Antiretroviral Therapy Interruption Research Articles

Reconceptualizing Research on HIV Treatment Outcomes Among Criminalized Groups

Reconceptualizing Research on HIV Treatment Outcomes Among Criminalized Groups

Effect of intermittent interleukin-2 therapy on CD4+ T-cell counts following antiretroviral cessation in patients with HIV

Interleukin (IL)-2 therapy impacts T-cell homeostasis. Whether IL-2 expanded CD4(+) T cells may persist following viral rebound has not been fully investigated. Patients with CD4(+) T cells 500/μl or more and HIV RNA less than 50 copies/ml were randomized to continue antiretroviral therapy (ART) either alone (n = 67) or combined with three IL-2 cycles (n = 81; 6 million units) twice daily for 5 days at weeks 0, 8, and 16 before stopping ART (week 24). Patients were followed up to 168 weeks. At week 24, median CD4(+) T-cell counts were 1198 and 703 cells/μl in the IL-2 and control groups, respectively (P < 0.001). At week 72, 27% (IL-2 group) and 45% (control group; P = 0.03) of patients were in failure (defined as no interruption of ART at week 24, CD4 drop below 350 cells/μl or ART resumption). After week 24, a biphasic decline (before and after week 32) of CD4 was noted -106 and -7 cells/μl per month in controls and -234 and -17 in IL-2 group (all P ≤ 0.0001). At week 96, IL-2-expanded CD4(+)CD25(+) T cells remained higher than in the control group (26 vs. 16%, P = 0.006). In IL-2-treated patients, CD4(+)CD25(+) T cells persisting despite viral replication allow a longer period of ART interruption.

Impact of antiretroviral therapy interruption on plasma biomarkers of cardiovascular risk and lipids: 144‐week final data from the STOPAR study

The aim of the study was to investigate changes in plasma biomarkers of cardiovascular risk and lipids in a CD4-guided antiretroviral therapy interruption study. This was a substudy of a prospective, randomized, multicentre treatment interruption study. At months 12, 24 and 36, monocyte chemotactic protein-1 (MCP-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), interleukin-6 (IL-6), interleukin-8 (IL-8), soluble CD40 ligand (sCD40L), soluble P-selectin (sP-selectin), and tissue plasminogen activator (t-PA) were measured using a multiplex cytometric bead-based assay. Total cholesterol (total-c), high-density lipoprotein cholesterol (HDL-c) and triglycerides (TG) were determined using standard methods. Fifty-four patients were included in the study [34 in the treatment continuation (TC) arm and 20 in the treatment interruption (TI) arm]. There were no differences at baseline between the groups, except in CD4 cell count, which was higher in the TI arm (P = 0.026), and MCP-1, which was higher in the TC arm (P = 0.039). MCP-1 and sVCAM-1 were increased relative to baseline at the three study time-points in the TI arm, with no changes in the TC arm. Soluble CD40L and sP-selectin were increased at month 36 in both arms, with a greater increase in the TI arm (P = 0.02). t-PA was increased in both arms at the three time-points. Total-c, HDL-c and low-density lipoprotein cholesterol (LDL-c) were decreased in the TI arm at the three time-points, with no changes in the total-c/HDL-c ratio. HIV viral load positively correlated with MCP-1 at months 12 and 24. Regression analysis showed a significant negative association of HDL-c with MCP-1 and sVCAM-1. A significant increase in cardiovascular risk biomarkers persisting over the prolonged study period was seen in the TI arm. This factor may contribute to the increased cardiovascular risk observed in previous studies.

Incarceration Predicts Virologic Failure for HIV-Infected Injection Drug Users Receiving Antiretroviral Therapy

