Use of lopinavir/ritonavir in HIV-infected patients failing a first-line protease-inhibitor-containing HAART

Marco Bongiovanni1,*, Elisabetta Chiesa1, Antonio Di Biagio2, Paola Meraviglia3, Amedeo Capetti4, Federica Tordato1, Paola Cicconi1, Patrizia Biasi1, Teresa Bini1 and Antonella d'Arminio Monforte1

1 Institute of Infectious and Tropical Diseases, Ospedale Luigi Sacco, University of Milan, Via G.B. Grassi 74, 20157 Milano, Italy; 2 Institute of Infectious Diseases, University of Genoa, Genoa, Italy; 3 Second Division of Infectious Diseases, Ospedale Luigi Sacco, Milan, Italy; 4 First Division of Infectious Diseases, Ospedale Luigi Sacco, Milan, Italy


* Corresponding author. Tel: +39-023-9042677; Fax: +39-023-560805; Email: marco.bongiovanni{at}unimi.it

Received 20 October 2004; returned 27 October 2004; revised 9 February 2005; accepted 7 March 2005


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Conclusions
 References
 
Objectives: The long-term virological efficacy of lopinavir/ritonavir-containing highly active antiretroviral therapy (HAART) in HIV-infected patients failing a first-line protease inhibitor (PI)-based regimen is still unclear.

Methods: An observational study was carried out from December 2000–December 2002 on 111 consecutive patients starting lopinavir/ritonavir. The primary end-point was virological success (HIV RNA <50 copies/mL in two consecutive determinations). CD4 outcome, lipid levels and adverse events were recorded. The Kaplan–Meier method and log-rank test were used to estimate the time-dependent probability of reaching the end-point using intention-to-treat and on-treatment approaches.

Results: Ninety-six patients obtained virological success during follow-up; Kaplan–Meier analysis showed that the time-dependent probability of obtaining this end-point was 78.4% at month 12 and 85.8% at month 24. The median CD4+cell count increased by 118 cells/mm3 from baseline to month 12 and by 153 cells/mm3 to month 24. Thirty-one patients discontinued lopinavir/ritonavir: 16 because of drug-related toxicities, six for simplification, five because of virological failure, one patient was lost at follow-up and three died. An elevation in lipid parameters was observed, but only a minority of patients developed a grade 3 or higher hypertriglyceridaemia and/or hypercholesterolaemia. Among the 15 patients not reaching virological success, five had ≤5 mutations in the protease region known to reduce susceptibility to lopinavir/ritonavir (one discontinued lopinavir/ritonavir because of gastrointestinal intolerance), five had no mutations (two discontinued lopinavir/ritonavir because of gastrointestinal intolerance) and five showed ≥6 mutations (all discontinued lopinavir/ritonavir); however, of the patients who discontinued lopinavir/ritonavir none achieved HIV RNA <50 copies/mL on subsequent regimens.

Conclusions: Lopinavir/ritonavir was highly effective and well tolerated in HIV-infected patients failing a first-line PI-based HAART.

Keywords: HIV therapy , LPV/r , virological failure , genotype resistance


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Conclusions
 References
 
The introduction of potent antiretroviral agents into clinical practice has resulted in a marked improvement of survival in HIV-infected subjects, following the suppression of HIV replication and the consequent recovery of the immune functions.14 However, numerous patients discontinue antiretroviral treatment due to the development of drug-related side effects or virological failure, with persistent HIV replication.5 Therapeutic management of such patients is of particular concern to avoid the accumulation of drug mutations, which can reduce HIV susceptibility to the currently available antiretroviral agents. Lopinavir is a potent protease inhibitor (PI) co-formulated with a low dose of ritonavir (lopinavir/ritonavir), which inhibits the 3A4 isoenzyme of cytochrome P 450 leading to higher plasma lopinavir levels.6 The resulting mean trough concentrations of lopinavir are at least 75 times as high as the protein-binding corrected IC50 (concentration required to inhibit 50% of replication in vitro) for wild-type HIV.7 Its potency is due to these high in vivo plasma concentrations and the fact that it provides a high genetic barrier: this latter characteristic means that viruses with up to five mutations associated with lopinavir resistance remain susceptible to the drug, those with six or seven mutations are intermediately susceptible, and only those with more than eight mutations are considered resistant.8,9 Current guidelines suggest the use of lopinavir/ritonavir in both naive and heavily pre-treated patients.10,11 Despite numerous reports regarding the efficacy of lopinavir/ritonavir-containing regimens,1216 few data are available about long-term virological efficacy in HIV-infected patients failing a first-line PI-based regimen. This report describes the virological outcome in such HIV-infected patients.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Conclusions
 References
 
