Late Breakers from Geneva
Remune, an HIV Immunogen, Stimulates Anti-HIV Cell Mediated Immunity in Conjunction with HAART
Dr. Fred Valentine reported the preliminary efficacy of immune stimulation with a killed-gp120-depleted whole-HIV preparation (Remune) as supplementary immunotherapy in HAART-treated patients [3]. This study is highly timely in view of the work by Bruce Walker and others suggesting that maintenance of anti-HIV lymphocyte proliferative responses is a key determinant in long-term survival. Forty-three HIV infected patients were treated with HAART and given Remune or adjuvant alone at weeks four, 16, and 28. At week 20, the patients showed significant viral load decreases and CD4+ cell increases. More significantly, the Remune treatment (but not adjuvant alone) stimulated strong lymphocyte proliferative responses to a variety of HIV antigens (gag, env) across several viral clades, in spite of the fact that Remune is clade-specific (clade A for env and clade G for gag). While it is too soon to know if there will be a long-term benefit, the in vitro analysis of cell-mediated immunity in Remune-treated patients suggests that immune stimulation may enhance HAART.
HAART Marches On
NVP-Based 4-Drug Salvage Regimen Effective
In an exciting late-breaker poster, Dr. Steven Deeks of the University of California at San Francisco presented a comparative trial between nevirapine (NVP) + abacavir (ABC) + 2 protease inhibitors (PIs) versus a nucleoside analogue (NRTI) + ABC + 2 PIs (the 2 PIs were NFV + SQV-soft gel capsules). The trial included 20 patients who had failed indinavir-based therapy. The NVP+ABC+ 2 PIs combination outperformed the NRTI based salvage regimen by an impressive two logs of viral load suppression at week 20 (p = 0.05). While expanded trials of NVP-based salvage therapy will clearly be important to confirm this finding, the magnitude of the effect was promising and suggests a powerful synergy between nevirapine and the new highly potent NRTI, abacavir [1].
ABT-378/Ritonavir Safe and Effective
Dr. Anthony Japour presented a late-breaker oral report on the unique ABT-378/ritonavir combination [2]. ABT-378 is a new protease inhibitor under development at Abbott Laboratories which, when combined with low doses of ritonavir (100 mg BID), has its bioavailability boosted 50- to 100-fold and its half-life extended to about 24 hours. The enhancement of ABT-378 levels is specific to ritonavir and is not seen with other protease inhibitors or P450 inhibitors. Today's report was on a phase II study known as M97-720 that has randomized 32 treatment-naive patients to either ABT-378/RTV at 200/100 mg BID or 400/100 mg BID. After three weeks of dual PI therapy, subjects added d4T/3TC to their treatment. The interim data for the 11 patients who have completed 24 weeks of therapy shows that 10 (91%) have viral loads below detection (400 copies/mL). ABT-378/RTV recipients had an average CD4+ increase of 150 cells/mm3. ABT-378/RTV was well tolerated; patients reported a 16% incidence of abnormal stools and a 10% incidence of headache, none of which led to therapy discontinuation. If the finished phase II study shows durability of the effect Abbott plans to market a combined pill of ABT-378/ritonavir.
Two-Drug Maintenance Therapy Fails After 26 Weeks of Four-Drug HAART Induction.
Disappointing early results from the ADAM (Amsterdam Duration of Antiretroviral Management) study were presented by M. Reijers [4]. Forty-three patients who received 26 weeks of HAART (d4T+3TC+SQV+NFV) with good response were then randomized to either (i) continued "induction" therapy with 4-drug HAART, (ii) 2-drug maintenance with d4T+NFV, or (iii) 2-drug maintenance with SQV+NFV. Just 10 weeks after randomization, four of seven (57%) d4T+NFV recipients and five of seven (71%) SQV+NFV recipients had significantly increased HIV viremia, while only one of 11 (9%) of the individuals who continued 4-drug HAART had breakthrough viral replication. The unfortunate news is that simplified, low-pill burden, two-drug maintenance regimens as practised in this study and, previously, in ACTG 343 and the French Trilege study, cannot be recommended at present.
Safety of Anti-Retroviral Therapy in Pregnancy
Pointing out that many pregnant women are now treated with HAART regimens although we only have solid safety data for AZT, Dr. Patrizio Lorenzi reported on a retrospective registry analysis of pregnancies in Swiss, HIV-infected mothers [5]. From 10/96 to 5/98, 37 pregnant women have been identified; most were on NRTIs, and 43% were on PI-containing HAART regimens. Not surprisingly, the major adverse drug reaction among pregnant mothers was anemia (15/37), with lower frequencies of leukopenia, thrombocytopenia, nausea, and glucose intolerance. Among the 30 infants born thus far, adverse reactions were: (i) prematurity (birth at less than 37 weeks) in 33%, (ii) non-life threatening intracerebral hemorrhage (ICH) in two of 30 cases (both exposed to nucleosides analogues and indinavir), and (iii) extrahepatic biliary atresia in one of 30 cases (exposed to AZT/3TC/indinavir). While the sample size is small and there was no control group of demographically and clinically similar women without HIV infection, further investigation of a potential association between malformations and ICH with HAART therapies is warranted. As Dr. Lorenzi pointed out, an international online registry is probably the best way to accomplish this.
(Note: Dupont issued a warning that pregnant women or women of child-bearing age should not take Sustiva, as it caused severe birth defects in monkeys.)
Nerve-Growth Factor Effective for HIV-Sensory Neuropathy
Dr. Justin McArthur of Johns Hopkins University presented the interim results with ACTG 291 investigating the safety and efficacy of recombinant human nerve growth factor rhNGF for HIV neuropathy [6]. Two hundred and seventy (270) patients were randomized to placebo, 0.1 mcg/kg rhNGF, or 0.3 mcg/kg rhNGF administered subcutaneously twice weekly for 18 weeks. The endpoints were self-administered pain intensity questionnaires (Gracely pain scale), as well as neurologic exam, and an assessment of improvement by interview with a blinded investigator. The pain scores showed a significant decline for both doses of rhNGF over 18 weeks with best results in the 0.3 mcg/kg rhNGF group. There was no effect on HIV viral load. Twenty-five percent (25%) of patient receiving low dose rhNGF and 48% receiving high dose complained of injection site pain (a known adverse effect of rhNGF) but in no case was it treatment limiting. In summary, rhNGF is the first specific therapy for HIV-associated demyelinating peripheral neuropathy. It shows efficacy with only modest injection sited pain in this phase II trial. Genentech, the manufacturer, is considering an expanded access program in late 1998.
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