Treatment outcomes in HIV infected patients older than 50 years attending an HIV clinic in Harare, Zimbabwe: A cohort study.

There is a growing number of older people living with HIV (OPLHIV). While a significant proportion of this population are adults growing into old age with HIV, there are also new infections among OPLHIV. There is a lack of data describing the outcomes of OPLHIV who commenced antiretroviral therapy (ART) after the age of 50 years in sub-Saharan Africa. We conducted a cohort study of patients who enrolled in care at Newlands Clinic in Harare, Zimbabwe, at ages ≥50 years between February 2004 and March 2020. We examined demographic characteristics, attrition, viral suppression, immunological and clinical outcomes. Specifically, we described prevalent and incident HIV-related communicable and non-communicable comorbidities. We calculated frequencies, medians, interquartile ranges (IQR), and proportions; and used Cox proportional hazards models to identify risk factors associated with death. We included 420 (57% female) who commenced ART and were followed up for a median of 5.6 years (IQR 2.4-9.9). Most of the men were married (n = 152/179, 85%) whereas women were mostly widowed (n = 125/241, 51.9%). Forty per cent (n = 167) had WHO stage 3 or 4 conditions at ART baseline. Hypertension prevalence was 15% (n = 61) at baseline, and a further 27% (n = 112) had incident hypertension during follow-up. During follow-up, 300 (71%) were retained in care, 88 (21%) died, 17 (4%) were lost to follow-up, and 15 (4%) were transferred out. Of those in care, 283 (94%) had viral loads <50 copies/ml, and 10 had viral loads >1000 copies/ml. Seven patients (1.7%) were switched to second line ART during follow-up and none were switched to third-line. Higher baseline CD4 T-cell counts were protective against mortality (p = 0.001) while male sex (aHR: 2.29, 95%CI: 1.21-4.33), being unmarried (aHR: 2.06, 95%CI: 1.13-3.78), and being unemployed (aHR: 2.01, 95%CI: 1.2-3.37) were independent independent risk factors of mortality. There was high retention in care and virologic suppression in this cohort of OPLHIV. Hypertension was a common comorbidity. Being unmarried or unemployed were significant predictors of mortality highlighting the importance of sociologic factors among OPLHIV, while better immune competence at ART commencement was protective against mortality.

Introduction

The number of older people living with HIV (OPLHIV) above the age of 50 years continues to grow due to the increased life expectancy of people living with HIV. In 2019, the proportion of OPLHIV among all people living with HIV was estimated to have risen to 21% globally, from 8% in 2000 [1, 2]. Low- and middle-income countries (LMIC) have the highest numbers of OPLHIV and this number will increase further [2]: several studies suggest that the proportion of OPLHIV will more than double by 2030 [3-5]. This population includes both people with chronic HIV infection from early adulthood and new infections among older adults for reasons including lack of information on safe sex and a lower likelihood of protected sex, especially among older men, compared to younger people [6].

OPLHIV have been shown to have better virologic outcomes and adherence to antiretroviral therapy (ART) than younger people, but have higher mortality and slower immune recovery [7-9]. Compounding the age-related thymic contraction, HIV infection affects both B- and T-cell function leading to accelerated immunosenescence and consequently increased risk of non-AIDS related, age associated comorbidities in elderly patients [4, 10, 11]. Management of OPLHIV requires a multidisciplinary team approach, taking into account the onset of non-communicable diseases, premature ageing, and an increased risk of drug-to-drug interactions and drug toxicities due to polypharmacy [4]. Polypharmacy also complicates selection of ART regimens and the increased chronic pill burden may lead to treatment fatigue [12]. Several studies have shown that men have lower uptake of ART services, increased severity of HIV disease at ART initiation and higher mortality on ART in sub-Saharan Africa [13-15].

To our knowledge, there are no studies from Zimbabwe to document outcomes of ART in OPLHIV. However, there are emerging data on ART outcomes of OPLHIV in sub-Saharan Africa [16, 17]. With an estimated hypertension prevalence of 30%, a diabetes prevalence of 5%, and an increasing incidence of cancer in the Zimbabwean general population, it is imperative to study the prevalence of these non-communicable diseases among OPLHIV [18-20]. In addition, antiretrovirals that continue to be used in Zimbabwe such as abacavir, efavirenz, zidovudine and lamivudine may increase the risk of cardiovascular disease [21].

In this study, we present the sex-stratified prevalence of chronic non-communicable diseases, HIV viral suppression, immunological and clinical outcomes of older patients who registered for HIV management at an HIV clinic in Harare, Zimbabwe between February 2004, and March 2020.

Methods

Study design and ethics statement

This study was conducted within the ongoing International epidemiological Databases to Evaluate AIDS Southern Africa (IeDEA) cohort study of patients attending the Newlands Clinic in Harare, Zimbabwe [22, 23]. The study was approved by the Newlands Clinic Research Team and received ethical approval from the Medical Research Council of Zimbabwe (MRCZ No. A1336). Participants provided written informed consent.

Study setting

Newlands Clinic is a referral outpatient clinic providing comprehensive HIV care which is supported by the Ruedi Luethy Foundation, a Swiss-based Private Voluntary Organization. Newlands Clinic was established in February 2004 and operates under a Public-Private Partnership with the Ministry of Health and Child Care of Zimbabwe. Apart from providing antiretroviral therapy to people living with HIV, the clinic also provides, among other services, onsite laboratory investigations, psychosocial support, reproductive health services including cervical cancer screening, dental services, food support, and bus fare assistance. The patient population is predominantly from communities with high prevalence of poverty and unemployment in the Greater Harare area. Further details on the clinic’s operations are provided elsewhere [24]. Newlands Clinic is part of the Southern African region of the International epidemiological Databases to Evaluate AIDS Southern Africa (IeDEA), an international research consortium of HIV observational databases that includes four regional networks in sub‐Saharan Africa [23].

Study procedure

We included all patients aged 50 years or more, who were ART naïve at the time of registration, and started ART at the clinic. Patients were followed from the date of ART commencement until they were transferred out, lost to follow up, or died. Follow up of patients still in care was censored on April 30, 2020. We abstracted demographic, clinical and laboratory data from patient records stored in the clinic’s password protected electronic medical record. Abstracted records were anonymized by removing names and assigning sequential numeric identifiers. We defined baseline CD4 count as a CD4 count closest to the date of initiating ART within 90 days before ART commencement. HIV viral load (VL) measurements were available at the clinic from the year 2014 onwards. The most recent CD4 T-cell count and VL were defined as the last measured CD4 T-cell count or viral load for each patient. CD4 T-cell counts were measured using the CyFlow® Counter (Flow cytometer) and CD4 easy count kits. HIV viral loads were measured using the COBAS® AmpliPrep/COBAS® TaqMan® HIV-1 Test, version 2.0.

