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Structured Treatment Interruption in Patients with Multidrug-Resistant Human Immunodeficiency Virus
 
 
  New England Journal of Medicine, Vol 349:837-846, Aug 28, 2003, Number 9
 
Jody Lawrence, M.D., Douglas L. Mayers, M.D., Katherine Huppler Hullsiek, Ph.D., Gary Collins, M.S., Donald I. Abrams, M.D., Ronald B. Reisler, M.D., Lawrence R. Crane, M.D., Barry S. Schmetter, B.S., Thomas J. Dionne, B.A., Jennifer M. Saldanha, R.N., Michael C. Jones, R.N., John D. Baxter, M.D., for the 064 Study Team of the Terry Beirn Community Programs for Clinical Research on AIDS
 
Comments by Jules Levin: at the IAS Conference in Paris there was a panel discussion where Jody Lawrence discussed her study and Christine Katlama was in the audience and went to the microphone to discuss her study. Studies are in patient population with advanced HIV and with drug resistance. As you may know there is controversy because Katlama reports patients in her study can see reversion of mutant virus during interruption and she claims reversion may help short term CD4 and viral load benefit; therefore interruption has benefit. Lawrence study does not find reversion during interruption provides CD4 and viral load benefit. It is not established that reversion during interruption can provide benefit. Evidence does not support benefit & safety to interruptions in this patient population. Any short term benefit does not appear to translate into longer term benefit. Risks, however, include drug resistance and infections if CD4 count is low. When returning to therapy CD4 increase may be blunted.
 
Study authors in the NEJM publication say:
 
"...This randomized study was designed specifically to assess the clinical outcome of a structured interruption of treatment. Although there were equal numbers of deaths in each group, significantly more primary disease-progression events occurred in the treatment-interruption group. Our results indicate that in patients with multidrug-resistant HIV infection, it is best to continue treatment with an optimized antiretroviral regimen and avoid the use of treatment interruption......
 
".....We hypothesized that a four-month structured interruption of treatment would improve the subsequent treatment response owing to a switch in the predominant HIV population from highly resistant virus to wild-type virus during the interruption. A previous study reported that reversion to wild-type virus occurred 2 to 15 weeks after therapy was discontinued. A 16-week interruption was chosen to allow adequate time to maximize the reversion to wild-type virus while minimizing the risk of a decline in the CD4 cell count. We found that the treatment-interruption group had poorer overall outcomes than the control group, despite partial or complete reversion of the HIV mutant population to the wild type in 64.0 percent of the patients in the treatment-interruption group.....
 
......Preliminary subgroup analyses of the treatment-interruption group in our study suggest that patients whose virus reverted to wild type during treatment interruption had better virologic and CD4 cell responses after the reinitiation of therapy than did patients whose virus did not revert to wild type. However, the former group also had higher CD4 cell counts and lower HIV RNA levels at study entry (data not shown). Despite these differences, the rates of clinical events were similar in these two subgroups. More important, the CD4 cell response among the patients in the treatment-interruption group whose virus reverted to wild type was not superior to the CD4 cell response in the control group.... A decline in the CD4 cell count during treatment interruption has been reported in previous studies. In our study, although the CD4 cell count recovered after the reinitiation of treatment, it remained consistently lower in the treatment-interruption group than in the control group throughout a period of 20 months.... In our study, nearly half of all disease-progression events occurred in patients with a base-line CD4 cell count of less than 50 per cubic millimeter. The two most common primary disease-progression events were esophageal candidiasis and P. carinii pneumonia. The greater frequency of these events in the treatment-interruption group was not attributed to the rates of use of imidazoles or P. carinii prophylaxis. These results demonstrate the risks of treatment interruption and emphasize the importance of prophylaxis against opportunistic infections in patients with HIV infection in whom treatment is interrupted for any reason....
 
"......In the treatment-interruption group, the mean HIV RNA level at eight months was 1.2 log copies per milliliter lower than the base-line value in those who had a partial or complete shift in drug-resistance patterns by the four-month visit and 0.5 log copies per milliliter lower in those who did not have such a shift (P=0.01). At the eight-month visit the respective mean change in CD4 cell counts from base line was an increase of 16 cells per cubic millimeter and a loss of 34 cells per cubic millimeter (P=0.01). The risk of disease progression was not significantly different between those with a shift in the pattern of drug resistance and those without a shift (hazard ratio, 1.14; P=0.82)."
 
