Early antiretroviral therapy for HIV-infected patients admitted to an intensive care unit (EARTH-ICU): A randomized clinical trial

Márcio M Boniatti; José Augusto S Pellegrini; Leonardo S Marques; Josiane F John; Luiz G Marin; Lina R D M Maito; Thiago C Lisboa; Lucas P Damiani; Diego R Falci

doi:10.1371/journal.pone.0239452

. 2020 Sep 21;15(9):e0239452. doi: 10.1371/journal.pone.0239452

Early antiretroviral therapy for HIV-infected patients admitted to an intensive care unit (EARTH-ICU): A randomized clinical trial

Márcio M Boniatti ^1,^*, José Augusto S Pellegrini ¹, Leonardo S Marques ², Josiane F John ¹, Luiz G Marin ², Lina R D M Maito ³, Thiago C Lisboa ⁴, Lucas P Damiani ⁵, Diego R Falci ⁶

Editor: Felipe Dal Pizzol⁷

¹Critical Care Department, Hospital de Clínicas de Porto Alegre, Universidade La Salle, Porto Alegre, Brazil

²Critical Care Department, Hospital Nossa Senhora da Conceição, Porto Alegre, Porto Alegre, Brazil

³Critical Care Department, Hospital São Vicente de Paulo, Passo Fundo, Brazil

⁴Critical Care Department, Hospital de Clínicas de Porto Alegre, Instituto de Pesquisa HCor, Universidade La Salle, Porto Alegre, Brazil

⁵Instituto de Pesquisa HCor, Sao Paulo, Brazil

⁶Infectious Disease Department, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil

⁷Universidade do Extremo Sul Catarinense, BRAZIL

Competing Interests: The authors have declared that no competing interests exist.

^✉

* E-mail: mboniatti@hcpa.edu.br

Roles

Márcio M Boniatti: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Supervision, Writing – original draft, Writing – review & editing

José Augusto S Pellegrini: Conceptualization, Formal analysis, Investigation, Methodology, Project administration, Writing – original draft, Writing – review & editing

Leonardo S Marques: Conceptualization, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing

Josiane F John: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Writing – original draft, Writing – review & editing

Luiz G Marin: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Writing – original draft, Writing – review & editing

Lina R D M Maito: Investigation, Methodology, Writing – original draft, Writing – review & editing

Thiago C Lisboa: Formal analysis, Methodology, Writing – original draft, Writing – review & editing

Lucas P Damiani: Formal analysis, Methodology, Writing – original draft, Writing – review & editing

Diego R Falci: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing

Felipe Dal Pizzol: Editor

PMCID: PMC7505451 PMID: 32956419

Abstract

Background

Highly active antiretroviral therapy (HAART) has reduced HIV-related morbidity and mortality at all stages of infection and reduced transmission of HIV. Currently, the immediate start of HAART is recommended for all HIV patients, regardless of the CD4 count. There are several concerns, however, about starting treatment in critically ill patients. Unpredictable absorption of medication by the gastrointestinal tract, drug toxicity, drug interactions, limited reserve to tolerate the dysfunction of other organs resulting from hypersensitivity to drugs or immune reconstitution syndrome, and the possibility that subtherapeutic levels of drug may lead to viral resistance are the main concerns. The objective of our study was to compare the early onset (up to 5 days) with late onset (after discharge from the ICU) of HAART in HIV-infected patients admitted to the ICU.

Methods

This was a randomized, open-label clinical trial enrolling HIV-infected patients admitted to the ICU of a public hospital in southern Brazil. Patients randomized to the intervention group had to start treatment with HAART within 5 days of ICU admission. For patients in the control group, treatment should begin after discharge from the ICU. The patients were followed up to determine mortality in the ICU, in the hospital and at 6 months. The primary outcome was hospital mortality. The secondary outcome was mortality at 6 months.

Results

The calculated sample size was 344 patients. Unfortunately, we decided to discontinue the study due to a progressively slower recruitment rate. A total of 115 patients were randomized. The majority of admissions were for AIDS-defining illnesses and low CD4. The main cause of admission was respiratory failure. Regarding the early and late study groups, there was no difference in hospital (66.7% and 63.8%, p = 0.75) or 6-month (68.4% and 79.2%, p = 0.20) mortality. After multivariate analysis, the only independent predictors of in-hospital mortality were shock and dialysis during the ICU stay. For the mortality outcome at 6 months, the independent variables were shock and dialysis during the ICU stay and tuberculosis at ICU admission.

Conclusions

ClinicalTrials.gov, NCT01455688. Registered 20 October 2011, https://clinicaltrials.gov/show/NCT01455688

Introduction

Highly active antiretroviral therapy (HAART) has changed the natural history of patients infected with human immunodeficiency virus (HIV). Before HAART’s advent, the disease was potentially fatal. After the introduction of HAART, HIV began to acquire the characteristics of chronic disease, with a substantial improvement in survival [1–3]. The rates of intensive care unit (ICU) admission have also changed, especially for the spectrum of diseases not associated with acquired immunodeficiency syndrome (AIDS) as an initial diagnosis [4–6]. Although such diseases are becoming more common, opportunistic infections are still the main cause of hospitalization in intensive care, especially in poor countries or among patients with low adherence to treatment or those who have difficulty accessing the health system [7, 8].

HAART has reduced HIV-related morbidity and mortality at all stages of infection and reduced transmission of HIV [9–16]. Two large clinical trials evaluating the optimal timing to start HAART demonstrated an approximately 50% reduction in morbidity and mortality among subjects with HIV and CD4+ > 500 cells / mm3, randomized to receive HAART immediately compared to late onset [10, 11]. Currently, the immediate start of HAART is recommended for all HIV patients, regardless of the CD4 count [17]. There are several concerns, however, about starting treatment in critically ill patients. Unpredictable absorption of medication by the gastrointestinal tract, drug toxicity, drug interactions, limited reserve to tolerate the dysfunction of other organs resulting from hypersensitivity to drugs or immune reconstitution syndrome (IRIS), and the possibility that subtherapeutic levels of drug may lead to viral resistance are the main concerns [18]. Some retrospective studies have found a decrease in mortality among patients with HAART in the ICU [19, 20], while others have failed to show this difference [21, 22]. A recent meta-analysis suggested increased survival for patients treated with HAART during ICU admission [23]. To date, however, no randomized clinical trial has been conducted to test this hypothesis. Thus, the objective of our study was to compare, in relation to hospital mortality, the early onset (up to 5 days) with late onset (after discharge from the ICU) of HAART in HIV-infected patients admitted to the ICU.

Material and methods

This was a randomized, open-label clinical trial enrolling HIV-infected patients admitted to the ICU of a public hospital in southern Brazil between January 2012 and December 2015. Patients were consecutively evaluated for inclusion if they were older than 18 years and had 1) CD4 cell count lower than 350 cells/ml in the 3 months prior to the study, 2) CD4 cell count between 350 cells/ml and 500 cells/ml and age > 55 years, coinfection with hepatitis B virus or hepatitis C virus, neoplasia, viral load > 100,000 copies/ml or elevated cardiovascular risk, or 3) an AIDS-defining disease, which were the criteria required for HIV treatment indication in Brazil, during the period of study. Patients with regular use of HAART, pregnancy, impossibility to use the enteral route, tuberculous meningitis, cryptococcal meningitis, ICU length of stay > 5 days prior to randomization or who refused to sign the informed consent were excluded from the study.

