Plasma Viral Load Measurements Research Articles

HIV-1 low-level viraemia predicts virological failure in first-line and second-line ART-experienced individuals in India: A retrospective longitudinal study.

To study the prevalence of low-level viraemia (LLV) and its association with virological failure (VF). We conducted a retrospective analysis of 3498 participants at YRG CARE, Chennai, India (2013-2018) on antiretroviral therapy (ART) for ≥6 months with two or more plasma viral load (pVL) measurements. Results were stratified for those with pVL <1000 copies/mL: fully suppressed (FS) (pVL <40), low-LLV (pVL 40-199), mid-LLV (pVL 200-399), and high-LLV (pVL 400-999). The study assessed the association with VF (pVL >1000 copies/mL) using Cox proportional hazard model. Among 3498 participants, 2965 (84.8%) were FS and 533 (15.2%) were LLV. During the follow-up, 348 (10%) experienced VF, with 222 (6.3%) experienced after LLV (42% of LLV) and 126 (3.6%) experienced after FS (4.3% of FS). When compared with FS, those with LLV had a greater risk of VF [adjusted hazard ratio (aHR) = 12.7; 95% confidence interval (CI): 10.2-15.9]. First-line participants had a higher VF incidence (aHR = 15.8, 95% CI: 11.4-21.9) than second-line participants (aHR = 5.6, 95% CI: 4.1-7.7). Those with high-LLV had the highest VF risk (aHR = 22.856, 95% CI: 15.204-34.359 vs. aHR = 8.186, 95% CI: 5.564-12.043, for first-line vs. second-line participants, respectively), followed by those with mid-LLV (aHR = 13.375, 95% CI: 8.327-21.483 vs. aHR = 6.261, 95% CI: 4.044-9.695) and low-LLV (aHR = 12.976, 95% CI: 7.974-21.118 vs. aHR = 4.158, 95% CI: 2.826-6.119). The prevalence of LLV was intermediate in our study population. There was a higher risk of VF among individuals with LLV, and this risk increased with the increasing levels of LLV. Close monitoring of individuals experiencing LLV could help in the early identification of VF.

Comparison of serum and plasma viral load measurements in human immunodeficiency virus type 1 infection

The diagnosis of human immunodeficiency virus 1 (HIV) infections is reliant on viral nucleic acid testing (NAT). HIV viral load (VL) is generally measured in plasma samples.We evaluated and compared plasma HIV VL results with those obtained using serum samples, the aim being to enable the use of serum in urgent contexts where plasma is not available. Our findings indicated a very high correlation between the HIV VL results obtained in plasma and in serum.

Healthcare and treatment experiences among people diagnosed with HIV before and after a province-wide treatment as prevention initiative in British Columbia, Canada

IntroductionIn 2010, the Canadian province of British Columbia (BC) initiated the Seek and Treat for Optimal Prevention of HIV/AIDS (STOP HIV/AIDS) program to improve HIV testing, linkage to care, and treatment uptake, thereby operationalizing the HIV Treatment as Prevention (TasP) framework at the population-level. In this analysis, we evaluated self-reported HIV care experiences and therapeutic outcomes among people diagnosed with HIV prior to and after implementation of this provincial program.MethodsA cross-sectional analysis was performed on the baseline data of a cohort of people living with HIV (PLWH) (19 years and older) in the province of BC sampled from July 2016 to September 2018. All participants consented to linking their survey data to the provincial HIV treatment registry. Individuals diagnosed with HIV from January 1 2000—December 31 2009 were classified as pre-intervention and those diagnosed January 1 2010—December 31 2018 as post-intervention cohorts. Bivariate analyses were run using Chi-square and Wilcoxon Rank Sum tests. Cox proportional hazards regression model demonstrates time to antiretroviral therapy (ART) initiation (from HIV baseline) and virological suppression (2 consecutive plasma viral load measurements < 200 copies/ml).ResultsOf the 325 participants included in this analysis, 198 (61%) were diagnosed with HIV in the pre-intervention era and 127 (39%) in the post-intervention era. A higher proportion of participants in post-intervention era were diagnosed at walk-in clinics (45% vs. 39%) and hospitals (21% vs. 11%) (vs pre-intervention) (p = 0.042). Post-intervention participants had initiated ART with less advanced HIV disease (CD4 count 410 vs. 270 cells/ul; p = 0.001) and were less likely to experience treatment interruptions at any point in the 5 years after HIV diagnosis (17% vs. 48%; p < 0.001). The post-intervention cohort had significantly more timely ART initiation (aHR: 5.97, 95%CI 4.47, 7.97) and virologic suppression (aHR: 2.03, 95%CI 1.58, 2.60) following diagnosis, after controlling for confounders.ConclusionsWe found favourable treatment experiences and more timely ART initiation and virologic suppression after a targeted TasP provincial program. Our results illustrate the importance of accessible low-barrier HIV testing and treatment in tackling the HIV epidemic.

