Assessment of the toxicity of different antiretroviral drugs and their combinations on Sertoli and Leydig cells.

The human immunodeficiency virus continues to pose a significant global public health challenge, affecting millions of individuals. The current treatment strategy has incorporated the utilization of combinations of antiretroviral drugs. The administration of these drugs is associated with many deleterious consequences on several physiological systems, notably the reproductive system. This study aimed to assess the toxic effects of abacavir sulfate, ritonavir, nevirapine, and zidovudine, as well as their combinations, on TM3 Leydig and TM4 Sertoli cells. The cell viability was gauged using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) and neutral red uptake (NRU) assays. Reactive oxygen species (ROS) production was assessed via the 2',7'-dichlorofluorescein diacetate (DCFDA) test, and DNA damage was determined using the comet assay. Results indicated cytotoxic effects at low drug concentrations, both individually and combined. The administration of drugs, individually and in combination, resulted in the production of ROS and caused damage to the DNA at the tested concentrations. In conclusion, the results of this study suggest that the administration of antiretroviral drugs can lead to testicular toxicity by promoting the generation of ROS and DNA damage. Furthermore, it should be noted that the toxicity of antiretroviral drug combinations was shown to be higher compared to that of individual drugs.

Detection of unreported usage of the antiretroviral drug lamivudine in two blood donors.

BACKGROUND: Unreported HIV antiretroviral (ARV) drug usage by blood donors compromises the ability to detect evidence of HIV infection in blood screening tests and represents a risk for blood transfusion safety. Our objective was to determine the frequency of undeclared ARV drug use by blood donors with altered HIV markers. STUDY DESIGN AND METHODS: This was a retrospective cross-sectional analysis of donations that were tested for HIV antibody (ab), antigen (ag), and RNA by chemiluminescent immunoassay and nucleic acid screening tests. Positive samples were retested and were subjected to ARV drug testing by high-performance liquid chromatography-tandem mass spectrometry. RESULTS: Of 345,252 blood donations, 361 (0.1%) were positive on initial testing. Samples from 296 (81.9%) of these donations were available for further analysis. The presence of HIV ab/ag and/or RNA was confirmed in 83 (28.0%) of these samples. All 296 bloods were subjected to ARV testing. The ARV drug lamivudine, at 11.3 and 6.7 ng/mL, was detected in 2 of 83 (2.4%) donations that were HIV positive. Other drugs were not detected. CONCLUSION: Unreported ARV usage was identified in two candidates for blood donation. More intensive efforts to educate donors about disclosure and to investigate the extent of this phenomenon in Brazil are needed.

Transitioning Long-Acting Products to a Generic Marketplace: What's Missing?

Development of and increased access to generic oral medications to treat high-burden diseases including human immunodeficiency virus (HIV), tuberculosis, viral hepatitis, and malaria have had a major impact on reducing global morbidity and mortality. However, access and adherence to these life-saving treatments remains limited for some of the most vulnerable and underserved populations, for whom stigma, control, and discretion are critical to decisions around care. Current efforts to develop long-acting formulations to treat and prevent these conditions could overcome many of these barriers. However, generic manufacturing of these innovative products will be required to ensure affordable access to the communities and patients in greatest need. Strategic investments in new infrastructure will be required even before markets and manufacturing costs are clear, to ensure that access to these new products is not delayed, particularly for patients in low- and middle-income countries. Unlike conventional oral medications, long-acting products require greater investment for formulation, packaging, and delivery. The requirement for long-term bioequivalence studies will introduce additional delays in regulatory approval of generic long-acting products, and expedited approval pathways must be developed. Lessons learned from the development of long-acting hormonal contraceptives and long-acting antiretroviral products may provide a way forward.

The LEAP Process: Streamlining the Development of Long-Acting Products and Formulations for Infectious Diseases.

