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Prevalence of Pretreatment and Acquired HIV-1 Mutations Associated with Resistance to Lamivudine or Rilpivirine: A Systematic Review

Prevalence of Pretreatment and Acquired HIV-1 Mutations Associated with Resistance to Lamivudine... Antiviral Therapy 2019; 24:393–404 (doi: 10.3851/IMP3331) Original article Prevalence of pretreatment and acquired HIV-1 mutations associated with resistance to lamivudine or rilpivirine: a systematic review 1 1 1 2 3 1 Vani Vannappagari *, Leigh Ragone , Cassidy Henegar , Jean van Wyk , Dannae Brown , James Demarest , 2 1 1 4,5 2 Romina Quercia , Marty St. Clair , Mark Underwood , Jose M Gatell , Annemiek de Ruiter , Michael Aboud ViiV Healthcare, Research Triangle Park, NC, USA ViiV Healthcare, Brentford, UK ViiV Healthcare, Abbotsford, Australia Hospital Clinic/IDIBAPS, University of Barcelona, Barcelona, Spain ViiV Healthcare, Barcelona, Spain *Corresponding author e-mail: vani.x.vannappagari@viivhealthcare.com Background: Pretreatment and acquired drug resist- Most prevalent DRMs resistant to lamivudine or rilpiv- ance mutations (DRMs) can limit antiretroviral therapy irine were at positions E138 (4%), V179 (1%) and M184 effectiveness. (1%). Estimated acquired DRM prevalence was 58% for Methods: We review prevalence of DRMs with resistance any NRTIs and 67% for any NNRTIs, most frequently at to nucleoside reverse transcriptase inhibitors (NRTIs) and positions M184 (58%) and Y181 (21%). non-nucleoside reverse transcriptase inhibitors (NNRTIs), Conclusions: This review suggests low risk of lamivudine- focusing on lamivudine and rilpivirine, from 127 articles or rilpivirine-resistant mutations in treatment-naive, with >100,000 individuals with HIV-1 infection. HIV-1-infected individuals. Results: Estimated global prevalence of pretreatment resistance to any NRTI was 4% and to any NNRTI was 6%. Introduction With recent advances in antiretroviral therapy (ART), the transmission of drug resistance to a newly infected HIV-1 infection can be considered a treatable chronic individual [6]. illness [1], and individuals with HIV-1 with high lev- Current treatment guidelines recommend 2 nucleo- els of adherence to highly effective ART have a life side reverse transcriptase inhibitors (NRTIs) in com- expectancy approaching that of HIV-negative individ- bination with a third drug from the non-nucleoside uals [2]. However, there remain several challenges to reverse transcriptase inhibitor (NNRTI), integrase ensuring that individuals with HIV are able to achieve strand transfer inhibitor (INSTI) or protease inhibi- and maintain viral suppression, including treatment tor (PI) drug classes [7–9]. In the US Department of adherence and ART resistance, as well as factors that Health and Human Services and European AIDS Clini- limit treatment such as stigma, delayed diagnosis, cal Society guidelines, the 2-drug regimen (2DR) of the discrimination and lack of access to health care [3]. INSTI dolutegravir (DTG) plus the NRTI lamivudine Socioeconomic disadvantages include unemployment, (3TC) is an alternative option as initial ART for indi- attempting to immigrate to another country, language viduals when a preferred option is not available [7,8]. barriers and mental health challenges such as depres- Individuals with HIV-1 infection with viral suppression sion [4]. These factors are interrelated, as a lack of may wish to switch therapy to a more simplified regi- resources can negatively affect adherence [5], and men or to manage comorbidities or drug–drug interac- poor adherence can lead to development of HIV drug tions [7–9]. For these individuals, 2DRs, such as DTG resistance mutations (DRMs), which may also lead to plus the NNRTI rilpivirine (RPV), DTG plus 3TC, or a ©2019 International Medical Press 1359-6535 (print) 2040-2058 (online) 393 AVT-19-RV-4565_Vannappagari.indd 393 AVT-19-RV-4565_Vannappagari.indd 393 22/11/2019 11:22:16 22/11/2019 11:22:16 V Vannappagari et al. boosted PI with 3TC, are recommended options [7–9]. as reported by authors. If only absolute numbers or In treatment-experienced adults with HIV-1 infection percentages were reported, the unreported values were and drug resistance, guidelines recommend a new regi- calculated. If data were only presented in a graphical men of two or three fully active agents [7–9]. As a result format, visual estimates were used to determine missing of a high barrier to resistance with second-generation values. Estimates were recorded as not applicable (NA) INSTIs and boosted PIs [10,11], DRMs are more likely when it could not be ascertained from the Methods sec- to limit the effectiveness of the treatment regimen tion that the screening method included the particular through decreased sensitivity to the NRTI or NNRTI DRM or when it could not be ascertained that all DRMs component, particularly in 2DRs consisting of DTG in screened were reported in the Results section (for exam- combination with either 3TC or RPV. To assess the risk ple, studies reporting most frequently observed DRMs). of NRTI and NNRTI resistance in treatment-naive indi- In cases in which multiple individual mutations with viduals in the general population who may be treated resistance to either 3TC/FTC or RPV were reported, with a 2DR, it is important to determine the prevalence but resistance to NRTIs or NNRTIs as a class were of pretreatment DRMs in individuals infected with not reported, the class estimates were recorded as NA. HIV-1 who have had no ART exposure. Regional prevalence estimates were calculated as per- There have been many reports that have included centages using n values corresponding to all studies that data on pretreatment and acquired DRM rates from assessed the mutation in question (that is, excluding n different geographic locations and varied populations. values from studies with NA values for that mutation). Thus, there are a large number of reports that can be Results were reported as global and regional prevalence analysed to provide a comprehensive review of global of substitutions identified at the codons associated with and regional prevalence rates for DRMs. The objec- DRMs resistant to 3TC/FTC or RPV by codon, as well tive of this review was to use a systematic search of as codons where DRMs associated with resistance to published literature reporting data on DRM prevalence NRTIs or NNRTIs as a class occur. Mutations resist- to determine the prevalence of important pretreatment ant to the NRTI or NNRTI classes were reported in and acquired mutations conferring resistance to NRTIs this review as described in the source publications and and NNRTIs, specifically 3TC and RPV, as these are may have included mutations with resistance to NRTIs/ components of DTG-based 2DRs. NNRTIs other than 3TC/FTC and RPV. Prevalence of pretreatment or acquired mutations were reported sep- arately. Pretreatment mutations referred to mutations Methods that occurred in articles that described the individuals Search strategy and selection criteria as ART-naive. Acquired mutations referred to those We conducted a systematic literature search in PubMed that occurred after virological failure. through 6 July 2018, using keywords related to geographic regions, specific DRMs and HIV. The geographic regions Results included in the analysis were Africa, Latin  America, Search results Middle East and North Africa, Europe, North America, Southeast Asia and Asia Pacific. Keywords for specific The literature search retrieved 529 articles, 402 of DRMs were selected to identify mutations associated which were removed. Reasons for removal included with resistance to 3TC or RPV at the following codons: full text not available, data not relevant or not reported K65, K70, Q151 and M184 for 3TC resistance and L100, numerically and small n values. This