Nurses measured blood pressure during routine clinic visits after the patient had been seated for at least 5 minutes, with the arm supported at the level of the heart and elbow flexed slightly. Nurses ensured the arm was not constricted by tight clothing and placed the cuff on naked skin with the centre of the bladder over the brachial artery. Diagnosis of hypertension was made when a patient’s systolic or diastolic blood pressure was above 140mm Hg or above 90mm Hg, respectively, on two or more days. Risk reduction of major adverse cardiovascular events using aspirin was only provided for patients with history of myocardial infarction. Type II diabetes mellitus was diagnosed when a patient had a random plasma glucose > 11mmol/L or a fasting plasma glucose ≥ 7mmol/L. We grouped all forms of chronic arthritis, excluding gouty arthritis and reported them as arthritis.

Patients attended clinic visits at varying intervals determined by the doctors. Those with active comorbid conditions were seen more frequently while stable patients were seen less frequently. The longest interval between visits was 90 days. Patients who missed visits were followed up by a phone call which was recorded in the clinic’s database. Patients without an attended visit for more than 90 days were identified using a system generated report and followed up by a phone call, or a home visit if the phone call follow-up was unsuccessful. When the patient could not be contacted through these strategies, they would be recorded as being lost to follow up.

We used frequencies, medians, and interquartile ranges to describe the cohort. The Wilcoxon Rank-Sum test was used to assess differences in skewed continuous variables across categories, and ordinary least-squares regression was used to determine a change in continuous variables over time. The square-root of CD4 T-cell counts was used to normalize the data, and regression analysis was used to compare changes in CD4 T-cell counts for each year on ART. The Chi-square test was used to compare categorical variables. We used Cox Proportional Hazards models to assess risk factors of death. Potential risk factors analyzed were sex, age at enrollment, being married, being unemployed, having attended secondary or higher education, year of recruitment, having a WHO clinical stage 3 or 4 condition at ART baseline, baseline CD4 T-cell count and being hypertensive at enrollment. Potential risk factors of death were individually analyzed in univariate analyses. We included all potentially relevant risk factors (sex, age at ART commencement, marital status, education, ART baseline WHO clinical stage, ART commencement period, and being hypertensive) in a multivariable Cox Proportional Hazards model to determine independent risk factors of death. In the multivariable model, CD4 counts were grouped as <100 (severely immune-suppressed), 100–199 (moderately immune-suppressed), and ≥200 (relatively immune-competent). We used Stata (version 13.1, College Station, TX, USA) for all statistical analyses.

Results

During the study period, 420 patients aged 50 years or older were enrolled into care at Newlands Clinic, 241 (57.4%) being female. The median age at ART commencement was 55 years (IQR: 52–59). There was no difference in ART commencement age between males and females (p = 0.241). More men were married (n = 152, 84.9%) compared to 58 women (24.4%), while 125 (52.5%) women were widowed compared to 15 (8.4%) men. Seventy-eight (45.1%) men were formally employed compared to 61 (26.5%) women, while 161 women (70.0%) were unemployed compared to 75 (43.4%) men. A total of 123 men (68.7%) had secondary or tertiary education compared to 126 (52.3%) women. Most patients (59.9%) were classified in WHO clinical stage 1 or 2 at ART commencement (Table 1). Three patients had a malignancy at the time of ART commencement.

Table 1

Baseline characteristics of older people enrolling for ART at Newlands Clinic (N = 420).

Characteristic	Frequency (%)‡			p-Value (chi2 test)
	Female	Male	Total
	n = 241 (57.4)	n = 179 (42.6)
Age at ART commencement, median (IQR)	54 (52–59)	55 (52–60)	55 (52–59)	0.241§
Marital Status				<0.001
Married	58 (24.1)	152 (84.9)	210 (50.0)
Single	26 (10.8)	4 (2.2)	30 (7.1)
Divorced	29 (12.0)	8 (4.5)	37 (8.8)
Widowed	125 (51.9)	15 (8.4)	140 (33.3)
Unknown	3 (1.2)	0	3 (0.7)
Employment Status				<0.001
Formally Employed	61 (26.5)	78 (45.1)	139 (34.5)
Self-employed	3 (1.3)	11 (6.4)	14 (3.5)
Retired	5 (2.2)	9 (5.2)	14 (3.5)
Unemployed	161 (70.0)	75 (43.4)	236 (58.6)
Education				0.007
None	31 (12.9)	12 (6.7)	43 (10.2)
Primary	84 (34.9)	44 (24.6)	128 (30.5)
Secondary	89 (36.9)	86 (48.0)	175 (41.7)
Tertiary	37 (15.4)	37 (20.7)	74 (17.6)
WHO stage†				0.727
1	81 (33.9)	51 (29.1)	132 (31.9)
2	67 (28.0)	49 (28.0)	116 (28.0)
3	64 (26.8)	52 (29.7)	116 (28.0)
4	27 (11.3)	23 (13.1)	50 (12.1)
CD4 T-cell count (cells/μL), median (IQR)				0.045
Overall	171 (89–291)	144 (79–236)	158 (86–275)
2004–2010	139 (70–198)	120 (63–181)	127 (67–191)
2011–2015	221 (97–323)	181 (97–287)	199 (97–305)
2016–2020	238 (122–485)	124 (84–305)	196 (102–393)
Log viral load (copies/ml), mean± SD	4.3 ± 1.3	4.8 ± 1.3	4.5 ± 1.3	0.031₤
Comorbidities
Diabetes	8 (3.3)	9 (5.0)	17 (4.0)	0.380
Hypertension	43 (17.8)	18 (10.1)	61 (14.5)	0.025
Chronic Cardiac Failure	3 (1.2)	0	3 (0.7)	-
Arthritis	1 (0.4)	2 (1.1)	3 (0.7)	0.398
Malignancies	2 (0.8)	1 (0.6)	3 (0.7)	0.744
Chronic Kidney Disease	1 (0.4)	2 (1.1)	3 (0.7)	0.398

Unless otherwise specified

†414 patients had a recorded baseline WHO stage

₤148 patients had baseline HIV viral load, difference calculated by t-test

§Wilcoxon Rank-Sum test

Attrition

The 420 patients were followed up for a total of 2612 person-years. The median duration of follow up was 5.6 years (IQR: 2.4–9.9). At the time of analysis (30 April 2020), 300 (71.4%) patients were still in care. During follow-up, 88 patients died (21.0%), 17 (4.1%) were lost to follow up, and 15 (3.6%) were transferred to other facilities (Table 2). Among those that died, 29 (33.0%) died during the first six months after ART commencement, and 38 (43.2%) during the first year. There was no difference in proportion of males died (23.5%) compared to females (19.1%) (p = 0.276). The median age of patients in care at the time of analysis was 63.6 years (IQR: 58.6–67.0).

