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Third Line Therapy Options

April 1999

In contrast to the numerous treatment strategy options now available to people who are just starting first or second line anti-HIV therapy, limited choices are available to people exploring "third line" therapy options. Third line therapy refers to any treatment regimen used after two initial rounds of therapy have proven unable to maintain HIV suppression. This could be due either to the failure of the drugs or a person's inability to tolerate the medications. So far there have been very few studies of third line therapy. Thus, there is more guesswork and less science guiding third line therapy decision-making.

Many people -- patients and physicians alike -- have resorted to a "let's try everything" approach, which some describe as "megaHAART" (mega Highly Active AntiRetroviral Therapy). Such regimens frequently employ six to nine drugs at once, most of which the patient has previously used. Even though the person is likely to be resistant to many if not all the drugs, the hope is that using so many drugs will somehow produce a significant effect. However, it is not known how long people can tolerate taking so many drugs, let alone how long they will work. Ideally, combinations of new therapies that have new mechanisms of attacking HIV are likely to be most successful.

T-20: A New Therapy for the Third Line

The only new therapy on the immediate horizon that has a new mechanism of slowing HIV replication is called T-20 (pentafuside), the first of a class of drugs known as fusion inhibitors. T-20 inhibits HIV by blocking the virus from fusing with an immune cell.

The drug was studied in a group of 78 people with an average viral load of 100,000 copies HIV RNA and an average CD4+ cell count of 100. Most importantly, study participants had previously used an average of nine different drugs. Most had used three or more currently available protease inhibitors and many had already used up all three classes of anti-HIV drugs. This was truly a difficult population in which to test a new drug -- a true examination of third line therapy.

"In this context, it is somewhat remarkable that T-20 worked at all, since almost any other known approach to therapy would likely have failed completely."

People received one of six different doses of T-20. Participants had been either off all anti-HIV medications for at least two weeks before starting T-20 or they could add T-20 to their existing regimen. Consequently, many people used T-20 as single drug therapy, something that would rarely if ever be done in people with such advanced disease. In this short-term study, those receiving the highest two doses, 50mg and 100mg twice daily by subcutaneous (subQ, under the skin) injections (total daily doses of 100mg and 200mg respectively) had the best anti-HIV responses. At the end of the 28-day study, people receiving the 50mg subQ twice daily dose had a viral load reduction of 0.6 logs (four-fold change) in HIV RNA while the 100mg subQ twice daily dose group had a 0.7 logs reduction (five-fold change). However, all but the people who received the very lowest dose still achieved some degree of anti-HIV activity.

While on the surface these results may not seem impressive, the majority of study participants had failed all available therapies and were taking T-20 alone. In this context, it is somewhat remarkable that the drug worked at all, since almost any other known therapy would likely have failed altogether. Further, these results showed that people who entered the study with lower HIV levels (below 100,000 copies HIV RNA) had better anti-HIV responses [0.8 and 1.4 log reductions in HIV RNA levels (6 and 25 fold) on the 50mg and 100mg subQ dose respectively]. People with pre-study HIV levels of over 100,000 copies HIV RNA had a 0.3 and 0.4 log reduction in HIV RNA levels (2 and 2.5 fold reduction) on the 50mg subQ dose and 100mg subQ dose respectively.

Most importantly, the drug appears to be active even in people who had developed resistance to all other currently available therapies. This is exactly the kind of response needed if we are to find a successful third line treatment. The results also suggest that, although T-20 is active against HIV in people who have developed resistance to the currently available drugs, it should be used in combination with other drugs, preferably ones that are new to the individual. As additional new drugs become available, it is likely that the potency of regimens containing T-20 may improve.

A significant drawback to T-20 is that the drug will never exist in pill form. Today, it requires simple, twice daily injections, similar to those that diabetics take. Some people may find this troublesome, but others, such as those who are tired of taking large handfuls of pills every day, may welcome the change in administration methods. Other means of administration are being explored.

"The most important aspect of this study is that T-20 appears to be active even in people who had developed resistance to all other currently available therapies."

At least two other fusion inhibitor drugs are under development. The manufacturer of T-20 is developing a second fusion inhibitor, reported to be many times more potent than T-20.

MegaHAART: Throwing Everything at the Problem

Another third line therapy study employed the megaHAART strategy. Fifty-two people, who were failing a protease inhibitor-containing regimen and had a viral load of over 100,000 copies HIV RNA and a CD4+ cell count of about 100, participated in this study. Almost no participants had previously used the non-nucleoside reverse transcriptase inhibitor (NNRTI) class of drugs. People had extraordinarily high HIV levels at study entry, with a median viral load of 560,000 copies HIV RNA.

