Clinical Outcome of Lopinavir/Ritonavir (Kaletra) as HIV Second-line Treatment: A Retrospective Study at a Single Center Malaysian Tertiary Hospital

2.0 Recommendations and auditable outcomes

5.0 What to start

7.0 Managing virological failure

Drug switching and virologic-based endpoints in trials of antiretroviral drugs for HIV infection.

To describe outcomes in patients starting first-line antiretroviral regimens including lopinavir/ritonavir (LPV/r) in a routine clinic setting. Previously naïve patients starting LPV/r-containing antiretroviral therapy were included in the study. Virological failure was defined as the first of two viral loads >500 HIV-1 RNA copies/mL more than 6 months after starting LPV/r. Cumulative percentages experiencing virological failure were calculated using Kaplan-Meier methods. A total of 195 individuals had a median follow-up time of 1.7 years. At 48 weeks, 87.9, 77.4 and 71.6% of patients with pretreatment CD4 counts of <50, 50-200 and >200 cells/microL, respectively, remained on LPV/r. By 48, 72 and 96 weeks, 2.2, 3.0 and 5.0% of patients, respectively, had experienced virological failure, ignoring treatment changes but censoring follow-up at discontinuation of all antiretrovirals; these percentages became 24.0, 33.7 and 42.3% when LPV/r discontinuation was considered as virological failure. Censoring those who stopped LPV/r with a viral load <50 copies/mL and considering as virological failures those who stopped LPV/r with a viral load >50 copies/mL gave 12.1, 14.6 and 17.0% virological failure at 48, 72 and 96 weeks, respectively. Median CD4 count increases at 24, 48 and 72 weeks were 167, 230 and 253 cells/microL, respectively. Few patients experienced virological failure whilst on a LPV/r-based regimen, although it was not uncommon for patients in our clinic with higher baseline CD4 counts to discontinue LPV/r.

Objective To evaluate the virological and immune responses of Lopinavir/Ritonavir (LPV/r) based second-line regimen in elderly acquired immunodeficiency syndrome (AIDS) patients who failed first line regimens. Methods This was a retrospective cohort study. Elderly patients (≥50 years) who switched to LPV/r-based second-line antiretroviral therapy with human immuno-deficiency virus (HIV) RNA >1 000 copies/mL after more than 1 year of first-line treatment were recruited from Zhengzhou No.6 People Hospital from January 2010 to December 2011. The virological and immunological data during 60-month treatment were collected. Multivariate logistic regression was used to explore the risk factors associated with virological failure or immunological failure of 60-month second-line therapy. Results Totally 256 patients were enrolled with 109 male and 147 female. 89.5% were plasma donator. The median age at the time of switching to LPV/r based second-line regimen was 61 years old. Twelve out of the 256 cases were detected for genotypic drug resistance and ten of them were resistant to drugs. No resistance to protease inhibitor (PI) was found. After switching to LPV/r based second-line regimen, HIV viral suppression (HIV RNA≤400 copies/mL) rates at 12, 24, 36, 48, 60 months were 69.5%, 78.4%, 79.0%, 79.7%, and 83.2%, respectively. The CD4+ T cell counts were (313±135) /L at 12 months, (377±151) /L at 24 months, (396±155) /L at 36 months, (389±163) /L at 48 months and (412±147) /L at 60 months, which were all significantly higher than that at the initiation of therapy ([243±146] /L, t=19.092, 18.598, 12.843, 8.516 and 12.980, respectively; all P<0.05). After switching to LPV/r based second-line regimen for 60 months, 43 patients occurred virological failure and 48 patients occurred immunological failure. Multivariate logistic regression showed that poor adherence (OR=48.5, 95% CI: 15.9—98.4, P<0.01) and ART drug toxicity (OR=4.5, 95% CI: 2.6—11.3, P<0.01) were the main factors associated with virological failure at 60 months. Poor adherence (OR=15.1, 95% CI: 6.89—33.3, P<0.01), CD4≤100 /L at the time of switching therapy (OR=10.5, 95% CI: 5.1—21.7, P<0.01), concomitant medications (OR=3.6, 95% CI: 1.6—4.1, P<0.01) were main factors associated with immunological failure at 60 months. Conclusions Elderly patients (≥50 years) who failed first line regimen should switch to LPV/r contained regimen as early as possible. Adherence education should be strengthened, drug toxicity as well as complications of treatment should be managed in time and concomitant medications should be reduced. Key words: Acquired immunodeficiency syndrome; Antiretroviral therapy; Viral load; Immune response; ≥50 years old

Similar Efficacy of Lopinavir/Ritonavir-Containing Regimens Among Clades B and F HIV-1-Infected Individuals in Brazil

