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. 2011 Oct 24;90(2):128–138C. doi: 10.2471/BLT.11.093260

Effect of cotrimoxazole on mortality in HIV-infected adults on antiretroviral therapy: a systematic review and meta-analysis

Effet du cotrimoxazole sur la mortalité des adultes infectés par le VIH sous thérapie antirétrovirale: examen systématique et méta-analyse

Efecto de cotrimoxazol en la mortalidad de adultos infectados por el VIH que reciben tratamiento antirretrovírico: examen sistemático y metaanálisis.

تأثير كوتريموكسازول على الوفيات في البالغين المصابين بفيروس العوز المناعي البشري على العلاج المضاد للفيروسات: استعراض منهجي وتحليل تلوي

用于成年人抗逆转录病毒疗法的复方新诺明 复方新诺明对感染艾滋病毒成年人抗逆转病毒治疗死亡率的效果：系统评价和统计分析

Влияние котримоксазола на уровень смертности ВИЧ-инфицированных взрослых при проведении антиретровирусной терапии: систематический обзор и мета-анализ

Amitabh B Suthar a, Reuben Granich b,✉, Jonathan Mermin c, Annelies Van Rie a
PMCID: PMC3302556  PMID: 22423164

Abstract

Objective

To determine whether cotrimoxazole reduces mortality in adults receiving antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection in low- and middle-income countries through a systematic review and meta-analysis.

Methods

PubMed and Embase were searched for randomized controlled trials and prospective and retrospective cohort studies that compared mortality or morbidity in HIV-infected individuals aged ≥ 13 years on cotrimoxazole and ART and on ART alone. The Newcastle–Ottawa Quality Assessment Scale was used to assess selection, confounding and measurement bias. Publication bias was assessed using Egger’s and Begg’s tests. Sensitivity analysis was performed because the I-squared statistic indicated substantial heterogeneity in study results. A random-effects model was used for meta-analysis.

Findings

Nine studies were included. Begg and Egger P-values for the seven that reported the effect of cotrimoxazole on mortality were 0.29 and 0.49, respectively, suggesting no publication bias. The I-squared statistic was 93.2%, indicating high heterogeneity in study results. The sensitivity analysis showed that neither the follow-up duration nor the percentage of individuals with World Health Organization stage 3 or 4 HIV disease at baseline explained the heterogeneity. The summary estimate of the effect of cotrimoxazole on the incidence rate of death was 0.42 (95% confidence interval: 0.29–0.61). Since most studies followed participants for less than 1 year, it was not possible to determine whether cotrimoxazole can be stopped safely after ART-induced immune reconstitution.

Conclusion

Cotrimoxazole significantly increased survival in HIV-infected adults on ART. Further research is needed to determine the optimum duration of cotrimoxazole treatment in these patients.

Introduction

In 2010, there were 1.8 million deaths among the 34 million people infected with the human immunodeficiency virus (HIV).1 Of these deaths, 1.2 million occurred in the 22.9 million HIV-infected Africans.1 Antiretroviral therapy (ART) has transformed HIV infection into a manageable chronic condition and the World Health Organization (WHO) currently recommends ART for individuals with a CD4+ T lymphocyte (CD4 cell) count ≤ 350 cells/µL.2 In 2010, 42% of the 9 million individuals in need of treatment globally were receiving ART.3 Unfortunately, in low-income countries patients are started on ART at lower CD4 cell counts than in high-income countries: in 2006, the median count was reported to be 108 cells/µL and 234 cells/µL in these two types of countries, respectively.4 Moreover, after adjusting for immunodeficiency at baseline, mortality during the first months of ART was higher in low-income countries than in high-income countries.4,5 High mortality rates early in ART have been documented in Africa,6 the Caribbean,7 Latin America7 and south-eastern Asia.8,9 Consequently, additional interventions are needed to decrease early mortality during ART in low- and middle-income countries.

