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. The virological and immunological consequences of structured treatment interruptions in chronic HIV-1 infection. Stimulation of HIV-specific cellular immunity by structured treatment interruption fails to enhance viral control in chronic HIV infection. Structured antiretroviral treatment interruptions in chronically HIV-1-infected subjects. Long-term clinical follow-up, without antiretroviral therapy, of patients with chronic HIV-1 infection with good virological response to structured treatment interruption. HIV therapy after treatment interruption in patients with multiple failure and more than 200 CD4+ T lymphocyte count. Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia. Effect of prolonged discontinuation of successful antiretroviral therapy on CD4 T cells: a controlled, prospective trial. Changes in CD4+ T-cell differentiation phenotype during structured treatment interruption in patients with chronic HIV-1 infection.
For patients with human immunodeficiency virus (HIV) infection, structured treatment interruption (STI) is an attractive alternative strategy to continuous treatment, particularly in resource-restrained settings, because it reduces both side effects and costs. One major concern, however, is the development of resistance to antiretroviral drugs that can occur during multiple cycles of starting and stopping therapy.
                HIV genotypic drug resistance was investigated in 20 HIV-infected Thai patients treated with highly active antiretroviral therapy (HAART) and CD4 cell count-guided STI after dual nucleoside reverse-transcriptase inhibitor (NRTI) treatment. Resistance was tested at the time of the switch from dual-NRTI treatment to HAART and when HAART was stopped during the last interruption.
                After STI, one major drug-resistance mutation occurred (T215Y), and, in the 4 samples with preexisting major mutations (D67N [n=2], K70R [n=2], T215Y [n=2], and T215I [n=1]), the mutations disappeared. All mutations in the HIV protease gene were minor mutations already present, in most cases, before STI was started, and their frequency was not increased through STI, whereas the frequency of reverse-transcriptase gene mutations significantly decreased after the interruptions. After the 48-week study period, no patients had virological failure. Long-term follow-up (108 weeks) showed 1 case of virological failure in the STI arm and 1 in the continuous arm. No virological failure was seen in patients with major mutations.
                Major HIV drug-resistance mutations were not induced through CD4 cell count-guided treatment interruptions in HIV-infected patients successfully treated with HAART after dual-NRTI therapy. Some individuals with chronic HIV-1 infection have discontinued their drug therapy with consequent plasma virus rebound. In a small number of patients, a delayed or absent rebound in plasma virus load has been noted after drug cessation, apparently associated with prior drug interruptions and autologous boosting of HIV-1 specific immune responses. We hypothesized that cyclic structured treatment interruptions structured treatment interruptions (STI) could augment HIV-1 specific immune responses in chronic HIV-1 infection, which might help to control HIV-1 replication off therapy.
                We initiated an STI pilot study in 10 antiretroviral treatment-naive HIV-1 chronically infected subjects with baseline CD4 T-cell counts > 500 x 10(6) cells/l and plasma viral load > 5000 copies/ml who received highly active antiretroviral therapy (HAART) for 1 year with good response (plasma viral load < 20 copies/ml for at least 32 weeks). Three cycles of HAART interruption were performed.
                In all of the patients viral load rebounded, but doubling times increased significantly between the first and third stops (P = 0.008), and by the third stop, six out of nine subjects had a virological set-point after a median 12 months off therapy that was lower than baseline before starting HAART (ranging from 0.6 log(10) to 1.3 log(10) lower than baseline) and in four it remained stable below 5000 copies/ml. Those subjects who controlled viral replication developed significantly stronger HIV-1 specific cellular immune responses than subjects lacking spontaneous decline (P < 0.05). During viral rebounds no genotypic or phenotypic changes conferring resistance to reverse trancriptase inhibitors or protease inhibitors was detected, but mean absolute CD4 T-cell counts declined significantly, although never below 450 x 10(6)/l and the mean value at 12 months off therapy was significantly higher than the pre-treatment level (P = 0.004).