ABSTRACT
 
Background: We compared two strategies for treating patients infected with multidrug-resistant human immunodeficiency virus (HIV).
 
Methods: Patients with multidrug-resistant HIV and HIV RNA levels of more than 5000 copies per milliliter were randomly assigned to a four-month structured interruption of treatment followed by a change in antiretroviral regimen (treatment-interruption group) or to an immediate change in regimen (control group). Genotypic and phenotypic resistance testing was performed. Disease progression, death, and changes in genotypic resistance, CD4 cell counts, HIV RNA levels, and quality of life were assessed.
 
Results: After a median follow-up of 11.6 months, disease progression or death occurred in 22 of the 138 patients in the treatment-interruption group and in 12 of the 132 patients in the control group (P=0.01), with a hazard ratio of 2.57 (95 percent confidence interval, 1.2 to 5.5) for the treatment-interruption group. There were eight deaths in each group. In the treatment-interruption group, the mutant HIV populations completely or partially reverted to wild type by four months in 64.0 percent of patients. As compared with the control group, the treatment-interruption group had a mean CD4 cell count that was 85 cells per cubic millimeter lower from months 0 through 4 (P<0.001), 47 cells per cubic millimeter lower from months 5 through 8 (P<0.001), and 31 cells per cubic millimeter lower after eight months (P=0.11). The mean HIV RNA levels were 1.2 log copies per milliliter higher (on a base-10 scale) in the treatment-interruption group during months 0 through 4 (P<0.001), but they were not significantly different from those in the control group after month 4. The overall quality of life was similar in the two groups.
 
Conclusions: In patients infected with multidrug-resistant HIV, structured interruption of treatment was associated with greater progression of disease and did not confer immunologic or virologic benefits or improve the overall quality of life.
 
STUDY BACKGROUND
 
The best therapeutic approach to patients infected with multidrug-resistant human immunodeficiency virus (HIV) that does not respond to treatment is uncertain. Continuing partially effective antiretroviral therapy may preserve the CD4 cell count in the short term but may jeopardize future treatment options by promoting further resistance over time. Thus, alternative strategies are needed.
 
Interruptions of antiretroviral treatment are increasingly being used for treatment failure and to help manage the toxic effects of therapy. Although treatment interruption may lead to a decline in the CD4 cell count and an increase in the viral load, it has also been associated with the reemergence and predominance of a more sensitive (wild-type) viral population in patients with multidrug-resistant HIV. Some studies have suggested that this change in the pattern of resistance may be associated with a better virologic response when treatment is reinitiated. However, more recent randomized studies have reported conflicting results, raising questions about the effect of this strategy. The Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) initiated a randomized clinical trial of structured interruption of treatment (CPCRA 064) to address this issue.
 
RESULTS
 
Patients and Follow-up
 
Of the 270 patients, 138 were assigned to the treatment-interruption group and 132 to the control group. Base-line characteristics were similar in the two groups. The most common prior opportunistic infections were Pneumocystis carinii pneumonia (in 32.6 percent), esophageal candidiasis (in 15.9 percent), and Mycobacterium avium complex infection (in 6.3 percent). According to the treatment history, 96.7 percent of the patients had prior exposure to all three classes of drugs used for HIV infection, including protease inhibitors, nucleoside reverse-transcriptase inhibitors, and nonnucleoside reverse-transcriptase inhibitors. According to the viral genotype, 76.7 percent of patients were infected with HIV that had at least one major resistance mutation for each of these three classes of drugs, and 48.1 percent were infected with HIV that had broad resistance to all three classes. The mean number of drugs (of 16 tested) to which the viruses were sensitive was 2.2 according to genotype and 5.1 according to phenotype. The median follow-up was 11.6 months. Fewer than 2 percent of patients were lost to follow-up.
 
