NEWS BRIEFS.

Protein linked to HIV entry.

A protein molecule found in dendritic cells, which commonly line the rectum, cervix and vagina, appears to be the means of transportation allowing HIV to enter the body. Research published in Cell (100, p. 587, 2000) identifies the protein, named DC-SIGN, as a key molecule that readily attaches to HIV and may actually help protect the virus from deterioration as it is transported to the lymph nodes. Another study published in AIDS (14, p. 647, 2000) implicates Langerhans cells in the transmission of HIV. Langerhans cells are dendritic, recirculating, antigen presenting cells found in the epidermis. These cells are believed to transmit HIV to lymphoid tissues where viral infection oft lymphocytes then occurs.

HIV infection, smoking and emphysema.

Researchers at Ohio State University have found that HIV may accelerate the onset of emphysema for infected patients who smoke. The conclusions, published in the Annals of Internal Medicine (132, p. 369, 2000), are based on a cross-sectional study that looked at 114 HIV-infected individuals who did not have AIDS-related pulmonary complications. These subjects were matched with 44 uninfected controls based on smoking history and age. While emphysema was identified in only 1 of the 44 controls (just over 2%), 17 of the 114 HIV-infected subjects developed emphysema (almost 15%). The median age of the subjects was 33 years, a relatively young age to be developing this disease. The researchers believe that cytotoxic T lymphocytes play a role in the pathogenesis of emphysema.

Quadruple HAART therapy?

A report from SPICE, a multicenter trial in Europe, suggests that quadruple highly active antiretroviral therapy (HAART) may be more effective than triple therapy in patients with high viral loads or who are antiretroviral experienced. Patients with baseline viral loads of 10,000 copies/mL or greater were assigned to 1 of 4 treatment arms:

A. saquinavir (Fortovase) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs),

B. nelfinavir (Viracept) plus 2 NRTIs,

C. saquinavir/nelfinavir with 2 NRTIs or

D. saquinavir/nelfinavir.

By intent to treat analysis at 48 weeks, 47% of patients in group C (quadruple therapy) had viral loads less than 50 copies/mL compared to 42%, 38% and 26% for groups A, B and D, respectively. Patients with viral loads less than 400 copies/mL at 48 weeks were 61% for group C compared to 42% for group A, 50% for group B and 39% for group D. Patients in group C had significantly longer time to relapse (as defined in the study). The authors state that at least 50% of study participants were antiretroviral therapy naive, and that subjects were stratified according to whether they had received previous antiretroviral therapy. However, data were not presented according to stratification. Complete results of the study are published in the Journal of Acquired Immune Deficiency Syndromes (23, p. 128, 2000).

Clarithromycin appears safe with indinavir or amprenavir.

Two recent studies have concluded that the co-administration of clarithromycin and amprenavir (Agenerase) or clarithromycin and indinavir (Crixivan) is safe. The first study (Antimicrob Agents Chemother, 44, p. 978, 2000) found that clarithromycin increased levels of amprenavir in healthy subjects by 18% and lowered the total clearance of amprenavir by 15%. However, the interactions observed are not considered clinically significant. Amprenavir had no effect on the pharmacokinetics of clarithromycin. The second study (Clin Pharmacol Ther, 67, p. 351,. 2000) showed that the co-administration of indinavir and clarithromycin increased the plasma concentrations of both drugs and decreased levels of a clarithromycin metabolite. These interactions are also not considered clinically significant.

ABT-378/r interaction with efavirenz.

A recent report from Study M98-957, an ongoing Phase II study in which efavirenz (Sustiva) is co-administered with ABT-378/r (lopinavir), has found an interaction between the two drugs. The study is being conducted in patients who are experienced with multiple protease inhibitors but who have not been treated with non-nucleoside reverse transcriptase inhibitors (NNRTIs). The study showed that efavirenz lowers the trough levels of lopinavir in the blood. High trough levels of protease inhibitors are considered important for achieving maximum antiviral activity. Lopinavir is coformulated with the drug ritonavir (Norvir). Abbott Laboratories (the maker of lopinavir) recommends that the dose of lopinavir be increased to 4 capsules every 12 hours. The normal dose is 3 capsules every 12 hours.

Weighing the potential benefits of dual NRTI therapy.

