MAJOR ARTICLE HIV/AIDS

Long-Term Immunologic and Virologic Responses in Patients with Highly Resistant HIV Infection Who Are Treated with an Incompletely Suppressive

Antiretroviral Regimen Downloaded from https://academic.oup.com/cid/article/45/8/1085/345921 by guest on 23 September 2021

Tejal Gandhi,1 Vijayalakshmi Nagappan,1,a Sandro Cinti,3 Wei Wei,2,a and Powel Kazanjian1 1University of Michigan Health System, 2University of Michigan School of Public Health, and 3Ann Arbor Veterans Affairs Medical Center, Ann Arbor, Michigan

Background. Some treatment-experienced patients with highly drug-resistant human immunodeficiency virus (HIV) infection have no option but to continue to receive an incompletely suppressive regimen (ISR). Weperformed a study to determine their long-term immunologic and virologic responses to ISR, to investigate risks for im- munologic or virologic failure, and to examine for the occurrence of new drug-resistance mutations. Methods. Antiretroviral treatment–experienced HIV-infected patients with a genotype sensitivity score р1, an HIV load 11000 copies/mL, and no available optimized regimen were included in the study. The proportion of patients treated with ISR who developed immunologic failure (defined as a 25% reduction in the CD4 cell count у from the baseline level) and virologic failure (defined as a 0.5-log10 increase in the HIV load from the baseline level) was determined. Cox proportional hazards analysis was used to investigate variables associated with im- munologic or virologic failure. New drug-resistant mutations were calculated in 27 patients with sequential ge- notypes available. Results. Forty-seven patients (median duration of prior antiretroviral therapy, 89 months; median CD4 cell count, 277 cells/mm3; and median HIV load, 19,728 copies/mL) had multiple HIV mutations (a median of 5 nucleoside reverse-transcriptase inhibitor mutations, 1 nonnucleoside reverse-transcriptase inhibitor mutation, and 6 protease inhibitor mutations; median genotype sensitivity score, 0) at baseline. By 48 months after ISR use, 43% had developed immunologic failure, and 22% had developed virologic failure. None of the studied variables (i.e., age, !50 years; baseline HIV load, 1100,000 copies/mL; baseline CD4 cell count, !200 cells/mm3; or inclusion of lamivudine in the treatment regimen) were associated with immunologic or virologic failure. New nucleoside reverse-transcriptase inhibitor mutations occurred in 63% of patients, and new primary protease inhibitor mutations occurred in 52.6% of protease inhibitor recipients. No deaths occurred. A total of 8.5% of patients experienced a new AIDS-defining event. Conclusions. Most patients with highly drug-resistant HIV infection who were treated with an ISR maintain durable immunologic and virologic responses. New drug-resistant mutations occur frequently.

Some antiretroviral-experienced patients with highly load !50 copies/mL) while continuing to receive an- drug-resistant HIV infection may be unable to achieve tiretroviral therapy [1–5]. Certain patients with highly complete virologic suppression (defined as an HIV-1 drug-resistant HIV infection for whom an optimized regimen is not available may have no option but to continue to receive an incompletely suppressive regi-

Received 1 May 2007; accepted 13 June 2007; electronically published 14 men (ISR), because drug treatment interruptions are September 2007. not always feasible [6–8]. The development of new a Present affiliation: St. John’s Hospital, Detroit, Michigan (V.N.); and Amgen, Thousand Oaks, California (W.W.). agents for antiretroviral-experienced patients has not Reprints or correspondence: Dr. Powel Kazanjian, Div. of Infectious Diseases, abolished the therapeutic niche for ISR, because viremia University of Michigan Health System, 1500 E. Medical Center Dr., Rm. 3119 TC, Ann Arbor, MI 48109-5378 ([email protected]). may persist in some patients who receive an optimized Clinical Infectious Diseases 2007;45:1085–92 background regimen in combination with a new agent 2007 by the Infectious Diseases Society of America. All rights reserved. [1–5]. Although an undetectable HIV load cannot be 1058-4838/2007/4508-0025$15.00 DOI: 10.1086/521937 achieved, some degree of virologic suppression [6, 7]

