Study sample
For the study period between April 1, 2008 and April 30, 2019, a total of 8,813 patients with a diagnosis of HIV were identified; of these, data on 4,293 patients aged ≥ 18 years treated with any ART regimens were extracted and 4,087 patients met the inclusion criteria and were included in the analysis. Among the included patients, 94 (2.3%) patients received a 2-ART on their index date and were classified as the 2-ART cohort. There were 3,993 (97.7%) patients who received a 3-ART and were classified as the 3-ART cohort. Figure 2 illustrates the flow of patient inclusion. The median duration of follow-up was 712 days and 701 days in the 2-ART cohort and the 3-ART cohort, respectively.
Baseline And Clinical Overview
Of the 94 patients in the 2-ART cohort, the mean age was 54.4 years (SD 12.7 years) and 87.2% were male. In contrast, the 3-ART cohort was significantly younger with a mean age of 43.4 years (SD 11.7 years) and included significantly more males (93.8%). The proportion of patients having hemophilia was greater in the 2-ART cohort than in the 3-ART cohort (12.8% vs. 2.1%; p < 0.0001). (Table 1).
Table 1
| 2-Drug | 3-Drug | P-value |
Demographics (at Index) | | | | | |
Age | 94 | | 3993 | | |
Mean (SD) | 54.40 (12.70) | | 43.40 (11.70) | | < 0.0001 |
Median (Q1, Q3) | 53 (44, 64) | | 42 (35, 50) | | |
Min, max | 27,82 | | 18,90 | | |
Gender (n, %) | | | | | |
Male | 82 | 87.23% | 3745 | 93.79% | 0.0101 |
Female | 12 | 12.77% | 248 | 6.21% | |
Hemophilia (n, %) | | | | | |
Yes | 12 | 12.77% | 84 | 2.10% | < 0.0001 |
No | 82 | 87.23% | 3909 | 97.90% | |
Year of index date (n, %) | | | | | |
Cluster 1 (April 1, 2008- September 30, 2014) | 21 | 22.34% | 1057 | 26.47% | < 0.0001 |
Cluster 2 (October 1, 2014- June 30, 2016) | 26 | 27.66% | 420 | 10.52% | |
Cluster 3 (July 1, 2016 - April 1, 2019) | 47 | 50.00% | 2516 | 63.01% | |
Clinical background Summary | | | | | |
Co-medications | | | | | |
N with at least other 1 medication class | 87 | 92.55% | 2996 | 75.03% | < 0.0001 |
Mean (SD) | 8.28 (6.71) | | 4.99 (4.61) | | < 0.0001 |
Median (Q1, Q3) | 6 (4, 11) | | 3 (2, 7) | | |
Min, max | 1,34 | | 1,42 | | |
AIDS-defining conditions | | | | | |
N with at least 1 condition | 62 | 65.96% | 1708 | 42.77% | < 0.0001 |
Mean (SD) | 1.74 (0.87) | | 1.77 (1.04) | | 0.8441 |
Median (Q1, Q3) | 2 (1, 2) | | 1 (1, 2) | | |
Min, max | 1,4 | | 1,7 | | |
Charlson Comorbidity Index | 94 | | 3993 | | |
Mean (SD) | 6.85 (2.3) | | 5.32 (1.63) | | < 0.0001 |
Median (Q1, Q3) | 6 (5,8) | | 5 (4,6) | | |
Min, max | 4,14 | | 0,17 | | |
Charlson comorbid conditions | | | | | |
Congestive Heart failure | 25 | 26.60% | 202 | 5.06% | < 0.0001 |
Dementia | 0 | 0.00% | 17 | 0.43% | N/A |
Chronic pulmonary disease | 28 | 29.79% | 940 | 23.54% | 0.1592 |
Rheumatologic disease | 4 | 4.26% | 49 | 1.23% | 0.0326 |
Mild liver disease | 41 | 43.62% | 1330 | 33.31% | 0.0364 |
Diabetes with chronic complications | 18 | 19.15% | 163 | 4.08% | < 0.0001 |
Hemiplegia or paraplegia | 2 | 2.13% | 30 | 0.75% | 0.1669 |
Renal disease | 32 | 34.04% | 192 | 4.81% | < 0.0001 |
Any malignancy, including lymphoma and leukemia | 16 | 17.02% | 294 | 7.36% | 0.0005 |
Moderate or severe liver disease | 5 | 5.32% | 23 | 0.58% | 0.0004 |
Metastatic solid tumor | 2 | 2.13% | 37 | 0.93% | 0.2257 |
HIV | 94 | 100.00% | 3990 | 99.92%* | N/A |
Other relevant systemic diseases | | | | | |
