk/) and AFNI (3D Skull Strip for skull stripping of monkey brain data). The raw DWI data were preprocessed to correct for eddy currents, susceptibility-related biases, and animal motion. The data were then fitted using the DIT-tensor fitting technique available in FSL. Four types of diffusivity maps were created: fractional anisotropy (FA), a measure of the directionality of water diffusion; mean diffusivity (MD), a measure of water diffusivity in the transverse directions (https://www.nitrc.org/projects/rmdtitemplate/) (Preprocessing of macaque DWI data was performed in accordance with previous studies using FMRIB Software Library (FSL) (rections . Each ofmplate/)   . The temmplate/) . Two neu2.4.3Microstructural properties were examined within the 76 white matter areas defined by the DTI-WM atlas for rhesus monkeys. All WM structures were assessed in our analysis. Each WM region of interest (ROI) was examined longitudinally for changes over time. These microstructural changes were examined at baseline and at 10 days, 4 weeks, 12 weeks, 24 weeks, and 36 weeks after virus inoculation.2.4.4Statistical analyses were performed using SPSS software . Group differences between macaques with cART and those without cART, the effect of time on microstructural characteristics, and the interaction effects of cART treatment and time were determined using a two-factor mixed design ANOVA. Of the 10 HIV-infected monkeys, five were randomly assigned to cART treatment, and the other five received no treatment. Thus, the between-subject factor had two levels. Over a 36-week period, microstructural characteristics were measured at six time points corresponding to six levels of the within-subject factor. These stages were baseline [time 1], after 10 days [time 2], after 4 weeks [time 3], after 12 weeks [time 4], after 24 weeks [time 5], and after 36 weeks at the end of the program [time 6].Corrections for multiple comparisons were performed using a false discovery rate . Correlation analyses between imaging markers and clinical measures  were determined using Pearson correlations.33.1Differences in age and weight at baseline were not significant . A significant time by group interaction was detected for weight (P < 0.001), plasma viral load (P < 0.001), CSF viral load (P < 0.001), peripheral blood CD4 T cell count (P < 0.001), and CD4/CD8 ratio (P < 0.001), which supported increasingly divergent trajectories among three groups.A sharp increase in viral load was observed, and viremia arrived at its peak within 2 weeks in almost all SIV infected macaques. Plasma viral load in macaques without treatment subsequently declined and reached a plateau in 5 weeks. Macaques with cART treatment showed a dramatic increase within 5 weeks, after which they showed a continuous decline.CSF viral load decreased to nadir at 24 weeks post-infection (wpi) and rose again afterward in the group without treatment. With cART, the viral load in the CSF dropped more dramatically and was undetectable in three macaques at 36 wpi.There were reductions in CD4 T cell count and CD4/CD8 ratio with SIV infection that were alleviated by cART. After the introduction of cART, the CD4/CD8 ratio showed a tendency to increase.Weight loss was seen in the SIV-cART group at 5 wpi, and the SIV-cART+ group showed a slight weight increase starting at 12 wpi  (p = 0.029244), posterior part of the internal capsule (left) (PLIC-L) (p = 0.023222), fornix (FX) (p = 0.041225), left brainstem (p = 0.0173969), right brainstem (p = 0.024109), left anterior limb of the internal capsule (ALIC-L) (p = 0.0162715), right anterior limb of internal capsule (ALIC-R) (p = 0.01556), and right sagittal striatum (SS-R) (p = 0.0190229) at FA, and in the adjacent white matter of the amygdala (AA-WM-RR) (p = 0.004665), posterior limb of the internal capsule – left (PLIC-L) (p = 0.0232217) (p = 0.0451514), and right sagittal striatum (SS-R) (p = 0.0292208) on MD. By 24 weeks after inoculation, changes had occurred in the posterior limb of the right internal capsule (PLIC-R) (p = 0.0426243), corpus callosum (GCC) (p = 0. 0192415), body of the corpus callosum (BCC) (p = 0.032449), outer capsule – left (EC-L) (p = 0.01540547) (p = 0.0447482), and striaterminalus – right (ST-R) at FA (p = 0.0029465), and PLIC-R (p = 0.016532) (p = 0.0328549) at MD 5.3.3After cART, we found no changes in BCC or FX for FA and MD; no progression in AA-WM R for MD or PLIC-R and PLIC-L for FA; slow progression in STG-WM-L, GCC, CP-R, and CP-L; and no effects on PLICR, ALIC-R, SS-R, or ST-R 5.3.4We examined the relationships between clinical measurements, such as plasma CD4 T cell count, CD4/CD8 ratio, plasma viral load, and CSF viral load, and altered DTI metrics with high significance in macaques treated with cART. We confirmed that increased MD and FA were associated with decreased CD4T cell counts in only one region in AA-WM-R, and only a positive relationship was seen for ST-R. Additionally, MD was associated with a low CD4/CD8 ratio in GCC, ALIC-R, PLIC-L, and ALIC-L, and there were positive relationships with the ratio in ST-R and AA-WM-R, with regular cART treatment. CP-R and CP-L showed positive correlations with FA Table 1.3.5We also estimated the correlations between clinical metrics such as CD4 T cell count and CD4/CD8 ratio and altered DTI metrics with high significance. We found that decreased FA was associated with decreased numbers of CD4 T cells in PLIC-L, PLIC-R, and CP-R in monkeys without treatment. Increased MD was associated with low CD4 T cell counts in PLIC-R and PLIC-L, except for in STG-WM-L, where there was a positive relationship. For the CD4/CD8 ratio, an increase in MD was associated with a decrease in CD4/CD8 in PLIC-R, FX, and ST-R Table 3.4The current study investigated longitudinal structural changes in brain white matter in 10 SIV-mac239-infected monkeys with and without regular cART treatment. We found significant white matter structural changes in these monkeys that consisted of higher mean diffusion and lower fractional anisotropy, as determined by DTI. The results showed that these effects increased with time. Furthermore, we found that significant white matter disruption occurred as early as 4 weeks after inoculation and that damage could be mitigated or even reversed with regular cART. In addition, DTI metric changes correlated significantly with clinical measures such as CD4 T cell count, CD4/CD8, plasma viral load, and CSF viral load.The etiology underlying white matter changes in HIV-infected individuals is still unclear. Possible pathophysiological mechanisms include synaptodendritic damage, inflammation, demyelination, and even microvascular abnormalities that correlate with concomitant cardiovascular risk factors, particularly hypertension. In the context of HIV, on the basis of DTI acquisition parameters, FA reflects the axonal structural integrity aspect, which reflects the cytoskeleton and membrane integrity  and the via monocytes and perivascular macrophages. The virus then replicates and causes neuronal damage mainly through neuroinflammatory mechanisms triggered by infected microglial cells. Inflammation occurs selectively in dopamine-rich areas of the brain, including subcortical areas, particularly the dopamine-rich basal ganglia, leading to subcortical dementia , which may shed light on the underlying neuropathological mechanisms and illustrate the impact of timely cART on imaging findings, immune indicators, and the relationship between them. In our study, we longitudinally examined white matter changes in rhesus macaques with and without regular cART treatment from baseline and 10 days, 4 weeks, 12 weeks, 24 weeks, and 36 weeks after inoculation. In the present study, changes were first observed 4 weeks after inoculation in the amygdala, superior temporal gyrus (STG), posterior part of the internal capsule (left), fornix, bilateral brainstem, and bilateral anterior limb of the internal capsule (ALIC-L) at FA, and the posterior limb of the internal capsule-left (PLIC-L) and right sagittal striatum (SS -R) at MD, suggesting that these regions are more susceptible to SIV infection. Studies have shown that HIV enters the central nervous system very early after seroconversion dementia –50. Our dementia –54. The dementia . A previdementia . In addidementia . Regardidementia .Twelve weeks after inoculation, the PLIC-R, GCC, BCC, EC-L, and ST-R regions showed significant changes at FA, and PLIC-R was altered at MD. Early cerebral infiltration of HIV may occur before antiretroviral drugs are administered, exposing the surrounding white matter to neurotoxic effects before effective viral suppression occurs. Periventricular white matter, such as CC, has been suggested to be particularly vulnerable to viral attack because of its proximity to the CSF, which is an HIV reservoir that can transmit the virus within 8 days of infection –61. Studvia oxidative stress, as demonstrated in vitro and in animal models  at the Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences .Conceptualization: JL. Data collection: DL, YQ, XA, SH, YG. Methodology: BN. Data analysis: JL, BN. Supervision: HL. Writing—original draft: JL, BN. Writing—review & editing: XH, HL. All authors contributed to the article and approved the submitted version.


