Are probiotics contraindicated in patients with AIDS or HIV with CD4 counts of less than 200?

Are probiotics contraindicated in patients with AIDS or generally safe? HIV with CD4 counts of less than 200?

Comment by InpharmD Researcher

There is limited published literature on the safety of probiotics for individuals with Acquired Immune Deficiency Syndrome (AIDS). However, some studies demonstrate the safety and possible benefit of probiotics in patients with Human Immunodeficiency Virus (HIV) who have not progressed to AIDS though the efficacy data are conflicting. Meta-analyses and randomized controlled trials report little to no adverse events with HIV patients ingesting live organisms, with one analysis reporting a number needed to harm of 7,369. Available data in 4 patients with CD4 count below 200 cells/μL suggests probiotics may be safe, but additional data are required. Case reports have also reported bacteremia patients with CD4 counts ≤55 cells/μL receiving probiotics.

Background

According to the 2017 guidelines from the National Institutes of Health (NIH) and the HIV Medicine Association of the Infectious Diseases Society of America (AIDSinfo), the effectiveness and safety of probiotics have not been adequately studied in HIV-infected patients with diarrheal illnesses. [1]

A 2018 systematic review was conducted to characterize infection complications from probiotic ingestion. A total of 60 case reports and 7 case series were included (n= 93). Patients on immunosuppressive drugs included those on corticosteroids, chemotherapy, and immunobiologics, and accounted for 14 of 93 patients (15%). A univariate analysis did not significantly suggest a link between death and HIV status (0 associated deaths) or use of immunosuppressive drugs (5 [27.8%] deaths). Another review, published in 2019, also describes case reports of systemic infection in immunocompromised patients taking probiotics. The authors note a trend relating low leukocyte count, neutropenia, and high inflammatory markers to traversal of gut-dwelling probiotic strains into the bloodstream. While these reports are rare, they suggest the use of probiotics may not be harmless to immunocompromised patients. [2, 3]

A review from 2010 mentions that among HIV patients, several studies have been conducted to assess the safety of probiotic interventions. When treated with L. reuteri SD2112, no safety concerns arose among moderately immune-compromised HIV patients (>350 CD4+ cells/μl). In another study of severely immune-compromised HIV patients (≤200 CD4+ cells/μl), no safety concerns were detected with use of L. rhamnosus, but this study only included 4 patients with CD4 counts <200 cells/μL. There are five case studies of lactobacillemia that have been reported in end-stage AIDS patients. Of these, three patients were reported to have central venous catheters and one patient to have pneumonia, all of whom had extremely low CD4 counts (≤55 CD4+ cells/μl). The authors state that no indication exists to avoid oral probiotic use in HIV populations, but close monitoring of safety parameters is recommended. [4]

A 2003 evidence-based review sought to determine the safety of lactobacilli and bifidobacteria used as probiotics in foods, particularly regarding the risk of opportunistic infections in immunocompromised and pediatric patients. Overall, infectious diseases related to lactobacilli and bifidobacteria are considered to be extremely rare, but the incidence of lactobacilli infection, when it does occur, is mostly in patients with severe underlying conditions. While immunocompromised patients are admittedly more vulnerable to opportunistic infections, at the time of writing no published evidence suggested that consumption of probiotics that contain lactobacilli or bifidobacteria increases the risk of opportunistic infection in these patients. Two clinical studies from 1998 and 2000 to study the safety of lactobacillus supplementation in patients with human immunodeficiency virus (HIV) described no notable safety concerns. While the use of probiotic lactobacilli or bifidobacteria was determined to present a negligible safety concern in immunocompromised patients, more efficient screening/testing criteria (e.g., animal models) were suggested for future studies. [5], [6], [7]