Factors affecting optimal adherence to antiretroviral therapy and viral suppression amongst HIV-infected prisoners in South Ethiopia: a comparative cross-sectional study

BackgroundMaintaining optimal adherence and viral suppression in people living with HIV (PLWH) is essential to ensure both preventative and therapeutic benefits of antiretroviral therapy (ART). Prisoners bear a particularly high burden of HIV infection and are highly likely to transmit to others during and after incarceration. However, the level of treatment adherence and viral suppression in incarcerated populations in low-income countries is unknown. This study aimed to determine factors affecting optimal adherence to antiretroviral therapy and viral suppression amongst HIV-infected prisoners in South Ethiopia.MethodsA comparative cross-sectional study was conducted between June 1, 2019 and May 31, 2020 to compare the level of adherence and viral suppression between incarcerated and non-incarcerated PLWH. Patient information including demographic, socio-economic, behavioral, and incarceration-related characteristics were collected using a structured questionnaire. Medication adherence was assessed according to self-report and pharmacy refill. Plasma viral load measurements undertaken within the study period were prospectively extracted to determine viral suppression. Univariate and multivariate logistic and fractional regression models were used to analyse data.ResultsSeventy-four inmates living with HIV (ILWH) and 296 non-incarcerated PLWH participated in the study. While ILWH had a significantly higher pharmacy refill adherence compared to non-incarcerated PLWH (89 vs 75%), they had a slightly lower dose adherence (81% vs 83%). The prevalence of viral non-suppression was also slightly higher in ILWH (6.0%; 95% confidence interval (CI): 1.7–14.6%) compared to non-incarcerated PLWH (4.5%; 95%CI: 2.4–7.5%). Overall, missing ART appointments, dissatisfaction with ART services, inability to comply with a specified medication schedule, and types of methods used to monitor the schedule (e.g., news time on radio/TV or other social cues) were significantly associated with non-adherence according to self-report. In ILWH specifically, accessing ART services from a hospital, inability to properly attend clinic appointments, depressive symptoms, and lack of social support predicted NA. Viral non-suppression was significantly higher in males, people of age 31to 35 years and in those who experienced social stigma, regardless of their incarceration status.ConclusionsSub-optimal dose adherence and viral suppression are generally higher in HIV-infected prisoners in South Ethiopia compared to their non-incarcerated counterparts. A multitude of factors were found to be responsible for this requiring multilevel intervention strategies focusing on the specific needs of prisoners.

Elevated Plasma Viral Loads in Romidepsin-Treated Simian Immunodeficiency Virus-Infected Rhesus Macaques on Suppressive Combination Antiretroviral Therapy.

Replication-competent human immunodeficiency virus (HIV) persists in infected people despite suppressive combination antiretroviral therapy (cART), and it represents a major obstacle to HIV functional cure or eradication. We have developed a model of cART-mediated viral suppression in simian human immunodeficiency virus (SIV) mac239-infected Indian rhesus macaques and evaluated the impact of the histone deacetylase inhibitor (HDACi) romidepsin (RMD) on viremia in vivo. Eight macaques virologically suppressed to clinically relevant levels (<30 viral RNA copies/ml of plasma), using a three-class five-drug cART regimen, received multiple intravenous infusions of either RMD (n = 5) or saline (n = 3) starting 31 to 54 weeks after cART initiation. In vivo RMD treatment resulted in significant transient increases in acetylated histone levels in CD4(+) T cells. RMD-treated animals demonstrated plasma viral load measurements for each 2-week treatment cycle that were significantly higher than those in saline control-treated animals during periods of treatment, suggestive of RMD-induced viral reactivation. However, plasma virus rebound was indistinguishable between RMD-treated and control-treated animals for a subset of animals released from cART. These findings suggest that HDACi drugs, such as RMD, can reactivate residual virus in the presence of suppressive antiviral therapy and may be a valuable component of a comprehensive HIV functional cure/eradication strategy.

