Antiretroviral Drug Resistance and Resistance Testing

International AIDS Society–USA Topics in HIV Medicine Perspective Antiretroviral Drug Resistance and Resistance Testing Antiretroviral resistance testing should be performed in newly diagnosed be present, even if not detected in the patients with acute or recent HIV infection and at the time of treatment circulation, when therapy is eventually failure, and there is growing support for testing in newly diagnosed, treat- initiated. Genotypic analysis is pre- ment-naive patients with chronic infection as well. Genotypic testing is pre- ferred over phenotypic testing in this ferred for baseline screening, because it is more sensitive than phenotypic setting, primarily because it is more testing for the presence of mixed populations of drug-susceptible and sensitive for the detection of mixtures - resistant virus and because it is less expensive. Phenotypic testing provides of susceptible and resistant virus, quantitative information on the degree of resistance and is also able to which would be expected if reversion assess interactions among mutations. As a result, it can be particularly use- to wild-type had begun to occur at the ful in determining treatment options for treatment-experienced patients time of testing. Genotyping is also with multi-drug resistant virus. In many cases, there may be advantages to faster and less expensive. the use of both tests. This article summarizes a presentation on antiretroviral resistance and resistance testing by Joel E. Gallant, MD, MPH, at the Resistance to nRTIs 8th Annual Clinical Conference for Ryan White CARE Act clinicians in New Orleans in June 2005. Resistance patterns after initial failure of commonly used nRTI backbones Resistance Testing in Treatment- and the resistance map for the indi- classes in 3.1% (Bennet, CROI, 2005). vidual nRTIs are shown in Figure 1. In naive Patients Although it was once believed that patients in whom a combination that The International AIDS Society–USA, acquired resistant strains would be includes lamivudine plus either the US Department of Health and quickly replaced by wild-type virus, it zidovudine or stavudine is failing, the Human Services, and European guide- has become clear that resistant virus M184V mutation is always the first to lines recommend antiretroviral resis- persists for prolonged periods. This appear. It is eventually followed by tance testing for primary HIV infection phenomenon probably reflects the cumulative acquisition of thymidine and in cases of treatment failure. fact that only the resistant strain is analogue-associated mutations (TAMs) These guidelines also recommend or transmitted, so that reversion to wild- if treatment with the nonsuppressive encourage consideration of testing in type virus requires “back mutation,” a regimen is continued. It should be chronic infection of less than 2 years’ more time-consuming process than noted that TAMs are completely pre- duration. the selection of pre-existing wild-type ventable mutations; they should US surveillance data indicate that strains that occurs in treatment-expe- become less common in the future, transmission of resistant virus is a sub- rienced patients. In one recent study, since patients with suppressive stantial and growing problem. Data the average time to reversion to wild- options should not be left on a failing gathered in 2003 and 2004 from 787 type virus after identification of resis- thymidine analogue-based regimen. newly diagnosed antiretroviral therapy- tant strains among newly infected There are 6 TAMs: M41L, D67N, K70R, naive subjects from 89 sites in 6 states patients was 375 days for NNRTI-resis- L210W, T215Y/F, and K219Q/E/N/R; indicate the presence of resistance to at tant virus and 362 days for nRTI-resis- the presence of these mutations con- least 1 antiretroviral drug class in tant virus; no reversion was seen with fers cross-resistance to all nRTIs, with 14.5% of cases, including resistance to up to 2 years of follow-up for PI-resis- the degree of nRTI cross-resistance nucleoside analogue reverse transcrip- tant virus (Little, CROI, 2004). For this increasing as the number of TAMs tase inhibitors (nRTIs) in 7.1%, nonnu- reason, there is growing support for increases (Johnson et al, Top HIV Med, cleoside analogue reverse transcriptase resistance testing in chronically infect- 2005). The acquisition of TAMs is inhibitors (NNRTIs) in 8.4%, protease ed, treatment-naive patients. However, slowed by the presence of the M184V inhibitors (PIs) in 2.8%, and 2 or more despite the persistence of mutant mutation, which also serves to partial- virus after infection, the diagnostic ly counter the effects of TAMs on sus- yield of resistance testing is highest ceptibility to zidovudine, tenofovir, Joel E. Gallant, MD, MPH, is Associate with earlier testing. It is therefore rec- and stavudine. Figure 2 shows the fold Professor of Medicine and Epidemiology at ommended that resistance testing be change in drug susceptibility as a func- Johns Hopkins University School of performed at the time of HIV diagno- tion of the