Current status of antiretroviral therapy

Figures & data

Table 1. General characteristics of nucleoside analogue reverse inhibitors.

Generic name	Dosing forms	Usual dose	Dosage change in renal insufficiency	Major adverse effects*	Food effects	Additional comments
ABC	100-mg capsules, 300-mg tablet	300 mg b.i.d., 600 mg/day	No	Hypersensitivity reactions^‡	No food restrictions	Increased hypersensitivity with once-daily dosing
ABC/ 3TC	600-mg ABC/ 300-mg 3TC tablet	1 tablet/day	Yes	Hypersensitivity reactions	No food restrictions
ABC/ 3TC/ ZDV	300-mg ABC/ 150-mg 3TC/ 300-mg ZDV tablet	1 tablet b.i.d.	Yes	Hypersensitivity reactions, bone marrow suppression	No food restrictions
Didanosine	125-, 200-, 250-, 400-mg enteric-coated capsule	1 capsule every 12 h	Yes	Nausea, pancreatitis, peripheral neuropathy, lipoatrophy	Empty stomach	250-mg dose with TDF
FTC	200-mg capsule	1 capsule/day	No	Hyperpigmentation	No food restrictions	Active against hepatitis B
FTC/ TDF	200-mg FTC/ 300-mg TDF tablet	1 tablet/day	Yes	Possible renal impairment	No food restrictions	Active against hepatitis B
3TC	150-mg tablet	150 mg b.i.d., 300 mg/day	Yes	Minimal toxicity	No food restrictions	Active against hepatitis B
Stavudine	15-,20-, 30-, 40-mg capsule	1 capsule b.i.d.	Yes	Peripheral neuropathy, hyperlipidaemia, lipoatrophy	No food restrictions	Adults < 60 kg, use 30 mg b.i.d.
TDF	300-mg tablet	1 tablet/day	Yes	Possible renal impairment	No food restrictions	Active against hepatitis B
ZDV	100-mg capsule, 300-mg tablet	1 tablet b.i.d.	Yes	Nausea, bone marrow suppression	No food restrictions

*Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of all nucleoside analogues and are believed to be caused by NRTI/NtRTI-induced mitochondrial damage. The deoxynucleoside analogue reverse transcriptase inhibitors (zalcitabine, stavudine, didanosine) have a higher potential to cause mitochondrial DNA depletion than other NRTI/NtRTIs.

^‡Hypersensitivity reactions have been reported in ∼ 5% of patients receiving ABC. ABC should be discontinued as soon as a hypersensitivity reaction is first suspected, and should not be restarted because life-threatening hypotension and death may occur.

3TC: Lamivudine; ABC: Abacavir; FTC: Emtricitabine; NRTI: Nucleotide analogue reverse transcriptase inhibitors; NtRTI: Nucleotide reverse transcriptase inhibitors; TDF: Tenofovir; ZDV: Zidovudine.

Table 2. General characteristics of the currently available non-nucleoside analogue reverse transcriptase inhibitors.

Generic name	Available forms	Usual dose	Food effect	Metabolism and elimination	Major adverse effects	Additional comments
Delavirdine	100- or 200-mg tablets	400 mg t.i.d.	None, can take with or without food	CYP3A4 substrate, inhibits its own metabolism	Rash, rare Stevens-Johnson syndrome, headache, elevated transaminases	Avoid St. John’s Wort and be aware of potential for serious drug interactions
Efavirenz	50-, 100-, 200-mg capsules or 600-mg tablets	600 mg/day	Take on an empty stomach	CYP3A4 substrate and can induce its own metabolism	Rash, rare Stevens-Johnson syndrome, CNS symptoms: including dizziness, somnolence, insomnia, abnormal dreams, amnesia, agitation, hallucinations and euphoria, hyperlipidaemia, elevated transaminases, teratogenic in primate studies	Avoid in pregnancy, CNS symptoms usually subside after 2 – 4 weeks of treatment, false-positive cannabinoid test
Nevirapine	200 mg/day for 14 days then increase to 200 mg b.i.d.	200 mg tablets or 50 mg/ 5 ml oral suspension	None, can take with or without food	Metabolised by CYP3A4 and CYP2B6: induces both enzymes 20 – 25%	Rash including occasional Stevens-Johnson syndrome, hepatitis, hyperlipidaemia	Fatal hepatitis has not been observed when nevirapine is given as single doses to mothers or infants for prevention of mother-to-child HIV transmission

CYP: Cytochrome P450.