Montreal Cognitive Assessment Performance in HIV/AIDS: Impact of Systemic Factors

A large proportion of people living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) suffer from neurocognitive impairment (NCI). The causes of the NCI are multifold in HIV infection although a subset of HIV/AIDS patients are affected by the spectrum syndrome, HIV-associated neurocognitive disorder (HAND). We investigated the Montreal Cognitive Assessment (MoCA) in relation to clinical, demographic and laboratory findings as well as its ability to predict symptomatic HAND (sHAND) among patients with HIV/AIDS. All subjects were receiving regular HIV care including CD4+ T cell counts, plasma viral load measurements, clinical evaluations and antiretroviral therapy. The diagnosis of sHAND was based upon clinical, neuroimaging, and neuropsychological assessments. Among HIV-1 seropositive subjects (n=125), ethnicity, education and employment were positively correlated with their MoCA scores (p<0.05). In contrast, polypharmacy, central nervous system penetration-effectiveness (CPE) score, antiretroviral drug exposure, substance use and nucleoside/nucleotide reverse transcriptase inhibitor side effects were negatively correlated with MoCA scores (p<0.05). Of note, MoCA scores were not associated with CD4 T cell nadir levels, age, peak viral load, or veterans aging cohort study index. In subjects with or without sHAND, mean MoCA scores differed (sHAND, 22.8±3.51; non-HAND 25.2±2.64) (p<0.05) with a receiver operating characteristic curve showing an area under curve of 0.71 and an optimal MoCA cut-off value of 23.5 when compared to the established diagnostic paradigm. MoCA scores were generally lower in this HIV/AIDS population compared to reported scores in the general population. MoCA performance was associated with multiple clinical variables but displayed limited predictive utility in detecting sHAND.

Temporal trends in prognostic markers of HIV-1 virulence and transmissibility: an observational cohort study

Measures of CD4 T-cell count and HIV-1 plasma viral load before antiretroviral therapy are proxies for virulence. Whether these proxies are changing over time has implications for prevention and treatment. The aim of this study was to investigate those trends. Data were derived from the Concerted Action on SeroConversion to AIDS and Death in Europe (CASCADE) collaboration of mainly European seroconverter cohorts. Longitudinal CD4 cell counts and plasma viral load measurements before the initiation of antiretroviral therapy or AIDS onset were analysed by use of linear or fractional polynomials mixed models adjusting for all available potential confounders. Calendar time effects were modelled through natural cubic splines. 15 875 individuals seroconverting from 1979 to 2008 fulfilled the inclusion criteria; 3215 (20·3%) were women; median follow-up was 31 months (IQR 14-62); dropout before starting antiretroviral therapy or AIDS onset was 8·1%. Estimated CD4 counts at seroconversion for a typical individual declined from about 770 cells per μL (95% CI 750-800) in the early 1980s to a plateau of about 570 cells per μL (555-585) after 2002. CD4 cell rate of loss increased up to 2002. Estimated set-point plasma viral loads increased from 4·05 log10 copies per mL (95% CI 3·98-4·12) in 1980 to 4·50 log10 copies per mL (4·45-4·54) in 2002 with a tendency of returning to lower loads thereafter. Results were similar when we restricted analyses to various subsets, including adjusting for plasma viral load assay, censored follow-up at 3 years, or used variations of the main statistical approach. Our results provide strong indications of increased HIV-1 virulence and transmissibility during the course of the epidemic and a potential plateau effect after about 2002. European Union Seventh Framework Programme.

