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. Structured antiretroviral treatment interruptions in chronically HIV-1-infected subjects. HIV dynamics and T-cell immunity after three structured treatment interruptions in chronic HIV-1 infection. Structured treatment interruption in chronically HIV-1 infected patients after long-term viral suppression. All4You! A randomized trial of an HIV, other STDs, and pregnancy prevention intervention for alternative school students. The virological and immunological consequences of structured treatment interruptions in chronic HIV-1 infection. A prospective, randomized trial of structured treatment interruption for patients with chronic HIV type 1 infection. Stimulation of HIV-specific cellular immunity by structured treatment interruption fails to enhance viral control in chronic HIV infection. Selection of drug-resistant HIV-1 mutants in response to repeated structured treatment interruptions. Changing sexual behavior among gay male repeat testers for HIV: a randomized, controlled trial of a single-session intervention. Randomized, controlled trial of therapy interruption in chronic HIV-1 infection. Effect of prolonged discontinuation of successful antiretroviral therapy on CD4 T cells: a controlled, prospective trial. Influence of prior structured treatment interruptions on the length of time without antiretroviral treatment in chronically HIV-infected subjects. Effects of a peer-led behavioral intervention to reduce HIV transmission and promote serostatus disclosure among HIV-seropositive gay and bisexual men. A randomized control trial of Internet-delivered HIV prevention targeting rural MSM. Control of HIV during a structured treatment interruption in chronically infected individuals with vigorous T cell responses. Emergence of minor populations of human immunodeficiency virus type 1 carrying the M184V and L90M mutations in subjects undergoing structured treatment interruptions. CD4+ cell-count-guided treatment interruptions in chronic HIV-infected patients with good response to highly active antiretroviral therapy. Role of structured treatment interruption before a 5-drug salvage antiretroviral regimen: the Retrogene Study. Short-cycle structured intermittent treatment of chronic HIV infection with highly active antiretroviral therapy: effects on virologic, immunologic, and toxicity parameters. Relevance of HIV-1-specific CD4+ helper T-cell responses during structured treatment interruptions in patients with CD4+ T-cell nadir above 400/mm3. Long-term clinical follow-up, without antiretroviral therapy, of patients with chronic HIV-1 infection with good virological response to structured treatment interruption. Efficacy of sexually transmitted disease/human immunodeficiency virus sexual risk-reduction intervention for african american adolescent females seeking sexual health services: a randomized controlled trial. Changes in CD4+ T-cell differentiation phenotype during structured treatment interruption in patients with chronic HIV-1 infection. Outcomes and lessons from a pilot RCT of a community-based HIV prevention multi-session group intervention for gay men. A randomized controlled trial to test an HIV-prevention intervention for Latino gay and bisexual men: lessons learned. HIV therapy after treatment interruption in patients with multiple failure and more than 200 CD4+ T lymphocyte count. A STD/HIV prevention trial among adolescents in managed care. Randomized controlled trial of a safer sex intervention for high-risk adolescent girls. A cytostatic drug improves control of HIV-1 replication during structured treatment interruptions: a randomized study. Reducing the sexual risk behaviors of HIV+ individuals: outcome of a randomized controlled trial. HIV RNA in plasma rebounds within days during structured treatment interruptions. A prospective trial of structured treatment interruptions in human immunodeficiency virus 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. 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. To evaluate whether controlled re-exposures to autologous HIV-1 could boost HIV-specific immunity and limit virus replication in patients with chronic HIV-1 infection.
                Subjects with at least 2 years virus suppression during antiretroviral therapy and a CD4 : CD8 ratio > 1 were randomly assigned to interrupt highly active antiretroviral treatment (HAART) three times (n = 12) or to continue their previous HAART (n = 14).
                In 10/12 interrupter patients a rebound of HIV-1 RNA was detected in all three structured treatment interruptions (STI). Plasma virus doubling time was shorter during the first STI than in the second and third STI, corresponding to an average 13% reduction in viral basic reproductive rate. However, the mean time before plasma viral load rose to > 50 copies/ml was significantly shorter in the second and third STI. The average frequency of HIV-specific CD8 T cells in the interrupter patients at the end of the third STI cycle was significantly higher compared with the baseline and the end of the first STI. A substantial increase in HIV-specific CD8 T cell frequencies was found in four interrupter patients, whereas there were no changes in all 14 non-interrupter individuals. A weak p24-specific T helper response developed in 5/12 interrupter patients compared with no response in non-interruptors, but these responses were transient and disappeared rapidly.
                The increase in the control of viral replication, and positive effects of STI on immune responses in this population should encourage the further development of HIV-specific immune-based therapeutic strategies. To investigate the virological and immunological impact of a structured treatment interruption (STI) in a cohort of HIV-1 chronically infected patients with a further long-lasting effective virus suppression.
