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.

Assessment of swallowability and acceptability of scored darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed-dose combination (FDC) tablets in HIV-1-infected children aged ≥6 to <12 years, using matching placebo tablets: A randomized study.

BACKGROUND: Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed-dose combination (FDC) was developed as a once-daily, complete antiretroviral (ARV) regimen therapy to address the need for simplified protease inhibitor-based ARV regimens. This study assessed the swallowability and acceptability for long-term use of scored placebo tablets matching the D/C/F/TAF FDC tablets in children living with HIV-1. METHODS: This study (NCT04006704) was a Phase 1, open-label, randomized, single-dose, 2-period, 2-sequence crossover study in children living with HIV-1, aged ≥6 to <12 years and weighing ≥25 to <40 kg, on a stable ARV regimen for ≥3 months. Participants were asked to swallow whole (size, 21 × 11 × 7 mm) and split matching placebo D/C/F/TAF tablets. Swallowability of the matching placebo D/C/F/TAF tablets (primary endpoint) was assessed by observers. Acceptability of taking matching placebo D/C/F/TAF tablets and current ARVs was evaluated by participants using a 3-point questionnaire. Participants rated the acceptability for long-term daily use of the placebo D/C/F/TAF tablets, and observers assessed how easily caregivers could split a scored tablet by hand, using 3-point questionnaires. RESULTS: Among the 24 participants who enrolled and completed the study, 95.8% (23/24) were able to swallow the whole and split matching placebo D/C/F/TAF tablets after 1 or 2 attempts. Most participants (>70%) rated the acceptability of tablets for long-term daily use as acceptable or good to take. Breaking the tablets was considered easy or OK by 79.2% (19/24) of caregivers. CONCLUSION: Scored D/C/F/TAF FDC tablets are swallowable - with whole favoured over split - and considered at least acceptable for long-term daily intake in children living with HIV-1 aged ≥6 to <12 years. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04006704.

Impact of switching to injectables cabotegravir and rilpivirine on sleep disturbances in a cohort of people living with HIV.

BACKGROUND: Recently, injectable cabotegravir/rilpivirine (ICAB/RPV) became available for HIV treatment. However, there are no real-life data on the impact of switching to ICAB/RPV on sleep disturbances (SD). Therefore, we aimed at assessing and investigating this aspect in our cohort. METHODS: A SD multidimensional assessment (Epworth Sleepiness scale, Insomnia severity Index, Berlin Questionnaire, and Pittsburg Sleep Quality Index, PSQI) was performed to all people who consented before starting ICAB/RPV and 12 wk after the switch. Demographics, life-style habits, laboratory, and clinical data were collected from medical health records. RESULTS: To June 2023, 46 people were included, 76.1% males, with a median age of 48.5 (IQR: 41-57), 50% had multimorbidity, 13% was on polypharmacy. Median age with HIV and CD4 + T cell count nadir were 10 (5-19.5) years and 360 (205-500) cell/mm3, respectively. The reason to start a long-acting strategy was person's choice in all cases. Baseline antiretroviral regimens were mostly: tenofovir alafenamide/emtricitabine/rilpivirine (39.1%) and dolutegravir/lamivudine (32.6%). No significant changes were observed in any of the scores for each questionnaire, but for a worsening PSQI. 37% people reported a subjectively improved sleep quality, even if statistically significant changes were not observed in almost all the sleep parameters. CONCLUSIONS: To the best of our knowledge, this is the first study exploring impact of switching to ICAB/RPV on SD. Despite integrase inhibitor have been associated with SD, we did not observed a negative impact on sleep quality after the switch to ICAB/RPV. More studies and with larger number of people are necessary to confirm our results.

Relative Bioavailability of Dolutegravir (DTG) and Emtricitabine/Tenofovir Alafenamide Fumarate (F/TAF) Administered as Paediatric Tablet Formulations in Healthy Volunteers.

BACKGROUND AND OBJECTIVE: Within the UNIVERSAL project (RIA2019PD-2882) we aim to develop a paediatric dolutegravir (DTG)/emtricitabine (FTC or F)/tenofovir alafenamide (TAF) fixed-dose combination. To inform dosing of this study, we undertook a relative bioavailability (RBA) study in healthy volunteers to investigate a potential pharmacokinetic effect when paediatric formulations of DTG and F/TAF are taken together. METHODS: Participants received all of the following treatments as paediatric formulations in randomised order: a single dose of 180/22.5 mg F/TAF; a single dose of 30 mg DTG; a single dose of 180/22.5 mg F/TAF plus 30 mg DTG. Blood concentrations of DTG, FTC, TAF, and tenofovir (TFV) were measured over 48 h post-dose. If the 90% confidence intervals (CIs) of the geometric least squares mean (GLSM) ratios of area under the curve (AUC) and maximum concentration (Cmax) of each compound were within 0.70-1.43, we considered this as no clinically relevant PK interaction. RESULTS: A total of 15 healthy volunteers were included. We did not observe a clinically relevant PK interaction between the paediatric DTG and F/TAF formulations for the compounds DTG, FTC, and TFV. For TAF, the lower boundaries of the 90% CIs of the GLSM ratios of the AUC0-∞ and Cmax fell outside our acceptance criteria of 0.70-1.43. CONCLUSIONS: Although TAF AUC and Cmax 90% CIs fell outside the pre-defined criteria (0.62-1.11 and 0.65-1.01, respectively), no consistent effect on TAF PK was observed, likely due to high inter-subject variability. Moreover, there are several reasons to rely on TFV exposure as being more clinically relevant than TAF exposure. Therefore, we found no clinically relevant interactions in this study.

