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 = 0.42) (Table 3). There were no significant differences in the 12-week follow-up log10 plasma HIV-1 RNA levels between the treatment groups when stratified by the other infecting helminth species (Fig. 2). There was a trend for decrease in plasma HIV-1 RNA among individuals with A. lumbricoides co-infection who were treated with albendazole (−0.54 log10 plasma HIV-1 RNA; 95% CI, −1.17 to 0.09 log10 copies/ml) (P = 0.09) (Table 3).
Stool was provided for repeat analysis by 88 participants in the albendazole arm (81.5%) and by 80 participants in the placebo arm (80%) at the 12-week follow-up visit (P = 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 = 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 albendazole 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 infection at the follow-up visit.
There were no adverse events reported during the course of this study.
The present study is the first randomized placebo-controlled study to determine effects of eradication of soil-transmitted helminths on markers of HIV-1 progression. It provides compelling evidence to suggest significant CD4 benefit of albendazole in A. lumbricoides-co-infected individuals. Previous observational studies on soil-transmitted helminth infection and HIV-1 have yielded inconsistent results and were limited in ability to control for confounding effects because of their observational design [12–16]. This study yields several important findings. First, a 3-day course of albendazole resulted in significantly higher CD4 cell counts in A. lumbricoides-infected individuals when compared with placebo. The direction of effect on plasma HIV-1 RNA levels in the A. lumbricoides-infected individuals was consistent with the CD4 findings. Benefits of albendazole were seen despite overall light intensities of helminth infection and despite the detection of helminths in some albendazole recipients following treatment, suggesting persistence or re-infection.
Our data provide evidence to support previous models suggesting that immune modulation due to helminth infection may affect HIV-1 progression, including effects on both CD4 cell counts and plasma HIV-1 RNA viral load in co-infected individuals [17,18]. Helminth infection leads to significant immune activation, which results in increased HIV-1 replication in both blood and lymphoid tissue and is a key correlate of HIV-1 disease progression [2,17,19–26]. In addition, chronic helminth infection is characterized by a dominant Th2 immune profile with subsequent reductions in HIV-1-specific cellular immune responses, which may decrease immune control of HIV-1 replication [17,27–30]. A. lumbricoides is significantly larger than other intestinal helminths and induces a more highly skewed Th2 response than do other helminth species [31–35]. In this clinical trial, treatment of A. lumbricoides co-infection resulted in significantly higher CD4 cell counts than placebo after 12 weeks of follow-up, perhaps suggesting that decreased cytotoxic T lymphocyte (CTL) responses due to helminth infection may contribute to the observed effect of A. lumbricoides treatment on CD4 cell count. The differences in effect between helminth species observed in this study are consistent with previous reports of species-specific differences in observational HIV-1-infected helminth-infected cohorts, specifically with treatment of A. lumbricoides and Mansonella species [12,14,16]. Further evaluations of the effects of individual species of helminths on markers of immune activation and HIV-1-specific immune responses are needed to clarify the mechanisms underlying this observation.
The principal strengths of this study were its randomized, double-blind, placebo-controlled design and the inclusion of multiple, geographically diverse sites in Kenya. The study used robust biologic markers of HIV-1 progression (CD4 cell counts and plasma HIV-1 RNA). Despite these strengths, there were several potential limitations of this study. Most individuals enrolled in this study (>96%) had low burdens of helminth infection based on WHO criteria. Intensity of helminth infection has been correlated with HIV-1 viral load . Thus, it is possible that the low intensity of helminth infections resulted in less likelihood of detecting benefit from helminth eradication. The study was also limited by a relatively short duration of follow-up (3 months). However, deferring treatment of helminth-infected individuals for a longer time period may not be acceptable to participants.
Although the low worm burden in the cohort may have decreased the likelihood of detecting a treatment effect, the intensity of helminth infection in this cohort reflects the population dispersion of helminth infection among adults in Africa. In contrast to children, adults are typically infected with low worm burdens with most helminth species other than hookworm . Demonstrating an effect in this low-intensity population suggests a more generalizable effect than a trial restricted to individuals with high worm burden. Low worm burden in the cohort is further evidenced by our observation that only 40% of individuals receiving placebo in this cohort had detectable helminth ova at follow-up, despite all of these individuals having detectable helminths at enrollment. This underscores the limitations of stool screening, which has low sensitivity for detection of low burdens of helminth infection . It is therefore likely that our initial screening failed to detect individuals with low helminth burden who may have benefited from treatment. In addition, some of the individuals included in the study with hookworm or T. trichiura may have also harbored undetected A. lumbricoides infection. Empiric deworming of all HIV-1-infected individuals residing in helminth-endemic regions without stool screening is therefore an alternative strategy that deserves further study.
Other bacterial, viral and parasitic co-infections may have unique effects on host–immune and immune–HIV interactions and interventions to treat or prevent these infections may alter HIV-1 progression by different mechanisms. As evidence for the benefits of treating these various co-infections emerges, the role of combined interventions should also be assessed.
We would like to thank all of the participants and the clinics and organizations caring for persons living with HIV/AIDS who participated in this study; the staff of the University of Washington/KEMRI/FHCRC; Ben Piper, Dr Frederick Kirui, Jonathan Chebotibin, Beryl Obura, Loice Wangari Mbogo, Andele Nyambura, Benendine Bukachi, Josephine Gichuhi; Sandy Emery, Alun Davies, Professor Zvi Bentwich, Dr Cameron Page, Dr Monique Wasunna, Dr Kevin Marsh, Dr Jack Nyamongo, Dr Ernest Makhoha; Glaxo-Smith-Kline who provided all study medication and placebo; Alpha-Tec, USA who provided all stool collection containers. This paper was published with permission of the Director of the Kenya Medical Research Institute (KEMRI).
This research was supported by the Royalty Research Fund at the University of Washington and the US National Institutes of Health (NIH) research grant, CFAR SUPP OAR FWA00006878. All active drug (albendazole) and placebo were provided at no cost by Glaxo-Smith-Kline. All stool collection containers were provided by Alpha-Tec, USA.
Judd L. Walson: lead investigator, involved in development of the proposal, implementation of the study, data collection and preparation of the manuscript. Phelgona Apondi Otieno: co-principal investigator, involved in development of the proposal, submission for local ethical clearance, recruitment of study staff, data collection and review of the manuscript. Margaret Mbuchi: participated in the design of the study, implementation and participant recruitment and collection of data. Barbra Richardson: participated in study design, analysis of data, and interpretation of results. Barbara Lohman-Payne: participated in study design as well as the collection and interpretation of data. Steve Wanyee Macharia: participated in study design as well as the collection and management of data. Julie Overbaugh: participated in the implementation of the study and the data analysis, contributed to the interpretation of results. James Berkley: participated in study design and implementation, contributed to the data analysis and preparation of the final manuscript. Eduard Sanders: involved in the implementation of the study at a site and in review of the manuscript. Michael Chung: involved in the implementation of the study at a site and in review of the manuscript. Grace John-Stewart: participated in study design, obtaining funding, and provided input on analyses and writing the manuscript.
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