Project Inform - September, 1998

More recently, however, there has been a focus on the use of highly active antiretroviral therapy (HAART) which does not include the use of a protease inhibitor. These `protease sparing' regimens are designed to achieve two goals. First, if successful, they will allow people to save protease inhibitors, generally considered the most potent class of drugs, for later use if they should experience an increase in HIV levels. This permits the patient and doctor to develop long-term strategies intended to spread out the effectiveness of therapy over the longest possible period of time. Secondly, this approach might make it possible to initiate HAART without risking the incidence of certain side effects that may be attributed to the use of protease inhibitors (see Therapy Side Effects Update). These side effects have led some physicians to become cautious about using protease inhibitors in people in early stage disease. However, not all researchers agree that these side effects are caused directly by protease inhibitors. Some have shown data which suggests that they are a result of sustained suppression of HIV replication, while others have argued that they may be an effect of HIV itself. If the side effects are not caused by protease inhibitors, people may also get them while using other highly potent combinations, regardless of whether or not the combination includes a protease inhibitor.

Protease Sparing Regimens

One important study compared AZT (Retrovir^®) + 3TC (Epivir^®) + indinavir (Crixivan^®), AZT + 3TC + efavirenz (Sustiva^®) and indinavir + efavirenz. Four hundred and fifty people who had not previously taken anti-HIV therapy and who had a mean CD4+ cell count of 345 and a mean viral load of about 60,000 copies HIV RNA participated in this study. The data were analyzed by three different methods and AZT + 3TC + efavirenz was superior to AZT + 3TC + indinavir regardless of the methods of analysis applied. There was also a trend suggesting that efavirenz + indinavir may be superior to AZT + 3TC + indinavir, which is considered one of the most potent combinations. The results after 24 weeks, using the most conservative analysis, are shown in Table 1 below.

Table 1 : Efavirenz Combination Study Results

One important observation from this study was that even people with high viral loads (>100,000 copies HIV RNA) had the same level of antiviral response as people with lower viral loads. Previous studies had shown that other NNRTIs were not as effective in suppressing HIV replication in people with high viral loads. Previous studies, however, used a different and perhaps less potent package of drugs in the combination (AZT and ddI, rather than AZT and 3TC).

The results from this study are encouraging because they suggest that a protease sparing and easier to use regimen may be at least as effective as one of the more highly regarded combinations using a protease inhibitor. However, scientists raise a number of concerns about these findings and generally believe it may be too early to draw a final conclusion.

Since the data was reported after only 24 weeks, it is not clear how long the anti-HIV activity of the AZT + 3TC + efavirenz regimen will last. Many researchers are concerned that no matter how potent they are in the short-term, the use of NNRTI drugs like efavirenz in a combination presents an easier target for developing resistance since such drugs can be rendered useless by as little as a single mutation. In contrast, the better protease inhibitors often require the virus to develop two or more mutations before they are seriously weakened. This can only be answered by longer-term comparison studies, and therefore this study has now been enlarged to include over 1,500 people and will begin to examine long-term antiviral responses from the three treatment groups. A second concern raised about the existing data is that people in the group receiving AZT + 3TC + indinavir seemed to fare somewhat less well than others on the same regimen in other studies. Thus, it is not entirely clear if the results are truly representative.

Abacavir

Another study which some people have characterized as a protease sparing regimen showed that AZT + 3TC + abacavir (Ziagen^®, formerly 1592), a new NARTI (in the same class as AZT and 3TC), was superior to AZT + 3TC. One hundred and seventy-three people who had not previously taken anti-HIV therapy received AZT + 3TC + abacavir or AZT + 3TC. People were allowed to switch to abacavir and/or other approved antiretroviral therapies if their viral loads were above 400 copies HIV RNA after 16 weeks of the study. The results after 16 weeks are shown in Table 2 below.

