Highlights•

Variation in HIV care linkage/treatment initiation across nations/settings in SSA

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Low HIV care linkage and treatment initiation rates in most settings in SSA

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Health care delivery factors affected care linkage/treatment initiation in adults

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Psychosocial/perceptual/sociodemographic factors associated with late care linkage

AbstractBackground

Late treatment initiation threatens the clinical and public health benefits of antiretroviral therapy (ART). Quantitative synthesises of the existing evidence related to this is lacking in sub-Saharan Africa (SSA), which would help ascertain the best evidence-based interventions. This review aimed to systematically synthesise the available literature on factors affecting linkage to care and ART initiation amongst HIV-infected adults in SSA.

Methods

Systematic searches were undertaken on four databases to identify observational studies investigating factors affecting both HIV care outcomes amongst adults (age ≥19 years) in SSA, and were published between January 1, 2015 and June 1, 2021. RevMan-5 software was used to conduct meta-analyses and Mantel-Haenszel statistics to pool outcomes with 95% confidence interval and <0.05 level of significance.

Results

Forty-six studies were included in the systematic review, of which 18 fulfilled requirements for meta-analysis. In both narrative review and meta-analyses, factors related to health care delivery, individual perception and sociodemographic circumstances were associated with late linkage to care and delays in ART initiation.

Conclusion

This review identified a range of risk factors for late linkage to care and delayed ART initiation amongst HIV-infected adults in SSA. We recommend implementation of patient-centred intervention approaches to alleviate these barriers.

Key wordsAbbreviations: AHR (Adjusted hazards ratio), AIDS (Acquired immunodeficiency syndrome), APRR (Adjusted prevalence risk ratio), ART (Antiretroviral therapy), ARVs (Antiretrovirals), CD4 (cluster of differentiation-4), CI (Confidence interval), EPHPP (Effective public health practice project), HIV (Human immunodeficiency virus), OR (odds ratio), PICT (Provider initiated counselling and testing), PLWH (People living with HIV), PRISMA (Preferred reporting items for systematic reviews and meta-analyses), PROSPERO (Prospective register of systematic reviews), RR (Relative risk), SSA (sub-Saharan Africa), TB (tuberculosis), USD (United States dollars), VCT (Voluntary counselling and testing), UNAIDS (The Joint United Nations Programme on HIV/AIDS), WHO (World Health Organization)

Background

Antiretroviral therapy (ART) has transformed HIV infection from a fatal to a potentially manageable chronic disease and has significantly elongated the life expectancy of people living with HIV (PLWH) (Trickey et al., 2017). In addition to its effect in preventing acquired immunodeficiency syndrome (AIDS) and non-AIDS related comorbidities and mortality (Granich et al., 2015;Lundgren et al., 2015), early initiation of ART significantly reduces new HIV infections by suppressing viral concentration in PLWH (Na et al., 2013;Cohen et al., 2016).

While international guidelines recommend linkage to care and initiating ART at the time of diagnosis (a strategy known as “Test and Treat”) (World Health Organization, 2015), PLWH in sub-Saharan African (SSA) countries often commence ART at advanced stages of infection (at CD4 count <200cells/mm3 and/or WHO clinical sage III/IV) (Plazy et al., 2015;Nash et al., 2016;van der Kop et al., 2016;Fomundam et al., 2017). High prevalence of late linkage to care (Fomundam et al., 2017;Gesesew et al., 2018;Rentsch et al., 2018) and ART initiation (Brown et al., 2016;Nash et al., 2016;Ngom et al., 2018) has been reported in many SSA countries.

Individual studies reported various structural, psychosocial, perceptual and sociodemographic circumstances as risk factors for late linkage to HIV care and ART initiation amongst PLWH in SSA. Among structural factors, barriers to health care delivery, such as distance to a health care facility have been commonly reported (Kwobah et al., 2016;van der Kop et al., 2016;Yakob and Ncama, 2016). Psychosocial circumstances, including low social support, inability to disclose HIV status in fear of stigma, have been found to affect linkage to care and ART initiation (Dorward et al., 2017;Lambert et al., 2018). In addition, perceptions of the health benefits of early ART (Camlin et al., 2016;Teklu et al., 2017) and an acceptance of HIV positive status (Nash et al., 2016;Reddy et al., 2016;Kulkarni et al., 2017) have been strongly linked to the level of the patients’ engagement in care and ART initiation. Sociodemographic characteristics, such as younger age, male gender, lacking a partner, having a low wealth index and being employed have also been frequently reported to be associated with late linkage to care and delays in ART initiation (Nyika et al., 2016;Billioux et al., 2017;Dorward et al., 2017;Teklu et al., 2017).

Previous reviews in the region also emphasised the influence of these factors on linkage to care and ART initiation. The reviews showed that transport cost associated with distant health care facilities, shortage of staff and poor quality health services mainly constituted supply side challenges (Govindasamya et al., 2012;Lahuerta et al., 2013;Ahmed et al., 2018). Socially, a fear of status disclosure due to stigma, and low social support led to delays in linkage to care and treatment initiation (Govindasamya et al., 2012;Lahuerta et al., 2013;Ahmed et al., 2018). At an individual level, low CD4 count and associated feelings of being healthy at earlier stages of the disease, low knowledge of treatment benefits, male gender, younger age and being employed were associated with late linkage to care and ART initiation (Govindasamya et al., 2012;Lahuerta et al., 2013;Ahmed et al., 2018).