This study protocol was consistent with the ethical principles of the Declaration of Helsinki and was previously approved by an institutional committee of research ethics. Written informed consent was obtained from each included patient or from the next of kin. The study protocol was recorded in the ClinicalTrials.gov database (NCT01455688) prior to initiation.

The study was conducted in a clinical-surgical ICU of a tertiary public hospital in southern Brazil. The hospital has 843 beds, with approximately 26,000 hospitalizations per year. The ICU has 59 beds, of which 14 are postoperative beds used after major surgery, and the remaining beds are clinical beds.

Randomization was performed by random generation of sequences by software (www.randomizer.org) in a ratio of 1:1. Randomization in blocks of 10 was performed and stratified according to the SAPS III. Concealment of allocation was ensured by sealed, opaque, sequentially numbered envelopes.

Patients randomized to the intervention group had to start treatment with HAART within 5 days of ICU admission. For patients in the control group, treatment should begin after discharge from the ICU. The HAART scheme was determined by a hospital infectologist accompanying HIV-infected patients admitted to the ICU. All other interventions were defined by the assistant team.

Data included the age, sex, reason for admission to the ICU, location prior to admission to the ICU (emergency, ward or other hospital) and SAPS III. Admission was considered AIDS-related if the main admission diagnosis was an AIDS-defining illness [24]. The following therapeutic modalities in the ICU were recorded: invasive mechanical ventilation, hemodialysis or hemofiltration and the use of vasoactive drugs. The following data on HIV infection were recorded for each case at ICU admission: CD4 cell count and viral load, if available within 3 months of admission, and opportunistic infections. The following HAART data were recorded: scheme chosen, time to onset, adverse effects and need for suspension or modification of the regimen. HAART has been defined as a combination of 3 or more antiretrovirals belonging to at least two classes of the following: protease inhibitors, nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors, according to Brazilian guidelines at time of diagnosis.

The diagnosis of pneumocystosis was confirmed if P. jirovecii was identified in the bronchoalveolar lavage with silver staining. The diagnosis of tuberculosis was based on identification of the agent in tissues or sputum with acid-fast staining. The presumptive diagnosis of pneumocystosis or tuberculosis was made if the patient had a compatible medical history and physical examination, and the assistant team started treatment. Cryptococcal meningitis was diagnosed with India's positive ink test for fungi, a positive cerebrospinal fluid culture or a positive cryptococcal antigen detection test. The presumptive diagnosis of cerebral toxoplasmosis was accepted if the patient presented with a lesion with a mass effect and/or contrast impregnation in the cranial computed tomography associated with neurological alteration. Diagnosis of cytomegalovirus (CMV) infection was performed through CMV serology (IgG) plus histopathological findings in pulmonary or gastrointestinal biopsies. Shock was defined as the need for vasopressors to maintain a mean arterial pressure > 65 mmHg. Acute Respiratory Distress Syndrome (ARDS) was defined as respiratory dysfunction characterized by acute onset, bilateral opacities on chest radiography and a PaO2 / FiO2 ratio ≤ 300 with final expiratory pressure or continuous positive airway pressure ≥ 5 cmH₂O [25].

The patients were followed up to determine mortality in the ICU, in the hospital and at 6 months. The primary outcome was hospital mortality. The secondary outcome was mortality at 6 months.

Statistical analysis

The sample was calculated to verify a reduction in hospital mortality of 15%, considering 55% of mortality in the control group, with a significance level 5% and study power 80%. The calculated sample size was 344 patients (172 patients in each group). As we did not reach the calculated sample size, we performed the conditional power (CP) computation a posteriori. CP is the probability that the final study result will be statistically significant, given the data observed thus far and a specific assumption about the pattern of the data to be observed in the remainder of the study, such as assuming the original design effect, or the effect estimated from the current data, or under the null hypothesis. In many clinical trials, a CP computation at a pre-specified point in the study, such as mid-way, is used as the basis for early termination for futility when there is little evidence of a beneficial effect [26]. We decided to discontinue the study due to a progressively slower recruitment rate. Nevertheless, the calculated conditional power assuming the original estimated effect was 49.5%, and the observed effect from the current data was only 3.2%, suggesting futility.

Continuous variables were described as means ± standard deviation or medians and interquartile range, according to normality criteria. Categorical variables were shown as frequencies and proportions. Differences between groups at baseline were analyzed with a t-test for two independent samples or the Wilcoxon-Mann-Whitney U test according to normality criteria. Fisher's exact test was applied to the categorical variables.

The primary analysis was made by unadjusted intention-to-treat comparisons between the two study groups in relation to the primary and secondary outcomes. To examine the association between early or late onset of HAART and other variables of interest with hospital mortality and mortality at 6 months, a univariate logistic analysis was performed with hospital mortality and mortality at 6 months as dependent variables. A multivariate model was constructed to identify variables independently associated with hospital mortality and mortality at 6 months. For multivariate analysis, early or late initiation of HAART was maintained as a variable of interest. Other variables defined a priori were variables previously reported in the literature with an association to these outcomes or those plausibly associated. In addition, we included any variable that resulted in a value of p <0.20 in the univariate analysis. The regression was then constructed through stepwise forward, excluding the variables without significant association in each step, until the final model. All analyses were performed using IBM SPSS Statistics, version 20.0 (IBM corp., Armonk, NY, USA) and R (version 3.6.0). Statistical significance was set at 0.05.

Results

A total of 268 HIV-infected patients were admitted to the ICU during the study period. Of these, 153 were excluded, mainly because of previous regular use of HAART. Thus, 115 patients were randomized (Fig 1). In December 2015, we decided to discontinue the study due to a progressively slower recruitment rate in the previous 12 months. Follow-up of patients was extended until June 2016 to verify 6-month mortality of included patients. The sociodemographic and clinical characteristics of patients are described in Table 1. The majority of admissions were for AIDS-defining illnesses and low CD4+ cell counts (median <50 cells / ml). The main cause of admission was respiratory failure. Nearly half of the patients had tuberculosis or pneumocystosis. All patients required mechanical ventilation during the ICU stay.

Fig 1 — HAART, highly active antiretroviral therapy; ICU, Intensive Care Unit.

Table 1. Demographic and clinical variables.

Variables	Early onset (n = 57)	Late-onset (n = 58)	p
Sex, male, n (%)	33 (57.9)	35 (60.3)	0.79
Age, years, mean ± SD	43.5 ± 10.3	45.6 ± 12.3	0.33
HIV diagnosis, month, median (IQR)	2.0 (0–48.0)	7.5 (0–72.0)	0.62
Source, n (%)			0.70
Emergency	28 (49.1)	33 (56.9)
Ward	28 (49.1)	24 (41.4)
Another hospital	1 (1.8)	1 (1.7)
Length of stay prior to ICU admission, days, median (IQR)	4.0 (2.0–10.5)	4.0 (2.0–9.0)	0.69
Cause of admission, n (%)			0.86
Respiratory failure	33 (57.9)	40 (69.0)
Sepsis	12 (21.1)	8 (13.8)
Neurologic	8 (14.0)	7 (12.1)
Gastrointestinal	1 (1.8)	1 (1.7)
Cardiovascular	2 (3.5)	1 (1.7)
Postoperative	1 (1.8)	1 (1.7)
AIDS-related illness, n (%)	38 (66.7)	42 (72.4)	0.50
SAPS III, mean ± SD	72.4 ± 13.0	73.0 ± 12.5	0.81
CD4 count, median (IQR)	37,0 (15.0–106.25)	48.5 (16.0–128.25)	0.54
Viral load, median (IQR)	124,935.0 (25,897.0–475,336.5)	186,418.0 (33,745.5–500,000.0)	0.54
Tuberculosis, n (%)	23 (40.4)	28 (48.3)	0.39
Cryptococcosis, n (%)	3 (5.3)	7 (12.1)	0.19
Cytomegalovirus infection, n (%)	9 (15.8)	7 (12.1)	0.56
Toxoplasmosis, n (%)	7 (12.3)	3 (5.2)	0.18
Pneumocystosis, n (%)	27 (47.4)	33 (56.9)	0.31
Mechanical ventilation, n (%)
On admission	49 (86.0)	52 (89.7)	0.55
During ICU stay	57 (100)	58 (100)	-
Dialysis, n (%)	26 (45.6)	20 (34.5)	0.22
Shock, n (%)	43 (75.4)	46 (79.3)	0.62
ARDS, n (%)	21 (36.8)	23 (39.7)	0.76