French researchers reported results from a study of 130 members of an observational patient cohort (J Acquir Immune Defic Syndr, 23, p. 255, 2000). Subjects were antiretroviral naive HIV-infected patients who started with CD4 T cell counts greater than 350 cells/[mm.sup.3]. Median baseline viral load was 33,100 copies/mL (range 11,400-86,000 copies/mL). Most subjects (75%) were given zidovudine (Retrovir) plus zalcitabine (Hivid) or zidovudine plus didanosine (Videx). The researchers found that after one year of dual NRTI antiretroviral therapy, the median CD4 T cell count increased by 80 cells/[mm.sup.3], with 96% of patients remaining at levels greater than 350 cells/[mm.sup.3]. The median viral load decreased by 1.6 log. This report did not describe the development of viral resistance or mutations. The researchers stated that the study indicates better virologic performance of a dual NRTI regimen in patients with moderate or low HIV RNA levels. They also postulated that other combinations, such as didanosine plus stavudine (Zerit), might have produced better virologic or immunologic effects. In conclusion, they suggested "good immunologic results even without corresponding virologic success can be associated with favorable clinical outcome." The authors also noted that holding back antiretroviral therapy is an alternative at early stages of HIV infection, but that patients should be subject to "regular clinical, immunologic, and virologic surveillance." They recommend further studies to compare the benefits and risks of these different therapeutic strategies in moderately immunosuppressed patients.

NIH begins study of Remune.

Clinical studies of the therapeutic vaccine Remune conducted by the National Institutes of Health (NIH) are set to begin in the US. The vaccine will be compared to standard antiretroviral drug therapy for HIV. The study will involve 472 volunteers and will be completed over 96 weeks. As of this issue's publication, enrollment in this study has been halted pending protocol revision.

Revised labeling for amprenavir oral solution.

The labeling for amprenavir oral solution has been changed because of potential safety concerns with the drug's high propylene glycol content. The solution is contraindicated in infants and children under 4 years of age, pregnant women, patients with hepatic (liver) or renal (kidney) failure and patients being treated with disulfiram or metronidazole (Flagyl). In addition, some patients, including certain ethnic populations (Asians, Eskimos, Native Americans) and women, may not be able to adequately metabolize and eliminate propylene glycol and should be aware of the potential for adverse events. Drinking alcoholic beverages is not recommended while taking amprenavir oral solution. Patients taking the solution should be monitored for adverse events associated with excess propylene glycol intake, including seizures, stupor, tachycardia (rapid heart rate), hyperosmolality (excessive ion concentrations in the plasma, characterized in part by increased thirst), lactic acidosis, renal toxicity and hemolysis (the destruction of red blood cells). Propylene glycol can be removed from the body by hemodialysis. Amprenavir oral solution should only be used when amprenavir capsules or other protease inhibitor formulations cannot be used. Whenever possible, switching patients from the solution to the capsule form of amprenavir is recommended. Adverse reactions should be reported to the FDA MedWatch program (800.332.1088). For more information contact Glaxo Wellcome at 888.825.5249.

More evidence of osteoporosis with PIs.

A study published in AIDS (14, p. F63, 2000) confirms a link between the use of protease inhibitors (PIs) and decreased bone mineral density, clinically known as that included PIs. Another 35 subjects were HIV-infected but not taking PIs, and 17 subjects were HIV-negative. The investigators evaluated overall bone density and bone density in thigh bone. The measurements in 50% of those subjects taking PIs showed signs of osteoporosis and osteopenia. The risk of developing osteoporosis was more than twice as high in the group taking PIs than in the HIV-negative controls. The researchers also concluded that these risks were independent of metabolic complications associated with body fat redistribution.

Study links diabetes with PI use.

Research published in the Journal of Biological Chemistry (In Press) has found that PIs inhibit insulin-stimulated glucose uptake in adipocytes (fat cells). This effect was dose-dependent, and was particularly evident with the glucose transport protein Glut4. Indinavir was tested, but the effects were also seen with amprenavir and ritonavir, thus implicating the entire class of PIs. The researchers suggest that this mechanism may be the direct cause of insulin resistance observed in HIV-infected patients who take PIs. They also note that insulin resistance appears to precede symptoms of fat redistribution ("lipodystrophy) and therefore may be a cause.

...And on a positive note.

Therapy with PIs appears to inhibit CD4 and CD8 T cell apoptosis (programme cell death), possibly explaining in part the rise in CD4 T cell counts often seen in response to HAART. Studies in vitro and in vivo showed significant inhibition of apoptosis in these cell populations. These effects were not seen with reverse transcriptase inhibitors. The work, published in AIDS Research and Human Retrovirus (16, p.559, 2000), suggests that the inhibition of apoptosis is a distinct mechanism from the drugs' suppression of viral load.