Use of Drug-level Testing and Single-genome Sequencing to Unravel a Case of Human Immunodeficiency Virus Seroconversion on Pre-exposure Prophylaxis

Spinelli, Matthew A; Lowery, Brentton; Shuford, Jennifer A.; Spindler, Jonathan; Kearney, Mary F; McFarlane, Jenny; McDonald, Cheryl; Okochi, Hideaki; Phung, Nhi; Kuncze, Karen; Jee, Kathryn; Johannessen, D. T.; Anderson, Peter L.; Smith, Dawn K.; Defechereux, Patricia; Grant, Robert M.; Gandhi, Monica

doi:10.1093/cid/ciaa1011

Cited by 7 publications

(8 citation statements)

References 11 publications

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“…HIV acquisition in the setting of high levels of PrEP adherence has been described in several individuals previously; all were men from North America, Europe, or Asia [54][55][56][57][58][59]. Notably, several of these cases had evidence of resistance only to FTC (M184V) without mutations conferring TDF resistance, suggesting that PrEP breakthrough can occur with FTC resistance alone [54].…”

Section: Discussionmentioning

confidence: 86%

HIV incidence after pre-exposure prophylaxis initiation among women and men at elevated HIV risk: A population-based study in rural Kenya and Uganda

et al. 2021

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Background Oral pre-exposure prophylaxis (PrEP) is highly effective for HIV prevention, but data are limited on HIV incidence among PrEP users in generalized epidemic settings, particularly outside of selected risk groups. We performed a population-based PrEP study in rural Kenya and Uganda and sought to evaluate both changes in HIV incidence and clinical and virologic outcomes following seroconversion on PrEP. Methods and findings During population-level HIV testing of individuals ≥15 years in 16 communities in the Sustainable East Africa Research in Community Health (SEARCH) study (NCT01864603), we offered universal access to PrEP with enhanced counseling for persons at elevated HIV risk (based on serodifferent partnership, machine learning–based risk score, or self-identified HIV risk). We offered rapid or same-day PrEP initiation and flexible service delivery with follow-up visits at facilities or community-based sites at 4, 12, and every 12 weeks up to week 144. Among participants with incident HIV infection after PrEP initiation, we offered same-day antiretroviral therapy (ART) initiation and analyzed HIV RNA, tenofovir hair concentrations, drug resistance, and viral suppression (<1,000 c/ml based on available assays) after ART start. Using Poisson regression with cluster-robust standard errors, we compared HIV incidence among PrEP initiators to incidence among propensity score–matched recent historical controls (from the year before PrEP availability) in 8 of the 16 communities, adjusted for risk group. Among 74,541 individuals who tested negative for HIV, 15,632/74,541 (21%) were assessed to be at elevated HIV risk; 5,447/15,632 (35%) initiated PrEP (49% female; 29% 15–24 years; 19% in serodifferent partnerships), of whom 79% engaged in ≥1 follow-up visit and 61% self-reported PrEP adherence at ≥1 visit. Over 7,150 person-years of follow-up, HIV incidence was 0.35 per 100 person-years (95% confidence interval [CI] 0.22–0.49) among PrEP initiators. Among matched controls, HIV incidence was 0.92 per 100 person-years (95% CI 0.49–1.41), corresponding to 74% lower incidence among PrEP initiators compared to matched controls (adjusted incidence rate ratio [aIRR] 0.26, 95% CI 0.09–0.75; p = 0.013). Among women, HIV incidence was 76% lower among PrEP initiators versus matched controls (aIRR 0.24, 95% CI 0.07–0.79; p = 0.019); among men, HIV incidence was 40% lower, but not significantly so (aIRR 0.60, 95% CI 0.12–3.05; p = 0.54). Of 25 participants with incident HIV infection (68% women), 7/25 (28%) reported taking PrEP ≤30 days before HIV diagnosis, and 24/25 (96%) started ART. Of those with repeat HIV RNA after ART start, 18/19 (95%) had <1,000 c/ml. One participant with viral non-suppression was found to have transmitted viral resistance, as well as emtricitabine resistance possibly related to PrEP use. Limitations include the lack of contemporaneous controls to assess HIV incidence without PrEP and that plasma samples were not archived to assess for baseline acute infection. Conclusions Population-level offer of PrEP with rapid start and flexible service delivery was associated with 74% lower HIV incidence among PrEP initiators compared to matched recent controls prior to PrEP availability. HIV infections were significantly lower among women who started PrEP. Universal HIV testing with linkage to treatment and prevention, including PrEP, is a promising approach to accelerate reductions in new infections in generalized epidemic settings. Trial registration ClinicalTrials.gov NCT01864603.

