Highlights of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)
More than 11,000 physicians, infectious diseases specialists, research scientists, healthcare professionals, and members of patient advocacy groups gathered from around the world at the 41st ICAAC, held in Chicago, Illinois, from December 16-19, 2001, to hear the latest developments in the monitoring, prevention, control, and treatment of infectious diseases. As usual at this meeting, special consideration was given to HIV/AIDS. Particular emphasis was placed on the prevalence of antiretroviral resistance in the USA, using an enhanced assay for measuring drug susceptibility, a novel triple nucleoside combination in one capsule for more convenient dosing, the value of proactive treatment switching, the improvement and simplification of antiretroviral regimens, and new antiretrovirals, particularly those with activity in treatment-experienced patients with high levels of nucleoside resistance.
The first estimate of HIV drug resistance in the HIV-infected population as a whole, during the first three years of HAART (highly active antiretroviral therapy) (1996-1999) strongly suggests that this is much higher than initially thought, with more than three-quarters of HIV patients with a measurable viral load who are taking antiretroviral agents in the U.S. carrying viral strains resistant to at least one of the drugs they are on, reported Dr. Douglas D. Richman, professor of medicine and pathology, Center for AIDS Research, University of California, San Diego, and director of the Research Center for AIDS and HIV Infection, Department of Veterans' Affairs San Diego Health Care System, San Diego, California.
Blood plasma samples taken in 1999 from 1647 men and women enrolled in the HIV Cost and Service Utilization Study (HCSUS), a longitudinal study representative of all HIV-infected adults throughout the U.S. who received medical care in early 1996, were evaluated for HIV drug susceptibility. Resistance assays were performed on banked frozen (-70°C) specimens of plasma collected from each subject at enrollment. The HIV drug susceptibility was determined by testing plasma samples, using the PhenoSense HIV-1 assay (Virologic) a new phenotypic assay. This approach has been shown to significantly enhance viral resistance testing. Of the 1647 samples, 1167 (71%) has more than 500 HIV RNA copies/ml, and 1080 (93%) of these were successfully pheno-typed. Results were weighted to represent the 132,442 (63%) of the 209,000 US adult HIV patients under care in early 1996 who survived until 1999, who had more than 500 HIV RNA copies/ml.
The estimated prevalence of individuals with signs of drug resistance to at least one of the drugs in their treatment regimen was 78%, while 51% of patients had resistance to more than one antiretroviral agent. The prevalence of drug resistance varied by drug class, being 70% for nucleoside reverse transcriptase inhibitors (NRTI), 31% for non-nucleoside reverse transcriptase inhibitors (NNRTI), and 42% for protease inhibitors. Also, the prevalence of resistance was significantly higher in persons taking antiretroviral "cocktails" of three or more drugs at the time of testing (87%) than those who had received antiretroviral therapy but stopped before testing (41%).
While drug resistance is most commonly seen in patients receiving treatment, up to 20% of newly diagnosed HIV-infected patients have a resistant form of the virus, even before they themselves start antiretroviral therapy. Interestingly, factors linked to better access to HIV treatment were correlated with increased drug resistance. Most at risk were non-Hispanic white males, men having sex with other men, and those with higher education and private medical insurance. On the other hand, patients with more expert and experienced health providers have a better outcome.
These findings point to the importance of drug resistance testing as this can identify which drugs will or will not be effective for a patient. Unfortunately, resistance testing varies around the United States, with some insurance carriers providing coverage and some who do not. In California and a number of other states, however, this has become the standard of care.
Results from the TRIZAL study point out that replacing current triple highly antiretroviral therapy (HAART) with the single tablet combination of lamivudine, zidovudine, and abacavir (TrizivirTM, GlaxoSmithKline) offers a class-sparing simplified maintenance therapy for HIV-infected individuals, with equivalent efficacy to continued HAART, according to Dr. Christine Katlama, infectious diseases specialist, tropical, parasitic, and infectious diseases service, Hopital Pitie Salpetriere, Paris, France.
