HIV-1 drug resistance and resistance testing

Abstract

The global scale-up of antiretroviral (ARV) therapy (ART) has led to dramatic reductions in HIV-1 mortality and incidence. However, HIV drug resistance (HIVDR) poses a potential threat to the long-term success of ART and is emerging as a threat to the elimination of AIDS as a public health problem by 2030. In this review we describe the genetic mechanisms, epidemiology, and management of HIVDR at both individual and population levels across diverse economic and geographic settings. To describe the genetic mechanisms of HIVDR, we review the genetic barriers to resistance for the most commonly used ARVs and describe the extent of cross-resistance between them. To describe the epidemiology of HIVDR, we summarize the prevalence and patterns of transmitted drug resistance (TDR) and acquired drug resistance (ADR) in both high-income and low- and middle-income countries (LMICs). We also review to two categories of HIVDR with important public health relevance: (i) pre-treatment drug resistance (PDR), a World Health Organization-recommended HIVDR surveillance metric and (ii) and pre-exposure prophylaxis (PrEP)-related drug resistance, a type of ADR that can impact clinical outcomes if present at the time of treatment initiation. To summarize the implications of HIVDR for patient management, we review the role of genotypic resistance testing and treatment practices in both high-income and LMIC settings. In high-income countries where drug resistance testing is part of routine care, such an understanding can help clinicians prevent virological failure and accumulation of further HIVDR on an individual level by selecting the most efficacious regimens for their patients. Although there is reduced access to diagnostic testing and to many ARVs in LMIC, understanding the scientific basis and clinical implications of HIVDR is useful in all regions in order to shape appropriate surveillance, inform treatment algorithms, and manage difficult cases.

Keywords: Antiretroviral therapy; Diagnostic test; Drug resistance; HIV-1; Mutations; Surveillance.

Figure 1

ARV potency versus genetic barrier to resistance. Abbreviations: ARV: antiretroviral; VL: viral load; ABC: abacavir; ATV/r: boosted atazanavir; DRV/r: boosted darunavir; DTG: dolutegravir; EFV: efavirenz; FTC: emtricitabine; EVG: elvitegravir; T20: enfuvirtide; ETR: etravirine; 3TC: lamivudine; LPV/r: boosted lopinavir; MVC: maraviroc; NVP: nevirapine; RAL: raltegravir; RPV: rilpivirine; and TDF: tenofovir. ARVs in black font are nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs), those in purple font are non-NRTIs (NNRTIs), those in blue font are protease inhibitors (PIs), those in red font are integrase strand transfer inhibitors (INSTIs), and those in green font are entry inhibitors. ARVs appearing together in the same ellipse should be considered to have roughly equivalent potencies and genetic barriers to resistance.

Figure 2

Summary of nucleoside/nucleotide reverse transcriptase inhibitor drug resistance mutations Bold/underline: High-level reduced susceptibility or virological response. Bold: reduced suceptibility or virological response. Plain text: reduced susceptibility in combination with other NRTI-resistance mutations. Asterisk: increased susceptibility. Additional NRTIs: Stavudine (d4T) and didanosine (ddI) are no longer recommended. TAMs: Thymidine analog mutations. Selected by AZT and d4T and facilitate primer unblocking. Non-TAMs prevent NRTI incorporation. MDR: Multidrug resistance mutations. T69 insertions occur with TAMs. Q151M occurs with non-TAMs and accessory mutations A62V, V75I, F77L, and F116Y. M184VI: Although they cause high-level in vitro resistance to 3TC/FTC, they are not contraindications to 3TC/FTC because they increase TDF and AZT susceptibility and decrease viral replication fitness. Additional mutations: K65N is similar but weaker than K65R. K70GQ is similar to K70E. T69D and V75MT reduce susceptibility to d4T and ddI. T215SCDEIV (T215 revertants) evolve from T215YF in the absence of NRTIs. E40F, E44DA, D67GE, V118I, and K219NR are accessory TAMs. T69 deletions occur in combination with K65R and/or Q151M. With K65R (but not Q151M) they increase AZT susceptibility. References: http://hivdb.stanford.edu/DR/NRTIResiNote.html.