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Section: Discussionmentioning

confidence: 86%

HIV incidence after pre-exposure prophylaxis initiation among women and men at elevated HIV risk: A population-based study in rural Kenya and Uganda

et al. 2021

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“…Twelve case reports have been published of individuals who seroconverted on TDF or TDF/FTC PrEP after 5 months to 4 years of use despite detectable drug exposure [38][39][40][41][42][43][44][45][46][47][48][49]. Of these twelve, three breakthrough infections were wild-type (no resistance mutations), one on-demand TDF/FTC PrEP case from San Francisco had FTC-associated M184V only [43], one daily TDF PrEP case from Germany had K65R only [46], and one case from KwaZulu-Natal on daily TDF/FTC PrEP had both K65R and M184V [48].…”

Section: Key Pointsmentioning

confidence: 99%

“…Of these twelve, three breakthrough infections were wild-type (no resistance mutations), one on-demand TDF/FTC PrEP case from San Francisco had FTC-associated M184V only [43], one daily TDF PrEP case from Germany had K65R only [46], and one case from KwaZulu-Natal on daily TDF/FTC PrEP had both K65R and M184V [48]. The remaining six had complex multiclass resistance profiles that included M184V and/or K65R with thymidine analog mutations and/or NNRTI resistance mutations, indicating transmission of the resistant virus from a partner who may have undergone multiple ART switches [38][39][40][41][42]47].…”

Section: Key Pointsmentioning

confidence: 99%

How could HIV-1 drug resistance impact preexposure prophylaxis for HIV prevention?

Parikh

Mellors

2022

Current Opinion in HIV and AIDS

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Purpose of reviewTo review current laboratory and clinical data on the frequency and relative risk of drug resistance and range of mutations selected from approved and investigational antiretroviral agents used for preexposure prophylaxis (PrEP) of HIV-1 infection, including tenofovir disproxil fumarate (TDF)-based oral PrEP, dapivirine ring, injectable cabotegravir (CAB), islatravir, lenacapavir and broadly neutralizing antibodies (bNAbs). Recent findingsThe greatest risk of HIV-1 resistance from PrEP with oral TDF/emtricitabine (FTC) or injectable CAB is from starting or continuing PrEP after undiagnosed acute HIV infection. By contrast, the dapivirine intravaginal ring does not appear to select nonnucleoside reverse transcriptase inhibitor resistance in clinical trial settings. Investigational inhibitors including islatravir, lenacapavir, and bNAbs are promising for use as PrEP due to their potential for sustained delivery and low risk of cross-resistance to currently used antiretrovirals, but surveillance for emergence of resistance mutations in more HIV-1 gene regions (gag, env) will be important as the same drugs are being developed for HIV therapy.

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“…The DOT Diary app showed a high level of concordance with FTC-TP and TFV-DP levels (91.0% and 85.3%, respectively), suggesting that this method of measuring adherence is substantially better than self-reported measures [ 17 , 36 – 38 ], which often over-report adherence levels because of social desirability [ 39 – 42 ]. Segmental hair levels provide a benefit over DBS levels because they can be used to measure PrEP use over a longer period of time, with drug levels from each centimeter of hair reflecting adherence over previous 4-week periods [ 43 ]. However, DOT Diary offers advantages over both measures, because it allows both for longitudinal measurement of adherence over extended periods of time, as well as providing greater granularity on patterns of adherence; measuring hair levels also requires trained personnel and a clinic visit.…”

Section: Discussionmentioning

confidence: 99%

Randomized Controlled Trial of Automated Directly Observed Therapy for Measurement and Support of PrEP Adherence Among Young Men Who have Sex with Men

et al. 2022

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Measurement of adherence to oral pre-exposure prophylaxis (PrEP) in real-time has been challenging. We developed DOT Diary, a smartphone application that combines automated directly observed therapy with a PrEP adherence visualization toolkit, and tested its ability to measure PrEP adherence and to increase adherence among a diverse cohort of young men who have sex with men (MSM). We enrolled 100 MSM in San Francisco and Atlanta and randomly assigned them 2:1 to DOT Diary versus standard of care. Concordance between DOT Diary measurement and drug levels in dried blood spots was substantial, with 91.0% and 85.3% concordance between DOT Diary and emtricitabine-triphosphate and tenofovir-diphosphate, respectively. There was no significant difference in the proportion of participants with detectable PrEP drug levels at 24 weeks between study arms. These results suggest DOT Diary is substantially better than self-reported measures of adherence, but additional interventions are needed to improve PrEP adherence over time.

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Use of Drug-level Testing and Single-genome Sequencing to Unravel a Case of Human Immunodeficiency Virus Seroconversion on Pre-exposure Prophylaxis

Cited by 7 publications

References 11 publications

HIV incidence after pre-exposure prophylaxis initiation among women and men at elevated HIV risk: A population-based study in rural Kenya and Uganda

HIV incidence after pre-exposure prophylaxis initiation among women and men at elevated HIV risk: A population-based study in rural Kenya and Uganda

How could HIV-1 drug resistance impact preexposure prophylaxis for HIV prevention?

Randomized Controlled Trial of Automated Directly Observed Therapy for Measurement and Support of PrEP Adherence Among Young Men Who have Sex with Men

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