Featured Literature
Engel N, Dumond JB, Kashuba ADM, Cottrell ML. Optimizing On-Demand Tenofovir Disoproxil Fumarate/Emtricitabine Dosing in Women for HIV Prevention. J Inf Dis. 2025 Sept 11. Online first: https://doi.org/10.1093/infdis/jiaf459
Due to ongoing interest in exploring safe and effective on-demand pre-exposure prophylaxis (PrEP) dosing strategies for cisgender women, investigators used a previously published pharmacokinetic/pharmacodynamic (PK/PD) model to identify regimens that could achieve protective drug exposure in the female genital tract over five to 10 days post-sex. Protective thresholds were defined as any concentration profile achieving ≥90 percent of maximal protection (EC90). Tested regimens extended the 2-1-1 reference schedule across three to four days: three-day regimens included 2-2-1 and 2-2-2, while four-day regimens included 2-1-1-1, 2-2-1-1, 2-2-2-1, and 2-2-2-2. The proportion of predicted profiles achieving ≥EC90 at five, seven, and 10 days post-sex was calculated (these time points were selected based on the general belief that HIV propagates and disseminates to regional lymph nodes over a three- to six-day window following a transmission event, and that local dissemination occurs within about six days).
At five days, all regimens demonstrated >80 percent achievement of EC90. Extending to four days of dosing increased the proportion achieving EC90 to >80 percent at seven days. Investigators concluded that their model suggests prevention of HIV using on-demand TDF/FTC dosing is likely for female genital tract exposures, with >80 percent reaching EC90 for five days after sex. A fourth day of dosing is required to extend protection from five to seven days post-sex.
Commentary
These data, which were shared at CROI 2025, suggest that four-day, on-demand dosing strategies involving a “loading” double-dose of F/TDF may offer high levels of protection for female genital tract exposures. Although the selected model did not account for all conditions and potential variables of interest, these are highly compelling findings which warrant further clinical evaluation to confirm study observations, discern whether safety and tolerability differences might favor a particular dosing strategy, and advance our understanding of how to optimize PrEP options for cisgender women.
Featured Literature
Gilbert M, Ferré VM, Guilbaud R, et al. How should APOBEC3-induced resistance mutations be considered in the management of antiretroviral therapy? J Antimicrob Chemother. 2025 Sept 29:dkaf353. doi:10.1093/jac/dkaf353
This was a retrospective, single-center study examining virologic outcomes among people with hypermutated PBMC DNA sequences containing APOBEC3 induced resistance mutations (APOMuts). Three potential “at risk” regimen types were evaluated: three-drug combinations containing a 3TC or FTC-based NRTI backbone paired with an NNRTI (with at least one drug impacted by APOMut in the RT gene); two-drug combinations containing 3TC or FTC plus an INSTI (impacted by APOMut in either RT or INSTI); and two-drug combinations containing an NNRTI plus INSTI (impacted by APOMut in either RT or INSTI). PBMC DNA genotypes were ordered as part of routine clinical care, and the ANRS I MIE Resistance Study Group consensus Sanger protocol was used. People with a history of relevant mutations identified on plasma RNA genotyping were excluded.
Investigators identified 38 people who were receiving or were started on therapy that could potentially be impacted by the APOMut detected. The most prevalent APOMuts were M184I (n=21), M230I (n=11), and E138K (n=10). Virologic suppression < 50 copies/mL was maintained in 34/38 (90%) of individuals. For the four cases of virologic failure, investigators identified ART interruption or poor adherence: in one case, an emergent N155H was identified on plasma RNA genotype testing.
Commentary
Given ongoing uncertainty around the role and interpretation of HIV proviral DNA testing (particularly given concerns related to quality control and test reporting practices), studies such as these may be helpful when considering whether and how to implement such testing into routine clinical care. Although study size was limited, authors note their findings support the assessment that APOBEC3-mediated mutations do not actually compromise potentially impacted treatment regimens. Further, they emphasize the value of collaborative approaches (e.g., multidisciplinary team meetings) involving virologists and clinicians to ensure accurately informed interpretation and application of test results when considering ART modification.