In our study, during December 2000–December 2002, we included 111 HIV-infected consecutive patients starting lopinavir/ritonavir-containing highly active antiretroviral therapy (HAART). The patients, from five Italian centres for Infectious Diseases, had failed a first-line PI-based HAART. All the patients had plasma HIV RNA viraemia >3 log10 copies/mL at the time of lopinavir/ritonavir initiation.

Their demographic characteristics, plasma HIV levels and CD4+ cell counts at baseline were recorded, as were data concerning metabolic parameters (total serum cholesterol, serum triglycerides and serum glucose, all obtained under fasting conditions) and their previous antiretroviral treatments. In accordance with our usual clinical practice, HIV RNA measurements were performed at baseline and then every 3 months using the branched chain DNA (b-DNA) technique (Chiron, Inc., detection limit 50 copies/mL). CD4+ cell counts were performed at the same time-points using the Elite flow cytometer (Coulter Corporation, Miami, FL, USA).

We defined virological success as the achievement of two consecutive HIV RNA measurements of <50 copies/mL during follow-up. Immunological outcome and serum lipid increase were also evaluated, as were the reasons for lopinavir/ritonavir discontinuation and drug-related side effects.

Statistical analysis

The changes in CD4+ cell counts and HIV RNA levels during follow-up were evaluated by t-test. The survival analyses were performed using both an intention-to-treat (ITT) approach and an on-treatment (OT) approach. In the analyses, the time to virological success was defined as the time needed to obtain two consecutive measurements of HIV RNA <50 copies/mL. The Kaplan–Meier method and log-rank test were used to estimate the time-dependent probability of reaching such end-points.

The SPSS 11.0 for Windows 98 statistical software package was used for all of the analyses.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Conclusions
 References
 
The study involved 111 HIV-infected patients (76.6% male), 47.7% of whom were in CDC stage C. The median age was 38 years (range 22–75). Fifty-two patients (46.8%) had a CD4+ cell count of <200 cells/mm3 at baseline. The median CD4+ count was 212 cells/mm3 (range 1–769), and the median HIV RNA plasma level was 4.36 log10 copies/mL (range 3.08–6.34). The median duration of the previous PI-based regimen was 603 days (range 65–1815). Previous HAART was discontinued because of virological failure by all the patients; in particular, 93 (83.8%) failed a PI plus two nucleoside reverse transcriptase inhibitors (NRTIs)-based HAART and 18 (16.2%) failed a PI plus an NRTI plus a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART before lopinavir/ritonavir initiation (Table 1).


View this table:
[in this window]
[in a new window]
 
Table 1. Combinations failed

 
Eighty-seven (78.4%) patients received lopinavir/ritonavir plus 2–3 NRTIs, 20 (18.0%) added an NRTI and an NNRTI and four added two NRTIs and a PI (3.6%) according to the genotypic resistance test performed at the time of virological failure (Table 2).


View this table:
[in this window]
[in a new window]
 
Table 2. Antiretroviral drugs included in the lopinavir/ritonavir-containing HAART

 
During a median follow-up of 996 days (range 562–1302), using an ITT approach, median HIV RNA levels progressively decreased, to <50 copies/mL starting from month 3 (baseline versus month 3: P=0.0001; baseline versus month 12: P=0.0001) throughout the observation. The percentage of patients with undetectable HIV RNA during follow-up is shown in Figure 1. By the OT approach the virological outcome was comparable.



View larger version (8K):
[in this window]
[in a new window]
 
Figure 1. Percentage of patients with undetectable HIV RNA ( copies/mL) during follow-up.

 
ITT analysis showed that 96 patients (86.5%) obtained virological success; the Kaplan–Meier estimate of the probability of such an end-point was 78.4% (95% CI: 70.8–86.0%) at month 12 and 85.8% (95% CI: 79.3–92.3%) at month 24. These results were also confirmed by OT analysis.

