Human Immunodeficiency Virus-1 Drug Resistance Mutations in Iranian Treatment-experienced Individuals.

BACKGROUND: Human immunodeficiency virus-1 infection still remains a global health threat. While antiretroviral therapy is the primary treatment option, concerns about the emergence of drug-resistance mutations and treatment failure in HIV-infected patients persist. OBJECTIVE: In this study, we investigated the development of drug resistance in HIV-1-infected individuals receiving antiretroviral therapy for 6-10 years. METHODS: In this cross-sectional study, we evaluated 144 people living with HIV-1 who had received antiretroviral therapy for at least 6 years. Plasma specimens were collected, and the HIV-1 viral load and drug-resistance mutations were assessed using molecular techniques. RESULTS: The demographic and epidemiological characteristics of the participants were also analyzed: Twelve [8.3%) of the studied patients showed a viral load over 1000 copies per/mL, which indicates the suboptimal response to antiretroviral therapy. Significant correlations were found between viral load and CD4 count, as well as epidemiological factors, such as vertical transmission, history of imprisonment, and needle stick injuries. Drug resistance mutations were detected in 10 (83.3%) of patients who failed on antiretroviral therapy, with the most common mutations observed against nucleoside reverse transcriptase inhibitors (5 (41.7%)) and non-nucleoside reverse transcriptase inhibitors (9 (75%)). Phylogenetic analysis revealed that 12 patients who failed treatment were infected with CRF35_AD. CONCLUSION: Our study provides important insights into the characteristics and development of drug resistance in HIV-1-infected individuals receiving long-term antiretroviral therapy in Iran. The findings underline the need for regular viral load monitoring, individualized treatment selection, and targeted interventions to optimize treatment outcomes and prevent the further spread of drug-resistant strains.

Characterization of HIV-1 Reservoirs in Children and Adolescents: A Systematic Review and Meta-Analysis Toward Pediatric HIV Cure.

OBJECTIVE: To conduct a comprehensive, systematic review of the profile of HIV-1 reservoirs in children and adolescents with perinatally acquired HIV infection. STUDY DESIGN: Randomized and nonrandomized trials, cohort studies, and cross-sectional studies on HIV reservoirs in pediatric populations, published between 2002 and 2022, were included. Archived-drug resistance mutations (ADRMs) and the size of reservoirs were evaluated. Subgroup analyses were performed to characterize further the data, and the meta-analysis was done through random effect models. RESULTS: Overall, 49 studies from 17 countries worldwide were included, encompassing 2356 perinatally infected participants (48.83% females). There are limited data on the quantitative characterization of viral reservoirs in sub-Saharan Africa, with sensitive methodologies such as droplet digital polymerase chain reaction rarely employed. The overall prevalence of ADRMs was 37.80% (95% CI 13.89-65.17), with 48.79% (95% CI 0-100) in Africa, 42.08% (95% CI 6.68-82.71) in America, 23.88% (95% CI 14.34-34.90) in Asia, and 20.00% (95% CI 10.72-31.17) in Europe, without any difference between infants and adolescents (P = .656). Starting antiretroviral therapy (ART) before 2 months of age limited the levels of HIV-1 DNA (P = .054). Participants with long-suppressed viremia (>5 years) had lower levels of HIV-1 DNA (P = .027). Pre- and post-ART CD4 ≤29% and pre-ART viremia ≥5Log were all found associated with greater levels of HIV-1 DNA (P = .038, P = .047, and P = .041, respectively). CONCLUSIONS: The pooled prevalence of ADRMs is high in perinatally infected pediatric population, with larger proviral reservoir size driven by delayed ART initiation, a shorter period of viral suppression, and immunovirological failures. Thus, strategies for pediatric HIV functional cure should target children and adolescents with very early ART initiation, immunocompetence, and long-term viral suppression.

[Drug dispensation at both community and hospital pharmacy, the highly active antiretrovirals example]. / Le double circuit de dispensation, exemple des traitements antirétroviraux : quelle pertinence ?

