Multidrug-resistant HIV-1 Research Articles

Pharmacokinetics of long-acting lenacapavir in participants with hepatic or renal impairment.

Lenacapavir is a novel, first-in-class, multistage inhibitor of HIV-1 capsid function approved for the treatment of multidrug-resistant HIV-1 infection in combination with other antiretrovirals for heavily treatment-experienced people with HIV. Two Phase 1, open-label, parallel-group, single-dose studies assessed the pharmacokinetics (PK) of lenacapavir in participants with moderate hepatic impairment [Child-Pugh-Turcotte (CPT) Class B: score 7-9] or severe renal impairment [15 ≤ creatinine clearance (CLcr) ≤29 mL/min] to inform lenacapavir dosing in HIV-1-infected individuals with organ impairment. In both studies, a single oral dose of 300 mg lenacapavir was administered to participants with normal (n = 10) or impaired (n = 10) hepatic/renal function who were matched for age (±10 years), sex, and body mass index (±20%). Lenacapavir exposures [area under the plasma concentration-time curve from time 0 to infinity (AUCinf) and maximum concentration (Cmax)] were approximately 1.47- and 2.61-fold higher, respectively, in participants with moderate hepatic impairment compared to those with normal hepatic function, whereas lenacapavir AUCinf and Cmax were approximately 1.84- and 2.62-fold higher, respectively, in participants with severe renal impairment compared to those with normal renal function. Increased lenacapavir exposures with moderate hepatic or severe renal impairment were not considered clinically meaningful. Lenacapavir was considered generally safe and well tolerated in both studies. These results support the use of approved lenacapavir dosing regimen in patients with mild (CPT Class A: score 5-6) or moderate hepatic impairment as well as in patients with mild (60 ≤ CLcr ≤ 89 mL/min), moderate (30 ≤ CLcr ≤ 59 mL/min), and severe renal impairment.

Mechanism of action, resistance, interaction, pharmacokinetics, pharmacodynamics, and safety of fostemsavir

The Food and Drug Administration (FDA) has licensed many antiretroviral medications to treat human immunodeficiency virus type 1 (HIV-1), however, treatment options for people with multi-drug resistant HIV remain limited. Medication resistance, undesirable effects, prior tolerance, and previous interlacement incapacity to deliver new drug classes all lead to the requirement for new medication classes and drug combination therapy. Fostemsavir (FTR) is a new CD-4 attachment inhibitor medicine that was recently authorized by the United States FDA to treat HIV-1. In individuals with multidrug-resistant (MDR) HIV-1, FTR is well tolerated and virologically active. According to recent investigations, drug combination therapy can positively affect MDR-HIV. The mechanism of action, resistance, interaction, pharmacokinetics, pharmacodynamics, and safety of FTR has been highlighted in this review.

HIV-1 capsid and viral DNA integration.

HIV-1 capsid protein (CA)-independently or by recruiting host factors-mediates several key steps of virus replication in the cytoplasm and nucleus of the target cell. Research in the recent years have established that CA is multifunctional and genetically fragile of all the HIV-1 proteins. Accordingly, CA has emerged as a validated and high priority therapeutic target, and the first CA-targeting antiviral drug was recently approved for treating multi-drug resistant HIV-1 infection. However, development of next generation CA inhibitors depends on a better understanding of CA's known roles, as well as probing of CA's novel roles, in HIV-1 replication. In this timely review, we present an updated overview of the current state of our understanding of CA's multifunctional role in HIV-1 replication-with a special emphasis on CA's newfound post-nuclear roles, highlight the pressing knowledge gaps, and discuss directions for future research.

