Important note: Information in this article was accurate in December 2002. The state of the art may have changed since the publication date.
American Foundation for AIDS Research, December 2002
Gretchen Schmelz Armstrong
More than 2,500 experts gathered in November for Glasgow's biennial International Congress on Drug Therapy in HIV Infection. The conference setting imparted a European flavor to the proceedings, which tackled the ongoing themes of antiretroviral therapy — when to start therapy, how to start, pharmacology and drug toxicities. Metabolic side effects, in particular, garnered a renewed focus.
Scientists have known since 1994 that cells cultured outside the body convert AZT to triphosphorylated d4T—the medically active form of d4T with three phosphates attached. Cells convert AZT, d4T and all other nucleoside analogs to the drugs' biologically active triphosphate forms, but they ordinarily do not convert one drug to another.
Now, Jacques Grassi and his colleagues at the University Hospital of Bicêtre outside of Paris report that the same phenomenon occurs in the body. While perfecting a test to detect triphosphorylated d4T inside cells, the researchers found d4T in cell samples that they expected to test negative. These cells came from volunteers on AZT, not d4T. Grassi subsequently looked at cells from everyone taking AZT in his study and found d4T in every sample. d4T concentrations ranged from 3% to 37% of the concentrations of triphosphorylated AZT.
"We don't find any d4T in the blood," said Grassi. "It is an intracellular process. It is not reversible—people on d4T do not make AZT. That makes sense because chemically that would be very difficult. The concentration of triphosphorylated d4T is always lower than the total concentration of AZT. And also, it is very specific. We do not see this with people not on AZT or d4T therapy."
This discovery raises questions about how much triphosphorylated d4T contributes to AZT's efficacy and toxicity profile. Studies in recent years have implicated d4T as a major factor in peripheral fat loss (lipoatrophy) among people on anti-HIV therapy. d4T also is highly prone to cause such short-term side effects as neuropathy. AZT can lead to reduced levels of red and white blood cells or muscle wasting. These toxicities may result from inhibition of the mitochondria, the cells' energy-producing units.
In addition, prior AZT seems to compromise d4T's effectiveness. Researchers have related this loss of anti-HIV activity to the emergence of drug-resistant HIV and/or decreasing cellular phosphorylation of AZT and d4T.
If there is d4T mixed with the AZT inside cells, either drug's overall effects on both the body and HIV might turn out to be similar. The question is fraught with commercial implications as well as medical ones.
Grassi speculates that so far, because the molecules are so different, it appears that most of AZT's side effects result from AZT itself. But the same may not be true for the few people who convert large amounts of AZT to d4T. "This is an important finding," concluded Grassi, "because this proves that by looking at intracellular metabolism we can see relevant things that may explain particular efficacy and toxicities."
On the experimental drug front, Robert Murphy of Northwestern University in Chicago reported interim 12-week results from BMS AI424-044, a substudy of AI424-008. AI424-008 compared 400 mg or 600 mg atazanavir daily to nelfinavir 1,250 mg twice daily (both combined with d4T/3TC). At the end of the 48-week 008 study, the 69 people assigned to take nelfinavir could switch to the 400 mg atazanavir dose, and 63 did so. The intent of 044 was to observe the changes in blood lipids of those who switched. The substudy also compared the lipid changes with those of the participants who started on atazanavir in the 008 study.
Twelve weeks after switching from nelfinavir to atazanavir, patients' mean lipid levels dropped (total cholesterol, from 213 to 175 mg/dL; low-density lipoprotein cholesterol, from 138 to 104 mg/dL; and triglycerides from 156 to 108 mg/dL). As for adverse events, serious or life-threatening blood bilirubin elevations occurred in 23% of the 400 mg atazanavir group, 35% of the atazanavir 600 mg atazanavir group, and 10% of the group that switched to 400 mg atazanavir after 48 weeks on nelfinavir.
In the latebreaker session, Dirk Schürmann of Charité University Hospital in Berlin shared 48-week results from the 660-person SOLO study. The trial tested a once-daily combination of 1,400 mg fosamprenavir (which the body breaks down into the protease inhibitor amprenavir) plus 200 mg ritonavir against a control consisting of 1,250 mg nelfinavir twice daily. Trial participants also took abacavir and 3TC twice daily.
