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

  1. Tejal Gandhi1,
  2. Vijayalakshmi Nagappan1,a,
  3. Sandro Cinti3,
  4. Wei Wei2,a, and
  5. Powel Kazanjian1⇓
  1. 1University of Michigan Health System, Michigan
  2. 2University of Michigan School of Public Health, Michigan
  3. 3Ann Arbor Veterans Affairs Medical Center, Ann Arbor, Michigan
  1. Reprints or correspondence: Dr. Powel Kazanjian, Div. of Infectious Diseases, University of Michigan Health System, 1500 E. Medical Center Dr., Rm. 3119 TC, Ann Arbor, MI 48109–5378 (pkazanji{at}umich.edu).

  • ↵a Present affiliation: St. John's Hospital, Detroit, Michigan (V.N.); and Amgen, Thousand Oaks, California (W.W.).

 
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Abstract

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). We performed a study to determine their long-term immunologic and virologic responses to ISR, to investigate risks for immunologic 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 ⩽1, an HIV load >1000 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 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 immunologic or virologic failure. New drug-resistant mutations were calculated in 27 patients with sequential genotypes 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, >100,000 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 drug-resistant HIV infection may be unable to achieve complete virologic suppression (defined as an HIV-1 load <50 copies/mL) while continuing to receive antiretroviral therapy [1–5]. Certain patients with highly drug-resistant HIV infection for whom an optimized regimen is not available may have no option but to continue to receive an incompletely suppressive regimen (ISR), because drug treatment interruptions are not always feasible [6–8]. The development of new agents for antiretroviral-experienced patients has not abolished the therapeutic niche for ISR, because viremia may persist in some patients who receive an optimized background regimen in combination with a new agent [1–5]. Although an undetectable HIV load cannot be achieved, some degree of virologic suppression [6, 7] and immunologic response [7, 9–13] can be attained by continuing ISR, possibly because of compromised viral fitness related to the selection of drug-resistance mutations [7, 12, 14, 15]. Such treatment responses, albeit not ideal, may provide some continued benefit by reducing progression to AIDS or death [16].

Nonetheless, the durability of virologic reduction and immunologic responses in patients with high-level drug-resistant HIV infection who are treated with an ISR for a prolonged time remains unresolved. The durability of responses to ISR remains relevant today, because resistance [17–19], intolerance, and incomplete virologic responses to newly licensed agents have already been described [1–5]. Prior studies evaluating responses to salvage treatment regimens [9–13] did not include patients with extensive treatment experience [9, 10, 12] or high-level drug resistance [9–13], and they lacked long-term follow-up [7, 20–23]. In addition, these studies have focused on simplification of regimens [24] or on switches to mega-HAART (i.e., HAART that includes >4 HIV agents) [6, 25] rather than on maintenance of a full, unsimplified ISR. Concerns have been raised regarding the risk of development of new mutations [20, 23] if ISR is continued for prolonged periods. Furthermore, questions remain regarding which variables, such as inclusion of lamivudine in a full ISR [24, 26–28] and baseline HIV load or CD4 cell count, may be associated with immunologic or virologic responses.

We studied patients with highly drug-resistant HIV infection who had no viable treatment options and who continued to receive a full, unsimplified ISR. Our aims were to determine the durability of immunologic and virologic responses, to ascertain whether certain risk factors were associated with development of immunologic or virologic failure, and to describe the acquisition of drug-resistance mutations in this population.

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Methods

Study population and study definitions. This longitudinal observational cohort was performed at the University of Michigan Health Center and Ann Arbor Veterans Affairs Center (Ann Arbor, MI) from January 1999 to July 2005. HIV-infected patients who had an HIV RNA level >1000 copies/mL for >3 months while receiving an ISR, who had no optimized regimen available, and whose baseline CD4 cell count was ⩾25 cells/mm3 greater the lowest value at any point prior to commencement of the ISR (i.e., the nadir value), regardless of their absolute nadir CD4 cell count, were eligible for the study. We included patients who had some degree of CD4 cell response at baseline, to measure the durability of immunologic responses in patients receiving an ISR. Patients were then included if their virus had resistance (as defined below) to at least 2 drugs in their ISR (genotype sensitivity score, ⩽1), as determined by results of an HIV genotype testing performed at the time of study entry (i.e., baseline) or before study entry. Patients remained in the study as long as the entire ISR was continued without simplification or introduction of additional agents. Patients were removed from the study if their ISR was discontinued, simplified, intensified, or switched to a new, effective, alternative regimen that contained at least 2 active new drugs when such agents (i.e., enfuvirtide and tipranavir) became available during the study period; patients were also removed from the study if they died. Patients were excluded if they achieved an HIV load <400 copies/mL on 2 consecutive occasions while receiving the ISR or had received IL-2 ⩽1 month before study entry.

