Light at the end of the tunnel grows brighter for persons with HIV
At the recent 4th National Aids Conference, Dr Charles Hicks, Senior Global Medical Director, ViiV Healthcare, US, spoke about the evolution of HIV care and how future advancements will impact the lives of persons living with HIV. Hicks, who is only recently joined ViiV Healthcare, said the cure for HIV is still likely far in the future. In the meantime, the only option is antiretroviral therapy (ART). However, despite the absence of a cure, the outlook for patients living with HIV has improved by leaps and bounds since the first antiretroviral zidovudine (AZT) was released.
The sky is much brighter now
Being one of the earliest healthcare professionals to become involved in the treatment of HIV, Hicks recalls seeing some of the earliest patients presenting with the illness in San Francisco circa 1981. These were patients with what appeared as rashes and fever plus other symptoms which were confounding physicians. Some of those patients turned out to have Kaposi’s sarcoma, which was extremely rare at that point in time. There was no antiretroviral therapy available at the time and Hicks said: “We could only offer you as management, the kinds of suggestions your mother might have given you—eat a healthy diet, get plenty of rest and exercise regularly.” Luckily, HIV treatment progressed relatively quickly, and by 1987 AZT was made available for persons with HIV. In the early days of treatment, the HIV clinic where Hicks worked with had weekly meetings to discuss the rare patients who managed to achieve undetectable viral load. “Nowadays, we have meetings to discuss patients who did not achieve undetectable viral load. That’s how far we’ve come.”
About 10 years after the introduction of AZT, dawned the age of highly active antiretroviral therapies (HAART) where the combination of certain ARTs resulted in effective virus control but being successful with the treatment was difficult in terms of adherence as it involved multiple pills taken at different times of the day. By 2006, the world began to see single-tablet, three drug regimens which were able to achieve virologic suppression with a one pill a day dosage.
We still need new pharmaceutical agents
Even though new regimens are effective and can bring a person with HIV to undetectable viral load levels, the search for newer and better alternatives is far from being over. Hicks revealed that 56 percent of new HIV-1 infections occur in people under 35 years of age and the estimated duration of expected life for persons who get infected with HIV at age 30 is around 75 years. This means many patients may be on ART for 40 years or more. The year 2020 will see more than 50 percent of US citizens living with HIV-1 surpassing the 50 year or older mark.
As people living with HIV get older, most will inevitably develop comorbidities. The treatment of these co-morbid conditions will likely require them to have to take more pills for these age-related conditions. These additional drugs may very well interact with existing HIV treatments. The tolerability of existing regimens could also be better as some patients are unable to tolerate the side effects of treatment. Hicks noted that kidney, liver and/or metabolic issues are still a concern with existing regimens. Certain regimens still require specific timing and multiple doses a day, which make adherence an issue. Resistance is also an issue affecting a percentage of patients. The issue of resistance is one that cannot be ignored. Last, but not least is the issue of cost. In countries such as Malaysia and other developing economies, cost is a big factor in determining the regimens used.
Current conventional wisdom states that HIV should be treated with a 3-drug treatment regimen, noted Hicks. One new 3-drug combination involving non-nucleoside reverse transcriptase inhibitors (NNRTI) is doravirine (DOR)+ two nucleoside reverse transcriptase. DOR’s efficacy and safety was established in the DRIVE-FORWARD trial, which was a multicenter, randomized, double blind phase III study. Participants were randomly assigned (at a 1:1 ratio) to receive oral DOR 100 mg or darunavir (DRV) 800 mg plus ritonavir (RTV) 100 mg once daily, with two investigator-selected NRTIs (tenofovir and emtricitabine or abacavir and lamivudine) for up to 96 weeks. It demonstrated the DOR arm’s noninferiority to standard therapy, but Hicks said the more important observation from the trial was the fact that the DOR arm was very well-tolerated. Hicks said: “It lacks the central nervous system side effects; it has good activity against resistant viruses including those with common NNRTI mutations; and it has very few metabolic interactions.” [Lancet 2018;5(5):PE2011-E220]
Another three-drug regimen is one involving darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF), recently approved in a once-daily single-tablet dosing regimen. The efficacy and safety of the darunavir-based single tablet regimen was established in the AMBER and EMERALD trials. “For AMBER, the rate of suppression at 48 weeks was 91.4 percent for single tablet regiment … while for the EMERALD trial, 94.9 percent patients on the (darunavir single tablet arm) achieved virologic success at 48 weeks. So, these are excellent data which led to the licensing of the single tablet regimen of darunavir/cobicistat.”
