Sourced Compiled and Edited by Paul Blanchard
Medical Consultant
12 th World AIDS Conference28 June - 3 July 1998, Geneva, Switzerland
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28 June - 3 July 1998, Geneva, Switzerland |
Upwards of 12,000 delegates attended the 12th World AIDS Conference, the major international conference which takes place every two years. In addition to basic and clinical science (which ATP exclusively reports), the World AIDS conference also has numerous presentations on epidemiology, prevention, public health and social science. As with this years Retrovirus conference a steady infiltration of both laboratory and clinic based immunological studies was evident. Continued concern over the long-term tolerability and durability of current combination antiretrovirals manifests as a desire to understand host-based mechanisms of virological control.
Conference Report - Part One
ANTIRETROVIRALS AND TREATMENT STRATEGIES
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Poster Session 12229 & Late Breaker Oral Session 22489: ADAM study: Induction-maintenance therapy in HIV-1 infection: Early results.
Three- or four-drug antiretroviral therapy is hard to take reliably and can be associated with short-term, and perhaps long-term side effects as we are learning with the metabolic toxicity's reported in association with protease inhibitor use. Therefore, investigators are beginning to test a treatment strategy that features an aggressive initial combination followe d by a scaled-back maintenance therapy. There is a scientific rationale to support this approach. Almost all of the virus that is measured in viral load assays is produced in productively infected cells -- activated, CD4+ lymphocytes. We know that HIV replicates rapidly in infected individuals with the viral life cycle lasting a little over one day, and the life-span of infected cells is approximately two days. Therefore, if viral replication can be totally inhibited it would not take a long time until all of the productively infected cells are eliminated from the body. What's left is a smaller population of chronically infected cells and latently infected cells that produce far less virus than that made by the productively infected cell population. Perhaps fewer drugs would be needed to stop viral replication in these cells.
A multi-centre study in the Netherlands, the ADAM study, was designed to test this hypothesis. 62 treatment naïve patients with baseline viral loads > 1,000 copies/mL and CD4+ counts > 2 00 cells/mm3 were treated with an initial combination of d4T + 3TC + nelfinavir (750 mg tid) + saquinavir-hgc (600 mg tid) for 26 weeks. Those patients with viral loads < 50 copies/mL at weeks 25 and 26 were eligible to be randomised to receive one of three maintenance therapies: d4T + NFV, NFV + SQV-hgc, or continue on the original four-drug combination.
The patients' mean baseline viral load was 4.5 log (about 50,000) copies/mL and the mean baseline CD4+ count was 400 cells/mm3. At the present time, 31 patients have been randomised to a maintenance therapy and 25 have been followed for an additional 12 weeks. Of those patients who remained on the four-drug induction regimen, 1/11 (9%) experienced a rebound in viral load to quantifiable levels, while 9/14 (64%) of those whose treatment was scaled back to a 2-drug combination had a rebound in viral load. The authors did not state which if either or the 2-drug therapies were more likely to fail.
The authors looked at several variables to determine if there were factors associated with viral load rebound among patients on 2-drug maintenance therapy. Baseline CD4+ counts and viral loads were not predictive of rebound, nor were changes in CD4+ or CD8+ counts on therapy. The most significant predictor of failure was the rate of clearance of HIV RNA after the initiation of therapy. 80% of those patients whose viral loads remained below quantifiable levels on maintenance therapy had a viral load < 50 copies after 4 weeks of induction therapy. However, it took 16 weeks for the viral loads to go below 50 copies/mL for 80% of patients whose viral loads rebounded on 2-drug maintenance.
This study was similar in approach to two others that were presented at the last Retrovirus Conference in Chicago. In ACTG 343, patients were given induction therapy with ZDV + 3TC + IDV for 24 weeks, and were randomised to ZDV + 3TC or IDV monotherapy, or continued on the three drug combination if viral loads were < 200 copies/mL at weeks 16, 20 and 24. Those patients assigned to the less intense maintenance therapies were much more likely to experience a rebound in their viral load above 200 copies/mL than those who continued on the three drugs. In the TRILEGE study, patients also had induction therapy with ZDV + 3TC + IDV. After only 16 weeks of induction, patients were randomised to continue on 3-drug therapy or a scaled back maintenance therapy if their viral load was < 50 copies/mL. Again patients on the less intense treatment were more likely to have viral load rebound.