Developing long-acting products and formulations for infectious diseases is a nontrivial undertaking that is frequently classified as high risk and low reward by the pharmaceutical industry. The Long-Acting/Extended Release Antiretroviral Research Resource Program (LEAP) was founded in 2015 with the support of the National Institutes of Health to encourage, promote, and accelerate the development of such products. Assessment methodology for any new proposal brought to this group is part of a framework-the LEAP Process-that includes a landscape analysis of what is currently available in the public domain. This is followed by in silico modeling and simulation offered as a service to the relevant scientific community. A variety of preclinical and clinical outcome metrics are applied to each new agent as part of a continuous feedback loop to improve product characteristics. This allows us to catalog knowledge gaps and barriers that can be addressed by engaged stakeholders. Results are communicated in scientific articles, reviews, and position papers. This undertaking serves to de-risk discovery, development, and implementation by bridging the gaps between academic, regulatory, and industrial investigators, and by engaging those in the community who will be the eventual users of these medicines. The LEAP Process has supported formulations now approved for human immunodeficiency virus, as well as products in clinical and preclinical development for tuberculosis and hepatitis viruses B and C.

Reduced Chronic Lymphocyte Activation following Interferon Alpha Blockade during the Acute Phase of Simian Immunodeficiency Virus Infection in Rhesus Macaques.

Pathogenic human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection of humans and rhesus macaques (RMs) induces persistently high production of type I interferon (IFN-I), which is thought to contribute to disease progression. To elucidate the specific role of interferon alpha (IFN-α) in SIV pathogenesis, 12 RMs were treated prior to intravenous (i.v.) SIVmac239 infection with a high or a low dose of an antibody (AGS-009) that neutralizes most IFN-α subtypes and were compared with six mock-infused, SIV-infected controls. Plasma viremia was measured postinfection to assess the effect of IFN-α blockade on virus replication, and peripheral blood and lymphoid tissue samples were analyzed by immunophenotypic staining. Consistent with the known antiviral effect of IFN-I, high-dose AGS-009 treatment induced a modest increase in acute-phase viral loads versus controls. Four out of 6 RMs receiving a high dose of AGS-009 also experienced an early decline in CD4+ T cell counts that was associated with progression to AIDS. Interestingly, 50% of the animals treated with AGS-009 (6/12) developed AIDS within 1 year of infection compared with 17% (1/6) of untreated controls. Finally, blockade of IFN-α decreased the levels of activated CD4+ and CD8+ T cells, as well as B cells, as measured by PD-1 and/or Ki67 expression. The lower levels of activated lymphocytes in IFN-α-blockaded animals supports the hypothesis that IFN-α signaling contributes to lymphocyte activation during SIV infection and suggests that this signaling pathway is involved in controlling virus replication during acute infection. The potential anti-inflammatory effect of IFN-α blockade should be explored as a strategy to reduce immune activation in HIV-infected individuals.IMPORTANCE Interferon alpha (IFN-α) is a member of a family of molecules (type I interferons) that prevent or limit virus infections in mammals. However, IFN-α production may contribute to the chronic immune activation that is thought to be the primary cause of immune decline and AIDS in HIV-infected patients. The study presented here attempts to understand the contribution of IFN-α to the natural history and progression of SIV infection of rhesus macaques, the primary nonhuman primate model system for testing hypotheses about HIV infection in humans. Here, we show that blockade of IFN-α action promotes lower chronic immune activation but higher early viral loads, with a trend toward faster disease progression. This study has significant implications for new treatments designed to impact the type I interferon system.

SHIVA - a web application for drug resistance and tropism testing in HIV.

BACKGROUND: Drug resistance testing is mandatory in antiretroviral therapy in human immunodeficiency virus (HIV) infected patients for successful treatment. The emergence of resistances against antiretroviral agents remains the major obstacle in inhibition of viral replication and thus to control infection. Due to the high mutation rate the virus is able to adapt rapidly under drug pressure leading to the evolution of resistant variants and finally to therapy failure. RESULTS: We developed a web service for drug resistance prediction of commonly used drugs in antiretroviral therapy, i.e., protease inhibitors (PIs), reverse transcriptase inhibitors (NRTIs and NNRTIs), and integrase inhibitors (INIs), but also for the novel drug class of maturation inhibitors. Furthermore, co-receptor tropism (CCR5 or CXCR4) can be predicted as well, which is essential for treatment with entry inhibitors, such as Maraviroc. Currently, SHIVA provides 24 prediction models for several drug classes. SHIVA can be used with single RNA/DNA or amino acid sequences, but also with large amounts of next-generation sequencing data and allows prediction of a user specified selection of drugs simultaneously. Prediction results are provided as clinical reports which are sent via email to the user. CONCLUSIONS: SHIVA represents a novel high performing alternative for hitherto developed drug resistance testing approaches able to process data derived from next-generation sequencing technologies. SHIVA is publicly available via a user-friendly web interface.

