Because of the progressive nature of the disease, it is the HIV infection that is treated as the clinical problem, rather than focusing on the end stage (that is, AIDS) alone. Virtually every step in the HIV replication cycle is a potential target for an antiviral drug, but only those directed against reverse transcriptase, viral protease, viral fusion and integration have so far been used successfully (Figure 1). Used early in the infection, a combination of three different drugs administered together can reduce the plasma viral load to undetectable levels, at least temporarily.

Fig1. Highly active antiretroviral therapy (HAART). 1Choice of a drug regimen is individualized based on criteria such as tolerability, drug–drug interactions, convenience/adherence, and possible baseline resistance. The availability of well-tolerated combination antiretroviral tablets that can be dosed once daily has greatly simplified early treatment of human immunodeficiency virus infection. CCR5 = C-C chemokine receptor type 5 that can function as viral coreceptor.

1. Strategy for multiple-drug therapy in treating HIV infections: Unlike DNA polymerase, which makes few mistakes in the replication of DNA because of its proofreading activity, reverse transcriptase has no ability to proofread. Therefore, DNA synthesis by the viral reverse transcriptase produces many errors (about one per cycle of synthesis). This results in mutations in all of the HIV genes and accumulation of a pool of mutant viruses in any individual patient. In the presence of an antiviral drug, there is strong selection for mutations that confer resistance to that drug, and the high mutation rate ensures that such mutations will occur. The answer to this therapeutic dilemma has been to simultaneously use multiple drugs that act on different steps in the viral replication cycle because the probability of several different mutations occurring concurrently in the targeted genes in the same genome is low. In addition, certain drug combinations are synergistic, the effect on reducing viral load being considerably greater than merely the sum of the individual drug effects. The use of potent combination regimens can limit viral replication and dissemination to lymphoid tissue, creating a smaller reservoir of chronically infected cells, and limiting the potential for viral mutations (acquired during the replicative process) that could lead to acquisition of drug resistance. However, even this approach is not entirely effective because HIV also exhibits a relatively high rate of recombination, enabling mutations from two different genomes to be combined into one virus particle.

2. Early therapy: Approaches to therapy are evolving as more is learned about the nature of the disease. For example, it has been determined that the steady-state level of replicating virus in the plasma (that is, the “viral load”) is a prognostic indicator of the rate of progression to AIDS. This has led to the principle that HIV infection should be treated as aggressively and as early as possible, minimizing the initial spread of the virus. Not only does this approach yield a lower steady-state level of virus, but it has the additional advantage of increased drug efficacy insofar as drugs are administered at a time when mutants are still rare.

3. Highly active antiretroviral therapy: Currently, combinations of various drugs described below that are given three at a time are being evaluated for efficacy, both in short-term reduction of viral load and/or increase in CD4+ cell count and in long-term survival. Choice of a drug regimen is individualized based on criteria such as tolerability, drug–drug interactions, convenience/adherence, and possible baseline resistance. [Note: All such multiple-drug therapies are commonly referred to as “highly active antiretroviral therapy,”or HAART (see Figure 1).] Unfortunately, although multidrug therapies can lower the viral load to undetectable levels, virus reemerges if HAART is stopped, indicating that the HIV has not been eradicated. Therefore, with current drug therapy, HIV continues to exist in sanctuaries, such as the CNS, testes, lymphoid tissue, and nonreplicating T-lymphocyte reservoirs. Thus, HIV infection is currently both chronic and incurable.

a. Nucleoside and nucleotide analog reverse transcriptase inhibitors: Reverse transcriptase inhibitors prevent the copying of the HIV RNA genome into a proviral DNA genome. There are both nucleoside analogs and nonnucleoside inhibitors of the viral reverse transcriptase. Nucleoside and nucleotide analogs inhibit primarily by serving as chain terminators after insertion into the growing DNA chain by the reverse transcriptase. Resistant mutants inevitably arise after long-term treatment with any one of these drugs. However, because cross-resistance is incomplete, zidovudine (AZT) in combination with one of the other drugs has been successful in minimizing the effect of mutation. Significant adverse effects accompany use of these drugs. The use of combined therapy in some cases permits less toxic doses to be administered.

