However, the story isn't over -- active research programs have continued to improve PIs, attempting to retain the potency strengths of PIs while addressing the previous limitations.
In the winter of 1995-96, the introduction of the first HIV protease inhibitors (saquinavir, indinavir and ritonavir) revolutionized the medical care of persons living with HIV infection. The addition of a PI to dual nuke therapy resulted finally in the suppression circulating HIV to undetectable levels.
Several early clinical trials showed the ability of PI-containing HAART to suppress HIV and increase CD4 cell counts. Subsequently, several studies reported dramatic reduction in the death rate in HIV infected individuals.
Early HIV-1 protease inhibitors treatments involved many pills (sometimes more than 10 a day) and frequent dosing schedules. Saquinavir, indinavir, ritonavir, nelfinavir and lopinavir/ritonavir all needed to be taken with a mind towards diet. Only amprenavir (APV) does not have a food requirement. Dosing of indinavir needed even more behavioral changes; the need to drink lots of water to avoid kidney stones. The recent reformulation of nelfinavir (NFV), from a 250 mg tablet to a 625 mg tablet is a recent effort to lower the pill burden of this PI -- from 10 a day to 4.
Short-term side effects of PI-based therapy are well known, with frequent gastrointestinal problems, like, nausea and diarrhea. These side effects often resulted in treatment discontinuation. Making matters worse, long-term toxicities (or fear of toxicity) emerged as we treated people longer with PI therapies. One main area of concern was body fat changes, now called, lipodystrophy. While it is increasingly understood that significant risk for lipodystrophy is often raised by non-drug factors, (such as severity of HIV disease or age) many early reports erroneously placed the sole blame for lipodystrophy on the PIs. Nevertheless, many PWAs would choose to avoid HIV therapy altogether, in order to avoid the stigmatizing effects of lipodystrophy.
Elevations in the blood chemicals cholesterol and triglyceride have been in persons taking all early PIs. Ritonavir-boosting generally makes these elevations even greater. The reason this is concerning is that abnormal cholesterol and triglycerides can raise one's risk of heart disease.
Ultimately, these limitations made adherence tough and negatively affected quality of life. It is clear that side effect aversion was a significant negative factor in taking pills -- a real problem in a world where long-term success requires near-perfect adherence. This issue is so significant that in one study, PWAs were willing to trade years of life and risk death in order to avoid medication side effects.
Over time, multiple studies showed the superiority of NNRTI-based therapy, compared with PI-based therapy, even among the most ill patients, those with high viral loads or very low CD4 cell counts. Recent improvements in the formulation of the non-nuke efavirenz has yielded a one pill per day drug -- an industry benchmark.
Pharmacological boosting of lopinavir results in a clinically relevant product, the co-formulated lopinavir/ritonavir (LPV/RTV, Kaletra). In key studies, regimens that contained the boosted PI lopinavir/ritonavir were shown to be more potent than those that contained nelfinavir, and improved responses were seen in persons with very high viral loads. Because of these studies LPV/RTV is currently a component of one of the "preferred" initial antiretroviral regimens for initial therapy, a demotion of "unboosted" PIs to the alternate position.
Current boosted PIs are improvements from the early days, but limitations persist. Co-formulated lopinavir/ritonavir and the new 625 mg formulation of nelfinavir are good efforts in lowering the pill burden. Gastrointestinal side effects and elevations in cholesterol remain problems and for some persons, serious intolerance to ritonavir makes boosting an unacceptable option.
Early clinical trials (called studies AI424-007, -008) showed that the ATV was about as potent as NFV, with similar proportions of patients achieving undetectable viral loads and similar increases in CD4 cell rise. Elevations in blood levels of bilirubin were frequently observed, particularly among persons who received the highest dose (600 mg qd). In the latest clinical trial, AI424-045, therapy-naive persons received either unboosted ATV or efavirenz (Sustiva) with fixed dose ZDV/3TC (Combivir). This study showed that unboosted ATV seems to work as well as efavirenz. This is one of very few clinical trials that has compared a newer PI to efavirenz and suggests similarity between the two classes of drugs for first line therapy.
