The Burden of Pretreatment HIV Drug Resistance in Trinidad and Tobago

Abstract

Strategies to improve the scale-up of antiretroviral therapy (ART) for patients with HIV in Trinidad and Tobago, including the adoption of the “Test and Treat All” policy, have accompanied an increase in the number of patients with pretreatment HIV drug resistance (PDR) in the country. However, the scale of this public health problem is not well established. The objective of this study was to estimate the prevalence of PDR and evaluate its impact on viral suppression among patients with HIV receiving care at a large HIV treatment center in Trinidad and Tobago. We retrospectively analyzed data from the Medical Research Foundation of Trinidad and Tobago of patients newly diagnosed with HIV who had HIV genotyping performed. PDR was defined as having at least one drug-resistant mutation. We assessed the impact of PDR on achieving viral suppression within 12 months of ART initiation, using a Cox extended model. Among 99 patients, 31.3% had PDR to any drug, 29.3% to a non-nucleoside reverse transcriptase inhibitor (NNRTI), 3.0% to a nucleoside reverse transcriptase inhibitor, and 3.0% to a protease inhibitor. Overall, 67.1% of the patients who initiated ART (n = 82) and 66.7% (16/24) of patients with PDR achieved viral suppression within 12 months. We found no significant association between PDR status and achieving viral suppression within 12 months [adjusted hazard ratio: 1.08 (95% confidence interval: 0.57–2.04)]. There is a high prevalence of PDR in Trinidad and Tobago, specifically driven by NNRTI resistance. Although we found no difference in virologic suppression by PDR status, there is an urgent need for an effective HIV response to address the many drivers of virologic failure. Accelerating access to affordable, quality-assured generic dolutegravir and adopting it as the preferred first-line ART therapy are critical.

Introduction

HIV drug resistance (HIVDR) presents a major obstacle to the global community's commitment to eliminating HIV as a public health threat by 2030. The significant gains achieved in the rapid scale-up of antiretroviral therapy (ART) have paralleled the rise in HIVDR that may compromise the effectiveness and sustainability of ART programs, particularly in low- and middle-income countries (LMICs).¹ For example, in Latin America, countries such as Argentina, Brazil, Mexico, and Colombia have reported increasing national estimates of HIVDR between 9.8% and 12.8% in ART-naïve populations. HIVDR is still trending upward over time.^2,3

In the absence of an effective response to HIVDR, morbidity and mortality will increase due to HIV treatment failure, and more resources will be needed to meet the demand for more expensive second- and third-line ART regimens.^4
–6 For example, one study conducted a model-based analysis to estimate the potential health and economic impact of pretreatment HIVDR (PDR) in sub-Saharan Africa (SSA) from the period 2016 to 2030.

The authors found that even a moderate increase in HIVDR could lead to a significant rise in AIDS-related deaths, new infections, and treatment costs. Specifically, with a mean PDR level of 15%, 16% of AIDS deaths (890,000 deaths), 9% of new infections (450,000), and 8% (US$ 6.5 billion) of ART program costs in SSA will be attributable to HIVDR.⁴ Accordingly, concerted efforts to address the increasing levels of HIVDR led to the development of a 5-year Global Action Plan on HIVDR (2017–2021) to monitor and respond to this global health threat.⁷

Research has demonstrated that mutations in the HIV genome confer resistance to antiretroviral (ARV) drugs and suppress immunological response leading to virologic failure.⁸ PDR may be identified in individuals who are ARV naive, those initiating ART, or those with prior exposure who are reinitiating treatment. Essentially, PDR can result from transmission during infection (e.g., transmitted drug resistance), acquisition after exposure to ARV medications (e.g., acquired drug resistance), or a combination of both.⁹

Between 2014 and 2018, among individuals initiating first-line ART in 12 of 14 LMICs, >10% exhibited high levels of PDR attributed to non-nucleoside reverse transcriptase inhibitors (NNRTIs),⁹ while levels of nucleoside reverse transcriptase inhibitor (NRTI) (0.3%–6.8%) and protease inhibitor (PI) mutations (0%–5.7%) have been relatively low.² Typically, in these countries, baseline genotypic testing for PDR is not routinely carried out to guide ART initiation. Thus, the choice of first-line HIV regimens is often guided by standard clinical guidelines, which may not be adequate in the presence of drug resistance and may lead to virologic failure.^10
–12

