Important note: Information in this article was accurate in January 2005. The state of the art may have changed since the publication date.
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There were relatively few studies on antiretroviral therapy and investigational antiretroviral agents presented at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held in Washington, D.C. earlier this fall. Nevertheless, some of the data presented were important and worthy of commentary.
Antiretroviral Therapy With Approved Agents
Tenofovir + Emtricitabine vs Zidovudine/Lamivudine: GS 934
Brian Gazzard presented preliminary 24-week data from GS934 that expanded on an announcement from Gilead Sciences released shortly before the conference [Abstract H-1137c]. The 934 study is an open-label trial in which over 1,000 treatment-naïve patients were randomized to receive either tenofovir DF (TDF) + emtricitabine (FTC) or coformulated zidovudine (AZT)/lamivudine (3TC), both in combination with efavirenz (EFV). The TDF + FTC arm was associated with superior efficacy by an intent-to-treat (ITT), time to loss of virologic response (TLOVR) analysis, with 73% and 65% of patients achieving a viral load <50 c/mL at 24 weeks, respectively (P=0.038). There was no difference in response by as-treated analysis; the difference in efficacy was explained entirely by the fact that more patients in the AZT/3TC arm dropped out (21%, compared to 11% in the TDF + FTC arm, P=0.01). Discontinuation due to adverse events, especially anemia, was also more common among AZT/3TC recipients (9% vs 3%). The anemia was significant: Among those who discontinued treatment for this reason, the median hematocrit dropped from a baseline value of 40% to a nadir of 22%. Interestingly, patients who failed therapy at 24 weeks frequently had the M184V mutation or EFV resistance, but no patient had thymidine analog mutations (TAMs) or the K65R mutation.
These results are not particularly surprising. Clinicians have long been familiar with the early side effects and hematologic toxicity associated with AZT. In fact the results from both arms of the study are consistent with what has been observed with TDF- and AZT-containing regimens in other studies. While these early results have clear implications for treatment-naïve patients initiating therapy, they are less relevant to patients currently taking and tolerating AZT/3TC-containing regimens. However, the study is ongoing and is planned to continue through 96 weeks. It will be especially interesting to see longer-term DEXA data from this trial, to determine whether there is a difference in the emergence of lipoatrophy between the two arms.
Concerns about Didanosine + Tenofovir
Several studies presented at ICAAC raised concerns about the NRTI backbone of didanosine (ddI) + TDF, resulting in a “Dear Health Care Provider” letter from Bristol-Myers Squibb, advising clinicians to “use caution when coadministering TDF, ddI EC, and either EFV or NVP in treatment-naïve patients with high baseline viral loads.”
An earlier trial found an unacceptably high rate of virologic failure and emergence of resistance in patients taking the triple-NRTI regimen of TDF, didanosine (ddI) and 3TC [Gemseck J, et al. Conf Retroviruses Opportunistic Infect. 2004 Feb 8-11;11th: (abstract 51), raising the question of whether TDF + ddI would be an acceptable NRTI backbone if combined with a more potent third agent. At ICAAC Graeme Moyle presented data from a small trial in which 70 patients were randomized to receive initial therapy with EFV plus either ddI + 3TC or ddI + TDF [Abstract H-566]. Virologic failure was more common in the ddI + TDF arm (4/34) than in the ddI + 3TC arm (0/36); all failures occurred among patients with baseline viral loads >100,000 c/mL and CD4 counts <200 cells/mm3. These results echo results from a study involving the same regimen presented by Podzamczer at the XIII International HIV Drug Resistance Workshop earlier this year [Antiviral Therapy 2004; 9:S172 (Abstract 156)].
Concerns were also raised about the CD4 response to regimens containing TDF + ddI. Soriano presented data from a retrospective study from Spain comparing patients treated with regimens containing TDF + ddI, TDF alone, ddI alone, or neither agent [Abstract H-1132]. Patients receiving TDF + ddI experienced a decline from baseline in absolute CD4 count. It should be noted that these patients were initially receiving full doses of ddI; when the dose of ddI was subsequently reduced to compensate for the TDF interaction, the CD4 count rose [Negerdo E, et al. Abstract 561]. The potential mechanism is unclear, and the study is limited by the decreasing sample size over time in the ddI + TDF groups. Nevertheless, it provides one more reason to be wary of the combination of ddI and TDF.
Perhaps the best reason not to use the TDF + ddI backbone (and, by extension, combinations of ABC + ddI or ABC + TDF) in naïve patients is the lack of data from clinical trials, in contrast to the wealth of data supporting the use of 3TC- and FTC-containing combinations. Such combinations may be considered, however, in NRTI-experienced patients when guided by resistance test results, especially in patients with TAMs, for whom emergence of K65R is less of a concern.
