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Drug Safety Apr 2024Progressive multifocal leukoencephalopathy (PML) was first described among patients affected by hematological or solid tumors. Following the human immunodeficiency virus... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Progressive multifocal leukoencephalopathy (PML) was first described among patients affected by hematological or solid tumors. Following the human immunodeficiency virus (HIV) epidemic, people living with HIV have represented most cases for more than a decade. With the diffusion of highly active antiretroviral therapy, this group progressively decreased in favor of patients undergoing treatment with targeted therapy/immunomodulators. In this systematic review and meta-analysis, the objective was to assess which drugs are most frequently related to PML development, and report the incidence of drug-induced PML through a meta-analytic approach.
METHODS
The electronic databases MEDLINE, EMBASE, ClinicalTrials.gov, Web of Science and the Canadian Agency for Drugs and Technologies in Health Database (CADTH) were searched up to May 10, 2022. Articles that reported the risk of PML development after treatment with immunomodulatory drugs, including patients of both sexes under the age of 80 years, affected by any pathology except HIV, primary immunodeficiencies or malignancies, were included in the review. The incidence of drug-induced PML was calculated based on PML cases and total number of patients observed per 100 persons and the observation time. Random-effect metanalyses were conducted for each drug reporting pooled incidence with 95% confidence intervals (CI) and median (interquartile range [IQR]) of the observation time. Heterogeneity was measured by I statistics. Publication bias was examined through funnel plots and Egger's test.
RESULTS
A total of 103 studies were included in the systematic review. In our analysis, we found no includible study reporting cases of PML during the course of treatment with ocrelizumab, vedolizumab, abrilumab, ontamalimab, teriflunomide, daclizumab, inebilizumab, basiliximab, tacrolimus, belimumab, infliximab, firategrast, disulone, azathioprine or danazole. Dalfampridine, glatiramer acetate, dimethyl fumarate and fingolimod show a relatively safe profile, although some cases of PML have been reported. The meta-analysis showed an incidence of PML cases among patients undergoing rituximab treatment for multiple sclerosis (MS) of 0.01 cases/100 persons (95% CI - 0.08 to 0.09; I = 20.4%; p = 0.25) for a median observation period of 23.5 months (IQR 22.1-42.1). Treatment of MS with natalizumab carried a PML risk of 0.33 cases/100 persons (95% CI 0.29-0.37; I = 50%; p = 0.003) for a median observation period of 44.1 months (IQR 28.4-60) and a mean number of doses of 36.3 (standard deviation [SD] ± 20.7). When comparing data about patients treated with standard interval dosing (SID) and extended interval dosing (EID), the latter appears to carry a smaller risk of PML, that is, 0.08 cases/100 persons (95% CI 0.0-0.15) for EID versus 0.3 cases/100 persons (95% CI 0.25-0.34) for SID.
CONCLUSIONS
A higher risk of drug-related PML in patients whose immune system is not additionally depressed by means of neoplasms, HIV or concomitant medications is found in the neurological field. This risk is higher in MS treatment, and specifically during long-term natalizumab therapy. While this drug is still routinely prescribed in this field, considering the efficacy in reducing MS relapses, in other areas it could play a smaller role, and be gradually replaced by other safer and more recently approved agents.
Topics: Male; Female; Humans; Aged, 80 and over; Natalizumab; Leukoencephalopathy, Progressive Multifocal; Canada; Immunologic Factors; Multiple Sclerosis; HIV Infections
PubMed: 38321317
DOI: 10.1007/s40264-023-01383-4 -
Pharmaceutics Oct 2023The clinical outcomes of antiretroviral drugs may be modified through drug interactions; thus, it is important to update the drug interactions in people living with HIV... (Review)
Review
BACKGROUND
The clinical outcomes of antiretroviral drugs may be modified through drug interactions; thus, it is important to update the drug interactions in people living with HIV (PLHIV).
