Off-label use of combined antiretroviral therapy, analysis of data collected by the Italian Register for HIV-1 infection in paediatrics in a large cohort of children

Background Early start of highly active antiretroviral therapy (HAART) in perinatally HIV-1 infected children is the optimal strategy to prevent immunological and clinical deterioration. To date, according to EMA, only 35% of antiretroviral drugs are licenced in children < 2 years of age and 60% in those aged 2–12 years, due to the lack of adequate paediatric clinical studies on pharmacokinetics, pharmacodynamics and drug safety in children. Methods An observational retrospective study investigating the rate and the outcomes of off-label prescription of HAART was conducted on 225 perinatally HIV-1 infected children enrolled in the Italian Register for HIV Infection in Children and followed-up from 2001 to 2018. Results 22.2% (50/225) of included children were receiving an off-label HAART regimen at last check. Only 26% (13/50) of off-label children had an undetectable viral load (VL) before the commencing of the regimen and the 52.0% (26/50) had a CD4 + T lymphocyte percentage > 25%. At last check, during the off label regimen, the 80% (40/50) of patients had an undetectable VL, and 90% (45/50) of them displayed CD4 + T lymphocyte percentage > 25%. The most widely used off-label drugs were: dolutegravir/abacavir/lamivudine (16%; 8/50), emtricitbine/tenofovir disoproxil (22%; 11/50), lopinavir/ritonavir (20%; 10/50) and elvitegravir/cobicistat/emtricitabine/ tenofovir alafenamide (10%; 10/50). At logistic regression analysis, detectable VL before starting the current HAART regimen was a risk factor for receiving an off-label therapy (OR: 2.41; 95% CI 1.13–5.19; p = 0.024). Moreover, children < 2 years of age were at increased risk for receiving off-label HAART with respect to older children (OR: 3.24; 95% CI 1063–7.3; p = 0.001). Even if our safety data regarding off-label regimens where poor, no adverse event was reported. Conclusion The prescription of an off-label HAART regimen in perinatally HIV-1 infected children was common, in particular in children with detectable VL despite previous HAART and in younger children, especially those receiving their first regimen. Our data suggest similar proportions of virological and immunological successes at last check among children receiving off-label or on-label HAART. Larger studies are needed to better clarify efficacy and safety of off-label HAART regimens in children, in order to allow the enlargement of on-label prescription in children.

Cost-savings and potential cost-savings through the distribution of generic antiretroviral drugs within the statutory health insurance market of Germany between January 2017 and June 2019

Background Recent patent losses for antiretroviral drugs (ARV) have led to the debate of cost-saving through the replacement of patented drugs with generic drugs. The split of recommended single-tablet regimens (STR) into their single substance partners is one of the considerations mentioned in said debate. Particularly, generic tenofovir disoproxil/emtricitabine (TDF/FTC) is expected to hold untapped cost-saving potential, which may curb increasing overall expenditures for combined antiretroviral therapy (cART) within the statutory health insurance (SHI) of Germany. Methods Data of ARV reimbursed by the SHI were used to describe the trends of defined daily doses (DDD) as well as the revenue within the German ARV market. They were also used to determine the cost-savings of moving to generic drugs. The time period observed was between January 2017 and June 2019. The potential cost-savings were determined with following assumption in mind: the maximum possible use of generic ARV, including 1) the split of STR and replacing all substance partners with generic ones, and 2) replacing patented tenofovir alafenamide/emtricitabine (TAF/FTC) with generic TDF/FTC. Results Throughout the observation period, the DDD of generic ARV increased nearly five-fold while their revenue increased more than four-fold. Total cost-saving showed a sharp increase over the same period, with generic TDF/FTC accounting for a share of around 70%. The largest potential cost-saving could have been achieved through replacing patented TAF/FTC with generic TDF/FTC, peaking at nearly 10% of total revenue, but showing decreasing trends in general. Conclusion The progressive distribution of generic ARV ensured increasing cost-savings, but consequently curbed the potential cost-savings. Unique price reductions of generic TDF/FTC have played a pivotal role for these effects. In any case, substituting with generic ARV should not fail to adhere to the treatment guidelines and continue to consider the medical requirements for the treatment.

Trans cohort metabolic reprogramming towards glutaminolysis in long-term successfully treated HIV-infection

Despite successful combination antiretroviral therapy (cART), persistent low-grade immune activation together with inflammation and toxic antiretroviral drugs can lead to long-lasting metabolic flexibility and adaptation in people living with HIV (PLWH). Our study investigated alterations in the plasma metabolic profiles by comparing PLWH on long-term cART(>5 years) and matched HIV-negative controls (HC) in two cohorts from low- and middle-income countries (LMIC), Cameroon, and India, respectively, to understand the system-level dysregulation in HIV-infection. Using untargeted and targeted LC-MS/MS-based metabolic profiling and applying advanced system biology methods, an altered amino acid metabolism, more specifically to glutaminolysis in PLWH than HC were reported. A significantly lower level of neurosteroids was observed in both cohorts and could potentiate neurological impairments in PLWH. Further, modulation of cellular glutaminolysis promoted increased cell death and latency reversal in pre-monocytic HIV-1 latent cell model U1, which may be essential for the clearance of the inducible reservoir in HIV-integrated cells.

