Clinical study of 400mg efavirenz treatment in newly diagnosed patients with HIV/AIDS.

The efficacy of 400mg efavirenz (EFV) once daily is reported to be similar to that of 600mg EFV. However, EFV-related toxic and side effects of 400mg EFV are significantly reduced. Here, the feasibility of reducing EFV to 400mg once a day in HIV-infected/AIDS patients was evaluated. Fifty patients were included. Patients were given 3TC+TDF+400mg EFV (n=25) or 3TC+TDF+600mg EFV (n=25). The proportion of patients with HIV RNA < 40 copies/mL and the adverse events served as the primary and secondary outcomes, respectively. HIV inhibition rates of the 3TC+TDF+400mg EFV group and 3TC+TDF+600mg EFV group were both 56.52% at week 24 and respectively 100%, 91.3% at week 48. During 48 weeks, 27 cases of adverse events were reported in the 3TC+TDF+400mg EFV group, lower than those in the 3TC+TDF+600mg EFV group, which had 39 cases. Compared with the 3TC+TDF+400mg EFV group, the incidence of transaminase, dizziness, hyperlipidemia and rashes all increased in the 3TC+TDF+600mg EFV group (P>0.05). No serious adverse events of the central nervous system occurred. The incidence of depression, sleep disturbance, and vertigo were similar (P>0.05). The efficacy of 400mg EFV is comparable to 600mg EFV. However, patients receiving 400mg EFV have fewer adverse events.

A validated method for simultaneous quantification of four antiretrovirals in dried blood spot and plasma using LC-MS/MS: Application to efavirenz therapeutic drug monitoring in pregnant patients.

INTRODUCTION: The specific physiological background induced by pregnancy leads to significant changes in maternal pharmacokinetics, suggesting potential variability in plasma concentrations of antiretrovirals. Pregnant HIV patients exposed to subtherapeutic doses, particularly in the last trimester of the pregnancy, have higher chances to transmit the infection to their children. Therefore, the therapeutic drug monitoring of antiretrovirals in HIV pregnant patients would be of great value. OBJECTIVES: This study aimed to develop and validate a sensitive liquid chromatograph tandem mass spectrometry (LC-MS/MS) method for simultaneous quantification of efavirenz, raltegravir, atazanavir, and ritonavir in dried blood spots (DBS) and plasma. DESIGN AND METHODS: The analytes were extracted from the DBS punch and plasma with a mixture of methanol:zinc sulfate 200 mM (50:50, v/v) and 100 % methanol, respectively. For the chromatographic separation a Shim-pack® C18, 4.6 mm × 150 mm, 5 µm column was used. Detection was performed in a 3200-QTRAP® mass spectrometer, with a run time of 6 min. RESULTS: The assay was linear in the range of 15-1,000 ng/mL for raltegravir, 50-10,000 ng/mL for both atazanavir and ritonavir, 50-5,000 ng/mL for efavirenz. Precision and accuracy at these concentrations were less than 15 % for all analytes. Raltegravir, atazanavir, and ritonavir were stable for seven days at 23 °C and 40 °C, whereas efavirenz was stable for twenty-four hours at the same conditions. CONCLUSIONS: The method was successfully applied to quantify efavirenz in DBS samples obtained from HIV-1 infected pregnant volunteers under antiretroviral therapy. The concentrations of efavirenz in DBS and plasma were comparable according to Passing-Bablok regression and Bland-Altman analysis.

The use of suboptimal antiretroviral therapy when applying for migration to Australia: a case series.

Background Australia imposes restrictions for people living with HIV (PLHIV) applying for permanent residency (PR), including spending less than AUD51,000 on medical costs over 10years. Some PLHIV opted for suboptimal and cheaper antiretroviral therapy (ART) regimens to increase their chances of receiving PR. We collated a case series to examine PLHIV on suboptimal ART because of visa issues. Methods We identified all patients applying for a PR in Australia who obtained nevirapine, efavirenz or zidovudine between July 2022 and July 2023 from the Melbourne Sexual Health Centre. Pathology results and records detailing psychological issues relating to the patients' wishes to remain on suboptimal ART were extracted from clinical records by two researchers. Results We identified six patients with a mean age of 39years migrating from Asian and European countries. Three patients used efavirenz, and three used nevirapine. All desired to remain on cheaper, suboptimal ART to stay below visa cost thresholds, which they considered to aid favourably with their application. Four displayed stress and anxiety arising from visa rejections, appeal deadlines and the lengthy visa application process. Conclusions Despite access to more effective and safer ART, we identified patients who chose to remain on cheaper ART to improve chances of obtaining an Australian visa, potentially putting their health at risk. We found significant evidence of stress and anxiety among patients. There is a need to review and revise current migration policies and laws in Australia that discriminate against PLHIV and jeopardise public health.