b. The nonnucleoside reverse transcriptase inhibitors: These drugs act by targeting the reverse transcriptase itself. They bind in a noncompetitive, reversible manner to a unique site on the enzyme, altering its ability to function. Their major advantage is their lack of effect on the host’s blood-forming elements and lack of cross-resistance with nucleoside analog reverse transcriptase inhibitors.

 c. Protease inhibitors: The products of the gagandpolgenes are translated initially into large polyprotein precursors that must be cleaved by the viral protease to yield the mature proteins. Protease inhibitors, which include ritonavir, nelfinavir, saquinavir, amprenavir, indinavir, and lopinavir interfere with the processing of the polyproteins in the budding virion and result in noninfectious particles (Figure 2). However, viral resistance develops if protease inhibitors are used alone. Further, lipodystrophy (redistribution of fat, so that the limbs become skinny, and fat is deposited along the abdomen and the upper back) and hyperglycemia can occur with these drugs.

Fig2. Role of human immunodeficiency virus protease in viral replication.

 d. Fusion inhibitor: Enfuvirtide is a 36 amino acid peptide that binds to gp41 and inhibits the fusion of HIV with the membrane of the host cell.

e. Integrase inhibitor: Raltegravir targets the viral enzyme that catalyses the integration of the proviral DNA into the host's genome. Only one drug of this class is currently approved, although others are in clinical trials. This potent drug has few side effects or negative drug interactions.

f. Coreceptor blockers: Maraviroc is a CCR5 antagonist that interferes with binding and entry of the virus into susceptible cells. Circulating virus must be genotyped before the drug is utilized to determine whether the inhibitor will block virus entry, because not all variants are CCR5-tropic.

4. Effect of HAART on the incidence of opportunistic infections: The incidence of opportunistic infections in AIDS patients is decreasing in response to widespread use of aggressive multidrug treatment. This is true for virtually all opportunistic infections (Figure 3).

Fig3. Incidence of selected opportunistic infections in patients with HIV infection. [Note: The shaded area labeled “HAART” indicates the period of wide availability of highly active anti retroviral therapy (HAART). The decline in opportunistic infections after 1995 largely reflects the effect of HAART.]

5. Perinatal treatment: Zidovudine when administered to HIV 1–infected pregnant women during the second and third trimesters of pregnancy, followed by administration to the infants during the first 6 weeks of life, reduces risk of maternal–infant transmission of HIV-1 from approximately 23 percent to 8 percent. The availability of this effective intervention, which decreases perinatal transmission of HIV-1, has led to increased efforts to screen all pregnant women (with their consent) for the presence of HIV-1 infection. Postnatal transmission of HIV via breast milk can, however, occur.

6. Pre-exposure prophylaxis: Three trials have investigated different populations: heterosexual couples in East Africa in which one per son was HIV positive, and the other was not; sexually active young adults in Botswana; and, in the United States and other countries, MSM. In each trial, Truvada, a once-daily tablet containing tenofovir and emtricitabine, significantly reduced the risk of acquiring HIV infection. The drug is already approved to treat HIV infection but must be used in combination with other drugs to pre vent the emergence of resistant HIV strains. The drug is useful for people at high risk of infection, like MSM with multiple sex partners, and individuals who are in relationships with someone who is HIV positive.

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مكتب المتولي الشرعي للشؤون النسوية ينظّم ورشة تدريبية في كتابة الخبر الصحفي

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مواضيع ذات صلة

DNA Tumor Viruses

Rhabdoviridae

Human T-cell Lymphotropic Viruses, Types 1 and 2

Congenital Rubella Infection

Treatment of Hepatitis C

Acute and Chronic Hepatitis C

Hepatitis C

Pathogenesis and clinical significance of HIV

Transmission of HIV

HIV replication

Hepatitis D

Prevention and Treatment of hepatitis B