ICDCD Selected Highlights
from Jules Levin, NATAP
This is the second report of highlights from ICDCD: Intl Conference on the Discovery and clinical Development of Antiretroviral Therapies, Dec 13-17 1998, St Thomas US Virgin Islands
Maximal Viral Suppression is Required to Sustain Response
Julio Montaner reported an analysis of 3 studies in which reducing viral load below 50 or 20 copies/ml was crucial in maximizing a person's ability to sustain a durable virological response to therapy. Keeping viral load this low prevents or at least delays resistance, virological failure, drug failure, and cross-resistance to other drugs in the same class.
The duration of suppression in this study was defined to be the time that pVL remained below 1000 copies/ml. Only patients with pVL above 1000 copies/ml were eligible. 92/102 patients from AVANTI 2 (AZT/3TC/IDV vs AZT/3TC), 90 of 105 patients from AVANTI 3 (AZT/3TC/NFV vs AZT/3TC), and 129 of 151 patients from INCAS (AZT/ddI//NVP vs AZT/NVP vs AZT/ddI) were included in this analysis. Using estimates from Kaplan Meier curves 55% of subjects who attained a pVL nadir of 20 copies/ml in the INCAS trial, 81% of those in AVANTI 2, and 74% of those in AVANTI 3 sustained pVL below 1000 copies/ml for 48 weeks.
Conversely only 6% of the subjects in INCAS whose nadir was >20 copies/ml, 30% of those in AVANTI 2, and 34% of those in AVANTI 3 sustained pVL below 1000 copies/ml for 24 weeks.
Hydroxyurea (HU)
Franco Lori, who has lead research into HIV therapy with HU, discussed its use. He said-"HU acts on a cellular enzyme to inhibit replication of HIV. This cellular enzyme, ribonucleotide reductase, is not prone to mutation, and resistance to HU has never been reported during 35 years of clinical experience. Furthermore, HIV variants, resistant to didanosine (DDI), are significantly more sensitive to this drug in the presence of HU. The propensity of HU and ddI to generate low or no virus escape supports the use of combinations based on these drugs as first line therapy. On the other hand, the capability of HU to compensate for DDI resistance justifies the use of this combination also in salvage therapy after prolonged use of DDI.
HU might be also combined with T or C nucleoside analogues, like stavudine (D4T) or lamivudine (3TC), because it appears to enhance the anti-HIV activity of these agents in vitro by increasing their intracellular phosphorylation. This may be of particular interest for salvage strategies following disruption of NRTI treatment regimens (i.e. using d4T or 3TC and HU in AZT experienced patients).
HU has been shown to be well tolerated at the low doses (1000 mg/day) used in HIV infected patients. RIGHT 702 is a scheduled clinical trial that will determine the optimal dose and schedule of HU administration.
HU has cytostatic effect (limits replication) on CD4 and CD8 T-lymphocytes. This might explain the lack of robust increase of CD4 T-lymphocytes with a good increase of CD4/CD8 ratio after HU containing regimens. These cytostatic effects may be beneficial: (1) mathematical models support the idea that decreasing CD4 T-lymphocytes reduces HIV replication by subtracting target cells to the virus; (2) the cytostatic effect on the CD8 T-lymphocyte population would prevent the exhaustion of these cells that may occur as a result of their excessive activation during HIV infection. The combined beneficial effects on both CD4 and CD8 T-lymphocytes could facilitate control of HIV and prevent immune system damage or restore previously compromised immune functions."
HU is being studied with a once-a-day regimen (1000 mg). Preliminary results suggest it might be effective once-a-day. Some of theories about how HU may work expressed above by Lori in the last paragraph remain to be confirmed. Studies to better identify how and when to use HU are ongoing by Bristol-Myers Squibb and the ACTG.