HIV/AIDS • CID 2007:45 (15 October) • 1085 and immunologic response [7, 9–13] can be attained by con- study entry (i.e., baseline) or before study entry. Patients re- tinuing ISR, possibly because of compromised viral fitness re- mained in the study as long as the entire ISR was continued lated to the selection of drug-resistance mutations [7, 12, 14, without simplification or introduction of additional agents. Pa- 15]. Such treatment responses, albeit not ideal, may provide tients were removed from the study if their ISR was discon- some continued benefit by reducing progression to AIDS or tinued, simplified, intensified, or switched to a new, effective, death [16]. alternative regimen that contained at least 2 active new drugs Nonetheless, the durability of virologic reduction and im- when such agents (i.e., enfuvirtide and tipranavir) became munologic responses in patients with high-level drug-resistant available during the study period; patients were also removed HIV infection who are treated with an ISR for a prolonged from the study if they died. Patients were excluded if they time remains unresolved. The durability of responses to ISR achieved an HIV load !400 copies/mL on 2 consecutive oc- remains relevant today, because resistance [17–19], intolerance, casions while receiving the ISR or had received IL-2 р1 month and incomplete virologic responses to newly licensed agents before study entry. Downloaded from https://academic.oup.com/cid/article/45/8/1085/345921 by guest on 23 September 2021 have already been described [1–5]. Prior studies evaluating re- Patient data, including demographic characteristics, clinical sponses to salvage treatment regimens [9–13] did not include AIDS-related events (as assessed using the 1993 Center for Dis- patients with extensive treatment experience [9, 10, 12] or high- ease Control and Prevention AIDS surveillance definition [29]), level drug resistance [9–13], and they lacked long-term follow- death, CD4 cell count, HIV load, and genotypic measurements, up [7, 20–23]. In addition, these studies have focused on sim- were extracted from the electronic database system (Clinical plification of regimens [24] or on switches to mega-HAART Patient Data Management System; Solutions TM). The insti- (i.e., HAART that includes 14 HIV agents) [6, 25] rather than tutional review board at each participating center approved the on maintenance of a full, unsimplified ISR. Concerns have been protocol. We used previously defined criteria to assess im- raised regarding the risk of development of new mutations [20, munologic and virologic failure [24, 30]: immunologic failure 23] if ISR is continued for prolonged periods. Furthermore, was defined as a 25% reduction in the CD4 cell count, com- questions remain regarding which variables, such as inclusion pared with the baseline value (i.e., the value at the time of ISR of lamivudine in a full ISR [24, 26–28] and baseline HIV load initiation), that persisted for at least 3 months while the patient or CD4 cell count, may be associated with immunologic or received the ISR [24, 30]; and virologic failure was defined as virologic responses. у a 0.5-log10 increase in the HIV load, compared with the base- We studied patients with highly drug-resistant HIV infection line value, that persisted for at least 3 months while the patient who had no viable treatment options and who continued to received the ISR [24, 30]. receive a full, unsimplified ISR. Our aims were to determine Genotype sensitivity score and mutation analysis. At base- the durability of immunologic and virologic responses, to as- line, the GenotypR Plus genotype test (California Specialty Lab) certain whether certain risk factors were associated with de- was used to calculate the genotype sensitivity score—that is, velopment of immunologic or virologic failure, and to describe the total number of antiretroviral drugs in the patient’s ISR to the acquisition of drug-resistance mutations in this population. which the patient’s HIV isolate demonstrated genotypic sus- ceptibility—as has been previously defined [1, 31]. A value of METHODS 0 was assigned if there was genotype evidence of resistance to Study population and study definitions. This longitudinal a particular drug, and a value of 1 was assigned if there was observational cohort was performed at the University of Mich- no genotypic evidence of resistance to that drug. Mutations igan Health Center and Ann Arbor Veterans Affairs Center were interpreted in accordance with current International AIDS (Ann Arbor, MI) from January 1999 to July 2005. HIV-infected Society–USA drug resistance testing guidelines for HIV-1 mu- patients who had an HIV RNA level 11000 copies/mL for 13 tation analysis [32]. According to these guidelines, primary months while receiving an ISR, who had no optimized regimen protease inhibitor (PI) resistance mutations were defined as available, and whose baseline CD4 cell count was у25 cells/ mutations at protease positions 30, 46, 48, 50, 82, 84, and 90; mm3 greater the lowest value at any point prior to commence- secondary PI resistance mutations were defined as mutations ment of the ISR (i.e., the nadir value), regardless of their ab- at protease positions 10, 20, 24, 32, 33, 36, 47, 53, 54, 63, 71, solute nadir CD4 cell count, were eligible for the study. We 73, 77, and 88. Nucleoside reverse-transcriptase inhibitor included patients who had some degree of CD4 cell response (NRTI) resistance mutations were defined as mutations at re- at baseline, to measure the durability of immunologic responses verse-transcriptase positions 41, 44, 62, 65, 67, 69, 70, 74, 75,77, in patients receiving an ISR. Patients were then included if their 115, 116, 118, 151, 184, 210, 215, and 219. Nonnucleoside virus had resistance (as defined below) to at least 2 drugs in reverse-transcriptase inhibitor (NNRTI) resistance mutations their ISR (genotype sensitivity score, р1), as determined by were defined as mutations at reverse-transcriptase positions results of an HIV genotype testing performed at the time of 100, 103, 106, 108, 181, 188, 190, 225, 230, and 236.

