Antiretroviral Therapy

Rationale and Background Pathophysiology of HIV Infection

General Guidelines Specific Guidelines

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Rationale and Background

The past several years have shown great advances in the management of HIV disease. All patients with HIV infection, including those with very advanced disease, may benefit from antiretroviral therapy. Because of the rapidly changing nature of clinical practice in this area, expertise should be sought when initiating or changing drug regimens.

The following recommendations are based on our current understanding of the pathophysiology of HIV disease and the results of clinical trials. They reflect updated guidelines of US Department of Health and Human Services (DHHS) and the International AIDS Society USA Panel.


Pathophysiology of HIV Infection

Contrary to earlier understanding, viral replication occurs throughout the course of HIV infection at astonishing rates. It is estimated that 1010 viral particles are produced each day. The patient's immune system keeps pace with this activity during the clinical latency period. However, in the absence of effective antiretroviral treatment, the immune system ultimately reaches a "point of exhaustion," at which viral replication exceeds its ability to produce CD4 cells. This leads to a decline in immunologic function and the development of clinical manifestations including opportunistic infections and neoplasms.

The rate of viral replication is thought to stabilize after primary infection at a particular level or "set point." This level may be maintained within a ten-fold range over months and possibly years. The viral load is highly correlated with the rate of disease progression and mortality.

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General Guidelines

The primary goal of antiretroviral therapy should be "to keep the viral load as low as possible for as long as possible." Maximal suppression of the virus makes it more difficult for resistance to develop. Partial suppression results in the emergence of "quasi-species," which are pre-existing resistant mutant strains in the viral population. These are present because of the rapid turnover of HIV and the many random errors made during replication. They predominate in the context of ineffective treatment because of a competitive advantage over pansensitive ("wild type") virus.

Between 50 and 80 percent of patients started on combination antiretroviral therapy will achieve maximal viral suppression, and this effect is durable in the majority. Medication adherence is key. Second and subsequent attempts at viral suppression are less often successful. Current antiretroviral regimens are not curative probably because of persistence of HIV in quiescent CD4 lymphocytes and because of "sanctuary sites," which are regions of the body, such as central nervous system and gonads, in which some drugs do not penetrate well.

Combination antiretroviral therapy is now considered the standard of care for HIV infection. Monotherapy and less potent combination regimens lead to the development of viral resistance within weeks to months. The Food and Drug Administration has approved sixteen antiretroviral agents (nineteen formulations). They are classified by their mode of action against the virus into the following categories: 1) nucleoside reverse transcriptase inhibitors (NRTIs); 2) non-nucleoside reverse transcriptase inhibitors (NNRTIs); and 3) protease inhibitors (PIs).

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Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Generic Name	Abbreviation	Brand Name
zidovudine	ZDV, AZT	Retrovir
didanosine	ddI	Videx
zalcitabine	ddC	HIVID
stavudine	d4T	Zerit
lamivudine	3TC	Epivir
abacavir	ABC	Ziagen
tenofovir (nucleotide agent)		Viread

Fixed dose combination preparations include ZDV/3TC (Combivir) and ZDV/3TC/ABC (Trizivir).

Non-nucleoside Reverse Transcriptase Inhibitors
Generic Name	Abbreviation	Brand Name
nevirapine	NVP	Viramune
delavirdine	DLV	Rescriptor
efavirenz	EFV	Sustiva

Protease Inhibitors
Generic Name	Abbreviation	Brand Name
saquinavir	SQV	Invirase [hard gel], Fortovase [soft gel]
ritonavir	RTV	Norvir
indinavir	IDV	Crixivan
nelfinavir	NFV	Viracept
amprenavir	APV	Agenerase
lopinavir/ritonavir	LPV	Kaletra

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Dosing, toxicity, and other information for individual agents are described in the drug glossary. Antiretroviral agents vary considerably in their dosing and frequency, how they should be administered (with food or when fasting), their side effect profiles, and their potential interactions with other drugs.

Specific Guidelines

When should antiretroviral therapy be initiated?

Antiretroviral therapy is recommended in HIV-infected patients who meet any of the following criteria:

• CD4 count < 350/mm³
  
• viral load above 55,000 copies/ml (PCR) or 30,000 (bDNA)
  
• symptomatic disease regardless of CD4 cell count or HIV viral load
  
• HIV seroconversion within prior six months
  
• pregnancy
  

PCR = polymerase chain reaction; bDNA = branched-chain DNA.

Baseline laboratory testing, including CD4 cell count and viral load measurement, should be performed before initiating therapy. Because of variability in test results, it may be prudent to repeat the baseline CD4 count and viral load before initiating therapy.

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What agents should be used?

Combination therapy using three drugs is recommended as initial therapy in most patients. This should include two NRTI agents given in conjunction with one or more PIs or an NNRTI. Three NRTIs also have been used by some clinicians in this setting, although supporting data are more limited. A regimen including either a PI or efavirenz should be considered in patients with a very low CD4 cell count or high viral load measurement. The use of all monotherapies; d4T with ZDV; and ddC with ddI, d4T, or 3TC should be avoided.

Patient adherence to medical therapy is essential. Frequently missed doses will render a drug regimen ineffective and lead to the development of resistance. Missing as few as 5 to 10 percent of doses will decrease the likelihood of achieving viral suppression. Every effort should be made to address factors, such as active substance abuse or significant psychological problems, which may interfere with medication adherence (Table 1).