Table 2

Retention in care and attrition of a cohort of older people enrolling for ART at Newlands Clinic.

Status	Frequency (%)
	Female (n = 241)	Male (n = 179)	Total (N = 420)
In care	179 (74.3)	121 (67.6)	300 (71.4)
Deceased	46 (19.1)	42 (23.5)	88 (21.0)
Lost to follow up	9 (3.7)	8 (4.5)	17 (4.0)
Transferred	7 (2.9)	8 (4.5)	15 (3.6)

Antiretroviral therapy

The median baseline CD4 at ART commencement was 158 cells/uL (IQR: 86–274). Females had a higher median baseline CD4 count of 171 (IQR: 89–291) compared to males (median: 144 cells/uL; IQR: 79–236; p = 0.04). Overall, baseline CD4 T-cell counts increased by 11.8 cells/uL per year (95% CI: 7.9–15.6, p<0.01), but the increase among females (15.4 cells/uL per year, 95% CI: 9.9–21.0) was higher than among males (7.0 cells/μL per year, 95% CI: 2.3–11.6) (Fig 1). One hundred and forty-eight patients had a baseline HIV viral load with a mean ± SD of 4.5 log copies/ml ± 1.3.

Fig 1

Baseline CD4 count distribution over ART initiation years by sex (two records with CD4 count >1000 cells/μL omitted in the graph).

Most patients (n = 390, 92.9%) were initiated on a first-line ART regimen containing a non-nucleoside reverse transcriptase inhibitor (NNRTI) (efavirenz or nevirapine) and two nucleo(t)side reverse transcriptase inhibitors (NRTI). The top three starting regimens were tenofovir + lamivudine + efavirenz, stavudine + lamivudine + nevirapine, and zidovudine + lamivudine + nevirapine with 124 (29.5%), 95 (22.6%), and 91 (21.7%) patients, respectively.

Overall, 178 (42.4%) patients experienced at least one treatment adverse effect. The antiretrovirals most discontinued due to adverse events were nevirapine, stavudine, zidovudine and tenofovir disoproxil fumarate (TDF). The top five overall adverse effects were peripheral sensory polyneuropathy comprising 46.1% (n = 82) of all adverse effects, renal toxicity (n = 26, 14.6%), lipodystrophy (n = 17, 9.6%), zidovudine induced anaemia (n = 12, 6.7%) and grade 3 or 4 liver toxicity (n = 12, 6.7%). Stavudine-induced peripheral neuropathy accounted for 34.8% of all adverse events (n = 62).

Overall, seven patients experienced treatment failure and were switched to second-line ART comprising of a ritonavir boosted protease inhibitor (atazanavir or lopinavir) and two NRTIs. None of the patients failed second line ART. Among the 300 patients in care at the time of analysis, 283 (94.3%) had suppressed viral loads (<50 copies/ml), while 10 (3.3%) had viral loads >1000 copies/ml and seven (2.3%) had low-level viremia (50–1000 copies/ml). Among those with viral loads >1000 copies/ml, 5/10 had been receiving ART for less than 24 weeks. Among those who died, 28 (31.8%) had been receiving ART for less than 24 weeks.

From a median baseline CD4 T-cell count (IQR) of 158 cells/μL (86–274), median CD4 T-cell counts gradually increased from years 1–5 of follow-up to 254 cells/μL (181–399), 305 cells/μL (221–452), 348 cells/μL (249–464), 353 cells/μL (236–465), and 374 cells/μL (273–522) (Fig 2).

Fig 2

CD4 T-cell count distribution across follow-up time (3 outliers, 2 Year 0 and 1 Year 1, with CD4 count >1250 cells/uL omitted from graph) (p<0.01).

Comorbidities

During follow-up, the most common incident comorbidities were hypertension, arthritis (all types of chronic arthritis), and chronic kidney disease (CKD) with 112 (26.7%), 83 (19.8%) and 73 (17.4%) new diagnoses, respectively (Table 3). Among the 300 patients in care at the end of follow-up, 148 (49.3%) had a diagnosis of hypertension with more females (n = 103, 57.5%) being hypertensive than males (n = 45, 37.2%) (p = 0.003). Among patients in care, 26 (8.7%) had a most recent estimated glomerular filtration rate (eGFR) <60mL/min/1.73m2, with 22 in CKD stage 3, and four in CKD stage 4. Of these 26 patients with CKD stage 3 or 4, 20 were female. Twenty-four (5.7%) patients, mostly female (18/26) had incident malignancies. Among females, eight were diagnosed with cervical carcinoma in situ III (stage zero cervical cancer), and five with cervical cancer. Other cancer types among women with one patient each were Kaposi’s sarcoma, non-Hodgkin’s lymphoma, myosarcoma, hepatoma and ocular malignancy not specified. Among males, two patients had Kaposi’s sarcoma, two had multiple myeloma, one had cancer of the penis and another had lymphoma.

Table 3

Incident comorbidities among older patients receiving ART at Newlands Clinic (2004–2020).

Comorbid Condition	Frequency (%)
	Female (n = 241)	Male (n = 179)	Total (N = 420)
Tuberculosis	26 (10.8)	27 (15.1)	53 (12.6)
Diabetes	6 (2.5)	7 (3.9)	13 (3.1)
Hypertension	71 (29.5)	41 (22.9)	112 (26.7)
Chronic Cardiac Failure	7 (2.9)	6 (3.4)	13 (3.1)
Arthritis	58 (24.1)	25 (14.0)	83 (19.8)
Chronic Kidney Disease	42 (17.4)	31 (17.3)	73 (17.4)
Malignancy	18 (7.5)	6 (3.4)	24 (5.7)

Overall, 259 (61.7%) of participants had at least one chronic non-communicable disease (NCD) whether prevalent at baseline or diagnosed during follow-up, excluding cervical carcinoma in situ III and vulvar intraepithelial neoplasia III. More females had NCDs (n = 163, 67.4%) than males (n = 96, 53.6%) (p < 0.004).