left 127 articles K101, E138, V179, Y181, Y188, G190 and M230 for to be included in the global and regional analyses. The RPV resistance. The DRMs with resistance to 3TC also identified articles included study periods from 1995 to have resistance to emtricitabine (FTC) and are referred to 2017 and included >60,000 participants worldwide as 3TC/FTC-resistant DRMs in this manuscript. The spe- for analysis of pretreatment resistance mutations and cific DRMs included in the search were M184I, M184V, >30,000 participants worldwide for analysis of acquired K65R, K65E, K65N, Q151M, K70E, L100I, K101E, resistance mutations. Africa had the highest number of K101P, E138A, E138G, E138K, E138Q, E138R, V179L, articles identified in the search of any region (n =30) Y181C, Y181I, Y181V, Y188L, G190E and M230L [12]. [13–42]. However, the European region had the high- A full list of keywords included in the search are included est number of participants for analysis of pretreatment in Supplemental Table 1 in Additional file 1. Identified resistance mutations (n=33,957 for NRTI-associated articles were manually searched for relevance and the mutations; n=34,201 for NNRTI-associated mutations) prevalence rates within specific countries, which excluded [43–60], and Southeast Asia had the highest number of most clinical trials and multinational cohorts. participants for analysis of acquired resistance muta- Prevalence estimates were manually determined from tions (n=26,772 for NRTI-associated mutations; 26,568 the references. When possible, prevalence was included for NNRTI-associated mutations) [61–69]. 394 ©2019 International Medical Press AVT-19-RV-4565_Vannappagari.indd 394 AVT-19-RV-4565_Vannappagari.indd 394 22/11/2019 11:22:17 22/11/2019 11:22:17 HIV-1 mutations with resistance to lamivudine and rilpivirine Global prevalence estimates in 2.5% (n=17/672) and pretreatment NNRTI resistance The estimated global prevalence of pretreatment DRMs were observed in 10.3% (n=144/1,391) of study DRMs was 4% (n=2,719/60,567; range, 2% [Asia participants, compared with 4.5% (n=2,719/60,567) and Pacific] to 6% [North America]) for those associ- 5.7% (n=3,605/63,158), respectively, in all studies. ated with NRTI resistance [16,18,25,28,30–32,35– The most frequent pretreatment DRMs by region are 38,40,43,44,46,48,49,51–60,70–111] and 6% shown in Figure 2B; mutations at position V179 were (n=3,605/61,402; range, 3% [Asia Pacific] to 8% the most frequent DRMs in Southeast Asia (5.6%), [Africa and North America]) for those associated with Latin America (5.2%) and Africa (1.9%); mutations at resistance to any NNRTI (Figure 1) [16,18,25,28,30– position E138 were the most frequent DRMs in Europe 39,41,70–85,99,100,102,104,106–120]. The only (6.8%) and North America (1.6%); and mutations at pretreatment DRMs estimated to occur in >1% of the position M184 were the most frequent DRMs in Asia global population were 3TC/FTC-associated DRMs at Pacific (1.6%) and the Middle East and North Africa position M184 (1%), and RPV-associated DRMs at (1.1%). Drug resistance mutations at position M184 positions E138 (4%) and V179 (1%; Figure 2A). are associated with resistance to 3TC/FTC, while those In a subset of studies that exclusively enrolled partici- at positions E138 and V179 are often associated with pants in the past 5 years (2013–present), the rates of the resistance to RPV [121]. most frequent pretreatment DRMs were mostly consist- Global estimated prevalence of acquired DRMs ent with the full data set (Figure 2A). One exception was was 58% (n=17,073/29,218) for resistance to V179, which had a prevalence rate of 4.2% (n=21/500) in any NRTI and 67% (n=20,834/31,016) for resist- studies enrolling participants from 2013 to present com- ance to any NNRTI in patients following viro- pared with 1.3% (n=283/21,969) in all studies. In this sub- logical failure (Figure 3) [13–29,44,45,47,50,60– set of studies, pretreatment NRTI DRMs were observed 69,77,80,81,85,91,101,103,104,109,122–134]. Figure 1. Frequency of TDRs to any NRTI or NNRTI by region NRTI PDR NNRTI PDR 7.9 7.7 7.2 6.0 5.9 5.7 5.1 4.8 4.6 4.5 4.5 4.0 2.9 2.8 1.9 0 N. R0 n= 2,082 2,914 33,957 33,957 1,961 1,961 1,669 1,669 17,951 17,951 1,756 2,947 2,950 60,567 61,402 Africa Europe Latin MENA North Southeast Asia Total America America Asia Pacic Data are shown from references that reported transmitted drug resistance (TDR) to nucleoside reverse transcriptase inhibitors (NRTIs) and/or non-nucleoside reverse transcriptase inhibitors (NNRTIs) as a class. MENA, Middle East and North Africa; NR, not reported; PDR, pretreatment drug resistance. Antiviral Therapy 24.6 395 AVT-19-RV-4565_Vannappagari.indd 395 AVT-19-RV-4565_Vannappagari.indd 395 22/11/2019 11:22:17 22/11/2019 11:22:17 Reported drug resistance per patient naive to treatment, % V Vannappagari et al. Figure 2. Frequency of TDRs at codons associated with RPV and 3TC/FTC resistance NNRTI PDR A NRTI PDR NNRTI PDR (2013–present) NRTI PDR (2013–present) 4.3 4.2 3.9 1.3 1.1 0.7 n= 16,786 460 21,969 500 40,212 2,061 E138 V179 M184 M184 E138 V179 6.8 5.6 5.2 2.8 2.4 1.9 1.6 1.6 1.5 1.5 1.4 1.4 1.1 1 0.7 0.6 0.6 0.5 0.2 0.1 NR 0.0 n= Africa Europe Latin MENA North Southeast Asia America America Asia Pacic (A) Global frequency of specific drug resistance mutation (DRMs) by codon. (B) Most frequent specific DRMs by codon by region (≥1%). FTC, emtricitabine; MENA, Middle East and North Africa; NNRTI, non-nucleoside reverse transcriptase inhibitor; NR, not reported; NRTI, nucleoside reverse transcriptase inhibitor; PDR, pretreatment drug resistance; RPV, rilpivirine; TDR, transmitted drug resistance; 3TC, lamivudine. The highest rates of acquired DRMs for both NRTIs [n=86/378]; NNRTIs, 19% [n=70/378]). In the subset and NNRTIs were reported in Africa (NRTIs, 77% of studies that enrolled patients only in the past 5 years [n=702/917]; NNRTIs, 80% [n=730/908]), and the (2013–present), global estimates of acquired DRMs were lowest were reported in North America (NRTIs, 23% consistent with the full data set (Figure 4A). Acquired 396 ©2019 International Medical Press AVT-19-RV-4565_Vannappagari.indd 396 AVT-19-RV-4565_Vannappagari.indd 396 22/11/2019 11:22:17 22/11/2019 11:22:17 3,968 11,700 9,112 8,579 3,295 2,338 2,338 1,669 1,629 1,669 15,401 6,380 4,179 2,282 1,775 Reported drug resistance Reported drug resistance per patient naive to treatment, % per patient naive to treatment, % HIV-1 mutations with resistance to lamivudine and rilpivirine Figure 3. Frequency of ADRs to any NRTI or NNRTI by region NRTI NNRTI 80.4 76.6 76.4 70.1 69.2 67.2 66.3 58.0 58.4 56.8 60 55.1 52.5 47.0 30.2 22.8 18.5 n= 917 908 2,633 2,633 450 450 149 149 378 378 24,602 26,409 89 89 29,218 31,016 Africa Europe Latin MENA North Southeast Asia Total America America Asia Pacic Data are shown from references that reported acquired drug resistance (ADR) to nucleoside reverse transcriptase inhibitors (NRTIs) and/or non-nucleoside reverse transcriptase inhibitors (NNRTIs) as a class. MENA, Middle East and North Africa. NRTI DRMs were observed in 59% (n=281/475) of acquired 3TC/FTC DRMs were at position M184 participants and acquired NNRTI DRMs were observed (70%; n=2,255/3,240); the most frequent acquired RPV in 60% (n=284/475) of participants. Across all regions, DRMs were at position Y181 (19%; n=611/3,191). the most frequently acquired DRMs were the 3TC/FTC- associated mutations at position M184 (range, 20% Regional prevalence estimates: Europe [Asia Pacific] to 70% [Africa]; Figure 4B). In European studies, there were 33,957 people with data related to pretreatment NRTI-associated DRMs Regional prevalence estimates: Africa and 34,201 people with data on NNRTI-associated In the African region, DRM data were available from DRMs (Supplemental Tables 6 and 7 in Additional 3,995 individuals for