Important note: Information in this article was accurate in March 2002. The state of the art may have changed since the publication date.
• TMC 125: TMC 125 is a second-generation NNRTI from Tibotec-Virco that demonstrates in vitro activity against HIV that carries high-level resistance to the three currently available NNRTIs. At ICAAC in December, we heard exciting results from a phase 2 trial in which antiretroviral therapy-naïve patients taking TMC 125 monotherapy experienced an astonishing 1.92 log drop in viral load after only 7 days [Gruzdev, ICAAC 2002, Abstract 1-668]. At the CROI, Joep Lange retrospectively compared these results to those from the ERA trial, in which treatment naïve patients received AZT, 3TC, ABC, NVP, and IDV [Sankatsing, Abstract 5]. Patients on this 5-drug, 3-class regimen had a drop in viral load of 1.76 log10 c/mL, similar to that seen with TMC 125 monotherapy. Although such cross-trial comparisons are always suspect, this is clearly a promising agent.
Of course, the real test for a second generation agent like TMC 125 is its ability to suppress virus resistant to currently available NNRTIs. Brian Gazzard presented data from Tibotec-Virco’s C207 trial, in which 16 patients failing therapy with an NNRTI-based regimen were switched to TMC 125 (900 mg bid) for 7 days [Abstract 4]. At baseline, participants had high-level resistance to all available NNRTIs (mean 256-fold decrease in susceptibility to EFV), while susceptibility to TMC 125 was decreased by a mean of 3.2-fold (median 2.2-fold). Three patients had a single NNRTI mutation (103N or 188L); 8 had 2 mutations; 3 had 3 mutations; and one patient had 4 NNRTI mutations. After 7 days on TMC 125, participants experienced a mean decline in viral load of 0.86 log10 c/mL; 44% had a decrease of >1 log. These results demonstrate promising activity against NNRTI-resistant virus. The reason for the more modest change in viral load compared to that seen in the naïve patients described above is unclear. Possible explanations include cross-resistance among the NNRTIs or residual drug interactions between the failing NNRTI and TMC 125. Interestingly, however, there was no relation between serum levels or baseline NNRTI susceptibility and virologic response.
• DPC 083: DPC 083 is another second generation NNRTI with impressive activity against NNRTI-resistant virus, though the data presented at this conference do not clearly establish its future or its role in therapy. In trial 201, naïve patients were treated with EFV or one of three doses of DPC 083 (50, 100, or 200 mg qd) plus two NRTIs [Ruiz, Abstract 7]. Efficacy data were not presented in detail, but the four arms were said to be “highly effective.” Patients taking DPC 083 were less likely to experience neuropsychiatric side effects than those taking EFV, but over half of the patients in the DPC 083 200 mg arm had rash, and 14 of 35 discontinued therapy because of rash. The 100 mg dose will be studied in phase III trials in naïve patients, but whether this will be the optimal dose for NNRTI-resistant patients has not been determined.
Ruiz also presented results from the 203 trial involving patients treated with 100 or 200 mg daily of DPC 083 after failing therapy with an NNRTI-based regimen [Abstract 6]. Not surprisingly, virologic response was correlated with the incorporation of new NRTIs in the new combination. However, the poor recruitment, high drop-out, and large number of protocol violations make this an inconclusive study, and one that does not allow dose selection for this patient population.
• Atazanavir: Atazanavir (ATV) is a new protease inhibitor from Bristol-Myers Squibb, expected to be the next approved PI and the first to be dosed once daily. Follow-up data from trials previously discussed in The Hopkins HIV Report [see Gallant, HHR 2002, 14(1):1] were presented, once again pointing out the fact that ATV does not cause the problems with cholesterol and triglyceride elevation that have been observed will all other protease inhibitors [Piliero, Abstract 706-T]. As noted in previous discussions of this drug, potency appears to be equivalent to that of nelfinavir. Follow-up data were also presented from the BMS 009 trial, in which ATV/SQV (400/1200 and 600/1200 mg qd) was compared with RTV/SQV (400/400 mg bid) in PI-experienced patients [Haas, Abstract 42]. After 48 weeks, patients in all three arms had viral load reductions >1 log10 c/mL, though data on percent undetectable were not presented. Not surprisingly, the lipid profile was more favorable in patients treated with ATV/SQV than with RTV/SQV.