In Trinidad and Tobago, an estimated 11,000 people were living with HIV in 2019, and the national HIV program fell short of achieving the ART coverage goal of 90%, with only 73% of patients with HIV receiving treatment.¹³ By the end of 2019, only 67% of patients with HIV had suppressed viral loads (VLs) in the country.¹³ Studies have reported that ∼70%–90% of people who experience treatment failure have PDR, most of which are due to NNRTI drug resistance mutations.^14
–16

In the National HIV and AIDS Policy 2020–2030 developed by the Government of Trinidad and Tobago in 2010,¹⁷ one of the challenges listed as hampering the country's HIV response was the lack of an effective surveillance system for monitoring HIVDR. As such, HIVDR prevalence in Trinidad and Tobago is not well established. Therefore, we sought to estimate the prevalence of PDR and evaluate its impact on viral suppression among patients with HIV receiving care at a large HIV treatment center in Trinidad and Tobago.

Methods

We retrospectively analyzed data from the Medical Research Foundation of Trinidad and Tobago (MRFTT) of patients who were newly diagnosed with HIV and who had HIV genotyping test performed between March 5, 2018, and February 1, 2019.

MRFTT offers free HIV services through appointments and walk-in visits, and serves ∼72% of patients with HIV in Trinidad and Tobago. At intake, patients are assigned a unique identification number linked to routinely collected information obtained from standardized national HIV data collection tools. Data are stored in MRFTT's electronic medical records/health information system that records demographic, clinical, and laboratory information about the patient at each visit.

Patients aged ≥18 years who were ARV naïve at the time of treatment initiation (baseline date) were included in the analysis (n = 102). Patients with evidence of ART use (baseline VL <200 copies/mL) (n = 3) were excluded. Follow-up for the cohort was until February 1, 2020, allowing for a maximum follow-up duration of 12 months.

As previously published,¹⁸ plasma was extracted and purified ribonucleic acid (RNA) was amplified by reverse transcription polymerase chain reaction (RT-PCR) using the QIAamp viral RNA kit (QIAGEN) and Titan OneStep RT-PCR kit (Roche), respectively. The sequences of the primers used for amplification and sequencing were as described in the World Health Organization (WHO) manual for HIVDR testing using dried blood specimens.¹⁹ Sequencing was carried out according to standard laboratory practices and procedures using established WHO-accredited HIV genotyping protocols. ABI 3730 XL was used to identify the sequences, which were later stored on a database. The Calibrated Population Resistance Tool in Stanford HIV Database program²⁰ was used to determine PI, NRTI, and NNRTI drug resistance variants.

The primary explanatory variable was PDR status (yes and no) defined as having at least one drug-resistant mutation. Demographic variables included sex, age (at baseline) (18–29, 30–39, and ≥40 years), education (primary education or less, secondary education, and vocational), and marital status [single (including never married, divorced, and separated) and married (married and common law)]. Common-law marriage refers to a legally recognized relationship between a couple who has cohabited continuously for a minimum of 5 years but has not formally registered their marriage.

Clinical and laboratory variables included history of AIDS diagnosis [consistent with the WHO definition of advanced HIV disease (Stage 3 or 4²¹)] categorized as “yes” and “no,” time from HIV diagnosis to drug resistance genotyping test (defined as the length of time in years from the date of HIV diagnosis to drug resistance genotyping), pretreatment CD4 count, VL test date and result, regimen line of therapy (first, second, and third), and class of ART regimen (NNRTI, NRTI, and PI).

Trinidad and Tobago adheres to WHO guidelines²² on using ARV drugs for HIV treatment and prevention. The choice of specific regimens may vary depending on factors such as drug availability, individual patient characteristics, and resistance patterns. In summary, the guidelines recommend that the first-line regimen for HIV treatment is initiated for all individuals, regardless of CD4 count or clinical stage, and typically includes two NRTIs, and either an NNRTI or an integrase strand transfer inhibitor. If the first-line treatment fails, a second-line regimen is recommended, usually consisting of two NRTIs and preferably a ritonavir-boosted PI.