Chronic disease medicines

Overall, 245 (58.3%) patients were receiving at least one additional chronic disease medicine other than ART (median = 2, IQR: 1–4). A higher proportion of females 156 (64.7%) were receiving additional chronic disease medicines compared to males (49.7%) (p = 0.002). Sixty-eight (16.2%) patients had more than three additional chronic disease medicines, and 24 (5.7%) (16 females and 8 males) were receiving more than five. The top five most used chronic disease medicines were the antihypertensives hydrochlorothiazide (16.1%), amlodipine (12.6%), nifedipine (12.6%), enalapril (9.7%), and atenolol (8.9%).

Risk of death

In the univariate analysis, increasing enrolment age, unemployment, and baseline WHO status 3 or 4 (HR: 2.66 (1.72–4.12), p < 0.001) were significant predictors of death while increasing baseline CD4 T-cell counts were protective. Low CD4 T-cell counts, male sex, being unmarried and being unemployed were independent risk factors of death with male patients being twice as likely to die compared with females (Table 4). Patients who initiated ART with CD4 T-cell counts continued to have higher mortality rates throughout the follow-up period (Fig 3).

Table 4

Analysis of risk factors of all-cause mortality among older patients receiving ART at Newlands Clinic (2004–2020).

Characteristic	Hazard Ratio (95%CI)	p	Adjusted Hazard Ratio (95% CI)	p
Sex
Female	-	-	-	-
Male	1.27 (0.84–1.93)	0.262	2.29 (1.21–4.33)	0.010
ART commencement age	1.04 (1.0–1.1)	0.076	1.03 (0.99–1.07)	0.200
Married	-	-	-	-
Unmarried	1.27 (0.83–1.93)	0.273	2.06 (1.13–3.78)	0.019
Employed	-	-	-	-
Unemployed	1.75 (1.08–2.85)	0.024	2.01 (1.2–3.37)	0.008
Highest Education
Primary or none	-	-	-	-
Secondary or tertiary	0.77 (0.51–1.18)	0.230	0.83 (0.53–1.31)	0.428
ART Period
2004–2010	-	-	-	0.242
2011–2015	1.20 (0.75–1.92)	0.450	1.54 (0.93–2.56)
2016–2010	0.80 (0.38–1.69)	0.558	1.09 (0.49–2.39)
Baseline CD4 T-cell count (cells/μL)
<100	-	-	-	0.001
100–199	0.63 (0.39–1.02)	0.058	0.72 (0.44–1.16)
≥200	0.38 (0.22–0.67)	0.001	0.35 (0.19–0.63)
Prevalent Hypertension	0.59 (0.29–1.22)	0.157	0.76 (0.36–1.6)	0.464

Baseline WHO clinical stage was omitted from multivariable analysis due to collinearity with baseline CD4 T-cell count.

Fig 3

Kaplan-Meier curve showing survivor estimates by baseline CD4 T-cell categories adjusted for sex, employment, and marital status.

Increasing baseline CD4 T-cell counts were associated with lower likelihood of failing ART (p = 0.017), whereas being male, unemployed, or unmarried were not associated with failing ART. Among patients still in care, the number of patients with unsuppressed viral loads was too low to assess for association between independent risk factors of death and having unsuppressed viral loads.

Discussion

We present the treatment outcomes of OPLHIV who enrolled into care at Newlands Clinic in Harare, Zimbabwe, between February 2004, and April 2020. In this cohort, most patients were severely immune suppressed at enrolment, with significant differences between males and females in marital status, employment, and education. Hypertension was the most prevalent baseline and incident comorbidity, disproportionately affecting women. At analysis, 71.4% of patients were still in care, while 21% had died and only 4% had been lost to follow-up. ART related adverse effects were common, with 42% experiencing at least one side effect. ART was highly successful, with 94% of patients who had received ART for over six months being virally suppressed at the time of analysis. Over half of the patients (58%) received concomitant chronic disease medicines with their ART, mostly antihypertensives. Low baseline CD4 T-cell counts, being unmarried, being unemployed and being male were independent risk factors of all-cause mortality.

To our knowledge, this is the first study profiling outcomes of ART among OPLHIV in Zimbabwe. Our cohort was similar in sex distribution to other African cohorts that are comprised of more women than men [25-27]. Most of the women were widows in contrast to men who were mostly married. This difference is common in sub-Saharan Africa, where widows are less likely to remarry than widowers [28]. Older patients with HIV face a number of challenges that may affect their quality of life. Loss of partners and friends may lead to social isolation, depression and poor adherence to medicines [29]. The imbalance between men and women regarding education and employment is also reflected in this cohort, with more men having received education and being employed compared with women.

This study spans across a long period during which the WHO recommendations on CD4 T-cell count thresholds for ART commencement changed from <200 cells/μL to <350 cells/μL in 2010, then to <500 cells/μL in 2013, and finally “Treat-All” from 2015 [30, 31]. Nevertheless, the median baseline CD4 T-cell count at the start of ART only increased each year modestly, with a better improvement in baseline CD4 T-cell counts among women over time compared with males in line with findings from aggregated data from the IeDEA and the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) cohorts [32]. Nevertheless, many patients still presented with severe immunodeficiency and high viral loads (4.8 log copies/ml) across the study period [13]. This observation reinforces the call for interventions that target men for HIV testing and ART initiation.

Retention in care of 71.4% after a median follow up time of 5.6 years (IQR: 2.4–9.9) was comparable with that of a younger population (74.4%) at 36 months with a median age of 35 years (IQR: 28–42) in the Zimbabwe National ART Program and higher than that observed in a Kenyan cohort study (54%) at 36 months [33, 34]. However, unlike with this larger Zimbabwean study of younger patients wherein 98% of attrition was due to loss to follow-up, 74% of attrition in our cohort was due to death. Retention in care was also higher and loss to follow-up lower than that from an aggregated analysis of data from IeDEA sites in Africa at five years of follow-up (66% retention in care and 18.8% LTFU in point adjusted analyses) [35]. Implementation of patient follow-up measures as employed by Newlands Clinic is more challenging for the National Program and other facilities that have much larger cohorts under their care.

Viral suppression was high amongst those patients in care at 94%. While there are conflicting data on viral suppression and immune recovery among older patients initiating ART [4], our cohort showed remarkable recovery during follow up with statistically significant increases in median CD4 T-cell counts with each year on ART. Stavudine has been discontinued as an ART option due to its high side effects profile that includes peripheral neuropathy, lipodystrophy, lactic acidosis and pancreatitis [36]. Peripheral sensory polyneuropathy was the most common ART adverse effect in this study. Older age has been shown to be associated with peripheral neuropathy in both HIV infected and uninfected people [37, 38]. Zidovudine and tenofovir disoproxil fumarate are still in use in LMIC and clinicians should continue to monitor elderly patients for adverse effects while on these medicines.

