Prevalence and factors associated with physical function limitation in older West African people living with HIV.

Although physical function decline is common with aging, the burden of this impairment remains underestimated in patients living with HIV (PLHIV), particularly in the older people receiving antiretroviral treatment (ART) and living in sub-Saharan Africa (SSA). PLHIV aged ≥50 years old and on ART since ≥6 months were included (N = 333) from three clinics (two in Côte d'Ivoire, one in Senegal) participating in the International epidemiological Databases to Evaluate AIDS (IeDEA) West Africa collaboration. Physical function was measured using the Short Physical Performance Battery (SPPB), the unipodal balance test and self-reported questionnaires. Grip strength was also assessed. Logistic regression was used to identify the factors associated with SPPB performance specifically. Median age was 57 (54-61) years, 57.7% were female and 82.7% had an undetectable viral load. The mean SPPB score was 10.2 ±1.8. Almost 30% had low SPPB performance with the 5-sit-to-stand test being the most altered subtest (64%). PLHIV with low SPPB performance also had significantly low performance on the unipodal balance test (54.2%, p = 0.001) and low mean grip strength (but only in men (p = 0.005)). They also showed some difficulties in daily life activities (climbing stairs, walking one block, both p<0.0001). Age ≥60 years (adjusted OR (aOR) = 3.4; CI95% = 1.9-5.9,), being a female (aOR = 2.1; CI95% = 1.1-4.1), having an abdominal obesity (aOR = 2.1; CI95% = 1.2-4.0), a longer duration of HIV infection (aOR = 2.9; CI95% = 1.5-5.7), old Nucleoside reverse transcriptase inhibitors (NRTIs) (i.e., AZT: zidovudine, ddI: didanosine, DDC: zalcitabine, D4T: stavudine) in current ART (aOR = 2.0 CI95% = 1.1-3.7) were associated with low SPPB performance. As in western countries, physical function limitation is now part of the burden of HIV disease complications of older PLHIV living in West Africa, putting this population at risk for disability. How to screen those impairments and integrate their management in the standards of care should be investigated, and specific research on developing adapted daily physical activity program might be conducted.

Introduction

According to UNAIDS, 6.7 million people aged 50 and older were living with HIV worldwide in 2017, a phenomenon that increased steadily since 1995 [1]. Sub-Saharan Africa (SSA) represents the region with the largest number of older people living with HIV (PLHIV) (4.1 million) [1]. With massive and rapid access to antiretroviral therapy (ART), the overall improvement in HIV medical care services, and the dramatic change in the demographics of the HIV-infected population, HIV infection can now be considered as a chronic disease worldwide. Older patients receiving ART are thus an increasing population group and have an increased risk of developing age-associated non-communicable comorbidities [2,3].

With aging, alteration of physical function (i.e. functional limitation and disability) are more common. Independence and social life are clearly related to physical function in older adults [4]. A functional limitation is a strong predictor of disability, hospitalization, nursing home admission, and mortality in aging [5,6]. In the context of HIV infection, this problem has long been neglected although up to 30% of PLHIV in Canada, for instance, have complaints about their physical function [7]. Recent US data showed that PLHIV are affected by those impairments even at middle age [8]. In France, it has been reported that one of two middle-aged PLHIV had poor limb muscle performance [9], that the performance deteriorated over time and that was associated with subsequent falls [10]. In Cote d’Ivoire, one study reported a higher prevalence of physical function limitation (34%) in middle-aged PLHIV, with older age and higher BMI being associated with low performance [11].

As those impairments emerge as an important public health issue, there is a risk of a significant burden on the healthcare systems and human resources, especially in SSA. Few data are available in SSA, particularly in PLHIV aged 50 years and above. The aim of our study was to describe the prevalence and identify factors associated with physical function impairment in PLHIV aged 50 years and above living in West Africa.

Methods

Study population

This study is a part of an ancillary project within the West Africa network of the International epidemiological Databases to Evaluate AIDS (IeDEA) of the US National Institutes of Health (https://www.iedea.org/regions/west-africa/) [12]. This cross-sectional analysis is part of a 2-year longitudinal study evaluating different aspects of aging with HIV (cognition, physical function, depression and frailty) with a follow-up still ongoing. By convenience, the study was conducted in three urban clinics with a large case load of PLHIV in two different countries: the infectious and tropical disease department of the Treichville University Hospital, the referral public clinic (CePReF) in Yopougon Attié Hospital (Abidjan, Côte d’Ivoire), and the infectious and tropical disease department of the Fann University Hospital (Dakar, Senegal). The inclusion period of the study was between February 2016 to November 2017.

Patients were eligible if they were adults living with HIV-1, 50 years old or older, and on ART for at least 6 months. We excluded patients having history of cerebral opportunistic infection, neurological pathology (history of stroke, Parkinson disease), current disabling opportunistic infection, meningitis, sensitivo-motor paralysis, psychiatric illness (including psychotropic treatment), cancer under treatment or respiratory or cardiac insufficiency.

The national ethics committee of each participating country approved the protocol (Senegal: Conseil National d’Ethique de la Recherche en Santé (CNERS), protocol SEN15/74; Côte d’Ivoire: Comité National de l'Ethique et de la Recherche, protocol n°009/IMSLS/CNER-k). All the patients gave their written consent before being included in the study.

Socio-demographic and medical data

Patients’ characteristics including information on socio-demographics, anthropometry, medical history, HIV clinical data, and also substance use (tobacco, drugs, and alcohol with the AUDIT-C (a score ≥3 for women or ≥4 for men was considered as hazardous drinking) have been collected through basic questions and medical examination.

Professional activity was defined in two categories: employed and unemployed. The Body Mass Index (BMI) was calculated by dividing the weight (in kilograms) by the height (in meters squared) and divided into three categories: overweight/obesity when BMI ≥25 kg/m2, normal when 18 ≤ BMI <25 and low when <18 kg/m2. Abdominal obesity was defined by an abdominal circumference ≥80 cm in women and ≥94 in men [13].

Concerning medical data, patients were asked if they have ever been diagnosed with any chronic diseases (hypertension, diabetes, hyperlipidemia, migraine, arthrosis, tuberculosis, etc.). The initial clinical stage using Centers for Disease Control and Prevention (CDC) definition was used (A, B, or C) [14]. Exposure to zidovudine (AZT), didanosine (ddI), stavudine (D4T), zalcitabine (DDC) in the initial and the current ART treatment was studied through a categorical variable (yes/no). Adherence to ART was defined as the percentage of tablets the patient declared to have taken over seven days (in comparison to the prescribed total number of tablets over this period).

Physical function limitation

Physical function limitation was evaluated with different tests of physical performance, and by self-reported measures. These tests were conducted by trained staff following standard procedures. Each time was recorded with a digital stopwatch.

The Short Physical Performance Battery (SPPB) [15] assesses low extremity function using three timed components in the following order: balance, gait speed, and low limb strength (5 times sit-to-stand test - 5STS). A score between 0 to 4 was attributed to each subtest, depending on the performance as defined in the Guralnik et al. standard procedures [15]. The sum of the three components comprised the final SPPB score with a possible range from 0 to 12 (12 indicating the highest degree of low extremity functioning). For physical limitation, as defined by Guralnik et al [15], poor physical performance was defined as a total SPPB score ≤9. To describe in detail which SPPB subtest was the most altered, we used these following cutoffs: a score <4, except for walking speed (the cutoff < = 0.8m/s was used [16]).

The unipodal balance test [17] consists of standing on one leg as long as possible (max 30 seconds), with open eyes. The test was repeated two times. The best performance from the 2 tests was used for the analyses. The unipodal balance test was considered as failed when the patient could not stand this position for 30 seconds.

A “physical function impairment” variable was also described. A patient was considered as having physical function impairment if at least more than one test (i.e. balance, gait speed, 5-STS or unipodal balance test) was altered, as defined above in the text for each test.

