PI Perspective #24

April 1998     View PDF

New Drugs on The Horizon

Recent advances in anti-HIV treatment have primarily come not from new therapies but from better understanding in how to use existing drugs, such as new combinations and simplified dosing regimens. While there are new drugs in development, most are simply improved versions of existing drugs or new drugs of the same type as those currently available. These new therapies are likely to only offer incremental benefits in the form of simplified dosing and reduced side effects but seldom with better activity against HIV. As such, new drugs in the pipeline will offer more and better choices for people starting therapy or those with limited prior use, they are unlikely to offer any substantial benefits for people who have developed high level resistance to most of the currently available anti-HIV therapies. Consequently, the people with the greatest need for new therapies are still left with limited options.

Most studies continue to test new drugs primarily in people who are relatively healthy and with little or no prior use of anti-HIV therapies. Manufacturers focus on this group because it is much easier to show good antiviral activity in such people. In contrast, people who have been on extensive prior therapies usually respond less well to new drugs and have a higher risk of developing side effects. As a result, there is little information to guide the choice of a second or third treatment regimen after an initial combination loses its ability to suppress viral replication. Moreover, there is almost no reliable information on how to treat people who have been on all or almost all of the existing therapies.

New Drugs in Development

Efavirenz
Efavirenz is likely to be the next anti-HIV drug to be approved by the Food and Drug Administration (FDA) and is expected to be in pharmacies by the fall of 1998. Results from studies are very encouraging. Efavirenz was previously shown to work well in antiviral naive patients in a two-drug combination with a protease inhibitor. A new study suggests that it is equally effective in the same population in three-drug combinations with AZT + 3TC. The study compared a three-drug efavirenz combination to a two-drug combination with NRTIs, mimicking similar studies done with three-drug protease inhibitor based combinations. One hundred and thirty-seven previously untreated people with a mean CD4+ cell count of 370 and viral load of about 50,000 copies of HIV RNA were assigned to receive either AZT + 3TC or AZT + 3TC + efavirenz. Participants received 200mg, 400mg or 600mg of efavirenz once daily. After 24 weeks of the study, the results are shown in Table 1.

Table 1
Regimen	% with <400 copies HIV RNA	% with <40 copies HIV RNA*	Mean CD4+ increase
AZT + 3TC	65%	15%	90
AZT + 3TC + 200 EFV	96%	83%	170
AZT + 3TC + 400 EFV	91%	68%	175
AZT + 3TC + 600 EFV	100%	67%	110
EFV= efavirenz, *week 16 results

The three-drug combination here appear to be as potent as most three-drug combinations employing a protease inhibitor. All three doses were generally well tolerated with nausea, headache, fatigue and dizziness being the most commonly reported side effects. The dose of efavirenz that is currently used in the clinical studies is 600mg once daily. Efavirenz should be taken before going to bed to reduce the likelihood of developing neurological side effects, such as mania, depression and other mood disorders. Efavirenz is currently available under an expanded access program for most HIV-infected people who require a new drug to build an effective combination.

Comment:
While the results of the triple combination study with efavirenz and AZT plus 3TC must be considered somewhat preliminary, they strongly support the notion that many people can achieve the goal of effective therapy—sustained viral suppression below the limit of detection—using a three-drug combination anchored by a non-nucleoside RT inhibitor (NNRTI). The rationale for using such a combination is that it preserves the use of a protease inhibitor for use in a different combination. In effect, using such a strategy would give a person two Highly Active Antiretroviral Therapy (HAART) regimens which could be used one after the other. The current standard approach, as recommended in the Federal Guidelines, is to initiate therapy with the standard approach, a three-drug combination including a protease inhibitor. The problem with the standard approach is that it leaves a person with few effective options if and when it fails since all studies to date agree that switching to a second protease inhibitor after the first one fails seldom produces a strong and durable response. Using an approach based with initial therapy based on a drug in the NNRTI class should have little or no effect on one’s later ability to use a protease inhibitor combination.

