Less Pills, Less Doses - Simpler Drug Combinations for HIV

Many studies presented at the 12th World AIDS Conference in Geneva looked at ways of simplifying combination therapies for HIV. Combination therapies for HIV are now commonly called HAART which stands for Highly Active AntiRetroviral Therapy. It is well known that the more complicated a drug combination is, the harder it is to keep taking the drugs regularly. Some of the available anti-HIV drugs are being studied with new dosing schedules, and several experimental drugs offer the promise of once or twice daily dosing.

The other important concern is the long term side effects being seen with protease inhibitor-based combinations. Many reports at the Geneva conference showed that high levels of fats in the blood (cholesterol and triglycerides) can be a side effect of protease inhibitors. Doctors are worried that this problem can lead to serious medical conditions such as coronary artery disease (CAD). In fact, there has already been a report of this problem happening in a few people taking protease inhibitors. The doctor who wrote this report, Keith Henry, MD, is worried that even small increases in serum cholesterol may be serious, because they can represent a large increase in what are called low-density lipoproteins (LDL, sometimes known as "bad" cholesterol), along with a decrease in high-density lipoproteins (HDL - these aren't so bad). To make matters worse, the high triglyceride levels that are also part of this problem can make it harder to measure cholesterol levels correctly.

The potential side effects of protease inhibitors have led to greater interest in "protease-sparing" HAART - combinations of anti-HIV drugs that can control the virus without using a protease inhibitor. This saves protease inhibitors for use as part of a second-line combination if the first combination stops working. Several different studies presented in Geneva tried protease-sparing combinations, some with very good results.

Efavirenz (Sustiva, formerly DMP266)

The best results were reported with a new once-daily drug called efavirenz (trade name Sustiva). The company that makes Sustiva, Dupont Pharma, did a study to compare a combination including their drug to one of the most widely used "standard of care" combinations: AZT (Retrovir), 3TC (Epivir) and indinavir (Crixivan). This study was unusual, because lot of drug companies still like to study their new drugs in three drug combinations that are compared to older two-drug combinations, because this usually makes their new drug look good (See abacavir study, below).

The study randomly placed people in one if three groups: One group took AZT, 3TC and Sustiva. The second group took AZT, 3TC and Crixivan. The third group took a two-drug combination of Sustiva with Crixivan. Participants in this study hadn't taken 3TC, NNRTIs or protease inhibitors before.

Results were presented after six months. In terms of the number of people whose viral load dropped below 400 copies (too low for the standard viral load test to measure, sometimes misleadingly called "undetectable"), more people got this result in the AZT/3TC/Sustiva group (about 75%, or three quarters of all the people in this group) than in the AZT/3TC/Crixivan group (about 56%, a bit more than half the people in this group) or in the Sustiva/Crixivan group (about 65%).

These results were based on viral load information from all study participants, whether or not they stayed on the drugs for the whole study - this is known as an "intent-to-treat analysis". This may sound like a weird way of looking at study results, but if you only count people who stay on the drugs it's easy to end up with a biased result. If you only count viral load results from people who stay on the drugs, these are often the people who are responding best. The drug can then end up looking really great even if half the study participants drop out because of side effects.

The researchers did also look at the results from people that stayed on treatment the whole six months, and 94.5% of people in the AZT/3TC/Sustiva group had viral loads less than 400 copies, compared to 88.6% of those taking AZT/3TC/Crixivan. However, this difference is not large enough to be "statistically significant." In scientific language, this means that the difference is too small to be sure that it didn't happen by chance. These results, which are only from people that stayed on their drugs, show less difference between the Sustiva and Crixivan groups than the "intent-to-treat" results described in the previous paragraph. This might lead you to guess that more people dropped out of the study from the group taking Crixivan, and you'd be right. 38% (more than a third) of the people in the AZT/3TC/Crixivan group dropped out of the study compared to 21% (about 1 in 5) of the people in the AZT/3TC/Sustiva group.