An undetectable polymerase chain reaction signal in routine HIV plasma viral load monitoring is associated with better virological outcomes in patients receiving highly active antiretroviral therapy

The aim of the study was to assess whether patients with undetectable viraemia [a negative polymerase chain reaction result (PCR(neg) )] and those with plasma viral load (PVL) < 40 HIV-1 RNA copies/mL but a detectable (positive) PCR signal (PCR(pos) ) had different outcomes in terms of the development of blips and virological failure (VF). A multicentre observational database analysis was carried out. Data for patients whose highly active antiretroviral therapy (HAART) regime had been unchanged for ≥ 6 months by 1 January 2008, whose first two PVL measurements of 2008 were < 40 copies/mL and who had at least five PVL measurements between 1 January 2008 and 31 December 2010 were extracted from a multicentre observational database of 4928 patients receiving HAART. PVL assays used during this period had a detection threshold of 20 or 40 copies/mL. Undetectable PVL at baseline (BL PCR(neg) ) was defined as PCR(neg) at the first two PVL determinations of 2008. Multivariable Cox regression analysis was performed to investigate factors associated with the occurrence of blips and VF, defined as two consecutive PVL measurements > 40 copies/mL. Of the 1957 patients included in the study (mean age 47 years; median antiretroviral exposure 10.3 years), 1312 had BL PCR(neg) . Outcome events included 322 blips and 139 VFs, with incidence rates being significantly lower in patients with BL PCR(neg) than in those with BL PCR(pos) [13.0% vs. 23.4% (P < 0.0001) and 5.1% vs. 11.2% (P < 0.0001), respectively]. In multivariable analysis, BL PCR(neg) was associated with a reduced risk of blips [hazard ratio (HR) 0.58; 95% confidence interval (CI) 0.47-0.73; P < 0.0001] and VF (HR 0.44; 95% CI 0.31-0.62; P < 0.0001). Patients with PCR(neg) had better virological outcomes than those with PVL < 40 copies/mL but detectable viraemia. This suggests that the 'no-signal' information provided by currently commercially available HIV RNA quantification assays should be used routinely.

CD4 cell count and the risk of AIDS or death in HIV-Infected adults on combination antiretroviral therapy with a suppressed viral load: a longitudinal cohort study from COHERE.

Most adults infected with HIV achieve viral suppression within a year of starting combination antiretroviral therapy (cART). It is important to understand the risk of AIDS events or death for patients with a suppressed viral load. Using data from the Collaboration of Observational HIV Epidemiological Research Europe (2010 merger), we assessed the risk of a new AIDS-defining event or death in successfully treated patients. We accumulated episodes of viral suppression for each patient while on cART, each episode beginning with the second of two consecutive plasma viral load measurements <50 copies/µl and ending with either a measurement >500 copies/µl, the first of two consecutive measurements between 50-500 copies/µl, cART interruption or administrative censoring. We used stratified multivariate Cox models to estimate the association between time updated CD4 cell count and a new AIDS event or death or death alone. 75,336 patients contributed 104,265 suppression episodes and were suppressed while on cART for a median 2.7 years. The mortality rate was 4.8 per 1,000 years of viral suppression. A higher CD4 cell count was always associated with a reduced risk of a new AIDS event or death; with a hazard ratio per 100 cells/µl (95% CI) of: 0.35 (0.30-0.40) for counts <200 cells/µl, 0.81 (0.71-0.92) for counts 200 to <350 cells/µl, 0.74 (0.66-0.83) for counts 350 to <500 cells/µl, and 0.96 (0.92-0.99) for counts ≥500 cells/µl. A higher CD4 cell count became even more beneficial over time for patients with CD4 cell counts <200 cells/µl. Despite the low mortality rate, the risk of a new AIDS event or death follows a CD4 cell count gradient in patients with viral suppression. A higher CD4 cell count was associated with the greatest benefit for patients with a CD4 cell count <200 cells/µl but still some slight benefit for those with a CD4 cell count ≥500 cells/µl.

