Structured treatment interruption in patients with multidrug-resistant human immunodeficiency virus. HIV therapy after treatment interruption in patients with multiple failure and more than 200 CD4+ T lymphocyte count. Benefit of treatment interruption in HIV-infected patients with multiple therapeutic failures: a randomized controlled trial (ANRS 097). Role of structured treatment interruption before a 5-drug salvage antiretroviral regimen: the Retrogene Study. Kinetics of disappearance of resistance mutations and reappearance of wild-type during structured treatment interruptions. Interruption of reverse transcriptase inhibitors or a switch from reverse transcriptase to protease inhibitors resulted in a fast reappearance of virus strains with a reverse transcriptase inhibitor-sensitive genotype. Changes in CD4 lymphocyte counts after interruption of therapy in patients with viral failure on protease inhibitor-containing regimens. Royal Free Centre for HIV Medicine. No benefit of a structured treatment interruption based on genotypic resistance in heavily pretreated HIV-infected patients. Re-occurrence of HIV-1 drug mutations after treatment re-initiation following interruption in patients with multiple treatment failure. Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia. Persistence of drug-resistant HIV-1 after a structured treatment interruption and its impact on treatment response. Virological and immunological effects of treatment interruptions in HIV-1 infected patients with treatment failure. Shift in HIV resistance genotype after treatment interruption and short-term antiviral effect following a new salvage regimen.
We compared two strategies for treating patients infected with multidrug-resistant human immunodeficiency virus (HIV).
                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.
                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.
                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.
                Copyright 2003 Massachusetts Medical Society The aim of the study was to investigate the safety and efficacy of a salvage therapy initiated after interrupting treatment in patients with virological failure and more than 200 CD4(+) T lymphocyte count. In this prospective study, 77 patients who received failing regimens had stopped completely all medication for 3 months before starting an optimised regimen consisting of 3-5 drugs. Patients were tested for HIV resistance before and after treatment interruption. Discontinuation of therapy for 3 months was associated with a median increase in HIV RNA of 1.1 log(10), a median decrease in CD4(+) T cell count of 136 x 10(6)/L and five clinical events related to HIV, but no AIDS-defining event. Eighty-seven percent of patients showed a shift from a drug resistant genotype to a wild-type genotype based on the major resistance mutations. Forty-seven percent of patients with a genotype shift reached fewer than 200 HIV RNA copies/ml of plasma 6 and 12 months after treatment resumption whereas none of those without a genotype shift did so (P = 0.03). However, the genotypic shift was not associated with a sustained virological response by multivariate analysis. The use of a new therapeutic class of compound in the salvage regimen was the only predictor of the sustained virological response. Salvage therapy with 3-5 drugs after interrupting treatment for 3 months can be a safe and effective strategy provided the HIV disease is not too advanced. Randomised trials in this population are needed to assess the clinical benefit of this strategy. Both highly potent antiretroviral drug rescue therapy and treatment interruption have been suggested to be effective in patients with multiple treatment failure.
                To assess both the benefits and risks of an 8-week treatment interruption associated with a six to nine-drug rescue regimen in patients with multiple treatment failures.
                A randomized comparative controlled trial in 19 university hospitals in France.
                Sixty-eight HIV-infected patients with multiple previous treatment failures and CD4 cell counts less than 200 x 10(6) cells/l and plasma HIV-1-RNA levels of 50,000 copies/ml or greater.
                The primary efficacy outcome was the proportion of patients with at least a 1 log10 decrease (copies/ml) in the plasma HIV-1-RNA level after 12 weeks of therapy.
                Treatment interruption followed by multidrug salvage therapy led to a greater proportion of patients achieving virological success (i.e. 1 log10 decrease) at 12 weeks compared with patients receiving multidrug therapy alone (62 versus 26%, intent-to-treat analysis; P = 0.007). The median decrease in the HIV-1-RNA level was -1.91 and -0.37 log10 copies/ml (P = 0.008), respectively. Treatment interruption led to an increase in the number of sensitive drugs of the multidrug regimen (71 versus 35% of regimen with at least two sensitive drugs; P = 0.004). Factors associated with virological success were treatment interruption, the reversion of at least one mutation to wild type, adequate plasma drug concentration, and the use of lopinavir.