Another theoretical but practical advantage of initiating therapy with a NNRTI-based combination using a drug like efavirenz is this type of drug has generally fewer and less severe potential side effects than protease inhibitors. People who are asymptomatic and just beginning therapy tend to be less willing to put up with side effects. Thus, such a combination might lead to better adherence to therapy, especially when one of the main drugs is used only once a day.

It may take more than a year before these new approach is addressed clearly in the Federal Guidelines, but this new data on an efavirenz-based triple combination is difficult to ignore. On the surface, it would appear to offer a superior approach to treatment strategy. For now, it is important to note that such a strategy is not right for everyone. It should be limited to the kinds of people who were actually treated in the studies. Thus, initial therapy based on a three-drug combination including a NNRTI and two NRTIs makes sense primarily for people who (1) have not used any prior antiviral treatment, (2) who are essentially symptom free, and (3) have a viral load below 50,000. A better level of response might be seen if a lower viral load limit were employed. People who do not meet this description should continue to employ the standard three-drug combinations including a protease inhibitor.

Some voices may still argue that it is best for everyone to begin with the combinations which include a protease inhibitor and no one can say that this is wrong. However, it fails to address the question of long-term strategy, and fails to recognize how effective some of the three-drug NNRTI-based combinations have proven in clinical trials. The best NNRTI data, exemplified by the current efavirenz study described above, seems equal to the responses seen in most three-drug protease inhibitor based combinations, and it is in fact superior to the response shown for some standard combinations. It is too early to know whether a NNRTI-based combination will be as durable and keep people below the limit of detection for as long as a good standard combination, but the results have continued to look good after 1 year in at least one such study (a three-drug combination which included nevirapine (Viramune).

One question which cannot yet be clearly answered is whether all of the current NNRTIs (delavirdine (Rescriptor), efavirenz and nevirapine) are equally effective for use in such a strategy. The answer is uncertain because the three drugs have been studied in very different ways. In terms of raw numbers, the combination with efavirenz does appear to be somewhat more potent than the others, but it is hard to say if this is true reflection of the power of the drug or the way in which it was used.

Three alternative ways have been suggested to employ a drug like efavirenz in clinical strategies. One is to use it in a three drug combination along with one NRTI and one protease inhibitor. Surely, this will produce a highly potent response. Many researchers are concerned, however, that if the regimen fails, the patient will have exhausted not one but both classes of highly active drugs (protease inhibitors and NNRTIs) in a single step because there is such a high level of cross-resistance within these two categories of drugs.

A second approach would employ a drug like efavirenz in a simple, two-drug regimen along with a potent protease inhibitor. Studies of efavirenz have shown this approach to be at least equal to most three-drug regimens which include a protease inhibitor. The main advantage gained here would be simplicity of use and thus better compliance. However, the same objection applies, in that failure would harm both classes of drugs.

A third alternative is to add or switch to a NNRTI based combination after a patient has failed an initial protease inhibitor. So far, no study has shown this to be an effective strategy. Many physicians have already employed this strategy by default, since there were few other choices left for many people. As a general rule, however, the more antiviral drugs people have used previously, the less responsive they are to the next drug or drugs. If researchers believe that protease inhibitors are the most potent drugs presently available, then there would be little reason to expect a NNRTI to work well after a patient fails on a protease combination. In contrast, in earlier stages of HIV infection, all drugs tend to be at their best. Thus, if researchers believe that NNRTIs are inherently any less potent than protease inhibitors, an argument can easily be made that suggests that if a person intends to use a NNRTI, it may be best to use it earlier, rather than later, in the course of disease.