The median CD4+ cell count steadily increased during all the study visits. The median increase was 118 cells/mm3 ( ± 67) from baseline to month 12 and 153 cells/mm3 ( ± 30) to month 24. Among 94 patients still on study at month 24, 81 (86.2%) had a CD4+ cell count >200 cells/mm3 with 51 (54.3%) having a CD4+ cell count >350 cells/mm3. The remaining 13 patients had a median CD4 cell count of 136 cells/mm3 (range 49–199).

Thirty-one patients (27.9%) discontinued lopinavir/ritonavir after a median of 670 days (range 142–1066): 16 because of toxicity (eight hyperlipidaemia, seven gastrointestinal intolerance, one hepatic failure), six for HAART simplification, five because of virological failure, one patient was lost at follow-up and three patients died (two owing to Pneumocystis carinii pneumonia and one owing to peritonitis). Gastrointestinal intolerance (including nausea, diarrhoea, vomiting and abnormal stools) was the most common adverse event of mild/moderate intensity: 72 patients reported such an adverse event without discontinuing lopinavir/ritonavir. Other adverse events (including headache, asthenia, abdominal meteorism and abdominal discomfort) were reported less often. Four AIDS-defining events were recorded among our patients: three cases of P. carinii pneumonia (two of these patients died) and one case of oesophageal candidiasis.

At lopinavir/ritonavir initiation, elevations in serum triglycerides (>750 mg/dL) and total cholesterol (>300 mg/dL) classified as grade 3 or greater according to NCAP definition,17 were observed in one and two patients, respectively. At month 12, four patients (3.6%) had grade 3 triglyceride levels and five patients (4.5%) had grade 3 total cholesterol elevations; at month 24, three patients (3.2%) and two patients (2.1%), respectively, had grade 3 triglyceride and total cholesterol abnormalities. A significant increase was observed for mean values of triglycerides and total cholesterol from baseline to month 3 (+107 mg/dL and +28 mg/dL, respectively); afterwards, such parameters were stable throughout the study. Sixty-three patients (56.8%) had triglycerides <180 mg/dL at lopinavir/ritonavir initiation, compared with 26 (23.4%) at month 12 and with 13 (13.8%) at month 24; 77 patients (69.4%) had total cholesterol <190 mg/dL at lopinavir/ritonavir initiation compared with 47 (42.3%) at month 12 and with 30 (31.9%) at month 24. Fifty patients (45.0%) started a lipid-lowering drug during lopinavir/ritonavir treatment, 38 were prescribed fibrates (including fenofibrates or gemfibrozil) and 12 were prescribed statins (pravastatin). No patient had been treated for hyperlipidaemia before lopinavir/ritonavir initiation. At month 6, patients taking a lipid-lowering drug had mean triglycerides and cholesterol levels of 458 mg/dL (SD ± 244) and 234 mg/dL (SD ± 42), respectively. Lipid parameters showed a slight but not significant decrease during observation among these patients: at month 12, triglycerides and cholesterol levels were 408 mg/dL (SD ± 191) and 212 mg/dL (SD ± 47) and at month 24 were 382 mg/dL (SD ± 181) and 202 mg/dL (SD ± 32), respectively.

Among the 15 patients not reaching virological success, eight (53.3%) discontinued lopinavir/ritonavir: five for persistence of detectable serum levels of HIV RNA and three for gastrointestinal intolerance. Genotypic analysis of viral isolates of these patients performed during the observation are summarized in Table 3. All patients not reaching virological success but discontinuing lopinavir/ritonavir for reasons other than toxicity had at least six mutations in the protease region at positions known to reduce lopinavir/ritonavir susceptibility (L10I/F/R/V, K20M/R, L24I, V32I, L33F, M46I/L, I47V, I50V, F53L, I54V/L, L63P, A71V/T, G73S, V82A/F/T/S, I84V and L90M).18 Their antiretroviral regimen was modified according to the genotypic test, but none of them achieved HIV RNA <50 copies/mL after HAART modification. Only one patient discontinuing lopinavir/ritonavir for reasons other than virological failure and four continuing lopinavir/ritonavir without virological success developed mutations in the protease region, but all of them had less than five mutations (Table 3). However, patients discontinuing lopinavir/ritonavir without reaching virological success had a substantial benefit with regard to CD4+ cells, increasing from 197 cells/mm3 at baseline to 259 cells/mm3 at discontinuation (P < 0.01).