At 48 weeks, 68% of people in the fosamprenavir/ritonavir arm and 65% of those in the nelfinavir arm suppressed viral load to below 400 copies/mL. According to Schürmann, this was a "noninferiority study." The trial was not designed to show that one treatment was better than the other, and the difference was not statistically significant.
Although more people experienced virologic failure on nelfinavir compared with those on fosamprenavir (15% versus 4%), more people on fosamprenavir prematurely discontinued the study compared with those on nelfinavir (25% versus 15%). The top three adverse events of at least moderate severity were diarrhea (9% versus 16% in the nelfinavir group), nausea (7% versus 5%) and vomiting (6% versus 4%). There was a jump in triglycerides in the fosamprenavir group, from 150 mg/dL at baseline to approximately 240 mg/dL at the end of 48 weeks. The mean increase was not as large in the nelfinavir group, where it increased from 150 mg/dL at baseline to 210 mg/dL in the same period.
These studies reflect the growing concern for diagnosing and ameliorating the alterations in lipid and sugar metabolism that occur during HIV therapy. These metabolic perturbations heighten the risk of heart disease and diabetes. More dramatic are the visible changes in fat distribution — loss of fat below the skin and/or accumulation of fat deposits around the central organs. Clinicians still lack a precise way to measure or diagnose such "lipodystrophy."
A precise diagnostic definition of the lipodystrophy syndrome or syndromes is essential for several reasons, primarily for recording accurate adverse event data in clinical trials and for following patients receiving care. In addition, guidelines for treating lipodystrophy — and third-party payment for treatment — will depend on strict diagnostic criteria.
Conflicting descriptions have emerged from data from the HIV Lipodystrophy Case Definition Study and the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) Study, both of which were presented at Glasgow. "There have been moments in which the differences have become more highlighted than they ought to have been," said William Powderly of Washington University in St. Louis. Powderly was the only clinician who participated in both studies. "I think it is more a reflection of the personalities involved than a truly scientific problem."
In the Case Definition Study led by Andrew Carr of St. Vincent's Hospital in Sydney, Australia, researchers recruited 417 HIV-positive people identified as having lipodystrophy by their doctors' and their own subjective assessment. The researchers additionally recruited 371 HIV-positive people who did not think that they had lipodystrophy, nor did their doctors. Carr then looked for differences between the two groups and came up with scoring system by which a physician could diagnose lipodystrophy with about 80% accuracy.
The factors involved in the lipodystrophy score were age, gender, HIV duration, HIV disease stage, waist-to-hip ratio, anion gap (a measure of blood electrolyte balance), high-density lipoprotein cholesterol, trunk-to-limb fat ratio, leg fat percent and visceral-to-subcutaneous abdominal fat ratio. Using trunk CT and DEXA scans to reveal adipose tissue patterns only slightly improved diagnostic accuracy.
In contrast to the Case Definition study, the FRAM investigators gave questionnaires about body image to both HIV-positive and -negative men. The survey was bi-directional, so participants could report if they noticed gain or loss in peripheral or visceral (central) fat. Trained investigators also independently evaluated the participants. Of the 357 HIV-positive men surveyed so far, 40% reported loss of peripheral fat, and many who reported peripheral fat loss also reported central fat loss. The chief FRAM investigator, Carl Grunfeld of the San Francisco Veterans Affairs Medical Center has concluded that although someone may experience peripheral fat loss and central fat gain, they are not statistically linked. In short, they are two separate syndromes.
"Carl [Grunfeld] is correct in that it does not appear when you look at a large cross-sectional study like FRAM that the two are necessarily linked," said Powderly, who attempted to put both presentations in context. "It is also true as Andrew [Carr] has pointed out that the two tend to occur together. It's unusual to see a patient who exclusively has one or the other. Where there has been some contention and controversy is that the case definition worked on the assumption that it was one syndrome. It didn't discriminate between those that gained or lost fat. It simply asked, ‘Do you think you have lipodystrophy?' Now as it turned out, the majority of those involved in the case definition felt that they had done both. What Grunfeld's data suggest is that the two do not necessarily go hand in hand."
Powderly also stressed that prospective studies will offer a more accurate picture of the syndrome, or syndromes. "The one disadvantage of both of these studies is that they are one-time-only cross-sectional studies, and depending on when you look at the patient and the evolution of these changes, you may see one phenomenon being more prominent over the other. When in fact the data from the prospective studies suggest that these changes are occurring over time."