Oat Bran Tablets Improves PI-Induced Diarrhea
M Hoffman reported that taking oat bran tablets improved PI-induced diarrhea. 51 patients who reported PI-induced diarrhea were given two unprocessed oat bran tablets (750 mg/tab) with each dose of PI and adjusted as needed based on response. After two weeks of use, patients were asked to complete a second 7-question survey. They were asked to complete a 13-question survey prior to starting the oat bran tablets.
Mean baseline CD4 was 317 and viral load was 52,000 copies/ml.Prior to use of oat bran, 21.6% classified symptoms as Grade 1 (mild), 56.6% as Grade 2 (moderate) and 21.6% as Grade 3 (severe). Mean grade for all patients was 2.0. After two weeks of oat bran tablet use, 30% reported normal stools, 45% reported Grade 1 and 25% reported Grade 2-3 diarrhea. Mean grade fpr all patients was 1.04. 84% of patients described their symptoms post-oat bran treatment as moderately or dramatically improved. 90% of patients were continuing to take oat bran tablets after two weeks of use. One patient reported diarrhea symptoms worsened while taking oat bran tablets. No other side effects were reported to be associated with the use of oat bran tablets. Retail cost of oat bran tablets is less than $5 a month. The author said additional studies are needed to determine if oat bran has a positive effect on serum cholesterol in patients on PI therapy.
Switching From NFV TID to NFV BID
Two small studies were reported in which the participants were switched from taking NFV three times a day to taking nelfinavir twice a day. RM Novak of the University of Illinois reported a retrospective analysis of 12 men and 12 women who had been taking NFV TID and were switched to NFV BID in an inner city HIV clinic. Poor adherence was reported to the TID regimen in 12/14 (86%) of study participants. Two persons had another switch in therapy at the time of switch to BID. Patients had been on NFV TID regimen for a median of 46 weeks and a mean of 42 weeks prior to switching. Mean viral load on NFV TID was 3.01 log (about 1000 copies/ml), and 3/14 (21.4%) were below the level of detection (2.6 log). After changing to NFV BID for a mean followup of 17 weeks, the mean viral load fell to 2.65 log, with 6/11 (54.5%) falling below the limit of detection. No study participants stopped therapy due to intolerance.
In a second study R Post of McDowell Healthcare Center and J Brake of Agouron Pharmaceuticals showed data from a small study of switching patients in a community HIV clinic from NFV TID to NFV BID. Patients were clinically stable and on HAART regimen including NFV TID for at least 3 months with HIV RNA by bDNA <500. Thirty patients were randomized to continue their NFV 750 mg TID regimen or to NFV 1250 mg bid while continuing the other drugs in their regimen. In each group, 14 patients were evaluable. At month 6, the VL by bDNA was undetectable in 11/14 in the TID group and 13/14 in the BID group. VL by PCR was undetectable in 9/14 in the TID group and 8/14 in the BID group. Switch in dosing was reported as well tolerated. No serious adverse events were reported. Authors said baseline VL> detection by PCR did not predict VL > detection at 6 months. Two subjects in the TID group had poor adherence with VL >13,000. For adherent subjects maximum VL was 2,000 in TID group and <1,000 in BID group. The authors concluded that individuals could be safely and effectively switched from a NFV TID to a NFV BID regimen with a comparable daily dose of NFV.
Effective Reduction of Maternal Infant HIV Transmission in the Berlin Cohort
I Grosch-Woerner and A Schaeffer reported it was possible to reduce mother-to-child transmission near zero through combined intervention strategies of antiretroviral HIV prophylaxis and caesarian section before labor. The authors said it has become clear that maternal-fetal HIV transmission is multifactorial. Morover, it has become evident that labor is an important transmission risk factor and that ceasarian section before labor is therefore an effective procedure to prevent vertical transmission.
A cohort in Berlin was started 2.5 years ago. The protocol for them contains the systematic antiretroviral prophylaxis with antepartum AZT starting in week 32+0 of pregnancy, preoperative AZT according to the 076-protocol and postnatal AZT (1.3 mg per kg intravenously every 6 hours for 10 days). The caesarian section was conducted in week 36+0, in the case of labor earlier of course. Till now there have been 63 pregnancies and "no child has been HIV-infected". The authors recommend this protocol to be used in general.