Use of chloroquine in reducing mother to child transmission of HIV-1 during breastfeeding

Chloroquine (CQ) has been shown to inhibit HIV-1 replication in vitro as well as in vivo, thereby indicating its use as an effective drug in limiting mother to child transmission of HIV-1 during breastfeeding. We show that HIV-1 replication on CD4 + T-lymphocytes can be reduced in the presence of CQ and show that the reduced replication is producer cell specific and that viruses generated in the presence of CQ are not inhibited for their subsequent infectivity and replication. By analysing the gp120 envelope protein sequences from virus passaged over a long period of time in the presence or absence of CQ we demonstrate variant evolution patterns of the envelope. We also demonstrate that HIV-1 produced in the presence of CQ have a reduced capacity for the transfer by Raji-DCSIGN cells to CD4+ T-lymphocytes indicating another means whereby virus replication may be reduced in vivo. We conducted a Phase I/II, randomized, placebo-controlled study to evaluate chloroquine (CQ) administration to reduce HIV-1 RNA levels in human milk. Thirty HIV-1 positive pregnant Rwandese women (CQ n = 20; placebo n = 10) were enrolled in a 16 week study, with the treatment group receiving a 200 mg oral dose of CQ daily. Base-line plasma viral load (pVL) measurements and CD4 counts were determined prior to delivery with pVL, breast milk VL (bmVL) and CQ levels measured at wk0, wk8 and wk16. For selected mothers the envelope C1C4 gp120 region was DNA sequenced and analyzed. A higher concentration of CQ in breast milk compared to plasma (over 2.5 fold) was observed after 8 and 16 weeks of treatment. CQ levels in plasma correlated to those in the left and right breast milk (P = 0.002 and P = 0.003, respectively). Additionally, a link between high CQ concentrations in plasma and high CD4 counts (P < 0.001) was observed. No alterations in bmVL were observed with CQ treatment whilst pVL increased significantly (P = 0.001). In over half of the CQ treated individuals there was a greater than 5 fold increase in pVL which was observed by week 8 of treatment. No specific alterations in the gp120 envelope sequences could be associated with CQ treatment. Our results indicate that CQ administration is associated with increased pVL in early breastfeeding mothers from Rwanda which cautions against the use of CQ in such individuals. from Fifth Dominique Dormont International Conference. Mother-to-child transmitted viral diseases: from transmission to children care

Episodes of low-level viral rebound in HIV-infected patients on antiretroviral therapy: frequency, predictors and outcome

The rate, predictors and outcome following episodes of low-level viral rebound (LLVR) in HIV patients on highly active antiretroviral therapy (HAART) are unknown. Retrospective assessment of all HIV patients who experienced LLVR episodes on HAART at one institution from January 1999 to December 2006. LLVR was defined as plasma HIV-RNA between 51 and 500 copies/mL after at least two consecutive undetectable plasma viral load measurements made during the last 6 months. Virological failure was defined as plasma HIV-RNA >500 copies/mL. Out of 2720 HIV patients on successful HAART during the 8 year study period, 779 (28.6%) developed at least one LLVR episode. Only 655 patients who kept unchanged their HAART regimen following LLVR episodes were further examined. After 12 weeks, undetectable viraemia was regained in 458 (71%), which were considered as blips. In contrast, 66 (9%) LLVR episodes were followed by virological failure, and drug resistance mutations developed in most cases, mainly rtM184V (66%) and rtK103N (29.5%). Plasma HIV-RNA remained between 51 and 500 copies/mL at 12 weeks in the remaining 131 (20%) patients with LLVR episodes. In the multivariate analysis, only plasma HIV-RNA levels at the time of LLVR predicted subsequent virological failure. Episodes of LLVR in HIV patients on successful HAART are relatively common and represent transient events (blips) in most cases (71%). Keeping the same treatment regimen, virological failure follows in <10% of the cases. Plasma HIV-RNA level at the time of LLVR is the best predictor of subsequent failure.