AIM
To update clinically relevant drug interactions in PLHIV on antiretroviral therapy with novel drug interactions published from 2017 to 2022.
METHODS
A systematic review in Medline/PubMed database from July 2017 to December 2022 using the Mesh terms antiretroviral agents and drug interactions or herb-drug interactions or food-drug interactions. Publications with drug interactions in humans, in English or Spanish, and with full-text access were retrieved. The clinical relevance of drug interactions was grouped into five levels according to the gravity and probability of occurrence.
RESULTS
A total of 366 articles were identified, with 219 (including 87 citation lists) were included, which allowed for the identification of 471 drug interaction pairs; among them, 291 were systematically reported for the first time. In total 42 (14.4%) and 137 (47.1%) were level one and two, respectively, and 233 (80.1%) pairs were explained with the pharmacokinetic mechanism. Among these 291 pairs, protease inhibitors (PIs) and ritonavir/cobicistat-boosted PIs, as well as integrase strand transfer inhibitors (InSTIs), with 70 (24.1%) and 65 (22.3%) drug interaction pairs of levels one and two, respectively, were more frequent.
CONCLUSIONS
In PLHIV on antiretroviral therapy, we identify 291 drug interaction pairs systematically reported for the first time, with 179 (61.5%) being assessed as clinically relevant (levels one and two). The pharmacokinetic mechanism was the most frequently identified. PIs, ritonavir/cobicistat-boosted PIs, and InSTIs were the antiretroviral groups with the highest number of clinically relevant drug interaction pairs (levels one and two).
PubMed: 37896248
DOI: 10.3390/pharmaceutics15102488 -
The Annals of Pharmacotherapy Nov 2023Several cases of Fanconi syndrome (FS), a severe form of nephrotoxicity, have been reported in patients with HIV on tenofovir-containing antiretroviral therapy. A... (Review)
Review
OBJECTIVE
Several cases of Fanconi syndrome (FS), a severe form of nephrotoxicity, have been reported in patients with HIV on tenofovir-containing antiretroviral therapy. A systematic review of the published literature on tenofovir-related FS in patients with HIV was conducted.
DATA SOURCES
PubMed and Embase were queried to identify articles in English published between January 2005 and June 2023, reporting tenofovir-related FS in adults with HIV. Preclinical studies, conference/poster abstracts, commentaries and responses, and review papers were excluded.
STUDY SELECTION AND DATA EXTRACTION
Of the 256 articles screened, 57 met the inclusion criteria. These comprised 37 case reports, 11 case series, 1 cross-sectional study, 1 case-control study, 4 cohort studies, 1 single-arm open-label clinical trial, 1 sub-analysis of clinical trials, and 1 pooled analysis of clinical trials.
DATA SYNTHESIS
Among 56 cases on which information was abstracted, median age at FS diagnosis was 50 years, 51.8% were men, and duration of tenofovir use ranged from 6 weeks to 11 years. Ritonavir was co-prescribed in almost half the cases. In observational and interventional studies, incidence of FS was low. Many studies reported resolution of FS symptoms after tenofovir discontinuation. All FS occurrences were identified in those on tenofovir disoproxil fumarate (TDF), except for one patient on tenofovir alafenamide (TAF).
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE
Continuous monitoring of signs and symptoms of renal and bone toxicity is essential for patients with HIV on tenofovir-containing therapy.
CONCLUSIONS
Occurrence of FS is low in patients with HIV treated with tenofovir-based regimens. Concomitant use of ritonavir may increase risk of FS. TAF may be a safer alternative than TDF in terms of nephrotoxicity.
PubMed: 37932920
DOI: 10.1177/10600280231206703 -
Clinical Pharmacokinetics Sep 2023The life expectancy of people living with HIV (PLWHIV) has significantly improved in recent decades, mostly due to antiretroviral (ARV) therapy. Aging can affect the...
