Original Article
Structured Treatment Interruption in Patients with Multidrug-Resistant Human Immunodeficiency Virus
N Engl J Med 2003; 349:837-846August 28, 2003
- 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.
Media in This Article
Figure 1
Kaplan–Meier Estimates of the Cumulative Incidence of Progression of Disease or Death.Figure 2
Mean Changes in CD4 Cell Counts (Panel A) and Plasma HIV RNA Levels (Panel B).Article Activity
- Article
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 term1,2 but may jeopardize future treatment options by promoting further resistance over time.3,4 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.5-11 Some studies have suggested that this change in the pattern of resistance may be associated with a better virologic response when treatment is reinitiated.9,12,13 However, more recent randomized studies14,15 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.
Methods
Study Population
Patients were enrolled at 16 units of the CPCRA, a consortium sponsored by the Division of AIDS of the National Institute of Allergy and Infectious Diseases. The CPCRA conducts clinical research on HIV infection and the acquired immunodeficiency syndrome (AIDS) in U.S. primary care settings. The institutional review board of each unit approved the protocol, and all patients or their parents or guardians gave written informed consent. HIV-infected patients 13 years of age or older were eligible if they had an HIV RNA level of more than 5000 copies per milliliter at the time of screening and genotypic evidence of multidrug-resistant virus (defined in Supplementary Appendix 1). The antiretroviral regimen had to remain stable from 14 days before screening through randomization. Patients were excluded from enrollment if they had an active opportunistic infection requiring treatment, had recently taken interleukin-2, had been vaccinated or had an illness judged to influence the HIV RNA level, or were pregnant or breast-feeding.
Study Design
CPCRA 064 was a randomized, nonblinded, multicenter trial in which eligible patients were randomly assigned to either a four-month structured interruption of treatment followed by the initiation of an optimized antiretroviral regimen (the treatment-interruption group) or the immediate initiation of an optimized antiretroviral regimen (the control group). Random assignments were made with the use of a permuted-block design in a 1:1 ratio and stratification according to the CPCRA unit. To assist with the selection of an optimized regimen, clinicians were given the results of both the genotypic and phenotypic antiretroviral-resistance tests performed at screening.
The primary outcome of the study was disease progression or death. Disease progression was defined as the first confirmed or probable16 occurrence of an AIDS-defining condition on the basis of the classification of the Centers for Disease Control and Prevention.17 An end-points committee whose members were unaware of the patients' treatment assignments reviewed all disease-progression events. Secondary outcomes included changes from base line in HIV RNA levels, CD4 cell counts, and genotypic resistance; self-reported adherence to the assigned regimen; adverse events; targeted symptoms; and quality of life, measured with the use of the physical and mental health summary scales of the Medical Outcomes Study 12-item Short-Form General Health Survey (SF-12).18 Scores on each scale range from 0 (worst) to 100 (best). It was recommended that treatment be resumed before the specified four-month period in the event of disease progression or a 50 percent decrease in the CD4 cell count. The importance of adherence to standard guidelines for prophylaxis against opportunistic infections was emphasized.19,20
Patients were assessed at base line, monthly for eight months, and every four months thereafter. The data collected included the medical history, CD4 cell count, and HIV RNA level (Amplicor HIV-1 Monitor assay, Roche). Changes in antiretroviral therapy, disease-progression events and deaths, and severe or life-threatening (grade 4) events were reported as they occurred. Plasma-derived viral RNA was used for antiretroviral-resistance testing at screening and during follow-up with the use of genotypic (TRUGENE HIV-1 Genotyping Kit and OpenGene DNA Sequencing System, Bayer Diagnostics) and phenotypic (Antivirogram, Virco)21 assays. The sensitivity of each drug was reported on genotypic testing as sensitive, intermediate, or resistant, according to the CPCRA genotypic interpretive algorithm.
Monitoring
Enrollment opened in June 2000. The data and safety monitoring board of the Division of AIDS of the National Institute of Allergy and Infectious Diseases reviewed interim findings every three to six months. Reversion to wild-type virus and declines in the CD4 cell count were monitored in the treatment-interruption group. In addition, the differences between the treatment groups in the rates of disease progression and CD4 cell count and HIV RNA levels were monitored. On June 26, 2002, the board recommended that the study be closed to further enrollment owing to an inferior response of the CD4 cell count and an increased risk of disease progression in the treatment-interruption group. The results presented herein represent data from the 270 patients analyzed in the review by the data safety and monitoring board.
Statistical Analysis
We designed the study with a statistical power of 80 percent to detect a 33 percent reduction in the incidence of progression of disease or death in the treatment-interruption group, assuming that 60 percent of patients in the control group would have such events within 24 months and that there would be 200 primary events. A total of 480 patients were to be enrolled and followed for a minimum of two years. Proportional-hazards models, Kaplan–Meier curves, and log-rank tests were used to compare the treatment groups with respect to disease progression or death, adverse events, and the time to recovery of the CD4 cell count. The censoring date for the analyses of the time to a clinical event was May 9, 2002. Longitudinal regression models, with adjustment for base-line values and the CPCRA unit, were used to compare changes in CD4 cell counts and HIV RNA levels. Analysis of variance was used to compare changes in symptoms and quality-of-life scores.18 All analyses were conducted according to the intention-to-treat principle, stratified according to the CPCRA unit, and based on a two-sided type I error with an alpha value of 0.05.
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 (Table 1Table 1
Base-Line Characteristics of the Patients.). 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 (defined in Supplementary Appendix 1). 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) (Table 2Table 2
Incidence of Progression of Disease or Death. and Figure 1Figure 1Kaplan–Meier Estimates of the Cumulative Incidence of Progression of Disease or Death.). 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) (Table 2). 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
Figure 2AFigure 2
Mean Changes in CD4 Cell Counts (Panel A) and Plasma HIV RNA Levels (Panel B). shows the mean changes in CD4 cell counts in the two treatment groups. 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 (Figure 2B). 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. Table 3Table 3
Patients with a Plasma Viral Load of Less Than 400 Copies per Milliliter. shows the percentage of patients with fewer than 400 copies of HIV RNA per milliliter in each treatment group at each visit. The percentage with such 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.
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.13 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.7-9,11,12,14,15,22 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.14,15 The GIGHAART study15 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,14 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.5,8-10 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 study22 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,14,15 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.
Supported by grants (5U01AI042170-10 and 5U01AI046362-03) from the National Institute of Allergy and Infectious Diseases, National Institutes of Health.
