Albendazole treatment of HIV-1 and helminth co-infection: a randomized, double-blind, Steve Wanyee , Julie OverbaughJames Berkley, Objective: Several co-infections have been shown to impact the progression of HIV-1infection. We sought to determine if treatment of helminth co-infection in HIV-1-infected adults impacted markers of HIV-1 disease progression.
Design: To date, there have been no randomized trials to examine the effects of soil-transmitted helminth eradication on markers of HIV-1 progression.
Methods: A randomized, double-blind, placebo-controlled trial of albendazole(400 mg daily for 3 days) in antiretroviral-naive HIV-1-infected adults (CD4 cell count>200 cells/ml) with soil-transmitted helminth infection was conducted at 10 sites inKenya (Clinical NCT00130910). CD4 and plasma HIV-1 RNA levels at 12weeks following randomization were compared in the trial arms using linear regression,adjusting for baseline values.
Results: Of 1551 HIV-1-infected individuals screened for helminth infection, 299 werehelminth infected. Two hundred and thirty-four adults were enrolled and underwentrandomization and 208 individuals were included in intent-to-treat analyses. MeanCD4 cell count was 557 cells/ml and mean plasma viral load was 4.75 log10 copies/ml atenrollment. Albendazole therapy resulted in significantly higher CD4 cell countsamong individuals with Ascaris lumbricoides infection after 12 weeks of follow-up(þ109 cells/ml; 95% confidence interval þ38.9 to þ179.0, P ¼ 0.003) and a trend for0.54 log10 lower HIV-1 RNA levels (P ¼ 0.09). These effects were not seen withtreatment of other species of soil-transmitted helminths.
Conclusion: Treatment of A. lumbricoides with albendazole in HIV-1-coinfected adultsresulted in significantly increased CD4 cell counts during 3-month follow-up. Given thehigh prevalence of A. lumbricoides infection worldwide, deworming may be animportant potential strategy to delay HIV-1 progression.
ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins Keywords: co-infection, helminth, HIV-1 progression aCentre for Clinical Research, bCentre for Geographic Medicine Research Coast, Kenya Medical Research Institute, cDepartmentof Pediatrics, University of Nairobi, Nairobi, Kenya, dDepartment of Medicine, eDepartment of Biostatistics, fDepartment ofEpidemiology, University of Washington, gHuman Biology Division, Fred Hutchinson Cancer Research Center, Seattle,Washington, USA, and hCentre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Headington, UK.
Correspondence to Dr Judd L. Walson, 325 Ninth Ave, Box 359909, Seattle, WA 98104, USA.
Tel: +1 206 543 4278; fax: +1 206 543 4818; e-mail: Received: 29 December 2007; revised: 10 February 2008; accepted: 7 April 2008.
ISSN 0269-9370 Q 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
ParticipantsStudy participants were recruited from existing HIV-1 The majority of HIV-1-infected individuals in settings Care and Treatment programs at 10 sites geographically with high HIV-1 seroprevalence do not yet meet criteria dispersed throughout Kenya using a mobile study team.
for initiation of antiretroviral therapy (ART). Interven- Study sites were the Kibera AMREF/CDC Clinic, Homa tions to delay HIV-1 progression are needed to maximize Bay District Hospital, Kerugoya District Hospital, Coptic the health of these individuals and delay the time until Hope Clinic (Nairobi), Mbagathi District Hospital, initiation of antiretroviral treatment. There is evidence Thika District Hospital, Kisumu District Hospital, Kisii from observational studies that treatment of some co- District Hospital, Machakos District Hospital and the infections may delay HIV-1 disease progression.
Kilifi District Hospital. Participants were eligible forscreening if they were HIV-1 seropositive, at least 18 years Soil-transmitted helminths are among the most prevalent of age, not pregnant and were not eligible for initiation of infections of humans worldwide. More than 2 billion ART based on World Health Organization (WHO) people are estimated to be infected with soil-transmitted guidelines (CD4 cell count <200 cells/ml, any stage 4 and helminths and the geographical distribution of these some stage 3 disease) Exclusion criteria also included infections overlaps considerably with regions of high having ever used antiretroviral drugs, having taken HIV-1 seroprevalence Helminth co-infection has medicine for helminth infection in the preceding been hypothesized to be one factor driving the HIV-1 6 months, evidence of active tuberculosis (TB) treatment epidemic in Africa A randomized clinical trial of in the past 3 months and clinical signs of severe anemia.
