Abstract
Background
Viral load monitoring is crucial for identifying treatment failure in HIV/AIDS patients, as low viremia is essential for public health as HIV cannot spread undetectable. This study aimed to assess the sustained virological recovery rate and potential factors affecting HIV patients in Tigray, Northern Ethiopia, receiving combination treatment.
Methods
HIV infected individuals receiving highly active antiretroviral therapy (HAART) were the subjects of the retrospective, cross-sectional investigation held from July 2018 to December 2020. Using a standardized checklist, data was taken from the Tigray Health Bureau database and aligned with data from the Tigray Health Research Institute (THRI). SPSS version 25.0 was used to analyze the data. Predictors for persistent virological recovery were identified based on baseline viral load, baseline CD4 count, current and baseline age, loss to follow-ups, adherence, and WHO clinical presentations. The correlations between each factor and the categorical outcome variables were evaluated using Pearson’s χ2. To determine the determinants impacting virological recovery, multivariate logistic regression analyses were performed. Significant relationship levels were established at p < 0.05.
Results
7689 HIV infected individuals with a mean age of 43 ± 13 years were recruited on HAART with a female predominance of 64.4% with 95% CI: 58.3–76.3. At enrollment to ART sizable portion of the research participants 43.7%, and 38% were in the productive age ranges of 16–30 and 31–45 years old respectively. The overall virological recovery was 90.9% with significant variations among male and female participants AOR; 4.24; 95% CI, 2.97–6.03) and (P < 0.001).
Conclusion
Male participants showed less recovery, with high baseline CD4 count, long therapy stays, and suppressed viral load being key predictors. The virological recovery (90.9%) remains below the global average which is 95%. Regular assessment of treatment response patterns and drug list combinations is crucial for HIV virological recovery to be sustained. Early enrollment in HAART, tailored interventions, baseline viral load monitoring, longitudinal studies, and gene sequencing are crucial for virological recovery and identifying genetic and behavioral factors contributing to treatment resistance.
Keywords: CD4, HAART, HIV, Tigray, Viral load, Virological recovery
Introduction
Highly Active Antiretroviral Therapy (HAART) is a treatment for HIV/AIDS that involves combining at least three antiretroviral medications, including abacavir, protease inhibitors, non-nucleoside reverse-transcriptase inhibitors, boosted protease inhibitors, and integrase strand transfer inhibitors (INSTIs), particularly Dolutegravire [1–4]. Ethiopia as a country outlined national treatment guidelines for comprehensive HIV prevention, care and treatment that align with global recommendations, particularly those from WHO emphasizing a fixed-dose combination of tenofovir disoproxil fumarate (TDF), lamivudine, dolutegrvire (DTG) called TLD as the recommended first-line ART regimen for adults and adolescents [5, 6]. HAART is a treatment that sustainably suppresses HIV viral load, restores immunologic function, reduces HIV-related morbidity and mortality, and significantly improves the prognosis and quality of life for HIV/AIDS patients [7]. The effectiveness of treatment depends on factors like antiviral resistance, drug interactions, and individual preferences. Generic versions of HAART have made it more accessible, while advancements in antiretroviral therapy have led to more effective medications [8, 9].
Approximately 39.9.6 million people live with HIV globally and 1.3 million acquired new infection with recorded death of 630,000 as of 2023. Over 80% of the 39 million HIV-affected individuals worldwide are from the WHO Africa region., including 1.8 million children [5]. The UNAIDS aim of 95% coverage by 2025 is still unrealistic despite rising coverage [10]. Investing in research, education, awareness campaigns, and access to ART, along with comprehensive HIV prevention techniques like pre-exposure prophylaxis, condoms, and safe sexual practices, is crucial for combating HIV [11].
ART has reduced HIV morbidity and mortality rates, but challenges such as medication adherence, drug resistance, high costs, stigma, and discrimination need to be addressed for sustainability [12–14]. ART therapy effectiveness is influenced by patient adherence, regimens, laboratory monitoring, physician understanding, and biological factors. Regular communication and patient education are crucial for optimal viral suppression and immunologic recovery [15, 16]. The study examines the recovery rate and influencing factors of HIV-infected individuals receiving highly active antiretroviral therapy (HAART) in Tigray, Northern Ethiopia.
Methods
Study design, setting and data source
This retrospective, cross sectional study was conducted in Tigray region between July 2018 to December 2020 and analyzed viral loads in 7689 HIV patients on HAART for at least 24 weeks. The data was sourced from the Tigray Regional Health Bureau’s database and THRI, providing detailed clinical, immunological, therapeutic, and viral characteristics.
Source and study population
All HIV infected individuals were the source population for this study. whereas, HIV infected individuals attending ART in public health facilities for at least 6months were the study population for this research.
Inclusion and exclusion criteria
The study included patients with complete demographic, treatment, clinical, baseline, and current immunological and viral load data who were receiving HAART for at least six months and who were sent to THRI for HIV viral load analysis from July 2018 to December 2020, excluding those with redundant data, outside the Tigray Region, and private sector hospitals.
Sampling procedure
From July 2018 to December 2020, 7689 patients with virological test records were retrieved from Tigray’s public health facilities database (Fig. 1).
Fig. 1.