Dr. Abrams reports having received consulting fees from Abbott, Gilead Pharmaceuticals, GlaxoSmithKline, and Merck; Dr. Baxter having received consulting or lecture fees from Agouron Pharmaceuticals, Bayer Diagnostics, Boehringer Ingelheim, Celera Diagnostics, and GlaxoSmithKline; Dr. Crane having received consulting or lecture fees from Bristol-Myers Squibb, Boehringer Ingelheim, Gilead Pharmaceuticals, GlaxoSmithKline, and Roche Pharmaceuticals and grant support from Bristol-Myers Squibb and Boehringer Ingelheim; and Dr. Lawrence having received consulting fees from Johnson & Johnson Research.
We are indebted to the patients who participated in the study; to Barbara Brizz, Harry Dohnert, Gerald Friedland, Marie Hoover, Denise Kirschner, Caron Lee, Carlos Malvestutto, Sharon Mannheimer, Ana Martinez, John Matts, Veronica Miller, John Omanoff, Carla Pettinelli, Patricia Reitenga, Alex Rinehart, Kandrea Shipp, David Stein, Mark Tanner, Werner Verbiest, Rita Verheggen, Dean Winslow, and Alyssa Zweibel for their collaboration and contributions to the conduct of the study; to David Cohn, Wafaa El-Sadr, Fred Gordin, and Jim Neaton for their thoughtful comments and manuscript review; and to Virco and Visible Genetics/Bayer Diagnostics for providing laboratory support.
Source Information
From the Department of Medicine, Positive Health Program, San Francisco General Hospital, University of California, San Francisco, San Francisco (J.L., D.I.A., M.C.J.); Infectious Disease Research, Henry Ford Hospital, Detroit (D.L.M.); the Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis (K.H.H., G.C.); the National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS, Bethesda, Md. (R.B.R.); the Department of Medicine, Wayne State University School of Medicine, Detroit (L.R.C.); Social & Scientific Systems, Silver Spring, Md. (B.S.S.); the Washington Regional AIDS Program, Washington, D.C. (T.J.D.); the Denver Public Health Department, Denver (J.M.S.); and the Department of Medicine, Cooper Hospital, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, Camden (J.D.B.).
Address reprint requests to Dr. Lawrence at the University of California, San Francisco, San Francisco General Hospital, 3180 18th St., Suite 305, San Francisco, CA 94110, or at jlawrence@php.ucsf.edu.
Other participating investigators are listed in the Appendix.
Appendix
The following centers and investigators participated in the study: AIDS Research Alliance of Chicago — R. Luskin-Hawk, R. Verheggen, M. Schultz; Bronx AIDS Research Consortium — E. Telzak, J. McGowan, J. Shuter; Community Consortium of San Francisco — P.A. Pell, C.C. Child; Denver Community Program for Clinical Research on AIDS — D. Cohn, R. Fernandez, F. Moran; Harlem AIDS Treatment Group — E. Monde, L. Fuentes; Henry Ford Hospital — N. Markowitz, L. Faber, L. Makohon; Houston AIDS Research Team — H. Cuervo, R. Manning, R. Arduino; Louisiana Community AIDS Program — S. Pablovich, J. Walker; Philadelphia Field Initiated Group HIV Trials — E. Tedaldi; New England Program for AIDS Clinical Trials — M. Kozal, L. Andrews, L. Daley; North Jersey Community Research Initiative — R. Sawyer, P. Andrew; Richmond AIDS Consortium — E.J. Fisher, P.W. Dodson, M.L. Howe; Southern New Jersey AIDS Clinical Trials — K. Casey, D. Condoluci, C. Graeber; the Research and Education Group (Portland, Oreg.) — J. Sampson, S. Peterson, D. Antoniskis; Washington Regional AIDS Program — B. Standridge, S. McHugh, A. Labriola; Wayne State University — M. Farrough, J. Kosmyna.
- References
References
1
Deeks SG ,Barbour JD ,Martin JN ,Swanson MS ,Grant RM . Sustained CD4+ T cell response after virologic failure of protease inhibitor-based regimens in patients with human immunodeficiency virus infection. J Infect Dis 2000;181:946-953
CrossRef | Web of Science | Medline2
Deeks SG ,Barbour JD ,Grant RM ,Martin JN . Duration and predictors of CD4 T-cell gains in patients who continue combination therapy despite detectable plasma viremia. AIDS 2002;16:201-207
CrossRef | Web of Science | Medline3
Barbour JD ,Wrin T ,Grant RM , et al. Evolution of phenotypic drug susceptibility and viral replication capacity during long-term virologic failure of protease inhibitor therapy in human immunodeficiency virus-infected adults. J Virol 2002;76:11104-11112
CrossRef | Web of Science | Medline4
Kantor R ,Fessel WJ ,Zolopa AR , et al. Evolution of primary protease inhibitor resistance mutations during protease inhibitor salvage therapy. Antimicrob Agents Chemother 2002;46:1086-1092
CrossRef | Web of Science | Medline5
Youle M ,Janossy G ,Turnbull W , et al. Changes in CD4 lymphocyte counts after interruption of therapy in patients with viral failure on protease inhibitor-containing regimens. AIDS 2000;14:1717-1720
CrossRef | Web of Science | Medline6
Devereux HL ,Youle M ,Johnson MA ,Loveday C . Rapid decline in detectability of HIV-1 drug resistance mutations after stopping therapy. AIDS 1999;13:F123-F127
CrossRef | Web of Science | Medline7
Delaugerre C ,Valantin MA ,Mouroux M , et al. Re-occurrence of HIV-1 drug mutations after treatment re-initiation following interruption in patients with multiple treatment failure. AIDS 2001;15:2189-2191
CrossRef | Web of Science | Medline8
Deeks SG ,Wrin T ,Liegler T , et al. Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia. N Engl J Med 2001;344:472-480
Full Text | Web of Science | Medline9
Miller V ,Sabin C ,Hertogs K , et al. Virological and immunological effects of treatment interruptions in HIV-1 infected patients with treatment failure. AIDS 2000;14:2857-2867
CrossRef | Web of Science | Medline10
Tebas P ,Henry K ,Mondy K , et al. Effect of prolonged discontinuation of successful antiretroviral therapy on CD4+ T cell decline in human immunodeficiency virus-infected patients: implications for intermittent therapeutic strategies. J Infect Dis 2002;186:851-854[Erratum, J Infect Dis 2002;186:1198.]