ACTG 343 and TRILEGE differed than the ADAM study in several important aspects. In the former two studies induction therapy included three drugs rather than four. In the ADAM study patients were required to have viral loads < 50 copies/mL to be eligible for randomisation to the maintenance phase compared to < 200 copies/mL in ACTG 343. It is now known that some of the patients who failed on maintenance therapy on ACTG 343 had quantifiable viral loads between 50 - 200 copies/mL. Despite a potentially more aggressive induction phase in the ADAM study compared to the others (although there really is no data comparing indinavir as the only PI in a 3-drug combination with NLV + SQV as a PI combo in a 4-drug regimen), it is clear that the induction-maintenance strategies foll owed by these three studies are not adequate to provide durable suppression of virus replication. Future induction-maintenance studies will include more aggressive induction therapy for longer periods of time, followed by 3-drug maintenance therapies that may be more easily tolerated than combinations including protease inhibitors.
Coverage: Ian Frank, M.D.
Source: The Body.
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With concern over long-term tolerability of multi-drug regimens induction-maintenance is an area of treatment strategy that still needs exploring. The ADAM study is due to be published in The Lancet on July 25 th . A related poster (abs. 42259) showed that the rate of decline of VL during induction was significantly correlated with NFV concentrations in plasma. It should now be considered whether rapidly achieving <50 copies is a prerequisite of durable suppression outside of an induction-maintenance setting. If a naï ve patient is still >50 copies at 4 weeks, does this mean the initial regimen is not sufficiently intense? If so, what should we do - add more drugs? Retrospective analysis should now be performed on triple therapy trials to look at initial rate of VL reduction in those who have sustained VL below detection for prolonged periods (>2-3 yrs). Care must be taken with the use of the term "failure". Too often "failure" is talked of in terms of the patient failing the therapy, whereas, even with adherence issues it is obviously the reverse. The drug regimens fail in their applicability and usefulness to the patient. A further question to consider is how the different classes of compound may affect rapidity of decline. PI's, NNRTI's and nucleoSIDE analogues are active in their native, orally administered form, allowing quick onset of action. Nucleotide analogues, however, require intracellular phosphorylation to become active. Different compounds also differ in their activities in active and resting cells and in whether they act pre or post-transcription. Hydroxyurea also seems to have it's own class effect where VL may fall steadily to <50 copies over more than 6 months and then be suppressed for long periods (see article below). Should we now be inducing with potent, rapidly acting compounds that do not require cellular activation? (eg. Dual PI + NNRTI + nucleoSIDE + fusion inhibito rs) then switching to maintenance with simplified regimen (eg. NNRTI + 2NA's)? Could induction be even better achieved (theoretically) with i.v. initiation of compounds to ensure rapid high plasma concentrations? This might then be followed by individual titration of drug levels while oral dosing (with long-term checking) in the maintenance phase? With initiation of therapy appearing a crucial factor in longer-term viral suppression, it may well be judged that we failed to appreciate the importance of the first move against this wily opponent. More intensive regimens are clearly needed as 30% of naïve patients, and a higher proportion of experienced patients do not achieve <500 copies/mL let alone <50 copies with current triple therapy. The trade-off is that more drugs might help those for whom increased potency is required, but not those for whom current regimens are already adequate. Further work needs to be done on predicting who falls into which category. |
Presentations from four separate studies highlighted the importance of high baseline viral load in the success or failure of antiretroviral therapy to produce durable suppression of viraemia.
Graeme Moyle of the Chelsea & Westminster Hospital, London presented the SPICE study (abs. 12222), a prospective randomised trial of the safety and activity of saquinavir soft-gel capsule (SQV-sgc) plus nelfinavir (NFV) with or without 2 NRTI's compared to either SQV-sgc + 2 NRTI's or NFV + 2 NRTI's in PI naïve patients. Standard doses of NRTI's were used and NFV was given at 750mg tid, SQV-sgc was dosed at 1200mg tid in the single PI and 800mg tid in the double PI containing arms.
Mean baseline plasma HIV-RNA and CD4+ cell counts were well matched across all arms at 4.8 log copies/mL and 301 cells/mm3 respectively, 54% were antiretroviral naï ve. All patients initiated at least one new NRTI at commencement of study and crossovers were allowed after 16 weeks for intolerance, virologic non-response or relapse.