                Twelve HIV-1 chronically infected adults who had maintained viral suppression (< 20 copies/ml) for more than 2 years, as well as a CD4:CD8 ratio > 1 for a median time of 22 months, were included in the study. Participants interrupted their antiretroviral treatment during a maximum period of 30 days or until a viral load rebound > 3000 copies/ml was detected. The same prior antiretroviral regimen was resumed after STI. Kinetics of plasma viral rebound was evaluated every 2 days during the treatment interruption period. Flow cytometry and cell proliferation assays were performed before and after STI. Genotypic resistance was assessed at the time of treatment resumption.
                No adverse events occurred during the interruption period. In two patients no viral rebound was detected after 30 days of treatment interruption. In the remaining 10 patients, viral load became detectable (> 20 copies/ml) at a median time of 14 days after treatment interruption. Afterwards, viral load increased exponentially with a mean t1/2 of 1.6 days. Treatment was successfully resumed in all patients. No resistance-conferring mutations associated with the pre-interruption antiretroviral regimen were detected. The percentage of CD4 and CD8 lymphocytes did not vary during the STI period; however, the level of expression of T-cell activation antigen CD38 on CD8 T cells increased significantly in response to viral rebound. Four patients gained T-helper cell responses to recall antigens (tuberculin and tetanus toxoid), two of who developed an HIV-specific response to p24.
                STI in chronically HIV-1-infected patients is not associated with reductions in CD4 T lymphocytes or to clinical complications in this group of patients after 2 years of effective plasma viral suppression. Viral load rebounds in most but not all patients, without evidence of selection of resistance-conferring mutations. Thereafter, viraemia can be effectively controlled by antiretroviral agent reintroduction. HIV-specific T-helper cell responses may be achieved after one cycle of treatment interruption suggesting some degree of immune-stimulation. These data do not discard consecutive cycles of STI as a therapeutic strategy to boost HIV-specific immunity in order to maintain viral replication under effective control. This study evaluated All4You!, a theoretically based curriculum designed to reduce sexual risk behaviors associated with HIV, other STDs, and unintended pregnancy among students in alternative schools. The study featured a randomized controlled trial involving 24 community day schools in northern California. A cohort of 988 students was assessed four times during an 18-month period using a self report questionnaire. At the 6-month follow-up, the intervention reduced the frequency of intercourse without a condom during the previous 3 months, the frequency of intercourse without a condom with steady partners, and the number of times students reported having intercourse in the previous 3 months. It also increased condom use at last intercourse. These behavioral effects were no longer statistically significant at the 12- and 18-month follow-ups. The All4You! intervention was effective in reducing selected sexual risk behaviors among students in alternative school settings; however, the effects were modest and short term. 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. Structured treatment interruption was evaluated in 74 patients who had been pretreated with antiretrovirals, consisting of 2 nucleoside reverse-transcriptase inhibitors (NRTIs) for 1 year followed by 3 years of highly active antiretroviral therapy containing a protease inhibitor.
                Patients with a CD4 cell count of > or =350 cells/microL and a plasma viral load of <50 copies/mL were randomized to 3 therapy arms: (1) continuous therapy, (2) CD4 cell count-guided theory, and (3) week-on/week-off (WOWO) therapy. The efficacy and safety of structured treatment interruption and antiretroviral use were evaluated in human immunodeficiency type 1 (HIV-1)-infected patients. The study end points were percentage of patients who developed AIDS or who died and a CD4 cell count of > or =350 cells/microL. Intergroup differences were analyzed using analysis of variance and Kruskal-Wallis tests.
                Baseline characteristics at the start of the structured treatment interruption were similar. At week 48, no patient had died, and 1 patient in the WOWO group had an AIDS-defining condition. The proportions of patients with a CD4 cell count of > or =350 cells/microL were 100%, 87%, and 96% in treatment arms 1, 2, and 3, respectively. The percentages of weeks of antiretroviral use were 100%, 41.1%, and 69.8% in arms 1, 2, and 3, respectively. The adverse events were not significantly different among arms (P=.27). Thirty-one percent of patients in the WOWO group experienced virological failure.
                WOWO therapy maintained a CD4 cell count of > or =350 cells/microL in almost all patients but was associated with high virological failures rates (possibly resulting from previous dual-NRTI therapy), indicating that this strategy is less useful. Receipt of CD4 cell count-guided therapy resulted in comparable clinical outcomes to continuous therapy and may save antiretroviral-associated costs, but this needs to be confirmed by a larger trial. 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. A new HIV-1 treatment strategy based on repeated structured treatment interruptions (STI) is currently being evaluated in clinical trials to determine whether immune cell-mediated control of viral replication can be stimulated by intermittent periods of viral replication. The potential for selection of drug-resistant quasi-species remains a major concern of such a treatment strategy.
                Plasma and peripheral blood lymphocyte (PBL) samples from 12 patients who had three consecutive STIs were studied. Genotypic analysis was based on population and clonal sequencing. Drug susceptibility and their corresponding replication capacities were evaluated by a single-cycle growth assay.