CrossRef | Web of Science | Medline11
Deeks SG, Wrin T, Hoh R, et al. Virologic and immunologic evaluation of structured treatment interruptions in HIV-1 infected patients experiencing long-term virologic failure. Presented at the Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, January 30–February 2, 2000. abstract.
12
Izopet J ,Massip P ,Souyris C , et al. Shift in HIV resistance genotype after treatment interruption and short-term antiviral effect following a new salvage regimen. AIDS 2000;14:2247-2255
CrossRef | Web of Science | Medline13
Deeks SG ,Grant RM ,Wrin T , et al. Persistence of drug-resistant HIV-1 after a structured treatment interruption and its impact on treatment response. AIDS 2003;17:361-370
CrossRef | Web of Science | Medline14
Ruiz L ,Ribera E ,Bonjoch A , et al. Virological and immunological benefit of a salvage therapy that includes kaletra plus fortovase preceded or not by antiretroviral therapy interruption in advanced HIV-infected patients with multidrug resistance mutations (48 weeks follow-up). Antiviral Ther 2002;7:Suppl 1:S126-S126 abstract.15
Katlama C, Dominguez S, Duvivier C, et al. Long-term benefit of treatment interruption in salvage therapy (GIGHAART ANRS 097). Presented at the 10th Conference on Retroviruses and Opportunistic Infections, Boston, February 10–14, 2003. abstract.
16
Green LA ,Rhame FS ,Price RW , et al. Experience with a cross-study endpoint review committee for AIDS clinical trials. AIDS 1998;12:1983-1990
CrossRef | Web of Science | Medline17
1993 Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep 1992;41:1-19
18
Ware J, Kosinski M, Keller S. SF-12: how to score the SF-12 Physical and Mental Health Summary Scales. 3rd ed. Lincoln, R.I.: QualityMetric, 2000.
19
Kaplan JE ,Masur H ,Holmes KK . Guidelines for preventing opportunistic infections among HIV-infected persons -- 2002: recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. MMWR Recomm Rep 2002;51:1-52
Medline20
1999 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. MMWR Recomm Rep 1999;48:1-59, 61
21
Cohen CJ ,Hunt S ,Sension M , et al. A randomized trial assessing the impact of phenotypic resistance testing on antiretroviral therapy. AIDS 2002;16:579-588
CrossRef | Web of Science | Medline22
Lundgren JD, Vella S, Paddam L, et al. Interruption/stopping antiretroviral therapy and the risk of clinical disease: results from the EuroSIDA Study. Presented at the Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, February 24–28, 2002. abstract.
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CrossRef2
Katherine Huppler Hullsiek, Birgit Grund. (2011) Considerations for Endpoint Selection When Designing HIV Clinical Trials. Current Infectious Disease Reports
CrossRef3
Andrea L Ciaranello, Shahin Lockman, Kenneth A Freedberg, Michael Hughes, Jennifer Chu, Judith Currier, Robin Wood, Charles B Holmes, Sandy Pillay, Francesca Conradie, James McIntyre, Elena Losina, Rochelle P Walensky. (2011) First-line antiretroviral therapy after single-dose nevirapine exposure in South Africa: a cost-effectiveness analysis of the OCTANE trial. AIDS 25:4, 479-492
CrossRef4
Mark A. Boyd, Andrew M. Hill. (2010) Clinical Management of Treatment-Experienced, HIV/AIDS Patients in the Combination Antiretroviral Therapy Era. PharmacoEconomics 28, 17-34
CrossRef5
Panel de expertos de Gesida, Plan Nacional sobre el Sida. (2010) Documento de consenso del Grupo de Estudio de Sida/Plan Nacional sobre el Sida respecto al tratamiento antirretroviral en adultos infectados por el virus de la inmunodeficiencia humana (actualización enero 2010). Enfermedades Infecciosas y Microbiología Clínica 28:6, 362.e1-362.e91
CrossRef6
Dmitri E Iarikov, Melina Irizarry-Acosta, Claudia Martorell, Carol A Rauch, Robert P Hoffman, Daniel J Skiest. (2010) Use of HIV Resistance Testing After Prolonged Treatment Interruption. JAIDS Journal of Acquired Immune Deficiency Syndromes 53:3, 333-337
CrossRef7
Roger Paredes, Bonaventura Clotet. (2010) Clinical management of HIV-1 resistance. Antiviral Research 85:1, 245-265
CrossRef8
Bin Wang, Dominic E. Dwyer, Choo Beng Chew, Chenda Kol, Zhong Ping He, Hemal Joshi, Megan C. Steain, Anthony L. Cunningham, Nitin K. Saksena. (2009) Sensitive detection of the K103N non-nucleoside reverse transcriptase inhibitor resistance mutation in treatment-naïve HIV-1 infected individuals by rolling circle amplification. Journal of Virological Methods 161:1, 128-135
CrossRef9
Marios M. Hadjiandreou, Raúl Conejeros, D. Ian Wilson. (2009) Planning of patient-specific drug-specific optimal HIV treatment strategies. Chemical Engineering Science 64:18, 4024-4039
CrossRef10
Rosario C. Mata, Fernando Flor-Parra, Pompeyo Viciana, Luis F. López-Cortés, Pilar Pérez-Romero. (2009) Virological and immunological stability in HIV infected patients undergoing partial-treatment interruption. Journal of Clinical Virology 45:4, 362-366
CrossRef11
Bret J. Rudy, John Sleasman, Bill Kapogiannis, Craig M. Wilson, James Bethel, Leslie Serchuck, Sushma Ahmad, Coleen K. Cunningham. (2009) Short-Cycle Therapy in Adolescents after Continuous Therapy with Established Viral Suppression: The Impact on Viral Load Suppression. AIDS Research and Human Retroviruses 25:6, 555-561