OBJECTIVES: Highly active antiretroviral therapies against the human immunodeficiency virus are available for patients in France in community pharmacy or in hospital pharmacy. More than 20 years after the implementation of the dual delivery system, it seems necessary to question the relevance of the dual dispensing circuit both in terms of service provided to patients and expenditure for health insurance. METHODS: The health insurance files were used to quantify the delivery of antiretrovirals therapies in the community pharmacy and in the hospital pharmacy. A survey was performed involving patients to find out their point of view on dispensing in hospital pharmacy and were the patients came from. The differential cost from the health insurance point of view between the two delivery system was calculated on the basis of the quantities delivered and the purchase prices at the hospital center in 2018. RESULTS: More than 80% of the quantities of antiretrovirals therapies are now delivered by community pharmacies. The arguments in favor of the antiretrovirals therapies dispensation by hospital pharmacy forwarded by patients are the anonymity and constant medicines availability. Health insurance is required to refund a drug at different prices depending on the delivery place, for about 37€ per box in favour of hospital dispensing. CONCLUSION: This study presents a complete inventory of the dual delivery system for antiretroviral therapies. Hospital and community therefore remain complementary to welcome outptients who will seek different delivery methods there. Little known to patients and professionals, this dual delivery system generates complexities at the stages of prescription, dispensing and reimbursement. It only concerns a minority of patients and its benefit for health insurance seems uncertain.

When the Cure Becomes the Problem: A Case Report of Immune Reconstitution Inflammatory Syndrome Associated With Varicella Encephalitis.

Immune reconstitution inflammatory syndrome (IRIS) describes a constellation of inflammatory symptoms that develop following the initiation of antiretroviral therapy (ART) in patients with advanced human immunodeficiency virus (HIV). Here, we present a case of a 39-year-old male-to-female transgender patient with advanced HIV who was started on ART during a hospitalization for acute encephalopathy due to a combination of methicillin-resistant Staphylococcus aureus (MRSA) meningitis and varicella encephalitis. After adequate treatment of these infections and five weeks after initiation of ART, she developed inflammatory symptoms of malaise, fever, and tachycardia, as well as laboratory findings of leukocytosis consistent with an inflammatory process. Infectious workup did not reveal any evidence of a new infection, and no other undiagnosed inflammatory processes were discovered to explain these symptoms. A diagnosis of IRIS was suspected, possibly induced by a prior varicella infection. Diagnosis of IRIS can be difficult due to heterogeneous symptoms, differing etiologies, variable patient presentations, and the lack of universal diagnostic criteria. As instances of IRIS are not uncommon in patients with a low CD4 count who start on ART, there should be a high index of suspicion when patients present with inflammatory symptoms after initiation of ART. With increased recognition of the disease and improved standardization of diagnostic criteria, more could be understood about the underlying disease process which may allow for better targeted therapies and individualized treatments for patients who develop the immune reconstitution inflammatory syndrome.

Comparative Assessment of Serum Selenium Status in HIV-Infected and Non-infected Children: A Pilot Study in a Tertiary Hospital in Nigeria.

Background Selenium is an essential micronutrient that plays a crucial role in a wide range of physiological processes, including immune responses. Selenium deficiency has been recognized as an associated factor in the progression of HIV to advanced HIV disease and/or mortality. Although selenium supplementation has been shown to reduce hospitalizations and improve cellular immunity, the evidence remains mixed. This study aimed to determine the prevalence of selenium deficiency and its relationship with HIV disease markers in HIV-infected children at the Lagos University Teaching Hospital. Methodology This is a cross-sectional, comparative, pilot study of plasma concentrations of selenium in HIV-infected (n = 30) and non-infected (n = 20) children enrolled in the pediatric HIV clinic of the Lagos University Teaching Hospital, Lagos, Nigeria, from May 2019 to May 2021. HIV-infected children were on stable antiretroviral therapy (ART) with an undetectable viral load. The serum concentration of selenium was measured using the automated atomic absorption spectrophotometer (hydride generation method). Logistic regression was used to study the effect of selenium status on the levels of HIV disease markers (CD4 count, viral load, weight, opportunistic infections) in the study participants. Results The median age of all participants was nine (4-12) years, with 74% being boys. The mean selenium concentrations were lower in HIV-infected children (91.1 ± 12.0 µg/L) compared to the comparison group without HIV (147.8 ± 4.9 µg/L) (p = 0.001). After controlling for age, ART duration, markers of HIV infection, and other potentially confounding variables, participants with selenium deficiency had approximately 11-fold odds of increased hospital admissions (adjusted odds ratio = 10.57, 95% confidence interval = 1.58 to 70.99; p = 0.015). Conclusions In this study, selenium concentrations were significantly lower in HIV-infected children than in the HIV-negative comparison group. Lower serum selenium concentrations were associated with increased hospitalizations. Although our findings suggest the potential need for selenium supplementation for children living with HIV in Nigeria, further studies are warranted to determine the safety and efficacy of selenium supplementation in this key population.