schistosomiasis treatment in 130 HIV-1-infected indi-viduals found that treatment was associated with significantly lower rise in plasma HIV-1 RNA Potentially eligible study participants were identified at Although suggestive of potential associations between each site by clinic staff and referred for helminth helminth infection and HIV-1 progression, the patho- screening. At screening visits, each participant was genesis of schistosomiasis, and consequently its inter- informed of the aims and procedures of the study and actions with HIV-1, may differ from other helminths.
assessed for eligibility. Female participants were asked to Several observational studies have yielded conflicting provide a fresh urine sample for b-human chorionic data regarding the association between soil-transmitted gonadotropin (HCG) testing. Men and b-HCG- helminth treatment and HIV-1 progression To date, negative women were asked to provide stool for no randomized clinical trials have been conducted to analysis. Baseline demographic and medical history determine the effect of treatment of soil-transmitted was obtained from participants at the time of screening.
Participants were provided with stool collectioncontainers and instructions on specimen collection, If helminth eradication can delay HIV-1 progression, it is and requested to collect stool within 6 h of the screening a simple intervention that could be widely and rapidly visit. Individuals with evidence of albendazole-treatable implemented, with significant public health impact.
pathogenic soil-transmitted helminths on microscopy We conducted a randomized, double-blind, placebo- were invited to be enrolled in the trial. Individuals with controlled trial to determine whether albendazole schistosomiasis or infection with Taenia species were treatment in HIV-1 and helminth coinfected individuals treated with open-label praziquantel (and albendazole if impacts markers of HIV-1 disease progression, specifically co-infected with other helminths) and were not CD4 cell count and plasma HIV-1 RNA.
enrolled. Individuals with no evidence of helminthinfection were counseled on basic hygiene andavoidance of helminth exposure and were not enrolledin the randomized trial.
Individuals with documented soil-transmitted helminth infections treatable with albendazole (Ascaris lumbricoides, Antiretroviral-naive HIV-1 seropositive adults with evi- hookworm species, or Trichuris trichiura) were invited to dence of co-infection with albendazole-treatable soil- attend an additional informed consent session in which transmitted helminths were eligible for enrollment.
the aims and the procedures of the trial were reviewed.
Eligible individuals were randomized to receive either Individuals were enrolled in the trial after written 400 mg albendazole or placebo once daily for 3 consecutive days and were followed up after 12 weeks. The study was performed baseline clinical examinations and collected approved by the Kenya Medical Research Institute Ethical additional clinical and demographic information on all Review Board and the University of Washington participants at enrollment. Blood was collected for repeat Institutional Review Board. All participants provided HIV-1 serologic testing, measurement of CD4 lympho- written informed consent. The study was registered under cytes and plasma HIV-1 RNA levels. Participants were Clinical Trials Registration identifier: NCT00130910.
randomly assigned to two groups using a 1 : 1 allocation Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
HIV-1 and helminth co-infection Walson et al.
scheme with block randomization of 30 patients and plasma HIV-1 RNA levels in the two arms stratified by following a random allocation list generated indepen- dently. Prelabeled, sequentially numbered treatmentpacks were used. Both the active drug (albendazole) and an identical appearing placebo were provided by the Based on an estimated difference in CD4 cell count of drug manufacturer. Investigators, clinic staff and patients 40 cells/ml between the groups and using data from a were blinded to study-group assignment. The first dose of previously accrued observational HIV-1 cohort in study medication was taken at enrollment and was directly Kenya, we determined that 200 individuals were observed. The remaining doses were dispensed to the required to detect a difference of 40 cells/ml between patient. Enrolled participants were scheduled to return the two study arms using a two-sided test, with an for follow-up at a single visit 12 weeks after random- estimated standard deviation of 100 cells/ml, a power of ization. Participants were given two stool collection vials 80% and a 5% type I error, allowing for 15% loss to (plain and preservative) and asked to return for the follow-up This sample size also gave 90% power to follow-up visit with a stool sample collected into both detect a difference of 0.5 log10 copies/ml of plasma HIV- vials within 6 h of the appointment.
1 RNA between the groups using a two-sided test,assuming a standard deviation of 1.1 log10 copies/ml, and At the 12-week follow-up visit, all female participants were asked to provide an additional fresh urine sample for b-HCG testing and blood was collected for CD4 lympho- Analyses were conducted with SPSS version 15 (Chicago, cytes and plasma HIV-1 RNA levels. Participants with Illinois, USA). Following a data analysis plan developed evidence of helminth infection at the 12-week visit were prior to unblinding, a modified intent-to-treat analysis treated with either open-label albendazole or praziquantel was conducted. Individuals who were found to be HIV-1 or both as indicated regardless of randomization arm.