1596. Efficacy and Safety of Long-Acting Subcutaneous Lenacapavir in Heavily Treatment-Experienced People with Multi-Drug Resistant HIV: Week 104 Results

Abstract Background Lenacapavir (LEN) is a highly potent, long-acting, first-in-class inhibitor of HIV-1 capsid protein for the treatment of HIV-1 infection in adults with multidrug resistance (MDR) in combination with other antiretrovirals. Methods CAPELLA is an ongoing, phase 2/3 study in heavily treatment-experienced people with HIV-1 with multidrug-resistance. Participants received oral LEN for loading followed by subcutaneous LEN Q6M in addition to an investigator-selected optimized background regimen (OBR). After reporting the efficacy and safety data through 52 weeks (W), the protocol was amended to allow longer follow up; we report W104 results. Results Of 72 participants enrolled (36 in each cohort), 25% were female, 38% were Black, median age was 52 years, 64% had CD4 <200 cells/µL, and 46% had HIV-1 resistant to all 4 major classes (NRTI, NNRTI, PI, INSTI). One participant (of 72) decided not to continue in the post-W52 extension. At W104, 62% (44/71) had HIV-1 RNA <50 c/mL via FDA Snapshot algorithm, and 14% (10/71) had HIV-1 RNA >50 c/mL; 24% discontinued for reasons other than lack of efficacy (13/71) or had missing data but were on study drug (4/71). When analyzed as missing=excluded, 81% (44/54) had HIV-1 RNA <50 c/mL. CD4 count increased by a median 97 cells/µL (Q1 to Q3: 18 to 224) and the proportion of participants with CD4 count ≥200 cells/µL increased from 36% (26/72) at baseline to 71% (39/55) at W104. Fourteen participants had emergent LEN resistance (9 previously reported), 6 of whom subsequently suppressed while continuing LEN. The median (Q1–Q3) duration of follow-up on LEN was 125 (111–140) weeks. One participant discontinued due to injection site nodule at W52 (Grade 1, previously reported); no participant discontinued due to an AE after W52. Most common AEs (excluding injection site reactions [ISRs] and COVID-19) were diarrhea and nausea (19% each, +5% each since W52, respectively). LEN-related ISRs were mostly mild-to-moderate. Conclusion In people with MDR HIV-1 and limited treatment options, LEN in combination with an OBR was well tolerated and maintained virologic suppression at W104. These data support the use of LEN for treatment of people with MDR HIV-1. Disclosures Onyema Ogbuagu, MD, Gilead Sciences, Inc: Advisor/Consultant|Gilead Sciences, Inc: Honoraria|Janssen: Advisor/Consultant|Viiv: Advisor/Consultant Edwin DeJesus, MD, Gilead Sciences, Inc: Advisor/Consultant|Theratechnology: Advisor/Consultant|Theratechnology: Honoraria Mezgebe Berhe, MD, MPH, Gilead Sciences, Inc: Clinical Trial Investigator Gary J Richmond, MD, Gilead Sciences, Inc: Grant/Research Support|Glaxo Smith Kline: Grant/Research Support|Insmed: Grant/Research Support|TaiMed: Grant/Research Support Peter J Ruane, MD, Gilead Sciences, Inc: Advisor/Consultant|Viiv: Advisor/Consultant|Viiv: Honoraria Gary I. Sinclair, MD, Abbvie: Grant/Research Support|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Janssen: Honoraria|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Honoraria|Thera: Advisor/Consultant|Thera: Grant/Research Support|Thera: Honoraria|ViiV: Advisor/Consultant|ViiV: Grant/Research Support|ViiV: Honoraria Moti N Ramgopal, MD, Abbvie: Honoraria|Gilead Sciences, Inc: Advisor/Consultant|Gilead Sciences, Inc: Honoraria|Janssen: Advisor/Consultant|Janssen: Honoraria|Merck: Advisor/Consultant|Viiv: Advisor/Consultant|Viiv: Honoraria William Sanchez, MD, Gilead Sciences, Inc: Grant/Research Support|GSK: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support Gordon E Crofoot, MD, Gilead Sciences, Inc: Clinical Trial Investigator Nicolas A Margot, MA, Gilead Sciences, Inc: Employee|Gilead Sciences, Inc: Stocks/Bonds Hui Wang, PhD, Gilead Sciences, Inc: Employee|Gilead Sciences, Inc: Stocks/Bonds Hadas Dvory-Sobol, PhD, Gilead Sciences, Inc: Employee|Gilead Sciences, Inc: Stocks/Bonds Martin Rhee, MD, Gilead Sciences, Inc: Employee|Gilead Sciences, Inc: Stocks/Bonds Jared Baeten, MD, PhD, Gilead Sciences, Inc: Employee|Gilead Sciences, Inc: Stocks/Bonds Sorana Segal-Maurer, MD, Gilead Sciences, Inc: Advisor/Consultant|Gilead Sciences, Inc: Honoraria|Janssen: Advisor/Consultant|Janssen: Honoraria|Theratechnologies: Advisor/Consultant|Theratechnologies: Honoraria|Viiv: Advisor/Consultant|Viiv: Honoraria