Some researchers thought that a HAART combination based on an NNRTI drug like Sustiva would not work as well in people with high viral loads. To answer this question, the researchers looked at what happened to people who began the study with viral loads over 100,000 copies. It turned out that 90% of the people in this group who took AZT/3TC/Sustiva had viral loads less than 400 copies after six months, showing that the drug can work well even if the viral load is high.

The major side effects from Sustiva are on the central nervous system, although in this study they didn't cause many people to stop taking the drug. These side effects included dizziness, sleeplessness and anxiety. The lead doctor for this study said the side effects seemed to get better after a couple of weeks, but this often gets said about drug side effects and isn't always true for everybody. There were also more cases of rash in the group taking Sustiva than in the group taking Crixivan. Researchers are looking for reasons why Sustiva causes central nervous system side effects. In earlier studies of Sustiva at lower doses (200 mg a day or 400 mg a day), there were fewer side effects reported. There are concerns that 600 mg a day may be too high a dose for some people, particularly people with lower body weight.

The results of this study suggest that triple combinations using 2 nucleoside analog drugs (NRTIs: these include AZT, ddI, d4T, ddC and 3TC) and Sustiva can be just as effective, if not more so, than standard HAART combinations that include protease inhibitors.

Abacavir (Ziagen)

Abacavir is a new nucleoside analog anti-HIV drug. This drug is made by Glaxo-Wellcome. This company decided to study their new drug in combination with two of their older drugs, AZT and 3TC. Unlike the study described above, this three drug combination was compared to a two-drug combination of AZT and 3TC. Two drug combinations have not been generally recommended for HIV treatment for some time now, particularly those that include 3TC. HIV can develop resistance to 3TC within two weeks if it's used in a two-drug combination. To be fair, Glaxo-Wellcome is now doing a study comparing AZT/3TC/abacavir to AZT/3TC/Crixivan but results are not yet available. Perhaps they should have done this study sooner.

The results of the abacavir/AZT/3TC study presented in Geneva showed, not surprisingly, that after three months more people taking abacavir/AZT/3TC had viral loads less than 400 copies than those taking AZT/3TC. About 75% of people taking three drugs got this result as compared to 35% in the two drug group. Since this study has only been going on for three months, it's to soon to tell if abacavir in combination with two other NRTIs will be a good treatment strategy. More long term information, and the results of the study comparing abacavir to Crixivan, will hopefully provide clearer answers to this question.

In terms of side effects, there were some big differences between this study and the Sustiva study described above. Nearly half (47%) the participants in the three drug group experienced nausea (feeling sick), although this wasn't all that different from the two drug group where 41% of people had the same problem. About a third (31-34%) of the people in the three drug group experienced malaise (weak, sick feeling), fatigue (tiredness) and vomiting compared to a about a quarter (20-25%) of the people in the two drug group. These side effects may be another reason to be cautious about the idea of using abacavir/AZT/3TC as a first line treatment combination.

One abacavir side effect that has been widely reported is a potentially serious allergic reaction. A report in Geneva collected information from several large abacavir studies to try and get a better idea how many people get this reaction. Even though more people are now taking the drug than ever before, the allergic reaction seems to happen to about 3% (roughly 1 out of every 33) of people who take the drug. The symptoms can include: fever, rash, nausea, mouth or throat sores, conjunctivitis (a swelling of the tissue around the eyes) and breathing problems. It's important to note that only about half the people who've had this reaction to abacavir have gotten a rash. Anyone who gets this allergic reaction after starting abacavir should be taken off the drug, AND IT MUST NOT BE TRIED A SECOND TIME. The allergic symptoms come back much worse if the drug is tried a second time. At least one person has died as a result of restarting abacavir after having this allergic reaction.

abacavir and amprenavir (Agenerase)

Other studies of abacavir presented in Geneva showed that it can have a strong anti-HIV effect. One study used a two drug combination of abacavir with an experimental Glaxo-Wellcome protease inhibitor called amprenavir (trade name Agenerase, formerly known as 141W94/VX478). There were 41 people in this study who hadn't taken any HIV drugs and were still very healthy - the average T4 cell count was 756, and the average viral load was a little less than 30,000 copies. After 48 weeks (nearly a year) everyone that stayed on the study drugs had viral loads less than 500 copies. Larger studies need to be done to see if this two-drug combination may be as good as current three-drug HAART combinations.