Pharmacokinetics and safety of coformulated bictegravir, emtricitabine, and tenofovir alafenamide in children aged 2 years and older with virologically suppressed HIV: a phase 2/3, open-label, single-arm study.

BACKGROUND: Coformulated bictegravir, emtricitabine, and tenofovir alafenamide is a single-tablet regimen and was efficacious and well tolerated in children and adolescents with HIV (aged 6 years to <18 years) in a 48-week phase 2/3 trial. In this study, we report data from children aged at least 2 years and weighing 14 kg to less than 25 kg. METHODS: We conducted this open-label, multicentre, multicohort, single-arm study in South Africa, Thailand, Uganda, and the USA. Participants were virologically suppressed children with HIV, aged at least 2 years, weighing 14 kg to less than 25 kg. Participants received bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) once daily, switching to bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) upon attaining a bodyweight of at least 25 kg. The study included pharmacokinetic evaluation at week 2 to confirm the dose of coformulated bictegravir, emtricitabine, and tenofovir alafenamide for this weight band by comparing with previous adult data. Primary outcomes were bictegravir area under the curve over the dosing interval (AUCtau) and concentration at the end of the dosing interval (Ctau) at week 2, and incidence of treatment-emergent adverse events and laboratory abnormalities until the end of week 24 in all participants who received at least one dose of bictegravir, emtricitabine, and tenofovir alafenamide. This study is registered with ClinicalTrials.gov, NCT02881320. FINDINGS: Overall, 22 participants were screened (from Nov 14, 2018, to Jan 11, 2020), completed treatment with bictegravir, emtricitabine, and tenofovir alafenamide (until week 48), and entered an extension phase. The geometric least squares mean (GLSM) ratio for AUCtau for bictegravir was 7·6% higher than adults (GLSM ratio 107·6%, 90% CI 96·7-119·7); Ctau was 34·6% lower than adults (65·4%, 49·1-87·2). Both parameters were within the target exposure range previously found in adults, children, or both". Grade 3-4 laboratory abnormalities occurred in four (18%) participants by the end week 24 and six (27%) by the end of week 48. Drug-related adverse events occurred in three participants (14%) by the end of week 24 and week 48; none were severe. No Grade 3-4 adverse events, serious adverse events, or adverse events leading to discontinuation occurred by the end of week 24 and week 48. INTERPRETATION: Data support the use of single-tablet coformulated bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) for treatment of HIV in children aged at least 2 years and weighing 14 kg to less than 25 kg. FUNDING: Gilead Sciences.

Physiologically based Pharmacokinetic Model Validated to Enable Predictions Of Multiple Drugs in a Long-acting Drug-combination Nano-Particles (DcNP): Confirmation with 3 HIV Drugs, Lopinavir, Ritonavir, and Tenofovir in DcNP Products.

Drug-Combination Nanoparticles (DcNP) are a novel drug delivery system designed for synchronized delivery of multiple drugs in a single, long-acting, and targeted dose. Unlike depot formulations, slowly releasing drug at the injection site into the blood, DcNP allows multiple-drug-in-combination to collectively distribute from the injection site into the lymphatic system. Two distinct classes of long-acting injectables products are proposed based on pharmacokinetic mechanisms. Class I involves sustained release at the injection site. Class II involves a drug-carrier complex composed of lopinavir, ritonavir, and tenofovir uptake and retention in the lymphatic system before systemic access as a part of the PBPK model validation. For clinical development, Class II long-acting drug-combination products, we leverage data from 3 nonhuman primate studies consisting of nine PK datasets: Study 1, varying fixed-dose ratios; Study 2, short multiple dosing with kinetic tails; Study 3, long multiple dosing (chronic). PBPK validation criteria were established to validate each scenario for all drugs. The models passed validation in 8 of 9 cases, specifically to predict Study 1 and 2, including PK tails, with ritonavir and tenofovir, fully passing Study 3 as well. PBPK model for lopinavir in Study 3 did not pass the validation due to an observable time-varying and delayed drug accumulation, which likely was due to ritonavir's CYP3A inhibitory effect building up during multiple dosing that triggered a mechanism-based drug-drug interaction (DDI). Subsequently, the final model enables us to account for this DDI scenario.