365. Durable efficacy and robust CD4+ T-cell count improvement observed across age, race, sex, and geographic subgroups of heavily treatment-experienced people with multidrug-resistant HIV-1 after 240 weeks of fostemsavir treatment

Abstract Background Fostemsavir (FTR), the prodrug of the first-in-class attachment inhibitor temsavir, is indicated in combination with other antiretrovirals (ARVs) for heavily-treatment experienced (HTE) people with multidrug-resistant HIV-1 unable to construct suppressive regimens. After ∼5 years in the phase 3 BRIGHTE study, overall virologic response rate (HIV-1 RNA < 40 c/mL, Snapshot) with FTR + optimized background therapy (OBT) was 45% (120/267) in the Randomized Cohort (RC) and 22% (20/92) in the Non-Randomized Cohort (NRC). We present long-term efficacy of FTR + OBT among subgroups in BRIGHTE. Methods BRIGHTE included HTE adults with HIV-1 (N=371) failing their current ARV regimen (HIV-1 RNA > 400 c/mL) with ≤ 2 fully active and approved ARVs remaining. Participants with 1 or 2 ARVs entered the RC and received open-label FTR + OBT after an 8-day blinded placebo-controlled period; those with 0 ARVs entered the NRC and received open-label FTR + OBT from Day 0. Virologic and immunologic responses were analyzed by baseline (BL) demographics and disease characteristics. Results Of 371 participants (RC, n=272; NRC, n=99), 290 (78%) were male, 166 (45%) were aged ≥ 50 years, and 259 (70%) were White. Virologic response rates were generally comparable among subgroups and consistent with overall response rate (Table 1). Similar efficacy was observed in RC participants with 1 or 2 fully active ARVs in OBT, while both RC and NRC participants with high BL viral loads or low BL CD4+ T-cell counts had lower response rates. Nearly all subgroups demonstrated robust and continuous increases in CD4+ T-cell count from Weeks 96 to 240, with mean change from BL exceeding 200 cells/mm3 in all RC subgroups, including those with BL viral loads ≥ 100,000 c/mL or CD4+ T-cell counts < 20 cells/mm3 (Table 2). Conclusion Virologic response with FTR + OBT in HTE adults with advanced HIV-1 and limited treatment options was durable over ∼5 years, with no major differences among subgroups based on age, sex, race, or geographic region. Robust and continuous CD4+ T-cell increases were also observed, with numerically greater improvements in subgroups with lowest BL CD4+ T-cell counts. These data highlight the role of FTR as a treatment option for HTE people with multidrug-resistant HIV-1 regardless of demographic or disease characteristics. Disclosures Alftan Dyson, PharmD, GSK: Stocks/Bonds|ViiV Healthcare: Employment Judith A. Aberg, MD, Emergent BioSolutions: Institutional research grants|Frontier Technologies: Institutional research grants|Gilead: Institutional research grants|GSK: Advisor/Consultant|GSK: Institutional research grants|Janssen: Institutional research grants|Merck: Advisor/Consultant|Merck: Institutional research grants|Pfizer: Institutional research grants|Regeneron: Institutional research grants|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Institutional research grants Jean-Michel Molina, MD; PhD, Aelix: Advisor/Consultant|Gilead: Advisor/Consultant|Merck: Advisor/Consultant|ViiV Healthcare: Advisor/Consultant Isabel Cassetti, MD, Gilead: Advisor/Consultant|Gilead: Institutional research grants|GSK: Advisor/Consultant|Janssen: Institutional research grants|Merck: Advisor/Consultant|Merck: Institutional research grants|ViiV Healthcare: Institutional research grants Michael Kozal, MD, ViiV Healthcare: Grant/Research Support|ViiV Healthcare: Royalties/Licenses for chapters authored for UpToDate Bo Li, PhD, GSK: Employment|GSK: Stocks/Bonds Manyu Prakash, PhD, GSK: Stocks/Bonds|ViiV Healthcare: Employee Andrew Clark, MD, GSK: Stocks/Bonds|ViiV Healthcare: Employee Allan R. Tenorio, MD, GSK: Stocks/Bonds|ViiV Healthcare: Employee Amy Pierce, BS, GSK: Stocks/Bonds|ViiV Healthcare: Employee Max Lataillade, DO, GSK: Stocks/Bonds|ViiV Healthcare: Employee