In cases of second-line treatment failure, a third-line regimen is considered, involving newer, more potent ARV agents such as dolutegravir and an optimized background regimen based on resistance testing. Other variables included HIV transmission risk category [a self-report of mode of HIV acquisition categorized as heterosexual contact and male-to-male sexual contact (men who have sex with men, MSM) or other], history of substance use [yes (including past or current substance use of marijuana or cocaine) and no], and history of incarceration (current/ever and never).

Descriptive statistics were used to describe the study population as well as the number and proportion of patients by PDR status, overall and stratified by explanatory variables. Differences in PDR status for each stratification variable were compared using Pearson's chi-square or Fisher's exact test for categorical variables and the Kruskal–Wallis tests for continuous variables, as appropriate. Using binomial proportions, we computed the prevalence [and the corresponding 95% confidence intervals (CIs) estimated by the Clopper–Pearson “exact” method] of drug-resistant mutation, overall, by ART regimen class and drug-resistant HIV strains based on the WHO surveillance drug resistance mutation (SDRM) list.²³

In brief, the WHO SDRM list presents an updated compilation of drug resistance mutations for monitoring PDR. Assembled by an international panel of experts, the list aims to identify mutations that are likely to be associated with PDR and have implications for first-line ART regimens. The mutations are classified based on the three principal classes of ARV drugs: NRTIs, NNRTIs, and PIs. The revised SDRM list encompasses 93 mutations, consisting of 34 NRTI-resistance mutations at 15 reverse transcriptase positions, 19 NNRTI-resistance mutations at 10 reverse transcriptase positions, and 40 PI-resistance mutations at 18 protease positions.

The NRTI mutations correspond to resistance to drugs such as zidovudine, lamivudine, emtricitabine, and tenofovir, while NNRTI mutations exhibit resistance to drugs such as efavirenz and nevirapine. As for PIs, the mutations demonstrate resistance to medications, including ritonavir, atazanavir, and lopinavir. These drugs listed are available in Trinidad and Tobago.

In addition, we evaluated the impact of PDR on achieving viral suppression within 12 months of baseline visit (defined as the first date with VL <200 copies/mL) among patients who initiated ART through a time-to-event analysis. At MRFTT, VL testing is routinely performed every 6 months but may be done more frequently if clinically indicated. We calculated the proportion of persons achieving viral suppression within 12 months. If a patient was lost to follow-up or reached the study's conclusion without experiencing the event, their data were considered censored.

Using the Kaplan–Meier estimates and the log-rank test, we compared the median time to viral suppression for subgroups of each explanatory variable. Next, we fitted univariable Cox models to estimate the relative hazard of viral suppression and 95% CI associated with each explanatory variable. Finally, we fitted a multivariable extended Cox model using the stepwise selection procedure with an entry and removal significance level set at 0.25. PDR, as the primary explanatory variable, was forced to stay in the model.

To account for the change in the regimen line of therapy that may have occurred due to changes in a patient's clinical condition, we included this variable as a time-varying covariate. All statistical tests were conducted using SAS/STATv14.2.²⁴ p < .05 was considered statistically significant. This study met the criteria for exemption from review by the Campus Research Ethics Committee at the University of West Indies, St. Augustine.

Results

The analytic cohort included 99 patients with genotypic drug resistance test results. Most patients were male, aged 18–39 years, single, and with secondary education (Table 1). Ninety-one patients had information on the most recent ART regimen; 72.5% were receiving first-line ART regimens (tenofovir/emtricitabine/efavirenz), 22.0% were on second-line ART (atazanavir/ritonavir or lopinavir/ritonavir-based regimen), and 5.5% on third-line ART (raltegravir or darunavir/ritonavir or etravirine-based regimen).

Table 1.

Demographic and Clinical Characteristics of Patients by Pretreatment HIV Drug Resistance, 2018–2020 (n = 99)

