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Resisting Resistance
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Resisting Resistance: Strategic Approaches to Preventing and Coping with Resistance to Antiretroviral Drugs
In a presentation by Dr. Doug Richman, from the University of California, San Diego,
entitled "Resisting Resistance: Strategic Approaches to Preventing and Coping with Resistance to Antiretroviral Drugs," [abstract
S53] many analogies were made to what took place during the tuberculosis era in the 1950s, and many of the graphic presentations from that time looked strikingly similar
to resistance curves of today evolving antiretrovirals.
Resistant HIV-1 mutants exist in untreated patients. While HIV-1 has 104 nucleotides and a mutation rate of 3 x 10-5 nucleotides/replication cycle, the expectation is that mutations are occurring at
least once every time the virus replicates. Since replication is so robust, it is likely that a mutation occurs at each possible
site everyday. Under drug pressure, mutations are likely to be selected in any patient, unless there has been complete suppression
of viral replication. Without complete suppression, therapy will lead to selection of resistant virus and clinical failure.
The new paradigm then has switched from partial suppression and greater than 0.5 log10 viral load decreases to that of complete suppression or reduced viral burdens to
"below the level of detection," a number that appears to be getting smaller every day.
Evidence exists that we can completely suppress viral production with existing therapeutic
regimens. A decline in antiviral activity in a variety of tissues such as tonsil, gastrointestinal, lymph, cerebral spinal
fluid, and semen has now been well-documented. There is also evidence that plasma levels can be sustained at undetectable levels
for up to three years in patients treated in the early protease inhibitor trials. When long-term suppressive therapy is abruptly
withdrawn, the rebounding virus is genetically the same as the original one suppressed before therapy was initiated. Finally,
in some aggressively treated adults and infants with acute infection, antibody responses have actually declined or disappeared.
Failure of potent protease-containing regimens does occur and is usually due to poor
compliance, drug interactions that reduce the potency of the compound(s), malabsorption, and/or baseline resistance due to prior
drug history. Strategies that clinicians should consider in order to avoid this complication should take into consideration
the following:
Strategies for Delaying or Preventing the Emergence of Drug Resistance
1. Potent drugs with single point mutations (3TC, Non-nucleosides) should be reserved
for combination strategies.
2. Adding one drug to a failing regimen is substandard practice.
3. Patients must be provided with a strong educational support system and not just handed
a pile of drug prescriptions.
4. Start therapy early in the infectious course when the patient's condition is less
complex and the immune system has suffered less immunologic deterioration.
5. The goal of therapy is complete viral suppression.
6. Patient adherence to the drug schedule is critical.
Author: Joel Gallant, MD and Robert Murphy, MD
Source: healthcg.com
These principles are now standard practice at leading UK clinics. However, as patients
may also fail on therapy, it remains important to consider future therapy options, whilst not compromising on potency of the
combination, when starting therapy.
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Viral Load and Protease Inhibitors: The Lower the Better
More data was presented on the importance of treating patients until the viral load
decreases to undetectable levels. Previous studies have shown that baseline viral load correlates with prognosis and that change
in viral load in response to therapy correlates with clinical outcome. This group examined the duration of antiviral response
in a group of 32 patients who had been compliant with their medications, which included ritonavir, and who had developed a rebound
in their viral RNA while on therapy and who had mutations in the protease gene at positions 20, 33, 36, 46, 54, 71, 82, 84,
and 90. The timing of the rebound was defined as the day the viral load increased 0.3 log or more. If there was no initial response
of greater than 0.5 log, the rebound day was defined as the day after initiating therapy, and if the rebound was less than 0.3
log it was defined as the day after the nadir (lowest point). Thirty-one of the patients had the viral nadir within 12 weeks
of initiating therapy. The duration of this effect was not correlated with either baseline RNA level or the amount of initial decline.
There was a strong correlation between duration of effect and nadir level [abstract 603].