                Consistent with a loss of phenotypic susceptibility to lamivudine, the M184V mutation was detected by genotypic analysis (direct and clonal sequencing) in plasma samples collected from two patients at the end of the second or third STI. Longitudinal analysis of patient samples revealed a step-wise increase in the M184V mutation in each patient virus population over successive STIs, despite the lower replicative capacity associated with this mutation in the absence of antiviral agents.
                Drug-resistant virus can rise to high frequencies in chronically HIV-1 infected individuals during consecutive STIs. Evolution of resistance is likely to be more important in patients with prior suboptimal therapies, particularly when few mutations are required for resistance. Maximum care should be taken in designing STI protocols that minimize development of drug-resistant mutations that may lead to treatment failure. Thus, drug-resistance testing may be useful before restarting treatment during STI studies. High-risk sexual behavior is increasingly prevalent among men who have sex with men (MSM) and among men with a history of repeat testing for HIV.
                The study assessed whether one counseling intervention session focusing on self-justifications (thoughts, attitudes, or beliefs that allow the participant to engage in high-risk sexual behaviors) at most recent unprotected anal intercourse (UAI) is effective in reducing future high-risk behaviors among HIV-negative men.
                A randomized, controlled, counseling intervention trial was conducted at an anonymous testing site in San Francisco, California, between May 1997 and January 2000. Participants were 248 MSM with a history of at least one previous negative HIV test result and self-reported UAI (receptive or insertive) in the previous 12 months with partners of unknown or discordant HIV status. Two intervention groups received standard HIV test counseling plus a cognitive-behavioral intervention, and two control groups received only standard HIV test counseling. Follow-up evaluation was at 6 and 12 months.
                Number of episodes of UAI with nonprimary partners (of unknown or discordant HIV status) in the 90 days preceding the interview was measured via self-report during face-to-face interview.
                A novel counseling intervention focusing on self-justifications significantly decreased the proportion of participants reporting UAI with nonprimary partners of unknown or discordant HIV status at 6 and 12 months (from 66% to 21% at 6 months and to 26% at 12 months, p =.002; p <.001) as compared with a control group when added to standard client-centered HIV counseling and testing.
                A specific, single-session counseling intervention focusing on a reevaluation of a person's self-justifications operant during a recent occasion of high-risk behavior may prove useful in decreasing individual risk behavior and thus limiting community-level HIV transmission. Approaches to limiting exposure to antiretroviral therapy (ART) drugs are an active area of HIV therapy research. Here we present longitudinal follow-up of a randomized, open-label, single-center study of the immune, viral, and safety outcomes of structured therapy interruptions (TIs) in patients with chronically suppressed HIV-1 infection as compared to equal follow-up of patients on continuous therapy and including a final therapy interruption in both arms.
                Forty-two chronically HIV-infected patients on suppressive ART with CD4 counts higher than 400 were randomized 1:1 to either (1) three successive fixed TIs of 2, 4, and 6 wk, with intervening resumption of therapy with resuppression for 4 wk before subsequent interruption, or (2) 40 wk of continuous therapy, with a final open-ended TI in both treatment groups. Main outcome was analysis of the time to viral rebound (>5,000 copies/ml) during the open-ended TI. Secondary outcomes included study-defined safety criteria, viral resistance, therapy failure, and retention of immune reconstitution. There was no difference between the groups in time to viral rebound during the open-ended TI (continuous therapy/single TI, median [interquartile range] = 4 [1-8] wk, n = 21; repeated TI, median [interquartile range] = 5 [4-8] wk, n = 21; p = 0.36). No differences in study-related adverse events, viral set point at 12 or 20 wk of open-ended interruption, viral resistance or therapy failure, retention of CD4 T cell numbers on ART, or retention of lymphoproliferative recall antigen responses were noted between groups. Importantly, resistance detected shortly after initial viremia following the open-ended TI did not result in a lack of resuppression to less than 50 copies/ml after reinitiation of the same drug regimen.