	Total population n	Patients without PDR n (%)	Patients with PDR n (%)	p ^*
Total participants	99	68 (68.7)	31 (31.3)
Sex				.0617^*
Female	39	31 (45.6)	8 (25.8)
Male	60	37 (54.4)	23 (74.2)
Age (years)				.8316^*
18–29	31	20 (29.4)	11 (35.5)
30–39	31	22 (32.4)	9 (29.0)
40+	37	26 (38.2)	11 (35.5)
Marital status				.5136^*
Single	66	44 (66.7)	22 (73.3)
Married	30	22 (33.3)	8 (26.7)
Missing	3
Education				.8498^*
Primary education or less	11	7 (11.3)	4 (14.8)
Secondary education	69	49 (79.0)	20 (74.1)
Vocational	9	6 (9.7)	3 (11.1)
Missing	10
HIV transmission risk category				.9110^*
Heterosexual	71	49 (72.1)	22 (71.0)
MSM/other^a	28	19 (27.9)	9 (29.0)
History of substance use				.6738^*
Yes	35	23 (34.3)	12 (38.7)
No	63	44 (65.7)	19 (61.3)
Missing	1
History of incarceration				.5600^*
Current/ever	16	10 (14.7)	6 (19.4)
Never	83	58 (85.3)	25 (80.7)
AIDS diagnosis				.1338^*
Yes	29	17 (25.0)	12 (40.0)
No	69	51 (75.0)	18 (60.0)
Missing	1
Time from HIV diagnosis to drug resistance test				.3800^*
One year or less	82	55 (82.1)	27 (90.0)
More than a year	15	12 (17.9)	3 (10.0)
Missing	2
Pretreatment CD4 count (cells per mL)
Median (IQR)		435.5 (259.0–626.5)^c	399.0 (129.0–567.0)^d	.3020^**
Regimen line of therapy^b				.1130^*
First line	66	51 (78.5)	15 (57.7)
Second line	20	11 (16.9)	9 (34.6)
Third line	5	3 (4.6)	2 (7.7)
Missing	8

Other represents two patients who identified as being lesbian/bisexual.

Regimen indicates the most recent line of therapy during the study period.

Missing, n = 8.

Missing, n = 4.

p-value for chi-square/Fisher's exact test as appropriate.

p-value for the Kruskal–Wallis test.

ART, antiretroviral therapy; IQR, interquartile range; MSM, men who have sex with men; PDR, pretreatment drug resistance.

PDR was detected in 31 patients (31.3%), of whom 23 (74.2%) were male, 20 (64.5%) were aged 18–39 years, and 22 (71.0%) reported heterosexual mode of HIV transmission. Most patients with PDR were diagnosed with HIV ≤1 year before their baseline visit (90.0%), and were still on a first-line ART regimen (57.7%) during the study period. Approximately one-third of patients with PDR were on a second-line ART regimen.

Of the 31 patients with PDR, two were administered a third-line regimen. Most patients began first-line ART before resistance genotyping results were available. If these results indicated drug resistance, patients were switched to alternative regimens. A small group on third-line ART likely faced intolerance to NNRTI-based regimens or had HIV-associated neurocognitive disorders, necessitating specialized treatment. In addition, the median pretreatment CD4 count was 399.0 cells/mL [interquartile range (IQR):129.0–567.0], and the majority were not diagnosed with AIDS (60%), indicative of less-advanced infection in this cohort. Differences between subgroups of explanatory variables by PDR status were not significant.

Thirty-one patients (31.3%) had at least one drug-resistant mutation (95% CI: 22.4–41.4), 29.3% had resistance to NNRTIs (95% CI: 20.6–39.3), 3.0% to NRTIs (95% CI: 0.6–8.6), and 3.0% to PIs (95% CI: 0.6–8.6) (Table 2). SDRM-listed mutations were present in 15 patients with NNRTI-resistant mutations [15.2% (95% CI: 8.7–23.8)], 2 patients with NRTI mutations [2.0% (0.3–7.1)], and 2 with PI mutations [2.0% (0.3–7.1)] (Table 3). The most prevalent SDRM-listed and non-SDRM–listed mutations seen among the cohort were K103N/NS/KN [12.1% (6.4–20.2)] and V179D/VD [9.1% (4.2–16.6)] (Table 4), respectively. For non-SDRM–listed mutations, other frequent mutations included V106I/VI [3.0% (0.6–8.6)] for NNRTIs, K70AT/KT [2.0% (0.3–7.1)] for NRTIs, and Q58E [2.0% (0.3–7.1)] for PIs.

Table 2.

Prevalence of Drug Resistance Mutations Among Patients in Care, 2018, n = 99

	n	Prevalence (95% CI)
Type of HIV drug resistance mutation
Any HIVDR mutation^*	31	31.3 (22.4–41.4)
Non-nucleoside reverse transcriptase inhibitor	29	29.3 (20.6–39.3)
Nucleoside reverse transcriptase inhibitor	3	3.0 (0.6–8.6)
Protease inhibitor	3	3.0 (0.6–8.6)

Four patients had two-class resistance or “multidrug” resistance.