View this table:
[in this window]
[in a new window]
 
Table 3. Genotypic mutations in patients not reaching virological success

 

    Conclusions
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Conclusions
 References
 
In this observational study, the use of lopinavir/ritonavir in HIV-infected subjects failing a first-line PI-based HAART led to virological success (defined as at least two consecutive measurements of HIV RNA < 50 copies/mL) in most patients: ITT analysis revealed a 78.4% probability of success after 12 months of treatment and an 85.8% probability of success after 24 months of treatment. This finding in a clinical setting confirms the high potency of lopinavir/ritonavir already reported by other trials.1115 Among patients not achieving virological success, five had a genotypic test showing >5 mutations known to reduce HIV susceptibility to lopinavir/ritonavir. Four patients continued lopinavir/ritonavir-containing HAART despite the presence of ≤5 mutations in the protease region, according to published data.8,13 We also observed a progressive increase in CD4 cell counts, with a significant improvement in immunological condition. Also, patients not reaching virological success had a substantial improvement in their immunological condition; this finding can explain the maintenance of a failing regimen in such a population.

Among 31 patients discontinuing lopinavir/ritonavir, 16 developed drug-related toxicities, mainly gastro-intestinal and metabolic. Several patients reported gastro intolerance, but only seven discontinued lopinavir/ritonavir for this reason. More than two-thirds of patients developed triglyceride or cholesterol elevation during lopinavir/ritonavir-containing HAART; however, only a few of them experienced a grade 3 or greater metabolic toxicity, suggesting that this adverse event was of moderate grade. Fifty patients started a fibrate or a statin: the use of lipid-lowering drugs does not seem to be associated with a significant reduction of these abnormalities, as suggested by other published findings.19,20

The limitations of our study are mainly due to its observational nature, so that definitive conclusions cannot be drawn; however, at the moment controlled trials on long-term efficacy and tolerability of PI-containing salvage HAART are rarely performed.21 Nevertheless, our results confirm, in a clinical setting, that lopinavir/ritonavir is a valid option for the treatment of PI-experienced HIV-infected patients. Prospective studies are required better to assess the effectiveness and good tolerability of this compound in clinical practice.


    Acknowledgements
 
This work was supported by a grant from the Italian Institute of Health AIDS Project (No. 50D.06).


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Conclusions
 References
 
1 . Palella, F. J., Delaney, K. M., Moorman, A. C. et al. (1998). Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. New England Journal of Medicine 338, 853–60.[Abstract/Free Full Text]

2 . Mocroft, A., Vella, S., Benfield, T. L. et al. (1998). Changing patterns of mortality across Europe in patients infected with HIV-1. Lancet 352, 1725–33.[CrossRef][ISI][Medline]

3 . Hoggs, R. S., O'Shaughnessy, M. V., Gataric, N. et al. (1997). Decline in deaths from AIDS due to new antiretrovirals. Lancet 349, 1294.[CrossRef][Medline]

4 . Detels, R., Munoz, A., McFarlane, G. et al. (1998). Effectiveness of potent antiretroviral therapy on time to AIDS and death in men with known HIV infection duration. Journal of the American Medical Association 280, 1497–503.[Abstract/Free Full Text]

5 . d'Arminio Manforte, A., Cozzi Lepri, A., Rezza, G. et al. (2000). Insights into the reasons for discontinuation of the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naive patients. AIDS 14, 499–507.[CrossRef][ISI][Medline]

6 . Sham, H. L., Kempf, D. J., Molla, A. et al. (1998). ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrobial Agents and Chemotherapy 42, 3218–24.[Abstract/Free Full Text]

7 . Masquelier, B., Breilh, D., Neau, D. et al. (2002). Human immunodeficiency virus type 1 genotypic and pharmacokinetic determinants of the virological response to lopinavir-ritonavir-containing therapy in protease inhibitor-experienced patients. Antimicrobial Agents and Chemotherapy 46, 2926–32.[Abstract/Free Full Text]

8 . Isacson, J., Kempf, D. J., Calvez, V., et al. (2002). Quantitative estimate of the effect of individual baseline mutations in HIV protease on the virologic response to lopinavir/ritonavir therapy in heavily antiretroviral-experienced patients. In Ninth Conference on Retrovirus and Opportunistic Infections, Seattle, WA, USA, 2002, 559. Poster 559-T. Foundation for Retrovirology and Human Health, Alexandria, VA, USA.