In conclusion, our cohort demonstrates that DTG+3TC is an effective treatment strategy for virologically-suppressed PLWHIV independent of age, sex, and HIV stage, as well as a safe and durable strategy.Dolutegravir (DTG) based dual therapies for treating PLWHIV are a standard of care nowadays. Switching to DTG and lamivudine (3TC) safety and efficacy were proven in TANGO randomized clinical trial. This multicenter retrospective study included 1032 HIV virologically suppressed patients switching to DTG+3TC from 13 Spanish hospitals. DTG+3TC provided high rates of undetectable viral load over 96%, corresponding to 96.6% (889/921) at 24 weeks, 97.5% (743/763) at 48 weeks, and 98.3% (417/425) at 96 weeks. No significant differences are evident when comparing the total population according to sex, presence of comorbidity, or presence of AIDS. The analysis for paired data showed an increase in CD4+ cell count. A statistically significant increase in CD4+ lymphocyte count was found in those without comorbidities in the three-time series analyzed [average increase at 24 weeks: 48.7 (SD: 215.3) vs. 25.8 (SD: 215.5),  For the last 25 years, antiretroviral therapy (ART) for treating people living with HIV (PLWHIV) has stood on three-drug regimens 3-DR). They, most commonly, were designed as a backbone of two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) with a third agent, either a retroviral protease inhibitor (PI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), or more recently, an integrase strand transfer inhibitor (INSTI) . Neverth-DR. TheyAn initial breakthrough was made by several trials that combined lamivudine (3TC) with different PI . DolutegAlthough DTG plus 3TC has proved its non-inferiority in terms of virological suppression and its durability as a treatment strategy, data regarding its impact on immune activation and inflammation are lacking. Therefore, this study aimed to collect real-life data in a multicenter cohort of PLWHIV treated with DTG plus 3TC as a switch strategy, not only in terms of virological suppression, safety, and durability, but also in terms of its immunological impact through the evolution of the CD4/CD8 ratio in these patients, a marker considered to be a surrogate marker of immune activation and systemic inflammation ,10. DataFrom 1 November 2020 to 1 August 2021, a retrospective multicentre study was conducted at 13 hospitals in Spain. Data from 1032 virologically suppressed HIV patients over 18 years old who switched to DTG plus 3TC were collected. Included variables comprise demographics, HIV infection, comorbidities, efficacy in viral suppression, and immune recovery, safety, and tolerability. Since the experimental design requires the study to compare CD4+ and CD8+ lymphocyte counts in individuals at different stages, these data should be considered matched data. Undetectable HIV viral load was considered when <50 copies/mL.REDcap was used as an online electronic database .The primary outcome  was evaluated by determining the percentage of patients with undetectable viral load at weeks 24, 48, and 96 after switching. Virological failure was defined as the presence of an HIV viral load over 50 copies/mL during follow-up.Secondary outcomes were: (a) patients’ immune recovery evolution through measuring total plasma CD4+/CD8+ cells count and CD4+/CD8+ ratio; (b) adverse events throughout the whole follow-up period; and (c) investigating reasons that led clinicians to switch to DTG plus 3TC.t-test) and non-parametric (U-Mann-Whitney) tests based on the result of the Kolmogorov-Smirnov normality test. In contrast, the comparison of proportions was carried out using the Chi-square and Fisher tests. In all cases, statistical significance was defined as p < 0.05.All statistical analyses were performed using R software . Data for continuous quantitative variables are presented as medians and interquartile ranges (IQR). Qualitative variables are presented as percentages. Demographics, comorbidities, HIV infection, and diagnosis were compared by gender, the number of comorbidities, and the presence of AIDS. The contrast of medians between the different groups analyzed was compared with parametric .Additionally, differences in CD4+ and CD8+ lymphocyte count and CD4+/CD8+ ratio were calculated between the baseline and the three-time points analyzed  when data were available. Positive values or values greater than zero indicate an increase in the parameter under study. In this case, the average values of each difference are again contrasted according to the three defined population groups and represented graphically in the form of violin plots. Finally, we assessed whether the difference observed at the intra-group level was significant by applying paired means tests , and 192 (18.6%) were with three or more comorbidities. Dyslipidaemia was the most frequent one (20.4%), followed by hypertension (11.5%) and chronic liver disease (10.3%). Patients with associated comorbidities were older than those without, In addition, 27.9% (192) of overall patients had been diagnosed with hepatitis B virus infection, but only 10/192 (5.3%) presented a positive HBs antigen during the switch to DTG+3TC. On the other hand, 3/56 patients (5.7%) in the comorbidity group showed positive HBs antigen and were on treatment with entecavir. No issues were found within this aspect.During follow-up, available data provided high rates of undetectable viral load over 96%, corresponding to 96.6% (889/921) at 24 weeks, 97.5% (743/763) at 48 weeks, and 98.3% (417/425) at 96 weeks. No significant differences are evident when comparing the total population according to sex, presence of comorbidity, or presence of AIDS. Nevertheless, there is a tendency related to more virological failures in the groups without comorbidities or AIDS. In those patients with virological failure, no resistance mutations were found when drug resistance tests were performed.p-value = 0.050; a mean increase at 48 weeks: 75.1 (SD: 232.9) vs. 42.3 (SD: 255.6), p-value = 0.003; a mean increase at 96 weeks: 120.1 (SD: 205.0) vs. 63.8 (SD:275.3), p-value = 0.003]. When this analysis was performed comparing patients with and without AIDS, a significant reduction (p < 0.05) was observed in the number of CD8+ lymphocytes in the subgroup without AIDS at 48 and 96 weeks , as well as an increase in CD8+ lymphocyte count in the group with AIDS .Immune status was assessed through the median baseline CD4+ and CD8+ lymphocyte count and CD4+/CD8+ ratio . No signRegarding immune status, patients with AIDS presented, as expected, a lower lymphocyte count (around 150–200 cells/mm3 less than non-AIDS patients) without paired data analysis. Nevertheless, the absolute value of CD8+ lymphocytes remained constant in both groups. This trend translates into a lower CD4+/CD8+ ratio in the AIDS group up to week 48 of dual DTG plus 3TC therapy.Adverse events (AEs) were scarce and only reported in 14 patients (1.4%). They included renal toxicity in 5 (0.5%), central nervous system toxicity in 8 (0.8%), and gastrointestinal issues in 1 (0.1%). Only three (0.29%) patients discontinued treatment because of AEs.The efficacy and safety of DTG plus 3TC for treating virologically-suppressed PLWHIV without resistance mutations against DTG and 3TC were settled by the TANGO randomized clinical trial . SimilarBeyond this demographic data, in the intention-to-treat exposed population of the TANGO study, 344 patients (93.2%) had an HIV plasma viral load lower than 50 copies/mL at 48 weeks. In our cohort, in the intention-to-treat, 97.5% of patients achieved viral suppression of fewer than 50 copies/mL. Thus, our study confirms and reaffirms the results depicted in the pivotal clinical trial of DTG plus 3TC as a switch study, lining up with some other real-life data from smaller cohorts with similar results ,14.Another relevant issue on behalf of DTG plus 3TC treatment is its safety, as severe adverse effects are rarely reported, leading to durability and infrequent switch to other treatment strategies due to adverse effects. Instead, central nervous system events are the most frequently reported AE leading to treatment discontinuation. This data correlates with the TANGO trial  and otheA systematic review of the efficacy and safety of DTG plus 3TC from clinical trials and real-life cohorts  revealedOn behalf of CD4+ T cell count and CD4+/CD8+ ratio after switching, our study shows how CD4+ T cell count increased sequentially and significantly from baseline to 96 weeks. Remarkably, this increase was independent of sex, comorbidities, or pre-existing AIDS infection stage. In addition, a reduction in the absolute CD8+ value is also observed in the non-AIDS group.Our study was designed and carried out during the most challenging days of the coronavirus disease 2019 (COVID-19) pandemic, requiring extra effort by bedside clinicians. Thus, a simple and user-friendly database was developed with a small number of variables to recruit centers. Unfortunately, it led to several limitations that may have clinical implications. They include the study’s retrospective nature; a lack of clinically interesting data, such as body weight gain; and data regarding archived M184V, commonly missing in medical records. Nevertheless, it has undoubted strengths that complement the clinical trials’ data. First, it represents real-life data in the most challenging time of last decades, the COVID-19 pandemic, in which proper adherence to the treatment was probably tackled by many circumstances, adding additional stress to this treatment strategy in terms of performance. Furthermore, this issue probably makes this cohort a completely differential one, as the circumstances in which this dual strategy has been evaluated, with patients having problems accessing their medication or physicians, were unprecedented. These facts have been well described previously ,22. ThusIn conclusion, our cohort confirms previous data from the TANGO study. Furthermore, it demonstrates that DTG+3TC is an effective treatment strategy for virologically-suppressed PLWHIV independent of age, sex, and HIV stage, as well as a safe and durable strategy, even under the stress of the COVID-19 pandemic. In addition, a potential immunological benefit in terms of CD4+ lymphocyte count and increased CD4+/CD8+ ratio is also suggested.


