Advertisement
The Body: The Complete HIV/AIDS Resource
Follow Us Follow Us on Facebook Follow Us on Twitter Download Our App
Professionals >> Visit The Body PROThe Body en Espanol
  
  • Email Email
  • Printable Single-Page Print-Friendly
  • Glossary Glossary
  • PDF PDF

Drugs! Drugs! Drugs!
An Overview of the Approved Anti-HIV Medications

Kaletra (Lopinavir/Ritonavir, LPV)

Fall 2003/Winter 2004

Kaletra (lopinavir/ritonavir, LPV) is one of the strongest and most prescribed protease inhibitors on the U.S. market today. Its approval by the FDA in September 2000 marked the first time that a protease inhibitor (PI) was designed and approved as a boosted drug -- the capsules contain the active drug, lopinavir, along with a small amount of Norvir (ritonavir). Kaletra was approved at the same time for use in adults and children. Resistance to Kaletra doesn't develop as quickly as it does with other PIs (at least those not boosted with low-dose Norvir), and many people whose HIV is resistant to other PIs benefit from Kaletra. Its ability to lower viral load dramatically and keep virus levels low for as long as several years and its relatively favorable resistance profile make Kaletra a valuable option for people just starting treatment as well as for those whose HIV no longer responds to other PIs.


Background

Kaletra has enjoyed wide use since its release in 2000. Its appeal, however, is largely the work of an already approved PI, Norvir. Early studies had shown that, by itself, lopinavir was a relatively weak drug, particularly against HIV with resistance to other PIs. At the same time that Abbott Laboratories was developing what would come to be called Kaletra, research was finding that adding low doses of Norvir to other PIs could help those drugs overcome existing resistance. The same was true when low-dose Norvir was added to lopinavir. So Abbott, which also manufactures Norvir, decided to test and market both drugs together in one pill -- a smart move. Kaletra proved itself by lowering viral loads in people starting antiretrovirals as well as those who had already been on at least one PI. Kaletra's convenient co-formulation and benefits for people with PI cross-resistance set a new precedent. Many other PIs continue to be tested for possible use with low-dose Norvir, led by Kaletra's example.

Study M98-863 compared Kaletra to Viracept in 653 people who had never been on treatment. Trial participants also took two NRTIs. After 60 weeks, 64% of those on Kaletra had viral loads below 50 compared to 53% on Viracept. Study M97-720 also showed Kaletra to be effective in people who had never been on antiretrovirals. This 100-person study compared three doses of Kaletra taken with two NRTIs. After 48 weeks, it became clear that one dose (400 mg lopinavir/100 mg ritonavir) worked better than the others, and everyone in the study was switched to that dose. By 96 weeks, 78 people had viral loads below 50. And after four years on their Kaletra combination, 70 people still had viral loads below 50 copies. These impressive results show that a Kaletra regimen can maintain undetectable viral loads for up to four years.

Several studies have also demonstrated Kaletra to be effective for people who have taken PIs before. Study M98-957 enrolled 56 people who had been on at least two other PIs and had viral loads over 1,000 copies. Most of the participants had resistance to multiple PIs. They took one of two doses of Kaletra twice a day (533/133 or 400/100) together with Sustiva (efavirenz) and two NRTIs. After six months, more people on the higher dose had viral loads below 50 (82% compared to 69%), which prompted the study investigators to switch everyone in the trial to the 533/133 mg dose for the remainder of the study. After 48 weeks, 56% had viral loads below 50 copies. Among those, 52% had more than five PI-associated mutations (changes in HIV's genetic structure), indicating that the drug had a great deal to offer people who had tried and failed other PIs in the past. Clinical trials are now looking at various high doses of Kaletra in people who have high-level resistance to other PIs.

Advertisement
In study M97-765, 70 people who weren't responding to treatment and whose virus was resistant to at least one PI, switched their PI to one of two doses of Kaletra -- the approved dose or a higher one that included twice as much Norvir. Everyone in the study also took Viramune (nevirapine) and two NRTIs. After 72 weeks, the response in both groups was equivalent: overall, 57% had viral loads below 50 copies. And after 96 weeks, 49% had viral loads below 50 copies. These results showed Kaletra to be effective in people who had previously used other PIs. This study also suggests that adding more Norvir to Kaletra doesn't necessarily offer any additional benefit, although this strategy is still being investigated.


Side Effects

Kaletra's most common side effect is diarrhea. In Study M98-863, almost as many people on Kaletra had diarrhea as those on Viracept (16% vs. 17%), although the diarrhea for people on Kaletra was much milder after the first three weeks. Other possible side effects of Kaletra include nausea, shortness of breath, abdominal pain, weakness, swelling in the legs, headache, and vomiting. People taking Kaletra may also experience increases in liver enzymes, and less than 1% of people develop pancreatitis (inflammation of the pancreas).


Drug Interactions

Kaletra interacts with other medications, including other antiretrovirals. Its most significant interactions are with the NNRTIs Sustiva and Viramune. Kaletra levels can decrease by 40% and 55% respectively when taken with these drugs -- increasing the Kaletra dose is usually recommended. On the other hand, Kaletra can increase levels of Crixivan and Invirase/Fortovase, which may require dose adjustments. Kaletra can also increase levels of Agenerase (amprenavir), which usually requires decreasing the Agenerase dose, and possibly increasing the Kaletra dose as well.