CI, confidence interval; HIVDR, HIV drug resistance.

Table 3.

World Health Organization Surveillance of Transmitted Drug-Resistant (Surveillance Drug Resistance Mutation) HIV Strains²²

	n	Prevalence (95% CI)
NNRTI-resistance mutation	15	15.2 (8.7–23.8)
G190A	1	1.0 (0–5.5)
K103N/NS/KN	12	12.1 (6.4–20.2)
L100I	1	1.0 (0–5.5)
Y188L	1	1.0 (0–5.5)
NRTI-resistance mutation	2	2.0 (0.3–7.1)
T215C	1	1.0 (0–5.5)
T69D	1	1.0 (0–5.5)
PI-resistance mutation	2	2.0 (0.3–7.1)
I54V	1	1.0 (0–5.5)
M46I	1	1.0 (0–5.5)
L76V	1	1.0 (0–5.5)
V82F	1	1.0 (0–5.5)

NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor.

Table 4.

Other Drug-Resistant HIV Strains^*

	n	Prevalence (95% CI)
NNRTI-resistance mutation	16	16.2 (9.5–24.9)
E138EK	1	1.0 (0–5.5)
F227FL	1	1.0 (0–5.5)
P236PL	1	1.0 (0–5.5)
V179D/VD	9	9.1 (4.2–16.6)
V106I/VI	3	3.0 (0.6–8.6)
V108I	1	1.0 (0–5.5)
NRTI-resistance mutation	3	3.0 (0.6–8.6)
A62V	1	1.0 (0–5.5)
K70AT/KT	2	2.0 (0.3–7.1)
V75I	1	1.0 (0–5.5)
M41ML	1	1.0 (0–5.5)
PI-resistance mutation	2	2.0 (0.3–7.1)
Q58E	2	2.0 (0.3–7.1)

Other drug-resistant HIV strains indicate resistance-associated mutations not listed in the WHO SDRM.

n, total number of patients; SDRM, surveillance drug resistance mutation; WHO, World Health Organization.

In total, 82 of the 99 patients who underwent genotypic testing initiated ART during the study period. Among the 17 patients who did not commence treatment, 9 died before therapy initiation, while the remaining individuals declined therapy. Overall, 67.1% (55/82) of the patients who initiated ART achieved VL suppression within 12 months.

Patients without PDR (67.2%), men (78.0%) or persons aged 18–29 (69.2%) or ≥40 years (65.5%), and those who were single (70.9%), MSM or reported other mode of transmission (80.0%) were more likely to achieve viral suppression within 12 months. Notably, 68.4% of patients on a second-line ART regimen achieved viral suppression within 12 months, whereas 67.8% of patients on first-line and 50% on third-line ART regimens achieved viral suppression within 12 months.

Among the patients who initiated ART between 2018 and 2019, the median number of VL tests measured was 2 (IQR: 2, 3), and the median duration of observation (which corresponds to the length of time between baseline and last VL measurements) was 6.7 months (IQR: 5.0, 9.1). On average, the median time to achieve viral suppression was 6.9 months (95% CI: 6.6–7.7). Although longer median time to viral suppression was seen in patients with PDR [7.7 (95% CI: 5.4–9.3)] compared with patients without PDR [6.9 (6.6–7.6)], there was no significant difference between the groups (p = .6025).

Compared with men, women had longer median time to viral suppression (p = .0471). Subgroups with longer median time to viral suppression than the cohort average were as follows: age 18–29 years or ≥40 years, having a vocational education, MSM or reported other mode of HIV transmission, having no history of substance use or an AIDS diagnosis, ever or currently incarcerated, received an HIV diagnosis more than a year before baseline, and being on a third-line ART regimen (Table 5).

Table 5.

