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Advances in Research:
Second and Third Line Therapy

September 1999

The benefits of highly active antiretroviral therapy (HAART) have been confirmed in numerous studies, and reports have shown encouraging reductions in hospitalizations due to HIV-related complications and deaths. For some people, however, these benefits may be starting to wane as their viral loads increase and/or their CD4+ cell counts decrease due to the development of drug resistance. They are now in search of second and third line anti-HIV therapy regimens. The "Second International Workshop on Salvage Therapy," held in Toronto, focused on how to treat people in these situations.


Second Line Therapy

AIDS Clinical Trials Group (ACTG) study 359 followed 277 people using a second line anti-HIV regimen. Volunteers had an average viral load of about 32,000 copies HIV RNA and an average CD4+ cell count of about 229. All had previously received at least six months of indinavir (Crixivan®) but were now experiencing detectable viral load. None had previously taken non-nucleoside reverse transcriptase inhibitors (NNRTIs). Also, none had taken other protease inhibitors. Participants were selected to receive one of six different regimens:

  1. RTV (400mg bid) + SQV (400mg bid) + DLV (600mg bid);
  2. RTV (400mg bid) + SQV (400mg bid) + ADV (120mg qd);
  3. RTV (400mg bid) + SQV (400mg bid) + DLV (600mg bid) + ADV (120mg qd);
  4. NFV (750mg tid) + SQV (800mg tid) + DLV (600mg bid);
  5. NFV (750mg tid) + SQV (800mg tid) + ADV (120mg qd); or
  6. NFV (750mg tid) + SQV (800mg tid) + DLV (600mg bid) + ADV (120mg qd).

qd=once a day; bid=twice a day; tid=three times a day

After 16 weeks of the study, only 30% of the participants had viral load reductions to below 500 copies HIV RNA and only 19% had CD4+ cell count increases. People taking delavirdine in addition to their new protease inhibitor assignments experienced significantly better anti-HIV responses than people taking adefovir, possibly because delavirdine improves the level of some of the other drugs in the blood. There were no noted differences, overall, in responses between those receiving ritonavir- or nelfinavir-containing regimens. The results after 16 weeks are listed in Table 1.

Table 1

Combination Regimen
% <500 copies HIV RNA
RTV + SQV + DLV
33
RTV + SQV + ADV
20
RTV + SQV + DLV + ADV
31
NFV + SQV + DLV
48
NFV + SQV + ADV
16
NFV + SQV + DLV + ADV
38

RTV=ritonavir; SQV=saquinavir; DLV=delavirdine; ADV=adefovir; NFV=nelfinavir

 

This study begs for cautious analysis for a number of reasons. First, the relatively small size and short duration of the study made it unlikely to find statistically significant differences among the six separate drug combinations. Much of the outcome may be due to chance. The overall results are disheartening with, at best, about 50% of the participants sustaining anti-HIV responses. Adding adefovir as a fourth drug did not result in increased anti-HIV effects, although this may be due to unexpected multiple drug interactions. It was observed that combining delavirdine and adefovir resulted in adefovir decreasing delavirdine levels by 50% in blood, which resulted in a 50% decrease of saquinavir levels.

Furthermore, studies conducted by Gilead Sciences, the developers of adefovir, suggest that the potency of adefovir increases when used with 3TC (and possibly abacavir). People in this study did not receive 3TC and, as a result, may have reduced any anti-HIV effects that adefovir might have contributed as part of a second line regimen.


Third-Line Regimens

No standard of care exists for people considering a third line regimen, but many researchers use an approach now commonly referred to as megaHAART. MegaHAART essentially involves combining as many anti-HIV drugs as possible without causing severe side effects. Researchers in Vancouver have used this approach with some degree of success. Results from two separate observational studies were presented. (In an "observational study" people are not assigned to any rigid protocol and are allowed to take whatever seems appropriate, perhaps under some general guidelines. This type of study then simply collects data on what happened to volunteers. Such studies are not considered very precise or accurate but sometimes provide useful information that is used to guide future study design).

The first group involved 98 people with a median viral load of about 62,000 copies HIV RNA and CD4+ cell counts of 175. The second involved 79 people with a median viral load of about 55,000 copies HIV RNA and CD4+ cell counts of 200. All had previously taken about seven anti-HIV drugs before starting megaHAART regimens.

In the first group, people had used anti-HIV drugs for about 40 months compared to about 30 months in the second group. During the observation period of the study, participants typically received up to nine anti-HIV drugs including two protease inhibitors, four nucleoside analogue reverse transcriptase inhibitors (NARTIs), two NNRTIs and hydroxy-urea. Where possible, people used therapies they had not previously taken.

Results from the first group show that about 40% of the participants had viral loads below 400 copies HIV RNA after 52 weeks of treatment. Those in the second group were not followed as long, but after 20 weeks of megaHAART, 48% achieved viral suppression below 400 copies HIV RNA. In an analysis looking at predictors of anti-HIV response, viral load at study entry (the lower your viral load the more likely you would sustain an anti-HIV response) and phenotypic resistance at study entry (the more drugs you are sensitive to the more likely you would sustain response) were correlated with anti-HIV response.


