Salvage Study Using RTV+IDV+Hydroxyurea; Immune Reconstitution
from Jules Levin

Sunday April 18 and Monday April 19 RIGHT held a conference titled "Targeting HIV Reservoirs and Reconstituting the Immune System". RIGHT was founded by Franco Lori who has been driving hydroxyurea research for several years. On Sunday several speakers discussed immune reconstitution but much of the discussion was repeated from Retrovirus in February. There was limited new clinical information except an important update of 28 week data from Mike Youle on his salvage study using 5 drugs or more including RTV/IDV and hydroxyurea. This data is below. Of note, Robert Siliciano reemphasized that he felt the latent reservoir of replication competent HIV DNA in CD4 memory cells did not decay at all or if it does it's so slow that eradication of this reservoir would take over 60 years. Anthony Fauci showed his IL-2 data (retrospective analysis) which he has previously reported. It's discussed in more depth in the just published NATAP newsletter posted to the NATAP web site. HIV was not detectable in the reservoir mentioned above in 6/14 individuals receiving IL-2 + HAART when they looked at 10 to 30 million cells. When they looked at 110 to 330 million cells 3/14 had no detectable virus. Follow-up studies are required to confirm this suggestion that IL-2 can drive HIV from this reservoir. Nonetheless, other potential reservoirs for HIV remain: CSF, semen, etc. Fauci said he intends to follow this up with studies looking at the host and its microenvironment as factors in controlling HIV, as well as IL-2 studies. He thinks use of specific cytokines may play a role in controlling HIV after stopping therapy.

The subject of interrupting and stopping HAART was discussed at length in the conference and in the hallway with researchers. The NATAP newsletter has a lengthy discussion of this information which was discussed at length at the Retrovirus Conference. This is a hot topic and researchers are fully aware of the need to try and understand why some individuals were reported at Retrovirus to remain undetectable after interrupting and stopping HAART. A number of researchers from Europe and the USA told me they are planning or have already started studies to explore this. The ACTG will be starting a study (A5063) looking at this question. In this study, people who have been <50 copies/ml will be asked to interrupt therapy. They will be followed closely. If viral load rebounds to a certain level people will be placed back on therapy and interruption will be tried again after a specified period of time. I know of a number of individuals considering doing this on their own. I would not do that. Let the researchers try to sort this out. This study will be conducted at 4 sites: Dr Gulick at Cornell in NYC, Dr Ian Frank in Philadelphia (I think he's at U of Penn), Dr Joe Eron at UNC, and I forgot the 4th. But the study is still in planing stages and first must be approved by NIH and FDA so it could be 2 months before starting.

There will likely be a study soon giving Remune to individuals undetectable on HAART. Therapy interruption will be explored in this study. Brigette Autran has started a study in France exploring HAART interruption. Emil Toma from Montreal Canada presented his unusual study design for exploring this subject. He will give study volunteers a flu shot, GMCSF, intensification with adefovir and hydroxyurea while on HAART; and Remune thereafter. There was considerable discussion at this meeting about the importance of dendritic cells. HIV presents itself to these cells after HIV infection and these cells are involved in the response of the immune system to HIV. A number of researchers are looking at ways to improve their knowledge about this and to utilize these cells in improving the response to HIV by the immune system. Low dose IL-12 was mentioned as a potential treatment to effect these cells and will receive research attention.

Several other therapeutic approaches to treating HIV were discussed but are in early research--HIV DNA vaccine, genetic immunization, stem cell therapy, etc. Rob Murphy reported preliminary information from ACTG 347 on semen and CSF reservoirs after treatment with amprenavir monotherapy and triple therapy with AZT/3TC. Amprenavir penetrates the CSF and has antiviral activity in the CSF and in seminal cells. Further analysis will be reported as more data is collected and reviewed. But about 10% of patients who reduce viral load in plasma can have high viral load in semen. This has been previously reported. So in most cases HIV reduced in plasma parallels reduction in seminal cells but there is a small percentage of people where there is no correlation and retain high VLs in semen.

Several open-label observational studies conducted in South Africa using hydroxyurea+ddI or hydrea+DDI+D4T were reported. The results were surprisingly good with higher than expected percentages of people achieving undetectable VL. If a person's viral load is relatively low using hydroxyurea is a viable option for initial therapy. This saves the NNRTI, PI and possibly abacavir options for future use. Data on abacavir suggests that d4T is least likely to cause cross-resistance to abacavir. So starting therapy with d4T+DDI may leave the abacavir option open. One study conducted in South Africa suggested hydrea's role induction/maintenance. One could start therapy with a PI+hydrea+D4T+DDI. After being undetectable for a while a person could stop the PI and continue with hydrea+D4T+DDI.

Finally, possibly the most important data reported at the meeting. Mike Youle first reported data from this open-label study at the Virgin Islands mtg in December and again at Retrovirus. I've been reporting each update. Sixty-three highly treatment experienced individuals received a 5 or more drug backbone regimen consisting of a double PI+efavirenz+DDI+D4T+hydrea. About 42 or more individuals received RTV/IDV at various dosing combinations: 800/400, 800/100, 600/200. The double PI regimen was individualized based on what the person could tolerate based on previous experience with PIs. So some individual received NLF+IDV, NLF+SQV or RTV+SQV. Median baseline CD4 was 125 and viraL load was 63,000 copies/ml. But 31 individuals had >750,000 copies/ml. A few switched their NNRTI from EFV to NVP.After 28 weeks with 20 individuals available for analysis, there was a median VL drop of 3.05 log (range 1.04 to 3.77). Median CD4 increase was 120. And 85% had below 400 copies/ml. Youle said higher baseline viral loads and the number of prior drugs used were associated with a more likelihood of failure. He said for every log of higher viral load at baseline a person had a 40% less chance of being undetectable. Before starting this salvage regimen study participants were off all drugs for >4 weeks. Youle said for every month off therapy there was a 15% increased likelihood of being undetectable with this salvage regimen. This goes against current opinion. Resistance researchers believe that if a person has resistance to a drug and stops taking it resistance would emerge after restarting that drug. Veronica Miller presented a study at Retrovirus showing similar results as Youle. It is discussed in the NATAP newsletter on the web site. Youle is currently conducting an <50 copy test analysis.