Physical performance

Self-reported measures

Additionally, daily physical function tasks were evaluated based on self-reported difficulties in daily physical function such as climbing stairs, raising arm, carrying a 5kg grocery bag, walking a long distance, participating in community activities, and visiting family. Each difficulty was evaluated with a Likert scale (no difficulty / mild / moderate / severe / extreme difficulties or cannot do).

Grip strength

As SPPB assesses low extremity function and to have a complete description of muscular function in our PLHIV, the handgrip strength (kg) was measured to evaluate upper extremity maximal isometric muscle strength. The measure was realized in a standard way, twice consecutively in the dominant hand using a calibrated Jamar hydraulic hand dynamometer. The maximum value of the 2 trials was used for the analysis. For grip strength, as no normative data obtained from a population with similar characteristics to ours were available, low grip strength was defined as a performance less to the median obtained in each gender group (male/female).

Measures of functional status

Activities of the daily living (ADL) [18] and Instrumental activities with daily living (IADL) [19] scales were used to evaluate the autonomy of the patients. The ADL and IADL scores range from 0 to 6 and 0 to 4, respectively (0 indicating the lowest degree of autonomy).

Other covariates

The practice of physical activity was evaluated with the WHO Global Physical Activity Questionnaire (GPAQ) [20], collecting information on physical activity in three situations: at work, during moving from one place to another, and during hobbies. The last question evaluates physical inactivity (how many hours do you spend sitting or lying down during a day (without sleeping). For the present study, we focused on global scores: physical inactivity (the patient did not do physical activities at work or in leisure: yes/no) and intensity of physical activity (limited to moderate vs high) which were calculated following the GPAQ analysis guide instructions.

Statistical analysis

The characteristics of the study sample were described with numbers and proportions as variables were presented in categorical variables. The median and interquartile range (IQR) for describing the age and duration of the disease variables were also provided. For each physical function tests, mean scores and standard deviation were provided. Grip strength was only described according to gender.

For each test and the “physical function impairment” variable, the prevalence of low performance was reported. As SPPB has been used for >20 years to measure physical performance in older adults [15] and as it is a complete brief battery feasible to implement in HIV clinical care [21], the further analyses focused on this test. Associations between low SPPB performance and both other tests performance and daily physical activities were evaluated with Chi-2 tests, except for grip strength for which the Student T-test was performed in each gender group separately.

Factors associated with low SPPB performance were evaluated with univariable and multivariable logistic regression analyses. The multivariable logistic regression models included all variables associated with the dependent variable with a p-value ≤0.2 in univariable analyses. Unbalanced variables (85%/15%) were excluded from the analyses. The final model was obtained with a backward selection, and we considered significant associations at p < 0.05. “Inclusion centers” variable was included as a cofounder in each model. The goodness of fit of the final model was evaluated with the Hosmer-Lemeshow test (p>0.05).

A multivariable imputation of missing data was performed with a Random Forest procedure. No significant difference was observed between the two databases (with and without missing data). The database with imputed missing data was used for the logistic regression analyses.

Statistical analyses were computed using R software.

Results

Characteristics of the sample

A total of 333 patients were included in our study. The median (IQR) age was 57 (54–61) years old. Among them, 35.1% were aged 60 years and older, 57.7% were female, and 50.7% had a primary school or a lower level of education. Half of them lived alone (53.7%) and almost half of them were unemployed (46.8%) (Table 1).

Table 1

Characteristics of the study sample (N = 333).

Characteristics	Number	Percentages (%)
Socio-demographic data
Age (years)
50–59	216	64.9
60 et +	117	35.1
Gender
Male	141	42.3
Female	192	57.7
Marital status
In couple	154	46.2
Alone	179	53.7
Level of education
Primary or less	169	50.7
Secondary or more	164	49.2
Professional activity
Employed	177	53.1
Not employed	156	46.8
Anthropometric and medical data
Abdominal obesity (mis. 1)	177	53.1
Overweight/obesity (mis. 1)	126	37.8
Hypertension (mis. 1)	73	21.9
History of tuberculosis	72	21.6
Arthrosis (mis. 1)	52	15.6
History of neurological disease	47	14.1
Migraine	34	10.2
History of trauma (mis. 2)	22	6.6
Diabetes	20	6.0
Other medical problem (mis. 3)	14	4.2
Hyperlipidemia (mis. 2)	12	3.6
B or C hepatitis (mis. 1)	9	2.7
HIV Clinical data
Duration of infection (months)
[7.29,88.4]	111	33.3
(88.4,131]	112	33.6
(131,317]	110	33.1
Clinical disease stages at ART initiation
A	100	30.1
B	181	54.3
C	48	14.4
Missing	4	1.2
Nadir CD4 (cells/μl)
<200	203	60.9
≥200	120	36.1
Missing	10	3.0
More recent CD4 (cells/μl)
<500	162	48.6
≥500	168	50.4
Missing	3	1.0
Detectable Viral load	48	14.4
Missing	56	16.8
Initial treatment including AZT, ddI, D4T, DDC†	227	68.2
Current treatment including AZT, ddI, D4T, DDC	85	25.5
Poor Adherence	19	5.7
Substance use
Hazardous drinkers	24	7.2
Tobacco use (current/former)	59	17.7
Drug consumption (mis. 1)	6	1.8
Physical function Mean performance ± SD *
SPPB (score)	10.2 ±1.8
5STS (time–seconds)	12.5 ±3.5
Walking speed (m/s)	1.3 ±0.3
Activities of daily living (score = 6)	321	96.4
Instrumental Activities of daily living (score = 4)	330	99.1
Physical inactivity	148	44.4

Abbreviations: ART: Antiretroviral, AZT: Zidovudine, ddI: Didanosine, DDC: Zalcitabine, D4T: Stavudine, mis.: Missing, m/s: Meter per second, SPPB: Short Physical Performance Battery, 5STS: Five Sit-To-Stand, SD: Standard deviation.

*Unipodal test results are presented in Table 2 only (categorical variable).

† Others drugs included in ART could be: 3TC: Lamivudine, ABC: Abacavir, ATV: Atazanavir, DRV: Darunavir, EFV: Efavirenz, FTC: Emtricitabine, LPV: Lopinavir, NVP: Névirapine, RTV: Ritonavir or TDF: Ténofovir.

Table 2

Prevalence of physical function impairment for each test.

Tests	Prevalence (%) [95%CI]**
SPPB (score ≤9)	28.8 [24.0–33.7]
SPPB subtests
5STS (score<4)	64.2 [59.0–69.3]
Walking speed (speed < = 0.8m/s)	27.0 [22.2–31.8]
Balance (score <4)	16.2 [12.2–20.2]
Unipodal balance (Vereeck et al, 2008)	38.6 [33.4–43.8]
Physical function impairment	45.6 [40.2–50.9]

Abbreviations: CI: Confident Interval, SPPB: Short Physical Performance Battery, 5STS: Five Sit-to-Stand, m/s: meter per second.

** The prevalence data is for the patients who scored below the cut off values.

Among these patients, 53.1% had abdominal obesity and 37.8% were overweight or obese. Less than a quarter ever had hypertension (21.9%) and/or tuberculosis (21.6%). Other comorbidities (diabetes, hyperlipidemia, migraine, and arthrosis) were less prevalent (6%, 3.6%, 10.2% and, 15.6%, respectively).

The majority of patients had an undetectable viral load (68.8%), half of them had CD4≥500 (50.4%) and 60.9% had a Nadir CD4 <200. The median (IQR) duration of HIV infection was 108 months (68.9–141.4). Fourteen percent (14.4%) were on stage C at ART initiation. Concerning ART, 68.2% had AZT, ddI, D4T, DDC included in their initial treatment whereas only 26.7% had those molecules in their current treatment.

