• New Agents in ART Experienced Patients
• Two- vs Three-Class Salvage in NRTI-Experienced Patients
• Blips and Low-Level Viremia: When to Switch
• Immune Based Therapies and Therapeutic Vaccination
• Conclusions

The treatment of antiretroviral therapy experienced patients is critically linked to using available data to construct a new regimen with adequate potency and tolerability. This article will review data presented at the 9th CROI on: The efficacy of new drugs in experienced patients, the meaning of “blips” and low level viremia in treatment experienced patients, and the role of immune-based therapies (notably IL-2) and therapeutic vaccines in treating HIV-infected patients.

New Agents in ART Experienced Patients

• Tenofovir DF (TDF) is a nucleotide reverse transcriptase inhibitor that was recently approved by the FDA exclusively on the basis of safety and efficacy data in ART experienced patients. Final 48-week data was presented from Study 907, in which heavily experienced HIV-infected individuals were randomized to receive TDF 300 mg qd or placebo in combination with their current antiretroviral regimen for 24 weeks, followed by open label TDF in all participants from week 24 on [Squires, Abstract 413-W]. TDF was as well tolerated as placebo and produced a durable 0.6 log₁₀ reduction in HIV RNA.

The signature resistance mutation selected in vitro by TDF, K65R, is rarely seen in vivo [Margot, Abstract 414-W]. There has been considerable interest in the association of classic thymidine-associated mutations (TAMs) in predicting the efficacy of TDF, and this was addressed by Miller from Gilead [Abstract 43]. Baseline genotype and phenotype assays were performed in subjects in Studies 902 and 907. There was a dose-response relationship, with greater numbers of TAMs at baseline associated with a poorer response to TDF. More importantly, however, mutations at amino acid residues 41 and 210 were particularly associated with decreased efficacy (Table 1, below).

M. Miller pointed out that there are two minority pathways of TAM development: 67, 70, and 219 or 215, 41, and 210. The former path is associated with a good response to TDF, while the latter is associated with a poor response. Multiple TAMs will clearly prove to be the primary mechanism of resistance to TDF, although high-level resistance is occasionally mediated by the K65R mutation or the T69S double insertion [Abstract 43]. Miller also presented results of a recursive analysis of baseline phenotypic susceptibility to TDF, which suggested two clinically relevant cutoffs. Patients with <1.4-fold change in the 50% inhibitory concentration (IC₅₀) experienced a 0.77 log₁₀ decrease in HIV RNA; patients with an IC₅₀ between 1.4-fold and 3.8-fold experienced a 0.47 log₁₀ decrease in HIV RNA, while those with an IC₅₀ >3.8-fold demonstrated a 0.24 log₁₀ decrease in HIV RNA, consistent with high level resistance.

• T-20 is the first in a novel class of anti-retroviral agents, the fusion inhibitors, and is anticipated to play a major role in salvage therapy. Results were presented from an open-label trial in which 71 PI-experienced, NNRTI-naïve participants were randomized to receive a regimen of ABC/RTV/APV/EFV or this regimen plus varying doses of T-20 (50, 75 or 100 mg bid) [Lalezari, Abstract 418-W]. Approximately two-thirds of the subjects had failed >2 prior PI-based regimens.

Considering the T-20 recipients in aggregate, 55% achieved HIV RNA <400 c/mL at 48 weeks compared to 37% in the placebo arm, and the corresponding CD4 cell increases were 132 and 90 cells/mm³. Though there was evidence of a dose-response relationship between viral load reduction and T-20 dose, 31% in the highest T-20 dose arm discontinued the study due to adverse effects (particularly local injection site reactions) compared to approximately 6% in the lower dose arms and 15% in the control arm. Notably, patients in the higher dose T-20 arms had to receive two injections bid (four daily) of the 50 mg/mL formulation. A new 100 mg/mL preparation (which only requires one injection bid) has been determined to be bioequivalent to the 50 mg/mL preparation and hopefully will make the higher T-20 dose more tolerable [Wheat, Abstract 417-W].

• Atazanavir (ATV) is a protease inhibitor (PI) in late-stage development at Bristol-Myers Squibb, with a remarkably low propensity for raising lipids that is likely to be the first PI approved for qd administration. Although the potency of ATV has not been striking, and this agent is not anticipated to be a heavy-hitter in PI salvage, results were presented from a trial in which HIV-infected patients with a history of prior virologic failure on a PI were randomized to receive 2 NRTIs plus either ATV 400 mg qd + SQV 1200 mg qd, or ATV 600 mg qd + SQV 1200 mg qd, or RTV 400 mg + SQV 400 mg bid [Haas, Abstract 42]. At baseline, 88% of patients had prior PI exposure, and 30% were NNRTI experienced. Results at 48 weeks are shown in Table 2 (below). By intent-to-treat analysis, only about 40% of patients achieved a 1 log₁₀ reduction in HIV RNA or were <400 c/mL at 48 weeks, and proportions were similar in the three study arms. However, the RTV/SQV arm was plagued by a substantially higher dropout rate due to regimen intolerance (30% compared to approximately 10% in the ATV arms). Notable is the favorable lipid profile with ATV/SQV compared to RTV/SQV, although unconjugated hyper-bilirubinemia was more common with ATV, and was dose-related.

