Long-term safety and impact of immune recovery in heavily treatment-experienced adults receiving fostemsavir for up to 5 years in the phase 3 BRIGHTE study.

Introduction: Fostemsavir is a gp120-directed attachment inhibitor approved for heavily treatment-experienced (HTE) adults with multidrug-resistant HIV-1. We provide detailed week 240 safety results from the BRIGHTE study and evaluate the impact of immune recovery on safety outcomes. Methods: The phase 3 BRIGHTE trial is ongoing; data for this analysis were collected from the first participant's first visit (February 23, 2015) through the last participant's last visit for week 240 (March 22, 2021). Safety endpoints were assessed in participants who received fostemsavir + optimized background therapy. In participants with baseline CD4+ T-cell count <200 cells/mm3, exposure-adjusted adverse event (AE) rates were assessed among subgroups with or without CD4+ T-cell count ≥200 cells/mm3 at any time during 48-week analysis periods through week 192. Results: Through a median of 258 weeks (range, 0.14-319) of treatment, discontinuations due to AEs occurred in 30/371 (8%) participants. Serious AEs were reported in 177/371 (48%) participants, including 16 drug-related events in 13 (4%) participants. Thirty-five (9%) deaths occurred, primarily related to AIDS or acute infections. COVID-19-related events occurred in 25 (7%) participants; all resolved without sequelae. Among participants with baseline CD4+ T-cell count <200 cells/mm3, 122/162 (75%) achieved CD4+ T-cell count ≥200 cells/mm3 at week 192. Exposure-adjusted AE rates were markedly lower among participants achieving CD4+ T-cell count ≥200 cells/mm3 at any time vs those sustaining <200 cells/mm3. No new AIDS-defining events were reported after week 48 in participants with CD4+ T-cell count ≥200 cells/mm3. Conclusions: Cumulative safety findings through the BRIGHTE 240-week interim analysis are consistent with other trials in HTE participants with advanced HIV-1 and comorbid disease. Reduced rates of AIDS-defining events and AEs were observed in participants with immunologic recovery on fostemsavir-based treatment. Clinical trial number: NCT02362503, https://clinicaltrials.gov/study/NCT02362503.

Evaluación del impacto de la pandemia de COVID-19 en el seguimiento y tratamiento de gestantes con sífilis y sus parejas: análisis comparativo con un período prepandémico / Evaluation of the impact of the COVID-19 pandemic onthe follow-up and treatment of pregnant women with syphilis and their partners: comparative analysis with a pre-pandemic period

Se realizó un estudio observacional descriptivo transver-sal retrospectivo de las gestantes con nuevo diagnóstico de sífilis atendidas en el Hospital Materno Infantil de San Isidro "Dr. Carlos Gianantonio" durante los años pandé-micos 2020-2021. Se asistieron 108 gestantes con sífilis: 69 en 2020 y 39 en 2021. El tratamiento de aquellas que finalizaron el embarazo al momento de realizar este estu-dio (n=95) fue adecuado en el 78% (74) de los casos, en el 16,8% (16) fue inadecuado y el 5,2 % (5) perdió el segui-miento. El 11% presentó reinfección durante el embarazo. Con respecto a las parejas (n=103), el 84,6% (88) tenía una relación estable; se testeó al 70% (73) de las parejas, de las cuales el 45% (33) tenía VDRL positiva y se trató al 88% (29). Los resultados del estudio no muestran diferencias significativas en los indicadores evaluados (tratamiento adecuado y reinfección de la gestante y testeo/tratamien-to de la pareja) al comparar los períodos prepandémico (2018-2019) vs. pandémico (2020-2021)