Sexually transmitted infections in people with multidrug-resistant HIV.

Retrospective, cohort analysis including people with four-class drug-resistant HIV. Bacterial sexually transmitted infections (STIs) had an incidence of 1.3/100-person-years-of-follow-up (PYFU) in men (3.5/100-PYFU in MSM) whereas no STIs were diagnosed in women. The occurrence of STIs in this fragile population might be related to the achievement of good HIV infection control; however, given the remaining risk of virological failure and possible transmission of a multidrug-resistant virus, STI prevention counselling and HIV viremia monitoring should be prioritized.

Successful Multidrug-Resistant Tuberculosis Treatment Without HIV Viral Suppression: A Missed Opportunity.

Coinfection with multidrug-resistant tuberculosis (MDR-TB) and HIV is common, but few published studies examine how undergoing MDR-TB treatment affects HIV disease indicators. Using data from a nested, retrospective cohort of people with HIV (PWH) and successful MDR-TB treatment outcomes, we built multivariable regression models to explore correlates of HIV viral suppression at MDR-TB treatment completion. Among 531 PWH successfully treated for MDR-TB, mean age was 37.4 years (SD 10.2, interquartile range 30-43), 270 (50.8%) were male, 395 (74.4%) were virally suppressed at MDR-TB outcome, and 259 (48.8%) took bedaquiline. Older age (adjusted odds ratio [aOR] 1.04, 95% confidence interval [CI]: 1.01 to 1.06) increased odds of viral suppression, while having a prior TB episode (aOR 0.45, 95% CI: 0.31 to 0.64), having a detectable viral load at MDR-TB treatment initiation (aOR 0.17, 95% CI: 0.09 to 0.30), living in a township (aOR 0.49, 95% CI: 0.28 to 0.87), and being changed from efavirenz-based antiretroviral therapy (ART) to a protease inhibitor due to bedaquiline usage (aOR 0.19, 95% CI: 0.04 to 0.82) or not having an ART change while on bedaquiline (aOR 0.29, 95% CI: 0.11 to 0.75) lowered odds of viral suppression. Changing from efavirenz to nevirapine due to bedaquiline usage did not significantly affect odds of viral suppression (aOR 0.41, 95% CI: 0.16 to 1.04). Increased pill burden and adverse treatment effects did not significantly affect HIV viral suppression while switching ART to a protease inhibitor to accommodate bedaquiline or not changing ART while taking bedaquiline did, suggesting that PWH and MDR-TB may benefit from additional support if they must switch ART.

Week 240 Efficacy and Safety of Fostemsavir Plus Optimized Background Therapy in Heavily Treatment-Experienced Adults with HIV-1.