Hemodialysis (artificial kidney, chronic maintenance dialysis) | 6 | 6.38% | 6 | 0.15% | < 0.0001 |
Cardiovascular diseases | 12 | 12.77% | 178 | 4.46% | 0.0012 |
Hypertension | 50 | 53.19% | 765 | 19.16% | < 0.0001 |
Lipid disorders | 40 | 42.55% | 711 | 17.81% | < 0.0001 |
Bone Disorders | 17 | 18.09% | 251 | 6.29% | < 0.0001 |
Peripheral Neuropathy | 0 | 0.00% | 0 | 0.00% | N/A |
Any Diabetes | 48 | 51.06% | 871 | 21.81% | < 0.0001 |
Psychiatric disorders | 39 | 41.49% | 1446 | 36.21% | 0.2931 |
Hepatitis B/C Co-Infection | 24 | 25.53% | 878 | 21.99% | 0.4129 |
*Although all patients included in the analysis had an HIV diagnosis code, not all 3-drug patients had a diagnosis for HIV using the Charlson Comorbidity HIV codes; which does not include B23 (HIV disease resulting in other conditions), yet was used for the study population definition. |
Co-medications
Of patients in the 2-ART cohort, 92.6% had been prescribed at least one class of co-medication with a mean of 8.3 different co-medication classes (based on ATC level 4 code) during the follow-up period. The top five most common co-medication classes were proton pump inhibitors, angiotensin II antagonists, calcium antagonists, anti-gout preparations, and non-barbiturates and statins [see Additional file 1]. In contrast, 75.0% of patients in the 3-ART cohort have been prescribed a co-medication, with a lower mean number of different co-medication classes (5.0; p < 0.0001) [see Additional file 2]. The most commonly prescribed co-medications in the 3-ART cohort included systemic antihistamines, non-barbiturates, proton pump inhibitors, non-steroidal anti-rheumatics, and other anti-ulcerants.
Aids-defining Conditions And Comorbidities
AIDS-defining conditions varied between the 2- and 3-ART cohorts; 66.0% of patients on 2-ART had an AIDS-defining condition compared with 42.8% of those on 3-ART [see Additional file 3]. AIDS-defining conditions other than an AIDS diagnosis were present in 42.6% and 31.6% of the 2- and 3-ART cohorts, respectively. A diagnostic code for AIDS itself was found in 52.1% and 24.8% of the 2- and 3-ART cohorts, respectively. The top 5 most common AIDS-defining conditions other than AIDS itself was the same for both cohorts: pneumocystis (20.2% and 22.1%), cytomegalovirus disease (17.0% and 10.5%), tuberculosis (6.4% and 6.4%), non-Hodgkins lymphoma (4.3% and 3.2%), and encephalopathy (4.3% and 2.5%).
Comorbidities
Nearly all Charlson comorbid conditions were more prevalent in the 2-ART cohort than in the 3-ART cohort (mean score 6.9 vs. 5.3), with the largest differences found for mild liver disease (43.6% vs. 33.3%), congestive heart failure (26.6% vs. 5.1%), renal disease (34.0% vs. 4.8%), diabetes with chronic complications (19.2% vs. 4.1%), and malignancies (17.0% vs. 7.4%) (Table 1). In addition, the 2-ART cohort also showed a significantly higher prevalence of all other relevant systemic diseases, except for psychiatric disorders and hepatitis B/C co-infection.
Treatment Patterns
Among patients on a 2-ART, NRTI-sparing regimens comprised the majority of all 2-ARTs (71.3%) (Fig. 3a). Overall, the most common class combinations for this cohort were PI + INSTI (33.0%) and NNRTI + INSTI (31.9%). Among patients treated with a 3-ART, the most common drug class combinations were INSTI + 2NRTI (66.6%), followed by PI + 2NRTI (20.5%) and NNRTI + 2NRTI (12.9%). The top common antiretroviral drug combinations for both cohorts are presented in [Additional file 4].