A retrospective cross-sectional descriptive observational study of pregnant women with a new diagnosis of syphilis treated at the San Isidro Maternity Hospital during the 2020-2021 pandemic years was carried out. 108 pregnant women with syphilis were assisted: 69 in 2020 and 39 in 2021. The treatment of those who ended their pregnancy at the time of this study (n=95) was adequate in 78% (74) of the cases, 16,8% (16) were inadequate and 5.2% (5) lost follow-up. 11% presented reinfection during pregnancy. Regarding the couples (n=103), 84.6% (88) had a stable relationship, 70% (73) of the couples were tested, of which 45% (33) had positive vdrl and were treated 88% (29). The results of the study do not show significant differences in the indicators evaluated (adequate treatment and reinfection of the pregnant woman and testing/treatment of the partner) when comparing the pre-pandemic (2018-2019) vs. pandemic (2020-2021) periods

[Cohort of pregnant and postpartum women with COVID-19. Comparative analysis between two pandemic waves]. / Cohorte de gestantes y puérperas con COVID-19. Análisis comparativo entre dos olas pandémicas.

INTRODUCTION: The clinical presentation of pregnant women with COVID-19 varied according to the time of the pandemic. OBJECTIVE: The clinic, complications and lethality were described, as well as a comparative analysis of the clinical presentation during the first two pandemic waves of pregnant and postpartum women with COVID-19. METHODS: An observational prospective cohort study of pregnant women assisted in the Municipal Maternity of San Isidro was carried out between 04/01/2020 and 07/31/21. RESULTS: The infection was confirmed in 103 pregnant women, 76.7% had a mild condition, 18.4% moderate and 4.8% severe. 59% were assisted by telemedicine, 41% were admitted and 2.9% required mechanical ventilation. Most had a good evolution and the case fatality rate was < 1% (n = 1). At the time of this analysis, 78% of the women had completed pregnancy. 41% of them presented some type of complication, the most frequent being: premature rupture of the membrane 42%, arterial hypertension and other associated pathologies (including a patient with preeclampsia) 27% and preterm delivery 18%. In the comparative analysis between the first two pandemic waves, there was a higher proportion of moderate/severe cases (p = 0.016) and the indication for mechanical ventilation was significantly higher (p = 0.048) in 2021. DISCUSSION: These findings support the need for prioritize this group of patients to implement preventive strategies.

Introducción: La presentación clínica de las gestantes con COVID-19 fue variando según el momento de la pandemia. Objetivo: Se describió la clínica, complicaciones y letalidad, así como un análisis comparativo de la presentación clínica durante las dos primeras olas pandémicas de las gestantes y puérperas con COVID-19. Métodos: Se realizó un estudio de cohorte prospectivo observacional de las gestantes asistidas en la Maternidad Municipal de San Isidro entre el 01/04/2020 al 31/07/21. Resultados: Se confirmó la infección de 103 gestantes, de las cuales el 76.7% cursó un cuadro leve, 18.4% moderado y 4.8% grave. El 59% fueron asistidas por telemedicina, el 41% se internó, de las cuales el 2.9% requirieron asistencia respiratoria mecánica (ARM). La mayoría tuvo buena evolución y la tasa de letalidad fue < 1% (n = 1). Al momento del presente análisis el 78% de las mujeres habían finalizado la gestación. El 41% de ellas, presentó algún tipo de complicación, siendo lo más frecuente: ruptura prematura de membrana 42%, hipertensión arterial y otras patologías asociadas (incluyendo una paciente con preeclampsia) el 27% y parto pretérmino el 18%. En el análisis comparativo entre las dos primeras olas pandémicas, hubo una mayor proporción de casos moderados/graves (p=0.016) y fue significativamente mayor la indicación de ARM (p=0.048) en el 2021. Discusión: Estos hallazgos avalan la necesidad de priorizar a este grupo de pacientes para implementar estrategias preventivas.