Cotrimoxazole contains two antibiotics: sulfamethoxazole and trimethoprim. Cotrimoxazole provides good coverage against gram-positive bacteria (e.g. Streptococcus pneumoniae), gram-negative bacteria (e.g. Escherichia coli and non-typhoid Salmonella), protozoa (e.g. Isospora belli, Toxoplasma gondii and Plasmodium falciparum) and fungi (e.g. Pneumocystis jirovecii). The patent for cotrimoxazole has expired and it costs around 7 United States dollars for 1 year of daily therapy.10 In high-income countries, cotrimoxazole is used in adults with HIV infection as chemoprophylaxis against P. jirovecii pneumonia and T. gondii infection.11 Randomized trials that included ART-naïve Africans found that cotrimoxazole improved survival while reducing the risk of malaria, pneumonia, sepsis, isosporiasis, T. gondii encephalitis, wasting and Kaposi’s sarcoma.12–14 However, a Senegalese trial that used half the recommended adult cotrimoxazole dose reported no mortality benefit in ART-naïve adults.15 A study in Uganda showed that treating HIV-infected adults with cotrimoxazole and ART reduced mortality in their uninfected children and the number of orphans.16

In settings where the health-care infrastructure is limited, WHO recommends cotrimoxazole for adults with WHO clinical stage 2, 3 or 4 HIV infection.17 If the prevalence of HIV infection is high, however, WHO recommends that all infected adults be treated because cotrimoxazole reduces morbidity irrespective of clinical disease stage or CD4 cell count and because it simplifies cotrimoxazole distribution.17

Common causes of mortality in adults receiving ART in low- and middle-income countries include sepsis, tuberculosis, Crytptococcus neoformans meningitis, T. gondii encephalitis, P. jirovecii pneumonia, Kaposi’s sarcoma and chronic diarrhoea.6,18–20 Given the results of earlier trials,12–14 cotrimoxazole may decrease both mortality and morbidity in adults with HIV infection, regardless of ART status. The aim of this study was to carry out a systematic review of the effect of cotrimoxazole on mortality and morbidity in individuals aged 13 years or more who were receiving ART for an HIV infection.

Methods

This systematic review was conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.21 The PubMed and Embase databases were searched systematically in December 2010 for randomized controlled trials and prospective and retrospective cohort studies on the effect of daily cotrimoxazole in HIV-infected individuals aged 13 years or more who were receiving ART. The search strategies (Table 1, available at: http://www.who.int/bulletin/volumes/90/2/11-093260) were designed with a specialist librarian and there were no language, publication or date restrictions. The primary outcome of interest was death. Secondary outcomes were hospitalization, incident events synonymous with WHO clinical stage 3 or 4 HIV disease, incident malaria events and adverse events leading to hospitalization or cotrimoxazole cessation. The Cochrane Central Register of Controlled Trials and the International Standard Randomized Controlled Trial Number Register were searched using the terms “cotrimoxazole” and “antiretroviral therapy”.

Table 1. Search strategies for publications on cotrimoxazole’s effect on mortality and morbidity in adults with human immunodeficiency virus (HIV) infection receiving antiretroviral therapy (ART).

Search number PubMed search terms Search number Embase search terms
1 HIV infections (MeSH term) 1 HIV
2 Acquired immunodeficiency syndrome (MeSH term) 2 AIDS
3 AIDS-related opportunistic infections (MeSH term) 3 Terms used in search 1 or 2
4 AIDS 4 Antiretroviral
5 HIV 5 Anti-retroviral
6 Terms used in search 1 or 2 or 3 or 4 or 5 6 HAART
7 Antiretroviral therapy, highly active (MeSH term) 7 cART
8 Anti-infective agents (MeSH term) 8 ART
9 Antiretroviral 9 Terms used in search 4 or 5 or 6 or 7 or 8
10 Anti-retroviral 10 Cotrimoxazole
11 HAART 11 Co-trimoxazole
12 ART 12 CPT
13 cART 13 Trimethoprim-sulfamethoxazole
14 Terms used in search 7 or 8 or 9 or 10 or 11 or 12 or 13 14 Sulfamethoxazole-trimethoprim
15 Trimethoprim-sulfamethoxazole combination (MeSH term) 15 Terms used in search 10 or 11 or 12 or 13 or 14
16 Cotrimoxazole 16 Mortality
17 Co-trimoxazole 17 Death
18 CPT 18 Hospitalization
19 Terms used in search 15 or 16 or 17 or 18 19 Adverse event
20 Mortality (MeSH term) 20 Terms used in search 16 or 17 or 18 or 19
21 Death (MeSH term) 21 Terms used in searches 3 and 9 and 15 and 20
22 Hospitalization (MeSH term)
23 Mortality
24 Death
25 Hospitalization
26 Adverse event
27 Terms used in search 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27
28 Terms used in searches 6 and 14 and 19 and 27
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AIDS, acquired immunodeficiency syndrome; cART, combination antiretroviral therapy; CPT, cotrimoxazole preventive therapy; HAART, highly active antiretroviral therapy; MeSH, medical subject heading.