Viral Suppression Among Patients on Antiretroviral Therapy Aged ≥18 Years, 2018–2020 (n = 82)

	Total^c n	Viral suppression within 12 months ^d n (%)	Median time to viral suppression within 12 months (95% CI)	Log-rank test
Total participants	82	55 (67.1)	6.9 (6.6–7.7)
PDR				0.6025
Yes	24	16 (66.7)	7.7 (5.4–9.3)
No	58	39 (67.2)	6.9 (6.6–7.6)
Sex				0.0471
Female	32	16 (50.0)	8.2 (6.7)^e
Male	50	39 (78.0)	6.7 (5.8–7.2)
Age (years)				0.8924
18–29	26	18 (69.2)	7.6 (5.9–9.3)
30–39	27	18 (66.7)	6.7 (5.1–8.2)
40+	29	19 (65.5)	7.1 (5.8–9.0)
Marital status				0.8958
Single	55	39 (70.9)	6.8 (6.0–9.0)
Married	25	15 (60.0)	6.9 (5.9–9.0)
Missing	2
Education				0.9712
Primary education or less	10	5 (50.0)	6.9 (3.6)^e
Secondary education	60	43 (71.7)	6.8 (6.2–8.5)
Vocational	7	4 (57.1)	7.7 (2.8)^e
Missing	5
HIV transmission risk category				0.9721
Heterosexual	57	35 (61.4)	6.9 (6.6–7.7)
MSM/other^a	25	20 (80.0)	7.2 (5.8–9.4)
History of substance use				0.4683
Yes	27	17 (63.0)	6.9 (5.7–10.6)
No	54	37 (68.5)	7.0 (6.1–8.2)
Missing	1
History of incarceration				0.2205
Current/ever	12	7 (58.3)	9.8 (5.5)^e
Never	70	48 (68.6)	6.9 (6.2–7.6)
AIDS diagnosis				0.7118
Yes	18	9 (50.0)	6.9 (5.1)^e
No	64	46 (71.9)	7.0 (6.7–8.2)
Time from HIV diagnosis to drug resistance test				0.1669
One year or less	69	48 (69.6)	6.8 (5.9–7.6)
More than a year	12	6 (50.0)	8.8 (6.0)^e
Missing	1
Regimen line of therapy^b				0.7167
First line	59	40 (67.8)	6.9 (6.6–8.2)
Second line	19	13 (68.4)	6.8 (5.0–9.1)
Third line	4	2 (50.0)	12.0 (5.8)^e

Other represents two patients who identified as being lesbian/bisexual.

Regimen indicates the most recent line of therapy during the study period.

Total excludes 17 patients who did not initiate antiretroviral therapy before the end of the study.

Excludes 13 patients lost to follow-up and 14 patients who did not achieve viral suppression before the end of the study.

The upper boundary of the 95% CI is missing because its value was beyond 12 months.

In the multivariable extended Cox proportional hazard model, after controlling for other factors, we found no significant association between PDR status and achieving viral suppression within 12 months [adjusted hazard ratio (AHR): 1.08 (95% CI: 0.57–2.04)]. Conversely, compared with men, women were less likely to achieve viral suppression within 12 months [AHR: 0.40 (95% CI: 0.19–0.84)]. For the only other variables retained in the full model, HIV transmission risk category and history of incarceration, we observed no significant association with these variables and achieving viral suppression within 12 months (Table 6).

Table 6.

Crude and Adjusted Hazard Ratios and 95% Confidence Intervals of Time from HIV Genotypic Drug Resistance Testing to Achieving Viral Suppression Within 12 Months

	Time to viral suppression (VL <200 copies/mL)
	HR (95% CI) n = 97	AHR (95% CI) ^c n = 92
PDR	1.13 (0.66–1.93)	1.08 (0.57–2.04)
Female sex	0.59 (0.33–1.04)	0.40 (0.19–0.84)
Age (years)
18–29	1.03 (0.57–1.88)	—
30–39	1.13 (0.59–2.17)	—
40+	ref	—
Marital status
Single	ref
Married	1.04 (0.57–1.90)	—
Education
Primary education or less	0.92 (0.33–2.60)	—
Secondary education	ref	—
Vocational	0.87 (0.31–2.43)	—
HIV transmission risk category
Heterosexual	ref	ref
MSM/other ^a	0.98 (0.57–1.67)	0.61 (0.31–1.19)
History of substance use	0.78 (0.43–1.41)	—
History of incarceration
Current/ever	0.59 (0.29–1.22)	0.5 (0.2–1.2)
Never	ref	ref
Time of HIV diagnosis to drug resistance mutation test
One year or less	ref	—
More than a year	0.63 (0.30–1.32)	—
AIDS diagnosis	0.85 (0.40–1.80)	—
Regimen of therapy^b
First line	ref	—
Second line	1.42 (0.62–3.26)	—
Third line	0.71 (0.17–2.98)	—

Bolded value shows significance at p < .05.

