Glasgow Highlights- Report # 4

From Jules Levin

Tues Nov 10, 5:30pm

• William Powderly, an ACTG investigator, said there are 82% less opportunistic infections now because of HAART.
• Using HAART may be the best treatment and prophylaxis against opportunistic infections due to its effect of improving the immune system
• You may be familiar with the fact that some people experience an inflammatory response shortly after beginning HAART. They may experience a flare-up of herpes, MAC, etc. This may be a good sign. It means the immune system is reconstituting an ability to respond to an already present infection. These flare-ups are treatable and do not mean HAART is not effective.
• The higher a person's viral load the greater the risk for developing an opportunistic infection. As well, the CD4 count is a predictor for an OI.
• Reducing viral load and increasing CD4s above 200 decrease risk for PCP
• A CD4 count <50 is associated with a 5.9 fold increased risk for PCP. An undetectable viral load reduces risk for PCP by 85%.
• An analysis of ACTG 320 (IDV+AZT+3TC vs AZT/3TC); the last clinical endpoint study) by Judith Currier showed reduced viral load and increased CD4 lowers risk foe developing an OI.
• Effect of viral load on PCP; this table shows the relative hazard for developing PCP; If viral load is between 30,000 to 60,000 copies/ml the risk of developing PCP is increased 4 fold; if VL is 60-90,000 c/ml, risk is 8 times greater, and if VL is >90,000 c/ml, risk increases to 11 times greater:

Viral Load	30-60,000 cop/ml	60-90,000 cop/ml	>90,000 cop/ml
	4	8	11

If CD4 is <200 risk of PCP is 3.7 times greater

Can a person stop taking prophylaxis against OIs if they respond well to HAART?

There is preliminary data supportive of that discontinuing prophylaxis is a reasonable option if a person experiences sustained adequate increases in CD4s. But individuals situations may vary. A erson should consult with their doctor. The NATAP web site has a recent report on 1 year data from 2 studies showing no one developed PCP following successful HAART. Preliminary data suggests prophylaxis for CMV and MAC may be discontinued. Powderly said there are ongoing ACTG studies exploring this question and that the best protection against Ois is to maximize the effect of HAART. If a person has incomplete viral suppression Powderly thinks the risk for OIs will return.

Reducing viral load to <50 copies/ml is the best protection against OIs and to prevent rebound of viral load. It appears to be the best chance for a durable improvement in one's immune system.

Hydroxyurea (HU) as Part of a Salvage Therapy

There is a poster at Glasgow on the safety of HU for individuals with more advanced HIV. I will review that upon return to the Big Apple. However, an abstract discussed the effect on viral load from HU in a salvage situation in combination with multiple drugs. 8/14 reduced their viral load <500 copies/ml; 3 of the 8 individuals had a rebound in viral load upon their next viral load assay; 5/8 remained <500 copies/ml upon their next VL assay. I'll review and report the data on the poster upon return to NYC but there appear to be several interesting aspects to this study. After sorting through the data, HU appeared to be effective as part of a multi-drug combination if the combination is selected properly for the person in mind. 4 individuals in the study for whom the HU combination appears to be effective used HU without ddI but with D4T in one case, with abacavir in a second case, with d4T+3TC in a 3rd case, and another with d4T. Several other drugs were also used in each case so it is not a tight study but the data suggests to me that HU may work with abacavir and d4T as it does with ddI. This is a preliminary notion because we do NOT have in vitro or in vivo data showing that HU has a similar relationship with abacavir or d4T as it does with DDI. In vitro data was reported in Geneva showing HU effects PMPA ans adefovir similarly as it effects DDI. But studies in humans are needed to confirm that. At Geneva Steve Miles of UCLA presented data suggesting HU had a similar effect with d4T as it does with ddI but there was no supportive evidence except clinical benefit. I have spoke with Bristol Myers about this and they have said they are exploring d4T used with HU.

Two New NNRTIs-DPC961 & DPC963

DuPont Pharma presented preclinical data on two new NNRTIs they are developing. This data suggests the 2 new NNRTIs may not be cross-resistant with efavirenz and may be more potent than efavirenz. The data suggests they may be active against virus with the K103N mutation. This is the main mutation in the development of resistance to efavirenz. In monkeys DuPont achieved higher drug concentrations in blood with the two new NNRTIS than acheived with efavirenz. The implication is that if you develop resistance to efavirenz these two new NNRTIs may be effective. Of course,this will have to be established in clinical studies with individuals who have the K103N.

New Potentially Potent Combination: Delavridine+Nelfinavir BID

Delavirdine (DLV) has been the step-child of NNRTIs. Although DLV was prematurely highly criticized by many 52 week data reported earlier this year showed when used in combination with AZT/3TC in a group with limited AZT experience-68% had <400 copies/ml and 58% had <50 copies/ml. However, it has always possessed a charactertistic that I felt if is it was figured out how to use it may translate into an effective tool for HIV treatment. Delavridine is the only one of the 3 approved NNRTIs that increases drug blood levels of PIs. NATAP Reports reported in previous issues the preliminary pharmacokinetics data showing that delavirdine increases blood levels of nelfinavir (NFV) by about 100%, ritonavir by about 80% and indinair two-fold. This report can be found on the NATAP web site. A clinical study of 63 individuals using DLV with NFV and NRTI(s) was presented at Glasgow. There are 4 arms in the study: DLV+NFV+d4T, DLV+NFV+ddI, NFV+d4T+DDI, and the key arm-DV+NFV+d4T+DDI. More details on this study will be reported in followup reports but I'll report here the 12 week data on the 4-drug arm. Although DLV is currently administered 3 times per day, in this study each drug was administered twice daily (BID).

The mean baseline CD4 was 344 and the median viral load was 4.84 log (69,000 copies/ml). Patients were required to be naïve to NFV, d4T, NNRTIs, and PIs. Prior DDI experience of less than 1 month was permitted. After 12 weeks, individuals in the 4-drug regimen experienced-

Mean increase in CD4:	+200 cells
Mean reduction in viral load:	-3.5 log
% of patients below 400 copies/ml:	100%

How to use this approach still remains in question. The combination of DLV and indinavir (IDV) has been used in some instances to salvage indinavir failures. If a person failed IDV due to inadequate drug levels of IDV, combining DLV with IDV may address that problem. There have been anecdotal reports that DLV+IDV resulted in nice reductions in VL for individuals who failed IDV. Using DLV+NFV appears o be a potent therapy but if a person develops resistance to both drugs they can have cross-resistance in both classes of drugs-PIs and NNRTIs. However, the Keith Henry study suggests that ritonavir+saquinavir+NRTIs salvaged about 70% of nelfinavir failures; and, participants in that study had remained on nelfinavir for a prolonged period of time after failing nelfinavir. Switching PI therapy immediately after failure increases chance for success with 2nd PI regimen. Remaining on a faiing PI allows resistance mutations to accumulate. This increases the risk of not being able to respond to a 2nd PI regimen. Can NFV+DLV be used as salvage therapy? We don't know the answer to that question but I think it may be useful as salvage therapy. Twenty-four week data from this study will be available in early '99.

Read NATAP web site for follow-up reports from Glasgow.

www.natap.org