Highlights of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)
In a phase III, multicenter, international, randomized, open-label, parallel group, 48-week study, 251 patients were randomized in a 2:1 fashion to receive either 908 1,400 mg (2 tablets twice daily) or 1,250 mg of nelfinavir (5 tablets twice daily). Both groups took the medications in combination with abacavir (Ziagen, GlaxoSmithKline) 300 mg twice daily and lamivudine (3TC) (Epivir, GlaxoSmithKline 150 mg twice daily.
Nelfinavir was selected as the comparator arm since it is a commonly used PI in this patient population. In addition, the study was conducted as an open-label trial to more accurately reflect the real-world differences in pill burden between the two regimens (2 tablets of 908 twice a day versus 5 tablets of nelfinavir twice a day). It also should be noted that this study had considerable ethnic and gender diversity with 44 percent of patients being Hispanic, 31 percent being of African descent, and 31 percent of the total group being female.
At 24 weeks, 73 percent of 166 patients taking 908 achieved undetectable viral loads (<400 copies/mL) compared to 54 percent of 83 patients who received nelfinavir. Among persons with a high viral load (>10,000 copies/mL), 908 showed greater potency than nelfinavir, 71 percent achieving a viral load <400 copies/mL and 42 percent achieving a viral load <50 copies/mL compared to 55 percent and 11 percent respectively.
Overall, the incidence of dose-limiting adverse events and severe laboratory abnormalities was low in both groups, with only diarrhea being significantly more common in nelfinavir-treated patients than in those on 908 (17 percent vs. 5 percent). The reason 908 is so well tolerated is that it is a water-soluble tablet formulation of the prodrug of amprenavir. In this reformulation of the PI, lipids are not needed and it is these compounds which are responsible for most of the side effects. Also, while the overall rates of discontinuation were similar in both study groups in the NEAT study, more subjects withdrew due to insufficient viral response in the nelfinavir group (11 percent) compared to the 908 group (2 percent).
"In summary," Dr. Nadler declared, "908 is a much more convenient, well-absorbed, more tolerable agent which has broad activity in patients with moderate to severe HIV infection."
These data are from Study 903, an ongoing, three-year, randomized, double-blind, active controlled trial being carried out in the United States, Europe, and South America. The study was designed to compare the efficacy and safety of tenofovir DF, lamivudine (3TC) (Epivir, GlaxoSmithKline) and efavirenz (Sustiva, DuPont) with a regimen of stavudine, 3TC and efavirenz in 600 ART-naive, HIV-infected patients. To maintain the blinded nature of the study, patients in the tenofovir DF arm received one tablet twice daily of stavudine placebo while patients in the stavudine arm received one tablet once daily of tenofovir DF placebo.
Interim data through 48 weeks showed that 87 percent of patients in both treatment arms achieved HIV RNA <400 copies/mL, with HIV RNA levels <50 copies/mL in 82 percent and 81 percent of the tenofovir DF and stavudine arms respectively. Mean increases in CD4 cells also were comparable in the two treatment groups, being 169 cells/mm3 in the tenofovir group and 167 cells/mm3 in the stavudine group.
Of particular importance, statistically significant differences in lipid changes were demonstrated between the tenofovir-DF and stavudine treatment groups, as measured by changes in fasting levels of triglycerides and total cholesterol. In the tenofovir-DF arm, mean increases from baseline were 12 mg/dL in triglycerides and 29 mg/dL in total fasting cholesterol. In contrast, mean increases from baseline in triglycerides were 84 mg/dL and 57 mg/dL in total fasting cholesterol in the stavudine arm. Also, the incidence of nucleoside analogue-associated toxicities such as peripheral neuropathy and lipodystrophy was only 3 percent in the patients who received the tenofovir DF-based regimen compared to 10 percent in the stavudine group.