Summary of Structured Treatment Interruption
 
Of the 138 patients in the treatment-interruption group, 36 (26.1 percent) had early termination of treatment interruption (mean, 2.3 months). Reasons for early termination (which are not mutually exclusive) included a decline in CD4 cell counts (in 80.6 percent of patients), an increase in plasma HIV RNA levels (in 38.9 percent), and disease progression (in 5.6 percent). Drug-resistance patterns had shifted partially (changes in all major reverse-transcriptase or protease mutations, but not both) or completely (changes in all major reverse-transcriptase and protease mutations) to wild type in 34.7 percent of patients at two months (43 of the 124 patients who underwent testing) and in 64.0 percent of patients at four months (73 of 114). Of the patients whose drug-resistance patterns showed a complete shift by the four-month visit, 45.0 percent (18 of 40) had had a complete shift by the two-month visit.
 
Treatments Prescribed
 
The first regimen prescribed after randomization included a mean of 3.6 drugs (2.2 nucleoside reverse-transcriptase inhibitors, 0.2 nonnucleoside reverse-transcriptase inhibitor, and 1.2 protease inhibitors) in the treatment-interruption group and 3.8 drugs (2.2 nucleoside reverse-transcriptase inhibitors, 0.2 nonnucleoside reverse-transcriptase inhibitor, and 1.4 protease inhibitors) in the control group. Lopinavir was significantly more likely to be included in the regimen for patients in the treatment-interruption group than in the regimen for those in the control group (68.8 percent vs. 50.8 percent, P=0.007), whereas amprenavir was less likely to be included (17.4 percent vs. 31.8 percent, P=0.009), as were ritonavir (12.8 percent vs. 29.5 percent, P=0.001) and stavudine (36.7 percent vs. 52.3 percent, P=0.02). The mean number of sensitive drugs included in the first regimen in the treatment-interruption group was 0.9 according to viral genotype and 1.5 according to viral phenotype. In the control group, the respective values were 0.8 and 1.8.
 
Adherence
 
Self-reported adherence to antiretroviral therapy was similar in the two groups and was reported to be 100 percent by the majority of patients at each visit (data not shown). Adherence to the assigned treatment was measured on the basis of the mean percentage of follow-up time in which antiretroviral therapy was prescribed. During the first four months (the defined period of treatment interruption), antiretroviral therapy was prescribed for 16.5 percent of the follow-up time in the treatment-interruption group (reflecting early reinitiation of therapy in some patients) and 96.0 percent of the follow-up time in the control group. After month 4, the percentage of follow-up time in which therapy was prescribed was 92.1 percent in the treatment-interruption group and 88.8 percent in the control group.
 
The CD4 cell count from the previous month was used in determining adherence to standard guidelines for prophylaxis against opportunistic infections during months 0 through 4. Adherence to P. carinii pneumonia prophylaxis was at least 89.0 percent in the treatment-interruption group and 83.6 percent in the control group. Adherence to M. avium complex prophylaxis was at least 72.5 percent in the treatment-interruption group and 63.6 percent in the control group. The percentage of patients receiving prophylaxis against P. carinii pneumonia and M. avium complex infection did not differ significantly between the two groups at any visit.
 
Disease Progression and Death
 
A total of 22 patients in the treatment-interruption group and 12 in the control group reached the primary end point of disease progression or death (hazard ratio for the treatment-interruption group, 2.57; 95 percent confidence interval, 1.2 to 5.5; P=0.01). There were eight deaths in each group. Death was a primary (first) event for five patients in the treatment-interruption group and seven in the control group. Of the 17 patients in the treatment-interruption group who had disease progression, 7 (41.2 percent) had esophageal candidiasis, 4 (23.5 percent) had P. carinii pneumonia, 3 (17.6 percent) had cryptosporidiosis, 2 (11.8 percent) had lymphoma, and 1 (5.9 percent) had cytomegalovirus infection. Of the five patients in the control group who had disease progression, one each had esophageal candidiasis, cryptosporidiosis, cytomegalovirus infection, M. avium complex infection, and herpes simplex infection. Of the eight cases of esophageal candidiasis, one occurred at each of months 1, 2, 3, and 12 in the treatment-interruption group; two cases, one in each treatment group occurred at month 8; and two cases in the treatment-interruption group occurred at month 16. The percentage of patients receiving imidazoles (antifungal agents) during follow-up ranged from 15 to 36 percent and did not differ significantly between the groups except at months 6 and 8, when it was lower in the treatment-interruption group. The incidence of oral candidiasis (not considered a primary end point) was 21 percent in the treatment-interruption group and 20 percent in the control group.
 