Study AI424-045 is an ongoing study that compares boosted ATV/RTV (300 mg/100 mg qd) versus lopinavir/ritonavir versus ATV/SQV (saquinavir) in therapy-experienced persons. Patients received tenofovir as part of the randomized treatment (in conjunction with a NRTI). Preliminary 24-week data from this study was recently presented. The proportion of persons with viral load below LOQ (level of quantification or undetectable) was similar in the ATV/RTV and LPV/RTV groups, whereas the ATV/SQV groups tended to have poorer response. The 48-week data from this trial is anxiously awaited. It is tempting, though premature, to speculate that ATV/RTV will have comparable potency and tolerability in treatment-naive persons.
The principle and characteristic side effect associated with ATV therapy is elevations in the blood level of bilirubin, a condition called hyperbilirubinemia. Bilirubin is a byproduct of liver metabolism. Hyperbilirubinemia was the most common laboratory abnormality in ATV clinical trials. Clinical cases of jaundice yellowing of the skin have been reported in 11% of all study subjects; 9% reported yellowing of the eyes ("scleral icterus"), though these events rarely resulted in having to stop the medicine. These clinical symptoms are reversible upon treatment discontinuation or interruption.
Mild abnormalities in the electrical patterns in the heart occurred in some patients during clinical studies. These changes were asymptomatic but, because of this cautionary note, ATV should be used with caution in persons with preexisting cardiac conduction abnormality.
In the NEAT study, subjects either received 908 twice daily or nelfinavir. While CD4 cell count rises were similar in both groups, a greater percentage of 908 subjects achieved undetectable viral loads especially those with high baseline viral loads, suggesting superior potency of 908.
The SOLO trial evaluated boosted, once-daily 908/RTV versus nelfinavir. In this study, similar percentages of subjects achieved undetectable viral loads at 48 weeks. In an exploratory analysis, a greater percentage of persons with very high baseline HIV viral loads (>500,000 copies/mL) or very low CD4 counts (<50 cells/mm3) achieved undetectable viral loads when they received 908 than NFV. More NFV subjects discontinued therapy because of virologic failure; more 908 subjects discontinued because of non-virologic reasons.
Like amprenavir, 908 causes rash in a small percentage of patients, ranging from 2% to 7% in recent studies. Small increases in cholesterol were seen in therapy-naive persons who received 908.
Lower pill burden and improved tolerability compared with previous unboosted PIs is desirable -- the two pill per day atazanavir and the four pill per day 908 have achieved pill counts similar to the original, highly successful formulation of efavirenz. Pill counts also are lower than the industry standard lopinavir/ritonavir. Compared to early unboosted PIs, gastrointestinal tolerability is much improved.
Is PI drug discovery complete with atazanavir and 908? Low though current pill count might be, there still is room for improvement. Limitations of our existing data set remain -- evaluation for long-term safety or complications requires long-term monitoring of study subjects and an improved understanding of how HIV disease occurs. Drug-drug interactions remain problematic for most PI medications, particularly for atazanavir. The optimal choice of which medication class or medication combination to use continues to be the subject of debate.
The newer PIs will change the care for persons living with HIV. The improved tolerability and low pill count of new PIs will challenge the place that non-nukes now hold as first-line therapies. For persons who have inherited NNRTI resistance, PIs must be components of first-line combinations. It has been suggested that persons with very advanced disease might be more appropriately treated with PIs, because of their higher genetic barrier to resistance and the general low likelihood of getting high level PI drug resistance. For persons with high risk of heart disease, atazanavir's lipid profile makes this drug an attractive option. Lastly, for the many persons who are currently successfully taking first-line PIs, the newer drugs offer options for treatment simplification with fewer pills and improved tolerability.
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