One other piece of possible good news was reported from this study. The researchers did not see increases in cholesterol and triglyceride levels in the blood even though amprenavir is a protease inhibitor and the study lasted nearly a year. As mentioned earlier in this report, this side effect has been reported with long term use of all the other available protease inhibitors. However, because this was a small study, it's too soon to be certain that amprenavir won't cause this side effect.

Hydroxyurea

Hydroxyurea is an old anti-cancer drug that may help NRTI drugs work better. Of the available NRTIs, ddI (Videx) seems to get the most help from hydroxyurea. Several studies have suggested that hydroxyurea can help ddI work even if HIV has developed resistance to ddI alone.

A study presented in Geneva compared four different ddI-based combinations: ddI/d4T/hydroxyurea, ddI/hydroxyurea, ddI/AZT, and ddI/d4T. People started the study with an average T4 cell count of 350 and viral loads averaging 30,000. After six months, results were available for 118 people.

In the ddI/d4T/hydroxyurea group, 75% of people had viral loads less than 400 copies, but their T4 cells only increased by 30 cells. Researchers think that the small T4 cell count increase is due to hydroxyurea's blocking of production of new cells. This may not be a problem for people with over 200 T4 cells, since other studies clearly show that serious infections are rare when the T4 cell count stays above this number. For people with lower counts, hydroxyurea should probably be used with caution. In contrast, only 50% of people in the ddI/d4T group had viral loads less than 400 copies after six months but the average T4 cell count increased by 90 cells.

The other two groups did less well in terms of anti-HIV effect. 40% of people taking ddI/hydroxyurea saw their viral loads drop below 400 copies, and their T4 cells increased by an average of just 17 cells. Although only 35% of people taking AZT/ddI had a viral load under 400, the average T4 cell increase in this group was similar to the ddI/d4T group at over 90 cells.

In terms of side effects, 13% of people in the triple drug group experienced drops in the number of lymphocytes, a problem known as lymphopenia. The same thing happened to 9% of people taking ddI/hydroxyurea, 5% taking ddI/d4T and 7% taking AZT/ddI.

The small numbers of people in each group of this study make it difficult to get a clear idea of how hydroxyurea should be used. Although it's proven that hydroxyurea can add extra anti-HIV effect to some NRTI combinations, it seems to work best in people that do not need a large boost in T4 cell counts. Hydroxyurea based combinations may offer another protease-sparing HAART option for people early in their HIV infection, but until studies are done that compare different HAART combinations for people in this position it's hard to know for sure.

In another study of hydroxyurea presented in Geneva, side effects were much more of a problem than in the study described above. This study looked at people with an AIDS diagnosis who were not responding to any available treatments and tried d4T (Zerit), 3TC and hydroxyurea. Although there was a surprising drop in viral load that averaged over 90%, the side effects were severe. Several people (9/18) experienced anemia (low red blood cells) and needed blood transfusions or treatment with bone marrow stimulants. Neutropenia (low white blood cells) was also a problem in this study. One person experienced bone marrow failure and there were two deaths. Hydroxyurea should clearly be used with great caution in people with more advanced disease.

More once daily dosing

There are several available anti-HIV drugs (in addition to the experimental drug Sustiva, described above) that may still work if they are taken once a day. Several small studies have investigated once daily dosing of ddI (Videx), usually at 300 or 400mg a day, dependent on body weight. The results suggest that ddI works as well taken once a day as it does when taken twice a day. Based on these results, some doctors are already prescribing ddI once daily, although this has not yet been officially approved by the US Food and Drug Administration (FDA). The company that makes the drug, Bristol Myers-Squibb, is waiting for results of a large study of once daily ddI before asking the FDA if they can change the currently recommended dosing.