Schematic Presentation of the Sampling Procedure
Operational definitions
Adherence level to ART refers to the extent to which a person’s behavior taking medication, following a diet, or executing lifestyle changes corresponds with agreed recommendations from a healthcare provider and is usually calculated by dividing doses taken by prescribed doses and categorized as good (> 95%), fair (85–95%), and poor (< 85%) [17, 18].
Virological recovery is defined as achieving HIV-1 RNA viral load suppression to < 1000 copies/mL after at least 6 months of consistent ART, in accordance with WHO guidelines. A patient was considered recovered if they had a durable viral load of < 1000 cps/mL even after 48 weeks on ART and continued until the most probable recent stay, while a patient was not recovered if viral replication persisted unsuppressed for those with a viral load level of ≥ 1000 cps/mL even after 48 weeks and more.
Highly Active Anti-Retroviral Therapy (HAART) is a combination of antiretroviral treatments involving at least three drugs, including one non-nucleoside reverse-transcriptase inhibitor (NNRTI), a protease inhibitor (PI), and/or abacavir, or a combination of both (13, 14).
Ethical approval and consent given
This article was organized as continuation of our previously submitted article which was approved by The Ethical review committee of the Tigray Health Research institute with reference number of THRI/4031/0740/16. Furthermore, supportive letter to use the data sets available was received from Tigray Health Research Institute and Tigray Health Office multi sectoral prevention and control of HIV /AIDS core process owner with reference numbers of THRI/403/0015/16 and THO21/120,089/16 respectively.
Data collection tools and procedure
Data was retrieved from the database using a pre-structured, standardized checklist. The socio-demographic (baseline and current age, gender), clinical (baseline and current WHO staging), adherence, treatment-related (drug regimen and type), viral load and CD4 baselines and recent levels are all included in the checklist. Microsoft Excel 2010 was used to enter and process all of the data in the database. SPSS version 25.0 was then used to clear and verify the data’s completeness as well as analysis.
Laboratory testing procedure
The THRI reference laboratory used reverse transcription PCR to extract and quantify HIV RNA viral load using the Abbott 2000sp and Abbott 2000rt automated equipment (Abbott Molecular, USA). In brief, 0.2 mL of plasma was collected and HIV RNA was extracted using Abbott’s m2000sp automated sample preparation equipment. The extracted RNA was then analyzed using the Abbott m2000rt quantitative Real-Time PCR (Abbott Molecular, USA) to test for HIV viral load, which has an HIV RNA detection level of 40 to 10 million copies/mL, according to the manufacturer’s instructions. The virological recovery after ART initiation was evaluated by comparing baseline data and recent viral load levels, categorized as none-suppressed or suppressed according to WHO criteria. Individuals with sustained viral suppression (< 1000 cps/mL) after 48 weeks on ART were classified as virologically recovered (1), while those without suppression (> 1000 cps/mL) were categorized as virologically not recovered (2).
The base line and most recent CD4 count were done at respective healthcare facilities using fluorescence activated cell sorter, the recent and baseline CD4 count results of each client were sent either aliening with the standard viral load referral format to THRI or sent in to the district health information system in the regional health bureau monthly from the health facilities. Data was extracted by complementing the two data sources. Immunological response after ART initiation was assessed. Data was categorized based on the findings as per the standard guide line as, < 200 cells/ mm3,201–500 cells/mm3, and > 501 cells/ mm3.
Quality assurance
The data extracted from the database was reviewed for completeness and consistency in Microsoft Excel. Histograms and normal probability plots were used to statistically verify the data’s normality. To determine the viral load of patient samples in THRI, negative, low, medium, and high positive controls were examined. To assess the validity of each health institution laboratory’s CD4 count run, quality controls for the count were conducted using low, medium, and high controls. Every client’s most recent CD4 count and the results of their baseline CD4 and viral load count were reported to the Tigray Regional Health Bureau via the Health Management Information System (HMIS) or sent in requisition format to the THRI reference laboratory for routine viral load determination. The data contains only the unique ART number and medical record identification HIV infected individuals. This maintains confidentiality through out the analysis and then after.
Data analyses
The study used Microsoft Excel 2010 to record data, which was then analyzed using SPSS version 25.0 to quantify the proportion of HIV patients on HAART and their persistent virological recovery level and factors associated with virological recovery. Descriptive analysis of socio-demographic characteristics was used to represent frequencies and percentages for categorical variables, while bivariate logistic regression was used to determine the presence or absence of an association between independent variables and outcome variables. Pearson’s χ2 was used to analyze the association between factors and outcome variables. Covariates with a p-value of < 0.25 in bivariate analysis and a co-linearity matrix index of ≤ 0.7 were included in the multivariate logistic regression analysis model to determine the final factors. The results were reported using odds ratios and 95% confidence intervals, with significance level set at p ≤ 0.05.
Results
Characteristics of the study population
Of the 7689 HIV patients with a mean age of 43 ± 13 years who were recruited on HAART, 4955 (64.4%) and 2734 (35.6%) were females and males, respectively (Table 1). At the time of ART commencement, 3360 (43.7%) and 2923 (38%) participants were in the productive age ranges of 16–30 and 31–45 years old, respectively. The study found that 35.5% of participants had been on antiretroviral therapy for at least 13 years, while 72.3% of patients showed strong adherence to the treatment.
Table 1.
