Glasgow Report # 3

Tuesday, Nov 9

Following are some selected highlights from the Glasgow conference. There is a lot of focus at this meeting on developing immune based therapies to supplement HAART. IL-2, Remune and other approaches are being intensely reseached. Tomorrow, Agouron and Immune Response Corp will discuss Remune + HAART. Today, David Cooper reported a meta-analysis of several IL-2 studies showing enormous increase in CD4 although we knew that. In addition, in his analysis 14 individuals in the group not receiving IL-2 had AIDS events while 9 did in the group receiving IL-2. Two question remains-do these CD4 increases from IL-2 improve the immune system as do CD4 increases from HAART?; and, can administering IL-2 folowing viral load reduction from HAART increase immunity, increase virological improvements from HAART, and can IL-2 reduce or empty the reservoir of integration competent proviral DNA in memory CD4s. Also, can this virus be knocked off after exiting the reservoir. Studies are being planned to answer this question.

HIV Specific CD4 Response in Chronic Infection Reported. Today, Brigette Autran delivered an oral presentation in a Plenary session. She has been conducting leading research for the last two years on immunological reconstitution and HAART. She did the first or one of the first studies on the effect of HAART on the production of naïve CD4 cells. Today, she reported several important pieces of information from her ongoing studies of HAART & immune reconstitution

• She reported that she has observed in her study patients an HIV specific CD4 response in some individuals following full suppression of viral load with HAART. But she did not detect this with first look. She had to use a sensitive measure to detect it. As far as I know this is the ONLY report of an HIV specific CD4 response detected in chronic infection following HAART. AS you may know Bruce Walker has reported seeing this response after treatment with HAART during acute infection. Fred Valentine reported he may have obsered similar response in chronic infection following treatment with Remune after reducing viral load wit HAART. But Autran is the first that I know of to report this in chronic infection after treatment with HAART. She is researching how to stimulate this response with an immune based therapy. She may have further infoormation at Human Retrovirus Conference in Jan '99.
• CD4s can be normalized in individuals heavily pretreated but it takes longer than with individuals who start treatment earlier. For individuals with low CD4s it can take a couple of years. She thinks it can take 4-8 years to reach normal naïve CD4 levels. But during that time they must have continuous full suppression of viral load
• The magnitude of viral load suppression leads to the steepest increase in CD4. Her data extends to 18 months and she reported that of several factors she explored such as baseline CD4 or baseline vira load, only the magnitude of viral load reduction correlates with the best increases in naïve CD4. This resoration of the CD4s can occur for individuals with advanced HIV as well as those who begin treatment earlier. She said it is limited only by he inability to maintain low viral load. Lowering viral load to <50 copies/ml or lower and maintaining that over the course of years is the best hope for restoring the immune system
• The source for these new naïve CD4 is uncertain. They may be coming from the thymus or they may come from other sources.
• The ability to restore response to recall antigens is also a function of the magnitude of viral load suppression and its maintenance

Switch from PI Regimen to NNRTI Regimen

C Rottman from Germany reported on a study where individuals with <500 copies/ml on a PI regimen were switched to a once-a-day nevirapine+ddI+3TC regimen. Participants had varied treatment background. Overall, 18/24 (75%) had <500 copies/ml at week 32, and 13/24 had <20 copies/ml. Additionally, CD4 increased 48 from baseline. However, if you are undetectable on a PI regimen a 75% success rate of switching is not good enough, in my opinion.But, for those individuals who were NNRTI naïve prior to switching to NVP+DDI+3TC they reported two different results--16/16 had <500 copies/ml and in a second table 90% <500 copies/ml. I'll have to check.

All 3 drugs have long intracellular halflives.

Adding Abacavir As Intensification. C Katlama presented data from her study where Individuals being treated with HAART but who had viral load between 50 and 400 intensified their regimen by adding aacavir. On average, they had a 0.44 log reduction in viral load. About 40% became undetectable. If their baseline viral load was <5000 copies/ml, 62% became undetectable. Individuals who had 3TC resistance appeared to do better than individuals without 3TC resistance. However, individuals with 3 AZT mutatins did not respnd well to abacavir. This study underscores that abacavir can be used in early intensification. If you recently started treatment but have not reached below 50 copies by say for example week 12 you can consider using abacavir with or without an additional drug to intensify your regimen to reach 50 copies/ml.

Switching to a Salvage Therapy When Viral Load is Low. Robert Murphy reported on a salvage therapy after individuals failed amprenavir monotherapy in ACTG study. The patients viral load was low (24,000 copies/ml) when they switched to the salvage regimen. And, they switched fquickly after failure. CD4s were about 340. They received a 4-drug regimen of indinavir+3TC=d4T+nevirapine. Individuals on the other arm of the study who virologicaly faied also received this regimen. After 60 weeks about 80% had <500 copies/ml. This suggests what several researchefforts have also suggested and what I have been recommending in NATAP newsletters as a preventative measure to avoid resistance and failure-monior viral load every 4-6 weeks; if viral rebound is detected, consider switching your PI regimen immediately; because if you catch it quickly you may be able to avoid resistance mutations from causing cross-resistance; staying on a failing regime will result in a buildup of resistance and cross resistance to other PIs. The best chance to respond to a 2nd PI is to catch viral load rebound right away and switch therapy. You may want to check which drugs you may be resistant with by using a resistance test, but they are not always accurate.

Indinavir+Ritonavir. Yesterday, Abbott Labs reported preliminary data on this potent combination. In one study, 7/7 had <40 copies/ml at week 52. In a second study the median VL decrease was 3.6 log in the 17 patients who reached week 24; 100% of patients had <500 copies by week 16 which was sustained at week 24; 80% had <80 copies/ml. The median rise in CD4 cells was 165. Regimen was reported to be well-tolerated. As well, preliminary eidence indicated suppressio of viral load for individuals who failed saquinavir or indinavir. They received only the 2-drug regimen of ritonavir+indinavir.

CSF Viral Load Following Ritonavir+Saquinavir. In a small study of a few individuals, after 48 weeks CSF viral load remained detectable following ritonavir+saquinavir alone. But after adding d4T+3TC CSF viral load was reduced to undetectable.