Across published studies, there are variations in definitions of HIV care-related health outcomes as well as contextual differences associated with the risk factors for late linkage to care and delayed ART initiation. The resulting lack of unequivocal evidence has substantially impeded successful implementation of available interventions as well as the development of novel strategies for improving care linkage and ART initiation (Govindasamy et al., 2014;Fox et al., 2016). Whilst systematic reviews have been conducted on this topic in SSA (Govindasamya et al., 2012;Lahuerta et al., 2013;Ahmed et al., 2018), a few have quantitatively focussed on factors of various levels relating to late linkage to care or delays in ART initiation. Further, most were conducted before the endorsement of the “Test and Treat” strategy (World Health Organization, 2015), underscoring the need for more inclusive and up to date information. Our review aimed to systematically synthesise the available evidence on barriers to care linkage and ART initiation amongst adult PLWH in SSA in order to suggest contextually tailored intervention strategies.

Methods

This review was reported based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA) (Page et al., 2021) (see Supplementary file 1). The review protocol has been published at the International Prospective Register of Systematic Reviews (PROSPERO; Number: CRD42021264398) (Fuge et al., 2021) (see Supplementary file 2).

Eligibility criteria

Studies: We reviewed observational studies analysing factors affecting linkage to HIV care and/or ART initiation in the target population. Qualitative and intervention-based studies were not considered as the aim of the review was to quantify risk factors in a natural setting.

Participants: The review included adults diagnosed with HIV (as WHO defines: ≥19 years of age (World Health Organization, 2015)) in SSA. Studies conducted on specialised population groups that may have a particular risk for the health outcomes under investigation such as: people younger than 19 years of age, sex workers, men having sex with men, pregnant women, tuberculosis (TB) patients and serodiscordant couples were excluded.

Exposures: Structural factors pertaining to healthcare access and other healthcare delivery barriers (e.g. distance to a healthcare facility), psychosocial and personal determinants of late presentation for HIV care and ART initiation (such as the influence of social support, status disclosure, and perceptions of early treatment initiation) were exposures of interest in the review. We also assessed the influence of sociodemographic factors such as age, gender, marital status, and other characteristics.

Comparators: While no restriction was made based on whether a study had used comparators, individuals without an exposure of interest were considered as the control group when comparisons were made.

Outcome measures: Rates of linkage to HIV care and ART initiation over a certain period of time (as defined by individual studies) were considered the main outcomes of the review. No restriction was made on the inclusion of studies based on the definition of the outcomes.

Information sources and search strategy

We conducted systematic searches in databases including MEDLINE, PubMed, Web of Science and Emcare. The search strategy was designed using the concepts ‘HIV/AIDS’, ‘ART’ and ‘Linkage to HIV Care or Initiation of ART’ and names of countries in SSA. Terms related to the concepts were used and combined with the MEDLINE filter. The search strategy for MEDLINE was: HIV or Human Immunodeficiency virus or AIDS or Acquired Immunodeficiency Syndrome or (HIV or AIDS or HIV-AIDS or Acquired Immunodeficiency Syndrome or Human immunodeficiency virus).tw,kf. and ART or Antiretroviral Therapy or Highly Active antiretroviral therapy and "linkage to care" or "presentation to care" or start* or initiate* or (antiretroviral* or anti-retroviral* or HAART or ART or anti-hiv).tw,kf. and (Angola or Benin or Botswana or Burkina Faso or Burundi or Cape Verde or Cameroon or Central African Republic or Chad or Comoros or Democratic Republic of the Congo or Congo or Cote D'ivoire or Equatorial Guinea or Eritrea or Eswatini or Ethiopia or Gabon or Gambia or Ghana or Guinea or Guinea-Bissau or Kenya or Lesotho or Liberia or Madagascar or Malawi or Mali or Mauritania or Mauritius or Mozambique or Namibia or Niger or Nigeria or Rwanda or “Sao Tome and Principe” or Senegal or Seychelles or Sierra Leone or Somalia or South Africa or South Sudan or Sudan or Tanzania or Togo or Uganda or Zambia or Zimbabwe). We adapted the search terms to use with other bibliographic databases along with database-specific filters. Studies involving adults (≥19 years), published in English language since 2015 and indexed up to June 1, 2021 were retrieved. We selected a period from 2015 for the review as this was the time when WHO announced the new “Test and Treat” Strategy (World Health Organization, 2015).

Study selection and risk of bias assessment

One review author (TGF) performed screening of articles for their relevance to the review question with titles and abstracts. After removal of duplicate and irrelevant articles, the same author performed a full text review on the retrieved articles based on a protocol published in advance (Fuge et al., 2021). Three independent assessors (including the first author of the review –TGF) conducted a quality assessment (risk of bias) of the retrieved articles using the Effective Public Health Practice Project (EPHPP) Quality Assessment Tool for Quantitative Studies (see Supplementary file 3). The quality assessment process considered the following characteristics: representativeness of participants (selection bias), appropriateness of the study design to answer study objectives, control of potential confounders, validity and reliability of data collection methods and completeness of outcome data (withdrawals and dropouts). Disagreements between the assessors were resolved by discussion and decided by a final independent assessment where required.

Data abstraction

We used a format adapted from the Cochrane Systematic Review Checklist for Data Collection to extract data (see Supplementary file 4). Separate data extraction formats were used for linkage to care and ART initiation. The data extraction form included information regarding author, year, country, population, method, measurements, exposures, results, and conclusions. We contacted corresponding authors of seven primary studies for additional data regarding an exposure of interest versus the outcomes

Data synthesis

We provided a narrative review of the results across studies regarding exposures and outcomes. We conducted a meta-analysis when at least two studies measured the same exposure and outcome, using comparable definitions. A Fixed-Effect model was used when the number of studies was small (n<5) and when a substantial difference was observed between sample sizes, which could limit the generalisability of the findings beyond the included studies (Borenstein M et al., 2007:;Tufanaru et al., 2015); otherwise, a Random-Effects Model was applied to pool the outcomes with odds ratios and to calculate 95% confidence intervals. Heterogeneity between studies in effect measures was determined using Chi2 test and I2 statistic, and an I2 value of 75% was considered as high heterogeneity (Higgins et al., 2003). We used RevMan-5 software (Review Manager, 2014) to calculate pooled odds ratios by applying Mantel-Haenszel statistics for each outcome and a forest plot to present the results.

