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What's New in Treatment Information?

Excerpts from Hotline Memos of November 2001
from the Information Department of Project Inform

December 2001

Atazanavir: A New Protease Inhibitor

Results from a study comparing two doses of atazanavir (BMS-232632, Zrivada) to nelfinavir were recently presented in Athens, Greece. Both drugs are protease inhibitors. The study enrolled 467 people with a median viral load of about 50,000 copies HIV RNA and CD4+ cell count of about 275.

None of the volunteers had taken anti-HIV therapy before, and they all received nelfinavir (1,250mg twice a day) or atazanavir (400mg or 600mg once a day). In addition, all of them took d4T and 3TC.

Not surprisingly, people on nelfinavir were more likely to develop diarrhea, a well-known side effect of the drug. Those taking atazanavir were more likely to have headaches, abdominal pain and increases in bilirubin levels. People using the higher dose of atazanavir were more likely to stop taking it due to side effects.

There was, on average, very little change in triglyceride or cholesterol levels among the people taking atazanavir while those on nelfinavir had significant increases in these lab markers. Changes in these markers have sometimes been associated with changes in body shape, called lipodystrophy. For more information on lipodystrophy, call Project Inform's Hotline.

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Results After 48 Weeks
 
% <400 copies
HIV RNA
% <50 copies
HIV RNA
HIV RNA drop
ATV (400mg)/d4T/3TC
65%
31%
2.51 logs
ATV (600mg)/d4T/3TC
62%
36%
2.58 logs
NFV/d4T/3TC
59%
38%
2.31 logs
ATV=atazanavir      NFV=nelfinavir


Indinavir or Boosted Indinavir?

Results from the Danish BEST study suggest that taking indinavir with low-dose ritonavir may not be well tolerated. This study enrolled 323 people, all taking indinavir 800mg three times a day in addition to two other anti-HIV drugs at study entry and had viral load below 500 copies. Volunteers either continued taking indinavir three times a day or switched to indinavir/ritonavir (800mg/100mg both taken twice a day) in addition to their other anti-HIV therapies.

After 48 weeks, 74% of the people who stayed on indinavir had viral load below 500 compared to only 58% of those who switched to indinavir/ritonavir. This difference is almost entirely due to an increase in side effects among those on indinavir/ritonavir. Over twice as many people had to stop and/or switch therapy because of side effects compared to those on the three times daily indinavir regimen. Most side effects included gastrointestinal intolerance, kidney stones, blood in the urine (hematuria) and elevations in lipid levels (lab markers for triglycerides and cholesterol).


TMC-125: A New NNRTI

Early results show that a new NNRTI, TMC-125, has potent activity against HIV. We have previously reported on a related drug, TMC-120, which also showed potent activity and is still in development. Eighteen people, all of whom had not taken anti-HIV therapy before, participated in this study. Twelve received 900mg TMC-125 twice a day for seven days and six received a placebo. After seven days of therapy, people on TMC-125 had an average viral load decrease of about 2 logs (99%) and an average CD4+ cell count increase of 100.


New-Fill Injections: Cosmetic Surgery for Facial Wasting

Results from a French pilot study of New-Fill (polyactic acid) shows that it may help increase the thickness of the cheek fat pad. Some people have experienced fat loss (lipoatrophy), thought to be associated with anti-HIV therapy and in particular the nucleoside analogue (NRTI) drugs. This study involved four injections of New-Fill (3cc in each cheek) at days 0, 15, 30 and 45. A fifth injection was given at day 60 if there was inadequate response.

Fifty people participated and all had a marked reduction in fat tissue in the cheeks (sunken cheeks) as measured by ultrasonography (ultrasound that produces an image). At the time of the report, four people had received three injections, 29 had four injections and 17 had five. All dramatically improved, with most having "normalized" cheeks. Some experienced some swelling at the injection site.


Lipodystrophy: Do Some Therapies Pose More of a Threat?

Interim analysis of a study shows that different potent anti-HIV regimens have different effects on cholesterol and triglyceride levels. This study enrolled 258 people (half women), all had not taken anti-HIV therapy before. Average viral load at study entry was about 30,000 copies and average CD4+ cell count was about 350. Volunteers took abacavir/Combivir, nelfinavir/Combivir or d4T/3TC/nelfinavir.

After 24 weeks, there were no real differences in anti-HIV activity among the three groups, with 49-59% of the people experiencing viral load suppression to under 400 copies. However, there were major differences in changes in triglyceride and cholesterol levels among them. People on the nelfinavir combinations saw their cholesterol levels increase substantially compared to those on abacavir who only had a slight increase. However, only people taking d4T/3TC/nelfinavir had substantial increases in triglyceride levels while the other two groups only had minor increases. Cholesterol and triglyceride increases have been associated with lipodystrophy in some people.


