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D. Anti-HIV Therapy


The huge resources that had gone into HIV research had resulted in the development of a large number of anti-HIV agents. Therapy of HIV is complicated by the fact that the HIV genome is incorporated into the host cell genome and can remain there in a dormant state for prolonged periods until it is reactivated. Effective therapy must be directed against both free virus and virus-infected cells. Although a number of substances with in vitro anti-HIV activity have been described, only a few drugs exhibit anti-HIV activity in vivo at tolerable toxicities.

1. Anti-Retroviral Agents

The main group of substances described are;

  1. Nucleoside analogues reverse transcriptase inhibitors. AZT, DDC, DDI and lamuvidine.

  2. Non-nucleoside analogue reverse transcriptase inhibitors e.g. Nevirapine

  3. HIV Protease inhibitors e.g. Ritonavir, Indivavir. They are the most potent inhibitors of HIV replication to date.

Zidovudine (AZT) was the first anti-viral agent shown to have beneficial effect against HIV infection. However, after prolonged use, AZT-resistant strains rapidly appears which limits the effect of AZT. Recent clinical trials reported significant benefit in the use of combination therapy over the use of monotherapy. The rationale for this approach is that by combining drugs that are synergistic, non-cross-resistant and no overlapping toxicity, it may be possible to reduce toxicity, improve efficacy and prevent resistance from arising. In fact, significant success has now been reported for trials involving multiple agents including protease inhibitors. The aim of anti-HIV therapy has now shifted from simply delaying the progression of disease to finding a permanent cure. We have now entered the era of highly active anti-retroviral therapy (HAART).

The current consensus is that one should give  a potent combination of agents HAART right from the start when treatment is indicated. The most popular combination is AZT and lamivudine plus a protease inhibitor. Lamivudine has greater anti-retroviral activity that AZT alone and is active against many AZT-resistant strains without significant increase in toxicity. Among protease inhibitors, indinavir (IDV) is more potent than saquinavir and appears to have fewer drug interactions and short-term adverse effects than ritonavir. In currently recommended doses, AZT prophylaxis is well-tolerated with health workers; short-term toxicity associated with higher doses primarily includes GI symptoms, fatigue, and headache. In HIV-infected adults, 3TC can cause GI symptoms, and rarely pancreatitis. IDV toxicity includes GI symptoms and after prolonged use, mild hyperbilirubinaemia (10%), and kidney stones (4%).Below is a table of some of the drugs available.

It is generally agreed that treatment should be started when CD4<500/ml or viral load >5000 to 10000 copies/ml (bDNA assay). If CD4 count >500/ml but viral load >5000 to 10000 copies/ml (bDNA assay), then recommendations vary. It may then be advisable to treat those who are compliant and committed. The actual recommendations as to when to commence treatment, and the regimen to use varies greatly between different countries.    

 

A. Nucleoside Reverse Transcriptase Inhibitor  

1. AZT
 
 

2. ddI

3. ddC

4. Stavudine

5. Lamivudine

(3TC)

6. Abacavir

200 mg po or IV tds
 
 

125-250 mg bd

0.75 mg q8h

30-40 mg bd

150 mg bd 
 
 

300 mg bd

Bone marrow suppression (anaemia, granulocytopenia), headache, malaise, nausea

Pancreatitis, peripheral neuropathy, minor GI and CNS symptoms 

Peripheral neuropathy, oral ulcers, minor GI and CNS symptoms

Peripheral neuropathy, minor GI and CNS symptoms

Well-tolerated, minor GI and CNS symptoms reported may be due to AZT rather than 3TC. Pancreatitis was reported in 15% of patients in paediatric trials

3% develop hypersensitivity reaction: fever malaise, rash, GI symptoms.

 

B. Non-Nucleoside Reverse Transcriptase Inhibitor  

1. Nevirapine
 
 

2. Delaviridine
 
 

3. Efavirenz

200 mg po (single dose), then 400 mg/day
 

400 mg qds

600mg once daily

Rash
 
 

Transient rash, P450 inhibitor
 
 

Initial dizziness, insomnia, transient rash, P450 inducer

 

C. HIV Protease Inhibitors  

1. Saquinavir

2. Indivavir

3. Ritonavir
 
 

4. Nelfrinavir

5. Amprenavir

6. Lopinavir/
Ritonavir

600 mg tds

800mg po tds

600 mg po bd
 
 

750 mg tds

1200 mg bd

400+100mg bd

headache, neutropenia

kidney stones, bilirubinaemia

Although side-effects are common, they are usually mild and consist mainly of GI symptoms

Diarrhoea common, which may respond to Ultrase MT20 enzyme preparations; occasional nausea

Rash (20%), diarrhoea, nausea 

GI side effects common but mild.

