Long-term safety and impact of immune recovery in heavily treatment-experienced adults receiving fostemsavir for up to 5 years in the phase 3 BRIGHTE study.

Introduction: Fostemsavir is a gp120-directed attachment inhibitor approved for heavily treatment-experienced (HTE) adults with multidrug-resistant HIV-1. We provide detailed week 240 safety results from the BRIGHTE study and evaluate the impact of immune recovery on safety outcomes. Methods: The phase 3 BRIGHTE trial is ongoing; data for this analysis were collected from the first participant's first visit (February 23, 2015) through the last participant's last visit for week 240 (March 22, 2021). Safety endpoints were assessed in participants who received fostemsavir + optimized background therapy. In participants with baseline CD4+ T-cell count <200 cells/mm3, exposure-adjusted adverse event (AE) rates were assessed among subgroups with or without CD4+ T-cell count ≥200 cells/mm3 at any time during 48-week analysis periods through week 192. Results: Through a median of 258 weeks (range, 0.14-319) of treatment, discontinuations due to AEs occurred in 30/371 (8%) participants. Serious AEs were reported in 177/371 (48%) participants, including 16 drug-related events in 13 (4%) participants. Thirty-five (9%) deaths occurred, primarily related to AIDS or acute infections. COVID-19-related events occurred in 25 (7%) participants; all resolved without sequelae. Among participants with baseline CD4+ T-cell count <200 cells/mm3, 122/162 (75%) achieved CD4+ T-cell count ≥200 cells/mm3 at week 192. Exposure-adjusted AE rates were markedly lower among participants achieving CD4+ T-cell count ≥200 cells/mm3 at any time vs those sustaining <200 cells/mm3. No new AIDS-defining events were reported after week 48 in participants with CD4+ T-cell count ≥200 cells/mm3. Conclusions: Cumulative safety findings through the BRIGHTE 240-week interim analysis are consistent with other trials in HTE participants with advanced HIV-1 and comorbid disease. Reduced rates of AIDS-defining events and AEs were observed in participants with immunologic recovery on fostemsavir-based treatment. Clinical trial number: NCT02362503, https://clinicaltrials.gov/study/NCT02362503.

Pregnancy Management in HIV Viral Controllers: Twenty Years of Experience.

(1) Background: The evidence base for the management of spontaneous viral controllers in pregnancy is lacking. We describe the management outcomes of pregnancies in a series of UK women with spontaneous HIV viral control (<100 copies/mL 2 occasions before or after pregnancy off ART). (2) Methods: A multi-centre, retrospective case series (1999-2021) comparing pre- and post-2012 when guidelines departed from zidovudine-monotherapy (ZDVm) as a first-line option. Demographic, virologic, obstetric and neonatal information were anonymised, collated and analysed in SPSS. (3) Results: A total of 49 live births were recorded in 29 women, 35 pre-2012 and 14 post. HIV infection was more commonly diagnosed in first reported pregnancy pre-2012 (15/35) compared to post (2/14), p = 0.10. Pre-2012 pregnancies were predominantly managed with ZDVm (28/35) with pre-labour caesarean section (PLCS) (24/35). Post-2012 4/14 received ZDVm and 10/14 triple ART, p = 0.002. Post-2012 mode of delivery was varied (5 vaginal, 6 PLCS and 3 emergency CS). No intrapartum ZDV infusions were given post-2012 compared to 11/35 deliveries pre-2012. During pregnancy, HIV was detected (> 50 copies/mL) in 14/49 pregnancies (29%) (median 92, range 51-6084). Neonatal ZDV post-exposure prophylaxis was recorded for 45/49 infants. No transmissions were reported. (4) Conclusion: UK practice has been influenced by the change in guidelines, but this has had little impact on CS rates.

Fostemsavir and ethinyl estradiol drug interaction: Clinical recommendations for co-administration.

