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(ATDN) Combination Treatment - Study Results




 

Treatment Review No. 23 - December 1996

There are two parts to this article. The first looks at research studies of combinations of anti-HIV drugs that seem to be able to reduce HIV levels very effectively. Research studies are also known as clinical trials. These studies are done to see how well new treatments work in people. Most of the studies included in this report are ongoing, because the idea of combination anti-HIV therapy is still new. If you'd like information about ongoing research studies contact The Network at (800) 734-7104.

The second part of this article looks at other drug combinations that have been shown to significantly lower the level of HIV in the blood, but not reduce it below measurable levels. Some of these combinations have also been shown to improve health and extend life. Now that the ideal goal of treatment is to reduce the activity of HIV as much as possible, these drug combinations may not be the best option, unless the viral load is not that high to start with. Researchers know that HIV will eventually get resistant to any drug combination that does not reduce viral activity effectively, and drug resistant HIV will limit future treatment options. Consider all the options carefully. Some options work far better when you haven't taken other anti-HIV drugs before.

For a full description of all the drugs mentioned in this article - including the many different names - see the drug glossary.

We've looked at the information from different combination treatment studies, made comments where appropriate, and asked some questions about the study results. These questions should help when making treatment decisions * What were the side effects? * At what stage of HIV disease were the participants? * How many people left the study before it finished, and why did they leave? * What was the anti-HIV effect? Did the treatments reduce levels of the virus, and for how long? * What was the effect on the immune system?. Did it seem to recover? * Had the people had previous treatment?. If they had, for how long on average, and which drugs? * What other options would I have if these treatments stopped working? AZT, 3TC and indinavir (Crixivan) Side Effects: The main side effects seen only in a few people in this study have been nausea and kidney stones. It is recommended that people taking indinavir drink 1.5 liters of water a day to try and prevent kidney stones. Indinavir has to be taken every 8 hours on an empty stomach, or with a small, low fat snack. An example of a snack is juice and a bowl of corn flakes with skim milk.

Stage of HIV: People that received the triple combination started the study with an average T4 cell count of 143.

Left the Study: In this study, 7 out of 97 left the study early. One person left the study because of mild nausea. Two left to use other treatments that were not permitted in this study. One left to treat his KS, which improved at the start of the study, but began to progress later on.

Anti-HIV Effect: 26 people in this study have been followed for 36 weeks. 21 of the 26 have so little virus in their blood that it could not be found using the viral load test. 6 out of the 7 people that have now been on the combination for 48 weeks still have undetectable viral load.

The Immune System: The average T4 cell count increase was 125. People that received the triple combination started the study with an average T4 cell count of 143. After 36 weeks their average T4 cell count had risen to 264. Previous Treatment: People in this study had already been taking AZT for an average of over two years, so it is likely that the strong anti-HIV effects of the triple combination were mainly due to people starting two new drugs (3TC and indinavir) at the same time. This is because HIV often gets resistant to the effects of AZT.

Other Options: If this combination stops working because of drug resistance, there are various possible anti-HIV drug combinations that might be effective. However, there have not yet been any studies conducted in people who are resistant to AZT, 3TC and indinavir. Many researchers are concerned that getting resistant to the effects of one protease inhibitor may stop any other protease inhibitor from working.

Drugs that might be considered include new drugs called non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as nevirapine (Viramune) and delavirdine (Rescriptor). d4T (Zerit) and ddI (Videx) might also be used as part of a combination. Some doctors are trying a combination of the protease inhibitors saquinavir and ritonavir, although it is not yet known how well this will work if HIV has become resistant to indinavir. The experimental protease inhibitor nelfinavir (Viracept) is currently available through an expanded access program for people that aren't benefitting from approved protease inhibitors. It is not yet known whether nelfinavir will work against HIV that is resistant to other protease inhibitors. Several new anti-HIV drugs are also in clinical trials, such as 1592U89 (Abacavir), adefovir dipivoxil (PMEA), PMPA, F-ddA, DMP-266, or VX-478 (the Vertex protease inhibitor).

AZT, ddI (Videx), nevirapine (Viramune) Comments: This study started before results of studies combining AZT and 3TC were released. The combination of AZT and 3TC may have stronger anti-HIV effects than AZT and ddI, so a triple combination of AZT, 3TC and nevirapine may produce better results than those seen in this study. A study of AZT/3TC/nevirapine is ongoing at the moment.

Previous studies of nevirapine in people who had already taken anti-HIV drugs did not show very good results. HIV becomes resistant to the effects of nevirapine very quickly when the drug is used alone or in combination with just one other anti-HIV drug.

Side Effects: The main side effects seen in this study were nausea, vomiting, diarrhea and rash.

Stage of HIV: People started the study with an average T4 cell count of 387.

Left the Study: Out of 51 people receiving the triple combination of AZT, ddI and nevirapine, 3 people left the study due to a rash they got from nevirapine. Several other people are reported to have stopped taking the ddI because of side effects, but they didn't leave the study.

Anti-HIV Effect: Of the 34 people that have been followed for a year, approximately 20 people are reported as still having undetectable viral load in their blood.