Efficacy and safety of the attachment inhibitor fostemsavir + optimized background therapy (OBT) were evaluated through 48 and 96weeks in the phase 3 BRIGHTE trial in heavily treatment-experienced (HTE) adults failing their current antiretroviral regimen. Here, we report 240-week efficacy and safety of fostemsavir + OBT in adults with multidrug-resistant human immunodeficiency virus (HIV)-1 in BRIGHTE. Heavily treatment-experienced adults failing their current regimen entered the randomized cohort (RC; 1-2 fully active antiretrovirals available) or non-randomized cohort (NRC; no fully active antiretrovirals available) and received open-label fostemsavir + OBT (starting Day 8 in RC and Day 1 in NRC). Endpoints included proportion with virologic response (HIV-1 RNA < 40copies/mL, Snapshot), immunologic efficacy, and safety. At Week 240, 45% and 22% of the RC and NRC, respectively, had virologic response (Snapshot); 7% of the RC and 5% of the NRC had missing data due to coronavirus disease 2019 (COVID-19)-impacted visits. In the observed analysis, 82% of the RC and 66% of the NRC had virologic response. At Week 240, mean change from baseline in CD4+ T-cell count was 296cells/mm3 (RC) and 240cells/mm3 (NRC); mean CD4+/CD8+ ratio increased between Weeks 96 and 240 (RC 0.44to0.60; NRC 0.23to0.32). Between Weeks 96 and 240, four participants discontinued for adverse events, one additional participant experienced a drug-related serious adverse event, and six deaths occurred (median last available CD4+ T-cell count, 3cells/mm3). COVID-19-related events occurred in 25 out of 371 participants; all resolved without incident. Through ~5years, fostemsavir + OBT demonstrated durable virologic and immunologic responses with no new safety concerns between Weeks 96 and 240, supporting this regimen as a key therapeutic option for HTE people with multidrug-resistant HIV-1. ClinicalTrials.gov, NCT02362503.

Rescue therapy with an albuvirtide-based antiretroviral regimen in an HIV-infected child with multidrug resistance and multiple opportunistic infections: a case report

BackgroundManaging multidrug-resistant (MDR) HIV infections in children is particularly challenging due to the lack of experience with new drugs in the pediatric setting. Second-line albuvirtide (ABT) with an optimized antiretroviral background therapy was approved for adults and adolescents after first-line treatment failure. This paper describes the treatment outcomes and adverse effects of an ABT-based dual-active antiretroviral treatment regimen in a child with MDR HIV strains.Case presentationA 13 year-old Chinese female patient infected with MDR HIV strains showed a decrease in viral load (from 4.48 log10 to 1.73 log10) and an increase in CD4 + T cells (from 15 to 308 cells/µl) after 12 months of treatment with an ABT-based antiretroviral regimen. The child showed no relevant drug-related adverse reactions.ConclusionsThe case reported here could suggest that an ABT-based antiretroviral therapy might be beneficial and without relevant toxicity in children with MDR HIV. Infectiologists specializing in managing HIV should be prepared to manage an increasing number of children with MDR HIV. ABT might be a new treatment option for MDR HIV infection in children.

Long-acting lenacapavir protects macaques against intravenous challenge with simian-tropic HIV

Long-acting subcutaneous lenacapavir (LEN), a first-in-class HIV capsid inhibitor approved by the US FDA for the treatment of multidrug-resistant HIV-1 with twice yearly dosing, is under investigation for HIV-1 pre-exposure prophylaxis (PrEP). We previously derived a simian-tropic HIV-1 clone (stHIV-A19) that encodes an HIV-1 capsid and replicates to high titres in pigtail macaques (PTM), resulting in a nonhuman primate model well-suited for evaluating LEN PrEP invivo. Lenacapavir potency against stHIV-A19 in PTM peripheral blood mononuclear cells invitro was determined and subcutaneous LEN pharmacokinetics were evaluated in naïve PTMs invivo. To evaluate the protective efficacy of LEN PrEP, naïve PTMs received either a single subcutaneous injection of LEN (25mg/kg, N=3) or vehicle (N=4) 30 days before a high-dose intravenous challenge with stHIV-A19, or 7 daily subcutaneous injections of a 3-drug control PrEP regimen starting 3 days before stHIV-A19 challenge (N=3). Invitro, LEN showed potent antiviral activity against stHIV-A19, comparable to its potency against HIV-1. Invivo, subcutaneous LEN displayed sustained plasma drug exposures in PTMs. Following stHIV-A19 challenge, while all vehicle control animals became productively infected, all LEN and 3-drug control PrEP animals were protected from infection. These findings highlight the utility of the stHIV-A19/PTM model and support the clinical development of long-acting LEN for PrEP in humans. Gilead Sciences as part of a Cooperative Research and Development Agreement between Gilead Sciences and Frederick National Lab; federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024/HHSN261201500003I; NIH grant R01AI078788.