Because Kaletra contains Norvir, the list of other interactions is long and includes some antihistamines, tranquilizers, sleeping pills, antiarrhythmics (used to regulate an erratic heartbeat), and ergot alkaloids (used to treat migraines). Combining Kaletra with any of these drugs may cause serious or even life-threatening reactions. Other drugs that shouldn't be used with Kaletra include Zocor (simvastatin), lovastatin (Mevacor or Atocor), and St. John's wort (hypericum). Levels of Lipitor (atorvastatin), Nizoral (ketoconazole), and certain anticonvulsants are also affected by Kaletra and should be used with caution. (Refer to Norvir's many drug interactions.)

Using other drugs with Kaletra may require some dose tweaking. Kaletra levels can decrease by 75% when taken with the anti-tuberculosis drug rifampin, so it may be necessary to take additional Norvir or increase the Kaletra dose. On the other hand, levels of Biaxin (clarithromycin) and Mycobutin (rifabutin) can increase by 77% and 300% respectively when combined with Kaletra and may need to have their doses lowered.

Levels of the oral contraceptive ethinyl estradiol can decrease by 42% when taken with Kaletra, so an alternative or additional method of protection is recommended. Levels of Viagra (sildenafil) can be eleven times higher when taken with Kaletra, so starting with a lower dose of Viagra and increasing it every 48 hours, if necessary, can help reduce the risk of serious side effects.

Kaletra may also lower methadone levels by as much as 53%, so the methadone dose may need to be increased to avoid symptoms of opiate withdrawal.


When to Consider It

For people who start treatment with a protease inhibitor, both the U.S. Department of Health and Human Services and the British HIV Association treatment guidelines recommend Kaletra as part of a preferred regimen. These two sets of guidelines differ significantly from one another in many ways but, because the data from study M98-863 is so compelling, both agree that if you're going to start treatment with a PI regimen, Kaletra is generally the one to use. Kaletra can also be beneficial as part of a later treatment regimen for people who have been on other antiretrovirals, including other PIs.

Few people taking Kaletra so far have developed resistance to it. None of the participants on Kaletra in study M98-863 developed resistance to it, while 48% of those on Viracept developed resistance to that PI. Similarly, people in three other trials with viral loads over 1,000 copies while on Kaletra developed no resistance to the drug but, rather, to the NRTIs they were taking. People who took Kaletra in M98-863 also developed no cross-resistance to other PIs, while 48% of those on Viracept did.

What is particularly beneficial about Kaletra's resistance profile is that several mutations are necessary for the virus to become resistant to the drug. One study indicates that between seven and ten mutations are necessary, while another study indicates that as few as four mutations are necessary.

Cross-resistance is also possible but hasn't been seen in great numbers so far. Among the PIs likely to affect how well Kaletra works are Crixivan, Norvir, and Agenerase -- having resistance to any of these may preclude or decrease the effectiveness of Kaletra. More information is needed about the cross-resistance profile of Kaletra and which PIs are likely to be effective if the virus becomes resistant to this drug.


Good to Know

  • Because Kaletra is a co-formulation of two drugs in one capsule, people sometimes take Kaletra with just one other drug, thinking that they're on a three-drug combination. But Kaletra counts as only one drug -- the small amount of ritonavir in Kaletra doesn't work to slow down HIV replication. Kaletra contains only enough ritonavir to boost lopinavir levels, turning a relatively weak drug into a strong one, and is intended to be taken with at least two other antiretrovirals.

  • Once-a-day dosing of Kaletra is now being studied in clinical trials.


Pregnancy

Kaletra is classified as an FDA pregnancy category C drug. Long-term animal studies show a delay and/or defect in the formation of bones in the skeletal system in rats whose mothers were given high doses. This doesn't necessarily mean that the same would be true in humans. Kaletra has not been studied in pregnant women. Kaletra should be used during pregnancy only when the potential benefit outweighs the potential risk to the mother and fetus.


Dose

Kaletra comes in two forms: capsules and liquid. Each capsule contains 133 mg of lopinavir (the main drug in Kaletra) and 33 mg of ritonavir. The total daily dose is 800/200 mg, taken as three capsules twice a day. The liquid formulation is 80 mg/mL lopinavir with 20 mg/mL ritonavir, and the standard dose is 5 mL twice a day. Both the capsule and liquid forms should be taken with food.

Most adults don't like the liquid because of the bitter taste, but for children it's the only option. The liquid formulation is recommended for children ages 6 months to 12 years, and the dose is based on weight. For those weighing less than 15 kg (33 pounds), the twice-daily dose is 12 mg (lopinavir)/3 mg (ritonavir), and for those weighing between 15 and 40 kg (33-88 pounds), the twice-daily dose is 10/2.5 mg. Adolescents weighing more than 88 pounds should take the adult dose.

FDA Approval: 2000

Manufacturer: Abbott Laboratories

Patient Assistance Program: 800-222-6885





  
  • Email Email
  • Printable Single-Page Print-Friendly
  • Glossary Glossary
  • PDF PDF

This article was provided by AIDS Community Research Initiative of America. It is a part of the publication ACRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.
 

Tools
 

Advertisement