The authors have declared that no competing interests exist.
Conceived and designed the experiments: CP GJS JW BR. Performed the experiments: MK CP BS. Analyzed the data: CP KY BR GJS. Contributed reagents/materials/analysis tools: CP KY BS MK JW BR GJS. Wrote the first draft of the manuscript: CP. Contributed to the writing of the manuscript: KY JW BR GJS. Enrolled patients: MK CP BS. Agree with the manuscript’s results and conclusions: CP KY BS MK JW BR GJS. All authors have read, and confirm that they meet, ICMJE criteria for authorship.
Cotrimoxazole (CTX) prophylaxis is recommended by the World Health Organization (WHO) for HIV-1-infected individuals in settings with high infectious disease prevalence. The WHO 2006 guidelines were developed prior to the scale-up of antiretroviral therapy (ART). The threshold for CTX discontinuation following ART is undefined in resource-limited settings.
Between 1 February 2012 and 30 September 2013, we conducted an unblinded non-inferiority randomized controlled trial of CTX prophylaxis cessation versus continuation among HIV-1-infected adults on ART for ≥18 mo with CD4 count > 350 cells/mm3 in a malaria-endemic region in Kenya. Participants were randomized and followed up at 3-mo intervals for 12 mo. The primary endpoint was a composite of morbidity (malaria, pneumonia, and diarrhea) and mortality. Incidence rate ratios (IRRs) were estimated using Poisson regression.
Among 538 ART-treated adults screened, 500 were enrolled and randomized, 250 per arm. Median age was 40 y, 361 (72%) were women, and 442 (88%) reported insecticide-treated bednet use. Combined morbidity/mortality was significantly higher in the CTX discontinuation arm (IRR = 2.27, 95% CI 1.52–3.38;
CTX discontinuation among ART-treated, immune-reconstituted adults in a malaria-endemic region resulted in increased incidence of malaria but not pneumonia or diarrhea. Malaria endemicity may be the most relevant factor to consider in the decision to stop CTX after ART-induced immune reconstitution in regions with high infectious disease prevalence. These data support the 2014 WHO CTX guidelines.
ClinicalTrials.gov
In a randomized controlled non-inferiority trial, Christina Polyak and colleagues assess whether CTX prophylaxis remains important among HIV+ adults on ART in a malaria-endemic setting.
AIDS has killed 39 million people over the past three decades, and 35 million people (mostly living in resource-limited countries) are currently infected with HIV, the virus that causes AIDS. HIV, which is usually transmitted through unprotected sex with an infected individual, gradually destroys CD4 lymphocytes and other immune system cells. Because destruction of the immune system leaves HIV-infected individuals susceptible to “opportunistic” infections, early in the AIDS epidemic, most HIV-positive individuals died within ten years of infection. In 1996, effective antiretroviral therapy (ART)—drug regimens that stop HIV replicating and allow the immune system to recover its ability to fight infections—became available. For people living in affluent countries, HIV/AIDS became a chronic condition, but because ART was expensive, HIV/AIDS remained fatal in resource-limited countries. In 2003, the international community began to work towards achieving universal access to ART. Now, at least a third of people living with HIV have access to ART, and the global mortality (death) rate from HIV/AIDS is falling.
To prevent opportunistic infections, the World Health Organization (WHO) recommends cotrimoxazole (CTX) prophylaxis for HIV-infected individuals. CTX is a combination of two antimicrobial drugs that is active against a range of bacterial, fungal, and parasitic infections; prophylactic antimicrobials are taken to prevent infection. CTX decreases morbidity (illness) and mortality among HIV-infected individuals primarily by reducing the rates of malaria, pneumonia, diarrhea, and severe bacterial infections. The 2006 WHO guidelines for CTX prophylaxis recommend that, in resource-limited countries, HIV-infected patients whose CD4 count is ≤350 cells/mm3 blood should take CTX and that, in settings with a high prevalence of HIV infection and limited health infrastructure, all HIV-infected adults should take CTX. However, these guidelines were developed before access to ART was scaled-up, and CTX prophylaxis has risks (for example, drug toxicity) as well as benefits. In this unblinded non-inferiority randomized controlled trial, the researchers investigate the effects of CTX discontinuation among ART-treated HIV-infected adults in Kenya. A randomized controlled trial compares the outcomes of individuals randomly assigned to different treatments; in an unblinded trial, everyone involved in the trial knows who is taking which treatment; a non-inferiority trial investigates whether one treatment is not worse than another treatment.