The 2-ART cohort comprised of 1.9% of all patients from April 1, 2008 to September 30, 2014 (representative of 1st generation INSTI), 5.8% between October 1, 2014 and June 30, 2016 (representative of 2nd generation INSTI), and 1.8% between July 1, 2016 and April 30, 2019 (representative of TAF). Among patients in the 2-ART cohort, NRTI-sparing regimens were frequently found in all time periods examined (Fig. 3b). Within the 2-ART cohort, the first time period (April 1, 2008 to September 30, 2014) had the highest proportion of NRTI-sparing regimens (76.2%), with the proportion decreasing slightly to 69.2% in the second time period (October 1, 2014 to June 30, 2016), then leveling out at 70.2% in the last time period (July 1, 2016 to April 30, 2019). Over time, there was a shift in drug class among NRTI-sparing regimens among the 2-ART cohort. Specifically, PI + INSTI (61.9%) regimens were dominant in the first time period (April 1, 2008 to September 30, 2014), but NNRTI + INSTI regimens were most common from October 1, 2014 to April 30, 2019.
Switch Analyses
ART regimen switch occurred more often in the 2-ART cohort (33.0%; 31/94) than in the 3-ART cohort (21.2%; 845/3993). The switch rate was 20.88 switches/100 person-years (95% CI: 14.68–29.68) in the 2-ART cohort, and 10.34 switches/100 person-years (95% CI: 9.66–11.06) in the 3-ART cohort; however, no statistical comparisons were made (Table 2). In the time-to-switch analysis, around 25% of patients in the 2-ART cohort had their first switch within one year, while only 10% of patients in the 3-ART cohort had their first switch within one year. As presented in the Kaplan-Meier curve, the higher switch rate in the 2-ART cohort was most evident prior to year 5 of follow-up. However, due to the small patient sample, long-term switch rates were more difficult to evaluate [see Additional file 5].
Table 2
Treatment switching patterns
| N | Switch rate (/100 person years) | Lower CI | Upper CI |
Any Switch | 876 | 10.52 | 9.85 | 11.24 |
2-Drug regimen cohort | 31 | 20.88 | 14.68 | 29.68 |
2-Drug to 2-drug switches | 3 | | | |
2-Drug to 3-drug switches | 24 | | | |
2-Drug to 4-drug switches | 4 | | | |
3-Drug regimen cohort | 845 | 10.34 | 9.66 | 11.06 |
3-Drug to 3-drug switches | 832 | | | |
3-Drug to 4-drug switches | 9 | | | |
3-Drug to 1-drug switches | 4 | | | |
Switch sensitivity analyses* | | | | |
Any Switch | 130 | 6.43 | 5.42 | 7.64 |
2-Drug regimen cohort | 19 | 29.24 | 18.65 | 45.84 |
2-Drug to 2-drug switches | 2 | | | |
2-Drug to 3-drug switches | 13 | | | |
2-Drug to 4-drug switches | 4 | | | |
3-Drug regimen cohort** | 111 | 5.67 | 4.71 | 6.83 |
3-Drug to 3-drug switches | 107 | | | |
3-Drug to 4-drug switches | 2 | | | |
3-Drug to 1-drug switches | 2 | | | |
*subset of patients with at least 1 year follow-up and 1 prior switch |
**Only patients who additionally switched to another 3-drug regimen were included. |
Of all switches in the 2-ART cohort, 77.4% (24/31) was from 2-ART to 3-ART (Table 2). All switch patterns for the 2-ART cohort are presented in [Additional file 6]. The most common switching patterns were from PI + NRTI to PI + 2NRTI and PI + INSTI to INSTI + 2NRTI. Only 9.7% (3/31) of all switches in the 2-ART cohort were from a 2-ART to another 2-ART. In the 3-ART cohort, because patients could not switch to a 2-ART by definition, 98.5% (832/845) of all switches were to another 3-ART (rather than to a 1- or 4-drug regimen). The most prevalent switch pattern was from PI + 2NRTI to INSTI + 2NRTI. About 1% of 3-ART switching patients changed to a 4-drug regimen, such as adding a PI to INSTI + 2NRTI regimen.
Sensitivity analysis demonstrated that in the subset of patients with at least 1 year follow-up and 1 prior switch, the switch rate (per 100 person-years (PY)) was higher among the 2-ART cohort (29.24/PY; 95% CI: 18.65–45.84/PY) compared to the 3-ART cohort (5.67/PY; 95% CI: 4.71–6.83/PY).