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Number of Patients | Viral Nadir (copies/mL) | Duration of Maximum Response (days)
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16 | >1,000 | 60 (+/- 26) |
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9 | 200-1,000 | 102 (+/- 25) |
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7 | <200 | 207 (+/- 81) |
The R2 value of a fitted curve was excellent (0.855). These data suggest that, to
achieve a durable response, it is crucial for the viral load to be reduced to undetectable levels. The explanation may be that when
viral load is incompletely suppressed, resistance mutations occur at a greater frequency -- no replication, no mutation. These
results also suggest that if a new change in therapy is made and the result is incomplete suppression, other combinations/additions
should be sought.
A similar observation of this nadir effect on subsequent durability of response was made by John Mellors in his session on combining
protease inhibitors [no abstract available].
Response to therapy at 12 weeks, was scrutinised dividing study participants into
those who had 1000 or fewer HIV RNA copies/mL at that point and those who had more, as well as those who had 200 or fewer HIV RNA
copies/mL at 12 weeks and those who had more. These groups were tracked through 24 weeks, then the percentage with 200 or fewer
HIV RNA copies/mL was calculated. The results showed that inability to achieve a robust viral load reduction by 12 weeks is a
strong predictor of therapeutic failure.
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HIV RNA at week 12 (copies/mL) | % with HIV RNA <200 copies/mL at week 24 | |
| < = 1000 | 98 p <0.005 |
| > 1000 | 25
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| < = 200 | 93 p=0.036 |
| > 200 | 66 |
Further analysis of this 12-week breakdown and of other ritonavir study results by
Abbott's Dale Kempf, PhD, suggests that viral load should decrease to below 200 copies/mL when protease-inhibitor-naive individuals
begin an antiprotease regimen if they are to achieve a lasting effect. His analysis included 32 persons from three trials,
including the saquinavir/ritonavir study, whose viral load rebounded during treatment. All but one reached their lowest viral load
point by 12 weeks of therapy. The duration of the maximal response correlated strongly with the value at this nadir--the lower
the nadir, the longer the response.
If a patient's viral load does not sink below 200 copies/mL by week 12, Kempf recommended
intensifying the regimen to achieve that goal. That strategy was followed in the saquinavir/ritonavir trial. Seven modest
responders added stavudine (d4T) plus lamivudine (3TC) to the two protease inhibitors after 12 weeks, and the extra antivirals
did drive HIV RNA levels below the 200-copy point in all seven individuals.
Source: healthcg.com & IAPAC
Other investigators have suggested that patients starting with a high viral load,
say > 100,000 copies/mL may take longer that 12 weeks to reach undetectable. There has also been some discussion of an apparent
slower decay in viral load amongst patients who have been infected with HIV for a long time - more than 10 years for example. These
patients may have a larger reservoir of infected cells. Anecdotal reports of slow responders where viral load gradually decays
to undetectable over more than six months do not seem to suggest that these subjects are potential future treatment failures.
The data with adding d4T/3TC to an incompletely suppressive regimen underline the
potential for using viral load to cost effectively provide antiviral therapy viz. Starting with 2 drugs and if viral load is detectable
at week 12 to add a third agent. This approach, and the possibility of withdrawing additional agents after an undetectable
result will require clinical trial validation.
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Resolution AND Reactivation of Opportunistic Infections Following Combination Therapies
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The Impact of Protease Inhibitors on O.I.s
The clinical course of 52 HIV-infected patients with baseline CD4+ cell counts < 50/mm3 who were treated with various antiretroviral combinations including at least one
protease inhibitor was described by Kaspar and colleagues of the David Powell Health Center, Austin, Texas [abstract 358]. Of the
52 patients, 11 achieved a stable re-expansion in CD4+ cell count to > 50/mm3 whereas 41 patients were refractory to combination therapy and had continued CD4+
cell counts < 50/mm3. Both groups were similar in terms of baseline median CD4+ cell counts and plasma
HIV RNA levels, duration of disease, age, gender, and other relevant clinical and demographic variables.
Within the successful CD4+ cell expansion group, one patient (9%) developed a new
opportunistic infection (OI), two patients (18%) were hospitalised, one patient (9%) died, and nine patients (82%) maintained stable
weight and reported feeling well. The corresponding proportions in the group without CD4+ cell reconstitution were 34%, 44%,
25%, and 27%. All of the differences in clinical endpoints between the two groups were statistically significant.
