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8th Annual Retrovirus Conference |
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Highlights about Treatment Interruptions in HIV/AIDS
By Harvey S. Bartnof, MD
Dr. Bartnof is Staff Physician at AVERI, the AIDS Virus Education and Research Institute.
There were 22 presentations at the 8th Annual Retrovirus Conference that addressed treatment interruptions in HIV/AIDS, including one oral session about the topic. Treatment interruption strategies should be considered highly experimental and risky due to the potential for developing drug resistance in some cellular or organ compartments, reseeding immune system reservoirs with newly rebounded HIV, acute HIV symptoms, and a decrease in the CD4 count that can lead to life-threatening AIDS opportunistic conditions. Currently, treatment interruptions are best performed in the research setting. No patient should stop treatment for HIV until he/she has discussed the issue with a knowledgeable HIV/AIDS physician. The reports about treatment interruptions can be divided into 3 general categories:
Treatment interruptions have several names and readers need to be careful about the specifics when attempting to understand these reports. The most common name is STI or Structured (also Strategic or Supervised, planned) Treatment Interruption(s). Another is SIT or Structured Intermittent Therapy, which refers to stopping and starting treatment at regular time intervals, without regard to viral loads or CD4 counts. Due to a similar strategy that is used to treat certain cancers, this approach also has been called "pulse" therapy. Another specific is whether the report represents observations after interrupting therapy once ("discontinued") or several sequential STIs separated by periods when treatment was restarted. Lastly, an important consideration is that almost all of these reports represent very small numbers of patients that make it difficult to apply the results to all patients.
| PART I: STI After HAART Was Started During Primary HIV Infection (PHI) | |||
| 1st presentation > | 2nd presentation > | 3rd presentation > | 4th presentation > |
There were four presentations that addressed this topic and they included only a total of 49 patients: this precludes broad conclusions and applicability to other patients. Some generalizations about these studies are:
1st
presentation
During his "State-of-the-Art" lecture about
STIs, Bruce Walker, MD of Harvard Medical School in Boston, Massachusetts first
reviewed the potential benefits of treatment
interruptions for HIV infection. They include: to improve immune responses to
HIV; to decrease toxicities associated with HAART; and to "repopulate"
with drug-sensitive HIV. (This third goal applies to situation "III"
above, when there is drug-resistant, detectable virus.)
Dr. Walker presented an update about 14 patients enrolled in their study. When first diagnosed with PHI, they had a very high mean viral load of 7 log (10 million) copies per milliliter. The mean duration of HAART before STI was approximately 18 months, with a range of 9 months to 3 years. The study protocol included restarting HAART if, during the STI, the viral load increased to greater than 50,000 copies per milliliter once or to greater than 5,000 copies per milliliter for three consecutive weeks.
The results were that, after one STI, 46% of the patients spontaneously "controlled" HIV with an undetectable viral load for a minimum duration of over 2 months, up to a maximum of approximately 15 months. Control was achieved after an initial increase in viral load that spontaneously decreased. This meant that the other half of patients did not control HIV during the first STI and had viral rebound that did not spontaneously decrease. However, this group of six patients had enhanced control of HIV after the second STI. This is shown by a 5-fold increase in the mean time they were able to be off HAART, when comparing the second STI (184 days or approximately 6 months) to the first STI (36 days or 1 month). Five of those six patients showed a significant increase in duration of HIV control (the sixth had approximately the same). Dr. Walker also reported that the magnitude and breadth of the immune response to HIV in those patients had increased significantly during the second STI, when compared to the first. Those responses were "CTL" (cytotoxic [cell-killing]) CD8 lymphocyte responses. However, two of those patients did have late viral rebound during the second STI, occurring as late as approximately 10 months into the second STI.
One of the three patients on their third STI has a viral load of 2,150 copies per milliliter after almost 5 months. (The other two patients have only had a third STI duration of two days.) One of the 14 patients has had a fourth STI of almost five months duration, with a viral load of 7,445 copies per milliliter. These 14 patients will be followed for additional observations.
Regarding starting HAART during PHI, Dr. Walker then reviewed several lines of reasoning as to why early treatment with HAART may provide significant benefits for patients, with or without subsequent STIs. First, 8 research groups have shown that decreasing the HIV viral load in PHI is associated with improved T helper cell (lymphocyte) responses against HIV, when compared to no treatment at that time or to starting treatment later. Other benefits Dr. Walker discussed included comparing patients who started HAART during PHI versus starting during chronic infection. Those include an increased magnitude of immune responses (measured by a "stimulation index" of CD8 cells against HIV "gag" [core protein] in the laboratory) and the breadth of CTL responses against HIV. Also, he emphasized that there is much less HIV viral diversity in PHI or early infection than in chronic infection. Early treatment would hinder HIV's becoming more diverse (increased "quasispecies"), and a less diverse virus would be easier to control by the immune system.
Dr. Walker ended his talk with nine conclusions about treating HIV during PHI and subsequent STI(s):
Dr. Walker then listed 10 key questions about STI for current research:
2nd
presentation
Martin Markowitz,
MD of the Aaron Diamond AIDS Research Center in New York presented an update
of 15 HIV patients who stopped HAART (treatment cessation or one STI) after
2.6-5.0 years of uninterrupted therapy and suppressed HIV. All patients had
started HAART during or shortly after primary HIV infection (PHI). Ten of the
patients (2/3) also received four injections of an experimental HIV vaccine
("ALVAC vCP1452, recombinant canarypox" vaccine with four HIV genes
along with an HIV recombinant "gp160" component). The injections were
given into the muscle at time zero, days 30, 90 and 180.