seronegative on repeat testing or who had initial CD4 cell Participants who did not provide stool for analysis at the 12- counts of <200 cells/ml but whose CD4 cell count results week visit were presumptively treated with albendazole were unavailable at randomization were excluded from 400 mg/day for 3 days. Women who were pregnant at the analysis. Viral loads were log10 transformed before follow-up visit and who were either positive for helminths analysis. Baseline characteristics of the participants were by stool analysis or who did not provide stool for analysis compared between the two arms using chi-square tests for were referred to the antenatal care clinic at the site where categorical variables and Student’s t-tests for normally Primary analyses were conducted to evaluate the effect oftreatment on the follow-up CD4 cell count and log All randomized participants underwent repeat HIV-1 plasma HIV-1 RNA levels. Linear regression (analysis of serological testing for HIV-1 using Determine rapid test covariance, ANCOVA) was performed adjusting for qualitative immunoassay (Abbott, Japan). The CD4 initial CD4 cell count for the CD4 cell count outcome, lymphocyte count was determined using Multiset soft- ware on a FACSCalibur machine (Becton Dickinson, RNA outcome Intent-to-treat analyses were repeated after stratifying by infecting helminth species.
All individuals with a given helminth species (whether Plasma HIV-1 RNA was quantified using the Gen-Probe single or multiple species) were included in each stratified HIV-1 viral load assay, which has been shown to quantify analysis and a separate analysis was conducted on those the subtypes of HIV-1 prevalent in Kenya individuals with multiple species of helminth co-infection. Analysis of variance was conducted to Each participant provided stool samples in a plain determine the effect of interaction between each species collection vial (AlphaTec, California, USA) and a vial of helminth on CD4 cell count outcomes.
containing preservative (ProtofixCLR, AlphaTec). Eachstool sample was processed and evaluated using wetpreparation, Kato-Katz and formol-ether concentrationtechniques by an experienced laboratory technician. Thepresence of protozoa or helminth eggs was recorded and the burden of infection based on number of eggs per gram of stool was calculated according to WHO criteria Between March 2006 and June 2007, we screened 1551individuals for helminth co-infection. Of these individ- uals, a total of 299 (19.3%) were infected with at least one The primary study outcomes were CD4 cell counts and species of helminth. A total of 29 individuals (1.9%) had log10 plasma HIV-1 RNA levels in the two study arms.
documented schistosomiasis infection, of which eight Secondary outcomes included CD4 cell counts and log10 (27.6%) were also infected with other soil-transmitted Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
29 with Schistosomiasis 17 found to have CD4 count <250 cells/mm311 did not return to be enrolled 3 with clinical tuberculosis 2 took helminth medication within 6 months 1 with signs/symptoms of anemia 1 pregnant female 1 declined to participate Fig. 1. Flow chart of study enrollment.
helminths. These individuals were not eligible for counts or plasma HIV-1 RNA levels between the study inclusion in the study, were provided open-label arms in the intent-to-treat population or when stratified treatment, and were not enrolled. Two hundred and thirty-five individuals were eligible to participate in thestudy and 208 individuals were included in the final intent-to-treat analysis; 108 randomized to treatment and Of the 208 individuals included in the analysis, 148 100 to placebo The mean age of the participants (71.2%) were infected with hookworm species, 54 was 34 years (range, 18–65 years) and 83.1% were female.
(26.0%) with A. lumbricoides and 24 (11.5%) were There were no significant differences at enrollment infected with T. trichiura. Nineteen individuals (9.1%) between the randomization arms with regard to were infected with more than one soil-transmitted helminth species. Almost all infections (96.2%) were enrollment, the mean CD4 cell count was 557 cells/ml classified as ‘light’ burdens based on WHO guidelines .
(SD, 273 cells/ml) and the mean plasma HIV-1 RNA level Two individuals with hookworm infection (1.4%) had was 4.75 log10 copies/ml (SD, 1.0 log10 copies/ml). There moderate and two (1.4%) had heavy burdens of infection.
were no significant differences between baseline CD4 cell There were three moderate A. lumbricoides infections Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
HIV-1 and helminth co-infection Walson et al.
Table 1. Characteristics of the study participants at baseline.
burden of infection were infected with more than onehelminth species.