The impact of antiretroviral therapy in resource-limited settings and current HIV therapeutics.

Four million people of the global total of 35 million with HIV infection are from South-East Asia. ART is currently utilized by 15 million people and has led to a dramatic decline in the mortality rate, including those in low- and middle-income countries. A reduction in sexually transmitted HIV and in comorbidities including tuberculosis has also followed. Current recommendations for the initiation of antiretroviral therapy in people who are HIV+ are essentially to initiate ART irrespective of CD4 cell count and clinical stage. The frequency of HIV testing should be culturally specific and based on the HIV incidence in different key populations but phasing in viral load technology in LMIC is an urgent priority and this needs resources and capacity. With the availability of simplified potent ART regimens, persons with HIV now live longer. The recent WHO treatment guidelines recommending routine HIV testing and earlier initiation of treatment should be the stepping stone for ending the AIDS epidemic and to meet the UNAIDS mission of 90*90*90.

Pharmacogenetics of plasma efavirenz exposure in HIV-infected adults and children in South Africa.

AIMS: Genetic factors, notably CYP2B6 516G→T [rs3745274] and 983T→C [rs28399499], explain much of the interindividual variability in efavirenz pharmacokinetics, but data from Africa are limited. We characterized relationships between genetic polymorphisms and plasma efavirenz concentrations in HIV-infected Black South African adults and children. METHODS: Steady-state mid-dosing interval efavirenz concentrations were measured. We genotyped 241 polymorphisms in genes potentially relevant to efavirenz metabolism and transport, including ABCB1, CYP2A6, CYP2B6, CYP3A4, CYP3A5, NR1I2 and NR1I3. RESULTS: Among 113 participants (59 adults and 54 children), minor allele frequencies for CYP2B6 516G→T, 983T→C, and 15582C→T [rs4803419] were 0.36, 0.07, and 0.09, respectively. Based on composite CYP2B6 15582/516/983 genotype, there were 33 extensive metabolizer, 62 intermediate metabolizer and 18 slow metabolizer genotypes. Median (IQR) mid-dose efavirenz concentrations were 1.44 (1.21-1.93) µg ml(-1), 2.08 (1.68-2.94) µg ml(-1) and 7.26 (4.82-8.34) µg ml(-1) for extensive, intermediate and slow metabolizers, respectively. In univariate analyses, a model that included composite genotype best predicted efavirenz concentrations (ß = 0.28, 95% CI 0.21, 0.35, P = 2.4 × 10(-11)). Among individual CYP2B6 polymorphisms, 516G→T best predicted efavirenz concentrations (ß = 0.22, 95% CI 0.13, 0.30, P = 1.27 × 10(-6)). There was also associations with 983T→C (ß = 0.27, 95% CI 0.10, 0.44, P = 0.002) and 15582C→T (ß = 0.11, 95% CI 0.01, 0.22, P = 0.04). Associations were consistent in adults and children. No other polymorphisms were independently associated with efavirenz concentrations. CONCLUSIONS: Composite CYP2B6 genotype based on CYP2B6 516G→T, 983T→C, and 15582C→T best described efavirenz exposure in HIV-infected Black South African adults and children.

Long-acting prescriptions and therapy for HIV-1 from market launch to the present in Germany (May 2021 to December 2023).