The mean duration between first PHI symptoms and starting HAART was 65 days. Before HAART was started, the mean baseline HIV viral load was 4.7 log (50,118) copies per milliliter, with a mean CD4 count of 542 cells per microliter. At the time of starting the STI, the mean HAART duration was 39 months, while the mean CD4 count was 829 cells per microliter, representing an increase of 287 cells per microliter. The HIV RNA was undetectable with a lower limit of 50 copies per milliliter. However, one annual episode of detectable viral load was permitted for enrollment.
The results were as follows. After starting the STI, all patients had viral rebound that occurred within a mean of 26 days. The viral doubling time (time until the HIV viral load doubled) was 2.2 days, leading to a mean peak viremia of 4.3 log (19,950) that spontaneously decreased to a mean of 2.9 (794) log copies per milliliter. That spontaneous decrease was associated with improved immune responses to HIV (increased "stimulation index" and "CTL" response, see Walker report above). The total mean time of the STI (off therapy) was 9.2 months for the 15 patients, with a mean CD4 cell decrease of 231 cells per microliter and a mean resulting viral load of 4 log (10,000) copies per milliliter. During the STI, three of 15 (20%) patients had spontaneous control of HIV with a lower limit of 500 copies per milliliter. Interestingly, two of those three patients were "heterozygous for CCR5 delta-32" (mutation associated with more benign HIV disease course). However, the total follow-up of each of those three patients was only 3 months. The other 12 patients have remained with persistent HIV viremia during the STI, and their CD4 count increases while taking HAART were lost entirely during the STI. Seven of 15 (47%) decided to restart HAART. There were no differences between those who did and did not receive the therapeutic vaccine injections. The authors concluded that one STI (treatment cessation) after starting HAART during or shortly after PHI, with or without the ALVAC therapeutic vaccine, did not lead to an undetectable viral load for the majority (80%) of the patients.
3rd
presentation
A third presentation
about STI after HAART was started during or up to 5.5 months after PHI was presented
by P. Hermans, MD of CHU in Gent, Belgium. Dr. Hermans described 13 patients
(23% women, 7% African) who were followed prospectively. Before HAART, the median
CD4 count was 735 cells per microliter, with a median viral load of 4.5 log
(31,622) copies per milliliter. In the study, anti-HIV therapy was to be restarted
if the viral load increased to greater than 10,000 copies per milliliter. Before
the STI, the median duration of viral load undetectability (limit 400 copies
per milliliter) was 18 months (range 4 to 37). At least six had an undetectable
load with a lower limit of 50 copies per milliliter. Note that 31% of the patients
were only taking two NRTI drugs (AZT [zidovudine, Retrovir] plus ddI [didanosine,
Videx]), meaning a non-HAART regimen. Prior to the STI, the median CD4 count
was 917 cells per microliter.
The results at the oral presentation were as follows. During the STI, there was a rapid decrease in CD4 cell counts, while CD8 cell counts ("suppressor/cytotoxic [cell-killing]") increased. After a mean STI follow-up of 8.6 months (longest 34 months), the viral load rebounded to a mean of 3.5 log (3,160) copies per milliliter. Interestingly, 5 of them (38%) controlled HIV with an undetectable viral load (limit 400 copies per milliliter) either without rebound or with rebound and subsequent suppression. Three of those five had an undetectable load with a lower limit of 50 copies per milliliter and included the one patient with 34 months of follow-up. Among the remaining 62% who had viral rebound, the mean load was 4.4 log (25,118) copies per milliliter after a mean follow-up of approximately 5 months. At least 6 patients restarted anti-HIV therapy due to viral rebound and/or CD4 count decreases, and resuppressed virus to less than 50 copies per milliliter. Dr. Hermans reported that those who had viral rebound during the STI tended to have a higher percentage of lymphocytes with immune "activation markers" ("CD8+DR+") pre-STI than those who did not rebound. Several other pre-STI factors were found to be unrelated to viral control during the STI, including CD4 cell count, CD4/CD8 cell ratio, duration of viral suppression, and whether patients were taking HAART or non-HAART regimens.
Dr. Hermans concluded, "Virological control defined as [viral load less than] 1,000 [copies per milliliter] is therefore achievable in 30-40% of PHI treated patients after stopping [anti-HIV] therapy." Also, "activation markers" as a predictive factor for viral suppression during STI should be investigated further. In addition, restarting HAART after an STI "should be delayed until at least two consecutive values of viral load above a certain value is reached (to be defined), but [a] viral load less than 1,000 copies per milliliter at six months off therapy could be considered as a valuable end-point." Lastly, Dr. Hermans concluded that their 40% rate of viral undetectability is significantly higher than the 5% [or lower] rate of spontaneous viral suppression to less than 1,000 copies per milliliter ["viral set-point"] without any treatment [as in "long-term non-progressors"].
4th
Presentation
The fourth presentation
about STI after HAART was started during or shortly after PHI was authored by
J.M. Miro, MD of the University of Barcelona in Spain. The interim results of
seven patients (14% women) were presented. For enrollment, the initial HAART
regimen must have led to an undetectable viral load (limit 20 copies per milliliter)
and a CD4 count greater than 500 cells per microliter for at least 12 months.