Results

The electronic literature search identified 2597 articles, of which 451 were duplicates and 2064 were irrelevant to the review question (based on the title and abstract appraisal). An additional 36 articles were removed after the full text review that was based on the eligibility criteria (i.e. studies conducted on ineligible populations, qualitative studies, intervention studies, review articles or articles lacking the desired outcomes: not reporting on linkage to care or ART initiation). Among the remaining 46 studies that were included in the review, 18 met the criteria for meta-analysis. Figure 1 depicts the selection process and number of articles excluded and retrieved at each stage.

Fig. 1Study flow diagram. Study selection process and reasons for exclusion.

Study characteristics

The characteristics of the 46 included studies are presented in Tables 1 and 2. Almost half (46%) of the studies were from eastern Africa: nine from Ethiopia, five from Kenya, three from Tanzania and two each from Uganda and Rwanda. Those from southern Africa (South Africa, Malawi, Mozambique and Zimbabwe) accounted for 39% of the review articles. Six studies were from western and central Africa: two from Cameroon, and one each from Guinea-Bissau, Nigeria, Senegal and Cape Verde. One study used a clinic-based cohort across four countries (Uganda, Kenya, Tanzania and Nigeria). More than half (52%) of the studies used a (mostly retrospective) cohort design (Odeny et al., 2015;Ogoina et al., 2015;Plazy et al., 2015;Teasdale et al., 2015;Brown et al., 2016;Honge et al., 2016;Reddy et al., 2016;Billioux et al., 2017;Dorward et al., 2017;Hoffman et al., 2017;Maheu-Giroux et al., 2017;Sanga et al., 2017;Teklu et al., 2017;Boeke et al., 2018;Bor et al., 2018;Gebru et al., 2018;Gesesew et al., 2018;Lopez-Varela et al., 2018;Luma et al., 2018;Ngom et al., 2018;Rane et al., 2018;Katz et al., 2019;Onoya et al., 2020) while 19 studies employed a cross-sectional design (Haskew et al., 2015;Boyer et al., 2016;Kwobah et al., 2016;Nash et al., 2016;Takah et al., 2016;van der Kop et al., 2016;Cholera et al., 2017;Fomundam et al., 2017;Franse et al., 2017;Hoffman et al., 2017;Kulkarni et al., 2017;Kayabu et al., 2018;Anlay et al., 2019;Larsen et al., 2019;Lifson et al., 2019;Maughan-Brown et al., 2019;Esber et al., 2020;Lilian et al., 2020;Maughan-Brown et al., 2021). The remaining three studies employed a case-control design (Gelaw et al., 2015;Moreira et al., 2016;Nyika et al., 2016). Twenty-one studies reported on linkage to HIV care (Gelaw et al., 2015;Haskew et al., 2015;Honge et al., 2016;Kwobah et al., 2016;Moreira et al., 2016;Nyika et al., 2016;Reddy et al., 2016;Takah et al., 2016;van der Kop et al., 2016;Dorward et al., 2017;Fomundam et al., 2017;Maheu-Giroux et al., 2017;Sanga et al., 2017;Boeke et al., 2018;Gesesew et al., 2018;Kayabu et al., 2018;Luma et al., 2018;Rane et al., 2018;Lifson et al., 2019;Hoffman et al., 2020;Maughan-Brown et al., 2021) (Table 1), seventeen on ART initiation(Odeny et al., 2015;Ogoina et al., 2015;Plazy et al., 2015;Teasdale et al., 2015;Boyer et al., 2016;Brown et al., 2016;Nash et al., 2016;Hoffman et al., 2017;Bor et al., 2018;Gebru et al., 2018;Ngom et al., 2018;Anlay et al., 2019;Katz et al., 2019;Larsen et al., 2019;Esber et al., 2020;Lilian et al., 2020;Onoya et al., 2020) and the rest eight reported both outcomes (Billioux et al., 2017;Cholera et al., 2017;Franse et al., 2017;Kulkarni et al., 2017;Teklu et al., 2017;Lopez-Varela et al., 2018;Rentsch et al., 2018;Maughan-Brown et al., 2019) (Table 2).

Table 1Characteristics of studies investigating linkage to HIV care.

AHR: Adjusted hazards ratio; AOR: Adjusted odds ratio; APRR: Adjusted prevalence risk ratio; ART: Antiretroviral therapy; ARV: Antiretroviral; ASHR: Adjusted sub-hazard ratio; CBSS: Community-based serosurvey; HBT: Home-based testing; OR: Odds ratio; PICT: Provider initiated counselling and testing; RR: Relative risk; TB-Tuberculosis; USD: United States dollars; VCT: Voluntary counselling and testing; WHO: World Health Organization

Table 2Characteristics of studies investigating initiation of antiretroviral therapy.

AHR: Adjusted hazards ratio; AIDS: Acquired immunodeficiency syndrome; AOR: Adjusted odds ratio; APRR: Adjusted prevalence risk ratio; ARR: Adjusted relative risk; ART: Antiretroviral therapy; ARV: Antiretroviral; ASHR: Adjusted sub-hazard ratio; OR: Odds ratio; PICT: Provider initiated counselling and testing; RR: Relative risk; TB-Tuberculosis; VCT: Voluntary counselling and testing; WHO: World Health Organization

*Studies included in other categories

Methodological quality

Almost three-quarters (72%) of the studies were assessed as ‘moderate’ or ‘strong’ quality in regard to ensuring the representativeness of participants, and 61% of them were scored as ‘moderate’ regarding the appropriateness of the study design. Most studies (70%) were assessed as having a strong performance in controlling confounders (i.e., controlled at least 80% of relevant confounders). Only ten (22%) studies described the validity and/or reliability of the data collection tools, of which three studies were assessed as ‘strong’ in this regard. Similarly, nine (20%) studies considered the risk of drop-out and withdrawal, and three of them reported a follow-up rate of more than 80% (a strong performance). This criterion was inapplicable in most (67%) of the studies. Overall, one study was assessed as ‘strong’ and 24 other studies (52%) were assessed as having a moderately strong methodological quality on the EPHPP tool (see Supplementary file 5).