Source: IAPAC
Current recommendations for prophylaxis of opportunistic infections are to use the
lowest
CD4 count an individual had registered prior to any antiretroviral treatment (or
IL-2 administration) to guide the need for prophylaxis. This would seem prudent until further information on the competence of newly
expanded lymphocytes is established.
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Triple Combination Antiviral Therapy as Treatment for Cryptosporidiosis and Microsporidiosis
Clearance of chronic intestinal cryptosporidiosis and microsporidiosis in HIV-infected
patients receiving triple antiretroviral combination therapy including a protease inhibitor was reported by Benhamou and colleagues
of H pital Pitie-Salpetriere, Paris. The study included 15 HIV-infected patients with
chronic cryptosporidiosis or microsporidiosis who were receiving triple combination antiretroviral therapy including indinavir or
ritonavir for a mean of 3.8 months prior to enrolment.
All patients had identifiable Cryptosporidia or Microsporidia in stool for a mean
of 10 months before starting triple combination antiretroviral therapy. Of the 15 patients, 13 had chronic diarrhoea ( > 3 watery
stools/day). Diarrhoea disappeared in 12 patients during combination antiretroviral therapy, and 11 patients (all with microsporidiosis)
had no identifiable parasites on subsequent stool examinations. In patients receiving combination antiretroviral therapy,
the mean increase in body weight was 2.1 kg, the mean CD4+ cell count increased from 56/mm3 at baseline to 115/mm3 (P < 0.01), and the mean HIV RNA level decreased from 312,745 copies/mL at baseline
to 5788 copies/mL (P < 0.05) during follow-up.
Resolution of antibiotic-resistant cryptosporidiosis and microsporidiosis in HIV-infected
patients receiving combination antiretroviral therapy including a protease inhibitor was reported by Carr and colleagues
of St. Vincent's Hospital, Sydney, Australia. A group of 9 patients with diarrhoea caused by cryptosporidiosis or microsporidiosis
(duration, 5-18 months) refractory to antimicrobial therapy were treated with combination antiretroviral therapy including at
least one protease inhibitor.
Diarrhoea improved in all patients within 12 weeks, and the patients ceased all analgesic,
antidiarrhoeal, and antimicrobial therapies. The patients gained a median of 10 kg during follow-up (3-14 months), and
parasites were no longer detectable in the stool in 8 of the 9 patients. During treatment, the median CD4+ cell count increase was
163/mm3, the median CD8+ cell increase was 143/mm3, and the median HIV RNA reduction was 2 logs. The investigators noted that CD8+ cells
mediate host immunity to parasites, and that protease inhibitors, but not reverse transcriptase inhibitors, stimulate reconstitution
of CD8+ cells.
These results are not surprising since Flanigan and colleagues proved in 1992 that
patients whose CD4 counts went above 180 while receiving AZT were able to overcome cryptosporidiosis within one month [Flanigan
et al]. This suggests that improved immune function (a decrease in viral load and an increase in CD4 cells) can help overcome these
parasites. Hopefully, these results will be demonstrated again when data from Phase III triple combination therapy studies
become available.
Resolution of symptoms of crypto & microsporidiosis do not necessarily equate to eradication.
If CD4/immune function declines, the disease may recur. In non-HIV infected adults, however, crypto is a transient diarrhoeal
illness, suggesting in some patients who achieve substantial improvements in immune function, eradication of organisms
may be possible.
Cost effectiveness data reported by several investigators using viral load driven
management of HIV and double or triple therapy underlined the view that whilst pharmacy costs for antivirals may increase, cost
for O.I. drugs are reduced and utilisation of other health care resources (particularly in-patient
care) declines. It is sad that this understanding of the economic value of combination therapy has not yet reached the minds
of many purchasing authorities in the U.K.
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Failure to Prevent CMV-Disease and Reactivation of Subclinical MAI infection with Combination Antiretroviral Therapy
While it is generally thought that potent combination regimens that include a protease
inhibitor and two nucleoside reverse transcriptase inhibitors results in an improvement in CD4+ cell count, drop in viral load,
and decrease in clinical endpoints, results appear not to be so clear regarding the clinical endpoints. Two reports noted that
the improved immunologic activity associated with potent combination therapy actually unmasked clinically significant Mycobacterium
avium complex infection in lymph tissue. Investigators from Vancouver reported five patients, and another group in Boston
reported three patients for whom effective antiretroviral therapy resulted in clinical deterioration manifesting as fever and
lymphadenopathy within three weeks [abstracts 351 & 352].