• Tipranavir: Tipranavir (TPV), an investigational PI from Boehringer Ingelheim, has a unique resistance profile making it an attractive agent for patients with PI-resistant virus. It is co-administered with ritonavir to improve pharmacokinetics and drug levels, but the optimal dose regimen has not been determined. Trials involving TPV were presented at last year’s ICAAC and were discussed in the last issue of The Hopkins HIV Report. Schwartz and colleagues looked at development of TPV resistance in patients enrolled in a phase II trial of two TPV/RTV dose regimens after failure of their second PI-based regimen [Abstract 562-T]. They found that TPV resistance was uncommon in this group of highly PI-experienced patients, and that virologic response to TPV was not predicted by the number of baseline PI mutations. Only 14% showed decreased susceptibility to TPV after 104 weeks on the TPV/RTV regimen, associated with a mean of 16 proteasemutations. Development of >10-fold resistance occurred infrequently.
• Tenofovir DF: By the time tenofovir DF (TDF) made its big debut at ICAAC in December, it had already been approved by the FDA. Nevertheless, we hadn’t seen data from naïve patients until CROI. Results were presented from a small trial in which 10 patients with viral loads >10,000 c/mL (mean 4.3 log10 c/mL) were treated with tenofovir monotherapy (300 mg qd) and underwent intensive virologic monitoring [Louie, Abstract 3]. The mean decrease in viral load was 1.5 log10 c/mL by day 21, and mean 1st phase viral load decay was approximately 0.4 log/d. As with the TMC 125 monotherapy trial, these results were retrospectively compared with data from previous studies. Using the combination of LPV/RTV + EFV + 3TC + TDF as a standard (1st phase slope -0.99 log/d), the potency of TDF monotherapy was similar to that of RTV monotherapy (-0.34 log/d). Thus, the efficacy of TDF was comparable to that of a PI, and was approximately 40% of an intensive HAART regimen. Most of the data on TDF’s potency come from trials in experienced patients with NRTI resistance, and we are accustomed to thinking of this drug in terms of a modest 0.6 log decline in viral load. This small study hints at greater potency in naïve patients, findings that will need to be confirmed in the Gilead 903 trial, which we can expect to hear about this summer in Barcelona at the World AIDS Conference.
• Once-daily Lopinavir/Ritonavir: The impressive results seen with lopinavir/ritonavir (Kaletra) in both naïve and experienced patients have been explained primarily by the high drug levels and long half-life of lopinavir when boosted with ritonavir. When given at the standard dose of 3 capsules (400/100 mg) bid, trough levels of lopinavir exceed the IC50 for wild-type virus by over 75-fold. These characteristics have made it a logical candidate for once-daily administration. Data were presented from a pilot trial (N=38) comparing bid (3 capsules, or 400/100 bid) with qd (6 capsules, or 800/200 qd) dosing of LPV/RTV [Bertz, et al., Eron, et al. Abstract 409-W]. In an intent-to-treat, missing=failure analysis at 48 weeks, 79% and 74% had viral loads <50 mL, respectively. No increase in gastrointestinal side effects was noted in the qd arm. The median inhibitory quotient was >40 in both groups, and the median trough level was >2.8 ug/mL. There were no differences in AUC24 or Cmax; however, the Cmin was approximately 44% of that seen in the bid arm, and trough levels were considerably more variable with the once daily dose. This preliminary report suggests that once daily dosing of LPV/RTV may be possible, especially in patients without pre-existing protease inhibitor resistance. In PI-resistant patients, however, the clear advantage of this drug is its high trough level, an advantage that could be diminished with once daily administration.
• Stavudine Extended Release Formulation: A new extended release (XR) formulation of stavudine may be approved soon, joining a growing list of once-daily therapy options. Pharmacokinetic data were presented from a sub-study of BMS 096 involving16 treatment-naïve patients taking either d4T XR 100 mg qd or standard, immediate-release (IR) d4T 40 mg bid (with dose adjustment for patients weighing less than 60 kg) over 14 days [Abstract 430-W]. Richard Pollard presented preliminary 24-week results from BMS 099, a large, placebo-controlled, randomized, phase 3 trial comparing d4T XR with d4T IR combined with 3TC and efavirenz [Abstract 411-W]. By intent-to-treat analysis, results were similar in the two arms, with 80% and 82% of patients achieving HIV RNA <400 c/mL in the XR and IR groups, respectively, and 55% in each arm achieving <50 c/mL in both arms. Adverse events were similar in both groups, with peripheral neuropathy occurring in 2% of the XR group and 4% of the IR group.