The researchers enrolled 500 HIV-infected adults living in a malaria-endemic region of Kenya (an area where malaria is always present) who had been treated with ART for ≥18 months, who had a CD4 count of >350 cells/mm3, and who were taking CTX. Half the participants continued to take CTX; the remainder stopped taking CTX. After 12 months of follow-up, the combined rate of morbidity (malaria, pneumonia, and diarrhea) and mortality was significantly higher in the CTX discontinuation arm than in the CTX continuation arm (a significant difference is one that is unlikely to have happened by chance). The difference in this primary outcome between the trial arms was driven by malaria morbidity—there were 33 cases of malaria in the CTX discontinuation arm but only one case in the CTX continuation arm. By contrast, the rates of pneumonia and diarrhea did not differ significantly between the trial arms.
Because the difference between the two trial arms in terms of the primary endpoint was greater than the researchers’ predefined non-inferiority limit, these findings suggest that CTX discontinuation is inferior to CTX continuation among ART-treated, immune-reconstituted HIV-infected adults living in a malaria-endemic region. The accuracy of these findings may be affected by the lack of blinding—the clinicians’ care decisions and the patients’ threshold for seeking care may have been influenced by their knowledge of their trial arm assignment. Overall, however, these findings suggest that malaria endemicity should be considered when making decisions about whether to stop CTX after ART-driven immune reconstitution. Indeed, in December 2014, following the release of preliminary data from this trial and the completion of an independent trial on CTX discontinuation, WHO issued supplemental guidelines on CTX prophylaxis. These state that CTX prophylaxis can be discontinued for HIV-infected adults who are clinically stable on ART and have evidence of immune recovery and viral suppression but recommend that CTX prophylaxis be continued regardless of CD4 cell count or HIV/AIDS clinical stage in settings where malaria is endemic and/or severe bacterial infections are common.
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Cotrimoxazole (CTX), fixed-dose trimethoprim-sulfamethoxazole, is a low-cost and widely utilized broad spectrum antibiotic used to prevent opportunistic infections in patients with human immunodeficiency virus type 1 (HIV-1). Prophylaxis with CTX has been shown to decrease mortality, morbidity, and hospitalizations among HIV-infected adults [
Recommendations for CTX use in adults with HIV-1 vary by setting. In the United States and Europe, CTX is recommended for HIV-1-infected adults with severe immunosuppression (CD4 count < 200 cells/mm3) to prevent
In resource-limited countries, the threshold for CTX discontinuation following ART remains undefined. The 2006 World Health Organization (WHO) guidelines recommend CTX prophylaxis for HIV-1-infected patients with a CD4 cell count of ≤350 cells/mm3 [
At the time of our protocol submission, there were no randomized trial data on the effects of discontinuing CTX following ART in resource-limited settings. However, prior to study initiation, a randomized controlled trial (RCT) conducted in Uganda demonstrated an increased incidence of malaria and diarrhea among ART-treated adults who discontinued CTX compared to those who continued [
We conducted an RCT among adults on ART with evidence of immune recovery (ART for ≥18 mo and CD4 count > 350 cells/mm3) to determine whether discontinuation of CTX was non-inferior to continued CTX prophylaxis in decreasing morbidity. Following completion of our RCT, the WHO published supplemental guidelines on the use of CTX [
We conducted an unblinded, two-arm randomized non-inferiority clinical trial. Two study arms were compared: individuals in the CTX continuation arm continued CTX per Kenyan national guidelines (160 mg trimethoprim/800 mg sulfamethoxazole daily), and individuals in the CTX discontinuation arm discontinued CTX at the time of enrollment. The primary aim of the trial was to determine whether CTX prophylaxis can be discontinued in ART-treated, immune-reconstituted adults without significant harm.