                Treatment interruption was beneficial for treatment-experienced HIV-infected patients with advanced HIV disease and multidrug-resistant virus. We evaluated the efficacy of a 5-drug salvage regimen, preceded by a 12-week, structured treatment interruption (STI), in 46 multidrug-treated, human immunodeficiency virus type 1-infected patients with detectable viremia. Patients were randomly assigned to receive a 5-drug salvage regimen immediately (noninterruption [NI] group; n=24 patients) or after 12 weeks of STI (interruption [I] group; n=22 patients). At week 48, 45% of patients in the I group and 46% of patients in the NI group had virus loads <50 HIV-1 RNA copies/mL (P=.619). No differences in CD4 cell counts were seen between groups at week 48 (P=.734). A complete reversion to wild-type genotype was detected in 35% of patients in the I group, but this phenomenon did not affect the virological response. The only overall baseline factor associated with ensuing virus suppression was a lower number of nucleoside reverse-transcriptase inhibitor-resistant mutations (relative risk, 0.66; 95% confidence interval, 0.47-0.93; P=.021). A prior STI seems to confer no additional benefit to subsequent virological or immunological outcomes of a salvage regimen. To monitor the disappearance of resistance-associated mutations and reappearance of wild-type (WT) virus during structured treatment interruptions (STI) using DNA sequencing and line probe assay.
                Eleven HIV-1-infected patients participating in the MUTAVIR study undergoing a 3-month STI after multi-HAART failure were monitored biweekly. Genotypes were assessed by sequencing and VERSANT HIV-1 Resistance Assays (LiPA).
                At treatment interruption, 54 mutations in total were identified with both methods among the patients. LiPA provided a result for 93.3% of the codons at baseline. For 37 mutations, a complete reversion of mutant to WT was observed with one of the two methods. Among these, LiPA detected mutations in 23 codons for 7 to 52 days longer, in 10 codons for the same period, and in four codons for a shorter time than sequencing. Similarly, LiPA detected 35 WT codons 8 to 86 days earlier, and 15 at the same time point as sequencing. A sharp reduction in the number of mutations was observed at the time of viral load increase in five of the 11 patients. Taking only the codons detected by LiPA into consideration, two patients showed a complete reversion to WT according to both genotyping assays at the end of the STI period.
                The determination of the timepoint at which a virus population of an HIV-1 patient undergoing STI reverts to WT is dependent on the assay used. The viral load increase in most patients is compatible with the outgrowth of virus with fewer or no mutations. To study the effect of the interruption of reverse transriptase inhibitor (RTI) therapy or a switch from RTI to protease inhibitors, on the genotypic drug-resistance pattern of plasma HIV-1.
                Nine patients who completely stopped all medication, and five patients who switched from a treatment with RTI to a regimen containing protease inhibitors only, were studied. Direct sequencing of the plasma HIV-1 RT and protease gene was performed on follow-up samples taken before and after the interruption of treatment.
                Comparison of the amino acid sequence of the RT and protease genes in successive samples showed the rapid reappearance of wild-type viral variants in 12 of the 14 patients studied. Wild-type virus replaced the mutant strains 14 days to 2 months after the interruption of therapy, even in patients with a long treatment history.
                The results of this study indicate the sustained lower fitness of mutant strains in vivo. As a result, wild-type virus remains capable of outcompeting the RT or protease mutant strains very fast after removal of the drug. These findings highlight the importance of 'treatment history' in addition to genotypic and phenotypic markers determined at one time-point, when making therapeutic decisions for patients. To describe the short-term changes in CD4 lymphocyte counts after the interruption of antiretroviral HIV therapy in order to increase the understanding of CD4 lymphocyte dynamics, and so that appropriate monitoring strategies can be designed.
                We studied 35 HIV-infected patients with late-stage disease who had therapy interruptions leading to high viral load levels, median greater than 750 000 RNA log10 copies/ml, and in whom two CD4 cell counts (median 28 days apart) were available before beginning a salvage regimen.
                Overall, there was a substantial decline in CD4 cell counts from a median of 125 to 83 cells/mm3 in the average 28 day period, with median proportionate and absolute losses of 26% and 24 cells/mm3 per month, respectively (P < 0.008). This tended to be greater in individuals studied sooner after interrupting therapy (P = 0.03) and in those with CD4 cell counts above the pre-therapy baseline (P = 0.06). There was a strong negative correlation between the proportionate increase in viral load and the absolute change in CD4 cell count (-0.66, P = 0.0002).
