Clinical Management of HIV Infection Objectives of Clinical Therapy (II)
The aim of HIV therapy is threefold. The first objective is to lower viral load to undetectable levels and hold it there. Lowering viremia protects the immune system from depletion of CD4+, which is the second goal of therapy because a functioning immune system protects against OIs. Ultimately, the purpose of therapy is to preserve the overall health of the patient at optimal status. Therapeutic failure can emerge as worsening of virologic, immunologic, or general clinical status of the patient.
HIV Lab Studies/Blood Analysis
HIV testing and diagnosis should always be carried out under the CDC Guidelines for Counseling, Testing, and Referral (CDC, 2001). The patient’s best interest requires early diagnosis to preserve the broadest possible range of treatment options in managing the disease. Once antibody testing establishes diagnosis, two other tests for markers of HIV infection are important in managing the illness. Viral load tests of the amount of virus in the bloodstream indicate the expected rate of disease progression. The higher the viral load, the faster the disease is expected to progress. White blood cell tests for counts of CD4+ lymphocyte cells or percent of CD4+ cells in the total lymphocyte cell population indicate how far the disease has progressed in suppressing the immune system. These tests are used to determine when to initiate therapy, relative success of therapy, and when to change therapy. Both viral load tests and CD4+ cell counts are recommended upon diagnosis of HIV seropositive status to establish a baseline, at initiation of ARV therapy, 4 weeks later, and then every 3 to 4 months thereafter. Resistance testing is used to determine the optimal therapy choice either prior to initiation of therapy or when current therapy fails.
HIV Antibody Detection and Antigen Identification Tests
Screening for HIV infection is by the detection of antibody specific to the virus in the blood by the reactive enzyme-linked immunosorbent assay (ELISA). A second positive ELISA followed by a positive Western blot detection of several HIV antibodies confirms diagnosis. The patient is termed HIV seropositive because the blood analysis or serology is positive for HIV.
If acute HIV infection is suspected, a negative ELISA may be followed by a Western blot and a plasma HIV RNA test. Acute HIV infection, which precedes seroconversion, is defined by detection of HIV RNA in the plasma on the same day as a negative Western blot for antibodies (Princeton, 2003). Seroconversion should be verified 3 to 4 months later by an ELISA. Sensitivity and specificity of these tests are greater than 98%; however, indeterminate results can be obtained.
Patients with high-risk exposure should be retested in 2 to 3 months. Patients with indeterminate serology and a low-risk behavior history are almost never positive, and retesting is optional.
The ELISA and Western blot test processes are time- and labor-intensive. The consequence of the delay in producing test results is a low return rate of patients to obtain the test outcomes. Some other serologic tests have been developed to speed the return of results to 20 minutes or less after testing. The Food and Drug Administration (FDA) approval of both a urine sample and a saliva sample test (OraQuick ADVANCE®) has improved consumer acceptance of testing because needle sticks are not required and the tests can be administered in a community setting. All of these tests must be administered by clinical personnel. However, one FDA-approved home test kit is on the market, Home Access® Express HIV Test. The test sample may be taken by anyone, but must be mailed to a laboratory for analysis. Results are available within 3 days to a month. Importantly, detection of the HIV antigen, p24, can be made as early as 16 days after infection, before antibodies to HIV are produced by the immune system. Since August 1995, all blood and plasma donations have been screened for p24 to better insure the safety of blood product transfusions in compliance with an FDA mandate (Stine, 2008).
Viral Load Testing
Viral load tests are used for evaluating and monitoring the effectiveness of ARV therapy. Lower levels of virus in the blood are associated with reduced risk for progression to AIDS status, infection, transmission, and death. Successful ARV therapy will diminish or stabilize viral load. An increasing viral load while on ARVs is indicative of virologic failure and possibly the emergence of viral resistance. The sensitivity of tests for viral load has been improving rapidly. Currently, the HIV-1 DNA PCR test can detect as few as 1 to 10 copies of HIV proviral DNA (Bartlett & Gallant, 2005). The most desirable range of viremia is undetectable. An undetectable viral load is prognostic of the best clinical outcome, but it does not mean that HIV has been eradicated. Viremia is a measure of HIV in the blood only. Other reservoirs of virus reside in lymph tissues, bone marrow, the brain, genital secretions, and within the cells of the immune system. The FDA recognizes three quantitative determinations of viral load: one is reverse transcriptase-PCR (RT-PCR), the branched-chain DNA assay (bDNA), and, most recently, nucleic acid sequence- based amplification (NASBA) (Bartlett & Gallant, 2005). These assays give different numbers for the same patient sample because the bDNA detects more viral subtypes than the RT-PCR and may differ from NASBA results as well. Therefore, it is inappropriate to compare results from the different tests.