Most primary end points occurred after month 4 (hazard ratio for the treatment-interruption group, 2.97; 95 percent confidence interval, 1.21 to 7.32; P=0.02), not during the treatment-interruption period of months 0 through 4 (hazard ratio, 1.64; P=0.50). A multivariate model that included the treatment group, base-line CD4 cell count, base-line HIV RNA level, and presence or absence of a history of progression of disease was used to predict the likelihood of disease progression or death. Significant predictors were the treatment group (hazard ratio, 2.74 [95 percent confidence interval, 1.25 to 5.98] for the treatment-interruption group as compared with the control group; P=0.01) and the base-line CD4 cell count (hazard ratio, 1.38 [95 percent confidence interval, 1.11 to 1.72] for each decrement of 50 cells per cubic millimeter; P=0.004). Base-line HIV RNA levels and a history of disease progression were not significant predictors.
 
CD4 Cell Counts and Plasma HIV RNA Levels
 
For months 0 through 4, the mean CD4 cell count was higher by 85 cells per cubic millimeter in the control group than in the treatment-interruption group (P<0.001). The estimated median time for the CD4 cell count to exceed base-line values was 4.9 months in the treatment-interruption group. In this group, however, the CD4 cell count remained consistently lower than in the control group; the mean differences for months 5 through 8 and months 9 through 20 were 47 cells per cubic millimeter (P<0.001) and 31 cells per cubic millimeter (P=0.11), respectively.
 
HIV RNA levels increased during the treatment-interruption period. The mean HIV RNA levels were higher by 1.2 log (on a base-10 scale) copies per milliliter in the treatment-interruption group than in the control group for months 0 through 4 (P<0.001). However, after the defined treatment-interruption period, the HIV RNA levels in both groups remained suppressed below the base-line value by approximately 0.8 log copies per milliliter. The percentage with viral suppression peaked in each group approximately four months after the initiation of the optimized regimen.
 
In the treatment-interruption group, the mean HIV RNA level at eight months was 1.2 log copies per milliliter lower than the base-line value in those who had a partial or complete shift in drug-resistance patterns by the four-month visit and 0.5 log copies per milliliter lower in those who did not have such a shift (P=0.01). At the eight-month visit the respective mean change in CD4 cell counts from base line was an increase of 16 cells per cubic millimeter and a loss of 34 cells per cubic millimeter (P=0.01). The risk of disease progression was not significantly different between those with a shift in the pattern of drug resistance and those without a shift (hazard ratio, 1.14; P=0.82).
 
Adverse Events, Symptoms, and Quality of Life
 
There were no significant differences between the two groups in adverse events, symptoms, or overall quality of life. Thirty-one patients in the treatment-interruption group and 30 patients in the control group had a grade 4 adverse event (hazard ratio for the treatment-interruption group, 1.03; P=0.92). Through month 12, no serious (grade 4) symptoms were reported in either group. As compared with the control group, the treatment-interruption group had a transient improvement in the SF-12 physical component score for quality of life. The change from base line to two months was +1.7 in the treatment-interruption group and –0.4 in the control group (difference, 2.1; P=0.04). The physical and mental component scores did not differ significantly between the two groups at any other visit.
 
Author Discussion
 
This randomized trial compared the effect of a structured interruption of treatment with continued antiretroviral therapy on clinical outcomes in patients with multidrug-resistant HIV infection. In this population, a structured interruption of treatment was associated with a greater number of clinical events. In addition, patients assigned to treatment interruption did not have a greater immunologic or virologic benefit than the patients in the control group. Adverse events, adherence to treatment, and the quality of life were similar in the two groups.
 