Switch to bictegravir/emtricitabine/tenofovir alafenamide from dolutegravir-based therapy.

OBJECTIVE: To evaluate the efficacy and safety of 96 weeks of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) treatment in participants switching from dolutegravir (DTG)-based therapy. DESIGN: Studies 1489 (NCT02607930) and 1490 (NCT02607956) were phase 3 randomized, double-blind, active-controlled, first-line therapy trials in people with HIV-1. After 144 weeks of DTG-based or B/F/TAF treatment, participants could enter a 96-week open-label extension (OLE) of B/F/TAF. METHODS: A pooled analysis evaluated viral suppression (HIV-1 RNA <50 copies/ml) and changes in CD4 + cell count at OLE Weeks 48 and 96, treatment-emergent resistance, safety, and tolerability after switch from a DTG-based regimen to B/F/TAF. Outcomes by prior treatment were summarized using descriptive statistics and compared by two-sided Wilcoxon rank sum test. RESULTS: At OLE Week 96, participants who switched to B/F/TAF ( N  = 519) maintained high levels of virologic suppression (99.5 and 99.1% in those switching from DTG/abacavir/lamivudine and DTG+F/TAF, respectively) and CD4 + cell count, with no treatment-emergent resistance to B/F/TAF. Twenty-one participants experienced drug-related adverse events after switching, with diarrhea, weight gain, and headache occurring most commonly. There were no cases of proximal renal tubulopathy, drug-related Grade 4 adverse events, or serious adverse events. Two participants discontinued B/F/TAF due to treatment-related adverse events. Participants who switched from DTG/abacavir/lamivudine experienced statistically significant greater weight gain than those who switched from DTG+F/TAF; however, median weight change from the blinded phase baseline to OLE Week 96 was numerically similar across treatment groups. CONCLUSION: This medium-term analysis demonstrates the safety and efficacy of switching to B/F/TAF from a DTG-containing regimen in people with HIV-1.

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.

Safety and Efficacy of Long-Acting Injectable Agents for HIV-1: Systematic Review and Meta-Analysis.

BACKGROUND: HIV-1 infection continues to affect global health. Although antiretrovirals can reduce the viral load or prevent HIV-1 infection, current drugs require daily oral use with a high adherence level. Long-acting antiretrovirals (LA-ARVs) significantly improve medication adherence and are essential for HIV-1 prophylaxis and therapy. OBJECTIVE: This study aimed to investigate the safety and efficacy of long-acting cabotegravir (CAB-LA) and long-acting rilpivirine (RPV-LA) in the prevention and treatment of HIV-1 infection. METHODS: PubMed, Embase, and the Cochrane Library were searched for studies from database inception to November 12, 2022. We included studies that reported efficacy and safety data on LA-ARV intervention in people living with HIV and excluded reviews, animal studies, and articles with missing or duplicate data. Virological suppression was defined as plasma viral load <50 copies/mL 6 months after antiviral therapy initiation. We extracted outcomes for analysis and expressed dichotomous data as risk ratios (RRs) and continuous data as mean differences. Depending on the heterogeneity assessment, a fixed- or random-effects model was used for data synthesis. We performed subgroup analyses of the partial safety and efficacy outcomes of CAB-LA+RPV-LA. The protocol was registered with the Open Science Framework. RESULTS: We included 12 trials comprising 10,957 individuals, of which 7 were prevention trials and 5 were treatment trials. CAB-LA and RPV-LA demonstrated safety profiles comparable with those of the placebo in terms of adverse event-related withdrawal. Moreover, the efficacy data showed that CAB-LA had a better effect on HIV-1 prevention than tenofovir disoproxil fumarate-emtricitabine (17/5161, 0.33% vs 75/5129, 1.46%; RR 0.21, 95% CI 0.07-0.61; I2=70%). Although CAB-LA+RPV-LA had more drug-related adverse events (556/681, 81.6% vs 37/598, 6.2%; RR 12.50, 95% CI 3.98-39.23; I2=85%), a mild or moderate injection site reaction was the most common reaction, and its frequency decreased over time. The efficacy of CAB-LA+RPV-LA was comparable with that of daily oral drugs at 48 and 96 weeks (1302/1424, 91.43% vs 915/993, 92.2%; RR 0.99, 95% CI 0.97-1.02; I2=0%), and a high level of virological suppression of 80.9% (186/230) was maintained even after 5 years of LA-ARV use. Similar efficacy outcomes were observed in both treatment-naive and treatment-experienced patients (849/911, 93.2% vs 615/654, 94%; RR 0.99, 95% CI 0.96-1.02; I2=0%). According to the questionnaires, more than 85% of people living with HIV favored LA-ARVs. CONCLUSIONS: LA-ARVs showed favorable safety profiles for both the prevention and treatment of HIV-1 infection and were well tolerated. CAB-LA has more satisfactory efficacy than tenofovir disoproxil fumarate-emtricitabine, significantly reducing the rate of HIV-1 infection. CAB-LA+RPV-LA maintains virological suppression for a long time and may be a viable switching strategy with enhanced public health benefits by reducing transmission. However, further trials are required to confirm the efficacy of these drugs.