PIs have many potential drug interactions (Tables 2, 3, and 4). Some agents are contraindicated for co-administration, and others may require dosage adjustment. Medication lists should be carefully reviewed prior to beginning therapy with these agents to determine the need for dosage or drug modification.

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How should antiretroviral therapy be monitored?

Patients started on antiretroviral therapy should return in four weeks to assess toxicity of the regimen and to repeat the CD4 cell count and viral load. If the drug regimen is well tolerated, the CD4 cell count is rising, and the viral load is maximally suppressed, it is continued, and repeat laboratory parameters are obtained in three months.

When should an antiretroviral drug regimen be modified?

Indications for modification of a drug regimen include the inability to tolerate medication(s), inadequate viral load suppression or rising viral load, declining CD4 cell count, or clinical disease progression. A rising viral load is often the first evidence of resistance and should be repeated. This finding also should prompt inquiry into the patient's medication adherence. If it has been compromised, every effort should be made to address those factors involved, and the viral load should be repeated one month later before considering modification of the regimen.

If a modified antiretroviral regimen is necessary, how should new drugs be chosen?

If the regimen is being changed because of development of viral resistance, an entirely new combination that does not share cross-resistance with current drugs is recommended. A careful prior antiretroviral drug history is important in selecting new agents, and HIV resistance testing is also useful in this setting (see below). The genotype test provides a genetic "blueprint" of the predominant viral strain, and the phenotype test provides a drug-sensitivity profile. Expert consultation is recommended for providers with limited clinical experience in interpreting these tests.

If the regimen is being modified because of toxicity to one drug, a single agent of the same class may be substituted for it.

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HIV Resistance Testing

The genotype test determines the presence of specific mutations in the HIV genome that correlate with clinical resistance to individual antiretroviral drugs. Results are generally interpreted using rules-based algorithms. The phenotype test measures the inhibitory concentration (50% or 90%) of drugs and compares them to values seen with a pansensitive ("wild type") strain. Changes of greater than 2.5- to 4-fold are reliably detected. Results are generally categorized as sensitive, resistant, or intermediate. Genotype testing is more readily available and less costly than phenotype testing but provides an indirect measure of susceptibility. Both tests examine only the predominant viral strain isolated, and may miss resistant "quasi-species." Because of this, they are good at identifying drugs to which the virus is resistant but may be of limited help in predicting which ones will be effective.

Lipodystrophy Syndrome and Other Complications

In addition to specific toxicities listed for individual drugs, lipodystrophy syndrome has been reported in some patients on combination antiretroviral therapy, especially regimens containing d4T and/or PIs. This syndrome consists of body morphology changes (deposition of fat in abdomen, breasts, and neck; loss of fat in face and extremities), metabolic complications (hyperlipidemia, glucose intolerance/diabetes mellitus), or both. Its epidemiology and pathogenesis are not yet fully understood, and its optimal management is unknown. Lactic acidosis with a variety of clinical manifestations (peripheral neuropathy, pancreatitis, myopathy, steatosis with liver failure) has been described in patients on NRTI-based regimens. Routine screening for this condition in asymptomatic individuals is not recommended. However, in patients on NRTI-based regimens who have unexplained constitutional or gastroinitestinal symptoms, a venous lactate level is recommended. Premature osteopenia/osteoporosis and avascular necrosis of the hips have also been reported in HIV-infected patients on long-term antiretroviral therapy.

Unresolved Questions

There are several questions about antiretroviral therapy that are still unanswered and that are the subject of ongoing research. Included among these are the following:

How durable is the effect of combination antiretroviral therapy?

What is the optimal role of genotypic and phenotypic testing?

What is the pathophysiology of long-term complications?

Special Considerations in Pregnant Women

Zidovudine (ZDV) has been shown to decrease the transmission of HIV from mother to child. AIDS Clinical Trials Unit (ACTG) study 076 demonstrated that treating HIV-infected women with ZDV during the second and third trimesters of pregnancy through delivery and treating the newborn can reduce the risk of vertical transmission by two-thirds. More recent data suggest that other antiretroviral drugs may also be effective.

HIV-infected women should be treated with antiretroviral therapy using standard criteria. During pregnancy, ZDV is often prescribed as part of such a regimen. The combination of ddI and d4T should be avoided because of case reports of severe lactic acidosis and pancreatitis. Efavirenz is contraindicated because of demonstrated teratogenicity in laboratory animals.

Recommended Antiretroviral Regimen

• Maternal Rx during 2nd and 3rd Trimesters: Combination therapy should include ZDV 100 mg po five times/day whenever feasible in the clinical setting.
  
  
• Intrapartum Rx: ZDV intravenously during labor and delivery; 2 mg/kg loading dose over 2 to 1 hour followed by continuous infusion of 1 mg/kg per hour through delivery.
  
  
• Newborn Rx: ZDV syrup 2 mg/kg po 4 doses/day for 6 weeks; start within 8 to 12 hours of birth. If infant is NPO, IV ZDV (1.5 mg/kg over one-half hour every 6 hours) can be given.

 

 

Table 1. Factors Having Negative Impact on Medication Adherence

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Comments about these guidelines are welcome and can be sent to the author at hlibman@caregroup.harvard.edu