These are difficult questions for which hard answers do not yet exist. The Federal Guidelines Panel will undoubtedly struggle with them for much of the next year or two. No one can say with absolute certainty which strategy (start with NNRTI vs. start with protease inhibitor) will produce the overall best response. The probable answer is that “it depends.” Factors to consider include a patient’s initial viral load, stage of disease progression, tolerance for side effects, etc. But for now, it seems clear that at least for some people, an initial therapy strategy based on a drug like efavirenz plus two NRTI’s may make good sense. Researcher and clinicians need to be careful to avoid setting up any particular approach to therapy as hard dogma. New information must be allowed to lead to new strategies.

Abacavir
Abacavir is a new drug of the NRTI class. Preliminary results from a study combining abacavir with various protease inhibitors show good anti-HIV activity in almost all combinations tested. Seventy-eight people with an average CD4+ cell count of 349 and viral load of about 55,000 copies of HIV RNA, who have not been previously treated with any anti-HIV drugs, received abacavir + amprenavir (a new protease inhibitor described later in this article), abacavir + indinavir, abacavir + nelfinavir, abacavir + sgc saquinavir (Fortovase) or abacavir + ritonavir. The doses used were 300mg twice daily of abacavir, 1,200mg twice daily of amprenavir, 800mg three times daily of indinavir, 1,200mg three times daily of saquinavir and 600mg twice daily of ritonavir. Results after 16 weeks were as shown in Table 2.

Table 2
Regimen	Median viral load reduction	% < 400 copies HIV RNA
ABV + amprenavir	2.42 logs	11/13 (85%)
ABV + indinavir	1.83 logs	7/10 (70%)
ABV + nelfinavir	2.49 logs	7/9 (78%)
ABV + saquinavir	1.98 logs	7/13 (54%)
ABV + ritonavir	1.63 logs	9/12 (75%)
ABV = abacavir

The most commonly reported side effects included nausea, vomiting, diarrhea and headache. Serious adverse events reported include fever, skin rash, diarrhea and drug reaction. Four people had to discontinue treatment due to hypersensitivity to abacavir. In all of the abacavir studies conducted so far, between 2–5% of the participants have developed hypersensitivity to the drug. This reaction is usually systemic (throughout the body) and includes fevers, malaise, nausea, vomiting and sometimes rash. The hypersensitivity appears relatively soon after starting abacavir (3–42 days) and resolves one to two days after stopping the drug. It is important NOT to try and take abacavir again (re-challenge) if there was hypersensitivity to the drug, as the subsequent reaction is potentially fatal.

Additional studies of abacavir have attempted to define its level of cross-resistance to other drugs in its class. These studies suggest that the drug will be most potent in people using therapy for the first time, but that the drug will still have a significant level of activity for people who developed resistance to only one or two other drugs of this type. However, its activity drops strongly in people who have developed resistance to two or more NRTI drugs.

Amprenavir
Results from a small study show that a combination of amprenavir and other protease inhibitors offers significant anti-HIV activity. Thirty-four people with an average CD4+ cell count of 393 and a viral load of about 44,000 copies of HIV RNA received either amprenavir + indinavir, amprenavir + sgc saquinavir (Fortovase), amprenavir + nelfinavir or amprenavir + AZT + 3TC. The doses used were 800mg three times daily of amprenavir, 750mg three times daily of nelfinavir, 800mg three times daily of indinavir and 800mg three times daily of saquinavir (note that this is less than the recommended standard dose of saquinavir). None of the participants had previously taken a protease inhibitor. The results, after 16 weeks of the study are shown in Table 3.

Table 3
Regimen	Median viral load drop	% < 400 copies HIV RNA	% < 20 copies HIV RNA
APV + IDV	3.75 logs	5/6 (83%)	4/6 (67%)
APV + SQV	2.94 logs	5/5 (100%)	2/5 (40%)
APV + NFV	1.84 logs	3/6 (50%)	3/6 (50%)
APV + AZT + 3TC	2.79 logs	2/3 (67%)	2/3 (67%)
APV = amprenavir

Side effects noted in the study included diarrhea, tingling, numbness, nausea, vomiting, abdominal pain, flatulence and headache. Some preliminary drug interaction results shows that indinavir increases amprenavir levels by about 30–40% in blood. Amprenavir had no effect on indinavir levels.