An interim analysis at 48 weeks revealed the following proportions of patients with <50 copies/mL of plasma HIV-RNA. It should be noted that these results used a more rigorous analysis of intent-to-treat and <50 copies/mL.
| <50 copies @ 48 weeks | |
| SQV-sgc + NFV + 2NRTI's | 51% |
| SQV-sgc + 2 NRTI's | 42% |
| NFV + 2NRTI's | 42% |
| SQV-sgc + NFV | 35% |
Although no statistical analysis was performed for the 48 week data there appears to be a favourable trend for better virological suppression in the 2 PI + NRTI's arm.
When week 48 virological results were analysed according to baseline viral load there was a clear dissociation of benefit between the 3-drug and 4-drug arms for those patients stratified to either >63,000 or <63,000 copies/mL. The 4-drug (double PI-based) combination performed much better in those with >63,000 copies/mL at baseline. Benefit of the 4-drug arm was also found to be greater in those with prior NRTI experience.
Three further studies (two retrospective cohort reviews and one prospective cohort study) also revealed an effect of baseline viral load at initiation of therapy on subsequent degree and durability of suppression.
Julio Montaner and colleagues examined the role of baseline plasma viral load as a predictor of response to triple therapy in a population-based cohort of 331 treatment-naï ve patients in British Columbia (abs. 22359). All patients started therapy with PI based triple therapy combinations (46% IND/3TC/d4T, 28% IND/3TC/ZDV, 14% SQV/3TC/ZDV). Subjects were stratified according to baseline viral load (< or >600,000 copies/mL) and primary outcome was a decrease in VL to <500 copies/mL on two consecutive measures during treatment. Median follow-up was eleven months. Initial combinations included. Baseline demographics and clinical characteristics, including CD4+ count, were similar across the 2 groups. Multivariate analysis controlling for gender, age, AIDS, CD4 count at baseline and months on therapy revealed that subjects with a VL >600,000 copies were 6 4% less likely to experience a decrease to <500 copies on two consecutive measures (OR = 0.36; 95% CI: 0.16-0.84) than those with a lower baseline VL.
Daniel Paris and colleagues (abs. 22349) performed a retrospective analysis of 274 patients in a clinic based cohort from Zurich. All patients were prescribed PI containing triple combination regimens between October '95 and March '97. Results presented showed:
| Prior Treatment | Numbers (%) |
| Nucleoside naïve | 5/74 (7%) |
| Nucleoside experienced | 46/200 (33%) |
| All Patients | 51/274 (19%) |
| Risk factor | OR value (all p=<0.05) |
| High baseline VL | OR=2.41 per log VL |
| Addition of PI to established NA's | OR=5.18 compared to naïve patients |
| Treatment with saquinavir | OR=3.55 compared to indinavir |
| Duration of prior NA therapy | OR=1.33 per year |
Failure to maintain VL <500 copies/mL occurred in 32% of all patients initially experiencing a decline to <500 copies (71/223). 20% of these were NA-naï ve (14/69) and 37% were NA-experienced (57/154). None of the risk factors for initial failure to achieve <500 copies/mL (including high baseline VL) were predictive of subsequent rebound after suppression below 500 copies.
A prospective study by Michael Saag reported similar findings (abs. 22363) Virologic success after treatment initiation or change of regimen (beginning March '97) was defined as sustained suppression of VL below 5,000 copies/mL for the period of observation (median 8.2 months). 120 patients were included in the study with a median baseline viral load and CD4 cell count of 4.8log copies/mL and 162 cells/mm3 respectively.
Virologic success (as defined above) was seen in 41% of participants. Successful control of viraemia was seen in those with lower baseline VL (35,855 vs 82,057 copies/mL; p=0.01) and fewer prior ART regimens (3 vs 5; p=0.001).
Author: Paul Blanchard
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Once again, these data suggest that more aggressive initial therapy may be needed for patients with higher baseline viral loads. "High" baseline viral load has been shown to be a predictor of poor response in several previous studies including IDV-based regimens and ACTG175. It is yet to be determined what value "high" might actually mean . The >63,000 copies value determined in the SPICE study seems rather low, but is in keeping with the MACS in which >50,000 copies (in untreated subjects) was the highest risk group for disease progression. |
It has been previously reported (Chicago Retrovirus Conference) that switching of PI's early during virologic failure in study ACTG333 may have been an important factor in the activity of the second line PI. Two presentations at Geneva also identified early switching as a predictor of success when dual PI (RTV/SQV) therapy was used following virologic failure of a single PI containing regimen.