pretreatment NRTI-associated file 1) [43–60]. Pretreatment DRMs with NRTI resist- DRMs and 4,013 individuals for pretreatment NNRTI- ance were observed in 4% (n=1,371/33,957) of indi- associated DRMs (Supplemental Tables 2 and 3 in viduals with HIV in the tested population, and pretreat- Additional file 1) [16,18,25,28,30–41]. Among studies ment DRMs with NNRTI resistance were observed in that reported DRMs by drug class, 3% (n=61/2,082) 5% (n=1,553/33,957). The most frequently observed had NRTI-associated DRMs and 8% (n=224/2,914) pretreatment 3TC/FTC DRMs were at position M184 had NNRTI-associated DRMs. The most frequently (1%; n=67/11,700); the most frequent RPV DRMs observed pretreatment 3TC/FTC DRMs in Africa were were at positions E138 (7%; n=624/9,112) and V179 at position M184 (1%; n=54/3,968); the most fre- (1%; n=53/8,579). Data related to acquired DRMs quent pretreatment RPV DRMs were at positions V179 with resistance to NRTIs and NNRTIs were avail- (2%; n=16/851) and E138 (2%; n=11/731). Data on able for 2,633 individuals (Supplemental Tables 8 acquired DRMs were reported for 3,240 individuals and 9 in Additional file 1) [44,45,47,50,60]. Resist- for NRTI-associated DRMs and 3,191 individuals for ance to NRTIs was observed in 70% (n=1,846/2,633), NNRTI-associated DRMs (Supplemental Tables 4 and whereas resistance to NNRTIs was observed in 52% 5 in Additional file 1) [13–29,42]. Among reports with (n=1,382/2,633). The most common acquired 3TC/ available data, 77% (n=702/917) and 80% (n=730/908) FTC DRMs in Europe were at position M184 (51%; had acquired DRMs conferring resistance to the NRTI n=1,344/2,633); the most common acquired RPV and NNRTI classes, respectively. The most frequent DRMs were at position G190 (20%; n=532/2,633). Antiviral Therapy 24.6 397 AVT-19-RV-4565_Vannappagari.indd 397 AVT-19-RV-4565_Vannappagari.indd 397 22/11/2019 11:22:18 22/11/2019 11:22:18 Reported drug resistance per patient after virological failure, % V Vannappagari et al. Figure 4. Frequency of ADRs at codons associated with RPV and 3TC/FTC resistance A NNRTI ADR NRTI ADR NNRTI ADR (2013–present) NRTI ADR (2013–present) 61.4 58.4 20.9 19.9 18.3 20 17.3 13.3 12.0 11.5 10.3 44,002 1,811 54,327 1,811 38,282 1,811 21,969 1,811 54,189 1,673 n= M184 Y181 G190 K70 K101 M184 Y181 G190 69.6 60 55.1 51.0 50.0 48.8 41.0 31.5 21.3 20.5 20.2 19.1 18.8 16.8 16.0 14.3 11.9 7.7 5.0 4.0 2.6 1.9 n= Africa Europe Latin MENA North Southeast Asia America America Asia Pacic (A) Global frequency of specific drug resistance mutations (DRMs) by codon. (B) Most frequent acquired drug resistance (ADRs) by codon by region (≥20%). MENA, Middle East and North Africa; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; RPV, rilpivirine; 3TC/FTC, lamivudine/emtricitabine. Regional prevalence estimates: Latin America file 1) [70–80]. Out of individuals with available data, In reports from Latin America, 3,295 individuals with pretreatment NRTI-associated DRMs were reported in HIV had data available for analysis of pretreatment 5% (n=95/1,961), and pretreatment NNRTI-associated DRMs (Supplemental Tables 10 and 11 in Additional DRMs were reported in 7% (n=142/1,961). The most 398 ©2019 International Medical Press AVT-19-RV-4565_Vannappagari.indd 398 AVT-19-RV-4565_Vannappagari.indd 398 22/11/2019 11:22:18 22/11/2019 11:22:18 3,240 3,191 3,191 2,633 2,633 2,633 3,921 3,544 3,544 5,464 16,369 26,772 26,568 26,514 1,772 1,822 1,822 Reported drug resistance Reported drug resistance per patient after virological failure, % per patient after virological failure, % HIV-1 mutations with resistance to lamivudine and rilpivirine common pretreatment 3TC/FTC DRMs were at position available data. The most common acquired 3TC/FTC M184 (1%; n=18/3,295); the most common pretreatment DRMs were at position M184 (49%; n=2,668/5,464); RPV DRMs were at positions V179 (5%; n=122/2,338) the most common acquired RPV DRMs were at posi- and E138 (3%; n=65/2,338). Acquired DRM data tion Y181 (8%; n=1,259/16,369). were available for 3,921 individuals in Latin America (Supplemental Tables 12 and 13 in Additional file 1) Regional prevalence estimates: Southeast Asia [77,80,122–124]. Mutations resistant to the NRTI class In the subset of countries in Southeast Asia, 2,021 were seen in 76% (n=344/450) of individuals, whereas individuals had data on pretreatment DRMs (Sup- DRMs resistant to the NNRTI class were observed plemental Table 22 in Additional file 1) [112–118]. in 58% (n=261/450). The most frequently observed None of the reports included data on NRTI-associated acquired 3TC/FTC DRMs were at position M184 (55%; DRMs; 5% of individuals had pretreatment NNRTI- n=2,162/3,921); the most frequent acquired RPV DRMs associated DRMs (n=90/1,756). These DRMs included were at position G190 (19%; n=668/3,544). those at positions V179 (6%; n=21/377), E138 (2%; n=9/377) and Y181 (1%; n=22/1,974); the rest were Regional prevalence estimates: Middle East and North <1%. Data were available for 26,772 and 26,568 Africa individuals in Southeast Asia for 3TC/FTC- and RPV- Although there were relatively few studies (n=5) reporting associated acquired DRMs, respectively (Supplemental on pretreatment DRMs from the Middle East and North Tables 23 and 24 in Additional file 1) [61–69]. There Africa, 1,669 individuals with HIV had DRM data avail- were NRTI-resistant DRMs in 57% (n=13,976/24,602) able from the identified reports (Supplemental Tables 14 of individuals and NNRTI-resistant DRMs in 69% and 15 in Additional file 1) [81–85]. Pretreatment DRMs (n=18,287/26,409). The most common acquired with resistance to the NRTI and NNRTI classes were 3TC/FTC DRMs were at position M184 (50%; reported in 4% (n=75/1,669) and 6% (n=100/1,669) of n=13,397/26,772); the most common acquired RPV the population, respectively. The most common 3TC/ DRMs were at positions Y181 (32%; n=8,369/26,568) FTC DRMs were at position M184 (1%; n=18/1,669); and G190 (21%; n=5,650/26,514). no DRMs associated with RPV resistance were reported in ≥1% of individuals. Data on acquired DRMs were Regional prevalence estimates: Asia Pacific available from 200 individuals, with 47% (n=70/149) In studies from countries in the Asia Pacific region, 4,179 and 30% (n=45/149) reported to have DRMs with and 4,088 individuals had data for DRMs associated with resistance to the NRTI and NNRTI classes, respectively NRTIs and NNRTIs, respectively (Supplemental Tables (Supplemental Tables 16 and 17 in Additional file 1) 25 and 26 in Additional file 1) [100–111,119,120]. Pre- [81,85,125–127]. The most common acquired 3TC/FTC treatment DRMs with resistance to NRTIs and NNRTIs DRMs were at position M184 (41%; n=82/200) and the as a class were observed in 2% (n=55/2,947) and 3% most common acquired RPV DRMs were at position (n=83/2,950) of individuals, respectively. The most fre- E138 (6%; n=11/200). quently observed pretreatment 3TC/FTC DRMs were at position M184 (2%; n=65/4,179); the most frequent Regional prevalence estimates: North America pretreatment RPV DRMs were at position V179 (2%; In North America, data were available for pretreatment n=27/1,775). Acquired DRM data were reported for 1,772 DRMs from 19,563 individuals with HIV (Supplemen- and 1,822 individuals for NRTI- and NNRTI-associated tal Tables 18 and 19 in Additional file 1) [52,86–99]; DRMs, respectively (Supplemental Tables 27 and 28 in 6% (n=1,062/17,951) and 8% (n=1,413/17,951) had Additional file 1). Resistance to the NRTI and NNRTI mutations resistant to the NRTI and NNRTI classes, classes were reported for 55% (n=49/89) and 66% respectively. The most frequent pretreatment 3TC/FTC (n=59/89), respectively, among individuals with available DRMs were at position M184 (1%; n=216/15,401); data [101,103,104,109,131–134]. The most common the most frequent pretreatment RPV DRMs were acquired 3TC/FTC