1086 • CID 2007:45 (15 October) • HIV/AIDS Statistical analysis. Mean CD4 cell count and HIV load 4; median number of NNRTIs, 1; and median number of PIs, responses to ISR were plotted according to duration ISR ther- 3. The median nadir CD4 cell count was 105 cells/mm3, and apy. Kaplan-Meier curves were used to determine the per- the median baseline CD4 cell count was 277 cells/mm3. The centage of the patients in whom immunologic or virologic median nadir HIV load was 63,115 copies/mL, and the median failure did not occur during the study period. For 27 patients baseline load was 19,728 copies/mL. At baseline, the median who had at least 1 sequential genotype test performed during age was 47 years. No patient was excluded from the study the follow-up period while receiving an ISR, the mean numbers because he or she achieved a transient HIV load !400 copies/ of new NRTI, NNRTI, and PI mutations were calculated and mL but otherwise met inclusion criteria. recorded. Risk factors for the development of immunologic Table 2 shows that the number of mutations within each failure and virologic failure were determined using a Cox pro- antiretroviral class was high at baseline. The median number portional hazard multivariate regression model. The risk factors of NRTI mutations was 5; in all, 42 (90%) of 46 patients had analyzed included the following: age, !50 years; nadir CD4 cell у 2 thymidine analogue mutations (TAMs), and 35 (74.5%) of Downloaded from https://academic.oup.com/cid/article/45/8/1085/345921 by guest on 23 September 2021 3 count, !100 cells/mm ; genotype sensitivity score, 0; baseline 47 had у3 TAMs. Of the patients with !2 TAMs, 1 patient had HIV load, 1100,000 copies/mL; baseline CD4 cell count, !200 multinucleotide resistant mutation (Q151M), 1 had a K70R 3 cells/mm ; and use of lamivudine or emtricitabine in the ISR. mutation, and 1 had prolonged viremia during a prior course of zidovudine treatment. All patients either had a M184 I/V RESULTS mutation documented by genotype at study entry (n p 40 ) or Baseline characteristics. The baseline demographic, clinical, suspected on the basis of a history of taking a lamivudine- and genotypic characteristics for the 47 treatment-experienced containing regimen during active viral replication (n p 7 ). The patients who enrolled in the study are outlined in table 1. median number of NNRTI and PI mutations was 1 and 6, Patients had a median duration of antiretroviral treatment be- respectively; 72.3% of patients had 12 primary PI mutations fore receipt of the ISR of 89 months (interquartile range [IQR], (table 2). The ISR contained a PI in 72.3% of patients and an 59–113 months) and had previously received the following NNRTI in 36.1%. The patient population had high-level, mul- number of drugs within each class: median number of NRTIs, tidrug-resistant HIV infection. The median genotype sensitivity

Table 1. Demographic characteristics, baseline clinical data, and pre- vious antiretroviral therapy for the 47 study patients.

Characteristic Value Demographic characteristic Age, years 47 (42–54) Male sex, percentage of patients 93.6 HIV risk factor, percentage of patients Male-male sex 70 Injection drug use 6 Othera 24 Clinical data CD4 cell count, cells/mm3 Nadir 105 (27–178) Baseline 277 (157–424) HIV RNA level, copies/mL Nadir 63,115 (24,600–197,294) Baseline 19,728 (4375–65,900) Duration of follow-up, months 27 (12.5–42) Prior antiretroviral therapy Duration of prior antiretroviral therapy, months 89 (59–113) No. of NRTIs 4 (4–5.5) No. of NNRTIs 1 (1–2) No. of PIs 3 (2–4)

NOTE. Data are median values (interquartile range), unless otherwise indicated. NNRTI, nonnucleoside reverse-transcriptase inhibitor; NRTI, nucleoside reverse-transcrip- tase inhibitor; PI, protease inhibitor. a Includes blood transfusion, vertical transmission, and heterosexual sex.