Fostemsavir (Rukobia)

&#x0D; CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class.&#x0D; The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec.&#x0D; This review assesses fostemsavir (Rukobia), 600 mg, extended-release tablets, oral.&#x0D; Indication: For adults with HIV-1 who are heavily treatment-experienced and have multidrug-resistant HIV-1, and for whom it is otherwise not possible to construct a suppressive antiviral regimen due to resistance, intolerance, or safety considerations.&#x0D;

Efficacy and safety of the novel capsid inhibitor lenacapavir to treat multidrug-resistant HIV: week 52 results of a phase 2/3 trial

Lenacapavir, a first-in-class HIV-1 capsid inhibitor, is in development as a long-acting agent for treating and preventing HIV-1. We aimed to evaluate the efficacy and safety of lenacapavir with an optimised background regimen in adults living with multidrug-resistant HIV-1 up to 52 weeks. This ongoing, international, phase 2/3 trial at 42 sites included adults living with multidrug-resistant HIV-1. In cohort 1, 36 participants were randomly assigned (2:1) to add oral lenacapavir (600 mg, days 1 and 2; 300 mg, day 8) or placebo to an existing failing regimen. At day 15, those on oral lenacapavir received subcutaneous lenacapavir 927 mg every 26 weeks; those on placebo started lenacapavir (2-week oral lead-in then subcutaneous). Cohort 1 started an optimised background regimen on day 15. In cohort 2 (non-randomised), 36 participants started an optimised background regimen concurrent with lenacapavir (oral to subcutaneous). Here we report the secondary endpoints of plasma HIV-1 RNA of less than 50 copies per mL or less than 200 copies per mL at week 52 (US Food and Drug Administration snapshot algorithm) in cohort 1 along with results for cohorts 1 and 2 combined. This trial is registered with ClinicalTrials.gov, NCT04150068, and clinicaltrialregister.eu, EudraCT 2019-003814-16 and is ongoing. Of 72 participants, 46 (64%) had CD4 counts of less than 200 cells per μL and 38 (53%) had no more than one fully active antiretroviral drug at baseline. In cohort 1, 30 of 36 participants (83%, 95% CI 67-94) had less than 50 HIV-1 RNA copies per mL and 31 of 36 participants (86%, 71-95) had less than 200 HIV RNA copies per mL, at week 52. In all, nine participants (four in cohort 1, five in cohort 2) had emergent lenacapavir resistance; four resuppressed (HIV-1 RNA <50 copies per mL) while maintaining lenacapavir use. One participant discontinued study drug owing to injection site reaction. In participants with multidrug-resistant HIV-1, subcutaneous lenacapavir in combination with an optimised background regimen resulted in a high rate of virological suppression up to 52 weeks. Gilead Sciences.

Green-adapted spectrophotometric determination of fostemsavir based on selective bromophenol blue extraction; reduction of hazardous consumption using computational calculations

A computationally-assisted and green spectrophotometric method has been developed for the determination of fostemsavir, a recently FDA-approved drug used in combination with antiretroviral drugs to treat multidrug-resistant HIV-1 infection. The method was developed using computational studies and solvent selection based on green chemistry principles. The density functional theory method was employed to identify bromophenol blue as the preferred acid dye for efficient extraction of fostemsavir. The solvent selection process involved a careful evaluation of the green ranking of solvents, which led to the use of water as the solvent. The method involved the extraction of fostemsavir with bromophenol blue to form a yellow ion-pair complex, which exhibited maximally sharp peaks at 418 nm, enabling sensitive visible spectrophotometric determination of fostemsavir in bulk and pharmaceutical preparations. The extraction procedures were optimized, and the method was demonstrated to be sensitive over the concentration range of 2–12 μg/mL fostemsavir. Furthermore, the method was evaluated with respect to green chemistry principles using the analytical eco-scale, the green analytical method index, and analytical greenness metric approach, all of which confirmed that the data obtained by the proposed method were environmentally acceptable.