Patient data, including demographic characteristics, clinical AIDS-related events (as assessed using the 1993 Center for Disease Control and Prevention AIDS surveillance definition [29]), death, CD4 cell count, HIV load, and genotypic measurements, were extracted from the electronic database system (Clinical Patient Data Management System; Solutions TM). The institutional review board at each participating center approved the protocol. We used previously defined criteria to assess immunologic and virologic failure [24, 30]: immunologic failure was defined as a 25% reduction in the CD4 cell count, compared with the baseline value (i.e., the value at the time of ISR initiation), that persisted for at least 3 months while the patient received the ISR [24, 30]; and virologic failure was defined as a ⩾0.5-log10 increase in the HIV load, compared with the baseline value, that persisted for at least 3 months while the patient received the ISR [24, 30].

Genotype sensitivity score and mutation analysis. At baseline, the GenotypR Plus genotype test (California Specialty Lab) was used to calculate the genotype sensitivity score—that is, the total number of antiretroviral drugs in the patient's ISR to which the patient's HIV isolate demonstrated genotypic susceptibility—as has been previously defined [1, 31]. A value of 0 was assigned if there was genotype evidence of resistance to a particular drug, and a value of 1 was assigned if there was no genotypic evidence of resistance to that drug. Mutations were interpreted in accordance with current International AIDS Society–USA drug resistance testing guidelines for HIV-1 mutation analysis [32]. According to these guidelines, primary protease inhibitor (PI) resistance mutations were defined as mutations at protease positions 30, 46, 48, 50, 82, 84, and 90; secondary PI resistance mutations were defined as mutations at protease positions 10, 20, 24, 32, 33, 36, 47, 53, 54, 63, 71, 73, 77, and 88. Nucleoside reverse-transcriptase inhibitor (NRTI) resistance mutations were defined as mutations at reverse-transcriptase positions 41, 44, 62, 65, 67, 69, 70, 74, 75,77, 115, 116, 118, 151, 184, 210, 215, and 219. Nonnucleoside reverse-transcriptase inhibitor (NNRTI) resistance mutations were defined as mutations at reverse-transcriptase positions 100, 103, 106, 108, 181, 188, 190, 225, 230, and 236.

Statistical analysis. Mean CD4 cell count and HIV load responses to ISR were plotted according to duration ISR therapy. Kaplan-Meier curves were used to determine the percentage of the patients in whom immunologic or virologic failure did not occur during the study period. For 27 patients who had at least 1 sequential genotype test performed during the follow-up period while receiving an ISR, the mean numbers of new NRTI, NNRTI, and PI mutations were calculated and recorded. Risk factors for the development of immunologic failure and virologic failure were determined using a Cox proportional hazard multivariate regression model. The risk factors analyzed included the following: age, <50 years; nadir CD4 cell count, <100 cells/mm3; genotype sensitivity score, 0; baseline HIV load, >100,000 copies/mL; baseline CD4 cell count, <200 cells/mm3; and use of lamivudine or emtricitabine in the ISR.

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Results

Baseline characteristics. The baseline demographic, clinical, and genotypic characteristics for the 47 treatment-experienced patients who enrolled in the study are outlined in table 1. Patients had a median duration of antiretroviral treatment before receipt of the ISR of 89 months (interquartile range [IQR], 59–113 months) and had previously received the following number of drugs within each class: median number of NRTIs, 4; median number of NNRTIs, 1; and median number of PIs, 3. The median nadir CD4 cell count was 105 cells/mm3, and the median baseline CD4 cell count was 277 cells/mm3. The median nadir HIV load was 63,115 copies/mL, and the median baseline load was 19,728 copies/mL. At baseline, the median age was 47 years. No patient was excluded from the study because he or she achieved a transient HIV load <400 copies/mL but otherwise met inclusion criteria.

Figure 1
Figure 1

Changes in mean CD4 cell counts (A) and mean HIV RNA levels (B) from baseline, according to duration of receipt of an incompletely suppressive regimen (ISR), for the 47 study patients.

