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Structured Treatment Interruptions
Reported by Mike Youle, MD, Royal Free HIV Clinic, London, UK
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Treatment interruption, stopping therapy pro-term and fixed period intermittent on-off therapy schedules have all been proposed, discussed and to some degree studied over the past couple of years. A number of things about these strategies are clear, much more is less so. When treatment is stopped viral load rebounds usually to around the level pre-treatment and over the next few months CD4 cell counts decline at a variable rate that appears to have little predictability. Some small studies (none randomised) have hinted that this strategy is more successful in those people who were treated at seroconversion and that the further along in HIV disease you go the more risky interrupting therapy that has suppressed HIV, will be. Tantalizing data, first shown at the 8th European Conference on Clinical Aspects and Therapy in HIV in Athens in October 2001 appeared in the Giga-HAART study, from Christine Katlama's group in Paris. This was the first controlled data to build on work by our group, that of Steve Deeks from UCSF and of Veronica Miller formerly of Frankfurt that showed that potential benefits existed in short term treatment interruptions in salvage patients who then recommenced a new regimen.
(editorial note:interim results from the Giga-HAART study showed patients who interrupted therapy for 8 weeks prior to starting a potent salvage 8-drug regimen had better viral load reductions than patients who switched immediately to the potent regimen without taking an interruption. These results are relatively short-term, about 24 weeks. Researchers continue to follow these patients. Will the benefits hold up over the longer-term? Will resistance emerge? The idea for this concept is that perhaps viruses with drug resistance became more sensitive to drugs during the interruption; perhaps the drug resistance became less noticeable to the drugs. But it is felt by many resistance researchers that even if the drug resistance is low or fades to the background during interruption, resistance is still there behind the surface. And it may resurface after time. Katlama reported tolerability was ok. Median CD4 count was 27 and viral load over 100,000 prior to the interruption or therapy change. This approach to using an interruption needs further research.
Several studies have found that drug resistance can develop in time after interruptions in a certain percentage of patients. The risk for developing resistance remains not well characterized. There are additional questions that need answers relating to other potential negative consequences that may result from an interruption or sequential STIs. Is there a risk that results from repopulating viral reservoirs such as the brain or CSF, as discussed below. As reported in a Retrovirus report for NATAP on immunology by David Margolis, Douek reported at Retrovirus (LB7) that during interruption he found HIV infected a percentage of HIV specific CD4 memory cells. Stopping therapy when CD4s are so low can be risky. The results from the EuroSida study, discussed below, suggest that there may be an independent benefit in terms of disease progression just by being on therapy, regardless of CD4 count or viral load. The potential benefit from interrupting therapy is that perhaps metabolic abnormalities (cholesterol, tryglycerides, sugar) may improve. Body changes might improve. Interruptions offer a break from the hardship of constant adherence. Further research is needed. Can these potential benefits and risks related to interruptions be balanced? Further research is ongoing to explore this).
So this conference was always going to be a forum for synthesizing new data into the idea that interruption of antiviral suppression may be a double-edged sword. What you gain by lower toxicity and lack of pills may be offset by physical and laboratory changes showing that HIV was once more attacking the immune system. The fundamental question of course still stands, do you gain any delay in disease progression by treatment that is not available if you delay treatment until the risk of disease occurrence is higher. So the "Treat now or Treat later" discussion is intricately linked to the question of treatment interruption. An in depth meeting convened by The Forum for Collaborative Research will be held later this month in Montreal to discuss the multifarious aspects of treatment interruption. In addition there is now a large clinical endpoint study called Optima that will examine 1300 patients who are 3 class failures and who will be randomised to have a 3-6 month treatment interruption versus immediate switch to a salvage regimen (similar to the giga-HAART approach). Also they will be randomised to take standard 3 -drug optimised HAART regimen or a Mega-HAART 5 or more drug regimen. This trial is now open to recruitment in the US through VA hospitals, across Canada and the UK and should provide some more definitive answer as to the utility of this approach in later stage disease.