Two poster presentations reported the failure of a robust immunologic response to
triple antiretroviral therapy to prevent development of cytomegalovirus disease or viraemia. Mark Jacobson from the University of
California, San Francisco, reported on five patients with CD4+ counts below 85 cells/mL receiving a highly suppressive antiretroviral
regimen. CD4+ counts increased to more than 195 cells/mL in all patients. All five developed cytomegalovirus retinitis.
These findings suggest that the CD4 cell increase associated with such regimes may not fully protect against cytomegalovirus retinitis,
and, raise the possibilities that cytomegalovirus retinitis may occur in patients with CD4+ counts significantly higher
that 50 cells/mL [abstract 353].
A group from Paris reported similar findings in 210 patients with a mean CD4+ count
of 37 cells/mL who were treated with a protease inhibitor in combination with nucleoside reverse transcriptase inhibitors. Eight
of these patients developed cytomegalovirus disease or viraemia in a mean time of 37 days from initiation of antiviral therapy.
The authors were concerned that the robust CD4+ count rise associated with the antiretroviral therapy did not offer protection
from cytomegalovirus disease [abstract 354].
While the news was gloomy regarding reactivation of cytomegalovirus and Mycobacterium
avium complex, other investigators reported improvement in clinical conditions that were temporally related to the institution
of highly suppressive antiretroviral therapy. Improvements or resolutions of cryptosporidiosis; progressive multifocal leukoencephalopathy;
wasting; microsporidiosis; and anaemia, leukopenia, and thrombocytopenia were reported. The immunologic improvement
associated with highly suppressive antiretroviral therapy appears to be disease- and/or pathogen-specific. Despite the limitations
of full immunologic reconstitution, the expectation is that the positive clinical benefits would result in a decrease in overall
days of hospitalisation and morbidity [abstracts 355, 356, & 357].
Ref: Flanigan T, Ramratnam B, Graeber C, et al. Prospective trial of paromomycin for
cryptosporidiosis in AIDS. Am J Med 100:370-72, 1992.
Source: IAPAC & healthcg.com
Given that expansion of the immune repertoire does not rapidly occur with therapy,
it is not surprising that new O.I.s continue to occur in some patients emphasising that vigilance must be maintained.
Unmasking of MAI may, however, be seen as a positive sign of increased reactivity within the
immune system. As with TB, many of the clinical symptoms of MAI are produced by the hosts immune reaction to the microorganisms.
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Restoration of Immune Function by Protease Inhibitors may Cause Relapse of Sulpha Allergy
Four patients with AIDS seen for medical care in Boston were admitted for fever of
unknown origin after beginning indinavir 7 to 21 days before presentation. Of interest, all four had required dose reduction or
desensitisation for treatment of a previously documented TMP-SMX drug hypersensitivity reaction. CD4 counts varied between 11 and
480 cells/mL while hospitalised, with one patient experiencing a CD4 cell count increase from 89 to 480 cells/mL within several
weeks of initiating indinavir. All four subjects were found to have TMP-SMX-related drug fevers that resolved within a week on
removal of TMP-SMX and not after stopping indinavir. All four were able to continue Indinavir and were prophylaxed with dapsone
[abstract 535].
Source: healthcg.com
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Immune Reconstitution with Highly Suppressive Antiretrovirals or Interleukins?
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Immune Reconstitution with Triple Therapy
The effects of a potent three-drug antiretroviral regimen on proliferative responses,
delayed type hypersensitivity, and other functional aspects of the immune response were reported in a late breaker session by
Michael Lederman, MD of Case Western Reserve University [abstract LB13].
The study cohort included ZDV-experienced, 3TC- and ritonavir-naive patients with
CD4+ cell counts of 100 to 300/mm3. The patients were treated for 12 weeks with the combination of ZDV, 3TC, and ritonavir.
