Anti-Retrovirus Drugs

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Chapter: Essential pharmacology : Antiviral Drugs

These are drugs active against human immunodeficiency virus (HIV) which is a retrovirus. They are useful in prolonging and improving the quality of life and postponing complications of acquired immunodeficiency syndrome (AIDS) or AIDSrelated complex (ARC), but do not cure the infection.


ANTI-RETROVIRUS DRUGS

 

These are drugs active against human immunodeficiency virus (HIV) which is a retrovirus. They are useful in prolonging and improving the quality of life and postponing complications of acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC), but do not cure the infection. The clinical efficacy of anti-retrovirus drugs is monitored primarily by plasma HIV-RNA assays and CD4 lymphocyte count carried out at regular intervals.

 

The first antiretrovirus (ARV) drug Zidovudine was developed in 1987. Over the past 20 years, 20 drugs belonging to 3 classes have been introduced and a large number of others are under development.

 

NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIS)

 

Zidovudine It is a thymidine analogue (azidothymidine, AZT), the prototype NRTI. After phosphorylation in the host cell—zidovudine triphosphate selectively inhibits viral reverse transcriptase (RNAdependent DNA polymerase) in preference to cellular DNA polymerase.

 


 

On the template of single-stranded RNA genome of HIV a double-stranded DNA copy is produced by viral reverse transcriptase. This DNA translocates to the nucleus and is integrated with chromosomal DNA of the host cell, which then starts transcribing viral genomic RNA as well as viral mRNA. Under the direction of viral mRNA, viral regulatory and structural proteins are produced. Finally, viral particles are assembled and matured. Zidovudine thus prevents infection of new cells by HIV, but has no effect on virus directed DNA that has already integrated into the host chromosome. It is effective only against retroviruses. Zidovudine itself gets incorporated into the growing viral DNA and terminates chain elongation. Resistance to AZT occurs by point mutations which alter reverse transcriptase enzyme. In the past, when AZT was used alone, >50% patients became nonresponsive to AZT within 1–2 years therapy due to growth of resistant mutants.

 

Pharmacokinetics  The oral absorption of AZT is rapid, but bioavailability is ~65%. It is quickly cleared by hepatic glucuronidation (t½ 1 hr); 15–20% of the unchanged drug along with the metabolite is excreted in urine. Plasma protein binding is 30% and CSF level is ~50% of that in plasma. It crosses placenta and is found in milk.

 

Dose Adults 300 mg BD; Children 180 mg/m2 (max 200 mg) 6–8 hourly.

 

RETROVIR, ZIDOVIR 100 mg cap, 300 mg tab, 50 mg/5 ml syr VIROZ, ZIDOMAX, ZYDOWIN 100 mg cap, 300 mg tab. (to be taken with plenty of water).

 

Adverse Effects Toxicity is mainly due to partial inhibition of cellular DNA polymerase. Anaemia and neutropenia are the most important and doserelated adverse effects.

 

Nausea, anorexia, abdominal pain, headache, insomnia and myalgia are common at the start of therapy but diminish later.

 

Myopathy, lactic acidosis, hepatomegaly, convulsions and encephalopathy are infrequent.

 

Interactions Paracetamol increases AZT toxicity, probably by competing for glucuronidation. Azole antifungals also inhibit AZT metabolism. Other nephrotoxic and myelosuppressive drugs and probenecid enhance toxicity. Stavudine and zidovudine exhibit mutual antagonism by competing for the same activation pathway.

 

Use

 

Zidovudine is used in HIV infected patients only in combination with at least 2 other ARV drugs. However, its efficacy as monotherapy in AIDS has been confirmed in the past. HIVRNA titer is reduced to undetectable levels and CD4 count increases progressively. Immune status is improved and opportunistic infections become less common. There is a sense of wellbeing and patients gain weight. AZT also reduces neurological manifestations of AIDS and new Kaposi’s lesions do not appear. Mortality among AIDS patients is reduced. It has also been shown to slow the progression of HIV infection, including escalation of ARC to full blown AIDS. However, beneficial effects are limited from a few months to a couple of years after which progressively non-responsiveness develops.

 

AZT, along with one or two other ARV drugs is the standard choice for post exposure prophylaxis of HIV, as well as mother to offspring transmission.

 

Didanosine (ddI)  It is a purine nucleoside analogue which after intracellular conversion to didanosine triphosphate competes with ATP for incorporation in viral DNA, inhibits HIV reverse transcriptase and terminates proviral DNA. Antiretroviral activity of didanosine is equivalent to AZT. Mutational resistance develops, but only few AZT resistant mutants are nonresponsive to didanosine also. Now it is used only in combination regimens.

 

Dose: 200 mg BD (for > 60 kg BW), 125 mg BD (< 50 kg BW) 1 hour before or 2 hour after meals.

 

DINEX EC, DDRETRO, VIROSINE DR 250 mg, 400 mg tabs.

