Report # 5 from Glasgow, Scotland

Glasgow Highlights - Report # 5

From Jules Levin

Wednesday, 9:40 pm

Today at the Pharmacia & Upjohn Symposium, interesting data was reported on a 4-drug combination. You have to consider that it is a small study but if it holds up a new treatment option is available. This study compares 4 regimens; there are about 20 participants in each arm at the start of the study:

delavirdine (DLV)+AZT+indinavir (IDV)
DLV+3TC+IDV (600mg tid)
AZT+3TC+IDV (800mg tid)
and the key arm-DLV+AZT+3TC+IDV (600mg tid)

As I stated in yesterday's highlights, co-administration of DLV with PIs leads to increased mean drug concentration of IDV (100%), nelfinavir (113%), ritonavir (70%), and saquinavir (500%). This may allow for reduction in PI doses and change dosing from 3 times per day to twice per day for DLV and the PIs, although ritonavir and nelfinavir can be used twice a day. Reducing IDV to twice per day can have a significant impact on adherence.

The baseline CD4 count was 240 and the viral load was 4.9 log (79,500 copies/ml). At week 32, for the 6 individuals with available data in the 4 drug arm of DLV+IDV+AZT/3TC:

the reduction in viral load from baseline is about 3 log
6/6 had <400 copies/ml
6/6 had <40 copies/ml
CD4s increased about 160

Upon return to NYC I'll try to report more details. How can DLV plus a PI(s) be used? P&U needs to research this therapeutic approach for salvage therapy. For example, after failing nelfinavir a possible treatment could include RTV+SQV+DLV, or DLV+IDV, or amprenavir+IDV+DLV. If a person fails IDV or RTV, a possible regimen could include amprenavir+NFV+DLV. NFV increases amprenavir Cmin about significantly. But, P&U needs to study these regimens to see how effective they could be.

NFV reduces DLV Cmin by 40% but that may not effect the DLV dose.

Remune+HAART

At the Agouron Symposium today, Guiseppe Pantaleo an immunologist at Beaumont Hospital in Lausanne Switzerland and Ronald Mitsuyasu an immunologist at UCLA gave a very nice overview of HIV and the immune system. They discussed how HAART improves the immune system and in what ways HAART does not improve the immune system. Upon return to NYC I hope to report their presentations. A you may know Fred Valentine an immunologist from NYU reported in Geneva that after a month on HAART Remune, a therapeutic HIV vaccine, was administered to study participants with chronic HIV infection. Previously it was doubted that a CD4 response to HIV antigens could be mounted by individuals with chronic infection. Bruce Walker had detected such a response by treating individuals in acute infection with HAART. In Valentine's study a strong HIV specific CD4 response was detected following HAART+Remune. Several weeks ago Agouron reported that at week 32 13/15 participants had <1 copy/ml, while 6/12 in the control group who received IDV+2 NRTIs had <1 copy/ml. The baseline viral load was only 8000 copies/ml.

A number of studies are being designed to explore the use of Remune+HAART. The goal is to see if the immune system can be stimulated to the extent that it might control HIV replication with HAART than HAART alone. Another goal is to see if Remune+HAART can control the immune system enough so that a person could stop HAART. In the Valentine study almost 90% responded to Remune+HAART. Company officials said at this meeting that it can take longer than 32 weeks for some individuals to respond to Remune. I told company officials at this meeting that they need to explore HAART+Remune in two populations--individuals with low CD4s, and individuals who had low CD4s and increased their CD4s due to HAART.

A lot of attention is being paidto developing Remune and to developing other immune based therapies as adjuncts to HAART. The ACTG is planning seeral studies, one of which may explore using IL-2 plus Remune with HAART. IL-2+HAART is also being explored. As well, other immune based therapies are being researched.

HIV in Semen

PL Vernazza reported today that although HIV RNA can be well suppressed in semen following HAART, HIV DNA is not suppressed as well. Therefore, HIV can be transmitted sexually although one's viral load in blood is undetectable. Steve Taylor reported data from 6 individuals receiving RTV+SQV+d4T. During a 12 hour dosing period in one patient neither RTV nor SQV fully exceeded the IC90 or the IC95 (protein corrected estimates) in seminal fluid despite adequate blood levels. The median seminal plasma/blood plasma peak and trough ratio for RTV was 2% and 3.6%, respectively. The corresponding values for SQV were 3.6% and 1.9%, respectively. Median baseline blood plasma and seminal viral loads were 18,000 copies/ml (n=7) and 4,600 copies/ml (n=6), respectively. By week 24 both compartments had undetectable viral loads for all 6 patients.

Taylor said this data indicates poor penetration of the protease inhibitors RTV & SQV in semen. Taylor said it the d4T may have been the drug that lowered viral load in semen below detection. Earlier in the meeting it was reported that CSF viral load was not adequately reduced by RTV+SQV alone. Taylor said his experience is similar to the reported penetration of CSF by PIs. Unlike in the CSF where there is no protein, in semen there is protein and it is likely that free drug entering the semen will also become highly bound.

Read NATAP web site for follow-up reports.