Nucleoside Analogue Reverse Transcriptase Inhibitor Options: A

International AIDS Society–USA Topics in HIV Medicine

Perspective Nucleoside Analogue Reverse Transcriptase Inhibitor Options: A Re-examination of the Class The main options for dual nucleoside (or nucleotide) analogue reverse tran- tion in the tenofovir/emtricitabine scriptase inhibitors (nRTIs) as a component of initial antiretroviral therapy group. It is also of interest that the regimens are tenofovir/emtricitabine, zidovudine/lamivudine, and aba- characteristic M184V/I lamivudine- cavir/lamivudine as fixed-dose combinations. Resistance to nRTIs can limit associated resistance mutation, which usefulness of many of the drugs in the class. Investigation of triple nRTI reg- also occurs with emtricitabine, was imens has shown that zidovudine/lamivudine/abacavir does not provide less common in the tenofovir/emtric- benefits compared with dual nRTIs plus efavirenz and that others (teno- itabine group, adding to other obser- fovir/lamivudine/abacavir and didanosine/lamivudine/abacavir) are associat- vations that there is a lower frequency ed with very high virologic failure rates. Further, 4-nRTI regimens are under of M184V mutations with emtric- investigation. The article summarizes a presentation on nRTIs made by Scott itabine versus lamivudine in the set- M. Hammer, MD, at the International AIDS Society–USA course in New York ting of early virologic failure. It is very in March 2006. The original presentation is available as a Webcast at likely that the difference in virologic www.iasusa.org. outcome with the 2 regimens is not related to any difference in intrinsic Dual nRTIs in Initial Treatment nent of initial treatment has been part- potency, but rather to better tolerability ly motivated by results of the Gilead of the tenofovir/emtricitabine/efavirenz The audience at the International 934 trial (Gallant et al, N Engl J Med, regimen, resulting in a smaller propor- AIDS Society–USA course in New York 2006). The trial showed that teno- tion of patients being discontinued from in March 2006 was posed the follow- fovir/emtricitabine/efavirenz (n=244) study treatment due to adverse events. ing question: When initiating therapy was associated with a significantly Discontinuation due to adverse in an antiretroviral therapy-naive per- greater rate of reduction of plasma events occurred in 4% of the teno- son with no other illnesses, and with HIV RNA level to below 400 copies/mL fovir/emtricitabine arm versus 9% of normal laboratory results and drug- at 48 weeks than zidovudine/lamivu- the zidovudine/lamivudine arm, with susceptible virus, which of the follow- dine/efavirenz (n=243; 84% vs 73%, anemia alone resulting in discontinua- ing dual nucleoside (or nucleotide) respectively, P=.002). tion of 6% of patients in the zidovu- analogue reverse transcriptase inhib- Findings of interest with regard to dine/lamivudine arm. A nonrandom- itor (nRTI) components (to be com- resistance in this trial included the ized substudy of this trial also showed bined with nonnucleoside reverse absence of the characteristic K65R greater loss of limb fat in the zidovu- transcriptase inhibitors [NNRTIs] or a tenofovir-associated resistance muta- dine/lamivudine group. protease inhibitor [PI]) do you choose: (1) zidovudine/lamivudine as a fixed-dose combination (FDC) (2) abacavir/lamivudine FDC (3) tenofovir/lamivudine (4) tenofovir/ didanosine (5) tenofovir/emtricitabine FDC (6) stavudine/didanosine (7) abacavir/tenofovir (8) zidovudine/didanosine The majority of audience responders selected tenofovir/emtricitabine as an FDC (57%) and most of the remainder (28%) selected zidovudine/lamivudine, with these choices being fairly representative of current use patterns in US treatment centers. The use of tenofovir/emtricitabine as a compo-

Dr Hammer is the Harold C. Neu Professor of Medicine and Chief of the Division of Figure 1. Proportions of patients with suppression of plasma HIV RNA level to less than 200 Infectious Diseases at Columbia University copies/mL and less than 50 copies/mL by treatment on intent-to-treat analysis in ACTG Medical Center. A5095. Adapted from Gulick et al, JAMA, 2006.