Clinical Trials That Have Changed Clinical Practice and Care of Pregnant People With HIV.

Over the last 4 decades, significant advances in the care of HIV during pregnancy have successfully reduced, and nearly eliminated, the risk of perinatal HIV transmission. The baseline risk of transmission without intervention (25% to 30%) is now <1% to 2% in the United States with contemporary antepartum, intrapartum, and postnatal interventions. In this review, we discuss 3 landmark clinical trials that substantially altered obstetric practice for pregnant individuals with HIV and contributed to this extraordinary achievement: 1) the Pediatric AIDS Clinical Trials Group 076 Trial determined that antepartum and intrapartum administration of antiretroviral drug zidovudine to the pregnant individual, and postnatally to the newborn, could reduce the risk of perinatal transmission by approximately two-thirds; 2) the European Mode of Delivery Collaboration Trial demonstrated performance of a prelabor cesarean birth before rupture of membranes among pregnant people with viremia reduced the risk of perinatal transmission compared with vaginal birth; and 3) the International Maternal Pediatric Adolescent AIDS Clinical Trials Network 2010 Trial identified that dolutegravir-containing, compared with efavirenz-containing, antiretroviral regimens during pregnancy achieved a significantly higher rate of viral suppression at delivery with shorter time to viral suppression, with fewer adverse pregnancy outcomes. Collectively, these trials not only advanced obstetric practice but also advanced scientific understanding of the timing, mechanisms, and determinants of perinatal HIV transmission. For each trial, we will describe key aspects of the study protocol and outcomes, insights gleaned about the dynamics of perinatal transmission, how each study changed clinical practice, and relevant updates to current practice since the trial's publication.

Prevalence of HIV Drug Resistance Mutations among Treatment-Naive People Living with HIV in a Tertiary Care Center in India.

India has the third-largest number of people living with HIV (PLHIV) in the world. A national program provides free access to standard uniform antiretroviral therapy. However, the program is not monitored by comprehensive drug resistance surveys. The aim of this study was to determine the prevalence of HIV drug resistance mutations (DRMs) among treatment-naive PLHIV in a large antiretroviral treatment center of the national program. This cross-sectional study was done in 2017 and involved 200 consecutive treatment-naive PLHIV. A target fragment of 1,306 bp in the reverse transcriptase and protease regions was amplified. Identification of mutations and drug resistance interpretation was done by HIV Genotypic Resistance Interpretation and International Antiviral Society-USA list. Sequencing was successful in 177 samples. The majority (98.8%; 175/177) belonged to subtype C. Nineteen of 177 patients (10.7%; 95% CI: 6.2%-15.3%) had at least one major DRM. The prevalence of non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations was 10.2% (18/177). The most frequent mutations were E138A/K, A98G, K103N, V179D, and K101H/E. The prevalence of nucleoside reverse transcriptase inhibitor (NRTI) mutations was 1.1% (2/177). None of the samples had major protease inhibitor resistance mutations. The prevalence of NNRTI mutations in this study was >10%, crossing the threshold recommended by the WHO to change the NNRTI-based first-line regimen to non-NNRTI based. In 2021, the national program replaced efavirenz with dolutegravir in the first-line regimen of tenofovir, lamivudine, and efavirenz. As the majority (64%) of PLHIV in India are accessing free ART from the national program, this study highlights the need for regular nationally representative drug resistance surveys for optimizing antiretroviral regimens in the program.

Efficacy and effect on lipid profiles of switching to ainuovirine-based regimen versus continuing efavirenz-based regimen in people with HIV-1: 24-week results from a real-world, retrospective, multi-center cohort study.