Clinical-epidemiological characterization of women who received post-exposure HIV prophylaxis in a public hospital in Porto Alegre, Rio Grande do Sul / Caracterização clínico-epidemiológica de mulheres que receberam a profilaxia pós-exposição ao HIV em um hospital público de Porto Alegre, Rio Grande do Sul

Introduction: Prevention strategies are key to combating the epidemic of infections such as HIV and syphilis. The epidemiological scenario of Porto Alegre/RS for these infections shows the need for greater efforts in the area of prevention, seeking to characterize both the population that uses these strategies and the services involved in the care of exposed people. Objective: This study aimed to characterize the clinical and epidemiological profile of patients who received post-exposure prophylaxis (PEP) to HIV treated in a public hospital in Porto Alegre/RS. Methods: This is a retrospective, research, descriptive study based on the Clinical Protocol and Therapeutic Guidelines for PEP, updated in 2018 by the Ministry of Health. Prophylaxis request forms and medical records of patients treated were analyzed. Results: The population consisted of 87 women who received PEP from January to September 2019. There was a predominance of women aged between 20 and 29 years old (55.2%). The most frequent sexual exposure was consensual (69.0%) followed by sexual assault (31.0%). Porto Alegre was the place of residence of most patients (73.6%). The most frequently used therapeutic regimen was the combination of atazanavir, ritonavir, and tenofovir plus lamivudine. On the first visit, 8.0% of the patients showed reactive results for the treponemal syphilis test. Only 23.0% and 14.9% of patients returned for anti-HIV tests in the first and third months after exposure, respectively, and the results were non-reactive. Only 19 patients (21.8%) attended the consultations between 0 and 28 days after PEP. Conclusion: It was identified that a considerable percentage of women already had reactive serology for syphilis, most women did not return for follow-up within 28 and 90 days after the first consultation, more than half of the women were aged between 20 and 29 years old, and the most frequent sexual exposure was consensual. In this sense, efforts are needed, such as adequate counseling, adoption of interventions such as sending messages by cell phone, telephone calls, and preparation of educational materials, seeking to improve adherence to treatment and follow-up in the service, which is important given the scenario of epidemiology in Porto Alegre.Keywords: HIV. Sexually transmitted diseases. Post-exposure prophylaxis. Disease prevention

Introdução: Estratégias de prevenção são fundamentais para o combate à epidemia de infecções como o vírus da imunodeficiência humana (HIV) e sífilis. O cenário epidemiológico de Porto Alegre/RS para essas infecções mostra a necessidade de maiores esforços na área de prevenção, buscando caracterizar tanto a população que utiliza essas estratégias quanto os serviços envolvidos no atendimento das pessoas expostas. Objetivo: Caracterizar o perfil clínico-epidemiológico das pacientes que receberam a profilaxia pós-exposição (PEP) ao HIV atendidas em um hospital público de Porto Alegre/RS. Métodos: Trata-se de um estudo retrospectivo, documental, descritivo e baseado no Protocolo Clínico e Diretrizes Terapêuticas para PEP, atualizado em 2021 pelo Ministério da Saúde. Foram analisados os formulários de solicitação da profilaxia e prontuários das pacientes atendidas. Resultados: A população foi composta de 87 mulheres que receberam a PEP no período de janeiro a setembro de 2019. Predominaram mulheres com idades entre 20 e 29 anos (55,2%). A exposição sexual mais frequente foi a consentida (69,0%), seguida pela violência sexual (31,0%). Porto Alegre foi o local de residência da maioria das pacientes (73,6%). O esquema terapêutico utilizado com maior frequência foi a combinação com atazanavir, ritonavir e tenofovir associado à lamivudina. No primeiro atendimento, 8,0% das pacientes demonstraram resultados reagentes para o teste treponêmico de sífilis. Retornaram para a realização dos testes anti-HIV no primeiro e terceiro mês após a exposição apenas 23,0 e 14,9% das pacientes, respectivamente, e os resultados foram não reagentes. Apenas 19 delas (21,8%) compareceram às consultas entre zero e 28 dias posteriores à PEP. Conclusão: Foi identificado que um percentual considerável de mulheres já apresentava sorologia reagente para sífilis, a maioria das mulheres não retornou para o seguimento no período de 28 e 90 dias após o primeiro atendimento, mais da metade delas tinha idade entre 20 e 29 anos e a exposição sexual mais frequente foi a consentida. Nesse sentido, são necessários esforços como aconselhamento adequado, adoção de intervenções como o envio de mensagens pelo celular, ligações telefônicas e elaboração de materiais educativos, buscando a melhoria da adesão ao tratamento e do acompanhamento no serviço, o que é importante diante do cenário epidemiológico de Porto Alegre.Palavras-chave: HIV. Infecções sexualmente transmissíveis. Profilaxia pós-exposição. Prevenção

