More than 5 million HIV-1-infected persons are currently receiving antiretroviral therapy (ART) globally (http://www.globalhealthfacts.org/data/topic/map.aspx?ind=10), resulting in dramatic reductions of HIV-1-related morbidity and mortality. The WHO recommends a simplified public health approach to ART prescription to reach HIV-1-infected persons who live in resource-limited settings (RLSs) (http://whqlibdoc.who.int). First-line ART is suggested with a nonnucleoside reverse transcriptase inhibitor (NNRTI) and two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), representing potent, safe and relatively inexpensive regimens. Virologic suppression rates on first-line ART commonly exceed 80% at 1 year on treatment among patients who are retained in care . In the event of first-line ART failure, second-line ART is available in many RLSs, which consists of a boosted protease inhibitor-containing regimen in combination with two NRTIs. Second-line ART also provides high rates of plasma HIV-1 RNA suppression at 1 year, with approximately 75% of patients achieving levels less than 400 copies/ml if they remain in care .
Despite the therapeutic successes of ART, considerable challenges remain. Monitoring of plasma HIV-1 RNA levels is not available in most RLS, and as a result, first-line ART failure is often identified by either immunological or clinical changes that may occur long after loss of virologic suppression. The delay in identifying ART failure has been shown to lead to the accumulation of complex resistance profiles that impact susceptibility to NRTIs and their future use [2–6]. It is unknown to what extent the inclusion of NRTI in second-line ART regimens contributes to antiretroviral activity given these observations. In the worst-case scenario, NRTIs may only expose patients to the increased risk of drug-related toxicities and add cost to second-line ART.
Previous studies of boosted protease inhibitor monotherapy in treatment-naive HIV-1-infected persons have suggested that most adherent patients can achieve significant virologic suppression, albeit less robust than that achieved with three-drug, multiclass drug combinations [7,8]. Interestingly, despite observations of low-level viremia among boosted protease inhibitor monotherapy recipients, studies to date have rarely identified the evolution of drug resistance mutations in the HIV protease gene . In RLSs with limited availability of alternative antiretroviral medications and extensive NRTI resistance following first-line virological failure, boosted protease inhibitor monotherapy could represent a viable option for second-line ART. The A5230 study of the AIDS Clinical Trial Group (ACTG) was designed to evaluate the activity and tolerability of second-line ART with lopinavir/ritonavir (LPV/r) monotherapy in a pilot study among persons experiencing virologic failure on a first-line regimen containing an NNRTI and two NRTIs. The study has a 24-week primary endpoint with continued long-term follow-up to 2 years; here we present the primary analysis results.
ACTG A5230 is an open-label, multicenter pilot study of LPV/r monotherapy in individuals failing a first-line regimen containing an NNRTI and two NRTIs, (NCT00357552). The study was conducted at five Clinical Research Sites, including three sites in Africa (Lilongwe, Malawi; Moshi, Tanzania; and Johannesburg, South Africa) and two sites in Asia (Chiang Mai, Thailand; and Chennai, India). The primary objective of the study was to demonstrate that LPV/r monotherapy provides at least a 65% virologic response rate in this patient population, defined as achieving and maintaining HIV-1 RNA levels less than 400 copies/ml for at least 24 weeks while on LPV/r monotherapy.
Eligible individuals had documented HIV-1 infection with two methods of antibody and/or antigen or nucleic acid detection, and were 18 years or older. They must have received a first-line regimen containing an NNRTI and two NRTIs for at least 6 months continuously, and have a plasma HIV RNA-1 level between 1000 and 200 000 copies/ml within 30 days of study entry. Eligible individuals were also required to have the following laboratory values: hemoglobin more than 8 mg/dl, platelets more than 50 000/μl, estimated creatinine clearance more than 60 ml/min, aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase less than three times the upper limit of normal, and total bilirubin less than 2.5 times the upper limit of normal. Pregnant or breastfeeding women and persons with prior protease inhibitor use, a serious medical condition within the previous 14 days, active substance abuse or evidence of chronic hepatitis B infection as documented by a positive hepatitis B surface antigen result were excluded. All individuals provided written informed consent.