Healthcare Resource Consumption and Related Costs in Patients on Antiretroviral Therapies: Findings from Real-World Data in Italy.

This real-world analysis conducted on administrative databases of a sample of Italian healthcare entities was aimed at describing the role of therapeutic pathways and drug utilization in terms of adherence, persistence, and therapy discontinuation in HIV-infected patients under antiretroviral therapies (ART) and Tenofovir Alafenamide (TAF)-based regimens on healthcare resource consumption and related direct healthcare costs. Between 2015 and 2019, adults (≥18 years) prescribed with TAF-based therapies were identified and characterized in the year prior to the first prescription (index-date) for TAF-based therapies and followed-up until the end of data availability. Overall, 2658 ART-treated patients were included, 1198 of which were under a TAF-based regimen. TAF-based therapies were associated with elevated percentages of adherence (83.3% patients with proportion of days covered, PDC > 95% and 90.6% with PDC > 85%) and persistence (78.5%). The discontinuation rate was low in TAF-treated patients, ranging from 3.3% in TAF-switchers to 5% in naïve. Persistent patients had lower overall mean annual healthcare expenditures (EUR 11,106 in persistent vs. EUR 12,380 in non-persistent, p = 0.005), and this trend was statistically significant also for costs related to HIV hospitalizations. These findings suggest that a better therapeutic management of HIV infection might result in positive clinical and economic outcomes.

Immune Reconstitution Inflammatory Syndrome Presenting as Disseminated Kaposi Sarcoma.

We present a patient who was previously diagnosed with HIV and had multiple violaceous skin lesions at the time of his diagnosis. Following the initiation of antiretroviral therapy (ART), the number of lesions increased significantly and he developed shortness of breath, which prompted hospital admission for further workup. Biopsy of the skin lesions confirmed the diagnosis of Kaposi sarcoma (KS). Bronchoscopy with biopsy revealed KS lesions in his respiratory system. Imaging and biopsy confirmed KS invasion of lymph nodes. Due to widespread KS, he was diagnosed with immune reconstitution inflammatory syndrome (IRIS). Because of the lack of improvement on ART alone, he was started on chemotherapy, which decreased the size of existing skin lesions, stalled the development of new skin lesions, and led to symptom improvement. As a result of this case, we recommend that treatment teams have close follow-ups of patients started on ART and that they remain mindful of the possibility of IRIS. Disseminated KS may warrant a prompt response with chemotherapy to improve outcomes.

Highly Ambiguous HIV-1 Pol Positions Encoding Multiple Amino Acids Usually Result from Antiviral or Immune Selection Pressure.

HIV-1 pol nucleotide ambiguities encoding amino acid mixtures occur commonly during population-based genotypic drug resistance testing. However, few studies have addressed the validity of sequences with fully ambiguous codons (FACs) containing codons translatable to more than four amino acids. We identified 839 published HIV-1 pol sequences with 846 FACs at 131 positions and determined their distribution relative to 215 HLA-associated pol positions (HAPs) and 84 drug-resistance positions. Among HIV-1 reverse transcriptase (RT) and protease sequences from antiretroviral therapy (ART)-naive and -experienced persons, there was a strong correlation between the likelihood a position was a FAC and that it was an HAP (Spearman's correlation coefficient rho >0.40; p < 1e-6). Among HIV-1 RT sequences from ART-experienced persons, there was a correlation between the likelihood that a position was a FAC and that it was a drug-resistance position (rho = 0.2; p = 8e-4). In the context of population-based genotypic resistance testing, FACs usually result from antiviral or immune selection pressure.