The abstracts of all publications identified were reviewed independently by two of the authors (ABS and AVR). The full texts of all articles selected by one or both reviewers were then matched against the inclusion criteria and articles satisfying these criteria were included in the review (Fig. 1, available at: http://www.who.int/bulletin/volumes/90/2/11-093260). The references of all articles that met the inclusion criteria were also considered for incorporation into the systematic review.

Fig. 1.

Flow diagram of article selection for systematic review of cotrimoxazole’s effect on mortality and morbidity in adults with human immunodeficiency virus (HIV) infection receiving antireotroviral therapy (ART)

WHO, World Health Organization.

a One additional study was identified during the review of references for the eight studies meeting eligibility criteria.

Fig. 1

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Data were extracted from the articles included in the review using a standardized spreadsheet. The information collected included the name of the article’s first author, the year of publication, the study’s methods and design, the study population, the study intervention and control intervention, the duration of follow-up, inclusion and exclusion criteria, primary and secondary outcomes, and losses to follow-up.

In accordance with the recommendations of the Cochrane Collaboration,22 the Newcastle–Ottawa Quality Assessment Scale was used to identify bias in the cohort studies.23 This scale rates studies from 0 to 9 using eight criteria that cover three sources of bias: selection, confounding and measurement bias. Each criterion is worth one point except confounding bias, which is worth two points. Selection bias was assessed using four criteria: (i) the patient cohort receiving cotrimoxazole and ART was representative of adults receiving this treatment in the community from which the cohort was drawn; (ii) the cohort receiving ART alone was representative of the cohort on both cotrimoxazole and ART; (iii) cotrimoxazole use had been ascertained; and (iv) the majority of study participants were known to be asymptomatic (i.e. had WHO clinical stage 1 or 2 disease) at study baseline. A study was regarded as having addressed confounding due to the baseline level of immunodeficiency if the results had been adjusted for the baseline CD4 cell counts. Measurement bias was assessed using three criteria: (i) all deaths were validated; (ii) there was adequate follow-up to detect cotrimoxazole’s preventive effect on death (i.e. a median or mean follow-up period of at least 3 months), and (iii) ≤ 20% of study participants were lost during follow-up. A score of 7 to 9 indicated high methodological quality, a score of 4 to 6 indicated moderate quality, and a score of 0 to 3 indicated low quality.

Publication bias was evaluated using a funnel plot, with the treatment effect measure on the x-axis and the standard error of the log of the effect measure on the y-axis (details are available from the corresponding author on request). Egger’s and Begg’s tests were used to assess the symmetry of the funnel plot. Since the studies were similar enough to combine, a meta-analysis was performed and statistical heterogeneity was assessed. Effect measures were quantified as the natural log of the effect measure and the standard error24 as:

graphic file with name BLT.11.093260-M1.jpg

Since both χ2 and tau statistical tests of the heterogeneity of the magnitude of a treatment effect across studies depend on knowledge of the number of events in each study arm and this information was not available for all studies that met the inclusion criteria, an I-squared statistic was used. In practice, the I-squared statistic is calculated by subtracting the number of degrees of freedom from the Q-statistic and then dividing the result by the Q-statistic.25 Values of I-squared less than 25% indicate low heterogeneity, values near 50% indicate moderate heterogeneity and values above 75% indicate high heterogeneity.26 A random-effects statistical model is preferred when I-squared is ≥ 25%.27

Since the value of I-squared obtained for the studies included in this analysis was greater than 25%, a random-effects model was used to derive a summary estimate of the effect of cotrimoxazole on mortality. The possible causes of the observed heterogeneity, including the duration of follow-up and the percentage of participants who had WHO stage 3 or 4 disease at baseline, were explored by a sensitivity analysis. Unfortunately, neither the baseline viral load nor the baseline CD4 cell count could be included in the sensitivity analysis because data on the baseline viral load were not collected in most studies and data on the median or mean baseline CD4 cell count were collected in only four of the seven eligible studies reporting on the primary outcome. All analyses were performed using Stata version 10.0 (StataCorp. LP, College Station, United States of America).

Results

Details of the study participants and study designs described in the nine articles included in the systematic review are shown in Table 2 and Table 3, respectively. Of the nine, seven reported an estimate for the effect of cotrimoxazole on mortality,28–34 whereas three reported an estimate for the effect on morbidity.28,35,36 Two studies also reported the preventive effect on malaria.28,36 Assessment of publication bias indicated that three studies28–30 were of high methodological quality, while the other six31–36 were of moderate methodological quality (Table 4, available at: http://www.who.int/bulletin/volumes/90/2/11-093260). In addition, one on-going trial investigating when to stop cotrimoxazole during ART was identified.37 That trial involves 2000 individuals in Uganda and has a randomized, double-blind, placebo-controlled non-inferiority design. Its aim is to test the hypothesis that stopping cotrimoxazole in adults on ART will not increase morbidity or mortality and will decrease haematological adverse events. The results are due in 2014.