HIV/AIDS • CID 2007:45 (15 October) • 1087 Table 2. Genotype characteristics, by antiretroviral drug score was 0 (table 1); the ISR of all 13 patients with a genotype class at baseline, incompletely suppressive regimen (ISR) sensitivity score of 1 (28% of total) contained a susceptible received, and baseline genotype sensitivity score, for the agent. 47 study patients. CD4 cell count and HIV load responses and time to im-

Genotype characteristic Value munologic failure and virologic failure during receipt of an ISR. The median duration of follow-up for patients receiving NRTI mutations an ISR was 27 months (IQR, 12.5–42 months). Figure 1 shows Median no. (IQR) 5 (4–6) K65R 1 (2.1) that there were no substantial changes in the mean CD4 cell T69D/N/S 5 (10.6) count or HIV load in response to ISR, compared with baseline Insertion or deletion 67–69 1 (2.1) values, throughout the study period. Q151M 1 (2.1) Figure 2 shows the Kaplan-Meier curve of time to immu- L74V 12 (25.5) nologic and virologic failure for the entire population. Specif- Downloaded from https://academic.oup.com/cid/article/45/8/1085/345921 by guest on 23 September 2021 M 184I/V 40 (85.1) T215Y/F 36 (76.6) L210W 23 (48.9) K70R 17 (36.2) M41L 28 (59.5) у2 TAMsa 42 (89.4) у3 TAMsa 35 (74.5) Median no. of zidovudine mutations (IQR) 3 (3–4) NNRTI mutations Median no. (IQR) 1 (1–2) K103N 26 (55.2) Y181C/I, Y188C/H/L, or G190S/A/C/E 24 (51.1) K103N, Y181C/I, Y188C/H/L, or G190S/A/C/E 36 (76.6) PI mutations Median no. (IQR) 6 (2–7) D30N 6 (12.8) M46 I/L 24 (51.1) G48V 2 (4.2) I50V 3 (6.4) I54L/M/V 22 (46.8) V82A/F/T/S 17 (14.9) I84V 12 (25.5) L90M 20 (42.6) 12 Primary mutations 34 (72.3) ISR regimen Triple-NRTI–containing regimen 3 (6.4) PI-containing regimen 34 (72.3) Unboosted PIb 11 (23.4) Ritonavir-boosted PI 15 (31.9) Dual PI 1 (2.1) Unboosted PI and NNRTI combination 2 (4.3) Ritonavir-boosted PI and NNRTI combination 4 (8.5) NNRTI-containing regimenc 17 (36.1) Genotype sensitivity score Median (IQR) 0 (0–1) Score of 1, percentage of patients 28 Score of 0, percentage of patients 72

NOTE. Data are no. (%) of patients, unless otherwise indicated. IQR, interquartile range; NNRTI, nonnucleoside reverse-transcriptase inhibitor; NRTI, nucleoside reverse-transcriptase inhibitor; PI, protease inhibitor; TAMs, thymidine analogue mutations. a Figure 1. Changes in mean CD4 cell counts (A) and mean HIV RNA Includes M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E. b Percentages refer to the entire patient population. levels (B) from baseline, according to duration of receipt of an incompletely c Seven patients received both an NNRTI and a PI. suppressive regimen (ISR), for the 47 study patients.