Incarceration may lead to interruptions in antiretroviral therapy (ART) for persons receiving treatment for human immunodeficiency virus (HIV) infection. We assessed whether incarceration and subsequent release were associated with virologic failure for injection drug users (IDUs) who were previously successfully treated with ART. ALIVE is a prospective, community-based cohort study of IDUs in Baltimore, Maryland. IDUs receiving ART during 1998-2009 who successfully achieved an HIV RNA level below the limit of detection (<400 copies/mL) were followed up for development of virologic failure at the subsequent semiannual study visit. Logistic regression with generalized estimating equations was used to assess whether incarceration was independently associated with virologic failure. Of 437 HIV-infected IDUs who achieved undetectable HIV RNA for at least one study visit, 69% were male, 95% were African-American, and 40% reported at least one incarceration during follow-up. Virologic failure occurred at 26.3% of visits after a median of 6 months since achieving undetectable HIV RNA. In multivariate analysis accounting for demographic characteristics, drug use, and HIV disease stage, brief incarceration was strongly associated with virologic failure (adjusted odds ratio, 7.7; 95% confidence interval, 3.0-19.7), although incarceration lasting >30 days was not (odds ratio, 1.4; 95% confidence interval, .8-2.6). Among IDUs achieving viral suppression while receiving ART, virologic failure occurred with high frequency and was strongly associated with brief incarceration. Efforts should be made to ensure continuity of care both during and after incarceration to improve treatment outcomes and prevent viral resistance in this vulnerable population.

Reappearance of Minority K103N HIV-1 Variants after Interruption of ART Initiated during Primary HIV-1 Infection

BackgroundIn the Zurich Primary HIV infection study (ZPHI), minority drug-resistant HIV-1 variants were detected in some acutely HIV-1-infected patients prior to initiation of early antiretroviral therapy (ART). Here, we investigated the reappearance of minority K103N and M184V HIV-1 variants in these patients who interrupted efficient early ART after 8–27 months according to the study protocol. These mutations are key mutations conferring drug resistance to reverse transcriptase inhibitors and they belong to the most commonly transmitted drug resistance mutations.Methodology/Principal FindingsEarly ART was offered to acutely HIV-1-infected patients enrolled in the longitudinal prospective ZPHI study. Six patients harboring and eleven patients not harboring drug-resistant viruses at low frequencies prior to ART were included in this substudy. Minority K103N and M184V HIV-1 variants were quantified in longitudinal plasma samples after treatment interruption by allele-specific real-time PCR. All 17 patients were infected with HIV-1 subtype B between 04/2003 and 09/2005 and received LPV/r+AZT+3TC during primary HIV-1 infection (PHI). Minority K103N HIV-1 variants reappeared after cessation of ART in two of four patients harboring this variant during PHI and even persisted in one of those patients at frequencies similar to the frequency observed prior to ART (<1%). The K103N mutation did not appear during treatment interruption in any other patient. Minority M184V HIV-1 variants were detected in two patients after ART interruption, one harboring and one not harboring these variants prior to ART.ConclusionMinority K103N HIV-1 variants, present in acutely HIV-1 infected patients prior to early ART, can reappear and persist after interruption of suppressive ART containing two nucleoside/nucleotide analogue reverse transcriptase inhibitors and a ritonavir-boosted protease inhibitor.Trial RegistrationClinicaltrials.gov NCT00537966

CD4+ lymphocyte-based immunologic outcomes of perinatally HIV-infected children during antiretroviral therapy interruption.

To assess the characteristics and outcomes of antiretroviral treatment (ART) interruption (TI) in perinatally HIV-infected children. The Adolescent Master Protocol (AMP) of the Pediatric HIV/AIDS Cohort Study is a prospective cohort study that enrolled 7- to 16-year-old perinatally HIV-infected children between 2007 and 2009 from 15 sites in the United States and Puerto Rico. TI was defined as ART discontinuation for ≥ 3 months after ≥ 6 months of continuous ART. Subjects with and without TI were compared. Rates of change (slopes) in CD4 T-lymphocyte (CD4) count and percentage (%) per month during TI were calculated. Factors related to CD4 slope in univariable analyses were included in multivariable linear regression. Of 444 eligible AMP subjects, 101 (23%) had at least one TI. Subjects with TI were born in earlier years but were otherwise similar to those without TI. For 81 TI subjects with complete data, the median (range) CD4% and CD4 count slopes were -0.66% per month (-3.54% to +1.34% per month) and -12.7 cells per cubic millimeter per month (-148 cells/mm to +31 cells/mm per month), respectively. On multivariable linear regression, there was a trend for lower CD4% slope to be associated (P < 0.1) with female sex, higher CD4% at TI, and higher peak viral load before TI. Advanced HIV disease stage and numerous ART regimens were more common in TI subjects in the lowest (fastest declining) CD4% slope quartile. TIs in perinatally HIV-infected youth are common. During TIs, CD4 values decline on average but with high intersubject variability. Factors predicting CD4 slope during TI need further study.