Open in a new tab

By univariate analysis, the factors associated with hospital mortality were admission from the ward, SAPS III, shock and dialysis. In multivariate analysis, the only variables associated with in-hospital mortality, after controlling for other factors, were shock and dialysis during the ICU stay (Table 2). At 6 month, variables associated to mortality in multivariate analysis were shock and dialysis during the ICU stay and diagnosis of tuberculosis at ICU admission.

Table 2. Outcomes.

Outcome variables	Early onset (n = 57)	Late-onset (n = 58)	p
Length of ICU stay, days, median (IQR)	16.0 (9.0–27.0)	14.0 (10.0–20.25)	0.61^a
Length of hospital stay, days, median (IQR)	32.0 (18.25–54.0)	31.0 (21.0–53.5)	0.97^a
ICU mortality, n (%)	29 (50.9)	26 (44.8)	0.52^b
Hospital mortality, n (%)	38 (66.7)	37 (63.8)	0.75^b
6-month mortality, n (%)	39/57 (68.4)	42/53 (79.2)	0.20^b

Open in a new tab

^a Mann-Whitney U Test.

^b Chi-square test.

The patients' outcomes according to the group are described in Table 3. The primary outcome was not different between the groups. Also, there was no difference in length of hospital stay or in ICU and 6-month mortality.

Table 3. Univariate and multivariate analyses of variables associated with hospital mortality and 6-month mortality^a.

Variables	Hospital Mortality		Six-month Mortality
	Crude OR	Adjusted OR	Crude OR	Adjusted OR
Age	1.03 (0.99–1.07)		1.03 (0.99–1.07)
Early onset HAART	0.88 (0.41–1.90)		1.76 (0.74–4.20)
Source, ward	2.25 (1.01–5.02)		2.39 (0.97–5.88)
AIDS-related illness	0.97 (0.42–2.24)		0.85 (0.33–2.19)
Tuberculosis	2.13 (0.96–4.76)		4.33 (1.60–11.78)	4.00 (1.34–11.95)
Pneumocystosis	0.72 (0.33–1.56)		0.96 (0.41–2.23)
Cryptococcosis	5.32 (0.65–43.58)		-
SAPS III	1.04 (1.01–1.08)		1.05 (1.01–1.09)
CD4 count	1.00 (0.99–1.00)		0.99 (0.99–1.00)
Sepsis	3.61 (0.99–13.20)		3.58 (0.77–16.6)
Shock	5.42 (2.12–13.84)	3.60 (1.25–10.31)	5.36 (2.07–13.90)	3.16 (1.06–9.37)
Dialysis	5.11 (2.01–12.98)	3.14 (1.13–8.73	9.33(2.61–33.3)	5.31 (1.35–20.87)
Mechanical ventilation on ICU admission	0.72 (0.21–2.47)		1.14 (0.33–3.95)
ARDS	0.89 (0.41–1.96)		0.88 (0.37–2.08)

Open in a new tab

^a Logistic regression analysis.

Regarding the two study groups, the strategies for initiating HAART were different. The median number of days for initiation of HAART from ICU admission were 3.0 (2.0–4.0) days and 21.0 (16.5–28.0) days in the early-onset and late-onset groups, respectively (p <0.001). In the early-onset group, 4 (7.0%) patients did not initiate HAART because of hemodynamic instability and subsequent death prior to start of treatment. Seven (12.3%) had delayed onset (beginning after 5 days). In the late onset group, 37 (63.8%) patients did not initiate HAART during the hospital stay. The most common antiretroviral regimens used were tenofovir + lamivudine + efavirenz (n = 26; 35.1%), abacavir + lamivudine + efavirenz (n = 21, 28.4%) and zidovudine + lamivudine + efavirenz (n = 17, 23.0%). Regardless of the group, 11 (9.6%) patients had antiretroviral adverse effects: hepatotoxicity (n = 3, 2.6%), nephrotoxicity (n = 2, 1.7%) and hematological dysfunction (n = 6; 5.2%). Six (8.1%) patients required discontinuation of treatment, and 5 (6.8%) patients needed to change the regimen.

Discussion

Although the benefits of early HAART onset have been described in people living with HIV in many scenarios [9–12], in the intensive care setting, such benefits are still unclear. Concerns related to absorption, drug interactions, and development of resistance, together with the absence of clinical trials, hinder decision-making. In our study, we found no benefit from the early HAART strategy for HIV-infected patients admitted to the ICU. This is the only randomized clinical trial ever to test this hypothesis. Unfortunately, the early termination of the trial may have compromised the results.

In the general population of HIV-infected patients with opportunistic infections, early onset of HAART results in slower disease progression and lower mortality, probably from earlier immune reconstitution and viral suppression. Differently from the study period, it is recommended currently to prescribe HAART for all HIV patients, regardless of CD4 count [17]. In critical patients, the decision is more difficult due to the challenges related to drug interactions, dose, absorption and adverse effects [27–29]. There are no pharmacological or pharmacokinetic data for antiretrovirals in hemodynamically unstable patients. Drug interactions are expected with antiarrhythmics, anticonvulsants, antifungals, antibiotics or sedatives [30]. In addition, most drugs are only available orally, with unpredictable absorption in critically ill patients. Subtherapeutic concentrations, even for a few days due to poor absorption or pharmacokinetic interactions, may lead to the selection of resistant virus [31]. Finally, the toxicity of antiretrovirals should be remembered. In our study, 9.6% of the patients had an adverse event, all of which necessitated a change of regimen or suspension of treatment. In another study conducted in the ICU, the incidence of an adverse event requiring a change or discontinuation of antiretrovirals was 18% [20]. The decision to initiate HAART early in this setting should consider the risk of disease progression and these potential adverse events. Currently, this decision is made based on expert opinion.

Several retrospective studies have reported an increase in the survival of HIV-infected patients admitted to the ICU in recent decades since the advent of HAART [4, 22, 32]. The decrease in mortality may be the result of the change in the cause spectrum of admission of these patients, with non-AIDS-related diseases becoming more frequent. In addition, advances in intensive care probably contributed to improving the outcome of these patients. However, the benefit associated with the administration of HAART in the ICU is still poorly studied. A recent meta-analysis, which included 12 retrospective studies, showed a reduction in short-term mortality with the use of HAART during ICU admission [23]. This benefit persisted even after a sensitivity analysis regarding sample size, study origin and year of publication. However, no clinical trial was found in the systematic review. The conclusion of the study was restricted to the limitations of retrospective studies. It is possible that patients with the greatest potential benefit from the early use of HAART in the ICU would be patients admitted for AIDS-defining illnesses and with low CD4+ cell count, common characteristics in studies that demonstrate survival benefit [7, 33]. In our study, most patients had AIDS-defining disease as the cause of admission and CD4+ cell count < 50 cells/ml. Regardless, there was no reduction in mortality with the early onset of HAART.