A 2016 meta-analysis aimed to assess the risk of sepsis in patients with HIV ingesting live organisms. Out of 39 randomized controlled trials involving a total of 9,401 patients, zero events of bacteremia or fungemia were reported. The authors do mention there have been case reports published on HIV patients taking probiotics who developed sepsis, but these were not part of the analysis. Adverse events seen in these studies were expected (abdominal distention, flatulence). The calculated number needed to harm (NNH) for HIV patients taking probiotics is 7,369. The authors conclude that probiotic use seems practical and feasible due to the low incidence of adverse events, low cost, and potential for restoration of gut flora. [8]

Another meta-analysis from 2014 of 57 clinical studies (totaling 4,914 patients) states that probiotic and/or synbiotic administration in immune-compromised adults (HIV-infected, critically ill, underwent surgery or had an organ- or an autoimmune disease) is safe with regard to the evaluated probiotic strains, dosages, and treatment duration (median 28 days). This study also states that none of the allocated participants had a CD4+ T cell count below 200 cells/mm^3 which is the marker for clinical progression to AIDS and future studies are needed to the risks/benefit situation in individuals with AIDS. [9]

A 2016 systematic review investigated the effects of probiotics on CD4 counts among patients with HIV. A total of 13 studies were included, comprising both pediatric and adult patients, with 7 reporting significant outcomes. Most of these studies were conducted in lower-income countries, commonly in Africa. Studies varied in many aspects, including design, patient population, and method of probiotic supplement (e.g.., yogurt, nutritional supplement, formula, etc). Change in CD4 count from baseline was reported in all studies. The exclusion criteria varied between studies and weren’t always reported. Those that reported exclusion criteria excluded patients with baseline CD4 counts <200 cells/μL. In studies that did not report exclusion criteria, the mean baseline CD4 counts of patients were high enough that those with CD4 counts <200 cells/μL were either under or not represented. Results amongst the individual studies were mixed, with several noting statistically significant increases in CD4 counts from baseline, and others finding no significant difference. Additionally, many included studies were of relatively low quality, including limited sample sizes and lacking thorough dosing and safety data, particularly as it pertains to the impact on HIV progression. [10]

A 2021 systematic review and meta-analysis evaluated the effects of probiotic supplementation on AIDS-related diarrhea and CD4 cell counts in individuals living with HIV/AIDS. A total of 15 trials were included for analysis. Risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) were used to assess outcomes, including the incidence of diarrhea and changes in CD4 cell counts. Subgroup analyses were performed to explore the impact of variables such as supplementation duration, probiotic strains, and geographic region on outcomes. The studies featured diverse probiotic interventions, ranging in dosage from 10⁹ to 10¹⁰ colony-forming units (CFU) and administered over durations spanning from 15 to 296 days. Long-term probiotic use (greater than 30 days) significantly reduced the incidence of AIDS-related diarrhea, with an RR of 0.47 (95% CI: 0.29–0.76, p = 0.002). However, short-term supplementation was not associated with meaningful reductions in diarrhea incidence (RR = 0.76; 95% CI: 0.51–1.14, p = 0.19). Probiotics had no measurable effect on CD4 cell counts, as indicated by an MD of 21.24 (95% CI: −12.95–55.39, p = 0.22). Subgroup analyses revealed no significant differences based on probiotic strain or geographic region, though studies from North and South America suggested modest reductions in diarrhea. Sensitivity analyses confirmed the robustness of these results. However, there was a lack of safety data for analysis and more evidence is needed. [11]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Are probiotics contraindicated in patients with AIDS or generally safe? HIV with CD4 counts of less than 200?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-3 for your response.