CD4+ Cell Testing
Counts of CD4+ lymphocytes are an indicator of immune system health. Increased level of CD4+ cells correlate well with decreased risk of OIs and tumors. Immunologic failure is indicated by diminished CD4+ counts and correlates well with increased risk of OIs. Normal CD4+ cell counts are 800 to 1050/cubic milliliters (mm3), but even a count of 500/mm3 is considered high for the HIV-positive patient. In the high cell count range, there is no immediate danger. In the medium range of 200 to 500/mm3 serious symptoms are uncommon, but there is an increased risk for shingles, thrush, skin infections, and bacterial pulmonary infections. In the medium to low range of less than 350/mm3 ARV is offered to the patient, and preventative treatment, or prophylaxis, for some major infections is usually initiated (Bartlett & Gallant, 2005). A CD4+ cell count of less than 200/mm3 is an AIDS-defining condition.
When HIV can replicate in the presence of an ARV drug, it has the opportunity to mutate to avoid the drug’s activity. If a drug is unable to completely suppress HIV replication, viral resistance can emerge. Incomplete suppression can occur in a number of ways. The drugs prescribed may not be completely effective against the patient’s strain of HIV, or the patient may have difficulty adhering to the treatment regimen and miss doses of the drugs. Resistance testing can help in the selection process for an effective therapeutic treatment strategy. Two kinds of resistance testing are available: phenotypic and genotypic. In phenotypic testing, a sample of the patient’s HIV is exposed to various drugs, and the relative effectiveness of the drugs against that strain of HIV is measured. In genotypic testing the genetic structure of the patient’s HIV is determined and compared to the structure of ARV targets. Mutations in the patient’s HIV structure that are known to thwart ARV targets are identified. A rational choice for a salvage ARV regimen can be based on the results of this resistance testing. Phenotypic testing is the most diagnostic and will identify drugs that lack efficacy against the specific host’s mutant HIV strain, but is time consuming and costly ($800 to $1,000 per test). Genotypic testing is faster and less costly ($400 to $500 per test) than phenotypic testing, but will only identify the mutation of the host’s strain (Stine, 2008). Even though no therapies are tested, genotypic tests give an indication of which drug therapies may be successful.
The progress medical science is making toward eradicating HIV is encouraging. While it must be understood that antiretroviral agents (ARVs) cannot be considered a cure, they do represent viable, potent interventions for this infectious disease. A positive HIV test is not good news, but with these drugs, it is no longer an imminent death sentence. The advent of the newest pharmaceutical agents is too recent to know the duration of their clinical efficacy. Many HIV-positive people are living 15 years or longer with proper case management.
The first ARV, a nucleoside reverse transcriptase inhibitor (NRTI), was released in 1986. Therapeutic research during the 1990s developed two new classes of ARVs: protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). Studies of treatment with combinations of three to four of these drugs were found to slow progression of HIV infection to AIDS status and improve survival. The multidrug therapies are termed highly active antiretroviral therapy (HAART). The goal of anti-HIV therapy is to suppress viremia in order to preserve or restore immune function and to prevent the emergence of drug resistance and OIs by patient adherence to treatment regimen.
Since many ARVs were expedited through the development process, investigation of their long-term adverse effects, toxicities, and drug interactions must be continued. Some toxicities have become well recognized such as abnormal fat redistribution (dyslipidemia) and metabolic disorders, for example, glucose intolerance, hyperlipidemia, lactic acidosis, and hepatic steatosis (Princeton, 2003). Patient adherence is difficult to maintain since the treatment regimens are complex and laden with minor, but troubling, side effects. Complete patient compliance with therapy is vitally important because viral resistance to the drugs emerges as adherence diminishes (Masci, 2001).
The standard of care of the HIV+ patient changes with the accumulation of knowledge and the development of new drugs. Therefore, it is sometimes prudent to delay making therapeutic changes in anticipation of future drug development. The U.S. DHHS (October 10, 2005) as reported by Bartlett and Gallant (2005, p. 59) has revised the guidelines for initiation of anti-HIV treatment based on a combination of clinical symptomology, viral load, and CD4+ count. These guidelines are tiered in four levels:
- When the patient is asymptomatic, CD4+ cell count is above 350/mm3, and plasma HIV RNA is below 100,000 c/mL, most clinicians would delay initiating treatment and observe.
