Letermovir, an anti-cytomegalovirus (CMV) drug, is recommended as a prophylactic agent in patients at risk of CMV infection/reactivation after allogeneic hematopoietic stem cell transplant. We report the curative and pre...Letermovir, an anti-cytomegalovirus (CMV) drug, is recommended as a prophylactic agent in patients at risk of CMV infection/reactivation after allogeneic hematopoietic stem cell transplant. We report the curative and pre-emptive use of letermovir in two heart transplant recipients. In one patient with ganciclovir-resistant CMV, letermovir was successfully used to treat CMV colitis. In the second patient, letermovir was used as pre-emptive therapy for CMV reactivation, but did not prevent CMV esophagitis. In both cases, letermovir was successful for secondary prophylaxis. Curative use of letermovir may be considered if resistance or major adverse effect of other antivirals therapy is suspected.
Feld JJ, Lawitz E, Nguyen T
… +11 more, Lalezari J, Hassanein T, Martin P, Han SH, Dieterich D, Giard JM, De La Rosa G, Ahmad A, Luo E, Conery AL, Adda N
BACKGROUND: Chronic hepatitis B (CHB) remains a major cause of morbidity and mortality. EDP-514 is a potent core inhibitor of hepatitis B virus (HBV) that reduces viral load reduction in HBV-infected chimeric mice. This...BACKGROUND: Chronic hepatitis B (CHB) remains a major cause of morbidity and mortality. EDP-514 is a potent core inhibitor of hepatitis B virus (HBV) that reduces viral load reduction in HBV-infected chimeric mice. This first-in-human study evaluated the safety, tolerability, and pharmacokinetics (PK) of EDP-514 in healthy subjects and antiviral activity in patients with CHB. METHODS: In Part 1, 82 subjects received placebo or EDP-514 in fed or fasted state as single ascending doses of 50-800 mg and multiple ascending doses of 200-800 mg for 14 days. In Part 2, 24 HBV DNA-suppressed, nucleos(t)ide (NUC)-treated (i.e., NUC-suppressed) CHB patients received EDP-514 200-800 mg or placebo for 28 days. RESULTS: EDP-514 was well tolerated in healthy subjects and CHB patients with most adverse events of mild intensity. In Part 1, EDP-514 exposure increased in an approximately dose proportional manner up to 600 mg after single doses and up to 400 mg after 14-day dosing. In Part 2, EDP-514 exposure increased linearly with dose on Day 1 and Day 28, with some accumulation for Day 28 and median trough concentrations (C) approximately 20-fold above the protein-adjusted 50% effective concentration (EC) for the dose range. Mean change in HBV RNA from baseline to Day 28 was -2.03, -1.67, -1.87, and -0.58 log U/mL in the 200 mg, 400 mg, 800 mg, and placebo CHB groups, respectively. CONCLUSIONS: EDP-514 was well tolerated, had a PK profile supporting once daily dosing, and reduced HBV RNA levels in NUC-suppressed CHB patients.