Table 2. Participants in studies included in systematic review of cotrimoxazole’s effect on mortality and morbidity in adults with human immunodeficiency virus (HIV) infection receiving antiretroviral therapy (ART).

First author, year Study country Inclusion and exclusion criteria for study participants Percentage of participants with HIV disease at baseline
 Baseline CD4 cell count BMI or body weight
WHO stage 3 WHO stage 4
Walker, 201028 Uganda and Zimbabwe HIV-infected individuals aged ≥ 18 years with WHO stage 2 to 4 disease and a CD4 cell count ≤ 200 cells/µL but with no previous ART were included. Follow-up data from participants whose ART was interrupted were excluded 56 23 Median CD4 cell count: 83 cells/µL (IQR: 29–137) Median BMI: 21 kg/m2 (IQR: 19–24)
Hoffmann, 201029 South Africa Participants were ≥ 18 years old and ART-naïve at ART initiation. Those with a CD4 cell count < 250 cells/µL, WHO stage 4 disease regardless of CD4 cell count, or WHO stage 3 disease with a CD4 cell count < 350 cells/µL were eligible for ART at workplace clinics. Community clinics required participants to have a CD4 cell count < 200 cells/µL or WHO stage 4 disease for ART 27 35 Median CD4 cell count at ART initiation: 132 cells/µL (IQR: 60–206) 16%, 79% and 6% of participants weighed ≤ 60 kg, 61–75 kg and > 75 kg, respectively
Lowrance,200730 Malawi Individuals aged ≥ 15 years with WHO stage 3 or 4 disease or a CD4 cell count ≤ 200 cells/µL were included 63 24 13% of participants had a CD4 cell count < 200 cells/µL at ART initiation Not reported
Madec, 200731 Cambodia Individuals aged ≥ 13 years with WHO stage 4 disease or a CD4 cell count < 200 cells/µL were included 45 46 Median CD4cell count at ART initiation: 20 cells/µL (IQR: 6–78) Median BMI: 18.5 kg/m2 (IQR: 16.6–20.4) in men and 18.7 kg/m2 (IQR: 16.4–21.0) in women
Fairall, 200832 South Africa HIV-infected individuals aged ≥ 16 years who had been in contact with the programme at least twice were included 53 11 48.4% of participants had a baseline CD4 cell count < 200 cells/µL Median weight: 55 kg (IQR: 48–64)
van Oosterhout, 201033 Malawi ART-naïve individuals aged ≥ 18 years who started ART with a BMI < 18.5 kg/m2 were included. Those who were unable to follow instructions for ART, had active liver disease or were pregnant were excluded 64 28 Mean CD4 cell count for all participants initiating ART: 132 cells/µL Mean BMI: 16.5 kg/m2 for all participants initiating ART
Alemu, 201034 Ethiopia Participants were ≥ 15 years of age and received ART on at least two clinic visits. Those who started treatment at another location, who had previously received ART, whose baseline CD4 cell count was unknown, or whose personal information was missing were excluded 54 17 85% of participants had a CD4 cell count < 200 cells/µL at initiation of ART 15%, 45%, 30% and 10% of participants weighed ≤ 40 kg, 40–50 kg, 50–60 kg and ≥ 60 kg, respectively
Miiro, 200935 Uganda Adults aged ≥ 15 years who had had a WHO stage 4 disease event, who had a recurrent WHO stage 3 disease condition, who had tuberculosis and a CD4 cell count < 350 cells/µL, or who were asymptomatic with a CD4 cell count < 200 cells/µL were included. Those who started ART before joining the cohort or who enrolled in the DART trial were excluded 34 13 Median CD4 cell count for all participants on ART: 131 cells/µL Not reported
Campbell, 200936 Uganda Ugandans initiated ART if they had a CD4 cell count ≤ 250 cells/µL or WHO stage 3 or 4 disease, excluding pulmonary TB. Ugandans on ART for a mean 3.7 years were randomly assigned, by household, to continue or discontinue cotrimoxazole. For Ugandans randomized to discontinue cotrimoxazole, it was required that their two most recent CD4 cell counts be > 200 cells/µL. Not reported Not reported Median CD4 cell count for all participants: 489 cells/µL. Not reported
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BMI, body mass index; CD4 cell, CD4+ T lymphocyte; DART, Development of Anti-Retroviral Therapy in Africa; IQR, interquartile range; TB, tuberculosis; WHO, World Health Organization.