Social, Epidemiological, and Virological Characteristics from Peruvian Subjects Living with HIV-1/AIDS with Different Sexual Risk Behavior.

HIV-1 genetic diversity and resistance profile might change according to the risky sexual behavior of the host. To show this, we recruited 134 individuals between the years 2015 and 2017 identified as transgender women sex workers (TWSW, n = 73) and Heterosexual Military Officers (HET-MO, n = 61). After obtaining informed consent, we collected a blood sample to perform the HIV genotyping, CD4 cell count, and viral load. We used bioinformatics approaches for detecting resistance mutations and recombination events. Epidemiological data showed that both groups reported sexually transmitted diseases and they were widespread among TWSW, especially syphilis and herpes virus (35.6%). Illegal drugs consumption was higher among TWSW (71.2%), whereas condom use was inconsistent for both HET-MO (57.4%) and TWSW (74.0%). TWSW showed the shortest time exposition to antiretroviral therapy (ART) (3.5 years) and the lowest access to ART (34.2%) that conducted treatment failure (>4 logs). HIV-1 sequences from TWSW and HET-MO were analyzed to determine the genetic diversity and antiretroviral drug resistance. Phylogeny analysis revealed 125 (93%) cases of subtype B, 01 subtype A (0.76%), 07 (5.30%) BF recombinants, and 01 (0.76%) AG recombinant. Also, TWSW showed a higher recombination index (9.5%, 7/73) than HET-MO (1.5%, 1/68). HET-MO only showed acquired resistance (26.23%, 16/61), whereas TWSW showed both acquired as transmitted resistance (9.59% for each). In conclusion, TWSW and HET-MO showed significant differences considering the epidemiological characteristics, genetic diversity, recombination events, and HIV resistance profile.

Immunologic Change over 72 Weeks Following Raltegravir- Versus Efavirenz-Based Therapy in HIV/HCV-Coinfected Individuals in Vietnam.

The impact of HIV antiretroviral therapy (ART) on immune dysregulation associated with hepatitis C virus (HCV)/HIV coinfection is incompletely understood. We serially assessed monocyte activation (neopterin, sCD14, and sCD163) and T cell activation (HLA-DR, CD38) and immune exhaustion [program cell death protein 1 (PD1), TIGIT] in HIV/HCV-coinfected individuals who participated in a randomized trial performed in Vietnam designed to assess the hepatotoxicity of raltegravir (RAL)- versus efavirenz (EFV)-based therapy when used as first-time ART in combination with tenofovir disoproxil fumarate and emtricitabine. Baseline pre-ART values were compared with those from ART-naive HIV-monoinfected and HIV-seronegative individuals. Before ART, HIV/HCV-coinfected individuals had higher levels of neopterin, sCD14, and sCD163, and increased frequencies of CD38+HLA-DR+, PD1+, and TIGIT+ CD4 and CD8 T cells compared with ART-naive HIV-monoinfected or HIV-seronegative individuals (all p < .01). Most parameters did not normalize despite 72 weeks of ART. In particular sCD163 persisted at high levels. Improvement over 72 weeks in fibrosis as assessed by FibroScan® correlated with reductions in plasma sCD163 and in the frequencies of T cell activation, single PD1+, TIGIT+, and dual PD1+TIGIT+ CD8 T cells. A nonsignificant tendency toward more favorable effects on monocyte and T cell immune activation and on T cell exhaustion were seen with RAL-compared with EFV-based therapy. The initiation of ART in HIV/HCV-coinfected individuals is associated with incomplete improvement in monocyte and T cell immune activation and exhaustion, which was associated with some corresponding improvement in liver fibrosis.

Management of diabetes mellitus in people living with HIV: A single-center experience.