Background: In Europe, the combination of cabotegravir (CAB) with rilpivirine (RPV) has been approved as a dual injection long-acting (LA) therapy for the treatment of human immunodeficiency virus type 1 (HIV-1) infections in adults since December 2020. Studies have shown that between 36 and 61% of people living with HIV (PLWHIV) prefer LA therapy. However, there are no real-world data on the number of people receiving LA therapy, in Germany or internationally. The aim of this study was to assess the current situation and trends in usage of LA therapy for the treatment of HIV-1 in Germany. Methods: Based on pharmacy prescription data derived from Insight Health, the monthly number of prescriptions for oral CAB, CAB-LA, and RPV-LA over the entire period of availability in Germany was analyzed and evaluated (May 2021 to December 2023). The number of 1st and 2nd initiation injections and subsequent maintenance injections was calculated on the basis of the prescriptions for oral CAB initiation. Results: The bimonthly schedule resulted in two growing cohorts from September 2021 with an estimated 14,523 CAB-LA prescriptions over the entire period. Accordingly, in December 2023, there were approximately 1,364 PLWHIV receiving LA therapy, of whom 1,318 were receiving maintenance therapy. Only treatments with bimonthly regimens were carried out. Accounting for people not covered by statutory health insurance (~13%), a total of ~1,600 PLWHIV were receiving LA therapy in Germany in December 2023. The average rounded annual cost of therapy in 2023 was €11,940 (maintenance therapy with initiation) and €10,950 (maintenance therapy without initiation). Conclusion: To our knowledge, this is the first study of real-world use and number of people receiving LA therapy. A strength of our study is the nearly complete coverage of people with statutory health insurance in Germany. The predicted demand for LA therapy does not match the actual number of people receiving LA therapy. Although the number of PLWHIV receiving LA therapy increased steadily, they accounted for just under 2% of the estimated total number of people receiving HIV therapy in Germany in 2023, almost 2 years after the market launch. No significant increase in prescriptions is expected; on the contrary, the trend is leveling off and is unlikely to change drastically in the near future. Hence, the need for this mode of therapy in Germany appears to be limited. Follow-up studies at regular intervals on the further course would be useful and are recommended, as well as investigations into the possible reasons for the slow uptake to inform public health experts and possibly broaden treatment options.

In vitro phenotypes to elvitegravir and dolutegravir in primary macrophages and lymphocytes of clonal recombinant viral variants selected in patients failing raltegravir.

OBJECTIVES: The cross-resistance profiles of elvitegravir and dolutegravir on raltegravir-resistant variants is still controversial or not available in macrophages and lack extensive evaluations on wide panels of clonal variants. Thus, a complete evaluation in parallel with all currently available integrase inhibitors (INIs) was performed. METHODS: The integrase coding region was RT-PCR-amplified from patient-derived plasma samples and cloned into an HIV-1 molecular clone lacking the integrase region. Twenty recombinant viruses bearing mutations to all primary pathways of resistance to raltegravir were phenotypically evaluated with each integrase inhibitor in freshly purified CD4+ T cells or monocyte-derived macrophages. RESULTS: Y143R single mutants conferred a higher level of raltegravir resistance in macrophages [fold change (FC) 47.7-60.24] compared with CD4+ T cells (FC 9.55-11.56). All other combinations had similar effects on viral susceptibility to raltegravir in both cell types. Elvitegravir displayed a similar behaviour both in lymphocytes and macrophages with all the tested patterns. When compared with raltegravir, none to modest increases in resistance were observed for the Y143R/C pathways. Dolutegravir maintained its activity and cross-resistance profile in macrophages. Only Q148H/R variants had a reduced level of susceptibility (FC 5.48-18.64). No variations were observed for the Y143R/C (+/-T97A) or N155H variants. CONCLUSIONS: All INIs showed comparable antiretroviral activity in both cell types even if single mutations were associated with a different level of susceptibility in vitro to raltegravir and elvitegravir in macrophages. In particular, dolutegravir was capable of inhibiting with similar potency infection of raltegravir-resistant variants with Y143 or N155 pathways in both HIV-1 major cell reservoirs.

Combined Nano-Vector Mediated-Transfer to Suppress HIV-1 Infection with Targeted Antibodies in-vitro.

Introduction: Broadly neutralizing antibodies (bNAbs) have the ability to neutralize a considerable breadth of genetically diverse human immunodeficiency virus (HIV) strains. Passive immunization can potentially provide protection against HIV infection in animal models. However, the direct antibody infusion effect is limited due to the short half-life and deficient immunogenicity of the antibody. As an alternative strategy, we propose the use of nano viral vectors, specifically the adeno-associated virus (AAV), to continuously and systematically produce bNAbs against HIV. Methods: Plasmids expressing bNAbs PG9, PG16, 10E8, and NIH45-46 antibodies were constructed, targeting three different epitopes of HIV. Additionally, the bNAbs gene mediated by rAAV8 was administered to generate long-term expression with a single injection. We established both single and combined immunization groups. The neutralizing activity of antibodies expressed in mice sera was subsequently evaluated. Results: The expression of bNAbs in BALB/c mice can last for >24 weeks after a single intramuscular injection of rAAV8. Further studies show that neutralization of the HIV pseudovirus by sera from co-immunized mice with rAAV8 expressing 10E8 and PG16 was enhanced compared with mice immunized with 10E8 or PG16 alone. Conclusion: The prolonged expression of neutralizing antibodies can be maintained over long periods in BALB/c mice. This combined immunization is a promising candidate strategy for HIV treatment.