The study will then incorporate three STIs, each 8 weeks long, and will be separated
by 2-4 months of restarted HAART. After the third STI, HAART would not be restarted
if the CD4 count remained greater than 500 cells per microliter and the viral
load was less than 5,000 copies per milliliter. The second and third STI would
not take place if HIV were not resuppressed to an undetectable level (limit
20 copies per milliliter).
The 7 patients were started on HAART after a median of 10 weeks of first presenting with PHI symptoms ("flu"-like illness). Before HAART, the median CD4 count was 526 cells per microliter, with a median HIV RNA of 5.1 log (127,000) copies per milliliter. Before the STI, HAART was taken for a median of 24 months. The median CD4 count had increased to 886 cells per microliter with an undetectable viral load (limit 20 copies per milliliter).
The interim results were as follows for the seven enrolled patients who completed two STIs. During the first STI, all had HIV RNA rebound to a median peak of 4.6 log (37,000) copies per milliliter after two weeks; this was associated with a decrease in the CD4 count. Thereafter, two of them spontaneously decreased their viral load to an undetectable level (limit 200 copies per milliliter) and a third had greater than a 1-log copies per milliliter decrease. Any detectable viral load was resuppressed to an undetectable level when HAART was restarted. During the second STI, viral rebound again recurred in all patients. Yet, three of the seven patients (42%) then had a spontaneous decrease during the second STI.
Dr. Miro reported that during the first STI, "lymphoproliferative responses" (LPR) among CD4 cells directed against HIV developed in four patients; no LPR were detected prior to the first STI. The three patients who had a spontaneous HIV RNA decrease during the first STI were among those four patients who developed LPR against HIV. Also, two of four patients tested developed CD8 cell CTL (see Walker report above) responses against HIV during the first STI. In addition, Dr. Miro reported that no genotypic resistance was detected during the first two STIs. The researchers are planning to add interleukin-2 (IL-2, Proleukin) injections to the treatment regimen for the next group of seven patients in attempt to increase immune responses against HIV. However, a low dose of 750,000 units per square meter daily will be used.
| Part II: STI After HAART Was Started During Chronic Infection |
Largest
STI Study
Most of the reports about STIs fall into this category. C. Fagard, MD presented
an update of the largest STI trial, the
SSITT (Swiss-Spanish Intermittent Treatment Trial) with 128 patients (31% women).
In this study, patients must have had persistent viral undetectability (limit
50 copies per milliliter) for at least 6 months on HAART, without any prior
anti-HIV therapy. All were required to be naïve to the NNRTI (non-nucleoside
reverse transcriptase inhibitor) drug class. The study calls for 4
successive STIs, each 2 weeks long, and each followed by 2 months of restarted
HAART. At the end of those 4 cycles (40 weeks), HAART will be discontinued
for 12 weeks. Study endpoints at that time (one year into the study) will include
the percentage of patients who maintain a viral load less than 3.7 log (5,000)
copies per milliliter, the amplitudes of viral rebound during the 4 STIs, and
CD4 count changes.
Half of enrolled patients had a nadir (lowest) CD4 count less than 400 cells per microliter, while the other half had a nadir greater than that level. The pre-HAART median baseline CD4 count was 388 cells per microliter (range of 1-1,892), with a median viral load of 4.5 log (31,622) copies per milliliter (range 2.23-6.2 log or 70-1,584,893). Pre-STI, the median duration of HAART was 26 months, with a median 22 months of viral undetectability. HAART included one PI (protease inhibitor) and 2 NRTI drugs for 77%; 8% were taking non-HAART regimens with only 2 NRTI drugs. The median CD4 count before the first STI was 740 cells per microliter.
The interim results are as follows. For the 75% of patients who completed their 4th STI, 11% had no viral rebound, defined as a viral load less than 2 log (100) copies per milliliter. The median viral load during the 4th STI was approximately 2.9 log (708) copies per milliliter. High rebound (greater than 5 log or 100,000 copies per milliliter) during the 4th STI occurred among 3%. The highest percentage of no rebound was 13% that occurred during each of the first 2 STIs. The highest percentage of high rebound was 12% that occurred during the first STI. These various differences were not statistically significant. During the 8-week retreatment periods, 5-8% of patients during each period were not able to resuppress virus to a level less than 50 copies per milliliter. Another 4 patients had a CD4 count less than 400 cells per microliter during the 4th STI. These two negative outcomes represent a major risk for those who start an STI during chronic infection after successful HAART.
Completing the 52-week study to date includes 99 of participants (interim analysis). Among those, 21% had a viral load less than 5,000 copies per milliliter, the main study end-point ("responders"). However, 24% of those had a viral load less than that level before anti-HIV therapy was started. The "non-responders" at one year included many patients who were unable to resuppress virus to undetectability and a few with low CD4 counts, as mentioned above. Some were non-responders due to one or more high viral load measurements at any time (one result greater than 5.7 log [500,000]; two results greater than 5 log [100,000] or three results greater than 4.7 log [50,000] copies per milliliter). Half of non-responders were so designated due to a viral load greater than 5,000 copies at 52 weeks.