Treatment with albendazole was associated with a trend for higher CD4 cell counts at the 12-week follow-up visit when compared with placebo [þ37 cells/ml, 95% confidence interval (CI), À4.6 to þ78.7 cells/ml] (P ¼ 0.08) There was a highly significant effect of treatment among individuals with A. lumbricoides co- infection: individuals with ascariasis who received albendazole had a mean CD4 cell count at follow-up that was 109 cells/ml higher than those who received placebo (95% CI, þ38.9 to þ179.0 cells/ml) (P ¼ 0.003, There were no significant differences between the treatment arms in follow-up CD4 cell count among those infected with hookworm, T. trichiura, or those with mixed infection. Albendazole treatment was significantly more beneficial among individuals with A. lumbricoides co-infection than among those with other helminth Among the 208 individuals included in the intent-to- treat analysis, there were no significant differences in log10 plasma HIV-1 RNA levels between the treatment groups (P ¼ 0.42) There were no significant differences in the 12-week follow-up log10 plasma HIV-1 RNA aN ¼ 105 (albendazole), 100 (placebo).
levels between the treatment groups when stratified by bN ¼ 104 (albendazole), 97 (placebo).
the other infecting helminth species There was a N ¼ 105 (albendazole), 98 (placebo).
trend for decrease in plasma HIV-1 RNA among (5.6%) and one moderate T. trichiura infection (4.2%). No individuals with A. lumbricoides co-infection who were individuals with A. lumbricoides or T. trichiura infection treated with albendazole (À0.54 log10 plasma HIV-1 had heavy infections. All of the six individuals with RNA; 95% CI, À1.17 to 0.09 log10 copies/ml) (P ¼ 0.09) moderate burden and both individuals with heavy Table 2. Baseline laboratory values [mean (SD)] by arm.
Stool was provided for repeat analysis by 88 participants in the albendazole arm (81.5%) and by 80 participants in theplacebo arm (80%) at the 12-week follow-up visit (P ¼ 0.79). Individuals in the placebo arm were significantly more likely to have evidence of helminth infection at the 12-week follow-up visit than those in the albendazole arm (40.0 versus 21.6%, P ¼ 0.01). Of eight individuals with moderate or heavy burdens of infection at baseline and who provided stool for analysis at the follow-up visit, three had been randomized to albenda- zole and five had been randomized to placebo. None of the three individuals in the albendazole group had evidence of infection at the 12-week visit, whereas two of those in the placebo group had detectable helminth an ¼ 108 (albendazole), 100 (placebo).
bn ¼ 26 (albendazole), 28 (placebo).
n ¼ 76 (albendazole), 72 (placebo).
There were no adverse events reported during the course n ¼ 12 (albendazole), 12 (placebo).
en ¼ 7 (albendazole), 12 (placebo).
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Table 3. Difference in CD4 cell counts and HIV-1 RNA levels in treatment arm vs. placebo arm.
load in co-infected individuals Helminthinfection leads to significant immune activation, which The present study is the first randomized placebo- results in increased HIV-1 replication in both blood and controlled study to determine effects of eradication of lymphoid tissue and is a key correlate of HIV-1 disease soil-transmitted helminths on markers of HIV-1 pro- progression In addition, chronic helminth gression. It provides compelling evidence to suggest infection is characterized by a dominant Th2 immune significant CD4 benefit of albendazole in A. lumbricoides- profile with subsequent reductions in HIV-1-specific co-infected individuals. Previous observational studies on cellular immune responses, which may decrease immune soil-transmitted helminth infection and HIV-1 have control of HIV-1 replication A. lumbricoides is yielded inconsistent results and were limited in ability to significantly larger than other intestinal helminths and control for confounding effects because of their induces a more highly skewed Th2 response than do other observational design This study yields several helminth species In this clinical trial, treatment important findings. First, a 3-day course of albendazole of A. lumbricoides co-infection resulted in significantly resulted in significantly higher CD4 cell counts in A.
higher CD4 cell counts than placebo after 12 weeks of lumbricoides-infected individuals when compared with follow-up, perhaps suggesting that decreased cytotoxic T placebo. The direction of effect on plasma HIV-1 RNA lymphocyte (CTL) responses due to helminth infection levels in the A. lumbricoides-infected individuals was may contribute to the observed effect of A. lumbricoides consistent with the CD4 findings. Benefits of albendazole treatment on CD4 cell count. The differences in effect were seen despite overall light intensities of helminth between helminth species observed in this study are infection and despite the detection of helminths in some consistent with previous reports of species-specific albendazole recipients following treatment, suggesting differences in observational HIV-1-infected helminth- infected cohorts, specifically with treatment of A.
lumbricoides and Mansonella species Further Our data provide evidence to support previous models evaluations of the effects of individual species of suggesting that immune modulation due to helminth helminths on markers of immune activation and HIV- infection may affect HIV-1 progression, including effects 1-specific immune responses are needed to clarify the on both CD4 cell counts and plasma HIV-1 RNA viral mechanisms underlying this observation.
Fig. 2. Differences in 12-week follow-up CD4 cell counts and viral load.