Measurements

In most studies, the rate of linkage to care was determined based on the time since diagnosis (Reddy et al., 2016;Takah et al., 2016;Billioux et al., 2017;Cholera et al., 2017;Dorward et al., 2017;Franse et al., 2017;Kulkarni et al., 2017;Sanga et al., 2017;Teklu et al., 2017;Boeke et al., 2018;Kayabu et al., 2018;Lopez-Varela et al., 2018;Rane et al., 2018;Rentsch et al., 2018;Maughan-Brown et al., 2019;Hoffman et al., 2020;Maughan-Brown et al., 2021), and late presentation for care was defined as engagement in care at CD4 count <350cells/mm3 and/or WHO clinical stage III/IV (Gelaw et al., 2015;Haskew et al., 2015;Moreira et al., 2016;Gesesew et al., 2018;Luma et al., 2018). Five studies considered care engagement at CD4 count <200cells/mm3 as late linkage to care (Honge et al., 2016;Nyika et al., 2016;van der Kop et al., 2016;Gesesew et al., 2018;Lifson et al., 2019) and one study at CD4 count ≤100 cells/mm3 (Kwobah et al., 2016). One other study defined late linkage to care as diagnosis at CD4 count of ≤500 cells/mm3 and/or any of the WHO clinical stages (Fomundam et al., 2017). Interestingly, a study by Maheu-Giroux et al. (2017) in South Africa determined linkage to care by estimating the length of time between HIV infection and engagement in care.

Twelve of 25 ART initiation studies measured the rate of ART initiation after engagement in care (Ogoina et al., 2015;Boyer et al., 2016;Brown et al., 2016;Nash et al., 2016;Billioux et al., 2017;Cholera et al., 2017;Hoffman et al., 2017;Kulkarni et al., 2017;Bor et al., 2018;Gebru et al., 2018;Rentsch et al., 2018;Maughan-Brown et al., 2019) with two of these defining delayed ART initiation as commencing ART at CD4 count <150 cells/mm3 or at WHO clinical stage IV (Nash et al., 2016;Hoffman et al., 2017). One study defined delayed ART initiation as having a CD4 count below or at 200 cells/mm3 and/or AIDS defining illness at treatment start (Anlay et al., 2019). The remaining 12 studies measured the length of time between ART eligibility (based on guidelines available at a particular period of time) and ART initiation (Odeny et al., 2015;Plazy et al., 2015;Teasdale et al., 2015;Teklu et al., 2017;Lopez-Varela et al., 2018;Ngom et al., 2018;Larsen et al., 2019) or between HIV diagnosis and ART initiation including same day treatment (i.e. initiating treatment on the date of diagnosis) (Franse et al., 2017;Katz et al., 2019;Esber et al., 2020;Lilian et al., 2020;Onoya et al., 2020). In this review, we used more inclusive definitions for both outcomes. Accordingly, we defined late linkage to HIV care as engagement in care at CD4 count <350cells/mm3 or at WHO clinical stage III/IV, and delayed ART initiation as starting HIV medication at CD4 count <350cells/mm3 or WHO clinical stage III/IV.

Linkage to HIV care

Summary of care linkage results are presented in Table 1. Maheu-Giroux et al. (2017) identified a median time to care linkage after HIV infection of 4.9 years. Among studies that investigated the rate of linkage to care since diagnosis, the rate was within three months of diagnosis (Franse et al., 2017;Kayabu et al., 2018;Lopez-Varela et al., 2018;Rane et al., 2018;Rentsch et al., 2018;Maughan-Brown et al., 2019;Hoffman et al., 2020). The rate ranges from 24% in Tanzania (Rentsch et al., 2018) to 93% in South Africa (Rane et al., 2018). Two Tanzanian studies estimated the rate of linkage to care within six months of diagnosis and reported a rate of more than 70% (Reddy et al., 2016;Sanga et al., 2017). Contradictory results were reported by two studies, in Ethiopia (Teklu et al., 2017) and South Africa (Dorward et al., 2017); while the former study reported care engagement in 75% of PLWH within one week of diagnosis, only 46% were linked to care within 12-months in the latter. However, a more recent study in South Africa reported a rate of 55% within 12-weeks of diagnosis (Maughan-Brown et al., 2021).

From studies investigating the prevalence of late presentation for care, a South African study (Fomundam et al., 2017) reported a prevalence of 78% (late presentation: CD4 count ≤500 cells/mm3) whereas a Kenyan study (Haskew et al., 2015) identified 66% (late presentation: CD4 count ≤350 cells/mm3). Two Ethiopian studies (Gesesew et al., 2018;Lifson et al., 2019) reported prevalences of 67% and 60%, when considering baseline CD4 counts of <200 cells/mm3 as late presentation for care. Another study in Kenya (Kwobah et al., 2016) identified a prevalence of 23%, defining late presentation as engagement in care at CD4 count ≤100 cells/mm3.