Drug Failure Due To Low Drug Concentrations
V Calvez and others reported on study results from the MIKADO Trial in which 36 treatment-naive participants received d4T/ddC/Fortovase (SQV SGC). Among the 29 patients who remained on study combination until week 24, 10 had a viral load >200 copies/ml at this time. In order to understand the mechanism of failure, investigators analyzed RT and PI resistance in 10 patients with failure (Group 1, >200 copies/ml), and also SQV concentrations in plasma specimens collected at week 24 in group 1 and in 10 control patients without failure (group 2, <200 copies/ml). RT and PI genotypic analysis at day 0 and week 24 in group 1 revealed an acquisition of only one SQV associated mutation (L90M) in only 2 patients. Phenotypic study performed by RVA on plasma at day 0 and week 24 did not show any increase of SQV IC50 and IC90 in patients with and without L90M mutation.
SQV plasma concentrations were measured at week 24 and analyzed comparatively to therapeutic values. In group 1 (failure), all but one patient had SQV concentrations under the range of therapeutic values. The authors said this study strongly suggests that early failure to this combination is not in relation to viral resistance but most probably to medication non-adherence, pharmacological variabilities, and drug interactions. The patient's clinical records are still under investigation.
In my opinion, early failure due to the reasons listed above is not confined to this study regimen but can likely be applied to other HAART regimens. Failure due to pharmacological variabilities is receiving attention recently. It's suggested that a person could experience low drug absorption and/or fast drug clearance due to metabolism.
The ability to test for drug levels after starting therapy is being developed and tested. It may become commercially available in the near future.
Impact of Pharmacology
Jean-Pierre Somadossi, a pharmacology researcher at the University of Alabama Birmingham and in the ACTG, said at the meeting that several studies have reported the correlation between pharmaco-kinetic parameters of most protease inhibitors and antiviral response as assessed by plasma HIV viral load. The evaluation of pharmacological processes should be important in the virus-fighting potential of anitretroviral drugs. Pharmacological issues have recently been demonstrated to play a major role in antiviral drug regimen success or failure. A sub-optimal drug exposure may result from genetic polymorphism (mutations pre-existing initiation of therapy), inefficient drug activation/phosphorylation of nucleoside analogues (discussed below) and drug-drug interactions. Several studies have been reported which suggest a correlation between intracellular (inside a cell rather than in plasma) drug related activity (triphosphate levels) and antiviral response. (I believe other researchers have said pre-existing protease inhibitor mutations--polymorphisms--do not cause resistance to Pis; pre-existing mutations acquired through transmission of HIV may cause resistance).
Richard Hoetelmans, from the Slotervaart Hospital in Amsterdam, is a pharmacology researcher and discussed these issues. He said in the era of nucleoside reverse transcriptase inhbitors (NRTIs), monitoring of concentrations of these drugs in plasma seemed not very useful. NRTIs can be considered prodrugs, as they require intracellular activation to their pharmacologically active triphosphate derivatives. Since the correlation between concentrations of NRTIs in plasma and intracellular triphosphate derivatives is poor, therapeutic drug monitoring (TDM) was never an issue. Once monitoring of intracellular triphosphate concentrations becomes more practical this might change.