More information can be obtained at the following website www.optimatrial.org.
Does an Interruption Encourage Risk For Neurocognitive Dysfunction
So overall there were twenty-six presentations on this topic of STIs, including two late-breakers in Seattle. They fell into a number of subject groups. The first were those that examined the effects on the viral populations and immune function in different tissues when treatment was ceased. Andrew Leigh Brown from the University of Edinburgh worked with a group from UCSD led by Ellis to examine the dynamics of viral rebound in the cerebrospinal fluid (CSF) [49, 62].
(editorial note: Ellis reported in oral abstract 49 on 12 patients who had undetectable HIV viral load or had HIV above 400 copies/ml and then initiated an STI (treatment interruption). Their average Cd4 before interruption was 280. They had HIV for an estimated average of 5.5 years and were on their current regimen on average about 9.5 months. 6 patients had been exposed to 3 classes of HIV drugs, and 4 of the patients had been exposed to 2 classes of drugs. A series of lumbar punctures were taken on the patients. Ellis showed a representative patient whose HIV viral load in the plasma (blood) increased significantly about 10 days after stopping therapy and viral load in the CSF increased significantly about 10 days later. The patterns of rebound in CSF and plasma varied among the responses of patients which he showed. Viral load increased sometimes sooner than within 10 days and sometimes it took 20 days or longer. But in most cases he discussed viral load in CSF tended to significantly rebound to high levels shortly after the viral load rebound in plasma. He described one patient whose CSF & plasma viral load did not appreciably increase with followup of up to 100 days after the interruption.
Ellis offered the following conclusions. Among patients with established or chronic HIV infection (greater than 1 year), viral rebound in the CSF is the rule rather than the exception. CSF plasma rebound typically follows plasma. Future studies need to determine if CSF viral rebound during an STI increases subsequent risk for neurocognitive decline).
In two of nine patients studied where sufficient data points were available (understandably repeat lumbar punctures are not popular with patients), these was a difference between CSF and plasma viral kinetics. A rise in white cells (pleocytosis) in 4 subjects was seen following the viral burst (viral load increase in the CSF following treatment interruption) in the CSF suggesting that this is a response rather than a cause of viral turnover in the central nervous system. This work also appears to shed light on the issue that reducing viremia systemically may limit the entry of lymphocytes and linked virus into the CSF.
Further work to evaluate the source of virus when treatment is suspended came from the group of Lydia Ruiz and Martinez-Picardo in Badalona, Spain. They extensively examined the env sequences for 12 subjects over up to 4 sequential structured treatment interruptions (SSTI) [50]. Genetic analysis were performed for stretches of the genome for the envelope of the virus in DNA, plasma RNA and PBMC's. In some patients there was little shift in the genetic structure of emerging populations whilst in other there was a marked alteration. This may limit the ability of treatment interruptions to strengthen the HIV-specific cell-mediated immune responses since the exposed viral antigens keep changing during each SSTI. A single subject was more extensively studied and examination of plasma samples revealed that the HIV populations that emerged over successive interruptions probably reflect a combination of reactivation of archived populations and ongoing selection due to the effect of cytotoxic T-lymphocyte responses [531-M]. The role of neutralising antibodies in treatment interruptions was examined by a group of investigators working on the Swiss Spanish Intermittent Therapy Trial, where subjects had four cycles of 2 weeks off/8 weeks on therapy [243-T]. In 10 subjects at week 2 and 25 subjects after week 42 virus was isolated from PBMC's and examined for replicative capacity and for neutralising antibodies. Although neutralising antibody levels did not increase over the cycles of the study during the 4-6 treatment free period after the 4 cycles there was a significant increase in these antibodies (90% inhibition titres >1/1000). This occurred especially in the subgroup of subjects who had maintained control of viraemia throughout the study.