Third Line Therapy Commentary

These results suggest that it is possible for people who have been on multiple anti-HIV regimens to sustain an anti-HIV response by employing a megaHAART strategy. However, it is very difficult and costly to take up to nine different drugs every day, and many people cannot tolerate such an aggressive regimen. Although physicians associated with studies employing megaHAART suggest that people tolerate these complex combinations well, the patient volunteers tend to be much more critical of the difficulties involved.

On the surface, these results seem somewhat better than those reported in the ACTG 359 study, even though the patient volunteers had more severe problems with drug resistance. However, it is all but impossible to compare the outcomes of the studies because they were conducted in such completely different ways. While the ACTG 359 was perhaps too small and had too many controlled options to reach any clear conclusions, the Canadian observational study lacked controls of any kind, making it also difficult to interpret and analyze.


Treatment Interruptions

One of the most provocative subjects brought up at this meeting concerned treatment interruptions. The study that triggered the most discussion was reported by researchers from Frankfurt, Germany. This study followed 85 people who had an average viral load of 160,000 copies HIV RNA and CD4+ cell counts of 108. All had previously taken an average of six anti-HIV drugs. All of the participants received six to nine drugs as part of a megaHAART regimen.

The most intriguing part of this study included the responses noted among people who took a treatment interruption of more than two months before starting their megaHAART regimen. Among 50 people who did this, 39 had resistance tests performed before stopping their current regimen and again before starting their megaHAART regimen.

Twenty-six people showed evidence of a shift from a multi-drug resistant virus to a wild type virus (not resistant to HIV drugs, as measured by the currently available resistance tests). These 26 people showed evidence of resistance to about eight different anti-HIV drugs upon entering the study. As would be expected, those who interrupted therapy experienced a significant rise in viral load (0.7 log or five-times increase) while off treatment. No apparent predictors determined who was more likely to shift to wild type virus from those who continued to have multi-drug resistant virus. People who shifted to wild type virus had significantly better anti-HIV responses when they started their megaHAART regimen and sustained it better compared to those who continued to show evidence of multi-drug resistant virus. Seventy-two percent of people with the shift had viral loads below 500 copies HIV RNA after 24 weeks of megaHAART compared to only 17% of those who evidenced persistent multi-drug resistant virus.

A somewhat more ominous decline in CD4+ cell counts (almost 90 cell drop) was also noted. The people most likely to experience this decline in CD4+ cells were found to have earlier experienced a significant increase while on their first HAART regimens. Those who did not have an initial increase were also unlikely to have a decrease when going off therapy.

While these results of treatment interruptions are encouraging, they should be viewed with some caution:

More information on treatment interruptions can be found in the article Structured Treatment Interruption Workshop.

Another third line regimen study also involved treatment interruptions. In this study only about 15% of the participants had previously used a NNRTI, leaving them with more options for employing a new class of drug in their megaHAART regimen compared to the German group discussed above. This study enrolled 63 people with a viral load of about 63,000 copies and CD4+ cell counts of about 128. About 85% interrupted therapy for over four weeks before starting a megaHAART regimen, which primarily consisted of efavirenz, ddI, hydroxyurea, ritonavir and indinavir.

After 28 weeks of megaHAART, 85% showed viral loads below 500 copies with about 100 CD4+ cell count increases. Unfortunately, thirteen people stopped all anti-HIV therapies either because of side effects (mostly because of neurological side effects) or personal choice. People with higher viral loads before starting their treatment interruption were less likely to have sustained anti-HIV responses. People who took a treatment interruption were more likely to sustain a response.


Commentary

Clearly the most interesting aspect of this meeting were reports of success among people who took treatment interruptions before starting a third line megaHAART regimen. As a result, studies are now planned to look at treatment interruptions more carefully and to try to identify who may benefit from such an approach. For now, people facing a third line therapy decision and considering a treatment interruption are generally discouraged from doing so outside the context of studies.

One of the most critical aspects for people on third-line regimens is the lack of a standard of care. It is difficult to design studies to determine whether one approach is superior to another if there is no standard of care. Project Inform, along with Forum for Collaborative HIV Research, Treatment Action Group and Division of AIDS of the National Institutes of Health sponsored a meeting immediately following the "Second International Workshop on Salvage Therapy." The goal of The Challenges of the Clinical Trial Design in Evaluating HIV Antiretroviral Use in Heavily Pre-Treated Patients workshop was to determine what may be considered a standard of care for thirdline therapy; to define what can be considered a treatment success or failure; to define methods to determine the contribution of a single drug in a multi-drug regimen; methods to access multiple new drugs for third-line therapy studies; and to develop new protocols for evaluating third line regimens. A report of the meeting will be available shortly and can be obtained by calling Project Inform's National HIV/AIDS Treatment Hotline.


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