He continued, with the introduction of the protease inhibitors and non-nucleoside reverse transcriptase inhibitors, this picture has completely changed. PIs and NNRTIs do not need an activation step and are pharmacologically active by themselves. Clear pharmacokinetic-pharmacodynamic relationships have already been established. Since these drugs (PIs in particular) show large interindividual variation in exposure (drug levels in blood and other areas of body), they seem good candidates for TDM. For PIs, relationships have been (generally) established between exposure in plasma and efficacy in the short and long term. Additionally, high maximum concentrations of PIs are related to frequency of side effects for most representatives (drugs). So far, pharmaco-kinetic-pharmacodynamic relationships have been established for PIs, and to some degree for NNRTIs, and intracellular antiretroviral nucleotides. However, the proof that TDM of these agents will eventually lead to an improved efficacy and decreased toxicity of these drugs has not yet been provided (though it is now generally thought that TDM will provide additional benefit. In the Netherlands, a nation-wide, prospective study has now been initiated, in which the clinical value of TDM of antiretroviral drugs will be investigated (ATHENA).
Courtney Fletcher, a pharmacologist at the University of Minnesota, also discussed these issues. He said desirable pharmacologic characteristics for an antiretroviral drug include--
Pharmacological properties of an antiretroviral regimen that influence therapeutic success include--
Patients receiving the same dose of an antiretroviral drug will not have the same systemic or intracellular concentration because of interpatient variability in drug absorption, distribution (to different parts of body such as CSF, lymph tissue, brain, CD4 memory cells, etc), metabolism, and excretion. Pharmacological theory and available clinical data support relationships between drug concentrations and anti-HIV effect. Thus, variability in drug concentrations may lead to variability in antiviral effect.
Interim Results of Adult and Pediatric Phase I Studies of a New NRTI--FDDA
In the May issue of NATAP Reports, which is available on the NATAP web site in the Newsletter Section, we reported initial data from studies on this NRTI from the same family as DDI. Since FDDA is similar to DDI it's use with hydroxyurea will be explored. R Little reported early findings on FDDA research at the ICDCD meeting. FDDA has been reported to have little in vitro cross-resistance with other NRTIs, and once phosphorylated it has a long (20 hour) intracellular half-life, making twice or once daily dosing possible. Initial studies were short term of 4 and 12 weeks to evaluate FDDA's antiviral activity and dosing.
Oral bioavailability was about the same whether fasting or non-fasting (66% vs 63%, respectively). The data following in this paragraph was already reported in the May issue of NATAP reports, so it is not new. But, the preliminary data reported in the next paragraph on FDDA+NFV+d4T has not previously been reported. It was reported to be well-tolerated at doses which were used of up to 3.2 mg/kg twice daily or 4.5 mg/kg once daily in adults, and 100 mg/M2 twice daily in children. Some patients, particularly children, reported excess energy, and one child had an asymptomatic decrease in cardiac ejection fraction. Investigators said the relationship of these or a scattering of other adverse events to FDDA are unclear. Adult patients on the highest of two doses administered so far of FDDA (1.6 and 3.2 mg/kg twice daily) had a median decrease in plasma viral load by PCR of 0.42 log (range -1.26 to +0.38) at week 6.
Investigators said adult patients, most of whom have had extensive prior anti-HIV therapy, have now been followed for up to 24 weeks on the combination of FDDA (3.2 or 4.5 mg/kg once daily), d4T and NFV with "sustained decreases in their viral loads"; of 9 patients, 4 have had their viral load become undetectable (<200 copies/ml) on at least one occasion by HIC RNA PCR. This suggests that some individuals with prior NRTI experience and resistance may respond to FDDA. Investigators said anti-HIV activity from FDDA was also seen in a subset of children receiving 50 or 100 mg/m2 twice daily. The data reported above appears encouraging but is incomplete and preliminary so it is premature to conclude how effective FDDA will be in particular for treatment experienced inndividuals. Although in vitro data suggests little cross-resistance with other NRTIs it remains to be confirmed in human studies. With abacavir, Glaxo Wellcome conducted extensive studies in NRTI experienced individuals, and was able to show some characterization of the antiviral effect of abacavir in treatment experienced individuals. The sponsors of FDDA development, who are the NCI (Natl Cancer Institute) and US Biosciences), should conduct similar studies to establish the antiviral activity of FDDA in NRTI experienced individuals.