Joel Gallant and colleagues from Johns Hopkins University performed a retrospective analysis of 41 patients who had been switched from single (indinavir or nelfinavir) to dual PI containing (RTV/SQV) regimens due to inadequate virologic control. Virologic failure was defined as viral RNA >400 copies/mL on two cons ecutive measures or >1000 copies/mL on a single measure after 16 weeks (abs. 12330). A total of 23 indinavir failures and 6 nelfinavir failures were identified.
In contrast to data from other studies, RTV/SQV containing regimens were found to be effective and durable in a fair proportion of patients. Response to salvage therapy was defined as a VL less than or equal to 400 copies/mL at least 4 weeks after initiation of therapy:
| 1 st -line PI failed | Proportion responding | Mean duration of response |
| Prior indinavir | 13/23 | 42 months |
| Prior nelfinavir | 4/6 | 39 months |
The higher proportion of durable responders to RTV/SQV as a second-line protease inhibitor based combination in this study were thought to be due to the relatively low VL at the time of switch. Mean HIV -RNA at time of switch in the responders whom indinavir had failed was 6,368 vs.25,409 copies/mL in those who did not respond to subsequent SQV/RTV (p=0.04). Corresponding mean values in the nelfinavir group were 5,610 vs 10,889 (p=>0.05).
The authors conclude that although further validation is required, there is a suggestion, consistent with what is known about genotypic resistance patterns, that early switching may be more effective and durable than continued therapy of the failing regimen followed by a delayed switch.
Author: Paul Blanchard
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It appears that an "early" switching strategy may be a useful one if further credible options exist. The updated BHIVA guidelines suggest an upper threshold of <5000 copies/mL of VL before which the switch should take place. VL test results suggesting virological failure should always be repeated with the results rapidly obtainable to confirm a true rise, and not just a blip or even assay contamination. The need for further NA options and access to a new class is widely thought to be of value at switch. When no further options are available, it seems reasonable (if toxicity is not an issue) to remain on therapy, as there is a considerable time lag between virological and immunological/clinical regimen failure. Obviously treatment goals must take heed of declining options.
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Christopher Pilcher and colleagues from the University of North Carolina presented data from a retrospective review of viral load test results for 1,230 individuals from October 1996 to October 1997.
Viral load was determined by the Roche Monitor system with a lower limit of quantifiability of 400 copies/mL HIV-RNA. This assay can, however, have a variable limit of detection lower than 400 copies that varies between 1 and 400 copies/mL depending on the efficiency of PCR amplification in each run. This study divided patients who responded to antiretroviral therapy by a fall of HIV-RNA to <400 copies/mL into two groups:
Patient characteristics revealed that a larger proportion of patients in group 1 were being treated with two drugs only than in group 2 (52% vs 25%, p=0.005). It was also found that for those patients on stable therapy already suppressed below 400 copies/mL, those with low -level RNA detected (group 1) were 5 times more likely to have RNA above 400 copies on the next VL measure than those with RNA undetected (group 2), p=0.01.
The presenting authors concluded that the detection of RNA at levels below the quantifiability of th e standard assay may not be inconsequential and may represent viral replication, and highlighted the role of enhanced sensitivity assays in routine monitoring of patients who achieve <400 copies/mL.
