Important note: Information in this article was accurate in July 2004. The state of the art may have changed since the publication date. 
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Project Inform Perspectives 38 - July 2004
New drugs similar to those already approved are in the research pipeline; yet only one, tipranavir (from Boehringer Ingelheim), may get Food and Drug Administration (FDA) approval in 2004. Drugs of new classes and different modes of action are discussed elsewhere in this issue of S but they will not be in wider use for two years or more.
New drugs that impact the virus in different ways are needed in order to make the next major advance in the treatment of HIV disease. However, progress is also needed on improving existing drugs and providing options for people who are failing current regimens. This article discusses the progress on new protease inhibitors (tipranavir and TMC-114) and reverse transcriptase inhibitors (capravirine and Reverset).
Tipranavir has a different chemical structure than other currently available protease inhibitors, which may allow it to work against virus that is resistant to other drugs in this class. It is being studied in people who are taking anti-HIV drugs for the first time as well as in people who have been heavily treated and may have drug resistance.
The body clears tipranavir from the blood quickly, so each 500mg dose of tipranavir must be taken in combination with 200mg of ritonavir. The ritonavir helps keep tipranavir in the blood longer. Both drugs are taken twice daily.
Studies show the primary side effects of tipranavir so far are vomiting, diarrhea and nausea, none occurring in more than 5% of people. Most were able to be managed in studies by taking tipranavir with a light snack. The addition of ritonavir brings the potential for elevation in lipid markers (triglycerides) and liver related enzymes.
Preliminary results from large studies are expected by the end of summer. If favorable, the company is expected to apply for drug approval with the Food and Drug Administration (FDA). The company indicates that an expanded access program will open once the application for approval has been filed.
Tipranavir is available to a small number of people nationwide through an open label safety study (OLSS). The study is open to people living within 100 miles of a phase III study site and who need tipranavir to construct an active treatment regimen. It is currently limited to people with fewer than 100 CD4+ cells. The study hotline number is 800-632-2464.
Like tipranavir, TMC 114 (from Tibotec/Johnson & Johnson) is a protease inhibitor which may have activity against virus that has become resistant to other protease inhibitors. Recently, researchers reported on the completion of a small human study and a test tube (in vitro) resistance study. The goal of the small study was to assess safety and compare the anti-HIV activity of three different doses of TMC 114. Each dose (300mg twice daily, 600mg twice daily or 900mg once daily) was combined with a 100mg ritonavir booster.
The dosing schemes and viral load responses at the end of two weeks (14 days) follow:
Viral load responses at the end of two weeks were similar among the three dose groups. Reductions in virus were comparable whether the person entered the study with resistance to only one other protease inhibitor or to all of the approved protease inhibitors. In test tube studies, TMC114 was active even against virus with six or more protease resistant mutations. If these results hold up in larger studies, this could prove to be a very hopeful candidate for people who have problems with drug resistance in need of new treatment options.
Capravirine (from Agouron/Pfizer) is a non-nucleoside reverse transcriptase inhibitor (NNRTI), which belongs to the same class as efavirenz and nevirapine. Early data suggest that it may be active against virus that has become resistant to other NNRTI drugs. It was also found to be quite potent, producing up to 2 log drops in virus when dosed at 1,400mg twice daily. Development of capravirine was stalled when animal studies suggested that the drug might cause heart problems. A review of data from a small human study with close heart monitoring did not reveal heart-related side effects. Development is now proceeding.
In Europe, studies of capravirine are enrolling people who have never taken anti-HIV drugs. Studies in the U.S. and Canada are enrolling people who have been on failing regimens that included protease inhibitors and an NNRTI. The U.S. study will compare three different doses of capravirine + Kaletra + two NRTIs to Kaletra + two NRTIs. People interested in the study can call 1-800-323-4204 for more information.
D-D4FC (Reverset, from Pharmaset) is a nucleoside analog reverse transcriptase inhibitor (NRTI). Results from a small short-term study of people who have not taken anti-HIV drugs before suggest it may have potent anti-HIV activity. Taken as a single agent therapy (monotherapy, not together with other anti-HIV drugs) over a ten-day period at three different doses, D-D4FC produced the following drops in viral load:
While these viral load reductions are impressive, the study was very small and short-term. Other studies are needed to determine whether the drops in viral load can be sustained over time. Activists will also be pushing for drug interactions studies between D-D4FC and other existing drugs to ensure its usefulness as part of combination therapy.
The company developing the drug shared data from test tube studies showing that D-D4FC may be active against virus resistant to AZT, 3TC and other NRTIs. It is too early to draw conclusions about the resistance and cross-resistance patterns of D-D4FC, however. Nearly every new drug promises activity against drug resistant virus—only larger studies will tell if this holds true over time. A larger study will begin recruiting 180 treatment-experienced people later in 2004.
It is likely that the novel HIV treatment strategies discussed elsewhere in this publication will take at minimum several years before they are more widely available to people living with HIV. Some of those strategies are in their scientific infancy and will take even longer. In the meantime drugs like those discussed in this article offer promising alternatives to people who will need new drugs in the near future.
All four drugs (tipranavir, TMC-114, capravirine and D-D4FC) were developed with the goal of suppressing drug-resistant HIV. Together, they represent three of the four classes of approved drugs. Though not a revolutionary step forward, they nonetheless offer hope to people who will need them.
