PI Perspective #37

January 2004     View PDF     En español

Third Line Anti-HIV Therapy Options

Third line therapy, sometimes called salvage or rescue therapy, is a term describing treatment regimens for people who have few or limited anti-HIV drug options. This includes people who have failed at least two previous anti-HIV regimens and/or people with evidence of HIV resistance to at least one drug in each of three major classes (NRTIs, NNRTIs and PIs, see the Drug ID chart on page 9 for more information on the drugs in each class). True salvage or deep salvage therapy is when a person has literally no viable treatment options. Treatment failure is a general term that encompasses a number of reasons that a regimen is deemed to be not working. The specific reasons for failure determines if or how the individual drugs in a regimen might be used again as part of a future combination.

Virologic failure
In general, a treatment regimen is considered to have failed virologically if:

• viral load does not drop by at least 90% within the first six months on a regimen, and
• viral load becomes and remains (on at least two consecutive tests) detectable again after being undetectable on a regimen.

Virologic failure and the development of drug resistance
When HIV that can reproduce in the presence of drugs emerges, the drugs can no longer block HIV as effectively. This is called drug resistance. Cross resistance is when the virus that can continue to produce in the presence of one drug is also capable of reproducing in the presence of other drugs. The development of drug resistance and cross resistance can severely limit effective anti-HIV drug options.

There are two different kinds of tests that can help determine whether virus has become resistant to anti-HIV drugs. Both require that you have a viral load of at least 1,000 in order to provide useful information. Both tests can fail to detect drug resistance, because drug resistant virus may not be present in the blood sample being tested. The two tests, one called a genotype and the other a phenotype test, are used to determine which drugs your virus has become resistant to, and possibly the degree of resistance. Resistance tests provide the most meaningful results when they are conducted while a person is taking anti-HIV therapy and the information is likely most relevant to the drugs they are taking at the time of the test. Your history of anti-HIV drug use and your experiences with previous regimens will be critical to consider when choosing the “best” drugs to combine for your next regimen.

Expert guidance
When constructing a new regimen it is helpful to have expert guidance. In general, people who see an HIV-experienced doctor are less likely to experience HIV disease progression than people who see doctors with less experience treating HIV. It may be especially important to have experienced help in therapy choices and monitoring when making complex third line therapy decisions.

Not everyone has access to highly experienced doctors. In such cases a regional AIDS Education and Training Center (AETC) site may be able to provide expert consultation to your doctor. You may reach these centers on the internet at www.aids-ed.org or by having your doctor call 800-933-3413. The AETC Consultation Warm line is available only to doctors and other healthcare providers and does not give out treatment information directly to people living with HIV. Lastly, the online American Academy of HIV Medicine (www.aahivm.org) can guide doctors and patients to other doctors who have been certified as HIV specialists.

Constructing your next anti-HIV therapy regimen
The most ideal regimen contains at least two potent drugs for which you carry no drug-resistant virus, preferably drugs you’ve never used before. Numerous studies show that people who start a combination containing at least two new drugs will have a much greater degree and duration of viral suppression than people who start only one new drug.

For some people, the recently approved drugs, tenofovir, atazanavir and enfuvirtide, will be enough to construct a regimen containing two new drugs. For others, the advent of new drugs will only offer one viable drug. They will be dependent on expanded access programs or studies to access other new drugs. Activists are working with the pharmaceutical companies to increase the number of third line therapy studies and to enable people to use more than one expanded access program at a time to develop a more effective regimens. There are several new options that may be available through expanded access programs or studies. These include the following.

• Tipranavir is a protease inhibitor in large studies. It is taken twice daily boosted by small doses of ritonavir, and may have activity against virus that is resistant to other protease inhibitors.
• Fosamprenavir (GW-433908) is a new version of the approved protease inhibitor, amprenavir, and should be approved by the end of 2003. It is expected to have similar side effects and degree of cross resistance to other protease inhibitors as amprenavir.
• T1249 is a fusion inhibitor similar to enfuvirtide (T20). It is in large studies and has activity against virus resistant to enfuvirtide.
• Elvucitabine (ACH-126,443) is an NRTI nearing larger phases of study. It has activity against virus that carries the M184V mutation, which is a hallmark of 3TC and FTC resistance.

