This 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
]. This study yields several important findings. First, a 3-day course of albendazole resulted in significantly higher CD4 counts in A. lumbricoides
infected individuals when compared to 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 reinfection.
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 counts and plasma HIV-1 RNA viral load in co-infected individuals[17
]. 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
]. 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
]. A. lumbricoides
is significantly larger than other intestinal helminths and induces a more highly skewed Th2 response than do other helminth species[31
]. In this clinical trial, treatment of A. lumbricoides
co-infection resulted in significantly higher CD4 counts than placebo after 12 weeks of follow up, perhaps suggesting that decreased CTL-responses due to helminth infection may contribute to the observed effect of A. lumbricoides
treatment on CD4 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
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 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[36
]. 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 enrolment. This underscores the limitations of stool screening, which has low sensitivity for detection of low burdens of helminth infection[37
]. 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.
Our data suggest that treatment of helminth co-infection may be a practical and cost-effective intervention to delay disease progression in HIV-1 infected individuals in resource-limited settings. Studies conducted in Africa have estimated the average rate of CD4 decline at between 20 and 30 cells/mm3
]. An increase in CD4 count as seen with treatment of A. lumbricoides
in this study could potentially prolong the time to severe immunosuppression and need for antiretroviral medication by several years. A trend towards a 0.54 log10
copies/mL reduction in plasma HIV-1 RNA was seen with treatment of A. lumbricoides
in this study. Modeling of the effect of a vaccine that reduced HIV-1 RNA suggests that a reduction in viral load of this magnitude would delay progression to AIDS by 3.5 years and slow the need for antiretroviral medications by almost a full year[40
]. Current estimates suggest that as many as one and a half billion people are currently infected with A. lumbricoides
, predominantly in areas of the world with substantial burdens of HIV-1 infection[41
]. The public health and economic implications of such benefits are potentially enormous and warrant further investigation.
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 have shown that treatment of A. lumbricoides is associated with significant improvements in CD4 counts and may potentially reduce plasma HIV-1 RNA viral load. Further clinical trials are needed to evaluate the long-term durability of the response to deworming in HIV-1 co-infected individuals and to assess whether empiric therapy of all HIV-1 infected individuals in helminth endemic areas is warranted.