Cohorte de gestantes y puérperas con COVID-19. Análisis comparativo entre dos olas pandémicas / Cohort of pregnant and postpartum women with COVID-19. Comparative analysis between two pandemic waves

Resumen Introducción: La presentación clínica de las gestantes con COVID-19 fue variando según el momento de la pandemia. Objetivo: Se describió la clínica, complicaciones y letalidad, así como un análisis comparativo de la presentación clínica durante las dos primeras olas pandémicas de las gestantes y puérperas con COVID-19. Métodos: Se realizó un estudio de cohorte prospectivo observacional de las gestantes asistidas en la Maternidad Municipal de San Isidro entre el 01/04/2020 al 31/07/21. Resultados: Se confirmó la infección de 103 gestantes, de las cuales el 76.7% cursó un cuadro leve, 18.4% moderado y 4.8% grave. El 59% fueron asistidas por telemedicina, el 41% se internó, de las cuales el 2.9% requirieron asistencia respira toria mecánica (ARM). La mayoría tuvo buena evolución y la tasa de letalidad fue <1% (n = 1). Al momento del presente análisis el 78% de las mujeres habían finalizado la gestación. El 41% de ellas, presentó algún tipo de complicación, siendo lo más frecuente: ruptura prematura de membrana 42%, hipertensión arterial y otras pato logías asociadas (incluyendo una paciente con preeclampsia) el 27% y parto pretérmino el 18%. En el análisis comparativo entre las dos primeras olas pandémicas, hubo una mayor proporción de casos moderados/graves (p=0.016) y fue significativamente mayor la indicación de ARM (p=0.048) en el 2021. Discusión: Estos hallazgos avalan la necesidad de priorizar a este grupo de pacientes para implementar estrategias preventivas.

Abstract Introduction: The clinical presentation of pregnant women with COVID-19 varied according to the time of the pandemic. Objective: The clinic, complications and lethality were described, as well as a comparative analy sis of the clinical presentation during the first two pandemic waves of pregnant and postpartum women with COVID-19. Methods: An observational prospective cohort study of pregnant women assisted in the Municipal Maternity of San Isidro was carried out between 04/01/2020 and 07/31/21. Results: The infection was confirmed in 103 pregnant women, 76.7% had a mild condition, 18.4% moderate and 4.8% severe. 59% were assisted by telemedicine, 41% were admitted and 2.9% required mechanical ventilation. Most had a good evolution and the case fatality rate was < 1% (n = 1). At the time of this analysis, 78% of the women had completed pregnancy. 41% of them presented some type of complication, the most frequent being: premature rupture of the membrane 42%, arterial hypertension and other associated pathologies (including a patient with preeclampsia) 27% and preterm delivery 18%. In the comparative analysis between the first two pandemic waves, there was a higher proportion of moderate/severe cases (p = 0.016) and the indication for mechanical ventilation was significantly higher (p = 0.048) in 2021. Discussion: These findings support the need for prioritize this group of patients to implement preventive strategies

Omicron Breakthrough Infection After Heterologous Prime-Boost Vaccination Induces a Vigorous Antibody Response.

Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is usually asymptomatic or mild and appears to be poorly immunogenic at least in unvaccinated individuals. Here, we found that health care workers vaccinated with 2 doses of Sputnik V and a booster dose of ChAdOx1 mount a vigorous neutralizing-antibody response after Omicron breakthrough infection.

Comparative changes of lipid levels in treatment-naive, HIV-1-infected adults treated with dolutegravir vs. efavirenz, raltegravir, and ritonavir-boosted darunavir-based regimens over 48 weeks.