Mycobacterium avium complex (MAC) infection is predominantly seen in immunocompromised individuals, such as those with HIV infection and CD4 counts <50 cells/mm3. It commonly manifests with nonspecific signs and symptoms, such as weight loss, fevers, night sweats, diarrhea, lymphadenopathy, hepatosplenomegaly, and cytopenias. This is a case of disseminated MAC osteomyelitis in an HIV patient. The lack of constitutional symptoms, in this case, presented a diagnostic challenge. In addition, nonvertebral osteomyelitis is an uncommon manifestation, making this case of disseminated MAC osteomyelitis a unique presentation.Disseminated  Mycobacterium avium complex (MAC) is comprised of Mycobacterium avium and the closely related Mycobacterium intracellulare, both of which are ubiquitous in the environment. MAC is a frequent opportunistic infection seen in patients with HIV. Disseminated MAC is typically seen in advanced disease, and prophylaxis is generally initiated once CD4 counts fall below 50 cells/mm3. MAC infections have various clinical presentations in immunocompromised patients, including but not limited to, pulmonary disease, granulomatous hepatitis, lymphadenitis, colitis, brain abscess, osteomyelitis, skin and soft tissue abscesses, and more [and more ,2. ThereThis is a case of a 57-year-old man with a past medical history of recently diagnosed HIV, with an initial CD4 count of 90 cells/mm3, initiated on bictegravir/emtricitabine/tenofovir alafenamide, and prophylaxis with trimethoprim/sulfamethoxazole and acyclovir. Two months after the HIV diagnosis, the patient presented to the hospital with a left index finger infection. CT showed osteomyelitis of the distal phalanx of the index finger Figure . IncisioHe subsequently presented to our hospital less than two months after the previous hospital discharge with right foot pain and swelling, along with left-hand swelling. The patient initially attributed the pain to trauma from dropping a heavy bottle on his right foot. Absolute CD4 count at the time of hospitalization was 181 cells/mm3, improved from 90 cells/mm3 at the time of antiretroviral therapy (ART) initiation. Quantitative HIV-1 RNA polymerase chain reaction (PCR) also showed a viral load of 31 copies/mL, improved from 608,000 copies/mL. MRI of the right foot was performed, demonstrating a septic first tarsometatarsal joint with complex periarticular abscess, along with osteomyelitis of the medial cuneiform and first metatarsal base Figure . MRI of Fortunately, upon review of the patient’s medical records, AFB cultures from the previous hospitalization grew MAC at approximately 7.5 weeks from the time cultures had been obtained. Thus, a preliminary diagnosis of disseminated MAC osteomyelitis was made, and the patient was initiated on azithromycin and ethambutol. Rifamycin antibiotics were not used due to drug-drug interaction with the patient’s ART. Intraoperative right metatarsal AFB culture ultimately grew MAC resistant to linezolid and moxifloxacin.Disseminated MAC infection has been reported in patients with advanced immunosuppression caused by HIV, who are not on ART, or are not responding to ART therapy. While the localized infection is more often noted in patients on ART therapy . MAC ostThe pathogenesis of spinal infection possibly involves immune activity in response to ART medication as part of the immune reconstitution syndrome (IRIS). On the contrary, studies have shown non-spinal infection to manifest in the setting of lower CD4+ count, secondary to unchecked mycobacterial replication and dissemination. We note that despite CD4+ count above 50 cells/mm3 and immediate introduction of ART therapy at the time of diagnosis, this patient developed non-spinal disseminated MAC infection in two joints. Additionally, this study underscores the underrecognition of MAC osteomyelitis in HIV and should remain high on differential diagnoses, despite adequate CD4+ count and ART therapy. To make a diagnosis, a bone biopsy should be obtained, and AFB stain and/or cultures should be performed. Treatment of MAC infection generally consists of a combination of a macrolide plus ethambutol. Azithromycin or clarithromycin are commonly used agents from the macrolide class . MonotheMAC osteomyelitis may be an underdiagnosed condition in patients with HIV who are on ART with adequate CD4 counts. Clinicians should maintain a high index of suspicion for MAC osteomyelitis when preliminary cultures are unrevealing and infection is refractory to treatment, despite adequate CD4 counts and appropriate ART therapy. As AFB cultures may take weeks for the result, it may be prudent to initiate treatment for MAC osteomyelitis if clinical suspicion is high. Early diagnosis and administration of treatment may help prevent further joint involvement and damage, as well as multiorgan involvement from disseminated disease.


Although convenient single-tablet antiretroviral regimens have been developed to treat HIV in recent years, some patients have continued to take a multi-tablet treatment, nevirapine extended-release (NVP XR) plus two nucleoside reverse transcriptase inhibitors (NRTIs) due to its excellent safety profile. This observational study examined the demographic and clinical characteristics of HIV-positive patients who switched to dolutegravir plus lamivudine (DTG/3TC) from NVP XR plus 2 NRTIs, following discontinuation of NVP XR from the Canadian market.Virally suppressed (< 50 cps/mL) HIV-positive adults ≥18 years who switched from NVP XR plus 2 NRTIs to DTG/3TC between 20 August 2019 and 30 April 2020 were retrospectively identified from Electronic Medical Records housed at Spectrum Health in British Columbia, Canada. Baseline demographic and clinical characteristics were summarized using descriptive statistics at the date of first DTC/3TC prescription. Virologic control, CD4 cell count, weight-related changes and exploratory characteristics related to metabolic syndrome were summarized at baseline and at 12 ± 6-months post-switch using descriptive statistics. Reasons for treatment discontinuation were also captured.Sixty-nine patients were identified . Mean length of use (±SD) of NVP XR was 4.6 ± 2.6 years. Sixty-three (91.3%) persisted on DTG/3TC at the 12-month timepoint post-switch with 61 (96.8%) virally suppressed < 50 cps/mL and all 63 (100%) virally suppressed < 200 cps/mL. Among persistent patients with CD4 cell counts available, mean CD4 cell count (±SD) remained stable, increasing slightly from 724.4 ± 238.4 to 740.3 ± 240.6 cells/uL. All six (8.7%) patients who discontinued DTG/3TC, discontinued due to tolerability and not effectiveness reasons.Our findings are the first to examine real-world use of single-tablet, 2-drug DTC/3TC among patients who switched from multi-tablet, 3-drug NVP XR plus 2 NRTIs in Canada. The majority persisted on DTG/3TC and remained virally suppressed at the < 50 cps/mL level 12-months post-switch. This, coupled with excellent tolerability, demonstrates the effectiveness of DTG/3TC in maintaining viral suppression among a unique and stable group of older men.Joss de Wet, MBChB CCFP FCFP, Gilead: Advisor/Consultant|Gilead: Board Member|Gilead: Grant/Research Support|ViiV: Advisor/Consultant|ViiV: Board Member|ViiV: Grant/Research Support Joann K. Ban, PharmD, MSc, GlaxoSmithKline Canada Inc.: Employee Gustavo Verdier, BSc, BPharm, MBA, GlaxoSmithKline: Stocks/Bonds|ViiV Healthcare ULC: Salary Juejing Ling, MSc, GSK: Employee of IQVIA , a company that receives consulting fees from GSK. Andrean Bunko, MPH, GlaxoSmithKline Inc.: GSK contracted with IQVIA for this and other projects. I am acting as an author in capacity of my employment with IQVIA. Michael McKimm, BSc, ViiV Healthcare: employee.


Expanding access to effective antiretroviral therapy (ART) is a major tool for management of Human Immunodeficiency Virus (HIV) infection. However, rising levels of HIV drug-resistance have significantly hampered the anticipated success of ART in persons living with HIV (PLWH), particularly those from Africa. Though great strides have been made in Ghana toward achieving the UNAIDS “95-95-95” target, a substantial number of PLWH receiving ART have not attained viral suppression. This study investigated patterns of drug resistance mutations in ART naïve as well as ART-experienced PLWH receiving first-line regimen drugs from Ghana. In a cross-sectional study, blood samples were collected from HIV-1 infected adults (≥18 years) attending HIV/AIDS clinic at the Eastern Regional Hospital, Koforidua, Ghana from September to October 2017. Viral RNA isolated from plasma were subjected to genotypic drug resistance testing for Protease Inhibitors (PI), Reverse Transcriptase Inhibitors (RTI), and Integrase Strand Transfer Inhibitors (INSTI). A total of 95  HIV-1 infected participants were sampled in this study. Sixty percent (50/84) of the ART-experienced participants were controlling viremia . Of the 95 patient samples, 32, 34, and 33 were successfully sequenced for protease, reverse-transcriptase, and integrase regions, respectively. The dominant HIV-1 subtypes detected were CRF02_AG (70%), and A3 (10%). Major drug resistance associated mutations were only detected for reverse transcriptase inhibitors. The predominant drug resistance mutations were against nucleos(t)ide reverse transcriptase inhibitors (NRTI)—M184V/I and non-nucleos(t)ide reverse transcriptase inhibitors (NNRTI)—K103N. In the ART-experienced group, M184V/I and K103N were detected in 54% (15/28) and 46% (13/28) of individuals, respectively. Both mutations were each detected in 33% (2/6) of ART naïve individuals. Multiclass resistance to NRTI and NNRTI was detected in 57% of ART-experienced individuals and two ART naïve individuals. This study reports high-level resistance to NNRTI-based antiretroviral therapy in PLWH in Ghana. However, the absence of major PI and INSTI associated-mutations is a good signal that the current WHO recommendation of Dolutegravir in combination with an NRTI backbone will yield maximum benefits as first-line regimen for PLWH in Ghana. Infection with HIV-1 continues to be a major global public health issue. Globally, over two thirds of the estimated 37.7 million people living with HIV (PLWH) as of 2020 were from Sub-Saharan Africa . Indeed,In Ghana, the initiation of treat all policy has significantly expanded access to ART, however, only 66% of PLWH receiving ART have achieved viral suppression . Though 2 in the Eastern region of Ghana. Blood samples were collected from consenting participants between September and October 2017. Clinical and demographic data were obtained from hospital records for all consenting participants.In this cross-sectional study, we enrolled HIV-1 infected adults (≥18 years) attending an HIV/AIDS clinic at the Eastern Regional Hospital, Koforidua, Ghana. All participants resided in communities located within an area of 1,200 kmViral RNA was isolated from 200 μl of plasma samples using High Pure Viral RNA Kit  following the manufacturer’s protocol, and stored at −80°C until use. One-step reverse transcription PCR (RT-PCR) was performed for the PR, RT, and IN regions of the polymerase gene, using PrimeScript™ II High Fidelity One Step RT-PCR Kit  following the manufacturer’s protocol. This was followed by nested PCR using KOD–Plus–Ver.2  following manufacturer’s recommendation. Samples were then purified with the FavorPrep GEL/PCR Purification Kit , and sequenced using Big Dye Terminator cycle sequencing kit version 3.1  and 3730/3730xl DNA Analyzer . Details of primers  used arep less than 0.05 were considered significant.Statistical analyses were performed using GraphPad Prism version 9. Comparison between categorical variables between groups was performed with Fisher’s exact test. Continuous variables were assessed using Wilcoxon rank sum test. Values of n = 34, VL ≥ 1,000 copies/ml) was 204 cells/ml . All participants receiving ART were on first-line regimen consisting of two NRTI (Zidovudine + Lamivudine or Tenofovir disoproxil fumarate + Lamivudine) and one NNRTI (Efavirenz or Nevirapine). Majority  of participants receiving ART were on Tenofovir disoproxil fumarate + Lamivudine + Efavirenz combination first-line regimen . Eleven (11/95) were ART naïve while 84 were receiving ART . Three o regimen .n = 41): 28(68%), 31(76%), and 31(76%) for PR, RT, and IN, respectively. In 30 samples with both PR and RT sequences, 21(70%) were classified as CRF02_AG and 3(10%) as