Table 2: Abacavir Combination Study Results

Side effects reported were generally mild to moderate in severity, although people receiving abacavir appeared to experience more malaise, fatigue and headaches. As with the previous `protease sparing' regimen reported, it is unknown how long the anti-HIV response will last with this regimen, an even more serious question in this study because of the brief 16 weeks of data. Unlike the previous study, there was no comparison to a group which included a protease inhibitor. Thus it is somewhat unfair to compare the results from either treatment group to the experience of people receiving a traditional HAART regimen. The reason this is viewed as a potential "protease sparing" regimen—even though the needed study hasn't been conducted—is that the percentage of people reaching the limits of detection in the three-drug group looked at least superficially similar to what is seen in a typical three-drug combination which includes a protease inhibitor. The sponsor of abacavir, Glaxo Wellcome, is anxious to see this described as a protease sparing regimen for two reasons. First, it will allow them to market a HAART regiment composed entirely of Glaxo Wellcome drugs, and second it will allow very simple dosing of just two pills, twice a day (two abacavir and two Combivir^®, which is a single pill formulation which includes both AZT and 3TC).

If the long-term data holds up as well as the short-term findings, both the AZT + 3TC + abacavir and AZT + 3TC + efavirenz regimens may turn out to be attractive first-line regimens for people initiating anti-HIV therapy for the first time. Both regimens are dosed only twice a day (efavirenz is taken only once a day, however AZT and 3TC require twice a day dosing), have no food restrictions and involve fewer pills per dose which should result in easier adherence. Taking these regimens will clearly be easier than some of the protease inhibitor containing regimens which have food restrictions, have to be taken three times a day and involve large numbers of pills. Better adherence, rather than any superiority of the drugs, certainly may be one reason why the AZT + 3TC + efavirenz regimen proved superior to the AZT + 3TC + indinavir combination in the study mentioned above. Both abacavir and efavirenz are awaiting approval from the Food and Drug Administration (FDA) and should be available in pharmacies by October/November. Currently, both are widely available in expanded access programs as well.

While awaiting FDA approval and longer-term data, many HIV infected people may face some difficult questions based on this new information. Those just starting therapy need to weigh the convenience and protease-sparing advantages of these combinations against the lack of long-term data about their effectiveness. In contrast to the short term nature of the data presented on the new combinations, other less publicized study results at Geneva showed data on protease inhibitor based combinations which demonstrated successful viral suppression for as long as three years. Thus, for a while, people may be asked to choose between a proven long-term durable therapy that may be somewhat cumbersome to use, versus new combinations which are clearly easier to use but lack any evidence of long-term effectiveness. People already on protease inhibitor-based combinations may also struggle with the question of whether to switch to one of the easier regimens. This is an attractive proposition for those who are having trouble adhering to complex current regimens. Once again, the trade-off is between convenience and the uncertainty about long term effectiveness. Neither Project Inform nor anyone else can recommend one approach over the other since we all lack the long-term data. Thus, for now, this remains a judgment call which must be made by the patient and his or her physician.

Hydroxyurea

Hydroxyurea (HU, Hydrea^®) has garnered increasing attention and recent study results show that it might be particularly useful as part of a regimen for people who have not previously taken anti-HIV therapy and for people who have extensive prior use of anti-HIV therapy who are trying to creatively put together effective regimens. One of the largest studies with hydroxyurea included 183 people with an average CD4+ cell count of 350, a viral load of about 30,000 copies HIV RNA. Volunteers had not previously received anti-HIV therapy and were assigned to AZT + ddI, ddI + d4T, ddI + hydroxyurea or ddI + d4T + hydroxyurea. The dose of hydroxyurea used in this study was 500mg twice a day (total daily dose of 1,000mg). The results after 24 weeks of the study are shown in Table 3

Table 3: Hydroxyurea Study

There were no differences in the incidence of side effects between the four groups. Lymphopenia (a reduction in certain white blood cells) was the most common reported side effect affecting 5-13% of people in the four groups.