140 Perspective – nRTIs: A Re-examination of the Class Volume 14 Issue 4 October/November 2006

1.0 nRTI Interruption (n=8) 1.5 Enfuvurtide Interruption (n=22) Interruption of All Drugs 0.5 PI Interruption (n=20) 1.0 copies/mL) copies/mL) Lamivudine Monotherapy 10 0.0 10 0.5 (log (log

-0.5 0.0 Change in Plasma HIV RNA Level 04812162024 Change in Plasma HIV RNA Level 0481216 20 24 Week of Interruption Week

Figure 2. Effect of partial treatment interruptions (n=53) on viral load in patients with resistance to interrupted drugs (left). Adapted from Deeks et al, J Infect Dis, 2005. Complete treatment interruption vs continuation of lamivudine alone in patients (n=50) with multi-drug resistant virus (right). Adapted from Castagna et al, AIDS, 2006. nRTI indicates nucleoside (or nucleotide) analogue reverse transcriptase inhibitor; PI, protease inhibitor. nRTI Resistance the M184V or I and K65R mutations. to the inclusion of zidovudine/lamivu- Resistance can also occur via adeno- dine given the results of Gilead 934, Resistance mutations selected by sine triphosphate (ATP)-mediated exci- the combination continues to be wide- nRTIs are listed in the International sion of the anti-retroviral nucleoside ly used on the basis of individual AIDS Society–USA Drug Resistance that would otherwise terminate elon- choice and on the strength of the Mutations summary (Johnson et al, Top gation of the viral DNA chain. TAMs wealth of experience in using the HIV Med, 2006). There is a high degree permit ATP to bind to reverse tran- combination. Advantageous features of cross-resistance within the nRTI scriptase, where the ATP molecule of the 3 combinations listed include class. For example, the K65R mutation can excise the incorporated nucleo- the fact that each is available as an is associated with cross-resistance side analogue from the viral DNA. FDC. The tenofovir/emtricitabine com- among all the current nRTIs except As noted in Table 1, the presence of bination is active against hepatitis zidovudine, and the thymidine ana- TAMs can antagonize the K65R muta- B virus, providing an advantage in logue-associated mutations (TAMs) tion, whereas the presence of M184V coinfected patients. associated with zidovudine resistance, or K65R mutations, which result There has been concern about the codon 69-insertion complex, and in decreased analogue incorpora- cumulative renal toxicity with teno- the codon 151-complex can each con- tion, results in reduced zidovudine fovir, especially given the serious toxi- fer cross-class resistance. monophosphate excision and reduced city observed with its related forerun- There are 2 principal mechanisms zidovudine resistance. of nRTI resistance, and these mecha- ner adefovir when given at high doses. nisms can interact to further alter sus- Although serious renal toxicity con- ceptibility patterns (Clavel and Hance, Other Distinguishing Features of cerns with tenofovir have not been N Engl J Med, 2004). In brief, nRTI Dual nRTIs raised by clinical trial data, there have resistance can occur via mutations in been reports of tenofovir-related renal reverse transcriptase that interfere Table 2 lists some defining characteris- dysfunction in clinical experience and with the incorporation of the active tics of 3 commonly used dual nRTI in Investigational New Drug (IND) nucleoside analogue form into the options for combination with a PI or safety reports. It is now recommended growing DNA; such mutations include NNRTI in initial treatment. With regard that calculated creatinine clearance and urinalysis results, as well Table 1. Mechanisms of nRTI Resistance as serum-creatinine level, be obtained TAMs: M41L, D67N, K70R, at baseline in any patient starting L210W, T215F/Y, K219Q/E/N M184V K65R tenofovir. In addition to decreased Confer zidovudine resistance Confers lamivudine resistance Confers nonzidovudine renal function at baseline, risk factors via zidovudine monophos- via decreased lamivudine nRTI resistance via for renal dysfunction in patients phate excision triphosphate incorporation decreased analogue receiving tenofovir include diabetes incorporation and lower CD4+ cell count. Antagonize K65R Decreases zidovudine resistance Decreases zidovudine With regard to nRTI-associated via decreased zidovudine resistance via decreased mitochondrial toxicity, the results of a monophosphate excision zidovudine-monophos- recent study in a transgenic mouse phate excision model in cardiac tissue showed mito- nRTI indicates nucleoside (or nucleotide) analogue reverse transcriptase inhibitor; TAMs, chondrial damage with zidovudine thymidine analogue-associated mutations. and stavudine and not with lamivu-