                Cycles of 2- to 6-wk time-fixed TIs in patients with suppressed HIV infection failed to confer a clinically significant benefit with regard to viral suppression off ART. Also, secondary analysis showed no difference between the two strategies in terms of safety, retention of immune reconstitution, and clinical therapy failure. Based on these findings, we suggest that further clinical research on the long-term consequences of TI strategies to decrease drug exposure is warranted. 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. The influence of previous structured treatment interruptions (STIs) on the length of time off therapy when highly active antiretroviral treatment (HAART) is discontinued in chronically HIV-infected subjects was assessed. A comparative, retrospective clinical cohort study included patients with plasma viral load (VL) <50 copies/ml and CD4 cell count >500 cells/mm(3) who interrupted HAART. Fifteen patients interrupted HAART after six 2-weeks-off-/4-weeks-on therapy cycles (STI group) and 30 subjects discontinued HAART without previous STIs (NSTI group). The criteria for treatment resumption were development of AIDS-defining clinical events, VL >100,000 copies/ml or CD4 <350 cells/mm(3). Median (IQR) time off therapy was 48 (29-56) weeks in the STI group and 31 (8-77) weeks in the NSTI group (p < 0.15). After 48 weeks, 46% of the patients in the STI group and 40% in the NSTI group remained off HAART (p < 0.74). No patient developed AIDS-defining events and all but one achieved virological control after treatment resumption. The CD4 nadir was 341 (298-464) cells/mm(3) among patients who reinitiated HAART and 560 (364-682) cells/mm(3) in those who remained off therapy by week 48 (p <0.01). Likewise, CD4 count prior to treatment interruption was 902 (806-1040) cells/mm(3) and 1123 (924-1234) cells/mm(3) in subjects resuming and remaining off HAART, respectively (p = 0.03). No relationship between treatment resumption and pre-ART VL or with the time with undetectable VL before enrollment was found. CD4 nadir was a significant predictor for treatment reinitiation in a multivariate analysis. Previous STIs do not influence time off therapy when HAART is definitively discontinued in chronically HIV-infected subjects. CD4 nadir is an important factor in the treatment discontinuation decision. To evaluate the effects of an enhanced peer-led intervention on transmission risk behavior and serostatus disclosure of HIV-seropositive gay and bisexual men.
                A randomized intervention trial.
                HIV-seropositive gay and bisexual men were recruited from New York City and San Francisco and were randomly assigned to either a standard or an enhanced intervention. The standard intervention consisted of one session that provided safer sex information. The enhanced intervention consisted of six sessions and included safer sex information, interactive learning activities, and discussion groups that were facilitated by HIV-seropositive peers. Participants completed audio computer-assisted self interview (A-CASI) assessments at baseline and 3 and 6-month follow-ups. Optional testing for sexually transmitted infections was offered at baseline and the 6-month follow-up.
                A total of 811 participants met the inclusion criteria for outcome analyses. Of these, 85 and 90% were retained for the 3 and 6-month follow-ups, respectively. Compared with the standard intervention, fewer men assigned to the enhanced intervention reported unprotected receptive anal intercourse with a negative or unknown-serostatus partner at 3 months (21 versus 26%, P < 0.05). However, there were no other significant differences in transmission risk or serostatus disclosure at 3 or 6 months.
                The enhanced intervention was associated with only a limited reduction in transmission risk at 3 months relative to the standard intervention. The characteristics of the intervention that may have reduced its efficacy are identified and directions for future research are suggested. The Internet may be important for delivering human immunodeficiency virus (HIV) risk reduction to men who have sex with men (MSM) in rural areas. This randomized control trial (RCT) tested the acceptability and efficacy of an Internet-delivered HIV risk-reduction intervention. Two modules include a conversation between an HIV-negative man and an HIV-positive man, with interactive graphics. Ninety men were randomly assigned to intervention or wait-list control and 79% completed the study. An 'intent-to-treat' model was used. HIV/acquired immune deficiency syndrome (AIDS) knowledge, self-efficacy and outcome expectancies increased after participating in the intervention, and changes were maintained at 1-week follow-up. Participants said they would participate again. This RCT provides support for the acceptability and efficacy of the Internet for delivering HIV prevention messages to rural MSM. To study whether and under what circumstances HIV can be controlled in chronically infected patients.
                Nine patients treated with hydroxyurea and didanosine (PANDAs) were compared with 7 patients on highly active antiretroviral therapy (HAART) during an 8-week treatment interruption. Both groups had similar baseline viral load, CD4 count, and length of treatment. Treatment was resumed if viral rebound >10,000 copies/mL (virological failure) or CD4 count decrease below 200 cells/mm(3) (immunological failure) occurred in two consecutive measurements.
                None of the PANDAs failed. Viral rebound was spontaneously contained, and CD4 count remained stable. Four out of 7 patients in the HAART group failed to control HIV by week 6 and had to restart therapy due to either viremia rebound or CD4 decrease. Before therapy interruption, the PANDAs had a vigorous HIV-specific T cell immune response (median CD4VIR 1.2%), while the HAART-treated patients did not (median CD4VIR 0.2%) (CD4VIR represents the percentage of HIV-specific CD4 subpopulation expressing IFN-gamma within the total CD4 population [CD3+, CD4+, IFN-gamma+]). This difference was statistically significant (p =.002).