Atazanavir and side effectsResults from two studies confirm the benefits of the protease inhibitor atazanavir (Reyataz) with regard to side effects. Several studies show that other protease inhibitors can reduce insulin sensitivity in the body. Reduced insulin sensitivity can lead to diabetes. A study reported at the 11th Conference on Retroviruses and Opportunistic Infections (CROI) found that atazanavir had no effect on insulin sensitivity. A second study reported at CROI found that Kaletra had more negative effects on cholesterol and triglycerides than atazanavir+ ritonavir. People entering the study had elevated triglycerides and cholesterol from previous regimens. Those receiving atazanavir had reductions in both total cholesterol and triglycerides over 48 weeks. Total cholesterol dropped by 8% and fasting triglycerides dropped by 4%. In contrast, participants taking Kaletra had a 6% increase in total cholesterol and a 30% increase in fasting triglycerides. This is not to suggest that atazanavir has a lipid (fat) -lowering effect. Rather, an increasing number of studies have found that it simply does not have the negative effects on lipids that other drugs do. Though both studies presented here were rather small, they certainly suggest that atazanavir may be a reasonable alternative for people who have experienced lipid and insulin problems from other anti-HIV drugs. |
Genetics, race/ethnicity and efavirenz side effectsA study (ACTG5097) was designed to determine whether higher levels of efavirenz in the blood are related to side effects of the central nervous system (CNS). CNS side effects, including vivid nightmares, difficulty sleeping and mood changes have been reported in a number of efavirenz studies. Results of ACTG5097s were recently reported, finding a significant association between genetic factors, race and how quickly efavirenz is cleared from the bloodstream. ACTG5097s found that people who identified as black or Hispanic maintained higher blood levels of efavirenz than their white non-Hispanic counterparts. As might be expected, people with higher blood levels of the drug were more likely to stop taking it due to side effects. The study also found that while people with higher efavirenz blood levels did not develop CNS side effects more rapidly than those with lower blood levels, they were more likely to stop taking efavirenz because of them. This suggests that while CNS effects aren’t developing more rapidly among people with higher blood levels of drug, when they do occur they are more severe. Upon closer examination, researchers found a genetic variation that explained the difference in how people’s bodies processed efavirenz better than racial identification. This genetic variation, which affects how the liver functions, was found in 20% of black participants and only 3% of white participants. No data were presented regarding the percentage of Hispanic study participants who carry the gene. The genetic tests used in this study are unlikely to be available anytime soon. In the absence of access to these tests, Blacks and Hispanics who are taking efavirenz should be aware of a potential increased risk of side effects and continue careful monitoring. Further confirmation of the genetic variation, its impact on liver function and the people most likely to carry it is needed to determine its impact on peoples’ response to anti-HIV treatment. |
| Abbreviation | Generic Name | Brand Name | Pharmaceutical Co. |
|---|---|---|---|
| 3TC | lamivudine | Epivir | GlaxoSmithKline |
| ABV | abacavir | Ziagen | GlaxoSmithKline |
| AZT or ZDV | zidovudine | Retrovir | GlaxoSmithKline |
| CBV | 3TC + AZT | Combivir | GlaxoSmithKline |
| d4T | stavudine | Zerit | Bristol-Myers Squibb |
| d4T XR | stavudine extended release | Zerit XR | Bristol-Myers Squibb |
| ddC | zalcitabine | Hivid | Hoffman La Roche |
| ddI | didanosine | Videx | Bristol-Myers Squibb |
| ddI EC | didanosine enteric-coated | Videx EC | Bristol-Myers Squibb |
| FTC | emtricitabine | Emtriva | Gilead Sciences |
| TNV | tenofovir | Viread | Gilead Sciences |
| TZV | 3TC + ABV + AZT | Trizivir | GlaxoSmithKline |
| Abbreviation | Generic Name | Brand Name | Pharmaceutical Co. |
|---|---|---|---|
| DLV | delavirdine | Rescriptor | Agouron |
| EFV | efavirenz | Sustiva | Bristol-Myers Squibb |
| NVP | nevirapine | Viramune | Boehringer Ingelheim |
| Abbreviation | Generic Name | Brand Name | Pharmaceutical Co. |
|---|---|---|---|
| APV | amprenavir | Agenerase | GlaxoSmithKline |
| ATV | atazanavir | Reyetaz | Bristol-Meyers Squib |
| FPV | fosamprenavir | Lexiva | GlaxoSmithKline |
| IDV | indinavir | Crixivan | Merck |
| LPV | lopinavir + ritonavir | Kaletra | Abbott Laboratories |
| NFV | nelfinavir | Viracept | Agouron |
| RTV | ritonavir | Norvir | Abbott Laboratories |
| SQV (HGC) | saquinavir (Hard Gel Cap) |
Invirase | Hoffman La Roche |
| SQV (SGC) | saquinavir (Soft Gel Cap) |
Fortovase | Hoffman La Roche |
| Abbreviation | Generic Name | Brand Name | Pharmaceutical Co. |
|---|---|---|---|
| T20 | enfuvirtide | Fuzeon | Roche / Trimeris |
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