Plasma Load Discrepancies between the Roche Cobas Amplicor Human Immunodeficiency Virus Type 1 (HIV-1) Monitor Version 1.5 and Roche Cobas AmpliPrep/Cobas TaqMan HIV-1 Assays

We read with interest the findings of Damond et al. ([1][1]) showing the lack of agreement between plasma viral load measurements performed by the Cobas Amplicor human immunodeficiency virus type 1 (HIV-1) Monitor test, version 1.5 (Roche Molecular Systems, Inc., Branchburg, NJ) and the Cobas

Impact of genotypic drug resistance mutations on clinical and immunological outcomes in HIV-infected adults on HAART in West Africa

To analyse the association between the presence of resistance mutations and treatment outcomes. The impact of HIV-1 drug resistance mutations in African adults on HAART has so far never been reported. In 2004 in Abidjan, Côte d'Ivoire, 106 adults on HAART had plasma viral load measurements. Patients with detectable viral loads had resistance genotypic tests. Patients were followed until 2006. Main outcomes were serious morbidity and immunological failure (CD4 cell count < 200 cells/microl). At study entry, the median previous time on HAART was 37 months and the median CD4 cell count was 266 cells/microl; 58% of patients had undetectable viral loads, 20% had detectable viral loads with no major resistance mutations, and 22% had detectable viral loads with one or more major mutations. The median change in CD4 cell count between study entry and study termination was +129 cells/microl in patients with undetectable viral loads, +51 cells/microl in those with detectable viral loads with no mutations and +3 cells/microl in those with detectable viral loads with resistance mutations. Compared with patients with undetectable viral loads, those with detectable viral loads with resistance mutations had adjusted hazard ratios of immunological failure of 4.32 (95%CI 1.38-13.57, P = 0.01). One patient died. The 18-month probability of remaining free of morbidity was 0.79 in patients with undetectable viral loads and 0.69 in those with resistance mutations (P = 0.19). In this setting with restricted access to second-line HAART, patients with major resistance mutations had higher rates of immunological failure, but most maintained stable CD4 cell counts and stayed alive for at least 20 months.

Clinical Utility of Cytomegalovirus Viral Load Testing for Predicting CMV Disease in D+/R- Solid Organ Transplant Recipients

Despite prophylaxis, cytomegalovirus (CMV) disease is common in donor seropositive (D+)/recipient seronegative (R-) transplant patients after cessation of prophylaxis. Early detection of CMV may allow for pre-emptive therapy to prevent active disease. The clinical utility of quantitative plasma viral load measurements for predicting CMV disease was determined in 364 D+/R- organ transplant patients receiving prophylaxis (100 d of valganciclovir or oral ganciclovir). Measurements were performed every 2 weeks until day 100 and at months 4, 4.5, 5, 6, 8 and 12 post-transplant. CMV disease occurred in 64 (17.6%) patients by 12 months. Using a positive cut-off value of > 400 copies/mL, sensitivity was 38%, specificity 60%, positive predictive value 17%, and negative predictive value 82% for prediction of CMV disease. Therefore, routine monitoring would have predicted disease in only 24/64 (38%) patients. The test characteristics were not improved by changing the viral load cut-off point for defining a positive result. Similarly, single time point measures at the end of prophylaxis or month 4 had low sensitivity for disease prediction. Overall, regular CMV plasma viral load measurements were only of modest value in predicting CMV disease.

Sexual risk behaviors and implications for secondary HIV transmission during and after HIV seroconversion.

To determine the potential for secondary HIV transmission among newly HIV-infected men who have sex with men (MSM) during their HIV antibody seroconversion period, and for the 12 months after seroconversion. A cohort study. Risk assessment questionnaires administered before receipt of the first positive HIV antibody result, plasma and seminal viral load measurements, and risk assessments one month and quarterly after receipt of the first HIV-positive test, and generalized estimating equation modelling techniques to analyse behavioral trends. Of 66 seroconverters, more than half reported unprotected anal intercourse (UAI) with HIV-negative or unknown-serostatus partners during seroconversion, with 27% reporting insertive UAI with an HIV-negative partner. The initial median plasma viral load was 4.6 log/ml, the median seminal viral load was 2.7 log/ml, suggesting a high level of infectiousness. Compared with risk behavior during seroconversion, UAI with HIV-negative or unknown-serostatus partners was reduced after the receipt of positive antibody results; however, a substantial proportion of participants reported high-risk behaviors for transmission for 12 months of follow-up. After learning of their HIV infection, recent seroconverters did not reduce the risk of secondary transmission by engaging in proportionally more high-risk practices with HIV-infected partners (compared with HIV-negative or unknown-serostatus partners), or engaging in proportionally more receptive compared with insertive UAI. Substantial potential exists for secondary HIV transmission during and for one year after HIV seroconversion. Receipt of an HIV-positive test is associated with a significant reduction in risk behavior, reinforcing the need to identify and counsel recently HIV-infected MSM.