Author: Paul Blanchard
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Hydroxyurea
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This is a fascinating study by Franco Lori's group in Pavia, Italy (one of the major hydroxyurea proponents), in collaboration with some prominent groups elsewhere, notably Bruce Walker's lab at Harvard, and Bob Siliciano's lab at Hopkins. They treated 24 patients with a combination of HU, ddI and protease inhibitors for an average of 11.3 months. These patients were started on therapy soon after infection -- 10 treated before, 6 within 1 year and 8 after 1 year of seroconversion. Average baseline values were: plasma viraemia 455,700 copies/ml, CD4 499/ml. Plasma RNA became undetectable in all patients within 16 weeks and remained undetectable for up to 21 months. HIV RNA became undetectable in the semen of 6/6 patients. In the lymph nodes, HIV RNA was undetectable in 6/7 patients (<1 cell/4.4x10 7), as was HIV DNA in 2/6 patients (<1 cell/3x10 5 ). Using the Siliciano assays for hidden reservoir virus, replication competent HIV was recovered with an unusually low frequency (<1 cell/1x10 7 ) in 3/3 patients. Most interestingly, the patients had very strong T helper responses to HIV antigens. Bruce Walker has hypothesised that the specific T helper response is key in controlling viraemia in long term non progressors. In one patient, despite very low levels of latent provirus that could be recovered from resting lymphocytes, HIV did not rebound 1 year after interrupting the treatment. It is not clear whether the preserved T helper responses were simply due to starting early after seroconversion, or whether hydroxyurea had a unique effect in this setting.
Coverage: Andrew T. Pavia, M.D.
Source: The Body
Source: The Body
A study conducted in South America and Canada compared two HU inclusive combinations versus combinations of reverse transcriptase inhibitors without HU in 183 antiretroviral naive patients with CD4+ counts between 201-500 cells/mm 3. Results were presented up to week 24 with 118 of the patients reaching that timepoint. Patients received treatment with:
| AZT + ddI | d4T + ddI | ddI + HU | d4T + ddI + HU | |
| Reduction in viral load (log copies/mL) | 1.7 | 1.5 | 1.2 | 1.9 |
| % with viral load <400 copies/mL | 35 | 50 | 45 | 75 |
| CD4+ count increases | 100 | 90 | 10 | 30 |
Not surprisingly, viral load reductions were best in the patients receiving the triple therapy. Although viral load reductions were slightly less in patients on ddI + HU compared to that experienced by the patients on dual nucleosides, the proportion of patients with viral loads <400 copies/mL was comparable in all of the dual therapy groups. In this study adverse events were few. The principal toxicity of hydroxyurea is bone marrow suppression. The white blood cell lineage is effected more than red blood cells and platelets. However, neutropaenia occurred in only two patients on the study. Because hydroxyurea causes a relative lymphopaenia, CD4+ counts do not rise as high in those patients on the drug. CD4+ percentages do rise, but the absolute counts increase to a more modest extent, despite better suppression of viral replication.
These results are similar to other studies that have compared ddI or d4T + ddI with and without HU. In general, the addition of HU has produced an additional 0.5-0.7 log reduction in viral load when used in a combination. Thus far, HU has not been studied in patients at more advanced stages of disease that have other therapeutic options. The limited increases in CD4+ counts that have been seen in almost all studies with the drug may make this an agent that we reserve for patients with higher counts, or one that we add into a regimen after CD4+ counts have increased. Neutropaenia is the most commonly reported toxicity with HU. This side effect usually resolves within one or two weeks after the drug is held, and many patients can be restarted at a lower dose without recurrence. Other toxicity's reported with hydroxyurea include hair loss and skin ulcers. Additional studies designed to identify the optimal dose and frequency of adminis tration of HU are being planned.
Coverage: Ian Frank, M.D.
Source: The Body
Although HU has been used almost exclusively with adenosine analogues to date, one presentation of hydroxyurea together with d4T and 3TC suggested that there may be some benefit to using the drugs with other nucleoside analogues as well. Dr. Steven Miles and colleagues from UCLA used this triple combination to treat highly experienced patients who had no other options for therapy. These patients had already been treated with an average of 7 other antiretroviral combinations, and all had experienced virologic or clinical failure on d4T and 3TC, and presumably had virus resistant to both drugs. In addition, all of the patients had received at least two different combinations including protease inhibitors and had failed on these drugs as well.
Eighteen patients were enrolled in the study and their mean baseline viral load and CD4+ counts were approximately 480,000 copies/mL and 20 cells/mm 3 . Follow-up was of varying duration. Three patients had no response to therapy. However, among those responders, the mean maximal viral load reduction seen at any point in time was 1.7 log, with several patients experiencing viral load reductions of more than 3 logs! Dr. Miles stated that viral loads were rebounding in many patients -- not surprising in this group with very high viral loads. CD4+ count increases were not observed. Adverse drug events were more commonly seen in this study than in others focusing on patients at earlier stages of disease. Neutropaenia was seen in four patients; two patients needed blood transfusions; and one patient experienced bone marrow failure that had not resolved four months after the drug was stopped. Four patients had hair loss on study.