Tyagi A, Tong Y, Rabideau DJ
… +12 more, Reynolds Z, De Oliveira T, Lessells R, Amanyire G, Orrell C, Asiimwe S, Chimukangara B, Giandhari J, Pillay S, Haberer JE, Siedner MJ, META Study Investigators
BACKGROUND: Relationships between distinct antiretroviral therapy (ART) adherence patterns and risk of drug resistance are not well understood. METHODS: We conducted a nested case-control analysis within a longitudinal c...BACKGROUND: Relationships between distinct antiretroviral therapy (ART) adherence patterns and risk of drug resistance are not well understood. METHODS: We conducted a nested case-control analysis within a longitudinal cohort study of individuals initiating efavirenz-based ART. Primary outcomes of interest, measured at 6 and 12 months after treatment initiation, were: 1) virologic suppression, 2) virologic failure with resistance, and 3) virologic failure without resistance. Our primary exposure of interest was ART adherence, measured over the 6 months before each visit with electronic pill monitors, and categorized in three ways: 1) 6 months average adherence; 2) running adherence, defined as the proportion of days with average adherence over of less than or equal to 10%, 20%, and 30%; and 3) number of 3-, 7-, and 28-day treatment gaps in the prior 6 months. RESULTS: We analyzed data from 166 individuals (107 had virologic failure during observation and 59 had virologic suppression at 6 and 12 months). Average adherence was higher among those with virologic suppression (median 83%, IQR 58-96%) versus those with virologic failure with resistance (median 35%, IQR 20-77%, pairwise < 0.01) and those with virologic failure without resistance (median 21%, IQR 2-54%, pairwise < 0.01). Although treatment gaps generally predicted virologic failure ( < 0.01), they did not differentiate failure with and without drug resistance ( > 0.6). CONCLUSIONS: Average adherence patterns, but not the assessed frequency of treatment gaps, differentiated failure with versus without drug resistance among individuals initiating efavirenz-based ART. Future work should explore adherence-resistance relationships for integrase inhibitor-based regimens.
BACKGROUND: The GSK3732394 multivalent protein was developed as a novel, long-acting, antiretroviral biologic treatment regimen with three independent, non-cross-resistant mechanisms for inhibiting HIV-1 entry. METHODS:...BACKGROUND: The GSK3732394 multivalent protein was developed as a novel, long-acting, antiretroviral biologic treatment regimen with three independent, non-cross-resistant mechanisms for inhibiting HIV-1 entry. METHODS: A single-centre, Phase 1, double-blind, randomized, placebo-controlled study was conducted in healthy volunteers, using a 2-part adaptive study design: in Part 1, participants were randomized to receive subcutaneous injection of GSK3732394 or placebo (3:1) as single ascending doses (10-mg starting dose); in Part 2, participants were intended to receive multiple ascending doses. Primary and secondary objectives included safety, pharmacokinetics (PK) and pharmacodynamics (PD; cluster of differentiation four receptor occupancy [CD4 RO]) of GSK3732394 in healthy adults; PK/PD results in healthy volunteers were used to project HIV-1 treatment success. RESULTS: The most frequently reported adverse event was injection site reactions (ISRs; 8/18 [44%]). Most ISRs were mild (Grade 1-2; = 7); one participant experienced a Grade 3 ISR (erythema ≥10 cm). All ISRs were delayed in onset (after Day 10). GSK3732394 demonstrated linear PK across all cohorts. Clearance was faster than expected, and PK/PD results were lower than expected, with the maximum dose investigated (80 mg) achieving mean trough CD4 RO of ∼25% on Day 7. The study was terminated as the PK/PD model linking PK and CD4 RO indicated that the maximum planned doses would not achieve the desired therapeutic profile. CONCLUSIONS: This study demonstrated successful deployment of PK/PD dose relationships in the design and conduct of clinical trials by leveraging the findings toward predicting probability of success, resulting in appropriate early termination (ClinicalTrials.gov, NCT03984812).
Epstein-Barr virus-associated smooth muscle tumor (EBV-SMT) is a rare mesenchymal tumor which occurs in immunocompromised patients. The immune status is an important factor in the treatment of EBV-SMTs, but the efficacy...Epstein-Barr virus-associated smooth muscle tumor (EBV-SMT) is a rare mesenchymal tumor which occurs in immunocompromised patients. The immune status is an important factor in the treatment of EBV-SMTs, but the efficacy of antiretroviral therapy (ART) is not elucidated in acquired immune deficiency syndrome (AIDS) related EBV-SMTs. Here, we report the first successful case of a 29-year-old man with hepatic AIDS related EBV-SMT treated with ART solely. Positron emission tomography scan was useful for the evaluation of disease status. Recent advances in ART that enables to restore patient's immune status rapidly may change the treatment strategy in AIDS related EBV-SMT.
