The New Antiretroviral Arsenal

In less than one year, the options for managing HIV have more than doubled. The number of drugs approved to treat HIV infection has risen to nine, with two others now available to qualifying persons under expanded-access programs. We prepared this quick guide to help people orient themselves to the various drugs and their different names; these brief descriptions could not possibly be complete, and people with HIV must work with their physicians to be aware of the different possible side effects, and the other instructions which are essential for using these treatments correctly.

Generally no anti-HIV drug should be used alone, given the ease with which HIV develops resistance. Some drug combinations have been proven more effective--or have fewer side effects--than others. But much is still unknown about combination therapy, and most people must experiment intelligently with different combinations to see what will keep both their viral load and treatment-related toxicities as low as possible.

Most clinicians we know are now making treatment recommendations based on drug tolerance and viral load, rather than CD4 cell counts. The CD4 count is now used largely for deciding when to use prophylaxis therapies to prevent opportunistic infections.

We have listed the reverse transcriptase inhibitors first, followed by the protease inhibitors, followed by hydroxyurea, which was originally developed as an oncology drug, but which may work in a unique manner against HIV. Important note: The side effects described for each entry below are only the most common or important ones. Physicians and patients should always be prepared for other toxicities, which are described at length in the product inserts available at any pharmacy.

Reverse Transcriptase Inhibitors

These drugs work by inhibiting an enzyme -- reverse transcriptase -- which the virus needs to replicate.

* AZT, also called zidovudine, is marketed under the brand name Retrovir(R). AZT has been combined with all other antiretrovirals and may work especially well in combination with 3TC, indinavir, nevirapine or delavirdine. AZT is valuable for treating cognitive problems caused by HIV because it penetrates the central nervous system better than most of the other drugs. It can cause headaches and stomach upset, but these often go away after a couple weeks. Over extended periods of use, it can cause anemia (low production of red blood cells), neutropenia (low white cells) and myopathy (damage to muscle fibers). These problems resolve if the drug is discontinued. The usual prescription for AZT has been two capsules (200 mg) taken three times a day, but Glaxo-Wellcome will soon be offering a 300 mg capsule that can be taken twice daily. The dose used for treating cognitive or motor slowing or dementia is twice the regular dose: 1200 mg a day.

* ddI, also known as didanosine, is sold under the brand name VIDEX(R). ddI can be combined with any other antiretroviral, but may work especially well with d4T, nevirapine or hydroxyurea. However, ddI, ddC, and d4T can each cause peripheral neuropathy and pancreatitis, so any combination of these drugs must be carefully monitored. If you experience abdominal pain or tingling and numbness in your toes or fingers, stop taking these drugs and call your healthcare provider; otherwise, long-term damage may result. The usual prescription for ddI is two tablets (125 or 200 mg, depending on body weight) taken twice a day on an empty stomach with water.

* ddC, also called zalcitabine, is sold as HIVID(R). ddC can be combined with any other antiretroviral, but must be used cautiously with ddI or d4T, since all three drugs can cause neuropathy or pancreatitis. If you experience abdominal pain or tingling and numbness in your toes or fingers, stop taking these drugs and call your provider; otherwise, long-term damage may result. The usual prescription for ddC is one tablet (0.75 mg) taken three times a day.

* d4T, also known as stavudine, is marketed as Zerit(R). d4T can be combined with most other antiretrovirals and may work especially well with ddI or nevirapine. However, d4T must be used cautiously with ddI or ddC, since all three drugs can cause neuropathy and pancreatitis. If you experience abdominal pain or tingling and numbness in your toes or fingers, stop taking these drugs and call your provider; otherwise, long-term damage may result. The usual prescription for d4T is one capsule (30 or 40 mg, depending on body weight) taken twice a day.

* 3TC, also called lamivudine, is marketed as Epivir(R). 3TC can be combined with any other antiretroviral and may work especially well with AZT, nevirapine or delavirdine. 3TC may resensitize HIV to AZT in people whose virus has become resistant to AZT. It can cause headaches and insomnia in some people, but these usually go away after a few weeks. The usual prescription for 3TC is one tablet (150 mg) taken twice a day.

Non-Nucleoside Reverse Transcriptase Inhibitors

* Nevirapine is sold under the brand name Viramune(R). Nevirapine can be combined with most other antiretrovirals, but has not been widely studied in combination with delavirdine, hydroxyurea or the protease inhibitors. It may work especially well with AZT, ddI, d4T, or 3TC. Nevirapine can cause a serious rash, but this may be avoided by starting with a low dose, one tablet taken once a day for two weeks, and then doubled to the usual prescription: one tablet (200 mg) twice a day.