CrossRef12
Marios M. Hadjiandreou, Raul Conejeros, D. Ian Wilson. (2009) Long-term HIV dynamics subject to continuous therapy and structured treatment interruptions. Chemical Engineering Science 64:7, 1600-1617
CrossRef13
M. Zaccarelli, P. Lorenzini, V. Tozzi, F. Forbici, F. Ceccherini-Silberstein, C. Gori, R. D’Arrigo, M. P. Trotta, P. Narciso, C. F. Perno, A. Antinori, . (2009) Effect of Suppressing HIV Viremia on the HIV Progression of Patients Undergoing a Genotype Resistance Test after Treatment Failure. Infection
CrossRef14
Allan R. Tenorio, Hongyu Jiang, Yu Zheng, Barbara Bastow, Daniel R. Kuritzkes, John A. Bartlett, Steven G. Deeks, Alan L. Landay, Sharon A. Riddler. (2009) Delaying a Treatment Switch in Antiretroviral-Treated HIV Type 1-Infected Patients with Detectable Drug-Resistant Viremia Does Not Have a Profound Effect on Immune Parameters: AIDS Clinical Trials Group Study A5115. AIDS Research and Human Retroviruses 25:2, 135-139
CrossRef15
Gerond Lake-Bakaar. (2009) The effect of controlled therapy interruption in chronic HCV infection: Enhanced host immune response? A hypothesis. Journal of Clinical Virology 44:2, 149-151
CrossRef16
Giota Touloumi, Nikos Pantazis, Heide A Stirnadel, A Sarah Walker, Faroudy Boufassa, Philippe Vanhems, Kholoud Porter. (2008) Rates and Determinants of Virologic and Immunological Response to HAART Resumption After Treatment Interruption in HIV-1 Clinical Practice. JAIDS Journal of Acquired Immune Deficiency Syndromes 49:5, 492-498
CrossRef17
Ellen Tedaldi, Lars Peters, Jacquie Neuhaus, Massimo Puoti, Jürgen Rockstroh, Marina B. Klein, Gregory J. Dore, Amanda Mocroft, Vincent Soriano, Bonaventura Clotet, Jens D. Lundgren, . (2008) Opportunistic Disease and Mortality in Patients Coinfected with Hepatitis B or C Virus in the Strategic Management of Antiretroviral Therapy (SMART) Study. Clinical Infectious Diseases 47:11, 1468-1475
CrossRef18
Maryanne T. Vahey, Zhining Wang, Zhaohui Su, Martin E. Nau, Amy Krambrink, Daniel J. Skiest, David M. Margolis. (2008) CD4 + T-Cell Decline after the Interruption of Antiretroviral Therapy in ACTG A5170 Is Predicted by Differential Expression of Genes in the Ras Signaling Pathway. AIDS Research and Human Retroviruses 24:8, 1047-1066
CrossRef19
Martin S. Hirsch, Huldrych F. Günthard, Jonathan M. Schapiro, Françoise Brun‐Vézinet, Bonaventura Clotet, Scott M. Hammer, Victoria A. Johnson, Daniel R. Kuritzkes, John W. Mellors, Deenan Pillay, Patrick G. Yeni, Donna M. Jacobsen, Douglas D. Richman. (2008) Antiretroviral Drug Resistance Testing in Adult HIV‐1 Infection: 2008 Recommendations of an International AIDS Society–USA Panel. Clinical Infectious Diseases 47:2, 266-285
CrossRef20
Birgit Grund. 2008. Treatment Interruption. .
CrossRef21
Alessandro Soria, Mariangela Cavarelli, Stefania Sala, Anna Ida Alessandrini, Gabriella Scarlatti, Adriano Lazzarin, Antonella Castagna. (2008) Unexpected dramatic increase in CD4+ cell count in a patient with AIDS after enfuvirtide treatment despite persistent viremia and resistance mutations. Journal of Medical Virology 80:6, 937-941
CrossRef22
Joseph J. Eron. (2008) Managing Antiretroviral Therapy: Changing Regimens, Resistance Testing, and the Risks from Structured Treatment Interruptions. The Journal of Infectious Diseases 197:s3, S261-S271
CrossRef23
Junko Tanuma, Mamoru Fujiwara, Katsuji Teruya, Saori Matsuoka, Hikaru Yamanaka, Hiroyuki Gatanaga, Natsuo Tachikawa, Yoshimi Kikuchi, Masafumi Takiguchi, Shinichi Oka. (2008) HLA-A*2402-restricted HIV-1-specific cytotoxic T lymphocytes and escape mutation after ART with structured treatment interruptions. Microbes and Infection 10:6, 689-698
CrossRef24
Meena Lagnese, Eric S Daar. (2008) Antiretroviral regimens for treatment-experienced patients with HIV-1 infection. Expert Opinion on Pharmacotherapy 9:5, 687-700
CrossRef25
Carina A. Rodriguez, Sarah Koch, Maureen Goodenow, John W. Sleasman. (2008) Clinical implications of discordant viral and immune outcomes following protease inhibitor containing antiretroviral therapy for HIV-infected children. Immunologic Research 40:3, 271-286
CrossRef26
S. Mannheimer, L. Thackeray, K. Huppler Hullsiek, M. Chesney, E. M. Gardner, A. W. Wu, E. E. Telzak, J. Lawrence, J. Baxter, G. Friedland, for the Terry Beirn Community Progr. (2008) A randomized comparison of two instruments for measuring self-reported antiretroviral adherence. AIDS Care 20:2, 161-169
CrossRef27
I. Kousignian, S. Abgrall, S. Grabar, A. Mahamat, E. Teicher, E. Rouveix, D. Costagliola, . (2008) Maintaining Antiretroviral Therapy Reduces the Risk of AIDS-Defining Events in Patients with Uncontrolled Viral Replication and Profound Immunodeficiency. Clinical Infectious Diseases 46:2, 296-304
CrossRef28
Paul A. Volberding. 2008. Overview of Antiretroviral Therapy. , 135-148.
CrossRef29
Marianne Harris, P. Richard Harrigan, Julio S.G. Montaner. 2008. Antiretroviral Therapy of Drug-resistant HIV. , 537-545.
CrossRef30
Jason D. Barbour, Steven G. Deeks. 2008. Clinical Implications of HIV Fitness and Virulence. , 161-169.