The Immune System: People started the study with an average T4 cell count of 387. After a year the average T4 cell count of the 34 people taking the triple combination had increased by 140 cells.

Previous Treatment: No one in this study had taken any anti-HIV drugs before.

Other Options: Drugs that may work against virus that is resistant to these treatments include d4T, 3TC, and any protease inhibitor (saquinavir, ritonavir, indinavir, nelfinavir). HIV that is resistant to nevirapine is likely to be resistant to other NNRTI drugs such as delavirdine, although this has not yet been studied in people.

NNRTIs Some researchers are very encouraged by the results of the nevirapine study reported on here. Using NNRTI drugs like nevirapine as part of triple combination may be a good option for people starting HIV treatment for the first time. The chances of reducing HIV to undetectable levels using these treatments seems good. It also allows people time to learn more about protease inhibitors before they use them.

These drugs should never be used alone, as HIV becomes resistant to them very quickly. For a full description of the different NNRTI drugs see the drug glossary.

AZT, 3TC, nelfinavir (Viracept) Comments: Nelfinavir is an experimental protease inhibitor that is not yet available by prescription. It is expected to be approved by the Food and Drug Administration (FDA) in early 1997. Contact The Network for information about the Expanded Access program for this drug.

Side Effects: The main side effect seen in this study has been diarrhea.

Stage of HIV: People started the study with an average T4 cell count of 245.

Left the Study: Only 1 person left this study out of the 12 that started. The reason for leaving was liver toxicity and diarrhea. This is a very small study so it's hard to know what would happen in a larger group of people.

Anti-HIV Effect: After 16 weeks, all eleven people in the study had very low levels of HIV in their blood as measured by several different sensitive tests.

The Immune System: The average T cell rise was 100. People started the study with an average T4 cell count of 245. After 16 weeks their average T4 cell count had risen to 345.

Previous Treatment: No one in this study had taken any anti-HIV drugs before.

Other Options: Researchers do not know for certain which drugs would work against HIV if it becomes resistant to AZT and 3TC - drugs that may work include nevirapine, delavirdine, d4T and ddI and experimental drugs such as 1592U89, F-ddA and DMP-266. According to very preliminary study results, it seems that the approved protease inhibitors (saquinavir, ritonavir and indinavir) would still work against HIV that had gotten resistant to nelfinavir.

AZT, ddC (HIVID), ritonavir (Norvir) Side Effects: The side effects seen in this study include nausea, diarrhea, facial numbness (paresthesia) and toxicity to the liver. The ritonavir being used in this study was a liquid formulation. It was hoped that the new pill form of ritonavir would have less side effects, but people report that ritonavir, even as a pill, is a very tough drug to take.

Stage of HIV: People started the study with an average T4 cell count of 180.

Left the Study: Out of 32 people that started the study, 15 people left early due to side effects. That's almost half of the people on the study. Most of these people dropped out because of side effects caused by ritonavir.

Anti-HIV Effect: After 60 weeks, 9 of the 15 people that had made it that far had undetectable viral load in their blood.

The Immune System: People started the study with an average T4 cell count of 180. After 60 weeks the average T4 cell count of the 17 people that stayed in the study that long was 338 - but so many people had dropped out that these 17 people may have had higher T4 cell counts to start with.

Previous Treatment: No one in this study had taken any anti-HIV drugs before.

Other Options: Drugs that may work against HIV that is resistant to these treatments include d4T, 3TC, ddI, nevirapine, delavirdine, and possibly other protease inhibitors. Several anti-HIV drugs that are currently experimental may also be effective.

AZT, 3TC, ritonavir Comments: This study was done in a very small number of people who had only been HIV infected for 90 days or less. This period is known as primary infection. This study is being done to see if it is possible to cure HIV infection in people that have recently become infected. How this combination works in people that have been infected for a long time is not known.

Several different tests will be done after people have been on the study for a year to see if there is still virus in their bodies. If it turns out that HIV has not been eliminated by the treatments, the long term effects of reducing the amount of HIV in the body so early in the course of infection will not be known for many years.

Side Effects: The main side effects seen in this study were nausea, vomiting, diarrhea and paresthesias (numbing sensations on the skin).

Stage of HIV: People in this study had been HIV infected for 90 days or less. This period is known as primary infection.

Left the Study: Out of 12 people that started, 3 people left the study due to side effects or allergic reactions to ritonavir.

Anti-HIV Effect: All 9 people still in the study have no virus in their blood as measured by several different sensitive tests. The length of time people have been in the study ranges from 3 to 10 months.

The Immune System: Because the people in this study had only recently become HIV-infected, most had high T4 cell counts. The researchers looked at the ratio of T4 cells to T8 cells to see if the treatments had an effect on the immune system. The T4/T8 ratio is another way of measuring how well the immune system is doing. Most of the people in the study had an improvement in the T4/T8 cell ratio after treatment.

Previous Treatment: No one in this study had ever taken any anti-HIV drugs before.