The combination of atazanavir (ATV) plus lopinavir/ritonavir (LPV/r) has been used in practice. However, clinical data supporting its use are limited. The objective of this study was to evaluate the efficacy and tolerability of regimens with ATV + LPV/r in protease inhibitor (PI)-susceptible and PI-resistant patients. A retrospective review of 2703 charts was performed to identify all patients who received ATV + LPV/r. From June 2003 to January 2005, 33 patients received ATV + LPV/r with nucleoside reverse transcriptase inhibitors (NRTIs) for 3 months or more. Virologic success (HIV-RNA < 400 copies per milliliter) was achieved in 30 patients (91%) in a median of 10 weeks (range, 2-68). Nineteen of the 23 patients (83%) who had ultrasensitive viral load (VL) assays were nondetectable. Among patients with 6 or more protease resistance (PR) mutations (PI-resistant), 11 of 14 (79%) achieved virologic success. Eleven of those received phenotypic testing (10 Virtual Phenotype, VircoLab, Baltimore, MD). Despite predicted phenotypic resistance to ATV (6 patients) and LPV/r (7 patients), virologic success was achieved in 4 of 6 (67%) and 4 of 7 (57%), respectively. The 3 PI-resistant patients who were virologic failures had extensive prior LPV/r use, 8-11 PR mutations, and predicted phenotypic resistance to LPV/r, but 2 of 3 had CD4 increases with ATV + LPV/r. Overall, 28 patients (85%) continue to tolerate ATV + LPV/r for a median of 32 weeks follow-up (range, 12-76). Combination ATV + LPV/r with NRTIs appears safe, tolerable, and efficacious in PI-resistant patients (>/=6 PR mutations) and predicted phenotypic resistance to ATV and LPV/r. Further studies of ATV + LPV/r in HIV-treatment are warranted.

Efficacy and safety of switching from lopinavir/ritonavir-based regimens to bictegravir/emtricitabine/tenofovir alafenamide in people living with HIV: A multicenter retrospective study

British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy.

To identify potential causes and clinical implications of transient increases in plasma viral load (hereafter, "blips"). M99-056 and M02-418 were prospective, randomized trials evaluating the safety and efficacy of lopinavir/ritonavir (LPV/r) capsules administered twice per day or once per day to subjects infected with human immunodeficiency virus-1 (HIV-1). Plasma viral load was measured every 4 weeks (from baseline through week 24, excluding week 12 and week 20 in M02-418), every 8 weeks (from week 24 through week 48), and every 12 weeks (from week 48 through week 96). Blips were defined by 1 plasma viral load measurement of between 50-1000 copies/mL, immediately preceded and immediately followed by a measurement of <50 copies/mL. A medication event monitoring system was used to record the date and time subjects administered a dose of LPV/r. Of 228 subject enrolled, event monitor data were available for 223 (98%) subjects (92 of whom received twice-daily LPV/r therapy, and 131 of whom received once-daily therapy). Viral load blips (median plasma viral load, 82 copies/mL [range, 51-858 copies/mL]) were identified in 60 (27%) of the subjects (21 in the LPV/r twice-daily group and 39 in the LPV/r once-daily group). Neither the baseline plasma viral load nor the CD4(+) T cell count were associated with blips. During the week prior to a blip, the mean number of days that the subject administered the prescribed number of doses was lower than the number during a matched period for the same subject during which a blip did not occur (5.55 vs. 6.22 days; P = .007). Blips were not associated with virologic failure or the development of drug resistance. Blips were associated with decreased adherence, but not with virologic failure or development of drug resistance in these studies of LPV/r. Clinicaltrials.gov identifier: NCT00043966 .

