Abacavir for Salvage or Intensification
Newly approved abacavir (Ziagen), the sixth nucleoside analog, promises to be one of the most potent antiretroviral agents available for treatment of HIV infection. Unfortunately, most of the pivotal trials and clinical studies using abacavir have focused on persons with early or intermediate disease and no prior treatment. Such people have responded well since most have little or no cross-resistance due to pretreatment with other nucleosides, such as AZT, ddI and 3TC. Unsuccessful treatment with these drugs leads to the emergence of resistance mutations (usually at codons 74, 184 and 215 on the reverse transcriptase gene) that can render abacavir ineffective.
In very advanced populations who have exhausted all the available treatment options, abacavir is very unlikely to produce significant viral load reductions. This was demonstrated by the results of Glaxo study CNA2007, described in November at the 4th International Congress on Drug Therapy for HIV Infection held in Glasgow, Scotland, and the 36th Annual Meeting of the Infectious Diseases Society of America (abstracts and OP5.2 and 396, respectively -- see also Treatment Issues, November 1998, pages 1-3).
Protocol 2007 enrolled 101 HIV-positive persons with HIV RNA levels greater than 500 copies/ml of plasma and more than 20 weeks of previous treatment with one of the licensed protease inhibitors. All participants received amprenavir (1,200 mg twice daily), efavirenz (600 mg once daily) and abacavir (300 mg twice daily) for 16 weeks. They were stratified at the beginning of the study according to viral load (above or below 40,000 copies/ml) and previous exposure to NNRTIs (nonnucleoside reverse transcriptase inhibitors) nevirapine or delavirdine.
The majority of the participants had previously received an average of more than three protease inhibitors and five nucleoside analogs. Those participants with baseline viral loads above 40,000 copies/ml had the most antiretroviral drug exposure. After 16 weeks of follow-up, only 26% of the entire group had viral loads below 400 copies/ml, the limit of quantification on the standard PCR assay. Participants with high viral load and previous NNRTI exposure had the least response (7% went below 400 copies/ml). Those with low viral loads and naïve to NNRTIs had the best response (53% below 400 copies/ml). CD4 responses also were best for those with both low viral loads and lack of prior treatment with NNRTIs: a sustained 50 cell/mm3 rise compared to 20 to 30 cell/mm3 rises for the other subgroups.
The most common adverse effect was skin rash, which again was more common in persons with higher viral loads and previous NNRTI experience. Fourteen volunteers had to discontinue abacavir due to systemic flu-like symptoms or a rash that suggested a hypersensitivity reaction to abacavir. The incidence of hypersensitivity seen here is higher than in other populations (3% to 5%). Overcautious investigators may have discontinued some persons whose adverse reactions really were due to one of the other drugs or an intercurrent disease. Those who stopped abacavir remained on just efavirenz and amprenavir for the duration of the study. Narrowing therapy to the NNRTI/protease inhibitor two-drug combination may have further tipped the balance in favor of the NNRTI-naïve subgroup since everyone in the trial had long exposure to protease inhibitors and their HIV presumably was heavily cross-resistant to drugs in this class. Phenotypic and genotypic analyses of participants' HIV have just been reported at the 6th Conference on Retroviruses and Opportunistic Infections -- see the following article on salvage therapies.
Other presentations at the 6th Retrovirus Conference concerning abacavir's role in salvage regimens also reported discouraging results. ACTG 368, a trial enrolling people with only prior nucleoside analog experience, found that ABC was no better than placebo when added to a combination of efavirenz and indinavir (abstract LB15). Another trial, ACTG 372B, found that abacavir performed as weakly as other nucleoside analogs when used in regimens to rescue a group whose HIV could not be held in check by the AZT/3TC/indinavir combination (abstract 490).
For further details on these trials see the chart in "ACTG Salvage Therapy Trials."
Another potential use of abacavir is for "intensifying" therapy. Such intensification involves adding abacavir to established regimens that have proved less than maximally suppressive. Viral load has been reduced in a specific patient, but remains above the level of quantification three months or more after commencement of therapy.
One intensification study was presented at the 6th Retrovirus Conference (abstract 378) by Christine Katlama, M.D., and others from the Hôpital Pitié Salpêtrière in Paris. This study followed 185 volunteers with a maximum of 36 months of prior treatment of any sort. Their plasma viral loads at study entry ranged between 400 and 50,000 copies/ml (baseline median of about 4,000 copies/ml). CD4 counts were all over 100 cells/mm3 (baseline median of 410 cells/mm3). The volunteers remained on their previous antiretroviral therapy, to which either abacavir or placebo was added.
An intent-to-treat analysis found that 39% of the abacavir-receiving group had a viral load below 400 copies/ml at week 16. Only 8% of the control group had achieved that level. Prior 3TC did not significantly influence the results, with 42% of the 3TC-experienced group and 32% of the 3TC-naïve group reducing their viral loads to below 400 copies/ml after abacavir was added. CD4 responses were favorable for those who added abacavir (up 19 cells/mm3) compared to those who remained on their background antiretroviral therapy alone (down 3 cells/mm3). Although the presence of the 3TC-resistance mutation at codon 184 of the reverse transcriptase gene did not significantly affect response to abacavir intensification, three or more AZT-associated mutations with or without this 3TC mutation were associated with a lack of response. This study will continue until a total of 48 weeks of observation have been completed.
Another French study described at the 6th Retrovirus Conference (abstract 377) included 52 persons who had received AZT and 3TC for at least 12 weeks in previous studies. After 48 weeks of abacavir add-on therapy, 72% of participants were below 400 copies/ml, compared to 29% at baseline. The same analysis conducted with the ultrasensitive PCR assay found that 6% had viral loads below 20 copies/ml at baseline, whereas 49% had attained that level at week 48. CD4 cells increased by a median of 118 cells/mm3 during this period. Once again, prior therapy with 3TC and/or the presence of the codon 184 mutation (which results in insensitivity to 3TC) did not preclude a substantial antiviral response to abacavir. The most common side effects were nausea, vomiting, malaise, fatigue and sleep disorders.
When Abacavir Is Appropriate
The results of these salvage and intensification studies are consistent in showing a favorable response to abacavir for those who have persistently low but detectable viral loads despite a robust response to antiretroviral therapy. Selection of the patients most likely to respond will most likely entail access to genetic sequencing (genotype) or cell culture (phenotype) results regarding the viral resistance pattern for each patient. Since these assays are generally not available or not covered by insurance, using abacavir to intensify or rescue failing regimens will subject many to side effects and toxicities without added benefit.
Two or more drugs should be used when there is viral rebound (salvage or rescue). For intensification, the number and types of new drugs should be dictated by previous antiretroviral history and baseline viral load. Adding one potent drug like abacavir may be sufficient only in persons whose HIV does not pose the challenge of broad nucleoside analog cross-resistance.
This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.