ICDCD Highlights
Following are brief selected highlights from the Intl Conference on the Discovery and Development of Aniretroviral Therapies in St Thomas, Virgin Islands Dec 13-17, 1998. More detailed highlights will be prepared soon.
from Jules Levin, NATAP

Previously you requested study data supporting that switching a failing regimen early is the best way to limit cross-resistance. I sent you information from several small studies--ACTG 373, a study reported by Joel Gallant reported at last year's Retrovirus mtg showed more successful salvage of NFV or IDV failures when switches of treatment were made when pVL was low. At the recent ICDCD mtg in the Virgin Islands, Julio Montaner reported on a salvage study in which he recycled drugs. The success rate he reported was only 40% reached a pVL<400 copies/ml, and 26% had 2 pVLs <400 copies/ml. However, data from such a study always dependsa on many other factors which can influence failure. These percentages are not the point I'm trying to make. He reported that a multivariate analysis demonstrated that a low pVL at the time of starting the salvage regimen was a predictor of favorable virological response.

As I have been saying for a while switching therapy when pVL is low or immediately after detecting VL rebound from undetectable to detectable offers the best opportunity for a good response to the second regimen. If a person's VL rebounds you may want to perform a resistance test to check for resistance to the drugs in the failing regimen. However, upon VL rebound switching drugs immediately may be the only way to obtain a good response to the 2nd PI. If a person is on their first PI regimen and VL rebounds staying on a failing PI while virus replicates is expected to result in mutations to that PI accumulating. Switching to a 2nd PI immediately is expected to increase the chance to respond well to a 2nd PI regimen. Of course if switching to a new regimen you need other drugs in the new regimen to which the person is sensitive. You want to compose a regimen likely to maximize VL suppression and to sustain it. If a person has previously failed multiple PIs the situatuation may be more complicated. The best way to detect a rebound in VL quickly is to monitor VL in a person every 4-6 weeks.

IDV+RTV Salvage--

Previously I reported that 80% (34/45) of study participants still on this multiple drug regimen at week 24 had <400 copies/ml. I now have additional information on this study. Subjects were on PI regimens for greater than 6 months with a sustained VL >50,000 copies/ml and were treated with 5-7 drug regimens with a backbone of EFV+Hydroxyurea+DDI+RTV+IDV. Originally 400mgq12 hrs of RTV & IDV was used but then the dosing was changed to RTV 100mg q12h and IDV 800mg q12h in line with pharmacokinetics data observed.

Abacavir Treatment Intensification--

Data from this study was initially reported by C Katlama at the Glasgow mtg. See the Glasgow Reports on the NATAP web site to read the report on this study. 185 individuals with viral loads between >400 and <50,000 copies/ml and on stable anitretroviral therapy were randomized to receive abacavir or placebo. Subjects were further stratified by duration of prior NRTI therapy and prior 3TC use. Some of the preliminary results were--

--At week 16 39% had <400 copies in the abacavir arm while 8% had <400 copies/ml in the placebo arm (intent-to-treat); using an as-treated analysis it was 45% vs 6%, respectively.

--42% of those with prior 3TC use (intent-to-treat) had <400 copies/ml while 32% who were 3TC naive (ITT) had <400 copies/ml. 73% of those with 3TC baseline 184 mutation alone experienced a >1 log VL reduction or had <400 copies/ml. In line with previously observed abacavir resistance data, 3TC resistance alone did not prevent response to abacavir. Data on the percent below 50 copies/ml in this study will be reported in the next report. The concept of treatment intensification is one that is growing in acceptance as a treatment approach. It is discussed in detail in the current NATAP newsletter, available in hard copy format by sending a request to me by email containing your mail address. It will be posted to the NATAP web site soon <www.natap.org>

NATAP has been writing about treatment intensification since Abbott reported two years ago that d4T+3TC was added within 12-16 weeks to subjects receiving RTV+SQV alone in the first study of that double PI combination. Followup data showed that intensification in that study durably sustained viral load for individuals who had not reached undetectable on RTV+SQV alone.

