The Road Ahead

Treatment Horizons

The Road Ahead
New candidates hold promise for ARV therapy & therapeutic vaccines
by Mariel Selbovitz, MPH

The 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2014) took place on September 5–9 in Washington, D.C. ICAAC has long been a premier conference for HIV research with investigators from around the globe presenting on numerous topics and disease.

The session “On the Road to a Cure” featured presentations on the role of HIV reservoirs in HIV pathogenesis, the prospect of therapeutic immunization and where we are with eradication strategies. ART can inhibit HIV replication, suppress HIV viral loads in plasma to undetectable levels, and prevent disease progression. Yet ART alone is not curative. HIV persists in cellular reservoirs in treated individuals allowing the virus to rapidly re-emerge if treatment is stopped. The inability of the immune system to recognize cells harboring latent virus and to eliminate cells actively producing virus is the biggest challenge to finding a cure. Low level viral replication in latently infected cells likely contributes to the chronic immune activation, inflammation and immune dysfunction that persist in HIV patients, even those who have achieved durable viral suppression. In recent years, major research efforts have been dedicated to understanding the pathogenesis of persistent HIV infection and to strategies aimed at eradicating HIV in patients on ART. Current thinking is that a cure will require a combination of antiretroviral drugs, vaccination to induce an immune response that kills any cell-producing virus, and drugs that induce latently infected virus to produce enough virus to trigger immune elimination. At AIDS 2014, HDAC inhibitors were shown to not be a viable component of a strategy to eradicate HIV.

Therapeutic vaccines are part of the cure agenda, and there are several in clinical development by small biotechnology companies. Profectus BioSciences is developing TheraVax, a pDNA therapeutic HIV vaccine, delivered with GeneVax IL-12 adjuvant in 5 Phase I clinical trials. Theravectys, a French biotechnology company, is developing THV01, a lentiviral-based therapeutic vaccine currently in Phase IIa clinical trials. Biosantech, another French biotechnology company, is developing Tat Oyi, a Tat-based therapeutic vaccine currently in Phase IIb clinical trials. The outcomes of these trials are pending.

“What’s New in Antiretroviral Therapy” featured a presentation on new antiretroviral drugs in the pipeline by Joe Eron and a presentation on whether the time has come for nuc-sparing regimens by Mark Boyd. Cabotegravir is a long-acting integrase inhibitor in Phase IIa development by GlaxoSmithKline. The drug has demonstrated good antiviral activity and has appeared safe and well-tolerated in clinical trials to date, both as a daily pill and as a long-acting injection that may be administered monthly or even quarterly. Monthly cabotegravir injections for PrEP have already been studied with promising results in monkeys.

BMS-986001 is an NRTI in Phase IIb development by Oncolys BioPharma. As current NRTIs are associated with toxicities, there is a need for new NRTIs that have improved long-term safety and tolerability, potent antiviral activity, and limited cross-resistance to existing NRTIs. BMS-986001 was specifically designed to better target viral transcription with minimal toxicities and adverse events. In combination with efavirenz and lamivudine, the drug was found to have comparable efficacy to tenofovir in treatment-naive patients. While the popularity of nuke-sparing regimens is increasing with the development of extremely effective integrase inhibitors, there is still a need for new and improved NRTIs, which remain the backbone of ART regimens. (See this month’s Destination: Cure for more about this candidate.)

Doravirine is a new NNRTI in development by Merck that showed potent antiretroviral activity and good tolerability in combination with Truvada in a dose-finding study. NNRTIs are generally well-tolerated and well-suited for first-line HIV treatment, but, as a class, they are susceptible to resistance. Pre-clinical studies showed that doravirine has a distinct resistance profile and remains active against HIV with common NNRTI-resistance mutations, including K103N and Y181C. Doravadine is metabolized by the CYP34A enzyme, but is neither an inducer nor an inhibitor and is not expected to have major drug interaction concerns.

HIV integrase inhibitors and CCR5 inhibitors are the two newest classes of antiretrovirals. Resistance pathways for these two classes are complex and vary by different drugs within the same class. Cross-resistance within each class also limits future treatment options, although drugs with higher genetic barrier to resistance are now available. When to order genotypic and phenotypic tests and how to interpret them for these drugs are critical for patient management.

In his presentation, “Nuc-Sparing Regimens: Time Has Finally Come?,” Mark Boyd presented a review of evidence in support of nucleoside-sparing regimens. While two studies have shown that nuc-sparing regimens are as effective as those containing nucleosides, there is significantly more evidence that regimens containing NRTIs are much more durable and effective than those without.

“Current Clinical Issues in HIV Disease Management: an IAS USA Interactive, Case-Based Session” was designed to address challenges relevant to the management of patients with HIV infection. Presenters provided challenging cases to a panel of experts including issues and discussions on antiretroviral treatment in chronic HIV infection, pharmalogical issues, and bombshells in HIV treatment.

Although there were few major headline stories regarding the science presented at ICAAC, the research this year out of ICAAC 2014, AIDS 2014 and CROI 2014 have brought us many advances in our knowledge of HIV pathogenesis, drug development, ARV use and HIV remission/eradication research. Each study performed and presented at these important conferences helps to propel us just a little bit closer to the end of HIV.

Mariel Selbovitz, MPH, serves as the Chair of the Cornell ACTG Community Advisory Board and has authored over thirty abstracts and articles.