Socio-demographic characteristics and proportion of patients with virological recovery and identified contributing factors among 7689 patients taking ART
| Characteristics | Category | N (%) |
|---|---|---|
| Gender |
Male Female |
2734 (35.6) 4955 (64.4) |
| Age group in years (current) |
3–18 years 19–35 years 36–52 years ≥ 53 years |
2449 (31.9) 1273 (16. 6) 3416 (44.4) 551 (7.2) |
| Age at ART initiation |
> 46 years 31–45 years 16–30 years 1–15 years |
779 (10.1) 2923 (38) 3360 (43.7) 627 (8.2) |
| Time on ART |
> 13 years 10–12 years 7–9 years 4–6 years 6 months to 3 years |
2732 (35.5) 1995 (25.9) 1405 (18.3) 1101 (14.3) 456 (5.9) |
| Current ART regiment |
1st line regimen 2nd line regimen |
7005 (91.1) 684 (8.9) |
| ART drug combination at baseline for adults |
1a (d4T + NVP + 3TC) 1b (d4T + 3TC + EFV) 1c (AZT + 3TC + NVP) 1d (AZT + 3TC + EFV) 1e (TDF + 3TC + EFV) 1f (TDF + 3TC + NVP) |
1555 (20.2) 133 (1.7) 2373 (30.9) 399 (5.2) 2317 (30.1) 437 (5.7) |
| Children drug combinations at enrolment to therapy |
4a (d4T + 3TC + NVP) 4b (d4T + 3TC + NVP) 4c (AZT + 3TC + NVP) 4d (AZT + 3TC + EFV) |
114 (24) 95 (20) 171 (36) 95 (20) |
| Does ART drug combination changed? |
Yes No |
5941 (77.3) 1748 (22.7) |
| Maternal characteristics |
Non-pregnant Pregnant Breast feeding Not applicable |
4765 (62) 76 (1) 38 (0.5) 2810 (36.8) |
| If drug combination changed, why? |
Side effect/toxicity Availability of new drug Drug stock out Due to TB co-infection Treatment failure Age transition to adulthood Increase in BMI |
342 (4.4) 4289 (55.8) 380 (4.9) 94 (1.2) 646 (8.4) 171 (2.2) 19 (0.2) |
| Current ART drug combination of participants |
1j (TDF + 3TC + DTG) 1f (TDF + 3TC + NVP) 1e (TDF + 3TC + EFV) 1d (AZT + 3TC + EFV) 1c (AZT + 3TC + NVP) 1a (d4T + NVP + 3TC) 2f (AZT + 3TC + ATV/r) ABC + 3TC + DTG 2 h (TDF + 3TC + ATV/r) |
4137 (53.8) 57 (0.7) 2108 (27.4) 285 (3.7) 323 (4.2) 19 (0.2) 532 (6.9) 95 (1.2) 133 (1.7) |
| History of lost to follow up (LTF) | Yes | 1898 (24.7) |
| No | 5791 (75.3) | |
| Adherence to ART |
Poor (< 85%) Fair (85–95%) Good (> 95%) |
589 (7.7) 1461 (19) 5639 (73.3) |
| WHO stage at baseline |
T3/T4 T1/T2 |
4462 (58) 3227 (42) |
| Current WHO stage |
T3/T4 T1/T2 |
892 (11.6) 6797 (88.4) |
The majority of the study participants (7020 (91.3%)) were on 1st line antiretroviral medications. During the research, 4137 (53.8%) patients were receiving treatments based on the 1 J (TDF + 3TC + DTG) medication line combinations. At baseline ART treatment, 2373 (30.9) of adult patients were taking a combination of 1c (AZT + 3TC + NVP). Of the total patients (5941 (77.3%)) who changed their ART drug combination, 4289 (55.8%) were changed because of the availability of new treatment guideline.
Virological recovery patterns of HIV patients stratified by sex
The study considered the current and baseline HIV viral load levels to determine the virological recovery rate of the study participants. It was discovered that 6607 (85.9%) and 6986 (90.9%) of the subjects had suppressed baseline and most recent HIV viral load levels, respectively. On the other hand, the virological non-suppression rate at the most current levels, after 48 weeks on ART, was found to be 703 (9.1%). This indicates a 5% decline with each additional week spent on HAART. The virological non-suppression rate was 1082 (14.1%) after 24 weeks on ART.
Male participants had a higher virological non-suppression rate (475; 17.4%) than females (342; 12.5%), with a 4.9% difference at ART enrollment and a 5.2% difference in recent viral load levels. Female participants had a higher prevalence of viral suppression at baseline 4348 (87.5%) and recent viral load levels 4594 (92.7%). Females with longer HAART duration showed a 5.2% improvement in suppression compared to males who experienced a 4.6% change in suppression level (Table 2).
Table 2.
