Date Published: February 22, 2019
Publisher: BioMed Central
Author(s): Sarah E. Rutstein, Jane S. Chen, Julie A. E. Nelson, Samuel Phiri, William C. Miller, Mina C. Hosseinipour.
High rates of non-nucleoside reverse transcriptase inhibitors (NNRTI) resistance was a key consideration in the WHO policies transitioning first-line regimens to include integrase inhibitors (dolutegravir [DTG]). However, recent data suggests a relationship between DTG and neural tube defects among women exposed during conception, giving providers and policymakers pause regarding the planned regimen changes. We examined HIV drug resistance among a cohort of 46 acutely infected persons in Malawi. Our data demonstrates high levels of transmitted resistance, 11% using standard resistance surveillance mutations and 20% when additional NNRTI polymorphisms that may affect treatment response are included. High resistance rates in this treatment-naïve patient population reinforces the critical nature of DTG-based options in the context of public-health driven treatment programs.
Current WHO-recommended first-line antiretroviral therapy (ART) regimens include non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz in addition to two nucleoside analogue reverse transcriptase inhibitors . However, increasing prevalence of NNRTI resistance among those initiating ART have raised concerns regarding the public health implications of efavirenz-based first-line regimens [2–6], as people with NNRTI-resistance are up to three times as likely to fail first-line therapy [7–11]. In response to escalating resistance, alternative first-line regimens may be critical to preserve morbidity and mortality benefits of early ART, as well as delay or avoid costly switch to second-line ART.
We analyzed resistance patterns from peripheral blood specimens collected at time of enrollment among participants in a pilot study evaluating behavioral and biomedical interventions for persons with AHI in Lilongwe, Malawi. Participants were screened and enrolled into the study between June 2012 and January 2014. Description of screening and study protocols are described elsewhere (clinicaltrials.gov #NCT01450189) [17, 18]. AHI was defined as detectable HIV RNA with discordant or negative rapid HIV antibody tests. Where specimen volume allowed (39/46 specimens), repeat rapid antibody testing was conducted using rapid diagnostic assays (Determine™ HIV 1/2 Antibody [Abbott Diagnostics, Illinois US] and Uni-Gold Recombigen® HIV 1/2 [Trinity Biotech, Ireland]) to confirm antibody negative/discordancy. We did not screen for receipt of pre or post-exposure prophylaxis; PrEP was not available in Malawi at the time of the study and although remote exposure to PEP was possible, PEP exposure since the very recent infection acquisition was considered unlikely given that screening represented the first presentation to care for this cohort of acutely infected persons. Additional eligibility criteria included: above definition of AHI within 21 days of enrollment, age ≥ 18 years, and intention to remain in the Lilongwe area for the duration of study follow-up (52 weeks).
Among 59 persons identified with AHI, 46 were enrolled into the study . Of these 46 participants, 45 had resistance testing; nine (20%; 95% CI 10–35%) had at least one NNRTI resistance mutation detected (Table 1) and three had NRTI mutations detected (Table 2). There were no integrase mutations detected. Limiting likely transmitted drug resistance classification to those with mutations appearing in the SDRM list, five (11%; 95% CI 4–24%) had NNRTI resistance; the most frequent mutation was K103N, detected in four participants with any NNRTI mutations. The second most common mutation was E138A (3/9: 33%), a mutation that is not on the SDRM but which nonetheless may be clinically significant in its effect on treatment response.Table 1Demographics and resistance outcomesTotal (n = 46)N (%)No resistance (n = 36)N (%)Any resistance (n = 9)N (%)Age 18–2419 (41)14 (78)4 (22) 25–3420 (43)15 (75)5 (25) 35–446 (13)6 (100)0 (0) ≥ 451 (2)1 (100)0 (0)Sex Male28 (61)21 (78)6 (22) Female18 (39)15 (83)3 (17)Marital status Never married11 (24) Married23 (50) Separated/divorced/widowed12 (26)Viral load at screening ≤ 6 log10 copies/mL24 (53)19 (83)4 (17) > 6 log10 copies/mL21 (47)16 (76)5 (24)NNRTI resistance mutations frequencya A98G2 (4.4) E138A3 (6.7) K101E1 (2.2) K103N4 (8.9) K103Q1 (2.2) V179E1 (2.2) V90I1 (2.2) Y181C1 (2.2)NNRTI non-nucleoside reverse transcriptase inhibitorsaAmong 45 patients assessed for resistance at time of study entryTable 2HIV drug resistance mutation profilesProfile #NNRTI mutationNRTI mutation1A98Ga, K103NM184V, T215F2E138Aa3E138Aa4E138Aa, V179Ea5K103N6K103N7K103N8K103Qa9V90Ia, A98Ga, K101E, Y181CT69N10NoneK219RNNRTI non-nucleoside reverse transcriptase inhibitors, NRTI nucleoside reverse transcriptase inhibitors, WHO World Health OrganizationaDesignated mutations are not on the WHO surveillance of drug resistance mutations list and thus may be less likely to represent transmitted drug resistance