BACKGROUND AND OBJECTIVES: Long-term use of antiretroviral therapy (ART) to treat HIV infection has been associated with dyslipidemia and metabolic and cardiovascular complications. Available options for patients at risk of cardiovascular disease include antiretroviral drugs with improved lipid profiles. Dolutegravir is one of a new generation of HIV integrase inhibitors recently incorporated into the US Department of Health and Human Services, German, Spanish, and Italian HIV treatment guidelines as a preferred first-line third agent in combination with dual nucleoside reverse transcriptase inhibitor (NRTI) backbone therapies. To understand the lipid profile of dolutegravir in the context of combination ART, we analyzed the lipid outcomes at 48 weeks in ART-naive participants in four phase IIb-IIIb clinical trials. METHODS: Variables included in this analysis were total cholesterol (TC), low-density lipoprotein (LDL) cholesterol (LDL-C), high-density lipoprotein (HDL) cholesterol (HDL-C), TC/HDL ratio, and triglycerides at baseline and week 48. RESULTS: In a comparative analysis, dolutegravir demonstrated a broadly neutral effect on lipids versus efavirenz or ritonavir-boosted darunavir; in both comparisons, patients taking dolutegravir exhibited smaller increases in TC, LDL-C, and triglyceride levels. In comparison with raltegravir, dolutegravir exhibited a similar lipid profile, including small increases in TC, LDL-C, and triglyceride levels for both agents. In the pooled dolutegravir analysis, minimal increases in LDL-C and triglycerides were observed but mean values at 48 weeks remained below National Cholesterol Education Program target levels. HDL-C levels increased at 48 weeks, and the mean TC/HDL-C ratio was 0.6 at 48 weeks; these values are associated with a lower risk of cardiovascular disease. CONCLUSIONS: Together, these data show that dolutegravir has a safer lipid profile in combination ART and provides an important treatment option for older patients who may have other risk factors for metabolic syndrome or cardiovascular disease.

Mean CD4 cell count changes in patients failing a first-line antiretroviral therapy in resource-limited settings.

BACKGROUND: Changes in CD4 cell counts are poorly documented in individuals with low or moderate-level viremia while on antiretroviral treatment (ART) in resource-limited settings. We assessed the impact of on-going HIV-RNA replication on CD4 cell count slopes in patients treated with a first-line combination ART. METHOD: Naïve patients on a first-line ART regimen with at least two measures of HIV-RNA available after ART initiation were included in the study. The relationships between mean CD4 cell count change and HIV-RNA at 6 and 12 months after ART initiation (M6 and M12) were assessed by linear mixed models adjusted for gender, age, clinical stage and year of starting ART. RESULTS: 3,338 patients were included (14 cohorts, 64% female) and the group had the following characteristics: a median follow-up time of 1.6 years, a median age of 34 years, and a median CD4 cell count at ART initiation of 107 cells/µL. All patients with suppressed HIV-RNA at M12 had a continuous increase in CD4 cell count up to 18 months after treatment initiation. By contrast, any degree of HIV-RNA replication both at M6 and M12 was associated with a flat or a decreasing CD4 cell count slope. Multivariable analysis using HIV-RNA thresholds of 10,000 and 5,000 copies confirmed the significant effect of HIV-RNA on CD4 cell counts both at M6 and M12. CONCLUSION: In routinely monitored patients on an NNRTI-based first-line ART, on-going low-level HIV-RNA replication was associated with a poor immune outcome in patients who had detectable levels of the virus after one year of ART.

Safety and efficacy of GSK2248761, a next-generation nonnucleoside reverse transcriptase inhibitor, in treatment-naive HIV-1-infected subjects.

GSK2248761 is a novel, once-daily (QD), next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) with activity against efavirenz-resistant strains. Two phase I/IIa, double-blind, randomized, placebo-controlled studies investigated the antiviral activity, safety, and pharmacokinetics (PK) of several doses of GSK2248761 monotherapy in treatment-naive HIV-infected subjects. In the initial study, 10 subjects (8 active and 2 placebo) per dose received sequentially descending GSK2248761 monotherapy regimens of 800, 400, 200, and 100 mg QD for 7 days. Because a dose-response relationship was not identified, a second study examined a lower, 30-mg QD dose in 8 subjects (6 active and 2 placebo). Adverse events, viral load (VL), PK, and reverse transcriptase mutations were assessed and combined for analysis. Treatment with GSK2248761 for 7 days was well tolerated with no serious adverse events or discontinuations. The mean VL reductions from baseline on day 8 were 0.97, 1.87, 1.84, 1.81, and 1.78 log(10) copies/ml for GSK2248761 doses of 30, 100, 200, 400, and 800 mg QD, respectively. GSK2248761 PK (maximum drug concentration in serum [C(max)], area under the plasma concentration-time curve from 0 h to the end of the dosing interval [AUC(0-τ)], and concentration at the end of the dosing interval [C(τ)]) increased proportionally over the dose range of 30 to 800 mg QD. The relationship between short-term VL change and GSK2248761 PK was best described by a maximum-effect (E(max)) model using C(τ) (E(max) = 2.0; 50% effective concentration [EC(50)] = 36.9 ng/ml). No NNRTI resistance mutations emerged during the study. GSK2248761 at 100 to 800 mg QD for 7 days was well tolerated, demonstrated potent antiviral activity in treatment-naive HIV-infected subjects, and had favorable PK and resistance profiles. GSK2248761 is no longer in clinical development.

