Which helminth coinfections really affect HIV disease progression?
Institute for Global Health and the Department of Medicine, Division of Infectious Diseases, Vanderbilt University, Nashville, Tennessee, USA.
Received 8 September, 2008
Accepted 24 October, 2008
Correspondence to Kayvon Modjarrad, MD, PhD, Vanderbilt University, Institute for Global Health, 2525 West End Avenue, Suite 750, Nashville, TN 37203-1738, USA. E-mail: firstname.lastname@example.org
The study by Walson et al.  published in the recent issue of AIDS describes the results of the first randomized, placebo-controlled trial to evaluate the impact of soil-transmitted helminth infection on CD4+ cell count and viral load among HIV-1, geohelminth coinfected adults. Walson et al.  found that the elimination of Ascaris infection is associated with a mean 109 cell/μl rise in CD4+ cell count (P = 0.003) and a 0.54 log10 reduction in viral load (P = 0.09). Although these results lend support to the hypothesis that helminthes may have a direct impact on markers of HIV disease progression, the study is worth evaluating further methodologically as the interpretation of its results may have far-reaching implications for public health policy and practice.
The study by Walson et al.  contains multiple ambiguities, beginning with its analytic plan. It is unclear whether the authors compared the time-dependent trends in CD4+ cell counts and viral load between the two study arms or whether they evaluated cross-sectional differences in serial fashion. The difference between these two methods is significant as a 0.54 log10 viral load decline in the experimental arm is much less impressive if there were a concurrent drop in viral load of similar magnitude in the control arm. It would be helpful to have presented the mean CD4+ cell count and viral load for each helminth species, before and after treatment, in both arms. It is also unclear whether the authors accounted for the inherent variability of HIV-1 RNA measures. This is important when dealing with small viral load changes (<1.0 log10), as viral setpoint differences in the order of 0.3 log10 occur via natural variation [2–4]. These inherent fluctuations can affect statistical power calculations and potentially cause a regression-to-the-mean effect if not controlled for in the study's design or analysis.
It is not only the variability of viral load measures that could have affected the results, but also the absolute values. At a level of 4.75 log10, the mean baseline viral load of this study population is higher than other studies [5–8]. A subgroup analysis from our own cohort demonstrated that helminth elimination was associated with a greater viral load decline among individuals with a baseline viral load higher than 5.0 log10 . Walson et al.  report that mean baseline viral load of the Ascaris-infected participants was 0.21 log10 higher among experimental participants compared with the controls. For all other helminth species, viral loads were higher in controls compared with the experimental arm. Thus, it may be that the viral load decline was actually attributable to higher baseline HIV RNA levels and not to the particular helminth species.
In support of their findings, Walson et al.  cite previous studies that purportedly reported species-specific effects of helminth infection on HIV viral load and CD4+ cell count. However, in our study among Zambian adults , we reported that individuals with moderate to high intensity infections experienced a nonsignificant trend of 0.12 log10 viral load reduction after intestinal helminth clearance. These moderate-to-high intensity infections just happened to occur among individuals infected with Ascaris and hookworm. When we assessed the impact of each species on viral load (controlling for infection intensity), we found no species-specific differences.
Walson et al.  also claim that past studies were inherently limited because they were not randomized. The assertion is oversimplistic, as the validity of their results is diminished by the post-hoc nature of their stratified analysis. Findings that do not reflect an a priori hypothesis are prone to spuriousness. Multiple comparisons that are not planned from study outset inevitably yield a significant association, merely by chance alone. Such post-hoc analyses, therefore, can only generate and not test hypotheses . Walson et al.'s  a posteriori analysis, therefore, raises questions as to why HIV was impacted by infection with Ascaris, but not by hookworm or Trichuris.