Efficacy and Tolerability of Tenofovir/Lamivudine/Dolutegravir among Antiretroviral Therapy Naive Human Immunodeficiency Virus Infected Patients of a Tertiary Care Center in Eastern India.

BACKGROUND: Although many drug regimens have been used in the treatment of human immunodeficiency virus (HIV) infection, the National AIDS Control Organization (NACO) of India recommends the use of a fixed-dose combination of tenofovir/lamivudine/dolutegravir (TLD) as a first-line regimen since 2020. In spite of much global data on the use of this combination, experience in the Indian population is still limited. We aim to find out the efficacy and tolerability of this novel regimen, in a tertiary care center of Eastern India. MATERIALS AND METHODS: A descriptive observational study, longitudinal in design performed in the antiretroviral therapy (ART) center of a tertiary care hospital in Kolkata, West Bengal, India. All patients who attended the ART center from April 2021 to October 2022 were enrolled in the study following inclusion and exclusion criteria. A detailed history, clinical examination, necessary biochemical tests, and CD4 count of all patients were done at baseline. Subsequently, they were followed up for 6 months with monthly visits when they were enquired about any adverse effects requiring therapy interruptions. At the end of 6 months, CD4 count and viral load were measured. RESULTS: Out of a total sample of 249 patients, the TLD regimen was efficacious in 99.2% (n = 247) in whom viral load was suppressed to <1,000 copies/mL after 6 months of treatment. The regimen had to be temporarily discontinued in 6% of patients (n = 15). The most common cause of treatment interruption was hepatic dysfunction (3.2%) followed by cutaneous manifestation (2.4%). In 14 out of 15 patients, the regimen could be reintroduced and was safely tolerated afterward. Only one patient had to be shifted to an alternative regimen due to tenofovir-induced nephrotoxicity. Thus TLD was tolerated in 99.6% (n = 248) patients. CONCLUSION: The fixed-dose combination of TLD is a highly efficacious and well-tolerated first-line regimen for ART naïve patients with HIV infection having >95% adherence. How to cite this article: Sengupta D, Ghosh S, Pain S, et al. Efficacy and Tolerability of Tenofovir/Lamivudine/Dolutegravir among Antiretroviral Therapy Naive Human Immunodeficiency Virus Infected Patients of a Tertiary Care Center in Eastern India. J Assoc Physicians India 2023;71(9):72-74.

Tenofovir alafenamide: An initial experience at Groote Schuur Hospital, Cape Town, South Africa.

BACKGROUND: Hepatitis B virus (HBV) remains endemic in South Africa (SA), with a concomitantly high prevalence of HIV co-infection. Chronic kidney disease in these subpopulations also has a high prevalence. Tenofovir is an important component of management, but the associated risk of nephrotoxicity makes dosing a challenge in patients with impaired kidney function. A new formulation, tenofovir alafenamide fumarate (TAF), with a more favourable renal toxicity profile, is now available. OBJECTIVES: To evaluate our initial experience of TAF use at Groote Schuur Hospital, Cape Town. METHODS: We retrospectively reviewed patients with HBV mono-infection and HIV-HBV co-infection who were initiated on TAF since 2018. We recorded all relevant demographic, serological, virological and biochemical data from patient records. Adherence was documented by pill collection at the pharmacy. RESULTS: A total of 26 patients were included in the evaluation, median (interquartile range (IQR)) age 48 (39 - 51) years, 73% (n=19) male, 27% (n=7) hepatitis B e-antigen-positive, and 46% (n=12) HIV co-infected. The median (IQR) duration of treatment with TAF was 13 (9 - 15) months. The median (IQR) baseline creatinine level was 180 (130 - 227) µmol/L, with significant improvement at 12 months, 122 (94 - 143) µmol/L; p=0.017. Reflecting this change, the estimated glomerular filtration rate improved significantly from baseline to month 12 (42 (25 - 52) and 51 (48 - 68) mL/min/1.73 m2, respectively; p=0.023). Similarly, serum alanine aminotransferase (ALT) normalised from a baseline of 33 (18 - 52) to 18 (15 - 24) U/L at month 12 (p=0.012). HBV DNA viral load also declined, from a baseline of log10 4.04 (2.5 - 7.8) IU/mL to a median of <log10 1.3 IU/mL at month 12. HIV viral load was less than the lower level of quantification at months 6 and 12. CONCLUSIONS: TAF was well tolerated, with stable and significantly improving kidney function throughout a 12-month follow-up period. Serum ALT normalised, mirrored by declining HBV viral load. HIV viral load remained undetectable at 6 and 12 months.