DRMs were at position M184 (20%; at positions E138 (2%; n=5/317) and V179 (1%; n=363/1,772); the most common acquired RPV DRMs n=43/6,380). Data on acquired DRMs were available were at positions Y181 (16%; n=292/1,822), K101 (12%; for 5,464 and 21,455 individuals to determine DRMs n=220/1,822) and G190 (12%; n=217/1,822). associated with 3TC/FTC and RPV, respectively; only 378 individuals had available data to assess resistance Discussion to the NRTI and NNRTI classes as a whole (Supple- mental Tables 20 and 21 in Additional file 1) [91,128– In this review of 127 publications that reported data 130]. Acquired DRMs associated with resistance to the on the prevalence of pretreatment and acquired DRMs, NRTI and NNRTI classes occurred in 23% (n=86/378) a low estimated prevalence of pretreatment DRMs and 19% (n=70/378), respectively, of individuals with was observed. Acquired DRMs were observed in the Antiviral Therapy 24.6 399 AVT-19-RV-4565_Vannappagari.indd 399 AVT-19-RV-4565_Vannappagari.indd 399 22/11/2019 11:22:18 22/11/2019 11:22:18 V Vannappagari et al. majority of individuals following virological failure. In for acquired DRMs as well. Mutations at M184 confer the subset of studies that did not enrol any participants resistance to 3TC or FTC but reduce the fitness of the prior to 2013 (5 years prior to the search date), a higher virus [139]. Therefore, in an individual with a transmitted rate of mutations with resistance to any NNRTI and M184 virus, the mutation may not be detected if genotyp- mutations at position V179 were observed compared ing occurred after high viral replication in the acute phase with the full data set. Across regions, DRM rates were where wildtype subpopulations would outcompete the broadly similar, with the highest rates of pretreatment M184 virus. It is important to note that the effect of differ- NRTI resistance in North America (6%) and pretreat- ent mutations at a single codon can vary widely and that ment NNRTI resistance in Africa and North America combinations of specific mutations can have synergistic (8%). Africa had the highest observed rates of acquired effects on treatment resistance. For example, the effect of DRMs to any NRTI (77%) or NNRTI (80%). Of note, mutations at V179 on RPV susceptibility depends on the a relatively low rate of acquired NRTI and NNRTI specific substitution. While V179L is listed as a DRM in DRMs were observed in North America (23% and the RPV package insert [121], V179T has minimal effects 19%, respectively) compared with the global findings on RPV and minimal reductions of RPV sensitivity, and (58% and 67%, respectively). However, this difference V179F appears to only affect RPV susceptibility in com- should be interpreted with caution because class-level bination with Y181CF [12]. Mutations at codon E138, data on NRTI and NNRTI DRMs were only avail- including E138K/A/Q/G/R, have been associated with a able from 378 individuals, 329 of whom were from two- to fivefold reduction in susceptibility to RPV [12]. a single report of incarcerated individuals in North The E138K mutation alone reduces RPV sensitivity two- Carolina [91]. Resource and monitoring limitations to threefold, while the combination of E138K and the across regions may affect levels of pretreatment drug NRTI DRM M184I can cause a fivefold reduction in resistance. Recommendations from the World Health sensitivity and virological failure. In addition, E138A is Organization (WHO) and the International Antiviral a polymorphic substitution that occurs more frequently Society–USA call for routine surveillance of pretreat- in HIV-1 subtype C compared with other subtypes [140]. ment drug resistance in people initiating ART and for As a result, the baseline prevalence of the E138A substitu- closing gaps in services in resource-limited regions as tion may be higher in regions known to have higher rates means of reducing drug resistance [135,136]. of HIV subtype C compared with other regions [12,140]. For both pretreatment and acquired DRMs, resistance The M184V/I mutation alone can greatly reduce 3TC rates were higher for NNRTIs than for NRTIs overall. Pre- susceptibility (>100-fold), and M184V is often associated treatment resistance to NNRTIs was substantially higher with 3TC virological failure [12]. compared with NRTI resistance in both Africa (7.7% One limitation of this review was using specific muta- versus 2.9%) and Latin America (7.2% versus 4.8%). tions and country or region names as keywords; doing While the global and regional rates of pretreatment NRTI so may have excluded multinational cohorts and some and NNRTI resistance were generally low (<10%), there clinical trials. However, this review analysed >60,000 are data to suggest that pretreatment resistance may be patients across 48 countries discussed in 127 publica- greater at the local level in some countries or communi- tions, suggesting that the results and conclusions in this ties. For example, while the overall rate of NNRTI DRMs analysis are unlikely to be substantially altered if data in studies identified from Africa was 7.7%, there were from additional similar types of articles were included. individual reports showing rates >10%. These included a Overall, the rates of pretreatment DRMs were low report in adult female sex workers in South Africa (27%) across geographic regions for NRTIs and NNRTIs as and one in immunocompetent children in Cameroon classes and for substitutions at codons associated with (41%) [16,32]. In addition, survey data from the WHO resistance to 3TC/FTC and RPV specifically. These data have shown pretreatment NNRTI resistance >10% in suggest a low risk of resistance to ART regimens contain- six countries: Argentina, Guatemala, Namibia, Nicara- ing 3TC/FTC and RPV, supporting the use of 2DRs such gua, Uganda and Zimbabwe [137]. The higher rates of as DTG and 3TC (in treatment-naive individuals) and NNRTI resistance observed in these reports support the DTG and RPV (in individuals who are virologically sup- WHO recommendation for non-NNRTI regimens in pressed on a 3-drug regimen and are switching to a 2DR). countries with high levels of pretreatment NNRTI resist- ance [135] and the inclusion of an antiretroviral with a Acknowledgements high barrier to resistance (that is, INSTI or boosted PI) [10,138] in initial treatment regimens [7–9]. This study was funded by ViiV Healthcare. Literature In this review, pretreatment DRMs in ≥1% of the search and analysis, medical writing and editorial assis- population in the identified reports were at positions tance were provided under the direction of the authors E138 (4%), V179 (1%) and M184 (1%); of these, by Jonathan Morgan and Diane Neer, ELS, MedThink M184 (51%) was among the most common positions SciCom (Cary, NC, USA), and funded by ViiV Healthcare. 400 ©2019 International Medical Press AVT-19-RV-4565_Vannappagari.indd 400 AVT-19-RV-4565_Vannappagari.indd 400 22/11/2019 11:22:18 22/11/2019 11:22:18 HIV-1 mutations with resistance to lamivudine and rilpivirine 15. Brooks K, Diero L, DeLong A, et al. Treatment failure and Disclosure statement drug resistance in HIV-positive patients on tenofovir-based first-line antiretroviral therapy in western Kenya. J Int AIDS Soc 2016; 19:20798. Author disclosures are as follows: VV, LR, CH, JvW, 16. Coetzee J, Hunt G, Jaffer M, et al. 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Antiviral Res 2014; 107:31–34. mutations in HIV pol sequences from Argentinean patients under antiretroviral treatment: subtype, gender, and age issues. AIDS Res Hum Retroviruses 2012; 28:949–955. 124. Lopes CA, Soares MA, Falci DR, Sprinz E. The evolving genotypic profile of HIV-1 mutations related to antiretroviral treatment in the north region of Brazil. BioMed Res Int 2015; 2015:738528. Accepted 17 July 2019; published online 10 September 2019 404 ©2019 International Medical Press AVT-19-RV-4565_Vannappagari.indd 404 AVT-19-RV-4565_Vannappagari.indd 404 22/11/2019 11:22:18 22/11/2019 11:22:18 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Antiviral Therapy SAGE

