Table 1.

Select cancer agents with potential utility in HIV cure approaches

Agent(s)/class	Target(s)	Primary indication (established or in development for, if applicable)	Possible reservoir targets	Key toxicities	Regulatory status or phase of development	Current and completed cure trials
HDAC inhibitors	Inhibit histone deactylase to induce HIV transcription		Latency reversal
Valproic acid		Anticonvulsant; mood stabilizer; migraine headache		Hepatotoxicity, pancreatitis, bleeding and other hematopoietic disorders, teratogenicity	FDA-approved as antiepileptic	Several clinical studies completed evaluating valproic acid in cure trials
Vorinostat		Cutaneous T-cell lymphoma (CTCL)		Myelosuppression, thrombosis, gastrointestinal toxicity, electrolyte abnormalities, hyperglycemia, teratogenicity	FDA-approved for CTCL	Several clinical studies completed evaluating vorinostat in cure trials. Phase I/II trial underway to evaluate the effect of a single dose compared with multiple dosing regimens of vorinostat
Romidepsin		Peripheral T-cell lymphoma (PTCL), CTCL		Myelosuppression, ECG changes, EBV/HBV reactivation, teratogenicity	FDA-approved for PTCL, CTCL	Two trials underway: A phase I/II trial currently underway to evaluate escalating single-dose romidepsin (ACTG 5315) and an open phase I/IIa study with romidepsin and vacc4x, an HIV vaccine
Panobinostat		Not yet FDA-approved		Fatigue, cutaneous toxicity, GI disturbances, sleeplessness	In clinical development for multiple myeloma treatment	Recent phase I/II trial completed to evaluate safety and effects on latency reactivation with multiple doses of panobinostat
Ipilumumab and tremelimumab	Immune checkpoint inhibitors by targeting CTLA4	Malignant melanoma, potential applications for other solid tumors	Reverse T-cell exhaustion, improved HIV- specific immune response	Immune-mediated adverse reactions, which can be severe: enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. Some delayed reactions occurred after therapy cessation	Ipilumumab FDA-approved for melanoma; tremelimumab in phase I/II trials	None current, but correlatives centered on cure objectives are planned in an AIDS Malignancy Consortium trial in solid tumors in people with HIV
Nivolumab, pembrolizumab, Lambrolizumab, BMS-936559	Immune checkpoint inhibitors by targeting PD-1 or PDL1	Malignant melanoma following ipilumumab; in development for multiple solid and hematologic tumors	Reverse T-cell exhaustion, improved HIV-specific immune response	Immune-mediated adverse reactions, which can be severe: colitis, pneumonitis, others	FDA-approved for nivolumab, pembrolizumab in metastatic melanoma	BMS 936559 planned for evaluation in ACTG 5326
Sirolimus temsirolimus, everolimus and ridaforolimus	Mammalian target of rapamycin (mTor)	Immune suppression following transplantation	Arrest activated T cells in G phase	Increased risk of lymphomas, skin cancers, infection	All but ridaforolimus FDA approved. Indications: immunosuppressant, tuberous sclerosis complex, renal cell carcinoma	Sirolimus under evaluation against cure endpoints in ACTG 5337
Immunomodulatory derivatives of thalidomide (IMIDs; thalidomide, lenalidomide, pomalidomide)	Multiple via cereblon, including T cell costimulation, cytokine modulation, cell microenvironment	Hematologic malignancies including myeloma and lymphoma, alone or in combination; Kaposi sarcoma	Immune stimulation to clear reservoir cells; stem cell disruption	Hematologic cytopenias Neurologic (neuropathy and sedation, less with newer agents) Gastrointestinal disturbance Teratogenicity	FDA-approved for multiple myeloma in combination regimens	None cure-centered; trials in HIV associated malignancies are ongoing in Kaposi sarcoma for lenalidomide (AIDS Malignancy Consortium) and pomalidomide (National Cancer Institute)
Ibrutinib	Bruton's Tyrosine kinase and interleukin-2-inducible T-cell kinase (ITK) inhibitor	Mantle cell lymphoma, chronic lymphocytic leukemia, other hematological malignancies	Promotes apoptosis	Thrombocytopenia, renal impairment, cutaneous toxicity	FDA-approved for chronic lymphocytic leukemia	Trials in HIV associated malignancies underway (phase I safety study, AIDS Malignancy Consortium)
Imatinib	Multi-tyrosine kinase inhibitor including PDGFR, cKIT	Chronic myeloid leukemia, gastrointestinal stromal cell tumors	Promotes apoptosis	Cytopenias, gastroinstestinal toxicity	FDA approved for CML and GIST	None current
Gamma secretase inhibitors (PF-03084014, others)	Enzymatic components of the notch signaling pathway	Metastatic solid tumors; Kaposi sarcoma	Inhibits angiogenesis; may target stem cell cycling and renewal	Gastrointestinal toxicity dose limiting, but full safety profile not yet defined	Phase I/II studies under way in advanced solid tumors including breast and pancreatic, and planned in Kaposi sarcoma	Trial in HIV-associated Kaposi sarcoma is planned (AIDS Malignancy Consortium)

CML chronic myelocytic leukemia; CTLA cytotoxic T-lymphocyte-associated protein; EBV Epstein-Barr virus; ECG electrocardiogram; GI gastrointestinal; GIST GI stromal tumor; HBV hepatitis B virus; PD programmed death; PDL PD ligand; PDGFR platelet-derived growth factor receptor