Current Trend in Antiviral Therapy for Chronic Hepatitis B.

Since active hepatitis B virus (HBV) replication is the key driver of hepatic necroinflammation and disease progression, the treatment aim of chronic hepatitis B (CHB) is to suppress HBV replication permanently to prevent hepatic decompensation, liver cirrhosis and/or hepatocellular carcinoma and prolong survival. Currently, pegylated interferon (Peg-IFN), entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are the first-line drugs of choice. Peg-IFN therapy has been used rarely due to its subcutaneous injection and significant side effect profile. Once daily oral ETV, TDF and TAF can suppress HBV DNA profoundly but have no direct action on cccDNA of the HBV-infected hepatocytes, hence continuing long-term therapy is usually needed to maintain HBV suppression, but the ultimate goal of HBsAg loss was rarely achieved (10 year 2%). In addition, long-term NUC therapy comes with several concerns such as increasing cost, medication adherence and loss-to-follow-up. Studies, mainly from Taiwan, have shown that finite NUCs therapy of two to three years in HBeAg-negative patients is feasible, safe and has a great benefit of much increasing HBsAg loss rate up to 30%/5 year. These have led an emerging paradigm shift to finite NUC therapy in HBeAg-negative patients globally. However, off-NUC relapse with hepatitis B flares may occur and have a risk of decompensation or even life-threatening outcomes. Therefore, proper monitoring, assessment, and retreatment decisions are crucial to ensure safety. Ideally, retreatment should be not too late to ensure safety and also not too early to allow further immune response for further HBsAg decline toward HBsAg loss. Assessment using combined HBsAg/ALT kinetics during hepatitis flare is better than biochemical markers alone to make a right retreatment decision. The strategy of finite NUC therapy has set a benchmark of high HBsAg loss rate to be achieved by the new anti-HBV drugs which are under preclinical or early phase study.

Effect of switching from tenofovir disoproxil fumarate to tenofovir alafenamide on lipid profiles in patients with hepatitis B.

For long-term treatment of hepatitis B virus (HBV) infection, switching from tenofovir-disoproxil-fumarate (TDF) to tenofovir-alafenamide (TAF) may prevent renal dysfunction and bone loss. However, the precise effects of this switch on the blood lipid profile remain to be clarified. This is an important issue as TDF is known to have effects on both low- and high-density lipids. Therefore, our retrospective multi-center study aimed to evaluate the effects of switching from TDF to TAF on the lipid profile of patients with HBV infection. Samples were obtained prior to the switch from TDF to TAF and at 6-12 months after TAF initiation. In some cases, additional samples obtained pre- and post-TDF administration were available for analysis. Serum cholesterol levels, including oxidized-low-density lipoprotein (LDL) and non-high-density lipoprotein-cholesterol (HDL-c), and the rate of dyslipidemia, according to the NCEP-ATP III lipid risk classification, were analyzed. The data from 69 patients were analyzed, including 33 patients with pre- and post-TDF-initiation serum samples. Total cholesterol (T-chol), HDL-c, LDL-c, non-HDL-c, and oxidized LDL levels increased significantly after switching to TAF. With regard to sequential changes pre- to post-TAF, TDF was associated with significantly lower serum T-chol, HDL-c, and oxidized LDL-c levels, with T-chol, HDL-c, LDL-c, and oxidized LDL-c levels increasing significantly after the switch. The switch from TDF to TAF was also associated with an increase in the rate of dyslipidemia, from 33% to 39%, with an increase in the rate of severe dyslipidemia of 1.4% and 5.8%, based on T-chol and LDL-c levels. Of note, no cases of severe dyslipidemia were detected pre-TAF treatment. As oxidized LDL-c and non-HDL-c are strongly associated with atherosclerosis development, careful monitoring of lipid is needed after switching from TDF to TAF in this clinical population.

Optimized hydration dynamics in mucoadhesive xanthan-based trilayer vaginal films for the controlled release of tenofovir.