Soluble CD163 Made by Monocyte/Macrophages Is a Novel Marker of HIV Activity in Early and Chronic Infection Prior to and After Anti-retroviral Therapy

CD163, a monocyte- and macrophage-specific scavenger receptor, is shed during activation as soluble CD163 (sCD163). We have previously demonstrated that monocyte expansion from bone marrow with simian immunodeficiency virus (SIV) infection correlated with plasma sCD163, the rate of AIDS progression, and the severity of macrophage-mediated pathogenesis. Here, we examined sCD163 in human immunodeficiency virus (HIV) infection. sCD163 was elevated in the plasma of individuals with chronic HIV infection (>1 year in duration), compared with HIV-seronegative individuals. With effective antiretroviral therapy (ART), sCD163 levels decreased in parallel with HIV RNA levels but did not return to HIV-seronegative levels, suggesting the presence of residual monocyte/macrophage activation even with plasma viral loads below the limit of detection. In individuals with early HIV infection (≤1 year in duration), effective ART resulted in decreased sCD163 levels that were comparable to levels in HIV-seronegative individuals. sCD163 levels in plasma were positively correlated with the percentage of CD14+CD16+ monocytes and activated CD8+HLA-DR+CD38+ T lymphocytes and were inversely correlated with CD163 expression on CD14+CD16+ monocytes. With ART interruption in subjects with early HIV infection, sCD163 and plasma virus levels spiked but rapidly returned to baseline with reinitiation of ART. This study points to the utility of monocyte- and macrophage-derived sCD163 as a marker of HIV activity that links viral replication with monocyte and macrophage activation. These observations underscore the significance of monocyte and macrophage immune responses with HIV pathogenesis.

Hyaluronic Acid Levels Predict Increased Risk of Non-Aids Death in Hepatitis-Coinfected Persons Interrupting Antiretroviral Therapy in the Smart Study

In the SMART study, HIV-viral-hepatitis-coinfected persons were, compared with HIV-monoinfected persons, at higher risk of non-AIDS death if randomized to the antiretroviral therapy (ART) interruption strategy. We hypothesized that a marker of liver fibrosis, hyaluronic acid (HA), would be predictive of development of non-AIDS-related outcomes in coinfected participants in the SMART study. All participants positive for HCV RNA or hepatitis B surface antigen (HBsAg) and with stored plasma samples were included (n=675). Plasma samples were tested for HA (normal range 0-75 ng/ml) at baseline and months 6, 12 and 24 during follow-up in the drug conservation (DC; interrupt ART until CD4(+) T-cell count <250) group and the viral suppression (VS; continued use of ART) group. Time to non-AIDS death was investigated using Kaplan-Meier analysis. Overall, 52 (31 in DC and 21 in VS) coinfected participants died during follow-up. Coinfected participants who were randomized to the DC group with baseline HA>75 ng/ml had a cumulative risk of non-AIDS death of 24.6% after 36 months of follow-up compared with 9.3% for participants randomized to the VS group (P=0.005), while the cumulative risk for coinfected participants with HA ≤ 75 ng/ml was 4.1% (DC) and 4.7% (VS; P=0.76). The change in HA from baseline to month 24 was 8.3 ng/ml and 4.7 ng/ml in the DC and VS group (P=0.56), respectively. Interruption of ART was particularly unsafe in HIV-hepatitis-coinfected individuals if plasma HA was increased. HA changed very little during follow-up and was not influenced by differences in CD4(+) T-cell count or HIV viral load.

Unstructured treatment interruption of antiretroviral therapy in clinical practice: a systematic review

To characterize the frequency, reasons, risk factors, and consequences of unstructured anti-retroviral treatment interruptions. Systematic review. Seventy studies were included. The median proportion of patients interrupting treatment was 23% for a median duration of 150 days. The most frequently reported reasons for interruptions were drug toxicity, adverse events, and side-effects; studies from developing countries additionally cited treatment costs and pharmacy stock-outs as concerns. Younger age and injecting drug use was a frequently reported risk factor. Other risk factors included CD4 count, socioeconomic variables, and pharmacy stock outs. Treatment interruptions increased the risk of death, opportunistic infections, virologic failure, resistance development, and poor immunological recovery. Proposed interventions to minimize interruptions included counseling, mental health services, services for women, men, and ethnic minorities. One intervention study found that the use of short message service reminders decrease the prevalence of treatment interruption from 19% to 10%. Finally, several studies from Africa stressed the importance of reliable and free access to medication. Treatment interruptions are common and contribute to worsening patient outcomes. HIV/AIDS programmes should consider assessing their causes and frequency as part of routine monitoring. Future research should focus on evaluating interventions to address the most frequently reported reasons for interruptions.