1088 • CID 2007:45 (15 October) • HIV/AIDS cells/mm3; and inclusion of lamivudine in the ISR. Table 3 shows that there was an increased relative risk (RR) for nadir CD4 cell count !100 cells/mm3 with both immunologic and virologic failure, as well as for baseline HIV load 1100,000 copies/mL with immunologic failure. In addition, there was a decreased RR for inclusion of lamivudine in the ISR with im- munologic—but not virologic—failure. However, none of these variables attained a statistically significant association with ei- ther immunologic or virologic failure. During the study period, 4 patients (8.5% of study popu- lation) experienced a new AIDS-defining event (herpes simplex mucocutaneous ulcer for 11 month, HIV-associated dementia, Downloaded from https://academic.oup.com/cid/article/45/8/1085/345921 by guest on 23 September 2021 B cell lymphoma, and candida esophagitis) during receipt of the ISR. There were no deaths during the study period. New drug-resistance mutations during ISR. Twenty-seven patients underwent follow-up genotype testing while receiving the ISR (table 4). These patients were observed for a median period of 25 months. Nineteen patients (70.3%) were receiving an ISR that contained a PI, 11 patients (40.7%) were receiving and ISR that contained an NNRTI, and 2 patients (7.4%) were receiving a triple-NRTI ISR. Seventeen patients (63%) devel- oped a new major mutation directed against 1 of the 3 anti- retroviral classes. Seventeen patients (63%) developed new NRTI mutations; the median number of NRTI mutations per patient was 2 (IQR, 1–2), and the median number of new TAMs per patient was 1 (IQR, 1–2). Five (45.5%) of 11 patients who received an NNRTI-containing regimen developed a new NNRTI mutation; the median number of new NNRTI muta- tions per patient was 1 (IQR, 1–1). Sixteen (84.2%) of 19 patients who received a PI-containing regimen developed new PI mutations (primary or secondary); the median number of new primary or secondary PI mutations per patient was 3 (IQR, 1–4). Ten (52.6%) of 19 patients who received a PI agent de- veloped a new primary PI mutation alone; the median number of new primary mutations per patient was 1 (IQR, 1–1.75). Figure 2. Kaplan-Meier curves showing the percentage of patients Moreover, no new primary PI mutations occurred among pa- who do not develop immunologic failure (A) or virologic failure (B) while tients who were not receiving a PI agent, but a new PI mutation receiving an incompletely suppressive regimen (ISR). (polymorphism or secondary mutation) occurred in 2 (25%) of 8 of such patients. ically, immunologic failure occurred in 34.7% of the population at 24 months and in 43.4% at 48 months. Figure 2B demon- DISCUSSION strates that virologic failure occurred in 16% of the population at 24 months and in 21.7% at 48 months, indicating that not Our study shows that many patients with highly drug-resistant all patients who experienced immunologic failure also expe- HIV infection for whom an optimized regimen is unavailable rienced virologic failure. can have sustained immunologic and virologic responses to an Risk factors for immunologic and virologic failure and clin- ISR. Our results are consistent with the findings of previous ical outcomes. Table 3 shows the results of the Cox propor- studies evaluating CD4 cell count and HIV load responses in tional hazard multivariate analysis that was used to identify treatment-experienced patients [9–12] by showing that some statistical associations between the following variables and im- degree of immunologic and virologic response to ISR may be munologic or virologic failure: age, !50 years; nadir CD4 cell achieved by continuing an ISR. Moreover, our study had a count, !100 cells/mm3; genotype sensitivity score, 0; baseline longer follow-up period than other reports that have investi- HIV load, 1100,000 copies/mL; baseline CD4 cell count, !200 gated the efficacy of antiretrovirals in treatment-experienced

HIV/AIDS • CID 2007:45 (15 October) • 1089 Table 3. Variables independently associated with development of immu- nologic or virologic failure for the entire study population.

Type of failure, risk factors RR (95% CI) P Immunologic failure Baseline HIV RNA level, 1100,000 copies/mL 4.851 (0.464–50.66) .19 Age, 150 years 1.476 (0.439–4.96) .53 Nadir CD4 cell count, !100 cells/mm3 2.254 (0.598–8.50) .23 ISR containing lamivudine and M184I/V 0.537 (0.145–1.99) .35 Genotype sensitivity score, 0 1.584 (0.388–6.47) .52 Baseline CD4 cell count, !200 cells/mm3 0.382 (0.036–4.11) .43 Virologic failure 1 ϱ Baseline HIV RNA level, 100,000 copies/mL 0 (0- )1.0 Downloaded from https://academic.oup.com/cid/article/45/8/1085/345921 by guest on 23 September 2021 Age, 150 years 0.721 (0.139–3.74) .70 Nadir CD4 cell count, !100 cells/mm3 5.29 (0.854–32.79) .073 ISR containing lamivudine and M184I/V 2.40 (0.401–14.36) .34 Genotype sensitivity score, 0 1.42 (0.249–8.13) .69 Baseline CD4 cell count, !200 cells/mm3 0.967 (0.128–7.32) .97