Ligand-Receptor Interactions of Lamivudine: A View from Charge Density Study and QM/MM Calculations.

The nature and strength of interactions for an anti-HIV drug, Lamivudine, were studied in a pure crystal form of the drug and the ligand-receptor complexes. High-resolution single-crystal X-ray diffraction studies of the tetragonal polymorph allowed the drug's experimental charge density distribution in the solid state to be obtained. The QM/MM calculations were performed for a simplified model of the Lamivudine complex with deoxycytidine kinase (two complexes with different binding modes) to reconstruct the theoretical charge density distribution. The peculiarities of intramolecular interactions were compared with previously reported data for an isolated molecule. Intermolecular interactions were revealed within the quantum theory of 'Atoms in Molecules', and their contributions to the total crystal energy or ligand-receptor binding energy were evaluated. It was demonstrated that the crystal field effect weakened the intramolecular interactions. Overall, the energies of intermolecular interactions in ligand-receptor complexes (320.1-394.8 kJ/mol) were higher than the energies of interactions in the crystal (276.9 kJ/mol) due to the larger number of hydrophilic interactions. In contrast, the sum of the energies of hydrophobic interactions was found to be unchanged. It was demonstrated by means of the Voronoi tessellation that molecular volume remained constant for different molecular conformations (250(13) Å3) and increased up to 399 Å3 and 521(30) Å3 for the Lamivudine phosphate and triphosphate.

Bioactive Effects of Curcumin in Human Immunodeficiency Virus Infection Along with the Most Effective Isolation Techniques and Type of Nanoformulations.

Human immunodeficiency virus (HIV) is one of the leading causes of death worldwide, with African countries being the worst affected by this deadly virus. Curcumin (CUR) is a Curcuma longa-derived polyphenol that has attracted the attention of researchers due to its antimicrobial, anti-inflammatory, antioxidant, immunomodulatory and antiviral effects. CUR also demonstrates anti-HIV effects by acting as a possible inhibitor of gp120 binding, integrase, protease, and topoisomerase II activities, besides also exerting a protective action against HIV-associated diseases. However, its effectiveness is limited due to its poor water solubility, rapid metabolism, and systemic elimination. Nanoformulations have been shown to be useful to enhance curcumin's bioavailability and its effectiveness as an anti-HIV agent. In this sense, bioactive effects of CUR in HIV infection are carefully reviewed, along with the most effective isolation techniques and type of nanoformulations available.

Expression Profile and Biological Role of Immune Checkpoints in Disease Progression of HIV/SIV Infection.

During HIV/SIV infection, the upregulation of immune checkpoint (IC) markers, programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), T cell immunoglobulin and ITIM domain (TIGIT), lymphocyte-activation gene-3 (LAG-3), T cell immunoglobulin and mucin domain-3 (Tim-3), CD160, 2B4 (CD244), and V-domain Ig suppressor of T cell activation (VISTA), can lead to chronic T cell exhaustion. These ICs play predominant roles in regulating the progression of HIV/SIV infection by mediating T cell responses as well as enriching latent viral reservoirs. It has been demonstrated that enhanced expression of ICs on CD4+ and CD8+ T cells could inhibit cell proliferation and cytokine production. Overexpression of ICs on CD4+ T cells could also format and prolong HIV/SIV persistence. IC blockers have shown promising clinical results in HIV therapy, implying that targeting ICs may optimize antiretroviral therapy in the context of HIV suppression. Here, we systematically review the expression profile, biological regulation, and therapeutic efficacy of targeted immune checkpoints in HIV/SIV infection.

Factors associated with pregnancy uptake decisions among seropositive HIV people receiving antiretroviral therapy in sub-Saharan Africa: A systematic review.

AIM: This study determined the factors associated with pregnancy uptake decision among seropositive HIV people receiving antiretroviral therapy in sub-Saharan Africa. DESIGN: Systematic review. METHODS: The population, intervention, comparison and outcomes framework was adopted to search for literature after a scoping review using the preferred reporting items for systematic reviews and meta-analyses guidelines adopted in searching, and screening articles from four databases (PubMed, Cumulative Index to Nursing and Allied Health Literature, Embase, and Google scholar) to find 12 articles suitable for this study. RESULTS: Motivators of pregnancy uptake among HIV-positive women include desire to have children, knowledge about PMTCT, cultural duty for married women to have children, and household income. Demotivating factors included the modern method of contraception and burden associated with pregnancy. CONCLUSION: There is a need to improve on services that reduce conception-related risks especially for women who choose to conceive and to incorporate fertility-related counselling into HIV treatment services.