BACKGROUND AND OBJECTIVE
The life expectancy of people living with HIV (PLWHIV) has significantly improved in recent decades, mostly due to antiretroviral (ARV) therapy. Aging can affect the pharmacokinetics of drugs and, as a consequence, increase the risk of drug interactions and toxicity that may impact treatment. The aim of this study was to carry out a systematic review of the literature on the effect of aging on ARV pharmacokinetics.
METHODS
Searches were performed in the BVS, EMBASE and PUBMED databases until November 2022. All studies available in English, Spanish and Portuguese investigating the pharmacokinetics of ARV approved by the US Food and Drug Administration (FDA) from 2005 to 2020 were selected. Peer-reviewed publications were included if they met all criteria: adults (≥ 18 years of age) living with or without HIV; report any pharmacokinetic parameter or plasma concentration of at least one of the following ARVs: tenofovir alafenamide fumarate (TAF); doravirine (DOR), rilpivirine (RIL) and etravirine (ETR); darunavir (DRV), tipranavir (TPV) and fostemsavir (FTR); dolutegravir (DTG), raltegravir (RAL), bictegravir (BIC) and elvitegravir (EVG); maraviroc (MVC); ibalizumab (IBA); cobicistat (COBI). Pharmacokinetic parameters were reported stratified per age group: young adults (aged 18-49 years) or older (age ≥ 50 years) and all studies were evaluated for quality. The review protocol was registered in the PROSPERO database (registration number CRD42021236432).
RESULTS
Among 97 studies included, 20 reported pharmacokinetic evaluation in older individuals (age ≥ 50 years). Twenty five percent of the articles were phase I randomized clinical trials with HIV-negative participants and non-compartmental pharmacokinetic analysis presenting the parameters area under the curve (AUC) and peak drug concentration (C). Seven age-stratified studies evaluated BIC, ETR, DRV, DTG, DOR and RAL. We found publications with discordant results for ETR and DTG pharmacokinetics in different age groups. DRV exposure was highly variable but modestly increased in aging PLWHIV. In contrast, no influence of age on BIC, DOR and RAL exposure was observed. A variability in pharmacokinetic parameters could be observed for the other ARVs (TAF and MVC) in different age groups.
CONCLUSION
Exposure to DRV increases modestly with age, while exposure to BIC, DOR and RAL appears to be unaffected by age. As the available evidence to confirm a potential effect of aging on ARV pharmacokinetics is limited, further studies are necessary.
Topics: Young Adult; Humans; Aged; Adolescent; Anti-HIV Agents; Tenofovir; Pharmaceutical Preparations; Anti-Retroviral Agents; HIV Infections; Raltegravir Potassium; Adenine; Darunavir
PubMed: 37561283
DOI: 10.1007/s40262-023-01291-x -
BMC Infectious Diseases Aug 2023Evidence on the real-world effects of "Treat All" on attrition has not been systematically reviewed. We aimed to review existing literature to compare attrition... (Meta-Analysis)
Meta-Analysis
Attrition one year after starting antiretroviral therapy before and after the programmatic implementation of HIV "Treat All" in Sub-Saharan Africa: a systematic review and meta-analysis.
INTRODUCTION
Evidence on the real-world effects of "Treat All" on attrition has not been systematically reviewed. We aimed to review existing literature to compare attrition 12 months after antiretroviral therapy (ART) initiation, before and after "Treat All" was implemented in Sub-Saharan Africa and describe predictors of attrition.
METHODS
We searched Embase, Google Scholar, PubMed, and Web of Science in July 2020 and created alerts up to the end of June 2023. We also searched for preprints and conference abstracts. Two co-authors screened and selected the articles. Risk of bias was assessed using the modified Newcastle-Ottawa Scale. We extracted and tabulated data on study characteristics, attrition 12 months after ART initiation, and predictors of attrition. We calculated a pooled risk ratio for attrition using random-effects meta-analysis.