                This study shows that HIV can be controlled during therapy interruption in patients with established infection, and that control of viral replication correlates with vigorous anti-HIV specific immune responses. The use of structured treatment interruption (STI) in human immunodeficiency virus (HIV)-infected subjects is currently being studied as an alternative therapeutic strategy for HIV-1. The potential risk for selection of drug-resistant HIV-1 variants during STI is unknown and remains a concern. Therefore, the emergence of drug resistance in sequential plasma samples obtained from 28 subjects with chronic HIV infection was studied. They underwent 4 cycles of 2-week STI, followed by 8-week retreatment with highly active antiretroviral therapy identical to that used before STI, and they had never failed treatment before undergoing STI. At week 40, treatment was stopped for a longer period. Minor populations of drug-resistant variants were detected by quantitative real-time polymerase chain reaction, by use of allele-discriminating oligonucleotides for 2 key resistance mutations: L90M (protease) and M184V (reverse transcriptase). The approximate discriminative power was 0.1%. In 14 of 25 and in 3 of 25 subjects, the M184V and the L90M mutations, respectively, were detected as minor populations, at different times during STI. Overall, these results indicate that, in subjects undergoing multiple STIs, HIV-1 variants carrying drug-resistance mutations can emerge during periods of increased HIV-1 replication. To evaluate the safety of treatment interruption guided by CD4+ cell count in HIV-infected patients followed up prospectively.
                Patients on highly active antiretroviral therapy with CD4+ cell counts > 500 x 10(6) cells/l discontinued therapy with instructions to start therapy again before their CD4+ count dropped below 200 x 10(6) cells/l. Any patients who resumed therapy would be eligible to interrupt treatment again once their CD4+ cell count increased above 500 x 10(6) cells/l.
                Data on 71 HIV infected patients is reported. Their median nadir CD4+ cell count before antiretroviral treatment was 352 x 10(6) cells/l [interquartile range (IQR), 294-445 x 10(6) cells/l]. The median CD4+ cell count at the time of first interruption was 790 x 10(6) cells/l (IQR, 657-1041 x 10(6) cells/l). The median follow-up after starting the first treatment interruption was 28.3 months (IQR, 21.4-37.0 months). During the follow-up 49 patients restarted therapy and 22 patients remain off therapy; 24 patients have interrupted therapy twice, nine patients have interrupted therapy three times and six patients four times. No AIDS-defining illnesses occurred during the follow-up. The median duration of the first interruption was 15 months (IQR, 6-26 months). The overall reduction of time on therapy was 71.1%. The duration of the first interruption and the reduction of time on therapy were related to nadir CD4+ cell count. The patients who resumed HAART rapidly regained CD4+ cells and achieved viral suppression.
                If carefully monitored, treatment interruptions guided by CD4+ cell count in patients with an initially high CD4+ cell counts are clinically safe, decrease exposure to the drugs and do not reduce the efficacy of therapy when this is re-started. 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. Although continuous highly active antiretroviral therapy (HAART) is effective for many HIV-infected patients, it can be toxic and prohibitive in cost. By decreasing the total amount of time patients receive medications, intermittent HAART could reduce toxicity and cost. Therefore, we initiated a pilot study in which 10 HIV-infected individuals receiving effective therapy that resulted in levels of HIV RNA <50 copies per ml of plasma and CD4(+) T cell counts >300 cells per mm(3) of whole blood received repeated cycles of 7 days on HAART followed by 7 days off of HAART. Patients maintained suppression of plasma viremia for 32-68 weeks. There was no significant increase in HIV proviral DNA or replication-competent HIV in peripheral CD4(+) T cells or HIV RNA in peripheral blood or lymph node mononuclear cells. There was no significant change in CD4(+) T cell counts, no significant increase in CD4(+) or CD8(+) T cells expressing activation markers or producing IFN-gamma in response to HIV, no increase in CD4(+) T cell proliferation to p24 antigen, and no evidence for the development of resistance to HAART medications. There was a significant decrease in serum cholesterol and triglyceride levels. Thus, in this proof-of-concept study, short-cycle intermittent HAART maintained suppression of plasma viremia as well as HIV replication in reservoir sites while preserving CD4(+) T cell counts. In addition, there was a decrease in serum cholesterol and triglyceride levels. Intermittent therapy may be an important strategy to reduce cost and toxicity for HIV-infected individuals. To analyze the dynamics of both HIV-1-specific CD4 and CD8 T-cell responses during structured treatment interruptions (STIs) in chronically HIV-1-infected (CHI) patients and to correlate them with the viral set point achieved.
                Forty-five early-stage CHI patients who were on highly active antiretroviral therapy (HAART) for at least 1 year and underwent STI were included. Plasma viral load (VL), peripheral blood mononuclear cell (PBMC) lymphoproliferative (LPR) response to HIV p24 protein, and HIV-1 epitope-specific interferon-gammarelease from CD8 T cells were measured over a minimum study period of 2 years.