NOTE. ISR, incompletely suppressive regimen; RR, relative risk. patients [7, 20–23]. Thus, our study extends the findings of mutations present at baseline [23] has been hypothesized to these reports [7, 20–23] by showing that favorable CD4 cell explain why new mutations did not develop in all patients in count and HIV load responses to an ISR can be durable. these studies. In contrast to these studies, other reports have The findings of sustained immunologic and virologic re- not noted new drug-resistance mutations in patients with a sponses in our study remain relevant today. The recent avail- large number of baseline mutations who continued to receive ability of new agents for antiretroviral-experienced patients has a salvage regimen [7, 22, 37]. Owing to the different findings not removed a therapeutic niche for ISR for certain patients among studies, prospective trials are necessary to determine who remain viremic despite receipt of newly licensed agents. which baseline variables may contribute to new mutations after In particular, some patients with highly drug-resistant HIV the initiation of an ISR [20, 23]. infection who are treated with an optimized background reg- We were unable to identify any variable associated with im- imen in combination with a newly available agent (e.g., newly munologic or virologic failure. It is possible that the higher licensed PIs or inhibitors of CCR5 coreceptors or integrase) RRs for immunologic and virologic failure with a baseline HIV are unable to achieve complete virologic suppression. In fact, load 1100,000 copies/mL or a nadir CD4 cell count !100 cells/ drug-resistance mutations, which have already been witnessed mm3 may have represented significant associations, but our for the newer PI agents, and inhibitors to HIV entry, integrase, sample size was not large enough to detect one. Likewise, it is and maturation [17–19, 33, 34] may compromise the ability also possible that there was a significant association between of an optimized regimen to maintain durable virologic sup- lamivudine use and immunologic or virologic failure, as in- pression in patients with highly drug-resistant HIV infection. dicated by the lower RR for inclusion of lamivudine in the ISR. Thus, despite the availability of new agents today, some patients In contrast, a possible hypothesis to explain an absence of an with highly drug-resistant HIV infection may continue to have association would be a diminished virologic benefit due to no viable treatment option other than to continue to receive M184I/V resensitization to zidovudine in the patients in our an ISR for a prolonged period of time, to maintain increased population with at least 2 TAMs [38, 39]. Nonetheless, attempts CD4 cell count responses [6, 35] and HIV load reductions [7, to compare our results with the results of prior studies that 36]. have evaluated the efficacy of use of lamivudine in drug-ex- We found that new NRTI and PI drug-resistance mutations perienced patients are hampered by differences in design across occurred during our follow-up period in a considerable pro- studies, which have assessed lamivudine as part of an optimized portion of patients who continued to receive an ISR. Our ob- new regimen, a simplified regimen, monotherapy [24, 26–28], servation is consistent with 2 previous studies that found an or an entire ISR (present study). accumulation of new drug-resistance mutations in 75% [20] Several limitations of our study design deserve mention. A and 82% [23] of patients who continued to receive on a salvage multicenter study could have enrolled larger numbers of pa- regimen. A plateau or ceiling effect that may be attributable to tients to further evaluate the potential role of measurement of a large number of mutations [20] or to a certain pattern of phenotype and genotype in selecting an ISR, risk factors for

1090 • CID 2007:45 (15 October) • HIV/AIDS Table 4. Median number of new mutations and percentage of patients with mutations relevant to each class of antiretroviral therapy for the 27 patients who received an incompletely suppressive regimen and who had data on sequential genotypes available.

Percentage New mutationa Median (IQR) of patients New NRTI mutation while receiving ISRb 2 (1–2) 63.0 New NNRTI mutation while receiving NNRTI-containing ISRc 1 (1–1) 45.5 New PI mutations while receiving PI-containing ISRd 3 (1–4) 84.2 New primary PI mutations while receiving PI-containing ISR 1 (1–1.75) 52.6 New TAMs while receiving ISR 1 (1–2) 47.1