Background: Diabetes mellitus (DM) is more common in people living with HIV (PLWH) than in HIV-negative patients. Here we aimed to describe the response of PLWH with DM to glucose-lowering therapies in a reference hospital of northern Italy. Setting: 200 PLWH and DM were identified from the database of our clinic. Methods: Good control of DM was defined as having fasting glucose <130 mg/dl or HbA1c < 53 mmol/mol. The distribution of glucose-lowering therapies in PLWH was compared with that of HIV-negative patients with DM. Results: Mean total fasting glucose and HbA1C were 143 ± 50 mg/dl (51% exceeding the 130 mg/dl cutoff) and 51 ± 16 mmol/mol (30% exceeding the 53 mmol/mol cutoff), respectively. PLWH were less treated with dipeptidyl peptidase-4 inhibitors (1.7% versus 9.6%, p < 0.01) and sulfonylureas (3.3% versus 13.2%, p < 0.01), being conversely more frequently treated with metformin (53.8% versus 37.7%, p < 0.01), glifozins plus metformin (7.1% versus 2.0%, p < 0.05) or insulin plus other glucose-lowering agents (5.5% versus 0.5%, p < 0.01). Conclusion: An underuse of dipeptidyl peptidase-4 inhibitors was found which was, however, counterbalanced by a higher use of combination of drugs (including glifozins). A rational assessment of drug-drug interactions would contribute to a better selection of the best glucose lowering agent for each antiretroviral therapy.

Combined cART including Tenofovir Disoproxil, Emtricitabine, and Dolutegravir has potent therapeutic effects in HIV-1 infected humanized mice.

HIV-1 reservoirs persist in the presence of combined antiretroviral therapy (cART). However, cART has transformed HIV-1 infection into a chronic disease marked by control of HIV-1 viral load and mortality reduction. Major challenges remain, including viral resistance upon termination of cART and persistence and identification of tissue distribution of HIV-1 reservoirs. Thus, appropriate animal models that best mimic HIV-1 pathogenesis are important, and the current study complements our previously published validation of the CD34+ hematopoietic humanized mouse model for this purpose. Here we analyze viral suppression using the recently developed combination of antiretrovirals that include Tenofovir Disoproxil (TDF), Emtricitabine (FTC), and Dolutegravir (DTG), a choice based on recent clinical outcomes showing its improved antiretroviral potency, CD4+ T cell preservation, tolerability, and prevention of viral drug resistance compared to that of previous regimens. We used quantitative Airyscan-based super resolution confocal microscopy of selected mouse tissues. Our data allowed us to identify specific solid tissue reservoirs of human T cells expressing the HIV-1 core protein p24. In particular, lymph node, brain, spleen, and liver were visualized as reservoirs for residual infected cells. Marked reduction of viral replication was evident. Considering that detection and visualization of cryptic sites of HIV-1 infection in tissues are clearly crucial steps towards HIV-1 eradication, appropriate animal models with pseudo-human immune systems are needed. In fact, current studies with humans and non-human primates have limited sample availability at multiple stages of infection and cannot easily analyze the effects of differently administered combined antiretroviral treatments on multiple tissues. That is easier to manage when working with humanized mouse models, although we realize the limitations due to low human cell recovery and thus the number of cells available for thorough and comprehensive analyses. Nonetheless, our data further confirm that the CD34+ humanized mouse model is a potentially useful pre-clinical model to study and improve current anti-HIV-1 therapies.

Real-World Experience with Two-Drug Regimens in HIV-1-Infected Patients Beyond the Indication of Clinical Trials: 48 Weeks' Results.