Featured Literature
Ambrosioni J, Levi LI, Alagaratnam J, et al; The EACS Governing Board. Major revision version 13.0 of the European AIDS Clinical Society guidelines 2025. HIV Medicine. 2025 Oct 15. https://doi.org/10.1111/hiv.70120
European guidelines on HIV care were significantly updated, including a structural re-organization into two parts: prevention and management of HIV and related infections, and also prevention and management of co-morbidities and other relevant topics. For treatment naïve adults, preferred options remain: tenofovir (TXF) plus XTC with either dolutegravir or bictegravir or doravirine* (*review of baseline genotype is advised prior to using doravirine-based therapy to ensure no transmitted drug resistance); or XTC plus dolutegravir for people who are HBsAg-negative and have baseline viral load less than 500,000 copies/mL (this two-drug regimen is not recommended in cases of suspected oral PrEP failure).
Boosted darunavir-based three-drug combinations are still recommended for people who acquire HIV while on long-acting cabotegravir as pre-exposure prophylaxis (PrEP). For pregnant people with HIV, specifics on viral load monitoring frequency have now been added, based on pre-pregnancy viral load. Of note, dolutegravir is now included as a preferred first-line option in term newborns, based on results of the PETITE-DTG study. For people using oral PrEP who have an exposure where post-exposure prophylaxis (PEP) is indicated, the European panel advises taking two tablets of oral PrEP as soon as possible after the exposure, followed by one tablet daily until the initial medical evaluation occurs, to avoid delays in PEP initiation.
Commentary
These guidelines, recently released at the 20th European AIDS Conference, highlight an intentional shift towards inclusion of updated evidence and recommendations for the prevention and management of important comorbidities and coinfections affecting people with HIV. Similar to HHS guidelines, cardiovascular and metabolic health concerns are now increasingly emphasized, with new content on cardiovascular risk management and the importance of lifestyle and behavioral modifications.
Featured Literature
Orkin C, Kuritzkes DR, Katlama C, et al. Doravirine resistance patterns identified through Week 192 in the DRIVE-FORWARD and DRIVE-AHEAD Phase 3 clinical trials. JAIDS. 2025 Oct 23. doi:10.1097/QAI.0000000000003787.
This study describes resistance analyses conducted over four years in the DRIVE-FORWARD and DRIVE-AHEAD trials (which compared doravirine-based regimens to ritonavir-boosted darunavir- and efavirenz-based regimens, respectively, among participants without known baseline RT substitutions). Two groups were involved: (a) Initial Therapy participants (who remained on DOR for an additional 96-weeks in the open-label extension) and (2) Switch Therapy participants (who were initially randomized to the comparator regimen for 96-weeks then switched to DOR in the OLE). In the Initial Therapy group, 83 cases of PDVF were observed and 35 met criteria for resistance testing, which was successful in 34. In the Switch Therapy group, PDVF occurred in 26 participants between week 96 and week 192, and six met criteria for testing.
Of participants who discontinued treatment for reasons other than PDVF, 22 met criteria for testing, which was successful in 20. Overall, of the 60 participants with successful testing, treatment-emergent doravirine RAMs were detected in 16 (corresponding to 1.3% of the total 1249 participants): 12/747 (1.6%) in the Initial Therapy group and 4/502 (0.8%) in the Switch Therapy group. Most (13/16) had two or more doravirine RAMs, and specific mutations (listed in order of frequency) included: V106A/I/M/L, F227C/L/R, A98G, Y318F, H221Y, P225H, V108I, and Y188L. Emergent NRTI RAMs were detected in 16 (11 also had doravirine mutations), most commonly M184V/I, followed by A62V, V118I, and K65R.
Commentary
Following clinical trial participants out to four years, these results confirm that emergent resistance to doravirine is highly uncommon (both among people experiencing virologic failure on treatment but also among people who discontinue it for reasons other than virologic failure). Most cases were observed within the first year on doravirine, and development of additional NRTI resistance was also uncommon. Although emergent mutations observed in these trial participants were distinct from those associated with first-generation NNRTIs, in most cases participants were found to have more than one doravirine RAM, which may limit future treatment options.