We report a case of an infant with HIV receiving raltegravir granules for oral suspension and rifampicin-based TB prophylaxis. Raltegravir trough levels remained subtherapeutic and viral load increased during concurrent...We report a case of an infant with HIV receiving raltegravir granules for oral suspension and rifampicin-based TB prophylaxis. Raltegravir trough levels remained subtherapeutic and viral load increased during concurrent rifampicin therapy despite using double-dosed raltegravir. Even after rifampicin therapy, a higher dose was needed. This highlights the importance of therapeutic drug monitoring and dose adjustments of raltegravir in infants with rifampicin as comedication.
European Pregnancy And Paediatric Infections Cohort Collaboration Eppicc, Lyons A, Thompson L
… +25 more, Chappell E, Ene L, Galli L, Goetghebuer T, Jourdain G, Noguera-Julian A, Kahlert CR, Königs C, Kosalaraksa P, Lumbiganon P, Marczyńska M, Marques L, Navarro M, Naver L, Okhonskaia L, Prata F, Puthanakit T, Ramos JT, Samarina A, Thorne C, Voronin E, Turkova A, Giaquinto C, Judd A, Collins IJ
Antivir Ther
· 2022 Jun · PMID 36029009
·
Full text
BACKGROUND: Etravirine (ETR) is approved as a component of second or third-line antiretroviral treatment (ART) for children living with HIV. We assessed the outcomes of ETR-based ART in children in routine care in Europe...BACKGROUND: Etravirine (ETR) is approved as a component of second or third-line antiretroviral treatment (ART) for children living with HIV. We assessed the outcomes of ETR-based ART in children in routine care in Europe and Thailand. METHODS: Data on children aged <18 years at ETR start were pooled from 17 observational cohorts. Characteristics at ETR start, immunological and virological outcomes at 12 months, discontinuations, adverse events (AEs) and serious adverse events (SAEs) were described. Follow-up was censored at ETR discontinuation, death or last visit. RESULTS: 177 children ever received ETR. At ETR start, median [IQR] age was 15 [12,16] years, CD4 count 480 [287, 713] cells/mm, 70% had exposure to ≥3 ART classes and 20% had viral load (VL) <50 copies/mL. 95% received ETR in combination with ≥1 potent drug class, mostly protease inhibitor-based regimens. Median time on ETR was 24 [7, 48] months. Amongst those on ETR at 12 months (=141), 69% had VL<50 copies/mL. Median CD4 increase since ETR start (=83) was 147 [16, 267] cells/mm. Overall, 81 (46%) discontinued ETR by last follow-up. Median time to discontinuation was 23 [8, 47] months. Common reasons for discontinuation were treatment simplification (19%), treatment failure (16%) and toxicity (12%). Eight children (5%) had AEs causally associated with ETR, all dermatological/hypersensitivity reactions. Two were SAEs, both Stevens-Johnson Syndrome in children on regimens containing ETR and darunavir and were causally related to either drugs; both resolved following ART discontinuation. CONCLUSION: Children receiving ETR were predominantly highly treatment-experienced, over two-thirds were virally suppressed at 12 months.