RESULTS
Eight articles and one conference abstract (nine studies) out of 8179 screened records were included in the meta-analysis. The random-effects adjusted pooled risk ratio (RR) comparing attrition before and after "Treat All" 12 months after ART initiation was not significant [RR = 1.07 (95% Confidence interval (CI): 0.91-1.24)], with 92% heterogeneity (I). Being a pregnant or breastfeeding woman, starting ART with advanced HIV, and starting ART within the same week were reported as risk factors for attrition both before and after "Treat All".
CONCLUSIONS
We found no significant difference in attrition before and after "Treat All" one year after ART initiation. While "Treat All" is being implemented widely, differentiated approaches to enhance retention should be prioritised for those subgroups at risk of attrition.
PROSPERO NUMBER
CRD42020191582 .
Topics: Female; Pregnancy; Humans; Risk Factors; Breast Feeding; Cognition; HIV Infections; Africa South of the Sahara
PubMed: 37641003
DOI: 10.1186/s12879-023-08551-y -
Virology Journal Oct 2023Ethiopia is among the highly HIV-affected countries, with reported 12,000 and 12,000 AIDS-related deaths and incidents as per reports from 2021. Although the country has... (Review)
Review
BACKGROUND
Ethiopia is among the highly HIV-affected countries, with reported 12,000 and 12,000 AIDS-related deaths and incidents as per reports from 2021. Although the country has made a promising progress in antiretroviral therapy, recent studies have indicated that pretreatment drug resistance (PDR) is alarmingly increasing, which has become a challenge for the effectiveness of HIV treatment. Epidemiologic data on PDR is necessary to help establish ART regimens with good efficacy. Thus, this systematic review aimed to determine the trend analysis of PDR among ART-naïve individuals along with HIV variant dynamics in Ethiopia.
METHOD
HIV-1 pol sequences from studies conducted between 2003 and 2018 among ART-naïve Ethiopian individuals were retrieved from GenBank and analyzed for the presence of PDR mutations (PDRM) along with the analysis of HIV-1 variant dynamics. The Calibrated Population Resistance (CPR) tool Version 8.1 and the REGA HIV-1 Subtyping Tool Version 3 were used to determine the PDRM and HIV-1 genetic diversity, respectively.
RESULT
We identified nine studies and analyzed 1070 retrieved HIV-1 pol sequences in this systematic review. The pooled prevalence of PDR was 4.8% (51/1070), including 1.4% (15/1070), 2.8% (30/1070), and 0.8% (9/1070) for nucleoside reverse transcriptase inhibitor (NRTI), non-NRTI (NNRTI), and protease inhibitor (PI) resistance, respectively. NRTI and NNRTI concurrent PDRM were observed among 0.2% (2/799) of the analyzed sequences. The overall PDR prevalence has been increasing over the years. Though the prevalence of the NNRTI, NRTI, and PI PDR also increased over the years, the NNRTI increment was more pronounced than the others, reaching 7.84% in 2018 from 2.19% in 2003. The majority (97%; 1038/1070) of the genetic diversity was HIV-1 subtype C virus, followed by subtype C' (2%; 20/1038) and other subtypes (1%; 10/1038).
CONCLUSIONS
According to this systematic review, the overall pooled prevalence of PDR is low. Despite the low prevalence, there has been an increasing trend of PDR over the years, which implies the need for routine surveillance of PDRMs along with preventive measures. Hence, this supports the recently endorsed transition of ART regimens from NNRTI to integrase strand transfer inhibitor-based regimens recommended by the WHO. In addition, this finding underscores the need for routine baseline genotypic drug resistance testing for all newly diagnosed HIV-infected patients before initiating treatment to halt the upward trend of PDR.