Risk of HIV Progression in Therapy Interruptions in EuroSIDA Patients Group
written by Jules Levin and Mike Youle
Next were those studies that evaluated the effects of treatment interruption of 3 months or more on the progression of disease in prospective studies in patients who either interrupted or did not interrupt therapy. The largest of these came form the EuroSIDA cohort that represents large clinical centres across Europe and is a long established study that has been prospectively followed for many years [48]. This study received much attention and discussion by attendees at the Conference.
8,530 patients are followed in EuroSIDA. Jens Lundgren from Copenhagen presented data on 565 (16%) subjects who interrupted therapy in a cohort of 5385 patients representing 15,312 person years of follow up after commencing HAART up to the first interruption or last followup visit. There were 10,637 person years of followup from the start of HAART to the first new AIDS event/death or last followup visit, to assess the risk of disease progression.
Characteristics of the patients when they started HAART. 80% were male; average age 37; transmission risk: 48% MSM, 24% hetrosexual; HIV viral load 25,000; CD4 count 200; nadir (lowest ever) CD4 count 138; 31% previously had AIDS; on average patients started HAART in March 1997 (October 1996 through December 1998. Over the course of 60 months the number of patients interrupting therapy increased.
By the 60 month time point a total of 20% of patients had interrupted therapy.
What were the risk factors for patients who interrupted therapy? More females than men interrupted therapy (p=0.02). More IVDUs interrupted therapy than MSM (P<0.001). Patients from South (p<0.001) or Eastern Europe (p=0.005) tended to interrupt less frequently than patients from Central or Northern Europe. Patients tended to interrupt therapy the longer they were on therapy (p<0.001), with a 30% increase per calendar year. Patients with higher viral load on HAART tended to interrupt therapy more often (p<0.001). If a patient previously had AIDS that did not seem to indicate a propensity to interrupt therapy. Patients with higher CD4s tended to interrupt therapy (p=0.07).
At the time of interruption the median CD4 cell count was 228 and viral load was 4000. Patients lost about 30 cells on average over the first three months following the interruption. Viral load increased on average about 1 log during the first 3 months.
What is the pattern of disease progression observed (patients taking interruptions of 3 months or more)? There were 408 clinical events for patients while on HAART and 37 for patients off HAART. The death rate was 25% for the patients on HAART and was about 37% for patients off HAART. NHL was mentioned as occurring more often for patients on HAART. For patients off HAART pulmonary TB, PCP, and esophogeal candidiasis occurred. At the time of these events the average CD4 count was 111 in the on HAART group (23-239), and 23% of the events occurred when CD4s were above 250. Average viral load was 8000 (400 to 126,000). The average CD4 count off HAART when events occurred was 52 (12-120). The maximum CD4 count at which an event occurred was 250. Average viral load was 158,000 (20,000 to 500,000).
What was the incidence of clinical disease progression (interruptions of 3 months or more)? The rate (number of new AIDS events or deaths per 100 person years of followup) for patients who interrupted therapy was 20.3 (37/182) vs 3.9 (408/1054). Patients with less than 50 CD4s had a dramatically worse rate of disease progression to AIDS or death (80 [14/18] vs 35.5 [117/331), if they were off HAART. This suggests that being on HAART had a benefit regardless of CD4 count. For patients with 50-199 CD4s cells on their latest blood test, the rate of disease progression was also greater for patients off HAART (32.3 [18/56] vs 7.3 [163/2241]). Again, this suggests an independent benefit from being on HAART regardless of CD4 count. Interestingly, for patients with more than 200 CD4s there did not appear to be a difference in disease progression whether they took an interruption or stayed on HAART (2.8 rate for interrupters vs 1.6 rate when staying on HAART). This suggests that an interruption may be safer if CD4s are higher. This question is a controversial bone of contention. Some doctors feel it is relatively safe to take an interruption if CD4s are high enough. They fel if CD4s are too low a patient should be placed on prophylaxis medication of opportunistic infections. Other doctors feel an interruption is risky even if CD4s are higher. The uncertainties about what happened during an interruption concern them. As seen in the Ellis study, viral load in the CSF increases significantly during an interruption. It is assumed that viral load increases in many parts of the body and reservoirs after an interruption. The long-term effects of re-populating reservoirs with HIV and the gyrations in viral load in reservoirs are unknown. Will this wear out the immune system and reduce its long-term ability to control HIV? No one knows the answer to this question.