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HIV-1 and helminth co-infection Walson et al.
The principal strengths of this study were its randomized, RNA suggests that a reduction in viral load of this magnitude would delay progression to AIDS by 3.5 years inclusion of multiple, geographically diverse sites in and slow the need for antiretroviral medications by almost Kenya. The study used robust biologic markers of HIV-1 a full year Current estimates suggest that as many progression (CD4 cell counts and plasma HIV-1 RNA).
as 1.5 billion people are infected with A. lumbricoides, Despite these strengths, there were several potential predominantly in areas of the world with substantial limitations of this study. Most individuals enrolled in this burdens of HIV-1 infection The public health and study (>96%) had low burdens of helminth infection economic implications of such benefits are potentially based on WHO criteria. Intensity of helminth infection enormous and warrant further investigation.
has been correlated with HIV-1 viral load Thus, it ispossible that the low intensity of helminth infections Other bacterial, viral and parasitic co-infections may have resulted in less likelihood of detecting benefit from unique effects on host–immune and immune–HIV helminth eradication. The study was also limited by a interactions and interventions to treat or prevent these relatively short duration of follow-up (3 months).
infections may alter HIV-1 progression by different However, deferring treatment of helminth-infected mechanisms. As evidence for the benefits of treating these individuals for a longer time period may not be acceptable various co-infections emerges, the role of combined interventions should also be assessed.
Although the low worm burden in the cohort may have We have shown that treatment of A. lumbricoides is decreased the likelihood of detecting a treatment effect, associated with significant improvements in CD4 cell the intensity of helminth infection in this cohort reflects counts and may potentially reduce plasma HIV-1 RNA the population dispersion of helminth infection among viral load. Further clinical trials are needed to evaluate the adults in Africa. In contrast to children, adults are typically long-term durability of the response to deworming in infected with low worm burdens with most helminth HIV-1-coinfected individuals and to assess whether species other than hookworm Demonstrating an empiric therapy of all HIV-1-infected individuals in effect in this low-intensity population suggests a more helminth-endemic areas is warranted.
generalizable effect than a trial restricted to individualswith high worm burden. Low worm burden in thecohort is further evidenced by our observation that only 40% of individuals receiving placebo in this cohort haddetectable helminth ova at follow-up, despite all of these We would like to thank all of the participants and the individuals having detectable helminths at enrollment.
clinics and organizations caring for persons living with This underscores the limitations of stool screening, which HIV/AIDS who participated in this study; the staff of the has low sensitivity for detection of low burdens of University of Washington/KEMRI/FHCRC; Ben Piper, helminth infection It is therefore likely that our Dr Frederick Kirui, Jonathan Chebotibin, Beryl Obura, initial screening failed to detect individuals with low Loice Wangari Mbogo, Andele Nyambura, Benendine helminth burden who may have benefited from treat- Bukachi, Josephine Gichuhi; Sandy Emery, Alun Davies, ment. In addition, some of the individuals included in the Professor Zvi Bentwich, Dr Cameron Page, Dr Monique study with hookworm or T. trichiura may have also Wasunna, Dr Kevin Marsh, Dr Jack Nyamongo, Dr harbored undetected A. lumbricoides infection. Empiric Ernest Makhoha; Glaxo-Smith-Kline who provided all deworming of all HIV-1-infected individuals residing in study medication and placebo; Alpha-Tec, USA who helminth-endemic regions without stool screening is provided all stool collection containers. This paper was therefore an alternative strategy that deserves further published with permission of the Director of the Kenya Our data suggest that treatment of helminth co-infection This research was supported by the Royalty Research may be a practical and cost-effective intervention to delay Fund at the University of Washington and the US disease progression in HIV-1-infected individuals in National Institutes of Health (NIH) research grant, resource-limited settings. Studies conducted in Africa CFAR SUPP OAR FWA00006878. All active drug have estimated the average rate of CD4 decline between (albendazole) and placebo were provided at no cost by 20 and 30 cells/ml per year An increase in CD4 Glaxo-Smith-Kline. All stool collection containers were cell count as seen with treatment of A. lumbricoides in this study could potentially prolong the time to severeimmunosuppression and need for antiretroviral medi- Judd L. Walson: lead investigator, involved in develop- cation by several years. A trend toward a 0.54 ment of the proposal, implementation of the study, data log10 copies/ml reduction in plasma HIV-1 RNA was collection and preparation of the manuscript. Phelgona seen with treatment of A. lumbricoides in this study.
Apondi Otieno: co-principal investigator, involved in Modeling of the effect of a vaccine that reduced HIV-1 development of the proposal, submission for local ethical Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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