Table 3. General characteristics of currently available protease inhibitors

Generic name	Available forms	Usual dose	Food effect	Major adverse effects	Additional comments*
ATV	100-, 150- and 200-mg capsules.	400 mg/day or RTV 100 mg plus ATV 300 mg/day. Use boosted ATV for treatment- experienced patients.	Take with food and avoid antacids to increase bioavailability.	Indirect hyperbilirubinaemia, rash, prolongation of PR interval, gastrointestinal	Lowest risk of hyperlipidaemia among protease inhibitors. Avoid proton pump inhibitors. Avoid use with IDV as both cause hyperbilirubinaemia. Use only boosted ATV if taking tenofovir and monitor for tenofovir-related toxicity.
f-APV	Treatment-naive patients: f-APV 1400 mg b.i.d. or f-APV 1400 mg plus RTV 200 mg/day or f-APV 700 mg plus RTV 100 mg b.i.d. PI-experienced patients: f-APV 700 mg plus RTV 100 mg b.i.d. Use boosted f-APV if co-administered with EFV.	700-mg tablet.	Can be taken with or without food as food has no significant effect on pharmacokinetics.	Rash, gastrointestinal, hyperglycaemia, hyperlipidaemia, headache, hepatotoxicity	Contains a sulfa moiety.
IDV	800 mg every 8 h. With RTV: IDV 800 mg plus RTV 100 or 200 mg every 12 h. Adjust dose with hepatic insufficiency.	200-, 333-, 400-mg capsules.	If unboosted take on empty stomach or with light snack. RTV-boosted IDV can take with or without food.	Nephrolithiasis, hyperbilirubinaemia, gastrointestinal, insulin resistance, hyperglycaemia, hyperlipidaemia, hepatotoxicity	Avoid use with ATV as both cause hyperbilirubinaemia.
LPV/RTV	400/100 mg b.i.d. or 800/200 mg/day (Once-daily dose only for treatment-naive patients). Reduce dose with EFV or NVP: LPV 533 mg plus RTV 133 mg b.i.d.	133.3-mg LPV plus 33.3-mg RTV per capsule. Oral soloution: each 5 ml contains 400 mg LPV plus 100 mg RTV.	Take with meals.	Gastrointestinal (particularly diarrhoea), hyperlipidaemia (especially hypertriglyceridaemia), elevated transaminases, hyperglycaemia, hepatotoxicity	Oral solution is 42% alcohol.
Nelfinavir	750 mg t.i.d. or 1250 mg b.i.d.	250- or 625-mg tablets. Powder: 50 mg/g (level scoop).	Take with meals.	Gastrointestinal (particularly diarrhoea), hyperglycaemia, hyperlipidaemia, hepatotoxicity	Has an active metabolite (M8). Cannot be reliably boosted by RTV.
RTV	600 mg b.i.d. when used as sole protease.	100-mg capsules or 600-mg/ 7.5-ml liquid.	Take with meals.	Gastrointestinal, paresthesia, taste perversion, hyperlipidaemia, hyperglycaemia, hepatotoxicity	The most potent CYP inhibitor. Currently only used for its pharmacokinetic enhancement properties.
SQV-sgc	1200 mg t.i.d. With RTV: RTV 100 mg plus SQV-scg 1000 mg b.i.d.		Take with fatty snacks or meal. Levels increase up to sixfold with food.	Gastrointestinal, hepatotoxicity, hyperglycaemia
Tipranavir	500 mg b.i.d. with RTV 200 mg b.i.d.	250-mg capsules	Take with food. Bioavailability increased with high-fat meal.	Hepatotoxicity, rash, hyperlipidaemia (especially hypertriglyceridaemia), hyperglycaemia, gastrointestinal	Contains a sulfa moiety. Cannot be combined with many other protease inhibitors.