CrossRef31
Geoffrey J Yuen, Steve Weller, Gary E Pakes. (2008) A Review of the Pharmacokinetics of Abacavir. Clinical Pharmacokinetics 47:6, 351-371
CrossRef32
Hamid Hasson, Barbara Mantelli, Priscilla Biswas, Mauro Malnati, Nicola Gianotti, Andrea Vecchi, Silvia Nozza, Massimo Cernuschi, Enzo Boeri, Mario Clerici, Adriano Lazzarin, Alberto Beretta. (2007) Favorable outcome of ex-vivo purging of monocytes after the reintroduction of treatment after interruption in patients infected with multidrug resistant HIV-1. Journal of Medical Virology 79:11, 1640-1649
CrossRef33
T. Gandhi, V. Nagappan, S. Cinti, W. Wei, P. Kazanjian. (2007) Long-Term Immunologic and Virologic Responses in Patients with Highly Resistant HIV Infection Who Are Treated with an Incompletely Suppressive Antiretroviral Regimen. Clinical Infectious Diseases 45:8, 1085-1092
CrossRef34
Sharon L Walmsley, Anona Thorne, Mona R Loutfy, Natasha LaPierre, John MacLeod, Richard Harrigan, Benoit Trottier, Brian Conway, Joy R Hay, Joel Singer, Don Zarowny. (2007) A Prospective Randomized Controlled Trial of Structured Treatment Interruption in HIV-Infected Patients Failing Highly Active Antiretroviral Therapy (Canadian HIV Trials Network Study 164). JAIDS Journal of Acquired Immune Deficiency Syndromes 45:4, 418-425
CrossRef35
Jeffrey M Jacobson. (2007) Role of structured treatment interruption in HIV infection. Future HIV Therapy 1:1, 73-80
CrossRef36
Eric S. Rosenberg, Marie Davidian, H. Thomas Banks. (2007) Using mathematical modeling and control to develop structured treatment interruption strategies for HIV infection. Drug and Alcohol Dependence 88, S41-S51
CrossRef37
Seth L Welles, Greta R Bauer, Philip S LaRussa, Robert C Colgrove, Jane Pitt. (2007) Time Trends for HIV-1 Antiretroviral Resistance Among Antiretroviral-Experienced and Naive Pregnant Women in New York City During 1991 to Early 2001. JAIDS Journal of Acquired Immune Deficiency Syndromes 44:3, 329-335
CrossRef38
C Holkmann Olsen, A Mocroft, O Kirk, S Vella, A Blaxhult, N Clumeck, M Fisher, C Katlama, AN Phillips, JD Lundgren, . (2007) Interruption of combination antiretroviral therapy and risk of clinical disease progression to AIDS or death. HIV Medicine 8:2, 96-104
CrossRef39
Joel E. Gallant. (2007) Approach to the Treatment-Experienced Patient. Infectious Disease Clinics of North America 21:1, 85-102
CrossRef40
Rosario Sanchez, Joaquín Portilla, Adelina Gimeno, Vicente Boix, Coral Llopis, Jose Sanchez-Paya, Esperanza Merino, Maria Luz de la Sen, Carlos Muñoz, Sergio Reus, Joaquín Plazas. (2007) Immunovirologic consequences and safety of short, non-structured interruptions of successful antiretroviral treatment. Journal of Infection 54:2, 159-166
CrossRef41
Schlomo Staszewski. (2007) Treatment interruption in advanced failing patients. Current Opinion in HIV and AIDS 2:1, 39-45
CrossRef42
Jan van Lunzen, Christian Hoffmann. (2007) Virological rebound and its consequences during treatment interruption. Current Opinion in HIV and AIDS 2:1, 1-5
CrossRef43
Xiuqiong Bi, Hiroyuki Gatanaga, Kazuhiko Koike, Satoshi Kimura, Shinichi Oka. (2007) Reversal Periods and Patterns from Drug-Resistant to Wild-Type HIV Type 1 after Cessation of Anti-HIV Therapy. AIDS Research and Human Retroviruses 23:1, 43-50
CrossRef44
Steven G Deeks, Jeffrey N Martin. (2007) Partial treatment interruptions. Current Opinion in HIV and AIDS 2:1, 46-55
CrossRef45
Christian B Willberg, Douglas F Nixon. (2007) Treatment interruption in chronic HIV-1 infection: does it deliver?. Current Opinion in HIV and AIDS 2:1, 26-30
CrossRef46
Nitika Pant Pai, Marina B Klein. (2006) Structured treatment interruptions in chronic HIV management: where next?. Expert Review of Anti-infective Therapy 4:6, 909-912
CrossRef47
H. Hatano, P. Hunt, J. Weidler, E. Coakley, R. Hoh, T. Liegler, J. N. Martin, S. G. Deeks. (2006) Rate of Viral Evolution and Risk of Losing Future Drug Options in Heavily Pretreated, HIV-Infected Patients Who Continue to Receive a Stable, Partially Suppressive Treatment Regimen. Clinical Infectious Diseases 43:10, 1329-1336
CrossRef48
Christine Katlama, Jade Ghosn. (2006) Clinical trials for heavily pretreated patients: update in 2006. Current Opinion in HIV and AIDS 1:6, 495-501
CrossRef49
Matthew Bidwell Goetz, Monique R Ferguson, Xueliang Han, Greg McMillan, Marty St. Clair, Keith A Pappa, Daniel R McClernon, William A O???Brien. (2006) Evolution of HIV Resistance Mutations in Patients Maintained on a Stable Treatment Regimen After Virologic Failure. JAIDS Journal of Acquired Immune Deficiency Syndromes PAP,
CrossRef50
Andrew N Phillips, Cal Cohen, Jens D Lundgren. (2006) Issues in the design of trials comparing management strategies for heavily pretreated patients. Current Opinion in HIV and AIDS 1:6, 476-481
CrossRef51
Jody Lawrence, Katherine Huppler Hullsiek, Lisa M Thackeray, Donald I Abrams, Lawrence R Crane, Douglas L Mayers, Michael C Jones, Jennifer M Saldanha, Barry S Schmetter, John D Baxter. (2006) Disadvantages of Structured Treatment Interruption Persist in Patients With Multidrug-Resistant HIV-1. JAIDS Journal of Acquired Immune Deficiency Syndromes 43:2, 169-178
CrossRef52
Charles Hicks. (2006) Management of the highly experienced patient. Current Opinion in HIV and AIDS 1:5, 424-429
CrossRef53
Douglas D. Richman. (2006) Antiviral drug resistance. Antiviral Research 71:2-3, 117-121
CrossRef54
José Miguel Benito, Mariola López, Celia Ballesteros, Sara Lozano, Laura Capa, Pablo Barreiro, José Sempere, Juan Gonzalez-Lahoz, Vincent Soriano. (2006) Immunological and Virological Effects of Structured Treatment Interruptions following Exposure to Hydroxyurea Plus Didanosine. AIDS Research and Human Retroviruses 22:8, 734-743
CrossRef55
Zelalem Temesgen, Francesca Cainelli, Eric M Poeschla, Stacey AR Vlahakis, Sandro Vento. (2006) Approach to salvage antiretroviral therapy in heavily antiretroviral-experienced HIV-positive adults. The Lancet Infectious Diseases 6:8, 496-507
CrossRef56
Michael G. Rosenberg, Jacobo Abadi, Joanna Dobroszycki, Andrew Wiznia. (2006) Progress and challenges in antiretroviral therapy for HIV-infected children. Current Infectious Disease Reports 8:4, 324-331
CrossRef57
Nitika Pant Pai, Jody Lawrence, Arthur L Reingold, Jacqueline P Tulsky, Nitika Pant Pai. 2006. Structured treatment interruptions (STI) in chronic unsuppressed HIV infection in adults. .