* Delavirdine is available only to people with CD4 counts of 300 or less through an expanded-access program run by Upjohn, which calls the drug Rescriptor(R). An FDA advisory committee will consider full approval on November 22. Delavirdine can be combined with most other antiretrovirals, although it has not been widely studied in combination with nevirapine, hydroxyurea or the protease inhibitors. It may work especially well with AZT and 3TC. Like 3TC, delavirdine may resensitize the virus to AZT in people who have become resistant to that drug. Like AZT, delavirdine may be useful for HIV-related cognitive problems because it can penetrate the central nervous system. And like nevirapine, it can cause a rash in some people. The prescription for delavirdine is four pills (400 mg) taken three times a day.

Protease Inhibitors

These drugs target a different enzyme of the virus -- the HIV protease -- which is essential for HIV to make working copies of itself. More than with most drugs, it is very important not to miss doses of the protease inhibitors.

* Indinavir is sold under the brand name Crixivan(R). Indinavir can be combined with most other reverse transcriptase inhibitors, but has not been widely studied in combination with nevirapine or delavirdine, or hydroxyurea or the other protease inhibitors. It should definitely not be combined with ritonavir. Indinavir can cause stomach upset, kidney stones and generalized discomfort, although drinking plenty of fluids may prevent the kidney stones. It should be used with caution with certain other medications, so make sure your provider knows about everything you are taking. The usual prescription for indinavir is two capsules (800 mg) taken three times a day on an empty stomach with a large glass of water. Try not to miss any doses of this drug, or the virus could quickly become resistant.

* Ritonavir is marketed as Norvir(R). Ritonavir can be combined with most other antiretrovirals, but has not been widely studied in combination with nevirapine, delavirdine, or hydroxyurea. Ritonavir may work especially well with saquinavir, but only at doses tested in combination trials, and it should definitely not be combined with indinavir. There are many other medications that should be used with caution or not at all with ritonavir, so tell your provider exactly what you are taking. Ritonavir can cause stomach upset, generalized discomfort and tingling or numbness around the mouth. These might by avoided by starting with a low dose, three capsules taken twice a day with food, and adding one capsule each dose every couple days until the usual prescription is tolerated: six capsules (600 mg) taken twice a day. The capsules should be stored in a refrigerator. Try not to miss any doses of this drug, or the virus will quickly become resistant.

* Saquinavir is sold under the brand name Invirase(TM). Saquinavir can be combined with most other antiretrovirals, and may work especially well with ritonavir, but only using the low doses tested in combination trials. It has not been widely studied with hydroxyurea, nevirapine, delavirdine, or the other protease inhibitors. It should also be used with caution with certain other medications, so make sure your provider knows about everything you are taking. Saquinavir can cause mild stomach upset and sun sensitivity, but these are unusual. The usual prescription for saquinavir--unless combined with ritonavir--is three capsules (600 mg) taken three times a day with food. The current formulation of saquinavir is very poorly absorbed, but taking it with grapefruit juice helps to increase blood concentrations. A better formulation will probably be available next year. Try not to miss any doses of saquinavir, or the virus may become resistant.

* Nelfinavir was developed by Agouron Pharmaceuticals; its brand name is VIRACEPT(TM). It is available only through an expanded-access program to people with CD4 counts of 50 or less who can no longer tolerate or benefit from the other three protease inhibitors. Nelfinavir can be combined with most reverse transcriptase inhibitors, although it has not been studied in combination with delavirdine or nevirapine, or hydroxyurea. And because it is so recently available, we do not know anyone who has tried novel combinations with this drug. The criteria by which it is dispensed essentially prohibit the combination of nelfinavir with other protease inhibitors. It can cause stomach upset or headaches in some people, and should used with caution with certain other medications. The prescription for nelfinavir is three tablets (750 mg) taken three times a day with food.

Miscellaneous

* Hydroxyurea is marketed as Hydrea(R) and is used to treat melanoma, leukemia, ovarian, and head and neck cancers. It may fight HIV by partially inhibiting a human enzyme, called ribonucleotide reductase, which HIV needs. Hydroxyurea may work especially well with ddI. Like AZT, hydroxyurea can cause anemia and neutropenia, although this is unlikely using the low dose usually prescribed for HIV: one capsule (500 mg) daily. Note: While hydroxyurea is an approved drug for certain cancers, its use with HIV is experimental.