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.

13th Conference on Retroviruses and Opportunistic Infections

Denver, Colorado / February 5-8, 2006

Of the safety data presented at the CROI meeting, two of the most influential reports were generated by the D:A:D observational study, currently following more than 23,400 HIV infected patients from 11 study cohorts in Europe. In one presentation, cardiovascular (CV) risk was assessed according to exposure to protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs). In the other, the risk of death due to liver disease was evaluated according to exposure to any combination of antiretroviral agents.

D:A:D Results

In the first report, new data reinforced a previous analysis that increased exposure to PIs raises the risk of myocardial infarction (MI). As reported by Dr. Nina Friis Møller, Copenhagen HIV Programme, Hvidovre University Hospital, Copenhagen, Denmark, “There was a linear relationship between PI exposure and risk of MI after adjusting for age, prior history of CV disease, family history, smoking and body mass index.” After adjustments, the hazard ratio was 1.16 (95% CI, 1.10-1.23; P=0.0001) for each year of exposure.

In contrast, exposure to NNRTIs in this study, which now has 94,469 person-years of follow-up, was not associated with a significantly increased risk of MI. Although the hazard ratio for an MI on NNRTI therapy, after adjustments, was 1.05, this was associated with a broad confidence interval (95% CI, 0.98-1.13; P=0.017) that rendered it insignificant. Moreover, there was no clear linear relationship between duration of NNRTI exposure and increased MI risk.

In the D:A:D study evaluating risk of death due to liver disease, no strong association was found with exposure to combination antiretroviral therapy. In this evaluation, presented by Dr. Rainer Weber, University Hospital, Zurich, Switzerland, there were 76,893 person-years of follow-up available for analysis. Independent predictors of liver-related death were lower baseline CD4+ cell count, older age, intravenous drug use, and active hepatitis infection. However, antiretroviral therapy out to seven years, the extent of the analysis, did not suggest increased risk from antiretroviral drugs.

Renal Complications

In a similar epidemiologic study conducted from the medical records of 11,362 HIV-infected patients, exposure to the nucleotide reverse transcriptase inhibitor (NtRTI) tenofovir (TDF) was associated with a significantly increased risk of mild and moderate renal impairment. The odds ratio of renal insufficiency in patients who received a regimen containing TDF was 1.6 (95% CI, 1.5-1.8) compared to those who did not after controlling for other important factors known to affect renal function. The authors suggested that this risk should be considered in patients receiving the NtRTI.

According to Dr. James Heffelfinger, Centers for Disease Control, Atlanta, Georgia, “Physicians should monitor patients receiving TDF and consider that mild or moderate renal impairment may be drug-associated. Further research is needed to determine whether changing from TDF to a different antiretroviral agent in the setting of mild or moderate renal impairment is beneficial in terms of progression to severe renal impairment and long-term survival.”

Another study reviewing data from 10,343 patients exposed to TDF found that renal failure only occurred in 0.3% of patients over a four-year period, leading a team of authors led by Dr. Mark Nelson, Chelsea and Westminster Hospital, London, UK, to conclude that TDF is well tolerated and produces adverse events at a rate predicted in initial clinical trials. However, two prospective trials corroborated concern raised by the CDC data. In one, 17% of 222 patients with normal renal function who were initiated on TDF therapy demonstrated impaired renal functioning after one year. The authors of the study, led by Dr. Jodie Guest, Atlanta Veterans Affairs Medical Center, reported that renal insufficiency “appeared to be a cumulative toxicity with more than half of patients [with renal insufficiency on TDF] developing impairment after six months.” She noted that the rate of renal toxicity is higher than previously reported.

Combination Strategies

In another study, new data were drawn from a trial that randomized patients who were failing their current antiretroviral regimen to one of two doses of amprenavir/ritonavir plus efavirenz, the nucleoside reverse transcriptase inhibitor (NRTI) abacavir (ABC) and an additional NRTI if NNRTI-naïve, or the same regimen with TDF substituted for efavirenz if NNRTI-experienced. Although the median glomerular filtration rate (GFR) was similar between the two groups at baseline, there was a greater decline over time in the group receiving TDF.