AZT/3TC/ABC + TDF
While triple-NRTI regimens have fallen out of favor recently, there is still interest in the idea of a “quad regimen” involving coformulated AZT, 3TC, and abacavir (ABC) (Trizivir) plus TDF. Moyle presented 48-week results of the TIMS trial, in which 113 treatment-naïve patients were randomized to receive either AZT/3TC + EFV or AZT/3TC/ABC + TDF [Abstract H-1131]. AZT/3TC/ABC was administered twice a day in this study. At 48 weeks, two-thirds of the patients in each arm had a viral load <50 c/mL by ITT analysis. Failure was mostly due to discontinuation of therapy; only one patient, who was randomized to the quad arm, experienced virologic failure. Not surprisingly, fasting cholesterol levels were significantly higher in the EFV arm.
The same 4-drug regimen was studied in an uncontrolled, open-label study in which coformulated AZT/3TC/ABC was given once a day along with TDF to 113 treatment-naïve patients [DeJesus E, et al. Abstract H-564]. At week 24, 54% had a viral loads <50 c/mL by ITT missing=failure analysis. Virologic response was lower among patients with a baseline viral load >100,000 c/mL. Six of the 8 non-responders with genotype data had TAMs with or without M184V at 24 weeks.
This quad-NRTI regimen deserves further study, especially when dosed twice daily based on the results of Moyle’s study. It is relatively simple, spares both NNRTIs and PIs, and is especially attractive in the developing world, since there is no need for refrigeration and no concerns about interactions with rifampin. However, it would be premature to recommend this regimen now. Moyle’s study, while intriguing, was small and not powered to demonstrated non-inferiority. And DeJesus’s study raises questions about the potency of the once daily version of this regimen because of the marked difference in response between patients with high and low baseline viral loads. The relatively large number of patients with TAMs (in contrast to what might be expected in patients failing twice-daily AZT/3TC/ABC alone) also raises questions about whether inclusion of once-daily AZT in this regimen may not increase the risk for drug resistance.
It’s also worth speculating on whether the abacavir component of this four-drug regimen is necessary at all. The one remaining triple-NRTI combination that is still potentially viable but relatively untested is the combination of AZT, TDF, and either 3TC or FTC. This combination has an advantage over AZT/3TC/ ABC because the M184V mutation has beneficial effects on susceptibility to both AZT and TDF. There is certainly no reason to consider using such a combination in the developed world now. But the patent on AZT will be expiring soon, which will lead to growing interest in how to use low-cost generic AZT in simple, class-sparing regimens.
Efavirenz vs Boosted Indinavir in Patients With Advanced Disease
It is a commonly accepted dogma that patients with advanced HIV disease (i.e., those with high viral loads or low CD4 cell counts) “need” a PI, though there have never been strong data to support this assertion. José Miró presented data from a study in which 34 treatment-naïve patients with baseline CD4 counts <100 cells/mm3 (median 40 cells/mm3) were randomized to receive AZT/3TC plus either EFV or ritonavir-boosted indinavir (IDV/RTV 800/200 mg bid) [Abstract H-574]. At 38 weeks, virologic and CD4 response appeared to favor the EFV arm, though the differences did not achieve statistical significance in this small study. These results suggest that EFV was at least as effective as IDV/RTV, and that it can be considered a reliable option in patients with low CD4 counts. The more definitive study will be the large ongoing ACTG trial in which patients are randomized to receive two NRTIs plus either LPV/r or EFV.
Investigational Antiretroviral Agents
Tipranavir: The RESIST-1 Trial
Charles Hicks from Duke University presented 24-week data from the ongoing RESIST-1 trial, a randomized, open-label trial in which over 600 patients with 3-class experience treated with at least 2 PI-containing regimens were randomized to receive either ritonavir-boosted tipranavir (TPV/RTV 500/200 mg bid) or a comparator boosted PI (CPI) along with an optimized background regimen [Abstract H-1137a]. Entry criteria required that patients have at least 1 primary PI mutation but no more than 2 mutations at codons 30, 82, 84, and 90. The median baseline viral load was 4.8 log10 c/mL, and the median baseline CD4 count was 123 cells/mm3. At 24 weeks, 41.5% of TPV/r-treated patients achieved a viral load reduction of ≥1 log compared with 22.3% in the CPI arm by ITT analysis (P<0.001). Viral load reduction to <400 c/mL was achieved by 34.7% and 16.5%, respectively, (25.1% vs 10.0% for <50 c/mL, P<0.01 for both comparisons). Enfuvirtide (ENF) was included in the optimized background regimen in 36% of participants, and not surprisingly, use of ENF improved virologic response in both groups. For example, virologic suppression to <400 c/mL was achieved in 47.1% of TPV/r recipients who also took ENF compared to 34.7% overall, and in 21.9% of those in the CPI arm compared to 16.5% overall. Patients on TPV/r were more likely to have elevations in transaminases and lipids than those in the CPI arm, perhaps because of the higher dose of ritonavir.