- When the patient is asymptomatic, CD4+ cell count is 200 to 350/mm3, and plasma HIV RNA is at any value, the recommendation is to offer treatment. However, the recommendation’s strength is based on the patient’s interest in initiating therapy and the prognosis of disease-free survival.
- When the patient is asymptomatic, CD4+ cell count is less than 200/mm3, and plasma HIV RNA is at any value, the recommendation is to begin treatment.
- When the patient is symptomatic (e.g., sick, AIDS, OI, fever, etc.), the recommendation is to treat regardless of CD4+ cell count and plasma HIV RNA level.
HAART is the cornerstone of anti-HIV therapy. The use of only two ARVs or any monotherapy is not recommended because these therapies may not completely suppress HIV replication, thus allowing viral resistance to emerge. The hallmark of successful therapy is a 5- to 7.5-fold drop in viral load within 4 weeks and a 10-fold decrement within 8 weeks. The long-term goal of HAART is to maintain viral load that is below the limits of detection, that is, undetectable. Even when achieved, an undetectable viral load is not indicative of eradication of the virus. The purpose of suppressing the viral load is to permit the immune system to recover. This recovery is measured by an increase in CD4+ cells and improvement in the patient’s overall health status. The durability of the initial treatment regimen is predicated upon the efficacy of the drugs against the virus, their tolerability by the patient, and ultimately by the patient’s adherence to the regimen.
At the present time, there are at least 24 antiretroviral medications approved either individually or in co-formulation for HIV therapeutic intervention. These drugs are classified in three categories: reverse transcriptase inhibitors (RTIs), either nucleoside/nucleotide analogues (NRTIs), or nonnucleoside compounds (NNRTIs); HIV protease inhibitors (PIs); and HIV entry or integrase inhibitors. They include the following:
The DHHS guidelines of October 6, 2005, as reported in Bartlett and Gallant (2005, p. 61), provide for Preferred and Alternative Initial Regimens for HAART as outlined in the chart below.
|Drug Trade Name (Class)||Generic Names|
|Atripla™ (NRTI)||sustiva, viread, and emtriva|
|Combivir® (NRTI)||lamivudine and zidovudine|
|Emtriva® (NRTI)||emtricitabine (FTC)|
|Epivir® (NRTI)||lamivudine (3TC)|
|Epzicom™ (NRTI)||epivir and ziagen|
|Hivid® (NRTI)||zalcitabine (ddC)|
|Retrovir® (NRTI)||zidovudine (ZDV), azidothymidine(AZT)|
Preferred HAART offers two options:
- 1. efavirenz + (lamivudine or emtricitabine) + (zidovudine or tenofovir DF) — except for pregnant women or women with pregnancy potential1
- 2. lopinavir/ritonavir (co-formulated as Kaletra®) + (lamivudine or emtricitabine) + zidovudine
Alternative HAART offers 10 recommendations, which may be preferred in select patients:
■ efavirenz + (lamivudine or emtricitabine) + (didanosine or abacavir or stavudine) — except for pregnant women or women with pregnancy potential
■ nevirapine + (lamivudine or emtricitabine) + (zidovudine or stavudine or tenofovir or didanosine or abacavir) (avoid for initial therapy in women with CD4 courts > 250/ mm3 and men with CD4 courts > 400/ mm3 due to high rates of hepatotoxicity)
■ fosamprenavir + (lamivudine or emtricitabine) + (zidovudine or stavudine* or abacavir or tenofovir or didanosine)
■ fosamprenavir/ritonavir* + (lamivudine or emtricitabine) + (zidovudine or stavudine* or abacavir or tenofovir or didanosine)
■ atazanavir + (lamivudine or emtricitabine) + (zidovudine or stavudine* or abacavir or didanosine) or (tenofovir + ritonavir 100 mg/d)
■ indinavir/ritonavir* + (lamivudine or emtricitabine) + (zidovudine or stavudine* or abacavir or tenofovir or didanosine)
■ lopinavir/ritonavir (co-formulated as Kaletra’) + (lamivudine or emtricitabine) + (zidovudine or stavudine* or tenofovir or didanosine)
■ nelfinavir + (lamivudine or emtricitabine) + (zidovudine or stavudine* or abacavir or tenofovir or didanosine)
■ saquinavir (Invirase)/ritonavir* + (lamivudine or emtricitabine) + (zidovudine or stavudine* or abacavir or tenofovir or didanosine)
■ abacavir + lamivudine + zidovudine — only when an NNRTI- or a PI-based regimen cannot or should not be used
Since HIV can become resistant to all drugs, future treatment options could be limited by the initial and secondary drug choices. The medical follow-up of individuals on any pharmacological therapy must be maintained, as well as diligent case management, to closely monitor the patient’s condition and changing needs. Case management/medical issues associated with the use of these drugs include routine follow-up with general chemistry and hematological evaluations on a schedule established by the physician as well as monitoring of viral load and CD4+ counts.