CrossRef58
David A. Rier, Debbie Indyk. (2006) Flexible Rigidity. Social Work in Health Care 42:3-4, 133-150
CrossRef59
Rafik Samuel, Robert Bettiker, Byungse Suh. (2006) Antiretroviral therapy 2006: Pharmacology, applications, and special situations. Archives of Pharmacal Research 29:6, 431-458
CrossRef60
Beth Ann Griffin, Stephen Lagakos. (2006) Analysis of Failure Time Data Arising From Studies With Alternating Treatment Schedules. Journal of the American Statistical Association 101:474, 510-520
CrossRef61
Tim Niehues, Ulrich Baumann, Bernd Buchholz, Dominik Dunsch, Markus Funk, Christoph Königs, Martin Edelhäuser, Jennifer Neubert, Gundula Notheis, Uwe Wintergerst. (2006) Empfehlungen zur antiretroviralen Therapie bei HIV-infizierten Kindern. Monatsschrift Kinderheilkunde 154:6, 565-577
CrossRef62
Cunlin Wang, Saba W. Masho, Daniel E. Nixon. (2006) When to start antiretroviral therapy. Current HIV/AIDS Reports 3:2, 66-73
CrossRef63
T. F. Liu, R. W. Shafer. (2006) Web Resources for HIV Type 1 Genotypic-Resistance Test Interpretation. Clinical Infectious Diseases 42:11, 1608-1618
CrossRef64
Joseph C. Gathe, Robin Wood, Ian Sanne, Edwin Dejesus, Schürmann Dirk, Andrzej Gladysz, Cindy Garris, Naomi Givens, Robert Elston, Jane Yeo. (2006) Long-Term (120-Week) antiviral efficacy and tolerability of fosamprenavir/ritonavir once daily in therapy-naive patients with HIV-1 infection: An uncontrolled, open-label, single-arm follow-on study. Clinical Therapeutics 28:5, 745-754
CrossRef65
Manuel Battegay, Reto Nüesch, Bernard Hirschel, Gilbert R Kaufmann. (2006) Immunological recovery and antiretroviral therapy in HIV-1 infection. The Lancet Infectious Diseases 6:5, 280-287
CrossRef66
Karin J Metzner. (2006) Persistence of drug-resistant HIV-1 and possible implications for antiretroviral therapy. Future Virology 1:3, 377-391
CrossRef67
Antonella Castagna, Anna Danise, Stefano Menzo, Laura Galli, Nicola Gianotti, Elisabetta Carini, Enzo Boeri, Andrea Galli, Massimo Cernuschi, Hamid Hasson, Massimo Clementi, Adriano Lazzarin. (2006) Lamivudine monotherapy in HIV-1-infected patients harbouring a lamivudine-resistant virus: a randomized pilot study (E-184V study). AIDS 20:6, 795-803
CrossRef68
T. Gandhi, W. Wei, K. Amin, P. Kazanjian. (2006) Effect of Maintaining Highly Active Antiretroviral Therapy on AIDS Events among Patients with Late-Stage HIV Infection and Inadequate Response to Therapy. Clinical Infectious Diseases 42:6, 878-884
CrossRef69
Sarah Palmer, Valerie Boltz, Frank Maldarelli, Mary Kearney, Elias K Halvas, Diane Rock, Judith Falloon, Richard T Davey, Robin L Dewar, Julia A Metcalf, John W Mellors, John M Coffin. (2006) Selection and persistence of non-nucleoside reverse transcriptase inhibitor-resistant HIV-1 in patients starting and stopping non-nucleoside therapy. AIDS 20:5, 701-710
CrossRef70
Jacobo Abadi, Eli Sprecher, Michael G. Rosenberg, Joanna Dobroszycki, Jorge Sansary, Glenn Fennelly, Andrew Wiznia. (2006) Partial Treatment Interruption of Protease Inhibitor-Based Highly Active Antiretroviral Therapy Regimens in HIV-Infected Children. JAIDS Journal of Acquired Immune Deficiency Syndromes 41:3, 298-303
CrossRef71
Roger Bedimo, Ray Y. Chen, Andrew O. Westfall, James L. Raper, Jeroan J. Allison, Michael S. Saag. (2006) Sustained HIV Viral Suppression following Treatment Interruption: An Observational Study. AIDS Research and Human Retroviruses 22:1, 40-44
CrossRef72
Christine M Haggerty, Eleanor Pitt, Robert F Siliciano. (2006) The latent reservoir for HIV-1 in resting CD4+ T cells and other viral reservoirs during chronic infection: insights from treatment and treatment-interruption trials. Current Opinion in HIV and AIDS 1:1, 62-68
CrossRef73
Melanie Balduin, Saleta Sierra, Martin P Däumer, Jürgen K Rockstroh, Mark Oette, Gerd Fätkenheuer, Bernd Kupfer, Niko Beerenwinkel, Daniel Hoffmann, Joachim Selbig, Herbert J Pfister, Rolf Kaiser. (2005) Evolution of HIV resistance during treatment interruption in experienced patients and after restarting a new therapy. Journal of Clinical Virology 34:4, 277-287
CrossRef74
Sébastien Boucher, Patricia Recordon-Pinson, Didier Neau, Jean-Marie Ragnaud, Karine Titier, Muriel Faure, Hervé Fleury, Bernard Masquelier. (2005) Clonal analysis of HIV-1 variants in proviral DNA during treatment interruption in patients with multiple therapy failures. Journal of Clinical Virology 34:4, 288-294
CrossRef75
Constance Delaugerre, Gilles Peytavin, Stephanie Dominguez, Anne-Genevieve Marcelin, Claudine Duvivier, Karine Gourlain, Bahia Amellal, Mayeule Legrand, François Raffi, Dominique Costagliola, Christine Katlama, Vincent Calvez. (2005) Virological and pharmacological factors associated with virological response to salvage therapy after an 8-week of treatment interruption in a context of very advanced HIV disease (GigHAART ANRS 097). Journal of Medical Virology 77:3, 345-350
CrossRef76
Nitika Pant Pai, Jacqueline P Tulsky, Jody Lawrence, John M Colford, Arthur L Reingold, Nitika Pant Pai. 2005. Structured treatment interruptions (STI) in chronic suppressed HIV infection in adults. .