Participants received between five and seven anti-HIV drug regimens including efavirenz, hydroxyurea (Hy-drea®), ddI (dida-nosine, Videx®), ritonavir (Norvir®), indinavir (Crixivan®) with or without other nucleoside analogue drugs, AZT (zidovudine, Retrovir®), d4T (stavudine, Zerit®), 3TC (lamivudine, Epivir®) or ddC (zalcitabine, Hivid®). After 24 weeks, there was a 1,000-fold reduction in viral load (3 logs) and an average increase in CD4+ cell count of 125. About 65% of the participants had viral loads below 400 copies of HIV RNA.

These results suggest that treatment can regain control of viral replication if two conditions are met: (1) the patient must be able to tolerate an extraordinary number of drugs (five to seven), and (2) the patient must not have previously used or developed resistance to the NNRTI class of drugs. It seems that first time use of an NNRTI drug is critical to achieving success after HIV begins to break through the defense of the protease inhibitors. This may become a problem for many, however, since some sources recommend that people utilize NNRTI drugs as first line therapy. If this is done, the NNRTI class of drugs will not be available to help later in third line therapy.

In another megaHAART study, 24 of 37 participants had tests performed to determine which drugs they were resistant to before they select a new regimen. Volunteers then received six or more anti-HIV drugs and were followed for about eight months. Of the 24 people who had the resistance tests performed and who used this information to construct a mega-HAART regimen, there was an average viral load decrease of about two logs (100-fold reduction) and about a 100 CD4+ cell count increase. At the end of study, ten people had viral load levels below 500 copies HIV RNA; eight had initial viral load responses below the 500 copies HIV RNA limit but then had increases; and six people were never able to get below 500 copies HIV RNA.

Not surprisingly, this study found that people who were not completely resistant to all of the drugs had better responses compared to people who were completely resistant. However, some people who were completely resistant did mount good anti-HIV responses.

One interesting aspect of this study was that some patients stopped all use of their anti-HIV therapies for two to three months prior to starting this study (called a washout period). Apparently these people regained some degree of sensitivity to drugs to which they had previously shown resistance and all mounted good anti-HIV responses. This apparent ability to regain sensitivity to previously used drugs was probably only partial and unlikely permanent. However, it did seem sufficient to permit at least an initial high level of viral suppression. Thus, it often pushed viral load below the limit of detection on the ultrasensi-tive tests (less than 50 copies). Once this level was reached, viral replication apparently slowed so much that levels stayed below the limit of detection for several months. This phenomenon needs to be tested further in larger studies. If confirmed, it suggests that using a period of drug washout might play a very important role in third line therapy in the future. For now, however, it is hard to draw any absolute conclusions since the study was relatively small.

While the results from these two megaHAART studies are encouraging, it is not known how long people can or will be willing to take a large number of pills. Additionally, when this many different medications are combined, there is an increasing likelihood of side effects. Certainly in the second study, using the results of resistance testing to guide treatment choices appeared useful. Only larger studies that compare different regimens will provide direction for optimal approaches to developing a third line strategy.

"Second Line" Therapy When Nelfinavir Fails

A small study looked at the activity of ritonavir + saquinavir + d4T + 3TC in people who were failing a nelfinavir-containing regimen. All 26 participants had a good initial anti-HIV response to nelfinavir followed by increases in HIV levels. Participants entering this study had taken nelfinavir for about a year and had a mean viral load of about 45,000 copies HIV RNA and a mean CD4+ cell count of 222. After 48 weeks on the four-drug regimen, 14 of 24 people had HIV levels below 500 copies HIV RNA and an average 120 CD4+ cell count increase. Two people discontinued the study because of diarrhea associated with nelfinavir. This study observed that people who had pre-study HIV levels below 30,000 copies HIV RNA were significantly more likely to achieve HIV levels below 500 copies HIV RNA.

It's important to note that the study participants were only assumed to have failed on or developed resistance to nelfinavir, since no resistance tests were performed. The participants actually may have experienced either nelfinavir failure, or failure of one or two of the nucleoside drugs they were using (most likely 3TC). Whatever the real cause of initial failure, results suggest that the ritonavir/saquinavir combination is a reasonable second line therapy option capable of producing lasting results in about half the people who employ it.

Is It Time to Switch Off 3TC?

Another study examined the wisdom of a common practice: continuing to take 3TC even when resistant to the drug. This study, known as the AIDS Clinical Trials Group (ACTG) Study 370, enrolled 105 people who had previously been on a two nucleoside analogue combination including 3TC. Participants previously on ddI + 3TC or d4T + 3TC received AZT + 3TC + indinavir or AZT + delavirdine + indinavir. At the end of the 24-week study, the results were as follows:

AIDS Clinical Trials Group Study 370
Treatment Regimen Percent <200 copies HIV RNA Percent <50 copies HIV RNA
AZT+3TC+IDV 65% 50%
AZT+DLV+IDV 80% 75%

Clearly, those stopping 3TC and adding a new drug had superior viral suppression. One interpretation of this study suggests that it may not be wise to continue on 3TC, or perhaps any drug after developing resistance to it -- hardly a new concept. Most treatment strategies have long recommended switching to two new drugs when adding a third potent drug, like a protease inhibitor.