In an open-label comparison study of current triple HAART versus a switch to Trizivir, 209 patients were randomized to receive either Trizivir (106 pts) or to continue HAART (103 pts). Patients with plasma HIV-1 RNA less than 400 copies/mL for the previous six months and less than 50 copies/mL at screening were enrolled. Efficacy, safety, tolerability, adherence, and patient satisfaction were assessed after 48 weeks. The primary endpoint was treatment failure defined as virologic failure (2 consecutive HIV-1 RNA values over 400 copies/mL) or premature discontinuation of randomized treatment by 48 weeks. Treatment adherence was measured by a patient self-report questionnaire.
At week 48, proportions of treatment failures were equivalent in the Trizivir (22% 23/106) and continued HAART (22% 23/103) arms of the study. Virologic failure occurred in the first 24 weeks in five patients on Trizivir and one patient on continued HAART but three of the five in the Trizivir arm reached HIV/RNA less than 400 copies/mL by week 48. Premature discontinuation took place in 18 Trizivir-treated patients, 11 due to suspected hypersensitivity reaction, versus 22 patients on continued HAART. Furthermore, significant decreases in fasting total cholesterol and triglycerides were noted in the Trizivir arm of the study. Also, patients on Trizivir found their treatment easier to take.
Data from a multi-site study demonstrates that in opiate dependent patients with concurrent HIV disease and hepatitis C disease, the combination of the protease inhibitor nelfinavir (Viracept®, Agouron) as part of the antiretroviral therapy and methadone (Roxane) is safe, well tolerated, effective and durable, stated Dr. Lawrence S. Brown, Jr., senior vice president, Addiction Research and Treatment Corporation, Brooklyn, New York, and Clinical Associate Professor of Public Health, Weill Medical College of Cornell University, New York, New York.
Drug addiction is a continuing and major risk behavior associated with HIV disease and hepatitis C disease. Substance abuse is associated with a higher risk of hepatic toxicity in patients with concurrent HIV and hepatitis C infections, especially because of the potential for hepatotoxicity caused by antiretroviral agents, particularly some protease inhibitors. A retrospective chart review was carried out to identify persons at risk with HIV and hepatitis C co-infection enrolled in a large multi-clinical methadone maintenance treatment agency encompassing a total population of 2,800 patients who were being treated for drug addiction. Patients in the study must have nelfinavir as part of their antiretroviral therapy and must have been on a stable methadone dose for a month prior to initiating nelfinavir.
As of this report, 32 patients have been identified meeting those criteria, and have data available. Of these patients, 29 had been on a stable dose of methadone for 30 days or longer before starting nelfinavir treatment. Only two of the 29 patients reported nelfinavir-related diarrhea and both were moderate cases. The median length of nelfinavir treatment was 22 months. The prevalence of methadone dose adjustment by patients was only 17%, albeit 80% the patients had their methadone adjusted by a clinician. None of these HIV and hepatitis C co-infected patients needed to switch off of their nelfinavir-containing regimen either because of virologic failure or due to drug-related adverse events, demonstrating the efficacy, safety and durability of this approach. Further studies are needed to corroborate these findings.
Tenofovir DF (VireadTM, Gilead Sciences), a nucleotide analogue reverse transcriptase inhibitor (NtRTI) active against wild type and nucleoside-resistant HIV, has been shown to provide continued antiviral activity in treatment experienced patients with high levels of nucleoside resistance prior to tenofovir DF therapy, said Dr. Robert Schooley, professor of medicine and head of infectious diseases, University of Colorado, Denver, Colorado.
To reach these conclusions, a study was carried out consisting of a blinded phase (48-week randomized, placebo-controlled trial) and an open-label phase (median 100-week extension study). The blinded phase was a double-blind, placebo-controlled study in which 189 highly treatment-experienced HIV-positive patients were randomly assigned to placebo or tenofovir DF 75 mg, 150 mg, or 300 mg, administered in combination with their stable antiretroviral therapy, once daily as a single tablet for 24 weeks. At 24 weeks, the placebo group was switched to tenofovir DF 300 mg, with everything else remaining the same. Throughout the 48 weeks of treatment, tenofovir 300 mg once daily provided continued antiretroviral suppression, even considering that 94% of the study population had NRTI-associated resistant mutations at baseline and had been on antiretroviral therapy (ART) for at least 4.6 years.