Human immunodeficiency virus (HIV)-infected children and adolescents who are failing antiretrovirals may have a better virologic response when drug exposures are increased, using higher protease inhibitor doses or ritonavir boosting. We studied the pharmacokinetics and safety of high-dose lopinavir-ritonavir (LPV/r) in treatment-experienced patients, using an LPV/r dose of 400/100 mg/m(2) orally every 12 h (p.o. q12h) (without nonnucleoside reverse transcriptase inhibitor [NNRTI]), or 480/120 mg/m(2) p.o. q12h (with NNRTI). We calculated the LPV inhibitory quotient (IQ), and when the IQ was <15, saquinavir (SQV) 750 mg/m(2) p.o. q12h was added to the regimen. We studied 26 HIV-infected patients. The median age was 15 years (range, 7 to 17), with 11.5 prior antiretroviral medications, 197 CD4 cells/ml, viral load of 75,577 copies/ml, and a 133-fold change in LPV resistance. By treatment week 2, 14 patients had a viral-load decrease of >0.75 log(10), with a median maximal decrease in viral load of -1.57 log(10) copies/ml at week 8. At week 2, 19 subjects showed a median LPV area under the concentration-time curve (AUC) of 157.2 (range, 62.8 to 305.5) microg x h/ml and median LPV trough concentration (C(trough)) of 10.8 (range, 4.1 to 25.3) microg/ml. In 16 subjects with SQV added, the SQV median AUC was 33.7 (range, 4.4 to 76.5) microg x h/ml and the median SQV C(trough) was 2.1 (range, 0.2 to 4.1) microg/ml. At week 24, 18 of 26 (69%) subjects remained in the study. Between weeks 24 and 48, one subject withdrew for nonadherence and nine withdrew for persistently high virus load. In antiretroviral-experienced children and adolescents with HIV, high doses of LPV/r with or without SQV offer safe options for salvage therapy, but the modest virologic response and the challenge of adherence to a regimen with a high pill burden may limit the usefulness of this approach.

To study the control of viral replication in human immunodeficiency virus (HIV)-infected children on different salvage therapies. A retrospective observational study in 120 HIV-infected children was conducted. The children were divided into 3 groups according to their salvage therapies: (1) children receiving first line highly active antiretroviral therapy (HAART); (2) protease inhibitor-experienced children receiving second line HAART; (3) protease inhibitor-experienced children receiving HAART including lopinavir-ritonavir (LPV/r). The outcome variables examined were time to achieve viral load (VL) < or =400 copies/mL, success in achieving VL < or =400 copies/mL and time to virologic failure (VL >400 copies/mL). VL (HIV-RNA copies/mL) was quantified with reverse transcription-polymerase chain reaction molecular assay. For each protocol, survival analyses were conducted to determine the probability of achieving VL < or =400 copies/mL and rebound of VL. VL < or =400 copies/mL was achieved by 52.4% of children receiving first line HAART, 48.3% receiving second line HAART and 71.5% receiving HAART including LPV/r. Children receiving HAART including LPV/r reached VL < or =400 copies/mL in a shorter time than children receiving second line HAART (P = 0.017), but quite similar to children receiving first line HAART. In terms of adjusted relative risk, children receiving HAART including LPV/r were 3.36 [95% confidence interval (95% CI), 1.59, 7.07] more likely to achieve VL < or =400 copies/mL than children receiving a different second line HAART. VL rebound occurred in 68.2% children receiving first line HAART, 73.4% receiving second line HAART and 32.4% receiving HAART including LPV/r. Children receiving HAART that includes LPV/r has less incidence of VL rebound (P=0.013) and 3.29 (95% CI 1.04, 10.3) times less risk to achieve a VL rebound than children receiving a different second line HAART. HAART that includes LPV/r is able to control HIV replication more efficiently than other classic salvage antiretroviral therapies.

To evaluate virologic response rates of lopinavir/ritonavir (LPV/r) monotherapy as second-line antiretroviral treatment (ART) among adults in resource-limited settings (RLSs). An open-label pilot study of LPV/r monotherapy in participants on first-line nonnucleoside reverse transcriptase inhibitor three-drug combination ART with plasma HIV-1 RNA 1000-200 000 copies/ml. Participants were recruited from five sites in Africa and Asia within the AIDS Clinical Trials Group (ACTG) network. All participants received LPV/r 400/100 mg twice daily. The primary endpoint was remaining on LPV/r monotherapy without virologic failure at week 24. Participants with virologic failure were offered addition of emtricitabine and tenofovir (FTC/TDF) to LPV/r. Mutations associated with drug resistance were encountered in nearly all individuals screened for the study. One hundred and twenty-three participants were enrolled, and 122 completed 24 weeks on study. A high proportion remained on LPV/r monotherapy without virologic failure at 24 weeks (87%). Archived samples with HIV-1 RNA levels less than 400 copies/ml at week 24 (n=102) underwent ultrasensitive assay. Of these individuals, 62 had levels less than 40 copies/ml and 30 had levels 40-200 copies/ml. Fifteen individuals experienced virologic failure, among whom 11 had resistance assessed and two had emergent protease inhibitor mutations. Thirteen individuals with virologic failure added FTC/TDF and one individual added FTC/TDF without virologic failure. At study week 48, 11 of 14 adding FTC/TDF had HIV-1 RNA levels less than 400 copies/ml. In this pilot study conducted in diverse RLS, LPV/r monotherapy as second-line ART demonstrated promising activity.

British HIV Association (BHIVA) guidelines for the treatment of HIV‐infected adults with antiretroviral therapy (2006)