The manufacturer reports that amprenavir does not appear to share patterns of resistance with other protease inhibitors and thus might still prove useful after other protease inhibitors fail. However, at least one major university disagrees with the finding. Moreover, an initial small NIH study in people who had failed prior protease therapy was discouraging, even though amprenavir was used in combination with abacavir and other NRTIs. An ongoing study is testing whether antiviral activity might be restored in such people by putting them a combination of amprenavir, abacavir, and efavirenz. Results are not yet available from this study. For now, it seems unrealistic to expect this drug to be a remedy for people who have exhausted the previously available protease inhibitors.

Expanded Access
Three new drugs are currently available in expanded access programs—abacavir (Ziagen, formerly known as GW1592), adefovir (Preveon, formerly known as bis-POM PMEA) and efavirenz (Sustiva, formerly known as DMP266).

Program Numbers:
Abacavir (NRTI) 800-501-4672
(for anyone failing current therapy and requiring an additional new drug for treatment strategy)

Adefovir (NRTI) 800-445-3235
(for anyone failing current therapy and requiring an additional new drug for treatment strategy)

Efavirenz (NNRTI) 800-998-6854
(for anyone failing current therapy whose CD4+ has ever gone below 400 and requires an additional new drug for treatment strategy)

Adefovir (formerly bis-pom PMEA) and Bis-Poc PMPA
No new data have been recently presented from studies of adefovir, even though the manufacturer hopes to see the drug approved in 1998. The drug, of a slight different class called Nucleotide Analogue Reverse Transcriptase Inhibitors offered only modest potency against HIV in earlier studies, showing an average viral load reduction of * log or less. However, since it may also have activity against CMV infection, it’s dual activity may yet make it desirable, pending the outcome of the current studies.

Bis-Poc PMPA is another drug of the same type and from the same manufacturer, Gilead Sciences. Early studies have suggested that bis-poc PMPA is considerably more potent than its older brother, adefovir. Thirty-six people participated in a study of bis-poc PMPA (75, 150 or 300mg once daily orally). Most of the participants had previously received anti-HIV therapies (mostly nucleoside analogues, however about a third had been on a protease inhibitor). The design of the study was such that people had to discontinue taking their current medication before starting this study. Participants received a single dose of bis-poc PMPA followed by no drug for seven days and then drug for the next 28 days. The results at the end of the 28 days of therapy were as shown in Table 4.

Table 4
Dose PMPA	Viral load drop
Placebo	0.06 logs
25mg PMPA	0.32 logs
200mg PMPA	0.44 logs
300mg PMPA	1.22 logs

The most common side effects reported in the study included elevated creatine kinase levels (an enzyme that measures muscular function) and elevated liver function tests. Previously we reported on the results of a study using intravenous (direct injection into the vein) PMPA. Studies to evaluate higher doses of bis-poc PMPA are planned for the future.

FTC
Results from a small study of FTC (which is chemically similar to 3TC) shows very potent short-term anti-HIV activity. This study enrolled ten people who had not previously taken 3TC and received 25mg twice daily of FTC or 200mg once daily of FTC for 14 days. At the end of the 14-day study, the results were as shown in Table 5.

Table 5
Dose FTC	Viral load drop
25mg FTC twice daily	1.4 logs
200mg FTC once daily	2.1 logs

Both doses were very well tolerated with no significant side effects reported. One interesting observation from this study was that people on the low dose had no viral load reduction on the first three days of therapy while people on the higher dose had an immediate viral load reduction. Furthermore, the rate of reduction in viral load was greater in the group that received the higher dose. These are clearly very impressive results, especially since this study only looked at FTC alone. Furthermore, FTC has activity against hepatitis B virus and the possibility that FTC may be able to be taken just once a day makes this drug particularly attractive. However people who have developed resistance to 3TC are unlikely to benefit from FTC.

Lower Dose Maintenance

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