9 . Tsuchiya, K., Matsuoka, S., Hachiya, A. et al. (2001). Accumulation of lopinavir resistance-associated mutations over 3 years follow-up of patients on highly active antiretroviral therapy: implication in salvage therapy. AIDS 15, 1183–4.[CrossRef][ISI][Medline]

10 . Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. 29 October 2004. Developed by the Panel on Clinical Practices for treatment of HIV Infection convened by the Department of Health and Human Services (DHHS). [Online.] http://www.AIDSinfo.nih.gov (9 November 2004, date last accessed).

11 . The EACS (2003). Euroguidelines Group European guidelines for the clinical management and treatment of HIV-infected adults in Europe. AIDS 17, Suppl. 2, S3–S26.[CrossRef][ISI]

12 . Hicks, C., Brun, S., King, M., et al. (2001) Kaletra (lopinavir/ritonavir) therapy in single protease inhibitor experienced patients: 144-week follow-up. In Eighth European Conference on Clinical Aspects and Treatment of HIV Infection, Athens, Greece, 2001. Poster 220. European AIDS Clinical Society.

13 . Benson, C. A., Deeks, S. G., Brun, S. et al. (2002). Safety and antiviral activity at 48 weeks of lopinavir/ritonavir plus nevirapine and 2 nucleoside reverse-transcriptase inhibitors in human immunodeficiency virus type 1-infected protease inhibitor-experienced patients. Journal of Infectious Diseases 185, 599–607.[CrossRef][ISI][Medline]

14 . Romano, L., Peduzzi, C., Venturi, G. et al. (2002). Treatment with lopinavir/ritonavir in heavily pretreated subjects failing multiple antiretroviral regimens in clinical practice. Journal of Acquired Immune Deficiency Syndromes 30, 533–5.[ISI][Medline]

15 . Walmsley, S., Bernstein, B., King, M. et al. (2002). Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. New England Journal of Medicine 346, 2039–46.[Abstract/Free Full Text]

16 . Bongiovanni, M., Bini, T., Chiesa, E. et al. (2004). Lopinavir/ritonavir vs indinavir/ritonavir in antiretroviral naive HIV-infected patients: immunovirological outcome and side effects. Antiviral Research 62, 53–6.[CrossRef][ISI][Medline]

17 . Anonymous. (1993). Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment. Journal of the American Medical Association 269, 3015–23.[CrossRef][ISI][Medline]

18 . D'Aquila, R. T., Schapiro, J. M., Brun-Vezinet, F. et al. (2002). Drug resistance mutations in HIV-1. Topics in HIV Medicine 10, 21–5.[Medline]

19 . Martinez, E., Domingo, P., Galindo, M. J. et al. (2004). Risk of metabolic abnormalities in patients infected with HIV receiving antiretroviral therapy that contains lopinavir-ritonavir. Clinical Infectious Diseases 38, 1017–23.[CrossRef][ISI][Medline]

20 . Henry, K., Melroe, H., Huebesch, J. et al. (1998). Atorvastatin and gemfibrozil for protease-inhibitor-related lipid abnormalities. Lancet 352, 1031–2.[CrossRef][ISI][Medline]

21 . Johnson, M., Dejesus, E., Grinsztejn, B. et al. (2004). Comparison of atazanvir (ATV) with ritonavir or saquinavir vs lopinavir/ritonavir in patients with multiple virologic failures: BMS AI424-045 96 week results, In Seventh International Congress on Drug Therapy in HIV Infection, Glasgow, UK, 2004, Poster late breaker 14.4.





This Article
Abstract
Full Text (PDF)
All Versions of this Article:
55/6/1003    most recent
dki113v1
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Bongiovanni, M.
Articles by d'Arminio Monforte, A.
PubMed
PubMed Citation
Articles by Bongiovanni, M.
Articles by d'Arminio Monforte, A.