Prevalence of hypertension was high, as was its incidence during follow-up. This is consistent with previously published Zimbabwean data that estimated hypertension prevalence at 30% (95% CI: 19% - 42%) in the general population [18]. The prevalence of hypertension in this cohort at the end of follow-up (49.3%) was much higher than that of the general population, with a higher burden among females. Consequently, antihypertensives comprised the biggest proportion of additional medicines used by the participants in our cohort. Close to a fifth of patients developed CKD. This is also consistent with existing knowledge that the risk of CKD is high in PLHIV and increases with age [39]. Earlier studies in South Africa have also shown a high burden of hypertension, stroke, diabetes and obesity among OPLHIV [40]. Overall, women had a higher burden of NCDs compared with men. There are mixed findings on the distribution of NCDs among people living with HIV between men and women [41, 42]. Still, our findings are limited by our study design which used routinely collected clinical data and could not comprehensively assess for all important NCDs. Nevertheless, our findings reinforce the need for continuous hypertension and renal monitoring among OPLHIV.

Lower CD4 T-cell counts at ART commencement, being male, unmarried, or unemployed were independent risk factors of all-cause mortality in this cohort. Advanced immunosuppression, depicted by CD4 T-cell counts below 100 cells/μL, is an indicator of late ART initiation or presentation to care and is associated with high mortality across all age groups [33, 34, 43]. Male patients were twice as likely to die compared to women in our cohort in line with existing literature [13]. This difference could be explained by the higher viral loads and lower CD4 T-cell counts among male patients at ART initiation which are known to be associated with worse outcomes on ART [44]. Despite women being disproportionately affected by adverse social factors as well as hypertension, male patients still had a higher mortality risk in keeping with global general population trends [45]. The observed trend of persistently higher mortality throughout follow-up among people who initiated ART with lower CD4 T-cell counts and the lower baseline CD4 T-cell counts among men affirms the need for a shift in the HIV treatment strategy to improve the ART outcomes observed in men starting with enhanced enrolment strategies [15, 46]. The higher risk of mortality among unmarried people that we observed may be due to several factors including the effect of social relationships, including marriage, on mortality as well as a lack of treatment support [47, 48]. Unemployment was a significant risk factor of death in our cohort. Although employment alone is not a comprehensive wealth index indicator, this finding is in line with a study conducted in Manicaland, Zimbabwe where a high wealth index was protective against both HIV infection and HIV-related mortality [49].

The strength of this study is the high quality of the data, which is ensured by routine data quality checks conducted by clinicians and a data quality manager. However, our study was based on routinely collected data, and we note some of the limitations associated with this method. HIV viral load monitoring was introduced in 2014, and analysis of viral suppression outcomes before this period could not be done. Cause of death information was not available in the records of deceased patients presenting a limitation in our analysis of risk factors of mortality. Furthermore, our study spans a 16-year period during which mortality risk factors may have evolved significantly. The outcomes of this cohort may not be generalizable to other facilities that have a less comprehensive approach to ART management than provided by Newlands Clinic or have much higher patient to clinician ratios. However, these outcomes show what can be achieved in the care of OPLHIV.

Conclusion

Our study showed high HIV treatment success among OPLHIV, but with a high burden of hypertension, particularly among women. Low CD4 T-cell counts, male sex, being unmarried and being unemployed were independent predictors of mortality, highlighting the importance of social and socioeconomic factors in addition to the well described early ART for longevity among OPLHIV. We recommend psychosocial support programs to augment the “treat-all” approach aimed at providing ART early before severe immune suppression to improve longevity among OPLHIV.

The RECORD statement–checklist of items, extended from the STROBE statement, that should be reported in observational studies using routinely collected health data.

(DOCX)

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19 Mar 2021

PONE-D-20-32848

Treatment outcomes in HIV infected patients older than 50 years attending an HIV clinic in Harare, Zimbabwe: A Cohort Study

PLOS ONE

Dear Dr. Shamu,

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.

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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,

Hyang Nina Kim, M.D., M.Sc.

Academic Editor

PLOS ONE

Additional Editor Comments:

In methods, please define chronic kidney disease.

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

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2. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

3. As part of your revision, please complete and submit a copy of the RECORD checklist, a document that aims to improve reporting and reproducibility of observational studies that use routinely-collected data for purposes of post-publication data analysis and reproducibility: (http://record-statement.org). Please include your completed checklist as a Supporting Information file. Note that if your paper is accepted for publication, this checklist will be published as part of your article.

4. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide.

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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

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

Reviewer #1: Yes

Reviewer #2: Yes

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

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Reviewer #1: Yes

Reviewer #2: Yes

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

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Reviewer #1: Yes

Reviewer #2: Yes

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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: This well written manuscript describes HIV care and treatment outcomes as well as NCDs in OPLHIV starting HIV treatment aged 50 or older. Generally it is a well organized manuscript with clear methods, appropriate analysis, and sound discussion. I have only minor suggestions/questions for the authors:

1) For the definition of hypertension, on "two separate occasions" likely means two different days, as opposed to two measurements on the same day, but recommend clarification.

2) Recommend CD4 T cell count to CD4 cell count terminology

3) In the abstract, it appears that the number of men and women do not sum to the total studied, but then it becomes clear in the results that the numbers used in the abstract were just referring to the number with a given marital status. Consider showing the denominator of total n men and women in the abstract or another method to clarify.

4) In the introduction, it is stated that there is no similar data on OPLHIV in Zimbabwe - here would be a good place to comment briefly on the existence of OPLHIV data elsewhere in SSA, which is addressed in more detail in the discussion.

5) Recommend highlighting which were the adverse effects attributable to tenofovir, as this is a component the new standard first line regimen, TLD.

6) Would the study have captured aspirin use for risk reduction in those with HTN? Worth a comment, in my view.

7) the finding associated with increased risk of mortality and being unmarried merits some additional discussion.

Reviewer #2: This cohort study of 420 patients who are living with HIV and over 50 years old presenting for care and started ART at a clinic in Harare, Zimbabwe over a 16 year period. This cohort demonstrates a high mortality rate (21%) despite high rates of viral suppression (94%). High mortality correlated with delayed initiation of ART (WHO stage 3-4 at initiation) (aHR=3.0) and male sex (aHR=2.0) as well as indicators of poverty (unemployment) and being unmarried. I would recommend revising the analysis to include baseline CD4 count rather than WHO stage as a more objective measure of immunosuppression at initiation of ART. This manuscript is well written aside from some minor grammatical errors (e.g., inconsistent use of oxford comma) and includes interesting data that indicate the importance of considering gender and socioeconomic status when considering management of persons living with HIV who are >50 years old in order to reduce the risk of early mortality. This analysis adds to the evolving literature around aging and HIV and risk factors for mortality.