Prevalence of Pretreatment and Acquired HIV-1 Mutations Associated with Resistance to Lamivudine or Rilpivirine: A Systematic Review

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1359-6535
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2040-2058
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10.3851/imp3331
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Antiviral Therapy 2019; 24:393–404 (doi: 10.3851/IMP3331) Original article Prevalence of pretreatment and acquired HIV-1 mutations associated with resistance to lamivudine or rilpivirine: a systematic review 1 1 1 2 3 1 Vani Vannappagari *, Leigh Ragone , Cassidy Henegar , Jean van Wyk , Dannae Brown , James Demarest , 2 1 1 4,5 2 Romina Quercia , Marty St. Clair , Mark Underwood , Jose M Gatell , Annemiek de Ruiter , Michael Aboud ViiV Healthcare, Research Triangle Park, NC, USA ViiV Healthcare, Brentford, UK ViiV Healthcare, Abbotsford, Australia Hospital Clinic/IDIBAPS, University of Barcelona, Barcelona, Spain ViiV Healthcare, Barcelona, Spain *Corresponding author e-mail: vani.x.vannappagari@viivhealthcare.com Background: Pretreatment and acquired drug resist- Most prevalent DRMs resistant to lamivudine or rilpiv- ance mutations (DRMs) can limit antiretroviral therapy irine were at positions E138 (4%), V179 (1%) and M184 effectiveness. (1%). Estimated acquired DRM prevalence was 58% for Methods: We review prevalence of DRMs with resistance any NRTIs and 67% for any NNRTIs, most frequently at to nucleoside reverse transcriptase inhibitors (NRTIs) and positions M184 (58%) and Y181 (21%). non-nucleoside reverse transcriptase inhibitors (NNRTIs), Conclusions: This review suggests low risk of lamivudine- focusing on lamivudine and rilpivirine, from 127 articles or rilpivirine-resistant mutations in treatment-naive, with >100,000 individuals with HIV-1 infection. HIV-1-infected individuals. Results: Estimated global prevalence of pretreatment resistance to any NRTI was 4% and to any NNRTI was 6%. Introduction With recent advances in antiretroviral therapy (ART), the transmission of drug resistance to a newly infected HIV-1 infection can be considered a treatable chronic individual [6]. illness [1], and individuals with HIV-1 with high lev- Current treatment guidelines recommend 2 nucleo- els of adherence to highly effective ART have a life side reverse transcriptase inhibitors (NRTIs) in com- expectancy approaching that of HIV-negative individ- bination with a third drug from the non-nucleoside uals [2]. However, there remain several challenges to reverse transcriptase inhibitor (NNRTI), integrase ensuring that individuals with HIV are able to achieve strand transfer inhibitor (INSTI) or protease inhibi- and maintain viral suppression, including treatment tor (PI) drug classes [7–9]. In the US Department of adherence and ART resistance, as well as factors that Health and Human Services and European AIDS Clini- limit treatment such as stigma, delayed diagnosis, cal Society guidelines, the 2-drug regimen (2DR) of the discrimination and lack of access to health care [3]. INSTI dolutegravir (DTG) plus the NRTI lamivudine Socioeconomic disadvantages include unemployment, (3TC) is an alternative option as initial ART for indi- attempting to immigrate to another country, language viduals when a preferred option is not available [7,8]. barriers and mental health challenges such as depres- Individuals with HIV-1 infection with viral suppression sion [4]. These factors are interrelated, as a lack of may wish to switch therapy to a more simplified regi- resources can negatively affect adherence [5], and men or to manage comorbidities or drug–drug interac- poor adherence can lead to development of HIV drug tions [7–9]. For these individuals, 2DRs, such as DTG resistance mutations (DRMs), which may also lead to plus the NNRTI rilpivirine (RPV), DTG plus 3TC, or a ©2019 International Medical Press 1359-6535 (print) 2040-2058 (online) 393 AVT-19-RV-4565_Vannappagari.indd 393 AVT-19-RV-4565_Vannappagari.indd 393 22/11/2019 11:22:16 22/11/2019 11:22:16 V Vannappagari et al. boosted PI with 3TC, are recommended options [7–9]. as reported by authors. If only absolute numbers or In treatment-experienced adults with HIV-1 infection percentages were reported, the unreported values were and drug resistance, guidelines recommend a new regi- calculated. If data were only presented in a graphical men of two or three fully active agents [7–9]. As a result format, visual estimates were used to determine missing of a high barrier to resistance with second-generation values. Estimates were recorded as not applicable (NA) INSTIs and boosted PIs [10,11], DRMs are more likely when it could not be ascertained from the Methods sec- to limit the effectiveness of the treatment regimen tion that the screening method included the particular through decreased sensitivity to the NRTI or NNRTI DRM or when it could not be ascertained that all DRMs component, particularly in 2DRs consisting of DTG in screened were reported in the Results section (for exam- combination with either 3TC or RPV. To assess the risk ple, studies reporting most frequently observed DRMs). of NRTI and NNRTI resistance in treatment-naive indi- In cases in which multiple individual mutations with viduals in the general population who may be treated resistance to either 3TC/FTC or RPV were reported, with a 2DR, it is important to determine the prevalence but resistance to NRTIs or NNRTIs as a class were of pretreatment DRMs in individuals infected with not reported, the class estimates were recorded as NA. HIV-1 who have had no ART exposure. Regional prevalence estimates were calculated as per- There have been many reports that have included centages using n values corresponding to all studies that data on pretreatment and acquired DRM rates from assessed the mutation in question (that is, excluding n different geographic locations and varied populations. values from studies with NA values for that mutation). Thus, there are a large number of reports that can be Results were reported as global and regional prevalence analysed to provide a comprehensive review of global of substitutions identified at the codons associated with and regional prevalence rates for DRMs. The objec- DRMs resistant to 3TC/FTC or RPV by codon, as well tive of this review was to use a systematic search of as codons where DRMs associated with resistance to published literature reporting data on DRM prevalence NRTIs or NNRTIs as a class occur. Mutations resist- to determine the prevalence of important pretreatment ant to the NRTI or NNRTI classes were reported in and acquired mutations conferring resistance to NRTIs this review as described in the source publications and and NNRTIs, specifically 3TC and RPV, as these are may have included mutations with resistance to NRTIs/ components of DTG-based 2DRs. NNRTIs other than 3TC/FTC and RPV. Prevalence of pretreatment or acquired mutations were reported sep- arately. Pretreatment mutations referred to mutations Methods that occurred in articles that described the individuals Search strategy and selection criteria as ART-naive. Acquired mutations referred to those We conducted a systematic literature search in PubMed that occurred after virological failure. through 6 July 2018, using keywords related to geographic regions, specific DRMs and HIV. The geographic regions Results included in the analysis were Africa, Latin  America, Search results Middle East and North Africa, Europe, North America, Southeast Asia and Asia Pacific. Keywords for specific The literature search