A3  as A3 ,B. CRF06In this study, we classified major mutations as those defined in the 2019 edition of the IAS–USA drug resistance mutations list . ResistaAmong the six ART naïve patient RT sequences, major DR mutations were detected in two patients. Both patients possessed M184V/I, the only major NRTI resistance mutation detected in ART naïve sequences. For major NNRTI mutations, one patient possessed only K103N while the other possessed K103N in addition to V108I, Y181C, G190A, and E138A mutations.A profile of inferred levels of resistance to commonly used antiretrovirals is presented in Increasing rates of HIV drug-resistance has impeded the progress of ART in PLWH, particularly those from Africa. As of 2018, viral suppression was achieved in 66% of PLWH receiving ART in Ghana . LikewisIn Western and Central Africa, CRF02_AG has been the predominant HIV-1 subtype . ConsistWe report a high frequency of major mutations associated with resistance to NRTI (57%) and NNRTI (75%) in PLWH receiving ART. The pattern and frequency of the most common mutations, such as M184V/I, K103N, T215F/Y, G190A/S, P225H, Y181C, and V106A were consistent with reports from Ghana and other sub-Saharan African countries . The nonThe preferred first-line regimen in Ghana during the study period was Tenofovir disoproxil fumarate + Lamivudine + Efavirenz . Thus, mOur study is limited by our inability to ascertain the absence of previous ART usage in the patients we classified as ART naïve. Since undisclosed antiretroviral use in individuals presenting as treatment naive is common in Africa , we may Nonetheless, this study reports high-level resistance to NNRTI-based first-line regimens in Ghana in 2017 and provides evidence of the effectiveness of PI and INSTI in Ghana since no major DR mutations were detected against these drugs. The WHO currently recommends using dolutegravir in combination with an NRTI backbone as first-line regimen as well as second-line regimen for PLWH failing non-dolutegravir based regimen . This ishttps://www.ncbi.nlm.nih.gov/genbank/), accession number ON863360-ON863428.The data presented in the study are deposited in the GenBank repository -Ghana , and the Ethical Committee of National Institute of Infectious Diseases (NIID)-Japan . All study participants provided written informed consent to participate in this study.PP, EB, TK, MN, TMi, KI, WA, and TMa conceived and designed the experiments. GA-T, MA, SO, CA, DK, TA, and TMi contributed to demographic data and sample collection. PP, TA, CA, DK, and NN performed the experiments. PP, LR, and TK analyzed the data. PP, TK, and EB contributed to drafting the manuscript. HK, WA, and TMa critically reviewed and edited the manuscript and secured funding for this study. All authors contributed to the article and approved the submitted version.This study was supported by Japan Agency for Medical Research & Development (AMED) , and AMED-JICA .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Hypertriglyceridemia is associated with subclinical atherosclerosis and vascular inflammation even when low-density lipoprotein cholesterol levels are normal. However, few cohort studies on hypertriglyceridemia have been conducted in males with higher susceptibility to human immunodeficiency virus (HIV)-related deterioration of arterial structure and function. Our objective was to investigate the incidence of hypertriglyceridemia during treatment with combination antiretroviral therapy (cART) in males with HIV and explore its related risk factors.In this retrospective study, we included 309 males living with HIV (median age 31 years [interquartile range 26–42.5]) who initiated cART treatment in our hospital from January 2013 to December 2018. We collected follow-up data on serum triglycerides and other related information as of June 31, 2021. A Cox proportional hazards regression model was used to analyze the related risk factors.P = 0.004}, body mass index (BMI) ≥ 24.0 kg/m2 , borderline high triglyceride at baseline , and 3TC + zidovudine (AZT) + EFV regimen , or 3TC + TDF + lopinavir/ritonavir (LPV/r) regimen  were independent risk factors for hypertriglyceridemia.In 666.7 person-years, hypertriglyceridemia occurred in 140 patients (triglyceride ≥2.3 mmol/L [200 mg/dL]), and the incidence rate was 21.0 per 100 person-years . Multiple Cox regression analysis showed that baseline CD4/CD8 ratio < 0.20 : 1.381–5.296]; During the course of cART treatment, the incidence of hypertriglyceridemia in males with HIV was high. The main risk factors influencing its occurrence are a low baseline CD4/CD8 ratio, overweight and obesity, and the use of AZT or LPV/r in the cART regimen. With the advent of combination antiretroviral therapy (cART) with high antiviral efficiency, human immunodeficiency virus (HIV) infection has changed from a fatal to a chronic disorder, but the clinical use of cART has been associated with a wide range of metabolic disorders , 2. FurtLow-level inflammation and chronic immune activation act on lipids through various mechanisms, making them more prone to atherosclerosis . Heighte+ T lymphocyte count; and (4) the time interval from diagnosis to initial treatment was < 12 months. Exclusion criteria were: (1) patients who were taking lipid-lowering drugs; (2) baseline serum TG ≥ 2.3 mmol/L (200 mg/dL); (3) patients who were treated with cART before follow-up; and (4) those with tumors, autoimmune disease, kidney failure, and liver cirrhosis.This was a retrospective cohort study of people living with HIV who initiated cART treatment at the Fifth Medical Center of PLA General Hospital from January 1, 2013 to December 31, 2018. Inclusion criteria were: (1) individuals aged 18 years or older; (2) males living with HIV; (3) relevant clinical data such as baseline serum triglyceride (TG) levels, baseline HIV ribonucleic acid (RNA) level, and baseline CD4For eligible participants, serum TG levels and other relevant clinical data were collected from patients up to June 31, 2021. During the first 3 months after the start of cART, patients were followed up approximately once a month and then every 3 months . A patient was considered lost to follow-up if the interval between visits exceeded 12 months, or if the patient’s lipid data were missing for > 12 months.The primary endpoint was hypertriglyceridemia (serum TG ≥ 2.3 mmol/L [200 mg/dL]). The occurrence of serum TG ≥ 2.3 mmol/L was considered a target event during the follow-up period . For patients who switched to cART regimens during the follow-up, the first appearance of TG ≥ 2.3 mmol/L was taken as a node, and the cART regimen at that time was recorded. The relevant information of the participants included in the group mainly included demographic and clinical characteristics, and laboratory results. The demographic and clinical data collected included age, sex, body weight, height, mode of HIV acquisition, cART regimen, education level, time of HIV diagnosis, and presence of diabetes. Laboratory tests included TG (mmol/L), plasma glucose (mmol/L), total cholesterol (mmol/L), CD4 cell count (cells/μL), CD8 cell count (cells/μL), plasma HIV RNA (copies/mL), and alanine aminotransferase .According to current clinical practice guidelines for the treatment of dyslipidemia, it is recommended to start using statins when the serum TG > 2.3 mmol/L (200 mg/dL) . Hypertr2): BMI ≥ 24.0 kg/m2 was defined as being overweight or obese; 18.5–23.9 kg/m2 as normal; and <18.5 kg/m2 as being underweight [The diagnosis of HIV infection was made in accordance with the diagnostic criteria of the Chinese guidelines for the diagnosis and treatment of HIV/acquired immunodeficiency syndrome (AIDS) (2021 edition)” . Body maerweight . Liver ierweight . Hyperglerweight .All analyses were performed using Statistical Package for the Social Sciences (SPSS) version 25.0  or GraphPad Prism 9. The Shapiro–Wilk test was used to test whether the data conformed to a normal distribution. When continuous variables were normally distributed, the mean and standard deviation (SD) were used. When continuous variables were non-normally distributed, the median with interquartile range (IQR) was used. Categorical variables were summarized as numbers (%).As patients entered the cohort at different times, the incidence density was calculated to account for the occurrence of hypertriglyceridemia during follow-up. Person-years were counted on an individual basis, starting from the date cART treatment was initiated and ending with the time of hypertriglyceridemia detection, a follow-up period of 48 months, discontinuation of the cART regimen, last lipid test, or June 31, 2021, the final date of the follow-up, whichever occurred first. The incidence of hypertriglyceridemia was defined as the number of new cases during the follow-up period divided by the number of person-years of follow-up. The cumulative incidence and Kaplan–Meier curves of hypertriglyceridemia were drawn using GraphPad Prism 9, and the results of the log-rank test were calculated using GraphPad Prism 9. The approximate normal distribution method was used to calculate the 95% confidence interval (CI) for the incidence rate.P < 0.20 in univariate analysis were entered into a multiple Cox proportional hazard model. All reported P-values were two-sided. Statistical significance was set at P < 0.05. The adverse effects of dyslipidemia on blood vessels are a relatively slow process. In the first few months of initiating cART for people living with HIV, the relevant indicators may fluctuate due to the sudden effects of antiviral drugs. To make the research results more practical, we excluded events within 3 months of the baseline.Cox proportional hazards models were used to analyze risk factors for hypertriglyceridemia. Variables with A total of 309 males with HIV met the study criteria from January 1, 2013 to June 31, 2018 , CD8 cell count ≥1000 cells/μL (P = 0.045), HIV RNA load ≥5 log10 copies/mL (P = 0.017), borderline high TG at baseline (P < 0.001), 3TC + AZT + EFV (P < 0.001), and 3TC + TDF + LPV/r (P < 0.001) regimen were risk factors for hypertriglyceridemia in patients receiving cART treatment. Age, mode of HIV acquisition, education, ALT, plasma glucose, and TC levels were not significantly associated with hypertriglyceridemia in the univariate analysis , during which 140 patients developed hypertriglyceridemia with an incidence of 21.0/100 person-years , CD4/CD8 ratio < 0.20 , borderline high TG , 3TC + AZT + EFV regimen , or 3TC + TDF + LPV/r regimen  were statistically significant  during antiretroviral treatment in cART-naive people was 227.7/1000 person-years . One posMultivariate analysis showed that the incidence of hypertriglyceridemia in overweight or obese patients was higher than in those with normal weight. This suggests that overweight or obese patients should pay more attention to cART regimen selection. Simultaneously, they should pay attention to changing their lifestyle and reducing their weight to the normal range as soon as possible. The presence of CD4 cell counts < 200 cells/μL before treatment in people living with HIV usually indicates that the patient’s immunity has been severely damaged. At this time, even if patients with CD4 cell counts < 200 cells/μL receive the same cART regimen as those with CD4 cell counts > 350 cells/μL, patients’ immunity recovery is weak, never reaching the level achieved by patients with CD4 cell counts > 350 cells/μL. Grunfeld C et al. found that TG levels were above normal in patients with CD4 cell counts < 200 and approximately twice normal in symptomatic patients with AIDS . In our The HIV viral load is associated with the disease stage in patients and is relatively high in those who have just been infected or are in the AIDS phase. Statistically significant differences in the incidence of hypertriglyceridemia between the subgroup with geometric viral loads between 4.00 and 4.99 and the subgroup with geometric viral loads < 4.00 may reflect differences in the patient’s immunity. Patients with geometric viral loads < 4.00 had greater immunity. Because our inclusion criteria required < 12 months from the initial diagnosis to treatment, the time to infection for most patients may be short, and the virus causes less damage to the patient’s immunity. This may explain the small difference between the subgroup with a geometric viral load > 5.00 and the subgroup with a geometric viral load < 4.00. In combination with the associated CD4/CD8 