 

Oral absorption of didanosine is somewhat erratic due to acid lability. It is metabolized as well as excreted unchanged; t½ 1 to 1.5 hr. In contrast to AZT, it does not cause myelosuppression. The major doserelated toxicity is peripheral neuropathy and rarely pancreatitis. Diarrhoea, abdominal pain and nausea are the side effects.

 

Stavudine (d4T) It is also a thymidine analogue which acts in the same way as AZT. By utilizing the same thymidine kinase for activation, AZT antagonises the effect of stavudine. Resistance to stavudine develops as for other NRTIs.

 

It is well absorbed orally and rapidly metabolized (t½ 1.5 hr). The antiHIV efficacy of stavudine is comparable to AZT, and it is used in combination regimens. Peripheral neuropathy, lipodystrophy and rarely pancreatitis are the serious toxicies which have restricted its use.

 

Dose: 40 mg BD ( > 60 kg BW), 30 mg BD (< 60 kg BW) STAG, STAVIR, VIROSTAV 30, 40 mg caps.

 

Lamivudine (3TC) This deoxycytidine analogue is phosphorylated intracellularly and inhibits HIV reverse transcriptase as well as hepatitis B virus (HBV) DNA polymerase. Its incorporation into DNA results in chain termination. Most human DNA polymerases are not affected and systemic toxicity of 3TC is low. Point mutation in HIVreverse transcriptase and HBVDNA polymerase gives rise to rapid lamivudine resistance. Certain lamivudineresistant mutants become slow growing. Some crossresistance with ddI has been noted among HIV.

 

Oral bioavailability of 3TC is high and plasma t½ longer (6–8 hours). Intracellular t½ is still longer (> 12 hr). It is mainly excreted unchanged in urine.

 

Lamivudine is used in combination with other antiHIV drugs, and appears to be as effective as AZT. It is also frequently used for chronic hepatitis B. HBVDNA titre is markedly reduced and biochemical as well as histological indices of liver function improve. However, viral titres rise again after discontinuation. Even with continued medication HBV viraemia tends to return after 1 year due to emergence of resistant mutants.

 

Dose: For chronic hepatitis B—100 mg OD For HIV infection— 150 mg BD.

 

LAMIVIR 150 mg tab, 150 mg/ 5 ml soln; LAMIVIRHBV 100 mg tab; HEPTAVIR, LAMIDAC, LAMUVID, VIROLAM 100, 150 mg tabs;

 

Lamivudine is generally well tolerated. Side effects are few—headache, fatigue, nausea, anorexia, abdominal pain. Pancreatitis and neuropathy are rare. Hematological toxicity does not occur.

 

Abacavir (ABC) This guanosine analogue is a potent ARV drug that acts after intracellular conversion to carbovir triphosphate. Resistance to ABC develops slowly, and it exhibits little cross resistance with other NRTIs. Its oral bioavailability is 80% and it is mainly eliminated by metabolism. The plasma t½ is 1–1.5 hour, but intracellular t½ of active metabolite is >12 hours. Hypersensitivity reactions such as rashes, fever, flulike symptoms are the major problems. Some fatalities have occurred when patients developing the reaction were given further doses of ABC. Avoidance of alcohol is advised.

 

Dose: 300 mg BD or 600 mg OD.

 

ABAVIR, ABAMUNE 300 mg tab.

 

NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIS)

 

Nevirapine (NVP) and Efavirenz (EFV) These are nucleoside unrelated compounds which directly inhibit HIV reverse transcriptase without the need for intracellular phosphorylation. Their locus of action on the enzyme is also different. They are more potent than AZT on HIV1, but do not inhibit HIV2. Viral resistance to these drugs develops by point mutation and cross resistance is common among different NNRTIs, but not with NRTIs or PIs.

 

Nevirapine is well absorbed orally and is extensively metabolized in liver with a t½ of 30 hours. Oral absorption of efavirenz is incomplete (50%), but t½ is longer (48 hours) and it is totally metabolized. Both NVP and EFV modestly induce CYP 3A4, 2D6 enzymes and enhance their own metabolism as well as that of other drugs.

 

The NNRTIs are indicated in combination regimens for HIV, and have succeeded in reducing HIVRNA levels when an earlier regimen has failed.

 

Nevirapine Dose 200 mg/day, may be increased later to 200 mg BD.

 

NEVIMUNE, NEVIVIR, NEVIPAN, NEVIRETRO 200 mg tab

 

Rashes (commonest), nausea, headache are the usual side effects. Fever and rise in liver enzymes can occur. Nevirapine is potentially hepatotoxic. Avoid enzyme inducers (rifampin) and enzyme inhibitors (ketoconazole).

 

Efavirenz: Dose 600 mg OD on empty stomaCh. No. EFAVIR, VIRANZ 200 mg tab., EVIRENZ 200 mg cap, 600 mg tab.