                Patients with relatively advanced HIV infection interrupting antiretroviral therapy after failing a protease inhibitor-containing regimen require frequent monitoring because CD4 cell counts appear to fall quite rapidly, at least in the first few weeks after interruption. To evaluate the potential benefits of a tailored antiretroviral treatment interruption with duration based on the observed reversion of resistance mutations.
                In this open single-arm pilot study, 23 patients with multiple treatment failure interrupted therapy and underwent longitudinal genotypic resistance testing. Salvage gigatherapy was started when resistance mutations to at least two antiretroviral drug classes reverted. The primary endpoint was a fall in viral load by > 1 log10 copies/ml after 12 weeks of salvage therapy.
                Baseline median viral load was 5.14 log copies/ml and CD4 cell count 43 x 10 cells/l. Genotypic resistance testing showed a median of six, two and nine resistance mutations to nucleoside analogue reverse transcriptase inhibitors, non-nucleoside analogue reverse transcriptase inhibitors and protease inhibitors, respectively; viral strains were susceptible to no more than one drug in 17/23 patients. The median duration of treatment interruption was 24 weeks (range, 12-37), leading to median changes from baseline of + 0.54 log10 copies/ml and -30 x 10(6) cells/l. At the end of treatment interruption, plasma HIV was susceptible to at least three drugs in 16/23 patients. After 12 weeks of salvage multitherapy, only one patient had a decrease in viral load > 1 log copies/ml. All baseline resistance mutations recurred after treatment resumption. AIDS-defining events occurred in two-thirds of patients during the study period.
                In HIV-infected patients with multiple failures and no therapeutic options at baseline, significant reversion of resistance mutations after prolonged treatment interruption failed to restore antiviral efficacy of a salvage regimen and was clinically deleterious. Antiretroviral treatment interruption in 20 extensively pre-treated HIV-1 patients with treatment failure led to genotype viral reversion of at least one class of drug-mutation resistance in half of the patients. The only predictive factor of reversion was found to be the duration of interruption. The outgrowth of residual wild-type virus seems not to be a true genetic reversion because drug mutations are detected rapidly at salvage therapy re-initiation. In many patients with human immunodeficiency virus (HIV) infection, therapy with potent antiretroviral drugs does not result in complete suppression of HIV replication. The effect of cessation of therapy in these patients is unknown.
                Sixteen patients who had a plasma HIV RNA level of more than 2500 copies per milliliter during combination antiretroviral-drug therapy were randomly assigned, in a 2:1 ratio, to discontinue or continue therapy. Plasma HIV RNA levels, CD4 cell counts, and drug susceptibility were measured weekly. Viral replicative capacity was measured at base line and at week 12.
                Discontinuation of therapy for 12 weeks was associated with a median decrease in the CD4 cell count of 128 cells per cubic millimeter and an increase in the plasma HIV RNA level of 0.84 log copies per milliliter. Virus from all patients with detectable resistance at entry became susceptible to HIV-protease inhibitors within 16 weeks after the discontinuation of therapy. Drug susceptibility began to increase a median of six weeks after the discontinuation of therapy and was temporally associated with increases in plasma HIV RNA levels and decreases in CD4 cell counts. Viral replicative capacity, measured by means of a recombinant-virus assay, was low at entry into the study and increased after therapy was discontinued. Despite the loss of detectable resistance in plasma, resistant virus was cultured from peripheral-blood mononuclear cells in five of nine patients who could be evaluated. Plasma HIV RNA levels, CD4 cell counts, and drug susceptibility remained stable in the patients who continued therapy.
                Despite the presence of reduced drug susceptibility, antiretroviral-drug therapy can provide immunologic and virologic benefit. This benefit reflects continued antiviral-drug activity and the maintenance of a viral population with a reduced replicative capacity. Among treated patients with drug-resistant viremia, structured treatment interruptions often result in the re-emergence of drug-susceptible HIV-1. Theoretically, this may allow for a more durable response to salvage therapy. We therefore studied the long-term treatment outcome to antiretroviral therapy in a cohort of patients who had previously interrupted therapy, focusing on the determinants of treatment success versus failure.