Dr. Fagard reported some newer analyses that compared STI responders with non-responders. Even though the median CD4 count before anti-HIV therapy was not significantly different, pre-therapy median HIV viral load was significantly lower among responders (4.2 log or 16,595 copies per milliliter) than among non-responders (4.6 log or 39,810) copies per milliliter). The odds for not responding to STIs were 6-fold greater for each log increase of baseline viral load ("odds ratio" of 5.9). Moreover, none of 32 patients with a pre-treatment viral load greater than 4.8 log (60,000) copies per milliliter were responders. In a separate analysis, the density of HIV "mRNA" (messenger RNA or genetic material) per million immune "mononuclear" cells ("PBMCs") at STI start was insignificantly lower among responders (30 copies per million cells) than among non-responders (46 copies).
However, the density of cellular HIV DNA (incorporated among human genes in "chromosomes") was significantly lower at STI start among responders (43 copies per million cells or "PBMCs") than among non-responders (182 copies).
Another significant factor for being a responder at 52 weeks was no viral rebound during the first STI ("odds ratio" of 4.6). However, this was not absolute, since 58% of those without rebound during the first STI were non-responders at 52 weeks, while 13% with rebound during the first STI were classified as responders at 52 weeks. Not surprisingly, no viral rebound during all 4 STIs was significantly associated with being a responder at 52 weeks ("odds ratio" of 14). Also, CD8 cell immune responses ("Elispot spot-forming cells" concentration of lymphocytes producing "interferon gamma") against HIV antigens (different parts of HIV) increased significantly when comparing five different time points during the study. However, the relationship between those increases and being a responder or not has yet to be analyzed.
Dr. Fagard concluded that approximately "1 in 5 patients responded (stabilized viral load less than 5,000 copies per milliliter) after 12 weeks off drugs [after 4 consecutive STIs]." Also, a "viral load of greater than 60,000 copies per milliliter before ART (antiretroviral therapy) precluded response." In addition, "CTL [cytotoxic T lymphocyte], as measured by 'SPCs' (spot-forming cells), increases during the 4 cycles of interruption and re-treatment but the correlation between CTL and response remains to be investigated." This largest study of STI is ongoing.
"STOP
EARTH" Study
The results
of 10 patients in the "STOP EARTH" study from Spain were presented
by Felipe Garcia, MD from Barcelona. After 1 year of successful HAART (ritonavir
[Norvir], d4T [Zerit] and 3TC [Epivir]), three successive STIs of 4 weeks duration
were separated by restarted HAART, and then followed by a treatment interruption
of 1 year. Patients were compared to 20 "STOP EARTH" study control
patients who did not have the three 4-week STIs prior to the 1-year period off
treatment. Pre-HAART, all of these patients had chronic HIV infection, yet with
minimal immune deterioration (baseline CD4 count greater than 500 cells per
microliter). The pre-HAART viral load levels were greater than 5,000 copies
per milliliter. Dr. Garcia reported
that the STI patients had a significantly lower viral
load at the end of the year-off treatment (mean 4 log or 10,000 copies
per milliliter) than control patients (4.7 log or 50,118 copies per milliliter).
When compared to baseline, STI patients had a significantly
better mean change in viral load (decrease of 0.6 log or 4-fold),
compared to control patients (increase of 0.3 log or 2-fold). Also, STI patients
had a significantly better
mean change in CD4 counts (increase
of 140 cells over baseline) when compared to controls (decrease of 102 cells
per microliter from baseline). Lastly, Dr. Garcia reported that STI patients
had significantly higher levels of immune responses
to HIV than control patients, including "stimulation index"
(see Walker report above) to HIV "p24 antigen"
and "CTLs" (see above) against
HIV.
Other
Reports
There were several other reports about observations after sequential STIs among
patients who started HAART during chronic infection. In general, these reports
included small numbers of patients and were not randomized. Some included non-HAART
medications that were sometimes continued during some or all of the "off
HAART" periods. Those included hydroxyurea
(Hydrea, Droxia, anti-cancer/anti-sickle cell anemia drug) and/or IL-2
(interleukin-2, Proleukin). No definitive benefits for this approach were uniformly
reported.
Describing CD4 Cell Decreases After
Interrupting Treatment
Characteristics of the CD4 cell decline after interrupting
HAART for at least 20 weeks (one treatment interruption) were described
in a poster by Pablo Tebas, MD of Washington University in St. Louis, Missouri.
A total of 31 patients (55% women, 58% African American) from two US HIV/AIDS
practices were included, and had had an undetectable viral load (limit 500 copies
per milliliter) for at least 3 months while taking HAART. A significant proportion
of the women stopped treatment after giving birth. The retrospective ("looking
backwards" at patient information after events have occurred, not planned
beforehand) study included patients who stopped treatment due to personal preference
(56%), with the other 43% stopping due to drug toxicity. The median nadir (lowest)
CD4 count was 383 cells per microliter (range 216-544), with a median baseline
viral load of 4.5 log (29,845) copies per milliliter before treatment. After
a median 20 weeks of HAART, the median CD4 count increased to 635 cells per
microliter, with an undetectable viral load (limit 500 copies per milliliter).
The mean duration of follow-up after discontinuing HAART was 50 weeks, ranging
from 20 weeks to 2 ½ years.