We recruited HIV-infected individuals between February 1, 2012, and August 27, 2012, at the HIV Treatment and Care Clinic, known as the Patient Support Center (PSC), of Homa Bay District Hospital in western Kenya. Individuals were eligible for the study if they were ≥18 y old, HIV seropositive, and taking first-line antiretrovirals (ARVs) with evidence of immune recovery (ARVs for ≥18 mo and CD4 count > 350 cells/mm3). Additionally, participants had to be currently taking CTX for HIV and willing to return to the clinic every 3 mo for the 12-mo study follow-up period. We excluded individuals who were pregnant or breastfeeding, who were taking second-line ARVs, or who had a documented allergy to CTX.
The study protocol was approved by the ethical review committee of the Kenya Medical Research Institute and the institutional review boards of the University of Washington and the Walter Reed Army Institute of Research. All participants gave informed consent. Consent was written if literate and fingerprint if illiterate, with the signature of an independent witness. Vestergaard Frandsen donated insecticide-treated bednets and water filters. Alere donated cartridges for the Pima machines used for CD4 count measurements. Data were analyzed by co-author KY.
The study biostatistician at the University of Washington used a computer-generated blocked randomization sequence to assign participants (1:1) to either the CTX continuation or CTX discontinuation arm. Each participant’s arm allocation was concealed from study investigators, staff, and participants in a randomization envelope until the end of the enrollment visit, when the envelope was opened; participants and study staff were not masked to treatment assignment thereafter.
A history and physical examination was conducted at randomization and at 3-mo intervals during follow-up. At randomization, 6 mo, and 12 mo, specimens were obtained for a complete blood count with CD4 count per Kenyan guidelines [
Participants were encouraged to come to the clinic to see study providers for any illness as a sick visit. Sick visits included more intensive workup, with malaria rapid diagnostic test, thick/thin blood smears, and measurement of alanine aminotransferase level and HIV-1 RNA viral load, as clinically indicated and available. Moreover, participants were contacted every 2 wk by study counselors using text messaging or phone calls and asked about recent illness and compliance with study arm protocol. Any participant reporting any symptoms was asked to return to the clinic for evaluation by study staff. To decrease the risk of malaria and diarrhea in this cohort, we provided insecticide-treated bednets and water filters to all participants.
At the completion of the study, participants were transferred back to PSC care providers. Those who had stopped CTX were counseled on restarting CTX again as per Kenyan guidelines [
The primary morbidity/mortality endpoint was a composite of malaria, pneumonia, and diarrhea events and non-trauma mortality events. Malaria was defined as a fever, measured or self-reported, and either a positive rapid diagnostic test or thick smear showing the presence of parasites. Pneumonia was defined as fever, cough, or tachypnea and either a clinically abnormal chest examination or evidence of infiltrate on chest radiograph significant enough to require hospitalization. Diarrhea was defined as a self-report of three or more loose stools in a 24-h period in the past week. An independent clinician (J. Brooks, US Centers for Disease Control and Prevention) who was blind to arm assignment at the time of adjudication evaluated all serious adverse events (SAEs) and designated their likelihood of being research-related. Each event was deemed potentially related to the research if it could have been due to either CTX use or CTX discontinuation.
Prespecified secondary endpoints were 12-mo CD4 change and ART treatment failure. Treatment failure was defined by Kenya National AIDS & STI Control Programme guidelines and was categorized as clinical, immunologic, or virologic [
We estimated the needed sample size for the comparison of interest: the incidence rate ratio (IRR) comparing the rate of morbidity/mortality observed in the CTX discontinuation arm to the rate observed in the CTX continuation arm. We chose a non-inferiority limit of 1.25, thus planning to conclude non-inferiority of CTX discontinuation if the upper bound of the two-sided 90% confidence interval (CI) for the IRR was less than 1.25 [
For analysis of the primary endpoint, we calculated a combined morbidity/mortality incidence rate for each treatment arm. We used Poisson regression with robust error variance to estimate the IRR, using the natural logarithm of follow-up time as an offset variable. We conducted both intention-to-treat (ITT) and per-protocol (PP) analyses. ITT analyses assigned all follow-up time from a participant to that participant’s original randomization arm. In contrast, PP analyses reflected changes to CTX regimen. Specifically, for participants randomized to discontinue CTX who restarted CTX due to pregnancy, PP analyses excluded person-time following the restart of CTX.
