From
The AIDS Readerr
HAART Regimens: Do the Effects Last?
Report From Toronto
Author: Jeffrey Laurence, MD, The New York Hospital-Cornell University Medical College, New York City
Abstract
By mid-1997, some 100,000 individuals in the US were prescribed protease inhibitor-based regimens. Although most of the decline in AIDS-related deaths during the first 9 months of 1996 cannot be attributed to these new drugs, several small trials of protease-based regimens have shown an impact on survival at all stages of HIV disease. As noted previously in The AIDS Reader, however, the durability of this benefit is tenuous. And this uncertainty became a key point at the 37th ICAAC in Toronto. [The AIDS Reader 7(6):84-85, 1997. c 1997 SCP Communications, Inc.]
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From September 28 through October 1, more than 16,000 clinicians, scientists, pharmaceutical representatives, and reporters descended on Toronto for the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). It was fitting that this was the first time the meeting has been held outside the US, as about half of all the presentations concerned HIV and, as Dr. Peter Piot of UNAIDS noted, this is a "disease that has transformed the world."
A key point of contention raised in Toronto involved the extent to which advances based on highly active antiretroviral therapies (HAART), particularly those containing a protease inhibitor, could be sustained. By mid-1997, some 100,000 individuals in the US were prescribed protease inhibitor-based regimens. Although most of the decline in AIDS-related deaths over the first 9 months of 1996--reported with great fanfare this summer (CDC: MMWR 46:861-867, 1997)--cannot be attributed to these new drugs, several small trials of protease-based regimens have shown an impact on survival at all stages of HIV disease. As noted previously in The AIDS Reader, however, the durability of this benefit is tenuous. And this uncertainty became a key point in Toronto.
First, the good news. Dr. Roy Gulick of New York University gave a 2-year follow-up from Merck protocol 035, arguably the best of the original HAART regimens (Gulick R, et al: 37th ICAAC, Toronto, Canada, Sept. 28-Oct 1, 1997. Abstract I-89). Protocol 035 began as a double-blind study of 97 HIV-seropositive patients randomized to receive zidovudine (AZT) plus lamivudine (3TC) plus the protease inhibitor indinavir (IDV), versus AZT + 3TC, versus IDV. All had previously been treated with at least 6 months of AZT. Six months into this trial it became clear from other data that protease inhibitors offered an important benefit; most patients receiving the single- or double-drug therapies thus elected to switch to the triple combination. Now, at 100 weeks, it appears that those 31 patients on the original triple-drug therapy continue to do exceedingly well.
An important measure of HIV's destructive potential, the viral load, remains undetectable (fewer than 500 copies/mL of plasma) in 85% of those 31 participants. CD4+ T cells continue to increase, at least in terms of numbers, from an average rise of 150 cells/mm3 at year 1 of treatment to an average total elevation of 230 cells/mm3 at year 2. Those in the delayed use of triple-therapy arms fared much worse, however. Only 40% had an undetectable viral load at year 2, and there was an average increase in CD4+ T cells of only about 100/mm3 over baseline, with no continued rise during the second year.
Based on these results, Dr. Gulick and colleagues reached the following 2 conclusions:
Initial concurrent triple-drug anti-HIV therapy is clearly superior to delayed sequential therapy.
When antiretroviral regimens are changed because of clinical or virologic resistance, 2 new drugs should be added simultaneously.
But these salutary effects were not seen by many other clinicians, who reported that only about 50% of their patients maintained undetectable viral loads and T-cell elevations for more than 9 to 12 months. For example, Dr. Steven Deeks reported on 192 HIV-seropositive patients seen at the University of California San Francisco from March 1996 through March 1997 (Deeks S, et al: ibid. Abstract LB-2). Virologic failure on either indinavir or ritonavir used with other antiretrovirals occurred in 7.7% of nucleoside analog-naive patients and a staggering 57% of nucleoside analog-experienced individuals after at least 24 weeks of follow-up. Reasons for this discrepancy are unclear, but speculation centers around differences in patient populations.