A Canadian Critical Care Trials Group project in collaboration with the international forum for acute care trialists - Collaborative H1N1 Adjuvant Treatment pilot trial (CHAT): study protocol and design of a randomized controlled trial.

BACKGROUND: Swine origin influenza A/H1N1 infection (H1N1) emerged in early 2009 and rapidly spread to humans. For most infected individuals, symptoms were mild and self-limited; however, a small number developed a more severe clinical syndrome characterized by profound respiratory failure with hospital mortality ranging from 10 to 30%. While supportive care and neuraminidase inhibitors are the main treatment for influenza, data from observational and interventional studies suggest that the course of influenza can be favorably influenced by agents not classically considered as influenza treatments. Multiple observational studies have suggested that HMGCoA reductase inhibitors (statins) can exert a class effect in attenuating inflammation. The Collaborative H1N1 Adjuvant Treatment (CHAT) Pilot Trial sought to investigate the feasibility of conducting a trial during a global pandemic in critically ill patients with H1N1 with the goal of informing the design of a larger trial powered to determine impact of statins on important outcomes. METHODS/DESIGN: A multi-national, pilot randomized controlled trial (RCT) of once daily enteral rosuvastatin versus matched placebo administered for 14 days for the treatment of critically ill patients with suspected, probable or confirmed H1N1 infection. We propose to randomize 80 critically ill adults with a moderate to high index of suspicion for H1N1 infection who require mechanical ventilation and have received antiviral therapy for ≤ 72 hours. Site investigators, research coordinators and clinical pharmacists will be blinded to treatment assignment. Only research pharmacy staff will be aware of treatment assignment. We propose several approaches to informed consent including a priori consent from the substitute decision maker (SDM), waived and deferred consent. The primary outcome of the CHAT trial is the proportion of eligible patients enrolled in the study. Secondary outcomes will evaluate adherence to medication administration regimens, the proportion of primary and secondary endpoints collected, the number of patients receiving open-label statins, consent withdrawals and the effect of approved consent models on recruitment rates. DISCUSSION: Several aspects of study design including the need to include central randomization, preserve allocation concealment, ensure study blinding compare to a matched placebo and the use novel consent models pose challenges to investigators conducting pandemic research. Moreover, study implementation requires that trial design be pragmatic and initiated in a short time period amidst uncertainty regarding the scope and duration of the pandemic. TRIAL REGISTRATION NUMBER: ISRCTN45190901.

Antiviral activity and tolerability of amdoxovir with zidovudine in a randomized double-blind placebo-controlled study in HIV-1-infected individuals.