                VL set point during final STI was both significantly lower than, and positively correlated to, baseline VL (P < 0.0001: mean VL reduction 0.77 log10, and r = 0.42, P = 0.004, respectively). CD4 LPRs to p24 increased significantly (P = 0.001) between day 0 of the first STI cycle and 4th STI but decreased thereafter. VL set point during final STI was significantly and negatively correlated with LPRs to p24 at both 2nd STI and 4th STI. Nevertheless, at week 52, 12 weeks after the end of the last STI, LPRs were weak and transient in all patients and were not correlated with VL set point. Moreover, the magnitude and breadth of HIV-1-specific CD8 T-cell responses increased significantly (P < 0.0001) between day 0 and week 52. The largest increases occurred during the final STI. Even though VL reached set point by week 12 of the final STI, HIV-1-specific CD8 T-cell responses did not stabilize but rather increased until the end of the follow-up and did not correlate with plasma VL (r = 0.01, P = 0.88).
                STIs do not lead to control of viral replication in CHI patients, probably due to the fact that boosted CTL responses lack strong and durable helper T-cell responses. To reset the VL set point, new approaches that effectively augment and preserve helper T-cell responses should be investigated. 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. To evaluate the efficacy of an intervention to reduce incident sexually transmitted disease (STD) and enhance STD/human immunodeficiency virus (HIV)-preventive behaviors and psychosocial mediators.
                A randomized controlled trial of an HIV prevention program.
                Clinic-based sample in Atlanta, Georgia.
                African American adolescent females (N = 715), aged 15 to 21 years, seeking sexual health services. Participants completed an audio computer-assisted self-interview and provided self-collected vaginal specimens for STD testing. Intervention Intervention participants received two 4-hour group sessions and 4 telephone contacts over a 12-month period, targeting personal, relational, sociocultural, and structural factors associated with adolescents' STD/HIV risk, and were given vouchers facilitating male partners' STD testing/treatment. Main Outcome Measure Incident chlamydial infections.
                Over the 12-month follow-up, fewer adolescents in the intervention had a chlamydial infection (42 vs 67; risk ratio [RR], 0.65; 95% confidence interval [CI], 0.42 to 0.98; P = .04) or recurrent chlamydial infection (4 vs 14; RR, 0.25; 95% CI, 0.08 to 0.83; P = .02). Adolescents in the intervention also reported a higher proportion of condom-protected sex acts in the 60 days preceding follow-up assessments (mean difference, 10.84; 95% CI, 5.27 to 16.42; P < .001) and less frequent douching (mean difference, -0.76; 95% CI, -1.15 to -0.37; P = .001). Adolescents in the intervention were also more likely to report consistent condom use in the 60 days preceding follow-up assessments (RR, 1. 41; 95% CI, 1.09 to 1.80; P = .01) and condom use at last intercourse (RR, 1.30; 95% CI, 1.09 to 1.54; P = .005). Intervention effects were observed for psychosocial mediators of STD/HIV-preventive behaviors.
                Interventions for African American adolescent females can reduce chlamydial infections and enhance STD/HIV-preventive behaviors and psychosocial mediators of STD/HIV-preventive behaviors. Trial Registration clinicaltrials.gov Identifier: NCT00633906. 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. This paper presents the first outcome evaluation of multi-session groupwork for HIV prevention among gay men in the UK. This community-based RCT recruited 50 men, of whom 42% were HIV-positive or untested, and 32% reported status unknown or serodiscordant UAI in the previous 12 months. No knowledge, skills, attitudinal or behavioural differences were detected between intervention and control at baseline. At eight weeks, those attending the group reported significant gains over their control in making sexual choices, physical safety, HIV and STI transmission knowledge, and sexual negotiation skills. At 20 weeks, significant differences remained for HIV and STI transmission knowledge and comfort with sexual choices. Although no behavioural differences were detected, the aims of the National Prevention Strategy were met. This pilot RCT is appraised in the light of modest sample size and attrition, and recommendations for establishing behavioural outcomes are presented. This study has demonstrated that high-risk community samples can be recruited to multi-session interventions, and has provided feasibility data for future rigorous evaluation designs. At the time of this writing, no randomized controlled trial (RCT) of an intervention to reduce unsafe sex among Latino gay and bisexual men (LGBM) had been published. We report the results of an RCT conducted in New York City in which 180 LGBM were assigned either to an intervention developed specifically for this population or to a wait-list control group. The intervention was based on empowerment theory and used factors identified in prior research as determinants of unsafe sex. By eligibility criteria, all men had engaged in unprotected anal intercourse (UAI) within two months of the baseline assessment. At first (two months) and second (six months later) follow-up assessments, approximately half of the men in the experimental group reported no UAI. Yet, a similar proportion of the control group also reported no UAI. Baseline data indicate that although the men had been the subject of social oppression and sexual prejudice (homophobia), they did not feel disempowered, externally controlled or fatalistic, and they reported self-efficacy and intentionality to enact safer sex. Lessons learned are discussed, as well as notes of caution for future research employing a similar conceptual framework. 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. To determine if sexually transmitted diseases (STDs), including human immunodeficiency virus (HIV) infection, risk assessment, and education tools provided as part of office-based primary care reduce adolescent risky sexual behaviors.