Few patients reported substance use (hazardous drinkers or drug users <8%, except 17.7% for tobacco users (current/previous)).

In terms of the ADL and IADL instruments, 96.4% and 99.1% of the patients obtained the maximum score (6 or 4, respectively). Overall, 44.4% reported being physically inactive and, among those reporting being active, 53.4% reported limited to moderate intensity in their physical activity (data not shown).

Description of physical function, self-reported measures, and grip strength

The SPPB mean score was 10.2±1.8. Details in SPPB total and subscores are presented in supplementary data (S1 and S2 Figs). The mean time to perform the 5STS was 12.5 ±3.5 seconds. The mean walking speed was 1.3 ±0.3 meters per second.

Few patients reported moderate to extreme difficulties in daily physical function (<4%), except for climbing stairs (14.1%) and carrying a grocery bag (8.4%) (S1 Table). Among patients reporting those difficulties, few of them reported severe or extreme difficulties (<2.5%). Only 5.4% of the patients reported at least one fall in the past year.

For women, the mean grip strength was 24.7 ±7.7 kg with 43.2% showing low grip strength whereas, for men, the mean grip strength was 40.8 ±12.3 kg with 42.5% having low grip strength.

Prevalence of physical function impairment

Almost one-third of the patients had low SPPB performance (28.8%; 95% Confident Interval (CI): 24.0–33.6) (Table 2). Among the components of the SPPB, the 5STS was the most altered test (64.2% [59.0–69.3] had a score of less than 4) whereas less than 27% had low performance for balance or walking speed. Concerning unipodal balance, 38.6% had low performance. Overall, 45.6% [40.2–50.9] of the patients had physical function impairment.

Associations between SPPB performance and other tests

A significant association between SPPB score and unipodal test performance was observed (χ2 = 10.7, p = 0.001). Of 96 PLHIV with low SPPB performance, 54.2% had low performance on unipodal test. Concerning grip strength, men with low SPPB performance had significantly lower mean grip strength than men with high SPPB performance (35.7±9.1 kg vs 41.9±12.7, T = 2.94, p = 0.005). No significant difference was observed between both women’s groups (T = 0.94, p = 0.93).

SPPB performance and daily physical activities

A significant association was observed between low SPPB performance and physical inactivity (57.3%, χ2 = 8.3, p = 0.004). Low SPPB performance was also associated with limited to moderate intense activities (61.5%, χ2 = 11.2, p = 0.001). Concerning daily physical activities, low SPPB performance was also associated with difficulties in climbing stairs (45.8%, χ2 = 13.7) and walking one block (22.1%, χ2 = 14.6) (p<0.0001 for both).

Factors associated with low SPPB performance

In univariable models (Table 3), age ≥60 years (OR = 2.7; CI95% = 1.6–4.5), being a female (OR = 2.2; CI95% = 1.3–3.7), single (OR = 1.8; CI95% = 1.1–3.0) and unemployed (OR = 2.4; CI95% = 1.4–3.9) were associated with low SPPB performance. Patients with abdominal obesity (OR = 2.4; CI95% = 1.5–4.1), hypertension (OR = 2.2; CI95% = 1.2–3.8), diabetes (OR = 3.1; CI95% = 1.2–8.0), a longer duration of HIV infection (OR = 2.7; CI95% = 1.5–5.2), those who had AZT, DDI, D4T or DDC in their initial ART (OR = 1.9; CI95% = 1.1–3.4) and in their current ART (OR = 1.9; CI95% = 1.1–3.2) also had low SPPB performance.

Table 3

Analysis of factors associated with low SPPB performance in the study population.

Variables	Univariable model		Multivariable model
	OR (CI 95%)	p-value	aOR (CI 95%)	p-value
Age		<0.0001*
50–59 years old	1
≥60 years old	2.7 (1.6–4.5)		3.4 (1.9–5.9)	<0.0001*
Gender		0.004*
Men	1
Women	2.2 (1.3–3.7)		2.1 (1.1–4.1)	0.021*
Marital status		0.021*
In couple	1
Single	1.8 (1.1–3.0)
Level of education		0.280
Primary or less	1
Secondary or more	0.8 (0.5–1.2)
Professional activity		0.001*
Employed	1
Unemployed	2.4 (1.4–3.9)
BMI		0.339
Normal / underweight	1
Overweight/obesity	1.3 (0.8–2.1)
Abdominal obesity		0.001*
No	1
Yes	2.4 (1.5–4.1)		2.1 (1.2–4.0)	0.014*
Hypertension (ref.: no)†	2.2 (1.2–3.8)	0.006*
Hyperlipidemia (ref.: no)	1.9 (0.6–6.6)	0.265
Diabetes (ref.: no)	3.1 (1.2–8.0)	0.020*
B or C hepatitis (ref.: no)	0.6 (0.1–2.9)	0.585
Tuberculosis (ref.: no)	1.3 (0.7–2.3)	0.420
Migraine (ref.: no)	0.7 (0.3–1.7)	0.477
Arthrosis (ref.: no)	1.6 (0.8–3.1)	0.165
Other medical problem (ref.: no)	1.6 (0.5–5.0)	0.411
History of trauma (ref.: no)	0.4 (0.1–1.1)	0.115
History of neurological disease (ref.: no)	1.6 (0.8–3.2)	0.193
Duration of HIV infection (months)
[7.29,88.4]	1
(88.4,131]	1.8 (0.9–3.4)	0.071	1.5 (0.8–3.0)	0.238
(131,317]	2.7 (1.5–5.2)	0.002*	2.9 (1.5–5.7)	0.002*
Clinical disease stages
A	1
B	1.0 (0.6–1.8)	0.997
C	0.8 (0.3–1.7)	0.547
Nadir CD4 (cells/μl)
<200	1
≥ 200	1.3 (0.7–2.1)	0.366

Abbreviations: aOR: Adjusted Odds Ratio, ART: Antiretroviral therapy, BMI: Body Mass Index, CI: Confidence Interval, DDC: Zalcitabine, ddI: Didanosine, D4T: Stavudine, SPPB: Short Physical Performance Battery, OR: Odd ratio, RAL: Raltégravir, AZT: Zidovudine.

*results considered as significant (p<0.05).

†ref: no: means that the OR is computed taking this category “absence of this medical problem” as a reference.

In the multivariable model (Table 3), age 60 years and above (adjusted OR (aOR) = 3.4; CI95% = 1.9–5.9), being a female (aOR = 2.1; CI95% = 1.1–4.1), having an abdominal obesity (aOR = 2.1; CI95% = 1.2–4.0), a longer duration of HIV infection (aOR = 2.9; CI95% = 1.5–5.7) and AZT, DDI, D4T or DDC in their current ART (aOR = 2.0; CI95% = 1.1–3.7) remained associated with low SPPB performance.

Discussion

In the present study, in a large sample of PLHIV aged 50 years old and above, physical function limitation evaluated with the SPPB is observed in almost 30% of the patients. The 5STS seems to be the most altered sub-test in the SPPB. PLHIV with low SPPB performance also had low unipodal balance performance, and low mean grip strength (in men only). Low SPPB performance is mainly associated with being aged above 60, but also being female, having abdominal obesity, and longer duration of the disease. The use of old Nucleoside reverse transcriptase inhibitors (NRTIs) in the current ART is also associated with lower performance.