 

Side effects are headache, rashes, dizziness, insomnia and a variety of neuropsychiatric symptoms. It induces the metabolism of certain drugs and inhibits that of others.

 

RETROVIRAL PROTEASE INHIBITORS (PIS)

 

An aspartic protease enzyme encoded by HIV is involved in the production of structural proteins and enzymes (including reverse transcriptase) of the virus. The large viral polyprotein is broken into various functional components by this enzyme. This protease acts at a late step in HIV replication, i.e. maturation of the new virus pCh. No.s when the RNA genome acquires the core proteins and enzymes. Five protease inhibitors—Indinavir (IDV), Nelfinavir (NFV), Saquinavir (SQV), Ritonavir (RTV) and Lopinavir (in combination with ritonavir LPV/r) have been marketed in India for use against HIV. They bind to the protease molecule, interfere with its cleaving function, and are more effective viral inhibitors than AZT. Because they act at a late step of viral cycle, they are effective in both newly and chronically infected cells. Under their influence, HIV-infected cells produce immature noninfectious viral progeny—hence prevent further rounds of infection.

 

Oral bioavailability of PIs is variable (IDV and RTV ~65%, NFV >20%, SQV 15%) and their plasma t½ ranges from 2–5 hours. All are extensively metabolized by CYP3A4 and other CYP isoenzymes. All (especially ritonavir and lopinavir) are potent inhibitors of CYP3A4, while few other CYP isoenzymes are induced. The PIs interact with many drugs. Nelfinavir and ritonavir induce their own metabolism.

 

Monotherapy with one of these drugs in previously AZT treated patients reduced HIV viral levels, increased CD4 cell count and improved the clinical condition. However, viral resistance developed against the PIs over months due to selection of resistant mutants in a stepwise manner. Combination of NRTIs with PIs has been found more effective than either drug given alone, and triple therapy is more effective than double therapy. Current recommendations are to use a PI in combination with either two NRTIs or one NRTI + one NNRTI.

 

Because different PIs both inhibit and induce specific CYP isoenzymes to different extents, drug interactions with them are common and often unpredictable. Manufacturer’s package inserts should be consulted while co-prescribing any other drug. Specifically, metabolism of PIs is induced by rifampin and other enzyme inducers rendering them ineffective. Another problem in their use is the large tablet load. In case of different PIs, 6–18 tablets are to be taken daily, some on empty stomach, but others with meals; and this has to go on for months and years. Patient acceptability and compliance are often low. One of the strategies adopted to reduce the dose of IDV, LPV and SQV is to combine them with a low and subtherapeutic dose (100 mg) of ritonavir. By reducing first pass metabolism, ritonavir increases the bioavailability of the companion PI. This ‘boosted PI regimen’ permits reduction in the number/frequency of tablets to be taken each day. Lopinavir is marketed only in combination with ritonavir. Nelfinavir is not to be combined with ritonavir.

 

The most prominent adverse effects of PIs are gastrointestinal intolerance, asthenia, headache, dizziness, limb and facial tingling, numbness and rashes. Of particular concern are lipodystrophy (abdominal obesity, buffalo hump with wasting of limbs and face) and dyslipidaemia (raised triglycerides and cholesterol) which may necessitate hypolipidaemic drugs. Diabetes may be exacerbated. Indinavir crystalises in urine and increases risk of urinary calculi.

 

Indinavir It is to be taken on empty stomach; g.i. intolerance is common; excess fluids must be consumed to avoid nephrolithiasis.

 

Dose: 800 mg TDS (BD if taken with 100 mg RTV).

 

INDIVAN, INDIVIR, VIRODIN 400 mg cap.

 

Nelfinavir It is to be taken with meals and bioavailability is erratic. Often produces diarrhoea and flatulence; clinical efficacy may be somewhat lower than other PIs.

 

Dose: 750 mg TDS; NELFIN, NELVIR, NEIVEX 250 mg tab.

 

Ritonavir It is a potent PI; also a potent CYP3A4 inhibitor. Drug interactions, nausea, diarrhoea, paresthesias, fatigue and lipid abnormalities are prominent.

 

Dose: 600 mg BD, to be taken with food.

 

RITOMUNE, RITOMAX 100 mg cap; RITOVIR 250 mg tab.

 

Saquinavir Two types of formulations (hard gel and soft gel capsules) with differing, but low oral bioavailability have been produced. The tablet load is large and side effects are frequent; photosensitivity can occur. It is a weak inhibitor of CYP3A4.

 

Dose: 1200 mg TDS on full stomach; 1000 mg BD (with RTV 100 mg).

 

SAQUIN 200 mg tab.

 

Lopinavir It is available only in combination with RTV to improve bioavailability. Diarrhoea, abdominal pain, nausea and dyslipidaemias are more common.

 

Dose: 400 mg (with ritonavir 100 mg) BD with food.

 

RITOMAXL: lopinavir 133.3 mg + ritonavir 33.3 mg cap.

 

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