Despite better access to HIV treatment we need stronger evidence based guidance on treating people with serious complications of advanced HIV infection

Editor’s notes: The emphasis for scaling up HIV treatment usually focuses on outpatient and primary care clinics with increasing decentralization to the community.  It is therefore sobering to see the results of a randomized trial conducted at a national referral hospital in Zambia.  Andrews and colleagues report on 209 adults admitted to hospital with sepsis and hypotension, a combination referred to as septic shock.  Several important points emerge.  Almost 90% of patients admitted with this serious condition were HIV-positive.  Most had only been diagnosed with HIV infection in the last three months, and approximately half were taking ART.  The median CD4 count was only 70 cells per microlitre. Almost half had a history of having tuberculosis and one quarter were currently on anti-tuberculosis treatment at the time of admission to hospital. Most were also anaemic, with an average haemoglobin of 7.8 g/dl. Mortality from septic shock has been falling in Europe and the United States of America largely due to more intensive management of intravenous fluids and blood pressure.  The focus has been on strict protocols to ensure that all patients get the best treatment. However, there has been debate about the best approach to take when less sophisticated monitoring and supportive technology such as artificial ventilation is not available. In this Zambian tertiary hospital setting, only one patient was able to be managed in the intensive care unit due to resource constraints.  Patients were randomized to receive a protocolized intensive fluid and blood pressure resuscitation or to receive the more standard care with the responsible physicians making the decisions.  The death rate from this severe condition was very high.  85 of the 209 patients randomized died.  However, despite receiving more intravenous fluids, more blood transfusions and more drugs to raise blood pressure, the outcomes were worse in the group treated according to the protocol with 48% mortality compared to 33% in the standard care arm.  As always, the lesson is that many of these deaths could have been avoided if we were able to diagnose, link and treat people living with HIV much earlier in the course of their infection.  However, there is also an important caution that treatments that make good sense and seem the best course of action may in fact make the situation worse, even if the same treatments have been shown in other contexts to be beneficial.  Such information will only come from randomized trials, and the authors should be congratulated for being bold enough to conduct a high-quality study that should make us reflect on our preconceptions about how best to treat seriously ill patients in resource poor settings.

Andrade and colleagues have reviewed the literature in order to determine the best approach to treating critically unwell people living with HIV who are admitted to intensive care units.  They examined whether starting ARVs while the person was already critically ill was associated with better outcomes.  Patients in intensive care may already have many different medicines, as well as altered metabolism.  In addition, ARVs can provoke immune reconstitution inflammatory syndromes that have been shown to make outcomes worse in some serious conditions such as cryptococcal meningitis.  On the other hand, the evidence from patients with tuberculosis is clear – starting ARVs as soon as possible is associated with better outcomes.  In this review and meta-analysis, there was a clear short-term advantage to starting ARVs while the patient was still in intensive care.  The data were not sufficient to tell whether the longer-term outcome as also improved by the earlier start of ART.  One limitation is that all the studies reviewed were observational, and the decision to start ARVs was not randomized, so that it is plausible that clinicians may have started ARVs more willingly in those patients who were most likely to survive.  Nonetheless, in the absence of randomized trials, this study makes a strong case for starting ARVs promptly even in the sickest patients.

Effect of an early resuscitation protocol on in-hospital mortality among adults with sepsis and hypotension: a randomized clinical trial.

Andrews B, Semler MW, Muchemwa L, Kelly P, Lakhi S, Heimburger DC, Mabula C, Bwalya M, Bernard GR. JAMA. 2017 Oct 3;318(13):1233-1240. doi: 10.1001/jama.2017.10913.

Importance: The effect of an early resuscitation protocol on sepsis outcomes in developing countries remains unknown.

Objective: To determine whether an early resuscitation protocol with administration of intravenous fluids, vasopressors, and blood transfusion decreases mortality among Zambian adults with sepsis and hypotension compared with usual care.