                A randomized intervention trial with 3- and 9-month follow-up.
                Five staff-model managed care sites in Washington, DC (n = 19 pediatricians).
                Consecutive 12- to 15-year-olds receiving a general health examination; 81% minority. Participation rate = 215/432 (50%). Nine-month follow-up rate = 197/215 (92%).
                Audiotaped STD risk assessment and education about staying safe (safer = condoms, safest = abstinence).
                Adolescent-reported sexual intercourse and condom use.
                More intervention adolescents reported pediatrician discussion on 11/13 sexual topics. Although more vaginal intercourse (odds ratio [OR] = 2.46, 95% confidence interval [CI] = 1.04-5.84) was reported in the intervention group at 3 months, this was not true of overall sexual intercourse (OR = 1.55, 95% CI =.73-3.32). More sexually active adolescents reported condom use in the intervention group at 3 months (OR = 18.05, 95% CI = 1.27-256.03). At 9 months, there were no group differences in sexual behaviors; however, more signs of STD were reported by the control (7/103) than the intervention group (0/94).
                STD risk assessment and education tools administered in a single office visit facilitated STD/HIV prevention education. Any impact on sexual activity and condom use was short-lived. Further research is needed to develop brief, office-based sexual risk reduction for young adolescents. To determine the effect of an individualized safer sex intervention on condom use and recurrent sexually transmitted disease (STD) among female adolescents diagnosed as having an STD.
                Randomized controlled trial.
                Urban children's hospital adolescent clinic and inpatient service.
                One hundred twenty-three adolescents with cervicitis or pelvic inflammatory disease.
                Participants completed a questionnaire and then were randomized to receive standard STD education or to watch a videotape and have an individualized intervention session. Follow-up questionnaires were completed at 1, 3, 6, and 12 months. Intervention participants met with an educator at 1, 3, and 6 months to discuss interim sexual history and review the intervention.
                Change in self-reported condom use and recurrence of STD. Other self-reported behaviors, sexual risk knowledge, attitudes toward condoms, and condom use negotiation skills were also assessed.
                At 1 month, compared with control participants, intervention participants had increased sexual risk knowledge and more positive attitudes toward condoms and tended to use condoms more with a nonmain partner. At 6 months, fewer intervention participants than controls had sex with a nonmain sexual partner in the previous 6 months. At 12 months, intervention participants were less likely to have a current main partner and had a lower rate of recurrent STD than controls, but these differences were not significant.
                This individualized safer sex intervention may improve condom use and decrease the number of partners among adolescent girls who have had an STD. Studies with larger samples are needed to determine definitive intervention effects on recurrent STD in this high-risk population. To study the effect of highly active antiretroviral therapy (HAART) with and without hydroxyurea (HU) on changes in plasma viral load (VL) set-point, and on HIV-1-specific responses, after five cycles of structured treatment interruptions (STI).
                A group of 20 patients taking HAART for chronic HIV infection with VL < 20 copies/ml were randomized to continue HAART or HAART plus HU for 24 weeks followed by five STI cycles. HU was also stopped in cycles 1-3 but continued in cycles 4 and 5. The number of individuals maintaining a VL set-point < 5000 copies/ml during the fifth interruption were determined.
                VL remained < 5000 copies/ml in eight out of nine patients in the HU group and in four out of ten patients in the HAART group after a median 48 weeks of follow-up after the fifth interruption ( P=0.039). By STI cycle 5, there was a significant increase in the neutralizing activity (NA), in both magnitude and breadth of the total cytotoxic T lymphocyte (CTL) response and in lymphoproliferative response (LPR) from baseline. No significant differences were observed between HAART and HU groups in NA, CTL and LPR at any time-point. There were no differences in the NA titers at any time-point between responder and non-responder patients. There was a trend for higher CTL and LPR levels in responder patients (P= 0.10).
                In this randomized, controlled study of STI with cycles of HAART or HAART plus HU, a lower peak VL rebound and a lower VL set-point was achieved in patients continuing HU while other drugs were discontinued. HU did not blunt anti-HIV-1-specific responses; however, control of VL did not correlate with anti-HIV-1-specific cellular immune responses. Testing behavioral interventions to increase safer sex practices of HIV+ individuals has the potential to significantly reduce the number of new infections. This study evaluated a behavioral intervention designed to reduce the sexual risk behaviors of HIV+individuals. HIV+individuals (N = 387) who reported engaging in unprotected sex with HIV- or partners of unknown serostatus were randomly assigned to (a) a single counseling session targeting problem areas identified by the participant in 3 possible intervention domains (i.e., condom use, negotiation, disclosure); (b) a single-session comprehensive intervention that covered all 3 intervention domains; (c) the same comprehensive intervention, plus 2 monthly booster sessions; or (d) a 3-session diet and exercise attention-control condition. The median number of unprotected sex acts decreased from 14 at baseline to 6, 6, and 4 at 4-, 8-, and 12-month follow-ups, respectively. A repeated measures analysis of variance revealed a significant decrease in unprotected sex acts across all groups across time. A significant Group x Time interaction revealed that the comprehensive-with-boosters group had the most unprotected sex at 8-month follow-up as compared to the other 3 groups. These findings suggest that a brief intervention can result in large reductions in HIV transmission risks among HIV+individuals, but the relative benefit of one intervention approach over another remains unclear. To evaluate time to viral rebound in patients undergoing repeated structured treatment interruptions (STI).