Karaya gum, pectin and xanthan gum have been tested as candidates for manufacturing mucoadhesive trilayer films containing ethylcellulose and chitosan for the vaginal administration of the antiviral Tenofovir (TFV). The swelling profile correlated with the amount of mobile dipoles determined by impedance spectroscopy allows the determination of the hydration dynamics of these films. The fast water penetration has been demonstrated to favor the formation of polyelectrolyte complexes (PEC) via hydrogen or ionic bonds which would favor a controlled release. The incorporation of an inorganic drug release regulator induces the weakness of the polymeric chains thus enhancing the ionic mobility via the formation of low molecular weight PECs in films manufactured with karaya gum. Due to the different mechanical properties of the individual components, pectin-based films failed for a potential pharmaceutical formulation. However, mucoadhesive trilayer films produced with xanthan gum have demonstrated a moderate swelling, improved wettability and a controlled release of TFV.

Integration of pre-exposure prophylaxis services into public HIV care clinics in Kenya: a pragmatic stepped-wedge randomised trial.

BACKGROUND: Successful and sustainable models for HIV pre-exposure prophylaxis (PrEP) delivery in public health systems in Africa are needed. We aimed to evaluate the implementation of PrEP delivery integrated in public HIV care clinics in Kenya. METHODS: As part of Kenya's national PrEP roll-out, we conducted a stepped-wedge cluster-randomised pragmatic trial to catalyse scale-up of PrEP delivery integrated in 25 public HIV care clinics. We selected high-volume clinics in these regions (ie, those with a high number of people living with HIV enrolled in HIV care and treatment). Clinics (each representing a cluster) were stratified by region and randomly assigned to the order in which clinic staff would receive PrEP training and ongoing technical support using numbered opaque balls picked from a bag. There was no masking. PrEP provision was done by clinic staff without additional financial support. Data were abstracted from records of individuals initiating PrEP. The primary outcome was the number of people initiating PrEP per clinic per month comparing intervention to control periods. Other outcomes included PrEP continuation, adherence, and incident HIV infections. This trial is registered with ClinicalTrials.gov, NCT03052010. FINDINGS: After the baseline period, which started in January, 2017, every month two to six HIV care clinics crossed over from control to intervention, until August, 2017, when all clinics were implementing the intervention. Of 4898 individuals initiating PrEP (27 during the control period and 4871 during the intervention period), 2640 (54%) were women, the median age was 31 years (IQR 25-39), and 4092 (84%) reported having a partner living with HIV. The mean monthly number of PrEP initiations per clinic was 0·1 (SD 0·5) before the intervention and 7·5 (2·7) after intervention introduction (rate ratio 23·7, 95% CI 14·2-39·5, p<0·0001). PrEP continuation was 57% at 1 month, 44% at 3 months, and 34% at 6 months, and 12% of those who missed a refill returned later for PrEP re-initiation. Tenofovir diphosphate was detected in 68 (96%) of 71 blood samples collected from a randomly selected subset of participants. Six HIV infections were observed over 2531 person-years of observation (incidence 0·24 cases per 100 person-years), three of which occurred at the first visit after PrEP initiation. INTERPRETATION: We observed high uptake, reasonable continuation with high adherence, frequent PrEP restarts, and low HIV incidence. Integration of PrEP services within public HIV care clinics in Africa is feasible. FUNDING: National Institute of Mental Health and Bill & Melinda Gates Foundation.

Entecavir-associated thrombocytopenia.

Entecavir (ETV) is widely used in the treatment of hepatitis B, but there are only a few reports about entecavir-associated thrombocytopenia, and it is considered as an immediate response and inappropriate to continue the treatment with other nucleoside analogues. Now, we report the third case, and this case was delayed response and we switched to treatment with tenofovir (TDF). There was a 66-year-old female who was infected with hepatitis B virus (HBV). Her platelet count decreased from 111*109/L to 3*109/L and was prone to gum bleeding and skin ecchymosis after she received ETV treatment for 88 days. As a treatment option, ETV was replaced by TDF immediately, frequent platelets transfusions and thrombopoietin were applied for several days, daily prednisone of 50 mg was concomitantly taken, and then platelet count improved after 10 days. She was diagnosed with entecavir-associated thrombocytopenia after analysis of the temporal relationship and exclusion of other causes of thrombocytopenia by blood and bone marrow examinations. Our case suggested that the platelet count should be monitored regularly in patients during ETV treatment, and it may be a feasible option to choose TDF to maintain antiviral treatment when entecavir-associated thrombocytopenia occurs.

Effectiveness of tenofovir alafenamide for chronic hepatitis B patients with a poor response to the previously used nucleos(t)ide analogs.