Figure 2
Figure 2

Kaplan-Meier curves showing the percentage of patients who do not develop immunologic failure (A) or virologic failure (B) while receiving an incompletely suppressive regimen (ISR).

Table 1
Table 1

Demographic characteristics, baseline clinical data, and previous antiretroviral therapy for the 47 study patients.

Table 2 shows that the number of mutations within each antiretroviral class was high at baseline. The median number of NRTI mutations was 5; in all, 42 (90%) of 46 patients had ⩾2 thymidine analogue mutations (TAMs), and 35 (74.5%) of 47 had ⩾3 TAMs. of the patients with <2 TAMs, 1 patient had multinucleotide resistant mutation (Q151M), 1 had a K70R mutation, and 1 had prolonged viremia during a prior course of zidovudine treatment. All patients either had a M184 I/V mutation documented by genotype at study entry (n = 40) or suspected on the basis of a history of taking a lamivudine-containing regimen during active viral replication (n = 7). The median number of NNRTI and PI mutations was 1 and 6, respectively; 72.3% of patients had >2 primary PI mutations (table 2). The ISR contained a PI in 72.3% of patients and an NNRTI in 36.1%. The patient population had high-level, multidrug-resistant HIV infection. The median genotype sensitivity score was 0 (table 1); the ISR of all 13 patients with a genotype sensitivity score of 1 (28% of total) contained a susceptible agent.

Table 2
Table 2

Genotype characteristics, by antiretroviral drug class at baseline, incompletely suppressive regimen (ISR) received, and baseline genotype sensitivity score, for the 47 study patients.

CD4 cell count and HIV load responses and time to immunologic failure and virologic failure during receipt of an ISR. The median duration of follow-up for patients receiving an ISR was 27 months (IQR, 12.5–42 months). Figure 1 shows that there were no substantial changes in the mean CD4 cell count or HIV load in response to ISR, compared with baseline values, throughout the study period.

Figure 2 shows the Kaplan-Meier curve of time to immunologic and virologic failure for the entire population. Specifically, immunologic failure occurred in 34.7% of the population at 24 months and in 43.4% at 48 months. Figure 2B demonstrates that virologic failure occurred in 16% of the population at 24 months and in 21.7% at 48 months, indicating that not all patients who experienced immunologic failure also experienced virologic failure.

Risk factors for immunologic and virologic failure and clinical outcomes. Table 3 shows the results of the Cox proportional hazard multivariate analysis that was used to identify statistical associations between the following variables and immunologic or virologic failure: age, <50 years; nadir CD4 cell count, <100 cells/mm3; genotype sensitivity score, 0; baseline HIV load, >100,000 copies/mL; baseline CD4 cell count, <200 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 >100,000 copies/mL with immunologic failure. In addition, there was a decreased RR for inclusion of lamivudine in the ISR with immunologic—but not virologic—failure. However, none of these variables attained a statistically significant association with either immunologic or virologic failure.

Table 3
Table 3

Variables independently associated with development of immunologic or virologic failure for the entire study population.

During the study period, 4 patients (8.5% of study population) experienced a new AIDS-defining event (herpes simplex mucocutaneous ulcer for >1 month, HIV-associated dementia, 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%) developed a new major mutation directed against 1 of the 3 antiretroviral 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 mutations 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 developed a new primary PI mutation alone; the median number of new primary mutations per patient was 1 (IQR, 1–1.75). Moreover, no new primary PI mutations occurred among patients who were not receiving a PI agent, but a new PI mutation (polymorphism or secondary mutation) occurred in 2 (25%) of 8 of such patients.

Table 4
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.

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Discussion

Our study shows that many patients with highly drug-resistant HIV infection for whom an optimized regimen is unavailable can have sustained immunologic and virologic responses to an ISR. Our results are consistent with the findings of previous studies evaluating CD4 cell count and HIV load responses in treatment-experienced patients [9–12] by showing that some degree of immunologic and virologic response to ISR may be achieved by continuing an ISR. Moreover, our study had a longer follow-up period than other reports that have investigated the efficacy of antiretrovirals in treatment-experienced patients [7, 20–23]. Thus, our study extends the findings of these reports [7, 20–23] by showing that favorable CD4 cell count and HIV load responses to an ISR can be durable.

