Persistent low-Level viremia in persons living with HIV undertreatment: An unresolved status

Figures & data

Table 1. Association between persistent low-level viremia in PLWH under ART (current studies)

								ART regimen in pLLV
Year	STUDY	N	Follow-up (years)	pLLV patients (n)	pLLV definition (cp/mL)	VF definition (cp/mL)	VF (YES/NO)	NRTIs + PI/r	NRTIs + NNRTI/II	Others
2015	[27]	17,902	2.7	624	VL = 50–199	VL ≥ 200	Yes, between 200–499	351	273	-
				482	VL = 200–499			237	244	-
2015	[24]	2374	11	205	VL = 50–199	VL ≥200	Yes	135	70	-
2015	[23]	2276	1	127	VL ≤ 50	VL ≥ 200	No	114	108	-
				95	VL = 51–199					-
2017	[32]	1015	20	716	VL < 50	VL ≥ 1000	Yes, between 200–999	UNS	UNS	-
				46	VL = 50–199
				52	VL = 200–999
2018	[30]	5986	11	237	VL = 50–199	VL ≥ 500	Yes, between 200–499	100	124	13
				168	VL = 200–499			82	69	17
2018	[31]	70,930	9	9901	VL = 51–199	VL ≥ 1000	Yes	UNS	UNS	-
				3358	VL = 200–399
				3609	VL = 400–999
2019	[28]	2795	10	152	VL = 51–200	VL ≥ 200	Yes	UNS	UNS	-
				110	VL = 201–500
2019	[25]	2006	21.8	374	iLLV: VL = 50–199 on < 25% of measurements	VL ≥ 200* or > 1000**	Yes, in iLLV patients.	UNS	UNS	-
				152	pLLV: VL = 50–199 on ≥ 25% of measurements					-
2020	[33]	508	8	86	VL = 50–1000	VL > 1000	Yes	5	81	-

Notes: pLLV: Persistent low-level viremia, VF: Virological failure, VL: Viral load, cp/mL: Copies/mL; ART: Antiretroviral treatment; iLLV: Intermittent LLV; UNS: Unspecified. NRTI: Nucleoside reverse transcriptase inhibitors; PI: Protease inhibitors; NNRTI: Non-nucleoside reverse transcriptase inhibitors; II: Integrase inhibitors. * On two consecutive measurements. ** During ART and six months after initiation of ART.

Table 2. Resistance associated mutations (RAM) detected in patients with pLLV

STUDY	YEAR	VL (cp/mL)	Nfailure/Ntotal (%)	NRTI	NNRTI	PI	II
[46]	2010	< 300	270/449 (60)	M41L D67N K70R L210W T215F K219Q/E M184 V K65R L74V	K103N Y181C G190A V1081	L90M M461 V82A D30N	NA
		300–999	399/552 (72)
[11]	2011	50–1000	20/54 (37)	M184V A62A/V D67D/N K70K/P V75I	M230L/M K103N K101E V106M V106I Y188C/Y P225H/P V108I	D30D/N	NA
[15]	2015	50-500	11/48 (23)	M184V/I K219E L74V D67N L210W T215Y	L103N	L10F/I L33F/V I53L L63P I47V L76V G48V A71V V77I V82T I84V	T97A N155H T97A Y143C G163R
[39]	2013	50–1999	UNS	M184V	K103N Y188C	D30N L90M	NA
[45]	2011	50–200	209/396 (52.8)	UNS	UNS	UNS	NA
		201–500	201/287 (70)
		501–1000	179/242 (74)
[41]	2020	20–500	11/16 (68.8)	T215L/S D67DN/DE	V106I E138EA K103NS V179VD M230MI	K43T T74TP	G163R/K E138K L33LF E157Q G163R

Notes: pLLV: Persistent low-level Viremia; VL: Viral load; NRTI: Nucleoside reverse transcriptase inhibitors; NNRTI: Non-nucleoside reverse transcriptase inhibitors; PI: Protease inhibitors; II: Integrase inhibitors; UNS: Unspecified; NA: Not applicable. *Patients which LV was below to 500cp/mL was undetectable by sequencing.

Table 3. Published studies regarding different clinical consequences in pLLV vs. non-pLLV patients

