Effectiveness

Kaletra is a powerful anti-HIV drug. Studies suggest that approximately 75 to 90% of people who start treatment with Kaletra plus nucleoside reverse transcriptase inhibitors (NRTIs) achieve a viral load below 400 copies/ml after one year, and 70% maintain viral loads below 50 copies/ml after four years.1 2 3 4

Some patients in the original study of Kaletra in treatment-naive patients have been taking the drug for over six years, with persistently undetectable viral loads.5 The strength of current evidence in favour of Kaletra has led experts in the United Kingdom and the United States to recommend Kaletra as a preferred first-line protease inhibitor .

Kaletra-based regimens appear to be more potent than single protease inhibitor-based regimens in people who have not previously taken HIV treatment. For example, head-to-head studies have shown that Kaletra is more potent than nelfinavir (Viracept) and atazanavir (Reyataz).

K aletra has also been compared to other ritonavir (Norvir)-boosted protease inhibitors. For example, the MaxCmin2 study found that Kaletra is superior to ritonavir-boosted saquinavir (Invirase), with fewer people taking Kaletra dropping out due to side-effects.6 In contrast, the KLEAN study found that Kaletra is of similar effectiveness to ritonavir-boosted fosamprenavir (Telzir).7

Studies conducted in people who have previously taken protease inhibitors also suggest that Kaletra has similar efficacy to other ritonavir-boosted protease inhibitors. One study found that Kaletra and ritonavir-boosted atazanavir had similar outcomes in terms of viral loads and CD4 cell counts, despite less favourable effects on blood lipids with Kaletra. 8

A comparative study of Kaletra and ritonavir-boosted fosamprenavir showed equivalence in terms of the proportion of people achieving undetectable viral loads, although Kaletra may be superior in terms of the magnitude of viral suppression.9

In ACTG 5142, patients received one of three regimens: efavirenz+ 2 NRTIs, Kaletra (LPV/r) + 2 NRTIs, or an NRTI-sparing combination of efavirenz and Kaletra. The NRTI options were 3TC or FTC combined with stavudine (d4T), TDF, or zidovudine (ZDV). At the start of the study, the median viral load was approximately 100,000 copies/ml and the median CD4 cell count was 182 cells/mm3, suggesting that the study population had relatively advanced HIV disease and was starting treatment later than current guidelines recommended.

By intent-to-treat analysis, 89% of the participants receiving efavirenz-based triple therapy had viral loads below 50 copies/ml after 96 weeks, as compared with 77% receiving Kaletra-based triple therapy.10

The researchers were unclear why fewer participants on Kaletra-based triple therapy achieved viral loads below 50 copies/ml at week 96, compared with those on efavirenz-based triple therapy, since they found that the time to treatment-limiting toxicity was similar for all arms, and the proportion of grade 3 or 4 clinical adverse events was similar in each arm, at around 20%.

There is encouraging evidence that Kaletra is an effective component of salvage therapy. For example, Kaletra and nevirapine (Viramune) plus NRTIs suppressed viral load below 400 copies/ml in 70% patients after 48 weeks.11 Similar effects were observed when Kaletra was combined with efavirenz (Sustiva), with 65% of patients having undetectable viral loads after 48 weeks.12

Studies have examined the effects of combining Kaletra with the protease inhibitors saquinavir, indinavir (Crixivan) and atazanavir, with results indicating that these combinations are safe and effective.13 14 15 16

Because of its long half-life and high genetic barrier to resistance, Kaletra has been investigated as an option for monotherapy in treatment-naive and -experienced patients. At least three studies have demonstrated that switching from Kaletra or efavirenz (Sustiva) plus two NRTIs to Kaletra monotherapy leads to comparable virologic outcomes to patients randomised to remain on triple therapy after up to 48 weeks, with similar rates of resistance and blood fat elevations.17 18 19 20 21 However, these trials have generally found inferior levels of viral suppression to trials of combination therapy including Kaletra. 22

MONARK, a prospective, open-label, randomized, 96-week trial comparing the safety and efficacy of lopinavir/ritonavir monotherapy with a standard lopinavir/ritonavir plus zidovudine and lamivudine regimen as an initial treatment regimen in treatment-naive HIV-infected patients with HIV-RNA levels less than 100,000 copies/ml. At the week 48 on-treatment analysis, 80% in the monotherapy group and 95% of those on triple therapy achieved a viral load less than 400 copies/ml (intent to treat analysis was 64 v 75% respectively). This indicates that monotherapy should not be considered as a preferred treatment option for use in antiretroviral-naive patients.23

Recent studies have shown that levels of lopinavir in the cerebrospinal fluid are low, but they are sufficient to inhibit HIV replication in patients who are adherent to Kaletra. 24 25 26