Ainuovirine (ANV), a novel non-nucleoside reverse-transcriptase inhibitor (NNRTI), was approved in China in 2021. In a previous randomized phase 3 trial, ANV demonstrated non-inferior efficacy relative to efavirenz (EFV) and was associated with lower rates of dyslipidemia. In this study, we aimed to explore lipid changes in treatment-experienced people with human immunodeficiency virus (HIV)-1 (PWH) switching to ANV from EFV in real world. At week 24, 96.65% of patients in the ANV group and 93.25% in the EFV group had HIV-1 RNA levels below the limit of quantification (LOQ). Median changes from baseline in CD4 +T cell counts (37.0 vs 36.0 cells/µL, P = 0.886) and CD4+/CD8 +ratio (0.03 vs 0.10, P = 0.360) were similar between the two groups. The ANV group was superior to the EFV group in mean changes in total cholesterol (TC, -0.06 vs 0.26 mmol/L, P = 0.006), triglyceride (TG, -0.6 vs 0.14 mmol/L, P < 0.001), high-density lipoprotein cholesterol (HDL-C, 0.09 vs 0.08 mmol/L, P = 0.006), and low-density lipoprotein cholesterol (LDL-C, -0.18 vs 0.29 mmol/L, P < 0.001) at week 24. We also observed that a higher proportion of patients demonstrated improved TC (13.55% vs 4.45%, P = 0.015) or LDL-C (12.93% vs 6.89%, P = 0.017), and a lower proportion of patients showed worsened LDL-C (5.57% vs 13.52%, P = 0.017) with ANV than with EFV at week 24. In conclusion, we observed good efficacy and favorable changes in lipids in switching to ANV from EFV in treatment-experienced PWH in real world, indicating a promising switching option for PWH who may be more prone to metabolic or cardiovascular diseases.

Effects of Prolonged Administration of Tenofovir Disoproxil Fumarate-Containing Antiviral Regimen on Renal Function in Low-Risk of Kidney Injury HIV Patients.

This study intended to investigate the impact of long-term tenofovir fumarate (TDF) antiviral regimen on renal function in human immunodeficiency virus (HIV)-infected patients with low-risk of kidney injury. The observational study involving 100 HIV-infected patients without underlying diseases who achieved virological suppression and immunological recovery after sustained antiviral regimen of TDF+ lamivudine+ efavirenz (TLE) for 3.19 years. Renal function, including estimated glomerular filtration rate (eGFR), blood and urine ß2 microglobulin, and other parameters, was assessed every 3 months over a period of 2.5 years. The eGFR showed a slight increasement from 116.0 at month 0 to 119.7 at month 30. Blood ß2 microglobulin increased from 2.02 mg/L at month 0 to 2.77 mg/L at month 30. Compared to month 0, the difference in blood ß2 microglobulin was statistically significant at month 6 and months 12-30 (P < .05). The incidence of proximal renal tubular dysfunction fluctuated from 2% at month 0 to 2.5% at month 30. The urine ß2 microglobulin fluctuated from 0.5 (0.3-1.1) to 0.8 (0.5-1.35) mg/L at months 18-30, which was higher than 0.41 (0.18-1.1) mg/L at month 0 (P < .05). The abnormal concentration proportion of urine ß2 microglobulin fluctuated from 72.7% to 81.3% at months 18-30, which was higher than the proportion of 57.0% at month 0. The abnormal proportion of blood ß2 microglobulin, urine ß2 microglobulin, and proximal renal tubular dysfunction were not correlated with eGFR (r1 = 0.119, r2 = -0.008, r3 = -0.165, P > .05). Long-term TDF antiviral regimen in low-risk of kidney injury HIV-infected patients may lead to damage in the proximal renal tubules and glomeruli. Blood and urine ß2 microglobulin levels may be helpful in screening for renal dysfunction.

Pharmacokinetics of Single-Dose Versus Double-Dose Dolutegravir After Switching From a Failing Efavirenz-Based Regimen.