After 12 weeks of treatment, plasma HIV RNA levels fell a median of 2.8 logs, the median CD4+ cell count rose from 164 to
309/mm3 (P < 0.001), and the median CD8+ cell count rose from 685 to 1000/mm3 (P < 0.001).
After 12 weeks, naive CD4+ cell counts increased from 27 to 54/mm3 (P < 0.001) and memory CD4+ cell counts rose from 80 to 165/mm3 (P < 0.001). Naive CD8+ cell counts increased from 112 to 253/mm3 (P < 0.001) and memory CD8+ cells rose from 287 to 343/mm3 (P = NS).
The proliferation of CD4+ and CD8+ cells co-expressing activation antigen also decreased.
The proportion of CD4+ cells that co-expressed the CD38 and DR activation antigens decreased from 26% to 13% (P < 0.001),
and the proportion of CD8+ cells expressing these same antigens decreased from 60% to 31% after treatment (P < 0.001).
Plasma levels of tumour necrosis factor fell 30% (P < 0.05), and 10 of 33 patients
unresponsive to four skin test antigens developed a single new positive test. In contrast, 2 of 3 patients with an initially positive
skin test lost reactivity.
Ten of 33 patients developed new skin test reactivity to at least one antigen. Lymphoproliferative
responses varied depending on the antigen, but were clearly increased up to three-fold in greater than 40% of patients
to Candida and alloantigens even after 12 weeks of therapy. This study, and several others presented at this conference,
demonstrated that even short-term administration of such P.I. containing triple combinations and the resultant marked suppression
in viral replication can help partially restore normal immune function by increasing both naive and memory T cells, ameliorating
immune cell activation, and enhancing CD4 lymphocyte function. Whether long-term administration and continued suppression of
viral replication can lead to complete restoration of host immune function will require longer-term follow-up. Nevertheless, these
studies are encouraging and suggest that more focused work on intervention for immune reconstitution can take place using combination
antiretroviral therapy.
Source: IAPAC & Healthcg.com
Immune restoration by expansion of peripheral lymphocyte populations requires several
years after bone marrow transplants in leukaemic patients. This is also likely to be true in adults with HIV. Short term changes
in immune function are, however, encouraging.
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Can an HIV Ravaged Immune System Recover from the Viral Carnage -- Even If HIV Were Some Day to Be Shown Eradicable?
Several groups have begun to address this essential question by looking at restoration
of cutaneous anergy, repopulation of naive versus memory T lymphocytes, and CTL proliferation. As CD4+ T cell populations return
as a result of potent antiretroviral (and/or immune-based) therapy, the proportion of naive (CD45RA+) to memory (CD45RO+)
T cells has been reported to be heavily skewed in favour of the RO+ (memory) cells. This is important because memory cells are generally
thought capable of responding only to previously encountered antigen (hence the moniker "memory"), while it is the naive
T cells which are needed to generate an immune response to new invaders. In early analyses of several of the recent protease inhibitor
studies, investigators have reported seeing memory T cell populations return -- with few or no naive cells coming back.
In one research project presented [abstract 369], Mark Connors and his colleagues
documented a preferential loss of naive T-cells in 39 subjects as their CD4 cell counts declined from 500 to fewer than 50 cells/mL.
The Connors team then followed some of these same individuals as they were treated with antiretroviral combinations containing
indinavir, or IL-2 therapy and experienced significant CD4 cell responses. As has been reported by the NIAIDs Clifford Lane (among others), Connors et al. found that these CD4 count increases
only increased the immune repertoire that existed pre-treatment. That is, naive cells that had been lost did not magically reappear.
This was not exactly the answer physicians and their patients want to hear. Perhaps sensing the despair in the audience,
Connors was quick to point out that it is not completely implausible that, over longer-term follow-up, these naive cells might recover.