Acute respiratory failure remains the main reason for ICU admission in HIV-infected patients [23, 34], although the number of patients with AIDS-defining disease and opportunistic infections admitted to the ICU has decreased considerably in the last decades in regions with access to HAART [34]. Our population presented with a high prevalence of pneumocystosis and tuberculosis as causes of respiratory insufficiency, possibly explained by the poor immunological status of patients and epidemiological factors, since these are the most reportable AIDS-defining illness in Brazil.

The risk factors for hospital mortality identified in our study were consistent with factors previously identified in the literature [31, 35]. These are factors related to organic dysfunction and not to HIV-related characteristics. Similarly, Japiassu et al. verified that sepsis was the main factor associated with hospital mortality in a prospective cohort [8]. We have identified only the use of vasopressors and the need for renal replacement therapy as factors independently associated with hospital mortality. For mortality at 6 months, in addition to these two variables, the presence of tuberculosis was an independent risk factor. Several authors have reported that HIV-related variables have had little or no impact on mortality in patients admitted to the ICU, although they are associated with long-term outcome [22, 36, 37].

The high hospital and 6-month mortality observed in our study is similar to the mortality reported in other Brazilian studies [20, 38]. These results can be explained by the disease severity of our population, both in relation to poor immune status and critical illness (elevated SAPS III), and the difficulty in accessing the public health system. Regarding immunological status, 88% of the patients presented with CD4+ < 200 cells/ml, and 71% had CD4+ <100 cells/ml. This suggests that most patients had advanced AIDS, probably contributing to the poor outcome.

Our study has some limitations. First, we did not enroll the sample size calculated, which is concerning in negative studies. However, the conditional power considering the observed effect was only 3.2%, suggesting futility as there is little evidence of a beneficial effect. Second, the study was not blinded. Although this is a limitation, we believe its impact is lessened due to the nature of the primary outcome. Finally, the study was developed in a single center, which limits the generalization of the results.

Conclusions

Although the early termination of the study precludes definitive conclusions being made, early HAART administration for HIV-infected patients admitted to the ICU compared to late administration did not show benefit in hospital mortality or 6-month mortality. Further randomized, multicenter and larger sample size studies should be performed to better assess this hypothesis.

Supporting information

S1 Checklist. CONSORT 2010 checklist of information to include when reporting a randomised trial*.

(DOC)

Click here for additional data file.^{(216.5KB, doc)}

S1 Fig

(PNG)

Click here for additional data file.^{(155.9KB, png)}

S2 Fig

(PNG)

Click here for additional data file.^{(173.9KB, png)}

S3 Fig

(PNG)

Click here for additional data file.^{(105KB, png)}

S1 File

(DOCX)

Click here for additional data file.^{(48.7KB, docx)}

S2 File

(DOCX)

Click here for additional data file.^{(44.2KB, docx)}

S1 Data

(CSV)

Click here for additional data file.^{(14.8KB, csv)}

List of abbreviations

AIDS: Acquired immunodeficiency syndrome
ARDS: Acute respiratory distress syndrome
CMV: Cytomegalovirus
CP: Conditional power
HAART: Highly active antiretroviral therapy
HIV: Human immunodeficiency virus
ICU: Intensive Care Unite

Data Availability

We made the manuscript data available through file upload (as Supporting Information file).

Funding Statement

The author(s) received no specific funding for this work.