A second study of hydroxyurea involved chart reviews of 18 people with advanced HIV disease and who had been on extensive prior antiretroviral therapy. All of the charts reviewed were for people who fit this description who received d4T + 3TC + hydroxyurea (500mg twice a day, total daily dose of 1,000mg). The median reduction in HIV RNA levels was almost 1.8 logs after 8 weeks of therapy. However, people experienced significantly more side effects including severe anemia (decrease in red blood cells), neutropenia (decrease in neutrophils) and hair loss. Although people with advanced HIV disease in this study experienced a good antiviral response, these results also suggest that hydroxyurea may cause serious abnormalities in blood chemistry.

Comparing Protease Inhibitors

Two different studies comparing protease inhibitors showed slightly different results. A study conducted in Denmark enrolled 257 people, 161 of whom had previously taken NARTIs. In addition to two NARTIs, study participants received either indinavir, ritonavir (Norvir^®) or ritonavir + saquinavir (Invirase^®). Only results for people who had not previously been on anti-HIV therapy were presented, although it was noted that the results were similar for those who had been on previous NARTI treatments. People receiving combinations with indinavir or ritonavir + saquinavir were significantly more likely to achieve HIV RNA levels below 400 copies compared to people receiving regimens which included ritonavir as the only protease inhibitor. This is probably due to the fact that ritonavir was not well tolerated and about 35% of people receiving it discontinued because of side effects. The study also showed that people receiving ritonavir + saquinavir containing regimens were more likely to achieve HIV RNA levels below 20 copies than people receiving indinavir-containing regimens.

A second study comparing protease inhibitors followed 1,251 people who received either indinavir or ritonavir. All of the participants were in advanced stage disease (average CD4+ cell count was below 20) and had been previously treated with NARTIs. Most participants took one or two nucleoside analogue drugs along with the protease inhibitor. The risk of disease progression and death were the same between the two groups, however significantly more people had to discontinue the use of ritonavir because of side effects. One additional and very important observation was that people receiving ritonavir were 20 times more likely to have elevated triglyceride levels compared to people receiving indinavir. A similar difference is likely between ritonavir and other protease inhibitors. Many researchers and physicians believe that this finding suggests that people with a prior history or risk of pancreatitis and people at risk of heart disease not use ritonavir as their primary protease inhibitor.

Novel Combinations

Preliminary data from a small study combining indinavir and ritonavir show intriguing results. Thirty-eight people with different histories of prior anti-HIV therapy use received indinavir, ritonavir, d4T and 3TC. The dose of indinavir and ritonavir used was 400mg twice daily (total daily dose of 800mg) of each drug. Because of the lower dose of indinavir used in this study, one group of 12 people started this quadruple regimen after being on a stable regimen of ritonavir, saquinavir, d4T and 3TC, and all had a HIV RNA levels below 400 copies for over 6 months. Participants were able to take their medications with food and did not have to drink large amounts of water as is currently recommended with indinavir to prevent kidney stones. All of these participants continued to have HIV RNA levels below 400 copies after 52 weeks on the new combination, with the majority of participants having HIV RNA levels below 40 copies. Most of these volunteers also had a substantial secondary increase in CD4+ counts of over 100 cells (over and above any CD4+ cell count increase provided by their initial protease inhibitor regimen).

A second group of 18 had previously not taken anti-HIV therapy but had a high mean viral load of about 140,000 copies HIV RNA and a CD4+ cell count of about 370. All saw their viral loads drop below 400 copies after 32 weeks of therapy. The majority fell below 40 copies HIV RNA on the more sensitive test.

A final group of 8 people were failing on a regimen containing a protease inhibitor (4 on saquinavir and 4 on indinavir) and had a mean viral load of about 180,000 copies HIV RNA. All had at least a 1.5 log drop in HIV RNA levels. Side effects from this combination were relatively mild, the most common being mild diarrhea not requiring dose modification. There were no cases of kidney stones. It is not known whether this combination will result in a higher incidence of elevated triglyceride and cholesterol levels as have been thought to be associated with protease inhibitor use, particularly with ritonavir. If longer-term data continues to follow this initial pattern, the combination of ritonavir and indinavir will make a particularly attractive protease inhibitor combination, one which reduces the complexity, toxicity, and requirements of typical indinavir or ritonavir based combinations. The outlook, however, is now somewhat darkened by the problems being reported with ritonavir production (see Ritonavir Alert).