The concept of intensification can utilize any drugs that are suitable for the situation. In a separate abstract at ICDCD, V Soriano reported from a study that pVL at 3 months after starting therapy on HAART predicts the 1 year outcome. The ACTG data suggest noy achieving a .5 to 1 log VL reduction by week 4 or not reducing VL <400 copies/ml by week 8 may signal that patient may not reach or sustain a durable pVL reduction below detection. The NATAP newsletter has extensive discussion of this subject.

RTV+IDV in Treatment Naive--

Initial data from this study was reported at Glasgow and is reported in Glasgow highlights on NATAP web site, as well as in new NATAP Guide newsletter. Subjects in this study recd 2 NRTIs (d4T+3TC, AZT/3TC or d4t/DDI) plus IDV+RTV at a dosing of 400 mg twice daily. Median baseline RNA was 5.29 log and CD4 233. At week 12 86% had <400 copies/ml and 84% had <50 copies/ml. At week 24 VL was decreased by 3.6 log and 17/17 had <500 copies/ml, and 80% had <60 copies/ml.

Adverse Events Reported--40% of subjects developed adverse events. Most adverse events were reported to be mild diarrhea, initial nausea, and circumoral parasthesia during the first few weeks of treatment. 3 patients were reported to have stopped treatment due to adverse events.

DLV+IDV or NFV--

It was initially reported at Glasgow with followup data reported at ICDCD that combining DLV with IDV or NFV resulted in a potent antiviral effect in small preliminary clinical studies. See the NATAP Glasgow Highlights for more detail. And future reports will detail followup data. DLV is only NNRTI that increases blood levels of Pis (IDV 100%, NFV 100%, RTV 80%, SQV 500%). The increase in IDV bllod levels may permit the reduction of IDV dosing to twice daily. DLV+NFV can be dosed twice daily. Although these combinations appear preliminarily to be potent it still remains to identify how they should be used. A potent intial regimen including a PI+NNRTI may be durable but if resistance develops the person may have resistance to two important classes of drugs. The combination may be effective in salvage but further studies are needed.

Tolerability of HAART Reduced When Person has Hepatitis C--

DC Melvin reported that if a person was co-infected with HIV and Hep C they were less likely to tolerate HAART.The HCV+ group had significantly higher baseline ALT and AST (liver function tests). In 6 of the 45 HCV positive patients and in 2 of the non Hep C but HIV-infected persons HAART was discontinued due to liver toxicity. Authors reported baseline AST &ALT did not have effect on rate of liver toxicity.13.2% in the HCV+ group discontinued HAARTat 365 days and 2.7% in the group who did not have Hep C.. At 580 days these rates were 17% and 6.8%, respectively.

Opportunistic Infections Shortly After Beginning HAART--

The development of clinical symptoms secondary to previously silent opportunistic pathogens shortly after beginning HAART has been reported as a distinct clinical syndrome, and seems to be associated with inflammatory phenomena surrounding a rapid restoration of the immune system in previously immunosuppressed patients. 11 episodes (3.7%) were observed within the first 3 months of beginning HAART. Episodes of cerebral toxo (4 cases), PCP (2), and herpes zoster (2), and TB (1) occured in persons without previous AIDS defining illness, meanwhile a relapse of CMV retinitis and KS were seen, respectively, in another two patients. 4/11 patients had a CD4 count >200 before they began HAART, among which were one who developed PCP and another who suffered toxo. Authors recommended "close clinical monitoring should be considered during the first three months after starting HAART, even without severe immunosuppression".

Prevalence of Drug Resistance Mutations--

V Soriano of Spain used a genotypic assay (LiPA assay) to detect mutations to NRTIs, 12% of persons (in Spain) tested had NRTIs mutations. These were treatment naive individuals. The 12% was the same in testing conducted in 1993, 1997 and in the PI era. The author concluded there is no increase in prevalence. No mutations at codon 151 were detected. This is a a mutation associated with multi NRTI resistance that has been reported to occur generally at a very low level of prevalence. In 1997 the mutations detected were (n=75)-- 41 (3), 70 (5), 215 (1)--these are AZT mutations; in the PI era (n=25), 1 AZT mutation and 2 3TC mutations were detected (M184). In 1993 1 AZT, 1 ddI (74) and 1 3TC mutation were detected.

Additional reports on presentations from ICDCD will be prepared and reported.