Recent publications in older PLHIV from western countries reported similar results for the SPPB performance. In PLHIV aged 50 years or above living in the United States, it was reported a similar mean score (10.3 to 10.7) [21,22], a score similar to nearly 20-year older controls [21]. Another study in female PLHIV reported that 20% of them performed poorly with a median score of 11, but they discussed the possibility of a ceiling effect because of the participant’s age in their sample (i.e. median age: 49 years (range 40–66 years)) [23]. In a cohort of drug users (median age: 51 years old), HIV infection was also associated with a 30% higher risk of reduced physical performance [24]. Functional impairment is associated with low bone and muscle mass among persons aging with HIV-infection [25]. In PLHIV but also in the general population, low SPPB performance has already been associated with poorer outcomes such as having additional comorbidities, subsequent disability, falls, higher mortality, and hospitalization rates [15,21,24,26-29], highlighting the importance of the screening of this impairment.

The most altered component of the SPPB test was the 5STS as observed in middle-aged PLHIV in western countries [9,10] and in older PLHIV [21,22]. PLHIV needed more time to complete the test than controls [22] but less than the nearly 20-year older controls [21]. As recommended in an editorial in AIDS [30], the 5STS might be the most appropriate test to evaluate physical function in the standard care of PLHIV. Our results also showed that this test was the most altered, but the absence of normative data adapted to our population was a limit to go further in our investigation. The results presented here are the baseline data of a 2-year longitudinal study. Data collected during the follow-up will enable us to investigate the evolution of the 5STS and to describe the factors which best predict this decline.

Low SPPB performance has been associated with older age. The impact of aging on physical function is well-known and linked to age-related losses in skeletal muscle mass and low aerobic capacity [31,32]. Other studies from western and African countries reported an effect of age on physical function [9-11]. We also observed that PLHIV with abdominal obesity had low physical performance whereas no association was observed with BMI. The impact of nutrition and nutritional status on physical function limitation has already been observed [9,11]. People with excessive body mass may have more limited endurance-based performance [33] and also have increased cardiovascular risks. Finally, as shown by Richert et al [9], we observed that PLHIV with longer duration of the disease were more likely to have a low physical function whereas no significant association was observed with other HIV outcomes (CD4 or viral load). The long-term effect of the virus, inflammatory process, and direct or indirect effects of ART treatment could explain this association but further investigations need to be conducted. We also observed the effect of old NRTIs included in ART, such as Zidovudine, known as having myotoxic consequences. Further studies with a more detailed protocol evaluating the duration of exposition to those molecules could help to understand better the phenomenon.

Concerning grip strength, in accordance with other studies in PLHIV or African populations [21,34-36], the mean performance was lower in women than the men ones. In a recent US study in older PLHIV, similar grip strength as in our cohort was observed in women and men (26.5 kg and 38.2 kg respectively) [21]. Weaker grip strength has also been reported in African PLHIV in comparison to HIV-uninfected subjects [37,38]. Even if men’s grip strength was associated with low SPPB performance in our study, this was not the case for women. Because of the absence of normative data developed in SSA, we decided not to go any further in the interpretation of the data. As low grip strength is associated with bad outcomes (ie mortality, longer hospitalization, and physical function limitation) [39], it is important to standardize procedure [40] and to have regional specific data [41]. One study in Nigeria reported normative data for adults aged between 20 to 69 years old but with a small proportion of subjects aged ≥50 years old [34].

To our knowledge, this study represents the first opportunity to describe physical function in a large sample of older PLHIV in West Africa. However, some limitations have to be mentioned. First, we observed that the PLHIV included in the study reported few difficulties activities of daily living. The ADL and IADL are two scales usually used to evaluate the autonomy and the independence of older subjects (≥65 years old). Moreover, the questions in these scales might not be completely adapted to the West African population. Adapted scales have recently been published and might be more adapted to the African context [42]. Second, the generalizability of our results could be limited since we have included PLHIV from urban sites, under ART for at least 6 months, without important difficulties in activities of daily living and major neurologic complications or addictive behaviors. We may have selected the most adherent PLHIV and the most engaged in medical care. However, even in this population, poor physical functioning still occurs and should not be neglected. Interestingly, this population presented some specific characteristics and more specifically, more women than men were included and the majority did not report any substance use. Those characteristics could influence the generalizability of our results but also the comparison with other studies. Third, although we did not have a comparison group of HIV-negative adults included in the present study, we were able to compare our results to the prevalence of low SPPB performance reported in other papers. Fourth, the absence of normative data in grip strength adapted to our population was also a limit to go any further in some aspects of our investigation. Further studies are needed to depict this as it is an important point both for research and clinical domains. Fifth, even imputation for missing data was performed, the “viral load” variable presented some missing data, thus limiting the exploration of the association with SPPB performance.

Conclusions

Hence, despite a successful ART, the prevalence of physical function limitation in older PLHIV is high, and this burden impacts some daily activities. Longitudinal studies should be performed to assess the evolution of the physical function limitation, their predictors, and to evaluate in more detail their consequences on daily activities. The impact of bone density, not evaluated in this study, should also be assessed. Then, how to integrate the measurement and the management of physical function limitation in the standard of care should be investigated. As the 5STS was the most altered test, it could be interesting to perform it in standard care as recommended in western countries. Efforts are now needed to develop normative data in SSA populations. Finally, age and abdominal obesity were main factors associated with low physical performance. Practitioners need to promote the practice of physical activity and to educate their patients about a better diet to limit the occurrence of overweight and obesity, and so to prevent disability in older PLHIV. Further studies are needed to develop adapted interventions focusing on a daily physical activity program, that might limit the deterioration in physical performance and the bad consequences on daily life in this population.

Distribution of SPPB scores in the study population.

(DOCX)

Click here for additional data file.

Distribution of scores for each SPPB subtests in the study population.

(DOCX)

Click here for additional data file.

Self-reported difficulties in daily physical function.

(DOCX)

Click here for additional data file.

22 Apr 2020

PONE-D-20-01113

Prevalence and factors associated with physical function limitation in older West African people living with HIV

PLOS ONE

Dear Mrs Bernard,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Although both reviewers felt that this was an important study, they raised some significant concerns. These included the following:

1. The data were often repeated in table and text. In some areas, this became confusing. Certain specific data items were also missing (e.g. the self-reported values for the Lickert scale) and these should be addressed.

2. The ethics committee name and the approval number should be stated

3. One reviewer expressed concerns about the absence of a negative population. Although this was acknowledged as a limitation, this does raise concerns about the conclusions. If a median population value is used for comparison, this should be adequately justified and referenced.

In addition, both reviewers expressed that the written language required some editing

We would appreciate receiving your revised manuscript by Jun 06 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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Kind regards,

Elizabeth S. Mayne, M.D.

Academic Editor

PLOS ONE

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'Supported by the National Institute of Mental Health (NIMH), National Cancer Institute (NCI),

the Eunice Kennedy Shriver National Institute of Child Health & Human Development

(NICHD) and the National Institute of Allergy and Infectious Diseases (NIAID) of the U.S.

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Additional Editor Comments (if provided):

Although both reviewers felt that this was an important study, they raised some significant concerns. These included the following:

1. The data were often repeated in table and text. In some areas, this became confusing. Certain specific data items were also missing (e.g. the self-reported values for the Lickert scale) and these should be addressed.

2. The ethics committee name and the approval number should be stated

3. One reviewer expressed concerns about the absence of a negative population. Although this was acknowledged as a limitation, this does raise concerns about the conclusions. If a median population value is used for comparison, this should be adequately justified and referenced.

In addition, both reviewers expressed that the written language required some editing

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The paper contributes to the body of knowledge and has relevance. There are some grammatical errors to correct and a few statements that do not read well and need to be re-written. The conclusion is adequate. The recommendations make sense, and should include further research of the co-morbidity known and mentioned - bone health / density. Tut the glaring omission is the possible interventions and actions that could be taken (and researched) to address the findings. the mainstay of this would be appropriate rehabilitation.

Reviewer #2: In this manuscript the authors evaluated 333 older HIV positive patients living in West Africa to determine the prevalence of and factors associated with physical function impairment.