Other represents two patients who identified as being lesbian/bisexual.

Regimen indicates the most recent line of therapy during the study period.

Extended Cox regression model using stepwise selection.

—Variables were dropped from the model.

AHR, adjusted HR; HR, hazard ratio; VL, viral load.

Discussion

In this study, we investigated the PDR prevalence in patients initiating ART and attending a large HIV treatment center in Trinidad and Tobago. We found a high prevalence of drug-resistant HIV among this cohort of ARV drug-naïve patients. PDR was present in ∼3 in 10 patients and was largely driven by NNRTI resistance (29.3%), which is of utmost significance, given that NNRTI constitutes most of first-line regimens. The WHO recommends switching from NNRTI-based to dolutegravir-based first-line regimens in countries with levels of PDR reaching 10%.²

Although the new Trinidad & Tobago HIV treatment guidelines developed in January 2022 recommend a switch to a drug combination that includes dolutegravir for first-line treatment,²⁵ patients are not offered this option. Given that Trinidad and Tobago is classified as a high-income country by the World Bank, the Medicines Patent Pool's patent and licensing provisions for generic dolutegravir formulations, aimed at LMICs, do not apply to the country.²⁶ This restriction impedes the broad adoption of dolutegravir as a primary treatment alternative due to its high costs and unavailability. Dolutegravir is currently used in patients who are intolerant to NNRTI-based regimens and those with HIV-associated neurocognitive disorders who would benefit from regimen simplification.

More importantly, the prevalence of NRTI and PI drug-resistant mutations was lower in comparison with that of NNRTI, with each at 3.0%, providing opportunities for switching to alternative regimens. Other studies, including those conducted at the national level using WHO-recommended HIVDR survey methodology, have reported lower levels of PDR in the Americas. Recent national HIVDR surveys revealed the following prevalence estimates of PDR among treatment-naïve individuals: 12.8% in Argentina and 9.8% in Brazil (2014), 9.9% in Colombia (2016), and 11.1% in Mexico (2017).⁹

Only the PDR prevalence of 29.1% in Cuba in 2017⁹ was comparable with the observed PDR estimate in our study. Similarly, PDR prevalence for NNRTI in our study was higher than estimates from Argentina (10.9%) and Brazil (6.8%) in 2014, Colombia (6.3%) in 2016, Mexico (8.6%) and Cuba (22.8%) in 2017,⁹ and Peru from 2013 to 2017 (10–12%).²⁷

Our findings of a high PDR prevalence, particularly to NNRTIs, provide evidence of the increasing challenge to the success of the HIV national ART program in Trinidad and Tobago, which may threaten the substantial progress made toward achieving the global targets for epidemic control by 2030. If PDR prevalence remains at this level or rises further over time as in LMICs,² this may pose significant public health implications in terms of resource allocation and program planning in future years.⁴

Despite the high prevalence of PDR in our study, we observed that there was no significant association between PDR and achieving viral suppression within 12 months among patients who initiated ART. This finding is in contrast with other studies, given that PDR predicts poor virologic response.^11,12,28 A possible explanation is that in some cases, HIV strains undergo detrimental effects of reduced replication and pathogenicity after drug-resistant mutation-induced structural changes.^29,30

As such, patients with HIVDR may still benefit from standard first-line regimens with residual therapeutic activity and have comparable virologic outcomes as patients without HIVDR. To explore further whether treatment switches played a role in our nonsignificant findings, we conducted a post hoc analysis by examining the relationship between treatment switching and viral suppression status among patients with PDR who initiated ART.

Patients receiving only first-line regimens (69.2%) and those switching to any alternative regimens (63.6%) achieved viral suppression within 12 months, which were comparable with viral suppression rates in patients without PDR (67.2%), suggesting that other factors may play a role. It is worth noting that the significance of mutations regarding ARV resistance may vary depending on the HIV-1 subtype. Some mutations associated with resistance in one subtype may have different effects or be less prevalent in other subtypes.³¹

This variability in resistance mutations among HIV-1 subtypes can impact the effectiveness of ART and the interpretation of resistance testing results. It is also likely that pharmacological dosages and medication adherence, which is influenced by a combination of multifaceted factors (behavioral, social, and structural),³² could have an effect on viral suppression. However, we did not have sufficient information to explore these further.