ratio results, the high risk of hypertriglyceridemia may be associated with the low baseline immunity in our patient. The patient’s low immunity may lead to an increase in susceptibility to related inflammation and infection and eventually to an increase in TG levels .Our study showed that the risk of hypertriglyceridemia in patients with borderline high TG was 3.457 times higher than that in those with normal TG levels. For these patients, special lipid-lowering measures, such as strengthening physical exercise or targeted dietary changes, should be carried out at the same time as choosing the cART regimen. Ozemek et al. showed that physical activity and sports training could improve the cardiovascular health of adults living with HIV, and even in the presence of cardiovascular disease, it can help reduce the mortality rate . Among tThe advantages of our study lie in its longitudinal cohort design, which is more reliable than that of the cross-sectional design in confirming causality, and it is of great theoretical and practical significance to guide clinical practice by analyzing related risk factors from a clinical perspective. However, there are also limitations, such as only male participants and single centers containing only people living with HIV-1 were included. In the future, females can be included in the study, and the sample size can be expanded to verify further and promote the conclusion of this study.2, or borderline high TG at baseline during antiviral treatment, and pay special attention to patients who use the antiviral regimen, including AZT or LPV/r, and check their TG levels regularly.In conclusion, the incidence of hypertriglyceridemia was high in male cART-naive participants during antiviral treatment. Therefore, clinicians should pay attention to the changes in TG levels of patients with baseline CD4/CD8 ratio < 0.20, BMI ≥ 24.0 kg/m


Rapid switching from second-line to third-line antiretroviral therapy (TLART) is crucial for achieving viral suppression and reducing illness related to ART failure.This retrospective cohort study quantified the waiting periods for TLART initiation after virological failure on second-line therapy was detected, assessed factors associated with delays and assessed the outcomes of patients started on TLART.Data were abstracted from records of individuals eligible for TLART, and the time to TLART initiation was calculated. Reasons for delays were categorised according to patient, clinician and administrative processes.Fifty-four patients were eligible for TLART. The median delay from the date of first viral load > 1000 copies/mL on second-line therapy to the start of TLART was 640 days (interquartile range [IQR]: 451–983 days). Of the patients that failed second-line and had an application for TLART, 41 (75.6%) were eventually initiated on TLART, and 11 (20.4%) died while waiting. Delays were primarily due to non-response to the first unsuppressed viral load while on second-line ART: 467 days (IQR: 232–803 days).This study showed a prolonged waiting period for TLART initiation mainly between detected high viral load to requesting of resistance tests; many factors could have contributed, including clinicians’ delayed responses to elevated viral loads. Mortality was high before TLART could be initiated. The process of TLART initiation needs to be made more efficient. Healthcare services should be strengthened to (1) recognise and manage virological failure early and identify those eligible for resistance testing, (2) ensure access to resistance testing and appropriately skilled clinicians, and (3) streamline approvals and delivery of TLART. Resistance may be due to a complex interaction of multiple factors, including poor adherence, drug interactions, the low genetic barrier to resistance of some antiretroviral medications, drug stock-outs and delays in regimen switching after virological failure.6South Africa has the largest HIV epidemic and the largest population on antiretroviral therapy (ART) globally. In 2018, it was estimated that 62% of approximately 7.5 million HIV-infected individuals were on ART.7 Second-line failure was defined as two viral loads > 1000 copies/mL six months apart.4 During the period relevant to this study, the criteria for third-line eligibility were: > 1 year of a PI-based regimen with virological failure despite adherence support and evidence of PI resistance.10 During the period of this study, clinicians (doctors and nurse practitioners) could diagnose virological failure if a patient had been on a PI-based regimen for more than a year9 and had two detectable viral loads taken six months apart. Only then was a viral resistance test requested. Only when resistance mutations compromising lopinavir/ritonavir or atazanavir/ritonavir (the two PIs available for second-line) were present could a third-line regimen be considered.10At the time of this study, patients who failed non-nucleoside reverse transcriptase inhibitor (NNRTI) based first-line regimens were routinely switched to protease inhibitor (PI)-based second line.The protocol of switching patients to third-line antiretroviral therapy (TLART) in South Africa is a complex process requiring diagnosis, approval by a committee of experts, procurement of medication, delivery of medications, monitoring adherence and outcomes. An application is made to the TLART Committee, and only once their approval has been obtained and appropriate regimens recommended can provincial and hospital pharmacies make arrangements for procurement of the proposed regimen. Delays may occur at various points during this process, from recognition of virological failure to requesting resistance tests, obtaining results, submitting TLART applications, and receiving replies and recommendations from the TLART Committee. For this study, these delays have been classified as patient-related, clinician-related or administrative delays. The aim of this study was to quantify delays in TLART initiation, identify the consequences for patients and investigate factors associated with delays.This retrospective cohort study examined the clinical records of adult patients receiving second-line ART with documented PI resistance. The review period was between June 2015 and June 2019 in three hospitals in North West province, South Africa. This is the period when 2015 HIV guidelines were in place. This study was conducted in three district hospitals each serving a wide range of communities in the province where some patients travel long distances to hospital and some use government transport from local clinics and others use their own transport. In these hospitals second-line patients are mainly managed by doctors assisted by nursing staff. Two of these hospitals  have specialist support, while Joe Morolong (previously known as Vryburg) hospital gets telephonic specialist support from Tshepong hospital.Data were extracted from three sources: hospital TLART databases, the National Health Laboratory Service (NHLS), and Tier.Net, a national ART patient medical record and database. The resulting database has information on viral load tests, including the collection dates and results at the time of the initial diagnosis of second-line failure, HIV resistance assay results showing PI resistance and the date each specimen was taken, the dates the first application form was completed and then submitted to the TLART Committee, the date of response from the TLART Committee with ART recommendations and, finally, the date TLART was initiated.Further data were retrieved from individual hospital patient records to characterise factors contributing to delays. These included the date the doctor reviewed the patient’s PI resistance results, the date of the first-ever TLART prescription and the date it was dispensed, and the date patients returned to initiate TLART. We also documented the following adverse events occurring before TLART initiation: hospitalisation, opportunistic infections (WHO stage 3 and 4 infections), and death.P < 0.05. Key variables were average overall delay for TLART initiation and patient, clinician, and administration-related factors associated with the delay.Data were analysed using Stata 14.2 with a significance threshold of For this study, the overall delay was defined as the time from the first detected viral load (≥ 1000 copies/mL) after completing at least a year on second-line ART to the date the patient received TLART. The overall delay was stratified by hospital, age category and gender. The rank-sum test and the K-test for equality of medians were used to explore differences in total delay for the different strata.The proportion and the characteristics of those who died while waiting for TLART, those who were suppressed on TLART and factors related to suppression are also reported. The scores obtained from the laboratory database were defined as the sum of each mutation penalty score for a drug. Stanford scores were used to categorise resistance: less than 10 indicated susceptible; scores between 10 and 14 indicated potential low-level resistance; scores between 15 and 29 indicated low-level resistance; scores between 30 and 59 indicated intermediate resistance; scores of 60 or greater indicated high-level resistance.Clinician-related delays for the purpose of this study were: reaction to initial elevated viral loads in patients who have been on a second-line ART regimen for more than one year, delays in resistance testing once criteria for testing are met, and delay in drafting the application to the TLART Committee. The median time from the first viral load result > 1000 copies/mL after at least a year on second-line ART to the date of application to the TLART Committee was determined and then stratified by age, gender, hospital and number of elevated viral loads while on second-line treatment.Administrative delays evaluated, first, the time for responses from the TLART Committee, calculated from original submission to TLART Committee until the doctor received approval. Second, pharmacy-related delays considered the availability of TLART medications on the day of the first prescription to identify if drug availability contributed to TLART initiation delays. Administrative delays were stratified by age, gender and by study hospital.P < 0.25 in univariate analyses were included in the multivariable model.For this study, patient-related factors were defined as missed appointment dates or failing to collect treatment on the prescription date. A univariate and multivariable binomial model was used to determine patient-level factors independently associated with waiting times > 6 months. Patient factors included in multivariable analyses were age, gender, clinical history and viral loads. Variables with Approval was obtained from the University of Human Research Ethics Committee  and from the chief executive officers and the heads of internal medicine departments at the three study hospitals.During the study period 88 patients with PI resistance testing were registered at the NHLS in North West and 54 patients were enrolled into the study. Reasons for exclusion are shown in The baseline characteristics and outcomes of the 54 study patients are shown in The median delay from first viral load > 1000 copies/mL of the two viral loads done 6 months apart to submission of application to the TLART committee in the 54 study patients was 500 days (IQR: 301–805 days)  and 36 .Analyses of categorical variables associated with time to TLART application are shown in A total of 41 patients were started on TLART and 32 (74.4%) had viral load suppression 3–12 months after initiation of TLART. Some of these patients developed opportunistic infections during the time when they were still waiting for TLART. They had adverse events while waiting to initiate TLART, either an opportunistic infection or hospitalisation during the waiting period.11 The adverse outcomes described in this study could be reduced if patients with treatment failure were identified earlier and timeously switched to a more effective regimen. This study shows that approximately three-quarters of patients who switched to third-line therapy achieved viral suppression.This retrospective cohort study describes people living with HIV who failed second-line therapy and survived to have an application submitted to the South African TLART Committee. The median delay to initiate TLART was almost 18 months while patients continued ineffective second-line