Figure 3

Summary of non-nucleoside reverse transcriptase inhibitor drug resistance mutations. Bold/underline: High-level reduced susceptibility or virological response. Bold: reduced suceptibility or virological response. Plain text: reduced susceptibility in combination with other NNRTI-resistance mutations. Asterisk: increased susceptibility. Abbreviations: nevirapine (NVP), efavirenz (EFV), etravirine (ETR), rilpivirine (RPV). Synergistic combinations: V179D+K103R reduce NVP and EFV susceptibility >10-fold. Y181C+V179F cause high-level ETR and RPV resistance. ETR genotypic susceptibility score (GSS): Y181IV (3.0); L100I, K101P, Y181C, M230L (2.5); V90I, E138A, V179F, G190S (1.5); A98G, K101EH, V106I, V179DT, G190A (1.0); 3.0 high-level. V90I, A98G, V106I, E138A, V179DT, G190A/S have little effect on ETR susceptibility unless they occur with a bolded mutations. Additional accessory mutations: V90I (ETR), A98G (NVP, EFV, ETR, RPV), V108I, V179T (ETR), V179L (RPV), P225H (EFV), K238T (NVP, EFV), L318F (NVP). References: http://hivdb.stanford.edu/DR/NNRTIResiNote.html.

Figure 4

Summary of protease inhibitor drug resistance mutations. Bold/underline: High-level reduced susceptibility or virological response. Bold: reduced suceptibility or virological response. Plain text: reduced susceptibility in combination with other PI-resistance mutations. Abbreviations: atazanavir (ATV), darunavir (DRV), lopinavir (LPV). Administered with ritonavir for pharmacokinetic boosting (/r). Additional PIs: Fosamprenavir (FPV), indinavir (IDV), saquinavir (SQV), and tipranavir (TPV) are rarely used. Nelfinavir (NFV) is no longer recommended. FPV/r and IDV/r are never more active than DRV/r and rarely if ever more active than LPV/r vs resistant viruses. TPV/r is occasionally useful for salvage therapy as it can be active vs LPV/r and DRV/r-resistant viruses with mutations that increase TPV susceptibility. Expert consultation +/− phenotypic testing should be obtained prior to using FPV, FPV/r, IDV/r, SQV/r, and TPV/r. Additional mutations: D30N and N88D are major NFV-resistance mutations. L10F, V11I, K20TV, L23I, K43T, F53L, Q58E, A71IL, G73STCA, T74P, N83D, and L89V are common nonpolymorphic accessory mutations. L10RY, V11L, L24F, M46V, G48ASTLQ, F53Y, I54S, V82CM, I84AC, N88TG are rare nonpolymorphic variants. Hypersusceptibility: I50L (each PI except ATV); L10F, L24I, I50V, I54L (TPV); L76V (ATV, SQV, TPV); I47A (SQV); N88S (FPV). References: http://hivdb.stanford.edu/DR/PIResiNote.html.

Figure 5

Summary of integrase strand transfer inhibitor drug resistance mutations. Bold/underline: High-level reduced susceptibility or virological response. Bold: reduced suceptibility or virological response. Plain text: reduced susceptibility in combination with other INSTI-resistance mutations. Asterisk: increased susceptibility. Abbreviations: raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG). Additional mutations: H51Y, L74M, T97A, S153YF, G163RK, S230R, and R263K are relatively nonpolymorphic INSTI-selected accessoryresistance mutations. E92GV, E138T, Y143KSGA, Q148N, and N155ST are unusual variants at the positions listed above. P145S and Q146P are rare EVG-resistance mutations. G118R and F121Y are rare nonpolymorphic INSTI resistance mutations. References: http://hivdb.stanford.edu/DR/INIResiNote.html.