Structural, psychosocial, perceptual and sociodemographic factors were reported to be associated with late linkage to care. Eight studies identified healthcare delivery factors (Haskew et al., 2015;Kwobah et al., 2016;Reddy et al., 2016;Fomundam et al., 2017;Sanga et al., 2017;Boeke et al., 2018;Lopez-Varela et al., 2018;Rentsch et al., 2018). More than an hour travel time to reach a clinic (Kwobah et al., 2016;Rentsch et al., 2018), accessing care at a rural healthcare facility compared to an urban health facility, and having diagnosis through community-based approaches compared to health facility-based approaches were identified as risk factors for late linkage to care (Kwobah et al., 2016;Reddy et al., 2016;Sanga et al., 2017;Boeke et al., 2018;Lopez-Varela et al., 2018;Rentsch et al., 2018). In contrast, Fomundam et al. (2017) in South Africa identified a higher likelihood of late presentation for care in PLWH who were accessing care from urban health care facilities, as did Haskew et al. (2015) in those who were diagnosed through health facility-based approaches in Kenya.

Fifteen studies reported associations between perceptual or psychosocial factors and late linkage to care (Gelaw et al., 2015;Moreira et al., 2016;Nyika et al., 2016;Reddy et al., 2016;Dorward et al., 2017;Kulkarni et al., 2017;Maheu-Giroux et al., 2017;Sanga et al., 2017;Gesesew et al., 2018;Lopez-Varela et al., 2018;Luma et al., 2018;Rane et al., 2018;Maughan-Brown et al., 2019;Hoffman et al., 2020;Maughan-Brown et al., 2021). Testing because of illness (Moreira et al., 2016;Nyika et al., 2016;Reddy et al., 2016;Sanga et al., 2017;Luma et al., 2018), having a previous history of HIV diagnosis (Maheu-Giroux et al., 2017;Gesesew et al., 2018;Lopez-Varela et al., 2018), readiness for treatment (Maughan-Brown et al., 2019), holding a positive-outcome belief in care and using positive reframing as a coping strategy (Hoffman et al., 2020) increased the likelihood of linkage to care. Non-disclosure of HIV status (Gelaw et al., 2015;Dorward et al., 2017;Sanga et al., 2017;Maughan-Brown et al., 2019;Hoffman et al., 2020;Maughan-Brown et al., 2021), a desire for repeated testing (Kulkarni et al., 2017;Maughan-Brown et al., 2021), an experience or fear of stigma (Gelaw et al., 2015;Nyika et al., 2016;Maughan-Brown et al., 2019), having low household social support (Gelaw et al., 2015) and having severe depression and anxiety (Rane et al., 2018) increased delays in care linkage. Six studies reported perceptions related to clinical conditions as barriers to linkage to care (Kwobah et al., 2016;Takah et al., 2016;Teklu et al., 2017;Gesesew et al., 2018;Kayabu et al., 2018;Lopez-Varela et al., 2018). Four of these reported lower odds of linkage to care in PLWH having a higher CD4 count (≥500 cell/mm3) and/or a lower WHO clinical stage (I/II) (Takah et al., 2016;Teklu et al., 2017;Kayabu et al., 2018;Lopez-Varela et al., 2018). The remaining two linked the presence of TB co-infection with late linkage to care (Kwobah et al., 2016;Gesesew et al., 2018).

Sociodemographic characteristics such as: age, gender, marital status, employment and wealth index influenced linkage to care. Younger age (below 30 years) (Gelaw et al., 2015;Kwobah et al., 2016;Billioux et al., 2017;Dorward et al., 2017;Maheu-Giroux et al., 2017;Boeke et al., 2018;Gesesew et al., 2018;Lopez-Varela et al., 2018;Hoffman et al., 2020), male gender (Haskew et al., 2015;Honge et al., 2016;Kwobah et al., 2016;Nyika et al., 2016;Billioux et al., 2017;Dorward et al., 2017;Fomundam et al., 2017;Maheu-Giroux et al., 2017;Lifson et al., 2019), lacking a partner (Haskew et al., 2015;Honge et al., 2016;Billioux et al., 2017;Gesesew et al., 2018), being employed (Dorward et al., 2017;Luma et al., 2018) and having a low wealth index (Gelaw et al., 2015;Nyika et al., 2016) were most associated with late linkage to care.

ART initiation

Results of studies that investigated ART initiation are presented in Table 2. Two studies in South Africa (Lilian et al., 2020;Onoya et al., 2020) investigated same day ART initiation and reported prevalence of 20% and 40% respectively. Among studies that investigated the rate of ART initiation at various time intervals after diagnosis, one study in Rwanda (Franse et al., 2017) reported a rate of 52% within three months, and two studies in South Africa reported 72% (Onoya et al., 2020) and 62% (Katz et al., 2019) within one and six months of diagnosis respectively. Among studies that reported the rate of ART initiation within three, six and twelve months of care engagement, the rate ranged from 62% to 82% within three months (Boyer et al.;Maughan-Brown et al., 2019), 57% to 89% within six months (Boyer et al., 2016;Bor et al., 2018) and 59% to 92% within twelve months (Bor et al., 2018;Rentsch et al., 2018). One study in South Africa reported ART initiation in 50% of PLWH within one month of care engagement (Boyer et al.).

Six studies determined the rate of ART initiation at various time intervals after treatment eligibility (Odeny et al., 2015;Plazy et al., 2015;Teasdale et al., 2015;Teklu et al., 2017;Ngom et al., 2018;Larsen et al., 2019); within one, two and three months. The rate varied from 41% in Rwanda to 48% in Ethiopia within the first month (Teasdale et al., 2015;Teklu et al., 2017), 75% both in Kenya and South Africa within the second month (Odeny et al., 2015;Larsen et al., 2019), and from 67% in South Africa to 78% in Senegal within the third month (Boyer et al., 2016;Ngom et al., 2018).