therapy. The longest delays occurred in recognising and diagnosing second-line treatment failure by clinicians. The consequences of delaying a switch to more effective ART include accumulation of resistance mutations, opportunistic infections, hospitalisations and death. Indeed, 20% of the cohort died in this study while waiting for TLART. Similar negative consequences of delayed switching are described in Tanzania, which showed that delayed switching increased the risk of opportunistic infections and Shroufi et al. (2019) estimated that avoiding delayed switching can prevent 10 215 deaths annually in South Africa.11 as well one of the few studies that showed significant delays in switching patients to second-line ART.13 While there is no recommended time the process should take, there is global consensus that earlier switching of ART improves patient outcomes for those on failing regimens.18The delays reported in this study are similar to those observed in two South African studies that examined delays in switching to second-line regimens,13 A study from the Western Cape found that factors associated with the delays were predominantly health system-related and mainly pertained to patient referrals.17This study identified factors associated with switching delays, including clinician-related and administrative factors such as delayed response from the national TLART Committee and delayed applications for switching. There are no studies that have examined these delay factors. Others have reported modifiable programmatic factors such as insufficient prescriber notes and lack of availability of viral load results identified with delays in switching to second-line regimens in a study conducted in Durban, South Africa.While this study provides helpful insight into the process of TLART initiation, it was subject to some limitations. First, this study did not investigate the clinician’s knowledge of the proper process for TLART application nor their knowledge of advanced HIV management. Second, processes of the TLART Committee were not fully examined. Third, findings are likely to be context specific, and will be influenced by regional resource limitations such as staff capacity, training levels, efficiency of referral pathways, lab capacity and other health system factors. Finally, this study was limited to patients with identified PI resistance – a full understanding of the cascade of care for TLART should include all patients experiencing virologic failure on second-line ART.Future studies should assess the entire process the TLART Committee follows to make the final decision and evaluate what influences clinicians’ responses to high HIV viral loads and PI resistance results.We found prolonged waiting periods between virological failure and resistance testing, and between PI resistance detection and the initiation of TLART. Severe adverse events  occurred during these delays. The processes ending in TLART initiation needs to be made more efficient. Healthcare services should be strengthened to (1) recognise and manage virological failure early and identify those eligible for resistance testing, (2) ensure access to resistance testing and appropriately skilled clinicians, and (3) streamline approvals and delivery of TLART. The results compel further exploration into the many factors affecting these process steps to identify specific areas for quality improvement.


Jamaica did not achieve the UNAIDS 90-90-90 targets in 2020. This study aimed to examine trends and factors associated with uptake of HIV treatment among people living with HIV (PLHIV) in Jamaica and to assess the effectiveness of revised treatment guidelines.This secondary analysis used patient-level data from the National Treatment Service Information System. The baseline sample was 8147 PLHIV initiating anti-retroviral treatment (ART) between January 2015-December 2019. Descriptive statistics were used to summarize demographic and clinical variables and the primary outcome timing of ART initiation. Multivariable logistic regression was used to assess factors associated with ART initiation (same day vs 31+ days), using categorical variables for age group, sex and regional health authority. Adjusted odds ratios and 95% confidence intervals are reported.Most persons initiated ART at 31+ days  after the first clinic date or on the same day . Same day ART initiation increased from 37% to 51% over 5 years and was significantly associated with males , 2018 , 2019 . late HIV diagnosis  and viral suppression at the first viral load test . ART initiation at 31+days was associated with 2015  and 2016  compared to 2017.Our study shows that same day ART initiation increased between 2015–2019, however it remains too low. Same day initiation was associated with the years after Treat All implementation and late initiation before Treat All, providing evidence of the strategy’s success. In order to achieve the UNAIDS targets, there is a need to also increase the number of diagnosed PLHIV retained on treatment in Jamaica. Further studies should be conducted to understand important challenges to accessing treatment as well as differentiated care models to improve treatment uptake and retention. In 2019, The Caribbean region continued to have the second highest regional rate of HIV prevalence and second highest ratio of female to male cases after Sub-Saharan Africa . CompareThe Government of Jamaica has provided public access to HIV treatment since 2004 . There aTo improve treatment outcomes and achieve the 95-95-95 targets, the Ministry of Health and Wellness (MoHW) implemented the World Health Organization’s recommended Treat All (or Test and Start) strategy in 2017 . RandomiThe National HIV Strategic Plan recommends an analysis of factors associated with ART uptake in order to improve treatment outcomes. This study aims to describe PLHIV who accessed ART and assess factors associated with treatment uptake. This is the second paper in a series of manuscripts that aim to assess HIV treatment outcomes for Jamaica based on demographic and clinical factors as well as assess the implementation of Treat All. In a previous paper we demonstrated associations between routinely collected demographic variables and HIV stage of diagnosis and viral load status .This secondary analysis uses the National Treatment Site Information System (TSIS2). TSIS2 is a centralized case-based database, governed by the MoHW and currently used by all public, non-governmental and some private HIV treatment facilities in Jamaica. This dataset did not include private providers. TSIS2 stores patient level demographic and clinical data using over 100 variables.The MoHW Internal Review Board provided ethical approval (Study No: 2017/20). The dataset was extracted by the MoHW and fully anonymized before sharing with the study investigator, as a result patient consent was waived.The analytical sample consisted of 8147 PLHIV, 15 years and older, who initiated HIV treatment between January 2015 and December 2019.Bivariate analysis was used to assess routinely collected categorized demographic and clinical variables related to the pre-defined outcome:Timing of ART initiation based on the time interval between the first clinic date and the ART initiation date. If these dates were the same, patients were classified as having same-day ART initiation. Timing of ART initiation /days is reported using six categories .3 were characterized as achieving early diagnosis, while a baseline CD4 <350 cells/mm3 was defined as late diagnosis.The categorical variables assessed were: age group at time of treatment initiation, sex, location by regional health authority (RHA) and first viral load (vl) test status (suppressed <1000 copies/mL or non-suppressed ≥1000 copies/mL) as defined by the current national treatment guidelines . HIV staR Programme, version 3.5.3 [All categorical variables with a p-value <0.05 from the bivariate analyses were used in a multivariable logistic regression model to assess the factors associated with the binary primary outcome; ART initiation (31+ days vs. same day initiation). We report adjusted odds ratios and 95% confidence intervals. Data was analysed using on 3.5.3 .Persons initiating treatment were more likely to be female , 20–39 years  and located in the SouthEast Region  . OverallOnly 3% (n = 277) of the sample had preclinic ART initiation . For posThe proportion of PLHIV with same day ART initiation increased each year from 37% in 2015 to 51% in 2019  and therSame day ART initiation was associated with males compared to females , 15–19 years old compared to 20–39 years olds , persons located in the WRHA compared to those from SERHA , late HIV diagnosis  and viral suppression at the first viral load test  . Late AROur study population has slightly more females (54%) than males (46%). The majority of PLHIV (60%) are diagnosed early (CD4 ≥ 350); similar proportions initiate treatment on the same day and at 31+ days though same day treatment increased in 2018; and 47% were virally suppressed at their first viral load test.The overall proportion of PLHIV with same day ART initiation increased from 37% in 2015 to 51% in 2019. However, from 2015–2017 the proportions were similar and the increase occurred in 2018, one year after the “Treat All” strategy was implemented. This suggests that the strategy was successful, though in 2019 over one third (35%) of PLHIV still preferred to wait 31+ days before starting ART. PLHIV with a late diagnosis and therefore possibly symptomatic, were more likely to initiate treatment early. This means the sickest patients were being treated with urgency which did yield results of majority achieving a suppressed viral load at the first viral load test.Same day ART initiators were more likely to be male, 15–19 years old, located in the WRHA, had a late HIV diagnosis and virally suppressed at the first viral load test. Persons starting ART in 2018 and 2019 were also more likely to start treatment same day. So, a year after implementation of the new strategy, results were becoming evident. Males poor health seeking behaviour may explain late diagnosis which could result in clinical symptoms that prompt immediate treatment initiation. Same day ART initiation is a key goal of the Treat All strategy and while this is important to improving HIV outcomes, ensuring persons are also ready to start treatment is critical . EvidencAt the regional health level, same day initiation was more likely in the Northeast and Western Region compared to Southeast Region while late initiation was more likely in the Southern Region. This means implementation of the strategy may not have been consistent across the country and possibly delayed in the Southern Region. Increasing access to ART requires expanding several services and ensuring readiness at all levels of care.There was an overall increase in PLHIV starting treatment from 2015–2019, going from 1106 persons in 2015 and 1500 persons in 2016 to approximately 1800 persons starting treatment each year from 2017–2019. So, in conjunction with the scale up of same day treatment, the number of persons starting treatment also increased but there was no appreciable change for a three-year period. Loss to care between diagnosis and ART retention has been the most common problem in delivery of HIV treatment services  and JamaWe acknowledge there are demand side factors that affect patients’ ability to access treatment, such as social challenges but there is a lack of research exploring supply side factors which can affect service delivery, patient management and bridge the analysis gap. This has become particularly relevant within the context of the COVID-19 pandemic which saw resources being diverted or slowed . It shouWe recognize the limitations of the data. Improved accuracy is expected if the data was normally distributed ,27 but mOur study shows that same day ART initiation has increased between 2015 and 2019 however it remains too low. Same day initiation was associated with males, late HIV diagnosis, ART initiation in 2018–2019 and virally suppression at the first viral load test while late ART initiation was associated with initiation years 2015–2016. In order to achieve the UNAIDS targets, there is a need to also increase the number of diagnosed PLHIV retained on treatment. Further studies should be conducted to understand important challenges to accessing HIV treatment as well as differentiated care models to improve retention.