Evolution in Real-World Therapeutic Strategies for HIV Treatment: A Retrospective Study in Southern Italy, 2014–2020

Changes in HIV treatment guidelines over the last two decades reflect the evolving challenges in this field. Our study examined treatment change patterns throughout a 7-year period in a large Italian cohort of HIV patients as well as the reasons and direction of changes. Treatment-naïve and -experienced HIV patients managed by Cotugno Hospital of Naples between 2014 and 2020 were analyzed. During the period, the proportion of single-tablet regimen treatment sharply increased for the naïve and experienced patients. Regimens containing integrase strand transfer inhibitors rapidly replaced those containing protease inhibitor and non-nucleoside reverse transcriptase inhibitors. The use of the tenofovir alafenamide fumarate/emtricitabine backbone increased rapidly after its introduction in the Italian pharmaceutical market, making up 63.7 and 54.9% of all treatments in naïve and experienced patients, respectively, in 2020. The main reason for treatment changes was optimization and/or simplification (90.6% in 2018; 85.3% in 2019; 95.5 in 2020) followed by adverse effects and virological failure. Our real-world analysis revealed that the majority of treatment-naïve and treatment-experienced patients received antiretroviral drugs listed as preferred/recommended in current recommendations. Regimen optimization and/or simplification is a leading cause of treatment modification, while virologic failure or adverse effects are less likely reasons for modification in the current treatment landscape.

Comparative evaluation of the applicability of fixed-dose combined drugs in HIV therapy / Avaliação comparativa da aplicabilidade de drogas combinadas em dose fixa na terapia do HIV

The principal global pandemic is Acquired Immunodeficiency Syndrome (AIDS), the early diagnosis and the premature treatment is the main current strategies in combating the development and spread of the disease. Antiretroviral therapy is effective and safe, what is sought nowadays is compliance and convenience for the patient. Different countries adopt different combinations of antiretroviral drugs when using the fixed-dose combination (FDC). The study design was a meta-analysis with clinical trials, patients experienced and naïve of treatment. The Pubmed, Scopus, Embase, Web of Science and Cochrane databases were searched for studies reporting AIDS treatment. The primary outcome was viral load and another outcome is adverse events. The results of the main analysis included 5224 patients. Since there was significant heterogeneity between studies, random effects were selected, and they showed an event rate of 0.67 (95%CI from 0.57 to 0.77). The exploratory analysis showed the general drug effects are not consistently significant along time, and treatments of longer times are more efficient. Specifically, the random analyses of 6 months and 1 year did not show significant drug effects on viral load, while a significant effect of 71% (95% CI from 0.61 to 0.80) in a very heterogeneous analyses (I296%). First, d4T-3TC-NVP showed a mean rate of only 21% efficacy and the second, EFV-TDF-FTC did not reach statistical significance (p=0.07). This meta-analysis shows that fixed-dose combination therapy is tolerability, safety and effective, occurred viral load suppression between patients on FDC.

Predictors of COVID-19 vaccine acceptability among patients living with HIV in northern Nigeria: A mixed methods study

Background: People living with HIV (PLHIV) are at increased risk of COVID-19 acquisition, severe disease, and poor outcomes. Yet, little is known about COVID-19 vaccine hesitancy among PLHIV in high HIV burden countries such as Nigeria. Objective: This study aims to assess the acceptability of the COVID-19 vaccine and identify predictors and reasons for vaccine hesitancy among patients living with HIV and attending a tertiary hospital in Kano, northern Nigeria. Methods: Using a mixed-methods design, structured questionnaires were administered to a clinic-based sample of patients living with HIV (n=344), followed by 20 in-depth interviews with a sub-sample. Logistic regression and the framework approach were used to analyze the data. Results: Less than half (46.2%, n=159) of the respondents were willing to take the COVID-19 vaccine. Vaccine acceptance was higher among non-Muslim PLHIV (Adjusted Odds Ratio (aOR)=1.26, 95% Confidence Interval (95%CI): 1.10-4.00), persons with high-risk perception (aOR=2.43, 95%CI:1.18-5.00), those who were not worried about infertility-related rumors (aOR=13.54, 95%CI:7.07-25.94) and persons who perceived antiretroviral drugs are protective against COVID-19 (aOR = 2.76, 95%CI: 1.48-5.14). In contrast, vaccine acceptance was lower among persons who were not more concerned about the potential effects of COVID-19-HIV co-infection (aOR=0.20, 95%CI:0.10-0.39). The most common reasons for vaccine hesitancy included doubts about the existence of COVID-19, low-risk perception, anxiety about antiretroviral treatment-vaccine interactions, safety concerns, and infertility-related rumors. Conclusion: Covid-19 vaccine acceptance was low among PLHIV. COVID-19 vaccine acceptance was associated with respondents’ faith, risk perception, perception of the protective effects of antiretroviral treatment, concerns about COVID-19-HIV co-infection, and infertility-related rumors. Vaccination counseling should be integrated into HIV treatment services to improve COVID-19 vaccine uptake among PLHIV in Kano and similar settings.