Why HU would have activity with d4T and 3TC in this patient population that has already failed on these two drugs is not clear. In vitro, HU has additive effects in combination with non-adenosine analogues. Another possibility is that the concentration of those cellular enzymes responsible for metabolism of d4T and 3TC, particularly thymidine kinase and deoxycytidine kinase, increases after cells are exposed to HU. This could then lead to higher concentrations of d4T-triphosphate and 3TC-triphosphate, the active forms of the drugs, than those achievable in the absence of HU. These higher concentrations of the triphosphates may be able to overcome some degree of viral resistance such that the drugs regain some of their lost activity.
This report of HU with d4T and 3TC is intriguing, but should be considered preliminary. Dr. Miles stated that he would not treat these patients the same way if he could start this study again, but would take a more aggressive approach, adding additional drugs. Other studies investigating the use of HU as part of salvage regimens are being planned and some are underway.
Although CD4+ counts do not seem to rise in patients on HU, there is evidence that these cells regain lost function, and there was some early data presented suggesting that there may be some unique recovery of HIV-specific immunity in some patients receiving HU that has not been seen in patients treated with other maximally suppressive antiretroviral combinat ons.
Coverage: Ian Frank, M.D.
Source: The Body
Two abstracts were presented that explored the function of CD4+ cells in patients treated with HU inclusive combinations. One abstract reported on 24 patients, 10 treated prior to seroconversion during their acute HIV syndrome, 6 within one year and 8 after one year of seroconversion. All patients were treated with ddI, HU and indinavir. This cohort of patients includes the famous "Berlin patient," a patient who was treated during his acute HIV syndrome and eventually stopped therapy after approximately six months, only to maintain viral loads below quantifiable levels more than 18 months later.
Baseline CD4+ counts in these patients was 499 cells/mm 3, and these counts increased on average by 168 cells/mm 3 during the average 11 months of follow-up. This rise in CD4+ counts was atypical; as shown above, CD4+ counts don't usually rise in patients treated with HU. The elevation in these patients counts may be due to the fact that they received a protease inhibitor as part of their therapy, or it may be because a large proportion of these patients were treated during their acute infection, a time when CD4+ counts will transiently decline. These patients had significant increases in their memory CD4+ cell counts compared to a group of patients that elected not to receive treatment. In addition, the CD4+ cells of these patients were able t o proliferate in response to exposure to influenza antigen and other non-specific lymphoproliferative stimuli; CD4+ cells of the untreated control group did not respond in this fashion. Markers of immune activation were also measured in treated and untreated patients. CD38 and HLA-DR expression on CD8+ cells was lower in the treated group compared to the untreated group (increased expression of these markers predicts more accelerated disease progression). Lastly, CD28, a costimulatory T cell molecule essential for the development of normal proliferative responses to antigen on CD8+ cells, was expressed at higher levels in the treated patients.
In addition to these favourable immunologic responses, 9 of 11 patients studied demonstrated robust CD4+ proliferative responses to HIV antigens. [A discussion focusing on the development of the HIV specific immune response following infection will continue after this section on hydroxyurea.] The response of CD4+ cells to HIV antigens is typically lost in patients treated much beyond their acute HIV infection, and a recent study has shown that patients treated during their acute retroviral syndrome are able to maintain these HIV+ specific lymphoproliferative responses. Because a portion of these patients were treated prior to seroconversion, one can not conclude from this data that the patients' maintenance of a CD4+ lymphoproliferative response to HIV antigens was related to the their treatment with HU.
Coverage: Ian Frank, M.D.
Source: The Body
A far more provocative abstract presented as a late-breaker described another group of 12 patients treated with ddI + HU. This group of patients had CD4+ counts between 250 and 500 cells/mm 3 and a mean viral load of 51,795 copies/mL (range 602-173,166 copies/mL) prior to therapy, and all had established HIV infection. Viral loads declined progressively, but over a long period of time. After 40 weeks of treatment the patients' mean viral load was 1,847 copies/mL, and after 122 weeks it was 254, including 8 patients with detectable viral loads <50 copies/mL. A published report of virus analysed from these patients (Lori, et al: AIDS Research and Human Retroviruses 1997; 13:1403) demonstrated that these patients had mutations associated with ddI resistance. However, this ddI-resistant virus was inhibited by ddI in the presence of HU. Therefore, these pa tients have experienced something unique -- long periods of sustained inhibition of HIV replication and no viral load rebound, despite the development of resistant virus.