Baseline characteristics and virological recovery levels of 7689 participants stratified by sex
| Variables | Category | Total (n (%)) | Participants Sex | χ2 | p | |
|---|---|---|---|---|---|---|
| Male (n (%)) | Female (n (%)) | |||||
| Sex | 7689 (100) | 2734 (35.6%) | 4955 (64.4%) | |||
| Baseline viral load level (VL) after 24 weeks on ART |
Not suppressed (≥ 1000 cps/mL) Suppressed (< 1000 cps/mL) |
1082 (14.1) 6607 (85.9) |
475 (17.4) 2259 (82.6) |
607 (12.3) 4348 (87.7) |
4.15 | 0.04 |
| Most recent viral load level (> 48 weeks on ART) |
Not suppressed (≥ 1000 cps/mL) Suppressed (< 1000 cps/mL) |
703 (9.1) 6986 (90.9) |
342 (12.5) 2392 (87.5) |
361 (7.3) 4594 (92.7) |
5.78 | 0.05 |
| Virological recovery |
Recovered (persistently suppressed) Not-recovered (fail to-suppressed persistently) |
6986 (90.9) 703 (9.1) |
2392 (87.5) 342 (12.5) |
4594 (92.7) 361 (7.3) |
5.78 | 0.001 |
| CD4+ count at base line |
< 200 cells/ mm3 201–500 cells/mm3 > 501 cells/ mm3 |
2144 (27.9) 4480 (58.3) 1065 (13.9) |
859 (31.4) 1513 (55.3) 362 (13.2) |
1285 (25.9) 2967 (59.9) 703 (14.2) |
2. 64 | < 0.001 |
| Most Recent CD4+ count |
< 200 cells/mm3 201–500 cells/ mm3 > 501 cells/ mm3 |
1135 (14.8) 4004 (52.1) 2550 (33.2) |
408 (14.9) 1509 (55.2) 817 (29.9) |
727 (14.7) 2495 (50.4) 1733 (35) |
2.17 | < 0.001 |
| WHO stage at base line |
T3/T4 T1/T2 |
4462 (58) 3227 (42) |
1634 (59.8) 1100 (40.2) |
2828 (57.1) 2147 (42.9) |
5.24 | 0.022 |
| Most recent WHO stage |
T3/T4 T1/T2 |
892 (11.6) 6797 (88.4) |
209 (7.6) 2525 (92.2) |
683 (13.8) 4272 (86.2) |
6.47 | < 0.001 |
| Current adherence level to ART |
Poor (< 85%) Fair (85–95%) Good (> 95%) |
589 (7.7) 1461 (19) 5639 (73.3) |
910 (18.4) 551 (20.2) 1993 (72.9) |
399 (8.1) 910 (62.3) 3646 (73.6) |
5.87 | 0.053 |
| History of lost to follow up (LTF) |
Yes No |
1898 (24.7) 5791 (75.3) |
741 (27.1) 1993 (72.9) |
1157 (23.4) 3798 (76.6) |
13.3 | < 0.001 |
| Dose Baseline ART drug combination changed? |
Yes No |
5949 (77.4) 1740 (22.7) |
2305 (84.3) 429 (15.7) |
3644 (73.5) 1311 (26.5) |
7.44 | 0.006 |
| Why base line ART drug combination is changed? |
Side effect/ Toxicity Availability of new drugs Drug stock-out Due to TB co-infection Treatment failure Age transition Increase in BMI |
342 (5.8) 4297 (71.9) 381 (6.4) 75 (1.3) 693 (11.6) 171 (2.9) 19 (0.3) |
95 (4.1) 1752 (75.1) 96 (4.1) 19 (0.8) 258 (11.1) 95 (4.1) 19 (0.8) |
247 (6.8) 2545 (69.8) 285 (7.8) 56 (1.5) 437 (11.9) 76 (2.1) - |
11.6a | < 0.001 |
| Current ART Regiment | 1st line | 7020 (91.3) | 2483 (90.8) | 4537 (91.6) | ||
| 2nd line | 669 (8.7) | 251 (9.2) | 418 (8.4) | 1.23 | 0.27 | |
| Adult Base line ART drug combination |
1a (d4T + 3TC + NVP) 1b (d4T + 3TC + EFV) 1c (AZT + 3TC + NVP) 1d (AZT + 3TC + EFV) 1e (TDF + 3TC + EFV) 1f (TDF + 3TC + NVP) |
1555 (21.6) 133 (1.8) 2373 (32.9) 399 (5.5) 2317 (32.1) 437 (6.1) |
607 (25.4) 38 (1.6) 797 (33.3) 247 (10.3) 570 (23.8) 133 (5.6) |
948 (19.7) 95 (2.0) 1576 (32.7) 152 (3.2) 1747 (36.2) 304 (6.3) |
14.7 | 0.011 |
| Subjects current ART drug combination |
1 J (TDF + 3TC + DTG) 1f (TDF + 3TC + NVP) 1e (TDF + 3TC + EFV) 1d (AZT + 3TC + EFV) 1c (AZT + 3TC + NVP) 1a (d4T + 3TC + NVP) ABC + 3TC + DTG (FDC) 2 h (TDF + 3TC + ATV/r) 2f (AZT + 3TC + ATV/r) |
4137 (53.8) 57 (0.7) 2108 (27.4) 285 (3.7) 323 (4.2) 19 (0.2) 95 (1.2) 133 (1.7) 532 (6.9) |
1670 (61.1) 38 (1.4) 361 (13.2) 152 (5.6) 171 (6.3) 0 (0) 95 (3.5) 57 (2.1) 190 (6.9) |
2467 (49.8) 19 (0.4) 1747 (35.3) 133 (2.7) 152 (3.1) 19 (0.4) 0 (0) 76 (1.5) 342 (6.9) |
6.48 | < 0.001 |
| Child 1st line drug combination |
4a (d4T + 3TC + NVP) 4b (d4T + 3TC + EFV) 4c (AZT + 3TC + NVP) 4d (AZT + 3TC + EFV) |
114 (24.0) 95 (20) 171 (36) 95 (27.8) |
95 (27.8) 19 (5.6) 133 (38.9) 95 (100) |
19 (14.3) 76 (57.1) 38 (28.6) 0 (0) |
17.4 | < 0.001 |
| Age at ART initiation |
> 46 years 16–30 years 31–45 years 1–15 years |
779 (10.1) 3360 (43.7) 2923 (38) 627 (8.2) |