Table 3. Studies in systematic review of cotrimoxazole’s effect on mortality and morbidity in adults with human immunodeficiency virus (HIV) infection receiving antiretroviral therapy (ART) .

First author, year Study design Follow-up duration Cotrimoxazole
 Timing of cotrimoxazole initiation relative to ART initiation Analytical method used Variables included in the statistical model Losses to follow-up How losses to follow-up were addressed Risk of death or morbidity in individuals taking cotrimoxazole compared with those not taking cotrimoxazole
Received (No.) Not received (No.)
Walker, 201028 Prospective cohort study Median duration: 4.9 years (IQR: 4.5–5.3) 1959 1220 62% of participants initiated cotrimoxazole before ART initiation, 28% initiated cotrimoxazole after ART initiation, and 10% never initiated cotrimoxazole Marginal structural model Baseline variables: CD4 cell count, haemoglobin level, body mass index, history of a WHO stage 3 or 4 HIV disease event, age, sex, randomization year, WHO disease stage, monitoring group and study site. Time-dependent variables: CD4 cell count, haemoglobin level, time on ART and body mass index 198 of 3 179 participants (6%) were last seen alive more than 4 months before the end of follow-up Data from participants lost to follow-up was censored, although losses were infrequent and the effect of this censoring by additional weighting was small Adjusted OR for death on cotrimoxazole: 0.65 (95% CI: 0.50–0.85). There were 83 deaths during 8 128 person–years of follow-up on cotrimoxazole and 105 deaths during 6 086 person–years of follow-up off cotrimoxazole. Adjusted OR for malaria on cotrimoxazole: 0.74 (95% CI: 0.63–0.88). Adjusted OR for new or recurrent WHO clinical stage 3 or 4 disease events on cotrimoxazole: 0.85 (95% CI: 0.74–0.98)
Hoffmann, 201029 Prospective cohort study Mean duration: 0.77 years 7508 6589 Cotrimoxazole was initiated between 30 days before and 7 days after the initiation of ART Cox proportional hazards model Baseline variables: CD4 cell count, history of tuberculosis, WHO disease stage, sex and age. Time-updated variables: HIV RNA suppression 1186 participants (18%) not on cotrimoxazole and 901 on cotrimoxazole (12%) discontinued ART, left care or were lost to follow-up Data from participants who discontinued ART, left care or were lost to follow-up were censored Adjusted HR for death on cotrimoxazole: 0.64 (95% CI: 0.57–0.72). There were 558 deaths during 6 133 person–years of follow-up on cotrimoxazole and 732 deaths during 4 617 person–years of follow-up off cotrimoxazole
Lowrance, 200730 Retrospective cohort study 0.5 years 574 478 Cotrimoxazole was initiated after ART initiation Cox proportional hazards model Baseline variables: CD4 cell count, WHO disease stage, tuberculosis history, gender and age 22 of 574 participants who received cotrimoxazole, were lost to follow-up and 17 transferred out of the study. 51 of 478 patients not on cotrimoxazole, were lost to follow-up and 21 transferred out Data from participants lost to follow-up were excluded from the analysis Adjusted RR of death on cotrimoxazole: 0.59 (95% CI: 0.43–0.82). There were 57 deaths in 535 participants on cotrimoxazole and 73 deaths in 406 participants off cotrimoxazole
Madec, 200731 Prospective cohort study Median duration: 1.08 years (IQR: 5–21 months) Not reported Not reported Not reported Cox proportional hazards model Age, sex, WHO disease stage, CD4 cell count, haemoglobin level, body mass index, year of ART initiation, ART regimen and previous exposure to ART 37 participants (2.13%) were lost to follow-up Participants lost to follow-up were regarded as having died Adjusted HR for death on cotrimoxazole: 0.15 (95% CI: 0.11–0.21)
Fairall, 200832 Prospective cohort study Median duration: 0.33 years (IQR: 1–9 months) Not reported Not reported Not reported Marginal structural model Baseline variables: age, sex, district of residence, clinic, weight, CD4 cell count, tuberculosis status and ART status. Time-dependent variables: CD4 cell count, weight and ART status Not reported Not reported Adjusted HR for death on cotrimoxazole: 0.37 (95% CI: 0.32–0.42)
van Oosterhout, 201033 Retrospective cohort study 0.5 years 319 274 Cotrimoxazole was initiated before ART initiation Logistic regression model Age, sex, WHO disease stage, body mass index, haemoglobin level and baseline CD4 cell count 7 participants were lost to follow-up and 13 stopped ART after 14 weeks. 16 were lost to follow-up and 15 stopped ART after 26 weeks Not reported After 14 weeks, the adjusted OR for death on cotrimoxazole was 0.61 (95% CI: 0.38–0.96). After 26 weeks, it was 0.71 (95% CI: 0.46–1.11)
Alemu, 201034 Retrospective cohort study Mean duration: 2.01 years 240 31 Cotrimoxazole was initiated at or before ART initiation in 88.6% of participants Cox proportional hazards model Baseline variables: WHO disease stage and haemoglobin level 48 participants (18%) were lost to follow-up and 19 (7%) transferred to another facility Data from participants who were lost to follow-up or transferred to another facility were censored Adjusted HR for death on cotrimoxazole: 0.14 (95% CI: 0.05–0.37)
Miiro, 200935 Retrospective cohort study 1 year 179 32 Cotrimoxazole was initiated before ART initiation Logistic regression model ART, age, sex, baseline WHO disease stage, haemoglobin level and baseline CD4 cell count Data from participants followed up for less than 1 year were censored Data from 157 of the 219 participants (71.7%) were censored at the completion of follow-up RR for all-cause morbidity on cotrimoxazole: 0.66 (95% CI: 0.41–1.06), although all-cause morbidity was undefined
Campbell, 200936 Randomized trial 0.32 years 452 384 Not reported Not reported Not reported Not reported Not reported RR for malaria on cotrimoxazole 0.04 (95% CI: 0.01–0.17). RR for diarrhoea on cotrimoxazole 0.56 (95% CI: 0.43–0.77)
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CD4 cell, CD4+ T lymphocyte; CI, confidence interval; HR, hazard ratio; IQR, interquartile range; OR, odds ratio, RNA, ribonucleic acid; RR, relative risk; WHO, World Health Organization.