Immunomodulation of antiretroviral drug-suppressed chronic HIV-1 infection in an oral probiotic double-blind placebo-controlled trial
Design	Randomized, double-blind, placebo-controlled trial N= 17
Objective	To study the safety and immune effects of the probiotic Bacillus coagulans (BC) GBI-30, 6086, a gram-positive spore-forming bacterium with potential immunomodulatory effects
Study Groups	Probiotic (n= 10) Placebo (n= 7)
Inclusion criteria	Blood CD4⁺ T cell counts 250 cells/mm3 and plasma viremia measurements <50 HIV RNA copies/ml for at least 6 months, high functioning Karnofsky score ≥ 60%, baseline (within 30 days of study entry) blood values of absolute neutrophils >1,000 cells/mm3, hemoglobin >9 g/dl, platelets >75,000/mm3 , creatinine <1.5
Exclusion criteria	Active infections, treatment with other probiotics, any antibiotic therapy within 30 days, immunosuppressive drug treatments, malabsorption syndrome, and liver disease
Methods	Patients were randomized to receive a daily capsule containing either placebo or 2 billion colony-forming units of BC, with instructions to swallow the capsule with water regardless of meals.
Duration	August 9, 2010 to February 18, 2011
Outcome Measures	Assessment of Gastrointestinal Symptom Rating Scale (GSRS), CD4 ⁺ T cell counts, viremia
Baseline Characteristics		Probiotic (n= 10)	Placebo (n= 7)
	Age, years	49 ± 11	51 ± 6
	Baseline CD4⁺ T cell count, nadir/mm³	139 ± 115	223 ± 159
	Gastrointestinal symptoms were low for both groups at baseline.
Results	Endpoint	Probiotic (n= 10)	Placebo (n= 7)	p-value
	Changes in blood CD4⁺ T	+2.8%	-1.8%	0.018
	Viremia, RNA copies/mL	<40	<40	NS
	The probiotic was safe and well tolerated, and appeared to improve chronic gastrointestinal symptoms such as significant reductions in constipation scores at weeks 4 and 8 (p= 0.037 and p= 0.005).
Adverse Events	None reported
Study Author Conclusions	The data demonstrated the safety and possible benefit of this probiotic for residual inflammation in treated HIV-1 infection, although further study will be required to determine the immune pathways involved.
InpharmD Researcher Critique	Data are derived from an extremely limited sample size, and thus tolerability of probiotics reported may have been influenced by a lack of power.

References:

Yang OO, Kelesidis T, Cordova R, Khanlou H. Immunomodulation of antiretroviral drug-suppressed chronic HIV-1 infection in an oral probiotic double-blind placebo-controlled trial. AIDS Res Hum Retroviruses. 2014;30(10):988-95.

The efficacy and safety of probiotic Lactobacillus rhamnosus GG on prolonged, noninfectious diarrhea in HIV patients on antiretroviral therapy: A randomized, placebo-controlled, crossover study
Design	Randomized, placebo-controlled, crossover study N= 17
Objective	To evaluate the effect of supplemental probiotic Lactobacillus rhamnosus GG (LGG) on noninfectious diarrhea and gastrointestinal symptoms in HIV-infected patients on HAART and to assess the safety and tolerance of LGG in this patient population
Study Groups	Placebo (n= 8) Probiotic (n= 9)
Inclusion criteria	Documented HIV infection, regular HAART with no changes during the 3 preceding months, and persistent and prolonged (>28 days) noninfectious diarrhea in at least 3 days of a week with negative stool samples for enteric pathogens (bacteria, viruses, ova, and parasites)
Exclusion criteria	Hepatic or renal insufficiency, cancer, ongoing antibacterial therapy
Methods	Each patient received two weeks of either placebo or probiotic LGG followed by wash-out for 2 weeks. The patients that initially received the placebo then took probiotics and vice-versa for another two weeks before a final wash-out period. LGG was in the form of a juice-milk drink (containing viable LGG 1-5 x 10¹⁰ CFU/dose and lactose <1 g per 65-mL serving) and was to be taken twice daily. Patients kept a daily track of their gastrointestinal symptoms and stool passage.
Duration	10 weeks
Outcome Measures	Effect of LGG on gastrointestinal symptoms
Baseline Characteristics		At enrollment, n (%)	At the end of the study, n (%)
	Age, years	44.5 ± 10.4	-
	Male	14 (82%)	-
	CD4 lymphocyte count, x 10⁶/mm³	362 ± 249	362 ± 239
	HIV RNA viral load, log10 copies/mL	4.5 ± 4.9	4.6 ± 5.1
Results	There were no significant differences between the treatment groups in the frequency or the consistency of diarrhea. The number of days with watery stool when on LGG was slightly less than the placebo group (2.5 days vs 3.5 days, p= 0.355). No difference between LGG and placebo could be detected and the number of HIV RNA copies in the blood and CD4 cell counts remained stable during the study.
Adverse Events	None reported; no clinical infections due to lactobacilli were observed in study patients up to a six-month follow-up
Study Author Conclusions	Probiotic LGG preparation was well-tolerated in HIV infected patients. No significant differences in noninfectious diarrhea or gastrointestinal symptoms compared to placebo could be observed in this crossover study.
InpharmD Researcher Critique	Data are derived from an extremely limited sample size. As patients have a CD4 count of 362 at baseline, applicability of these findings to a patient population with CD4 counts <200 is uncertain.