418 (15.3) 702 (25.7) 1215 (44.4) 399 (14. 6) |
361 (7.3) 2658 (53.6) 1708 (34.5) 228 (4.6) |
6.9 | < 0.001 |
| Current age |
> 53 years 19–35 years 36–52 years 3–18 years |
2449 (31.9) 1273 (16. 6) 3416 (44.4) 551 (7.2) |
1101 (40.3) 190 (6.9) 1082 (39.6) 361 (13.2) |
1348 (27.2) 1083 (21.9) 2334 (47.1) 190 (3.8) |
6.88 | < 0.001 |
| Time on ART |
> 13 years 4–6 years 7–9 years 10–12 years 6 months–3 years |
2732 (35.5) 1101 (14.3) 1405 (18.3) 1995 (25.9) 456 (5.9) |
1044 (38.2) 437 (16) 436 (15.9) 722 (26.4) 95 (3.5) |
1688 (34.1) 664 (13.4) 969 (19.6) 1273 (25.7) 361 (7.3) |
5.69 | < 0.001 |
Note: (a) represents for 5 cells (35.7%) have expected count less than 5; ART: Anti-retroviral Therapy; BMI: body mass index
After 48 weeks of combination therapy, 6986 (90.9%) individuals experienced virological recovery, while 703 (9.1%) remained permanently unrecovered. HIV virological recoveries among male and female participants were 2392 (87.5%) and 4594 (92.7%), respectively. However, there were differences in recovery rates (5.2%) with extended ART stays (Fig. 2).
Fig. 2.
HIV Virological recovery and Viral load suppression patterns
Factors influencing HIV virological recovery
According to multivariate analysis; gender, age groups (16–30 years) at ART enrollment, participants’ current age(during study period) (3–52 years), participants who were on T1/T2 WHO clinical staging at baseline (AOR = 3.91, 95% CI: 2.96–5.16) and most recently (AOR = 2.87, 95% CI: 1.16–7.11), who showed fair adherence (85–95%) to ART (AOR = 4.11, 95% CI: 3.13–5.41) who had no history of missed follow-up appointments (AOR = 5.80, 95% CI: 3. 64-9.17), who accounted CD4 count level of 201–500 cells/mm3 (AOR = 3.93, 95% CI: 2.05–7.52) and > 501 cells/mm3 at ART enrollment (5.04, 95% CI: 2.07–12.29), participants with < 1000 cps/ml HIV viral load level at baseline (after 24 weeks on ART) (AOR = 3.34, 95% CI: 1.21–9.30) were significantly associated characteristics with persistently low viremia (Table 3).
Table 3.
Bivariate and multivariate logistic regression analysis on factors related to virological recovery among HIV patients on ART (n = 7689)
| Characteristics | Virological Response | COR (95% CI) | P value | AOR (95% CI) | P value | ||
|---|---|---|---|---|---|---|---|
| Recovered | Not recovered | ||||||
| Gender |
Female male |
4594 (92.7) 2392 (87.5) |
361 (7.3) 342 (12.5) |
1.86 (1.61–2.15) Ref. |
< 0.001 | 4.24 (2.97–6.03) | < 0.001 |
| Age at ART initiation |
> 46 years 16–30 years 31–45 years 1–15 years |
722 (92.7) 2999 (89.3) 2809 (96.1) 456 (72.7) |
57 (7.3) 361 (10.7) 114 (3.9) 171 (27.3) |
1.19 (0.92–1.55) 0.55 (0.42–0.74) 3.70 (2.77–4.94) Ref (1) |
0.17 < 0.001 < 0.001 |
1.13 (0.62–2.1) 2.16 (1.31–3.57) 0.66 (0.38–1.13) Ref. |
0.68 0.002 0.13 |
| Participants current age |
> 53 years 19–35 years 36–52 years 3–18 years |
2316 (94.6) 1064 (83.6) 3169 (92.8) 437 (79.3) |
133 (5.4) 209 (16.4) 247 (7.2) 114 (20.7) |
Ref. 3.02 (2.43–3.75) 1.40 (1.14–1.71) 4.44 (3.45–5.72) |
< 0.001 0.001 < 0.001 |
Ref. 7.37 (3.81–7.01) 8.74 (0.85–1.47) 14.7 (5.24–41.) |
0.001 < 0.001 < 0.001 |
| Time duration on ART |
> 13 years 4–6 years 7–9 years 10–12 years 6 months to 3 years |
2523 (92.3) 987 (89.6) 1291 (91.9) 1786 (89.5) 399 (87.5) |
209 (7.7) 114 (10.4) 114 (8.1) 209 (10.5) 57 (12.5) |
Ref. 1.39 (1.01–1.77) 1.07 (0.84–1.35) 1.41 (1.15–1.72) 1.72 (1.26–2.35) |
0.007 0.59 0.001 0.001 |
Ref. 1.18 (0.75–1.85) 2.21 (1.41–3.46) 0.71 (0.47–1.04) 4.94 (2.89–8.43) |
0.46 0.001 0.077 < 0.001 |
| WHO stage at base line |
T3/T4 T1/T2 |
4158 (93.2) 2828 (87.6) |
304 (6.8) 399 (12.4) |
Ref. 1. 93 (1.65–2.25) |
< 0.001 |
Ref. 3.91 (2.96–5.16) |
< 0.001 |
| Most recent WHO stage |
T3/T4 T1/T2 |
778 (87.2) 6208 (91.3) |
114 (12.8) 589 (8.7) |
Ref. 1.54 (1.24–1.91) |
< 0.001 |
Ref. 2.87 (1.16–7.11) |
< 0.001 |
| Current ART regiment |
2nd line 1st line |
627 (8.3) 6897 (91.7) |
95 (11. 6) 722 (88.4) |