For the first 24 weeks following LPV/r treatment initiation, individuals returned at weeks 2 and 4, and then every 4 weeks until week 24. At every study visit, a clinical assessment, list of concomitant medications, adherence interview using the ACTG Adherence Questionnaire  and pill count were performed. Serum chemistries, liver enzymes and hematology values were measured at weeks 4, 8, 12 and 24. Fasting lipid panels were done at study entry, and weeks 12 and 24. Plasma HIV-1 RNA levels were measured at study entry, and weeks 12, 16, 20 and 24. CD4+ cell counts were measured at study entry, and weeks 16 and 24. All laboratories participated in international quality assurance testing. With the exception of samples drawn at week 2 and 4, quantitation of HIV-1 RNA levels in A5230 was performed onsite in real time using a HIV-1 RNA assay approved by US Food and Drug Administration; week 2 and 4 samples were tested at the time of the week 12 sample. In a posthoc analysis, all week 24 samples with plasma HIV RNA-1 less than 400 copies/ml underwent further evaluation with the Abbott m2000rt RealTime assay (Abbott Laboratories, Abbott Park, Illinois USA; lower limit of detection 40 copies/ml) in one of three designated laboratories. Samples for genotypic resistance testing were collected on all individuals at the screening visit. Resistance testing was performed in-batch at two regional laboratories using ViroSeq (Celera Diagnostics, California, USA) as per manufacturer's instructions. Briefly, a 1.7 kb amplicon was generated by a reverse transcriptase-initiated PCR encompassing the entire protease and partial reverse transcriptase. Sequencing was performed with an ABI Prism 3100-Avant Genetic Analyzer (Applied Biosystems, Pleasanton, California, USA). HIV-1 subtype and drug resistance were determined from protease transcriptase and reverse transcriptase sequences and analyzed using the Stanford Algorithm Database [11,12].
All individuals received fixed dose combination (FDC) LPV/r 400/100 mg twice daily. If patients developed virologic failure, FDC emtricitabine 200 mg/tenofovir 300 mg (FTC/TDF) daily was added to LPV/r. Concomitant treatment with rifampin and other medications listed in the LPV/r package insert was prohibited.
The primary endpoint was remaining on LPV/r monotherapy without virologic failure at week 24. Virologic failure was defined as failure to suppress plasma HIV-1 RNA to less than 400 copies/ml by week 24 or confirmed rebound of plasma HIV-1 RNA levels to more than 400 copies/ml after confirmed suppression to less than 400 copies/ml. With some exceptions per protocol, discontinuation of LPV/r monotherapy was considered as a primary endpoint; exceptions included discontinuation for rifampin-based tuberculosis treatment, addition of antiretroviral drugs due to pregnancy and death with HIV-1 RNA levels less than 400 copies/ml.
The target sample size of 120 individuals was chosen to provide at least 90% power to show that LPV/r monotherapy could provide at least a 65% success rate over 24 weeks. This assumed that the true success rate of the strategy in this population is 76%, and used a one-sided type I error rate of 5%.
Baseline characteristics of the study population were compared across sites using nonparametric k-sample tests. The proportion of patients remaining on LPV/r monotherapy without virologic failure at week 24 was estimated with an exact 95% confidence interval. The proportion of patients with plasma HIV-1 RNA levels less than 400 copies/ml over time was estimated using intent-to-treat methods with missing/off treatment evaluation ignored (M = I) and considered as failure (≥400 copies/ml) (M = F); as treated analyses were also performed. Exact logistic regression was used to assess factors associated with the probability of failure; prior use of efavirenz (EFV) vs. nevirapine (NVP), prior therapy duration (>3 years, 1–3 years and <1 year), sex, baseline CD4+ cell count (<200 vs. >200 cells/μl), baseline plasma HIV-1 RNA levels (<10 000 vs. >10 000 copies/ml) and NRTI resistance (defined as K65R or thymidine analogue mutations vs. no NRTI resistance). In unplanned posthoc analyses, baseline HIV-1 RNA levels and rates of failure are described. All analyses were restricted to data from study entry to the scheduled week 24 visit. In order to provide information on the consequences of LPV/r monotherapy failure, the HIV-1 RNA and CD4+ cell count responses and resistance findings through week 48 are included from patients reaching a primary failure endpoint.
One hundred and twenty-three patients entered the study; their baseline characteristics are described in Table 1. The majority of them were women. The most common first-line ART regimen was NVP-containing, lamivudine (3TC)-containing and stavudine (d4T)-containing regimens (n = 63, 51%), and the majority of patients had received ART for more than 3 years (n = 70, 57%). The median plasma HIV-1 RNA level was 4.34 log10 copies/ml and 21 patients (17%) had levels more than 100 000 copies/ml. The median CD4+ cell count at study entry was 164 cells/μl and 70 patients (57%) had counts less than 200 cells/μl. Screening plasma HIV-1 RNA levels, the proportion of patients with baseline CD4+ cell counts below 100 cells/μl and the proportion of patients meeting WHO CD4+ cell count criteria for regimen failure  were found to differ by site (P = 0.016, P < 0.001, P = 0.002, P < 0.001, respectively), with patients from the South African site having significantly lower values for each parameter.
