Clinical trial NCT03366922: Evaluation of Artemisia Annua and Moringa
Official title: EVALUATION OF THE EFFECT OF ARTEMISIA ANNUA AND MORINGA OLEIFERA ON IMMUNOLOGICAL RESPONSE IN HAART HIV PATIENTS at MRRH
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: HIV Infections
Lead sponsor: Mbarara University of Science and Technology
Sponsor class: OTHER
Collaborators: name: ANAMED
First posted: 2017-12-08
Enrollment: 250
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants will be stratified according to baseline CD4 levels: 350 - 250, 249 - 150, below 149. Computer generated numbers will be used to assign selected participants into study groups using simple randomization method to either control group with HAART only, or HAART with Artemisia annua group or HAART with Artemisia annua and Moringa oleifera group of 1:1:1.
Primary purpose: TREATMENT

Brief summary: Introduction Artemisia annua L is a medicinal plant traditionally used for treatment of malaria and other diseases in China. The extract of leaves of the plant has been demonstrated in-vitro to have potent anti HIV effects and in vivo to improve levels of lymphocytes in laboratory animals. Effect on lymphocyte stimulation has also been observed in non HIV persons taking the leaves of the plant as a tea for malaria prophylaxis in Uganda.

Objective To determine the effect of A.annua L and Moringa oleifera leaf powder on CD4 cell count and other immunological indices in HAART HIV patients.

Materials and Methods In this study Artemisia annua leaf powder and Moringa leaf powder will be investigated. The study will be a three arm randomized Phase II study involving adult patients with HIV-infection on HAART with CD4 below 350. The CD4 cell count, and other immunological indices in patients receiving HAART will be compared with those patients receiving additionally Artemisia annua powder with Moringa oleifera powder or Artemisia annua powder alone. The study will be conducted at the HIV clinic in Mbarara Regional Referral Hospital while laboratory tests will be done at Mbarara University of Science and Technology clinical and pharmaceutical sciences laboratories.

Expected outcome The primary outcome will be change in mean (Median) CD 4 cell count. Secondary outcomes will be mean (or median) changes, viral load, complete blood count and other HIV associated immunological indices , Performance status and incidence of adverse effects like nausea, diarrhoea, weight gain and or loss.

Expected benefits Adequate immunological recovery is one of the desired outcomes in HIV care. HAART combinations do not directly aid immunological recovery and some patients fail to have adequate immunological recovery despite adequate suppression of viral load. There are many patients using herbal supplements but there is limited scientific clinical evidence on the benefit of these supplements in HAART patients.

Detailed description: HIV still remains a major public health burden in Uganda and Africa as a whole. It is estimated that about 36.9 million persons are infected worldwide with majority being in Africa. While most HIV persons in Uganda initiate HAART late sometimes with CD4 cell count below 350, making their immunological recovery very poor and putting them at higher risk of opportunistic infections, there are no established medicines for enhancement of immune responses.

Indeed a number of medicinal plants are reported to have anti-HIV effects and immune enhancement effect in vitro, however few to none have had their potential demonstrated in a controlled clinical study. This study will investigate A.annua supplemented with Moringa oleifera. Artemisia annua medicinal plant has been demonstrated to have immunological effects in laboratory studies as well as anti-HIV effects in vitro (Lubbe et al., 2012). Moringa oleifera has been reported to be used in up to 80% of HIV patients in Africa (Lubinga et al., 2012) and thus will be investigated as a nutritional supplement. Although there is improved access to testing and hence timely diagnosis for HIV with increased roll out of anti-retroviral therapy, many patients in resource limited settings still initiate HAART when the HIV-infection is in advanced stage. Initiation of HAART in patients with advanced HIV-infection has previously been associated with sub-optimal immunological recovery (Reda et al., 2012). In addition, in Uganda many HIV patients are reported to use herbal medicines in addition to HAART, including Aloe vera, Vernonia amygdalina and Moringa oleifera. (Lubinga et al., 2012). The challenge is that the clinical benefits of most of these herbal medicines remain unknown as well as their potential interactions with HAART. Artemisia annua powder which has been shown in vitro to have anti-HIV effects and in vivo to cause increase in monocytes and lymphocytes level (Lubbe et al., 2012; Ndhlala et al., 2016) is used by some HIV patients in Uganda claiming to improve their quality of life (Lubinga et al., 2012). However there are no data from controlled studies to prove these claims and thus enable adoption or rejection of Artemisia annua powder and Moringa oleifera as an adjunct to HIV treatment. Proof of beneficial effects of a given herbal remedy would provide an alternative to use of unproven herbal products as it is the case currently. Artemisia annua medicinal plant has been demonstrated to have immunological effects in laboratory studies as well as anti-HIV effects in vitro (Lubbe et al., 2012). Has a short plasma half-life. When given orally or rectally, dihydroartemisinin was safe and showed higher bioavailability in humans than artemisinin in an early pharmacokinetic study by Zhao et al (1993). The Cmax, Tmax, and T1/2 for orally delivered dihydroartemisinin were 0.13-0.71 mg/L, 1.33 h, approximately 1.6 h, respectively; for pure artemisinin they were 0.09 mg/L, 1.5 h, and 2.27 h, respectively. Alin et al (1996) compared orally delivered artemisinin and artemisinin-mefloquine combination therapy for treatment of P. falciparum malaria. Infected and uninfected patients had similar pharmacokinetic parameters. After a single dose, bioavailability of artemisinin was not altered. In the Ilet et al(2005) review of pharmacokinetic parameters of artemisinin and its derivatives, oral pure artemisinin doses ranged from about 6-11 mg kg/L in healthy subjects and Cmax was 0.15-0.39 mg/L. Dose seemed to have no major effect. An earlier study by Ashton et al (1998)compared increasing artemisinin doses of 250, 500, and 1000 mg per person and both Cmax and T1/2 showed dose-dependent increases of 0.21, 0.45, and 0.79 mg/L, and 1.38, 2.0, and 2.8 h, respectively, but Tmax remained relatively constant at 2.3-2.8 h. et al., (2011; 2012) has also found Artemisia tea at 2.5g dried leaves per adult infusion dose with 55-100mg artemisinin/L safe. Other pharmacokinetic studies have been duly added in the background section and show that artemisinin delivered by oral consumption of Artemisia annua dried leaves or encapsulated dried leaves of Artemisia Annua are generally safe (Weather et al., 2014; Elfawal et al., 2015; Desroslera and Weathers, 2016).

