September 24, 2015

September 24, 2015
HIV Antiretroviral Therapy: Past, Present and Future

Welcome to another day in my life. Today is Thursday and I hope you are having a beary safe and great week so far. Dab the AIDS Bear is getting ready to head to Jacksonville, Florida for the First Coast AIDS Walk and the ADAP Advocacy Summit in Washington, DC.

Introduction to Antiretroviral Therapy

In the 1980s and early 1990s, a positive HIV test came with a grim prognosis. Yet in the last two decades, antiretroviral therapy has dramatically improved the health of HIV-positive individuals. Today, the life expectancy of HIV-positive people approaches that of the average population. In fact, for some North American patients, life expectancy exceeds the average.

As the medical community learned more about HIV, experts realized that a combination of different antiretrovirals was far more effective than a single drug. Today, most patients are treated with a cocktail of three drugs. The pharmaceutical industry successfully coformulated many of these drugs into combination pills, so patients no longer have to take dozens of pills per day.

There are now 15-million people on treatment around the world. Despite these gains, there is more to learn about the optimal combination of antiretroviral drugs, and guidelines are still evolving.

During a presentation at IAS 2015, Roy M. Gulick, M.D., presented a history of antiretroviral therapy, described the current treatment landscape and discussed new developments in the field.

The History of Antiretroviral Therapy

In 1995, there were only four approved HIV drugs, and the benefits of combination therapy had not yet been established. From 1995 to 1996, two very important studies demonstrated that a combination of two nucleoside polymerase inhibitors (nukes) was more effective than one alone. In addition, new classes of drugs called polymerase inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) were on the cusp of approval.

Gulick was involved in studies showing that three-drug combinations were superior to two-drug combinations, results that were unanticipated at the time, he said during his presentation. These developments marked the start of combination therapy, and the drug cocktail that became standard treatment.

Improving on the Formula

Although the new principle of combination therapy led to potent and durable responses, the combination therapy of the 1990s was not without its problems. The treatment was extremely cumbersome for patients, requiring dozens of pills, fasting and a rigorous consumption schedule. Patients also experienced severe side effects. During the 1990s, approximately 10% of patients discontinued treatment due to side effects, Gulick said.

As additional drugs were approved, additional combination strategies were tested, leading to even better efficacy but even more pills. Thankfully, pharmaceutical companies began to offer coformulations -- combinations of several drugs in one pill -- while maintaining safety and effectiveness. Today, there is a "holy grail" regimen consisting of one pill taken once per day. Safer, more convenient drugs make it more likely that patients will stay on treatment. Overall, rates of viral suppression improve when pills are easier to swallow.

Current Shifts in Treatment Guidelines

Today, there are 15-million people on treatment worldwide. With 28 approved drugs across five different drug classes, how can the medical community be sure that these patients are receiving the best possible care? Gulick said that the drugs available today are probably the best the medical community can do in terms of virological efficacy. Instead of focusing their energy on developing new drugs, experts such as Gulick are now trying to find the best possible combination of currently available drugs. The gold standard is still two nukes plus one additional agent, but recent studies have shed new light on certain combinations.

Clinical guidelines are changing because of this new data. For example, Spanish guidelines now recommend two nukes plus an integrase inhibitor (removing NNRTIs and PIs from first-line options). Similarly, draft British guidelines propose removing abacavir/lamivudine (Epzicom, Kivexa) and efavirenz (Sustiva, Stocrin) from first-line options. The U.S. Department of Health and Human Services, of which Gulick is a co-chair, has changed its guidelines to eliminate NNRTIs and atazanavir (Reyataz) as a first choice for patients.medical community be sure that these patients are receiving the best possible care? Gulick said that the drugs available today are probably the best the medical community can do in terms of virological efficacy.

The Future of Antiretroviral Therapy

Today, some of the most important HIV drug developments are not discoveries of new drugs, but strides toward reducing the dose and improving the safety of currently available drugs. For example, tenofovir alafenamide fumarate (TAF) is essentially a new-and-improved version of tenofovir disoproxil fumarate (TDF, Viread). The new drug combination is just as effective as TDF, but leads to fewer bone problems, and likely fewer kidney problems.

Nevertheless, there are a few new drugs in the pipeline that could add to available options. For example, cenicriviroc is an interesting antiretroviral that also reduces inflammation. Drugs called broadly neutralizing antibodies (bNAbs) are in early studies as possible HIV-prevention medications, and could also be used for treatment, Gulick said. These new drugs, if approved, could be used in combination and hopefully reduce the dose needed keep patients healthy.

Another important area of drug development is in resistant strains of HIV. Some patients can no longer take traditional drugs because of drug resistance. One NNRTI called doravine shows promise in the lab. Drugs with totally new mechanisms of action (CD4 attachment inhibitors and maturation inhibitors) are also being investigated to help these patients.

The Bottom Line

Current antiretroviral therapy promotes healthy survival among patients. Today, the biggest barriers to effective treatment are access and cost.

In some countries, treatment access is limited to patients with a certain CD4+ count, although the START supports early treatment for all patients. Cost is also dropping with the growing availability of generics. The combination efavirenz/lamivudine/tenofovir now costs $135 per year. It's unclear if prices will go down further than this, Gulick said.

Although pricing and access challenges exist, antiretroviral therapy has had a remarkable impact on survival and quality of life for HIV-infected people around the world. One of the best examples of this positive impact comes from a Danish HIV cohort.

Before widespread use of antiretrovirals (1995-1996), a 25-year-old Danish male with HIV could expect to live to the age of 30. In the so-called "early-HAART (highly active antiretroviral therapy) era" (1997-1999), he could expect to live to 50, and in the "late-HAART era" (2000-2005), he could expect to live to 65 (median survivals).

High Expectations for 2020

"We can now safely say life expectancy [with HIV] approaches or exceeds that of population controls," said Gulick. Many people expect that those living with HIV today have an even higher life expectancy because they are tied into the health care system, helping them prevent and manage other diseases, he added.

Tracking the history of antiretroviral therapy and predicting future developments give Gulick confidence that the 90/90/90 targets can be met. This would mean that by 2020, 90% of people living with HIV would know their status, 90% would be treated with antiretroviral therapy and 90% would have viral suppression below detectable levels.

Hope you have a beary safe and great Thursday!

Until we meet again; here's wishing you health, hope, happiness and just enough.

big bear hug,

Daddy Dab