HIV in adults - Emerging treatments

Cabotegravir and rilpivirine

Cabotegravir is a novel integrase strand transfer inhibitor (INSTI), and rilpivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI). Extended-release injectable formulations of cabotegravir and rilpivirine are available and used together, and are the first long-acting injectable drugs to be approved for HIV. Cabotegravir and rilpivirine are approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). The US Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents with HIV recommends that cabotegravir and rilpivirine injection can be used as an optimisation strategy in people with HIV with sustained viral suppression for 3-6 months (optimal duration is not defined), who have good adherence and engagement in care, no baseline resistance to either drug, no prior virological failures; who do not have active or occult hepatitis B infection (unless the patient also is receiving an hepatitis B-active regimen); who are not pregnant or planning on becoming pregnant; and who are not receiving drugs with significant drug interactions with oral or injectable cabotegravir and rilpivirine. The panel recommends the use of cabotegravir and rilpivirine on a case-by-case basis in select individuals with persistent virological failure despite intensive adherence support on oral antiretroviral therapy (ART), provided there is no evidence of resistance to either drug.[78] The UK National Institute for Health and Care Excellence recommends cabotegravir and rilpivirine for the treatment of HIV in adults with virological suppression (HIV‑1 RNA <50 copies/mL) who are on stable ART, provided that they do not have any evidence of viral resistance to, and no previous virological failure with, any non-nucleoside reverse transcriptase inhibitors or integrase inhibitors.[145] Two randomised, open-label, multicentre, multinational phase 3 trials found that monthly administration of cabotegravir and rilpivirine were non-inferior to patients’ current ART for maintaining HIV suppression. Non-inferiority criteria at week 48 were met for the primary (HIV RNA ≥50 copies/mL) and key secondary (HIV RNA <50 copies/mL) efficacy endpoints.[146] Cabotegravir and rilpivirine may be initiated with oral cabotegravir and oral rilpivirine formulations for approximately one month prior to starting the intramuscular injections to assess tolerability, or the patient may proceed directly to starting injections without oral lead-in therapy. The injections are given every month or every 2 months. The most common adverse reactions include injection-site reactions, fever, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash.

Ibalizumab

Ibalizumab, an intravenous humanised monoclonal antibody fusion inhibitor that binds CD4, has been approved by the FDA and the EMA for adults who are heavily treatment-experienced and who cannot be successfully treated with other currently available therapies (e.g., multi-drug resistant HIV).[147] In a phase III trial, 43% of patients achieved HIV RNA suppression after 25 weeks of treatment (in combination with other antiretroviral drugs).[148] Patients with ongoing detectable viremia who lack sufficient treatment options to construct a fully suppressive regimen may be candidates for this drug.[78]

Lenacapavir

Lenacapavir, a first-in-class capsid inhibitor that is available as a long-acting injectable formulation and an oral formulation, has been approved by the FDA and EMA for the treatment of adults with HIV who cannot be treated successfully with other available treatments (e.g., intolerance, resistance, safety considerations). It is given in combination with other antiretrovirals. Safety and efficacy have been established through a randomised clinical trial with 72 participants.[149] Phase 2/3 trials are ongoing.[150][151] In one of these trials, lenacapavir (in combination with an optimised background regimen) resulted in a high rate of virological suppression for up to 52 weeks in patients with multidrug-resistant HIV.[151] Lenacapavir is also being studied for pre-exposure prophylaxis.[51][152] Lenacapavir may be recommended as part of an ART regimen in patients with virological failure.[78]

Fostemsavir

Fostemsavir, a first-in-class attachment inhibitor, works by binding directly to the glycoprotein 120 (gp120) subunit on the surface of the virus. It is approved by the FDA for the treatment of HIV in heavily treatment-experienced adults with multidrug-resistant HIV failing their current ART regimen due to resistance, intolerance, or safety considerations. In Europe, it is approved by the EMA for use in combination with other antiretrovirals for the treatment of adults with multidrug resistant HIV for whom it is otherwise not possible to construct a suppressive antiviral regimen. A phase 3, multicentre, cohort trial across 22 countries found that fostemsavir-based ART were generally well tolerated and increased virological and immunologic response rates through 96 weeks in heavily treatment-experienced patients with advanced HIV-1 and limited treatment options.[153] Fostemsavir may be recommended as part of an ART regimen in patients with virological failure.[78]

Maraviroc

Maraviroc, a CCR5 receptor antagonist, is approved in the US and Europe for the treatment of HIV. Maraviroc may be recommended as part of an ART regimen in patients with CCR5-tropic HIV (i.e., people with no detectable CXCR4-using virus) and virological failure.[78] It it the only CCR5 receptor antagonist currently available.

Islatravir

Islatravir, an investigational, first-in-class nucleoside reverse transcriptase translocation inhibitor (NRTTI), is currently in development and undergoing clinical trials. A combination of daily islatravir with doravirine maintained viral suppression up to 48 weeks in one phase 3 study, and was non-inferior to other ART. However, decreases in CD4 count and total lymphocyte counts did not support further development of this combination.[154][155] A combination of weekly islatravir with lenacapavir has advanced to phase 3 trials and has the potential to become the first weekly oral HIV treatment.[156]

PRO 140

PRO 140 (a humanised form of the PA14 antibody) is an investigational monoclonal antibody targeted against the C-C chemokine receptor type 5 (CCR5) receptor on T-lymphocytes that has shown significant antiviral activity in three small trials, but is still considered an investigational drug.[157]

Gene therapies

AGT103-T is an investigational single-dose, lentiviral vector-based gene therapy which is in development for the elimination of HIV. AGT103-T is made from blood cells using a process that increases the HIV-fighting ability of T-cells, and uses a gene therapy to help these cells survive in the body. The therapy is in phase 1 trials.[158]

NK cell-based therapies

NK cell-based immunotherapy aims to restore, boost, and modify NK cell activity. Various investigational therapies are currently undergoing clinical trials.[159]