Patients with HIV who adhere to antiretroviral (ARV) therapy can achieve and maintain viral suppression (defined as < 200 copies of HIV/mL). Integrated Health System Specialty Pharmacies (HSSPs) help patients overcome barriers to ARV adherence, but there are limited data on the impact of HSSPs on clinical outcomes. This study compared viral suppression for patients filling ARVs at UMass Memorial Specialty Pharmacy to those utilizing a non-integrated specialty pharmacy (non-HSSP).In this retrospective cohort study, patients aged ≥18 years with an HIV diagnosis, encounter at the UMass Memorial Medical HIV Clinic, an ARV medication order, and at least one viral load (VL) result between January 2018 and May 2022 were identified from the medical record. Data included: age, sex, race, ethnicity, comorbidities, and all VL results over the study period. Time of first HSSP fill date was used to identify patient start in the respective pharmacy. VL results were divided into time under HSSP or non-HSSP . The index time was first VL for patients in either the HSSP or non-HSSP group.To account for multiple VL measures per patient, a Generalized Estimating Equation logistic regression estimated odds ratios (OR) and a 95% confidence interval. An OR >1 indicates greater viral suppression.Viral load (VL) lab results were collected while patients were in Integrated Health System Specialty Pharmacies (HSSP) or Non-Integrated Specialty Pharmacy (Non-HSSP). Index time (time=0) is firts VL result while in HSSP or Non-HSSP. Examples of 3 patients timelines, each represents a lab result.Of the 889 patients identified, 326 provided VL results under HSSP while 681 contributed results for non-HSSP; 118 patients provided results for both groups . Of the 5,295 VL results, 2,028 were from HSSP patients and 3,267 from the non-HSSP group. Of the 5,295 total VLs, 90.6% indicated viral suppression, with the average rate of 91.0% in the HSSP group vs 86.0% in the non-HSSP group. Table 1 displays unadjusted and adjusted ORs estimates. The HSSP group had a higher rate of viral suppression . Sex, ethnicity, and race were not significantly associated with viral suppression, which decreased with Charlson Comorbidity Index (CCI) 1-3; increased with age; and increased over time (from index date of VL).Among patients evaluated at UMass Memorial HIV Clinic, those filling ARV medications at the HSSP demonstrated higher rates of viral suppression compared to patients utilizing a non-HSSP.Karen I. Salomon-Escoto, MD, Novartis: clinical trial PI Jonathan Kay, MD, Aker BioMarine AS: Grant/Research Support|Alvotech Swiss AG: Advisor/Consultant|Boehringer Ingelheim GmbH: Advisor/Consultant|Bristol Myers Squibb Co.: Advisor/Consultant|Fresenius Kabi: Advisor/Consultant|Galapagos NV: Grant/Research Support|Inmagene LLC: Independent Data Monitoring Committee member|Kolon TissueGene, Inc.: Independent Data Monitoring Committee member|Novartis Pharmaceuticals Corp.: Advisor/Consultant|Organon LLC: Advisor/Consultant|Pfizer Inc.: Advisor/Consultant|Samsung Bioepis: Advisor/Consultant|Sandoz Inc.: Advisor/Consultant|Scipher Medicine: Advisor/Consultant|Teijin Pharma Ltd.: Advisor/Consultant|Wolters Kluwer NV: Royalties for UpToDate


First, to offer best practice guidance for health practitioners working in the Southern African private sector. And, second, to offer guidance for those working in the public sector that complements public sector guidelines with more explanatory detail and advice for common clinical scenarios that are not covered in the public sector guidelines.A key principle is to harmonise the private and public sector guidelines wherever possible, so that unnecessary differences are eliminated. This is important because it allows for more consistent public health and educational messaging, and because patients may transition between the two sectors as their financial circumstances change. To facilitate this, individuals from the South African National Department of Health ART guidelines committee were part of the 2023 SAHCS ART guidelines committee. There are certain recommendations in the SAHCS Adult ART guidelines that are not included in the South African public sector guidelines for cost reasons  and in these situations, clinicians working in the public sector should follow the public sector guidelines. The guidelines only include treatment and diagnostic options available in southern Africa.Arguably the biggest change in the SAHCS ART guidelines 2023 iteration is the recommendation to recycle tenofovir (TDF) between first- and second-line regimens, instead of switching to zidovudine (AZT), as had previously been recommended.2 The results showed no difference between DTG and DRV/r, with excellent viral suppression rates of > 90% for both options at 48 weeks. Unexpectedly, the strategy of recycling TDF was shown to be non-inferior at 48 weeks, and superior by 96 weeks .3 This benefit of recycling TDF was seen even in patients with confirmed high-level resistance to TDF at baseline. The reasons for this finding are likely to be a combination of improved adherence due to a better tolerated once-daily regimen (as opposed to having to take less well-tolerated AZT 12-hourly), and the TDF K65R mutation’s residual ‘crippling’ effect on HIV viral replication.This guidance was derived from a group of trials published in short succession. The NADIA trial was a randomised trial that enrolled patients who were failing a first-line regimen consisting of tenofovir, lamivudine (3TC) or emtricitabine, and a non-nucleoside reverse transcriptase inhibitor (NNRTI). NADIA randomised participants in a two-by-two factorial manner to (1) dolutegravir (DTG) or darunavir/ritonavir (DRV/r) and (2) switching TDF to AZT, or continuing TDF for the nucleoside reverse transcriptase inhibitor (NRTI) backbone, in each case with 3TC.5 In the VISEND trial, participants on second-line tenofovir/lamivudine/dolutegravir (TLD) had a superior virological suppression rate at both < 1000 copies/mL and < 50 copies/mL VL thresholds compared to a protease inhibitor (PI)-based regimen that used AZT. In stages 1 and 2 of the ARTIST trial, 82% – 86% of patients on second-line TLD had a VL < 50 copies/mL at 24 weeks.The favourable findings in the NADIA trial with TDF recycling results were quickly supported by results from VISEND, a large randomised controlled trial conducted in Zambia, and ARTIST, a trial of patients in Cape Town.Put together, these trial findings support TLD as the second-line ART regimen of choice for those who fail an NNRTI-based first-line regimen. In this setting, TLD offers a more tolerable, once-daily, cheaper, and more scalable second-line regimen than previous AZT-based regimens. A further implication is that the switch from NNRTI-based therapy to TLD can now be made, regardless of the patient’s VL, since both 3TC/FTC and TDF can be recycled with DTG, whether or not there is resistance to these drugs.Thus, most people living with HIV can be expected to be on TLD, given that it is both the first-line therapy of choice as well as the recommended second-line therapy for those who have failed NNRTI-based first-line ART. Certain patients requiring third-line therapy after failing a second-line PI regimen may also be eligible for TLD. There are only limited exceptions to the recommendations for TLD, namely:Patients for whom TDF is contraindicated , in whom abacavir (ABC) or tenofovir alafenamide (TAF) should be considered.Patients who do not tolerate DTG, where efavirenz or rilpivirine (RPV) are alternatives.Rare patients who develop pure red cell aplasia on 3TC, who are. These patients can be switched to a dual regimen such as TDF + DTG .Patients who develop resistance to DTG. In these cases, DRV/r can be used instead, provided that DTG resistance is proven by resistance testing first.Patients who have developed PI-resistance on LPV/r or ATV/r-based second-line regimens and have cross-resistance to DRV/r. The guidelines recommend against prescribing TLD for such patients, but rather using TLD plus DRV/r unless there is high-level resistance to DRV/r.6 Abacavir-based regimens also offer potential adherence benefits since they can be given once-daily and are well tolerated. For these reasons, the guidelines recommend recycling ABC across first- and second-line ART for those patients in whom TDF is contraindicated, despite the lack of clinical trial data.The evidence for recycling TDF between first- and second-line ART is based on clinical trial data, but the same clinical trial data do not exist for recycling ABC, and it is not known whether the TDF evidence can be extrapolated to ABC. Virologically, the most common mutation seen with ABC is L74V rather than K65R, and there is evidence that the former causes a similar decrease in viral replication fitness to the latter.The implication of both TDF and ABC being recycled across regimens is that AZT therefore no longer forms part of any routinely recommended regimen – a welcome change given AZT’s propensity to cause mitochondrial toxicity.7 When used alone, TAF can be used down to an estimated glomerular filtration rate (eGFR) of 15 mL/min per m2, as well as in renal dialysis patients. However, in South Africa it is frequently co-formulated with emtricitabine, in which case its use is limited to patients with a minimum e GFR of 30 mL/min per m2. Thus the 2023 SAHCS guidelines recommend TAF as the drug of choice in patients with chronic hepatitis B, and either an e GFR of 30 mL/min per m2 – 50 mL/min per m2 or osteoporosis. It can also be used as an alternative to ABC in this e GFR range in patients without either of these two comorbidities. However, TAF has some downsides that the SAHCS guidelines committee felt precluded a broader frontline recommendation: compared to TDF it is associated with greater weight gain, an adverse lipid profile, and several important drug-drug interactions.For the first time, TAF is included as an option in the guidelines. This is an alternative tenofovir prodrug to TDF, with an improved renal and bone side-effect profile.11 Lopinavir is also associated with