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.

Eighth International Congress on Drug Therapy in HIV Infection

Glasgow, UK / November 12-16, 2006

As confirmed by Dr. Frank Post, King’s College Hospital, London, UK, “There is no doubt that antiretroviral therapy [ART] given for decades contributes to a wide and complex range of metabolic disturbances, distressing lipodystrophy, fat accumulation, renal impairment, cardiovascular and/or bone disease. Every additional year of HAART is associated with a further increase in risk which may not be readily or completely reversible.”

He noted that lipoatrophy might be prevalent in up to 75% of patients and occurs at an incidence of seven to eight cases/100 patient-years. Fat accumulation occurs at an incidence of nine cases/100 patient-years and HAART has generally been a risk factor for that disorder.

“About 25% of patients started on a [non-nucleoside reverse transcriptase inhibitor] NNRTI- or [protease inhibitor] PI-containing regimen will probably develop hypercholesterolemia, a figure which may rise to 40 to 50% for hypertriglyceridemia,” Dr. Post stated. “If body fat changes are present, this is further enhanced in hypertriglyceridemia, being present in almost 60% of patients, and adverse cholesterol profiles in 50%. In the 2NN study, about 25% of patients who started on either efavirenz or nevirapine suffered a significant increase in total cholesterol, LDL and triglycerides almost immediately after starting treatment. Similarly, about 25% of individuals treated with lopinavir/ritonavir [lopinavir/r] will develop raised cholesterol or triglycerides. Avoiding specific ART or switching ART is an important way to prevent those complications.”

Urging clinicians to choose antiretrovirals carefully, he pointed out that the nucleoside analogues abacavir (ABC) and tenofovir (TDF) are associated with less lipoatrophy and better lipid profiles then thymidine analogues. Nevertheless, if patients are switched to either TDF or ABC after lipoatrophy has developed, it may take many years to regain the lost fat. ABC has little effect on metabolic consequences, he noted, whereas stavudine, for example, is associated with increased glucose and insulin concentrations as well as insulin resistance. TDF and indinavir are associated with specific renal injury and TDF may also be linked to bone demineralization and hypophosphatemia.

Bone Disease and Renal Toxicity

Early studies suggest that osteopenia and osteoporosis may be related to PI-containing therapy because they suppress 1-a-25 hydroxylase activity and therefore interfere with vitamin D metabolism, Dr. Post explained. They may also increase osteoclast activity and inhibit osteoblast recruitment. Some NRTIs, zidovudine (AZT) and TDF may also affect bone function. Advanced HIV infection itself is also a risk factor for bone disease. He concluded, “Minimizing long-term toxicities is a crucial element from the outset of ART. We have to think of intervention strategies from the start.”

In view of the renal toxicity frequently reported with the use of TDF, researchers compared the toxicity profile of that compound with ABC both given in a PI or NNRTI-containing triple-drug regimen. Presenting study findings, Dr. Brian Gazzard, Consultant Physician and Research Director, Department of HIV/GU Medicine, Chelsea and Westminster Hospital, London, UK, reported that although similar viral loads and CD4+ responses were observed, TDF was associated with increased creatinine levels and reduced glomerular filtration rate (GFR), although the difference was minimal. He said 121 TDF patients experienced creatinine >97 µmol/L at a rate of 31/100 person-years; the rate among the 94 ABC-treated patients was 20/100 person-years. For GFR <91 mL/min/1.73 m2 in men and <88 in women, this was 176 in 211 person-years (rate=83) for TDF and 126 in 236 person-years for ABC (rate=53). Similar results were found among naive patients; six in the TDF arm and five in the ABC arm experienced a GFR <60 mL/min/1.73 m2.

In another study, of the 14 patients who had normal serum creatinine prior to TDF therapy, 11 presented with impaired renal function following TDF treatment which improved when TDF was stopped, according to co-investigator Dr. Clare Davies, Royal Free Hospital, London, UK. Seven had confirmed Fanconi syndrome, of whom four had evidence of global proximal tubular dysfunction and renal biopsy confirmed proximal renal tubular injury in three of them. She concluded that renal toxicity remains a concern in TDF-treated HIV-infected patients. “Our investigation suggests proximal tubular toxicity as the underlying mechanism.”