Topics: Humans; HIV-1; Anti-HIV Agents; HIV Infections; Reverse Transcriptase Inhibitors; HIV Seropositivity; Mutation; Genotype; Drug Resistance, Viral; Prevalence; Sequence Analysis
PubMed: 37880705
DOI: 10.1186/s12985-023-02205-w -
Reviews in Medical Virology Nov 2023Differentiated service delivery (DSD) models, such as adherence clubs (ACs), are client-centred approaches where clinically stable people living with HIV (PLHIV) meet to... (Meta-Analysis)
Meta-Analysis Review
Impact of differentiated service delivery models on retention in HIV care and viral suppression among people living with HIV in sub-Saharan Africa: A systematic review and meta-analysis of randomised controlled trials.
Differentiated service delivery (DSD) models, such as adherence clubs (ACs), are client-centred approaches where clinically stable people living with HIV (PLHIV) meet to receive various services, including psychosocial support, brief symptoms screening, and refills of antiretroviral medications, among others. We conducted a review to assess the impact of DSD models, including ACs, on sustaining retention in care (RC) and achieving viral suppression (VS) among PLHIV in sub-Saharan Africa. The review protocol was registered in PROSPERO (CRD42023418988). We searched the literature from PubMed, Scopus, Web of Science, Embase and Google Scholar from their inception through May 2023. Eligible randomised controlled trials of adherence clubs were reviewed to assess impact on retention and viral suppression. Random effect models were used to estimate the risk ratios (RR) and 95% confidence intervals (CI). The literature search yielded a total of 1596 records of which 16 randomised clinical trials were determined to be eligible. The trials were conducted in diverse populations among adults and children with a total of 13,886 participants. The RR between any DSD models and standard of care (SoC) was 1.09 (95% CI: 1.08-1.11, I : 0%, p: <0.96) and 1.01 (95% CI: 1.00-1.02, I : 0%, p: <0.85) for RC and VS, respectively. The RR between ACs and SoC was 1.01 (95% CI: 0.96-1.07, I : 84%, p: <0.01) and 1.02 (95% CI: 0.98-1.07, I : 77%, p: <0.01) for RC and VS, respectively. DSD models, including ACs, show comparable effectiveness to SoC in maintaining care and achieving viral suppression for stable PLHIV. To maximise adoption, an implementation science approach is crucial for designing effective strategies and overcoming challenges.
Topics: Adult; Child; Humans; Anti-HIV Agents; HIV Infections; Africa South of the Sahara; Viral Load; Randomized Controlled Trials as Topic
PubMed: 37655428
DOI: 10.1002/rmv.2479 -
Open Forum Infectious Diseases Apr 2024Achieving viral load suppression is crucial for the prevention of complications and deaths related to HIV infection. Ethiopia has embraced the worldwide 95-95-95 target,... (Review)
Review
BACKGROUND
Achieving viral load suppression is crucial for the prevention of complications and deaths related to HIV infection. Ethiopia has embraced the worldwide 95-95-95 target, but there is no national representative information regarding virological suppression. Therefore, this review aims to determine the pooled virological suppression rate and identify the pooled effect of contributing factors of viral suppression for HIV-positive patients on antiretroviral therapy in Ethiopia.
METHODS
We systematically searched websites and databases, including online repositories, to obtain primary studies. Two reviewers assessed the quality of the included articles using the Newcastle-Ottawa Scale appraisal checklist. Publication bias was checked using Egger's regression test, the heterogeneity of the studies was assessed using statistics and Q statistics, and a sensitivity analysis was performed to identify any outlier results in the included studies. The Der Simonian Laird random-effects model was used to estimate the overall proportion of viral suppression, and STATA 17 statistical software was used for all types of analysis.
RESULTS
A total of 21 eligible articles primarily conducted in Ethiopia using HIV program data were used for this quantitative synthesis. The overall pooled virological suppression rate was 71% (95% CI, 64%-77%). The pooled effects of poor adherence to ART (adjusted odds ratio [AOR], 0.33; 95% CI, 0.28-0.40), body mass index (18.5-24.9 kg/m; AOR, 1.8; 95% CI, 1.37-2.36), disclosure (AOR, 1.41; 95% CI, 1.05-1.89), absence of opportunistic infection (AOR, 1.68; 95% CI, 1.43-1.97), and high baseline viral load count (AOR, 0.65; 95% CI, 0.52-0.81) were identified as significant predictors of viral suppression.