Randomized Trial of Time-Limited Interruptions of Protease Inhibitor-Based Antiretroviral Therapy (ART) vs. Continuous Therapy for HIV-1 Infection

BackgroundThe clinical outcomes of short interruptions of PI-based ART regimens remains undefined.MethodsA 2-arm non-inferiority trial was conducted on 53 HIV-1 infected South African participants with viral load <50 copies/ml and CD4 T cell count >450 cells/µl on stavudine (or zidovudine), lamivudine and lopinavir/ritonavir. Subjects were randomized to a) sequential 2, 4 and 8-week ART interruptions or b) continuous ART (cART). Primary analysis was based on the proportion of CD4 count >350 cells(c)/ml over 72 weeks. Adherence, HIV-1 drug resistance, and CD4 count rise over time were analyzed as secondary endpoints.ResultsThe proportions of CD4 counts >350 cells/µl were 82.12% for the intermittent arm and 93.73 for the cART arm; the difference of 11.95% was above the defined 10% threshold for non-inferiority (upper limit of 97.5% CI, 24.1%; 2-sided CI: −0.16, 23.1). No clinically significant differences in opportunistic infections, adverse events, adherence or viral resistance were noted; after randomization, long-term CD4 rise was observed only in the cART arm.ConclusionWe are unable to conclude that short PI-based ART interruptions are non-inferior to cART in retention of immune reconstitution; however, short interruptions did not lead to a greater rate of resistance mutations or adverse events than cART suggesting that this regimen may be more forgiving than NNRTIs if interruptions in therapy occur.Trial RegistrationClinicalTrials.gov NCT00100646

Evolution of Drug-Resistant Viral Populations during Interruption of Antiretroviral Therapy

Analysis of a large number of HIV-1 genomes at multiple time points after antiretroviral treatment (ART) interruption allows determination of the evolution of drug-resistant viruses and viral fitness in vivo in the absence of drug selection pressure. Using a parallel allele-specific sequencing (PASS) assay, potential primary drug-resistant mutations in five individual patients were studied by analyzing over 18,000 viral genomes. A three-phase evolution of drug-resistant viruses was observed after termination of ART. In the first phase, viruses carrying various combinations of multiple-drug-resistant (MDR) mutations predominated with each mutation persisting in relatively stable proportions while the overall number of resistant viruses gradually increased. In the second phase, viruses with linked MDR mutations rapidly became undetectable and single-drug-resistant (SDR) viruses emerged as minority populations while wild-type viruses quickly predominated. In the third phase, low-frequency SDR viruses remained detectable as long as 59 weeks after treatment interruption. Mathematical modeling showed that the loss in relative fitness increased with the number of mutations in each viral genome and that viruses with MDR mutations had lower fitness than viruses with SDR mutations. No single viral genome had seven or more drug resistance mutations, suggesting that such severely mutated viruses were too unfit to be detected or that the resistance gain offered by the seventh mutation did not outweigh its contribution to the overall fitness loss of the virus. These data provide a more comprehensive understanding of evolution and fitness of drug-resistant viruses in vivo and may lead to improved treatment strategies for ART-experienced patients.

Evolution of HIV-1 Genotype in Plasma RNA and Peripheral Blood Mononuclear Cells Proviral Dna after Interruption and Resumption of Antiretroviral Therapy