We hypothesized that a four-month structured interruption of treatment would improve the subsequent treatment response owing to a switch in the predominant HIV population from highly resistant virus to wild-type virus during the interruption. A previous study reported that reversion to wild-type virus occurred 2 to 15 weeks after therapy was discontinued. A 16-week interruption was chosen to allow adequate time to maximize the reversion to wild-type virus while minimizing the risk of a decline in the CD4 cell count. We found that the treatment-interruption group had poorer overall outcomes than the control group, despite partial or complete reversion of the HIV mutant population to the wild type in 64.0 percent of the patients in the treatment-interruption group.
 
Prior studies of the use of a structured interruption of treatment in the setting of salvage therapy differ from our study in terms of their design, eligibility criteria, and study outcomes. Earlier studies were primarily nonrandomized; used virologic, rather than clinical, end points; and required only a history of prior exposure to multiple antiretroviral agents and drug classes rather than documented genotypic multidrug resistance before entry.
 
Two recently reported studies used a randomized clinical trial design. The GIGHAART study used a shorter (eight-week) period of treatment interruption and prescribed a combination of eight or more drugs in the new salvage regimen. Base-line CD4 cell counts were lower in that study (median, 27 cells per cubic millimeter) than in ours. In contrast to our results, the GIGHAART study found that the treatment-interruption group had better virologic and immunologic responses than the control group. The reasons for the discordant findings are not clear. Despite the use of a more intense salvage regimen, the control group in the GIGHAART study had a poorer virologic response than did the control group in our study. Only 22 percent of patients in the control group in the GIGHAART study were still receiving more than six drugs at 48 weeks. In our study, the overall virologic response after the reinitiation of treatment in the treatment-interruption group was similar to that in the control group. Both groups had a relatively good response, with a reduction from base line of approximately 0.8 log copies of HIV RNA per milliliter.
 
The results of the Retrogene study, which used a 12-week structured interruption of treatment, were consistent with those of our study. The investigators found no significant virologic advantage of treatment interruption, despite the reversion to wild-type virus in approximately two thirds of patients in the treatment-interruption group.
 
Preliminary subgroup analyses of the treatment-interruption group in our study suggest that patients whose virus reverted to wild type during treatment interruption had better virologic and CD4 cell responses after the reinitiation of therapy than did patients whose virus did not revert to wild type. However, the former group also had higher CD4 cell counts and lower HIV RNA levels at study entry (data not shown). Despite these differences, the rates of clinical events were similar in these two subgroups. More important, the CD4 cell response among the patients in the treatment-interruption group whose virus reverted to wild type was not superior to the CD4 cell response in the control group.
 
A decline in the CD4 cell count during treatment interruption has been reported in previous studies. In our study, although the CD4 cell count recovered after the reinitiation of treatment, it remained consistently lower in the treatment-interruption group than in the control group throughout a period of 20 months. To our knowledge, the question of whether the decline in the CD4 cell count associated with a structured interruption of treatment leads to an increase in clinical events relative to those in the control group has not been examined previously in a large, randomized trial with statistical power to address this question. The results of one observational data-base study suggested an increased risk of AIDS and death when therapy was stopped for at least three months, but it was not a study of a structured treatment interruption. In the recent randomized studies of a structured treatment interruption, there was no increase in clinical events in the treatment-interruption group, but the sample in these studies were not large enough to assess the issue accurately.
 
In our study, nearly half of all disease-progression events occurred in patients with a base-line CD4 cell count of less than 50 per cubic millimeter. The two most common primary disease-progression events were esophageal candidiasis and P. carinii pneumonia. The greater frequency of these events in the treatment-interruption group was not attributed to the rates of use of imidazoles or P. carinii prophylaxis. These results demonstrate the risks of treatment interruption and emphasize the importance of prophylaxis against opportunistic infections in patients with HIV infection in whom treatment is interrupted for any reason.
 
This randomized study was designed specifically to assess the clinical outcome of a structured interruption of treatment. Although there were equal numbers of deaths in each group, significantly more primary disease-progression events occurred in the treatment-interruption group. Our results indicate that in patients with multidrug-resistant HIV infection, it is best to continue treatment with an optimized antiretroviral regimen and avoid the use of treatment interruption.
 
 
 
 
 
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