The findings of sustained immunologic and virologic responses in our study remain relevant today. The recent availability of new agents for antiretroviral-experienced patients has not removed a therapeutic niche for ISR for certain patients who remain viremic despite receipt of newly licensed agents. In particular, some patients with highly drug-resistant HIV infection who are treated with an optimized background regimen in combination with a newly available agent (e.g., newly licensed PIs or inhibitors of CCR5 coreceptors or integrase) are unable to achieve complete virologic suppression. In fact, drug-resistance mutations, which have already been witnessed for the newer PI agents, and inhibitors to HIV entry, integrase, and maturation [17–19, 33, 34] may compromise the ability of an optimized regimen to maintain durable virologic suppression in patients with highly drug-resistant HIV infection. Thus, despite the availability of new agents today, some patients with highly drug-resistant HIV infection may continue to have no viable treatment option other than to continue to receive an ISR for a prolonged period of time, to maintain increased CD4 cell count responses [6, 35] and HIV load reductions [7, 36].

We found that new NRTI and PI drug-resistance mutations occurred during our follow-up period in a considerable proportion of patients who continued to receive an ISR. Our observation is consistent with 2 previous studies that found an accumulation of new drug-resistance mutations in 75% [20] and 82% [23] of patients who continued to receive on a salvage regimen. A plateau or ceiling effect that may be attributable to a large number of mutations [20] or to a certain pattern of mutations present at baseline [23] has been hypothesized to explain why new mutations did not develop in all patients in these studies. In contrast to these studies, other reports have not noted new drug-resistance mutations in patients with a large number of baseline mutations who continued to receive a salvage regimen [7, 22, 37]. Owing to the different findings among studies, prospective trials are necessary to determine which baseline variables may contribute to new mutations after the initiation of an ISR [20, 23].

We were unable to identify any variable associated with immunologic or virologic failure. It is possible that the higher RRs for immunologic and virologic failure with a baseline HIV load >100,000 copies/mL or a nadir CD4 cell count <100 cells/mm3 may have represented significant associations, but our sample size was not large enough to detect one. Likewise, it is also possible that there was a significant association between lamivudine use and immunologic or virologic failure, as indicated by the lower RR for inclusion of lamivudine in the ISR. In contrast, a possible hypothesis to explain an absence of an association would be a diminished virologic benefit due to M184I/V resensitization to zidovudine in the patients in our population with at least 2 TAMs [38, 39]. Nonetheless, attempts to compare our results with the results of prior studies that have evaluated the efficacy of use of lamivudine in drug-experienced patients are hampered by differences in design across studies, which have assessed lamivudine as part of an optimized new regimen, a simplified regimen, monotherapy [24, 26–28], or an entire ISR (present study).

Several limitations of our study design deserve mention. A multicenter study could have enrolled larger numbers of patients to further evaluate the potential role of measurement of phenotype and genotype in selecting an ISR, risk factors for immunologic and virologic failure, and the rate of immunologic failure after 20 months; could assess the role of more recently approved drugs that are currently used in ISRs; and could determine which mutation-guided agents could protect against immunologic or virologic failure. Such a study could also investigate whether use of a particular class of agent (PI or NNRTI) may be a risk factor for development of new mutations, determine the rate of development of new mutations, and assess the role of adherence to treatment. Finally, a prospective study that included the measurement of replicative capacity could provide insight into the impact of different agents on viral fitness and could also investigate potential associations between lamivudine use with immunologic or virologic failure.

Our study supports the usefulness of continuing a partially suppressive regimen in patients with high-level drug-resistant HIV infection who have no viable alternatives. Our findings regarding sustained responses to ISR remain relevant today, because some patients may not achieve complete virologic suppression, despite receipt of newer agents in combination with an optimized background regimen, and these patients have no option other than to continue to receive an ISR for an extended period [1–5]. Our finding that continuation of an ISR in the face of ongoing viral evolution may lead to the development of new drug-resistance mutations supports a potential role for a simplified, PI-sparing ISR to prevent additional mutations to the protease class [24]. Thus, additional studies of ISR in patients infected with highly drug-resistant HIV are indicated to identify which optimal mutation-guided agents to include, risk factors for immunologic and virologic failure, and agents that will minimize the risk for developing new mutations.

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acknowledgments

Potential conflicts of interest. All authors: no conflicts.

  • Received May 1, 2007.
  • Accepted June 13, 2007.
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  1. Clin Infect Dis. (2007) 45 (8): 1085-1092. doi: 10.1086/521937
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