Baseline resistance and subtyping
From the 114 screening samples that were successfully sequenced, nearly all patients had mutations associated with drug resistance. Most patients were found to have mutations associated with reduced susceptibility to 3TC (n = 108; 95%), EFV (n = 112; 98%) and NVP (n = 112; 98%). Based on genotyping of the protease transcriptase and partial reverse transcriptase, HIV-1 subtype C was found to be the most prevalent (66%), followed by AE (19%), A1 (7%) and D (6%).
Of 123 patients who entered the study, 122 completed 24 weeks of study follow-up; one patient died from a myocardial infarction deemed unrelated to treatment with a plasma HIV-1 RNA level less than 400 copies/ml at week 20. All patients remained on study treatment (LPV/r monotherapy or LPV/r with FTC/TDF) throughout the 24-week primary endpoint.
At week 24, 107 (87%) patients remained on LPV/r monotherapy without virologic failure (95% confidence interval 80–92). From week 16, more than 80% of patients had plasma HIV-1 RNA levels less than 400 copies/ml regardless of how missing data and premature treatment discontinuations were analyzed (Fig. 1). Of note, 95 of 102 patients (93%) entering with baseline plasma HIV-1 RNA levels less than 100 000 copies/ml had achieved HIV-1 RNA less than 400 copies/ml by week 16 compared with 19 of 21 (90%) with baseline levels more than 100 000 copies/ml. One hundred and two patients had plasma HIV-1 RNA levels less than 400 copies/ml at week 24. Among these 102 patients (panel within Fig. 1), 62 (61%) had plasma HIV-1 RNA less than 40 copies/ml, 30 (29%) had levels 40–200 copies/ml, seven (7%) had levels 201–400 copies/ml and three (3%) had levels more than 400 copies/ml (respectively, 413, 489 and 1712 copies/ml).
Fifteen patients met the criteria for virologic failure at week 24, and an additional patient had FTC/TDF added without virologic failure (total failures 16, 13%) (Fig. 2). Failure occurred in six of 21 patients (29%) entering with baseline plasma HIV-1 RNA levels more than 100 000 copies/ml; in contrast, of the 102 patients with baseline plasma HIV-1 RNA levels less than 100 000 copies/ml, 10 (10%) met virologic failure criteria. Among the 15 patients with virologic failure, protease transcriptase and reverse transcriptase sequences were obtained from 11 (73%); one individual had insufficient sample available and three samples could not be sequenced [HIV-1 RNA level <1000 copies/ml (two patients) and 1330 copies/ml (one patient)]. Protease transcriptase mutations not observed at study entry were identified in two patients; V82F in one and L33F, M46I, I54V, V82A and L90M in the second (Table 2). With regard to NRTI-associated mutations at the time of virologic failure, eight patients had between one and six mutations that were no longer detectable compared with mutations detected at screening. Five patients gained one NRTI-associated mutation from study entry to virologic failure. From study entry to virologic failure, no NNRTI-associated mutations were gained by any of the patients and in six patients NNRTI mutations were no longer detectable.
Predictors of virologic failure
In unadjusted and adjusted analyses, no associations between the potential predictors and virologic failure were apparent (P > 0.10).
By study week 48, 14 (88%) of the 16 primary endpoint failures intensified their treatment with FTC/TDF and 11 (79%) of 14 suppressed to less than 400 copies/ml following intensification (Fig. 2). Among the three patients who failed to suppress, one (33%) had newly emergent protease inhibitor-associated mutations at the time of virologic failure. Of the patients who suppressed to less than 400 copies/ml on treatment intensification, all were suppressed at study week 48. Table 2 lists the resistance profiles for patients at screening and at virologic failure, categorized by receipt of treatment intensification and virologic response. Among the 11 patients who suppressed HIV-1 RNA to less than 400 copies/ml, seven had at least one major NRTI-associated resistance mutation that could no longer be detected by population-based sequencing. The two patients who did not suppress HIV-1 RNA levels to less than 400 copies/ml either maintained the same number of NRTI-associated resistance mutations or gained a new mutation.
CD4+ cell count responses
CD4+ cell counts increased from a median (Q1–Q3) of 164 (82–268) cells/μl at study entry to a median of 268 (169–404) cells/μl at week 24. Among patients remaining on LPV/r monotherapy without primary endpoint failure at week 24, the median CD4+ cell count increase over 24 weeks was 102 (46–157) cells/μl compared with 111 (35–172) cells/μl for the primary endpoint failures.