• Tipranavir (TPV) is a PI in development at Boehringer Ingelheim that may play an important role in salvage therapy. Forty-one patients who had failed >2 prior PIs but were NNRTI naïve were treated with EFV 600 mg qd, RTV 100 mg bid, at least one new NRTI, and were randomized to either low- or high-dose TPV [Schwartz, Abstract 562-T]. The results from this study were complicated by the fact that the formulation of TPV was changed mid-way through, from hard-filled capsules (HFC) to the self-emulsifying drug delivery system (SEDDS) [see Gallant, HHR 2001,13(5):8]. TPV was associated with durable viral suppression through week 80, regardless of baseline protease resistance mutations (Table 3, below). During therapy, mutations emerged at protease codons 82 and 33 in four of six patients with reduced susceptibility to TPV.

Two- vs Three-Class Salvage in NRTI-Experienced Patients

ACTG 364 was a double-blind, placebo-controlled trial, comparing the efficacy of second line therapy with 2 drug classes vs 3 classes in exclusively NRTI-experienced patients [Albrecht, Abstract 425-W]. One hundred ninety-six subjects with screening HIV RNA >500 c/mL were randomized to 1-2 new NRTIs plus NFV, EFV, or NFV + EFV. By intent-to-treat analysis at 48 weeks, 71% in the triple-class arm, compared to 58% assigned to EFV and 48% receiving NFV achieved HIV RNA <50 c/mL. In pair wise comparisons, subjects in the triple-class arm had a statistically significantly lower risk of experiencing virologic failure (HIV RNA >200 c/mL) during follow-up than subjects in the other two arms. This study is somewhat dated, as patients treated exclusively with non-suppressive NRTI therapy (an inclusion criterion) are substantially less common than they were a few years ago. Additionally, resistance testing would presumably be used in such patients in order to assess the degree of NRTI resistance and the need for triple-class therapy.

Blips and Low-Level Viremia: When to Switch

Now that HIV RNA is routinely measured using ultrasensitive assays in patients on therapy, it is unclear what level of viral activity is associated with subsequent failure and should trigger a change in therapy. Havlir and colleagues have previously presented data that infrequent “blips,” defined as an HIV RNA >50 c/mL followed by suppression to <50 c/mL, were not associated with subsequent virologic failure in minimally-experienced patients treated with HAART [Havlir, et al. JAMA 2001;286:171]. At the 9th CROI, Havlir presented data from a similar analysis conducted on highly-experienced patients treated with salvage therapy in ACTG 398 [Abstract 93]. Approximately 25% of patients who achieved viral suppression in this trial experienced blips, which were not associated with prior antiretroviral exposure, baseline viral load, CD4 cell count, or resistance. Moreover, in this salvage trial, as in naïve patients, blips were not associated with subsequent virologic failure.

Using mathematical modeling, Di Mascio and colleagues evaluated blips in 123 naïve patients treated with HAART [Abstract 94]. Blips occurred randomly in approximately one out of every 10 viral load measurements in these patients and were independent of treatment duration. A blip was estimated to represent the release of 5 x 10⁸ viral particles, which corresponds to 3 x 10⁵ HIV-infected cells releasing virus. The latter is approximately the same size as the latent reservoir in resting T-cells, making it unlikely that blips represent release of virus from this compartment. The investigators hypothesized that blips were random cycles of viral replication, which are then rapidly cleared in another compartment.

Coakley and colleagues identified a cohort of 39 patients who had low-level viremia (defined as detectable HIV RNA <1,000 c/mL) for >12 months [Abstract 556-T]. Surprisingly, 32 of these 39 patients went on to maintain low-level viremia (non-progressors), compared to 7 who experienced viral rebound >1,000 c/mL (progressors) over a mean follow-up time of 22 months. While 90% had antiretroviral resistance by genotype assay, progressors were significantly more likely to have resistance to all agents in their regimen (86%) compared to non-progressors (27%). Progressors also had lower nadir CD4 cell counts (104 vs 278 cells/mm³) and higher peak viral loads (137,657 vs 50,527 c/mL), compared to non-progressors. The interesting finding from this study was that there is a subset of patients who are able to maintain low-level viremia for long periods of time without overt virologic failure. However, this is probably an inherently unstable state, where a tenuous balance is struck among drug pressure, viral resistance, viral fitness and immunologic response.

Immune Based Therapies and Therapeutic Vaccination

• IL-2: Extended follow-up data were presented from ANRS 079 [Levy, Abstract 514-M]. In this trial antiretroviral-naïve patients were randomized to receive either d4T/3TC/IDV alone (N=58) or HAART + IL-2 (N=58), given in 5-day cycles monthly (3 cycles), then bimonthly (7 cycles). After the formal end of the trial at week 74, 89% of participants agreed to continue in extended follow-up (64 more weeks on average), during which IL-2 was rarely used in either group. At last assessment the proportions maintaining HIV RNA <50 c/mL were similar in the two groups (78% for HAART alone and 76% for HAART + IL-2). The median changes in CD4 cell counts are shown in Table 4, below. The patients had a median CD4 count of approximately 350 cells/mm³ at enrollment. IL-2 must be administered by subcutaneous injection and is associated with considerable side effects. What remains unproven is whether the boost in CD4 counts mediated by IL-2 is associated with improved AIDS-free survival, or whether IL-2 would be helpful in targeted situations, as in patients with advanced disease who achieve viral suppression on HAART but have a poor immunologic response.