Data on two-drug regimens (2DRs) have shown high efficacy and tolerability in treatment-naive and treatment-experienced HIV-1 patients. Current guidelines recommend 2DRs as alternative to three-drug regimens (3DRs) to reduce long-term drug exposure and costs. Nevertheless, real-world experience with 2DR is limited. This study assessed the use of 2DR in routine clinical practice in a tertiary hospital. A retrospective, observational, descriptive study was performed on the use of dual therapy in adult HIV-1 patients. Individuals on antiretroviral treatment (ART) with dolutegravir plus lamivudine or dolutegravir plus rilpivirine who started 2DR between November 1, 2018, and April 30, 2019, were eligible for our study. Follow-up period was 48 weeks. Overall, 112 patients started 2DR; median age was 51 years and 88.4% were men. Most patients (97.3%) were treatment experienced before dual therapy, with 9.6 ± 8.0 years of prior ART on average. Around 96.4% of patients were virologically suppressed before 2DR. Most common reasons to start dual therapy were treatment simplification (49.5%), avoidance of long-term toxicities (21.1%), and intolerance to previous ART (18.3%). The main regimen used in dual therapy was dolutegravir plus lamivudine (98.2%). Only eight patients discontinued dual therapy; the main reason for discontinuation was toxicity. All patients who did not discontinue 2DR were virologically suppressed at week 48. ART simplification saved €130,117.58 during the study period. In our cohort, dual therapy was mainly used for virologically suppressed patients, before availability of the single-tablet 2DR. Switching to a 2DR may be a key option for treatment simplification and avoidance of long-term toxicities. Furthermore, 2DR could provide a more cost-effective alternative to 3DR.

Do All Integrase Strand Transfer Inhibitors Have the Same Lipid Profile? Review of Randomised Controlled Trials in Naïve and Switch Scenarios in HIV-Infected Patients.

In this study, we aim to explore the effects on lipids of integrase strand transfer inhibitors (INSTIs) in naïve and switch randomised controlled trials, and compare them with protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). We reviewed phase 3/4 randomised clinical trials in the Cochrane and PubMed databases that compare an INSTI with a boosted PI, an NNRTI, or another INSTI plus one or two nucleoside/nucleotide reverse transcriptase inhibitors (NtRTIs) in naïve patients and switching strategies in HIV-infected patients. We reported the baseline plasma concentration of total cholesterol (TC), low and high-density lipoprotein cholesterol (LDL-c, HDL-c), triglycerides (TG), and the TC/HDL-c ratio, as well as the change at weeks 48 and 96, when available. In naïve HIV-infected patients, raltegravir (RAL) and dolutegravir (DTG) have a more favourable lipid profile compared with NNRTI and boosted PI. Elvitegravir (EVG/c) has a superior lipid profile compared with efavirenz and is similar to that observed with ritonavir-boosted atazanavir except in TG, which increases less with EVG/c. In naïve patients, RAL, DTG, and bictegravir (BIC) produce a similar, slight increase in lipids. In switching trials, the regimen change based on a boosted PI or efavirenz to RAL, DTG, or BIC is associated with clinically significant decreases in lipids that are minor when the change is executed on EVG/c. No changes were observed in lipids by switching trials between INSTIs. In summary, RAL, DTG, and BIC have superior lipid profiles compared with boosted-PI, efavirenz, and EVG/c, in studies conducted in naïve participants, and they are associated with a clinically significant decrease in lipoproteins by switching studies.

Comparison of the Virological Response According to the Antiretroviral Regimens in Peruvian HIV Patients Who Presented the M184V Mutation in Two National Hospitals During the Years 2008 to 2019.

Introduction: In patients with HIV in antiretroviral treatment (ART) and virological failure to the first-line regimen, establishing a therapeutic regimen after having identified the M184V mutation, which confers ART resistance, represents a dilemma. Objective: To compare the virological response of the therapeutic regimens prescribed to patients with HIV who presented the M184V mutation in two national hospitals in Lima, Peru, during the years 2008 to 2019, and to determine the risk factors associated with poor virological response. Methods: A retrospective cohort study was developed based on the information of the HIV program participants with the M184V mutation. Results: A total of 175 participants were eligible for the study. The male sex predominated (75.4%), the current median age was 41 years [interquartile range (IQR) 35.84-47.47], and the time on ART was 89 months (IQR 57.7-124.53). The median initial viral load (VL) was 4.5 log10 copies/mL (IQR 3.97-5.09) and the time between genotyping and the change of therapy was 2 months (IQR 0-3.56). The most used antiretroviral regimen was protease inhibitor plus two nucleoside reverse transcriptase inhibitors (55.4%). With the protease inhibitor plus integrase inhibitor (PI + INI) ART, 69% less risk of poor virological response was obtained [p = .019 (confidence interval 95% 0.117-0.825)]. Conclusions: In patients with HIV and the M184V mutation, the PI + INI ART has shown a greater decrease in control VL and, thus, a good virological response. The risk factors associated with a poor virological response were the delay between genotyping and change of therapy, high levels of initial VL, and poor adherence among the participants.