The results showed that the mean "decay" (decline) was -16 CD4 cells per microliter per month. In general, there was an insignificantly faster decline of CD4 cells during the first 6 months after treatment interruption, when compared with months after that. Also, the rate of CD4 cell loss was significantly inversely associated with the magnitude of CD4 cell gain after HAART had been started previously. For example, a patient who had an increase of 400 cells per microliter while taking HAART had a faster rate of CD4 cell loss per month after discontinuing HAART, when compared to a patient with a CD4 count increase of only 50 cells per microliter on HAART who had a much slower rate of CD4 cell loss per month after discontinuing HAART. In other words, those who gained more cells on HAART had a faster rate of cell loss during the treatment interruption, while those with a minimal increase of cells on HAART had a slower rate of loss during interruption. The rate of CD4 cell loss was not related to the lowest CD4 count, baseline viral load, CD4 count before treatment interruption, type of HAART, or gender (sex).
Regarding HIV viral load changes, there were no significant differences when comparing the pre-HAART level to the "set-point" achieved during the treatment interruption. For 55% of patients, the pre-HAART and post-interruption viral loads were within 0.5 log (3-fold) copies per milliliter and for 88%, were within 1 log (10-fold). Also, the last viral load measurement during treatment interruption was highly correlated with the pre-HAART viral load. Interestingly, 61% of patients maintained a viral load that was less than pre-HAART levels, but 13% had an interruption level that was greater than 0.5 log (3-fold) greater than pre-HAART levels. None of the 31 patients developed an AIDS opportunistic condition during treatment interruption, due to the fact that there were very few patients whose CD4 counts decreased to levels less than 200 cells per microliter. Two patients did restart HAART and achieved an undetectable viral load. This report, even though it had a small number of patients and was retrospective, may help to guide physicians and patients with similar pre-HAART CD4 counts and viral loads as to what might be expected during a period of treatment interruption not associated with an opportunistic condition.
Dr. A. Phillips of the Royal Free Center for HIV Medicine in London reported CD4 count changes after treatment interruption of at least 4 weeks among 65 patients (20% women) with varying treatment histories. All had achieved CD4 count increases of at least 50 cells per microliter after a median of 43 weeks of HAART that was started during chronic HIV infection. HAART was started at a median CD4 count of 154 cells per microliter. The median duration of treatment interruption was greater than 24 weeks. Dr. Philips reported that the decline in CD4 count "occurs at a very variable rate." Some patients had a very rapid fall in their CD4 counts, yet "a substantial proportion maintain a CD4 count above their pre-HAART level, without treatment, for over 6 months." However, the median time for the CD4 count to return to pre-HAART levels was 25 weeks. There was a 60% probability of restarting HAART after 48 weeks of being off therapy.
Editorial comment:
Jan Van Lunzen reported in abstract 363 that functional t-cell defects reappear
during STI despite previous viral suppression. This is reported in more detail
in this article:
http://www.natap.org/2001/feb/retroconf/immunology021601.htm
Cycles of Treatment Interruptions at
the NIAID
An update about short and long cycles of treatment
interruptions was presented by Mark Dybul, MD of the NIAID (National
Institute of Allergy and Infectious Disease). The main purpose of these two
studies was to determine whether 1- or 2-week durations of treatment interruptions
might lead to less toxicity with lower drug costs, yet without losing virologic
suppression or CD4 count increases. Observations for an SIT (structured intermittent
therapy) of 7 days off-7 days on included
10 patients. Entry requirements included an undetectable viral load (limit 500
copies per milliliter) for at least 6 months (less than 50 copies per milliliter
twice at study entry) and a CD4 count greater than 300 cells per microliter
while taking HAART. The regimen was ritonavir/indinavir (Norvir/Crixivan) plus
d4T (stavudine, Zerit) and 3TC (lamivudine, Epivir). The study protocol called
for all patients stopping HAART for 7 days, and then restarting the same HAART
regimen for 7 days, in cycles, for a total of 24 months. "Failure"
in this study was defined as a viral load greater than 500 copies per milliliter
or a CD4 count decrease that was greater than a 25% decline from baseline on
two measurements taken after the "off-drug" periods.
The interim results showed that 9 of 9 patients maintained virologic suppression after 3-11 months. However, one of these patients had a 10-day discontinuation period at the second cycle due to non-adherence and transiently rebounded to approximately 3.5 log (3,101) copies per milliliter. After restarting the study protocol, virus was resuppressed with 3 cycles of follow-up. Three other patients did have occasional, low level "blips" in detectable virus. The 10th patient was off study due to non-adherence. At week 12, this patient stopped treatment for 3 weeks and rebounded to 4.3 log (20,142) copies per milliliter. Thereafter, continuous HAART led to resuppression of viral load to less than 50 copies per milliliter.
Regarding lymphocyte counts, no patient had a "consistent decline" in their CD4 cell count during 3-11 months of observation (6-22 cycles). Similarly, there was no significant change in the CD8 ("suppressor-cytotoxic") cell counts. There was no drug resistance detected in 3 patients whose CD4 cells were cultured and tested after 3 and 6 months, including genotype and phenotype (Virco Antivirogram) testing. Blood levels of indinavir after the 7th day off treatment were zero to trace when 4 of the patients were tested at baseline and after 3 and 6 months into the study.