Forty-eight-week data were presented from the HYDRILE trial, in which 69 patients who had failed a PI-containing regimen, but were naïve to NNRTIs and ABC were randomized to one of three groups: 1. d4T/ddI/ABC/EFV; 2. HAART + hydroxyurea (HU, 500 mg bid); or 3. HAART + HU + IL-2 [Lafeuillade, Abstract 424-W]. Patients had a mean CD4 count of 386 cells/mm³, a mean viral load of 4.0 log₁₀ c/mL, and had been exposed to a median of 4 NRTIs and 2 PIs. Intent-to-treat data at 48-weeks are shown in Table 5, below. Use of HU was associated with better viral suppression, and IL-2 mitigated the blunted CD4 response that is seen with HU. However, as has been noted in other trials and observational cohorts, discontinuations due to drug toxicity (pancreatitis, neuropathy, lactic acidosis) were significantly more common in the HU arms.

• Therapeutic vaccination has been proposed as a way to boost innate immune responses to HIV during therapy. Data from STI trials have suggested that HIV-specific helper T-cell response correlates with improved immune-mediated control of HIV and a lower viral load setpoint when HAART is stopped. However, this benefit seems to be restricted to patients who initiate HAART shortly following infection with HIV [Lori F, Lisziewicz J, JAMA 2001;286:2981]. Emilio Emini presented data form Merck’s HIV vaccine development program in a plenary talk [Abstract L5]. Emini discussed two vaccine candidates: a plasmid “naked” DNA vector and a replication-defective adenoviral vector. Preliminary data in monkeys suggest that a “prime-boost” scheme, where the plasmid vaccine is followed by the adenoviral vaccine, may be most effective in eliciting SIV-specific cellular immune response. Phase I results from HIV-negative volunteers were also presented, suggesting that both vaccines were well tolerated, and produced durable anti-HIV cellular immune responses in a majority of participants (particularly the adenoviral vaccine). Further development of these vaccines will be required (namely to include a greater variety of HIV antigens), and clinical efficacy remains to be evaluated in both HIV-negative or HIV-positive individuals (i.e., as therapeutic vaccination).

Two abstracts presented at this conference looked at therapeutic vaccination with Remune in patients with established HIV infection. Robbins and colleagues reported that significant increases in HIV-specific CD4 proliferative responses were seen in 5/5 patients on stable HAART treated with Remune compared to 0/4 patients treated with HAART alone [Abstract 315-W]. Bucy presented results from a trial in which patients with viral suppression on HAART were randomized to receive Remune (N=20) or placebo injections (N=8) [Abstract 314-W]. All patients then underwent a treatment interruption. The slope of the initial rise in HIV RNA following therapy interruption was significantly lower in the Remune arm than in the placebo arm, and 5/15 evaluable patients in the Remune group had a post-interruption peak HIV RNA <5,000 c/mL, compared to 1/6 in the placebo arm (P=NS). Trials are underway to evaluate Remune as an alternative to STI in recently infected individuals, who are more likely to have clinically meaningful responses, but are much harder to identify.

Conclusions

In summary, the recently approved drug, tenofovir, has modest potency in experienced patients, but is well tolerated and has a durable effect, with slow development of resistance. Data presented at this conference suggest that its role in true salvage will be limited, as TAMs (notably 41 and 210) are associated with lower efficacy. Ironically, this drug, which was approved on the basis of trials in ART-experienced patients, will likely be used more commonly in first line therapy or for intensification in early therapy. T-20 is the first representative of the fusion-inhibitor class likely to be approved, and will be important in salvage therapy, but probably not for early therapy, because it requires subcutaneous dosing. Tipranavir is a PI in development that appears to retain potency despite extensive baseline PI-resistance. In contrast, ATV appears to be a modestly potent PI that has minimal activity in deep PI salvage situations. However, once daily dosing and a favorable lipid profile make it an attractive candidate for early therapy.

IL-2 causes impressive CD4 gains when combined with HAART; however, the clinical benefits of this injected therapy remain to be proven. Finally, therapeutic vaccination may be a way to have our cake and eat it too, in that HIV-specific immune responses are boosted without the risk of letting HIV out of its cage, as with structured treatment interruptions. Based on STI studies, the likelihood of clinical benefit from therapeutic vaccination is likely to be greater for patients treated with HAART in early HIV infection than in those who initiate treatment in the chronic phase of HIV infection. It remains to be seen whether the promising “prime-boost” vaccine strategy, under study at Merck, will be more effective than STIs in eliciting a clinically meaningful cellular immune response in patients chronically infected with HIV.

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