a worse lipid profile compared to other PIs. Therefore, the sole recommendation for use for lopinavir is when a patient requires both a PI and rifampicin-based tuberculosis therapy, because double-dosed lopinavir/ritonavir remains the only PI that can used in this situation. In practice, this scenario is rare since DTG-based regimens can be used in second-line therapy in almost all scenarios.Although the 2020 SAHCS guidelines laid out a clear order of preference for the choice of PIs – darunavir as first choice, atazanavir as second, and lopinavir third – the 2023 guidelines are more emphatic in recommending against lopinavir in almost all circumstances. Several studies have shown significantly better viral suppression rates with darunavir compared to lopinavir, likely driven by lopinavir’s poor gastrointestinal side-effect profile and the need to take the drug twice daily.A rise in creatinine when patients are commenced on a DTG-based regimen is a common and vexing issue for clinicians. Dolutegravir inhibits organic cation transporter-2 (OCT-2), thereby inhibiting creatinine’s renal secretion. A rise in serum creatinine concentrations is therefore frequently seen with commencement of the drug. Serum creatinine typically rises within the first few days of starting the DTG, and plateaus after 1–2 weeks. Crucially, it does not represent renal damage and, if the drug is stopped, creatinine levels fall rapidly to baseline again. However, since DTG is typically co-administered with TDF, the clinician is faced with the unwelcome task of trying to distinguish benign DTG-induced creatinine rises with the much rarer but more sinister renal impairment associated with TDF. The 2023 SAHCS guidelines offer a pragmatic approach, based on the pattern of DTG rise observed in the South African-based ADVANCE trial see .The 2023 SAHCS guidelines contain several other substantive updates, including guidance on enhanced screening for tuberculosis and sexually transmitted infections, updated guidance on tuberculosis preventative therapy (now including options for rifapentine-based regimens), expansion of the module on HIV and mental health, and updates to the guidance on ART and HIV monitoring during pregnancy, amongst others. These are summarised in


Dolutegravir concentrations are reduced by efavirenz induction effect necessitating twice-daily dolutegravir dosing when coadministered. Efavirenz induction persists for several weeks after stopping, which could potentially select for dolutegravir resistance if switching occurred with unsuppressed human immunodeficiency virus type 1 (HIV-1) RNA levels and standard dolutegravir dosing. We evaluated the need for a lead-in supplementary dolutegravir dose in adults failing first-line tenofovir-emtricitabine-efavirenz (TEE).We conducted a randomized, double-blind, placebo-controlled, phase 2 trial in Khayelitsha, South Africa. Eligible patients had virologic failure (2 consecutive HIV-1 RNA ≥1000 copies/mL) on first-line TEE. Participants were randomly assigned (1:1) to switch to tenofovir-lamivudine-dolutegravir (TLD) with a supplementary 50 mg dolutegravir dose or placebo taken 12 hours later for 14 days. Primary outcome was proportion with HIV-1 RNA <50 copies/mL at week 24. This study was not powered to compare arms.10 copies/mL and 76% had baseline resistance to both tenofovir and lamivudine. One participant died and 2 were lost to follow-up. At week 24, 55 of 64  in the supplementary dolutegravir arm and 53 of 65 (82% [95% CI: 70%–90%]) in the placebo arm had HIV-1 RNA <50 copies/mL. Grade 3 or 4 adverse events were similar in frequency between arms. None of 6 participants (3 in each arm) eligible for resistance testing by 24 weeks developed dolutegravir resistance.One hundred thirty participants were randomized (65 to each arm). Median baseline HIV-1 RNA was 4.0 logOur findings do not support the need for initial dolutegravir dose adjustment in patients switching to TLD who failed first-line TEE.NCT03991013. Among adults switching to second-line tenofovir-lamivudine-dolutegravir with unsuppressed HIV-1 RNA levels and substantial baseline nucleoside reverse transcriptase inhibitor resistance, a high proportion achieved virologic suppression.Clinical Trials Registration. NCT03991013 Dolutegravir with 2 nucleoside reverse transcriptase inhibitors (NRTIs) is the World Health Organization (WHO)–recommended second-line antiretroviral therapy (ART) regimen for adults failing first-line regimens based on the nonnucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine or efavirenz . Based oTenofovir is less toxic than zidovudine  and is dEfavirenz induces drug metabolizing enzymes (UGT1A1 and CYP3A4) and transporters (P-glycoprotein and breast cancer resistance protein), which decreases dolutegravir exposure . Double-We previously conducted a prospective cohort study of recycled tenofovir and lamivudine with dolutegravir in second-line ART with a supplementary dolutegravir dose (50 mg twice daily) for 2 weeks to overcome efavirenz induction, and 85% achieved virologic suppression at week 24, despite 65% having resistance to both tenofovir and lamivudine at baseline . It is uARTIST is a noncomparative, randomized, double-blind, placebo-controlled, phase 2, 48-week trial of second-line TLD with or without a lead-in supplementary dolutegravir dose in patients with virologic failure on first-line TEE. A detailed protocol describing our methods has been published . We recr+ cell count <100 cells/µL; estimated glomerular filtration rate <50 mL/minute/1.73 m2; alanine aminotransferase >100 IU/L; total bilirubin more than twice the upper limit of normal; active opportunistic infection; active malignancy; pregnant or intention to become pregnant; breastfeeding; active psychiatric condition or substance abuse judged likely to impact adherence; and allergy or intolerance to one of the study drugs. Women of childbearing potential were required to receive effective contraception. On 14 July 2021, the study protocol was amended to include patients with CD4+ cell counts of between 50 and 100 cells/µL to facilitate recruitment.Eligible patients were adults (≥18 years old) with virologic failure (defined as 2 consecutive human immunodeficiency virus type 1 (HIV-1) RNA ≥1000 copies/mL 2–24 months apart) on a first-line regimen of tenofovir, emtricitabine (or lamivudine), and efavirenz. Exclusion criteria were CD4Participants were randomly assigned (1:1) to a second-line regimen consisting of tenofovir (300 mg), lamivudine (300 mg), and dolutegravir (50 mg), given as a once-daily fixed-dose combination tablet, with an additional lead-in dose of dolutegravir (50 mg) or placebo taken 12 hours later for the first 14 days. An independent pharmacist generated the randomization sequence before trial commencement using block randomization (block size of 10). The study pharmacists used sequentially drawn individually sealed opaque envelopes to assign a treatment arm when dispensing medication. All participants and study staff involved in clinical care were blinded to treatment allocation.10 decline in HIV-1 RNA from baseline, or if HIV-1 RNA was suppressed and subsequently rebound to ≥50 copies/mL, enhanced adherence counseling was performed, and HIV-1 RNA measurement was repeated after 2 weeks. If the repeat HIV-1 RNA was ≥500 copies/mL, a genotypic antiretroviral resistance test (GART) was performed. Baseline GART was performed retrospectively for all participants after completion of week 24 visits, on plasma samples stored at enrollment (with results not returned to clinicians). GART was performed at the National Health Laboratory Service Virology Laboratory at Tygerberg Hospital in Cape Town, South Africa, and drug susceptibility prediction was performed with the Stanford algorithm (version 9.1) ) participants in the supplementary dolutegravir arm and 36 of 45 (80% [95% CI: 65%–90%]) participants in the placebo arm. Time to virologic suppression by arm is shown in Six participants (3 in each arm) met protocol-defined criteria for GART by week 24; no participants developed dolutegravir resistance or acquired new resistance mutations to tenofovir or lamivudine. One participant in the supplementary dolutegravir arm developed virologic failure at week 16; GART detected no integrase resistance mutations and the participant reported poor adherence (corroborated by TFV-DP concentration <350 fmol/punch at week 12). There were 19 participants with HIV-1 RNA ≥50 copies/mL at week 24; 15 of 19 (79%) later resuppressed HIV-1 RNA <50 copies/mL with enhanced adherence counseling.+ cell count at week 24 was 88 cells/µL  in the supplementary dolutegravir arm and 75 cells/µL  in the placebo arm. Median increase in weight was 1.9 kg  over 24 weeks, to 78.1 kg in the supplementary dolutegravir arm, versus 1.4 kg  to 82.0 kg in the placebo arm. Median TFV-DP concentrations were similar between arms at baseline, 12 weeks, and 24 weeks  . IntermiIn ARTIST, we observed a substantial incidence of insomnia (13%) reported by participants at week 2 with no discernible difference in the proportion between arms; the majority of insomnia complaints were mild and did not reach clinical significance based on ISI scores, and 76% resolved by week 4. The incidence of insomnia we found is twice that reported in a meta-analysis of trial participants randomized to dolutegravir . HoweverOur study has limitations. First, our study was not powered to formally assess differences between arms. Although the sample size did not allow for a statistically powered comparison, our study was designed to rapidly generate data to supplement the findings from NADIA  and the The ARTIST study provides additional evidence that maintaining tenofovir and lamivudine with dolutegravir is effective and well tolerated in second-line ART. Our results provide evidence over 24 weeks that patients with unsuppressed HIV-1 RNA levels on first-line TEE can safely switch to second-line TLD without a lead-in supplementary dolutegravir dose to overcome efavirenz induction—however, it is possible that resistance will emerge at later timepoints.