HIV-related thrombocytopenia

Chronic thrombocytopenia is a common hematologic disorder in patients infected with the human immunodeficiency virus (HIV). Although often asymptomatic, the thrombocytopenia may be associated with a variety of bleeding abnormalities. The underlying pathophysiology includes accelerated peripheral platelet destruction and decreased (‘ineffective’) production of platelets from the infected megakaryocytes. HIV-related thrombocytopenia (HIV-TP) responds to antiretroviral therapy. Most studies have evaluated the use of AZT (zidovudine) and have shown increased platelet production. Combination therapy (HAART) also resulted in sustained platelet increases. When antiretroviral agents fail to improve the platelet count or cannot be used, other therapies, similar to those used in ‘classic’ immune thrombocytopenia (ITP), can be employed, including steroids, intravenous immunoglobulin (IVIg), intravenous anti-D or splenectomy. Anti-D treatment offers advantages for HIV-TP because the duration of effect appears to be significantly longer than the response duration after IVIg therapy (initial results of our open-arm study were confirmed by our randomized trial). Of note, follow-up of heavily treated patients showed no acceleration of CD4 decline and no change in plasma viral load measurements. Splenectomy has been used to treat HIV-positive patients with refractory thrombocytopenia. Although it is effective therapy, there are concerns about infections and selection of appropriate candidates. Other treatment modalities, such as interferon, vincristine, danazol, low-dose splenic irradiation and staphylococcal protein A immunoadsorption have shown limited success in HIV-TP. Alternatively, thrombocytopenia in HIV-infected patients may be treated with pharmacological hyperstimulation of megakaryocytopoiesis (administration of PEG-rHuMGDF or TPO). Latest evidence indicates that the chemokine receptor CXCR4 (coreceptor for the cellular entry of lymphotropic HIV strains) is expressed on megakaryocytes; as a result, the development of chemokine receptor antagonists may modify the course of the disease.

Kinetics of the T-cell receptor CD4 and CD8 V beta repertoire in HIV-1 vertically infected infants early treated with HAART.

To determine the kinetics and the relationship between the T-cell receptor V beta (TCRBV) complementary determining region 3 length, the CD4 T-cell count and HIV viral load changes in HIV-1 infected infants treated early with highly active antiretroviral therapy (HAART) during 1 year of follow-up. Two HIV-1 vertically infected infants, two HIV-1 vertically exposed uninfected and two healthy controls were analysed by spectratyping. Evaluation of viral load, CD4 naive and memory cell counts and a proliferation test were also carried out. Twenty-six families and subfamilies of the TCR on CD4 and CD8 T cells were analyzed by spectratyping. Flow cytometric analysis on peripheral blood mononuclear cells for CD4CD45Ra, CD4CD45Ro, CD8CD38, proliferation tests and plasma viral load measurements were performed at baseline, 1, 6 and after 12 months of therapy. HAART induced a marked reduction of viral load in both HIV-1 infected infants and an increase to normal CD4 T-cell count in the symptomatic infant. At baseline the TCRBV family distribution in the majority of CD8 and a few of the CD4 T cells was highly perturbed, with several TCRBV families showing a monoclonal/oligoclonal distribution. During HAART a normalization of the TCR repertoire in both CD8 and CD4 subsets occurred. TCR repertoire normalization was associated with a good virological and immunological response. These results suggest that complete and early virus replication control as a result of early HAART leads to a marked reduction of T-cell oligoclonality and is an essential prerequisite to the development of a polyclonal immune response in HIV-1 infected infants.