References

1.Palella FJ Jr, Delaney KM, Moorman AC et al. HIV Outpatient Study Investigators. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998;338:853–860. 10.1056/NEJM199803263381301 [DOI] [PubMed] [Google Scholar]
2.Moore RD, Keruly JC, Bartlett JG. Improvement in the health of HIV-infected persons in care: Reducing disparities. Clin Infect Dis 2012;55:1242–1251. 10.1093/cid/cis654 [DOI] [PMC free article] [PubMed] [Google Scholar]
3.Lewden C, Chene G, Morlat P et al. HIV-infected adults with CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach same mortality rates as the general population. J Acquir Defic Syndr 2007;46:72–77. [DOI] [PubMed] [Google Scholar]
4.Morris A, Creasman J, Turner J et al. Intensive care of human immunodeficiency virus-infected patients during the era of highly active antiretroviral therapy. Am J Respir Crit Care Med 2002;166:262–267. 10.1164/rccm.2111025 [DOI] [PubMed] [Google Scholar]
5.Palacios R, Hidalgo A, Reina C et al. Effect of antiretroviral therapy on admissions of HIV-infected patients to an intensive care unit. HIV Med 2006;7:193–196. 10.1111/j.1468-1293.2006.00353.x [DOI] [PubMed] [Google Scholar]
6.Boumis E, Petrosillo N, Girardi E et al. Changing patterns in the etiology of HIV-associated bacterial pneumonia in the era of highly active antiretroviral therapy. Eur J Clin Microbiol Infect Dis 2001;20:71–73. 10.1007/s100960000420 [DOI] [PubMed] [Google Scholar]
7.Croda J, Croda MG, Neves A, De Sousa dos Santos S. Benefit of antiretroviral therapy on survival of human immunodeficiency virus-infected patients admitted to an intensive care unit. Crit Care Med 2009;37:1605–1611. 10.1097/CCM.0b013e31819da8c7 [DOI] [PMC free article] [PubMed] [Google Scholar]
8.Japiassú AM, Amaâncio RT, Mesquita EC et al. Sepsis is a major determinant of outcome in critically ill HIV/AIDS patients. Crit Care 2010;14:R152 10.1186/cc9221 [DOI] [PMC free article] [PubMed] [Google Scholar]
9.Severe P, Juste MA, Ambroise A et al. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. N Engl J Med 2010;363:257–265. 10.1056/NEJMoa0910370 [DOI] [PMC free article] [PubMed] [Google Scholar]
10.INSIGHT START Study Group, Lundgren JD, Babiker AG et al. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med 2015;373:795–807. 10.1056/NEJMoa1506816 [DOI] [PMC free article] [PubMed] [Google Scholar]
11.TEMPRANO ANRS Study Group, Danel C, Moh R et al. A trial of early antiretrovirals and isoniazid preventive therapy in africa. N Engl J Med 2015;373:808–822. 10.1056/NEJMoa1507198 [DOI] [PubMed] [Google Scholar]
12.Kitahata MM, Gange SJ, Abraham AG et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med 2009;360:1815–1826. 10.1056/NEJMoa0807252 [DOI] [PMC free article] [PubMed] [Google Scholar]
13.Mofenson LM, Lambert JS, Stiehm ER et al. Risk factors for perinatal transmission of human immunode ciencyvirus type 1 in women treated with zidovudine. Pediatric AIDS Clinical Trials Group Study 185 Team. N Engl J Med 1999;341:385–393. 10.1056/NEJM199908053410601 [DOI] [PubMed] [Google Scholar]
14.Wood E, Kerr T, Marshall BD, et al. Longitudinal community plasma HIV-1 RNA concentrations and incidence of HIV-1 among injecting drug users: prospective cohort study. BMJ 2009;338:b1649 10.1136/bmj.b1649 [DOI] [PMC free article] [PubMed] [Google Scholar]
15.Cohen MS, Chen YQ, McCauley M et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011;365:493–505. 10.1056/NEJMoa1105243 [DOI] [PMC free article] [PubMed] [Google Scholar]
16.Reynolds SJ, Makumbi F, Nakigozi G, et al. HIV-1 transmission among HIV-1 discordant couples before and after the introduction of antiretroviral therapy. AIDS 2011;25:473–477. 10.1097/QAD.0b013e3283437c2b [DOI] [PMC free article] [PubMed] [Google Scholar]
17.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. 2018. Accessed [July 16, 2019]
18.Akgün KM, Miller RF. Critical Care in Human Immunodeficiency Virus-Infected Patients. Semin Respir Crit Care Med 2016;37:303–317. 10.1055/s-0036-1572561 [DOI] [PubMed] [Google Scholar]
19.Morris A, Wachter RM, Luce J, Turner J, Huang L. Improved survival with highly active antiretroviral therapy in HIV-infected patients with severe Pneumocystis carinii pneumonia. AIDS 2003;17:73–80. 10.1097/00002030-200301030-00010 [DOI] [PubMed] [Google Scholar]
20.Croda J, Croda MG, Neves A, De Sousa dos Santos S. Benefit of antiretroviral therapy on survival of human immunodeficiency virus-infected patients admitted to an intensive care unit. Crit Care Med 2009;37:1605–1611. 10.1097/CCM.0b013e31819da8c7 [DOI] [PMC free article] [PubMed] [Google Scholar]
21.Dickson SJ, Batson S, Copas AJ, Edwards SG, Singer M, Miller RF. Survival of HIV infected patients in the intensive care unit in the era of highly active antiretroviral therapy. Thorax 2007;62:964–968. 10.1136/thx.2006.072256 [DOI] [PMC free article] [PubMed] [Google Scholar]
22.Casalino E, Wolff M, Ravaud P, Choquet C, Bruneel F, Regnier B. Impact of HAART advent on admission patterns and survival in HIV-infected patients admitted to an intensive care unit. AIDS 2004;18:1429–1433. 10.1097/01.aids.0000131301.55204.a7 [DOI] [PubMed] [Google Scholar]
23.Andrade HB, Shinotsuka CR, da Silva IRF et al. Highly active antiretroviral therapy for critically ill HIV patients: A systematic review and meta-analysis. PLoS One 2017;12:e0186968 10.1371/journal.pone.0186968 [DOI] [PMC free article] [PubMed] [Google Scholar]
24.Centers for Disease Control and Prevention. Appendix A: AIDS-Defining Conditions. MMWR 2008;57(RR10):9. [Google Scholar]
25.Ranieri VM, Rubenfeld GD, Thompson BT et al. ARDS Definition Task Force. Acute respiratory distress syndrome: the Berlin definition. JAMA 2012;307:2526–2533. 10.1001/jama.2012.5669 [DOI] [PubMed] [Google Scholar]
26.Lachin JM. A review of methods for futility stopping based on conditional power. Stat Med 2005;24:2747–2764. 10.1002/sim.2151 [DOI] [PubMed] [Google Scholar]
27.Ramos GV, Guaraldo L, JapiassuÂ AM, Bozza FA. Comparison of two databases to detect potential drug-drug interactions between prescriptions of HIV/AIDS patients in critical care. J Clin Pharm Ther 2015;40:63–67. 10.1111/jcpt.12222 [DOI] [PubMed] [Google Scholar]
28.Heyland DK, Tougas G, King D, Cook DJ. Impaired gastric emptying in mechanically ventilated, critically ill patients. Intensive Care Med 1996;22:1339–1344. 10.1007/BF01709548 [DOI] [PubMed] [Google Scholar]
29.Wit FWNM Weverling GJ, Weel J, Jurriaans S, Lange JMA. Incidence of and risk factors for severe hepatotoxicity associated with antiretroviral combination therapy. J Infect Dis 2002;186:23–31. 10.1086/341084 [DOI] [PubMed] [Google Scholar]
30.Morquin D, Le Moing V, Mura T et al. Short- and long-term outcomes of HIV-infected patients admitted to the intensive care unit: impact of antiretroviral therapy and immunovirological status. Ann Intensive Care 2012;2:25 10.1186/2110-5820-2-25 [DOI] [PMC free article] [PubMed] [Google Scholar]
31.Meybeck A, Lecomte L, Valette M et al. Should highly active antiretroviral therapy be prescribed in critically ill HIV-infected patients during the ICU stay? A retrospective cohort study. AIDS Res Ther 2012;9:27 10.1186/1742-6405-9-27 [DOI] [PMC free article] [PubMed] [Google Scholar]
32.Narasimhan M, Posner AJ, DePalo VA, Mayo PH, Rosen MJ. Intensive care in patients with HIV infection in the era of higly active antiretroviral therapy. Chest 2004;125:1800–1804. 10.1378/chest.125.5.1800 [DOI] [PubMed] [Google Scholar]
33.Vargas-Infante YA, Guerrero ML, Ruiz-Palacios GM et al. Improving outcome of human immunodeficiency virus infected patients in a Mexican intensive care unit. Arch Med Res 2007;38:827–833. 10.1016/j.arcmed.2007.05.007 [DOI] [PubMed] [Google Scholar]
34.Cribbs SK, Tse C, Andrews J, Shenvi N, Martin GS. Characteristics and outcomes of HIV-infected patients with severe sepsis: continued risk in the post-highly active antiretroviral therapy era. Crit Care Med 2015;43:1638–1645. 10.1097/CCM.0000000000001003 [DOI] [PubMed] [Google Scholar]
35.Powell K, Lucian Davis J, Morris AM, Chi A, Bensley MR, Huang L. Survival for patients with human immunodeficiency virus admitted to the intensive care unit continues to improve in the current era of highly active antiretroviral therapy. Chest 2009;135:11–17. 10.1378/chest.08-0980 [DOI] [PMC free article] [PubMed] [Google Scholar]
36.Barbier F, Coquet I, Legriel S et al. Etiologies and outcome of acute respiratory failure in HIV-infected patients. Intensive Care Med 2009;35:1678–1686. 10.1007/s00134-009-1559-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
37.Vincent B, Timsit JF, Auburtin M, Schortgen F, Bouadma L, Wolff M, Regnier B. Characteristics and outcomes of HIV-infected patients in the ICU: impact of the highly active antiretroviral treatment era. Intensive Care Med 2004;30:859–866. 10.1007/s00134-004-2158-z [DOI] [PubMed] [Google Scholar]
38.Amâncio FF, Lambertucci JR, Cota GF, Antunes CM. Predictors of the short- and long-term survival of HIV-infected patients admitted to a Brazilian intensive care unit. Int J STD AIDS 2012;23:692–697. 10.1258/ijsa.2012.011389 [DOI] [PubMed] [Google Scholar]

PLoS One. doi: 10.1371/journal.pone.0239452.r001

Decision Letter 0

Felipe Dal Pizzol

29 May 2020

PONE-D-20-06158

Early antiretroviral therapy for HIV-infected patients admitted to an intensive care unit (EARTH-ICU): a randomized clinical trial

PLOS ONE

Dear Dr. Boniatti,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The reasons why of early termination should be adequately explained and discussed

Please submit your revised manuscript by Jul 13 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Felipe Dal Pizzol

Academic Editor

PLOS ONE

Journal requirements:

When submitting your revision, we need you to address these additional requirements:

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at http://www.plosone.org/attachments/PLOSOne_formatting_sample_main_body.pdf and http://www.plosone.org/attachments/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified whether consent was written or verbal/oral. If consent was verbal/oral, please specify: 1) whether the ethics committee approved the verbal/oral consent procedure, 2) why written consent could not be obtained, and 3) how verbal/oral consent was recorded. If your study included minors, please state whether you obtained consent from parents or guardians in these cases.

3. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This is a well-written study describing the results of a clinical trial to compare outcomes in ICU patients with differing onsets of ART initiation. The study addresses the data from a meta-analysis (Andrade, 2017) on the topic that indicated benefit for initiation of ART in the ICU. The study protocol is well described but recruitment to reach the calculated sample size of 172 patients per group was prematurely ended due to low enrollment with only 115 patients randomized. The failure to enroll the requisite number of patients compromises the trial design and this should be clearly stated in the abstract and throughout the manuscript. The authors need to further explain their rationale for early termination of the trial.

Minor comments:

Page 4, line 4 – the meaning of “inability to use the gastrointestinal tract” should be clarified.

Page 8 - the meaning of “…patients admitted for AIDS-defining illnesses and with poor immunoblot status…”

Reviewer #2: Overall, the methods and analyses seem to be performed well. I had a few comments with the aim of improving the description or methods.

1. (p.5) The language here suggests the trial was stopped early because of futility, but on p.6 the says the trip was stopped early due to slow recruitment. I suggest clearing this up and making sure these statements correspond with each other. Also, if there was some sort of planned interim analysis, please describe the criteria that were a priori chosen to stop for futility.

2. (p.6) Your variable selection appears to be a combination of bivariate screening and stepwise variable selection. With the sample sizes you have, stepwise variable selection procedures usually do not do a good job of finding the most appropriate model (e.g., https://doi.org/10.1002/sim.3943). Stepwise procedures and any p-value based selection have quite a bit of evidence suggesting that they are poor at selecting the appropriate variables. For a decent summary, see the link above. Bivariate screening is really just a form of stepwise selection. Sun et al. (http://dx.doi.org/10.1016/0895-4356(96)00025-X) found that bivariate screening can miss a variable that may be a confounder even when a p-value is as high as what you have. Generally, it's better to select based on more robust criteria, especially measures which assess the fit of the model or, better yet, a shrinkage-based estimator such as lasso or lars. I don't know where in SPSS this can be fit, but in R the glmnet package can do it.

3. (p.6) Although I know this is used quite a bit, I don't understand the term "independent predictors" in a multivariable model since the effect is dependent on the other predictors in the model. I recommend something along the lines of "after controlling for other factors". Also, I don't think it's "after multivariate analysis" makes sense since you are pulling the information from the model. Maybe "in the multivariate analysis".

4. It felt like survival analysis might have been a useful analysis in this trial. I'm curious if this was considered. I'm not sure the results would change, but it would seem the timing of the outcomes could have an impact.

5. Although the tables are pretty standard, I feel as though they need more descriptive titles. For instance, table 2 should say what the numbers are and what tests are used for the p-values. Probably some info on the sample as well. Table 3 should mention the statistical analyses used.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2020 Sep 21;15(9):e0239452. doi: 10.1371/journal.pone.0239452.r002

Author response to Decision Letter 0

19 Aug 2020

Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified whether consent was written or verbal/oral. If consent was verbal/oral, please specify: 1) whether the ethics committee approved the verbal/oral consent procedure, 2) why written consent could not be obtained, and 3) how verbal/oral consent was recorded. If your study included minors, please state whether you obtained consent from parents or guardians in these cases.

The informed consent was written. We made this clearer in the manuscript.

We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

We will update your Data Availability statement on your behalf to reflect the information you provide.

We made the manuscript data available through file upload (as Supporting Information file).

We appreciate the reviewer's comments. We made it clearer in the abstract and in the manuscript that the premature interruption of the trial may have compromised the results.

Minor comments:

Page 4, line 4 – the meaning of “inability to use the gastrointestinal tract” should be clarified.

We replaced "inability to use the gastrointestinal tract" by impossibility to use the enteral route

Page 8 - the meaning of “…patients admitted for AIDS-defining illnesses and with poor immunoblot status…”

We replaced "…patients admitted for AIDS-defining illnesses and with poor immunoblot status…" by "patients admitted for AIDS-defining illnesses and with low CD4+ cell count"

Reviewer #2: Overall, the methods and analyses seem to be performed well. I had a few comments with the aim of improving the description or methods.

We made it clearer that the trial interruption was due to a progressively slower recruitment rate. We did not perform interim analysis.

The selection of variables for the initial model was based on a combination of biological plausibility and bivariate screening. The regression model was then constructed through stepwise forward. We agree with the reviewer that stepwise forward selection may not be the most appropriate. We applied LASSO as requested by the reviewer. The R script is below:

library(glmnet)

library(ggplot2)

# Modelo LASSO Hospital Mortality

data_EARTHICU <- read.csv("~/Downloads/data_EARTHICU.csv", sep=";")

data_EARTHICU

xfactors <- model.matrix(data_EARTHICU$Hospital_mortality ~ data_EARTHICU$age + data_EARTHICU$control_treatment_group + data_EARTHICU$origin_ward + data_EARTHICU$AIDSrelated + data_EARTHICU$tuberculosis + data_EARTHICU$pneumocystosis + data_EARTHICU$cryptococosis + data_EARTHICU$saps3 + data_EARTHICU$cd4adm + data_EARTHICU$sepsis + data_EARTHICU$shock + data_EARTHICU$dialysis + data_EARTHICU$MV_adm + data_EARTHICU$ards)[, -1]

glmmod <- glmnet(xfactors, y=as.factor(data_EARTHICU$Hospital_mortality), alpha=1, family="binomial")

plot(glmmod, xvar="lambda")

coef(glmmod)[, 14]

# Modelo LASSO 6-month mortality

data_EARTHICU6 <- read.csv("~/Downloads/data_EARTHICU6.csv", sep=";")

xfactors6 <- model.matrix(data_EARTHICU6$Mortality_6_month ~ data_EARTHICU6$age + data_EARTHICU6$control_treatment_group + data_EARTHICU6$origin_ward + data_EARTHICU6$AIDSrelated + data_EARTHICU6$tuberculosis + data_EARTHICU6$pneumocystosis + data_EARTHICU6$cryptococosis + data_EARTHICU6$saps3 + data_EARTHICU6$cd4adm + data_EARTHICU6$sepsis + data_EARTHICU6$shock + data_EARTHICU6$dialysis + data_EARTHICU6$MV_adm + data_EARTHICU6$ards)[, -1]

glmmod6 <- glmnet(xfactors6, y=as.factor(data_EARTHICU6$Mortality_6_month), alpha=1, family="binomial")

plot(glmmod6, xvar="lambda")

coef(glmmod6)[, 14]

The coefficients for hospital mortality suggest the original model presented is OK, with only dyalisis and shock. LASSO regression coefficients are shown below:

> coef(glmmod)[, 14]

(Intercept) data_EARTHICU$age

-0.475622602 0.006561752

data_EARTHICU$control_treatment_group data_EARTHICU$origin_ward

0.000000000 0.000000000

data_EARTHICU$AIDSrelated data_EARTHICU$tuberculosis

0.000000000 0.081332622

data_EARTHICU$pneumocystosis data_EARTHICU$cryptococosis

0.000000000 0.241028316

data_EARTHICU$saps3 data_EARTHICU$cd4adm

0.000000000 -0.002027852

data_EARTHICU$sepsis data_EARTHICU$shock

0.190074265 0.884827694

data_EARTHICU$dialysis data_EARTHICU$MV_adm

0.664720062 0.000000000

data_EARTHICU$ards

0.000000000

The LASSO coefficients for 6 mo mortality suggest that cryptococcosis should also remain in the final model with dyalisis, shock and tuberculosis. LASSO Coefficients are shown below:

> coef(glmmod6)[, 14]

(Intercept) data_EARTHICU6$age

-0.15380567 0.00000000

data_EARTHICU6$control_treatment_group data_EARTHICU6$origin_ward

0.06275091 0.00000000

data_EARTHICU6$AIDSrelated data_EARTHICU6$tuberculosis

0.00000000 0.71715198

data_EARTHICU6$pneumocystosis data_EARTHICU6$cryptococosis

0.00000000 0.64094844

data_EARTHICU6$saps3 data_EARTHICU6$cd4adm

0.00000000 0.00000000

data_EARTHICU6$sepsis data_EARTHICU6$shock

0.00000000 0.69197132

data_EARTHICU6$dialysis data_EARTHICU6$MV_adm

0.98541680 0.00000000

data_EARTHICU6$ards

0.00000000

In the original logistic regression model presented, cryptococcosis bivariate OR was uncomputable and was removed from the final model due to numerical instability as this variable had an infinite estimated coefficient. This analysis will be available in supplementary material.