Nevirapine (Viramune) is another approved drug that may work given when given once a day. The standard dose is 200mg taken once a day for two weeks followed by 200mg taken twice a day. A study presented at the Geneva conference looked at 123 people that took nevirapine at 400mg once a day after the two week lead in at 200mg. The blood levels of nevirapine in these people stayed 250 times higher than the amount needed to block 90% of HIV production in the test tube. This study suggests pretty strongly that nevirapine could be given once daily. As with ddI, the FDA has not yet approved once-daily dosing of nevirapine.

3TC (Epivir) is another twice daily drug that may have the potential for simpler once daily dosing. This suggestion is based upon the length of time the drug stays inside cells in the body after each dose, as opposed to how much you can measure floating free in the blood. Two studies at the conference used 300 mg of 3TC dosed once daily instead of splitting it into two 150mg doses over the course of the day.

One study involved once daily dosing of all three of the drugs mentioned above, ddI, 3TC and nevirapine. This was a small study, and the combination was not compared to standard dosing. In 37 people that stayed on the combination, about 60% had viral loads below 500 copies after around 20 weeks. Ten people that stayed on the drugs for 40 weeks are all below this viral load cut-off of 500 copies. T4 cell counts have risen by an average of 100-200 cells.

Another small pilot study gave ddI and 3TC once daily along with the protease inhibitor indinavir (Crixivan) given twice a day. This study reported that 29 out of 32 people had viral loads below 400 copies after just one month of treatment. Only one person had dropped out at this point, and the average T4 cell count had doubled. Most people in this study had not taken HIV drugs before, and the average viral load at the start of the study was around 70,000 copies. After only a month, it's far too soon to tell if this combination will work over the long term.

All-in-all, once daily dosing of ddI, 3TC and nevirapine looks very promising. It's important to realize that these studies were based on the what's already known about these individual drugs. Not all drugs can simply be switched from three times a day dosing to twice a day, or from twice day to once a day. The anti-HIV drugs AZT, d4T, and abacavir, for example cannot be dosed once a day because they don't stay in the body long enough.

Twice-daily nelfinavir (Viracept)

Viracept is a protease inhibitor that's already approved for treating HIV. The approved dose is 750mg taken three times a day. A study comparing this standard dose to 1250mg taken twice a day was presented in Geneva. Both dose groups also took d4T (Zerit) and 3TC (Epivir) as part of their combination. After 48 weeks the two groups had similar results. About 80% of the people in each group had viral loads below 400 copies. Using a more sensitive viral load test that measures down to 50 copies, the two groups were still similar, with about 60% of people in each group having viral loads below this lower number. The average increase in T4 cells was also similar, with the twice daily group having an average increase of 189 cells and the three times a day group getting a 166 cell increase.

In terms of side effects, Viracept is well known for causing diarrhea. Twice daily dosing did not seem to cause more diarrhea than the standard dose, with roughly 1 in 10 people getting moderate to severe diarrhea (usually defined as 6-8 bowel movements a day) in both dosing groups. Four people dropped out of the study from the twice daily group, two because of diarrhea and two because of a rash. No-one dropped out of the study from the three times a day group because of side effects.

The results of this study have led many doctors to suggest that Viracept can be safely dosed at 1250mg twice daily instead of the current three times a day dose. It's likely that the company that makes Viracept will soon ask the Food and Drug Administration to approve this easier dosing schedule, but at the moment twice daily dosing of Viracept is still officially considered experimental.

Twice daily saquinavir (Fortovase)

Fortovase is the new version of the protease inhibitor saquinavir. Fortovase is slightly better absorbed than the old version of saquinavir (the trade name of the old version is Invirase). Fortovase is also given at double the dose of the old version of saquinavir (3,600mg a day instead of 1,800mg a day).

The approved dosing of Fortovase is 1,200mg three times a day. Early results of a study comparing the approved dose to a new dose of 1,600 mg twice daily were presented in Geneva. Both doses were given along with two NRTIs. After three months, there was not a big difference between groups in terms of increases in T4 counts and drops in viral load. However, three months is too soon to tell if the twice daily dosing will work as well as the three times a day over the long term.