Dr. Dybul also measured the amount of HIV in reservoirs of blood immune mononuclear cells. Three of the patients were tested at baseline and at 6 months. There was a small decrease from a mean "proviral" (in the chromosomes) HIV DNA level of 619 copies per 10 million blood mononuclear cells to 374 copies after the 7th day off HAART (at month 6). In a similar analysis, the frequency of "replication competent" (able to reproduce, grow) HIV in CD4 cells decreased from 3.25 "IUPM" (infectious units per million cells) at baseline to 0.27 IUPM after the 7th day off HAART, tested at month 6. It is difficult to establish any major significance to these results, given the small numbers of patients and small decreases. However, it would appear in this limited sampling, there were no increases in proviral DNA or in infectious HIV particles in cells that were examined, as a result of 7 days cycles of being off HAART. The absence of detectable drug resistance to indinavir and the maintenance of viral suppression are very encouraging. Potential changes in blood lipids, insulin resistance, fat redistribution, and immune responses against HIV were not reported. This study is ongoing.
Dr. Dybul also authored a second poster about a different schedule of interrupted therapy in cycles. This regimen is called "long cycle" structured intermittent therapy of HAART with 4 weeks off then 8 weeks on therapy, in cycles, up to 22 months. The results would represent 30% less medication. The enrollment criteria were the same as Dr. Dybul's "7 days on-7 days off" regimen above. A total of 70 patients will be enrolled and randomized to intermittent therapy or to continuous therapy without treatment interruptions. The study endpoints will be viral load and CD4 counts in the two arms, in addition to immune responses against HIV. The interim analysis included 47 patients who have enrolled. The mean baseline (pre-HAART and pre-interruption) CD4 counts and viral loads were not reported; however, the ranges were and they were somewhat similar to the "7 days off-7 days on" report above.
The interim results were as follows. All patients in the "interruption" arm had viral rebound during the "off drug" periods, up to 6 cycles. Dr. Dybul described "four patterns" of viral load changes during the "off" period for those randomized to the treatment interruption arm. Those results included 15 patients who had completed 3-6 cycles of "4 weeks off--8 weeks on" therapy. Only 20% were able to maintain greater than a 0.5 log (3-fold) copies per milliliter reduction in viral load when comparing the first with subsequent interruptions (pattern 1). In contrast were the 13% who maintained greater than a 0.5 log increase in viral load when comparing the first to subsequent interruptions (pattern 2). Another 27% maintained similar viral load levels during each interruption, although each patient in this category (pattern 3) had less than 3.8 log (6,000) copies per milliliter during the off periods. The remaining 40% (pattern 4) had variable increases and decreases in greater than 0.5 log when comparing treatment interruptions (i.e., no real pattern). When analyzing the viral load changes for all 15 patients that compared the first with the third treatment interruption, the mean decrease was 0.3 log (2-fold) copies per milliliter, which approaches the variability of the lab test itself and might not represent any significance.
Dr. Dybul analyzed those interruption patients who had any detectable viral load (greater than 50 copies per milliliter) at the end of the "on HAART" periods (after 8 weeks that HAART was resumed). Interestingly, 40% had a detectable load using those criteria. Note that the maximum load, however, for those eight patients was only 350 copies per milliliter. Not achieving undetectability to less than 50 copies per milliliter at the end of resumed HAART did not correlate with viral load increases during the "off" periods. However, the 40% level was nearly identical to the 38% rate of detectable viral load for "interruption" patients during 3-4 weeks of continuous HAART before they entered into the current study. Yet, the maximal level of detectability was only 145 copies per milliliter. When the 23 patients randomized to the "continuous" HAART arm were analyzed, 68% had at least one detectable viral load greater than 50 copies, with a maximal level of 1,244 copies per milliliter. Many of these various measurements of viral detectability would fall into the category of "blips" that might not have much predictive significance in studies to date.
CD4 count changes were reported for ten "interruption" patients who had completed four cycles. During the first "off" period, the mean CD4 count decreased by 17%. However, the levels returned to baseline during the "on-HAART" periods. When measuring CD4 levels during subsequent interruptions, they decreased by 3% during the 2nd one, 8% during the 3rd one and 1% during the 4th one. At the same time points, patients in the other "continuous HAART" arm had CD4 count changes that were: 4% increase (1st time point), 2% increase (2nd), 6% decrease (3rd), and 13% increase (4th). CD8 lymphocytes ("suppressor-cytotoxic") were essentially unchanged at the four time points for patients in both arms.
Drug resistance testing was reported for the 15 patients in the "interruption" arm who completed 2-5 cycles. No genotypic or phenotypic (Virco Antivirogram, decreased susceptibility) resistance was detected for 87% of patients. However, one patient had genotypic and phenotypic resistance to AZT (Retrovir) and 3TC (Epivir, both NRTI drugs) before entering the study and developed genotypic and phenotypic resistance to efavirenz (Sustiva, NNRTI drug) during the study. (Note that this patient's regimen included indinavir [Crixivan, PI drug], AZT, ddI [didanosine, Videx], and efavirenz.) However, four other patients who were taking efavirenz did not develop any drug resistance when tested. Even though the newly detected drug resistance was found only in one patient, this suggests extreme caution against using drug interruption strategies for specific patients with pre-existing drug resistance-particularly for a regimen with an NNRTI drug that has a long "half-life." (During an STI, efavirenz or nevirapine [Viramune] would remain active in the body for hours to days longer than the other discontinued drugs, creating a period of "monotherapy;" this would increase the risk of developing resistance.) Another patient had resistance (genotypic and phenotypic) to 3TC before the study, and this was maintained during the study. (This patient was taking 3TC, d4T [stavudine, Zerit] and indinavir and suppressed viral load to less than 265 copies per milliliter during the restarted HAART periods.)