We agreed with the reviewer and made the changes as suggested.

We added the survival analysis as Supplemental File.

exp(coef) exp(-coef) lower .95 upper .95

arv$control_treatment_group 0.8591 1.1641 0.5250 1.406

We added the information in the tables as suggested by the reviewer.

Attachment

Submitted filename: Response to reviewers.docx

Click here for additional data file.^{(33.9MB, docx)}

PLoS One. doi: 10.1371/journal.pone.0239452.r003

Decision Letter 1

Felipe Dal Pizzol

8 Sep 2020

Early antiretroviral therapy for HIV-infected patients admitted to an intensive care unit (EARTH-ICU): a randomized clinical trial

PONE-D-20-06158R1

Dear Dr. Boniatti,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Felipe Dal Pizzol

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: (No Response)

Reviewer #2: (No Response)

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: (No Response)

Reviewer #2: (No Response)

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: (No Response)

Reviewer #2: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: (No Response)

Reviewer #2: (No Response)

**********

6. Review Comments to the Author

Reviewer #1: (No Response)

Reviewer #2: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

PLoS One. doi: 10.1371/journal.pone.0239452.r004

Acceptance letter

Felipe Dal Pizzol

10 Sep 2020

PONE-D-20-06158R1

Early antiretroviral therapy for HIV-infected patients admitted to an intensive care unit (EARTH-ICU): a randomized clinical trial

Dear Dr. Boniatti:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Felipe Dal Pizzol

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Checklist. CONSORT 2010 checklist of information to include when reporting a randomised trial*.

(DOC)

Click here for additional data file.^{(216.5KB, doc)}

S1 Fig

(PNG)

Click here for additional data file.^{(155.9KB, png)}

S2 Fig

(PNG)

Click here for additional data file.^{(173.9KB, png)}

S3 Fig

(PNG)

Click here for additional data file.^{(105KB, png)}

S1 File

(DOCX)

Click here for additional data file.^{(48.7KB, docx)}

S2 File

(DOCX)

Click here for additional data file.^{(44.2KB, docx)}

S1 Data

(CSV)

Click here for additional data file.^{(14.8KB, csv)}

Attachment

Submitted filename: Response to reviewers.docx

Click here for additional data file.^{(33.9MB, docx)}

Data Availability Statement

We made the manuscript data available through file upload (as Supporting Information file).

[pone.0239452.ref001] 1.Palella FJ Jr, Delaney KM, Moorman AC et al. HIV Outpatient Study Investigators. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998;338:853–860. 10.1056/NEJM199803263381301 [DOI] [PubMed] [Google Scholar]

[pone.0239452.ref002] 2.Moore RD, Keruly JC, Bartlett JG. Improvement in the health of HIV-infected persons in care: Reducing disparities. Clin Infect Dis 2012;55:1242–1251. 10.1093/cid/cis654 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0239452.ref003] 3.Lewden C, Chene G, Morlat P et al. HIV-infected adults with CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach same mortality rates as the general population. J Acquir Defic Syndr 2007;46:72–77. [DOI] [PubMed] [Google Scholar]

[pone.0239452.ref004] 4.Morris A, Creasman J, Turner J et al. Intensive care of human immunodeficiency virus-infected patients during the era of highly active antiretroviral therapy. Am J Respir Crit Care Med 2002;166:262–267. 10.1164/rccm.2111025 [DOI] [PubMed] [Google Scholar]

[pone.0239452.ref005] 5.Palacios R, Hidalgo A, Reina C et al. Effect of antiretroviral therapy on admissions of HIV-infected patients to an intensive care unit. HIV Med 2006;7:193–196. 10.1111/j.1468-1293.2006.00353.x [DOI] [PubMed] [Google Scholar]

[pone.0239452.ref006] 6.Boumis E, Petrosillo N, Girardi E et al. Changing patterns in the etiology of HIV-associated bacterial pneumonia in the era of highly active antiretroviral therapy. Eur J Clin Microbiol Infect Dis 2001;20:71–73. 10.1007/s100960000420 [DOI] [PubMed] [Google Scholar]

[pone.0239452.ref007] 7.Croda J, Croda MG, Neves A, De Sousa dos Santos S. Benefit of antiretroviral therapy on survival of human immunodeficiency virus-infected patients admitted to an intensive care unit. Crit Care Med 2009;37:1605–1611. 10.1097/CCM.0b013e31819da8c7 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0239452.ref008] 8.Japiassú AM, Amaâncio RT, Mesquita EC et al. Sepsis is a major determinant of outcome in critically ill HIV/AIDS patients. Crit Care 2010;14:R152 10.1186/cc9221 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0239452.ref009] 9.Severe P, Juste MA, Ambroise A et al. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. N Engl J Med 2010;363:257–265. 10.1056/NEJMoa0910370 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0239452.ref010] 10.INSIGHT START Study Group, Lundgren JD, Babiker AG et al. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med 2015;373:795–807. 10.1056/NEJMoa1506816 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0239452.ref011] 11.TEMPRANO ANRS Study Group, Danel C, Moh R et al. A trial of early antiretrovirals and isoniazid preventive therapy in africa. N Engl J Med 2015;373:808–822. 10.1056/NEJMoa1507198 [DOI] [PubMed] [Google Scholar]

[pone.0239452.ref012] 12.Kitahata MM, Gange SJ, Abraham AG et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med 2009;360:1815–1826. 10.1056/NEJMoa0807252 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0239452.ref013] 13.Mofenson LM, Lambert JS, Stiehm ER et al. Risk factors for perinatal transmission of human immunode ciencyvirus type 1 in women treated with zidovudine. Pediatric AIDS Clinical Trials Group Study 185 Team. N Engl J Med 1999;341:385–393. 10.1056/NEJM199908053410601 [DOI] [PubMed] [Google Scholar]

[pone.0239452.ref014] 14.Wood E, Kerr T, Marshall BD, et al. Longitudinal community plasma HIV-1 RNA concentrations and incidence of HIV-1 among injecting drug users: prospective cohort study. BMJ 2009;338:b1649 10.1136/bmj.b1649 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0239452.ref015] 15.Cohen MS, Chen YQ, McCauley M et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011;365:493–505. 10.1056/NEJMoa1105243 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0239452.ref016] 16.Reynolds SJ, Makumbi F, Nakigozi G, et al. HIV-1 transmission among HIV-1 discordant couples before and after the introduction of antiretroviral therapy. AIDS 2011;25:473–477. 10.1097/QAD.0b013e3283437c2b [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0239452.ref017] 17.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. 2018. Accessed [July 16, 2019]