BACKGROUND: Dolutegravir exposure is reduced after switching from efavirenz, which could select for dolutegravir resistance if switching occurs during virologic failure. METHODS: We measured serial dolutegravir trough concentrations after switching from efavirenz in a clinical trial, which randomized some participants to a supplemental dolutegravir dose or placebo for the first 14 days. Changes in dolutegravir trough concentrations between days 3, 7, 14, and 28 were evaluated. The primary outcome was the geometric mean ratio of dolutegravir trough concentrations on day 7 versus day 28. RESULTS: Twenty-four participants received double-dose dolutegravir (50 mg twice daily) and 11 standard dose for the first 14 days. Baseline characteristics were 77% female, median age 36 years, CD4 cell count 254 cells/mm3, and HIV-1 RNA 4.0 log10 copies/mL. The geometric mean ratio (90% CI) of dolutegravir trough concentrations on day 7 versus day 28 was 0.637 (0.485 to 0.837) in the standard-dose group and 1.654 (1.404 to 1.948) in the double-dose group. There was a prolonged induction effect at day 28 in participants with efavirenz slow metaboliser genotypes. One participant in the double-dose group had a dolutegravir trough concentration below the protein-binding adjusted concentration needed to inhibit 90% of HIV-1 (PA-IC90) at day 3. CONCLUSIONS: No participants on standard-dose dolutegravir had dolutegravir trough concentrations below the PA-IC90. Slow efavirenz metaboliser genotypes had higher baseline efavirenz concentrations and more pronounced and longer period of induction postswitch. These findings suggest that a 14-day lead-in supplemental dolutegravir dose may not be necessary when switching from a failing efavirenz-based first-line regimen.

Virologic outcomes on dolutegravir-, atazanavir-, or efavirenz-based ART in urban Zimbabwe: A longitudinal study.

There are few data from sub-Saharan Africa on the virological outcomes associated with second-line ART based on protease inhibitors or dolutegravir (DTG). We compared viral load (VL) suppression among people living with HIV (PLWH) on atazanavir (ATV/r)- or DTG-based second-line ART with PLWH on efavirenz (EFV)-based first-line ART. We analyzed data from the electronic medical records system of Newlands Clinic in Harare, Zimbabwe. We included individuals aged ≥12 years when commencing first-line EFV-based ART or switching to second-line DTG- or ATV/r-based ART with ≥24 weeks follow-up after start or switch. We computed suppression rates (HIV VL <50 copies/mL) at weeks 12, 24, 48, 72, and 96 and estimated the probability of VL suppression by treatment regimen, time since start/switch of ART, sex, age, and CD4 cell count (at start/switch) using logistic regression in a Bayesian framework. We included 7013 VL measurements of 1049 PLWH (61% female) initiating first-line ART and 1114 PLWH (58% female) switching to second-line ART. Among those switching, 872 (78.3%) were switched to ATV/r and 242 (21.7%) to DTG. VL suppression was lower in second-line ART than first-line ART, except at week 12, when those on DTG showed higher suppression than those on EFV (aOR 2.10, 95%-credible interval [CrI] 1.48-3.00) and ATV/r-based regimens (aOR 1.87, 95%-CrI 1.32-2.71). For follow-up times exceeding 24 weeks however, first-line participants demonstrated significantly higher VL suppression than second-line, with no evidence for a difference between DTG and ATV/r. Notably, from week 48 onward, VL suppression seemed to stabilize across all regimen groups, with an estimated 89.1% (95% CrI 86.9-90.9%) VL suppression in EFV, 74.5% (95%-CrI 68.0-80.7%) in DTG, and 72.9% (95%-CrI 69.5-76.1%) in ATV/r at week 48, showing little change for longer follow-up times. Virologic monitoring and adherence support remain essential even in the DTG era to prevent second-line treatment failure in settings with limited treatment options.

Comparison of dolutegravir and efavirenz on depression, anxiety and sleep disorders in pregnant and postpartum women living with HIV.

BACKGROUND: Both dolutegravir and efavirenz are known to be effective in pregnancy and postpartum to prevent vertical transmission of HIV and to maintain maternal health. Both drugs have also been associated with neuropsychiatric symptoms. To what extent, these symptoms occur in pregnant and postpartum women, however, is not yet known. METHODS: This was a secondary analysis of the DolPHIN2 study, a multicentre randomized trial among women presenting late in pregnancy with untreated HIV - who received either a dolutegravir-containing or efavirenz-containing regimen. Longitudinal measures of depression, anxiety and sleep quality were analysed during pregnancy and up to 48 weeks postpartum. RESULTS: Among 268 women, median (IQR) Edinburgh Post Natal Depression Score (EPDS) scores were 8 (3-11) and highest at enrolment. In the dolutegravir and efavirenz arm, respectively, 23.7 and 25.6% had an EPDS score above 9, indicating possible or probable depression. Abnormal Hospital Anxiety Depression scores (HADS) (above 11) were seen at least once during follow-up in 42 of patients (15.7%), although no differences were seen between treatment arms. No association was found between EPDS, suicidality and HADS scores and the assigned regimen ( P  = 0.93, 0.97 and 0.18 respectively). Median (IQR) Pittsburgh Sleep Quality index (PSQI) scores for dolutegravir and efavirenz were 6 (5-7) and 5 (5-6.5), respectively, P  = 0.70. CONCLUSION: No statistically significant differences were observed between efavirenz-containing or dolutegravir-containing regimens. Rates of depression were high, but decreased over the course of time and confirm the need for psychological support after initial HIV diagnosis in pregnancy.