Almost 30% of HIV positive patients had decreased SPPB performance which was associated with increased age, being female, having abdominal obesity and a longer disease duration. The authors suggest that physical function limitation is part of the burden of HIV disease complications of older HIV positive patients living in West Africa.

The authors must be commended on tackling such a prominent issue and generating such an abundance of data. The results are interesting however the amount of data can be overwhelming particularly as it requires better organisation, often times making it difficult to clearly see the take home message.

Major concerns

- The greatest concerns about this manuscript is the lack of a control group and/or normative data. The authors do acknowledge this however it is difficult to reach some of the conclusions that they have without comparison to an age-matched HIV-negative control group. It was also particularly worrying that grip strength was compared to an artificially constructed median point within the study population.

- As previously stated, the structure of the manuscript is sometimes difficult to follow. Too many of the tabulated results are repeated in the text. This repetition also then tends to lose some results that are only written in text. Having said that there are an abundance of results, some of the results are actually missing (or the complete set is missing). For example, where are the likert scale results for the self-reported measures? Even if this data is included as an appendix it is important that all data is presented (i.e. all questions that were asked and prevalence of answers) so that the study is reproducible.

- Quite a few statements in the abstract and the conclusion are not supported by the data/study. Particularly statements implying that HIV is impairing physical function however this cannot be concluded without an HIV negative control group. Also stating that this population is at “higher risk of falls” (line 87) and “cardiovascular risks is a factor associated with lower physical performance (line 406)” do not have supporting data.

Minor concerns

- Sometimes the language is a little unclear. The manuscript’s flow and readability would benefit from a revision.

- Line 83 (abstract): what are the values in the brackets representing and comparing?

- Overall the abstract lacks test statistics and actual test results i.e. the mean SPBB score.

- It is mentioned that trained staff performed the SPPB – how many trained staff and was inter-rated reliability confirmed?

- Please provide references for the SPPB cutoff criteria for the subtests and the CDC clinical stages.

- Overall all the table headings requires more detail i.e. sample population etc. Currently they do not stand alone.

- Table 1

- What is meant by professional activity and where are the physical activity results. It is confusing throughout

text whether “active” is referring to physical activity or professional activity.

- Units of variables e.g. years not defined.

- Suggestion- rank medical data in order of prevalence for easier reading.

- Table 2

- It is not clear that the score means are overall for the total sample and the prevalence data is for the

patients who scored below the cutoff values.

- This data would be better represented as a box and whisker plot of the data to see the distribution/spread of

the data.

- Table 3

- Table 3 is not referred to in text.

- The table heading is misleading as not all factors in the table are associated with SPPB.

- What is meant by (ref.:no)?

- Define abbreviations.

- Stats analysis

- There are some discrepancies between what is stated in the stats analysis section and how the stats analysis

appears to have been done/not done. For example in the discussion, disease duration between 50 and 60+

year olds is compared but this is not mentioned in stats analysis.

- Line 285: It is unclear what the p value is denoting as significant.

- There are missing test statistics i.e. χ2 values for χ tests.

- Were association analyses and logistic regressions only performed for patients with lower SPPB scores?

Seems inappropriate to not include the entire sample.

- Although the authors show evidence of differences between 50 and 60+ year olds, it would be helpful for them to provide a justification for splitting the ages at this specific point?

- It is inappropriate to introduce results in the discussion section. For example comparison between male and female grip strength. Additionally, comparing and discussion grip strength between men and women isn’t relevant to study.

- Overall, the discussion paragraph about grip strength doesn’t add value to the manuscript.

- Line 191 (last paragraph before stats analysis) – should be moved to study population (makes the flow of the manuscript more consistent with the results).

- Please include the ethics number and ethics committee name.

- Line 286 – who are ‘other men’ that are referred to?

**********

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Reviewer #1: Yes: Demitri Constantinou

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

Submitted filename: PONE-D-20-01113_reviewer.pdf

Click here for additional data file.

4 Jun 2020

Review Comments to the Author

Reviewer #1:

The paper contributes to the body of knowledge and has relevance.

There are some grammatical errors to correct and a few statements that do not read well and need to be re-written. The conclusion is adequate. The recommendations make sense, and should include further research of the co-morbidity known and mentioned - bone health / density. Tut the glaring omission is the possible interventions and actions that could be taken (and researched) to address the findings. the mainstay of this would be appropriate rehabilitation.

We agree with the reviewer. We corrected grammatical errors and rephrased the conclusion to add these recommendations (lines 442-459, p22).

Reviewer #2:

In this manuscript the authors evaluated 333 older HIV positive patients living in West Africa to determine the prevalence of and factors associated with physical function impairment.

Almost 30% of HIV positive patients had decreased SPPB performance which was associated with increased age, being female, having abdominal obesity and a longer disease duration. The authors suggest that physical function limitation is part of the burden of HIV disease complications of older HIV positive patients living in West Africa.

The authors must be commended on tackling such a prominent issue and generating such an abundance of data. The results are interesting however the amount of data can be overwhelming particularly as it requires better organisation, often times making it difficult to clearly see the take home message.

Major concerns

- The greatest concerns about this manuscript is the lack of a control group and/or normative data. The authors do acknowledge this however it is difficult to reach some of the conclusions that they have without comparison to an age-matched HIV-negative control group. It was also particularly worrying that grip strength was compared to an artificially constructed median point within the study population.

We do agree with the reviewer. This study is nested in the IeDEA West Africa cohort, a large PLHIV cohort which aims to provide resources for diverse HIV/AIDS data, without including HIV-negative adults. We considered this work as a first step as it was done in other studies without control groups (Richert et al, 2011, Baronsky et al 2014, Branas et al, 2017). We proposed to add in the limitations of the study: « even we could compare the prevalence of low SPPB performance to other published data, we were unable to include HIV negative adults. This will be important in further studies » (lines 436-439, page 21).

Concerning grip strength, the variability in normative data between countries is important, the need to regional-specific normative data has been highlighted in a recent systematic review, and meta-analysis [38]. The variability of absolute values of grip strength is due to multiple factors, particularly health conditions and inactivity, parameters different across countries and could also be influenced by the procedure used to measure (ie table’s support, arm position, hand dominant or not) [39]. We presented grip strength here to describe the upper physical function, in complement to the description of lower physical function. The aim was not to report the prevalence of grip strength impairment but to only evaluate the association with SPPB scores. We added some descriptive information as done in the literature and also to allow comparisons with future data on this topic. According to the statistician of our team (HF), in this context, and as the median is computed from our sample data, it was the most adapted method. Finally, adding these data and discussing this point was a way to highlight the crucial need for normative data specific to West African PLHIV.

- As previously stated, the structure of the manuscript is sometimes difficult to follow. Too many of the tabulated results are repeated in the text. This repetition also then tends to lose some results that are only written in text. Having said that there are an abundance of results, some of the results are actually missing (or the complete set is missing). For example, where are the likert scale results for the self-reported measures? Even if this data is included as an appendix it is important that all data is presented (i.e. all questions that were asked and prevalence of answers) so that the study is reproducible.

We clarified this point. We modified tables 1& 2, and we added the Likert scale results in supplementary data. We checked redundancy in the text.

- Quite a few statements in the abstract and the conclusion are not supported by the data/study. Particularly statements implying that HIV is impairing physical function however this cannot be concluded without an HIV negative control group. Also stating that this population is at “higher risk of falls” (line 87) and “cardiovascular risks is a factor associated with lower physical performance (line 406)” do not have supporting data.

We rephrased the abstract and the conclusion.

Minor concerns

- Sometimes the language is a little unclear. The manuscript’s flow and readability would benefit from a revision.

The corrections have been made.

- Line 83 (abstract): what are the values in the brackets representing and comparing?

We rephrased the sentence to clarify (lines 71-72, page 3).

- Overall the abstract lacks test statistics and actual test results i.e. the mean SPBB score.