Moringa oleifera on the other hand has been reported to be used as a nutritional supplement and management of HIV infections in up to 80% of HIV patients in Africa (Monera et al., 2008; Lubinga et al., 2012; Popoola et al., 2013; Ndhlala et al., 2016; Roelofsen et al., 2017). Asare and colleagues (2012) also confirmed that intake of Moringa Oleifera is very safe at levels ≤ 1000 mg/kg b.wt. Monera and colleagues have also found out in a cross-over study that Co administration of Moringa oleifera Lam. leaf powder at the traditional dose did not alter the steady state pharmacokinetics of nevirapine in HIV infected adults (Monera Penduka et al., 2017).

A.3 OBJECTIVES List the major objectives/hypothesis, which have governed your choice of study design General objective

To determine the effect of Artemisia annua powder and Moringa oleifera on immunological and haematological response in patients on HAART.

Specific objectives

1. To determine effect of Artemisia annua in combination with Moringa oleifera on CD4 cell count in HIV patients on HAART.
2. To determine the effect of Artemisia annua with Moringa oleifera on viral load in patients on HAART.
3. To determine the effect of Artemisia annua with Moringa oleifera on full blood count and immunogloblins associated with HIV infections in HAART patients.
4. To determine the effect of Artemisia annua and Moringa oleifera on antiretroviral plasma drug level in patients on first line ART (UCG, 2016).
5. To determine the effect of Artemisia annua and Moringa oleifera on performance status and quality of life in HAART patients.
6. To profile any adverse effects of Artemisia annua and Moringa oleifera HIV patients on HAART.

Eligibility criteria: Inclusion Criteria:

1. Participant is 18 years of age and above
2. Participant is HIV positive
3. Participant is on HAART first line for at least one year.
4. Participant is mentally sound
5. Participant is living within 60 km radius from the clinic and will be remaining within the radius of 60 km from the clinic during the study period

h) Participant has a CD4 count less than 350cells/µl i.)Participant has normal haematological and biochemical indices J) ability to use phone SMS messaging K) Participant has signed the informed consent form

Exclusion Criteria:

1. Participant is pregnant
2. Participant does not consent to study
3. Participant with opportunistic infection
4. Participants using other herbal medicines
5. Participant living outside the radius of 60 km from the clinic

Primary outcomes:
measure: CD4 counts
timeFrame: Baseline, 6 and 12 months
Secondary outcomes:
measure: Viral load
timeFrame: Baseline, 6 and 12 months
measure: Complete Blood Count
timeFrame: Baseline, 6 and 12 months
measure: Immunoglobins
timeFrame: Baseline, 6 and 12 months
measure: Antiretroviral plasma drug level
timeFrame: Baseline, one and two weeks
measure: Patients perceptions on mental and physical quality of life
timeFrame: Baseline, 6 and 12 months
measure: Liver function biomarkers
timeFrame: Baseline, 6 and 12 months
measure: Side effects or adverse drug reactions
timeFrame: Baseline, 12 months
measure: Renal function biomarkers
timeFrame: Baseline, 6 and 12 months
Other outcomes:
Locations:
city: Mbarara
country: Uganda
facility: Mbarara Regional Referral Hospital
state: SouthWestern
Study officials:
References:
citation: Alin MH, Ashton M, Kihamia CM, Mtey GJ, Bjorkman A. Clinical efficacy and pharmacokinetics of artemisinin monotherapy and in combination with mefloquine in patients with falciparum malaria. Br J Clin Pharmacol. 1996 Jun;41(6):587-92. doi: 10.1046/j.1365-2125.1996.35116.x.
citation: Ashton M, Gordi T, Trinh NH, Nguyen VH, Nguyen DS, Nguyen TN, Dinh XH, Johansson M, Le DC. Artemisinin pharmacokinetics in healthy adults after 250, 500 and 1000 mg single oral doses. Biopharm Drug Dispos. 1998 May;19(4):245-50. doi: 10.1002/(sici)1099-081x(199805)19:43.0.co;2-z.
citation: Zhao KC, Song ZY. [Pharmacokinetics of dihydroqinghaosu in human volunteers and comparison with qinghaosu]. Yao Xue Xue Bao. 1993;28(5):342-6. Chinese.