 

2. Monitoring anti-HIV therapy  

a. Viral Load

  1. Initiation - viral load is now the preferred method of monitoring therapy. There should be >= 1 log reduction in viral load, preferably to less than 10,000 copies/ml HIV-RNA within 2-4 weeks after the commencement of treatment. If <0.5 log reduction in viral, or HIV-RNA stays above 100,000, then the treatment should be adjusted by either adding or switching drugs.

  2. Monitoring - viral load measurement should be repeated every 4-6 months if patient is clinically stable. If viral load returns to 0.3-0.5 log of pre-treatment levels, then the therapy is no longer working and should be changed.  

b. CD4 count

  1. Initiation - within 2-4 weeks of starting treatment, CD4 count should be increased by at least 30 cells/mm3. If this is not achieved, then the therapy should be changed.

  2. Monitoring - CD4 counts should be obtained every 3-6 months during periods of clinical stability, and more frequently should symptomatic disease occurs. If CD4 count drops to baseline (or below 50% of increase from pre-treatment), then the therapy should be changed.

 

c. Anti-HIV Drug Resistance Testing

Anti-retroviral  drug resistance testing has become part and parcel of patient management in N. America and W. Europe. Many studies in treatment experienced patients have shown strong associations between the presence of drug resistance and failure of the antiretroviral treatment regimen to suppress HIV replication.

  1. Genotypic Assays - genotypic assays detect drug resistance mutations that are present in the relevant viral genes (i.e. RT and protease). Some genotyping assays involve sequencing of the entire RT and protease genes, while others utilize oligonucleotide probes to detect selected mutations that are known to confer drug resistance. Genotyping assays can be performed relatively rapidly, such that results can be reported within 1-2 weeks of sample collection. Interpretation of test results requires an appreciation of the range of mutations that are selected for by various antiretroviral drugs, as well as the potential for cross-resistance to other drugs conferred by some of these mutations.

  2. Phenotypic Assays - phenotypic assays measure the ability of viruses to grow in various concentrations of antiretroviral drugs. Automated, recombinant phenotyping assays have recently become commercially available with turn-around times of 2-3 weeks; however, phenotyping assays are generally more costly to perform compared with genotypic assays. Recombinant phenotyping assays involve insertion of the RT and protease gene sequences derived from patient plasma HIV RNA into a laboratory clone of HIV. Replication of the recombinant virus at various drug concentrations is monitored by expression of a reporter gene and is compared with replication of a reference strain of HIV. The concentrations of drugs that inhibit 50% and 90% of viral replication (i.e. the IC50 and IC90) are calculated, and the ratio of the IC50s of the test and reference viruses is reported as the fold increase in IC50, or fold resistance. Interpretation of phenotyping assay results is complicated by the paucity of data on the specific level of resistance (fold increase in IC50) that is associated with failure of different drugs.

  3. Use in clinical setting - resistance assays may be useful in the setting of virological failure on antiretroviral therapy. Recent prospective data supporting the use of resistance testing in clinical practice come from trials in which the utility of resistance tests were assessed in the setting of virological failure. The VIRADAPT and GART studies compared virological responses to antiretroviral treatment regimens when genotyping resistance tests were available to help guide therapy with those observed when changes in therapy were guided solely by clinical judgment. The results of both studies indicated that the short-term virological response to therapy was significantly greater when results of resistance testing were available. Similarly, a recent prospective, randomized, multicenter trial has shown that therapy selected on the basis of phenotypic resistance testing significantly improves the virological response to antiretroviral therapy, compared with therapy selected without the aid of phenotypic testing. Thus, resistance testing appears to be a useful tool in selecting active drugs when changing antiretroviral regimens in the setting of virological failure.

The rapidity of developments in anti-HIV therapy makes it virtually impossible for this site to keep up. For the latest information on HIV and anti-retroviral therapy, I recommend the HIV page at Medscape.com

http://www.medscape.com

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Interferons