Ref. 1.47 (1.15–1.82) |
0.002 |
- 1.57 (0.94–2.61) |
0.083 |
| ART adherence |
Poor (< 85%) Fair (85–95%) Good (> 95%) |
437 (74.2) 1290 (88.3) 5259 (93.3) |
152 (24.8) 171 (11.7) 380 (6.7) |
Ref. 4.81 (3.89–5.95) 1.83 (1.51–2.20) |
< 0.001 < 0.001 |
Ref (1) 4.11 (3.13–5.41) 0.80 (0. 61–1.07) |
< 0.001 0.14 |
| History of lost to follow-up (LTF) |
Yes No |
1651 (87) 5335 (92.1) |
247 (13) 456 (7.9) |
Ref. 1.75 (1.48–2.06) |
< 0.001 | 5.80 (3. 64–9.17) | < 0.001 |
| Baseline-CD4 count |
< 200 cells/ mm3 201–500 cells/ mm3 > 501 cells/ mm3 |
1915 (90.2) 4046 (90.6) 987 (92.9) |
209 (9.8) 418 (9.4) 76 (7.1) |
Ref. 1.41 (1.07–1.86) 1.34 (1.04–1.73) |
Ref. 0.35 0.059 |
3.93 (2.05–7.52) 5.04 (2.07–12.29) |
< 0.001 < 0.001 |
| Most-recent CD4 count | < 200 cells/ mm3 | 740 (78) | 209 (22) | - | - | - | - |
| 201–500 cells/ mm3 | 3739 (93.4) | 266 (6.6) | - | - | - | - | |
| > 501 cells/ mm3 | 2469 (91.5) | 228 (8.5) | - | - | - | - | |
| Adult base line ART drug combination |
1a (d4T + 3TC + NVP) 1b (d4T + 3TC + EFV 1c (AZT + 3TC + NVP) 1d (AZT + 3TC + EFV) 1e (TDF + 3TC + EFV) 1f (TDF + 3TC + NVP) |
1422 (91.4) 133 (100) 2240 (94.4) 342 (85.7) 2108 (91) 418 (95.7) |
113 (8. 6) - 133 (5.6) 57 (14.3) 209 (9.0) 19 (4.3) |
2.05 (1.25–3.36) - 1.31 (0.79–-2.13) 3.66 (2.14–6.28) 2.18 (1.34–3.52) Ref. |
0.004 - 0.28 < 0.001 0.001 |
1.45 (0.84–2.49) - 0.98 (0.57–1.70) 2.34 (1.23–4. 65) 1.98 (1.17–3.37) |
0.17 0.95 0.01 0.01 |
| Dose ART 1st drug combination changed? |
Yes No |
5485 (92.3) 1501 (85.9) |
456 (7.7) 247 (14.1) |
Ref (1) 1.97 (1.67–2.33) |
< 0.001 |
Ref. 1.32 (0.16–10.6) |
0.79 |
| Reason why ART primary (1st ) drug combination is changed? | Side effect/ Toxicity | 285 (83.3) | 57 (16.7) | Ref (1) | Ref. | ||
| Availability of new drugs | 4164 (96.9) | 133 (3.1) | 0.16 (0.15–0.23) | < 0.001 | 2.84 (1.45–5.56) | 0.002 | |
| Drug stock-out | 323 (84.8) | 58 (15.2) | 0.89 (0.60–1.38) | 0.59 | 1.46 (0.82–2.58) | 0.189 | |
| Due to TB co-infection | 56 (74.7) | 19 (25.3) | 1.69 (0.93–3.07) | 0.081 | 1.73 (0.83–3. 61) | 0.144 | |
| Treatment failure | 617 (89) | 76 (11) | 0.61 (0.42–0.89) | 0.010 | - | 0.98 | |
| Age transition to adult hood | 57 (33.3) | 114 (66.7) | 10.0 (6.52–15.3)- | < 0.001 | 22.2 (9.03–54.9) | < 0.001 | |
| Increase in BMI | 19 (100) | - | - | - | - | - | |
| Current ART drug combination for all |
1 J (TDF + 3TC + DTG) 1f (TDF + 3TC + NVP) 1e (TDF + 3TC + EFV) 1d (AZT + 3TC + EFV) 2f (AZT + 3TC + ATV/r) 1c (AZT + 3TC + NVP) 1a (d4T + 3TC + NVP) ABC + 3TC + DTG 2 h (TDF + 3TC + ATV/r) |
4023 (97.2) 57 (100) 1823 (86.5) 171 (60) 475 (89.3) 228 (70.6) 19 (100) 76 (80) 114 (85.7) |
114 (2.8) 0 (0) 285 (13.5) 114 (40) 57 (10.7) 95 (29.4) 0 (0) 19 (20) 19 (14.3) |
Ref (1) - 5.51 (4.41–6.90) 23.5 (17.4–31.8) 4.23 (3.04–5.90) 14.7 (10.8–19.9) - 8.82 (5.16–15.0) 5.88 (3.49–9.89) |
- < 0.001 < 0.001 < 0.001 < 0.001 - < 0.001 < 0.001 |
Ref. - 6.87 (4.41–10.7) 15.3 (7.99–29.4) 2.95 (1.31–6. 67) 27.1 (14.9–49.2) - 0.95 (0.45–1.98) 3.40 (1.24–9.31) |
0.99 < 0.001 < 0.001 0.009 < 0.001 0.99 0.89 0.017 |
| Child 1st line drug combination | 4a (d4T + 3TC + NVP) | 95 (83.3) | 19 (16.7) | Ref (1) | - | - | |
| 4b (d4T + 3TC + EFV) | 57 (60) | 38 (40) | 3.33 (1.75–6.32) | < 0.001 | - | - | |
| 4c (AZT + 3TC + NVP) | 133 (77.8) | 38 (22.2) | 1.43 (0.77–2.63) | 0.25 | - | - | |
| 4d (AZT + 3TC + EFV) | 38 (40) | 57 (60) | 7.50 (3.59–14.2) | < 0.001 | - | - | |
| Maternal condition (female participants) | Non-pregnant | 4423 (92.8) | 342 (7.2) | 1.19 (1.05–1.34) | < 0.001 | - | - |
| Pregnant | 57 (75) | 19 (25) | 2.56 (1.51–4.37) | 0.001 | - | - | |
| Lactating mother | 19 (50) | 19 (50) | 7.70 (4.03–14. 6) | < 0.001 | - | - | |
| Not applicable D | 2314 (37.4) | 496 (33) | Ref. | ||||
| Viral load after 24 weeks on ART |
≥ 1000cps/mL < 1000 cps/mL |
512 (47.3) 6474 (98) |
570 (52.7) 133 (2.0) |
Ref. 5.41 (4.39–6.69) |
< 0.001 | 3.38 (1.21–9.30) | 0.016 |
