ICAAC Updates

Abstract # 1663 & 1664:  New Formulation of Videx. 

These two posters dealt with the bioequivalence studies of enterically coated Videx.  Videx currently is co-formulated with an antacid because Videx is unstable in the presence of stomach acid.  This has made Videx more challenging to take and adhere to then the other available nucleosides.  Bristol Myers Squibb (BMS), the makers of Videx have for sometime been attempting to improve the delivery mechanism for this drug.  They compared an enterically coated tablet that did not dissolve in the stomach but rather in the small intestine to an encapsulated beadlet formulation of Videx.  The encapsulated beadlet formulation of Videx more rapidly dissolved and entered the systems of the participants thus that formulation was chosen for further development.  When this beadlet formulation of Videx was compared with the currently available antacid tablets the AUC was similar.  Authors concluded: VidexÆ EC is equivalent to the chewable tablet in extent of exposure, but the formulations differ in rate of absorption. Dissolution of the coat was rapid once the BEADS emptied from the stomach. The performance of VidexÆ EC, relative to the tablet, is the same in healthy and HIV-infected subjects.Commentary:  Patients who are unable to tolerate the currently available form of Videx can ask their health care provider to contact the expanded access program for the beadlet formulation (877) 418-3889.  In order to qualify patients must need Videx to construct a viable antiretroviral regimen and be intolerant to the currently available formulation.  The FDA is expected within weeks to rule on the approval of this beadlet formulation.

HCV/HIC Co-Infection: ALT normal but 8/10 Persons had Fibrosis

Abstract # 175:  HCV and Liver Biopsies.   In yet another of the now many examples of why ALT is not an adequate marker for determining extent of liver damage, Hoffman-Terry and colleagues performed liver biopsies on 24 HIV co-infected patients.  14 of the 24 had elevated ALTís.  On biopsy, 14 out of 14 with elevated ALT showed moderate to severe fibrosis and 8 out of the 10 without elevated ALT also showed fibrosis.  2/8 had severe inflammation +/- fibrosis. Author concluded: While our study population was not large enough to achieve statistical significance, biopsy proven inflammation/fibrosis was evident in all patients with abnormal ALTs but also 8/10 of those with normal ALTs. Once again directing patients and clinicians to suggest liver biopsy for everyone who is co-infected with HIV and HCV.  In their conclusions the authors made an interesting observation among this small number of patients.  They noted that those who did not have elevated ALTís were those who had lower CD4ís.  They stated that this might be due to a decrease in immune activity against HCV leading to less hepatocyte destruction and thus less release of ALT into the bloodstream.  This will have to be confirmed in larger studies but it worth noting. Link to detailed NATAP web site report:

http://www.natap.org/sept2000/ICAAC/ICAAC_rpt_1_hcv_liver_enzyme_test_alt91900.htm

Methadone & Amprenavir

Abstract # 1649:  Amprenavir & Methadone interactions (Hendrix, Johns Hopkins Univ).  17 patients took part in an observational study to examine the effect of Amprenavir on Methadone levels in patients who were taking Methadone.  There was a 13% reduction in the active enantiomer of Methadone by the Amprenavir.  However no patient experienced symptoms of methadone withdrawal.  Commentary:  This is yet another study showing a decrease in methadone levels by a protease inhibitor.  Previous studies of nelfinavir and saquinavir have showed even greater reductions with those agents.  Still none of the proteases, in my clinical experience, lead to patients experiencing clinically significant opioid withdrawal.  The opioid withdrawal is still relegated to Nevirapine and Efavirenz.

Reports on individual response to PI-methadone experiences vary. I have heard for some individuals there are no withdrwal symptoms while for others there are withdrawal symptoms. So, I think one individual may experience a different response than another individual. Abstract: conclusion- Despite the modest decreases in the active (R)-MD AUC24 and Cmax, the lack of change in opioid PD effects indicate there is not a clinically significant interaction of APV with MD suggesting no alteration in MD or APV dosing is recommended when the drugs are coadministered. Results: Preliminary data (geometric LS mean ratio [90% CI]) for 12 subjects found that plasma (R)-MD and (S)-MD AUC24 decreased by 12 (1-21)% and 37 (28-46)%, respectively, and plasma (R)-MD and (S)-MD Cmax decreased by 24 (12-35)% and 45 (32-55)%, respectively. None of the 4 opioid PD measures changed from baseline in a repeated measures analysis (p>0.05). Within day peak/trough differences were detectable in pupil diameters and agonist symptoms throughout the study, regardless of APV dosing (p<0.01). APV Cmax and AUC24 were consistent with historical controls

