Clinically Relevant Transmitted Drug Resistance to First Line Antiretroviral Drugs and Implications for Recommendations

ABSTRACT Transmission of human immunodeficiency virus (HIV) drug resistance is well-recognized and compromises response to first-line therapy. However, the population dynamics of transmitted resistance remains unclear, although previous models have assumed that such transmission reflects direct infection from treated individuals. We investigated whether population-based phylogenetic analyses would uncover lineages of resistant viruses circulating in untreated individuals. Through the phylogenetic analysis of 14,061 HIV type 1 (HIV-1) pol gene sequences generated in the United Kingdom from both treatment-naïve and -experienced individuals, we identified five treatment-independent viral clusters containing mutations conferring cross-resistance to antiretroviral drugs prescribed today in the United Kingdom. These viral lineages represent sustainable reservoirs of resistance among new HIV infections, independent of treatment. Dated phylogenies reconstructed through Bayesian Markov chain Monte Carlo inference indicated that these reservoirs originated between 1997 and 2003 and have persisted in the HIV-infected population for up to 8 years. Since our cohort does not represent all infected individuals within the United Kingdom, our results are likely to underestimate the number and size of the resistant reservoirs circulating among drug-naïve patients. The existence of sustained reservoirs of resistance in the absence of treatment has the capacity to threaten the long-term efficacy of antiretroviral therapy and suggests there is a limit to the decline of transmitted drug resistance. Given the current decrease in resistance transmitted from treated individuals, a greater proportion of resistance is likely to come from drug-naïve lineages. These findings provide new insights for the planning and management of treatment programs in resource-rich and developing countries.

Download Full-text

The Impact of Transmitted Drug-Resistance on Treatment Selection and Outcome of First-Line Highly Active Antiretroviral Therapy (HAART)

JAIDS Journal of Acquired Immune Deficiency Syndromes ◽

10.1097/qai.0b013e3181c070d2 ◽

2010 ◽

Vol 53 (5) ◽

pp. 633-639 ◽

Cited By ~ 22

Author(s):

Loveleen Bansi ◽

Anna Maria Geretti ◽

David Dunn ◽

Teresa Hill ◽

Hannah Green ◽

...

Keyword(s):

Drug Resistance ◽

Antiretroviral Therapy ◽

Highly Active Antiretroviral Therapy ◽

Treatment Selection ◽

Transmitted Drug Resistance ◽

First Line ◽

Highly Active ◽

The Impact

Download Full-text

The impact of transmitted drug resistance on the natural history of HIV infection and response to first-line therapy

AIDS ◽

10.1097/01.aids.0000196172.35056.b7 ◽

2006 ◽

Vol 20 (1) ◽

pp. 21-28 ◽

Cited By ~ 71

Keyword(s):

Drug Resistance ◽

Natural History ◽

Hiv Infection ◽

Transmitted Drug Resistance ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

History Of ◽

The Impact

Download Full-text

Antiretroviral Drug Treatment of Individuals that Used Preexposure Prophylaxis (PrEP) Before Diagnosis

Current Treatment Options in Infectious Diseases ◽

10.1007/s40506-021-00246-9 ◽

2021 ◽

Author(s):

David A. M. C. van de Vijver ◽

Shreoshee Mukherjee ◽

Jeroen J.A. van Kampen

Keyword(s):