There are several reasons to change the components of a drug therapy including virologic, immunologic, and clinical failure of the therapy. The DHHS Guidelines for Changing Antiretroviral Regimens (April 2005), as reported in Bartlett and Gallant (2005, pp. 75—76), include assessing several characteristics of the treatment regimen, including the assessment of
Drug Profiles, by Class and Generic Name
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs) (n = 8, plus 5 in combination formularies)
This class of drugs provided the first efficacious antiretroviral treatment. They are analogs of the nucleosides or nucleotides used to build the DNA of the virus. When the reverse transcriptase enzyme uses an analog in the replication process, an incomplete virus is produced that is nonfunctional. Adverse reactions common to this class of drugs include lactic acidosis with or without hepatomegaly, and steatosis. Viral resistance to these drugs usually evolves from point mutations in the virus specific for the particular drug so that cross-resistance between drugs is usually incomplete.
Abacavir sulfate (ABC)
The trade name is Ziagen®. The limiting adverse effect to this drug is a hypersensitivity reaction, which can be fatal. The reaction usually occurs within the first 6 weeks of drug administration, but resolves after discontinuation of the drug. Abacavir is one of three drugs comprising Trizivir™. It is also co-formulated with 3TC as Epzicom™. There are no food restrictions.
The trade names are Videx® and Videx EC®. Using this medication can cause painful chronic peripheral neuropathies that produce a mild, reversible, stocking-and-glove pattern of discomfort in about 10% of individual users. Pancreatitis may occur in 1% to 2% and may be severe, even fatal. Toxicities can include headache, insomnia, rash, and gastrointestinal disturbances. The drug should be taken 1 hour before or 2 hours after a meal. Do not combine with d4T.
The trade name is Emtriva®. This drug may be taken once per day. Toxicity is minimal, but can manifest as hyperpigmentation. It has no food effects or drug interactions. It is co-formulated with TDF as Truvada™ and taken once per day. When combined with sustiva and viread, it is marketed as Atripla.
The trade name is Epivir®. Resistance to this drug can develop rapidly if monotherapy is used or if viral replication is not completely suppressed. There are no food restrictions and minimal toxicity. The drug is generally well tolerated, but side effects can include nausea, diarrhea, anemia, low white blood cell count, and pancreatitis (especially in children). Renal failure would require the dosage to be decreased. Lamivudine is one of three drugs comprising Trizivir™. It has also been approved for use with Zidovudine and marketed as Combivir’. It is co-formulated with ABC as Epzicom.
The trade name is Zerit®. A dose-related peripheral neuropathy occurs in 19% to 24% of individuals with advanced disease and in 14% of those with less advanced HIV disease. Other adverse
effects may include headache, lipoatrophy, gastrointestinal disturbances, anemia, neutropenia, pancreatitis, and elevated hepatic transaminases. Renal failure would require the dosage to be decreased. The drug may be taken without regard to food. Avoid combining with ddl, especially during pregnancy.
The trade name is Viread®. This is the only nucleotide analog currently approved for clinical use. The nucleotide analog does not require intracellular phosphorylation for activation, as do the nucleoside analogs. It may have broader activity than the other drugs of this class. Minimal toxicity but nephrotoxicity may occur. Adverse effects can include elevations in creatine kinase, hepatic transaminases, and triglycerides, neutropenia, fatigue, headache, and worsening of peripheral neuropathies. The drug has no food effect. It is combined with FTC as Truvada. When combined with sustiva and emtriva, it is marketed as Atripla.
The trade name is Hivid®. The major adverse effect is peripheral neuropathy presenting as a burning sensation. Other side effects include lactic acidosis, lipoatrophy, rash, stomatitis, fever, ototoxicity, anemia, leukopenia, and thrombocytopenia. Pancreatitis is rare, but can be fatal. Renal failure would require the dosage to be decreased. Do not take with didanosine. There are no food restrictions but cannot be taken with antacids.