Structured antiretroviral therapy interruption (TI) is discouraged because of poorer AIDS and non-AIDS-related outcomes, but is often inevitable in clinical practice. Certain strategies could reduce the emergence of resistance mutations related to TI. A total of 106 HIV-1-infected patients on stable HAART with undetectable plasma viral load were randomized to therapy continuation (n=50) or CD4(+) T-cell-guided TI (n=56). Staggered interruption involved stopping non-nucleoside reverse transcriptase inhibitors (NNRTIs) 7 days before the nucleoside backbone. Genotypic resistance testing (GRT) was performed on proviral DNA from peripheral blood mononuclear cells (PBMCs) at baseline and before each TI, and on plasma RNA after each TI. At baseline, GRT on PBMCs detected mutations in nine patients and only two major mutations were identified. GRT on plasma samples performed after TIs showed nucleoside reverse transcriptase inhibitors (NRTI), NNRTI and protease inhibitor major resistance associated mutations in 10/56, 3/46 and 1/8 patients receiving these drugs, respectively. Only in two patients had the same mutations been observed in GRT on PBMCs at baseline. Three patients presented virological failure after resumption of therapy, all receiving NNRTIs. In one of them, resistance mutations detected at failure had been also observed previously in GRT on plasma after TI. Staggered interruption of NNRTIs 7 days before the nucleoside backbone does not avoid resistance emergence completely, but does not necessarily lead to virological failure after treatment resumption. Plasma HIV-1 RNA genotype after the interruption and the patient's treatment history seem to be more useful than baseline proviral DNA genotype to assess the risk of virological failure after restarting therapy.

A randomized controlled trial of HIV therapeutic vaccination using ALVAC with or without Remune

Therapeutic HIV vaccination during the time of virologic suppression may delay or blunt viral load rebound after interruption of antiretroviral therapy (ART). The use of ALVAC, to enhance cytotoxic T-lymphocyte responses, with Remune, which provides CD4 T-cell help, may induce anti-HIV responses capable of controlling viral replication. CTN173 was a randomized, placebo-controlled double-blind study in which effectively treated HIV-infected individuals (viral load <50 copies/ml for more than 2 years) with CD4 nadir more than 250 cells/μl and current CD4 cell counts more than 500 cells/μl were randomized to receive: ALVAC with Remune, ALVAC alone or matching placebos over 20 weeks. At week 24, participants interrupted ART with intensive clinical, virologic and immunologic monitoring to week 48. Baseline characteristics of the 52 randomized participants were balanced between arms. Forty-eight participants who received all vaccinations interrupted ART at week 24. Median time to viral load more than 50 copies/ml tended to be greater in the two vaccine arms (24.5, 23.0 vs. 13.5 days in the placebo arm, P = 0.097 for combined vaccine groups vs. placebo), but subsequent viral load set-point was not different between groups. Significantly fewer participants in the two vaccine arms restarted ART or met CD4 criteria to do so (P = 0.024). Although ALVAC with or without Remune did not lower the viral load set-point, it tended to delay viral load rebound and was associated with a greater time to meet preset criteria to restart ART. Further investigations of those individuals who derived benefit from vaccination could provide important insights into HIV therapeutic vaccine development.

Non-adherence to antiretroviral treatment and unplanned treatment interruption among people living with HIV/AIDS in Cameroon: Individual and healthcare supply-related factors

In low-income countries, health system deficiencies may undermine treatment continuity and adherence to antiretroviral therapy (ART) that are crucial for the success of large-scale public ART programs. In addition to examining the effects of individual characteristics, on non-adherence to ART and treatment interruption behaviors – i.e. treatment interruption for more than 2 consecutive days during the previous 4 weeks, this study aims to extend our knowledge on the role played by healthcare supply-related characteristics in shaping these two treatment outcomes. These effects are examined using multilevel logistic models applied to a sub-sample of 2381 ART-treated patients followed-up in 27 treatment centers in Cameroon (ANRS-EVAL survey, 2006–2007).Multivariate models show that factors common to both non-adherence and treatment interruption include binge drinking (at the individual-level) and large hospital size (at the healthcare supply-level). Among the individual factors, financial difficulties of paying for HIV-care are the major correlates of treatment interruption [Adjusted Odds Ratio (AOR) 95% confidence interval (CI) = 11.73(7.24–19.00)]. By contrast, individual factors associated with an increased risk of non-adherence include: having a main partner but not living in a couple compared to patients living in a couple [AOR(95%CI) = 1.51(1.14–2.01)]; experience of discrimination in the family environment [AOR(95%CI) = 1.74(1.14–2.65)]; a lack of regular meals [AOR(95%CI) = 1.93(1.44–2.57)], and switching antiretroviral drugs (ARV) regimen [AOR(95%CI) = 1.36(1.08–1.70)]. At healthcare facility-level, the main correlate of ART interruption was antiretroviral stock-outs [AOR(95%CI) = 1.76(1.01–3.32)] whereas the lack of psychosocial support from specialized staff and lack of task-shifting to nurses in medical follow-up were both associated with a higher-risk of non-adherence [respective AOR (95%CI) = 2.81(1.13–6.95) and 1.51(1.00–3.40)].Results reveal different patterns of factors for non-adherence and treatment interruption behaviors. They also suggest that psychosocial support interventions targeted at the individual patient-level will not be sufficient to achieve favorable treatment outcomes if not combined with interventions focused on strengthening health systems, including appropriate drug supplies and human resources policies, as well as sustainable and equitable financing mechanisms.