In secondary analyses, we calculated IRRs comparing the CTX discontinuation arm to the continuation arm for each individual component of the morbidity/mortality outcome, as well as for subgroups defined by enrollment CD4 count (≤600 cells/mm3, >600 cells/mm3) and duration of ART at enrollment (≤5 y, >5 y). We also calculated IRRs for the rate of SAEs and the rate of all grade 2 or higher AEs. To estimate IRRs, we used Poisson regression as described above or exact Poisson regression where appropriate. We compared 12-mo change in CD4 count in the two groups using a linear mixed effects model that included main effects for arm, time, and a time–treatment arm interaction. This model used CD4 data collected at the scheduled enrollment, month 6, and month 12 study visits. We used Cox proportional hazards regression to compare time to ART treatment failure between arms.
An independent data safety and monitoring board (DSMB) was convened four times during the course of the study to review study procedures, participant retention, and safety data by arm and included review of any relevant new data. The DSMB adopted a safety stopping rule based on SAEs deemed potentially research-related (due to either discontinuing CTX or continuing CTX) by the DSMB safety monitor, who would be blind to arm assignment at the time of adjudication. Non-severe (i.e., grade 1 or 2) malaria, pneumonia, and diarrhea events were not included as criteria for early stopping, based on the rationale that rates of non-severe AEs in the CTX discontinuation arm may reflect rates in HIV-uninfected community members and could be offset by non-severe AEs related to CTX use. The interim safety analysis was conducted in accordance with the Lan–DeMets implementation of the O’Brien–Fleming boundary for harm; the alpha spending function was based on an information fraction equal to the interim number of events in all arms divided by the total number of expected events by the conclusion of the study. The interim analysis was conducted at an information fraction of 0.64, and the study stopping criterion was not met.
We used Stata version 12.1 [
Five hundred thirty-eight HIV-1-infected adults on ART were screened to meet the target sample size of 500 (
Characteristic | CTX Continuation Arm ( |
CTX Discontinuation Arm ( |
---|---|---|
184 (73.6%) | 177 (70.8%) | |
41 (34, 48) | 40 (34, 48) | |
Married | 156 (62.4%) | 165 (66.0%) |
Divorced/separated/widowed | 90 (36.0%) | 77 (30.8%) |
Single | 4 (1.6%) | 8 (3.2%) |
Less than primary | 15 (6.0%) | 18 (7.2%) |
Primary school | 156 (62.4%) | 149 (59.6%) |
Secondary school | 73 (29.2%) | 73 (29.2%) |
Vocational school | 3 (1.2%) | 6 (2.4%) |
University | 3 (1.2%) | 4 (1.6%) |
<5,000 | 201 (80.4%) | 187 (74.8%) |
≥5,000 | 49 (19.6%) | 63 (25.2%) |
5 (4, 7) | 5 (4, 7) | |
3 (2, 3) | 2 (2, 3) | |
Piped or well water | 135 (54.0%) | 133 (53.2%) |
Environmental water source | 115 (46.0%) | 117 (46.8%) |
Flush toilet | 7 (2.8%) | 11 (4.4%) |
Pit latrine | 196 (78.4%) | 202 (80.8%) |
Bush | 47 (18.8%) | 37 (14.8%) |
220 (88.0%) | 222 (88.8%) | |
207 (82.8%) | 214 (85.6%) | |
5 (2.0%) | 2 (0.8%) | |
598 (487, 695) | 591 (515, 719) | |
4.5 (3.1, 6.3) | 4.5 (3.2, 6.1) |
Data are given as
Study retention was similar in both arms (
Scheduled and unscheduled study follow-up visits gave 253.5 person-years of analysis time in the CTX continuation arm and 253.3 person-years of analysis time in the CTX discontinuation arm, among 500 total participants. Participants randomized to the CTX continuation arm self-reported that they took CTX every day in the past week at 90.5% of follow-up visits. By the month 12 study visit, eight of 250 (3.2%) participants randomized to the CTX discontinuation arm had restarted CTX due to pregnancy.