[pone.0239452.ref018] 18.Akgün KM, Miller RF. Critical Care in Human Immunodeficiency Virus-Infected Patients. Semin Respir Crit Care Med 2016;37:303–317. 10.1055/s-0036-1572561 [DOI] [PubMed] [Google Scholar]

[pone.0239452.ref019] 19.Morris A, Wachter RM, Luce J, Turner J, Huang L. Improved survival with highly active antiretroviral therapy in HIV-infected patients with severe Pneumocystis carinii pneumonia. AIDS 2003;17:73–80. 10.1097/00002030-200301030-00010 [DOI] [PubMed] [Google Scholar]

[pone.0239452.ref020] 20.Croda J, Croda MG, Neves A, De Sousa dos Santos S. Benefit of antiretroviral therapy on survival of human immunodeficiency virus-infected patients admitted to an intensive care unit. Crit Care Med 2009;37:1605–1611. 10.1097/CCM.0b013e31819da8c7 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0239452.ref021] 21.Dickson SJ, Batson S, Copas AJ, Edwards SG, Singer M, Miller RF. Survival of HIV infected patients in the intensive care unit in the era of highly active antiretroviral therapy. Thorax 2007;62:964–968. 10.1136/thx.2006.072256 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0239452.ref022] 22.Casalino E, Wolff M, Ravaud P, Choquet C, Bruneel F, Regnier B. Impact of HAART advent on admission patterns and survival in HIV-infected patients admitted to an intensive care unit. AIDS 2004;18:1429–1433. 10.1097/01.aids.0000131301.55204.a7 [DOI] [PubMed] [Google Scholar]

[pone.0239452.ref023] 23.Andrade HB, Shinotsuka CR, da Silva IRF et al. Highly active antiretroviral therapy for critically ill HIV patients: A systematic review and meta-analysis. PLoS One 2017;12:e0186968 10.1371/journal.pone.0186968 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0239452.ref024] 24.Centers for Disease Control and Prevention. Appendix A: AIDS-Defining Conditions. MMWR 2008;57(RR10):9. [Google Scholar]

[pone.0239452.ref025] 25.Ranieri VM, Rubenfeld GD, Thompson BT et al. ARDS Definition Task Force. Acute respiratory distress syndrome: the Berlin definition. JAMA 2012;307:2526–2533. 10.1001/jama.2012.5669 [DOI] [PubMed] [Google Scholar]

[pone.0239452.ref026] 26.Lachin JM. A review of methods for futility stopping based on conditional power. Stat Med 2005;24:2747–2764. 10.1002/sim.2151 [DOI] [PubMed] [Google Scholar]

[pone.0239452.ref027] 27.Ramos GV, Guaraldo L, JapiassuÂ AM, Bozza FA. Comparison of two databases to detect potential drug-drug interactions between prescriptions of HIV/AIDS patients in critical care. J Clin Pharm Ther 2015;40:63–67. 10.1111/jcpt.12222 [DOI] [PubMed] [Google Scholar]

[pone.0239452.ref028] 28.Heyland DK, Tougas G, King D, Cook DJ. Impaired gastric emptying in mechanically ventilated, critically ill patients. Intensive Care Med 1996;22:1339–1344. 10.1007/BF01709548 [DOI] [PubMed] [Google Scholar]

[pone.0239452.ref029] 29.Wit FWNM Weverling GJ, Weel J, Jurriaans S, Lange JMA. Incidence of and risk factors for severe hepatotoxicity associated with antiretroviral combination therapy. J Infect Dis 2002;186:23–31. 10.1086/341084 [DOI] [PubMed] [Google Scholar]

[pone.0239452.ref030] 30.Morquin D, Le Moing V, Mura T et al. Short- and long-term outcomes of HIV-infected patients admitted to the intensive care unit: impact of antiretroviral therapy and immunovirological status. Ann Intensive Care 2012;2:25 10.1186/2110-5820-2-25 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0239452.ref031] 31.Meybeck A, Lecomte L, Valette M et al. Should highly active antiretroviral therapy be prescribed in critically ill HIV-infected patients during the ICU stay? A retrospective cohort study. AIDS Res Ther 2012;9:27 10.1186/1742-6405-9-27 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0239452.ref032] 32.Narasimhan M, Posner AJ, DePalo VA, Mayo PH, Rosen MJ. Intensive care in patients with HIV infection in the era of higly active antiretroviral therapy. Chest 2004;125:1800–1804. 10.1378/chest.125.5.1800 [DOI] [PubMed] [Google Scholar]

[pone.0239452.ref033] 33.Vargas-Infante YA, Guerrero ML, Ruiz-Palacios GM et al. Improving outcome of human immunodeficiency virus infected patients in a Mexican intensive care unit. Arch Med Res 2007;38:827–833. 10.1016/j.arcmed.2007.05.007 [DOI] [PubMed] [Google Scholar]

[pone.0239452.ref034] 34.Cribbs SK, Tse C, Andrews J, Shenvi N, Martin GS. Characteristics and outcomes of HIV-infected patients with severe sepsis: continued risk in the post-highly active antiretroviral therapy era. Crit Care Med 2015;43:1638–1645. 10.1097/CCM.0000000000001003 [DOI] [PubMed] [Google Scholar]

[pone.0239452.ref035] 35.Powell K, Lucian Davis J, Morris AM, Chi A, Bensley MR, Huang L. Survival for patients with human immunodeficiency virus admitted to the intensive care unit continues to improve in the current era of highly active antiretroviral therapy. Chest 2009;135:11–17. 10.1378/chest.08-0980 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0239452.ref036] 36.Barbier F, Coquet I, Legriel S et al. Etiologies and outcome of acute respiratory failure in HIV-infected patients. Intensive Care Med 2009;35:1678–1686. 10.1007/s00134-009-1559-4 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0239452.ref037] 37.Vincent B, Timsit JF, Auburtin M, Schortgen F, Bouadma L, Wolff M, Regnier B. Characteristics and outcomes of HIV-infected patients in the ICU: impact of the highly active antiretroviral treatment era. Intensive Care Med 2004;30:859–866. 10.1007/s00134-004-2158-z [DOI] [PubMed] [Google Scholar]

[pone.0239452.ref038] 38.Amâncio FF, Lambertucci JR, Cota GF, Antunes CM. Predictors of the short- and long-term survival of HIV-infected patients admitted to a Brazilian intensive care unit. Int J STD AIDS 2012;23:692–697. 10.1258/ijsa.2012.011389 [DOI] [PubMed] [Google Scholar]

PERMALINK

Early antiretroviral therapy for HIV-infected patients admitted to an intensive care unit (EARTH-ICU): A randomized clinical trial

Márcio M Boniatti

José Augusto S Pellegrini

Leonardo S Marques

Josiane F John

Luiz G Marin

Lina R D M Maito

Thiago C Lisboa

Lucas P Damiani

Diego R Falci

Roles

Abstract

Background

Methods

Results

Conclusions

Introduction

Material and methods

Statistical analysis

Results

Fig 1. Flowchart for inclusion of patients in the study.

Table 1. Demographic and clinical variables.

Table 2. Outcomes.

Table 3. Univariate and multivariate analyses of variables associated with hospital mortality and 6-month mortalitya.

Discussion

Conclusions

Supporting information

List of abbreviations

Data Availability

Funding Statement

References

Decision Letter 0

Felipe Dal Pizzol

Roles

Author response to Decision Letter 0

Decision Letter 1

Felipe Dal Pizzol

Roles

Acceptance letter

Felipe Dal Pizzol

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases

Table 3. Univariate and multivariate analyses of variables associated with hospital mortality and 6-month mortality^a.