Results from a pioneering study using a once daily dosing regimen show good antiviral activity. Seventy intravenous drug users, of whom 56 were on methadone, polamidone or codeine, received ddI (400mg), 3TC (300mg) and nevirapine (Viramune^®, 400mg) once a day simultaneously. Most volunteers were also co-infected with hepatitis C (HCV) and about a third had previously taken anti-HIV therapies. People entering the study had a median CD4+ cell count of about 250 and a viral load of about 125,000 copies HIV RNA. After 24 weeks about 75% of the participants had HIV RNA levels below 500 copies and a median CD4+ increase of 150 cells, results which seem comparable to much more complex regimens which use protease inhibitors. The combination was generally well tolerated with 5 people having to discontinue therapy because of rash (associated, undoubtedly, with nevirapine). Additionally, people co-infected with HCV were also able to tolerate this regimen.

The results from this study are particularly interesting, as this is the first study to employ a highly active antiretroviral regimen taken only once a day. This dosing schedule would be ideal for people who have difficulty adhering to anti-HIV medications. Longer-term follow up of these study participants is important to know if their anti-HIV responses will hold up over the long haul. Further studies comparing once daily regimens to more traditional regimens would be helpful in order to understand if resistance develops more or less rapidly depending on the dosing schedule employed.

In a study of people with early stage disease, the combination of abacavir and amprenavir (Agenerase^®) showed potent activity. Forty-one people with an average CD4+ count of 756 cells, HIV RNA levels of about 26,000 copies and who had not been previously treated with anti-HIV therapies received abacavir (300mg twice a day for a total daily dose of 600mg) and amprenavir (1,200mg twice a day for a total daily dose of 2,400mg). All of the participants had less than 400 copies HIV RNA after 48 weeks of therapy and most volunteers had fewer than 50 copies HIV RNA. Like the study reported earlier which combined efavirenz and indinavir, these results suggest that it may be possible to construct effective HAART regimens using only two drugs, as long as both drugs provide high levels of antiviral action.

Commentary

Most recent studies have been conducted in people who have either never taken anti-HIV drugs or have had minimal prior therapy. Pharmaceutical companies prefer to test their drugs in this patient population because it is easier to show better antiviral activity. Moreover, such studies make it easier to see just how much of the overall antiviral effect can be attributed to the new drug. This is much more difficult to determine when treating people who have used many previous therapies. There continue to be fewer studies in people who have failed multiple therapies and, as a result, there is very little guidance on what combinations may benefit people in this situation. This area of research needs to be a priority for both the pharmaceutical companies developing new therapies as well as the government sponsored clinical trial networks. In the meantime, the wider availability of the resistance tests may help eliminate some of the guesswork (see Geno- and Phenotypic Resistance Tests) and some new therapies in development may be active against drug-resistant virus, but large clinical studies are needed to determine their usefulness for this population

©1998. This document is copyrighted by Project Inform, 205 13th Street, #2001, San Francisco, CA 94103. Treatment Hotline: 800-822-7422 (toll-free) or 415-558-9051 (in the San Francisco Bay Area and internationally) All Project Inform materials may be reprinted and/or distributed without prior permission. However, reprints may not be edited and must include the following text: "From Project Inform, for more information contact the Project Inform National HIV/AIDS Treatment Hotline, 800-822-7422." For permission to edit any Project Inform material for further publication, contact David Evans at the Project Inform office.

Project Inform, established in 1985 as a national, non profit, community-based HIV/AIDS treatment information and advocacy organization, serves HIV-infected individuals, their care-givers, and their healthcare and service providers through its national, toll-free treatment hotline, the PI Perspective and other information publications, educational Town Meetings, on-line services and research and drug access advocacy programs. All information is available free of charge; donations are strongly encouraged. For more information, contact the Project Inform National HIV/AIDS Treatment Hotline. Email: web@projinf.org; Website: http://www.projinf.org.

The original of this article can be found at http://www.projinf.org/pub/25/antiviral.html