References:

Salminen MK, Tynkkynen S, Rautelin H, et al. The efficacy and safety of probiotic Lactobacillus rhamnosus GG on prolonged, noninfectious diarrhea in HIV Patients on antiretroviral therapy: a randomized, placebo-controlled, crossover study. HIV Clin Trials. 2004;5(4):183-91.

Use of Probiotics in HIV-infected Children: A Randomized Double-blind Controlled Study
Design	Randomized double-blind controlled trial N= 77
Objective	To assess whether probiotics can improve immune response (CD4 cell counts) and reduce liquid stool episodes in HIV-infected children.
Study Groups	Probiotics (n= 38) Control (n= 39)
Inclusion Criteria	HIV infection, aged 2 to 12 years old, regular antiretroviral therapy with no changes during the preceding three months, attendance at the pediatric HIV infection reference service.
Exclusion Criteria	Diabetes, serious acute infection, allergy to bovine milk proteins, hospitalization, failed antiretroviral therapy (stopped taking for any reason).
Methods	Participants received either a probiotic formula (Bifidobacterium bifidum with Streptococcus thermophilus, 2.5 x 10^10 cfu) or a standard formula daily for 2 months. CD4 counts and stool quality were assessed at the beginning and end of the study.
Duration	2 months.
Outcome Measures	Primary: CD4 cell count Secondary: Stool consistency and frequency.
Baseline Characteristics		Probiotics (n= 38)	Control (n= 39)
	Age, years	6.33	7.12
	Female	50%	56.4%
	Treatment with highly active antiretroviral therapy	48.6%	61.5%
	Nutritional intake Energy intake, kcal/day Calories adequacy/age	2099 140	2152 148
	CDC immunologic category Severe Moderate Normal	2.66% 22.66% 25.35%	8% 22.66% 18.66%
Results	Endpoint	Probiotics (n= 38)	Control (n= 39)	p-Value
	CD4 count (cells mm^-3) enrollment	673 (528,962)	580 (337,821)	--
	CD4 count (cells mm^-3) end	791 (509,951)	538 (332,789)	--
	Log₁₀ CD4 enrollment	2.83 (±0.19)	2.69 (±0.33)	0.35
	Log₁₀ CD4 end	3.86 (±0.27)	2.67 (±0.30)	0.05
	ΔLog₁₀ CD4	0.04 (±0.19)	-0.26 (±0.16)	0.048
Adverse Events	No observed adverse effects from the probiotic supplementation.
Study Author Conclusions	Probiotics have immunostimulatory properties and may be helpful in the treatment of HIV-infected children to improve quality of life by enhancing immune response.
InpharmD Researcher Critique	The study's strengths include its randomized double-blind design and focus on a vulnerable population. Limitations include the short duration of the study, potential confounding factors not accounted for, and the lack of significant findings regarding diarrhea reduction. The authors did not compare changes in baseline CD4 count between patients who were and were not receiving antiretroviral therapy.

References:

Trois L, Cardoso EM, Miura E. Use of probiotics in HIV-infected children: a randomized double-blind controlled study. J Trop Pediatr. 2008;54(1):19-24. doi:10.1093/tropej/fmm066