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44th Annual Meeting of the Infectious Diseases Society of America

Toronto, Ontario / October 12-15, 2006

Guidelines from both the panel of the International AIDS Society-USA (IAS-USA) and the US Department of Health and Human Services (DHHS) 2006 suggest antiretroviral therapy (ART) is warranted when CD4+ T-cell counts drop below 200 cells/mm3 or when patients have symptomatic disease. In the “grey zone” between 200 and 350 cells/mm3, the DHHS suggests treatment should be offered, while the IAS-USA suggest treatment should be considered, especially when CD4+ T-cell counts are in the lower range, when viral load is >100,000 copies/mL or if there is a rapid decline in CD4+ T-cell counts.

Dr. Kevin Carmichael, Chief of Service, El Rio Special Immunology Associates, Tucson, Arizona, noted, “Since many new regimens are more tolerable, physicians are moving towards initiating therapy at CD+ T-cell counts closer to 350 cells/mm3 rather than at 200 cells/mm3.” He told the audience,“Current drugs are very effective. We realize the immune system [even when highly compromised] can recover and we know that patients will do well for quite some time.” To achieve and maintain viral control and preserve immune function, ART should be initiated early as it also helps prevent complications that are not entirely linked to CD4+ T-cell counts and may potentially decrease HIV transmission.

However, CD4+ T-cell count and viral load are not sufficient information to determine when to initiate ART; more importantly, the appropriate regimen “as the initial choice of therapy affects both initial success and emergent resistant patterns,” noted Dr. Carmichael.

On specific treatment strategies, guidelines support the use of either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a ritonavir-boosted protease inhibitor (PI/r) as initial therapy given in combination with two NRTIs. Boosted PI regimens are recommended as first-line treatment, based on data from the KLEAN (Kaletra versus Lexiva with Epivir and Abacavir in ART-Naïve Patients) trial which showed that fosamprenavir/r 700/ 100 mg b.i.d. vs. lopinavir/r 400/100 mg b.i.d. given with ABC plus lamivudine 600/300 mg q.d. essentially performed identically over the 48-week trial.There was no treatment-emergent PI resistance and few treatment discontinuations due to adverse events. Boosted PI regimens are also “very forgiving, in that if patients fail, they do not have high levels of resistance and they leave you with some place to go,”explained Dr. Carmichael.

Fixed-dose NRTI Combinations

The availability of three NRTI fixed-dose combinations either zidovudine plus lamivudine (ZDV/lamivudine), tenofovir plus emtricitabine (TDF/FTC) or abacavir plus lamivudine (ABC/lamivudine) has, to a certain extent, simplified ART regimens, although not equally for all combinations. DHHS guidelines recommend ZDV or TDF plus lamivudine or FTC as the preferred NRTI “backbone” while the IAS-USA include the addition of ABC/lamivudine as an initial backbone. Fixed-dose NRTI combinations are also enable better compliance, as patients prefer once-daily regimens where possible.

The once-daily TDF/FTC combination offers a regimen with few adverse events. It does, however, increase didanosine (ddI) levels and is associated, with rare incidents of renal toxicity. The use of the ZDV/lamivudine combination—the first single pill to emerge with two NRTIs—is supported by extensive clinical data, but patients do have to take it twice daily. It is associated with more adverse events and possible lipoatrophy. The ABC/lamivudine combination is a once-daily strategy with few adverse events or drug interactions. However, there is a hypersensitivity reaction (HSR) occurring in 3% to 8% of patients.

As indicated by Dr. Benjamin Young, Assistant Clinical Professor of Medicine, University of Colorado Health Sciences Center, Denver, the risk of a HSR occurring with ABC is lower among African Americans and far more likely to occur in patients with the HLA-B-5701 haplotype.

After introducing HLA-B-5701 testing, Australian researchers (Rauch et al. Clin Infect Dis 2006;43:99-102) found that the proportion of patients who stopped ABC because of HSR in the first six weeks of therapy dropped dramatically. Patients could be screened for this haplotype prior to initiating ABC therapy and HSRs potentially avoided.

Treatment success also depends on the potential for patients to adhere to therapy, which in turn is largely dictated by the tolerability of the regimen, as speakers here emphasized. Each of the three fixed-dose combinations are also associated with different resistance patterns, some of which may be harder to overcome with salvage regimens when patients fail (Table 1). Thus, Dr. Carmichael suggested that prior to initiating ART, physicians should consider resistance testing.

Resistance Considerations

The usage of ZDV/lamivudine is associated with the signature M184V mutation as well as thymidine analogue-associated mutations (TAMs). If patients develop low levels of resistance, they can still be salvaged with TDF and by ABC, ZDV and ddI if they develop intermediate resistance. (Of note, according to the guidelines, the use of ddI with stavudine should be avoided.) If patients develop the M184V or K65R mutation separately or both with TDF/FTC, they remain susceptible to ZDV as salvage, and to ABC, ddI and TDF if resistance is intermediate. Dr. Young concluded that understanding the attributes and liabilities of each medication, and then tailoring treatment to match patient’s risk factors, are both central to optimizing the safety and tolerability of ART regimens for individual patients.

Summary

While the three combinations of NRTIs have been developed to simplify management of ART-naïve patients, physicians must consider their impact on future options in the event of resistance. Long-term planning for resistance may be a critical factor in determining initial treatment. As such, resistance testing is recommended to assist in selecting initial ART regimens in order to optimize treatment outcome for patients.

Figure 1. Fixed-dose NRTI Combinations