number of TAMs with or Medicine, Associate Director of the Johns Hopkins AIDS Service, Baltimore, Maryland, sis, regardless of the current need for without the presence of the M184V and a member of the Board of Directors of therapy; it can be assumed that trans- resistance mutation. the International AIDS Society–USA. mitted resistance mutations will still There are different pathways to 138 Perspective – Antiretroviral Drug Resistance Volume 13 Issue 5 December 2005/January 2006 Abacavir K65R; L74V; Y115F; M184V and didanosine but maintained sus- class. There are limited prospects for Didanosine K65R; L74V ceptibility to thymidine analogues. sequential use of currently available Emtricitabine K65R; M184V/I K65R is the signature mutation of NNRTIs following virologic failure with Lamivudine K65R; M184V/I tenofovir; it can also emerge with aba- resistance. It had been proposed that Stavudine M41L; E44D; K65R; D67N; cavir, though L74V is more common. efavirenz would be active in cases of K70R; V118I; L210W; In the presence of zidovudine (and, to nevirapine failure due to the Y181C T215Y/F; K219Q/E a lesser extent, stavudine), the path- mutation, but poor results were Tenofovir K65R way involves the acquisition of the observed with clinical sequencing, Zidovudine M41L; E44D; D67N; K70R; M184V mutation and TAMs, resulting, possibly because of the presence of V118I; L210W; T215Y/F; as already noted, in resistance to both low levels of K103N not detected by K219Q/E thymidine analogues and other nRTIs. commercial assays. Mutations at Zidovudine/lamivudine ⇒ M184V TAMs A brief profile of nRTI resistance codons 190 and 225 are associated Stavudine/lamivudine ⇒ M184V TAMs mutations and their effects is shown with delavirdine hypersusceptibility, Zidovudine/lamivudine/ ⇒ M184V TAMs in Table 1, and some sequencing but there are no clinical data to sup- abacavir options in cases of specific mutations port delavirdine use in this setting. Tenofovir/emtricitabine ⇒ M184V K65R are shown in Table 2. Options in the There are some investigational sec- Abacavir/lamivudine ⇒ M184V L74V or K65R presence of TAMs depend on whether ond-generation NNRTIs that are M184V is present and on the particu- promising with regard to potential Figure 1. Top: Mutations that affect sus- lar resistance pathway exhibited. sequential use, such as TMC-125 and ceptibility to nucleoside (or nucleotide) Phenotypic testing may be useful TMC-278, and it is hoped that such analogue reverse transcriptase inhibitors when multiple TAMs are present. drugs will remain active in the pres- (nRTIs). Adapted with permission from the ence of the K103N and other muta- International AIDS Society–USA (Johnson Resistance to NNRTIs tions. However, it is currently advisable et al, Top HIV Med, 2005). For user notes to use NNRTIs only in fully virologically and updated figures, visit www.iasusa.org. Resistance mutations selected by suppressed patients. NNRTI resistance Bottom: Resistance patterns after initial NNRTIs are shown in Figure 3. NNRTI- mutations do not reduce replicative fit- failure of commonly used nRTI backbones. The longer arrow indicates the delay in associated resistance mutations, the ness of the virus as do some resistance emergence of thymidine analogue-associ- most common of which is K103N, are mutations to nRTIs or PIs. In addition, ated mutations (TAMs) caused by M184V, common at the time of virologic fail- continued use of an NNRTI in a non- which does not occur with K65R or L74V, ure and may occur as the first resis- suppressive regimen allows accumula- for which the arrow is shorter. tance mutations, even preceding the tion of additional NNRTI resistance detection of M184V. Most NNRTI resis- mutations that may jeopardize the tance is associated with high-level future use of the second-generation resistance for nRTIs. In the case of cross-resistance to other drugs in the NNRTIs now in development. zidovudine or stavudine therapy, as 1,000 yet unidentified factors can result in Zidovudine 10 Tenofovir Stavudine acquisition of either the M41L, L210W, 5 100 and T215Y TAMs or the D67N, K70R, and K219Q/E/N/R mutations. The for- 10 1 mer pathway is associated with high- 1 1 er-level zidovudine resistance, greater Fold Change -1 -1 -5 nRTI cross-resistance, and a smaller 01234 5 6 01234 5 6 0 1 234 5 6 decrease in resistance in the presence of the M184V mutation. The D67N, K70R, and K219Q pathway is associat- 5 Lamivudine Didanosine Abacavir ed with a lower level of zidovudine 100 resistance, less nRTI cross-resistance, 5 10 and a greater decrease in resistance when M184V is present. Unfortunately, 1 1 Fold Change 1 it appears to be the less common pathway. When abacavir, tenofovir, or -1 -5 -5 0123456 0123456 0123456 didanosine are used with lamivudine Number of TAMs or emtricitabine in the absence of thymidine analogues, the likely muta- Figure 2. Change in susceptibility as a function of the number of thymidine analogue-asso- tions are M184V, K65R, and L74V, ciated mutations (TAMs) and the presence of the M184V mutation.

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