For analysis of the primary composite endpoint of morbidity and mortality, a total of 111 morbidity events were observed (
Outcome or AE Category | Incidence per 100 Person-Years (Number of Cases) | IRR |
||
---|---|---|---|---|
CTX Continuation Arm (253.5 Person-Years Total) | CTX Discontinuation Arm (253.3 Person-Years Total) | |||
Combined outcome: malaria, pneumonia, diarrhea, and mortality | 13.4 (34) | 30.4 (77) | 2.27 (1.52, 3.38) | <0.001 |
Mortality | 0.4 (1) | 0.0 (0) | 1.00 (0.00, 39.02) |
0.99 |
Malaria | 0.4 (1) | 13.0 (33) | 33.02 (4.52, 241.02) | 0.001 |
Pneumonia | 2.8 (7) | 3.9 (10) | 1.43 (0.54, 3.75) | 0.47 |
Diarrhea | 9.9 (25) | 13.4 (34) | 1.36 (0.82, 2.27) | 0.24 |
SAEs | 4.3 (11) | 9.1 (23) | 2.09 (1.02, 4.27) | 0.043 |
Grade 3 or higher SAEs | 3.6 (9) | 7.1 (18) | 2.00 (0.90, 4.44) | 0.088 |
SAEs deemed potentially related to the research | 2.0 (5) | 5.1 (13) | 2.60 (0.93, 7.28) | 0.069 |
Grade 2 or higher AEs | 63.5 (161) | 99.5 (252) | 1.57 (1.29, 1.91) | <0.001 |
1IRRs estimated using Poisson regression with robust error variance, except where indicated.
2For test of null hypothesis: IRR = 1.
3Estimated with exact Poisson regression (median unbiased estimate) because of the low rate of mortality events.
By study follow-up month (A) and by calendar month (B). Error bars represent the 95% confidence intervals.
In subgroup analyses (Tables
Outcome | Enrollment CD4 Count ≤ 600 cells/mm3 | Enrollment CD4 Count > 600 cells/mm3 | |
---|---|---|---|
Combined outcome: malaria, pneumonia, diarrhea, and mortality | 4.33 (2.11, 8.86) | 1.46 (0.88, 2.42) | 0.015 |
Mortality | — | — | — |
Malaria | 18.71 (3.15, +Inf) |
19.25 (2.59, 143.38) | — |
Pneumonia | 1.42 (0.40, 5.04) | 1.35 (0.30, 6.01) | 0.96 |
Diarrhea | 3.99 (1.51, 10.54) | 0.66 (0.33, 1.31) | 0.003 |
Data given as IRR (95% CI). IRRs were estimated using Poisson regression with robust error variance, except where indicated.
1Estimated with exact Poisson regression (median unbiased estimate) because there were no observed malaria events in the CTX continuation arm. Inf, infinity.
2Due to the low rate of malaria events in the CTX continuation arm, separate models were used to estimate the malaria IRR in each subgroup. Thus, no interaction
Outcome | ART Duration ≤ 5 y | ART Duration > 5 y | |
---|---|---|---|
Combined outcome: malaria, pneumonia, diarrhea, and mortality | 2.28 (1.39, 3.75) | 2.22 (1.13, 4.35) | 0.94 |
Mortality | — | — | — |
Malaria | 32.19 (5.66, +Inf) |
10.23 (1.31, 79.58) | — |
Pneumonia | 2.22 (0.68, 7.18) | 0.34 (0.04, 3.28) | 0.15 |
Diarrhea | 1.04 (0.55, 1.97) | 2.19 (0.90, 5.34) | 0.18 |
Data given as IRR (95% CI). IRRs were estimated using Poisson regression with robust error variance, except where indicated.
1Estimated with exact Poisson regression (median unbiased estimate) because there were no observed malaria events in the CTX continuation arm. Inf, infinity.
2Due to the low rate of malaria events in the CTX continuation arm, separate models were used to estimate the malaria IRR in each subgroup. Thus, no interaction
Reported bednet use at enrollment was high, at 88%. Reported bednet use during follow-up was high (96.4%) and was similar between both arms.