Design, setting, and participants: Randomized clinical trial of 212 adults with sepsis (suspected infection plus ≥2 systemic inflammatory response syndrome criteria) and hypotension (systolic blood pressure ≤90 mm Hg or mean arterial pressure ≤65 mm Hg) presenting to the emergency department at a 1500-bed referral hospital in Zambia between October 22, 2012, and November 11, 2013. Data collection concluded December 9, 2013.

Interventions: Patients were randomized 1:1 to either (1) an early resuscitation protocol for sepsis (n = 107) that included intravenous fluid bolus administration with monitoring of jugular venous pressure, respiratory rate, and arterial oxygen saturation and treatment with vasopressors targeting mean arterial pressure (≥65 mm Hg) and blood transfusion (for patients with a hemoglobin level <7 g/dL) or (2) usual care (n = 105) in which treating clinicians determined hemodynamic management.

Main outcomes and measures: The primary outcome was in-hospital mortality and the secondary outcomes included the volume of intravenous fluid received and receipt of vasopressors.

Results: Among 212 patients randomized to receive either the sepsis protocol or usual care, 3 were ineligible and the remaining 209 completed the study and were included in the analysis (mean [SD] age, 36.7 [12.4] years; 117 men [56.0%]; 187 [89.5%] positive for the human immunodeficiency virus). The primary outcome of in-hospital mortality occurred in 51 of 106 patients (48.1%) in the sepsis protocol group compared with 34 of 103 patients (33.0%) in the usual care group (between-group difference, 15.1% [95% CI, 2.0%-28.3%]; relative risk, 1.46 [95% CI, 1.04-2.05]; P = .03). In the 6 hours after presentation to the emergency department, patients in the sepsis protocol group received a median of 3.5 L (interquartile range, 2.7-4.0 L) of intravenous fluid compared with 2.0 L (interquartile range, 1.0-2.5 L) in the usual care group (mean difference, 1.2 L [95% CI, 1.0-1.5 L]; P < .001). Fifteen patients (14.2%) in the sepsis protocol group and 2 patients (1.9%) in the usual care group received vasopressors (between-group difference, 12.3% [95% CI, 5.1%-19.4%]; P < .001).

Conclusions and relevance: Among adults with sepsis and hypotension, most of whom were positive for HIV, in a resource-limited setting, a protocol for early resuscitation with administration of intravenous fluids and vasopressors increased in-hospital mortality compared with usual care. Further studies are needed to understand the effects of administration of intravenous fluid boluses and vasopressors in patients with sepsis across different low- and middle-income clinical settings and patient populations.

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Highly active antiretroviral therapy for critically ill HIV patients: a systematic review and meta-analysis.

Andrade HB, Shinotsuka CR, da Silva IRF, Donini CS, Yeh Li H, de Carvalho FB, Americano do Brasil PEA, Bozza FA, Miguel Japiassu A. PLoS One. 2017 Oct 24;12(10):e0186968. doi:10.1371/journal.pone.0186968. eCollection 2017

Introduction: It is unclear whether the treatment of an HIV infection with highly active antiretroviral therapy (HAART) affects intensive care unit (ICU) outcomes. In this paper, we report the results of a systematic review and meta-analysis performed to summarize the effects of HAART on the prognosis of critically ill HIV positive patients.

Materials and methods: A bibliographic search was performed in 3 databases (PubMed, Web of Science and Scopus) to identify articles that investigated the use of HAART during ICU admissions for short- and long-term mortality or survival. Eligible articles were selected in a staged process and were independently assessed by two investigators. The methodological quality of the selected articles was evaluated using the Methodological Index for Non-Randomized Studies (MINORS) tool.

Results: Twelve articles met the systematic review inclusion criteria and examined short-term mortality. Six of them also examined long-term mortality (≥90 days) after ICU discharge. The short-term mortality meta-analysis showed a significant beneficial effect of initiating or maintaining HAART during the ICU stay (random effects odds ratio 0.53, p = 0.02). The data analysis of long-term outcomes also suggested a reduced mortality when HAART was used, but the effect of HAART on long-term mortality of HIV positive critically ill patients remains uncertain.

Conclusions: This meta-analysis suggests improved survival rates for HIV positive patients who were treated with HAART during their ICU admission.

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