Drug Resistance ◽

Drug Treatment ◽

Treatment Options ◽

Antiretroviral Drugs ◽

Anecdotal Evidence ◽

First Line ◽

Acute Hiv Infection ◽

Genotypic Resistance ◽

Preexposure Prophylaxis ◽

Antiretroviral Drug

Abstract Purpose of review The antiretroviral drugs, tenofovir and emtricitabine used as preexposure prophylaxis (PrEP), are also used in treatment of HIV. Drug resistance due to PrEP can therefore jeopardize future treatment options. This review discusses treatment of individuals that used PrEP in whom viral mutations against tenofovir (K65R) or emtricitabine (M184I/V) are found. Recent findings Although no studies systematically investigated the optimal treatment of individuals who used PrEP before diagnosis, there is anecdotal evidence that HIV including the K65R and/or M184I/V can be successfully treated using recommended first-line regimens. Summary Drug resistance can be ascribed to use of PrEP while having an unrecognized acute HIV infection, partial adherence to PrEP, and transmission of HIV resistant to PrEP drugs. First-line antiretroviral drug treatment in individuals who used PrEP before diagnosis must be optimized based on genotypic resistance test results. Individuals in whom M184I/V and/or K65R is detected can be treated with dolutegravir-based, bictegravir-based, or darunavir-based regimens plus tenofovir plus lamivudine or emtricitabine. Dual therapy using dolutegravir plus lamivudine is not recommended for induction therapy in individuals with viral mutations against the drugs used as PrEP. There is an urgent need to confirm the anecdotal evidence for successful treatment using first-line regimens.

Download Full-text

Transmitted drug resistance in ART-naive persons with acute/ early/ primary HIV infection: a systematic review and meta-analysis

10.21203/rs.3.rs-258833/v1 ◽

2021 ◽

Author(s):

Chun-Xiang GUO ◽

Ya-Xin WU ◽

Yang ZHANG ◽

Xin-Chao LIU ◽

Ai-Xin LI ◽

...

Keyword(s):

Drug Resistance ◽

Hiv Infection ◽

Meta Analysis ◽

Antiretroviral Drugs ◽

Cochrane Library ◽

Resistance Testing ◽

Transmitted Drug Resistance ◽

Acute Hiv Infection ◽

Early Primary ◽

The Cochrane Library

Abstract Background: In the absence of AIDS vaccine，antiretroviral therapy (ART) was the most effective tool to prevent and control the HIV pandemic. But the widespread use of ART has raised concerns about the emergence of HIV transmitted drug resistance (TDR). Acute HIV infection (AHI) was the most appropriate time to detect the spread of TDR. In this meta-analysis, our purpose was to evaluate the level of TDR in ART-naive patients with acute/ primary/ early HIV infection, and describe the critical drug-resistant mutations. Methods: We systematically reviewed 1192 studies published between January 1, 2008 and December 30, 2019 in PubMed, Web of Science, Embase, and the Cochrane Library, and selected 12 studies that meet our inclusion criteria. To evaluate the overall prevalence of TDR, we extracted raw data and analyzed prevalence estimates using Stata SE. Estimates of mixed-effects were calculated by random-effects meta-analysis, and the I²statistics were used to estimate the heterogeneity of all included studies.Results: The Data of this meta-analysis come from 12 observational studies, covering 3558 ART-naive individuals with PHI, AHI or EHI. The overall prevalence of HIV-TDR is 9.8% (95% confidence interval (CI): 7.2%–12.3%, p<0.001). Prevalence of resistance by drug class is highest for the NNRTIs at 5.9% (95% CI: 3.1%–8.6%, p<0.001), followed by NRTIs 3.4% (95% CI: 1.8%–5.0%, p<0.001) and PIs 3.4% (95% CI: 2.7%–4.0%, p<0.001). The prevalence of TDR to INIs is 0.3% (95% CI: -0.1%-0.7%, p<0.001), which is the lowest among all antiretroviral drugs.Conclusion: The overall prevalence of TDR is high among AHI patients who have never received ART. This emphasizes the importance of baseline drug resistance testing for public health surveillance and guiding the choice of ART. In addition, the prevalence of TDR to NNRTIs is the highest, while the TDR to INIs is the lowest. This may guide the selection of clinical antiretroviral drugs.

Download Full-text

Transmitted Drug Resistance in Antiretroviral Therapy-Naive Persons With Acute/Early/Primary HIV Infection: A Systematic Review and Meta-Analysis

Frontiers in Pharmacology ◽

10.3389/fphar.2021.718763 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chunxiang Guo ◽

Yaxin Wu ◽

Yang Zhang ◽

Xinchao Liu ◽

Aixin Li ◽

...