In a more detailed analysis, the Connors group looked at something called the V-beta
repertoire of HIV-infected persons in varying stages of disease. V-beta is the variable part of the T-cell receptor that recognises
antigen; changes in patterns of V-beta receptor expression reflect diversity of the immunological repertoire. A larger V-beta
repertoire signifies a broader immunological repertoire. Connors et al. found, unsurprisingly, that the depletion of V-beta
subfamilies and the pattern disruption within subfamilies was most pronounced in individuals with advanced HIV disease. In these
individuals (similar to what was seen with naive T cells), V-beta subfamilies that had been depleted where not restored even after
potent antiretroviral treatment or IL-2 therapy. Once again Dr. Connors pointed out that these subjects had been followed usually
less than one year; therefore the possibility exists that recovery of these V-beta subfamilies could occur with prolonged
effective treatment. However, at present it appears that HIV-infected individuals who have increases in their CD4 cell counts may
not have the same immune response repertoire as individuals with the same CD4 count who have not previously decreased to lower
levels.
Author: Joseph J. Eron, Jr., MD.
Source: healthcg.com
These reports underline the importance of initiation of therapy prior to significant
immune damage. It is likely to be easier to maintain a strong immune system than to restore a damaged one.
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Immunotherapy Clinical Trials
With the advent of highly suppressive antiretroviral therapy has come the opportunity
to explore immune reconstitution in patients at various stages of HIV infection and as a result of antiviral therapy itself
or in combination with cytokines or other potential immune restorative approaches.
In a morning session on immunopathogenesis and effects of therapy, a number of presentations
focused on phenotypic and functional immune changes that occur in patients receiving antiretroviral or other therapies.
J.B. Angel and colleagues from the University of Ottawa and Ottawa General Hospital
[abstract 33] studied various cell-mediated immune responses in 43 protease inhibitor na ve HIV-infected patients (CD4+ 100500 cells/mm3) who were treated on a trial of ritonavir plus saquinavir. As expected, CD4 counts
increased from a mean baseline of 270 cells/mm3 to 400 cells/mm3 at 24 weeks, and viral load decreased by a mean of 4.5 logs, with 75% having RNA
copies <200/mL by 24 weeks. Proliferative responses increased above baseline in 17/39 (41%) to HIV p24 antigens and in 30/34 (80%)
to PHA by 24 weeks. Similar increases were seen in PHA-induced IL-2 and LPS-induced IL-12, and increases in LPS-induced IL-10
were seen at 24 weeks, but not at four weeks. Changes in the proportion of cells expressing CD28 was also seen in CD8 cells, but
not in CD4 cells. These data suggest that potent antiretroviral therapy can induce rapid and sustained (i.e., to 24 weeks) changes
in cell-mediated proliferative responses and cytokine induction. Whether full immune restoration will be possible with long-term
suppressive therapy remains to be determined. Of interest was one anecdotal patient who had a fall in proliferative response
to HIV p24 antigen within two weeks of stopping therapy, which correlated with a rebound in HIV viral load.
The dynamics of CD4 helper cell subset reconstitution was evaluated in a group of
20 antiretroviral (ARV)-na ve patients treated with ZDV + ddC and ritonavir and compared to eight untreated
HIV control patients [abstract 34]. Using four-colour flow cytometric phenotypic markers, they were able to follow patients longitudinally
for up to 12 months after initiating therapy. A rapid fall in HIV viral load and an increase in absolute CD4 count were
seen early after starting therapy (day 15). This was accompanied by a marked increase in activated CD4 memory cells (CD45RO+RA-CD25+)
but without CD69+ proliferating cells. This was followed at months four to six by a decrease in the proportion of cells
with high activation markers (e.g., declines in CD25+, CD38+ and DR+ cells) and increases in CD4 + CD28+ cells. After six months
of therapy, increases in CD4 na ve cells (e.g., CD45RA+, 62L+) were seen. This would suggest a multi-phase effect
on CD4 cells beginning with initial mobilisation of mature activated memory CD4 cells soon after cessation of HIV replication,
followed by T cell deactivation and a late, i.e., greater than six-month, increase in na ve CD4 cells in some patients. The effect on CD8 cells remains to be determined.
This study suggests that at least in some patients who achieve good suppression of HIV replication that increases in CD4-na ve populations of cells can occur and perhaps may be sensitised or differentiated
to memory cells. This study has clear implications for the development of strategies for immune reconstitution.
