Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

47th Interscience Conference on Antimicrobial Agents and Chemotherapy

Chicago, Illinois / September 17-20, 2007

According to Dr. Kathleen Squires, Professor of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, most patients today receive one of three fixed-dose co-formulations as their initial backbone nucleoside reverse transcriptase inhibitor (NRTI), as recommended by HIV management consensus guidelines. The more controversial issue now is at what CD4+ cell count should treatment be considered, especially given that antiretroviral (ART) regimens are far simpler and better tolerated than in the past.

She noted that evidence suggests that a proactive approach preserves immune function better and prolongs lives of HIV-infected patients than waiting until later on in the course of the disease.

Dr. Squires presented data from the CASCADE study (Concerted Action on SeroConversion to AIDS and Death in Europe), which consisted of almost 10,000 patients with approximately eight years of follow-up. Marin et al. found that over half of the deaths that occurred in the cohort were due to non-AIDS-related causes, and that CD4+ cell counts were strongly related to mortality, including current and nadir CD4+ cell counts and the time spent at a CD4+ cell count below 350 cells/mm3 (IAS 2007, Abstract WEPEB019). Based on these observations, CASCADE researchers concluded that earlier initiation of combination ART might have an impact on fatal morbidities other than AIDS.

Several other studies presented at ICAAC supported their observations, including a post-hoc analysis of the SMART (Strategies for the Management of Antiretroviral Therapy) data. In SMART, patients with a CD4+ cell count >350 cells/mm3 who started and remained on ART were less likely to experience both AIDS-related and non-AIDS-related outcomes than those in whom ART was deferred (Emery et al. IAS 2007, Abstract WEPEB018).

Van Sighem et al. reinforced SMART data when they reported that the risk of AIDS and death was higher when HAART was initiated at a CD4+ cell count of between 200 and 350 cells/mm3—as was previously recommended in the Netherlands—than when treatment was initiated at CD4+ cell counts of between 350 and 500 cells/mm3 (IAS 2007, Abstract WEPEB080).

As reiterated at ICAAC, the HIV Outpatient Study (HOPS) study cohort, by Uy et al. also reported that patients in whom HAART was initiated at CD4+ cell counts >350 cells/mm3 were half as likely to develop any major resistance mutations than patients who started treatment at <200 cells/mm3, despite a twofold greater exposure to ART at the time of virologic failure. There was also a fivefold difference in the prevalence of both NRTI and NNRTI resistance mutations between these two CD4+ cell strata groups (IAS 2007, Abstract WEPEB017).

Further analysis from the HOPS cohort also showed that the incidence of NNRTI toxicities was considerably reduced when HAART was initiated at progressively higher CD4+ cell counts (Lichtenstein et al. IAS 2007, Abstract MOPEBO16).

Safety Concerns

Both the potency and durability of response of any given regimen are clearly paramount in the selection of an ART regimen. Nevertheless, each regimen has a different toxicity profile and tolerability and safety must be factored into selection criteria as well. Several studies presented here at ICAAC raised concerns about the use of tenofovir (TDF) and its effect on renal function, even in patients whose renal function was well preserved on initiation of treatment.

As presented by Dr. Ronald Reisler, Assistant Professor of Medicine, University of Maryland School of Medicine, Baltimore, changes in estimated glomerular filtration rate (eGFR) were evaluated retrospectively in 149 predominantly African-American men treated with TDF and another 68 men treated with abacavir (ABC). At the end of six months, patients on TDF had a significantly greater decline in eGFR at 11 mL/min/1.73 m2 than those on ABC (P<0.05) where eGFR dropped by 2 mL/min/1.73 m2.

Corresponding reductions in eGFR at the end of treatment were similar to six-month values at 12 mL/min/1.73 m2 for TDF patients and 4 mL/min/1.73 m2 for their ABC counterparts. Interestingly enough, “Declines in kidney function were more pronounced in patients with better kidney function,” Dr. Reisler noted, even though TDF patients were younger and had better kidney function than ABC patients at treatment outset. Notably, the decline in renal function was observed within the first six months of therapy, he added, and it is presumed to be reversible with discontinuation of TDF.

Dr. Benjamin Young, Assistant Clinical Professor of Medicine, University of Colorado, Denver, reported on his analysis of the effect of TDF on renal function in a group of 19 patients with past (n=6) or current (n=13) renal dysfunction. He and co-investigators found that two out of 13 patients with a baseline creatinine clearance of <50 mL/min had a decrease in creatinine clearance on TDF at the end of one year, while three had decreases in eGFR.

Overall, two out of 13 patients who had a creatinine clearance of <50 mL/min at treatment outset had a change in the stage of their chronic kidney disease at study end, even though, as Dr. Young stressed, “the presence of TDF in this patient population does not predict for worsening kidney function and, in fact, some of them had an improvement.” Dr. Young and colleagues found that patients who receive TDF on average have statistically significant decrements in their eGFRs even when they have relatively normal kidney function when treatment is initiated.

SHAPE and Hypersensitivity Testing

A prevailing concern in the past was the risk of triggering a hypersensitivity reaction upon introduction of ABC. That risk, however, has now been minimized if not virtually eliminated with the introduction of the new HLA-B*5701 assay. As noted in a poster by Dr. Claudia Martorell, Director and infectious diseases specialist, The Research Institute, Springfield, Massachusetts, the presence of the HLA-B*5701 allele is “strongly associated” with the development of hypersensitivity reactions to ABC. Symptoms of this reaction typically include fever, malaise, myalgia, fatigue and rash but because they are non-specific, “they can decrease diagnostic precision,” as she pointed out.

To that end, all patients with clinically suspected ABC hypersensitivity enrolled in SHAPE (Study of Hypersensitivity to Abacavir and Pharmacogenetic Testing), a retrospective case-controlled study, underwent ABC skin patch testing and HLA-B*5701 evaluation.

Results showed that all patients with immunologically-confirmed ABC hypersensitivity reactions were positive for HLA-B*5701. Investigators also found that symptoms of fever, malaise, myalgia and fatigue occurred more commonly in patients positive for the allele than those who were not, and that time to symptom onset within 21 days of treatment initiation was also more common in HLA-B*5701-positive participants than those who were negative.

As Dr. Martorell mentioned during the ICAAC sessions, results from PREDICT-1 (Prospective Randomised Evaluation of DNA Screening in a Clinical Trial) showed that the incidence of immunologically confirmed hypersensitivity reactions was zero in ABC-naïve patients who were prospectively screened with the HLA-B*5701 test, giving it a 100% negative predictive value for ABC hypersensitivity.

“ABC is excellent for treatment-naïve patients. It is one of the backbones of HIV therapy and it can be taken once a day, which is very convenient and people tolerate it very well,” Dr. Martorell told delegates. “The data from SHAPE are very reassuring. It will keep patients on the medication and it will decrease any anxiety in providers when prescribing it.”

With the development of the new HLA-B*5701 assay, pre-testing patients prior to initiation of ABC/3TC virtually eliminates the possibility of triggering a hypersensitivity reaction to ABC, and will allow patients who could benefit from a safe and effective drug regimen to either remain on the drug or begin treatment with it.