SA01 MHRA Notice of non-acceptance and response 1. The exclusion criteria do not address all contraindications for both investigational medicinal products (IMPs). The protocol needs to be updated to exclude patients with any contraindication to either of the IMPs. The exclusion criterion has been revised to list all contraindications and the full list of contraindications have been added to the protocol as appendix 4 for reference. 2. The statement in Section 4.4.3 of the protocol that investigators who opt to discontinue study drugs for an individual subject should discuss with the Chief Investigator prior to study drug discontinuation is not acceptable and needs to be removed. The statement has been removed as requested. 3. The listed methods of contraception in Appendix 3 are acceptable for this protocol but are not highly effective methods with a failure rate of less than 1% per year as described in the Clinical Trial Facilitation Group document for clarification of effective contraception in clinical trials: http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/ CTFG/2014_09_HMA_CTFG_Contraception.pdf . Highly effective needs to be removed from the title of Appendix 3 and the first paragraph needs to describe acceptable methods rather than highly effective methods. In addition, the appendix titles and references should be corrected as Appendix 3 is described and referenced as “Sample collection, processing and shipping” in some sections of the protocol. ‘Highly effective methods…’ title revised to ‘Acceptable methods for avoiding pregnancy in females of child bearing potential’. Statement about failure rates less than 1% removed. Sample collection, processing and shipping references have been removed from the protocol and replaced with ‘refer to lab manual’. 4. Section 4.4.1 of the protocol lists pregnancy as one of the reasons an investigator may discontinue study treatment.

SA02 Changes have been proposed in the protocol specifically in the update of the most recent SmPCs available for both the treatment arms.

SA03 The primary reasons for this substantial amendment are as follows:• The section on safety information within the study protocol has been updated to bring it in line with the current approved SmPCs for the trial.• Extension to the planned recruitment and study end date (Last patient last visit) • Addition of a new PI• Modification to the PIS (Patient Information Sheet) to bring it in line with current approved SmPC for IMPs • Modification to the Informed Consent Form (ICF) to bring it in line with trial requirements• Supply chain verification of trial labelled stock • Specific risk assessment

SA04 An annual update to the current approved SmPCs for the trialSymtuza SmPC dated 20 October 2021 Biktarvy SmPC dated 24 February 2022• Change to the HIV viral load minimum detection from <20 copies to <50 copies in line with standard of care in the secondary endpoint section of the protocol.• Removal of the metabolomics laboratory details in the protocol.

SA05 Site missed updated PIS from previews amendment (SA04). Annual updates to SmPC documents, which includes additional Special warnings and precautions for use, leading to changes to PIS which were not submitted as part of the SA 04 submission. Updated PIS forms will be submitted as part of this amendment to be reviewed.