| Most recent viral load level |
≥ 1000 cps/mL < 1000 cps/mL |
0 (0) 6986 (90.9) |
703 (100) 0 (0) |
- | - | - | - |
Note: D: indicates females who are at none child bearing age; COR: Crude Odds Ratio; AOR: Adjusted Odds Ratio; Ref::Reference value
The study found that the primary ART drug combination list for adults with HIV was influenced by the introduction of new drug types and the age transition to adulthood. Thosewho were on 1e (TDF + 3TC + EFV), 1d (AZT + 3TC + EFV), and 1c (AZT + 3TC + NVP) regimens were more likely to show HIV virological recovery. The study also found that the first and second-line therapies 2f (AZT + 3TC + ATV/r) and 2 h (TDF + 3TC + ATV/r) were more likely to show HIV virological recovery in the multi-variable analysis. These treatment-related variables were found to be more likely to contribute to HIV virological recovery.
Discussion
Although testing for viral load has become the preferred monitoring method for People living with HIV and allows for the identification of treatment failure, virological assessment is still the gold standard for following patients on antiretroviral therapy. HIV transmission decline is correlated with virological suppression [19–21]. A study found that individuals who received combination therapy for at least 24 weeks experienced a virological recovery rate of 6986 (90.9%), including long-term suppression and very low viral replication levels even 48 weeks later, comparable to research in Sub-Saharan Africa countries like Malawi [22] and South Africa [23]. The study’s findings were significantly higher than those from other regions, including Europe [24], the West (81.5%), East (87.3%), South (86.6%), and Central Africa (85.3%) from SSA [25]. The study’s results are likely lower than those from Uganda [26] and Vietnam [27], and fall short of the global 95% [28]. Variations in viral load analysis sites, PCR methods, research designs, patient age, socioeconomic factors, reporting thresholds, ART guidelines, adherence levels, drug accessibility, therapeutic regimens, and patient clinical and genetic presentations may cause differences.
Female partners are more likely to achieve long-term virological recovery in HIV-positive individuals using HAART (4.24; 95% CI (2.97–6.03)). Research from South Africa and the Democratic Republic of the Congo indicates that female partners are more likely to achieve long-term virological recovery in HIV-positive individuals [29, 30]. However, research from Ethiopia and South Africa contradicts our findings [31, 32]. The survey results show a gender disparity, with Ethiopia and South Africa having a higher proportion of men compared to the current survey, which has a slightly higher female majority.
Participants aged 16–30 at ART enrollment were twice as likely to have persistent viral load recovery as younger participants, while individuals aged 3–18 and adults aged 19–35 and 36–52 showed significantly better virological recoveries than reference categories over 53 years old. The rise on age enhances virologic response, as supported by other studies [33–35] and Latin American cohort data [36]. However, some studies found no difference in age variations, possibly due to differences in study designs, sample size, ART adherence, medication, and clinical settings [37–39].
The WHO clinical stages significantly impact viral suppression, with patients with WHO Stages I and II at enrollment and in recent ART engagements having lower expected odds of having a detected viral load compared to HIV patients with advanced AIDS disease. HIV patients with WHO stages III and IV exhibit higher viremia and aggravated immune suppression compared to those with stages I and II, a fact that is scientifically justified [37, 40]. Individuals in Stages III and IV were found to be in a severe state, with a high likelihood of developing a detectable viral load [37, 40, 41].