Zidovudine (AZT, ZDV)
The trade name is Retrovir®. Therapy-limiting effects may include bone marrow suppression resulting in anemia and leucopenia. Other side effects are headache, fatigue, lactic acidosis, lipoatrophy, rash, nausea, gastrointestinal disturbances, and seizures. A reversible myopathy may appear with prolonged use. This drug has been shown to decrease mother-to-child transmission. Zidovudine is one of three drugs comprising Trizivir™. It has also been approved for use with Lamivudine and marketed as Combivir’. The drug may be taken without regard to food.
Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) (n = 3)
This class of drugs differs structurally from the NRTIs. Rather than substituting a dysfunctional component in the DNA-building process, they actually bind to the reverse transcriptase, thus inactivating the enzyme of synthesis. Viral resistance to this class of drugs evolves rapidly if any single drug is used as a monotherapy. Broad cross-resistance between agents in this class is common. Many drug treatments for non-HIV conditions are incompatible with NNRTIs, and drug interactions must be checked before prescribing.
The trade name is Rescriptor®. Rash, headache, fatigue, and gastrointestinal disturbances are the common adverse effects. Other side effects include insomnia, myalgia, elevations in uric acid, transient elevations in liver functions, anemia, neutropenia, and thrombocytopenia. The drug has no food effects.
The trade name is Sustiva®. Rash commonly occurs early in treatment and then resolves within the month. Cholesterol may increase by 10% to 20% in some patients. Because this drug penetrates the blood—brain barrier, some central nervous system (CNS) disturbances may occur, including dizziness, changes in sleep and dreams, abnormal thinking, and difficulty concentrating. These symptoms typically resolve within a month. Delusions, abnormal behavior, depression, and elevated liver enzymes may also occur. Taking the drug at bedtime minimizes the drug effects on activities of daily living. Avoid taking the drug with high-fat meals and preferably on an empty stomach. The drug may be teratogenic. Avoid taking in first trimester. When combined with viread and emtriva, it is marketed as Atripla.
The trade name is Viramune®. Rash occurs in 7% to 15% of patients and is more common in women, but can usually be tolerated with antihistamine use. Other common adverse effects are headache, depression, and hepatitis—less commonly, fatigue, nausea, diarrhea, fever, myalgia, elevated liver function, and mean corpuscular volume. This drug is not compatible with oral hormone contraceptives. There are no food restrictions.
Protease Inhibitors (PIs) (n = 11, including 1 in a combination formulary)
This class of drugs inhibits HIV protease, the enzyme that cleaves viral polyproteins to functional HIV proteins. When protease is inhibited, infectious HIV virions are not produced. Toxicities generally appearing in this class of drugs are metabolic effects on lipids and glucose and body composition changes. Complete cross-resistance of the virus to PIs does not evolve initially. However, cross-resistance may broaden over time as mutations in the virus accumulate so that sequential use of PIs may not be possible. Many drug treatments for non-HIV conditions are incompatible with PIs, and drug interactions must be carefully checked before prescribing. The PIs are potent, but toxic, drugs; thus, their prescription is controversial in terms of cost-benefit analysis even though they are now considered standard of care. They have been shown to save lives, but at a price of damaged organ systems that may ultimately shorten lives (Stine, 2008).
The trade name is Agenerase®. The only formulations still available are pediatric capsules and oral solution. Fosamprenavir (Lexiva) is now preferred. The most common side effects are rash, paresthesia, and gastrointestinal disturbances. Because this drug is a sulfonamide, it must not be taken by those with hypersensitivity reactions to sulfa. This drug is not compatible with oral hormone contraceptives. Vitamin E supplements should not be taken. Amprenavir interacts with several other drugs, elevating serum levels of some drugs and itself being reduced in serum by others. A thorough reference should be consulted before prescribing. The drug should be taken an hour apart from antacids and didanosine. Avoid taking the drug with high-fat meals.
The seventh protease inhibitor was approved on June 20, 2003. Reyataz® (PI)/atazanavir is noteworthy for being given in a single pill, once per day, with food. As with all drugs in this class, a
significant safety concern is hyperlipidemia. Bristol-Myers Squibb Company of Princeton, New Jersey, produces it. The side effects include gastrointestinal intolerance, jaundice, and increased transaminases.