Similar Durability of Two Single Tablet Regimens, Dolutegravir/Abacavir/Lamivudine and Elvitegravir/Cobicistat/Tenofovir/Emtricitabine: Single Center Experience.

Integrase inhibitor is uniquely available as single tablet regimen (STR) in Korea. In this study, the durability until 96 weeks was compared between dolutegravir/abacavir/lamivudine (D/A/L) and elvitegravir/cobicistat/tenofovir/emtricitabine (E/T/E) in treatment naïve human immunodeficiency virus 1 (HIV-1) infected individuals. From 2014 to 2017, 153 and 234 subjects started D/A/L and E/T/E, respectively. During 96 weeks, 73 discontinued initial STR and the reason of discontinuation was typable in 44. The frequency of drug adverse event related discontinuation (AEDC) was higher in D/A/L (13.1% vs. 6.4%, P = 0.023) while most non-AE related discontinuations occurred in E/T/E (8/9), such as drug-drug interaction, meal requirement and virologic failure. AEDC occurred usually within 24 weeks (20/35) and D/A/L to E/T/E AEDC incidence rate ratio was 3.71 (95% confidence interval, 1.36-10.10) in this period. Regarding the durability, D/A/L and E/T/E revealed no significant difference at week 96 (P = 0.138) while durability of D/A/L was worse in the aspect of AEDC (P = 0.013).

Anti-HIV Activity of Standard Combined Antiretroviral Therapy in Primary Cells Is Intensified by CCR5-Targeting Drugs.

The efficacy of combined antiretroviral therapy (cART) against HIV-1 is evidenced by reduction of plasma viremia, disease progression, viral transmission, and mortality. However, major challenges still remain in HIV-1 management, especially the emergence of resistant strains and the persistence of viral reservoirs, apparent after cART treatment interruption. Efforts are ongoing to explore the most effective means to intensify cART and successfully control residual viral replication. We anticipate that the reduction by cART of HIV-1 reservoirs could be further enhanced by combining cART with entry inhibitors and drugs that silence CCR5 expression. CCR5-targeting drugs are attractive option because of their low side effects when combined with other antiretroviral drugs. The concept that their inclusion would be effective has been supported by the reduction in two long terminal repeat unintegrated circular DNA, a marker for new infections, when CCR5-targeting drugs are added to standard antiretroviral treatment. This study is, in part, an extension of our previous study demonstrating greater preservation of human CD4+ T-cells and CD4+/CD8+ cell ratios in HIV-infected CD34+ NSG mice when CCR5-targeting drugs were included with standard cART. In this study, we treated HIV-1-infected cell cultures with cART or cART plus CCR5-targeting drugs (maraviroc and rapamycin). We found that treatment intensification with CCR5-targeting drugs led to a significant reduction of HIV-1 replication in peripheral blood ononuclear cells (PBMCs), as judged by measured viral DNA copies and p24 levels. Our data provide proof of principle for the benefit of adding CCR5-targeting drugs to traditional, standard cART to further lower viremia and subsequently reduce viral reservoirs in clinical settings, while potentially lowering side effects by reducing cART concentrations.

Perspectives of injectable long acting antiretroviral therapies for HIV treatment or prevention: understanding potential users' ambivalences.