Keyword(s):

Drug Resistance ◽

Antiretroviral Therapy ◽

Hiv Infection ◽

Reverse Transcriptase ◽

Meta Analysis ◽

Antiretroviral Drugs ◽

Cochrane Library ◽

Transmitted Drug Resistance ◽

Reverse Transcriptase Inhibitors ◽

Primary Hiv Infection

Background: The widespread use of antiretroviral therapy (ART) has raised concerns about the emergence of HIV transmitted drug resistance (TDR). Acute HIV infection (AHI) was the most appropriate time to detect the spread of TDR. In this meta-analysis, our purpose was to evaluate the level of TDR in ART-naive patients with primary HIV infection (PHI)/AHI/early HIV infection (EHI) and to describe the critical drug-resistant mutations.Methods: We systematically searched the literature between January 1, 2008, and April 30, 2021, in PubMed, Web of Science, Embase, and the Cochrane Library. To evaluate the overall prevalence of TDR, we extracted raw data and analyzed prevalence estimates using Stata SE.Results: The data of this meta-analysis come from 12 observational studies, covering 3,558 ART-naive individuals with PHI, AHI, or EHI. The overall prevalence of HIV-TDR is 9.3% (95% CI: 6.8%–11.8%, I2 = 81.1%, in 11 studies). The prevalence of resistance by drug class is the highest for the nonnucleoside reverse transcriptase inhibitors (NNRTIs) at 5.7% (95% CI: 2.9%–8.5%, I2 = 96.6%, in 11 studies), followed by nucleoside reverse transcriptase inhibitors (NRTIs) at 3.4% (95% CI: 1.8%–5.0%, I2 = 86.3%, in 10 studies) and protease inhibitors (PIs) at 3.3% (95% CI: 2.7%–3.9%, I2 = 15.6%, in 10 studies). The prevalence of TDR to integrase inhibitors (INIs) is 0.3% (95% CI: 0.1%–0.7%, I2 = 95.9%, in three studies), which is the lowest among all antiretroviral drugs.Conclusion: The overall prevalence of TDR is at a moderate level among AHI patients who have never received ART. This emphasizes the importance of baseline drug resistance testing for public health surveillance and guiding the choice of ART. In addition, the prevalence of TDR to NNRTIs is the highest, while the TDR to INIs is the lowest. This may guide the selection of clinical antiretroviral drugs.

Download Full-text

PREVALENCE AND STRUCTURE OF HIV-1 DRUG RESISTANCE AMONG TREATMENT NAÏVE PATIENTS SINCE THE INTRODUCTION OF ANTIRETROVIRAL THERAPY IN THE RUSSIAN FEDERATION

HIV Infection and Immunosuppressive Disorders ◽

10.22328/2077-9828-2019-11-2-75-83 ◽

2019 ◽

Vol 11 (2) ◽

pp. 75-83 ◽

Cited By ~ 2

Author(s):

A. A. Kirichenko ◽

D. E. Kireev ◽

A. E. Lopatukhin ◽

A. V. Murzakova ◽

I. A. Lapovok ◽

...

Keyword(s):

Drug Resistance ◽

Reverse Transcriptase ◽

Russian Federation ◽

Antiretroviral Drugs ◽

Transmitted Drug Resistance ◽

Resistance Mutations ◽

Drug Resistance Mutations ◽

Treatment Naïve ◽

The Russian Federation ◽

Hiv 1

Aim: to analyze the prevalence, structure of drug resistance and drug resistance mutations in the protease and reverse transcriptase genes of HIV-1 among treatment naïve patients.Materials and methods. We analyzed protease and reverse transcriptase sequences from 1560 treatment naïve HIV-infected patients from all Federal Districts of the Russian Federation with the first positive immune blot during 1998–2017. Sequences were analyzed for the presence of drug resistance mutations and predicted drug resistance to antiretroviral drugs using two algorithms — Stanford HIVDR Database (HIVdb) and the 2009 SDRM list (CPR).Results. The prevalence of drug resistance mutations was 11,1%. More often the prevalence of drug resistance was found for non-nucleoside reverse transcriptase inhibitor drugs (rilpivirine, nevirapine, efavirenz). The prevalence of transmitted drug resistance associated with mutations from the SDRM list was 5,3%, which is classified by the WHO as a moderate level. However, it should be noted that since the large-scale use of antiretroviral drugs in the Russian Federation, there has been a trend towards a gradual increase in the level of the transmitted drug resistance, and in 2016 it has already reached 6,1%.Conclusion. The results demonstrate the need for regular surveillance of the prevalence of HIV drug resistance to antiretroviral drugs among treatment naïve patients in the Russian Federation.

Download Full-text