“A significant decline in the median calculated GFR was observed over 48 weeks in the TDF group but not in the group receiving efavirenz in the same study. TDF use was the only predictor of GFR decline using multiple regression analysis,” reported Dr. Melanie Thompson, AIDS Research Consortium of Atlanta.

Safety results were also the focus of one of the first well controlled randomized trials to compare different HAART strategies in Africa. In this multicentre study, 429 patients, of which 72% were women, were randomized to the NNRTI nevirapine or the NRTI ABC. Both were combined with lamivudine and zidovudine, which were administered in a single pill. Efficacy results of this study, which are not yet available, will be followed closely. However, the 24-week safety results, which were presented as a late-breaker at CROI, demonstrated that ABC was substantially better tolerated than the NNRTI.

“The primary end point of this analysis was serious adverse events. In total, 4.7% of those randomized to ABC and 10% of those randomized to nevirapine discontinued therapy. This difference was statistically significant [P=0.01],” reported Dr. Paula Munderi, Medical Research Council, Uganda Research Unit on AIDS, Entebbe. Although there were a variety of reasons for discontinuation, including pregnancy and withdrawal of consent, the biggest difference was serious adverse events, which occurred in 2% of patients randomized to ABC vs. 4.7% of those randomized to nevirapine, a strong trend that fell just short of statistical significance (P=0.06).

Dr. Munderi told delegates, “The incidence of hypersensitivity reactions on ABC in our study population was only 2%, which is lower than that previously reported. Overall, there was considerable overlap in the types of toxicities observed on ABC and nevirapine.”

The freedom of ABC from many of the most worrisome side effects associated with some other NRTIs, such as mitochondrial toxicity, has been one of the reasons that it is among agents frequently employed in first-line regimens. In addition, patients who develop resistance to ABC remain responsive to a substantial number of other NRTIs.

Episodic vs. Continuous Therapy

One of the most intriguing studies presented at CROI for the insight it provided on the relative safety of HAART regimens was not designed as a safety study. Rather, it compared a CD4-guided episodic therapy to a conventional continuous HAART regimen. Also presented as a late-breaker, the SMART study was halted prematurely because the episodic regimen was associated with an increased risk of short-term progression. However, the more surprising result may have been that the continuous regimen was also associated with a lower risk of MI, stroke, renal and hepatic complications, a relative benefit expected in the episodic arm.

“The rate of MI, stroke, coronary artery disease requiring surgery, renal and liver disease was 2.0 per 100 person-years in the CD4-guided arm vs. 1.2 per 100 person-years in those who remained on continuous therapy,” reported Dr. Wafaa El-Sadr, Columbia University College of Physicians and Surgeons, New York. “Episodic use of HAART as defined in the SMART protocol is inferior to continuous HAART. This strategy should not be recommended.”

In this study, 5472 patients in 33 countries were randomized to episodic therapy in which treatment was stopped if CD4+ cell counts were >350 cells/mm3 and then restarted when CD4+ cell counts fell <250 cells/mm3 or to conventional HAART. Although follow-up out to eight years was planned, the data and safety monitoring committee recommended that the study be stopped after only 14 months when the rate of progression of disease or death was more than twice as great (3.1 vs. 1.4 per 100 person-years; P<0.0001) in the episodic treatment arm.

Summary

In first-line therapy, improving safety rather than potency may be the most important challenge for maintaining HIV control long-term. While new epidemiologic data have associated PIs but not NNRTIs with an increasing risk of MI over time, the same dataset did not associate any antiretroviral regimen with an increased risk of liver toxicity. Conversely, a separate set of epidemiologic data indicated that TDF may increase renal toxicity. In another analysis, the NRTI ABC was associated with a trend for lower risk of adverse events than nevirapine, while a major study has suggested that many of the complications previously attributed to HAART occur less often when HIV is well controlled.