Another study that investigated immune reconstitution in HIV-infected patients was
presented by A. Carr et al. [abstract 35] and explored the effect of intermittent continuous infusion IL2 (CIV-IL2) or subcutaneous
injections of polyethylene glycosylated IL2 (PEG-IL2) on proliferative responses to mitogen, recall antigens or HIV antigens
in 16 patients. Although CD4 counts increased substantially in both IL2-treated groups, no major improvements were seen in proliferation
to any of the antigens at 16, 30, or 48 weeks. In addition, no differences in responses to HIV epitopes were detected
in IL2-treated patients. While these results may suggest a lack of quantifiable improvements in lympho-proliferative responses
to various mitogens or antigens with IL2, we must caution against over-interpretation of these data as baseline stimulation indices
in these patients were higher than typically seen in HIV patients, thus making detection of large improvements in immune function
difficult. Also, the rate of decline of certain responses such as tetanus toxoid was slower in the IL2 arms than in the antiviral
therapy alone arm, suggesting that IL2 may help preserve existing immune function, although it may not restore lost responses,
at least in the short term (less than one year).
Studies reported last year by Fauci et al. suggested that pre-treatment of cells with
interleukin-10 (IL-10), an anti-inflammatory cytokine which also has immunosuppressive activity, could inhibit cellular activation
and induction of HIV replication. The results of a single-dose phase I trial of IL-10 was reported by Weissman et al. [abstract
37] in a small number of HIV-infected patients with 200500 CD4 cells/mm3. Single doses of IL-10 of 1, 10, and 25 mcg/kg of IL-10 were infused into HIV patients
with no adverse clinical effects. Transient decreases in HIV viral load of up to 75%, which peaked at 6 - 12 hours, were seen.
This was paralleled by a decrease in LPS-induced TNF, IL-1, and IL-6 which lasted 2 - 12 hours after infusion. No decrease
in antigen-induced IL-2 secretion was observed. The investigators also reported an intriguing observation that CXCR4 (fusin) expression
on PBMCs was reduced up to 50% transiently after IL-10 infusion. This latter observation may help explain the decrease in
viral spread previously seen in vitro with IL-10 pre-treated cells. Further evaluation of this cytokine are planned. Caution will
need to be observed with this drug as this cytokine is immunosuppressive as well as anti-inflammatory in its effect.
A novel flow cytometricbased means of rapidly quantifying antigen-specific CD4 memory T-cells was described
by Picker et al. from the University of Texas Southwestern [abstract 38]. Their assay approach consists of a short (six-hour)
in vitro antigen stimulation of CD4 cells followed by a multi-parametric flow cytometric detection of CD45 RO+ cells which also
expressed a variety of intracellular cytokines (e.g., gamma interferon, TNF, IL-2 and IL-4). Using this technique, they were able
to identify CMV-specific effector cells which express various combinations of cytokines. Of interest is that expression of cytokines
in HIV-infected patients is not random, with gamma interferon and TNF-producing cells retained in higher frequency than
IL-2 and IL-4 producing cells. These findings will, of course, need to be confirmed in larger numbers of patients and this technology
applied to larger populations in order to determine if these patterns of antigen-specific memory cells have prognostic significance
with regards to risk of infection with various pathogens. Nevertheless, this technique opens the door for possible future
studies to evaluate rapidly and quantitatively the effects of anti-viral and immune-based therapies on pathogen-specific cellular
immunity.
Finally, an evaluation of early T-cell phenotypic changes after primary HIV infection
in three patients was reported by Little et al. from UC San Diego [abstract 39]. Using three-colour flow cytometric analysis,
they were able to show a rapid decline over two weeks prior to seroconversion of CD4 cells and particularly the CD45 RO- (na ve) population. This was followed by a selective loss of memory T cells (CD45 RO+),
cells expressing IL-two receptors (CD25+) and a loss of CD28+ cells. This suggests a selective loss of both functionally mature
(CD 28+) and dividing cells (CD25+). An increase in CD95 (FAS) expression on various CD4 sub-populations also suggests that many
of these cells have been primed for apoptosis. This study suggests a mechanism for the rapid decline in CD4 cells and in immune
function with acute HIV infection. Differences in immunologic response with acute infection or as a result of antiviral therapy
after acute infection may predict how a patient will ultimately respond to HIV infection or to early treatment.
Author: Ronald Mitsuyasu, MD
Source: healthcg.com
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