Therapy options after multiple treatment failures
It is possible to find successful therapy options even when a person cannot construct a new regimen that will contain two new drugs. The success of these strategies may not be equal to that of a completely new regimen, but they have produced favorable results in at least some people in studies reported to date. These strategies often require expert guidance and monitoring and may come with additional risks of side effects and disease progression. They include:

• staying on a regimen when it has failed virologically, but CD4+ cell counts are stable;
• interrupting therapy before starting a new regimen; and,
• constructing a new regimen, with expert guidance, that includes five or more drugs (sometimes called MegaHAART or GigaHAART).

Sticking with a “failing” regimen
When the virus changes and becomes resistant to some anti-HIV therapies, it sometimes reproduces less well. This has been shown to be particularly true with protease inhibitors, and with some NRTIs that cause the virus to develop what is called the M184V mutation. Some researchers refer to these changes in virus as a reduction in viral fitness or replication capacity. Reducing the ability of virus to replicate in people whose CD4+ counts remain high and stable may allow them to stay on regimens, with some degree of continued benefit, as they wait for new treatment options to become available.

One potential risk of remaining on therapy is the development of virus that carries multiple mutations conferring increasing resistance. This can further decrease the chance that other drugs will work. Also, several studies in treatment-experienced people have shown that allowing viral load to climb above 100,000 may lower the chance that the next regimen will work as well. Therefore, although the practice of remaining on a virologically failing regimen is becoming more common in third line therapy situations, it is far from ideal. Nevertheless, this strategy may be useful for some people awaiting new treatment options.

Interrupting therapy
Increasing benefits of previously used medications by interrupting therapy for a period of time before making a switch to a new (or recycled) regimen is under study. It is hoped that drug-resistant virus will fade into the background during the time when a person is not on treatment, allowing wild-type virus that is sensitive to the drugs to take over, giving people a more powerful and beneficial response to the new regimen.

The studies in this area are mixed, with one study showing a benefit to interrupting treatment before starting a next regimen and others showing no benefit. In each study, those interrupting therapy had a significant increase in viral load and a steep drop in CD4+ cell counts during the interruption. The main danger of treatment interruptions in third line settings is the risk for disease progression. In all studies conducted, people who attempt treatment interruptions typically lose at least 50% of their CD4+ cell count. For more information on treatment interruptions, see the article: What are STIs and What are the Goals of STIs?.

Treating with five or more drugs
A number of studies have looked at the potential benefits of multiple drug combinations following treatment failure. Although one study did look at a combination containing two NNRTIs (efavirenz and nevirapine), the majority include using at least two and possibly three protease inhibitors along with NRTI drugs. Up to four NRTIs are sometimes used. The challenges of such a strategy are obvious. The more drugs used the higher the risk for side effects and the greater the impact on quality of life. Thus far, such strategies have achieved only modest benefits in most cases.

Discussion
The first step in developing a third line therapy strategy is understanding the reasons why your current treatment regimen is no longer working and why other previous regimens have been deemed failures. This provides clarity on what options truly are available. Resistance testing is warranted to guide treatment decision-making.

Ideally, with the use of resistance testing, expert guidance and newly available treatments, a regimen that contains at least two drugs that are active against HIV is feasible. When this is not possible, expanded access programs and studies may offer alternatives. Some people may continue to receive health benefits from their current regimens even when viral load is increasing. Therefore, those who can safely wait for new drugs to become available in order to build a regimen with two active drugs may wish to do so. However, waiting until viral load climbs to 100,000 or higher, may cause future regimens to work less well.

There continue to be glimmers of hope in the data on third line therapy studies and Project Inform will continue to push for the needs of treatment-experienced people.

Adherence One factor that can lead to the development of resistance is adherence. Several studies show that people are far more likely to achieve and maintain undetectable viral loads when they are able to take more than 95% of their doses as prescribed. Identifying the reasons that adherence has been challenging and doing something about it is important. The Project Inform publication, Adherence: Keeping up with Your Meds, has helpful tips for identifying and overcoming adherence challenges. Even when adherence is nearly perfect, however, virologic failure can occur. A recent study found that drug resistant-virus could be found even in people who were adherent most of the time.

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