Effect of Treatment Interruption and Intensification of Antiretroviral Therapy on Health-Related Quality of Life in Patients with Advanced HIV

The effect of antiretroviral therapy (ART) interruption or intensification on health-related quality of life (HRQoL) in advanced HIV patients is unknown. To assess the impact of temporary treatment interruption and intensification of ART on HRQoL. A 2 x 2 factorial open label randomized controlled trial. Hospitals in the United States, Canada, and the United Kingdom. Multidrug resistant (MDR) HIV patients. Patients were randomized to receive a 12-wk interruption or not, and ART intensification or standard ART. The Health Utilities Index (HUI3), EQ-5D, standard gamble (SG), time tradeoff (TTO), visual analog scale (VAS), and the Medical Outcomes Study HIV Health Survey (MOS-HIV). There were no significant differences in HRQoL among the four groups during follow-up; however, there was a temporary significant decline in HRQoL on some measures within the interruption group during interruption (HUI3 -0.05, P = 0.03; VAS -5.9, P = 0.002; physical health summary -2.9, P = 0.001; mental health summary -1.9, P = 0.02). Scores declined slightly overall during follow-up. Multivariate analysis showed significantly lower HRQoL associated with some clinical events. Limitations. The results may not apply to HIV patients who have not experienced multiple treatment failures or who have not developed MDR HIV. Temporary ART interruption and ART intensification provided neither superior nor inferior HRQoL compared with no interruption and standard ART. Among surviving patients, HRQoL scores declined only slightly over years of follow-up in this advanced HIV cohort; however, approximately one-third of patients died during the trial follow up. Lower HRQoL was associated with adverse clinical events.

Interruptions of cART limits CD4 T-cell recovery and increases the risk for opportunistic complications and death

A major goal of antiretroviral therapy (ART) for HIV-1-infected persons is the recovery of CD4 T lymphocytes, resulting in thorough protection against opportunistic complications. Interruptions of ART are still frequent. The long-term effect on CD4 T-cell recovery and clinical events remains unknown. Immunological and clinical endpoints were evaluated in 2491 participants of the Swiss HIV Cohort Study initiating ART during a mean follow-up of 7.1 years. Data were analysed in persons with treatment interruptions (n = 1271; group A), continuous ART, but intermittent HIV-1 RNA at least 1000 copies/ml (n = 469; group B) and continuous ART and HIV-1 RNA constantly less than 1000 copies/ml (n = 751; group C). Risk factors for low CD4 T-cell counts and clinical events were analysed using Cox proportional hazards models. In groups A-C, CD4 T lymphocytes increased to a median of 427, 525 and 645 cells/μl at 8 years. In group A, 63.0 and 37.2% reached above 350 and 500 CD4 T cells/μl, whereas in group B 76.3 and 55.8% and in group C 87.3 and 68.0% reached these thresholds (P < 0.001). CD4 T-cell recovery directly depended on the cumulative duration of treatment interruptions. In addition, participants of group A had more Centers for Disease Control and Prevention B/C events, resulting in an increased risk of death. Major risk factors for not reaching CD4 T cells above 500 cells/μl included lower baseline CD4 T-cell count, higher age and hepatitis C virus co-infection. In persons receiving continuous ART larger CD4 T-cell recovery and a reduced risk for opportunistic complications and death was observed. CD4 T-cell recovery was smaller in persons with treatment interruptions more than 6 months.