Lundgren reported that age, being off HAART, and having had previous AIDS diagnosis was associated with a hazard for experiencing an AIDS event or death. The risk of death/AIDS was increased 5-fold if a patient was off HAART, and was the greatest risk factor for AIDS/death. A lower CD4 count and a higher viral load were also associated with risk for developing AIDS/death whether the patient was on or off HAART. But the risk was greater if the patient was off HAART. I think Lundgren said risk of progression decreased if patient re-initiated therapy. I think Lundgren reported that 45% of patients reinitiated therapy.
Lungren mentioned the limitations of his study. The interruptions were not structured therapy interruptions. Their may be some biased reasons why some patients interrupted therapy. For example, a patient may have been terminally ill. The implications from taking interruptions of less than 3 months were not studied. He summarized that the risk of interruptions in this study were closely linked to the latest CD4 count. Interruption is risky if you have a low CD4 count. Interruption does not appear unsafe id CD4s do not fall below 200/250. HAART appears to have a benefit not explained by its effect on CD4s and viral load. And this benefit disappears once you stop drugs, so Lundgren raised concern about interrupting therapy in patients with low CD4s and high viral load.
One observation I had from this study not mentioned was regarding the 20% rate of patients interrupting therapy. This reflects how many patients may be taking interruptions. I suspect many patients do not consult with their doctor before interrupting therapy. These numbers also reflect the difficulty some patients may experience in staying on their therapy or maintaining good adherence.
Lampe and co-workers followed all 237 people from the Royal Free Hospital Clinic who were naive to antiretrovirals when they started a HAART regimen and who reached a viral load < 400 copies/mL (within 32 weeks) or who reached a viral load < 50 copies/ml without viral rebound [536-M]. Twenty one percent of subjects were female; main HIV exposures were homosexual (60%) and heterosexual (34%) sex. The median age at start of HAART was 35 years. HAART was started on a median date of Dec 98 (IQR Sep 96 - Nov 00). Baseline median (IQR) viral load was 5.3 (4.8 - 5.7) log copies/mL and CD4 count 193 (75 - 302). Nucleoside drugs in the initial regimen were zidovudine/3TC 126 (53%), stavudine/3TC 76 (32%) and other 35 (15%). Other drugs were nevirapine 58 (25%), efavirenz 44 (19%), indinavir 56 (24%), ritonavir 21 (9%), nelfinavir 50 (21%) and ritonavir boosted PI 29 (12%).
Median time from start of HAART to first measured value 50 copies/ml was 180 days. 1342 viral load measures were made over a total 347 person-years of follow-up after the first viral load < 50 cps/ml - a median of one measure per 13.5 weeks (median over all patients of 3.8 per year). Maximum follow-up was 4.4 years. Overall 13 people (5.4%) experienced viral rebound (break-through) on therapy (rate 0.037 per person-year) representing one person with viral rebound per 26.7 person-years of follow-up. There was a (non-significant) trend towards lower rebound rate with increasing time from start of HAART.
