Clinical trial NCT00817713: Can Presumptive Anthelminthic Treatment Delay the Progression of HIV in ART-naïve Patients in Rural Africa?
Official title: Can Anthelminthic Treatment Delay the Progression of HIV? Randomised Open-label Trial Testing Presumptive Anthelminthic Treatment on Progression of HIV in ART-naïve HIV-positive Patients in a Rural African Setting With Presumed High Prevalence of Helminth Infections.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: HIV Infections
Helminthiasis
Keywords: Human Immunodeficiency Virus
Helminthiasis
treatment naive
co-infection
immune modulation
Lead sponsor: Swiss Tropical & Public Health Institute
Sponsor class: OTHER
Collaborators: name: Ifakara Health Research and Development Centre
name: Insel Gruppe AG, University Hospital Bern
name: Merck KGaA, Darmstadt, Germany
First posted: 2009-01-06
Enrollment: 295
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study focuses on one of the major health issues of Sub-Saharan Africa: multi-parasitism and co-infections. In particular this study aims to elucidate the interaction of helminths with HIV.

There is good reason to suspect a detrimental effect of helminth infection on the course of HIV infection. We hypothesize, that treatment of helminths in HIV- and helminth co-infected individuals leads to a reduction of HIV viral load. With a lower HIV RNA level one would expect a slower decline of CD4 cells and hence also a slower progression of the disease. Ideally this would lead to a prolongation of the chronic phase of HIV infection and to a delay in the time when anti-retroviral treatment needs to be started.

Detailed description: \* Background: On the basis of immunological considerations and in vitro trials on co-infections there is strong reason to suspect a detrimental effect of helminth infection on the course of HIV. The immunological answer very efficiently evoked by helminth infection is aimed at hijacking and suppressing the immune system in order to suit the requirements of the specific helminth. This permits helminths to cause chronic infection, often persisting over years and allowing some infecting worms to grow to several centimetres of length within their host. However, this immune modulation also affects non-related antigens (for example HIV) which would actually require a different line of immunological action.

Some clinical trials have been able to confirm this detrimental effect of helminths on HIV infection, while other trials failed to do so. A recent Cochrane review on clinical trials with HIV and helminth co-infection found an overall slight reduction of HIV viral load if helminth infection was treated. However there was no measurable effect on CD4 count or clinical staging of HIV. This might be explained by the fact that these trials were very heterogeneous in their set-up and were run for too short a time (max 6 months) to allow sufficient answers to these questions.

According to mathematical models, even a relatively modest reduction of HIV RNA by 0.5 log could delay the need to start combined antiretroviral therapy by about 3.5 years and potentially prolong the symptom-free phase of HIV-infection by nearly 1 year. On a population scale this could lead to substantial savings with regard to drug and clinical costs and on an individual level to an invaluable gain in drug-free and ideally also symptom-free life years.

* Objective: To assess the impact of presumptive anthelminthic treatment on HIV progression in patients infected with HIV in a rural setting with presumed high prevalence of helminth infection.
* Methods: Randomised open-label trial of presumptive triple anthelminthic treatment in HIV positive patients not yet requiring anti-retroviral treatment.

Eligibility criteria: Inclusion Criteria:

* HIV-positive patients
* most recent CD4-count \> 250 c/μl (latest within the previous 7 months)
* anti-retroviral treatment naïve
* age \>18 years
* provide written informed consent

Exclusion Criteria:

* Pregnant and lactating women in the first week of lactation
* Symptoms of severe anemia (or haemoglobin \<5g/dl within the precious 3 months)
* Symptoms of chronic diarrhea (defined as \>= 3 stools per day of loose consistency for more than 2 weeks)
* Patients on treatment for tuberculosis
* WHO clinical stage 3 disease and CD4-count \<350 c/μl
* WHO clinical stage 4 disease