Table 4. Newcastle–Ottawa Quality Assessment Scale scores for bias in studies included in systematic review of cotrimoxazole’s effect on mortality and morbidity in adults with human immunodeficiency virus (HIV) infection receiving antiretroviral therapy (ART) .

First author, year Sources of bias
 Total scorea
Selection bias
 Confounding bias
 Measurement bias
Cohort on cotrimoxazole and ART was representative of the average adult on this treatment in the communityb Cohort receiving ART alone was representative of the cohort on both cotrimoxazole and ARTb Cotrimoxazole use was ascertainedb Majority of participants were known to be asymptomatic at study baselineb Mortality estimates were adjusted for baseline CD4 cell countc Deaths were validatedb Median or mean follow-up of at least 3 monthsb ≤ 20% of participants were lost to follow-upb
Walker, 201028 1 1 1 0 2 1 1 1 8
Hoffmann, 201029 1 1 1 0 2 1 1 1 8
Lowrance, 200730 1 1 1 0 2 0 1 1 7
Madec, 200731 0 1 1 0 2 0 1 1 6
Fairall, 200832 1 1 0 0 2 1 1 0 6
Van Oosterhout, 201033 0 1 1 0 2 0 1 1 6
Alemu, 201034 1 1 0 0 0 1 1 1 5
Miiro, 200935 1 1 1 1 0 0 1 0 5
Campbell, 200936 1 1 1 1 0 0 1 1 6
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CD4 cell, CD4+ T lymphocyte.

a A score of 7 to 9 indicates high methodological quality, a score of 4 to 6 indicates moderate quality and a score of 0 to 3 indicates low quality.

b Yes =  1 point; No = 0 points.

c Yes =  2 points; No = 0 points.

The effect of cotrimoxazole on mortality reported in the seven studies in the meta-analysis is illustrated in Fig. 2. Begg and Egger P-values for publication bias in the studies were 0.29 and 0.49, respectively, which suggests the absence of publication bias. The summary estimate of the effect of cotrimoxazole on the incidence rate of death derived using a random-effects model was 0.42 (95% confidence interval, CI: 0.29–0.61). Survival was increased by either continuing cotrimoxazole at ART initiation,29,33–35 initiating cotrimoxazole at the same time as ART29,34 or initiating cotrimoxazole when the patient was stable on ART.28,30

Fig. 2.