References

  1. Murphy RL et al. ABT-378 / ritonavir plus stavudine and lamivudine for the treatment of antiretroviral-naive adults with HIV-1 infection: 48-week results. AIDS 15: 1-9, 2001
  2. Walmsley S et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med 346: 2039-2046, 2002
  3. Lichterfeld M et al. Superior virological efficacy of ritonavir-boosted protease inhibitor regimens compared to single protease inhibitor therapy. Eur J Med Res 8: 56-60, 2003
  4. Hicks C et al. Long-term safety and durable antiretroviral activity of lopinavir/ritonavir in treatment-naïve patients: 4 year follow-up study. AIDS 18: 775-779, 2004
  5. Gulick RM et al. Lopinavir / ritonavir (LPV / r)-based therapy in antiretroviral (ARV)-naïve, HIV-infected patients: 6-year follow-up of study 720. Seventh International Congress on Drug Therapy in HIV Infection, Glasgow, abstract P28, 2004
  6. Dragsted UB et al. A randomized trial to evaluate lopinavir / ritonavir versus saquinavir / ritonavir in HIV-1-infected patients: the MaxCmin2 trial. Antivir Ther 10: 735-743, 2005
  7. Eron J et al. The KLEAN study of fosamprenavir-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV infection over 48 weeks: a randomised non-inferiority trial. Lancet 368: 476-482, 2006
  8. Johnson M et al. Atazanavir plus ritonavir or saquinavir, and lopinavir / ritonavir in patients experiencing multiple virological failures. AIDS 19: 685-694, 2005
  9. Yates P et al. Optimising 908 / r in PI-experienced patients: a retrospective analysis of virological response based on baseline genotype after 8 weeks of therapy. Twelfth International HIV Drug Resistance Workshop, abstract 154, 2003
  10. Riddler SA et al. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med 358(20):2095-2106, 2008
  11. Benson CA et al. 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. J Infect Dis 185: 599-607, 2002
  12. Kempf DJ et al. Analysis of the virological response with respect to baseline viral phenotype and genotype in protease inhibitor-experienced HIV-1-infected patients receiving lopinavir / ritonavir therapy. Antivir Ther 7: 165-174, 2002
  13. Staszewski S et al. The CrixiLop Cohort Study: preliminary results from a salvage study of HIV-positive patients treated with indinavir and lopinavir / ritonavir without the addition of reverse transcriptase inhibitors. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, abstract H-853, 2003
  14. Stephan C et al. Pharmacokinetic comparison of single versus double boosted protease inhibitor regimen: effective saquinavir levels by co-administration with lopinavir / ritonavir. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 1119, 2003
  15. Staszewski S et al. The LOPSAQ study: 24 week analysis of the double protease inhibitor (PI) salvage regimen containing lopinavir (LPV / r) plus saquinavir (SQV) without any additional antiretroviral therapy. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 583, 2003
  16. Duvivier C et al. Dual boosted atazanavir / lopinavir / ritonavir containing regimen in HIV-1 infected pretreated patients: plasma trough concentration and efficacy results. Third International AIDS Society Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, abstract WePe3.2C10, 2005
  17. Arribas JR et al. Lopinavir / ritonavir as single-drug therapy for maintenance of HIV-1 viral suppression. A randomized, controlled, open label, pilot, clinical trial (OK Study): 48 weeks analysis. Third International AIDS Society Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, abstract WePe12.3C05, 2005
  18. Campo RE et al. Lopinavir / ritonavir maintenance monotherapy after successful viral suppression with standard highly active antiretroviral therapy in HIV-1 infected patients. AIDS 19: 447-449, 2005
  19. Nunes EP et al. 48-week efficacy and safety results of simplification to single agent lopinavir / ritonavir regimen in patients suppressed below 80 copies/ml on HAART. 16th International AIDS Conference, Toronto, abstract TuAb0103, 2006
  20. Cameron W et al. A two-year randomized controlled clinical trial in antiretroviral-naïve subjects using lopinavir/ritonavir (LPV/r) monotherapy after initial induction treatment compared to an efavirenz (EFV) 3-drug regimen (Study M03-613). 16th International AIDS Conference, Toronto, abstract THLB0201, 2006
  21. Arribas J et al. Lopinavir/ritonavir as single-drug maintenance therapy in patients with HIV-1 viral suppression: forty-eight week results of a randomized, controlled, open label, clinical trial (OK40 Study). 16th International AIDS Conference, Toronto, abstract THLB0203, 2006
  22. Chan-Tack KM et al. Lopinavir / ritonavir as single-drug therapy for maintenance of HIV-1 viral suppression. J Acquir Immune Defic Syndr 41: 531-532, 2006
  23. Delfraissy JF et al. Lopinavir/ritonavir monotherapy or plus zidovudine and lamivudine in antiretroviral-naive HIV-infected patients. AIDS 22(3): 385-393, 2008
  24. Capparelli EV et al. Lopinavir concentrations in cerebrospinal fluid exceed the 50% inhibitory concentration for HIV. AIDS 19: 949-952, 2005
  25. Yilmaz A et al. Cerebrospinal fluid and plasma HIV-1 RNA levels and lopinavir concentrations following lopinavir / ritonavir regimen. Scand J Infect Dis 36: 823-828, 2004
  26. Martin TM et al. Plasma and cerebrospinal pharmacokinetics and pharmacodynamics in subjects taking lopinavir / ritonavir. AIDS 20: 1085-1087, 2006