Primary outcomes:
measure: Difference in HIV viral load between intervention and control arm
timeFrame: one year
Secondary outcomes:
measure: Difference in CD4 counts between intervention and control arm
timeFrame: one year
measure: Difference in time to meet criteria for the initiation of anti-retroviral treatment
timeFrame: one year
measure: occurrence of severe adverse events
timeFrame: one year
Other outcomes:
Locations:
city: Ifakara
country: Tanzania
facility: Chronic Disease Clinic of St. Francis Designated District Hospital
state: Kilombero
Study officials:
affiliation: Swiss Tropical Institute, Ifakara Health Institute
name: Cornelia J. Staehelin, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Swiss Tropical & Public Health Institute
name: Christoph F. Hatz, MD, Prof.
role: STUDY_DIRECTOR
affiliation: Infectious Disease Unit, Inselspital, University Hospital Berne, 3010 Berne, Switzerland
name: Hansjakob Furrer, MD, Prof.
role: STUDY_CHAIR
affiliation: Ifakara Health Institute
name: Honorathy Urassa, MSc
role: STUDY_CHAIR
affiliation: Ifakara Health Institute
name: Baraka Amuri, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ifakara Health Institute
name: Salim Hamis, MD
role: STUDY_CHAIR
affiliation: Swiss Tropical & Public Health Institute
name: Juerg Utzinger, Prof.
role: STUDY_CHAIR
affiliation: Swiss Tropical & Public Health Institute
name: Erik Mossdorf, MD
role: STUDY_CHAIR
References:
citation: Walson JL, John-Stewart G. Treatment of helminth co-infection in HIV-1 infected individuals in resource-limited settings. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD006419. doi: 10.1002/14651858.CD006419.pub2.
citation: Walson JL, Otieno PA, Mbuchi M, Richardson BA, Lohman-Payne B, Macharia SW, Overbaugh J, Berkley J, Sanders EJ, Chung MH, John-Stewart GC. Albendazole treatment of HIV-1 and helminth co-infection: a randomized, double-blind, placebo-controlled trial. AIDS. 2008 Aug 20;22(13):1601-9. doi: 10.1097/QAD.0b013e32830a502e.
citation: Gupta SB, Jacobson LP, Margolick JB, Rinaldo CR, Phair JP, Jamieson BD, Mehrotra DV, Robertson MN, Straus WL. Estimating the benefit of an HIV-1 vaccine that reduces viral load set point. J Infect Dis. 2007 Feb 15;195(4):546-50. doi: 10.1086/510909. Epub 2007 Jan 5.
citation: Mohammed KA, Haji HJ, Gabrielli AF, Mubila L, Biswas G, Chitsulo L, Bradley MH, Engels D, Savioli L, Molyneux DH. Triple co-administration of ivermectin, albendazole and praziquantel in zanzibar: a safety study. PLoS Negl Trop Dis. 2008 Jan 23;2(1):e171. doi: 10.1371/journal.pntd.0000171.
citation: Brown M, Mawa PA, Kaleebu P, Elliott AM. Helminths and HIV infection: epidemiological observations on immunological hypotheses. Parasite Immunol. 2006 Nov;28(11):613-23. doi: 10.1111/j.1365-3024.2006.00904.x.
citation: Kallestrup P, Zinyama R, Gomo E, Butterworth AE, Mudenge B, van Dam GJ, Gerstoft J, Erikstrup C, Ullum H. 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 Dec 1;192(11):1956-61. doi: 10.1086/497696. Epub 2005 Oct 20.
citation: Brown M, Kizza M, Watera C, Quigley MA, Rowland S, Hughes P, Whitworth JA, Elliott AM. Helminth infection is not associated with faster progression of HIV disease in coinfected adults in Uganda. J Infect Dis. 2004 Nov 15;190(10):1869-79. doi: 10.1086/425042. Epub 2004 Oct 20.
citation: Elliott AM, Mawa PA, Joseph S, Namujju PB, Kizza M, Nakiyingi JS, Watera C, Dunne DW, Whitworth JA. 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 Jan-Feb;97(1):103-8. doi: 10.1016/s0035-9203(03)90040-x.
citation: Modjarrad K, Zulu I, Redden DT, Njobvu L, Lane HC, Bentwich Z, Vermund SH. Treatment of intestinal helminths does not reduce plasma concentrations of HIV-1 RNA in coinfected Zambian adults. J Infect Dis. 2005 Oct 1;192(7):1277-83. doi: 10.1086/444543. Epub 2005 Aug 25.
citation: Wolday D, Mayaan S, Mariam ZG, Berhe N, Seboxa T, Britton S, Galai N, Landay A, Bentwich Z. Treatment of intestinal worms is associated with decreased HIV plasma viral load. J Acquir Immune Defic Syndr. 2002 Sep 1;31(1):56-62. doi: 10.1097/00126334-200209010-00008.