The consequences of post-election violence on antiretroviral HIV therapy in Kenya

Over 1000 individuals were killed and 600,000 were displaced during post-election violence (PEV) in Kenya in 2008. Antiretroviral therapy (ART) depends on continuous access to medications which may have been interrupted due to PEV. In a mixed-methods retrospective review, treatment interruption of ART during PEV was measured among 2534 HIV-positive adults attending the Coptic Hope Center for Infectious Diseases in Nairobi, Kenya. Clients experiencing treatment interruption were compared between the PEV period (30 December 2007 to 28 February 2008) and the same time period one year earlier. Treatment interruption was defined as visiting the pharmacy ≥48 hours after antiretrovirals were calculated to have been completed. Despite clinical services remaining open throughout the PEV period, more clients (16.1%) experienced treatment interruption than during the comparison period (10.2%). Mean daily pharmacy visits were significantly lower (87 vs. 104; p < 0.006) and more variable (p = 0.03) during PEV. Among clients present at both periods (n = 1605), the odds of treatment interruption were 71% higher during PEV (95% confidence interval [CI], 34–118%). In multivariate analysis, men (odds ratio [OR], 1.37; 95% CI, 1.07–1.76) and clients traveling ≥3 hours to clinic (OR, 1.86; 95% CI, 1.28–2.71) were significantly more likely to experience treatment interruption. Clients affected by PEV were interviewed about factors associated with treatment interruption using semi-structured methods. Clients described fear, lack of transportation, and violence as contributing to treatment interruption. Widespread violence associated with the 2007 election in Kenya revealed the dependence of HIV patients on a stable civil society and infrastructure to access medications. Without the ability to maintain consistent HIV therapy, some patients face rapid treatment failure. HIV programs should have appropriate contingency plans wherever political instability may occur. Peace may be one of the most effective and most important public health interventions in Africa.

Boosted protease inhibitors and the electrocardiographic measures of QT and PR durations.

There are contradictory reports regarding the effects of protease inhibitors on the ECG measures of QT and PR interval durations. The effect of interrupting use of protease inhibitors on QT and PR progression is also unknown. This analysis included 3719 participants from the Strategies for Management of Antiretroviral Therapy (SMART) study, of whom 1879 were randomized to receive intermittent antiretroviral therapy (ART) (drug conservation group), whereas the rest received these drugs continuously (viral suppression group). Linear regression analysis was used to compare four ritonavir-boosted protease inhibitor (protease inhibitor/r) regimens [saquinavir (SQV/r), lopinavir (LPV/r), atazanavir (ATV/r), and other protease inhibitor/r], and nonboosted protease inhibitor regimens with nonnucleoside reverse transcriptase inhibitor (NNRTI) regimens for Bazett's (QTcB) and Fredericia's (QTcF) heart rate corrected QT and PR. Changes in QTcB, QTcF, and PR after 12 and 24 months of randomization were compared in the drug conservation group and viral suppression group. Average levels of QTcB, QTcF, and PR duration at entry were 415, 406, and 158 ms. At study entry, 49% of participants were taking an NNRTI (no protease inhibitor)-based regimen and 31% were prescribed a boosted protease inhibitor, the most common being LPV/r. After adjustment for baseline factors, QTcB and QTcF levels did not vary by boosted protease inhibitor group (P = 0.26 and P = 0.34, respectively). For those given any of the boosted protease inhibitors, QTcB was 1.5 ms lower than the NNRTI group (P = 0.04). Both boosted and nonboosted protease inhibitor-containing regimens were significantly associated (P < 0.01 for each) with longer PR intervals compared to the NNRTI group. After adjustment, the difference between boosted protease inhibitors and the NNRTI group was 5.11 ms (P < 0.01); for nonboosted protease inhibitors, this difference was 3.00 ms (P < 0.01). Following ART interruption, PR duration declined for both the boosted and nonboosted protease inhibitor groups and compared to the viral suppression group, significant changes in PR interval were observed 24 months after ART interruption of boosted protease inhibitors (P < 0.01). Different protease inhibitor-based regimens have a similar, minimal effect on QT compared to NNRTI-based regimens. All protease inhibitor-based regimens (boosted and nonboosted) were associated with prolongation of PR, and interruption of protease inhibitor regimens reduced the prolonged PR duration. Further research is needed to confirm the findings of this study and assess the clinical relevance of the differences.

Alpha interferon administration during structured interruptions of combination antiretroviral therapy in patients with chronic HIV-1 infection: INTERVAC ANRS 105 trial

Interferon-α administration during structured treatment interruptions (STIs) was studied in a phase III trial. We randomized 168 chronically infected HIV undetectable under combined antiretroviral therapy patients to have three STIs with or without α-interferon. The number of patients who had to resume treatment during post-STI follow-up was not significantly different between the two arms. Patients with a low CD4 nadir and a high baseline HIV-DNA had a higher risk of treatment resumption in the interferon arm.