These patients' naive and memory cell subsets of the CD4+ and CD8+ lymphocyte populations were analysed and compared to two control groups, untreated patients and uninfected individuals. During this study, CD4+ counts rose from a mean of 376 cells/mm 3 to 406 cells after 122 weeks, an increase of only 30 cells/mm 3. However, naive cells comprised 54.1% of the CD4+ T cells in the treated patients, compared to 23.8% of the CD4+ T cells in untreated patients and 54.2% in the HIV uninfected controls. Therefore, after two years of therapy, naive CD4+ T cells were present at a similar percentage a s was seen in a group of uninfected individuals. Naive CD8+ T cells also were present in higher percentages in the treated patients compared to the untreated patients (39.8% vs. 9.85%), but were still lower than in the uninfected individuals 48.8%).
The HIV specific immune response was also measured in these patients after 122 weeks of therapy. The CD4+ lymphoproliferative stimulation index to HIV antigens exceeded 10 in 5 of 12 patients. A stimulation index above 3 is considered a good response, and one a bove 10 is considered excellent. As will be discussed in the section on HIV immunity, this was an unexpected observation in a group of patients with established infection at the time therapy was initiated, with CD4+ counts less than 500 cells/mm 3 , and with ongoing viral replication for the majority of the treatment period in most patients. Although this is an intriguing finding, the lack of baseline analyses limits the conclusions that can be made. Clearly, we will need additional studies to determine if HU has a singular capacity to reconstitute HIV specific immune function. However, the HU experience has offered us an opportunity to re-examine the aphorism that total inhibition of viral replication is required to maintain therapeutic benefit and promote immune restoration.
Coverage: Ian Frank, M.D.
Source: The Body
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Additional to it's effects on ribonucleotide reductase, hydroxyurea may have beneficial effects as a cytostatic - limiting numbers of target cells (see DocFax 49). The described effects on anti -HIV CTL are also intriguing. Data sets although encouraging, are, however, small and largely uncontrolled - larger studies to assess the "added value" of HU are now needed. The Miles study also highlights the potential for serious adverse events in those with advanced HIV-disease. In such late disease settings lower doses or pulsed therapy needs to be examined. |
<In what might be the most important treatment presentation at the 12th World AIDS Conference (Geneva, June 28 - July 3), New York University immunologist Fred Valentine, M.D., reported a striking return of HIV-specific immune responses from a multicentre controlled trial of REMUNE(TM) (the Salk HIV treatment vaccine, being tested by the Immune Response Corporation of Carlsbad, California, and Agouron Pharmaceuticals, Inc. -in a 43-patient clinical trial where this potential treatment, called the HIV immunogen, was given to patients whose viral load had been very well suppressed by conventional antiretroviral treatment(1).
In almost all viral infections, control of the disease is associated with a very strong "lymphoproliferative response" (LPR)--the ability of certain immune-system cells in the blood to recognise the virus and then grow rapidly, producing many more such cells, which then mobilise other immune-system cells against the virus. With HIV infection, however, it has been known for years that the LPR to HIV is largely absent at all stages of disease--except for a small minority of patients, who do have a strong LPR against many antigens of HIV. These patients are always long-term nonprogressors, able to control the virus for many years and perhaps indefinitely, without treatment.
Dr. Valentine presented preliminary results of a controlled, double-blind clinical trial at eight medical centres, which clearly showed that lymphoproliferative responses like those of long-term nonprogressors can be induced by treatment in patients who otherwise would not have them . These responses were seen against an unrelated strain of HIV (not only against the HIV immunogen itself). Whether these induced responses are helpful like those which develop naturally (earlier in infection) will not be known until some patients stop th eir antiretrovirals and see if, or how rapidly, their viral load returns.
An excellent review of this area by Dr. Valentine and others appeared just before the Geneva conference in a supplement to the June issue of AIDS RESEARCH AND HUMAN RETROVIRUSES (2). This article referred to the study which Dr. Valentine presented in Geneva (described below); however, the data was blinded when that publication went to press.