Alvarez E, Campbell L, Tinago W
… +12 more, Garcia-Leon A, Walsh I, Brady JJ, Burling K, Noe S, Neuville MF, Jouret F, Jamshidian F, Graham H, Rhee M, Mallon PW, Post FA
BACKGROUND: Data on low bone mineral density (BMD) in people living with HIV (PLWH) are mainly derived from younger adults; little is known about how antiretroviral therapy (ART) and alterations in the renal-bone axis re...BACKGROUND: Data on low bone mineral density (BMD) in people living with HIV (PLWH) are mainly derived from younger adults; little is known about how antiretroviral therapy (ART) and alterations in the renal-bone axis relate to BMD in older PLWH. METHODS: Cross-sectional study of men > 50 years and post-menopausal women with HIV. Antiretroviral therapy exposure was stratified into four groups based on use of tenofovir disoproxil fumarate (TDF) and protease inhibitors (PI): non-TDF/non-PI, non-TDF/PI, TDF/non-PI, and TDF/PI. Bone mineral density was measured by dual X-ray absorptiometry (DXA). Bone turnover/regulatory markers and renal tubular function were analysed in stored plasma and urine samples. The association of ART exposure and bone/renal biomarkers on BMD was explored using logistic regression models. RESULTS: 247 individuals (median [IQR] age 57 [53, 65] years; 47% female; 13% of Black ethnicity; CD4 count 643 [473, 811] cells/mm; and 98% with HIV RNA < 200 copies/mL) were included. Bone turnover and renal tubular function differed significantly by ART exposure. In analyses adjusted for demographic and traditional renal/bone risk factors, exposure to TDF and PI was associated with a fourfold greater risk of low BMD at the femoral neck and exposure to TDF and/or PI with a threefold greater risk of low BMD at the lumbar spine. The relationship between ART and low BMD was not altered by further adjustment for bone turnover or renal tubular function markers. CONCLUSIONS: The associations between low BMD and ART exposure (TDF vs. non-TDF and boosted vs. unboosted third agents) were minimally affected by adjustments for bone and kidney biomarkers.
Bello G, Kagoli M, Chipeta S
… +19 more, Auld A, Chang JC, DeVos JR, Kim E, Mkungudza J, Payne D, Eliya M, Nyirenda R, Jahn A, Mzumara T, Mvula B, Dadabhai S, Namakhoma I, Babaye Y, Giron A, Jordan MR, Bertagnolio S, O'Malley G, Wadonda-Kabondo N
Antivir Ther
· 2022 Aug · PMID 35976773
·
Full text
BACKGROUND: Information on HIV drug resistance (HIVDR) prevalence in people newly diagnosed with HIV is limited. We implemented a cross-sectional study to estimate HIVDR prevalence among pregnant women recently infected...BACKGROUND: Information on HIV drug resistance (HIVDR) prevalence in people newly diagnosed with HIV is limited. We implemented a cross-sectional study to estimate HIVDR prevalence among pregnant women recently infected with HIV in Malawi. METHODS: The HIVDR study was nested within a routine antenatal clinic (ANC) sentinel surveillance survey. Dried blood spot samples were tested for recent infection using a limiting antigen antibody assay together with HIV viral load testing. HIV-1 protease and reverse transcriptase were sequenced using Sanger sequencing. Drug susceptibility was predicted using Stanford HIVdb algorithm (version 8.9). Weighted analysis was performed in Stata 15.1. RESULTS: Of the 21,642 pregnant women enrolled in the ANC survey, 8.4% (1826/21,642) tested HIV positive. Of these, 5.0% (92/1826) had recent HIV infection, and 90.2% (83/92) were tested by PCR. The amplification and sequencing success rate was 57.8% (48/83). The prevalence of any HIVDR was 14.6% (5/45) (95% CI: 4.7-36.8%), all of which indicated HIVDR to nonnucleoside reverse transcriptase inhibitors (NNRTIs). HIVDR to nucleoside reverse transcriptase inhibitors was 7.9% (2/45) (95% CI: 1.4-34.6%). Resistance to protease inhibitors currently in use in Malawi was not observed. CONCLUSIONS: Despite the low number of cases with presumed TDR, our study hints that resistance to NNRTIs was high, above the 10% target for regimen change. Further investigation is needed to establish the exact magnitude of presumed TDR among women recently infected with HIV. These findings support the transition to an integrase inhibitor-based first-line regimen for patients initiating or on ART.