Effect of dolutegravir-based versus efavirenz-based antiretroviral therapy on excessive weight gain in adult treatment-naïve HIV patients at Matsanjeni health center, Eswatini: a retrospective cohort study.

BACKGROUND: There is limited data on dolutegravir (DTG)-associated weight gain from settings with a dual burden of HIV and overnutrition. METHODS: In Eswatini (at Matsanjeni), among 156 and 160 adult patients on DTG-based and EFV-based antiretroviral therapy (ART), respectively, we studied excessive weight gain (BMI at 24 months ART greater than baseline and ≥25 kg/m2). RESULTS: The median BMI increase in DTG-based patients was 1.09 (IQR:-0.28,3.28) kg/m2 compared to 0.20 (IQR:-0.85,2.18) kg/m2 in EFV-based patients (p value = 0.001). DTG-based ART predicted excessive weight gain (aOR 2.61;95% CI:1.39-4.93). CONCLUSION: Practitioners should consider DTG-based regimens as one of the risk factors for overweight/obesity.

Modern antiretroviral regimens in pregnant women: virologic outcomes and durability.

OBJECTIVES: Data are lacking on the virologic efficacy and durability of modern antiretroviral treatment (ART) regimens during pregnancy. We compared virologic outcomes at delivery among women receiving dolutegravir versus other ART and the rate of change of the initial pregnancy regimen. DESIGN: Single-site retrospective cohort between 2009 and 2019. METHODS: We used univariable and multivariable generalized estimating equations to model the relationship between the maternal ART anchor and the proportion of women with a detectable viral load (greater than or equal to 20 HIV RNA copies/mL of plasma) closest to delivery (suboptimal virologic control) and with a detectable viral load at any time in the third trimester. We also compared changes in ART during pregnancy. RESULTS: We evaluated 230 pregnancies in 173 mothers. Rates of optimal virologic control at delivery did not significantly differ in mothers who received dolutegravir (93.1%), rilpivirine (92.1%), boosted darunavir (82.6%), or efavirenz (76.9%) but were significantly lower among mothers receiving atazanavir (49.0%) or lopinavir (40.9%). The odds of having a detectable viral load at any time in the third trimester was also higher for atazanavir and lopinavir. Raltegravir, elvitegravir, or bictegravir were used in less than 10 mothers at delivery, which precluded statistical analyses. The frequency of change in ART was significantly higher in mothers who initially received elvitegravir (68%) or efavirenz (47%) than dolutegravir (18%). CONCLUSION: Dolutegravir-containing, rilpivirine-containing, and boosted darunavir-containing regimens conferred excellent virologic control in pregnancy. Atazanavir and lopinavir, elvitegravir, and efavirenz were associated with either high rates of virologic failure or regimen change during pregnancy.

Blood glucose level and serum lipid profiles among people living with HIV on dolutegravir-based versus efavirenz-based cART; a comparative cross-sectional study.