Assessment of clinical and etiological factors in nail dyschromias

Healthy nails appear smooth and have consistent coloring. Nail dyschromias have a wide variety of presentation. There are numerous causes of discoloration of the nail affecting the nail plate, nail attachments, or the substance of the nail. Different pattern of nail dyschromias can point out certain dermatological or systemic diseases. To evaluate the causes of nail dyschromias in our clinical setting. Cross sectional observational study. 200 patients presenting with nail dyschromias were included in the study from April 2015 to July 2015. Detailed history was taken and cause for nail dyschromias was evaluated. 115 (57.5%) were males and 85 (42.05%) were females. The most seen nail dyschromia in this study was melanonychia (86.5%) followed by leukonychia (5%), blue chromonychia (5%), brown chromonychia (2%) yellow chromonychia (1.5%). The cause of nail dyschromias were:60 cases(%) were due to antiretroviral drugs, 25(12.5%) due to HIV, 30(15%) physiological melanonychia, 7(3.5% of onychomycosis, 8(4%) of lichen planus, 7(3.5%) of eczema, 15(7.5%) vitamin B12 deficiency, 10(5%) chemotherapy induced blue chromonychia, 3(1.5%) haematoma, 10(5%) leukonychia, 3(1.5%) jaundice 2(1%) Addison’s disease induced, 3(1.5%) cosmetic induced and 17(7.5%) due to other dermatological and systemic conditions. Examination of nail should always be a part of routine cutaneous examination and presentation with nail dyschromias should be worked up with the help of a good history and examination. Careful examination of the nail may help in identifying the root cause and many a times unravels some underlying systemic disorder

Factors Associated with Adherence to Antiretroviral Drugs among HIV Positive Patients Attending Selected Comprehensive Care Centers in Semi-Urban, Kenya

Management of Human Immunodeficiency Virus (HIV) is multipronged but its nerve centre is lifelong adequate and consistent use of antiretroviral drugs (ARVs). The overall objective of this study was to determine the factors associated with adherence to antiretroviral drugs among HIV positive patients attending selected Comprehensive Care Centres (CCC) in Kibwezi West Sub-county, Makueni County, Kenya. 385 respondents were recruited by systematic random sampling and interviewed. Three Focused Group Discussions (FGD) and two Key Informant Interviews (KII) were also conducted. Majority 364(94.5%) of the respondents were adherent to ARVs. There was a significant association between adherence to ARVs and gender {χ 2 (1) =4.636, p<0.05} with males likely to have poor adherence {OR 0.174 (95%CI 0.130, 0.233)}. Age was significantly associated with adherence {Likelihood Ratio G2 (4) =10.693, p<0.05} with older ages (above 65 years) likely to adhere. Living in the same house with someone on ARVs was significantly associated with adherence to ARVs {χ 2 (1) =3.997 p=<0.05} with respondents living in the same house with someone on ARVs likely to adhere {OR 0.144 (95%CI 0.103, 0.200)}. Majority of the respondents had adequate knowledge and positive attitude towards adherence to ARVs. FGDs and KIIs identified fear, stigma, not believing in oneself, participating in activities that hamper adherence such as drinking alcohol, ignorance, denial, lack of social support, busy work schedule poor attitude by health service providers, drug stock outs, distance and long waiting time as contributing to poor adherence to ARVs. In conclusion, constant education and awareness creation on importance of adherence to ARVs should be strengthened particularly during clinic appointments to maintain knowledge and enhance positive attitude towards adherence. Measures to improve adherence among the male and younger population should be strengthened. Key words: adherence, antiretrovirals age, gender, knowledge, attitude.

Immunogenetic features of HIV-infection and allergy comorbidity

Today, the comorbidity of infection caused by the human immunodeficiency virus (HIV) is an important problem due to the complexity of the selection of the optimal antiretroviral therapy and the diagnosing of associated pathological conditions. The study of the comorbidity of HIV-infection and allergy is an important area of research. This article presents a literature review on different types of comorbidity. Special attention is paid to the development of allergic reactions to antiretroviral drugs. The presence of an allergic reaction in a patient can cause low adherence to therapy and subsequent development of HIV resistance to the treatment. The review provides information on the possible causes of the development of hypersensitivity in HIV-infected patients. The data on the development of hypersensitivity reactions in response to treatment with the main classes of antiretroviral drugs (nucleoside and non-nucleoside reverse transcriptase inhibitors, synthesis inhibitors, protease inhibitors, integrase inhibitors, cysteine-cysteine chemokine receptor 5 inhibitors) are presented. The most common allergic reactions to these drug classes are itching and rash, as well as increasing hepatic transaminase levels and cough. The existing scientific data on allergic reactions to drugs prescribed for other concurrent conditions (tuberculosis, fungal diseases) is also considered. The examples of studies reflecting the relevance of using immunogenetic and molecular genetic approaches in the study of comorbidity of HIV-infection and allergy are given. The identification of immunogenetic markers of the development of the hypersensitivity to therapy will optimize the diagnostic and treatment algorithms, especially in complex comorbid conditions.