BACKGROUND: We monitored the quality of care for newly diagnosed people with HIV (PWH) in Spain, including linkage to care within 1 month of HIV diagnosis (LC-1Mo) and viral suppression within 3 months of HIV diagnosis (...BACKGROUND: We monitored the quality of care for newly diagnosed people with HIV (PWH) in Spain, including linkage to care within 1 month of HIV diagnosis (LC-1Mo) and viral suppression within 3 months of HIV diagnosis (VS-3Mo). METHODS: Longitudinal study based on The Cohort of the Spanish AIDS Research Network (CoRIS). We used logistic regression stratified by year of HIV diagnosis (2004-2013 and 2014-2019) to assess differences by sex, country of origin, HIV risk group, age, prior AIDS, HIV Viral Load, and CD4 cell count. RESULTS: The final analysis included 13,632 PWH: males 85%, men having sex with men (MSM) 61%, median age 35 years. LC-1Mo increased from 42% (95% CI, 38%-46%) in 2004 to 80% (95% CI, 77%-83%) in 2019 ( < 0.001). Median CD4 cell counts at ART initiation increased from <250/mm3 in 2004-2005 to >350/mm3 since 2012 ( < 0.001). The percentage of initial regimens based on integrase strand transfer inhibitors (INSTI) increased from 3% in 2004 to >70% from 2016 onwards ( < 0.001). VS-3Mo increased from 6% (95% CI, 4%-8%) in 2004 to 45% (95% CI, 41%-49%) in 2019 ( < 0.001). Worst results for LC-1Mo were found among PWH acquiring HIV by injection drug use and those born in Latin American Countries across all the study period. CONCLUSION: Care indicators have improved among newly diagnosed PWH in Spain over the last 15 years. Removal of CD4 cell counts limitations, and probably the increasing use of INSTI-based regimens was decisive for the progress made.
Wisch JK, Cooley SA, Yarasheski KE
… +6 more, Cade WT, Reeds DN, Nelson B, Alemu R, Burdo TH, Ances BM
Antivir Ther
· 2022 Jun · PMID 35730471
·
Full text
BACKGROUND: Substantial body composition alterations have been reported after starting combined antiretroviral therapy (cART). We characterized a cohort of chronically infected and virologically suppressed (VL < 50 copie...BACKGROUND: Substantial body composition alterations have been reported after starting combined antiretroviral therapy (cART). We characterized a cohort of chronically infected and virologically suppressed (VL < 50 copies/ml) men (≥50 years old) living with HIV (MLWH) who were switched to integrase inhibitors (INSTI), and compared their body composition parameters and proinflammatory/endocrine profiles to age-matched MLWH on integrase inhibitor free (non-INSTI) regimens, taking into account neighborhood-level measures of socioeconomic status (SES). In addition, we used previously published HIV-seronegative men of the same age as controls. METHODS: We used dual energy X-ray absorptiometry to quantify body composition parameters, and measured plasma proinflammatory/endocrine markers in 56 MLWH. We compared body composition to a publicly available dataset of 450 HIV-seronegative men of similar age. Within the MLWH group, body composition and plasma proinflammatory/endocrine markers were compared between individuals on INSTI and non-INSTI regimens, accounting for SES. RESULTS: Men living with HIV tended to have a greater android/gynoid ratio compared to HIV-seronegative men ( < 0.001). INSTI usage in MLWH was associated with lower adiposity measures when compared to non-INSTI, although these differences largely disappeared after controlling for SES. Proinflammatory/endocrine markers were similar for INSTI and non-INSTI MLWH. CONCLUSIONS: Among cART-experienced MLWH, those receiving INSTI-containing regimens had modestly lower adiposity compared to non-INSTI MLWH, although these differences were explained by SES.
