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Highlights of the 40th Interscience
Conference on Antimicrobial Agents and Chemotherapy (ICAAC)

January 2001

More than 16,000 physicians, infectious disease specialists, and other healthcare professionals from around the world met in Toronto, Ontario in September 2000 to hear the latest findings in the prevention, control, and treatment of infectious diseases. As is usual at this meeting, special consideration was given to HIV/ AIDS. Particular emphasis was placed on improving and simplifying antiretroviral treatment regimens, identifying risk factors to predict disease progression and delineating reasons for enhanced patient adherence. Listed below are summaries of some of these presentations.

Risk Factors Identified to Predict Short-Term Prognosis in HIV-Infected Patients

Using data collected from a large-scale European study, risk factors have been identified which predict clinical disease progression for HIV-infected patients on highly active antiretroviral therapy (HAART), according to Dr. Jens D. Lundgren, Hvidovre University Hospital, Hvidovre, Denmark.

"Most recently measured CD4 cell count, viral load, and hemoglobin were all independently related to the risk of clinical progression, as was the diagnosis of AIDS before starting HAART," Dr. Lundgren stated. "Using a score determined by adding the values calculated for each of these four independent risk factors can help the physician assess how well the antiretroviral therapy is working as well as the need for other therapies."

Until now, the risk factors for clinical disease progression for patients with HIV on HAART have been poorly defined. If these risk factors could be identified and a scoring system developed, physicians might more effectively treat their patients. In an attempt to determine the factors related to clinical progression and to derive a scoring system, 1847 patients previously enrolled in the EuroSIDA study, all of whom had CD4 cell counts, hemoglobin levels and HIV viral loads taken before and after initiation of HAART, were evaluated.

Overall, 154 of the patients experienced clinical progression after HAART was started. Of these clinical events, 45 were deaths, 65 were the first AIDS defining illness, and 44 were progressing to a new AIDS defining event. Groupings of the laboratory results permitted a scoring system to be established to assess clinical progression.

Protease Inhibitor Boosting Enhances Saquinavir Therapy

Protease inhibitor boosting, combining low-dose ritonavir (NorvirR, Abbott Labs) with another protease inhibitor, has been shown to enhance saquinavir (FortovaseR, Hoffmann-La Roche) therapy, while simplifying the overall therapeutic regimen, according to Dr. Calvin Cohen, research director of the Community Research Initiative of New England, and clinical instructor of medicine at Harvard Medical School in Boston.

"The theme of the year 2000 is using clinical pharmacology to maximize the success of treatment, Dr. Cohen stated. "With boosting, exposure of the PIs is increased so that effective plasma levels can be maintained for a longer period of time. Also, the patient's pill burden is decreased and, since ritonavir is at such a low dose, there is no need to take the drug with food."

Recent data has pointed out that when low-dose ritonavir is given together with saquinavir, the boosting effect is maximized for saquinavir. In patients with sensitive strains (wild type) of HIV, 1600 mg/100 mg once daily saquinavir/ritonavir has proven to be comparable to saquinavir given alone at 1200 mg three times daily, resulting in continued or improved viral suppression and a sustained increase in CD4 cell counts in the majority of patients. In patients with resistant HIV strains, higher drug concentrations are needed, so a 1000 mg/100 mg saquinavir/ritonavir regimen is recommended twice daily. This concept of once daily dosing for sensitive viruses and twice daily dosing for resistant viruses has been supported by data from pharmacological studies.

Replacing PI with Abacavir Simplifies Therapy

Replacing the protease inhibitor with the nucleoside analogue abacavir (ZiagenR, Glaxo Wellcome) in the patient's HAART regimen results in sustained virological suppression and a reduction in toxicity, while simplifying therapy and markedly improving patients' treatment satisfaction and lifestyle impact, stated Julio S. G. Montaner, M.D., an infectious disease specialist at St. Paul Hospital, Vancouver, British Columbia.

While protease inhibitor-containing HAART has proven efficacy, regimens are complex and may have long-term toxicity. In an attempt to simplify therapy and reduce toxicity, 105 patients on protease inhibitor-based regimen had the protease inhibitor switched to abacavir and 106 patients continued on the protease inhibitor. Plasma viral load was less than 50 copies/ml at screening, with no history of virological failure.

At 48 weeks followup, there were 13 treatment failures in the simplified therapy group (4 virological failures, 5 treatment-limiting toxicity, 4 other reasons) versus 26 treatment failures in the patients who continued on protease inhibitor (2 virologic failures, 15 treatment-limiting toxicity, 9 other reasons). If the measure of undetectable viral load was less than 50 copies/ml instead of less than 400 copies/ml, there were 11 virological failures in each group. Overall, however, time to treatment failure was much longer in the simplified abacavir arm. The CD4 cell counts were unchanged for both study groups. Early evidence of triglyceride and cholesterol reduction was seen in the patients on the abacavir-based regimen at week 16 of therapy.

Beginning at time zero up to 48 weeks of treatment, patients self-reported adherence and perceptions as to treatment satisfaction and lifestyle impact. At 48 weeks, adherence was reported in 92% of the abacavir group compared to 69% in the patients who continued on protease inhibitors. Treatment satisfaction improved by 22% compared to baseline in the abacavir arm and lifestyle impact improved by 33%, versus no change in either parameter for the protease inhibitor arm.