General comments:

1) Both male sex and increased years of uncontrolled viral load (low nadir CD4/high WHO stages) are independent risk factors for cardiovascular disease, and a high incidence rate of hypertension in this cohort, especially among female patients, is a notable mortality risk. However, the absence of cause of death data does not allow for further analysis and may reflect limited life expectancy for all adults in Zimbabwe. This should be more clearly indicated as a limitation of the analyses.

2) Given the long duration of 14 years over which this cohort was accrued, the authors should discuss the limitations of temporal trends that could have impacted mortality risks between 2004 and 2020.

3) Additional analyses may further illuminate the high mortality rate, especially since univariate analysis was not impacted by prevalent hypertension. In addition, differences by sex should be explored further by adjusting for CD4 count at treatment initiation. Longitudinal multivariate analysis of incidence hypertension, chronic kidney disease, malignancy, and TB would be needed to support the conclusions of this manuscript.

Specific comments:

1) Line 57 –Be more specific about special considerations for HIV care in aging adults living with HIV. Additionally, increased risk of opportunistic infections may not be true in the setting of viral suppression; please provide a reference and modify this comment as needed.

2) Lines 58-59 – Your data and the reference above indicate high rates of adherence in this demographic. Would you consider drug interactions altering drug availability or frequent changes in ART regimen to avoid drug interactions leading to disruptions more accurate that poor adherence?

3) Line 80- do you mean PLHIV (rather than OPLHIV) or does this clinic only provide care to patients over the age of 50 years old?

4) Line 84 – rather than using the term “vulnerable communities,” which implies weakness, UNAIDS terminology guidelines suggest using specific language such as “communities with high prevalence of poverty and unemployment.”

5) Line 132 – Clarify elderly, e.g., “420 patients 50 years or older…”

6) Line 152 – Given the elevated p-value, it would be appropriate to state that males and females died at a similar rate.

7) Line 202- If possible please clarify “cancer of the eye” or replace with “ocular malignancy not specified”

8) Risk of death analysis and Table 4

a) The baseline CD4 count was removed from the multivariate analysis because of collinearity with WHO stage. I would suggest removing WHO stage which is a more subjective measure than a CD4 count, especially given the apparent difference in CD4 count at initiation by sex (Figure 1) in the last decade.

b) Most participants provide multiple measures of blood pressure over time and the incidence of hypertension is quite high. It would be helpful to indicate what proportion of persons reported to have HTN were noted to have elevated BP at multiple visits.

c) Incidence of CKD, TB, and malignancy were also quite high. A longitudinal multivariate analysis of incident hypertension, CKD, TB, and malignancy correlation with mortality risk would be informative.

9) Lines 235-237, 251 – The authors note several differences between sexes in prevalence of social hardship and hypertension with females disproportionately impacted; however, male patients had a higher mortality rate. This warrants a comment from the authors.

10) Line 248 – Please clarify if you are referring to differences between males and females, sex, vs. social roles, genders. The word gender should be replaced with sex in this context.

11) Line 262 – Is this an observation from this cohort? Please ensure that these data on difference in baseline CD4 count and delayed treatment by sex are included in your results section. If these data are not available for your cohort, the reference to Western Cape cohort should be limited to the introduction section.

12) Line 269 – It is not possible to know if patients who died would have stayed in care if they were still living, and thus your data do not support your claim that older patients are more likely to remain committed to care than younger people, especially when the amount of patient tracking and staff outreach may differ at these different clinics.

13) Line 280 – Please comment on the prevalence of peripheral neuropathy and other side effects experienced in your cohort compared to other, younger cohorts.

14) Line 301-303 – Please explain your recommendation for enhancing enrollment strategies for males as a mechanism for reducing mortality among men living with HIV. It is curious that males had high rates of viral suppression but also had a high mortality rate. Figure 1 appears to show lower CD4 at initiation of ART, especially after 2011. Do you have additional data to explain higher mortality rate among males? Can risk of mortality among males be explained by CD4 count at initiation of ART?

15) Line 303-304 – Did unmarried patients have higher likelihood of failing treatment or uncontrolled viral loads? Please provide further data to explain the correlation between unmarried status and mortality in your cohort.

16) Line 320 – Please list all independent predictors of mortality not just WHO stage and unemployment.

17) Conclusion. The results mention the impact of TB and CKD but these were not included in your multivariate (or univariate) analyses. Were these predictors of mortality?

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Reviewer #1: Yes: Julie A. Ake

Reviewer #2: No

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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 PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Submitted filename: PONE_review_20210310.docx

Click here for additional data file.

3 May 2021

Response to Reviewers

Responses to the Editor

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Response

We have ensured that our manuscript is consistent with PLOS ONE’s requirements.

2. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Response

We have reviewed the reference list and have not found any retracted papers. We have also checked completeness of the references.

3. As part of your revision, please complete and submit a copy of the RECORD checklist, a document that aims to improve reporting and reproducibility of observational studies that use routinely-collected data for purposes of post-publication data analysis and reproducibility: (http://record-statement.org). Please include your completed checklist as a Supporting Information file. Note that if your paper is accepted for publication, this checklist will be published as part of your article.

Response

Thank you for this recommendation. We have uploaded a copy of the RECORD checklist in this re-submission.

4. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide.

Response

The data are currently stored at figshare.com available on the link https://doi.org/10.6084/m9.figshare.14525487.

Reviewer 1

1) For the definition of hypertension, on "two separate occasions" likely means two different days, as opposed to two measurements on the same day, but recommend clarification.

Response

Thank you for this comment. We have reviewed the sentence to read “Diagnosis of hypertension was made when a patient’s systolic or diastolic blood pressure was above 140mm Hg or above 90mm Hg, respectively, on two or more days”

2) Recommend CD4 T cell count to CD4 cell count terminology.

Response

We have replaced “CD4 cell count” with CD4 T-cell count.

3) In the abstract, it appears that the number of men and women do not sum to the total studied, but then it becomes clear in the results that the numbers used in the abstract were just referring to the number with a given marital status. Consider showing the denominator of total n men and women in the abstract or another method to clarify.

Response

Thank you for noting the discrepancy. We have corrected the figures in both the abstract and Table 1. We have added the denominator in the abstract for clarity.