*Please see text regarding metabolism and potential for serious drug–drug interactions involving the CYP system. ATV: Atazanavir; CYP: Cytochrome P450; EFV: Efavirenz; f-APV: Fosamprenavir; IDV: Indinavir; LPV: Lopinavir; NVP: Nevirapine; RTV: Ritonavir; SQV-sgc: Saquinavir soft gel cap.

Table 4. Investigational drugs in existing classes of antiretrovirals in advanced clinical development.

Drug	Development stage
Nucleoside/nucleotide analogues
Racivir	Phase I/II
Protease inhibitors
Darunavir (TMC-114)	Phase III
Brecanavir	Phase II
Non-nucleoside analogue reverse transcriptase inhibitors
Etravirine (TMC-125)	Phase III
Rilpivirine (TMC-278)	Phase II
BILR-355 BS	Phase IIa

Table 5. Investigational drugs in new classes of antiretrovirals in advanced clinical development.

Drug	Antiretroviral class	Development stage
TNX-355	Attachment inhibitor	II
PRO-140	CCR5 co-receptor antagonist	II
Vicriviroc (SCH-417,690)	CCR5 co-receptor antagonist	II/III
Maraviroc (UK-427,857)	CCR5 co-receptor antagonist	II/III
MK-0518	Integrase inhibitor	II/III
Bevirimat (PA-457)	Maturation inhibitor	IIa

Table 6. Antiretroviral drugs/components not recommended for initial therapy.

Antiretroviral drugs/component	Reason for not being recommended
Delavirdine	Inferior virological efficacy, inconvenient dosing
Didanosine plus tenofovir plus non-nucleoside analogue reverse transcriptase inhibitor	High rate of virological failure, immunological non-response
Enfuvirtide	No data in treatment-naive, patients, injectible
Indinavir (unboosted)	Inconvenient dosing
Ritonavir as sole protease inhibitor	High pill burden, gastrointestinal intolerance
Saquinavir soft gel capsule (unboosted)	Inferior virological efficacy, high pill burden
Tipranavir	No data in treatment-naive patients

Modified from the Department of Health and Human Services guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (May 4, 2006).

Table 7. Antiretroviral regimens or components that should not be offered at any time.

Antiretroviral drugs or components	Reason for not being recommended
Monotherapy	Inferior antiretroviral efficacy.
Two nucleotide analogue reverse transcriptase inhibitor regimens	Inferior antiretroviral efficacy.
Abacavir plus tenofovir plus lamivudine (or emtricitabine)	Inferior antiretroviral efficacy.
Tenofovir plus didanosine plus lamivudine (or emtricitabine)	Inferior antiretroviral efficacy.
Amprenavir oral solution	Contains large amount of the propylene glycol, which may be toxic in: • pregnant women, • children < 4 years of age, • patients with renal or hepatic failure, • patients on metronidazole or disulfiram.
Amprenavir oral solution plus ritonavir oral solution	Similar to propylene glycol for amprenavir, ethanol is the vehicle for oral ritonavir solution. Administering these together may lead to accumulation of either one of the vehicles.
Atazanavir plus indinavir	Additive toxicity: hyperbilirubinaemia.
Didanosine plus stavudine	Additive toxicities: peripheral neuropathy, pancreatitis, hyperlactataemia.
Efavirenz in first trimester of pregnancy or in women with significant child-bearing potential	Teratogenic.
Emtricitabine plus lamivudine	No benefit.
Nevirapine in women with CD4^+ > 250 cells/mm^3 or men with CD4^+ > 400 cells/mm^3	Hepatotoxicity.
Saquinavir hard gel capsule as single protease inhibitor	Inferior antiviral activity.
Stavudine plus zidovudine	Antagonistic.

