Medical Update -- 1996 -- Year in Review

THE "SPIRIT OF HOPE" seems a positive note in which to look at the ending of 1996 and the beginning of 1997. The development of antiretrovirals has been disappointing. However, the release of protease inhibitors has demonstrated amazing results. The protease inhibitors are a new class of antivirals that target the protease enzyme. The results of clinical trials have generated optimism and hope among clinicians and patients with the potential of impacting survival. Three protease inhibitors, saquinavir (Invirase), indinavir (Crixivan) and ritonavir (Norvir) were approved by the FDA during 1996. Nelfinavir (Viracept) is currently available through expanded access and should receive FDA approval early '97. Glaxo-Wellcome's protease inhibitor 141 (VX-478) is currently under study.

Invirase

Saquinavir (Invirase) was the first protease inhibitor to be released. Clinical trials show a 0.5-1.0 log decrease in viral RNA and a mean T-cell increase of 30-50 cells/mL. Saquinavir was initially studied in combination with AZT & ddC and was very tolerable. The most common side effects are headache and gastrointestinal intolerance (nausea, abdominal pain and diarrhea) occurring in 4-6% of people taking this combo. Saquinavir is prescribed at 600mg three times a day (comes in 200mg capsules). While saquinavir appears to be the most potent protease inhibitor in the test tube, the effect in people is limited by low absorption. Saquinavir should be taken with food to help increase absorption, there by increasing it's effectiveness.

Clinical trials have already concluded on a new gelatin capsule, with improved absorption. It should be ready for marketing early part of '97. The use of saquinavir in combination with ritonavir shows great promise.

Norvir

Ritonavir (Norvir) was the next protease inhibitor to be approved in March of '96. Data from a large study showed a benefit in survival in HIV-infected individuals with T-cells below 100. Clearly, the most impressive presentation at the XIth International AIDS Conference in Vancouver during July, was the combination of ritonavir, zidovudine (AZT) and lamvudine (3TC). This trial showed undetectable levels of RNA viremia in 80-90% of all patients treated for up to one year. Some people seem to be holding steady after eighteen months of this therapy. The most frequent side effects reported are nausea, vomiting, diarrhea, circumoral and peripheral parenthesis (numbness or tingling around the mouth and finger tips). Ritonavir has many drug interactions. One specifically of concern for women, is that ritonavir can decrease the effectiveness of birth control pills. Using a second form of contraception is recommended (latex protection is recommended for most sexual encounters). Slowly increasing the dose of ritonavir over a two week period can increase tolerability. Ritonavir has the advantage of twice daily dosing and it can be taken with food.

Crixivan

Indinavir (Crixivan) was approved by the FDA in April. Indinavir clinical trials have shown a dose-dependent antiviral effect at 800mg (400mg capsules) three times a day and a greater than 2 log decrease viral RNA when used with nucleosides (AZT, ddC, d4T or ddI). In all studies, indinavir was demonstrated to be safe and well tolerated. In addition, indinavir is under study for the treatment of thrombo-cytopenia (decreasing platelets) and Kaposi's sarcoma. Indinavir is usually well tolerated initially, however it requires three times daily dosing. Indinavir must be taken on an empty stomach or with a light, non-fat, non-protein diet every 8 hours. This can be a contraindication for some individuals who are wasting or suffer with gastrointestinal complications as a result of their HIV-infection or other medications. Common side effects of indinavir are nephrolithiasis (defined as flank pain, blood in the urine, or kidney stones) which were reported in 2-3% of people taking it. This can usually be avoided by consuming at least 1 liter of water every day. Gastrointestinal symptoms such as nausea and abdominal pain and headaches can also occur.

Viracept

Nelfinavir (Viracept) which is currently available through the expanded access program, may receive FDA approval in '97. (1.800.621.7111) Nelfinavir appears to be well tolerated and safe with the common side effect of mild to moderate diarrhea, controlled with an antidiarrheal medication. A new clinical trial will look at nelfinavir in combination with Zerit (d4T) and Lamuvidine (3TC) in antiretroviral naive women (women who have never taken HIV meds). This will be the first study to focus on antiretroviral therapy and the side effect profile in women. (call:213.343.8278)

Vertex

141W94 (VX-478) also known as the vertex compound, is the newest protease inhibitor under evaluation in clinical studies. VX-478 is a potent HIV protease inhibitor that appears to be an effective agent against AZT-resistant strains of HIV. Studies in animals show an accumulation of drug in the brain. This is an important finding because it means that the drug can attack the virus in the central nervous system. To date, AZT and nevirapine appear to be the only approved antiretroviral drugs that penetrate the central nervous system. At this time, there is no information about expanded access to VX-478.

Resistance

In terms of safety and tolerability, all five protease inhibitors have different side effect profiles. At what stage of infection should these potent inhibitors be used is a question that remains elusive. While there is a great deal of enthusiasm to start the protease inhibitors early, in combination with nucleoside analogues, there are many unanswered questions about their use. It may be reasonable to begin with combination nucleoside in people with CD4 under 500 and a measurable viral load. But, if a patient fails to achieve suppression of viral load or has declining CD4 counts, adding a protease inhibitor should be considered.

Drug resistance is a major problem in the treatment of HIV infection. It appears that cross resistance will be a problem for all of the protease inhibitors currently available. For this reason, compliance and dedication to a strict regimen is critical and may need to be maintained for many years. Protease inhibitors shouldn't be used as monotherapy but are prescribed with 2 other nucleosides (AZT, ddC, ddI, d4T). Recommendations suggest that when changing drug regimes, 2 drugs should be changed, not just adding a protease inhibitor. There is no information to indicate that opportunistic infection prophylaxis can safely be discontinued with the rise in T-cells. All five of these drugs are potent inhibitors of HIV protease enzyme and all are metabolized by the liver. The drugs vary in the amount that is absorbed, central nervous system penetration, dosing intervals, effects with food consumption, side effects, laboratory abnormalities, drug interactions, effects on viral load and T-cells. With the release of nelfinavir and VX-478, more hope can be offered to those individuals who are either intolerant or failing current therapies.

Additional drugs are still needed that can penetrate the central nervous system, urogenital tracts and lymph nodes where initial HIV-infection occurs. As HIV treatment becomes more complicated, it will be imperative that patients be referred to medical providers who specialize in HIV/AIDS care. Because studies have not been successful in enrolling very many women, we do not know how well the drugs are tolerated in women. (editors note: please mail in the survey on page 10.)

In the short amount of time that these drugs have been available, we are already seeing the impact on decreasing admission at LAC+USC Medical Center. Direct admits from 5P21 have declined from 80 in August of '95 to 21 during August of '96. Clinically, some patients have begun to demonstrate the clearing of diarrhea, improvement in their immune function and weight gain. This can be attributed to the efficacy of protease inhibitors as well as improvement in the management of opportunistic infections. The approval of protease inhibitors doesn't mean that the fight is over, but there seems to be light at the end of the tunnel. We still need to find effective treatment for individuals who can not tolerate protease inhibitors or who continue to progress while on these drugs. There is a tremendous and critical need for information to be gathered on women. Lives depend on it.