The last of the new three-drug regimens Hicks brought up was one involving the integrase inhibitor combination of bictegravir/emtricitbine/tenofovir alafenamide (B/FTC/TAF). In treatment naïve patients, the bictegravir-containing triple therapy proved to be noninferior compared with abacavir/dolutegravir/lamuvidine (ABC/DTG/3TC) and the dolutegravir/emtricitabine/tenofovir alafenamide (FTG/FTC/TAF) combination in clinical trials. [Lancet 2017; 390:2073-2082]
Hicks said the more recent idea that two-drug regimens could suffice was suggested by results of the ANDES trial, which was a randomized, open-label, phase IV study in Argentina, designed to compare dual therapy with DRV/RTV (800/100 mg) fixed dose combination, plus 3TC (300 mg), to standard triple therapy with DRV/RTV (800/100 mg) plus 3TC/TDF (300/300mg), fixed dose combination in treatment-naïve HIV-1 infected patients. ANDES established that the combination therapy of DRV/RTV plus 3TC was noninferior to standard triple therapy at 48 weeks in treatment naïve patients.
Hicks also alluded to the SWORD-1 and SWORD-2 studies, which pitted DTG/rilpivirine(RPV) against traditional triple therapy in a switch study format where HIV+ patients on suppressive 3-drug ART were randomized to continue their 3-drug regimens or to switch to the 2-drug combination of DTG/RPV. In addition to being very well-tolerated, the results of the SWORD-1 and SWORD-2 trials concluded that the dual therapy regimen was noninferior to standard triple therapy in maintaining HIV suppression in patients with stable HIV-1 virus load. [Lancet 2018;391(10123):839-849]
The GEMINI-1 and GEMINI-2 trials were also 2-drug therapy trials providing positive results on the use of DTG plus 3TC compared with a three-drug regimen of dolutegravir and two nucleoside reverse transcriptase inhibitors, TDF/FTC in treatment naïve HIV-1 infected adults with baseline viral loads less than 500,000 copies per mL. The studies achieved their primary endpoints of noninferiority based on plasma HIV-1 RNA<50 copies per mL at 48-weeks. Additionally, the safety profile of DTG/3TC were consistent with the product labeling for both the medicines, with no patient on either GEMINI studies developing treatment-emergent resistance. [doi.org/10.1016/S0140-6736(18)32462-0]
The newest approach to the use of 2-drug ART regimens involves long acting antiretrovirals, specifically long-acting injectable cabotegravir (CAB) plus long-acting injectable RPV. The two-drug proof of concept for these two drugs was provided by a study that used oral versions of the medications - the LATTE trial. The combination was then studied in injectable form in the LATTE-2 study, which arrived at the finding that the two-drug combination LA CAB plus LA RPV injected every 4 weeks or every 8 weeks was as effective as a daily triple oral therapy at maintaining HIV-1 viral suppression through 96 weeks. Importantly, this injectable is generally well-tolerated. As the long acting injectable regimen is new, Hicks said some concerns surround its use, eg, are emerging long-acting therapies as effective as oral therapies; how can resistance be prevented should patients miss doses; and can these agents be used as pre-exposure prophylaxis? These important questions will be valuable in determining the best approach to this new treatment strategy.
Things to look forward to
Hicks also touched briefly on upcoming drugs in the pipeline. The first is fostemsavir, which is a prodrug belonging to the gp120 attachment inhibitor group. It attaches to the gp120 protein on the outer surface of HIV, thus preventing the virus from attaching to CD4+ immune cells.
Next is ibalizumab, a humanized monoclonal antibody that binds to CD4 receptors. These receptors are primary receptors for HIV and ibalizumab functions as a post-attachment inhibitor, preventing HIV from entering CD4+ T-cells.
Lastly, Hicks introduced the GS-CA2 HIV capsid inhibitor, a novel molecule which inhibits multiple steps in the HIV capsid development cycle. The new molecule is highly active against major HIV-1 mutants and has no measurable cytotoxicity in target and non-target primary cells. While still in the very early development phase, GS-CA2 may prove to be more potent than currently available antiretrovirals.