4) In the introduction, it is stated that there is no similar data on OPLHIV in Zimbabwe - here would be a good place to comment briefly on the existence of OPLHIV data elsewhere in SSA, which is addressed in more detail in the discussion.

Response

Thank you for this comment. We have added a comment on data from the region.

5) Recommend highlighting which were the adverse effects attributable to tenofovir, as this is a component the new standard first line regimen, TLD.

Response

In the absence of definitive diagnoses of renal impairment which often require kidney biopsies, we could not objectively attribute specific adverse effects to TDF. However, as part of routine clinical care, TDF was stopped with presumptive diagnosis of TDF adverse effects.

6) Would the study have captured aspirin use for risk reduction in those with HTN? Worth a comment, in my view.

Response

We have added the statement “Risk reduction of major adverse cardiovascular events using aspirin was only provided for patients with history of myocardial infarction”. These patients are very few.

7) The finding associated with increased risk of mortality and being unmarried merits some additional discussion.

Response

We have added the statement “Older patients with HIV face a number of challenges that may affect their quality of life. Loss of partners and friends may lead to social isolation, depression and poor adherence to medicines”.

Reviewer 2

General comments:

1. Both male sex and increased years of uncontrolled viral load (low nadir CD4/high WHO stages) are independent risk factors for cardiovascular disease, and a high incidence rate of hypertension in this cohort, especially among female patients, is a notable mortality risk. However, the absence of cause of death data does not allow for further analysis and may reflect limited life expectancy for all adults in Zimbabwe. This should be more clearly indicated as a limitation of the analyses.

Response

Thank you for this comment. We have added this limitation in the paragraph discussing strengths and weaknesses of the study as highlighted below:

“Cause of death information was not available in the records of deceased patients presenting a limitation in our analysis of risk factors of mortality. Furthermore, our study spans a 16-year period during which mortality risk factors may have evolved significantly.”

2. Given the long duration of 14 years over which this cohort was accrued, the authors should discuss the limitations of temporal trends that could have impacted mortality risks between 2004 and 2020.

Response

Thank you for this comment. We have also added this limitation in the paragraph discussing strengths and weaknesses of the study as highlighted above.

3. Additional analyses may further illuminate the high mortality rate, especially since univariate analysis was not impacted by prevalent hypertension. In addition, differences by sex should be explored further by adjusting for CD4 count at treatment initiation. Longitudinal multivariate analysis of incidence hypertension, chronic kidney disease, malignancy, and TB would be needed to support the conclusions of this manuscript.

Response

Thank you for this comment. We analysed the mortality differences by sex adjusting for CD4 count alone and the difference was not apparent. However, adjusting for the other confounders showed that indeed sex is an independent risk factor. Instead of performing additional multivariable analyses on hypertension incidence, CKD, malignancy, and TB, we reviewed the conclusion to reflect findings that were observed in the original analysis. The conclusion now reads as follows:

“Our study showed high HIV treatment success among OPLHIV, but with a high burden of hypertension, particularly among women. Low CD4 T-cell counts, male sex, being unmarried and being unemployed were independent predictors of mortality, highlighting the importance of social and socioeconomic factors in addition to the well described early ART for longevity among OPLHIV. We recommend psychosocial support programs to augment the “treat-all” approach aimed at providing ART early before severe immune suppression to improve longevity among OPLHIV.”

Specific comments:

1. Line 57 –Be more specific about special considerations for HIV care in aging adults living with HIV. Additionally, increased risk of opportunistic infections may not be true in the setting of viral suppression; please provide a reference and modify this comment as needed.

Response

Thank you for this comment. We have reviewed the sentence as follows, “. Management of OPLHIV requires a multidisciplinary team approach, taking into account the onset of non-communicable diseases, premature ageing, and an increased risk of drug-to-drug interactions and drug toxicities due to polypharmacy”.

2. Lines 58-59 – Your data and the reference above indicate high rates of adherence in this demographic. Would you consider drug interactions altering drug availability or frequent changes in ART regimen to avoid drug interactions leading to disruptions more accurate that poor adherence?

Response

We agree with your comment. We have reconsidered and edited the sentence as follows: “Polypharmacy also complicates selection of ART regimens and the increased chronic pill burden may lead to treatment fatigue”.

3. Line 80- do you mean PLHIV (rather than OPLHIV) or does this clinic only provide care to patients over the age of 50 years old?

Response

Thank you for noting this error. We have corrected the sentence as follows:

“Apart from providing antiretroviral therapy to people living with HIV, the clinic also provides, among other services, onsite laboratory investigations, psychosocial support, reproductive health services including cervical cancer screening, dental services, food support, and bus fare assistance”.

4. Line 84 – rather than using the term “vulnerable communities,” which implies weakness, UNAIDS terminology guidelines suggest using specific language such as “communities with high prevalence of poverty and unemployment.”

Response

We have replaced “vulnerable communities” with the suggested terminology.

5. Line 132 – Clarify elderly, e.g., “420 patients 50 years or older…”

Response

We have removed the term “elderly” from this sentence and it now reads, “During the study period, 420 patients aged 50 years or older were enrolled into care at Newlands Clinic, 241 (57.4%) being female”

6. Line 152 – Given the elevated p-value, it would be appropriate to state that males and females died at a similar rate.

Response

Thank you for this observation. The sentence now reads, “There was no difference in proportion of males died (23.5%) compared to females (19.1%) (p = 0.276)”.

7. Line 202- If possible please clarify “cancer of the eye” or replace with “ocular malignancy not specified”

Response

Thank you for the suggestion. We have changed the term as suggested i.e., “ocular malignancy not specified”.

8. Risk of death analysis and Table 4

a) The baseline CD4 count was removed from the multivariate analysis because of collinearity with WHO stage. I would suggest removing WHO stage which is a more subjective measure than a CD4 count, especially given the apparent difference in CD4 count at initiation by sex (Figure 1) in the last decade.

Response

We have repeated the analysis with CD4 included and WHO stage excluded from the Cox model. Table 4 is now updated with new results.

b) Most participants provide multiple measures of blood pressure over time and the incidence of hypertension is quite high. It would be helpful to indicate what proportion of persons reported to have HTN were noted to have elevated BP at multiple visits.

Response

We agree that uncontrolled hypertension among hypertensive patients is interesting but would be better addressed as a different study. In the current study, we used the diagnosis variable to determine the burden of hypertension but we did not abstract individual blood pressure measurements from the database. As described in the methods section, a diagnosis of hypertension was made at the clinic when a patient’s systolic or diastolic blood pressure was above 140mm Hg or above 90mm Hg, respectively, on two or more days.

c) Incidence of CKD, TB, and malignancy were also quite high. A longitudinal multivariate analysis of incident hypertension, CKD, TB, and malignancy correlation with mortality risk would be informative.