After 48 weeks in the blinded phase, patients could elect to receive open-label tenofovir DF in the extension phase. A total of 135 patients who had completed the blinded phase elected to receive tenofovir DF 300 mg once daily along with background ART. Throughout 96 weeks or more of treatment, there has been infrequent (3%) development of retroviral therapy (RT) mutations and continued HIV RNA suppression. Also, at nearly two years, tenofovir DF 300 mg was well tolerated and the long term safety profile of the drug was comparable to that observed in the 24 week placebo-controlled period.
Saquinavir soft gel capsules (SQV) (Fortovase®, Roche) plus mini-dose ritonavir (RTV) (Norvir®, Abbott) once daily therapy provides potent HIV suppression and tolerability in a convenient, once-daily protease inhibitor regimen, according to Dr. Julio S. G. Montaner, Chair, AIDS Research, St. Paul's Hospital and University of British Columbia, Vancouver, British Columbia.
Based on SQV pharmacokinetics and the capability of ritonavir to enhance SQV therapy, a study was set up to evaluate the antiviral activity and the safety of a SQV/mini-dose RTV once-daily regimen to that of efavirenz (Sustiva®, Dupont) in HIV-positive patients. A total of 159 antiretroviral-naive patients with HIV RNA >5,000 copies per mL were randomized to either SQV 1600 mg plus RTV 100 mg once daily or efavirenz 600 mg once-a-day plus RTV 100 mg once daily or efavirenz 600 mg once-a-day, for 48 weeks, each in combination with two nucleoside analogs.
At baseline, the mean viral load was 4.78 log10 copies/mL in the SQV/RTV group and 4.72 log10 copies/mL in those receiving efavirenz and the mean CD4 cell counts/µL were 372 and 341 respectively. On-treatment analysis on HIV RNA below the level of quantification (BLQ 400) was 97% in patients treated with SQV/RTV and 94% in the efavirenz group and BLQ 50 of 83% and 90% respectively. The mean increase in CD4 cell count was +166 on SQV/RTV and +144 on efavirenz. Both regimens were well tolerated.
Preliminary data from a comparison study of epoetin alfa (Procrit®, Ortho Biotech) points out that a once-weekly dosing schedule of epoetin alfa is as safe and effective as a three times weekly dosing schedule in increasing hemoglobin levels and improving quality of life in the treatment of anemia in HIV-positive patients on antiretroviral therapy, declared Dr. Howard Grossman, Columbia University College of Physicians and Surgeons, New York, New York.
Epoetin alfa is indicated for three times-weekly dosing in the treatment of anemia related to therapy with zidovudine in HIV-positive patients. It is generally well tolerated and any adverse experiences supposedly associated with epoetin alfa are actually believed to be related to the disease process of acquired immunodeficiency syndrome, not to therapy with epoetin alfa. In this multicenter open-label study, 174 HIV-positive patients with hemoglobin levels of less than 12 g/dL while receiving antiretroviral therapy were randomized to receive either epoetin alfa 40,000 U once weekly (91 pts) or epoetin alfa 100/kg three times weekly (83 pts) for 16 weeks, with both schedules administered subcutaneously. The efficiency endpoints in this study were hemoglobin normalization and improvement of quality of life.
An interim analysis of the 16-week data demonstrated that the mean change in hemoglobin from baseline to end of study period in the once weekly group was 2.8 g/dL + 1.99 and 22.4 g/dL + 2.4 in the three times a week group. A significant improvement was noted in both hemoglobin levels and quality of life in both a study groups at 8 weeks that was maintained until the end of the study. There were no significant differences between the once weekly or three times weekly treatment regimens in either hemoglobin levels or quality of life at the last measurement. Both methods of epoetin alfa administration were well tolerated in this trial.
Art by Carlos N. Molina.
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.
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