141 International AIDS Society–USA Topics in HIV Medicine dine (Lewis et al, AIDS, 2006). The de- The high virologic failure rates are not lution within the total viral population. oxynucleotide-carrier molecule that is related to such factors as antagonism The potential use of quadruple responsible for normal transportation at the reverse transcriptase activity nRTI regimens remains under investi- of nucleotide triphosphates into mito- level, pharmacokinetic interactions gation. A recent small study compar- chondria was overexpressed in the affecting serum drug levels, or inter- ing the quadruple nRTI regimen of mouse model, resulting in reduplica- ference in intracellular phosphoryla- zidovudine/lamivudine/abacavir/teno- tion of mitochondrial cristae. The addition of 1 or more of the nRTIs. Rather, fovir with zidovudine/lamivudine/efav- tion of zidovudine or stavudine result- failure is related to a low genetic barri- irenz showed similar rates of viral sup- ed in loss of cristae, amorphous er to resistance and increased likeli- pression to less than 50 copies/mL at deposits, and destruction of the mito- hood of “convergent” resistance 48 weeks in intent-to-treat analysis chondria, whereas no such damage involving mutations to the component (67% vs 68%) and in on-treatment was observed when lamivudine was drugs, with the mechanism appearing analysis (100% vs 98%; Moyle et al, added. These findings indicate that to be lack of uniform distribution of Antivir Ther, 2006). selective transport of zidovudine and the different drugs to target cells. This stavudine triphosphates into the mito- chondria may be responsible for the finding emphasizes the importance of Residual Activity of nRTIs in the greater toxicity observed with these 2 achieving rapid, profound suppression Context of Resistance: of viral replication with drug combina- nRTIs. Abacavir has been discontinued Treatment Interruption Studies in 5% to 8% of patients because of tions and of ascertaining such an effect in vivo. A study of the evolution of hypersensitivity in clinical trials. The Recent findings on the strategy of the M184V and K65R mutations in hypersensitivity reaction is associated structured treatment interruption (STI) patients receiving tenofovir/lamivu- with the human leukocyte antigen of antiretroviral therapy are reviewed (HLA)-B5701 haplotype. dine/abacavir in the TONUS trial used both bulk sequencing and clonal in the contribution by Dr Benson in sequencing to detect minor variants this issue. In brief, STIs should not be Triple or Quadruple nRTIs? in the viral population (Delaunay et al, part of antiretroviral therapy strategies J Virol, 2005). The study showed that: in most settings according to currently Available data do not indicate that use (1) M184V evolves more quickly than available data. of triple nRTIs is a beneficial strategy K65R; (2) the 2 mutations first appear Data from studies of nRTI interrup- for initial treatment. The results of AIDS on separate viral genomes on clonal tion indicate that the agents possess Clinical Trials Group (ACTG) A5095 analysis; and (3) the mutations con- residual activity in vivo despite the showed that the combination of verge on the same genomes over presence of nRTI resistance mutations, zidovudine/lamivudine/abacavir was time. The findings emphasize that supporting the rationale for continuing inferior to dual-nRTI-plus-efavirenz bulk sequencing cannot be relied upon treatment with or recycling these regimens. However, the zidovudine/ to provide a complete picture of viral agents at later stages of treatment lamivudine/abacavir regimen is still resistance, with minor variant detec- when full viral suppression cannot be considered an alternative in such set- tion being essential to understanding achieved with available options. tings as intolerance of or resistance to the dynamics of resistance mutation evo- For example, as shown in Figure 2, PIs or NNRTIs. The trial also showed no difference in virologic response Table 2. Characteristics of Recommended Dual nRTI Options between the regimens of zidovudine/ in Initial Antiretroviral Therapy lamivudine/abacavir plus efavirenz Differential toxicity Resistance and zidovudine/lamivudine plus efav- Regimen Features concerns mutations irenz, with no differences being observed in proportions of patients with Tenofovir/emtricitabine FDC, once daily Renal dysfunction — M184V, K65R increased risk with diabetes, suppression of plasma HIV RNA level Both drugs active lower CD4+ cell count, or against HBV to less than 200 copies/mL or less than decreased renal function at 50 copies/mL (Figure 1) or time to first baseline virologic failure among all patients or among those with baseline plasma Zidovudine/lamivudine FDC, twice daily Anemia, mitochondrial M184V, TAMs dysfunction HIV RNA level above or below 100,000 copies/mL (Gulick et al, JAMA, 2006). Other studies have shown very Abacavir/lamivudine FDC, once daily Hypersensitivity reaction M184V, K65R high virologic failure rates (eg, 50% (HLA-B5701) to 90%) with the triple nRTI regimens of tenofovir/lamivudine/abacavir FDC indicates fixed-dose combination; HBV, hepatitis B virus; HLA, human leukocyte antigen; and didanosine/lamivudine/abacavir. nRTI, nucleoside (or nucleotide) analogue reverse transcriptase inhibitor; TAMs, thymidine ana- These regimens should not be used. logue-associated mutations.