retrieved 529 articles, 402 of DRMs were selected to identify mutations associated which were removed. Reasons for removal included with resistance to 3TC or RPV at the following codons: full text not available, data not relevant or not reported K65, K70, Q151 and M184 for 3TC resistance and L100, numerically and small n values. This left 127 articles K101, E138, V179, Y181, Y188, G190 and M230 for to be included in the global and regional analyses. The RPV resistance. The DRMs with resistance to 3TC also identified articles included study periods from 1995 to have resistance to emtricitabine (FTC) and are referred to 2017 and included >60,000 participants worldwide as 3TC/FTC-resistant DRMs in this manuscript. The spe- for analysis of pretreatment resistance mutations and cific DRMs included in the search were M184I, M184V, >30,000 participants worldwide for analysis of acquired K65R, K65E, K65N, Q151M, K70E, L100I, K101E, resistance mutations. Africa had the highest number of K101P, E138A, E138G, E138K, E138Q, E138R, V179L, articles identified in the search of any region (n =30) Y181C, Y181I, Y181V, Y188L, G190E and M230L [12]. [13–42]. However, the European region had the high- A full list of keywords included in the search are included est number of participants for analysis of pretreatment in Supplemental Table 1 in Additional file 1. Identified resistance mutations (n=33,957 for NRTI-associated articles were manually searched for relevance and the mutations; n=34,201 for NNRTI-associated mutations) prevalence rates within specific countries, which excluded [43–60], and Southeast Asia had the highest number of most clinical trials and multinational cohorts. participants for analysis of acquired resistance muta- Prevalence estimates were manually determined from tions (n=26,772 for NRTI-associated mutations; 26,568 the references. When possible, prevalence was included for NNRTI-associated mutations) [61–69]. 394 ©2019 International Medical Press AVT-19-RV-4565_Vannappagari.indd 394 AVT-19-RV-4565_Vannappagari.indd 394 22/11/2019 11:22:17 22/11/2019 11:22:17 HIV-1 mutations with resistance to lamivudine and rilpivirine Global prevalence estimates in 2.5% (n=17/672) and pretreatment NNRTI resistance The estimated global prevalence of pretreatment DRMs were observed in 10.3% (n=144/1,391) of study DRMs was 4% (n=2,719/60,567; range, 2% [Asia participants, compared with 4.5% (n=2,719/60,567) and Pacific] to 6% [North America]) for those associ- 5.7% (n=3,605/63,158), respectively, in all studies. ated with NRTI resistance [16,18,25,28,30–32,35– The most frequent pretreatment DRMs by region are 38,40,43,44,46,48,49,51–60,70–111] and 6% shown in Figure 2B; mutations at position V179 were (n=3,605/61,402; range, 3% [Asia Pacific] to 8% the most frequent DRMs in Southeast Asia (5.6%), [Africa and North America]) for those associated with Latin America (5.2%) and Africa (1.9%); mutations at resistance to any NNRTI (Figure 1) [16,18,25,28,30– position E138 were the most frequent DRMs in Europe 39,41,70–85,99,100,102,104,106–120]. The only (6.8%) and North America (1.6%); and mutations at pretreatment DRMs estimated to occur in >1% of the position M184 were the most frequent DRMs in Asia global population were 3TC/FTC-associated DRMs at Pacific (1.6%) and the Middle East and North Africa position M184 (1%), and RPV-associated DRMs at (1.1%). Drug resistance mutations at position M184 positions E138 (4%) and V179 (1%; Figure 2A). are associated with resistance to 3TC/FTC, while those In a subset of studies that exclusively enrolled partici- at positions E138 and V179 are often associated with pants in the past 5 years (2013–present), the rates of the resistance to RPV [121]. most frequent pretreatment DRMs were mostly consist- Global estimated prevalence of acquired DRMs ent with the full data set (Figure 2A). One exception was was 58% (n=17,073/29,218) for resistance to V179, which had a prevalence rate of 4.2% (n=21/500) in any NRTI and 67% (n=20,834/31,016) for resist- studies enrolling participants from 2013 to present com- ance to any NNRTI in patients following viro- pared with 1.3% (n=283/21,969) in all studies. In this sub- logical failure (Figure 3) [13–29,44,45,47,50,60– set of studies, pretreatment NRTI DRMs were observed 69,77,80,81,85,91,101,103,104,109,122–134]. Figure 1. Frequency of TDRs to any NRTI or NNRTI by region NRTI PDR NNRTI PDR 7.9 7.7 7.2 6.0 5.9 5.7 5.1 4.8 4.6 4.5 4.5 4.0 2.9 2.8 1.9 0 N. R0 n= 2,082 2,914 33,957 33,957 1,961 1,961 1,669 1,669 17,951 17,951 1,756 2,947 2,950 60,567 61,402 Africa Europe Latin MENA North Southeast Asia Total America America Asia Pacic Data are shown from references that reported transmitted drug resistance (TDR) to nucleoside reverse transcriptase inhibitors (NRTIs) and/or non-nucleoside reverse transcriptase inhibitors (NNRTIs) as a class. MENA, Middle East and North Africa; NR, not reported; PDR, pretreatment drug resistance. Antiviral Therapy 24.6 395 AVT-19-RV-4565_Vannappagari.indd 395 AVT-19-RV-4565_Vannappagari.indd 395 22/11/2019 11:22:17 22/11/2019 11:22:17 Reported drug resistance per patient naive to treatment, % V Vannappagari et al. Figure 2. Frequency of TDRs at codons associated with RPV and 3TC/FTC resistance NNRTI PDR A NRTI PDR NNRTI PDR (2013–present) NRTI PDR (2013–present) 4.3 4.2 3.9 1.3 1.1 0.7 n= 16,786 460 21,969 500 40,212 2,061 E138 V179 M184 M184 E138 V179 6.8 5.6 5.2 2.8 2.4 1.9 1.6 1.6 1.5 1.5 1.4 1.4 1.1 1 0.7 0.6 0.6 0.5 0.2 0.1 NR 0.0 n= Africa Europe Latin MENA North Southeast Asia America America Asia Pacic (A) Global frequency of specific drug resistance mutation (DRMs) by codon. (B) Most frequent specific DRMs by codon by region (≥1%). FTC, emtricitabine; MENA, Middle East and North Africa; NNRTI, non-nucleoside reverse transcriptase inhibitor; NR, not reported; NRTI, nucleoside reverse transcriptase inhibitor; PDR, pretreatment drug resistance; RPV, rilpivirine; TDR, transmitted drug resistance; 3TC, lamivudine. The highest rates of acquired DRMs for both NRTIs [n=86/378]; NNRTIs, 19% [n=70/378]). In the subset and NNRTIs were reported in Africa (NRTIs, 77% of studies that enrolled patients only in the past 5 years [n=702/917]; NNRTIs, 80% [n=730/908]), and the (2013–present), global estimates of acquired DRMs were lowest were reported in North America (NRTIs, 23% consistent with the full data set (Figure 4A). Acquired 396 ©2019 International Medical Press AVT-19-RV-4565_Vannappagari.indd 396 AVT-19-RV-4565_Vannappagari.indd 396 22/11/2019 11:22:17 22/11/2019 11:22:17 3,968 11,700 9,112 8,579 3,295 2,338 2,338 1,669 1,629 1,669 15,401 6,380 4,179 2,282 1,775 Reported drug resistance Reported drug resistance per patient naive to treatment, % per patient naive to treatment, % HIV-1 mutations with resistance to lamivudine and rilpivirine Figure 3. Frequency of ADRs to any NRTI or NNRTI by region NRTI NNRTI 80.4 76.6 76.4 70.1 69.2 67.2 66.3 58.0 58.4 56.8 60 55.1 52.5 47.0 30.2 22.8 18.5 n= 917 908 2,633 2,633 450 450 149 149 378 378 24,602 26,409 89 89 29,218 31,016 Africa Europe Latin MENA North Southeast Asia Total America America Asia Pacic Data are shown from references that reported acquired drug resistance (ADR) to nucleoside reverse transcriptase inhibitors (NRTIs) and/or non-nucleoside reverse transcriptase inhibitors (NNRTIs) as a class. MENA, Middle East and North Africa. NRTI DRMs were observed in 59% (n=281/475) of acquired 3TC/FTC DRMs were at position M184 participants and acquired NNRTI DRMs were observed (70%; n=2,255/3,240); the most frequent acquired RPV in 60% (n=284/475) of participants. Across all regions, DRMs were at position Y181 (19%; n=611/3,191). the most frequently acquired DRMs were the 3TC/FTC- associated mutations at position M184 (range, 20% Regional prevalence estimates: Europe [Asia Pacific] to 