We rephrased the abstract (lines 69 – 77, p 3).

- It is mentioned that trained staff performed the SPPB – how many trained staff and was inter-rated reliability confirmed?

Before the beginning of the study, a specific training was organized, including both theoretical and practical parts. The training was conducted by NDR who is a specialist in physical function and who worked in the Health AB study and the LIFE study and certified staff study personnel for this test in the LIFE study. She was assisted by CB. We trained four doctors in Cote d’Ivoire (2 in both sites) and one doctor and one clinical research nurse in Senegal.

During the practical part, each procedure was broken down: the trainers carrying out the procedures at the same time as the staff in training. Besides, for the same test (eg walking speed), one member of the team performed the task and the others (another person in training and the trainers) timed the time taken to do it. Then the timed times were compared. We obtained differences of less than one second on each measurement, confirming the reliability of the measures.

- Please provide references for the SPPB cutoff criteria for the subtests and the CDC clinical stages.

Concerning SPPB cutoff criteria: Based on Guralnik’s paper (Guralnik et al, 1994), for each subtest, when the score was <4, participants reported more need for help in activities of daily living or walking ½ mile and climbing stairs increasingly across scores’ categories. In this context, we have considered that patients with a score <4 had low physical function. This reference was cited in the manuscript.

Concerning the CDC clinical stages, we added the reference (line 145, page 6).

- Overall all the table headings requires more detail i.e. sample population etc. Currently they do not stand alone.

The corrections have been made (pages 12, 15, 17).

Table 1 :

- What is meant by professional activity and where are the physical activity results. It is confusing throughout text whether “active” is referring to physical activity or professional activity.

We corrected this confusing point. Professional activity was defined in two categories « employed/unemployed ». Physical activity results are now presented in the Table 1 (pages 12-13) and in a supplementary table (S1 Table) for the Likert scale.

- Units of variables e.g. years not defined.

- Suggestion- rank medical data in order of prevalence for easier reading.

The corrections have been made (pages 12-13).

Table 2

- It is not clear that the score means are overall for the total sample and the prevalence data is for the patients who scored below the cutoff values.

- This data would be better represented as a box and whisker plot of the data to see the distribution/spread of the data.

We decided to add in Table 1 (pages 12-13) the percentage of the maximum score for ADL and IADL and also to add mean score for each test to complete the description of the sample. In supplementary data, we also added histograms to describe in detail the SPPB scores (S1 and S2 Fig.) and the description of the Likert scale in supplementary data (S1 Table). To clarify, Table 2 now only concerns the prevalence of low performance for each score (page 15).

Table 3

- Table 3 is not referred to in text.

- The table heading is misleading as not all factors in the table are associated with SPPB.

- What is meant by (ref.:no)?

- Define abbreviations.

The corrections have been made (lines 336 & 343, page 16 + page 17).

Stats analysis

- There are some discrepancies between what is stated in the stats analysis section and how the stats analysis appears to have been done/not done. For example in the discussion, disease duration between 50 and 60+ year olds is compared but this is not mentioned in stats analysis.

We clarified this paragraph with adding information (lines 221-225, page 9).

Concerning the sentence in the discussion: the comparison of disease duration between 50 and 60+ year old was just to discuss the fact that the association between low SPPB performance and duration of the disease was not due to the age of the PLHIV. But as it was confusing, we removed the sentence (lines 398-400, page 20).

- Line 285: It is unclear what the p value is denoting as significant.

This point was clarified by adding a sentence: « A significant association between SPPB score and unipodal test performance was observed (p=0.001).” (lines 322-323, page 15)

- There are missing test statistics i.e. χ2 values for χ tests.

We added these informations in the text (lines 329-333, page 16).

- Were association analyses and logistic regressions only performed for patients with lower SPPB scores? Seems inappropriate to not include the entire sample.

Logistic regression analyses were performed in the whole sample. We described factors associated with low SPPB performance.

- Although the authors show evidence of differences between 50 and 60+ year olds, it would be helpful for them to provide a justification for splitting the ages at this specific point?

In another study conducted by our team (Bernard et al, 2018, DOI : 10.2147/HIV.S172198), we observed that PLHIV aged above 60 years old has poorer outcomes than the ones aged between 50 to 59 years old. They had an increased risk of mortality and lost to follow-up. In this context, we splitted the ages at this specific point.

- It is inappropriate to introduce results in the discussion section. For example comparison between male and female grip strength. Additionally, comparing and discussion grip strength between men and women isn’t relevant to study.

- Overall, the discussion paragraph about grip strength doesn’t add value to the manuscript.

We added the mean performance in the discussion because we discussed them with the data available in the literature. It was to facilitate the reading (not necessary to back to the results section to compare the values with the one in the literature). But we agree that it could be considered inappropriate so we removed this (lines 408-410, page 20).

Concerning the discussion on grip strength: as normative data are established according to gender, comparing men and women is often done and this comparison is often discussed in the literature. Unfortunately, we could not go further in the description of the data because of the absence of normative data in the West African population. As scarce data on grip strength are available in SSA, discussing this point was a mean to highlight this point. In this context, we decided to keep this paragraph in the discussion.

- Line 191 (last paragraph before stats analysis) – should be moved to study population (makes the flow of the manuscript more consistent with the results).

We moved this paragraph in the study population section (lines 133-149, page 6).

- Please include the ethics number and ethics committee name.

We added this information (lines 127-129, page 5).

- Line 286 – who are ‘other men’ that are referred to?

We clarified this point in the text (line 325, page 15).

27 Jul 2020

PONE-D-20-01113R1

Prevalence and factors associated with physical function limitation in older West African people living with HIV

PLOS ONE

Dear Dr. Bernard,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

This revision is significantly improved but a number of minor modifications have been suggested. These are included under reviewer 2's suggestions. We would also recommend English language editing,

==============================

Please submit your revised manuscript by Sep 10 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Elizabeth S. Mayne, M.D.

Academic Editor

PLOS ONE

Journal Requirements:

Additional Editor Comments (if provided):

The reviewers felt that this article was significantly improved but a number of minor alterations have been suggested including:

1. Some English Language editing

2. Clarification of some terminology utilised including, for example, concepts of adherence, the concept of a "recent" CD4+ T cell count. Where data are missing, this should be indicated as a limitation

3. In some cases, there should be clarification of the definitions of physical limitation and also of severe disability. Where there are overlapping categories, it should be indicated (this includes substance abuse)

4. Table 3 requires modification especially to include variables like marital status

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #3: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #3: This is an interesting article that deals with an understudied area of HIV management. The researchers produced important data which have implications for the clinical management of patients and are worthy of publication. The manuscript has already gone through one round of review. I found the comments made by reviewer 2 particularly pertinent and thorough but am of the opinion that the researchers have adequately addressed the concerns that had been raised. As is inevitable with a second round of review by a new reviewer, I do, however, have additional comments and questions for the researchers.

Lines 145 – 147: “Exposure to raltégravir (RAL), zidovudine (AZT), didanosine (ddI), stavudine (D4T), zalcitibine (DDC) in the initial ART treatment and also in the current ART

treatment was studied through a categorical variable (yes/no).” What is the reason for including RAL with the old NRTIs which are known to have significant toxicity and may be confounded by a longer duration of treatment? RAL is a different class (INSTI), has limited toxicity and has not been available for as long as the NRTIs listed, so would be expected to perform differently. [Please note that zalcitabine should be zalcitabine].

Lines 147 -149: The researchers should justify the selection of and provide a reference for their definition of adherence: “Adherence to ART was defined as the percentage of tablets the patient declared to have taken over 7 days (in comparison to the prescribed total number of tablets over this period).”

Line 170: “A ‘physical function impairment’ variable was also described including at least more than one test altered, as defined above.” How was this variable determined or what was it based on?