Host Genetics and Hypersensitivity

Pharmacogenomics in HIV seeks to understand the impact of genetic variants on response to medications, human predisposition to HIV drug toxicities and the likelihood of virologic responses. Dr. David Haas, Vanderbilt University, Nashville, Tennessee, remarked that variants across many genes are reported to affect pharmacokinetics, efficacy and/or toxicity of NRTIs, NNRTIs and PIs. The well-characterized ABC hypersensitivity reaction (HSR) is an excellent example of an immune-mediated drug reaction with a genetic basis, he told the audience.

The presence of HLA-B*5701 is the dominant risk factor for ABC-associated HSR. Deliberately averting the exposure to ABC in adults found to be carrying that allele by genetic screening has resulted in dramatic reductions in the incidence of ABC HSR, as findings have shown in Australian and UK studies. Individuals not carrying HLA-B*5701 also develop HSR, but in only 2 to 3% of cases.

Dr. Simon Mallal, Royal Perth Hospital, Australia, explained that since prospective genetic screening was begun to identify patients who should not be exposed to ABC, true immunologically mediated HSR has been effectively eliminated there. Not only has HSR dropped dramatically, so has over-diagnosis of HSR. An unexpected finding was that false positives also fell, so that genetic screening also had the effect of improving phenotypic precision. Prospective genetic screening, therefore, can be used to prevent HSRs by identifying those who should not receive ABC, he stated.

Dr. Laura Waters, Chelsea and Westminster Hospital, described the assessment by her group of the clinical value of routine, prospective HLA-B*5701 testing to reduce ABC hypersensitivity in 739 treatment-naive HIV-infected patients who were starting therapy or who were treatment-experienced and were being considered for a switch to ABC.

She reported that 54 (7.3%) were found to be positive for the HLA-B*5701 allele; of these, 14 remain treatment-naive. Eight of the remaining 40 had a history of ABC exposure prior to HLA testing and six had a history of symptoms compatible with HSR. Two had been given ABC previously, for six weeks and five years, respectively, with no signs of intolerance. Of the 564 patients already taking or subsequently starting ART, 224 received ABC; 23 discontinued the agent and seven of those tested positive for HLA-B*5701. Four of the 16 HLA-negative patients had symptoms suggesting HSR and three took a cutaneous patch test, with one presenting a positive skin reaction, Dr. Waters reported. The remaining 12 experienced non-specific symptoms or symptoms believed to be unrelated to HSR. The rate of discontinuation secondary to typical HSR was 4/224 (1.8%).

Dr. Waters explained that before the introduction of HLA testing, the historical overall discontinuation rate for such patients at her institution was 7.5%, which fell to 3% after prospective HLA-B*5701 testing was introduced. Yet four patients discontinued ABC for possible HSR, and one of those had a positive skin patch test with systemic symptoms. She concluded that her data highlight a need for maintaining clinical vigilance despite HLA-B*5701 negativity.

Observations from the KLEAN Study

According to Dr. Michael Youle, Director of HIV Clinical Research, Royal Free Hospital, London, UK, “Ideally, the clinician’s choice of ART combinations is based on randomized head-to-head clinical trials and evidence of durability of effect thereafter. However, true comparative data are only now becoming available. The KLEAN [Kaletra vs. Lexiva with Epivir and Abacavir in ART-Naive Patients] study published this year, for example, was the first randomized trial to directly compare two boosted PIs with a fixed-dose combination backbone of ABC/lamivudine (3TC) in ART-naive HIV-infected patients for a duration of 48 weeks.”

In KLEAN, ritonavir-boosted lopinavir b.i.d. (recommended by most guidelines because of its proven superiority over nelfinavir) was compared to fosamprenavir/r b.i.d., both given with the ABC/3TC fixed-dose combination. Dr. Youle told delegates that there were no differences between the treatment groups. Non-compliance and discontinuation rates were the same, and there were no significant differences in outcome between the two primary boosted PI patient groups at 48 weeks. He reported that 73% of participants randomized to fosamprenavir/r and 71% on lopinavir/r achieved viral loads <400 copies/mL; somewhat fewer (approximately 66%) achieved viral loads <50 copies/mL.

“The observed data are incredibly good for both drugs, making us feel that this is a good option for patients first-line,” Dr. Youle commented. “If patients take their therapy, almost 100% do well. Few subjects had protocol-defined virologic failure and there were no major PI-associated mutations or reduced phenotypic susceptibility to either PI. Both regimens were well tolerated.”

Dr. Youle added that once-daily fosamprenavir/r also provides an option to once-daily atazanavir/r for patients who do not want to risk developing hyperbilirubinemia, as demonstrated in the ALERT study, which compared those agents with a different backbone combination, and concluded that they were otherwise equally effective.