Another interpretation is that the superior results of the second regimen is due more to the addition of delavirdine than to dropping 3TC. Adding delavirdine means adding a second, highly potent new drug to the regimen along with indinavir. It seems obvious that this would work better than simply adding a single new drug, indinavir, while retaining two old ones likely to be affected by resistance. The additional potency seen with the delavirdine-containing regimen may also be explained in part by the result delavirdine has on increasing indinavir levels in the blood, perhaps effecting a greater and longer lasting anti-HIV response. Obviously, adding indinavir to a previously used two-drug regimen did not result in the best anti-HIV response.

Does Resistance Testing Help?

Results from a new study show that making treatment decisions based on the use of resistance testing produces significantly better results than decisions made without such test information. These results show that people who acted on resistance information had significantly better anti-HIV responses from therapy choices. Genotypic resistance tests examine samples of virus taken from a person and look for the presence of specific mutations in the virus which are known to be associated with resistance to certain drugs.

This study, also known as the GART (Genotypic Antiretroviral Resistance Test) study, enrolled 153 people who had experienced at least a three-fold increase in their HIV levels while on a three-drug regimen which included a protease inhibitor. At study entry, the participants had a median viral load of 25,000 copies HIV RNA, a CD4+ cell count of about 230. The majority of the participants were on either nelfinavir or indinavir.

"Results from a new study prove that making treatment decisions based on the use of resistance testing produces significantly better results than decisions made without such test information."

After twelve weeks of the study, the group who used genotypic resistance tests had a 1.2 log (16-fold) reduction in HIV RNA levels compared to 0.6 logs (four-fold) reduction in HIV RNA levels among people who did not get the test. Furthermore, people who followed expert recommendations had even larger reductions in HIV levels compared to those who did not follow the recommendations. This study suggests that resistance testing may be useful and may be critical for treatment success, especially when expert advice is followed. While not everyone has access to "expert advice," this study does confirm the value of seeking a second opinion when making major changes in your treatment regimen.


Results of third line therapy studies show some reasons for hope, they do not offer much guidance. Unfortunately, for now, third line therapy may require the use of more drugs than many people, in the short-term, are willing or able to tolerate. But it is clear that at least some people can cope with regimens of five to nine drugs, and that those who do generally achieve fairly good results. Still, all third line studies to date have been relatively small and uncontrolled, so it is unclear how well these results will apply to people in general medical practice.

The most hope for third line therapy comes from the addition of several new drugs, ideally from new classes of agents. But it has been difficult to get the different pharmaceutical companies to collaborate on third line therapy studies. An agreement from the Food and Drug Administration which allows these types of studies to support approval of a specific drug could make it easier to convince companies to work together. Because of the importance of third line therapy studies and the growing number of people running out of anti-HIV therapy options, Project Inform -- along with the Forum for Collaborative Research, the Treatment Action Group and the Division of AIDS of the National Institutes of Health -- is co-sponsoring a workshop to tackle and hopefully resolve some of these issues.

Gender Difference in
Nevirapine-Associated Rash

A study reported at the recent Chicago conference suggest that women are more likely to develop rash, especially severe rash, as a side effect of the anti-HIV drug nevirapine compared to men. Researchers looked at the medical records for 85 women and 176 men receiving nevirapine-containing anti-HIV regimens between 9/93 and 9/98. Overall, 26 people developed rash within the first 90 days of taking nevirapine, of whom twelve were women. Mild rashes were seen in four women and 13 men, whereas severe rashes were seen in eight women and one man.

In this study, rash was more likely seen in people with higher CD4+ cell counts (e.g. greater than 200), but was unaffected by differences in age, race or concurrent use of other medications. In other studies of nevirapine, severe rash was seen in only about 3% of people taking the drug. Overall, however, 85% of participants in studies of nevirapine have been men, so it is not clear how well this figure applies to women.

These recent findings underscore the need for including greater numbers of women in studies of new therapies, so that when gender differences exist they are readily apparent from early study results. Additionally, they suggest that women using nevirapine take special care to watch out for the development of rash and perhaps to use pretreatment, such as Benadryl®, to minimize the risk. It is common when using nevirapine to start therapy at half the standard dose for the first few weeks to minimize the risk of rash. Based on this new data, this practice may be even more important in women than in men.

National HIV/AIDS
Treatment Hotline

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