Nevirapine Combination Shows Greater Response Against HIV Than PI Combination

Preliminary data from the international COMBINE (Combivir-Nevirapine) Study strongly suggests that CombivirTM (ZDV 300 mg/3TC 150 mg, GlaxoWellcome) plus the nonnucleoside reverse transcriptase inhibitor (NNRTI) nevirapine (ViramuneR, Boehringer Ingelheim) was more effective in reducing HIV below the level of detection than a regimen of the protease inhibitor (PI) nelfinavir (ViraceptR, Agouron) plus Combivir, according to Daniel Podzamezer, M.D., professor of medicine, Hospital Princeps d'Espanya, Barcelona, Spain.

"This is important because the nevirapine-based regimen is much simpler for patients, requiring only two tablets in the morning and two in the evening," Dr. Podzamezer said. The COMBINE trial is a randomized, open, multicenter trial of 142 HIV-infected, previously untreated patients in 12 hospitals in Spain and Argentina. The study compares Combivir plus nelfinavir 250 mg twice daily or Combivir plus nevirapine 200 mg bid. A final analysis of the study is planned at 48 weeks.

All patients have completed nine months of followup. Close to 80% of patients had a baseline HIV RNA of over 100,000 copies/ml. At the 36 week followup, the proportion of patients, in the intent-to-treat analysis, with undectable levels of HIV (less than 200 copies/ml) was 70.8% of patients on the nevirapine-based regimen versus 55.5% for those in the nelfinavir-based regimen. The regimens were generally well tolerated, although some serious adverse events were reported. Overall, 39% of patients discontinued treatment, 18% due to intolerance and the remainder lost to followup. Discontinuation in the Combivir plus nelfinavir arm was usually due to gastro-intestinal symptoms, while in the Combivir plus nelfinavir, discontinuation was due to anemia and/or neutropenia.

No Difference in Adherence in Antiretroviral Regimens with Once or Twice Daily Agents

A survey, comparing adherence rates in HIV-infected persons taking combination therapy containing either nelfinavir (ViraceptR, Agouron) twice daily, nevirapine (ViramuneR, Boehringer Ingelheim) twice daily, or efavirenz (SustivaR, Dupont), once daily, when given together with two nucleoside reverse transcriptase inhibitors, show no difference in patient adherence to therapy; whether, protease inhibitor (PI) versus non-nucleoside reverse transcriptase inhibitor (NNRTI) or once daily versus twice daily, reported Andrew D. Luber, Pharm.D., executive director, Pacific Oak Research, Beverly Hills, California.

In this prospective multicenter study, utilizing an anonymous adherence survey, 206 HIV-infected adults receiving either nelfinavir twice daily (57 patients) or the NNRTIs efavirenz once daily (75 patients) or nevirapine twice daily (73 patients) as part of combination therapy containing two NNRTIs were surveyed for adherence to therapy. The objectives for the study were to identify the rate of adherence and compare adherence rates of twice daily dosing of nelfinavir with NNRTI-based therapies and to identify factors for non-adherence between the two types of therapies.

The data collected from this survey point out that once-daily and twice-daily regimens are the same in adherence rates, findings similar to those reported with other disease states. Chief reasons for non-adherence were simple forgetfulness, being busy with other things, or change in daily routine.

Novel Antifungal Agent Effective Against Esophageal Candidiasis

V-Echinocandin (Versicor Inc.), a novel antifungal agent, has been shown to be a safe and effective treatment for esophageal candidiasis, a fungal infection often seen in patients with AIDS, reported Richard J. White, Ph.D., chief scientific officer for Versicor, Inc., Fremont, California, and one of the co-authors of the study.

V-Echinocandin is one of a new class of antifungals known as the echinocandins, agents which destroy fungi rather than just inhibiting their growth. This is the first new group of antifungal agents in nearly 40 years and its prototype, V-Echinocandin, is being developed as a parenteral treatment for serious life-threatening systemic fungal infections.

In an open-label, randomized, international, multicenter study, 36 persons with esophageal candidiasis, 91.7% (33 pts) with AIDS, were randomized to a loading dose of 50 mg of V-Echinocandin followed by daily maintenance doses of 25 mg (50/25) or a loading dose of 70 mg followed by daily maintenance doses of 35 mg (70/35). For both treatment groups, the maximum treatment period was 14 to 21 days (therapy could be stopped on or after day 14 if clinical symptoms resolved.)

At study end, 29 of the 36 patients were evaluable, 16 persons on 50/25 and 13 individuals on 70/35 regimens. Assessment by endoscopy, a well-established procedure that evaluates clinical improvement, demonstrated an efficacy rate of 81% (13/16 patients) in the 50/25 treated patients and 85% (11 of 13 patients) for the 70/35 group, a trend toward improved efficacy being seen at the higher dose. The two treatment regimens had no clinically significant differences in safety and there were no drug-related serious adverse events.

Lawrence M. Prescott, Ph.D. is a freelance medical writer and a frequent contributor to Body Positive. He was previously employed as an infectious disease specialist with the World Health Organization.

Back to the January 2001 Issue of Body Positive Magazine.

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This article was provided by Body Positive. It is a part of the publication Body Positive.