Other Options: Drugs that might be considered include new drugs called non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as nevirapine (Viramune) and delavirdine (Rescriptor). d4T (Zerit) and ddI (Videx) might also be used as part of a combination. The experimental protease inhibitor nelfinavir (Viracept) is currently available through an expanded access program for people that aren't benefitting from approved protease inhibitors.

indinavir (Crixivan), AZT, ddI Comments: The combination of AZT, ddI and indinavir may not be as effective as AZT, 3TC and indinavir (see first study, above) against HIV. Indinavir and ddI are also difficult drugs to take in combination, because they need to be taken an hour apart, and they both have to be taken on an empty stomach.

Side Effects: The main side effects experienced by people in these studies were gastrointestinal (stomach and digestive system) upset, nausea and headache. There has only been one case of kidney stones reported in this study so far.

Stage of HIV: People started the study with an average T4 cell count of 150.

Left the Study: Out of 78 people that started this study, 10 left early due to gastrointestinal side effects which were thought to be caused by ddI.

Anti-HIV Effect: This study has been going on for six months. The 78 people in the study were divided into three groups. One group is taking a triple combination of AZT, ddI and indinavir. The second group is taking indinavir on its own. The third group is taking AZT and ddI. In the group taking the triple combination of AZT, ddI and indinavir, 60% of people have undetectable viral loads.

The Immune System: People started the study with an average T4 cell count of 150. After 24 weeks, people on the triple combination had an average T4 cell increase of 110 cells.

Previous Treatment: No one in these studies had taken anti-HIV drugs before.

Other Options: It is not yet known whether any other protease inhibitors will work against HIV that is resistant to indinavir. The experimental protease inhibitor nelfinavir (Viracept) is currently available through an expanded access program for people that aren't benefitting from approved protease inhibitors. Drugs that may work against HIV that is resistant to AZT and ddI include d4T, 3TC, nevirapine, delavirdine and several experimental anti-HIV drugs that are currently in clinical trials. saquinavir and ritonavir Comments: This study has not been going on for very long. It is the first study to test a combination of protease inhibitors. The anti-HIV effect of the combination seems strong, and may be an option for people whose virus is resistant to the effects of all the nucleoside analog anti-HIV drugs (AZT, ddI, ddC, d4T, 3TC). However, it would be a good idea for people to wait for more long-term information about this drug combination if they can.

People in this study have been divided into four groups. Group A is taking saquinavir 400 mg twice a day along with 400 mg of ritonavir twice a day. Group B is taking 400 mg of saquinavir twice a day and 600 mg of ritonavir twice a day (this is the standard dose of ritonavir). Group C is taking 400 mg of saquinavir three times a day and 400 mg of ritonavir three times a day. Group D is taking 600 mg of saquinavir twice a day and 600 mg of ritonavir twice a day. So far, information is available for groups A and B after 20 weeks on the study, and for groups C and D after 12 weeks on the study.

Side Effects: People in this study have experienced many side effects. Out of 128 people starting the study, 99 experienced numbing sensations known as paresthesias, 98 had diarrhea and 57 had nausea. Other side effects included fatigue and elevated levels of substances in the blood called triglycerides. Increases in liver function tests, sometimes severe, have also been noted, particularly in patients with underlying hepatitis. For most people in the study, these side effects are reported to have gotten better or gone away after the first few weeks.

Stage of HIV: The average T4 cell counts at the start of the study were 277 in Group A, 264 in Group B, 302 in Group C, and 251 in Group D.

Left the Study: This study is ongoing. At the last report, out of 128 people that started, 12 people had left the study. Eight of the drop-outs were from Group C, who were receiving the drugs three times a day. This group has now had their dosing schedule changed to twice a day.

Anti-HIV Effect: Most people in the study have had the levels of HIV in their bodies reduced to undetectable levels. Some people's levels of virus are not undetectable yet but are still going down.

The Immune System: T4 cell counts have increased an average of 75 in Group A, 120 in Group B, 100 in Group C and 120 in Group D.

Previous Treatment: People in this study were allowed to have taken nucleoside analog anti-HIV drugs (AZT, ddI, ddC, d4T, 3TC) before, but had to stop taking them before joining the study. No one in this study had taken protease inhibitors before.

Other Options: The experimental protease inhibitor nelfinavir (Viracept) is currently available through an expanded access program for people that aren't benefitting from approved protease inhibitors. It is not yet known whether nelfinavir will work against HIV that is resistant to both saquinavir and ritonavir.

Protease inhibitor combinations - the future? Researchers are hopeful that the new protease inhibitor nelfinavir (Viracept) may combine well with either saquinavir or indinavir. Early information about the safety and interactions of these drugs in HIV negative people is reported to be encouraging. Studies in people with HIV are planned. It is hoped that these combinations may work as well as the only protease inhibitor combination studied so far, ritonavir/saquinavir (described on this page), but with less side effects. The results of studies planned for next year will help show if this is true.



 


Copyright © 1996 -AIDS Treatment Data Network, Publisher. All rights reserved to AIDS Treatment Data Network. Reproduction of this article (other than one copy for personal reference) must be cleared through the AIDS Treatment Data Network. Email AIDS Treatment Data Network

Information in this article was accurate in December 1, 1996. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.