BACKGROUND: Antiretroviral therapy-linked metabolic abnormalities have become a growing concern among people living with HIV. There is limited data regarding the effects of dolutegravir-based treatment on blood glucose levels and serum lipid profiles in people living with HIV in Ethiopia. Thus, this study aimed to assess blood glucose levels and serum lipid profiles among people living with HIV on dolutegravir-based versus efavirenz-based therapy. METHOD AND MATERIALS: An institutional-based comparative cross-sectional study was conducted from 30 June 2021 to 30 August 2021. A total of 128 participants (64 in the dolutegravir-based group and 64 in the efavirenz-based group) were enrolled in the study. The Chi-square, independent t-test, Mann-Whitney U-test, and logistic regression were used as appropriate statistical tests using SPSS Version 26.0 for this study. A p-value of <0.05 was considered statistically significant. RESULT: The prevalence of hyperglycemia and dyslipidemia were 17.2% (11/64) and 79.7% (51/64) in the dolutegravir group, and 9.4% (6/64) and 75% (48/64) in the efavirenz group, respectively. The efavirenz group had significantly higher mean values of total cholesterol (190.73 ± 44.13 vs. 175.27 ± 37.67 mg/dl, p = 0.035) and high-density lipoprotein (47.53 ± 14.25 vs. 40.92 ± 13.17 mg/dl, p = 0.007) than the dolutegravir group. For a Kg/m2 increase in BMI and for each month's increase in the duration of HIV, the patients were 66% (AOR = 1.66, 95% CI: 1.13, 2.44), and 13% (AOR = 1.13, 95% CI: 1.03, 1.23) more likely to have hyperglycemia, respectively. In contrast, female patients were 3.04 times more likely to have dyslipidemia (AOR = 3.03, 95% CI: 1.14, 8.05) as compared to male patients, and with an increase in CD4 cell count of 1 cell/mm3, the odds of dyslipidemia increased by 0.3% (AOR = 1.003, 95% CI: 1.001, 1.006). CONCLUSION: Efavirenz-based therapy resulted in higher mean values of total cholesterol and high-density lipoprotein as compared with dolutegravir-based therapy. It is important to consider and evaluate high-density lipoprotein levels in HIV patients on dolutegravir-based therapy, and total cholesterol levels in people living with HIV on efavirenz-based therapy.

The long-term use of ART is thought to be one of the potential causes of metabolic abnormalities such as dysregulation of glucose and lipid metabolism.The burden of DTG-based cART-related metabolic abnormalities in resource-limited settings has not been well characterized.This study aimed to address these gaps by assessing blood glucose levels and serum lipid profiles among people living with HIV on DTG-based versus EFV-based regimens and identifying factors associated with hyperglycemia and dyslipidemia.

Comparison of Metabolic Effects of Three Different Treatment Combinations with Retrospective Real-life Data in People Living with HIV.

INTRODUCTION: Comorbidities are increasing in people living with HIV (PLHIV), and different treatment options have advantages and disadvantages. It is important to compare information from real-life treated cases. The aim of this study was to retrospectively evaluate the data on efficacy and clinical and laboratory findings during different antiretroviral therapies. METHODS: Retrospective file data of 47 PLHIV using Dolutegravir and Lamivudine (3TC/DTG), Tenofovir Alafenamide Emtricitabine and Elvitegravir Cobicistat (EVG/c/TAF/FTC) and Tenofovir Disoproxil Fumarate and Emtricitabine and Efavirenz (EFV/FTC/TDF) were analyzed. Data of the patients at baseline and 12 months after antiretroviral therapy (ART) were compared. RESULTS: About 47 PLHIV were included in the study. Of the patients, 22 (46.8%) were in the 3TC/DTG group, 19 (40.4%) in the EVG/c/TAF/FTC, and 6 (12.8%) in the EFV/FTC/TDF group. After 12 months of treatment, BMI, HIV-RNA, CD4, WBC, hemoglobin, MCV, PDW, RDW, platelet count, creatinine, eGFR, HDL, AST, glucose values of the 3TC/DTG group were significantly different (p<0.05). After 12 months of treatment, BMI, HIV-RNA, CD4 count, MCV, creatinine, eGFR, HDL, LDL, TG, TC, AST, and HOMA-IR values of the EVG/c/TAF/FTC treatment group were significantly different (p<0.05). After 12 months of treatment, HIV RNA, total bilirubin, and LDL values in the EFV/FTC/TDF treatment group were statistically different (p<0.05). CONCLUSION: All treatment groups showed a decrease in HIV-RNA and an increase in CD4 at the end of one year. While CD4 elevation is lower in EFV recipients than in integrase inhibitor (INSTI) recipients, weight gain is higher in INSTI recipients. While the lipid profile was more positively affected in the 3TC/DTG group, lipid profiles were more negatively affected in the EVG/c/TAF/FTC group, although liver and kidney functions were preserved.

Cost-effectiveness analysis of antiretroviral drugs for treatment-naive HIV infection in China.