                Fourteen chronically HIV-infected patients enrolled in the Swiss-Spanish Intermittent Treatment Trial (SSITT) underwent frequent blood sampling. Patients underwent four cycles of 2-week STI, followed by 8-week retreatment with the identical antiretroviral treatment (HAART) used before STI. At the fifth cycle, treatment was stopped for a longer period. Before each new STI, plasma viral load (VL) had to reach < 50 copies/ml. VL was measured during day 0 (last day on HAART) and on days 4, 8 and 14 during all five STI.
                During the first cycle, plasma HIV RNA increased to > 50 copies/ml (range, 67-88) in five patients at day 4, in eight patients (> 100 copies/ml) at day 8 and in 12 patients (> 100 copies/ml) at day 14. Cumulative analysis of the frequency of detectable HIV RNA at days 4, 8 and 14 compared with day 0 for all five cycles revealed nine patients with VL > 50 copies/ml [13 of 54 samples tested (24.1%); = 0.14] at day 4, 11 patients [33 of 58 samples tested (56.9%); < 0.0001] at day 8 and 12 patients [53 of 65 samples tested (81.5%); < 0.0001] at day 14.
                Significant viral replication can be induced during 1 week STI, and this may increase the risk of the emergence of drug resistance during long-term cycling. Therefore, short-term cycling strategies such as 1-week-on, 1-week-off treatment, although conceptually intriguing, should still be regarded as investigational and should be restricted to rigorously controlled clinical trials ideally involving patients who have never failed treatment before. According to the "autovaccination hypothesis," reexposure to human immunodeficiency virus (HIV) during treatment interruptions may stimulate the HIV-specific immune response and lead to low viremia after withdrawal of highly active antiretroviral treatment (HAART). Many patients who started HAART earlier in their disease course than is currently recommended would like to discontinue, but it is unknown whether it is safe to do so.
                To determine whether repeated treatment interruptions of HAART (1) stimulated the cytotoxic HIV-specific immune response and whether such stimulation correlated with low viremia off treatment, and (2) were safe with respect to clinical complications, development of viral resistance, and decline in CD4 cell counts.
                Interventional study with before-after comparison.
                Outpatient clinics of university hospitals in Switzerland and Spain.
                A total of 133 patients receiving HAART, with a median CD4 cell count of 740/ microL, and whose viral load had been undetectable for a median of 21 months.
                HAART was interrupted for 2 weeks, restarted, and continued for 8 weeks. After 4 such cycles, treatment was indefinitely suspended 40 weeks after study entry.
                HIV-specific cytotoxic T-cell responses were evaluated by interferon gamma enzyme-linked immunospot analysis. The proportion of "responders" (viral load <5000 copies/mL) was measured at weeks 52 and 96. HIV-related diseases and CD4 cell counts were recorded.
                Seventeen percent of patients (95% confidence interval, 11%-25%) were responders at week 52, and 8% at week 96. Low pre-HAART viral load and lack of rebound during weeks 0 to 40 predicted response. HIV-specific CD8+ T cells increased between week 0 (median, 343 spot-forming cells per million peripheral blood lymphocytes [SFC/106 PBL]) and week 52 (median, 1930 SFC/106 PBL), but there was an inverse correlation between response and the number of spot-forming cells. Eighty-five (64%) of 133 patients stopped therapy for at least 12 weeks, and 55 (41%) for at least 56 weeks. The median CD4 cell count decreased from 792/ microL to 615/ microL during the first 12 weeks without treatment, but stabilized thereafter. One patient (0.75%) developed drug resistance necessitating salvage treatment. There were no AIDS-related clinical complications.
                Results of this study do not favor the autovaccination hypothesis. Treatment interruptions did not provoke clinical complications, and there was little drug resistance. Comparative trials will have to show what benefit, if any, is associated with intermittent, as opposed to continuous treatment.
Timed-cycle STI have not been proven to be safe in the short term. Although CD4-guided STI strategy has reported favorable outcomes in the short term, the long-term safety, efficacy and tolerability of this strategy has not been fully investigated. Based on the studies we reviewed, the evidence to support the use of timed-cycle STI and CD4-guided STI cycles as a standard of care in the management of chronic suppressed HIV infection is inconclusive.