New therapy strategies focusing on long term
Drugs’ impact on heart is debated
As several new antiretroviral drugs near Food and Drug Administration approval, treatment strategies are focusing more intensely on the long-term benefits and risks of treatment as patients live longer and face new health problems.
"What is happening now is clinicians are starting to get more creative in tailoring regimens to patients’ concerns and lifestyles," says Douglas Mayers, MD, a researcher at Boehringer Ingelheim Pharmaceuticals in Ingelheim, Germany.
That was one of the louder take-home messages from the 10th Conference on Retroviruses and Opportunistic Infections, held Feb.10-14 in Boston. The conference was short on headline news, especially in the area of treatment. And while several new drugs are nearing FDA approval, most of the studies presented data on drugs that are several years away from reaching the market.
What most distinguishes these new drugs from existing treatment options is that they promise to make therapy not only more effective but simpler to take with fewer side effects.
Longer lives, new health problems
Long-term side effects were on the minds of many researchers, especially the impact of antiretroviral drugs (particularly protease inhibitors) on cardiovascular disease.
Friss Moller, MD, a researcher at the Copenhagen HIV Program, presented a study of 23,468 HIV-positive patients in Europe showing that the risk of having a heart attack while on medication increases 26% per year. Although the number of heart attacks was fairly low — 126 attacks, 36 of which were fatal — the study concluded that being on antiretroviral drugs meant a greater elevation in serum lipid levels.
The Copenhagen study was just one of numerous presentations at the conference showing significant increases in cardiovascular diseases now that patients on highly active antiretroviral therapy (HAART) are living longer. A study from Johns Hopkins University followed 6,711 HIV-positive patients for more than three years. Their risk for having a heart attack was twice as great if they were on protease inhibitors — a higher risk than from smoking cigarettes.
"What we are seeing at this conference is the rates of cardiovascular mortality are starting to go up in HIV patients as they live longer with the disease," Mayers says.
While some of the increase in disease is attributed to lifestyles of patients, many of whom are more likely to smoke and have other heart disease risk factors, some antiretroviral drugs are more risky than others, researchers note. Protease inhibitors, for example, pose the greatest risk because of their effect on increasing serum lipid levels, while non-nucleoside reverse transcriptase inhibitors (NNRTIs) have better lipid profiles.
Boehringer presented new data from its non-nucleoside reverse transcriptase inhibitor, nevirapine (Viramune), that included not only efficacy on viral load but also its impact on cholesterol.
The data came from the first-ever large scale randomized trial directly comparing the safety of two NNRTIs — nevirapine and efavirenz — in combination therapy for HIV-positive drug-naive patients.1
While the two drugs appeared comparable with respect to viral suppression, Boehringer pointed out that nevirapine is not only cheaper than efavirenz, but had a better lipid profile. Specifically, it said patients in the nevirapine regimens experienced a greater increase (37%) in HDL-c ("good") cholesterol than those in the efavirenz regimen (24%) over 48 weeks.
"I think it is becoming increasingly important and obvious that you want to avoid that risk if you can, so I would always go for the drug that is going to give that increase, if you have the option," says Joep Lange, MD, lead investigator for the International Antiviral Therapy Evaluation Center and professor of medicine at the University of Amsterdam.
Bristol-Myers Squibb presented data suggesting that long-term therapy with its protease inhibitor atazanavir resulted in sustained virologic suppression. Moreover, patients switching to atazanavir from nelfinavir (another protease inhibitor) exhibited not only improved virologic suppression but also a significant decrease in serum lipid levels.
Data from the long-term, open-label observational switch study showed that patients who switched from nelfinavir to atazanavir for 24 weeks of treatment experienced improved virologic suppression and a clinically significant reduction of total cholesterol, LDL (bad cholesterol) and triglycerides.