                A prospective observational study of the response to antiretroviral therapy in patients resuming therapy after a treatment interruption. Virological and immunological studies were performed every month for 3 months and then every 3 months.
                Twenty-four patients underwent a structured treatment interruption and resumed therapy after a variable period of time (median 20 weeks). The median duration of treatment after the treatment interruption was 109 weeks. A transient virological response was observed in all patients who resumed a regimen containing no drug to which their pre-interruption virus was fully susceptible. Virus isolated during virological failure was genotypically and phenotypically identical to the pre-interruption virus, exhibited reduced replicative capacity, and replicated at levels similar to the pre-interruption baseline. In contrast, durable viral suppression (< 200 copies/ml) was observed in patients who initiated a regimen containing only one drug to which their pre-interruption virus was fully susceptible. Despite viral suppression, the pre-interruption drug-resistant virus population remained detectable in two patients.
                Although drug-resistant HIV-1 persists at low levels during and after the interruption of therapy, durable suppression of this virus population may be achieved with a combination regimen containing only one fully active agent. To analyse the immunological and virological effects of treatment interruptions in HIV-1-infected patients with treatment failure and multidrug-resistant virus.
                Drug susceptibility was assessed using Antivirogram and genotypic analysis was based on population and clonal sequencing for 48 patients who had interrupted treatment (> or = 2 months).
                Treatment interruption resulted in viral load increases (mean 0.7 log 10 copies/ ml; P = 0.0001) and CD4 cell count decreases (mean 89 x 10(6) cells/l; P = 0.0001). A complete shift to wild-type virus at the phenotypic, genotypic and clonal level was observed in 28/45 patients. These patients differed from those that did not show a shift to wild type in baseline CD4 cell counts (192 versus 59 x 10(6) cells/l; P= 0.007) and in the relationship between baseline viral load and CD4 cell count (no correlation versus a significant negative correlation; P= 0.008). Response to re-initiation of treatment fell with increasing viral load [relative hazard (RH) 0.33; P= 0.001] and with increasing total number of drugs with reduced susceptibility (RH 0.51; P = 0.0003); it improved with the number of new drugs received (RH 2.12; P = 0.0002) and a shift to wild type (RH 5.22, P = 0.006).
                Changes in surrogate markers suggest that treatment provided benefit in spite of virological failure and resistant virus. Although patients with a shift to wildtype virus responded better in the short term to treatment re-initiation, the long-term effects are not known and the risk of immune deterioration needs to be carefully considered. To investigate the changes in genotypic drug-resistance pattern, plasma HIV RNA and CD4 cell count after treatment interruption and assess the short-term antiviral effect of a new salvage regimen.
                Prospective study of 38 patients with multiple failing regimens who had completely stopped all medication for 3 months before a three to five-drug regimen was reintroduced according to clinical guidelines.
                Patients were tested for HIV resistance before and after treatment interruption by population-based sequencing and clonal analysis of selected patients.
                Discontinuation of therapy for 3 months was associated with a median increase in HIV RNA of 0.4 log10 and a median decrease in CD4 cell count of 43 x 10(6)/l. Sixty-one per cent of patients had a shift from the drug-resistant genotype to a predominantly wild-type genotype. The patients significantly likely to show genotype reversion were those in Centers for Disease Control groups A or B, who had been exposed to few drugs, had a low plasma HIV RNA, or a high CD4 cell count. The only independent factor predicting genotype reversion was the clinical stage. The median change in plasma HIV RNA at month 3 after treatment reintroduction was -2.3 log10 copies/ml in patients who had genotype reversion compared with -0.6 log10 copies/ml in patients without genotype reversion (P = 0.004).
                Suspending treatment for 3 months after multiple failures could be a suitable strategy for optimizing salvage therapy provided it is instituted early, before the HIV disease becomes too advanced.
The current available evidence primarily supports a lack of benefit of STI before switching therapy in patients with unsuppressed HIV viremia despite ART. There is evidence of harm in attempting STI in patients with relatively advanced HIV disease, due to the associated CD4 cell decline and the increased risk of clinical disease progression. At this time, there is no evidence to recommend the use of STI in this clinical category of patients with treatment failure.