BACKGROUND: Amdoxovir acts synergistically with zidovudine in vitro and the combination prevents or delays the selection of thymidine analogue and K65R mutations. In silico studies have shown that a reduced dose of zidovudine (200 mg) results in decreased zidovudine-monophosphate levels, associated with toxicity, while maintaining zidovudine-triphosphate levels, which are associated with antiviral effects. Here, we aimed to assess the short-term tolerability and antiviral activity of amdoxovir in combination with reduced and standard doses of zidovudine. METHODS: The study was a double-blind, placebo-controlled study in HIV-1-infected patients not receiving antiretroviral therapy and with plasma HIV-1 RNA > or =5,000 copies/ml. Patients were randomized to 10 days of twice-daily treatment with 200 mg zidovudine, 300 mg zidovudine, 500 mg amdoxovir, 500 mg amdoxovir plus 200 mg zidovudine or 500 mg amdoxovir plus 300 mg zidovudine. The mean change in viral load (VL) log(10) and area under the virus depletion curve (AUC(VL)) from baseline to day 10 were determined. Laboratory and clinical safety monitoring were performed. RESULTS: Twenty-four patients were enrolled. The mean VL log(10) change was 0.10 with placebo, -0.69 with zidovudine 200 mg, -0.55 with zidovudine 300 mg, -1.09 with amdoxovir, -2.00 with amdoxovir plus zidovudine (200 mg) and -1.69 with amdoxovir plus zidovudine (300 mg). Amdoxovir plus zidovudine (200 mg) was significantly more potent than amdoxovir monotherapy in AUC(VL) and mean VL decline (P=0.019 and P=0.021, respectively), suggesting synergy. There was markedly decreased VL variability with the combination compared with amdoxovir alone. All adverse events were mild to moderate. CONCLUSION: The combination of amdoxovir plus zidovudine appeared synergistic with reduced VL variability. This combined therapy, including the use of a lower zidovudine dosage, warrants further development for the therapy of HIV infection.

Change to atazanavir/ritonavir treatment improves lipids but not endothelial function in patients on stable antiretroviral therapy.

OBJECTIVE: Protease inhibitors and other antiretroviral drugs have been associated with dyslipidemia, endothelial dysfunction, and increased cardiovascular disease risk. The protease inhibitor atazanavir has an advantageous lipid profile; we studied its effects on arterial function and other metabolic and inflammatory cardiovascular disease risk factors. DESIGN: Prospective, randomized, multinational trial in HIV-infected patients receiving stable protease inhibitor-based therapy with plasma HIV RNA less than 500 copies/ml and fasting low-density lipoprotein cholesterol more than 130 mg/dl, or triglycerides more than 200 mg/dl. METHODS: Patients were randomized to continue their current protease inhibitor or switch the protease inhibitor to atazanavir and continue ritonavir if given as a protease inhibitor booster for 24 weeks. Brachial artery flow-mediated dilation, lipoproteins, and inflammatory and metabolic markers were measured at baseline, week 12, and week 24. Median changes within (signed rank test) and between (Wilcoxon test) arms were calculated. RESULTS: Twenty-six patients switched to atazanavir (all continued on ritonavir); 24 remained on their protease inhibitor regimen. Median CD4 cell count was 499 cells/mul, total cholesterol 204 mg/dl, low-density lipoprotein cholesterol 122 mg/dl, and triglycerides 244 mg/dl. There were no significant changes in flow-mediated dilation after 12 and 24 weeks. At 24 weeks, significant changes in the atazanavir vs. continued protease inhibitor group were observed for total cholesterol (-25 vs. +1.5 mg/dl, P = 0.009), triglycerides (-58 vs. +3.5 mg/dl, P = 0.013), and nonhigh-density lipoprotein cholesterol (-27 vs. -0.5 mg/dl, P = 0.014). CONCLUSION: In dyslipidemic individuals with suppressed HIV RNA on stable therapy, changing the protease inhibitor to atazanavir/ritonavir for 24 weeks improved lipids; however, endothelial function, inflammatory, and metabolic markers did not change.

Lack of viral selection in human immunodeficiency virus type 1 mother-to-child transmission with primary infection during late pregnancy and/or breastfeeding.