BACKGROUND: Few studies have demonstrated the potency of tenofovir alafenamide (TAF) in patients with poor response to other nucleos(t)ide analogs (NAs). METHODS: We conducted a retrospective study comprising consecutive 40 patients exhibiting a poor response to other NAs, who subsequently received TAF-containing regimens. The primary outcome was the prevalence of virological response (VR) at each time and maintained virological response (MVR) under TAF-containing regimens until week 96. RESULTS: In the entire cohort, the prevalence of MVR was 71.1% (27/38). Further, poor tenofovir disoproxil fumarate (TDF) response was significantly associated with a lower prevalence of MVR (p = 0.014). In TDF-naïve patients, the prevalence of MVR was 92.3% (12/13) and 62.5% (5/8) in patients with lamivudine resistance (LAM-r) and entecavir resistance (ETV-r), respectively. Further, viral load and HBeAg status at baseline were associated with a lower prevalence of MVR (p = 0.013). Among the seven patients with prior TDF exposure, 2 patients achieved MVR. Among them, one patient with development of viral breakthrough during TDF/LAM achieved MVR after switching to TAF/ETV. In contrast, one of the five patients with non-MVR had three substitutions (rtS106C, rtD134N/S, and rtL269I) of quadruple mutations in addition to ETV-r. Other patients with rtA181T + rtN236T also could not achieve MVR. CONCLUSION: TAF exhibited high antiviral potency in patients with LAM-r and ETV-r. However, TAF potency was associated with previous TDF response, viral load, and HBeAg status at baseline. Additionally, a quadruple mutation may impact tenofovir resistance; however, further studies are needed to verify this.

HIV Incidence Among Pregnant and Nonpregnant Women in the FACTS-001 Trial: Implications for HIV Prevention, Especially PrEP Use.

BACKGROUND: During pregnancy and postpartum period, the sexual behaviors of women and their partners change in ways that may either increase or reduce HIV risks. Pregnant women are a priority population for reducing both horizontal and vertical HIV transmission. SETTING: Nine sites in 4 South African provinces. METHODS: Women aged 18-30 years were randomized to receive pericoital tenofovir 1% gel or placebo gel and required to use reliable modern contraception. We compared HIV incidence in women before, during, and after pregnancy and used multivariate Cox Proportional hazards models to compare HIV incidence by pregnancy status. RESULTS: Rates of pregnancy were 7.1 per 100 woman-years (95% confidence interval [CI]: 6.3 to 8.1) and highest in those who reported oral contraceptive use (25.1 per 100 woman-years; adjusted hazard ratio 22.97 higher than other women; 95% CI: 5.0 to 105.4) or had 2 children. Birth outcomes were similar between trial arms, with 59.8% having full-term live births. No difference was detected in incident HIV during pregnancy compared with nonpregnant women (2.1 versus 4.3%; hazard ratio = 0.56, 95% CI: 0.14 to 2.26). Sexual activity was low in pregnancy and the early postpartum period, as was consistent condom use. CONCLUSIONS: Pregnancy incidence was high despite trial participation being contingent on contraceptive use. We found no evidence that rates of HIV acquisition were elevated in pregnancy when compared with those in nonpregnant women. Risks from reductions in condom use may be offset by reduced sexual activity. Nevertheless, high HIV incidence in both pregnant and nonpregnant women supports consideration of introducing antiretroviral-containing pre-exposure prophylaxis for pregnant and nonpregnant women in high HIV prevalence settings.

Concentration of LDLR, degree of hepatic fibrosis and hepatic steatosis in patients with chronic hepatitis B infection treated with tenofovir disoproxil fumarate.

INTRODUCTION: Epidemiological data indicate that one-third of the world's population have serological markers of hepatitis B virus infection. Hepatic steatosis is often observed in patients with chronic liver diseases. The exact mechanisms of hepatic steatosis progression and the efficacy of antiviral therapy in patients with CHB and hepatic steatosis are not yet fully understood. OBJECTIVE: The aim of the study was to investigate the LDLR concentration and degree of hepatic fibrosis and hepatic steatosis in patients with chronic hepatitis B infection during tenofovir disoproxil fumarate therapy. MATERIAL AND METHODS: The study group consisted of 54 patients with CHB. The LDLR concentration, assessment of the degree of hepatic fibrosis, hepatic steatosis, total cholesterol, low density lipoprotein, high density lipoprotein and triglyceride concentrations, were assessed at the beginning of therapy, 6 months later, and 12 months after commencement of therapy. The control group consisted of 18 healthy individuals. RESULTS: The mean LDLR concentration in the studied groups was statistically significantly lower (p<0.05) than in the controls. The antiviral therapy based on TDF had no influence on the LDLR concentration and HBsAg level. CONCLUSIONS: The results indicate a statistically significant lower(p<0.05) concentration of LDLR in patients with chronic hepatitis B infection. Negative correlations between HBsAg level and LDLR concentration in patients with chronic HBV, at all stages of the study may indicate, that HBsAg protects hepatocytes from LDL accumulation.