Amprenavir and Lipodystrophy

A small intensive monitoring study shows that amprenavir can greatly increase triglyceride and cholesterol levels, contrary to reports that it does not affect these lipid markers. This study enrolled 16 people, all of whom had not previously taken a protease inhibitor, abacavir, d4T or 3TC. During the study, the volunteers received abacavir/3TC/amprenavir (two people used d4T instead of 3TC).

Overall there were no major changes in laboratory markers for diabetes, include fasting glucose and fasting insulin levels. There was, however, a decrease in insulin sensitivity after 48 weeks, but not before. People experienced a progressive increase in markers of fat processing, triglyceride levels and cholesterol levels. The good news is that HDL (good) cholesterol increased as well as LDL (bad) cholesterol resulting in no change in the overall ratio of HDL/LDL.

Additionally, participants saw an increase in weight, trunk fat and limb fat resulting in an overall increase in total body fat. There was also a trend towards an increase in lean tissue. One interesting observation is that insulin resistance developed after weight gain. This can potentially help in understanding the course of lipodystrophies.


d4T: A New Formulation

Results have been presented for the first time of a new once-a-day d4T, called d4T extended release or d4T XR. This study enrolled 150 people who had not taken anti-HIV therapy before with viral load of about 50,000 copies and CD4+ cell counts of about 300. Participants used either d4T XR or regular d4T plus 3TC and efavirenz.

The dose of d4T XR used was 100mg once a day for people weighing over 60kg (about 130 pounds) and 75mg once a day for those weighing less than 60kg. d4T XR results in lower peak and higher trough concentrations of the drug compared to regular d4T. Peak concentration refers to the highest amount of drug in the blood soon after taking a dose. Trough concentration refers to the lowest amount of drug in the blood after taking a dose.

Higher peak concentrations are sometimes associated with a higher risk of side effects. Lower trough concentrations are associated with developing anti-HIV drug resistance. It's assumed that lower peak concentrations of a drug will decrease side effects and higher troughs will decrease the risk of developing resistance.

At the end of 48 weeks, there was essentially no difference in response between the two groups, with about 50% of the participants having viral loads below 50 copies and an increase in CD4+ cell counts of about 200. There appeared to be slightly fewer people experiencing peripheral neuropathy (tingling or numbness around the extremities, especially fingers and toes) among those on d4T XR, although they experienced slightly more headaches. A larger study will truly determine the safety profile and effectiveness of d4T XR.


Tenofovir: New Kind of Anti-HIV Drug Gets Approved

Recently, the Food and Drug Administration (FDA) approved tenofovir for treating HIV infection in combination with other anti-HIV therapy. The approval was based primarily on the results from one study involving 550 people who were on anti-HIV therapy for at least eight weeks and had viral load of 400-10,000 copies.

Volunteers were randomly assigned to take tenofovir or placebo in a 2-to-1 fashion, resulting in 368 people on tenofovir and 182 on placebo. At the start the volunteers had, on average, been on anti-HIV therapy for 5.4 years and had viral load of about 2,300 copies and CD4+ cell count of about 427. The average decrease in viral load between the start of the study and week 24 was 0.59 logs among people taking tenofovir. Essentially no changes were noted among those on placebo. Additionally, about 45% and 22% of the participants had viral loads below 400 and 50 copies respectively compared to 13% and 1% respectively of those taking the placebo. Tenofovir was very well tolerated with no significant differences in moderate-to-severe side effects between the two groups.


Community Alert! T-20 Expanded Access

Starting November 27, 2001 at 3pm EST, a study allowing for access to the fusion inhibitor T-20 (Pentafuside) will begin. However, because there's a severe supply problem, this study is very limited and will only provide drug to 168 people in the US. Further, the study is restricted to the first 56 qualified physicians who call in on November 27, and they must have three qualified patients to enroll at that time. Physicians should call 1-888-722-6321 to register.

The study is limited to individuals who need T-20 to put together a viable anti-HIV regimen, must have a viral load over 10,000 copies and have a CD4+ cell count below 50. Physicians are encouraged to give first preference to people who have had an AIDS-defining opportunistic infection within the last 90 days and have a CD4+ cell count below 50 while taking potent anti-HIV therapy. Secondary preference is encouraged for people with CD4+ cell counts below 50 for the last 90 days despite taking potent therapy.




  
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This article was provided by Project Inform. It is a part of the publication What's New. Visit Project Inform's website to find out more about their activities, publications and services.
 
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