Transfusion-Acquired HIV: History, Evolution of Screening Tests, and Current Challenges of Unreported Antiretroviral Drug Use in Brazil.

Prevention of HIV acquisition by blood transfusion from its emergence to the present day is reviewed, and current challenges are delineated. The experience of Fundação Pró-Sangue/Hemocentro de São Paulo, Brazil, is highlighted in the quest for improvements in blood safety and the evolution of increasingly sensitive and specific screening tests. Concerns and establishing stringent criteria in the screening of potential blood donors are emphasized, and the current criteria for identifying and deferring candidates at high risk of acquiring sexually transmitted diseases are summarized. Future challenges relate to the identification of donors with unreported use of antiretroviral drugs for prophylaxis against possible HIV exposure or for treatment of an HIV infection whose viral expression is undetectable by current analyses. There is a need to better understand the motivation of HIV-exposed donors and to educate them about the risk of transfusion-mediated HIV transmission despite having low or undetectable viral loads. In situations in which traditional HIV RNA or antibody detection assays remain negative, more sensitive analyses are needed to identify potential donors at risk for HIV transmission.

A literature review of the patent application publications on cabotegravir - an HIV integrase strand transfer inhibitor.

Introduction: Studies presented in the patent applications demonstrate that a new integrase strand transfer inhibitor cabotegravir might be used as long-acting antiretroviral formulation or delivery system that reduces dosing frequency and may therefore increase adherence and thus pre-exposure prophylaxis (PrEP) and treatment efficacy against HIV. As announced in 2019, the developer ViiV Healthcare seeks US and EU approval of long-acting, injectable HIV treatment.Area covered: This review covers all the patent applications published until October 2019 with cabotegravir in the examples or claim section of the patent application document. The patent applications cover drug substance synthesis, solid-state forms, therapeutic applications, in vitro and in vivo efficacy as well as the potential formulations of cabotegravir alone or in combination with other anti-HIV agents.Expert opinion: The results from multiple clinical studies suggest that cabotegravir can be used as PrEP agent and treatment agent against HIV. Multiple studies use cabotegravir in combination with other anti-HIV agents such as rilpivirine. Cabotegravir in combination with rilpivirine is an interesting therapeutic, due to the possibility of formulating long-acting formulation with dosing interval of every 4 weeks or less, thus reducing daily pill burden and improving patient's compliance.

Which antiretrovirals should be prescribed as first-line treatments? Changes over the past 10 years in France.

OBJECTIVE: To describe the changes in first-line antiretroviral (ART) regimens in France between 2005 and 2015 and patients' characteristics related to the use of protease inhibitors in 2015. METHODS: We extracted all patients starting ART between 2005 and 2015 from a large prospective cohort. Regimens were classified as three nucleoside reverse transcriptase inhibitors (NRTI), or two NRTIs with a boosted protease inhibitor (bPI), with a non-nucleoside reverse transcriptase inhibitor (NNRTI), or with an INSTI. Patients' characteristics at the time of initiation were collected. A multinomial logit model was fitted to analyze characteristics related to the choice of regimen in 2015. RESULTS: We analyzed data from 15,897 patients. The proportion of patients starting with (i) a bPI decreased from 60% before 2014 to 38.1% in 2015; (ii) an NNRTI decreased from 30% to 17.8% in 2015; (iii) an INSTI gradually increased to 39.4% in 2015. In 2015, patients with an initial viral load ˃5 log copies/mL were less likely to receive NNRTI (OR=0.08) or INSTI regimens (OR=0.69) than bPIs. Patients with initial CD4+ T cell count ˂200/mm3 were less likely to receive an NNRTI (OR=0.28) or an INSTI regimen (OR=0.52) than a bPI. Women were less likely to receive an NNRTI (OR=0.79) or an INSTI regimen (OR=0.71) than a bPI; although this depended on age. CONCLUSION: The use of bPI as first-line ART declined sharply in France from 2005 to 2015. bPI remained of preferential use in patients with high viral load, low CD4+ T cell count, and in women.