CrossRef77
Andrew D Luber. (2005) Treatment strategies for highly treatment-experienced HIV-infected patients. Expert Review of Anti-infective Therapy 3:5, 815-823
CrossRef78
Jade Ghosn, Marc Wirden, Nadine Ktorza, Gilles Peytavin, Hocine Aït-Mohand, Luminita Schneider, Stéphanie Dominguez, François Bricaire, Vincent Calvez, Dominique Costagliola, Christine Katlama. (2005) No benefit of a structured treatment interruption based on genotypic resistance in heavily pretreated HIV-infected patients. AIDS 19:15, 1643-1647
CrossRef79
Andrea Antinori, Antonella Cingolani, Carlo Federico Perno. (2005) Structured treatment interruption in HIV-infected patients failing on multidrug therapy: is there a future for this strategy?. AIDS 19:15, 1691-1694
CrossRef80
Fatema A Legrand, Jacob Abadi, Kimberly A Jordan, Miles P Davenport, Steve G Deeks, Glenn J Fennelly, Andrew A Wiznia, Douglas F Nixon, Michael G Rosenberg. (2005) Partial treatment interruption of protease inhibitors augments HIV-specific immune responses in vertically infected pediatric patients. AIDS 19:15, 1575-1585
CrossRef81
M. Arnedo-Valero, F. Garcia, C. Gil, T. Guila, E. Fumero, P. Castro, J. L. Blanco, J. M. Miro, T. Pumarola, J. M. Gatell. (2005) Risk of Selecting De Novo Drug-Resistance Mutations during Structured Treatment Interruptions in Patients with Chronic HIV Infection. Clinical Infectious Diseases 41:6, 883-890
CrossRef82
Rosario C. Mata, Pompeyo Viciana, Arístides De Alarcón, Luis F. López-Cortés, Josefa Gómez-Vera, Mónica Trastoy, José M. Cisneros. (2005) Discontinuation of Antiretroviral Therapy in Patients with Chronic HIV Infection: Clinical, Virologic, and Immunologic Consequences. AIDS Patient Care and STDs 19:9, 550-562
CrossRef83
Berta Rodes, Federico García, Carolina Gutierrez, Javier Martinez-Picado, Antonio Aguilera, Maria Saumoy, Alex Vallejo, Pere Domingo, David Dalmau, Maria Angels Ribas, José Luis Blanco, José Pedreira, Maria Jesús Perez-Elias, Manuel Leal, Carmen de Mendoza, Vincent Soriano, . (2005) Impact of drug resistance genotypes on CD4+ counts and plasma viremia in heavily antiretroviral-experienced HIV-infected patients. Journal of Medical Virology 77:1, 23-28
CrossRef84
B Gazzard, . (2005) British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy (2005). HIV Medicine 6:S2, 1-61
CrossRef85
Mauro Zaccarelli, Valerio Tozzi, Patrizia Lorenzini, Maria P Trotta, Federica Forbici, Ubaldo Visco-Comandini, Caterina Gori, Pasquale Narciso, Carlo F Perno, Andrea Antinori. (2005) Multiple drug class-wide resistance associated with poorer survival after treatment failure in a cohort of HIV-infected patients. AIDS 19:10, 1081-1089
CrossRef86
Benjamin Jacobs, Nancy Neil, David M. Aboulafia. (2005) Retrospective Analysis of Suspending HAART in Selected Patients with Controlled HIV Replication. AIDS Patient Care and STDs 19:7, 429-438
CrossRef87
Concepción Amador, Francisco Pasquau, Javier Ena, Concepción Benito, Rosa F. Ruiz de Apodaca. (2005) Interrupción del tratamiento antirretroviral en pacientes con infección crónica por el virus de la inmunodeficiencia humana. Medicina Clínica 125:2, 41-45
CrossRef88
Joel E. Gallant. (2005) Approach to the Treatment-experienced patient. Current HIV/AIDS Reports 2:2, 83-89
CrossRef89
Alessandra Viganò, Laura Schneider, Vania Giacomet, Roberta Bianchi, Mirko Lo Cicero, Francesca Soster, Elisabetta Bulgheroni, Stefano Rusconi. (2005) Efficacy and tolerability of multiple drug therapy in HIV-infected children. Journal of Infection 50:5, 404-411
CrossRef90
Nicola Gianotti, Elena Seminari, Adriano Lazzarin, Enzo Boeri, Massimo Clementi, Anna Danise, Stefania Salpietro, Giuliana Fusetti, Antonella Castagna. (2005) Redistribution of Human Immunodeficiency Virus Type 1 Variants Resistant to Protease Inhibitors after a Protease Inhibitor-Sparing Regimen. AIDS Research and Human Retroviruses 21:6, 545-554
CrossRef91
José Tomás Ramos, María Isabel de José, Rosa Polo, Claudia Fortuny, María José Mellado, María Ángeles Muñoz-Fernández, José Beceiro, José María Bertrán, Cristina Calvo, Lourdes Chamorro, Luis Ciria, Sara Guillén, Raúl González-Montero, María Isabel González-Tomé, María Dolores Gurbindo, Pablo Martín-Fontelos, Jorge Martínez-Pérez, David Moreno, María Carmen Muñoz-Almagro, Antonio Mur, María Luisa Navarro, Carmen Otero, Pablo Rojo, Bárbara Rubio, Jesús Saavedra. (2005) Recomendaciones CEVIHP/SEIP/AEP/PNS respecto al tratamiento antirretroviral en niños y adolescentes infectados por el VIH. Enfermedades Infecciosas y Microbiología Clínica 23:5, 279-312
CrossRef92
Eric S. Daar, Douglas D. Richman. (2005) Confronting the Emergence of Drug-Resistant HIV Type 1: Impact of Antiretroviral Therapy on Individual and Population Resistance. AIDS Research and Human Retroviruses 21:5, 343-357
CrossRef93
Kimberly Struble, Jeffrey Murray, Ben Cheng, Thomas Gegeny, Veronica Miller, Roy Gulick. (2005) Antiretroviral therapies for treatment-experienced patients: current status and research challenges. AIDS 19:8, 747-756
CrossRef94
Antonella d??Arminio Monforte, Alessandro Cozzi-Lepri, Andrew Phillips, Andrea De Luca, Rita Murri, Cristina Mussini, Paolo Grossi, Andrea Galli, Tiziano Zauli, Maria Montroni, Paolo Tundo, Mauro Moroni. (2005) Interruption of Highly Active Antiretroviral Therapy in HIV Clinical Practice. JAIDS Journal of Acquired Immune Deficiency Syndromes 38:4, 407-416