Lenacapavir (Sunlenca®) for the treatment of HIV-1

STRUCTURE: Lenacapavir (previously GS-6207, brand name Sunlenca®) is a small molecule that selectively targets the HIV-1 capsid protein (CA, p24), which is a structural component of the virus. This is the first FDA-approved drug in the class of capsid protein inhibitors for clinical use in heavily treatment-experienced patients with multidrug-resistant HIV-1 infection. It has a molecular formula of C39H31ClF10N7O5S2 and a molecular weight of 968.28 g/mol.

Multiple imputation using chained equations for missing data in survival models: applied to multidrug-resistant tuberculosis and HIV data.

Missing data are a prevalent problem in almost all types of data analyses, such as survival data analysis. To evaluate the performance of multivariable imputation via chained equations in determining the factors that affect the survival of multidrug-resistant-tuberculosis (MDR-TB) and HIV-coinfected patients in KwaZulu-Natal. Secondary data from 1542 multidrug-resistant tuberculosis patients were used in this study. First, data from patients with some missing observations were deleted from the original data set to obtain the complete case (CC) data set. Second, missing observations in the original data set were imputed 15 times to obtain complete data sets using a multivariable imputation case (MIC). The Cox regression model was fitted to both the CC and MIC data, and the results were compared using the model goodness of fit criteria [likelihood ratio tests, Akaike information criterion (AIC), and Bayesian Information Criterion (BIC)]. The Cox regression model fitted the MIC data set better (likelihood ratio test statistic =76.88 on 10 df with P<0.01, AIC =1040.90, and BIC =1099.65) than the CC data set (likelihood ratio test statistic =42.68 on 10 df with P<0.01, AIC =1186.05 and BIC =1228.47). Variables that were insignificant when the model was fitted to the CC data set became significant when the model was fitted to the MIC data set. Correcting missing data using multiple imputation techniques for the MDR-TB problem is recommended. This approach led to better estimates and more power in the model.

Lenacapavir: a twice-yearly treatment for adults with multidrug-resistant HIV infection and limited treatment options

Introduction Lenacapavir , the compoundreviewed in this paper, is a novel, potent, and long-acting first-in-classHIV-1 capsid inhibitor that was granted breakthrough therapy designation forHIV treatment by the U.S. Food and Drug Administration in May 2019. Lenacapavirwas subsequently approved, in combination with other antiretroviral agents, forthe treatment of multidrug-resistant HIV in people with HIV who have limitedtreatment options due to safety, intolerance and resistance considerations,based on clinical trial data which demonstrated its efficacy, tolerability, andsafety for that population. Areas Covered This review draws uponpublished and unpublished data of lenacapavir (GS-6207) to discuss itschemistry, mechanism of action, pharmacokinetic and pharmacodynamic properties,as well as efficacy and safety observed in clinical trials; and an expertopinion section discusses its clinical uses, advantages, limitations, andpotential future applications. Expert Opinion Lenacapavir should beused in combination with at least 1 or 2 additional fully active agents, wherepossible, and adherence support is critical for selected companion drugs(particularly if self-administered) to optimize efficacy and preventtreatment-emergent resistance to lenacapavir. Providers should pay attention todrug-drug interactions when initiating lenacapavir.

EE472 US Cost-Effectiveness of Lenacapavir Plus Optimized Background Regimen Versus Other Treatments for Multi-Drug Resistant HIV

Lenacapavir (LEN), a first-in-class multi-stage HIV capsid inhibitor, is indicated in combination with an optimized background regimen (OBR) for the treatment of HIV-1 in heavily treatment-experienced (HTE) adults with multi-drug resistant (MDR) HIV-1 failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations. Historically, this population has had limited treatment options, leading to virologic failure and high risk of AIDS-related mortality. The health outcomes associated with LEN+OBR versus relevant comparators in this population were evaluated previously. This current analysis aimed to assess the cost-effectiveness of LEN+OBR.