In the 10-minute "late breaker" session at Geneva, Dr. Valentine gave a preliminary report of a 32-week clinical trial conducted at eight research centres; this trial had been completed, but only the first 20 weeks of data had been analysed and were available for the presentation. Forty-three patients were all given antiretroviral therapy (indinavir plus AZT plus 3TC). Four weeks later, they were vaccinated with either the REMUNE HIV immunogen, or a control vaccination. The active or control immunisation was repeated every three months.
The purpose of this study was to see if the lymphoproliferative response could be induced by immunisation when a patient's viral load was well suppressed by antiretroviral drugs; previous data had suggested that this might be possible. Other measurements included viral load (using an ultrasensitive test with a lower l imit of 40 copies), CD4 counts, and the level of the chemokine MIP- beta.
The REMUNE HIV immunogen--a vaccine-type treatment for persons already infected with HIV, designed by the late Dr. Jonas Salk and currently in a large phase III trial, is made from whole killed HIV from which the gp 120 envelope protein has been removed. It also contains an adjuvant (IFA or incomplete Freund's adjuvant; an adjuvant is used to make a vaccine work better. The control vaccine used in this trial consisted of the adjuvant alone.
According to a July 3 press release from New York University Medical Center, the 43 patients had a median CD4 count of 493 and a median viral load of 8,159 copies before they began the study.
The patients who received the HIV immunogen consistently developed strong lymphoproliferative responses like those of long-term nonprogressors; some of the volunteers who received the immunogen had stimulation indices in the hundreds. Those who received the control vaccination (adjuvant only, without the killed HIV) had very low stimulation indices, usually around three for envelope proteins and slightly higher for gag. Dr. Valentine also noted data from long-term follow-up of one of the Merck trials; patients who had been on the same antiretroviral regimen and had their virus undetectable for almost three years (but who had not received any HIV immunisation) had no spontaneous recovery of their lymphoproliferative response.
The LPR was tested by using different antigens--not only from the HIV immunogen itself, but also a recombinant p24, and most importantly, a whole virus from clade B--a strain of HIV very different from the one used to make the immunogen. Dr. Salk developed the immunogen using an early HIV isolate from a woman in Zaire. This virus was later found to be a natural recombinant, consisting of a clade A envelope and a clade G gag protein. This cross-clade reactivity of the immunogen (to the clade B virus) suggests that if this treatment turns out to be useful, it could be applied to different HIV strains in different parts of the world.
The immune response to a clade different from that of the antigen which induced it is unusual--but not especially surprising in this case, however, since this virus targets the gag protein, which tends to be relatively s imilar among different strains of HIV (the envelope differs much more, but this part of the virus is stripped off when the immunogen is made). The lymphoproliferative response recognises peptides, which are short fragments of proteins--and the peptides fr om different viruses are often the same.
Ref:
1. Valentine FT, DeGruttola V, Kaplan M, and others. Effects of HAART compared to HAART plus an inactivated HIV immunogen on lymphocyte proliferative responses (LPR) to HIV antigens. 12th World AIDS Conference, Ge neva, June 28 - July 3, 1998 [abstract # 31227 (late breaker session, #LB 9)].
2. Valentine FT, Paolino A, Saito A, and Holzman RS. Lymphocyte-proliferative responses to HIV antigens as a potential measure of immunological reconstitution in HIV disease. AIDS RESEARCH AND HUMAN RETROVIRUSES June 1998; volume 14, supplement 2, pages S-161 to S-166.
Author: John S. James
Source: AIDS TREATMENT NEWS Issue #298, July 10, 1998. Published twice monthly: Subscription and Editorial Office: P.O. Box 411256 San Francisco, CA 94141 Internet: aidsnews@aidsnews.org
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This important study leaves many questions unanswered. The most urgent is whether the patients who had lymphoproliferative responses induced in this way will benefit from it and perhaps become long-term nonprogressors. While it seems logical that the answer is yes, it is also possible that LPR is only a consequence or marker of a good immune response which controls the virus by some other mechanism; it might not be the cause of the viral control by long-term non progressors.
The volunteers in this trial were relatively early in HIV disease progression, but well past the stage of primary infection. No one knows how well the approach would work on persons with more advanced illness. The big question is if virologic control, and not rapid rebound on withdrawal of antiretrovirals will be seen in those patients with these induced responses? |