NOTE. There were 5 recipients of nonnucleoside reverse-transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) in the cohort of patients with follow-up genotype data. IQR, interquartile range; NRTI, Downloaded from https://academic.oup.com/cid/article/45/8/1085/345921 by guest on 23 September 2021 nucleoside reverse-transcriptase inhibitor; TAMs, thymidine analogue mutations. a Includes patients with major mutations. b Mutations at reverse-transcriptase positions 41, 44, 62, 65, 67, 69, 70, 74, 75,77, 115, 116, 118, 151, 184, 210, 215, and 219. c Mutations at reverse-transcriptase positions 100, 103, 106, 108, 181, 188, 190, 225, 230, and 236. d Includes both primary PI resistance mutations (i.e., mutations at protease positions 30, 46, 48, 50, 82, 84, and 90) and secondary PI resistance mutations (i.e., mutations at protease positions 10, 20, 24, 32, 33, 36, 47, 53, 54, 63, 71, 73, 77, and 88). immunologic and virologic failure, and the rate of immunologic Acknowledgments failure after 20 months; could assess the role of more recently Potential conflicts of interest. All authors: no conflicts. approved drugs that are currently used in ISRs; and could determine which mutation-guided agents could protect against References immunologic or virologic failure. Such a study could also in- vestigate whether use of a particular class of agent (PI or 1. Lalezari JP, Henry K, O’Hearn M, et al. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. NNRTI) may be a risk factor for development of new muta- N Engl J Med 2003; 348:2175–85. tions, determine the rate of development of new mutations, 2. Katlama C, Esposito R, Gatell JM, et al. Efficacy and safety of TMC and assess the role of adherence to treatment. Finally, a pro- 114/ritonavir in treatment experienced HIV patients: 24-week results of POWER 1. AIDS 2007; 21:395–402. spective study that included the measurement of replicative 3. Lalezari J, Goodrich J, DeJesus E, et al. Efficacy and safety of Maraviroc capacity could provide insight into the impact of different plus optimized background regimen in viremic ART-experienced pa- agents on viral fitness and could also investigate potential as- tients infected with CCR5-tropic HIV-1: 24 week results of a phase 2b/3 study in the US and Canada [abstract 104bLB]. In: Program and sociations between lamivudine use with immunologic or vi- abstracts of the 14th Conference on Retroviruses and Opportunistic rologic failure. Infections (Los Angeles). Alexandria, VA: Foundation for Retrovirology Our study supports the usefulness of continuing a partially and Human Health, 2007. suppressive regimen in patients with high-level drug-resistant 4. Cooper D, Gatell J, Rockstroh J, et al. Results of BENCHMARK-1, a phase III study evaluating the efficacy and safety of MK-0518 a novel HIV infection who have no viable alternatives. Our findings HIV-1 integrase inhibitor, in patients with triple class resistant virus regarding sustained responses to ISR remain relevant today, [abstract 105aLB]. In: Program and abstracts of the 14th Conference because some patients may not achieve complete virologic sup- on Retroviruses and Opportunistic Infections (Los Angeles). Alexan- dria, VA: Foundation for Retrovirology and Human Health, 2007. pression, despite receipt of newer agents in combination with 5. Hicks CB, Cahn P, Cooper DA, et al. Durable efficacy of tipranavir- an optimized background regimen, and these patients have no ritonavir in combination with an optimised background regimen of option other than to continue to receive an ISR for an extended antiretroviral drugs for treatment -experienced HIV-1 infected patients at 48 weeks in Randomized Evaluation of Strategic Intervention in period [1–5]. Our finding that continuation of an ISR in the multi-drug resistant patients with Tipranavir (RESIST) studies: an anal- face of ongoing viral evolution may lead to the development ysis of combine data from two randomised trials. Lancet 2006; 368: of new drug-resistance mutations supports a potential role for 466–75. 6. Lawrence J, Mayers DL, Huppler Hullsiek K, et al. Structured treatment a simplified, PI-sparing ISR to prevent additional mutations to interruption in patients with multidrug-resistant human immunode- the protease class [24]. Thus, additional studies of ISR in pa- ficiency virus. N Engl J Med 2003; 349:837–46. tients infected with highly drug-resistant HIV are indicated to 7. Deeks SG, Wrin T, Liegler T, et al. Virologic and immunologic con- identify which optimal mutation-guided agents to include, risk sequences of discontinuing combination antiretroviral drug therapy in HIV-infected patients with detectable viremia. N Engl J Med 2001; factors for immunologic and virologic failure, and agents that 344:472–80. will minimize the risk for developing new mutations. 8. The Strategies for Management of Antiretroviral Therapy (SMART)

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