Rapid Communications

Objective: To determine the ability of intermediate plasma viral load (pVL) measurements to predict virologic outcome at 52 weeks of follow-up in clinical trials of antiretroviral therapy. Methods: Individual patient data from three clinical trials (INCAS, AVANTI-2 and AVANTI-3) were combined into a single database. Virologic success was defined to be plasma viral load (pVL) <500 copies/ml at week 52. The sensitivity and specificity of intermediate pVL measurements below the limit of detection, 100, 500, 1000, and 5000 copies/ml to predict virologic success were calculated. Results: The sensitivity, specificity, and positive and negative predictive values of a pVL measurement <1000 copies/ml at week 16 to predict virologic outcome at week 52 were 74%, 74%, 48%, and 90%, respectively, for patients on double therapy. For patients on triple therapy, the sensitivity, specificity, and positive and negative predictive values of a pVL measurement <50 copies/ml at week 16 to predict virologic outcome were 68%, 68%, 80%, and 47%, respectively. Conclusions: For patients receiving double therapy, a poor virologic result at an intermediate week of follow-up is a strong indicator of virologic failure at 52 weeks whereas intermediate virologic success is no guarantee of success at 1 year. For patients on triple therapy, disappointing intermediate results do not preclude virologic success at 1 year and intermediate successes are more likely to be sustained.

Predicting HIV RNA Virologic Outcome at 52-Weeks Follow-Up in Antiretroviral Clinical Trials

Objective: To determine the ability of intermediate plasma viral load (pVL) measurements to predict virologic outcome at 52 weeks of follow-up in clinical trials of antiretroviral therapy. Methods: Individual patient data from three clinical trials (INCAS, AVANTI-2 and AVANTI-3) were combined into a single database. Virologic success was defined to be plasma viral load (pVL) <500 copies/ml at week 52. The sensitivity and specificity of intermediate pVL measurements below the limit of detection, 100, 500, 1000, and 5000 copies/ml to predict virologic success were calculated. Results: The sensitivity, specificity, and positive and negative predictive values of a pVL measurement <1000 copies/ml at week 16 to predict virologic outcome at week 52 were 74%, 74%, 48%, and 90%, respectively, for patients on double therapy. For patients on triple therapy, the sensitivity, specificity, and positive and negative predictive values of a pVL measurement <50 copies/ml at week 16 to predict virologic outcome were 68%, 68%, 80%, and 47%, respectively. Conclusions: For patients receiving double therapy, a poor virologic result at an intermediate week of follow-up is a strong indicator of virologic failure at 52 weeks whereas intermediate virologic success is no guarantee of success at I year. For patients on triple therapy, disappointing intermediate results do not preclude virologic success at I year and intermediate successes are more likely to be sustained.

Predicting HIV RNA virologic outcome at 52-weeks follow-up in antiretroviral clinical trials. The INCAS and AVANTI Study Groups.

To determine the ability of intermediate plasma viral load (pVL) measurements to predict virologic outcome at 52 weeks of follow-up in clinical trials of antiretroviral therapy. Individual patient data from three clinical trials (INCAS, AVANTI-2 and AVANTI-3) were combined into a single database. Virologic success was defined to be plasma viral load (pVL) <500 copies/ml at week 52. The sensitivity and specificity of intermediate pVL measurements below the limit of detection, 100, 500, 1000, and 5000 copies/ml to predict virologic success were calculated. The sensitivity, specificity, and positive and negative predictive values of a pVL measurement <1000 copies/ml at week 16 to predict virologic outcome at week 52 were 74%, 74%, 48%, and 90%, respectively, for patients on double therapy. For patients on triple therapy, the sensitivity, specificity, and positive and negative predictive values of a pVL measurement <50 copies/ml at week 16 to predict virologic outcome were 68%, 68%, 80%, and 47%, respectively. For patients receiving double therapy, a poor virologic result at an intermediate week of follow-up is a strong indicator of virologic failure at 52 weeks whereas intermediate virologic success is no guarantee of success at 1 year. For patients on triple therapy, disappointing intermediate results do not preclude virologic success at 1 year and intermediate successes are more likely to be sustained.