To ensure optimal delivery of quality ART services and the prevention of resistance emergence, the WHO recommends ∼5% second-line ART coverage and ≥90% VL suppression rates among people on treatment as part of programmatic strategic objectives.⁷ Notably, 22.0% of the patients in this study were receiving second-line ART regimens, which surpasses the WHO target, indicating optimal use of alternative treatment options. However, only 67.1% of patients initiating ART achieved viral suppression within 12 months during 2018–2020, implying the need for a comprehensive and effective HIV response to address the many drivers of virologic failure.

Our study is not without limitations. One limitation was that we could not ascertain whether patients were treatment naïve or reinitiating ART at the time of HIV genotypic resistance testing; therefore, the observed prevalence of PDR may be overestimated. Our study may have inadvertently included a small number of patients with prior exposure to ART, despite our efforts to exclude such cases. To minimize this possibility, we excluded individuals with clinical evidence of ART use (e.g., VL <200 copies/mL) at the time of ART initiation.

Furthermore, patients self-reported any previous ART initiation at intake, and the comprehensive health information system at the MRFTT enables queries to ascertain if a patient was previously on ART. Higher prevalence of HIVDR among ART reinitiators compared with treatment-naïve patients has been reported.⁷ Another limitation was that the limited sample size of our study could potentially influence the findings and might not accurately reflect the true prevalence of PDR within the country.

Nonetheless, the specimens were obtained from the MRFTT, which serves as the primary care provider for the vast majority of newly diagnosed individuals in the country (∼82.3% of all new HIV diagnoses during the fourth quarter of 2020). We acknowledge the limitations in using stepwise selection for the survival analysis, given the potential to introduce bias in the estimates. Even though we employed an a priori selection of covariates based on subject matter expertise for inclusion in the analysis, there is a possibility of excluding relevant variables during the procedure.³³ Despite this, our data-driven approach produced an AHR that remained consistent with the crude HR.

In conclusion, the prevalence of PDR and particularly PDR to NNRTI is high in Trinidad and Tobago. Available data suggest that as countries improve access to and scale-up of ART, further increases in PDR levels can occur. The WHO recommends countries to implement nationally representative HIVDR surveys to monitor the emergence and transmission of HIV drug resistance³⁴; however, Trinidad and Tobago is yet to implement one. Therefore, there is an urgent need to accelerate scale-up of HIVDR monitoring and surveillance strategies to provide timely epidemiological data, which is necessary to inform national treatment guidelines.

In addition, if PDR continues to rise in Trinidad and Tobago, upon initiation of care, patients should be assessed for PDR as standard of care to guide the choice of therapy. Lowering the costs of and expanding access to HIV genotypic resistance testing will lead to widescale adoption, thereby ensuring optimal treatment benefits to patients. However, in settings with limited resources, such as Trinidad and Tobago, with patent and licensing restrictions for generic dolutegravir formulations, accelerating access to affordable, quality-assured generic dolutegravir and adopting it as the preferred first-line ART therapy may yield greater benefits. Consequently, the resources allocated for baseline genotyping could be more effectively utilized in other areas.

Footnotes

Authors' Contributions

S.O.G. was involved in conceptualization, methodology, formal analysis, writing—original draft, and writing—review and editing. G.B. was involved in conceptualization, methodology, data extraction, and writing—review and editing. M.J.T. was involved in conceptualization, methodology, writing—review and editing, funding acquisition, and supervision. R.J.E. was involved in conceptualization, methodology, data extraction, writing—review and editing, and supervision.

Availability of Data and Materials

The data that support the findings of this study are available from the MRFTT, but restrictions apply to the availability of these data; thus, they are not publicly available. Permission can be requested by contacting the MRFTT.

Disclaimer

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This research was supported in part by the National Institute on Minority Health and Health Disparities of the National Institutes of Health Under Award Number NIMHD (U54MD012393), Florida International University Research Center in Minority Institutions.

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