Radically new types of HIV therapy could help eliminate the lipodystrophy problem (unless it is somehow inherent in recovery from chronic HIV infection). Therapeutic vaccines are one alternative approach that is gaining interest. The concept is to first suppress HIV with antiviral drugs. Then as the immune system recovers, build up anti-HIV immunity by introducing some of the virus's proteins into the body. It is hoped that this induced immunity will ultimately allow patients to discontinue the drugs without experiencing HIV rebound.
At Glasgow, Julianna Lisziewicz of the Research Institute for Genetic and Human Therapy in Washington, DC reviewed DermaVir, a novel topical vaccine developed at her institute. DermaVir contains the DNA form of HIV genes mixed with dextrose, water and a special adjuvant. Rubbing DermaVir on the skin allows the Langerhans cells—dendritic cells of the skin—to absorb the foreign DNA and take it with them as they move into nearby lymph nodes. The vaccine DNA uses the Langerhans cells to make HIV proteins. Segments of these proteins appear on the cell membrane and activate CD4 and CD8 cell defenses that can kill cells infected with real HIV.
Lisziewicz described the results of two monkey studies that used DermaVir in conjunction with antiviral drugs to treat SIV, the monkey version of HIV. In the first study, ten macaques with high SIV viral loads and signs of AIDS were randomized to receive continuous or intermittent therapy. The monkeys receiving intermittent therapy experienced consistent viral rebounds during six successive treatment interruptions. Adding DermaVir to later treatment cycles suppressed viral rebounds from a median 4.3 million copies/mL to less than 200. In the second study, 14 chronically SIV-infected macaques without AIDS were randomized to receive intermittent therapy plus or minus DermaVir. Those on intermittent therapy alone also experienced virus rebounds during treatment interruptions similar to the monkeys with AIDS. The monkeys randomized to also receive DermaVir progressively suppressed viral replication during treatment interruptions from a median 34,000 copies/mL to less than 200. In both studies, decreased viral load rebound correlated with heightened anti-SIV responses by CD4 and CD8 cells.
ACTG A5176, a trial sponsored by the US National Institutes of Health, will be the first trial to study this in humans. This preliminary safety and immunogenicity trial will administer DermaVir to 18 people with drug-suppressed viral loads below 50 copies/mL and CD4 counts above 350 cells/mm3. The investigators will immunize the volunteers with 0.4, 1.6 or 3.2 mg of DermaVir three times at six-week intervals. (Another six volunteers will receive a placebo formulation.)
DermaVir attracted a lot of attention at Glasgow, but the HIV therapeutic vaccine strategy has yet to prove itself after some 14 years of research. It received a new lease on life with the introduction of potent anti-HIV regimens. The drug combinations allow the immune system to function more normally even as their side effects raise qualms about long-term use.
More advanced trials are in progress using anti-HIV drugs plus other therapeutic vaccines, mainly the ALVAC recombinant canary pox vaccine. ALVAC cannot replicate in humans but produces immune-provoking HIV proteins in the cells that it invades after inoculation. Several trials also involve treatment interruptions to see how well vaccinated HIV-positive volunteers can control HIV on their own.
Taking advantage of vaccinated dendritic cells' ability to stimulate the immune system is a new wrinkle, but it is not unique to DermaVir. ACTG trial A5130 uses a method of infecting dendritic cells with ALVAC outside the body and then injecting them back under the source volunteer's skin. This, too, is a preliminary trial. It will enroll 30 persons with drug-suppressed viral loads below 50 copies/mL and CD4 counts above 400 cells/mm3. One arm will receive dendritic cell ALVAC and the other standard injections with ALVAC. Total follow-up time is 66 weeks and will include interruptions in anti-HIV drugs. There will be no information on how effective dendritic cell vaccination is in humans for some time. A comparative evaluation of different vaccines and vaccine strategies, if any of them seem effective, is yet further off.
The Glasgow conference was another demonstration of how much in HIV therapy remains unresolved, if not downright mysterious. On all these topics, further data are expected at the Conference on Retroviruses and Opportunistic Infections, the US national HIV research conference that will take place this February in Boston.
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