Bristol-Myers Squibb recently submitted a new drug application to the Food and Drug Administration (FDA) for atazanavir, an azapeptide viral protease inhibitor of HIV-1. It is the first new application for a protease inhibitor to be submitted with pharmacokinetic data supporting the potential for once-daily administration.
VA study contradicts other findings
Not all data emerging on cardiovascular disease are showing increased risk. A new study of more than 36,000 patients treated for HIV at Veterans Affairs health care facilities from 1993 to 2001 found a steady drop in the rate of deaths and hospital stays due to vascular problems.
"Fears about vascular disease as a side effect of these drugs shouldn’t keep patients and their doctors from using the best treatments available," says study leader Samuel Bozzetta, MD, an infectious disease specialist at the VA San Diego Health Care System.
The study, appearing in the Feb. 20 issue of the New England Journal of Medicine, may reassure doctors and patients who see benefits from HAART but worry about vascular complications, among other side effects.
As a caveat, however, Bozzetta warned that the study followed patients for only eight years, and that the findings may not reflect the seriousness of vascular disease with long-term HAART.
One problem is not knowing whether HIV itself can cause vascular disease. Indeed, some research has shown that HAART may protect against heart damage by suppressing the virus, he noted.
Other drugs in the pipeline
One of several new experimental drugs before the FDA is a enfurvitide (Fuzeon), a fusion inhibitor manufactured by Durham, NC-based Trimeris. A new class of drugs, fusion inhibitors block HIV from fusing with healthy cells. Enfurvitide is the furthest along in this family of drugs and is expected to receive FDA approval in March.
New data on an offspring of enfurvitide, T-1249, was presented at the conference.2 The study showed that patients who had developed resistance while on enfurvitide experienced a 92% average reduction in viral load after switching to T-1249, which is several years behind development and will begin Phase II trials later this year.
Another first in a new class of drugs is Tipranavir, a non-peptidic protease inhibitor manufactured by Boehringer Ingelheim Pharmaceuticals. A Phase II study of the drug in highly experienced HIV-positive patients showed significant reduction in viral loads. Large studies evaluating different doses of the drug are beginning at more than 280 centers in North America, Europe and Australia.
"These preliminary results suggest that tipranavir may be a promising option for patients who have few or no treatment options because of drug resistance," says Joseph Gathe, MD, a researcher at Therapeutic Concepts in Houston.
The first clinical data on TMC114, a next-generation protease inhibitor, showed significant antiviral activity in multiple PI-experienced HIV patients currently failing PI therapy. In the 50-patient study, the median reduction in plasma viral load was -1.35 log10 copies/ml HIV-1 RNA after 14 days of treatment.3
TMC114 is being developed by Tibotec, a Belgian pharmaceutical research and development company.
"These early clinical results of TMC114 in highly treatment-experienced patients are very positive" commented Wim Parys, MD, vice president of clinical development at Tibotec. "TMC114 was selected for clinical development on the basis of its novel in vitro antiviral profile and potency against PI-resistant HIV."
References
1. Van Leth F, Phanuphak P, Gazzard B, et al. Lipid changes in a randomized comparative trial of first-line antiretroviral therapy with regimens containing either nevirapine alone, efavirenz alone or both drugs combined, together with stavudine and lamivudine (2NN Study). Presented at the 10th Conference on Retroviruses and Opportunistic Infections. Boston; Feb. 10-14, 2003. Abstract No. 93.
2. Miralles G, Lalezari J, Bellos N, et al. T-1249 demonstrates potent antiviral activity over 10-day dosing in most patients who have failed a regimen containing enfurvitide. Presented at the 10th Conference on Retroviruses and Opportunistic Infections. Boston; Feb. 10-14, 2003. Abstract No. 141b.
3. Arasteh K, Clumeck N, Pozniak A, et al. First clinical trial results on antiretroviral activity, pharmacokinetics, and safety of TMC114. Presented at the 10th Conference on Retroviruses and Opportunistic Infections. Boston; Feb. 10-14, 2003. Abstract No. 8.
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