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Antimicrobial Agents and Chemotherapy

By Lawrence M. Prescott

December 1997

Close to 14,000 physicians, infectious disease specialists, research scientists, and other healthcare professionals from around the world gathered in Toronto, Ontario at the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy to hear about the latest advances in the prevention, treatment, and control of infectious diseases. An area of major concern at this meeting was HIV infection and AIDS. Listed below are some of the highlights of the meeting, with particular emphasis placed on new approaches in antiretroviral therapy.

Efavirenz Enhances Indinavir Therapy Long-Term

Efavirenz (Sustiva®, DuPont Merck), a new investigational anti-HIV agent belonging to the class of drugs known as non-nucleoside reverse transcriptase inhibitors, shows considerable value when used in combination antiretroviral therapy, according to Dr. Douglas L. Mayers, National Naval Medical Center, Bethesda, Maryland. Dosed once daily, efavirenz adds significant anti-HIV activity to therapy with the protease inhibitor indinavir (Crixivan®, Merck) and this activity is maintained long-term up to 48 weeks, the period followed to date. As a further advantage, efavirenz's once-daily dosing and low adverse event profile may improve patients' ability to adhere to prescribed combination regimens.

In a comparison study, 101 asymptomatic or mildly symptomatic HIV-infected persons were randomly assigned to efavirenz 200 mg initially up to 600 mg once daily, plus indinavir 800 to 1000 mg every eight hours (59 patients), or indinavir plus placebo (42 patients), with efavirenz plus d4T (Zerit®, Bristol Meyers Squibb) added to the indinavir arm at week 12. At the end of the 48-week period, 80% of the 90% of combination therapy-treated patients with undetectable plasma HIV-1 RNA (less than 400 copies/mL) in the Amplicor® assay had 0 copies/mL in an ultrasensitive assay. Furthermore, the CD4 count almost doubled in the efavirenz plus indinavir treatment group (approximately +240 cells/mm3), compared to the control group (approximately +150 cells/mm3).

Double Protease Inhibitor Combo Useful in Pretreated HIV-Infected Patients

Preliminary results point out that HIV RNA levels may be suppressed long-term in HIV-infected patients, most of whom had been treated previously with other anti-retroviral agents, when they are treated with a combination of nelfinavir (Viracept®, Agouron) and a new soft gel capsule (SGC) formulation of saquinavir (Fortovase®, Roche), according to Dr. Stephen Kravcik, staff physician, infectious diseases section, Ottawa General Hospital, Ottawa, Ontario, Canada.

Fourteen HIV-positive persons received nelfinavir 750 mg and saquinavir-SGC 800 mg three times daily. The concomitant administration of standard doses of nelfinavir increased patients' exposure to saquinavir SGC five-fold. Viral load fell below the level of detection (less than 500 copies/mL) in eight of the 10 individuals who were treated for 10 months with this combination, and the CD4 count increased by 117.5 cells/mm3.

The HIV mutation uniquely associated with resistance to nelfinavir was not detected in any of the 12 patients studied by genetic analysis after five to seven months of treatment with the protease inhibitor combination. Four persons, however, had mutations associated with decreased saquinavir sensitivity.

D4T/Saquinavir/Ritonavir Combo Produces Potent HIV Suppression

The triple drug regimen of d4T (Zerit®, BMS), a nucleoside analogue, and the two protease inhibitors saquinavir (Invirase®, Roche) and ritonavir (Norvir®, Abbott) achieves a highly potent viral load response. These findings occurred in a small study of patients with advanced HIV disease, with a low incidence of dose-limiting toxicity, stated Dr. Manuel Battegay, internal medicine, University Hospital, Basel, Switzerland, and a spokesperson for the Swiss HIV Cohort Study Group.

In this study, 56 HIV-1 infected patients with moderate to severe immunosuppression and previous antiretroviral therapy were entered into an open-labelled study and given d4T 30 to 40 mg daily, saquinavir 600 mg twice daily and ritonavir 400 to 600 mg twice daily for at least nine weeks. None of these individuals had previously been treated with d4T or protease inhibitors.

In 49 of the patients for whom nine week data were available, viral load fell to undetectable levels (less than 500 copies/mL) in 86% of the treatment group. The CD4 counts also increased by 102 cells/mm3 after nine months. Less than 10% of the patients discontinued study medications because of adverse events.

Ritonavir Addition to Nucleoside Analogues Improves Pediatric Treatment

The first large study in children with HIV comparing protease inhibitor-containing treatments pointed out that the addition of ritonavir (Norvir®, Abbott) to pediatric nucleoside analogue regimens produced significantly higher rates of undetectable HIV RNA at 12 weeks, whether the regimens were double or triple combinations, reported Dr. R. Yogev, Pediatric AIDS Clinical Trial Group, National Institutes of Health, Bethesda, Maryland.

In a randomized, open-label study (PACTG 338), 298 clinically stable, antiretroviral-experienced, HIV-infected children (ages 2-17 years) were randomly assigned to receive either zidovudine (Retrovir®, Glaxo Wellcome) plus 3TC (Epivir®, Glaxo Wellcome); d4T (Zerit®, Bristol Meyers Squibb) plus ritonavir; or zidovudine, 3TC, and ritonavir. At 12 weeks of treatment, an interim analysis of 162 of the youngsters showed that 14% (6/43) on zidovudine plus 3TC, 61% (28/46) on d4T plus ritonavir, and 57% (27/47) on zidovudine, 3TC, and ritonavir reached undetectable (less than 400 copies/mL) levels of HIV RNA. No unexpected drug-related toxicities or clinical progression were observed.

Highly Active Antiretroviral Therapy Reduces Opportunistic Infections

In this relatively new era of highly active anti-retroviral therapy (HAART), there have been promising findings that HAART strongly impacts the incidence of a variety of opportunistic infections in HIV-infected persons. Below are a number of short summaries pointing to the value of this approach

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