Mother-to-child transmission (MTCT) of human immunodeficiency virus type 1 (HIV-1) as described for women with an established infection is, in most cases, associated with the transmission of few maternal variants. This study analysed virus variability in four cases of maternal primary infection occurring during pregnancy and/or breastfeeding. Estimated time of seroconversion was at 4 months of pregnancy for one woman (early seroconversion) and during the last months of pregnancy and/or breastfeeding for the remaining three (late seroconversion). The C2V3 envelope region was analysed in samples of mother-child pairs by molecular cloning and sequencing. Comparisons of nucleotide and amino acid sequences as well as phylogenetic analysis were performed. The results showed low variability in the virus population of both mother and child. Maximum-likelihood analysis showed that, in the early pregnancy seroconversion case, a minor viral variant with further evolution in the child was transmitted, which could indicate a selection event in MTCT or a stochastic event, whereas in the late seroconversion cases, the mother's and child's sequences were intermingled, which is compatible with the transmission of multiple viral variants from the mother's major population. These results could be explained by the less pronounced selective pressure exerted by the immune system in the early stages of the mother's infection, which could play a role in MTCT of HIV-1.

Determinants of treatment access in a population-based cohort of HIV-positive men and women living in Argentina.

OBJECTIVE: To report emerging data on the use of highly active antiretroviral therapy (HAART) in Argentina by assessing patterns of HAART access and late vs early treatment initiation in a population-based cohort of adults infected with HIV type-1. DESIGN: The Prospective Study on the Use and Monitoring of Antiretroviral Therapy (PUMA) is a study of 883 HIV-positive individuals enrolled in the Argentinean drug treatment program. Individuals were 16 years of age and older and were recruited from 10 clinics across Argentina. METHODS: Sociodemographic and clinical characteristics were examined using contingency tables (Pearson chi-square test and Fisher exact test) for categoric variables and Wilcoxon rank-sum test for continuous variables. To analyze time to initiation of HAART we used Kaplan-Meier methods and Cox regression. RESULTS: Patients who initiated HAART were more likely to be older, have an AIDS-defining illness, be an injection drug user (IDU), have a lower median CD4 cell count, have a higher median viral load, and be less likely to be men who have sex with men (MSM). In multivariate analysis, AIDS-defining illness and plasma viral load were significantly associated with time to starting therapy. Patients who received late access were more likely to be diagnosed with AIDS and have higher median plasma viral loads than those receiving early access. CONCLUSION: Our results indicate that despite free availability of treatment, monitoring, and care in Argentina, a significant proportion of men and women are accessing HAART late in the course of HIV disease. Further characterization of the HIV-positive population will allow for a more comprehensive evaluation of the impact of HAART within the Argentinean drug treatment program.

Determinants of Treatment Access in a Population-based Cohort of HIV-positive Men and Women Living in Argentina.

OBJECTIVE: To report emerging data on the use of highly active antiretroviral therapy (HAART) in Argentina by assessing patterns of HAART access and late vs early treatment initiation in a population-based cohort of adults infected with HIV type-1. DESIGN: The Prospective Study on the Use and Monitoring of Antiretroviral Therapy (PUMA) is a study of 883 HIV-positive individuals enrolled in the Argentinean drug treatment program. Individuals were 16 years of age and older and were recruited from 10 clinics across Argentina. METHODS: Sociodemographic and clinical characteristics were examined using contingency tables (Pearson chi-square test and Fisher exact test) for categoric variables and Wilcoxon rank-sum test for continuous variables. To analyze time to initiation of HAART we used Kaplan-Meier methods and Cox regression. RESULTS: Patients who initiated HAART were more likely to be older, have an AIDS-defining illness, be an injection drug user (IDU), have a lower median CD4 cell count, have a higher median viral load, and be less likely to be men who have sex with men (MSM). In multivariate analysis, AIDS-defining illness and plasma viral load were significantly associated with time to starting therapy. Patients who received late access were more likely to be diagnosed with AIDS and have higher median plasma viral loads than those receiving early access. CONCLUSION: Our results indicate that despite free availability of treatment, monitoring, and care in Argentina, a significant proportion of men and women are accessing HAART late in the course of HIV disease. Further characterization of the HIV-positive population will allow for a more comprehensive evaluation of the impact of HAART within the Argentinean drug treatment program.

