Strategies for third line HIV therapy

May 2008     View PDF     En español

Therapy options after several failures

It’s possible to find a successful regimen even when you can’t construct a new one with two new drugs. The success of these strategies may not equal that of a completely new regimen, but they have produced favorable results in at least some people in studies to date. These strategies often need expert guidance and monitoring. They may also come with other risks of side effects and disease progression.

Staying on your “failing” regimen, with stable CD4s
Sometimes, when HIV changes and becomes resistant to some drugs, it may not reproduce as well. This is particularly true with protease inhibitors and some NRTIs — Emtriva (emtricitabine/FTC) and Epivir (lamivudine/3TC) — that cause HIV to develop the M184V mutation.

When HIV doesn’t reproduce as well on its own, for example with the M184V mutation, this is called a reduction in its viral fitness or replication capacity. So, when HIV has poorer viral fitness in people whose CD4 counts remain high and stable, it may allow them to stay on their “failing” regimens, with some benefit, as they wait for new treatments to become available.

A major risk when staying on a failing therapy is having HIV that
develops several mutations, which increases your chance for both resist­ance and cross resistance. Another risk is that as HIV levels climb above 100,000 in treatment experienced people, it may lower their chances that their next regimens will work as well. Although staying on a failing regimen is far from ideal, it may be useful for some people awaiting new drugs.

Interrupting therapy before starting a new regimen
Some studies have used a structured treatment interruption (STI) before switching to a new or recycled regimen. It was hoped that drug-resistant virus would fade into the background during the interruption. In theory, this would allow wild-type HIV (virus that’s sensitive to the HIV drugs) to take over, giving people a more beneficial response to the new regimen.

The results from these studies are mixed. One shows some benefit to taking an STI before starting a new regimen while others show none. In each, those who interrupted therapy had significant increases in their HIV levels and steep drops in their CD4 counts. The main danger of using STIs in third line therapy is the risk for serious disease progression. In all studies, people who tried STIs typically lost at least half of their CD4 counts. People who have low CD4 counts at any time are at the greatest risk from STIs.

There’s a growing body of evidence suggesting that STIs are risky. By far the most important study in this regard was the SMART study, which compared continuous HIV treatment to intermittent treatment guided by CD4 counts in about 6,000 people worldwide. As reported here, SMART was stopped early when higher rates of illness and death were seen among people in the intermittent group. Other studies, including PART, DART and TRIVICAN have found similar risks for STIs. For more information, read Project Inform’s publication, Structured Treatment Interruptions.

Creating a new regimen, with expert guidance,
with five or more drugs
Several studies have looked at the possible benefits of using multiple drug combinations after treatment failure. This is sometimes called megaHAART or gigaHAART. Although one study looked at a regimen with two NNRTIs (Sustiva and Viramune), most of them included using two and possibly three protease inhibitors along with NRTIs. Up to four NRTIs were sometimes used. The challenges of such a strategy are obvious. The more drugs a person uses, the higher their risk for side effects and the greater the possible impact on their quality of life.

At best, these strategies have provided only modest benefits in most cases and often increase side effects and greatly complicate managing drug interactions. The trend now is to try and reduce the number of drugs a person is on, when that can be done safely. In fact, the Federal Guidelines just added language on how and when to safely reduce the number of drugs a treatment experienced person is taking.

Creating your next regimen

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Blood levels of drugs