The statistics section is thorough and commendable. My only comment on this section is that there is no mention about whether the researchers had assessed for confounding or effect modification. This is especially important in case of evaluating the effect of the various antiretroviral agents – see later comment.

Line 251: “Almost half of them lived as a couple (46.3%)”. I would rather focus on the majority who lived alone, especially since this has been reported as an independent factor related to frailty, at least in men – see Kojima et al. Is living alone a risk factor of frailty? A systematic review and meta-analysis. Ageing Research Reviews Volume 59, May 2020, 101048. https://doi.org/10.1016/j.arr.2020.101048

Table 1:

The denominator in the section Anthropometric and medical data should be given since, judging by the percentages, they do all seem to be 333.

Clinical disease stages at ART initiation – specify that these are CDC stages.

Where data are missing (e.g. for nadir and more recent CD4 count) this should be indicated as such. What was regarded as a “more recent CD4” count?

Detectable Viral load – what was the viral load cut-off used for this variable?

“Poor Observance” should rather be poor adherence

To make sense of the comparison between antiretroviral medication, the other drugs should also be listed.

Something went wrong with the alignment of the second part of Table 1 – please correct.

Line 270: Arthrosis is a very non-specific term. Could the authors please explain what they mean by it?

Line 277: Few patients reported substance use (<8%). Since this cannot be understood from the table, where alcohol and drug use are reported separately and make up 9.02%, and since some people therefore seemingly overlap, the numbers adding up to this conclusion should be provided.

Table 2 is now much improved and easier to understand.

Lime 287 – 289: “Few patients reported moderate to severe difficulties in daily physical function (<4%), except for climbing stairs (14.1%) and carrying a grocery bag (8.4%). Among patients reporting those difficulties, less than 2.5% reported severe or extreme difficulties.” Overlapping categories (namely severe) make this difficult to follow.

Table 3 needs to be reworked to ensure alignment between the p-values in the various rows. It is not clear why all the variables meeting the inclusion criteria for entry into the multivariable model (e.g. marital situation; professional activity; hypertension; diabetes; CD4 count, etc) are not presented in this model.

Why are some p-values in the table underlined?

Some abbreviations are incorrect: ART is antiretroviral therapy and not just antiretroviral; CI is confidence interval and not confident interval.

Lines 362 – 363: “Physical function limitation seems to be more important for PLHIV aged above 60 years old, in women, for those with abdominal obesity and longer duration of the disease.” An association is not the same as importance.

Lines 363 - 364: “The use of certain molecules at the initial ART is also associated to lower performance.” This sentence has been deleted but the variable was found to be significantly associated with SPPB performance in the results. It is not clear why is has been deleted and why it is also not listed as a significant association in the abstract or discussion. However, before including this variable in the discussion, it should be clear whether it had been assessed for confounding e.g. by duration of treatment? In addition, could the researchers determine which component of SPPB performance was most affected by ART? This could inform their future work.

Line 371: “but they discussed the possibility of a ceiling effect in their sample.” The ceiling effect should be better explained.

Line 422: Abbreviations that have been introduced, such as ART, should be used throughout.

The language is greatly improved, but there are still a few sentences that should be corrected. To name but a few:

Abstract: line 62: “older ones” should rather be something like “older people”.

Abstract: line 70: “putting this population at disability” – should this be at risk for disability?

Line 113: “type-1 HIV” should be written as HIV-1.

Line 160: “following the standard procedures provided in Guralnik et al. paper”

Line 168: “If the patient could not stand on one leg 30 seconds…”

Matrimonial (Table 1) or marital situation (Table 3) should rather been marital status.

Line 436 - 437: “even we could compare the prevalence of low SPPB performance to other published data…”

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #3: No

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9 Sep 2020

Dear Editor-in-Chief,

Please find below the answers to the comments of the referees, point by point. In the revised manuscript, we highlighted the changes by using the track changes. Here, we indicate the corresponding lines and pages in the track manuscript of the changes.

Editor Comments:

The reviewers felt that this article was significantly improved but a number of minor alterations have been suggested including:

1. Some English Language editing

We corrected those points.

2. Clarification of some terminology utilised including, for example, concepts of adherence, the concept of a "recent" CD4+ T cell count. Where data are missing, this should be indicated as a limitation

We clarified the terminology. We added the presence of missing data as a limitation (lines 409-411, p. 21).

3. In some cases, there should be clarification of the definitions of physical limitation and also of severe disability. Where there are overlapping categories, it should be indicated (this includes substance abuse).

We clarified this point.

4. Table 3 requires modification especially to include variables like marital status.

This Table was updated.

Review Comments to the Author

Reviewer #3:

This is an interesting article that deals with an understudied area of HIV management. The researchers produced important data which have implications for the clinical management of patients and are worthy of publication. The manuscript has already gone through one round of review. I found the comments made by reviewer 2 particularly pertinent and thorough but am of the opinion that the researchers have adequately addressed the concerns that had been raised. As is inevitable with a second round of review by a new reviewer, I do, however, have additional comments and questions for the researchers.

Lines 145 – 147: “Exposure to raltégravir (RAL), zidovudine (AZT), didanosine (ddI), stavudine (D4T), zalcitibine (DDC) in the initial ART treatment and also in the current ART treatment was studied through a categorical variable (yes/no).” What is the reason for including RAL with the old NRTIs which are known to have significant toxicity and may be confounded by a longer duration of treatment? RAL is a different class (INSTI), has limited toxicity and has not been available for as long as the NRTIs listed, so would be expected to perform differently. [Please note that zalcitabine should be zalcitabine].

Among the side effects of RAL, functional disorders have been cited (dizziness in posture, peripheral neuropathy, paresthesia). For this reason, we initially decided to include this molecule in this categorical variable. In our sample, RAL was included in the current ART combination for 4 patients. No patient got RAL in their initial ART combination. So, few patients got RAL in their ART and none reported side effects. In this context and based on the reviewer’s comment, we decided to re-run the analysis without RAL in the variable. The results remain significant. The results (lines 307-328, p. 16), Table 3 (p. 17), and the Abstract are updated. We corrected the spelling in DDC in the text.

Lines 147 -149: The researchers should justify the selection of and provide a reference for their definition of adherence: “Adherence to ART was defined as the percentage of tablets the patient declared to have taken over 7 days (in comparison to the prescribed total number of tablets over this period).”

We used the clinical definition of ART adherence used in the local pharmacies located at the clinical sites where patients were included.

Line 170: “A ‘physical function impairment’ variable was also described including at least more than one test altered, as defined above.” How was this variable determined or what was it based on?

We clarified the sentence in the manuscript (lines 164-167, p. 8). This variable is a multidomain variable. A patient was considered as having physical function impairment if at least more than one test (i.e. balance, gait speed, 5-STS or unipodal balance test) was altered. For each test, we detailed in the Methods the cut-off used to define when the test was considered as altered (p. 8).

The statistics section is thorough and commendable. My only comment on this section is that there is no mention about whether the researchers had assessed for confounding or effect modification. This is especially important in case of evaluating the effect of the various antiretroviral agents – see later comment.

We used a backward selection, an automatic process that selects the model the best fitted to explain the dependent variable (i.e. altered or not SPPB performance). In this automatic process, collinearities and effect modifications are assessed automatically. “Inclusion centers” variable was included as a cofounder in each model

We checked for the interaction between ART treatment and duration. As the interaction was found as non-significant, we did not include it in the final model.

Line 251: “Almost half of them lived as a couple (46.3%)”. I would rather focus on the majority who lived alone, especially since this has been reported as an independent factor related to frailty, at least in men – see Kojima et al. Is living alone a risk factor of frailty? A systematic review and meta-analysis. Ageing Research Reviews Volume 59, May 2020, 101048. https://doi.org/10.1016/j.arr.2020.101048

We rephrased the sentence (lines 229-230, p. 11).