The Badalona group also presented a prospective study randomised subjects with multiple exposure to antiretrovirals to a 3 month treatment interruption or an immediate switch to a new salvage regimen that consisted of Lopinavir/ritonavir plus saquinavir soft-gel, 3TC, DDI and abacavir [421-W]. In the 22 subjects who had the treatment interruption (Group A) 13 (64%) showed a reversion to wild-type virus during this period, perhaps raising the question as to whether the period off treatment was long-enough. The outcomes, in this group, were compared to the 24 subjects from Group B who had an immediate switch to the salvage regimen. They showed no significant differences. Within 3 months after restarting therapy the CD4 count in this group was about the same as the patients who did not take a break in therapy. Longer-term follow-up in greater numbers of patients may however be required to show such differences. The other major Catalan research group of Jose Gatell evaluated the use of mycophenalate mofetil (MMF) and the cytostatic drug hydroxyurea in groups of patients who had started HAART close to seroconversion [534-M, 535M]. These were small studies 15 and 20 patients respectively but did show that blunting of viral load rebound occurred under both agents that appeared not to be related to decrease in cell turnover or from increase in apoptosis. Further larger studies would be valuable for each of these agents perhaps combined with another approach.
Therapeutic vaccination to maintain the benefits accrued during antiretroviral therapy has become an area of intense interest with several studies currently reaching a degree of fruition. For instance, the Quest study is currently evaluating the utility of a Canarypox vaccine, Remune, or both prior to cessation of HAART in subjects who have been treated just after seroconversion. The group of Franco Lori and Juliana Lisziewicz presented data evaluating the utility of a novel topical DNA immunisation (DermaVir) in preventing viral rebound during treatment interruptions in macaques [312-W]. Ten animals with late-stage AIDS were studied and randomised to continuous HAART, STI-HAART (3 weeks on 3 weeks off) and after 6 cycles were also given DermaVir (a composition of HIV DNA plus Langerhans cell stimulant called polyethylenimine-mannose designed to stimulate recognition of the DNA by the animals immune system). All the macaques on HAART alone were dead by month 7 whereas only one on STI-HAART had succumbed. Of the 3 monkeys who were then treated with DermaVir median viral load decrease during each subsequent interruption occurred until control at <200copies/mL was achieved. Clearly if this were possible to replicate in humans it would be highly significant and could open the door to combination HAART and immunotherapy combination studies.
Other studies also seemed to suggest this trend with different vaccinations. A NIH study using NYVAC-SIV in macaques showed similar blunting of viral rebound in immunised animals versus controls [313-W]. A pilot study nested within a Remune protocol evaluated the rise in viral RNA in subjects who stopped therapy for 6 weeks after suppressing to undetectable for at least 6 months [314-W]. In the 20 Remune patients the slope of the rise was 0.16log10copies/mL versus 0.21 in the 8 control subject who were only treated with the adjuvant IFA (p<0.05). The difference between the post interruption viral load level between the groups was not significant but the numbers of patients in the study precluded this being properly evaluated.
So many approaches are being taken to the Treatment Interruption scenario, using HAART, immunotherapy, cytostatic treatments and immune enhancing agents. This once again suggests that a combination of different interventions may be the best way to continue to support the inherent immune response to HIV.
Additional information on STIs reported at the Conference
Douek and colleagues from the NIH Vaccine Research Center added a cautionary
note about therapy interruptions (abstr. LB7). They identified populations
of T cells responding (i.e. producing interferon gamma) to either HIV
antigens or (as a control) CMV antigens, and sorted these cells by flow
cytometry in patients during a treatment interruption. Then using a novel
PCR technique, they compared the amount of proviral HIV DNA within the two
cell populations. The proportion of either population that was infected, as
evidenced by the presence of HIV DNA within them, was low. However,
HIV-specific memory CD4 cells were significantly more likely to be infected.
This could be looked at as bad news, or no news. In responding to sites of
HIV replication, like a firefighter these cells place themselves at risk.
Douek concluded that this phenomenon of HIV specifically infecting the very
cells that responds to it adds a cautionary note to the practice of STIs.