                Our findings suggest that STI in chronic HIV-1 infection might augment HIV-1-specific cellular immune responses associated with a spontaneous and sustained drop in plasma viral load in some subjects but at the potential cost of lower CD4 T-cell counts. Potent antiretroviral therapy (ART) suppresses HIV-1 viral replication and results in decreased morbidity and mortality. However, prolonged treatment is associated with drug-induced toxicity, emergence of drug-resistant viral strains, and financial constraints. Structured therapeutic interruptions (STIs) have been proposed as a strategy that could boost HIV-specific immunity, through controlled exposure to autologous virus over limited time periods, and subsequently control viral replication in the absence of ART. Here, we analyzed the impact of repeated STIs on virological and immunological parameters in a large prospective STI study. We show that: (i) the plateau virus load (VL) reached after STIs correlated with pretreatment VL, the amount of viral recrudescence during the treatment interruptions, and the off-treatment viral rebound rate; (ii) the magnitude and the breadth of the HIV-specific CD8(+) T lymphocyte response, despite marked interpatient variability, increased overall with STI. However, the quantity and quality of the post-STI response was comparable to the response observed before any therapy; (iii) individuals with strong and broad HIV-specific CD8(+) T lymphocyte responses at baseline retained these characteristics during and after STI; (iv) the increase in HIV-specific CD8(+) T lymphocyte frequencies induced by STI was not correlated with decreased viral set point after STI; and (v) HIV-specific CD4(+) T lymphocyte responses increased with STI, but were subsequently maintained only in patients with low pretreatment and plateau VLs. Overall, these data indicate that STI-induced quantitative boosting of HIV-specific cellular immunity was not associated with substantial change in viral replication and that STI was largely restoring pretherapy CD8(+) T cell responses in patients with established infection. The risks and benefits of structured treatment interruption (STI) in HIV-1-infected subjects are not fully understood. A pilot study was performed to compare STI with continuous highly active antiretroviral therapy (HAART) in chronic HIV-1-infected subjects with HIV-1 plasma RNA levels (VL) <400 copies per ml and CD4(+) T cells >400 per microl. CD4(+) T cells, VL, HIV-1-specific neutralizing antibodies, and IFN-gamma-producing HIV-1-specific CD8(+) and CD4(+) T cells were measured in all subjects. STIs of 1-month duration separated by 1 month of HAART, before a final 3-month STI, resulted in augmented CD8(+) T cell responses in all eight STI subjects (P = 0.003), maintained while on HAART up to 22 weeks after STI, and augmented neutralization titers to autologous HIV-1 isolate in one of eight subjects. However, significant decline of CD4(+) T cell count from pre-STI level, and VL rebound to pre-HAART baseline, occurred during STI (P = 0.001 and 0.34, respectively). CD4(+) T cell counts were regained on return to HAART. Control subjects (n = 4) maintained VL <400 copies per ml and stable CD4(+) T cell counts, and showed no enhancement of antiviral CD8(+) T cell responses. Despite increases in antiviral immunity, no control of VL was observed. Future studies of STI should proceed with caution. The present study assessed the long-term clinical follow-up of 26 of 60 human immunodeficiency virus (HIV)-positive patients who followed structured treatment interruption (STI) protocols and who, because of good virological response, did not resume receipt of highly active antiretroviral therapy (HAART). The plasma viral load (pVL) noted after > or =2 years without antiretroviral therapy remained significantly lower than the pVL noted before initiation of HAART, for 11 of the 26 patients (i.e., for 18% of the 60 patients who had STI performed). The CD4+ T cell count remained stable throughout the study. A low pVL at the end of follow-up was independently associated with a low CD8+CD38+ T lymphocyte count and a high stimulation index to p24 antigen after STI. In conclusion, approximately 2 years after STI, only a low proportion of patients who had a good immunological profile at the end of the STI period still had a good virological response. 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. 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. To compare continuous highly active antiretroviral therapy with a CD4 cell count-driven structured treatment interruption (STI) strategy. The primary end-point was the proportion of subjects maintaining CD4 cell count > 400 x 10 cells/l. Secondary end-points were to identify the dynamic and predictive variables of CD4 cell loss.
                The BASTA study is a randomized, controlled, prospective trial. Patients with CD4 cell counts > 800 x 10 cells/l were enrolled and the immunological threshold to resume therapy was set to the lower normal limit of CD4 cells for HIV-uninfected adults.
                Sixty-nine patients were randomized and followed for 64 weeks. At baseline, all had undetectable plasma HIV RNA and their mean CD4 cell count was 1077 x 10 cells/l. None of the patients showed a disease progression or any AIDS-defining event. At each time point, the proportion of subjects in the STI group that had a CD4 cell count < 400 x 10 cells/l was not statistically different from the control group. In all cases, the 95% confidence interval for this difference was smaller than +/-10%. However, 57% of patients with nadir CD4 cell count 200-350 x 10 cells/l reached a CD4 cell count < 400 x 10 cells/l. This was statistically different (P = 0.02) from the nearly 90% of patients with a nadir CD4 cell count 350-500 x 10 cells/l who maintained a CD4 cell count of > 400 x 10 cells/l.
                Prolonged STI in patients with fully suppressed virus and marked immune reconstitution is generally safe. The main predictor of CD4 cell decline is the nadir CD4 cell count. Pulse therapy warrants further careful prospective evaluation to investigate virological and clinical outcomes over a very long period. Markers of maturation and activation were measured on peripheral CD4+ T cells in chronically HIV-1-infected patients in a randomized, controlled pilot study of structured treatment interruption (STI). Eight subjects underwent 2 cycles of 1 month off and 1 month on highly active antiretroviral therapy (HAART), followed by a final 3-month interruption. During STI, CD4+ T-cell percentage remained relatively stable in 4 of 8 subjects. The remaining 4 STI subjects had significant rapid decline in CD4+ T-cell percentage during STI, followed by return to pre-STI baseline while on HAART. Changes in overall CD4+ T-cell percentage corresponded with fluctuations in the CD45RA+CCR7+ naive and CD45RA-CCR7+ central memory subsets. Subjects with variable CD4+ T-cell percentages tended to have higher pre-HAART plasma HIV-1 RNA set-points and experienced higher levels of plasma HIV-1 RNA rebound during STI. These results suggest that interruptions should be avoided whenever possible in patients on HAART with high plasma HIV-1 RNA set-points.
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.