The baseline CD4 cell count significantly influences HIV patients’ detectable viral load, with a higher count indicating a lower likelihood of detectable viral load, potentially promoting virological recovery even after extended therapy [42–44]. Low CD4 counts at treatment initiation can cause late HIV diagnosis, advanced AIDS, severe immunosuppression, and increased risk of opportunistic infections, leading to unmonitored viral replications [45, 46].
The study reveals that medication adherence significantly impacts viral load status, suggesting that fair adherent individuals may have lower viral load than good adherent patients [47–49]. The study suggests that patients who adhere to their prescribed medication may have lower virus replication and a longer life span, possibly due to effective counseling or proximity to adherence.
Patients on antiretroviral therapy (ART) for six months, three years, or seven years had a higher chance of virological recovery compared to those on ART for more than ten years; this finding was consistent with a study carried out in Nigeria [50]. Extended therapy is generally expected to lead to virological recovery in patients, but this may be questioned if regular patients are unable to adhere to their prescribed medications because in the long stay patients become reluctant due to false sense of security.
Teens who start antiretroviral therapy later in life have a lower risk of viral suppression, suggesting that users who are more “settled” in their care and control their viral expression are associated with long-term low viral replication, suggesting younger children may be more comfortable with their daily routine [44].
Virological recovery requires appropriate ART. In the current study, participants who were on the treatments of 1d (AZT + 3TC + EFV) and 1e (TDF + 3TC + EFV) at therapy initiation and on most recent therapy engagement were obtained to show low viral replication that implies persistent virological recovery compared to lamivudine (d4T) and Nevirapine (NVP) based therapy users as obtained from clinical trial based studies [51–53]. Previous studies from Ethiopia, Uganda, and Vietnam have shown that children on Efavrinz-based therapies have better outcomes for persistent virological suppression [42, 54, 55]. Variations in drug efficacy may be attributed to factors such as mitochondrial and hepatic toxicity, genetic variations, and drug suitability [56–58]. This study found that a suppressed viral load level after 24 weeks of therapy (at baseline) was linked to three times more persistently low viral replication even after 48 weeks and more being on treatment compared with a high viral load level at the base line which makes it difficult for persistent suppression even after more time being on therapy as reported from the studies [45, 59].
Limitations of the study
The study utilized a holistic approach to evaluate viral load, avoiding aggregates due to fragmented data and high data incompleteness. The retrospective design prevented causality, as behavioral, genetic, and residential characteristics influencing virological recovery were not considered. However, the frailty model was used to determine the observed variables’ effects after controlling for unmeasured ones.
Conclusion
Male participants showed less recovery, with high baseline CD4 count, long therapy stays, and suppressed viral load being key predictors. The virological recovery (90.9%) remains below the global average which is 95%. The study recommends targeted tailored interventions, baseline viral load testing and monitoring, regular assessment of treatment response patterns and drug regiments, in-depth research to investigate HIV virological recovery and gene sequencing. These strategies can halt viral non-recovery mechanisms, identify genetic factors contributing to treatment resistance, inform effective treatment regimens, and lead to personalized medicine approaches for improved virological outcomes. Combining strategies to reduce HIV transmission rates and promote comprehensive treatment and prevention is crucial. Understanding genetic factors influencing virological recovery is essential for developing effective treatment strategies, as it helps identify gene variants associated with treatment resistance.
Acknowledgements
The authors express gratitude to the Tigray Health Research Institute and Tigray Health Bureau staff and program leaders for their support and data set provision and to all data clerks and managers for their invaluable assistance in refining and organizing the data.
Abbreviations
- ABC
Abacavire
- ART
Anti-Retro viral Therapy
- ATV
Atazanavir
- AZT
Zidovudine
- CD4
T-Lymphocyte white blood cells
- DTG
Dultogravire
- EFV
Efavirenz
- FDC
Fixed Dose Combination
- HAART
Highly Active Anti-Retroviral Therapy
- HIV
Human Immunodeficiency Virus
- NNRTI
None Nucleotide Reverse Transcriptase Inhibitor
- NVP
Nevirapine
- PI
Protease Inhibitor
- TDF
TenofovirDisoproxilFumarate
- 3TC
Lamivudine
Author contributions
GT, MT, AG, HK and GG were involved in the study conception, design and data analysis.GT, TA, DW, GA1 and FA performed the data analysis, data interpretation, preparing tables and figures and were also the major contributors in drafting of the manuscript. MT, AG, GG, GA2 and HB were involved in the drafting, critically revising and refinement of the manuscript. GT involved in supervising and drafting of the manuscript too. GT, GG, HB and HK were major contributors to the writing and refinement of the final manuscript. All authors read and approved the final manuscript and the journal in to which the manuscript to be submitted.
Funding
Not applicable.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethical approval and consent given to the patients
Not applicable.
Human ethics and consent to participate
Human ethics and consent to participate are not applicable.
Consent for publication
Not applicable.
Clinical trail number registration
Data was extracted systematically from the database we have to produce our outcome of interest. So, no human subjects were directly involved in the research which implies no need for Clinical Trial number registration.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
No datasets were generated or analysed during the current study.