Various factors were reported to influence ART initiation, some of which were akin to those influencing linkage to care. Eight studies identified service delivery factors as barriers to ART initiation (Odeny et al., 2015;Plazy et al., 2015;Teasdale et al., 2015;Brown et al., 2016;Nash et al., 2016;Gebru et al., 2018;Lopez-Varela et al., 2018). Relative to diagnosis in voluntary counselling and testing (VCT) services, lower odds of ART initiation were reported in PLWH who were diagnosed at health care facilities with a high volume of patients, and in those who enrolled in care through inpatient wards and provider initiated counselling and testing (PICT) services (Odeny et al., 2015;Teasdale et al., 2015;Nash et al., 2016). While Brown et al. (2016) found a lower likelihood of initiating ART in PLWH who were diagnosed through community-based approaches compared to health facility-based approaches, Lopez-Varela et al. (2018) and Rentsch et al. (2018) identified no association between a testing modality and ART initiation. A lower likelihood of ART initiation was reported in PLWH residing more than 2km away from the nearest health care facility, in those who experienced perceived communication barriers with health care providers, and in those with low awareness about HIV care (Plazy et al., 2015;Nash et al., 2016;Gebru et al., 2018).

Eight studies reported perceptual or psychosocial factors relating to ART initiation (Plazy et al., 2015;Boyer et al., 2016;Nash et al., 2016;Kulkarni et al., 2017;Gebru et al., 2018;Katz et al., 2019;Maughan-Brown et al., 2019;Onoya et al., 2020). A lack of perceived susceptibility to, and understanding of the severity of, the consequences of late treatment, as well as a lack of belief in the health benefits of early treatment predisposed PLWH to delayed ART initiation (Gebru et al., 2018). Testing that was undertaken due to symptoms, and patients readiness to commence treatment, were positively associated with ART initiation (Nash et al., 2016;Maughan-Brown et al., 2019), however patient desire for repeated testing was found to predict delayed ART initiation (Kulkarni et al., 2017). Nash et al. (2016) found an association between psychological distress and delayed ART initiation, but Cholera et al. (2017) reported no association between these variables. While using any substance as a coping mechanism decreased the odds of ART initiation (Katz et al., 2019), PLWH who reported drinking alcohol were 76% less likely to initiate ART than those who did not (Maughan-Brown et al., 2019).

Factors related to social support (such as having a regular partner, living in a two-adult household and the presence of another household member taking ART) were positively associated with ART initiation (Boyer et al.;Onoya et al., 2020). Perceived social stigma and failure to disclose HIV status predicted delayed ART initiation (Maughan-Brown et al., 2019) although this finding has been contradicted by another study (Hoffman et al., 2017).

Fourteen studies identified clinical findings as risk factors for delayed ART initiation (Odeny et al., 2015;Ogoina et al., 2015;Plazy et al., 2015;Teasdale et al., 2015;Boyer et al., 2016;Brown et al., 2016;Nash et al., 2016;Teklu et al., 2017;Bor et al., 2018;Ngom et al., 2018;Anlay et al., 2019;Larsen et al., 2019;Esber et al., 2020;Lilian et al., 2020). A lower baseline CD4 count (<500 cells/mm3) and higher WHO clinical stages (III/IV) were positively associated with ART initiation (Odeny et al., 2015;Ogoina et al., 2015;Plazy et al., 2015;Teasdale et al., 2015;Boyer et al., 2016;Brown et al., 2016;Teklu et al., 2017;Bor et al., 2018;Ngom et al., 2018;Larsen et al., 2019;Esber et al., 2020), whereas the presence of TB co-infection and being a bedridden patient was found to negatively predict ART initiation (Nash et al., 2016;Anlay et al., 2019;Larsen et al., 2019). Nonetheless, in a study that assessed same day treatment (Lilian et al., 2020), ART initiators had a significantly less advanced HIV infection (CD4 count >100cells/mm3 and/or WHO stage I/II) compared to non-initiators.

Twelve studies identified sociodemographic characteristics including: age, gender, marital status and wealth index as predictors of ART initiation (Plazy et al., 2015;Teasdale et al., 2015;Boyer et al., 2016;Nash et al., 2016;Billioux et al., 2017;Teklu et al., 2017;Bor et al., 2018;Anlay et al., 2019;Larsen et al., 2019;Esber et al., 2020;Lilian et al., 2020;Onoya et al., 2020). Most studies analysing the influence of age on ART initiation reported younger age (below 25 years) as a risk factor for delayed ART initiation (Teasdale et al., 2015;Boyer et al., 2016;Billioux et al., 2017;Teklu et al., 2017;Bor et al., 2018;Esber et al., 2020). However, older PLWH (≥40 years of age) were less likely to take up same day ART compared to their younger counterparts (Lilian et al., 2020;Onoya et al., 2020). Similarly, except a study by Teasdale et al. (2015) in Rwanda, studies reported lower odds of ART initiation (including same day ART) in males than females (Nash et al., 2016;Billioux et al., 2017;Onoya et al., 2020). An increased likelihood of ART initiation was reported in married PLWH and in those who had a higher wealth index (Plazy et al., 2015;Billioux et al., 2017;Anlay et al., 2019).

Meta-analyses of factors affecting linkage to HIV care and ART initiation

Eighteen studies involving a combined total of 27,396 people were included in the meta-analyses to assess factors affecting linkage to care and ART initiation. People in younger age groups (Fig 2a; OR: 0.71; 95%CI: 0.55-0.91, I2 = 74%) and 45% (Fig 2b; OR: 0.55; 95%CI: 0.49-0.63, I2 = 0%) less likely to be linked to care and initiate ART respectively compared to older age groups (≥35 years). A study by Anlay et al. (2019) was removed from the analysis of the effect of age on ART initiation because of a high level of heterogeneity.

Figure 2Forest plot of associations between linkage to care and age (a), and ART initiation (b). Lower likelihood of linkage to care and ART initiation in people in younger age groups (<35 years).