First, prior treatment history. Participants in Merck protocol 035 had received long courses of AZT, and thus were pretolerant of its side effects. In addition, they had not taken 3TC or a protease inhibitor, and thus presumably harbored viral strains sensitive to these more potent agents. Second, and perhaps most important, was the issue of compliance. Merck 035 was a relatively small study, with a very low withdrawal rate. Such sustained participation is unusual.
By contrast, in the AVANTI 2 study (Gerstoft J, et al: ibid. Abstract I-87) comprising patients from Europe, Canada, and Australia, 27% of 103 HIV-seropositive drug-naive individuals who entered a protocol similar to Merck 035--AZT + 3TC versus AZT + 3TC + IDV--prematurely withdrew from the study (14 from the triple-drug arm and 13 from the double-drug arm). Such a high rate of withdrawal was not unique to IDV; side effects related to ritonavir were the cause of such dropouts in 26% of patients in another study (Opravil M, et al: ibid. Abstract I-94). In a pediatric trial of ritonavir, ACTG 338 (Yogev R, et al: ibid. Abstract LB-6), only 57% remained on full-dose drug by week 12, and 10% had discontinued medication altogether.
Several important findings in drug pharmacokinetics, and the development of a novel experimental agent, may improve adherence to HAART regimens.
A pilot, multicenter, open-label, randomized study compared 3 different dosage schedules of IDV--800mg every 8 hours, 1000mg every 12 hours, and 1200mg every 12 hours--with AZT + 3TC, both given every 12 hours (Nguyen BY, et al: ibid. Abstract I-91). Patients were naive to protease inhibitors and 3TC. Safety profiles were similar in all groups, but there was a very high dropout rate of 34.5% in the IDV 800-mg group. Of interest is the greater magnitude in CD4+ T-cell rise and vRNA decline with the every-12-hour IDV regimens. If this rise in T cells proves sustainable, the use of twice-daily IDV dosing, perhaps with the newly FDA-approved combination tablet of 3TC (150mg) + AZT (300mg) known as Combivir, may be a great boon to compliance.
A soft-gel formulation of the protease inhibitor saquinavir (SQV-SGC) provided a 10-fold increase in bioavailability over the previous hard-gel product (SQV-HGC). In an open-label randomized study of SQV-SGC + AZT + 3TC versus IDV + AZT + 3TC in 22 individuals without a history of 3TC or protease inhibitor use, decreases in vRNA and increases in CD4+ T-cell count were equivalent for both regimens (Borleffs JC, et al: ibid. Abstract I-92). No one had dropped out as of 24 weeks, and a "roll-over" is planned for any failing regimens, with drugs chosen based on phenotypic and genotypic viral resistance patterns now being collected.
DMP-266 (efavirenz) is a new non-nucleoside reverse transcriptase inhibitor. This peptide blocks the viral enzyme by allosteric interference. In one study involving 101 HIV-seropositive patients with a mean CD4+ T-cell count of 283 +/= 119, DMP-266 (200mg once per day) was used in combination with IDV (800mg every 8 hours) and contrasted with IDV monotherapy (Mayers D, et al: ibid. Abstract I-175). Sustained declines in viral load were maintained for 48 weeks on the combined regimen, with 90% having undetectable virus (fewer than 400 copies/mL, with 80% of these having fewer than 1 copy/mL). DMP-266 has a unique resistance mutation, K103N (Bacheler LT, et al: ibid. Abstract I-172).
Theoretically, early use of potent antiretroviral therapy should preserve immune function by decreasing the initial viral set-point and, by maintaining suppression of viral replication, retarding the rate of viral mutation. If we can address issues critical to patient compliance, then we might one day realize this potential.
About the Author
Dr. Laurence is Associate Professor of Medicine and Director of the Laboratory for AIDS Virus Research, The New York Hospital-Cornell University Medical College, New York City, and Senior Scientific Consultant for Programs, American Foundation for AIDS Research (AmFAR). He is Editor-in-Chief of The AIDS |