Forest plot of study and summary effect estimates for cotrimoxazole’s effect on death in adults with human immunodeficiency virus (HIV) infection receiving antiretroviral therapy (ART)

Note: The seven studies were included in the meta-analysis. The summary estimate of the treatment effect was calculated using a random-effects model. The risk is reported either as an odds ratio, a hazard ratio or a relative risk in the different studies. The centre of the squares represents the study point estimates while the horizontal lines represent the study 95% confidence intervals (CIs). The centre of the bottom quadrilateral represents the summary effect estimate, whereas its horizontal corners represent its 95% CI.

Fig. 2

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The Q-statistic and the I-squared statistic for the seven studies reporting on the primary outcome were 102.3 and 93.2%, respectively, indicating high heterogeneity.26 A sensitivity analysis that evaluated the effect of the median or mean number of years of follow-up indicated that the length of the study did not explain the heterogeneity (P = 0.85). Nor was the percentage of participants with symptomatic HIV infection (i.e. WHO stage 3 or 4 disease) at baseline found to provide an explanation on sensitivity analysis (P = 0.91).

Regarding cotrimoxazole’s effect on morbidity, Walker et al. reported that cotrimoxazole resulted in a reduction in the odds of malaria (odds ratio, OR: 0.74; 95% CI: 0.63–0.88).28 This effect was maintained throughout a follow-up period of 5 years. In addition, Walker et al. also reported that cotrimoxazole reduced the odds of new or recurrent WHO clinical stage 3 or 4 disease events (OR: 0.85; 95% CI: 0.74–0.98),28 whereas Miiro et al. reported a trend towards lower all-cause morbidity (relative risk, RR: 0.66; 95% CI: 0.41–1.06), although all-cause morbidity was undefined.35 A trial identified during the review of references of studies that met the inclusion criteria found that the risk of both malaria (RR: 0.04; 95% CI: 0.01–0.17) and diarrhoea (RR: 0.56; 95% CI: 0.43–0.77) was lower among Ugandans on ART who were randomized to cotrimoxazole than among those who were not.36 The patients had been receiving ART for a mean of 3.7 years, their median CD4 cell count was 489 cells/µL and 94% had a viral load < 400 RNA copies/mL.

Two studies gave details of adverse events associated with cotrimoxazole. Walker et al. reported 22 serious cotrimoxazole-related adverse events during 8128 person–years of treatment: all were either haematological adverse events, rash or hypersensitivity.28 Lowrance et al. reported that 10 of 574 patients on cotrimoxazole stopped treatment during 6 months of follow-up but did not state whether or not the cause was cotrimoxazole-related toxicity.30

Since only two of the eight studies followed participants for more than 13 months on average, it was difficult to gauge whether or not the survival benefit of cotrimoxazole waned after ART-induced immune reconstitution. However, Walker et al. did analyse the effect of the duration of cotrimoxazole combined with ART.28 They found that cotrimoxazole was associated with a substantial reduction in the odds of death between weeks 1 and 12 of the administration of cotrimoxazole combined with ART (OR: 0.41; 95% CI: 0.27–0.65) and that the reduction was sustained between weeks 12 and 72 (OR: 0.56; 95% CI: 0.37–0.86) but ceased to be evident after week 72 (OR: 0.96; 95% CI: 0.63–1.45). There was no evidence of variation in this effect resulting from an updated CD4 cell count.

It was also difficult to determine whether the survival benefit of cotrimoxazole was influenced by the baseline CD4 cell count since in six studies most participants initiated ART with a CD4 cell count of less than 200 cells/µL. However, Hoffmann et al. reported that the reduction in the hazard of death was substantial among individuals with a baseline CD4 cell count less than 200 cells/µL (hazard ratio, HR: 0.64; 95% CI: 0.56–0.72) and those with a baseline count between 200 and 350 cells/µL (HR: 0.62; 95% CI: 0.41–0.94) but was not significant among those with a count greater than 350 cells/µL at baseline (HR: 0.80; 95% CI: 0.38–1.70).29

Discussion

This systematic review indicates that cotrimoxazole reduced mortality in individuals aged 13 years or more who were receiving ART. The summary estimate of the effect of cotrimoxazole on the incidence rate of death was 0.42 (95% CI: 0.29–0.61). Although there was no evidence of publication bias in the studies included in the review, there was significant heterogeneity in the findings: the I-squared statistic was 93.2%. Unfortunately, only a limited sensitivity analysis could be performed because of differences in the variables recorded in the various studies. Nonetheless, the sensitivity analysis showed that neither symptomatic HIV infection (i.e. WHO stage 3 or 4 disease) nor the duration of follow-up explained the heterogeneity.