70% [Africa]; Figure 4B). In European studies, there were 33,957 people with data related to pretreatment NRTI-associated DRMs Regional prevalence estimates: Africa and 34,201 people with data on NNRTI-associated In the African region, DRM data were available from DRMs (Supplemental Tables 6 and 7 in Additional 3,995 individuals for pretreatment NRTI-associated file 1) [43–60]. Pretreatment DRMs with NRTI resist- DRMs and 4,013 individuals for pretreatment NNRTI- ance were observed in 4% (n=1,371/33,957) of indi- associated DRMs (Supplemental Tables 2 and 3 in viduals with HIV in the tested population, and pretreat- Additional file 1) [16,18,25,28,30–41]. Among studies ment DRMs with NNRTI resistance were observed in that reported DRMs by drug class, 3% (n=61/2,082) 5% (n=1,553/33,957). The most frequently observed had NRTI-associated DRMs and 8% (n=224/2,914) pretreatment 3TC/FTC DRMs were at position M184 had NNRTI-associated DRMs. The most frequently (1%; n=67/11,700); the most frequent RPV DRMs observed pretreatment 3TC/FTC DRMs in Africa were were at positions E138 (7%; n=624/9,112) and V179 at position M184 (1%; n=54/3,968); the most fre- (1%; n=53/8,579). Data related to acquired DRMs quent pretreatment RPV DRMs were at positions V179 with resistance to NRTIs and NNRTIs were avail- (2%; n=16/851) and E138 (2%; n=11/731). Data on able for 2,633 individuals (Supplemental Tables 8 acquired DRMs were reported for 3,240 individuals and 9 in Additional file 1) [44,45,47,50,60]. Resist- for NRTI-associated DRMs and 3,191 individuals for ance to NRTIs was observed in 70% (n=1,846/2,633), NNRTI-associated DRMs (Supplemental Tables 4 and whereas resistance to NNRTIs was observed in 52% 5 in Additional file 1) [13–29,42]. Among reports with (n=1,382/2,633). The most common acquired 3TC/ available data, 77% (n=702/917) and 80% (n=730/908) FTC DRMs in Europe were at position M184 (51%; had acquired DRMs conferring resistance to the NRTI n=1,344/2,633); the most common acquired RPV and NNRTI classes, respectively. The most frequent DRMs were at position G190 (20%; n=532/2,633). Antiviral Therapy 24.6 397 AVT-19-RV-4565_Vannappagari.indd 397 AVT-19-RV-4565_Vannappagari.indd 397 22/11/2019 11:22:18 22/11/2019 11:22:18 Reported drug resistance per patient after virological failure, % V Vannappagari et al. Figure 4. Frequency of ADRs at codons associated with RPV and 3TC/FTC resistance A NNRTI ADR NRTI ADR NNRTI ADR (2013–present) NRTI ADR (2013–present) 61.4 58.4 20.9 19.9 18.3 20 17.3 13.3 12.0 11.5 10.3 44,002 1,811 54,327 1,811 38,282 1,811 21,969 1,811 54,189 1,673 n= M184 Y181 G190 K70 K101 M184 Y181 G190 69.6 60 55.1 51.0 50.0 48.8 41.0 31.5 21.3 20.5 20.2 19.1 18.8 16.8 16.0 14.3 11.9 7.7 5.0 4.0 2.6 1.9 n= Africa Europe Latin MENA North Southeast Asia America America Asia Pacic (A) Global frequency of specific drug resistance mutations (DRMs) by codon. (B) Most frequent acquired drug resistance (ADRs) by codon by region (≥20%). MENA, Middle East and North Africa; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; RPV, rilpivirine; 3TC/FTC, lamivudine/emtricitabine. Regional prevalence estimates: Latin America file 1) [70–80]. Out of individuals with available data, In reports from Latin America, 3,295 individuals with pretreatment NRTI-associated DRMs were reported in HIV had data available for analysis of pretreatment 5% (n=95/1,961), and pretreatment NNRTI-associated DRMs (Supplemental Tables 10 and 11 in Additional DRMs were reported in 7% (n=142/1,961). The most 398 ©2019 International Medical Press AVT-19-RV-4565_Vannappagari.indd 398 AVT-19-RV-4565_Vannappagari.indd 398 22/11/2019 11:22:18 22/11/2019 11:22:18 3,240 3,191 3,191 2,633 2,633 2,633 3,921 3,544 3,544 5,464 16,369 26,772 26,568 26,514 1,772 1,822 1,822 Reported drug resistance Reported drug resistance per patient after virological failure, % per patient after virological failure, % HIV-1 mutations with resistance to lamivudine and rilpivirine common pretreatment 3TC/FTC DRMs were at position available data. The most common acquired 3TC/FTC M184 (1%; n=18/3,295); the most common pretreatment DRMs were at position M184 (49%; n=2,668/5,464); RPV DRMs were at positions V179 (5%; n=122/2,338) the most common acquired RPV DRMs were at posi- and E138 (3%; n=65/2,338). Acquired DRM data tion Y181 (8%; n=1,259/16,369). were available for 3,921 individuals in Latin America (Supplemental Tables 12 and 13 in Additional file 1) Regional prevalence estimates: Southeast Asia [77,80,122–124]. Mutations resistant to the NRTI class In the subset of countries in Southeast Asia, 2,021 were seen in 76% (n=344/450) of individuals, whereas individuals had data on pretreatment DRMs (Sup- DRMs resistant to the NNRTI class were observed plemental Table 22 in Additional file 1) [112–118]. in 58% (n=261/450). The most frequently observed None of the reports included data on NRTI-associated acquired 3TC/FTC DRMs were at position M184 (55%; DRMs; 5% of individuals had pretreatment NNRTI- n=2,162/3,921); the most frequent acquired RPV DRMs associated DRMs (n=90/1,756). These DRMs included were at position G190 (19%; n=668/3,544). those at positions V179 (6%; n=21/377), E138 (2%; n=9/377) and Y181 (1%; n=22/1,974); the rest were Regional prevalence estimates: Middle East and North <1%. Data were available for 26,772 and 26,568 Africa individuals in Southeast Asia for 3TC/FTC- and RPV- Although there were relatively few studies (n=5) reporting associated acquired DRMs, respectively (Supplemental on pretreatment DRMs from the Middle East and North Tables 23 and 24 in Additional file 1) [61–69]. There Africa, 1,669 individuals with HIV had DRM data avail- were NRTI-resistant DRMs in 57% (n=13,976/24,602) able from the identified reports (Supplemental Tables 14 of individuals and NNRTI-resistant DRMs in 69% and 15 in Additional file 1) [81–85]. Pretreatment DRMs (n=18,287/26,409). The most common acquired with resistance to the NRTI and NNRTI classes were 3TC/FTC DRMs were at position M184 (50%; reported in 4% (n=75/1,669) and 6% (n=100/1,669) of n=13,397/26,772); the most common acquired RPV the population, respectively. The most common 3TC/ DRMs were at positions Y181 (32%; n=8,369/26,568) FTC DRMs were at position M184 (1%; n=18/1,669); and G190 (21%; n=5,650/26,514). no DRMs associated with RPV resistance were reported in ≥1% of individuals. Data on acquired DRMs were Regional prevalence estimates: Asia Pacific available from 200 individuals, with 47% (n=70/149) In studies from countries in the Asia Pacific region, 4,179 and 30% (n=45/149) reported to have DRMs with and 4,088 individuals had data for DRMs associated with resistance to the NRTI and NNRTI classes, respectively NRTIs and NNRTIs, respectively (Supplemental Tables (Supplemental Tables 16 and 17 in Additional file 1) 25 and 26 in Additional file 1) [100–111,119,120]. Pre- [81,85,125–127]. The most common acquired 3TC/FTC treatment DRMs with resistance to NRTIs and NNRTIs DRMs were at position M184 (41%; n=82/200) and the as a class were observed in 2% (n=55/2,947) and 3% most common acquired RPV DRMs were at position (n=83/2,950) of individuals, respectively. The most fre- E138 (6%; n=11/200). quently observed pretreatment 3TC/FTC DRMs were at position M184 (2%; n=65/4,179); the most frequent Regional prevalence estimates: North America pretreatment RPV DRMs were at position V179 (2%; In North America, data were available for pretreatment n=27/1,775). Acquired DRM data were reported for 1,772 DRMs from 19,563 individuals with HIV (Supplemen- and 1,822 individuals for NRTI- and NNRTI-associated tal Tables 18 and 19 in Additional file 1) [52,86–99]; DRMs, respectively (Supplemental Tables 27 and 28 in 6% (n=1,062/17,951) and 8% (n=1,413/17,951) had Additional file 1). Resistance to the NRTI and NNRTI mutations resistant to the NRTI