Adherence levels were generally high throughout the 24 weeks; by self-report, 79–90% of patients responded that they had never missed a dose of study medication at each adherence assessment. Hypothesis-testing statistical analyses were not performed, but there appeared to be no differences in reported adherence between patients who were virologic successes compared with those who were failures.
Safety and tolerability
Thirty-one patients (25%) experienced grade 3 or 4 adverse events during LPV/r monotherapy (Table 3). The most common events included lipid elevations (one patient with grade 3 fasting triglycerides, six with grade 4 fasting triglycerides, five with grade 3 fasting low-density lipoprotein cholesterol and five with grade 3 fasting total cholesterol), elevations in fasting blood sugar (two patients with grade 3 and four with grade 4) and abnormalities in serum phosphorus (five patients with grade 3 hypophosphatemia).
This pilot study, conducted at five geographic sites with multiple HIV-1 subtypes represented, demonstrates promising antiretroviral activity of LPV/r monotherapy as second-line ART in NNRTI-experienced HIV-infected persons. Over 24 weeks, 87% of patients remained on LPV/r monotherapy with plasma HIV-1 RNA levels suppressed to less than 400 copies/ml with the lower limit on the estimated efficacy of the regimen of 80%, exceeding our target threshold of 65%. Among patients who developed virologic failure, treatment intensification with FDC FTC/TDF resulted in suppression to less than 400 copies/ml over 48 weeks for the majority of them.
As the number of HIV-1-infected persons on first-line ART grows, inevitably some will fail and need second-line ART. Currently, the numbers of patients switching to second-line regimens are relatively low, estimated at 3–5% [14–16], although it is likely that 15–25% of HIV-infected persons on first-line ART for at least 12 months have detectable plasma HIV-1 RNA . When plasma HIV-1 RNA monitoring is available, it does lead to earlier switches to second-line ART , and better outcomes have been associated with RNA less than 1000 copies/ml at the time of switching . Unfortunately, in many RLSs, RNA measurement is not available and first-line ART failure is recognized late, with the consequence of increasing patient numbers with extensive NRTI and NNRTI resistance mutations.
Other studies of second-line ART in RLS have demonstrated similar rates of virologic suppression with use of LPV/r–NRTI [17–19]. One study examined outcomes in 328 patients receiving LPV/r, zidovudine and didanosine as second-line ART; plasma HIV-1 RNA levels were available for 262 patients and 203 (77%) had levels less than 400 copies/ml after 1 year, comparable to our results with LPV/r monotherapy . Another study of second-line ART in 141 South African patients included the use of LPV/r and genotypic resistance testing to guide the choice of the two NRTIs . Baseline characteristics of the South African study population were similar to that of ACTG A5230 patients with a median plasma HIV-1 RNA of 17 000 copies/ml and 17% with RNA more than 100 000 copies/ml, although NRTI and NNRTI resistance was not as extensive as observed in our population. Seventy-seven percent of these patients suppressed to less than 400 copies/ml and 65% to less than 50 copies/ml at week 24, similar to the 87% of patients with less than 400 copies/ml and 50% (62/123) with less than 40 copies/ml observed in ACTG 5230. A third study of second-line ART with LPV/r, zidovudine, lamivudine and TDF among 109 persons in Malawi found that 85% of those surviving at 1 year had plasma HIV-1 RNA levels less than 400 copies/ml .
Previous trials of LPV/r monotherapy have observed findings of low-level viremia in first-line regimens, and randomized trials have demonstrated such viremia is significantly greater with monotherapy compared to three-drug LPV/r-containing regimens [7,8]. When week 24 samples for patients remaining on LPV/r monotherapy with plasma HIV-1 RNA levels less than 400 copies/ml in A5230 were re-tested using an ultrasensitive assay, low-level viremia was detected in 39% with the majority of samples measured in the 40–200 copies/ml range. The significance of low-level viremia is uncertain, with other trials of LPV/r maintenance monotherapy suggesting that it may remain stable for prolonged periods [20,21]. Numerous studies have demonstrated that resistance mutations in the protease gene are infrequent in persons receiving boosted protease inhibitors , even as monotherapy, despite this low-level viremia [9,21]. Similar observations were made in ACTG A5230 – only 7% (2/16) patients virologically failing LPV/r monotherapy had protease mutations that were not observed at study entry.