Dr. Dybul concluded that for those "patients who cannot receive continuous therapy…long cycle (structured intermittent therapy) may be an efficacious means to decrease the amount of HAART medication by 30%." The complete analysis of risks and benefits are unknown, since the study is ongoing. It will also be interesting to find out whether the STI strategy of 30% less medication will have any beneficial effects in terms of lower rates and/or severity of adverse effects associated with anti-HIV medication, including increased blood cholesterol, triglycerides (fats), insulin resistance and diabetes (high blood sugar), vascular (artery) disease including "heart attacks," osteopenia/osteoporosis (loss of bone mineral density) and fat redistribution.
| PART III: STI after a Detectable Viral Load with HAART or "Drug Failure" |
There were four presentations that addressed treatment interruption after a detectable HIV RNA with HAART. This has sometimes been called "drug failure" with drug-resistant HIV, although it usually represents drug-related virologic failure (detectable viral load) and sometimes, "immunologic failure" (referring to the CD4 count), but not necessarily "clinical failure" (referring to progression to clinical disease or illness or even death). As mentioned above, one reason for this strategy is the observation that interrupting HAART after virologic failure often leads to repopulation with drug-sensitive or "wild-type" (non-resistant, most common in the population) HIV that would respond better to a new course of therapy. Although, wild-type HIV has a higher "replication capacity" (ability to grow or reproduce) as measured by one cycle of the PhenoSense HIV (phenotype drug resistance) test from Virologic. Some researchers have classified certain drug-resistant virus strains as being less "fit," but the Grant report below is the second one to truly document this fact. Note that STI with "drug failure" usually occurs in a more advanced stage of HIV infection, often with previous AIDS illnesses and multi-drug resistance. It is in this population that STIs have led to life-threatening low levels of CD4 counts and documented opportunistic conditions and death in some patients.
481 Patient "Meta-Analysis" Study
One of the more interesting presentations in this STI classification was a "meta-analysis" (combined studies) of 481 patients from 7 locations including New York City, San Francisco, London (U.K.), Calgary (Alberta, Canada), Milan (Italy) and Frankfurt (Germany). The lead author was Dr. C. Sabin of the Royal Free University in London, UK. The inclusion criteria into the retrospective (analyzed after events have occurred) meta-analysis was a viral load greater than 3.7 log (5,000) copies per milliliter after a treatment interruption of at least 2 months that occurred after anti-HIV treatment with at least 3 drugs for at least 3 months.
The baseline information was significantly different when comparing each of the geographic locations for almost all reported variables. Yet, before any anti-HIV treatment, the median nadir (lowest) CD4 count was 90 cells per microliter (range zero to 663 cells) with a peak viral load of 5.5 log (301,995) copies per milliliter. The median baseline CD4 count immediately prior to the STI was 203 cells per microliter (range 1-992 cells) with a median viral load of 4.9 log (72,443) copies per milliliter. The median durations of total anti-HIV therapy, of total HAART, and of the current regimen before STI were 33 months, 17 months and just over 5 months, respectively. Ever achieving an undetectable viral load (limit not stated) had occurred among 20% for a median of 6 months. Patients had been exposed to median 6 prior anti-HIV drugs, including 92% with PI drug experience and 49% with NNRTI (non-nucleoside) drug experience. Therefore, the 481 patients had advanced HIV infection with multiple drug experience.
The results were as follows. During the treatment interruption, the CD4 count decreased significantly by a median (normalized) 53 cells, to 117 cells per microliter. This placed many patients at risk for life-threatening opportunistic infections. The median (normalized) increase in viral load was 0.26 log (1.8-fold) copies per milliliter, to 5.3 log (181,970) copies per milliliter. Changes in the CD4 count during the treatment interruption were greatest among those with a higher CD4 count before interruption and a lower nadir (lowest level) CD4 count. The median duration of treatment interruption was not reported. Dr. Sabin reported that the CD4 count loss during treatment interruption was predicted by the following equation:
12.35 + (0.57 X nadir [lowest] CD4 count) - (0.72 X pre-treatment interruption CD4 count).
The equation was validated with an "independent sample" (outside of the current study) and therefore might be applicable to other patients with similar baseline tests.
A total of 445 patients (93%) restarted an anti-HIV regimen with a median 3 drugs after the treatment interruption. Factors significantly associated with a CD4 cell response to the new regimen in two different statistical "multivariate models" included: higher CD4 count at the end of the treatment interruption (TI) period; lower viral load at the end of the TI period; and the total number of anti-HIV drugs started at the end of the TI period.
Dr. Sabin is planning additional research about the 481 patients, including drug resistance testing before and during the period of treatment interruption, correlates of that resistance with repopulation of "wild-type" virus during interruption and subsequent response to a new drug regimen, and the occurrence of opportunistic conditions during the interruption period and after treatment is restarted. Also, quality-of-life issues must be considered in future studies.
Response to "Salvage Therapy" after an STI with "Drug Failure"
Steven Deeks, MD of the University of California at San Francisco authored a presentation about 22 patients and their response to "salvage therapy" after an STI that occurred during "drug failure." In spite of these patients having moderately advanced HIV disease with significant drug resistance before the STI, response to salvage therapy was good, particularly when a new drug class was able to be included as part of the salvage regimen. Inclusion criteria for the observational study were: viral load greater than 500 copies per milliliter for at least one year while taking PI (protease inhibitor) drug-based HAART and a screening viral load greater than 2,500 copies per milliliter. Decision to restart treatment after an STI was made by the patients' primary physician; however, patients were encouraged to restart therapy if the STI led to a viral load increase greater than 1 log (10-fold) copies per milliliter or a CD4 cell loss of at least 50%.
