wide use, and at least five newer NNRTIs are in clinical trials. Generally, the NNRTIs are not nucleoside analogs, and they act in a completely different manner from NRTIs, by binding tightly to reverse transcriptase and preventing the enzyme from acting.
Protease inhibitors were a major addition to the anti-HIV arsenal. The first protease inhibitor, saquinavir, was approved for therapy in December 1995. Currently, there are at least six protease inhibitors approved for use, and more in clinical trials. Unlike the reverse transcriptase inhibitors, the protease inhibitors act late in HIV replication to prevent packaging of viral proteins in the virion. The impact of these inhibitors on the treatment of people with AIDS has in some cases been immediate and dramatic. For example, one 30-year-old woman with AIDS had exhausted all available AIDS therapies. She was a wasted 85 pounds, her hair had fallen out, and she coped with her fatigue by napping every 2 hours. She was given indinavir (a newer protease inhibitor) together with D4T and 3TC, and within a month, her hair grew back, she gained weight, she began skating, and her CD4+ cell count rose from 3 to more than 200 per microliter of blood.
HAART does not cure AIDS. Viremia becomes undetectable in only about half the cases, and even then, the viremia returns if the medications are discontinued. While it stops production of virions, it does not eliminate HIV provirus hidden in host cell genomes. In successful HAART, production of infectious virus is largely halted, many fewer CD4+ lymphocytes are killed, and so the CD4+ cell count rises. When the medications are stopped, persistently infected cells release infectious virions that can infect a new population of CD4+ cells, resulting in a quick rise in viremia. Many authorities now feel that the secret to controlling HIV disease lies ultimately in minimizing or eliminating body cells containing the hidden HIV genomes. These authorities are advocating HAART for the acute retroviral syndrome to prevent the buildup in the body of cells containing HIV provirus.
Many strains of HIV fail to respond to HAART because they have become resistant to the medications during past treatment. These resistant strains of HIV are transmissible to other persons. Toxic effects of the medications are another limitation of anti-HIV therapy. For example, AZT can cause anemia, low white blood count, vomiting, fatigue, headache, and muscle and liver damage. Painful peripheral nerve injury, inflammation of the pancreas, rash, mouth and esophagus ulceration, and fever are side effects of other NRTIs. Also, indinavir may be responsible for kidney stone formation, and ritonavir, another protease inhibitor, causes nausea and diarrhea. Diabetes mellitus is another potential side effect of protease inhibitors.
Finally, a big limitation of the use of anti-HIV medications is their cost. The cost of a combination of these medications can easily exceed $1,000 per month for either an asymptomatic or symptomatic individual and is expected to be required for life. While not considered excessive for a serious chronic disease in the United States, the cost of medications puts them completely out of reach for more than 90% of the world's HIV victims.
The main features of HIV disease are presented in table
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