A recent Thai study randomized patients failing first-line ART to either LPV/r monotherapy or LPV/r, FTC and TDF, and was conducted simultaneously with ACTG A5230 . They observed that the proportion of patients with viremia at levels 50–400 cells/ml after 48 weeks was significantly higher in the monotherapy arm (14 vs. 3%), leading them to conclude that three-drug second-line regimens were superior. A second randomized trial of LPV/r maintenance monotherapy vs. combination therapy (SARA trial) was conducted in Uganda and Zimbabwe among 192 patients who had received 24 weeks of second-line combination therapy including LPV/r . Plasma HIV-1 RNA was not monitored in real-time, but testing of archived specimens revealed that the combination therapy group had greater virologic suppression at week 24 (77 vs. 60%, <50 copies/ml). Genotypic resistance testing on 10 monotherapy patients with plasma HIV-1 RNA levels more than 1000 copies/ml revealed that a minority of patients had new protease mutations at the time of failure. Treatment intensification was not included in the SARA trial design, and the availability of real-time plasma HIV-1 RNA monitoring and intensification represent an important distinguishing feature of ACTG A5230.
The short-term virologic responses to FTC/TDF intensification in ACTG A5230 patients are encouraging, and similar responses were observed in the Thai trial in which eight of 17 patients in the LPV/r monotherapy arm suppressed to less than 50 copies/ml following intensification with FTC/TDF  and in trials of LPV/r monotherapy when NRTIs were added in patients with low-level viremia [21,22]. The strategy of LPV/r monotherapy followed by treatment intensification in the event of virologic failure may be critically important for future studies of LPV/r monotherapy. However, this strategy does impose the need for plasma HIV-1 RNA monitoring and associated costs that must be balanced against the high costs and potential toxicities of second-line regimens which empirically include NRTIs . An intriguing association was observed between reversion of NRTI resistance mutations detectable by population sequencing at virologic failure and response to FTC/TDF intensification in ACTG A5230, perhaps suggesting that some degree of re-sensitization may occur, although longer periods of observation are needed to assess the durability of responses and the potential impact of minor variants on longer term outcomes. The continued follow-up of all patients over 2 years on ACTG A5230 will provide more information on the durability of the strategy of LPV/r monotherapy with intensification with FTC/TDF.
This study does have a number of limitations. It is a pilot, open-label uncontrolled study and the results must be cautiously interpreted. A larger randomized trial comparing second-line ART with LPV/r monotherapy followed by FTC/TDF intensification for inadequate responses vs. three-drug LPV/r-containing ART is warranted. Further, the more intensive monitoring and support provided in a clinical trial may limit generalizing to responses in clinical cohorts. Finally, at present, we are only able to report results through the primary endpoint follow-up to week 24; follow-up in ACTG A5230 is ongoing and will continue until each patient has reached 104 weeks (expected in April 2012).
In summary, persons failing first-line ART with NNRTI-containing regimens have extensive NRTI and NNRTI resistance mutations, which may carry important implications for second-line ART choices. These pilot results suggest promising early responses to the strategy of second-line LPV/r monotherapy, coupled with further virologic suppression following intensification with FTC/TDF among persons with virologic failure.
The authors wish to thank all ACTG A5230 study patients for their participation. In addition, the authors thank the Clinical Research Site members and their supporting grants at the five sites who conducted ACTG A5230 (Drs Agnes Moses and Albert Mwafongo, UNC Project Lilongwe, U01AI069518; Drs Venance Maro and John Shao, KCMC, U01069484; Professor Thira Sirisanthana and Ms Patchanee Samutarlai, Chiang Mai University; Ms Petronilla Borain and Vuyokazi Jezile, University of Witswatersrand, U01AI38858; Ms Jabin Sharma and Dr Poongulali, YRGCARE, U01AI069432) and additional members of the ACTG A5230 Protocol Team (Heather Vezina, Amy Kambrink, Bernadette Jarocki, Vicki Bailey, A.K. Shrikrishnan and Eric Lawrence).
The project described was funded by award U01AI068636 from the National Institute for Allergy and Infectious Diseases, and was further supported by the National Institute of Mental Health and the National Institute of Dental and Craniofacial Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. J.A.B. is supported by NIH awards U01 AI069484, P30 AI64518, D43 TW006732, D43 CA153722 and HRSA award T84HA21123. M.R.N. is an employee of Abbott.
Funding support received from the National Institute for Allergy and Infectious Diseases of the United States National Institutes of Health, and Abbott. Drug supplies were provided by Abbott and Gilead Sciences Inc.
Conflicts of interest
There are no conflicts of interest.
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Keywords:© 2012 Lippincott Williams & Wilkins, Inc.
lopinavir/ritonavir monotherapy; resource-limited settings; second-line antiretroviral therapy