Modified from the Department of Health and Human Services guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (May 4, 2006).

Table 8. Revised WHO clinical staging system for HIV/AIDS.

Stage	Symtoms
Primary HIV infection	Asymptomatic Acute retroviral syndrome
Clinical stage 1	Asymptomatic Persistent generalised lymphadenopathy
Clinical stage 2	Moderate unexplained weight loss (< 10% of presumed or measured body weight) Recurrent respiratory tract infections Herpes zoster Angular cheilitis Recurrent oral ulcerations Papular pruritic eruptions Seborrhoeic dermatitis Fungal nail infections of fingers
Clinical stage 3: conditions where a presumptive diagnosis can be made on the basis of clinical signs or simple investigations	Severe weight loss (> 10% of presumed or measured body weight) Unexplained chronic diarrhoea for longer than 1 month Unexplained persistent fever (intermittent or constant for longer than 1 month) Oral candidiasis Oral hairy leukoplakia Pulmonary tuberculosis diagnosed in last 2 years Severe presumed bacterial infections (e.g., pneumonia, empyema, pyomyositis, bone or joint infection, meningitis, bacteraemia) Acute necrotising ulcerative stomatitis, gingivitis or periodontitis
Clinical stage 3: conditions where confirmatory diagnostic testing is necessary	Unexplained anaemia (< 8 g/dl), and or neutropenia (< 500/mm^3) and/or thrombocytopenia (< 50,000/mm^3) for more than 1 month
Clinical stage 4: conditions where a presumptive diagnosis can be made on the basis of clinical signs or simple investigations	HIV-wasting syndrome Pneumocystis pneumonia Recurrent severe or radiological bacterial pneumonia Chronic herpes simplex infection (orolabial, genital or anorectal of > 1 month’s duration) Oesophageal candidiasis Extrapulmonary tuberculosis Kaposi’s sarcoma CNS toxoplasmosis HIV encephalopathy
Clinical stage 4: conditions where confirmatory diagnostic testing is necessary	Extrapulmonary cryptococcosis including meningitis Disseminated non-tuberculous mycobacteria infection Progressive multifocal leukoencephalopathy Candida of trachea, bronchi or lungs Cryptosporidiosis Isosporiasis Visceral herpes simplex infection Cytomegalovirus infection (retinitis or of an organ other than the liver, spleen or lymph nodes) Any disseminated mycosis (e.g., histoplasmosis, coccidiomycosis, penicilliosis) Recurrent non-typhoidal salmonella septicaemia Lymphoma (cerebral or B-cell non-Hodgkin) Invasive cervical carcinoma Visceral leishmaniasis

Figure 1. Simplified schema of the HIV-1 life cycle. A. The interaction between the envelope proteins of the virus and CD4 receptor and co-receptors of the host cell leads to the binding of the viral envelope and the host cytoplasmic membrane. B. The viral reverse transcriptase enzyme catalyses the conversion of viral RNA into DNA. C. The proviral DNA enters the nucleus and becomes integrated into the chromosomal DNA of the host cell. This process is catalysed by the viral enzyme integrase. D. Expression of the viral genes leads to production of viral RNA and proteins. E. The protease enzyme cleaves the precursor gag and gag-pol proteins into functional mature products. F. Viral proteins as well as viral RNA are assembled at the cell surface into new viral particles and leave the host cell by a process called budding. During the process of budding, they acquire the outer layer and envelope. Reprinted from HIV infection in Mayo Clinic Internal Medicine Board Review 2004 – 2005, with permission of Mayo Foundation for Medical Education and Research. All rights reserved.

Figure 2. HIV cell entry. Reprinted with permission from TRIMERIS, INC. Copyright owned by TRIMERIS, INC. This diagram is for illustrative purposes only.

Figure 3. The Department of Health and Human Services-preferred regimens for first-line antiretroviral therapy.