• Once-Daily Saquinavir/Ritonavir: Cardiello reported on a trial of once daily saquinavir/ritonavir (SQV/RTV 1600/100 mg qd) plus two NRTIs in 62 patients fully suppressed on saquinavir (soft-gel capsule, 1400 mg bid) plus 2 NRTIs [Abstract 549-T]. Although the trial was uncontrolled, 91% maintained an HIV RNA <50 c/mL after 48 weeks of follow-up. In the FOCUS trial, presented in December at ICAAC [see Gallant, HHR 2002, 14(1):1], GI toxicity and drop-out was significantly higher in patients taking SQV/RTV once daily than in those on an EFV-containing arm. Future studies of the SQV/RTV combination as well as combinations of SQV with other PIs will investigate the use of hard-gel SQV (Invirase), which is generally better tolerated than the soft-gel formulation (Fortovase), and which achieves similar or even superior drug levels when combined with RTV [Kurowski, Abstract 432-W].
Perhaps the most dramatic way to simplify therapy is to discontinue it altogether. Bernard Hirschel from Geneva reviewed data on treatment interruption in a symposium entitled “Controversies in Antiretroviral Therapy” [Abstract S18]. In his talk he emphasized the negative results that have been observed with “strategic treatment interruption” (STI) strategies in chronically infected patients, in whom cycles of intermittent therapy do not appear to improve HIV-specific immunity or to blunt virologic rebound. Van Lunzen presented data from an STI trial in chronically infected patients which found that patients who interrupted therapy experienced rapid virologic rebound to baseline without change in virologic set-point despite the presence of HIV-specific CTL [Abstract 538]. The evidence supporting such an approach in patients treated during primary infection is stronger, though these patients are few and far between. The “structured intermittent therapy” (SIT) approach, in which patients go on and off therapy (e.g., 7-days on/7-days off) in order to lessen drug exposure, toxicity, and cost, appears promising, but remains highly experimental given the small numbers of patients who have been studied to date [Dybul M, et al. PNAS 2001;98:15161]. Finally, the strategy of “pulse therapy” is beginning to be tested in randomized, controlled clinical trials. In this approach, patients who have had good immunologic responses to HAART stop therapy periodically, resuming after they have reached a pre-established CD4 count threshold.
At the CROI, Lundgren presented data from the large EuroSIDA cohort on the dangers of what was termed “treatment interruption,” but might be better thought of as good old-fashioned non-adherence [Abstract 48]. The investigators identified patients who had been on HAART for more than 3 months and who then interrupted therapy for any reason for at least 3 months. A total of 5,385 patient initiated therapy (15,312 person-years of follow-up), and 776 interrupted therapy. Of those, 518 reinitiated therapy during the follow-up period. The cumulative probability of treatment interruption was 20% at 60 months. There were a total of 10,637 person-years of follow-up from the start of HAART to a first new AIDS-defining event, death, or the last follow-up. The patients in the cohort had fairly advanced disease: At HAART initiation, the average viral load was 4.4 log10 c/mL, and the average CD4 was 200 cells/mm3 with a nadir of 138 cells/mm3. Almost one-third had had AIDS-defining events. Factors associated with interruption included female gender (OR 1.31, p=0.02), injection drug use (OR 1.51, p<0.001), and higher viral load (OR 1.74, p<0.001). AIDS-defining events or death occurred in 408 patients on HAART (mean CD4 111 cells/mm3, HIV RNA 3.9 log10 c/mL) and 37 patients off HAART (CD4 52 cells/mm3, HIV RNA 5.2 log10 c/mL). Patients who interrupted therapy were at increased risk of AIDS and death compared to those who remained on treatment. However, there was no evidence of increased risk if the CD4 count remained above 200 cells/mm3. This study confirms the importance of CD4 count in determining the risk of complications and emphasizes the importance of continuing HAART in patients with advanced disease. However, it also suggests that treatment interruption may be safe provided CD4 counts are maintained at a high enough level. This appears to have been a group of patients with fairly advanced HIV disease who had strong indications for antiretroviral therapy. As such, they may not be representative of patients who are often considered for treatment interruption: those with earlier stage disease whose CD4 counts are expected to remain well above 200 cells/mm3 off therapy.
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