Recent clinical trial data showed that injectable long-acting antiretroviral treatment (LA-ART) every four or eight weeks could become an alternative option for HIV treatment or prevention. The purpose of our study was to explore perceptions and potential users' points of views of this new mode of administration through individuals' therapeutic itinerary and their singular history with ART. Between 2018 and 2019, a qualitative study was conducted in two University Hospitals in Paris, France. In-depth interviews were conducted with 15 virologically controlled People Living with HIV (PLWH) and 13 men on pre-exposure prophylaxis (PrEP) for at least six months. Interviews, focused on the daily experience with ART, were recorded, transcribed, and analyzed using thematic content analysis. Collected discourses were organized around three emergent concerns: social, material and experimental. Each of these concerns was perceived as ambivalent, balanced by skepticism and hope. It revealed the complexity of each individual's relationship to their HIV treatment or PrEP, leading to balance the injectable LA-ART popularity reported within clinical trials. This new mode of administration may be a suitable alternative for some PLWH and PrEP users, a "simplification" compared to the oral route. It opens a window for "customizable" ART-treatment according to individuals' lives.

Doravirine: a new non-nucleoside reverse transcriptase inhibitor for the treatment of HIV infection.

Doravirine is a new non-nucleoside reverse transcriptase inhibitor (NNRTI) that was approved by the United States Food and Drug Administration (FDA) on August 30, 2018, for the treatment of HIV infection in adult patients. The product was also approved in the E.U. and Japan in November 2018 and January 2020, respectively. It is currently available as a single stand-alone tablet as well as part of a single-tablet regimen in a fixed-dose combination with tenofovir disoproxil and lamivudine. Similarly to other NNRTIs, doravirine exerts its antiviral effect through a noncompetitive inhibition of HIV-1 reverse transcriptase. It has a novel resistance pathway so that it retains in vitro activity against clinically relevant NNRTI viral mutations K103N, Y181C and G190A. In randomized clinical trials, doravirine was noninferior to efavirenz- and darunavir-based regimens, with fewer adverse events. Doravirine has a more favorable drug interaction profile compared with earlier NNRTIs as it neither inhibits nor induces the cytochrome P450 3A4 (CYP3A4) enzyme. Doravirine has been added to the category of Recommended Initial Regimens in Certain Clinical Situations in the United States Department of Health and Human Services Antiretroviral Guidelines for Adults and Adolescents.

Brain microstructural changes support cognitive deficits in HIV uninfected children born to HIV infected mothers.

INTRODUCTION: Antiretroviral therapy (ART) is considered the most effective way to prevent perinatal transmission of human immunodeficiency virus (HIV). However, there is little knowledge about the effect of ART on the brain of HIV uninfected children born to HIV infected mothers (HUC). The current study evaluated the brain's microstructural integrity, and cognitive function in HUC compared to healthy children born to normal mothers (CHNM) and HIV infected children born to HIV infected mothers (HIC) to investigate the effect of in-utero exposure of ART on cerebral gray and white matter. MATERIALS AND METHODS: Forty nine HIC, 12 HUC and 18 CHNM underwent neuropsychological (NP) assessment and a brain MRI. Diffusion tensor imaging (DTI) data was used to generate fractional anisotropy (FA) and mean diffusivity (MD) maps. Voxel wise comparison for FA and MD was performed between three groups using an analysis of covariance (ANCOVA) including age and sex as covariates, and correction for multiple comparisons (false discovery rate (FDR), p â€‹< â€‹0.05 with minimum extended cluster size, 150 voxels). NP test scores were also compared between three groups using ANOVA with Post Hoc Bonferroni multiple comparison corrections (p â€‹< â€‹0.05). Significantly changed FA and MD values in different brain regions in HIC and HUC compared to CHNM were used for correlation analysis with NP test scores using Pearson's correlation. RESULTS: HIC and HUC groups showed significantly decreased NP test scores in various domain compared to CHNM. Significantly lower NP test scores was observed in HIC than those of HUC. HIC showed decreased FA and increased MD in multiple brain sites as compared to both CHNM and HUC. Decreased FA along with both increased and decreased MD in different brain regions was present in HUC compared to CHNM. Both positive and negative correlation of altered FA and MD values from different brain regions in HIC and HUC with NP test scores was observed. CONCLUSION: The presence of brain tissue changes and neurocognitive function deficit in absence of HIV infection in HUC indicates that ART may have a detrimental impact on the developing brain. The findings of the current study underscore the need for screening of ART exposed children for neurodevelopment and cognitive abnormalities at an early stage and call for access to early interventions, and nutritional and care programs.