Employed people and people who travelled for more than an hour to reach a clinic were more than 1.3 (Fig 3a; OR: 1.32; 95%CI: 1.14-1.52, I2 = 14%) and 1.2 (Fig 3b; OR: 1.27; 95%CI: 1.15-1.39, I2 = 57%) times more likely to be presented late for care, respectively. A study by Lifson et al. (2019) was excluded from the analysis of employment and presentation for care due to a high level of heterogeneity.

Figure 3Forest plot of associations between late presentation for care and employment (a), and travel time to a clinic (b). Higher likelihood of late presentation for care in employed people and people who were travelling for more than an hour to a clinic.

The likelihood of linkage to care decreased by 26% (Fig 4a; OR: 0.74; 95%CI: 0.62-0.87, I2 = 25%) in people who were unable to disclose their HIV status and by 50% (Fig 4b; OR: 0.50; 95%CI: 0.42-0.60, I2 = 0%) in those who had a baseline CD4 count >350cells/mm3 compared to CD4 count ≤350cells/mm3, but increased by 65% (Fig 4c; OR: 1.65; 95%CI: 1.16-2.34, I2 = 0%) in those who were diagnosed through health facility-based testing approaches compared to community-based approaches. Studies by Rentsch et al. (2018) and Sanga et al. (2017) were excluded from the analysis of a testing modality and linkage to care due to a high level of heterogeneity.

Figure 4Forest plot of associations between linkage to care and HIV status disclosure (a), baseline CD4 count (b) and testing modality (c). People who were unable to disclose their HIV status, had a higher CD4 count (CD4 count >350cells/mm3) and those who were diagnosed through community-based approaches were less likely to be linked to care.

Discussion

Timely initiation of ART is essential to prevent AIDS and non-AIDS related comorbidities and mortality (Granich et al., 2015;Lundgren et al., 2015), as well as reducing the likelihood of new HIV infections (Na et al., 2013;Cohen et al., 2016). This review demonstrated substantial disparities in the rates of linkage to HIV care and ART initiation across nations in SSA and between settings within a given nation. Overall, care linkage and treatment initiation rates are considerably low in most settings as compared to the second target of UNAIDS 95-95-95 goal, which aims to initiate treatment in 95% of HIV infected individuals (Joint United Nations Programme on HIV/AIDS (UNAIDS), 2015). Through the literature synthesis, we identified healthcare delivery (structural), psychosocial, perceptual and sociodemographic factors as determinants of late linkage to care and delayed ART initiation amongst HIV infected adults in SSA.

Structural factors

Our meta-analyses identified distance to ART sites as the main risk factor for late linkage to care in SSA countries. Similar findings have been reported by a previous review in which transport costs associated with distant ART clinics was the most cited barrier to care in the region (Govindasamya et al., 2012). Although PLWH tend to engage in care more when it is easily accessible (Plazy et al., 2015), many PLWH in SSA may be required to travel long distances, sometimes on foot, to access HIV care due to shortage of transport or associated costs (Lahuerta et al., 2013;Yakob and Ncama, 2016) . This could be a major concern for low wealth index PLWH households, and partially explain why they are less likely to be linked to HIV care and commence treatment. There have been substantial expansions of ART services in the region in recent years, yet only a few public health care facilities provide the services at a district level (Joint United Nations Programme on HIV/AIDS (UNAIDS), 2020), underscoring the need for the use of optimal task shifting (Boulle et al.;Crowley and Mayers, 2015) and service integration strategies (Topp et al., 2010) to reach all people who need treatment.

This systematic review and meta-analyses showed that PLWH initiate ART late when enrolled at clinics with a high volume of patients and diagnosed through community-based counselling and testing approaches. Community-based HIV testing approaches have substantially increased the number of people eligible for ART in SSA (Joint United Nations Programme on HIV/AIDS (UNAIDS), 2020). However, insufficiency of appropriately trained staff continues to be a main challenge to initiate treatment in all infected individuals (Baine and Kasangaki, 2014). Studies show that the more PLWH are satisfied with pre-ART care and understand the information given by service providers, the greater the likelihood of ART initiation (Odeny et al., 2015;Loeliger et al., 2016;Nash et al., 2016). In contrast, when clinic operating hours are not well tailored with PLWH's daily routines, timely clinic visits diminish, which leads to delays in treatment commencement (da Silva et al., 2015). This may help to explain why employed individuals are more likely to be linked to care late relative to their unemployed counterparts, as demonstrated from our meta-analyses. Enhancing after-hours services and workplace programs may help combat this problem, as would providing ART training for lower level health care staff (Mwai et al., 2013;Asiimwe et al., 2017).

Psychosocial factors

HIV status disclosure was significantly associated with an increased likelihood of linkage to care in the current meta-analyses, which is concordant with prior reviews conducted in SSA (Govindasamya et al., 2012;Lahuerta et al., 2013). Status disclosure enables PLWH to access social support which reduces the negative influence of social stigma, one of the barriers to accessing care in this review (Dorward et al., 2017;Ahmed et al., 2018). This is evidenced by the finding that married PLWH and those who lived with adults (particularly with those who use ART) are more likely to commence treatment. Conversely, failure to disclose HIV status increases the likelihood of care disengagement during pre-ART period (Shaweno and Shaweno, 2015). Expansion of the social networks of PLWH is important in this regard in addition to provision of appropriate counselling support, particularly for newly-diagnosed individuals (Salmen et al., 2015).

Findings regarding the effect of psychological distress on ART initiation were equivocal in our review. Previous studies have shown that the prevalence of depression is generally higher in HIV infection, and both pre- and post-HIV diagnosis depression may affect an individual's ability to seek or access regular care (Tegger et al., 2008;Bhatia et al., 2011;Cholera et al., 2017). Depressed PLWH are also at particular risk for substance misuse, which can lead to late care engagement (Gardner et al., 2005;Bhatia et al., 2011). Interventions aiming at integrating diagnosis and treatment of depression with HIV care may help improve ART initiation in this important population group.