OBJECTIVES: Fostemsavir, a prodrug of temsavir, is indicated for heavily treatment-experienced adults with multidrug-resistant HIV-1 infection, antiretroviral (ARV) intolerance, or safety considerations. Understanding drug-drug interactions (DDIs) is important in individuals taking fostemsavir with hormonal contraceptives or menopausal or gender-affirming hormonal therapies. METHODS: Effect of temsavir (active moiety) on the pharmacokinetics of ethinyl estradiol (EE) and norethindrone (NET) was evaluated in an open-label, single-sequence, four-cycle, four-treatment study in 26 healthy female participants (study 206279, NCT02480881). Relevant ARV-contraceptive interaction studies and guideline recommendations were reviewed; that information was then applied to other contraceptive methods and hormone-based therapies to predict the impact of fostemsavir co-administration. RESULTS: Temsavir increased EE concentrations by 40% and had no effect on NET concentrations. Fostemsavir co-administration with hormone therapy is not expected to impact hormone treatment efficacy. Fostemsavir did not impact progestin; therefore, progestin-only and non-hormonal contraceptives will not be impacted by fostemsavir. Recommendations for co-administration of fostemsavir and hormonal contraceptives or menopausal or gender-affirming hormone therapies are based upon known and predicted DDIs, ensuring adequate hormonal concentrations to maintain the target effect. CONCLUSIONS: Applying the results of Study 206279 and other relevant ARV-contraceptive studies, we recommend that when co-administering fostemsavir with combined oral contraceptives (COCs) and other oestrogen-based therapies, EE dose should not exceed 30 µg or equivalent, and caution is advised in the case of individuals with risk factors for thromboembolic events. Other oestrogen-based therapies may be co-administered with fostemsavir, with monitoring of oestrogen concentrations and appropriate dose adjustments. No impact of fostemsavir on COC efficacy is expected.

An observational study of initial HIV RNA decay following initiation of combination antiretroviral treatment during pregnancy.

BACKGROUND: In pregnancy, reduction of HIV plasma viral load (pVL) for the prevention of vertical transmission is time-constrained. The study primary objective is to investigate factors associated with faster initial HIV RNA half-life decay when combination antiretroviral treatment (cART) is initiated in pregnancy. METHODS: This was a multicentre, retrospective, observational study, conducted in south England, United Kingdom, between August 2001 and February 2018. Data were extracted from case notes of eligible women initiating cART during the index pregnancy. Anonymised data were collated and analysed centrally. Regression analyses were conducted to determine factors associated with faster HIV RNA half-life decay in the first 14 days after commencing cART (first-phase), and with achieving an undetectable maternal pVL by 36 weeks' gestation. We then assessed whether HIV- and obstetric- related parameters differed by antiretroviral third agent class and whether the proportions of women with undetectable pVL at 36 weeks' gestation and at delivery differed by antiretroviral third agent class. RESULTS: Baseline pVL was the only independent factor associated with faster first-phase HIV RNA half-life decay on commencing cART. Lower pVL on day 14 after starting cART was associated with an increased likelihood of achieving an undetectable pVL by 36 weeks' gestation. Integrase inhibitor-based cART was associated with a faster first-phase HIV RNA half-life decay on commencing cART. Overall, 73% and 85% of women had an undetectable pVL at 36 weeks' gestation and at delivery respectively, with no significant difference by antiretroviral third agent class. CONCLUSIONS: Only high baseline pVL independently contributed to a faster rate of first-phase viral half-life decay. pVL at 14 days after initiating cART allows early identification of treatment failure. In the first 14 days after initiating cART in pregnancy, integrase inhibitor-based cART reduced maternal pVL faster than protease inhibitor- and non-nucleoside reverse transcriptase-based cART. While our study findings support INSTI use when initiated in pregnancy especially when initiated at later gestations and in those with higher baseline pVL, other non-INSTI based cART with more data on safety in pregnancy also performed well.

Antenatal atazanavir: a retrospective analysis of pregnancies exposed to atazanavir.

INTRODUCTION: There are few data regarding the tolerability, safety, or efficacy of antenatal atazanavir. We report our clinical experience of atazanavir use in pregnancy. METHODS: A retrospective medical records review of atazanavir-exposed pregnancies in 12 London centres between 2004 and 2010. RESULTS: There were 145 pregnancies in 135 women: 89 conceived whilst taking atazanavir-based combination antiretroviral therapy (cART), "preconception" atazanavir exposure; 27 started atazanavir-based cART as "first-line" during the pregnancy; and 29 "switched" to an atazanavir-based regimen from another cART regimen during pregnancy. Gastrointestinal intolerance requiring atazanavir cessation occurred in five pregnancies. Self-limiting, new-onset transaminitis was most common in first-line use, occurring in 11.0%. Atazanavir was commenced in five switch pregnancies in the presence of transaminitis, two of which discontinued atazanavir with persistent transaminitis. HIV-VL < 50 copies/mL was achieved in 89.3% preconception, 56.5% first-line, and 72.0% switch exposures. Singleton preterm delivery (<37 weeks) occurred in 11.7% preconception, 9.1% first-line, and 7.7% switch exposures. Four infants required phototherapy. There was one mother-to-child transmission in a poorly adherent woman. CONCLUSIONS: These data suggest that atazanavir is well tolerated and can be safely prescribed as a component of combination antiretroviral therapy in pregnancy.