Gane E, Yuen MF, Kakuda TN
… +13 more, Ogawa T, Takahashi Y, Goeyvaerts N, Lonjon-Domanec I, Vaughan T, Schluep T, Hamilton J, Njumbe Ediage E, Hillewaert V, Snoeys J, Lenz O, Talloen W, Biermer M
BACKGROUND: JNJ-73763989 comprises two hepatitis B virus (HBV)-specific, liver-targeted N-galactosamine-conjugated short interfering RNA triggers, JNJ-73763976 and JNJ-73763924. JNJ-73763989 pharmacokinetics, safety and...BACKGROUND: JNJ-73763989 comprises two hepatitis B virus (HBV)-specific, liver-targeted N-galactosamine-conjugated short interfering RNA triggers, JNJ-73763976 and JNJ-73763924. JNJ-73763989 pharmacokinetics, safety and tolerability were assessed in two phase 1 studies: Japanese (NCT04002752), and non-Japanese healthy participants and chronic hepatitis B (CHB) patients also receiving the HBV capsid assembly modulator JNJ-56136379 and a nucleos(t)ide analogue (NA) (NCT03365947). METHODS: Healthy participant cohorts were double-blind and randomized to receive a single subcutaneous JNJ-73763989 dose (non-Japanese participants, 35, 100, 200, 300 or 400 mg; Japanese participants, 25, 100 or 200 mg) or placebo. JNJ-73763976 and JNJ-73763924 plasma concentrations were assessed over 48 h. CHB patients received JNJ-73763989 200 mg every 4 weeks plus daily oral JNJ-56136379 250 mg and NA in an open-label fashion. Safety and tolerability were assessed through Day 28 (healthy participants) or Day 112 (patients). RESULTS: Thirty non-Japanese ( = 4/dose; placebo, = 10) and 24 Japanese healthy participants ( = 6/dose; placebo, = 6) were randomized. JNJ-73763976 and JNJ-73763924 exposure generally increased in a dose-proportional manner. Mean plasma half-life was 4-9 h. No differences between pharmacokinetic parameters were apparent between non-Japanese and Japanese healthy participants. In the 12 CHB patients, mean JNJ-73763976, JNJ-73763924 and JNJ-56136379 plasma concentrations 2 h post-dose on Day 29 were 663, 269 and 14,718 ng/mL, respectively. In both studies, all adverse events were mild/moderate. CONCLUSION: JNJ-73763976 and JNJ-73763924 had short plasma half-lives and exposure generally increased in a dose-proportional manner; there were no pharmacokinetic differences between Japanese and non-Japanese healthy adults. JNJ-73763989 with or without JNJ-56136379 and NA was generally safe and well tolerated.
Musengimana G, Tuyishime E, Kiromera A
… +13 more, Malamba SS, Mulindabigwi A, Habimana MR, Baribwira C, Ribakare M, Habimana SD, DeVos J, Mwesigwa RCN, Kayirangwa E, Semuhore JM, Rwibasira GN, Suthar AB, Remera E
Antivir Ther
· 2022 Jun · PMID 35593031
·
Full text
BACKGROUND: We assessed the prevalence of acquired HIV drug resistance (HIVDR) and associated factors among patients receiving first-line antiretroviral therapy (ART) in Rwanda. METHODS: This cross-sectional study includ...BACKGROUND: We assessed the prevalence of acquired HIV drug resistance (HIVDR) and associated factors among patients receiving first-line antiretroviral therapy (ART) in Rwanda. METHODS: This cross-sectional study included 702 patients receiving first-line ART for at least 6 months with last viral load (VL) results ≥1000 copies/mL. Blood plasma samples were subjected to VL testing; specimens with unsuppressed VL were genotyped to identify HIVDR-associated mutations. Data were analysed using STATA/SE. RESULTS: Median time on ART was 86.4 months (interquartile range [IQR], 44.8-130.2 months), and median CD4 count at ART initiation was 311 cells/mm (IQR, 197-484 cells/mm). Of 414 (68.2%) samples with unsuppressed VL, 378 (88.3%) were genotyped. HIVDR included 347 (90.4%) non-nucleoside reverse transcriptase inhibitor- (NNRTI), 291 (75.5%) nucleoside reverse transcriptase inhibitor- (NRTI) and 13 (3.5%) protease inhibitor (PI) resistance-associated mutations. The most common HIVDR mutations were K65R (22.7%), M184V (15.4%) and D67N (9.8%) for NRTIs and K103N (34.4%) and Y181C/I/V/YC (7%) for NNRTIs. Independent predictors of acquired HIVDR included current ART regimen of zidovudine + lamivudine + nevirapine (adjusted odds ratio [aOR], 3.333 [95% confidence interval (CI): 1.022-10.870]; p = 0.046) for NRTI resistance and current ART regimen of tenofovir + emtricitabine + nevirapine (aOR, 0.148 [95% CI: 0.028-0.779]; p = 0.025), zidovudine + lamivudine + efavirenz (aOR, 0.105 [95% CI: 0.016-0.693]; p = 0.020) and zidovudine + lamivudine + nevirapine (aOR, 0.259 [95% CI: 0.084-0.793]; p = 0.019) for NNRTI resistance. History of ever switching ART regimen was