Perceptions related to clinical conditions

Our review showed that clinical circumstances such as having a higher baseline CD4 count (>350 cells/mm3) and lower levels of WHO defined clinical stages are associated with late linkage to care and delayed ART initiation. This is consistent with a narrative review conducted previously in the region, which reported initiation of ART at a very low CD4 count in most PLWH (Lahuerta et al., 2013). At asymptomatic stages of HIV infection (i.e., at high CD4 count and low WHO clinical stages), PLWH often feel healthy and may perceive that they do not need treatment (Reddy et al., 2016;Ahmed et al., 2018). During these stages, PLWH may also hesitate to accept a HIV positive diagnosis, thus requiring repeated testing that can lead to delayed linkage to care (Nash et al., 2016). However, the current review also demonstrated that HIV-related symptoms alone may not always be sufficient to prompt ART initiation, but patient readiness and confidence that the treatment is safe and efficient is also required. Structural factors related to prioritisation of the sickest patients, and low absorptive capacity of health care facilities may also contribute to initiation of ART at low CD4 count in SSA (Lahuerta et al., 2013). The rapid expansion of the program in the region may hopefully mitigate these structural barriers (Joint United Nations Programme on HIV/AIDS (UNAIDS), 2020) yet increasing PLWH's awareness of the health benefits of early ART initiation remains critical in ensuring treatment initiation in all infected individuals (World Health Organization, 2015).

TB co-infected and bed-restricted PLWH are less likely to be linked to care and initiate ART. In spite of HIV/TB treatment guidelines’ recommendation to initiate ART after the commencement of TB treatment (World Health Organization, 2003), PLWH with TB co-infection may be concerned about adverse drug interactions, pill burden and drug side-effects, and therefore forgo initiation of ART (Chilton et al., 2008;Maponga et al., 2015). PLWH may also be unable to attend clinic appointments due to severe medical conditions associated with the advancement of the disease.

Other perceptual factors

Using positive reframing as a coping strategy was found to be associated with a high rate of linkage to care. This is consistent with previous findings that showed the positive impact of a desire for good health on care engagement (Garrett et al., 2018). PLWH with such forethought commence ART hoping that their general health would be improved because opportunistic diseases could be prevented, which could also ultimately minimise social stigma due to HIV-related illnesses (Lambert et al., 2018).

Sociodemographic factors

In this review, males and younger PLWH (below 35 years of age) are more at risk of late linkage to care and delayed ART initiation compared to females and PLWH of older age groups (35 years and above) respectively. The lower rates of linkage to care and ART initiation in males and younger PLWH in the current review support findings of previous reviews conducted in SSA (Govindasamya et al., 2012;Lahuerta et al., 2013). PLWH of younger age groups are known to have low awareness of their HIV status, and are more likely to experience and adversely react to stigmatisation, as well as engage in substance use (United Nations Children's Fund (UNICEF), 2002), which is a significant predictor of delayed ART initiation in the current review. Moreover, younger PLWHA struggle with disclosure of their HIV status which may lead to limited access to information and material supports (Kenu et al., 2014;Greenhalgh et al., 2016).

Contextual and cultural norms related to masculinity can play a strong part in hampering health seeking behaviour in males (Skovdal et al., 2011;Ahmed et al., 2018). Females tend to be more engaged in health care systems through programs focusing on maternal health. Therefore, adaptation of health services and treatment options to the needs of men and younger people may help close the gaps in linkage to care and ART initiation.

In interpreting the findings of this review, the following important limitations should be considered. The included studies represent only a few nations of SSA, which restricts the generalisability of the findings. Representativeness is also restricted due to the wide variability of outcomes across geographical locations. Because most studies used a retrospective cohort or a cross-sectional design, causality between the exposure variables and the outcomes cannot be assured even though important risk factors for late linkage to care and delayed ART initiation have been adequately explored. Rates of linkage to care and ART initiation were measured at varying lengths of time using different reference points, which impacted the development of precise estimation of the outcomes. However, relatively more inclusive measures were taken to embrace a range of results in the analysis. As there has not been a standardised definition for delayed ART initiation, the included studies defined the outcome differently, following the available treatment eligibility guidelines within a particular period of time. To minimise this discrepancy, we used the highest and lowest cut points to ensure generalisability of the findings to all included studies. In addition to substantial heterogeneity between studies in effect measures (with respect to some of the exposure variables), only 54% of the included studies were scored at moderate or above in the overall quality assessment, which may lower the quality of evidence. Although the review used a systematic search strategy, there exists a possibility of missing relevant studies because screening was undertaken by a single reviewer and unpublished data were not explored. Due to time and resource constraints, we included only studies published in English language which may increase the risk of publication bias, and we did not report a funnel plot due to the small number of studies (n<10) included in the analysis for each exposure variable (Sedgwick and Marston, 2015). Finally, despite efforts in this regard, we were not able to contact authors of primary studies regarding incomplete data, which restricted the analysis of factors for delayed ART initiation.

Conclusions

This systematic review and meta-analyses identified a range of risk factors for late linkage to care and delayed ART initiation amongst HIV infected adults in SSA, which included: health service delivery, psychosocial, perceptual and sociodemographic circumstances. We recommend implementation of patient-centred intervention approaches to alleviate barriers and to reinforce best practices and lessons learned from high achieving settings to those with particular challenges.

Declarations

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

Not applicable.

Authors’ contributions

TGF developed the search strategy; conducted searching, screening of the articles, data extraction and analysis; drafted the manuscript. ERM participated in the quality assessment of the studies and subsequent revisions of the manuscript; GT contributed to and reviewed the manuscript.

Acknowledgements

We would like to acknowledge Mr Tariku Laelago and Mr Tadele Yohannes for assessing the quality of included studies.

Declaration of interests

☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

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