YEAR	STUDY	HIV Patients (cp/mL)	n	Follow up (years)	VF		MORTALITY			AIDS EVENTS		NADES				IMMUNE ACTIVATION
												GLOBAL		D-DIMER MARKER		IL-6		MICROBIAL TRANSLOCATION
					aHR 95% (CI)	p	aHR 95% (CI)		p	aHR 95% (CI)	P	aHR 95% (IC)	p	t-test 95% (CI)	p	Statistics 95% (CI)	p	Statistics 95% (CI)	p
2020	[58]	No pLLV (<50)	4177	7.5	NA		1(Reference)		<0.05	NA		1(Reference)	-	NA		NA		NA
		pLLV (50–199)	339				2.2 (1.3–3.8)					0.86 (0.50–1.5)	NS
		pLLV (200–999)	258				2.1 (0.96–4.7)					2.0 (1.2–3.6)	<0.05
2019	[62]	no pLLV (<50)	34	1	NA		NA			NA		NA		756 (157–3626)	0.038	NA		t-test = 1.30 (0.59–2.84)	0.62
		pLLV (50–999)	34											1114 (125–9917)				t-test = 1.23 (0.56–2.70)
2019	[28]	No pLLV (<50)	2533	10	1 (Reference)	-	NA			NA		NA		NA		NA		NA
		pLLV (51–200)	556		1.83 (1.10–3.04)	<0.05
		pLLV (201–500)	110		4.26 (2.65–6.86)	<0.05
2019	[25]	No pLLV (<50)	1090	21.8	1 (Reference)	-	NA			NA		NA		NA		NA		NA
		iLLV (50–199)	374		0.33 (0.21–0.52)	<0.0001
		pLLV (50–199)	150		3.46 (2.42–4.93)	<0.0001
		hLV (200–1000)	392		2.29 (1.78–2.96)	<0.0001
2018	[30]	No pLLV (<50)	5581	11	1(Reference)	<0.001	Analized with AIDS events.			1(Reference)	0.01	1 (Reference)	0.81	NA		NA		NA
		pLLV (50–199)	237		1.42 (0.70–2.58)					1.44 (0.69–3.03)		0.81 (0.37–1.75)
		pLLL (200–499)	168		3.25 (1.77–5.99)					2.89 (1.41–5.92)		0.83 (0.34–2.97)
2017	[32]	No pLLV (<50)	716	20	1 (Reference)	-	1 (Reference)		-	NA		NA		NA		NA		NA
		pLLV (50–199)	46		1.01 (0.23–4.31)	0.99	2.19 (0.90–5.37)		0.09
		pLLV (200–999)	52		3.14 (1.17–7.03)	<0.01	2.29 (0.98–5.32)		0.05
2017	[71]	No pLLV (<50)	113	4	NA		NA			NA		NA		NA		OR = 0.99 (0.96–1.02)	0.386	OR = 1.66 (1.32–2.08)	<0.001
		pLLV (50–200)	95
2015	[24]	No pLLV (<50)	2169	11	1 (Reference)	<0.001	NA			NA		NA		NA		NA		NA
		pLLV (50–199)	205		2.30 (1.66–3.20)
2015	[27]	No pLLV (<50)	16,796	2.7	1 (Reference)	<0.001	Analized with AIDS events.			1 (Reference)	NS	NA		NA		NA		NA
		pLLV (50–199)	624		1.38 (0.96–2.00)					1.19 (0.78–1.82)
		pLLV (200–499)	482		3.97 (3.05–5.17)					1.11 (0.72–1.71)
2013	[63]	No pLLV (<20)	39	UNS	NA		NA			NA		NA		NA		MED = 79 (61–105)	<0.05	MED = 4.1 (2.8–6.1)	NS
		pLLV (20–200)	13													MED = 90 (81–154)		MED = 6.1 (2.8–9.3)
2012	[73]	Healthy	15	UNS	NA		NA			NA		NA		NA		Rho = 0.217	0.017	Rho = −0.015	0.870
		pLLV (1–500)	122
2011	[61]	No pLLV (0)	210	5	NA		OR:0.99*	0.90		NA		NA		NA		1 (Reference)	-	NA
		pLLV (1–19)	137													LLM = 0.1 (−26, 35.5)	0.99
		pLLV(20–399)	236				OR: 1.01**	0.91								LLM = 0.7 (−23.5, 32.6)	0.96
		pLLV (400–1000)	237													LLM = −2.5 (−45.6, 74.8)	0.93

Table 4. Summary of the role of pLLV

SUMMARY: ROLE OF PLLV
CLINICAL IMPLICATIONS
Increased risk of developing VF		[24,25,27,28,30–33]
Nature of ART and adherence difficulties		[34–37]
Drug resistance mutations	Association	[11,15,16,39–41,46]
	Non association	[38,48–50]
ART intensification with Raltegravir not reducing pLLV		[51,52]
A second-line ART improving pLLV status		[40,53–56]
A second-line ART not improving pLLV status		[57]
MORTALITY AND AIDS EVENTS
Higher risk of mortality and AIDS events		[30,58]
No higher risk of mortality and AIDS events		[27,32,59–61]
IMMUNOLOGICAL ACTIVATION AND INFLAMMATION STATUS
Immune activation status		[14,70]
IL-6 levels	Association	[73]
	Non association	[61,63,71]
Relationship with MT (elevated levels of sCD14)		[63,71]
NON-AIDS DEFINING EVENTS (NADES)
Possible influence in the morbidity and mortality of NADES		[32,73,108,109]
Relationship with cardiovascular diseases		[58,62]
No association with NADES		[30,61]
ORIGIN OF PLLV
Viral reservoir		[130,131,133]
Relationship between viral reservoir and clonal expansion		[126,140–142]

Notes: pLLV: Persistent low-level patients, VF: Virological failure; ART: Antiretroviral treatment; AIDS: Acquired immunodeficiency syndrome; MT: Microbiotal translocation; NADES: Non-AIDS-defining events.

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Data availability statement

The data of this study are available from the corresponding author [VB].