associated with NRTI resistance (aOR, 2.53 [95% CI: 1.198-5.356]; = 0.016) and NNRTI resistance (aOR, 3.23 [95% CI: 1.435-7.278], p = 0.005). CONCLUSION: The prevalence of acquired HIV drug resistance (HIVDR) was high among patient failing to re-suppress VL and was associated with current ART regimen and ever switching ART regimen. The findings of this study support the current WHO guidelines recommending that patients on an NNRTI-based regimen should be switched based on a single viral load test and suggests that national HIV VL monitoring of patients receiving ART has prevented long-term treatment failure that would result in the accumulation of TAMs and potential loss of efficacy of all NRTI used in second-line ART as the backbone in combination with either dolutegravir or boosted PIs.
Adefovir, a nucleotide analog developed by John Martin, was a major breakthrough in the treatment of chronic Hepatitis B. Prior to adefovir, Hepatitis B treatment was limited to two therapeutic modalities, either interfe...Adefovir, a nucleotide analog developed by John Martin, was a major breakthrough in the treatment of chronic Hepatitis B. Prior to adefovir, Hepatitis B treatment was limited to two therapeutic modalities, either interferon, which carried significant side effects and was efficacious in a minority of patients, or lamivudine which showed no durable effects with short-term use and a high rate of resistance with long-term use. Adefovir was found to be effective in suppressing viral replication and in resolving the hepatic inflammation associated with hepatitis B with only rare instances of resistance. In this article, we appreciate John Martin's contribution to science and medicine as we review the landmark trials of adefovir that brought forth a new era of treatment of Hepatitis B.
John Martin's untimely death in March 2021 was a huge loss for us personally, Gilead Sciences, the company he built over 30 years and the scientific community concerned with antiviral therapies. We wish to honor John's l...John Martin's untimely death in March 2021 was a huge loss for us personally, Gilead Sciences, the company he built over 30 years and the scientific community concerned with antiviral therapies. We wish to honor John's legacy by retelling the discovery and history of Tamiflu and his contributions to it. Without his vision, persistence, and keen eye for opportunities, Tamiflu would not exist and Gilead's path would not have been the same. His strategic thinking around the first oral flu drug is still quite relevant today, when we are still in the SARS-CoV-2 pandemic. John explained it simply in an interview with the Science History Institute in May 2020: "…".
Tools to eliminate Hepatitis B and C have been available and in 2016, the World Health Assembly endorsed the Global Health Sector Strategy for Viral Hepatitis. However, the adoption of hepatitis elimination programs has...Tools to eliminate Hepatitis B and C have been available and in 2016, the World Health Assembly endorsed the Global Health Sector Strategy for Viral Hepatitis. However, the adoption of hepatitis elimination programs has remained slow. The Center for Disease Analysis created a universal registry, the Polaris Observatory, to support informed decision-making at the national, regional, and global level for HCV and HBV elimination. The observatory covers 110 countries for HCV and 135 countries for HBV and provides decision analytics, disease burden modeling, economic impact assessments, and training to help countries with their national hepatitis elimination programs. By providing reliable and up-to-date country specific data and analyses, demonstrating the impact of decisions, and providing costing estimates of national programs, our collaborating countries are making informed decisions. Our economic impact analyses also helped countries fund their elimination programs and negotiate prices. Polaris Observatory is an example of impactful private-public partnership where funding by the John C. Martin Foundation allowed support for informed decision-making by public agencies and national governments who would not/could not support such programs on their own. The catalytic funding allowed the Polaris Observatory to demonstrate the utility of such a program resulting in other donors to support this work. The Polaris Observatory is now supported through a portfolio of funders while our work and outputs remain independent to continue support for viral hepatitis elimination by year 2030.