Before the STI (during "drug failure"), the median baseline CD4 count was 217 cells per microliter and the median viral load was 4.6 log (39,810) copies per milliliter. CD4 counts and viral loads pre-therapy were not presented. The median duration of PI drug therapy was 36 months, with a median duration of "drug failure" that was 31 months. Median PI drug resistance was 56-fold decreased susceptibility, while median abacavir (Ziagen, NRTI drug) resistance was 10-fold decreased susceptibility. The median duration of the STI was 20 weeks (range 16-30). During the STI, a complete shift from PI drug resistance to "wild-type" (no PI drug resistance) occurred in 81%, while 72% had a complete shift from NRTI drug resistance to "wild-type." During the STI, the median viral load increase was 0.74 log (5.5-fold) with a median CD4 count decrease of 88 cells per microliter (range loss of 42 to 168 cells). During the STI, one patient developed a life-threatening AIDS opportunistic infection (PCP, pneumonia).
A "salvage" therapy was constructed using phenotype drug resistance results from samples obtained before the STI. The regimen for 86% of the 22 patients included 2 PI drugs (including low-dose ritonavir [Norvir]), at least 2 NRTI drugs and an NNRTI drug.
The results to "salvage" therapy were as follows. After 24 weeks of the new regimen, 68% were able to achieve CD4 count increases that were at least 90% of their pre-STI level. Dr. Deeks then focused on 11 of the 22 patients whose regimen included one new drug class: NNRTI for 9 of them and T-20 experimental fusion inhibitor for the other 2 patients. All 11 of them were also taking "recycled" NRTI drugs and 2 PI drugs. These 11 patients had a median viral load reduction of approximately 3 log (1000-fold) copies per milliliter with 100% of achieving an undetectable level (limit 200 copies per milliliter) and a CD4 count increase of approximately 150 cells per microliter. In contrast, the other 11 patients who did not use a new drug class had a median viral load decrease of approximately 1.5 log (32-fold) copies per milliliter reduction with only 27% achieving undetectability, yet with a median CD4 cell increase of approximately 100 cells per microliter. Salvage therapy led to the re-emergence of drug-resistant virus that also had decreased "replicative capacity" (ability to grow) using one cycle of the Virologic PhenoSense HIV phenotype drug resistance test. Dr. Deeks concluded, "With salvage therapy, most patients are able to regain CD4 cell numbers lost during their STI." He also said that STI may be particularly effective in heavily pretreated patients who remain naïve to [never took] a single therapeutic [drug] class." These patients will be followed, and it is quite possible that resistance will eventually develop to the new drug class in these patients that might lead to viral rebound and CD4 cell loss.
Drug-Resistant HIV is Truly 'Less Fit'
During the Late Breaker session, Robert Grant, MD, PhD of the University of California at San Francisco presented true viral "fitness" information about viruses from 12 patients in the Deeks study above. Dr. Grant compared the fitness of the dominant HIV "strain" before and during an STI. During the STI, this was "wild-type" (no mutations) HIV, while pre-STI, PI- and NRTI-drug resistant HIV dominated under the "selection pressure" of HAART. The rate of "wild-type" HIV overgrowth during the STI led to the determination that those strains were "more fit" by a factor of 3- to 36-fold. Those "in vivo" (in the living person) changes directly correlated with increased "replicative capacity" on one cycle of the PhenoSense HIV phenotype resistance test from ViroLogic. In turn, the fitness differences correlated with the increase in HIV viral load during the STI. Dr. Grant concluded that "PI-resistant HIV is markedly less fit than PI susceptible virus…[and that that] may account for persistent partial viral suppression observed with PI-resistant viremia." Also, that during treatment with HAART, "wild type virus appears to persist, albeit at very low levels." These results are important, since it may be possible one day to obtain a "fitness" (replicative capacity) test on the dominant HIV strain during "drug failure" while on HAART to help determine whether it would be beneficial to continue the same regimen. This might not be necessary if the nadir (lowest) CD4 count and peak viral load levels were available and those numbers were worse than those while "failing" a current HAART regimen.
Drug-Resistant HIV Does Not 'Disappear' During STI
In a related presentation, Dr. A. Hance of CRIV Bichat-Claude Bernard in Paris, France showed that an STI after "drug failure" with HAART does not cause drug-resistant HIV to disappear. He found that after 13 patients underwent an STI for 3 months, drug-resistant HIV could still be detected, even though genotype resistance testing indicated "wild type" HIV without any mutations. Such "minority" species were present in 1-10% of the total plasma (blood liquid without cells) virus, as measured by "real-time PCR" (polymerase chain reaction) testing. Interestingly, the minority resistant strains detected were not identical to the dominant strain pre-STI, but represented re-emergence of drug-resistant isolates that were present even earlier in the patients' treatment course. The major point is that drug-resistant HIV does not disappear during an STI, and may still be present as 'minority species' that could re-emerge and become dominant when specific HAART is restarted.
The 8th Annual Retrovirus Conference definitely added to our knowledge of Treatment Interruptions in HIV/AIDS. These strategies still must be considered experimental and risky. The findings after many of the above studies (and others) are completed will help to clarify the potential role of STIs in the treatment of HIV infection.
References
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