There were 34 SAEs, of which 27 were grade 3 or higher AEs (including one death), and 18 were deemed potentially related to the research (five in the CTX continuation arm and 13 in the CTX discontinuation arm) (
The estimated rate of grade 2 or higher AEs was 63.5 per 100 person-years in the CTX continuation arm and 99.5 per 100 person-years in the CTX discontinuation arm, a statistically significant difference (IRR = 1.57, 95% CI 1.29–1.91;
Analyses of 12-mo CD4 change included CD4 counts at enrollment, at month 6, and at month 12 for all participants contributing data at these time points. There was an increase in CD4 count of 28.8 cells/mm3/y (95% CI 7.8–49.9) in the CTX continuation arm and of 31.6 cells/mm3/y (95% CI 10.7–52.6) in the CTX discontinuation arm (
There were a total of nine ART treatment failure events: six immunologic treatment failures, two virologic treatment failures, and one clinical treatment failure. Five ART treatment failure events were in the CTX continuation arm, and four were in the CTX discontinuation arm. There was no statistically significant difference between arms in time to treatment failure (
In this randomized trial, we compared discontinuation of CTX prophylaxis with continuation of CTX prophylaxis in HIV-1-infected adults who had evidence of immune recovery following ART. Despite having received ART for a median of more than 4 y and having immune reconstitution, adults who stopped CTX prophylaxis had significantly higher incidence of the combined morbidity/mortality endpoint, driven by malaria morbidity. Of the 34 cases of clinical malaria that occurred during our study, 33 were in the CTX discontinuation arm. Malaria cases occurred despite all study participants having received insecticide-treated bednets and a high rate of reported bednet usage (88%).
Only one other randomized control trial to date has examined CTX discontinuation after ART initiation in adults in a resource-limited setting [
Data from this study were presented at the Conference on Retroviruses and Opportunistic Infections in 2014 [
The prior CTX discontinuation study in Uganda was stopped early after the researchers observed increased malaria, and therefore it had a limited follow-up time of up to 4 mo [
In contrast to other CTX discontinuation studies, we did not observe an increase in diarrhea in participants in the CTX discontinuation arm [
This study complements findings by Walker et al. [
Our study demonstrated low rates of treatment-limiting AEs such as hematological AEs, rash, or hypersensitivity among participants who continued CTX. All participants were on CTX at the study start, therefore likely limiting the group of participants who would have reactions to the antimicrobial and suffer from adverse effects. AEs were significantly more common among those who stopped CTX, consistent with prior studies [
Our study had several strengths and limitations. Because our study was an unblinded clinical trial without a placebo, clinician’s care decisions, as well as the patients’ threshold to come in for care, may have been influenced by trial arm. A second limitation, for statistical analyses, was an observed incidence of morbidity events that was lower than expected. Additionally, our study was limited to 12 mo of follow-up. A strength of the study was high retention (98% in each arm). The PSC at the Homa Bay District Hospital had a long history of collaboration with Médecins Sans Frontières and a reputation for excellent care, which contributed to retention in the trial. Participants had median CD4 counts approaching 600 cells/mm3 in both arms and had been on ART for a median of over 4 y with few prior hospitalizations in the past 3 mo. This, coupled with high retention, suggests that these patients may represent an elite subgroup of patients who took advantage of a strong PSC.
In conclusion, CTX discontinuation among ART-treated adults in a region with endemic malaria results in increased incidence of clinical malaria but not pneumonia or diarrhea. The implications are broad, and our results suggest that CTX prophylaxis should continue in regions with endemic malaria. However, in regions without malaria or with less endemicity, CTX cessation may be possible after immune recovery.
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We thank the participants in the Homa Bay community; the Homa Bay District Hospital and clinic staff; the PSC and the local and Médecins Sans Frontières staff for their collaboration; officials in the Kenya Medical Research Institute (KEMRI) and Kenyan Ministry of Health; our community advisory board; the KEMRI–University of Washington study team; the University of Washington Department of Global Health; the US Army Medical Research Unit–Kenya; the US Military HIV Research Program for its support; and the members of the independent DSMB for their expertise and guidance: Drs. Bryan Shepherd (Chair), John T. Brooks, James Campbell, Moses Kamya, Bernhards Ogutu, and Sten Vermund.
adverse event
antiretroviral therapy
antiretroviral
cotrimoxazole
data safety and monitoring board
human immunodeficiency virus type 1
incidence rate ratio
intention-to-treat
per-protocol
Patient Support Center
randomized controlled trial
serious adverse event
World Health Organization