Incidence, Temporal Trends, and Predictors of Thrombocytopenia Among HIV-Infected Persons Treated with Combined Antiretroviral Therapy (cART)

AbstractAbstract 69 Background:Thrombocytopenia (TP) is a relatively common disorder in HIV-infected Persons, and may be a challenging illness to treat, mainly because of its multifactorial aetiology. The underlying pathophysiology includes accelerated immune-mediated peripheral PLT destruction and impaired PLT production by the infected megakaryocytes of the bone marrow. Moreover, TP can also occur as a secondary phenomenon in HIV-positive patients, due to hypersplenism, bone marrow infiltration from infections of lymphoma, or myelosuppressive effects of medications. However, the epidemiology and predictors of TP in the era of potent HIV antiretroviral therapy has not been well defined. In a recent retrospective-matched case–control study of HIV-infected adult outpatients with (n=73) and without (n=73) TP, authors found that TP was significantly associated with HCV infection, cirrhosis, and uncontrolled HIV replication (Marks KM et al. J AIDS 2009). Antiretroviral therapy interruption among patients with well-controlled HIV infection has been associated with an increased incidence of thrombocytopenia, especially among those with a low baseline platelet count or a history of HIV-related thrombocytopenia (Bouldouyre MA et al. J AIDS 2009). Methods:The study was carried out in the Icona Foundation Study Cohort. All previously naïve starting cART with normal value of platelet count (PC) were included. TP has been defined as PC <100 × 109/L persisting in at least 2 consecutive determinations for at least 3 consecutive months. For each patient person-years of follow-up (PYFU) while receiving cART were calculated, and used to estimate the incidence rate of TP. A multivariable Poisson model was performed to elucidate the contribution of HIV viremia, immune reconstitution, HCV infection, ARV drug-class, and other potential risk factors for TP. Current HIV-RNA and CD4 count entered into the model as time-dependent covariates. Results:A total of 2,771 patients were included: 69.4% male, median age 36 yrs (IQR: 32–41), 38.5% HCV+. At initiation of cART, CD4 count and HIV-RNA were 295 cells/mmc and 4.75 log10 cp/mL, respectively. Mean value of baseline PC was 189 × 109/L (IQR 149–231). Overall patients contributed to 13,787 PYFU. During follow-up, 105 patients developed a TP accounting for an incidence rate of 7.6/1000 PYFU (95%CI 6.3–9.2). PC <20,000 was found in 5.7%, 20,000-50,000 in 12.4%, 50,000-100,000 in 81.4%. A trend for a reduction in the TP incidence rates over the last years was found (1997-1999: 9.8/1000 pyrs; 2000–2004: 4.6/1000 pyrs; 2005–2009: 4.5/1000 pyrs; P at Chi-square for temporal trend<0.001). At multivariable model, a higher risk of TP was associated with male gender (HR 1.99; 95%CI 1.19–3.32; P=0.008), and HCV co-infection (HR 3.45; 95%CI 2.23–5.33; P<0.001). Moreover, both lower level of current CD4 (HR 1.67 for 0–200 vs >350 cell/mmc; 95%CI 1.02–2.64; P=0.039) and detectable HIV viremia (HR 1.47 for each log10 cp/ml increase; 95%CI 1.25–1.73; P<0.001) were significantly associated with TP onset. No association with ARV drug-class was found. Conclusions:Thrombocytopenia remains a relatively common disorder in the late HAART era, with an overall 7.6 * 1000 PYFU, even if a trend for a reduced incidence over the last years was observed. In a large unselected cohort of antiretroviral naïve starting treatment, HCV co-infection, cirrhosis at baseline, uncontrolled HIV replication and lower current CD4 count were all independent predictors of TP. Furthermore in our study, the association with HCV-infection was independent from cirrhosis suggesting that mechanisms other than advanced liver disease may play a role in HIV/HCV-coinfected patients. In this cohort of treated patients, we found a strong association of TP with uncontrolled HIV replication and lower current CD4, these findings confirm the benefit of antiretroviral therapy on HIV-related thrombocytopenia.ON BEHALF OF THE ICONA FOUNDATION STUDY GROUP Disclosures:No relevant conflicts of interest to declare.