and NNRTI classes, classes were reported for 55% (n=49/89) and 66% respectively. The most frequent pretreatment 3TC/FTC (n=59/89), respectively, among individuals with available DRMs were at position M184 (1%; n=216/15,401); data [101,103,104,109,131–134]. The most common the most frequent pretreatment RPV DRMs were acquired 3TC/FTC DRMs were at position M184 (20%; at positions E138 (2%; n=5/317) and V179 (1%; n=363/1,772); the most common acquired RPV DRMs n=43/6,380). Data on acquired DRMs were available were at positions Y181 (16%; n=292/1,822), K101 (12%; for 5,464 and 21,455 individuals to determine DRMs n=220/1,822) and G190 (12%; n=217/1,822). associated with 3TC/FTC and RPV, respectively; only 378 individuals had available data to assess resistance Discussion to the NRTI and NNRTI classes as a whole (Supple- mental Tables 20 and 21 in Additional file 1) [91,128– In this review of 127 publications that reported data 130]. Acquired DRMs associated with resistance to the on the prevalence of pretreatment and acquired DRMs, NRTI and NNRTI classes occurred in 23% (n=86/378) a low estimated prevalence of pretreatment DRMs and 19% (n=70/378), respectively, of individuals with was observed. Acquired DRMs were observed in the Antiviral Therapy 24.6 399 AVT-19-RV-4565_Vannappagari.indd 399 AVT-19-RV-4565_Vannappagari.indd 399 22/11/2019 11:22:18 22/11/2019 11:22:18 V Vannappagari et al. majority of individuals following virological failure. In for acquired DRMs as well. Mutations at M184 confer the subset of studies that did not enrol any participants resistance to 3TC or FTC but reduce the fitness of the prior to 2013 (5 years prior to the search date), a higher virus [139]. Therefore, in an individual with a transmitted rate of mutations with resistance to any NNRTI and M184 virus, the mutation may not be detected if genotyp- mutations at position V179 were observed compared ing occurred after high viral replication in the acute phase with the full data set. Across regions, DRM rates were where wildtype subpopulations would outcompete the broadly similar, with the highest rates of pretreatment M184 virus. It is important to note that the effect of differ- NRTI resistance in North America (6%) and pretreat- ent mutations at a single codon can vary widely and that ment NNRTI resistance in Africa and North America combinations of specific mutations can have synergistic (8%). Africa had the highest observed rates of acquired effects on treatment resistance. For example, the effect of DRMs to any NRTI (77%) or NNRTI (80%). Of note, mutations at V179 on RPV susceptibility depends on the a relatively low rate of acquired NRTI and NNRTI specific substitution. While V179L is listed as a DRM in DRMs were observed in North America (23% and the RPV package insert [121], V179T has minimal effects 19%, respectively) compared with the global findings on RPV and minimal reductions of RPV sensitivity, and (58% and 67%, respectively). However, this difference V179F appears to only affect RPV susceptibility in com- should be interpreted with caution because class-level bination with Y181CF [12]. Mutations at codon E138, data on NRTI and NNRTI DRMs were only avail- including E138K/A/Q/G/R, have been associated with a able from 378 individuals, 329 of whom were from two- to fivefold reduction in susceptibility to RPV [12]. a single report of incarcerated individuals in North The E138K mutation alone reduces RPV sensitivity two- Carolina [91]. Resource and monitoring limitations to threefold, while the combination of E138K and the across regions may affect levels of pretreatment drug NRTI DRM M184I can cause a fivefold reduction in resistance. Recommendations from the World Health sensitivity and virological failure. In addition, E138A is Organization (WHO) and the International Antiviral a polymorphic substitution that occurs more frequently Society–USA call for routine surveillance of pretreat- in HIV-1 subtype C compared with other subtypes [140]. ment drug resistance in people initiating ART and for As a result, the baseline prevalence of the E138A substitu- closing gaps in services in resource-limited regions as tion may be higher in regions known to have higher rates means of reducing drug resistance [135,136]. of HIV subtype C compared with other regions [12,140]. For both pretreatment and acquired DRMs, resistance The M184V/I mutation alone can greatly reduce 3TC rates were higher for NNRTIs than for NRTIs overall. Pre- susceptibility (>100-fold), and M184V is often associated treatment resistance to NNRTIs was substantially higher with 3TC virological failure [12]. compared with NRTI resistance in both Africa (7.7% One limitation of this review was using specific muta- versus 2.9%) and Latin America (7.2% versus 4.8%). tions and country or region names as keywords; doing While the global and regional rates of pretreatment NRTI so may have excluded multinational cohorts and some and NNRTI resistance were generally low (<10%), there clinical trials. However, this review analysed >60,000 are data to suggest that pretreatment resistance may be patients across 48 countries discussed in 127 publica- greater at the local level in some countries or communi- tions, suggesting that the results and conclusions in this ties. For example, while the overall rate of NNRTI DRMs analysis are unlikely to be substantially altered if data in studies identified from Africa was 7.7%, there were from additional similar types of articles were included. individual reports showing rates >10%. These included a Overall, the rates of pretreatment DRMs were low report in adult female sex workers in South Africa (27%) across geographic regions for NRTIs and NNRTIs as and one in immunocompetent children in Cameroon classes and for substitutions at codons associated with (41%) [16,32]. In addition, survey data from the WHO resistance to 3TC/FTC and RPV specifically. These data have shown pretreatment NNRTI resistance >10% in suggest a low risk of resistance to ART regimens contain- six countries: Argentina, Guatemala, Namibia, Nicara- ing 3TC/FTC and RPV, supporting the use of 2DRs such gua, Uganda and Zimbabwe [137]. The higher rates of as DTG and 3TC (in treatment-naive individuals) and NNRTI resistance observed in these reports support the DTG and RPV (in individuals who are virologically sup- WHO recommendation for non-NNRTI regimens in pressed on a 3-drug regimen and are switching to a 2DR). countries with high levels of pretreatment NNRTI resist- ance [135] and the inclusion of an antiretroviral with a Acknowledgements high barrier to resistance (that is, INSTI or boosted PI) [10,138] in initial treatment regimens [7–9]. This study was funded by ViiV Healthcare. Literature In this review, pretreatment DRMs in ≥1% of the search and analysis, medical writing and editorial assis- population in the identified reports were at positions tance were provided under the direction of the authors E138 (4%), V179 (1%) and M184 (1%); of these, by Jonathan Morgan and Diane Neer, ELS, MedThink M184 (51%) was among the most common positions SciCom (Cary, NC, USA), and funded by ViiV Healthcare. 400 ©2019 International Medical Press AVT-19-RV-4565_Vannappagari.indd 400 AVT-19-RV-4565_Vannappagari.indd 400 22/11/2019 11:22:18 22/11/2019 11:22:18 HIV-1 mutations with resistance to lamivudine and rilpivirine 15. Brooks K, Diero L, DeLong A, et al. Treatment failure and Disclosure statement drug resistance in HIV-positive patients on tenofovir-based first-line antiretroviral therapy in western Kenya. J Int AIDS Soc 2016; 19:20798. Author disclosures are as follows: VV, LR, CH, JvW, 16. Coetzee J, Hunt G, Jaffer M, et al. 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Journal

Antiviral Therapy – SAGE

Published: Aug 1, 2019

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