The Body Covers: The 39th Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy
Managing HIV Disease for Life --
New Issues Challenges, and Opportunities
September 26, 1999
This talk reviewed the potential role for the use of hydroxyurea (HU) in treating HIV infection. It remains unique thus far, as it is the only agent identified that targets a cellular mechanism, and may thus have certain advantages over the antivirals now available, such as differences in the rate of resistance when using this approach. So far, over 500 patients have been studied when using HU in patients who are for the most part antiviral na&imul;ve, each time in combination with ddI, and sometimes stavudine as well. Dr. Lori summarized the results of four such studies: RIGHT 411 (Lori AIDS Res Hum Ret 1997, 13: 1403), the Swiss HIV Cohort Study (Rutschmann, AIDS 1998, 12(8), F71), BMS 055 (Federici, Geneva AIDS 12th WAC 1998 abs 12235) and ACTG 307 (Frank, 1998 Chicago CROI). In general, the results were similar, showing that the addition of HU produced an additional 0.5 log drop in RNA to the baseline regimen. The CD4 count increase may be blunted, but the CD4 percent increases have been similar to non-HU containing regimens. And so far, the incidence of significant marrow toxicity has been seen in <1% of treated patients when using a dose of 500 mg BID. There are concerns for increases in peripheral neuropathy when stavudine is given, although the results from randomized studies are still needed to better address this concern. The optimal dose and schedule of HU is still not known, and there is a randomized study underway, which is comparing both a range of doses of HU (from 600 mg to 1200 mg) and varying schedules (QD, BID and TID).Reference Abstract: Hydroxyurea and Its Role in HIV Disease
The ability to enhance immune control of HIV replication with HU was also reviewed. First, a study was done with patients who were treated during primary HIV infection before complete Western Blot seroconversion. (Lori, JID 1999, in press). Eleven patients, with a baseline viral load of 509K and CD4 count of 487 were treated with indinavir, didanosine and HU. After four months, the viral load was <50, and the CD4 count had increased by 154 cells/mm3. Over the first 20 weeks, activated CD8 cells decreased in number, while naïve CD8 cells increased. As these patients were treated during seroconversion, there was evidence of preserved HIV specific T helper responses seen, but this is usually not seen when treatment is initiated in a cohort of patients with chronic infection. This is at least in part due to the efficacy of HAART, with the suppression of expression of HIV antigens such that the immune system no longer needs to mount a response to HIV itself. However, studies of patients with long term control of HIV in the absence of treatment suggest that cellular immune responses are associated with control of HIV replication. This has been seen in the "Berlin" patient, who went on this same regimen, and had two treatment interruptions due to concomitant illness. After the second interruption, the patient remained off antivirals, with a viral load that has remained below 400 copies for two years.
It has generally been noted that the nadir of viral load is established in the first year of treatment, and if there is detectable HIV after six months, there is an increased likelihood of viral escape. Dr. Lori presented the results of a small study which appears to contradict these observations. Known as the Panda Cohort, twelve patients were treated with only ddI and HU (Lori, AIDS Res Hum Retr 1997, 15(7) 619). The initial viral load was 51795. After 40 weeks, the viral load was still 1847, and no patient had a viral load below 500 copies. Unlike current strategies, these patients remained on this same regimen. At week 122, eleven patients had a viral load below 500 copies, with a median of 254 in the cohort. Similarly, there was an increase in naïve CD4 and CD8 cells, approaching that which is seen in HIV negative controls. Further, there was evidence of vigorous HIV specific T helper responses observed in six of the 12 patients, which may account for some of the prolonged suppression seen.
These observations lead to the potential to reconsider approaches to generating an effective immune response while on treatment. Generating an immune response can be potentially effective in controlling HIV replication for the long term, with the potential to have less need for antiviral treatments. However, HAART treatment in general does not generate these responses due to the extent of suppression of HIV replication. One approach under active investigation is the use of periodic interruptions in treatment to "auto-immunize" the immune system with endogenous HIV, with careful attention to reinstituting treatment before HIV replication destroys these cells. Another is the possible role for HU to augment immune control of HIV replication, and allow a regimen that allows low level replication to remain effective over a longer time period than generally observed. The ongoing exposure of the immune system to HIV antigens in a regimen that simultaneously does not allow viral escape might allow HIV specific T helper cells to be generated which could result in the long term control of HIV replication as well.
Authored by: Franco Lori, M.D., Adjunct Professor, Georgetown University, Washington, D.C.
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