The trade name is Prezista®. In mid-2006 this drug received accelerated FDA approval as a salvage regimen when taken in combination with ritonavir. Prezista may be effective against HIV resistance developed to other PIs. In 2008 the FDA approved darunavir taken with ritonavir as an initial therapy. The drug must be taken with food and has many drug interactions.
The trade name is Lexiva®. This is the pro-drug to APV and is now the preferred form. The most common side effects are gastrointestinal disturbances, rash, and increased transaminase. Unlike APV, it has no food effects.
Indinavir sulfate (IDV)
The trade name is Crixivan®. Adverse effects that are noteworthy include nephrolithiasis, which occurs infrequently and requires a temporary interruption of treatment for 1 to 3 days. Adequate hydration is critical. Other side effects include rash, nausea, thrombocytopenia, headache, diarrhea, insomnia, stomatitis, asymptomatic hyperbilirubemia, and elevated hepatic transaminases. Indinavir interacts with several other drugs, elevating serum levels of some drugs and its own serum level being reduced by others. A thorough reference should be consulted before prescribing. The drug dose should be taken with water either 1 hour before or 2 hours after a meal.
Lopinavir is co-formulated with ritonavir to elevate its plasma concentration to therapeutic levels and marketed as Kaletra®. Adverse effects may include elevated triglycerides, cholesterol, hepatic enzymes, and glucose. Other side effects may be asthenia, headache, rash, diarrhea, nausea, and vomiting. Lopinavir inhibits the P450 CYP3A metabolic path and like other PIs has many drug interactions. A thorough reference should be consulted before prescribing. The drug dose should be taken with food.
Nelfinavir mesylate (NFV)
The trade name is Viracept®. Side effects are generally mild and are primarily diarrhea, but can include nausea, rash, depression, asthenia, and mild fatigue. Nelfinavir inhibits the P450 CYP3A metabolic path and like other PIs has many drug interactions. A thorough reference should be consulted before prescribing. The drug dose should be taken with food and can be dissolved in water.
The trade name is Norvir®. The most common side effects are gastrointestinal: nausea, diarrhea, vomiting, anorexia, abdominal pain, and taste perversion. Other adverse effects may include
paresthesias, elevated cholesterol, and elevated hepatic enzymes. Ritonavir binds to several cytochrome P450 isoforms, and interacts with several drugs. It will reduce levels of oral contraceptives and theophylline, among others. A thorough reference should be consulted before prescribing. Refrigeration is recommended. The drug should be taken with food.
The trade name is Invirase for the hard gel capsule and Fortovase for the soft gel capsule. Fortovase was discontinued as of February 2006. Adverse effects are generally mild and include diarrhea, nausea, and abdominal discomfort. Other side effects may include jaundice, elevated liver function, headache, confusion, seizures, rash, asthenia, and paresthesia. Saquinavir is metabolized by CYP3A4, and interactions with other drugs that affect that metabolic path are common. A thorough reference should be consulted before prescribing. The drug dose should be taken within 2 hours of a full meal.
The trade name is Aptivus®. Adverse effects are generally mild and include diarrhea, nausea, and abdominal discomfort. Other side effects may include elevated liver function, and rash, especially in women. The drug dose should be taken with a full meal.
HIV Entry or Integrase Inhibitors (n = 3)
These are new classes of drugs whose development was aimed at different viral targets from the RTIs and PIs. These drugs aim to block the virion’s entry to the immune cell (entry or fusion inhibitors) and its activation after synthesis (integrase inhibitors) (Ritchie, 2001).
The first of the fusion inhibitor (FI) class of medications received accelerated approval on March 13, 2003. Fuzeon® (FI)/enfuvirtide is remarkable because it is effective against HIV infection resistant to other currently available drugs, thus adding a new component to HIV therapy. The drug is given by subcutaneous injection. Adverse reactions may include allergic reaction, especially at the injection site, and increased risk for pneumonia. Roche Pharmaceuticals of Nutley, New Jersey, will distribute the drug under a license from Trimeris, Inc., of Durham, North Carolina.
The trade name is Selzentry®. This drug mechanism of action is to block the CCCR5 co-receptor, thus inhibiting entry to the CD4+ immune cell. It received FDA approval in August 2007. It is deemed useful for salvage therapy. Of importance, this drug is administered orally. Drug failure is anticipated to occur when the virus switches to using a different entry receptor.