Safe treatment interruptions in patients with nadir CD4 counts of more than 350 cells/microL: a randomized trial.

OBJECTIVE: To evaluate clinical, immunologic, and virologic performance of patients with nadir CD4 counts of >350 cells/microL upon treatment interruption. DESIGN: Randomized, open-label clinical trial of 48 weeks' duration. METHODS: Patients on effective highly active antiretroviral therapy, with nadir CD4 counts of >350 cells/microL and peak viral loads of <50,000 copies/mL were randomized to continue therapy or to interrupt antiretroviral medication. End points for patients with treatment interruption were CD4 counts of <350 cells/microL, viral loads of >1 log above the pretherapy values, or clinical symptoms attributable to HIV, at which point treatment was restarted. In the continuation group, the end points were virologic failure, opportunistic infections, and treatment discontinuation due to toxicities. RESULTS: Twenty patients were randomized to stop therapy and 16 patients to continue. Median CD4 counts at baseline were 643 cells/microL for the interruption group and 633 cells/microL for the continuation group. No end points were reached in the interruption group. By week 8, viral load returned to values comparable to those of pretherapy in all patients in the interruption group and remained stable until week 48. CD4 counts dropped in the interruption group (median loss of 156 cells/microL) at week 48. Significant decreases in venous lactate were observed in the interruption group. CONCLUSIONS: Treatment interruptions in patients with nadir CD4 counts of >350 cells/microL seem safe for at least 48 weeks. Pretherapy viral load appears as a valuable tool to predict its level at week 48.

Immunologic response to antiretroviral therapy in hepatitis C virus-coinfected adults in a population-based HIV/AIDS treatment program.

BACKGROUND: We sought to characterize the impact that hepatitis C virus (HCV) infection has on CD4 cells during the first 48 weeks of antiretroviral therapy (ART) in previously ART-naive human immunodeficiency virus (HIV)-infected patients. METHODS: The HIV/AIDS Drug Treatment Programme at the British Columbia Centre for Excellence in HIV/AIDS distributes all ART in this Canadian province. Eligible individuals were those whose first-ever ART included 2 nucleoside reverse transcriptase inhibitors and either a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor and who had a documented positive result for HCV antibody testing. Outcomes were binary events (time to an increase of > or = 75 CD4 cells/mm3 or an increase of > or = 10% in the percentage of CD4 cells in the total T cell population [CD4 cell fraction]) and continuous repeated measures. Statistical analyses used parametric and nonparametric methods, including multivariate mixed-effects linear regression analysis and Cox proportional hazards analysis. RESULTS: Of 1186 eligible patients, 606 (51%) were positive and 580 (49%) were negative for HCV antibodies. HCV antibody-positive patients were slower to have an absolute (P<.001) and a fraction (P = .02) CD4 cell event. In adjusted Cox proportional hazards analysis (controlling for age, sex, baseline absolute CD4 cell count, baseline pVL, type of ART initiated, AIDS diagnosis at baseline, adherence to ART regimen, and number of CD4 cell measurements), HCV antibody-positive patients were less likely to have an absolute CD4 cell event (adjusted hazard ratio [AHR], 0.84 [95% confidence interval [CI], 0.72-0.98]) and somewhat less likely to have a CD4 cell fraction event (AHR, 0.89 [95% CI, 0.70-1.14]) than HCV antibody-negative patients. In multivariate mixed-effects linear regression analysis, HCV antibody-negative patients had increases of an average of 75 cells in the absolute CD4 cell count and 4.4% in the CD4 cell fraction, compared with 20 cells and 1.1% in HCV antibody-positive patients, during the first 48 weeks of ART, after adjustment for time-updated pVL, number of CD4 cell measurements, and other factors. CONCLUSION: HCV antibody-positive HIV-infected patients may have an altered immunologic response to ART.