Interrupting Therapy while on NNRTIs

Abstract # 1545:  Stopping Efavirenz and resistance mutations?  Recently fear has been expressed regarding patients who are virologically suppressed on Sustiva and go on a drug holiday, stop or interrupt therapy for adverse events.  It has been hypothesized that they may be at high risk of developing clinically significant resistance due to the long halflife of Sustiva.  David Baker and Lee Bacheler of DuPont looked at patients who were participating in their pivitol 006 trial and compared the resistance profiles of those who virologically failed Sustiva versus those who ceased taking the drug while virologically suppressed.  As expected 10 out of the 10 patients who virologically failed Sustiva had the K103N mutation at the time of virologic failure.  However in 6 out of 7 patients who self discontinued Sustiva while virologically suppressed, they did not show evidence of the K103N mutation when they stopped Sustiva and their virus rebounded.  The patient who did show the K103N was sporadically adherent to Sustiva while taking the drug prior to interruption.  The method used was the VGI kit, which is sensitive down to about 10% of the viral species.  Commentary:  This is an important matter in this era of patients taking more drug holidays or STIís.  While this doesnít settle the question surrounding interruptions, resistance, and Sustiva, it does at least give us an initial hopeful report.  What is needed next are studies with larger number of individuals who cease Sustiva and then subsequently re-start therapy.  This will allow us to evaluate whether clinically significant resistance can develop through interruptions of Sustiva.  The NIH in their STI studies using Sustiva currently stops the Sustiva a few days prior to stopping other drugs with shorter half-lives.

Commentary from Jules Levin: This issue is complex and needs consideration of several issues. In theory, if a person has had <50 copies/ml for an extended period of time and has been completely adherent (not missed a dose), the risk appears less or little if stopping a triple regimen atonce (e.g. Sustiva-AZT./3TC). Virus is well suppressed in such a situation and ought not be expected to rebound into replication so easily and quickly. In theory, although EFV drug levels are decreasing incrementally over a few days it ought not to be a difference in such a situation described above. But that is theoretical. In reality, there is no way to know for sure if a person has been missing doses and how many. There is no way to know for sure if a person has experienced real viral load blips. No there is no way to know if viral load blips a person may have experienced is real. Sometimes blips can occur due to lab errors. that But if a person had had some non-adherence and some viral blips, in theory it's possible that upon interruption virus replication could occur more quickly and easily. Although these questions need to be answered with some studies, these are complex situations that are difficult to sort out. Predicting response after interruption depends on individual experiences. In sum, until studied further, there appears to be some risk when interrupting nevirapine or efavirenz, depending on an individual's experience.

In a second study reported on at ICAAC, 23 individuals on nevirapine+2 nukes with undetectable viral load interrupted therapy one or more times. Upon re-initiation, VL fell BLQ (<400) in 21 of 23 interruptions (91.3%). Non-adherence was associated with one failure, while viral isolates resistant to NVP were detected in the other.

Abstract 1546, Interrupting Nevirapine (Yozviak et al, Philadelphia Coll. of Osteopathic Med., Philadelphia, PA 2 Bornemann Internal Med., Reading, PA).  Retrospective chart review of all patients (N=536) seen 9/96 to 4/00 yielded 135 patients on NVP and dual NRTIs. Charts were abstracted for: NVP regimen, treatment duration, VL before/during ART-interruption, ART-i duration, and viral load after re-initiation. ART-i was defined as simultaneous cessation of entire regimen for >7 days. Undetectable was defined as <400 copies of HIV RNA per ml plasma (<50, if available). Results: Seventeen of 135 had viral load undetectable with documented ART-i followed by initiation of the same regimen. 2/17 had a 2nd ART-i and 2/17 had a 3rd ART-i yielding 23 total ART-i for analysis. Mean baseline VL was 108,276 (5.03 log10). Mean initial ART duration was 193 days. Mean ART-i duration was 58 days. Upon re-initiation, VL fell to ubdetectable (<400) in 21 of 23 interruptions (91.3%). Non-adherence was associated with one failure, while viral isolates resistant to NVP were detected in the other. Author concluded more study is needed.