Of special note, a sub-study analysis of 227 patients is being carried out to assess mitochondrial DNA levels to explore the effect of treatment on mitochondrial DNA and its potential association with adverse effects. Levels also were assessed for a control group of 49 uninfected males, as infection with HIV appears to result in decreased mitochondrial levels in untreated individuals. This analysis shows that patients treated with tenofovir DF experienced a significant median increase from baseline of 82 copies/cell of mitochondrial DNA, bringing the median level to that seen in the uninfected control group. In the stavudine-treated patients, however, the increase in mitochondrial DNA was only 18 copies/cell.
The MaxC min1 study was a 48-week, open-label, randomized, phase IV study, designed and coordinated by the Copenhagen HIV Investigator Program, and included 317 HIV-infected patients enrolled from 14 countries in North and South America and Europe. The primary objective was to evaluate differences in virological efficacy and toxicity among HIV-infected patients with a clinical need for a ritonavir-boosted PI treatment.
Patients received either 1,000 mg of saquinavir (n=148) or indinavir 800 mg (n=158), each co-administered with a small 100 mg dose of ritonavir, for 48 weeks. Eleven patients who were randomized did not initiate therapy. At baseline, no differences between the study arms were observed in demographic, clinical or laboratory variables, nor in the use of any antiretroviral drug prior to inclusions or at baseline.
The final analysis of 48-week efficacy and safety data showed that boosted saquinavir reduced HIV RNA to undetectable levels (<50 copies/mL) in a greater proportion of patients than boosted indinavir (57 percent vs. 46 percent) according to the most stringent "intent-to-treat" analysis, which considers dropouts as failures. In the "on treatment" analysis, which includes only patients who completed the treatment period, results between the two arms were comparable, 79 percent for saquinavir versus 77 percent for indinavir.
Most importantly, results from the study pointed out that boosted saquinavir had a markedly better lipid profile. Boosted indinavir led to significantly greater increases in lipid levels at 48 weeks compared to boosted saquinavir. This included increases in fasting total cholesterol (17 percent vs. 8 percent), LDL cholesterol (18 percent vs. 3 percent), and triglyceride levels (22 percent vs. 9 percent). These data point out that boosting saquinavir with mini-doses of ritonavir avoids the negative lipid impact of higher doses of ritonavir, while maintaining saquinavir's more favorable lipid profile compared to that of indinavir.
With regard to the safety profile, more treatment-limiting adverse events were reported in the boosted indinavir arm compared to the boosted saquinavir arm. In addition, more patients in the boosted saquinavir arm remained virologically suppressed on study drug at 48 weeks, probably because of a better toxicity profile.
While lopinavir/ritonavir has been studied in HIV-infected patients, both ART-naive and those previously treated, there is little information available on continued efficacy and safety. The M97-720 study, an ongoing phase II trial of lopinavir/ritonavir in combination with stavudine (d4T) (Zerit, Bristol-Myers Squibb) and lamivudine (3TC) (Epivir, GlaxoSmithKline) in ART-naive patients, was the first trial of lopinavir/ritonavir in HIV-infected patients and, therefore, provides the longest followup for patients treated with lopinavir/ritonavir. In this study, 100 ART-naive, HIV-infected patients were randomized to receive one of three dosage levels of lopinavir/ritonavir (200/100 mg twice daily, 400/100 mg twice daily, or 400/200 mg twice daily) together with d4T 40 mg twice a day and 3TC 150 mg twice a day given either after 3 weeks of monotherapy or from study entry. After 48 weeks, all patients were converted to open-label lopinavir/ritonavir 400/100 mg twice daily dosing with d4T and 3TC.
At four years followup, 72 patients remained in the study, and all of these achieved undetectable HIV RNA viral load of less than 400 copies/mL. This is significant because undetectibility prolongs the development of resistance and leads to long-term treatment success. In point of fact, no resistance to lopinavir/ritonavir has been seen in this patient population through the four years of therapy, another important factor since resistance is a leading cause of treatment failure. In addition, CD4 cell counts increased consistently from the beginning of the study through the four year treatment period, with a mean increase of 440 cells/mm among patients with values at both baseline and four years.