Table 1: The denominator in the section Anthropometric and medical data should be given since, judging by the percentages, they do all seem to be 333.

Clinical disease stages at ART initiation – specify that these are CDC stages.

Where data are missing (e.g. for nadir and more recent CD4 count) this should be indicated as such. What was regarded as a “more recent CD4” count?

Detectable Viral load – what was the viral load cut-off used for this variable?

“Poor Observance” should rather be poor adherence

To make sense of the comparison between antiretroviral medication, the other drugs should also be listed. Something went wrong with the alignment of the second part of Table 1 – please correct.

From the comments, we have updated and reformatted the Table 1 (p. 12-13).

We corrected the percentages in the Table 1. In the old version, the denominators varied depending on the number of missing data. Now, all the percentages are calculated using one denominator (N=333), and missing data are mentioned. We also added the presence of missing data as a limitation (lines 409-411, p. 21).

The most recent CD4 is the last measure of the CD4 available in the patient’s medical record.

The viral load cut-off was 50 copy/ml of blood (N=143). For 73 patients, the laboratory detection threshold was different (viral load was considered as undetectable when viral load was <100 copy/ml (N=69), or <200 copy/ml (N=1) or <300 copy/ml (N=3)). As the laboratory did, we considered these patients as having an undetectable viral load at these thresholds.

Line 270: Arthrosis is a very non-specific term. Could the authors please explain what they mean by it?

We used a medical definition of arthrosis. Arthrosis was defined as chronic and persistent pain in the joints. This could be caused by abnormal wear and tear of the cartilage and the entire joint. As we tested physical function and grip strength, this information was essential to identify patients with this condition, with a higher risk of pain to realize the tests.

Line 277: Few patients reported substance use (<8%). Since this cannot be understood from the table, where alcohol and drug use are reported separately and make up 9.02%, and since some people therefore seemingly overlap, the numbers adding up to this conclusion should be provided.

By <8%, we wanted to report that less than 8% were hazardous drinkers or reported drug use. Only two patients were both hazardous drinkers and drug users.

Table 2 is now much improved and easier to understand.

Lime 287 – 289: “Few patients reported moderate to severe difficulties in daily physical function (<4%), except for climbing stairs (14.1%) and carrying a grocery bag (8.4%). Among patients reporting those difficulties, less than 2.5% reported severe or extreme difficulties.” Overlapping categories (namely severe) make this difficult to follow.

We clarified this point (lines 270-273, p. 14).

Table 3 needs to be reworked to ensure alignment between the p-values in the various rows. It is not clear why all the variables meeting the inclusion criteria for entry into the multivariable model (e.g. marital situation; professional activity; hypertension; diabetes; CD4 count, etc) are not presented in this model. Why are some p-values in the table underlined? Some abbreviations are incorrect: ART is antiretroviral therapy and not just antiretroviral; CI is confidence interval and not confident interval.

We reworked Table 3 (p. 17-18).

Unbalanced variables (85%/15%) were excluded from the multivariable analysis. The final model was obtained with an automatic backward selection, and we considered significant associations at p < 0.05. This procedure is mentioned in the methods (lines 217-220, p 10). The statistician working in our team (HF) validated the procedure.

We corrected the abbreviations.

Lines 362 – 363: “Physical function limitation seems to be more important for PLHIV aged above 60 years old, in women, for those with abdominal obesity and longer duration of the disease.” An association is not the same as importance.

We rephrased this sentence (lines 332-335, p 18).

Lines 363 - 364: “The use of certain molecules at the initial ART is also associated to lower performance.” This sentence has been deleted but the variable was found to be significantly associated with SPPB performance in the results. It is not clear why is has been deleted and why it is also not listed as a significant association in the abstract or discussion. However, before including this variable in the discussion, it should be clear whether it had been assessed for confounding e.g. by duration of treatment? In addition, could the researchers determine which component of SPPB performance was most affected by ART? This could inform their future work.

We re-added this sentence in the Discussion section and added a sentence in the abstract. The association between this variable and SPPB performance is discussed in the Discussion section (lines 370-373, p 20).

As explained above, we used a backward selection. In this automatic process, collinearities and effect modifications are assessed automatically. We also checked for the interaction between ART treatment and disease duration. As the interaction was found as non-significant, we did not include it in the final model.

As suggested by the Reviewer and for information, we evaluated which component of SPPB was most affected by ART. It appeared that the ART variable was only associated with STS. However, even if it could be very interesting, we decided not to add this information in the manuscript. Indeed, we think that it would require more details, such as specific multivariate models to control that ART is associated with each part considering all other potential covariates. Furthermore, reviewers / readers could ask why we do not detail which component of the SPPB is affected by each factor associated with low SPPB performance. This level of detail does not seem to be under the scope of our paper.

Line 371: “but they discussed the possibility of a ceiling effect in their sample.” The ceiling effect should be better explained.

As SPPB is designed for older subjects, the ceiling effect was linked to participants' age, younger than our patients. We rephrased the sentence and added this information: “they discussed the possibility of a ceiling effect because of the participant’s age in their sample (i.e., median age: 49 years (range 40–66 years))” (lines 340-341, p.19).

Line 422: Abbreviations that have been introduced, such as ART, should be used throughout.

We corrected this point.

The language is greatly improved, but there are still a few sentences that should be corrected. To name but a few:

Abstract: line 62: “older ones” should rather be something like “older people”.

Abstract: line 70: “putting this population at disability” – should this be at risk for disability?

Line 113: “type-1 HIV” should be written as HIV-1.

We corrected those points.

Line 160: “following the standard procedures provided in Guralnik et al. paper”

We rephrased this part of the sentence (line 154, p 8).

Line 168: “If the patient could not stand on one leg 30 seconds…”

We rephrased this part of the sentence (lines 162-163, p 8).

Matrimonial (Table 1) or marital situation (Table 3) should rather been marital status.

We corrected this point using “marital status” in Tables 1 & 3.

Line 436 - 437: “even we could compare the prevalence of low SPPB performance to other published data…”

We rephrased the sentence (lines 404-406, p 21).

6 Oct 2020

Prevalence and factors associated with physical function limitation in older West African people living with HIV

PONE-D-20-01113R2

Dear Dr. Bernard,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Elizabeth S. Mayne, M.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #3: There are a few minor, and mostly editorial issues, that should be addressed but do not require re-review:

Line 256: “Concerning ART, 68.2% had AZT, DDI, DAT, DDC included in their initial treatment” – DAT should be d4T.

Lines 258-9: “Few patients reported substance use (hazardous drinkers or drug users <8%, except 17.7% for tobacco users (current/previous)).” Inside brackets should be square.

Small issues:

DDI should be ddI

D4T should be d4T

DDC should be ddC

Raltégravir should be raltegravir

Nucleoside reverse transcriptase inhibitors should not be capitalised.

Line 410-2: This sentence should be rewritten for clarity: “Fifth, even imputation for missing data was performed, the “viral load” variable presented some missing data, thus limiting the exploration of the association with SPPB performance”.

Table 1:

there are some numbers in the background that are overlapping with the text.

More recent CD4 should be Most recent CD4

I am satisfied with the explanation of how “detectable viral load” had been defined and think it would be helpful to add this as a footnote at the end of Table 1.

A few language errors remain and the manuscript will be improved by careful language editing. For instance, "on ART since ≥6 months" should be on ART for ≥6 months; "having an abdominal obesity" should just be abdominal obesity; "With aging, alteration of physical function ... are more common" should be is more common; etc.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #3: No

13 Oct 2020

PONE-D-20-01113R2

Prevalence and factors associated with physical function limitation in older West African people living with HIV

Dear Dr. Bernard:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

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on behalf of

Dr. Elizabeth S. Mayne

Academic Editor

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