INTRODUCTION: Dolutegravir (DTG)-based regimen was included in the expanded formulary of China's National Free Antiretroviral Treatment Program at the end of 2021. Yet high price of DTG and lack of health economic evaluation in China present barriers for implementation of the regimen. The study aims to investigate the lifetime cost-effectiveness of DTG-based regimen for treatment-naive HIV infection in China. METHODS: A decision-analytic Markov model was used to obtain the costs and effectiveness of four regimens: Arm A, efavirenz (EFV)-based regimen; Arm B, DTG-based regimen; Arm C, elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine (EVG/c/FTC/TAF) regimen; Arm D, abacavir/lamivudine/dolutegravir (ABC/3TC/DTG) regimen. The potential impact of national centralized drug procurement policy was assessed in scenario analysis. The results were further validated through sensitivity analysis. RESULTS: Compared with other three regimens, DTG-based regimen led to the fewest cumulative adverse reactions, opportunistic infections and deaths. Compared with EFV-based regimen, the base-case ICERs for DTG-based regimen were 13,357 (USD/QALY) and 13,424 (USD/QALY) from the healthcare system and societal perspective respectively. In the policy scenario analysis with the procurement price of DTG equal to that of LPV/r, DTG-based regimen would be dominant. The model results remained robust in sensitivity analyses. CONCLUSIONS: DTG-based regimen for treatment-naive patients is likely to be cost-effective and deserve wider implementation in China. This study strongly suggests the centralized procurement of DTG to minimize cost and maximize cost-effectiveness.

Unexpectedly low drug exposures among Ugandan patients with TB and HIV receiving high-dose rifampicin.

We characterized the pharmacokinetics of standard- and high-dose rifampicin in Ugandan adults with tuberculosis and HIV taking dolutegravir- or efavirenz-based antiretroviral therapy. A liver model with saturable hepatic extraction adequately described the data, and the increase in exposure between high and standard doses was 4.7-fold. This was lower than what previous reports of dose-exposure nonlinearity would predict and was ascribed to 38% lower bioavailability of the rifampicin-only top-up formulation compared to the fixed-dose combination.

Improvements in Patient-Reported Outcomes Following Initiation of Dolutegravir-Based or Low-Dose Efavirenz-Based First-Line Antiretroviral Therapy: A Four-Year Longitudinal Analysis in Cameroon (NAMSAL ANRS 12313 Trial).

BACKGROUND: We provide new and comprehensive evidence on the evolution of a wide range of patient-reported outcomes (PROs) in the NAMSAL ANRS 12313 trial in Cameroon (2016-2021)-the first randomized comparison of dolutegravir 50 mg (DTG) and low-dose efavirenz (ie, 400 mg; EFV400) in treatment-naive adults living with HIV-1 in sub-Saharan Africa. METHODS: We first described the evolution of PROs between baseline and week 192. Then, we used random-effects models to measure the effect of time since the initiation of antiretroviral therapy and the differential effect of DTG versus EFV400 on each PRO, adjusting for clinical, demographic, and socioeconomic factors, while accounting for unobserved heterogeneity and missing data. RESULTS: Among the 613 patients randomized (DTG arm, n = 310; EFV400 arm, n = 303), (1) physical and mental health-related quality of life improved by 13.3% and 6.8%, respectively, (2) the percentage of patients with depression, anxiety, and stress decreased from 23.3%, 23.0%, and 7.7% to 3.1%, 3.5%, and 0.4%, respectively, and (3) the mean number of HIV-related symptoms decreased from 7.2 to 3.0 ( P < 0.001). For most PROs, no significant difference was found between both arms, even when accounting for the effect of DTG on weight gain. Nevertheless, our results suggest smaller improvements in mental health outcomes in the DTG arm, with a 5 percentage point higher adjusted probability of having anxiety at week 192 ( P < 0.01). CONCLUSIONS: Although supporting the current World Health Organization guidelines recommending DTG-based and EFV400-based regimens as preferred and alternative first-line antiretroviral therapy, further studies should investigate medium-term mental health outcomes in patients on DTG. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02777229.

Effect of the Cannabinoid Agonist WIN 55,212-2 on Neuropathic and Visceral Pain Induced by a Non-Diarrheagenic Dose of the Antitumoral Drug 5-Fluorouracil in the Rat.