These data support the efficacy of TPV in patients with PI experience and resistance, and also emphasize the importance of including more than one active agent in a salvage regimen. Availability of this drug and other “second-generation” agents through clinical trials and expanded access programs will probably also increase the use of ENF, which many clinicians have been reluctant to use in highly experienced patients because for many such patients there were no other effective drugs available to combine it with.
Similar results were seen in the RESIST-2 study, which were presented recently by Pedro Cahn in Glasgow at the 7th International Congress on Drug Therapy in HIV Infection (November 14-18, Abstract PL14.3).
D-d4FC (Reverset) in NRTI-Experienced Patients
Robert Murphy presented data from a 10-day monotherapy study in which 8 patients added varying doses of D-d4FC to a failing regimen [Abstract H-1130]. The mean viral load reduction among those receiving D-d4FC was -0.8 log10 c/mL at day 10, although the response was somewhat lower among the 4 patients with 3-4 TAMs at baseline. A larger phase IIB trial in antiretroviral-experienced patients is ongoing, and should help to determine the role of this agent in patients with multiple TAMs.
A number of coreceptor antagonists are now in clinical development; those furthest along inhibit binding to the CCR5 coreceptor, thus preventing entry of HIV into the CD4 cell (See Shepherd J and Quinn T, HHR 2004;16(4):
1-4). Lalezari presented data from a 10-day dose-ranging study of 873140, a CCR5 inhibitor from GlaxoSmithKline [Abstract H-1137b]. There was a clear dose-response relationship, with subjects who received the highest dose (600 mg bid) experiencing a decline in viral load of over 1.6 log10 c/mL. The peak virologic effect occurred at day 12, 2 days after
discontinuation of the drug, an effect that was attributed to prolonged receptor occupancy. The drug was well tolerated; the most common side effects were mild and transient gastrointestinal problems.
One concern with use of CCR5 inhibitors is the potential for selection of pre-existing X4- or R5/X4-tropic virus, which could result in more rapid progression of HIV disease. A study by Moyle and colleagues demonstrated a higher prevalence of X4- or dual-tropic virus among patients with CD4 counts <100 cells/mm3 [Abstract H-1135], and Demarest presented data showing that while R5-tropic virus was most common among all groups of patients, the prevalence of X4- or dual-tropic virus was higher among treatment-experienced patients than among treatment-naïve patients [Abstract H-1136]. Two patients treated with 10 days of monotherapy with the Pfizer CCR5 antagonist, UK-427,857 developed dual-tropic virus during the course of the study, which appeared to emerge as a result of low-level pre-existing dual-tropic virus that had not been detected by the screening tropism assay, which has a detection threshold of approximately 10% [Lewis ME, et al. Abstract H-584b]. Phylogenetic analysis revealed that in one patient, dual-tropic virus was replaced by R5-tropic virus at day 40, one month after discontinuation of the study drug. However, the second patient continued to have significant levels of dual-tropic virus one year after completion of the study.
The most promising use of these agents, therefore, would be as a component of initial therapy, perhaps initiated at earlier stages of disease than is currently the practice. However, the competition for a role in initial therapy is fierce, given the convenience and tolerability of currently used agents.
Richard Nettles from Johns Hopkins University presented a study in which 10 patients on HAART with virologic suppression were intensively monitored to help characterize the phenomenon of “blips,” or transient episodes of low-level viremia [Abstract H-1134]. Viral loads were measured in two different laboratories three times a week over a 3-month study period. Nine of the 10 participants experienced at least one blip. The median duration of the blips was 60 hours, and the median magnitude was 79 c/mL. Interestingly, of the 18 blips observed during this study, only one was detected by both laboratories, suggesting that many blips may represent normal assay variation rather than true viremia. This possibility is further supported by the observation that no new mutations were detectable before, during, or after blips. The apparent lack of viral evolution is in contrast to data published by the same group demonstrating that emergence of resistance does occur in patients with low-level but persistent viremia [Nettles RE, et al. Clin Infect Dis. 2004 Oct 1;39(7):1030-7], a finding that has now been observed in a number of studies, including one presented at ICAAC this year [Edwards D, et al. Abstract H-176]. These data are reassuring, since blips are commonly seen in clinical practice. The challenge for clinicians is to know whether a detectable viral load represents an inconsequential blip or the beginning of virologic failure, an important distinction, given that viral loads in clinical practice are typically drawn every 3 months rather than 3 times per week.
The handful of studies on antiretroviral therapy that were presented at ICAAC this year helped us to learn more about the growing number of options for initial therapy and shed light on several promising investigational agents. We can expect to learn much more at the upcoming Conference on Retroviruses and Opportunistic Infections, to be held in February, 2005 in Boston, which will be extensively covered in The Hopkins HIV Report.
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