Raltegravir (MK 0158)
This drug received FDA approval in October 2007. It blocks HIV DNA from entering or fusing with human DNA, thus it is an integrase inhibitor. As with other new classes of anti-HIV drugs, it will be used primarily for salvage therapy.
Although HAART may durably suppress HIV replication without the emergence of viral resistance, the HIV variants hosted by a particular patient may still develop reduced susceptibility to current drugs through incomplete adherence to treatment regimen. Sometimes declines in immune function develop in the presence of viral suppression. The possibility also exists that the current HAART drugs will prove too toxic to be used indefinitely. Furthermore, HIV is known to be sequestered in memory cells of the immune system and harbored in other privileged sites in the body that are inaccessible to ARV therapeutics so that HIV cannot be eradicated from the body. New therapeutics will be required to facilitate salvage therapy. Ongoing basic and clinical research is aimed at addressing the need for superior drug efficacy, improved patient adherence, reduced toxicity, better tolerance, and more treatment options (Feinberg, 2002).
The antiretroviral agents currently approved for therapeutic intervention act to inhibit either the reverse transcriptase or the protease enzyme of viral synthesis or by barring HIV’s entry to the cell or to human DNA. New classes of drugs under current development are aimed at different viral targets, including disrupting HIV replication with zinc fingers and anti-sense drugs, assembly inhibitors and maturation inhibitors to interfere with HIV functioning (Stine, 2008). Early-access programs are available for qualifying patients to participate in studies of investigational drugs through the pharmaceutical company. Usually the primary care physician must initiate the recommendation of the patient to the program.
Opportunistic Infections and Malignancies
By weakening the immune system, HIV permits the opportunity for infectious disease and malignancy to attack any organ system. HIV is also known to alter the natural progression of several common infections such as syphilis and hepatitis B (HBV) and C (HCV). Most HIV/ AIDS-related mortality is caused by these comorbid conditions. The incidence of OIs varies between different transmission exposure populations such as MSM or IDUs. Prevalence of certain OIs varies with geographical region such as histoplasmosis, which is endemic to the Ohio and Mississippi River Valleys. However, the CD4+ cell count is a reliable marker for incidence of specific OIs. When the CD4+ cell count falls to between 250 and 500/mm3, HIV-positive individuals usually experience minor OIs such as oropharyngeal candidiasis (thrush) and the development of active tuberculosis disease. Cryptosporidiosis and tumors of Kaposi’s sarcoma or lymphoma may emerge with CD4+ cell counts between 150 and 200/mm3. When the CD4+ cell count range is between 75 and 125/mm3, more severe OIs such as Pneumocystis jiroveci pneumonia (PCP), Mycobacterium avium complex (MAC), herpes simplex virus (HSV), toxoplasmosis, cryptococcosis, and esophageal candidiasis may appear. Cytomegalovirus (CMV) retinitis occurs with CD4+ counts of less than 50/mm3. Prolonged survival has been shown with MAC and PCP prophylaxis as well as with HAART (Sande & Volberding, 1999). The U.S. Public Health Service and the Infectious Diseases Society of America developed guidelines for preventing OIs among persons infected with HIV in 1995 and updated them in 1997, 1999, and 2002. The major changes in the 2002 update primarily address the discontinuance of prophylaxis upon reconstitution of the immune system. Overall, as of this revised post, HAART is still recognized as the most effective approach to OI prevention. The guidelines address 19 OIs (CDC, 2002a). The more frequently reported HIV/AIDS-related malignancies and OIs and their preventions and standard treatments are described here.
Vaccination with influenza vaccine and pneumococcal vaccine is recommended for all HIV-infected adults. Hepatitis vaccination for HBV is the standard of care. Vaccination for hepatitis A (HAV) is recommended for those who have HCV or chronic liver disease or are sexually active and are seronegative for HAV. Diphtheria/tetanus vaccine should be boosted every 10 years. Other vaccines that should be administered in those not previously vaccinated include measles, mumps, and rubella, as well as inactivated polio. All live virus vaccines are contraindicated (Sande & Volberding, 1999; Bartlett, 2002; Princeton, 2003).