5-fluorouracil (5-FU) is an antineoplastic drug used to treat colorectal cancer, but it causes, among other adverse effects, diarrhea and mucositis, as well as enteric neuropathy, as shown in experimental animals. It might also cause neuropathic pain and alterations in visceral sensitivity, but this has not been studied in either patients or experimental animals. Cannabinoids have antimotility and analgesic effects and may alleviate 5-FU-induced adverse effects. Our aim was to evaluate the effects of the cannabinoid agonist WIN 55,212-2 on neuropathic and visceral pain induced by a non-diarrheagenic dose of 5-FU. Male Wistar rats received a dose of 5-FU (150 mg/kg, ip) and gastrointestinal motility, colonic sensitivity, gut wall structure and tactile sensitivity were evaluated. WIN 55,212-2 (WIN) was administered to evaluate its effect on somatic (50-100 µg ipl; 1 mg/kg, ip) and visceral (1 mg/kg, ip) sensitivity. The cannabinoid tetrad was used to assess the central effects of WIN (1 mg/kg, ip). 5-FU decreased food intake and body weight gain, produced mucositis and thermal hyperalgesia, but these effects were reduced afterwards, and were not accompanied by diarrhea. Tactile mechanical allodynia was also evident and persisted for 15 days. Interestingly, it was alleviated by WIN. 5-FU tended to increase colonic sensitivity whereas WIN reduced the abdominal contractions induced by increasing intracolonic pressure in both control and 5-FU-treated animals. Importantly, the alleviating effects of WIN against those induced by 5-FU were not accompanied by any effect in the cannabinoid tetrad. The activation of the peripheral cannabinoid system may be useful to alleviate neuropathic and visceral pain associated with antitumoral treatment.

Diagnostic accuracy of a point-of-care urine tenofovir assay, and associations with HIV viraemia and drug resistance among people receiving dolutegravir and efavirenz-based antiretroviral therapy.

INTRODUCTION: Novel point-of-care assays which measure urine tenofovir (TFV) concentrations may have a role in improving adherence monitoring for people living with HIV (PLHIV) receiving antiretroviral therapy (ART). However, further studies of their diagnostic accuracy, and whether results are associated with viraemia and drug resistance, are needed to guide their use, particularly in the context of the global dolutegravir rollout. METHODS: We conducted a cross-sectional evaluation among PLHIV receiving first-line ART containing tenofovir disoproxil fumarate at enrolment into a randomized trial in two South African public sector clinics. We calculated the diagnostic accuracy of the Abbott point-of-care immunoassay to detect urine TFV compared to liquid chromatography-tandem mass spectrometry (LC-MS/MS). We evaluated the association between point-of-care urine TFV results and self-reported adherence, viraemia ≥1000 copies/ml and HIV drug resistance, among people receiving either efavirenz or dolutegravir-based ART. RESULTS: Between August 2020 and March 2022, we enrolled 124 participants. The median age was 39 (IQR 34-45) years, 55% were women, 74 (59.7%) were receiving efavirenz and 50 (40.3%) dolutegravir. The sensitivity and specificity of the immunoassay to detect urine TFV ≥1500 ng/ml compared to LC-MS/MS were 96.1% (95% CI 90.0-98.8) and 95.2% (75.3-100.0), respectively. Urine TFV results were associated with short (p<0.001) and medium-term (p = 0.036) self-reported adherence. Overall, 44/124 (35.5%) had viraemia, which was associated with undetectable TFV in those receiving efavirenz (OR 6.01, 1.27-39.0, p = 0.014) and dolutegravir (OR 25.7, 4.20-294.8, p<0.001). However, in those with viraemia while receiving efavirenz, 8/27 (29.6%) had undetectable urine TFV, compared to 11/17 (64.7%) of those receiving dolutegravir. Drug resistance was detected in 23/27 (85.2%) of those receiving efavirenz and only 1/16 (6.3%) of those receiving dolutegravir. There was no association between urine TFV results and drug resistance. CONCLUSIONS: Among PLHIV receiving ART, a rapid urine TFV immunoassay can be used to accurately monitor urine TFV levels compared to the gold standard of LC-MS/MS. Undetectable point-of-care urine TFV results were associated with viraemia, particularly among people receiving dolutegravir. TRIAL REGISTRATION: Pan-African Clinical Trials Registry: PACTR202001785886049.