SOLSTICE: Combination Therapy for the Treatment of Chronic Hepatitis D Infection.

Participants may be enrolled into Cohort 1 (1a and 1b) or Cohort 2 (2a, 2b1 or 2b2, 2c), 3, 4, and 5. All participants still receiving VIR-2218 or VIR-3434 monotherapy at the time of implementation of Protocol Amendment 4 will switch to combination therapy at Week 132 (Cohort 2a, 2b1/2b2) or Week 112 (Cohort 3).

• VIR-2218 (Drug), also known as Elebsiran: VIR-2218 given by subcutaneous injection
• VIR-3434 (Drug), also known as Tobevibart: VIR-3434 given by subcutaneous injection
• NRTI (Drug): NRTI given orally.

Primary outcomes

• Proportion of participants with undetectable HDV RNA (< limit of detection [LOD]) or ≥ 2 log10 decrease in HDV RNA from baseline and alanine aminotransferase (ALT) normalization (ALT < upper limit of normal [ULN]) at Week 24 [Up to 24 Weeks]
• Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) [Up to 360 Weeks]

Secondary outcomes

• Proportion of participants with undetectable HDV RNA (less than LOD) or greater than/equal to 2 log10 decrease in HDV RNA from baseline and ALT normalization at Week 12, Week 48, Week 72, Week 96, Week 144, Week 192, Week 240, Week 288, and Week 336. [Up to 336 Weeks]
• Proportion of participants with undetectable HDV RNA (less than LOD) or greater than/equal to 2 log10 decrease in HDV RNA from baseline at Week 12, Week 24, Week 48, Week 72, Week 96, Week 144, Week 192, Week 240, Week 288, and Week 336. [Up to 336 Weeks]
• Proportion of participants with undetectable HDV RNA (less than LOD) at Week 12, Week 24, Week 48, Week 72, Week 96, Week 144, Week 192, Week 240, Week 288, and Week 336. [Up to 336 Weeks]
• Proportion of participants with HDV RNA < lower limit of quantitation (LLOQ) at Week 12, Week 24, Week 48, Week 72, Week 96, Week 144, Week 192, Week 240, Week 288, and Week 336. [Up to 336 Weeks]
• Change from baseline in HDV RNA at Week 12, Week 24, Week 48, Week 72, Week 96, Week 144, Week 192, Week 240, Week 288, and Week 336. [Up to 336 Weeks]
• Proportion of participants with ALT normalization at Week 12, Week 24, Week 48, Week 72, Week 96, Week 144, Week 192, Week 240, Week 288, and Week 336. [Up to 336 Weeks]
• Incidence of anti-drug antibodies (ADA) and titers of ADA to VIR-3434 at specified study visits up to Week 336 (for cohorts with VIR3434) [Up to 336 Weeks]
• Change from baseline in liver fibrosis at Week 48, Week 96, Week 144, Week 192, Week 240, Week 288, and Week 336. [Up to 336 Weeks.]: Liver Fibrosis will be measured by conventional Transient Elastography imaging technique reported in kPa.
• Change from baseline in Model for End Stage Liver Disease (MELD) score at Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 96, Week 144, Week 192, Week 240, Week 288, and Week 336. [Up to 336 Weeks]: MELD score will be calculated using serum bilirubin, serum creatinine, and International Normalized Ratio.
• Change from baseline in Child-Pugh-Turcotte (CPT) score at Week 24, Week 48, Week 72, Week 96, Week 144, Week 192, Week 240, Week 288, and Week 336. [Up to 336 Weeks]

Sex: All, ages: 18 Years to 69 Years

Inclusion Criteria:

* Male or female ages 18 to < 70 years at screening
* Chronic HDV infection for >/= 6 months
* On NRTI therapy for at least 12 weeks prior to day 1
* ALT>ULN and < 5x ULN
* Non-cirrhotic and CPT-A cirrhotic

Exclusion Criteria:

* Any clinically significant chronic or acute medical or psychiatric condition that makes the participant unsuitable for participation.
* History of significant liver disease from non-HBV or non-HDV etiology
* History of allergic reactions, hypersensitivity, or intolerance to study drug, its metabolites, or excipients.
* History of anaphylaxis
* History of immune complex disease
* History of autoimmune disorder
* History or evidence of alcohol or drug abuse
* Prior or concomitant therapy with an immunomodulatory agent, IFN-alpha, cytotoxic or chemotherapeutic agent, or chronic corticosteroids.
* Anti-HBs >10 mIU/mL at screening

• Results publication: Noack J, Anglero-Rodriguez Y, Gall J, Zhou J, LeBlanc S, Liebow A, Bakardjiev A, Hebner CM, Purcell LA, Jadhav V, Corti D, Lempp FA. Combination therapy with tobevibart and elebsiran potently reduces hepatitis B virus surface antigen levels in preclinical in vivo models. Antimicrob Agents Chemother. 2026 Mar 4;70(3):e0112725. doi: 10.1128/aac.01127-25. Epub 2026 Jan 26. PMID 41586499
• Results publication: Asselah T, Chattergoon MA, Jucov A, Streinu-Cercel A, Lampertico P, Wedemeyer H, Kennedy PT, Gane EJ, Bullard BL, Chow S, Santos D, Camus G, Lu Y, Pilowa C, Hwang C, Correll T, Agarwal K; SOLSTICE Trial Investigators. A Phase 2 Trial of Tobevibart plus Elebsiran in Hepatitis D. N Engl J Med. 2026 Jan 22;394(4):343-353. doi: 10.1056/NEJMoa2508827. Epub 2025 Nov 9. PMID 41211943