Of equal importance, lopinavir/ritonavir was well tolerated, as indicated by the low rate of study discontinuations due to drug-related adverse effects, with a dropout rate of only 7 percent. This is significant because well tolerated drugs with few side effects improve patient adherence and help improve quality of life.
To profile immunologic and virologic outcomes in HCV co-infected patients receiving PI-containing therapy for their HIV, a retrospective chart review was carried out in 1052 HCV/HIV co-infected patients who received at least 3 months of PI therapy. Safety data, viral load, CD4 cell count, and treatment history (both HIV and HCV) were collected from the charts of these HCV/HIV co-infected patients.
Of the 1,052 patients reviewed, 77 percent were male, the median baseline CD4 cell count was 240 cells/mm3, and the median viral load was 4.11 log10. Overall, there were 428 patients on nelfinavir, 364 on indinavir, 182 on saquinavir, 149 on ritonavir, and 8 on amprenavir. A total of 107 patients were on dual PIs. The mean time on PI-inclusive HAART was 39.5 months.
In evaluating liver toxicity, 3 percent of patients on nelfinavir had grade 3 or 4 elevation in AST, in contrast to 7 percent of indinavir-treated patients, 3 percent of those on ritonavir, and 7 percent of saquinavir patients. In addition, 4 percent of nelfinavir-treated patients had a grade 3 or 4 elevation in ALT compared to 7 percent of indinavir patients, 8 percent of those on ritonavir and 11 percent of the saquinavir group.
Throughout the course of this study, patients had a mean CD4 cell count of +118 cells/mm3 and a decrease in viral load of -1.09 log10, with 57 percent having a viral load less than 400 copies/mL. For nelfinavir patients at these same baseline CD4 cell counts and viral loads, increases in CD4 counts and decreases in viral load were equivalent to those reported for the total study population.
Atazanavir Displays a Distinct Resistance Profile of Possible Value in PI-Resistant Therapeutic FailuresAtazanavir (Bristol-Myers Squibb), a potent and effective once-daily, investigational protease inhibitor (PI), currently in Phase III clinical trials, has been shown to have a distinct resistance profile compared to six other PIs tested, with resistance being relatively modest in regard to the comparative PIs and atazanavir susceptibility being retained in clinical isolates resistant to some currently approved PIs, stated Richard J., Colonno, M.D., Bristol-Myers Squibb, Wallingford, Connecticut.
Genotypic and phenotypic analysis of 950 clinical isolates from atazanavir-treatment naive, but PI experienced HIV-infected individuals was performed to identify amino acid changes predictive of decreased susceptibility to atazanavir and other PIs. Viral samples from randomly selected patients in the Virco (n=28) and Virologic (N=32) collections and from three large-scale studies including atazanavir-based regimens vs. comparators in PI-experienced persons (n=138, n=302, and n=450) were subjected to phenotypic (Phenosense, Virologic) and genotypic (GeneSeq, Virologic and GenoSure, LabCorp) evaluations. More than a threefold change in susceptibility was designated as an indication of resistance.
In general, reductions in atazanavir susceptibility required several amino acid changes and were modest in degree. In addition, atazanavir displayed a distinct resistance profile among clinical isolates resistant to marketed PIs, with atazanavir susceptibility being retained in 85 percent of clinical isolates resistant to some currently approved PIs.
Analysis of the genotype profiles of 943 PI susceptible and resistant clinical isolates identified a possible correlation between specific amino acid changes at 14 amino acid residues and reduced susceptibility to atazanavir. Reduction in atazanavir required substitutions in 5 of these 143 amino acid residues identified. While no single substitution or combination were predictive of atazanavir resistance, the presence of any 5 of these substitutions correlated strongly with decreased atazanavir susceptibility. Because so many specific amino acid changes are needed to establish resistance and this is generally rare, atazanavir may prove to be of value in sustaining susceptibility and, thus, maintaining long-term antiretroviral treatment success, as well as for the treatment of patients with resistance to other PIs.
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.
This article was provided by Body Positive. It is a part of the publication Body Positive.