Response

The authors agree with this comment. However, we feel that in-depth analysis of the various aspects listed above would go beyond the scope of this current study and may be better done as separate studies.

9. Lines 235-237, 251 – The authors note several differences between sexes in prevalence of social hardship and hypertension with females disproportionately impacted; however, male patients had a higher mortality rate. This warrants a comment from the authors.

Response

We have added the following statement in the discussion: “Despite women being disproportionately affected by adverse social factors as well as hypertension, male patients still had a higher mortality risk in keeping with global general population trends”.

10. Line 248 – Please clarify if you are referring to differences between males and females, sex, vs. social roles, genders. The word gender should be replaced with sex in this context.

Response

We have removed the word “gender” from the sentence, and it now reads, “This difference is common in sub-Saharan Africa, where widows are less likely to remarry than widowers.”

11. Line 262 – Is this an observation from this cohort? Please ensure that these data on difference in baseline CD4 count and delayed treatment by sex are included in your results section. If these data are not available for your cohort, the reference to Western Cape cohort should be limited to the introduction section.

Response

We agree with your comment. We have removed this sentence.

12. Line 269 – It is not possible to know if patients who died would have stayed in care if they were still living, and thus your data do not support your claim that older patients are more likely to remain committed to care than younger people, especially when the amount of patient tracking and staff outreach may differ at these different clinics.

Response

Thank you for this comment. We have edited the sentence to read as, “However, unlike with this larger Zimbabwean study of younger patients wherein 98% of attrition was due to loss to follow-up, 74% of attrition in our cohort was due to death.”

13. Line 280 – Please comment on the prevalence of peripheral neuropathy and other side effects experienced in your cohort compared to other, younger cohorts.

Response

We have added the following sentence in the discussion, “Older age has been shown to be associated with peripheral neuropathy in both HIV infected and uninfected people”.

14. Line 301-303 – Please explain your recommendation for enhancing enrollment strategies for males as a mechanism for reducing mortality among men living with HIV. It is curious that males had high rates of viral suppression but also had a high mortality rate. Figure 1 appears to show lower CD4 at initiation of ART, especially after 2011. Do you have additional data to explain higher mortality rate among males? Can risk of mortality among males be explained by CD4 count at initiation of ART?

Response

We have added Figure 4 which is depicts Kaplan-Meier survival estimates of mortality by baseline CD4 T-cell counts adjusted for sex, employment, and marital status. From the observed curves, we have edited the comment in the discussion as follows: “The observed trend of persistently higher mortality throughout the follow-up period among people who initiated ART with lower CD4 T-cell counts and the lower baseline CD4 T-cell counts among men affirms the need for a shift in the HIV treatment strategy to improve the ART outcomes observed in men starting with enhanced enrolment strategies”.

15. Line 303-304 – Did unmarried patients have higher likelihood of failing treatment or uncontrolled viral loads? Please provide further data to explain the correlation between unmarried status and mortality in your cohort.

Response

This comment has been partly addressed in comment number 7 under Reviewer 1. In addition, we have added the following statements after Table 4:

16. Line 320 – Please list all independent predictors of mortality not just WHO stage and unemployment.

Response

Thank you for the comment. We have added all independent predictors of mortality to the conclusion.

17. Conclusion. The results mention the impact of TB and CKD but these were not included in your multivariate (or univariate) analyses. Were these predictors of mortality?

Response

Thank you for this comment. The conclusion has been reviewed as shown in the response to comment 3 under general comments.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

18 May 2021

PONE-D-20-32848R1

Treatment outcomes in HIV infected patients older than 50 years attending an HIV clinic in Harare, Zimbabwe: A Cohort Study

PLOS ONE

Dear Dr. Shamu,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but requires further clarifying revision. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jul 02 2021 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. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Hyang Nina Kim, M.D., M.Sc.

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments (if provided):

(1) Please address the reviewer's comment re line 64 (formerly line 57) that discusses accelerated immune senescence and disease progression in the elderly. The reviewer point outs: "increased risk of opportunistic infections may not be true in the setting of viral suppression; please provide a reference and modify this comment as needed."

(2) Table 4 requires further revision to remove reference to WHO staging in favor of baseline CD4 cell count which is more objectively assessed than the former. There also remains a footnote re WHO staging that will need to be removed.

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

[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.]

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 PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

24 May 2021

Thank you for the follow-up response to our re-submission. Below are responses to the two issues raised in the email dated 18 May 2021:

Comment 1

Please address the reviewer's comment re line 64 (formerly line 57) that discusses accelerated immune senescence and disease progression in the elderly. The reviewer point outs: "increased risk of opportunistic infections may not be true in the setting of viral suppression; please provide a reference and modify this comment as needed."

Response

We previously revised the original sentence suggesting increased risk of opportunistic infections (OI) as suggested by the reviewer and removed the OI connotation. The revised sentence reads as follows, “Management of OPLHIV requires a multidisciplinary team approach, taking into account the onset of non-communicable diseases, premature ageing, and an increased risk of drug-to-drug interactions and drug toxicities due to polypharmacy”. To improve clarity, we have revised the preceding sentence as well which now reads, “Compounding the age-related thymic contraction, HIV infection affects both B- and T-cell function leading to accelerated immunosenescence and consequently increased risk of non-AIDS related, age associated comorbidities in elderly patients”, with the relevant references added.

Comment 2

Table 4 requires further revision to remove reference to WHO staging in favor of baseline CD4 cell count which is more objectively assessed than the former. There also remains a footnote re WHO staging that will need to be removed.

Response

We have removed the row with WHO stage from Table 4 and indicated the unadjusted hazard ratio in the text. We have also corrected the Table 4 footnote which now reads, “Baseline WHO clinical stage was omitted from multivariable analysis due to collinearity with baseline CD4 T-cell count.”

Submitted filename: Response to Reviewers.pdf

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27 May 2021

Treatment outcomes in HIV infected patients older than 50 years attending an HIV clinic in Harare, Zimbabwe: A Cohort Study

PONE-D-20-32848R2

Dear Dr. Shamu,

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Kind regards,

Hyang Nina Kim, M.D., M.Sc.

Academic Editor

PLOS ONE

1 Jun 2021

PONE-D-20-32848R2

Treatment outcomes in HIV infected patients older than 50 years attending an HIV clinic in Harare, Zimbabwe: A cohort study

Dear Dr. Shamu:

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.

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Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Hyang Nina Kim

Academic Editor

PLOS ONE