CONCLUSIONS
The overall pooled percentage of virological suppression was low compared with the global target of viral suppression and the Ethiopian Public Health Institute report. Poor adherence, normal body mass index, disclosure, absence of opportunistic infection, and high baseline viral load count were factors contributing to viral suppression in Ethiopia. Responsible stakeholders should maximize their efforts to achieve the global target of virological suppression by addressing significant predictors.
PubMed: 38654969
DOI: 10.1093/ofid/ofae168 -
Cureus Sep 2023Tenofovir disoproxil fumarate (TDF) is an antiretroviral drug widely used as part of antiretroviral therapy (ART) to treat human immunodeficiency virus (HIV-1)... (Review)
Review
Tenofovir disoproxil fumarate (TDF) is an antiretroviral drug widely used as part of antiretroviral therapy (ART) to treat human immunodeficiency virus (HIV-1) infection. Negative effects of tenofovir include impaired kidney function, especially with long-term use. In studies conducted among HIV-positive individuals, we found evidence of extensive kidney damage associated with TDF use. Despite the therapeutic importance of this consequence, its continued use in ART regimens was not contraindicated. The therapeutic and long-term effects of TDF are a major concern. However, in countries or settings where resources are limited and renal function monitoring cannot be ensured, screening methods to detect ART-related renal failure are still supported by data. Therefore, it is safe to re-evaluate the use of TDF-based ART. However, adherence to guidelines may be hampered by insufficient laboratory testing in low- and middle-income countries. More research is also needed among people under 18 years of age and pregnant and breastfeeding mothers.
PubMed: 37872903
DOI: 10.7759/cureus.45787 -
ClinicoEconomics and Outcomes Research... 2024The World Health Organization (WHO) recommends dolutegravir (DTG), a human immunodeficiency virus (HIV) medicine, as the first- and second-line treatment for all... (Review)
Review
The World Health Organization (WHO) recommends dolutegravir (DTG), a human immunodeficiency virus (HIV) medicine, as the first- and second-line treatment for all populations because, when compared to an efavirenz (EFV) regimen, plus two nucleoside reverse transcriptase inhibitors (NRTIs) has demonstrated significant effectiveness in HIV suppression in persons. This study aims to review evidence of the cost-effectiveness of DTG in combination with tenofovir and lamivudine compared with the standard of care for HIV therapy. The systematic review involved searching electronic databases for articles published between January 2018 and May 2022. Electronic database sources include PubMed, ScienceDirect, and EBSCO for articles on DTG in combination with tenofovir and lamivudine as subjects with cost-effectiveness outcomes. The inclusion criteria in this systematic review were studies about the cost-effectiveness analysis (CEA) of DTG in combination with tenofovir and lamivudine, written in English. A total of 145 articles were identified from three databases. After removing nine duplicates, 142 articles were screened by title and abstract, excluding 123 articles. After a full-text screening of 19 articles, five articles were selected for further analysis. Five articles reviewed in sub-Saharan Africa, India, and China implemented different modelling methods for CEA but produced similar results. The results of these studies demonstrate that it is more cost-effective than standard care for HIV treatment. The study conducted in sub-Saharan Africa from 2018 to 2020 showed a cost-effective result with disability-adjusted life years averted (DALY averted) by 83%; in India, it resulted in incremental cost-effectiveness ratio (ICER) $130 per year of live-saved (YLS); and a study in China found that dolutegravir plus tenofovir and lamivudine led to 0.006 incremental quality-adjusted life years (QALYs) with cost savings of $64. The DTG regimen is cost-effective and recommended for HIV therapy in all studies that provide results.
PubMed: 38293254
DOI: 10.2147/CEOR.S439725