Tenofovir alafenamide fumarate is a lipophilic prodrug of tenofovir which is preferentially metabolized in lymphatic tissue resulting in high concentrations of tenofovir (TFV) and its active diphosphate metabolite inside...Tenofovir alafenamide fumarate is a lipophilic prodrug of tenofovir which is preferentially metabolized in lymphatic tissue resulting in high concentrations of tenofovir (TFV) and its active diphosphate metabolite inside the cells that replicate HIV. Due to its selectivity for these tissues, lower total doses of TAF can be administered relative to tenofovir disoproxil fumarate (TDF) which results in improved bone and renal biomarkers. Tenofovir alafenamide fumarate has become the "backbone" of multiple combination products for the treatment of HIV, combined with emtricitabine for PreP and as a monotherapy for the treatment or HBV.
Tenofovir-based pre-exposure prophylaxis (PrEP) revolutionized the global HIV prevention landscape. Prior to the proof-of concept trial in 2010, which demonstrated that tenofovir (TFV) could prevent sexual transmission o...Tenofovir-based pre-exposure prophylaxis (PrEP) revolutionized the global HIV prevention landscape. Prior to the proof-of concept trial in 2010, which demonstrated that tenofovir (TFV) could prevent sexual transmission of HIV, prevention options were largely limited to behavior change, condoms, and circumcision. Several subsequent studies evaluating oral tenofovir disoproxil fumarate (TDF) or the TDF/emtricitabine (FTC) combination as PrEP for HIV prevention provided evidence for regulatory approval and inclusion in national and international guidelines. By 2021, 1.5 million people had initiated oral tenofovir-based PrEP, contributing to declines in HIV incidence in some regions. Here we reflect on how oral tenofovir-based PrEP became an important component of combination HIV prevention programs across the globe.
BACKGROUND: Since immunoprophylaxis failure can occur if maternal serum hepatitis B virus (HBV) DNA levels are >200,000 IU/ml, tenofovir disoproxil fumarate (TDF) therapy has been investigated for preventing mother to ch...BACKGROUND: Since immunoprophylaxis failure can occur if maternal serum hepatitis B virus (HBV) DNA levels are >200,000 IU/ml, tenofovir disoproxil fumarate (TDF) therapy has been investigated for preventing mother to child transmission (PMTCT). METHODS: A literature search for maternal TDF therapy for PMTCT between 1/1/2015 and 7/1/21 on PUBMED, EMBASE, Cochrane, CNKI, and Wanfang databases was performed. Data from RCTs in English or Chinese were extracted and reviewed. The outcomes of interest included the efficacy and safety of TDF versus placebo for PMTCT. RESULTS: Among 11 RCTs identified from the databases, the risk-of-bias was low. All studies demonstrated that maternal TDF therapy initiated from the second or third trimester for highly viremic chronic hepatitis B mothers is highly effective and safe in the PMTCT of HBV, except one RCT performed in Thailand which showed no therapeutic advantage on TDF treatment versus placebo for PMTCT (0% vs 3% transmission). Recent emerging data suggest that maternal TDF therapy initiated at the 2nd or early 3rd trimester in mothers with HBV DNA >200,000 IU/ml achieved viremic control before delivery. In the 4-year long follow-up study for maternal TDF therapy, there were no impacts on infants' physical growth, psychological or mental development, and bone mineral density after fetal exposure to TDF. In the light of updated efficacy and safety data from RCTs, an algorithm was proposed. The approaches in resource-limit areas were discussed. CONCLUSIONS: TDF is safe for both mothers and infants as the preferred therapy for PMTCT in highly viremic mothers. TDF should be initiated at the second or early third trimester in the combination of the appropriate infants' immunoprophylaxis.