Lenacapavir (Sunlenca) for multidrug-resistant HIV.

The FDA has approved oral and injectable formulations of the HIV-1 capsid inhibitor lenacapavir (Sunlenca – Gilead) for use with other antiretroviral drugs to treat multidrug-resistant HIV-1 infection (MDR-HIV) in heavily treatment-experienced adults whose current regimen is failing. Lenacapavir is the third drug to be approved exclusively for treatment of MDR-HIV; the intravenously administered CD4-directed antibody ibalizumab-uiyk (Trogarzo) and the orally administered HIV-1 gp120-directed attachment inhibitor fostemsavir (Rukobia) were approved earlier.

Correlation of polymorphism in Toll-Like Receptor (TLR1 and TLR2) genes with susceptibility of pulmonary tuberculosis in Doda region of India

BackgroundPulmonary tuberculosis has emerged as one of the leading causes of deaths across the globe. The prevalence of Mycobacterium tuberculosis has also shown an increasing trend over the time which may be attributed to the increase in multidrug resistant strains and HIV epidemics. There are several factors like change in the gene structure and cellular activities of the host and the bacterium which may have changed the host response towards tuberculosis. Additionally, the recent reports have suggested that Toll-Like Receptors (TLRs) play an important role in the activation of immune responses against various pathogens. Therefore, this study has been designed to investigate the possible correlation of TLR gene polymorphism and prevalence of pulmonary tuberculosis. MethodThis study investigates 300 samples collected from patients with pulmonary tuberculosis (150) and healthy controls (150) from the Doda region of Jammu, India. For analysis purpose, DNA from the collected samples were isolated and subjected to sequence specific PCR amplification of TLR-1 and TLR-2 genes. The amplicons of TLR-1 and TLR-2 were further digested with restriction enzymes PvuII and Xbal, respectively, and visualized on agarose gel, subsequently. ResultThe results suggest that frequency of TLR2 gene polymorphism (73.9%) is high in the patients below the age of 50 years, whereas, frequency of TLR-1 gene polymorphism is high (71%) in the patients above 50 years of age (p = 0.005). Further, the restriction digestion analysis of TLR1 genes has shown that nearly 78% of the confirmed normal cases exhibit homozygous normal conditions followed by 12% cases with heterozygous conditions and 10% cases of homozygous mutants. Similarly for TLR2 genes, nearly 78.6% of the confirmed normal cases have shown homozygous normal conditions followed heterozygous conditions (12.6%) and homozygous mutants (8.6%). ConclusionThis study establishes a preliminary correlation between TLR polymorphism and tuberculosis.

Inflammation burden score in multidrug-resistant HIV-1 infection

Four-class drug-resistant (4DR) people living with HIV (PLWH) are a fragile population with a high burden of disease. No data on their inflammation and T-cell exhaustion markers are currently available. Inflammation, immune activation and microbial translocation biomarkers were measured through ELISA in 30 4DR-PLWH with HIV-1 RNA ≥50 copies/mL, 30 non-viremic 4DR-PLWH and 20 non-viremic non-4DR-PLWH. Groups were matched by age, gender and smoking habit. T-cell activation and exhaustion markers were assessed by flow cytometry in 4DR-PLWH. An inflammation burden score (IBS) was calculated from soluble marker levels and associated factors were estimated through multivariate regression. The highest plasma biomarker concentrations were observed in viremic 4DR-PLWH, the lowest ones in non-4DR-PLWH. Endotoxin core immunoglobulin G showed an opposite trend. Among 4DR-PLWH, CD38/HLA-DR and PD-1 were more expressed on CD4+ (p=0.019 and 0.034, respectively) and CD8+ (p=0.002 and 0.032, respectively) cells of viremic compared to non-viremic subjects. An increased IBS was significantly associated with 4DR condition, higher values of viral load and a previous cancer diagnosis. Multidrug-resistant HIV infection is associated with a higher IBS, even when viremia is undetectable. Therapeutic approaches aimed to reduce inflammation and T-cell exhaustion in 4DR-PLWH need to be investigated.