The authors postulate that Ascaris may have a greater impact on HIV pathogenesis because it is the largest geohelminth and, therefore, may stimulate host immunity more than other species. There are problems with this argument. First, there is no evidence that Ascaris activates host immunity more than other intestinal helminthes. Second, it is not the larger size of the organism but the greater intensity, invasiveness, and immunogenicity of the infection that likely would cause a more robust activation of host immunity . It is possible that Ascaris could influence HIV immunology more than other helminthes not because of its size or infectious load, but because it may more intimately interact with gut-associated lymphoid tissue implicated as integral to mechanisms of HIV immunopathogenesis . However, this might apply to other geohelminthes as well.
Ultimately, the results of the current study suggest that the story of HIV–helminth interactions is far from over. Additional, well designed studies must be conducted to more definitively address the issues raised, focusing not just on helminth infections as a whole, but species-specific effects as well.
1. Walson JL, Otieno PA, Mbuchi M, Richardson BA, Lohman-Payne B, Macharia SW, et al
. Albendazole treatment of HIV-1 and helminth co-infection: a randomized, double-blind, placebo-controlled trial. AIDS 2008; 22:1601–1609.
2. Yamashita TE, Modjarrad K, Munoz A. Variability of HIV-1 RNA before AIDS and highly active antiretroviral therapy. AIDS 2003; 17:1264–1266.
3. Brambilla D, Reichelderfer PS, Bremer JW, Shapiro DE, Hershow RC, Katzenstein DA, et al
. The contribution of assay variation and biological variation to the total variability of plasma HIV-1 RNA measurements. The Women Infant Transmission Study Clinics. Virology Quality Assurance Program. AIDS 1999; 13:2269–2279.
4. Bartlett JA, DeMasi R, Dawson D, Hill A. Variability in repeated consecutive measurements of plasma human immunodeficiency virus RNA in persons receiving stable nucleoside reverse transcriptase inhibitor therapy or no treatment. J Infect Dis 1998; 178:1803–1805.
5. Brown M, Kizza M, Watera C, Quigley M, Rowland S, Hughes P, et al
. Helminth infection is not associated with faster progression of HIV disease in coinfected adults in Uganda. J Infect Dis 2004; 190:1869–1879.
6. Modjarrad K, Zulu I, Redden DT, Njobvu L, Lane CH, Bentwich Z, et al
. Treatment of intestinal helminths does not reduce plasma concentrations of HIV-1 RNA in coinfected Zambian adults. J Infect Dis 2005; 192:1277–1283.
7. Kallestrup P, Zinyama R, Gomo E, Butterworth A, Mudenge B, van Dam GJ, et al
. Schistosomiasis and HIV-1 infection in rural Zimbabwe: effect of treatment of schistosomiasis on CD4 cell count and plasma HIV-1 RNA load. J Infect Dis 2005; 192:1956–1961.
8. Elliott AM, Mawa PA, Joseph S, Namujju PB, Kizza M, Nakiyingi JS, et al
. Associations between helminth infection and CD4+
T cell count, viral load and cytokine responses in HIV-1-infected Ugandan adults. Trans R Soc Trop Med Hyg 2003; 97:103–108.
9. Hochberg Y, Benjamini Y. More powerful procedures for multiple significance testing. Stat Med 1990; 9:811–818.
10. Turner JD, Jackson JA, Faulkner H, Behnke J, Else KJ, Kamgno J, et al
. Intensity of intestinal infection with multiple worm species is related to regulatory cytokine output and immune hyporesponsiveness. J Infect Dis 2008; 197:1204–1212.
11. Centilivre M, Sala M, Wain-Hobson S, Berkhout B. In HIV-1 pathogenesis the die is cast during primary infection. AIDS 2007; 21:1–11.
This article has been cited 2 time(s).
HistopathologyDisseminated infection caused by Sparganum proliferum in an AIDS patientHistopathology
AIDS Research and TherapySeroprevalence of Schistosomiasis and Strongyloides infection in HIV-infected patients from endemic areas attending a European infectious diseases clinicAIDS Research and Therapy
© 2009 Lippincott Williams & Wilkins, Inc.