142 Perspective – nRTIs: A Re-examination of the Class Volume 14 Issue 4 October/November 2006 cessation of nRTI treatment in the set- Presented by Dr Hammer in March 2006. dine/lamivudine/abacavir + efavirenz for initial HIV ting of nRTI resistance nevertheless First draft prepared from transcripts by therapy. [Abstract H-416a.] 45th Interscience Conference on Antimicrobial Agents and resulted in a marked increase in viral Matthew Stenger. Reviewed and updated by Dr Hammer in October 2006. Chemotherapy. December 16-19, 2005; load, whereas discontinuation of the Washington, DC. entry inhibitor enfuvirtide or PI treat- Financial Disclosure: Dr Hammer has served ment in the context of resistance had as a scientific advisor to Boehringer Gulick RM, Ribaudo HJ, Shikuma CM, et al. ACTG A5095; Three- vs four- drug antiretroviral regi- little effect on viral load. Ingelheim, Pfizer, Progenics, and Tibotec- mens for the initial treatment of HIV-1 infection: Virco. He has received grants and research As also shown in Figure 2, the con- a randomized controlled trial. JAMA, 2006; tinuation of lamivudine alone while support from Merck. 296(7): 769-781. stopping all other drugs in patients with resistance including the M184V lamivu- Hammer SM, Saag MS, Schechter M, et al. Suggested Reading Treatment for adult HIV infection: 2006 recom- dine resistance mutation nevertheless mendations of the International AIDS resulted in a markedly smaller increase Castagna A, Danise A, Menzo S, et al. Society–USA panel. JAMA. 2006;296:827-843. in viral load than did the stopping of all Lamivudine monotherapy in HIV-1–infected drugs, likely reflecting residual antiviral patients harbouring a lamivudine-resistant Johnson VA, Brun-Vézinet F, Clotet B, et al. activity or a viral fitness defect con- virus: a randomized, pilot study. AIDS. 2006; Update of the drug resistance mutations in HIV- 1: Fall 2006. Top HIV Med. 2006;14:125-130. ferred by the M184V mutation. 20:795-803. Clavel F, Hance AJ. HIV drug resistance. N Engl J Lewis W, Kohler JJ, Hosseini SH, et al. Med. 2004;350:1023-1025. Antiretroviral nucleosides, deoxynucleotide car- Conclusion rier and mitochondrial DNA: evidence support- Deeks SG, Hoh R, Neilands TB, et al. ing the DNA pol gamma hypothesis. AIDS. The leading dual nRTI options as com- Interruption of treatment with individual thera- 2006;20:675-684. ponents of NNRTI- or PI-based regi- peutic drug classes in adults with multidrug- mens (in the absence of drug resis- resistant HIV-1 infection. J Infect Dis. 2005; Moyle G, Higgs C, Teague A, et al. An open-label, 192:1537-1544. randomized comparative pilot study of a single- tance) are tenofovir/emtricitabine, class quadruple therapy regimen versus a 2-class zidovudine/lamivudine, and abacavir/ Delaunay C, Brun-Vezinet F, Landman R, et al. therapy regimen for individuals initiating antiretro- lamivudine as FDCs. Triple nRTI regi- Comparative selection of the K65R and M184V/I viral therapy. Antivir Ther. 2006;11:73-78. mens are not recommended, but mutations in human immunodeficiency virus zidovudine/lamivudine/abacavir type 1-infected patients enrolled in a trial of can be considered in select circum- first-line triple-nucleoside analog therapy (Tonus IMEA 021). J Virol. 2005;79:9572-9578. stances and zidovudine/lamivudine/ tenofovir is under study. The observa- Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir tion of very high virologic failure rates DF, emtricitabine, and efavirenz vs. zidovudine, with some triple nRTI combinations lamivudine, and efavirenz for HIV. N Engl J Med. underscores the need to understand 2006;354:251-260. the complexity of in vivo evolution of Gulick R, Ribaudo H, Shikuma C, et al. ACTG resistance. Quadruple nRTI regimens 5095: zidovudine/lamivudine/abacavir vs Top HIV Med. 2006;14(4):140-143 remain experimental. zidovudine/lamivudine + efavirenz vs zidovu- Copyright 2006, International AIDS Society–USA

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