Cotrimoxazole is safe, well tolerated, widely available and inexpensive. Although cotrimoxazole can help reduce the high early mortality rate in HIV-infected adults on ART in low- and middle-income countries, it is still not widely used. The slow increase in the uptake of cotrimoxazole has been associated with delays in the dissemination of recommendations on its use (either in stand-alone guidelines or integrated into ART guidelines), problems with drug procurement and supply, poor health-care infrastructure for managing patients before ART and inadequate systems for monitoring and evaluation.30 In addition to resolving these issues, the number of adults receiving cotrimoxazole could also be increased by raising awareness of its benefits and by using indicators to monitor its uptake both globally and at the level of individual treatment programmes.38 Moreover, treatment programmes could also provide forecasts of the future annual demand for cotrimoxazole by using local data on the number of individuals currently receiving or expected to start ART.30

Recently WHO and the Joint United Nations Programme on HIV/AIDS, as part of the Treatment 2.0 initiative,39 prioritized identifying, retaining and caring for people earlier in the course of HIV infection as a way of improving clinical and programmatic outcomes. Indeed, implementing ART earlier within existing guidelines has had a considerable impact: in South Africa, mortality during the first year of ART declined from 8.9 to 5.6% as the median CD4 cell count at ART initiation increased from 68 to 113 cells/µL.40 One way to facilitate earlier access to ART is through expanding HIV testing coverage. For generalized epidemics (i.e. when the prevalence of antenatal HIV infection is over 1%), WHO recommends carrying out provider-initiated HIV testing in all health facilities,41 particularly in patients with tuberculosis.42 Recent evidence suggests that community-based testing can identify individuals earlier in the course of HIV infection43 and increases knowledge of HIV status fourfold relative to health-facility-based testing.44 Reductions in mortality, costs and the rate of new infections will also depend crucially on maintaining good links with personnel monitoring and caring for individuals before they receive ART, on maximizing the retention rate and on initiating ART as early as permitted by national guidelines. These actions will help achieve the Millennium Development Goals on HIV infection.45 Unfortunately, at present over 50% of HIV-infected individuals are lost to care between diagnosis and the start of ART.46–49 Giving free cotrimoxazole can help increase the retention rate,50 provide an opportunity to assess an individual’s adherence to treatment before the start of ART51 and improve survival in those not on ART.52 Efforts to reduce early mortality in HIV-infected individuals and to increase retention rates in treatment programmes could be assisted by implementing intensified tuberculosis case-finding at every health-care visit and by providing free isoniazid to those with tuberculosis who do not have a cough, night sweats, weight loss or fever.53

For settings in which the health-care infrastructure is limited, WHO recommends discontinuing cotrimoxazole in adults who show good adherence to ART, have secure access to treatment and who have not had a new WHO stage 2, 3 or 4 disease event for at least 1 year.17 Data from the one study that reported the estimated effect of cotrimoxazole on mortality after 1 year of combined treatment with ART indicate that there was no reduction in mortality after 72 weeks of ART.28 For settings where the health-care infrastructure is good, WHO recommends discontinuing cotrimoxazole in adults who have received ART for at least 6 months and have a CD4 cell count greater than 350 cells/µL.17 The single study that provided an estimate of the effect of cotrimoxazole on mortality in adults on ART with a baseline CD4 cell count greater than 350 cells/µL suggested that cotrimoxazole had no effect.29

Two limitations of this systematic review were that most studies included had a short follow-up and that they did not include estimates of the effect of cotrimoxazole in adults with a high baseline CD4 cell count. Furthermore, only one randomized trial was identified. Although most studies did attempt to control for bias, prospective and retrospective cohort studies are susceptible to unmeasured confounding. Also, none of the studies assessed adherence to cotrimoxazole and ART. Finally, since the cause of the death was not reported in any study, the precise mechanism of cotrimoxazole’s beneficial survival effect is not clear.

Although the data considered in this review were limited and results from an on-going trial are still awaited, our findings support current WHO recommendations that the use of cotrimoxazole should be scaled up in HIV-infected individuals starting or receiving ART. Further research is needed to determine the optimum duration of cotrimoxazole treatment in adults receiving ART for an HIV infection.

Acknowledgements

Amitabh B Suthar is also affiliated with the Department of HIV/AIDS of the World Health Organization.

Competing interests:

None declared.

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