CrossRef95
José M. Eiros, Raquel Blanco, Cristina Labayru, Beatriz Hernández, Agustín Mayo, Raúl Ortiz de Lejarazu. (2005) Resistencias genotípicas en pacientes con infección por el virus de la inmunodeficiencia humana. Correlación con las pautas terapéuticas empleadas en su tratamiento. Medicina Clínica 124:16, 601-605
CrossRef96
Reto Nuesch, Jintanat Ananworanich, Sunee Sirivichayakul, Sasiwimol Ubolyam, Umaporn Siangphoe, Andrew Hill, David Cooper, Joep Lange, Praphan Phanuphak, Kiat Ruxrungtham. (2005) Development of HIV with Drug Resistance after CD4 Cell Count–Guided Structured Treatment Interruptions in Patients Treated with Highly Active Antiretroviral Therapy after Dual–Nucleoside Analogue Treatment. Clinical Infectious Diseases 40:5, 728-734
CrossRef97
Roberto Arduino. (2005) Editorial Commentary: CD4 Cell Count–Guided Treatment Interruption: Be Smart and Wait for More Evidence. Clinical Infectious Diseases 40:5, 735-737
CrossRef98
Trisha Acri, Andrew Coco, Kenneth Lin, Richard Johnson, Patrick Eckert. (2005) Knowledge of Structured Treatment Interruption and Adherence to Antiretroviral Therapy. AIDS Patient Care and STDs 19:3, 167-173
CrossRef99
J. Montaner, M. Harris, R. Hogg. (2005) Structured Treatment Interruptions: A Risky Business. Clinical Infectious Diseases 40:4, 601-603
CrossRef100
N Alatrakchi, C Duvivier, D Costagliola, A Samri, AG Marcelin, G Kamkamidze, M Astriti, R Agher, V Calvez, B Autran, C Katlama. (2005) Persistent low viral load on antiretroviral therapy is associated with T cell-mediated control of HIV replication. AIDS 19:1, 25-33
CrossRef101
Jintanat Ananworanich, Bernard Hirschel. (2005) Interrupting highly active antiretroviral therapy in patients with HIV. Expert Review of Anti-infective Therapy 3:1, 51-60
CrossRef102
Marianne Harris, Julio S. G. Montaner. (2004) Management of HIV-infected patients with multidrug-resistant virus. Current HIV/AIDS Reports 1:3, 116-121
CrossRef103
Acil Jaafar, Patrice Massip, Karine Sandres-Saun
, Corinne Souyris, Christophe Pasquier, Christian Aquilina, Jacques Izopet. (2004) HIV therapy after treatment interruption in patients with multiple failure and more than 200 CD4+ T lymphocyte count. Journal of Medical Virology 74:1, 8-15
CrossRef104
Patrick Willemot, Marina B Klein. (2004) Prevention of HIV-associated opportunistic infections and diseases in the age of highly active antiretroviral therapy. Expert Review of Anti-infective Therapy 2:4, 521-532
CrossRef105
M Sharland, S Blanche, G Castelli, J Ramos, DM Gibb, . (2004) PENTA guidelines for the use of antiretroviral therapy, 2004. HIV Medicine 5:s2, 61-86
CrossRef106
Rebecca A. Clark, Charles V. Sanders. (2004) An Update on Management of Persons with Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome: Introduction to Symposium. The American Journal of the Medical Sciences 328:1, 1-2
CrossRef107
Rebecca A. Clark, Ron Wilcox, C Lynn Besch. (2004) The Antiretroviral-Experienced Patient. The American Journal of the Medical Sciences 328:1, 10-16
CrossRef108
Bruno Ledergerber. (2004) Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes. The Lancet 364:9428, 51-62
CrossRef109
S. A. Springer, E. Pesanti, J. Hodges, T. Macura, G. Doros, F. L. Altice. (2004) Effectiveness of Antiretroviral Therapy among HIV-Infected Prisoners: Reincarceration and the Lack of Sustained Benefit after Release to the Community. Clinical Infectious Diseases 38:12, 1754-1760
CrossRef110
Michael Neely, Andrea Kovacs. (2004) Management of antiretroviral therapy in neonates, children, and adolescents. Current HIV/AIDS Reports 1:2, 97-104
CrossRef111
Andrea Kovacs, Mark Connors. (2004) HIV-1 and immune control: can we change the course of HIV-1?. The Lancet 363:9412, 833-834
CrossRef112
Daniel E. Kaufmann, Mathias Lichterfeld, Marcus Altfeld, Marylyn M. Addo, Mary N. Johnston, Paul K. Lee, Bradford S. Wagner, Elizabeth T. Kalife, Daryld Strick, Eric S. Rosenberg, Bruce D. Walker. (2004) Limited Durability of Viral Control following Treated Acute HIV Infection. PLoS Medicine 1:2, e36
CrossRef113
(2003) Structured Treatment Interruption for Patients with Human Immunodeficiency Virus Infection. New England Journal of Medicine 349:23, 2268-2269
Full Text114
Michael Neely, Andrea Kovacs. (2003) Management of antiretroviral therapy in neonates, children, and adolescents. Current Infectious Disease Reports 5:6, 521-530
CrossRef115
Ronald B. Reisler, Cong Han, William J. Burman, Ellen M. Tedaldi, James D. Neaton. (2003) Grade 4 Events Are as Important as AIDS Events in the Era of HAART. JAIDS Journal of Acquired Immune Deficiency Syndromes 34:4, 379-386
CrossRef116
P. M. Tarwater, M. Parish, J. E. Gallant. (2003) Prolonged Treatment Interruption after Immunologic Response to Highly Active Antiretroviral Therapy. Clinical Infectious Diseases 37:11, 1541-1548
CrossRef117
Eduardo Fernandez-Cruz, Joaquín Navarro, Carmen Rodriguez-Sainz, Juana Gil, Santiago Moreno, Juan Gonzalez-Lahoz, Javier Carbone. (2003) The potential role of the HIV-1 immunogen (Remune®) as a therapeutic vaccine in the treatment of HIV infection. Expert Review of Vaccines 2:6, 739-752
CrossRef118
Hirschel, Bernard, . (2003) Beware of Drug Holidays before HIV Salvage Therapy. New England Journal of Medicine 349:9, 827-828
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