The overall question that remains to be answered is whether HIV replication
can be controlled by novel strategies that pairs cycles of antiviral therapy
with cycles of immunotherapy, or whether slow but relentless infection of
responding antiviral cells eventually erodes the immune response. Research
so far has shown no evidence that therapy interruptions in persons
chronically infected with HIV results in improved control of HIV when off
HAART. Current studies continue to examine whether a drug holiday before
initiation of salvage therapy improves response, whether early treatment
within the first few months of therapy allows treatment of limited duration
with better control of HIV replication, or whether immunotherapies such as
HIV vaccines given during HAART allow HAART interruption with better control
of viral replication. This study illustrates at the single-cell level, the
cost of unrestrained viral replication resulting from an interruption.
Two additional articles add cautionary notes about treatment interruptions.
If a patient takes repeated interruptions obviously over time their average
viral load will increase and their average CD4 count will decline. The
studies below take a broad view cautioning about risks associated with this.
Total HIV Viral Load Over Time Predicts Death & AIDS Events
In an interesting study from the Swiss HIV Cohort Study (Eggar, abstract
471-M), researchers looked at the amount of viral load a patient has over
time and how that might predict disease progression. Eggar examined the area
under the viral load curve (AUC) as a measure of average viral burden and
assessed its value as a predictor of clinical progression. They also examined
cumulative drug exposure. A total of 2,324 patients who started HAART between
Sept 1, 1995, and Nov 30, 1998, who had a CD4 count and viral- load
measurement within 3 months before starting HAART and at least one follow- up
visit were included. The median viral burden over time was log 2.80 (630
copies/ml) copies (interquartile range 2.67 to 3.37).
The risk of progression to a new AIDS event or death was strongly related to
viral burden over time. Kaplan- Meier probabilities at 5 years were:
--7.2% for patients with viral burdens of less than 3.0 log copies/ ml per
year,
--20.6% for viral burdens of 3.0 log to 3.99 log,
--38.7% for viral burdens of 4.0 log to 4.99 log and
--79.1% for patients with viral burdens of 5 log or greater
Baseline CD4 cell count, a history of IVDU, and older age also predicted
disease progression, but baseline viral load, clinical stage, treatment
history, and sex did not. Drug exposure increased with increasing viral
burden.
Viral burden over time was a stronger determinant of clinical progression
than viral response in the first year after initiating HAART. Kaplan- Meier
probabilities at 5 years:
--11.0% for patients who achieved and maintained undetectable viral loads,
--15.9% for patients who achieved undetectable concentrations but had a viral
rebound,
--51.5% for patients who never achieved undetectable concentrations.
Probability of Progression to New AIDS Event or Death, using Kaplan-Meier
curves:
--22 times greater if average viral load was 100,000 or higher compare to 0
to 2.9 log (1000 copies)
--6.5 times if average viral load was 10,000 to 100,000, compared to 0 to 2.9
log
--3.3 times greater if average viral load was 1,000 to 10,000, compared to
0-2.9 log
Long-Term Affect of Therapy Interruptions On Average Cd4 Counts and Viral
Load
Over 2000 patients in the Swiss HIV Cohort study were analyzed over 4 years
to see how interruptions affected their CD4 count and viral load over time
(Kaufmann, LB8). They looked at patients who either took or did not take
interruptions, after starting HAART in 1996/1997. After 4 years, researchers
found that 64% had <400 copies/ml of viral load, but only 50% on patients who
interrupted therapy had undetectable viral load compared to 82% of patients
who did not interrupt therapy. Average CD4 increased from 200 before therapy
to 357. But again, CD4 increased only to 300 in patients who interrupted
therapy compared to 420 for patients who did not interrupt therapy. After 4
years patients who interrupted therapy were more likely to have less than 200
CD4s and less likely to have greater than 500 CD4, compared to patients who
did not interrupt therapy. 47% of patients who did not interrupt therapt vs
24% who interrupted therapy had greater than 500 CD4s. CD4 counts remained
below 200 in 6% of patients who did not interrupt therapy vs 29% of patients
who interrupted therapy. These differences were all statistically
significant.
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