Opportunistic Infection, Suppressive Therapy, and Treatment
Pulmonary disease is a major source of morbidity and mortality in HIV-infected individuals. The number one life-threatening OI for HIV-infected patients is PCP, which is suppressible with the prophylactic use of trimethoprim-sulfamethoxazole (TMP/SMX) (Bactrim or Septa), Dapsone, aerosolized pentamidine (NebuPent), or Atovaquone (Mepron). Bactrim has the advantage of also being prophylactic against Toxoplasma gondii and some other bacterial infections. Patients who are at risk of PCP are those with CD4+ counts of less than 200; those with oropharyngeal candidiasis; those with persistent fever of more than 2 weeks; and those who have had prior PCP. Treatment medications include TMP/SMX, Dapsone, pentamidine, Clindamycin/Primaquine, and Atovaquone (Mepron). Recurrent bacterial pneumonia is an AIDS indicator condition. Pneumococcal vaccination with Pneumovax is the standard of care. Empiric treatment should not be commenced until the infecting bacteria are characterized. Although penicillin-resistant strains are appearing, effective treatment can be made with second- and third-generation cephalosporins or TMP/SMX.
Mycobacterium tuberculosis (TB) is a frequent but treatable cause of morbidity and mortality in the HIV-positive population. Most HIV-associated TB disease is the result of activation of dormant TB infection and can emerge even in the presence of CD4+ counts in excess of 300. Biannual TB skin testing by purified protein derivative (PPD) is recommended. HIV infection alters the natural history of TB so that those who are HIV positive are far more likely to contract TB. Latent TB may be suppressed by isoniazid (INH) therapy given for 12 months. Although many strains of TB are becoming antibiotic resistant, TB can be treated and cured with a multidrug regimen usually commencing with four drugs, then reducing the number of drugs over the course of treatment. Some of the more common drugs of treatment include INH, rifampin (Rifadin), rifabutin (Mycobutin), ethambutol (Myambutol), and pyrazinamide (PZA).
Another frequently occurring, serious OI is Mycobacterium avium complex. MAC is a term for two related bacteria: Mycobacterium avium and Mycobacterium intracellulare (MAI). When CD4+ counts drop below 50, MAC can become disseminated, seriously eroding quality of life and reducing survival. MAC bacteremia is associated with fever/sweats, progressive anemia, painful joints, gastrointestinal cramping, nausea/vomiting, diarrhea, and wasting. Prophylaxis should be considered, after excluding TB, when the CD4+ count falls below 100. Azithromycin (Zithromax) is the preferred prophylactic, but two other drugs are also approved—clarithromycin (Biaxin) and rifabutin (Mycobutin)—for all HIV-infected patients with CD4+ counts of less than 100.
Fungal infections seen in HIV/AIDS patients include candidiasis, cryptococcosis, histoplasmosis, coccidioidomycosis, and aspergillosis. Candidiasis is the most commonly seen OI in HIV/AIDS patients and is seen at all stages of immunosuppression. Vaginal candidiasis (yeast), followed
by oropharyngeal (thrush) and esophageal candidiasis, is the usual order of presentation of this infection. Candidiasis is routinely being treated topically with ketoconazole (Nizoral), clotrimizole (Nystatin, Gyne-Lotrimin), or miconazole (Monistat 3) when possible, reserving the systemic drugs such as fluconazole (Diflucan), amphotericin, and itraconazole (Sporanox) for more severe fungal infections. Cryptococcus neoformans is the most frequently occurring life-threatening fungal infection, usually affecting those with CD4+ counts below 50. Cryptococcosis most often presents as disseminated disease. Cryptococcal meningitis is the most common manifestation, but pneumonia is also seen. This infection should be treated aggressively with amphotericin, followed by suppressive therapy with fluconazole. Histoplasmosa capulatum is endemic to the Midwestern United States and found in bird droppings. It causes acute pulmonary disease. The preferred therapy for disseminated histoplasmosis is amphotericin. Coccidioides immitis is endemic to the Southwestern United States and Mexico. Most patients with this infection have CD4+ counts under 250. The clinical presentation of coccidioidomycosis is acute pulmonary infection. Disseminated disease should be treated with amphotericin, followed by suppressive therapy with ketoconazole or fluconazole for life. Aspergillosis is seen infrequently and usually only in advanced AIDS. The lungs are most commonly involved, and secondarily the brain. The treatment of choice is amphotericin.
Cytomegalovirus (CMV) infection is a common HIV-related pathogen causing retinitis, colitis, and encephalopathy. Most people are infected with dormant CMV, but active disease emerges in 20% to 40% of HIV/AIDS patients, particularly in those with CD4+ counts of less than 50. CMV retinitis accounts for the 75% to 85% of CMV disease and is the leading cause of blindness in AIDS patients. Symptoms include blurry vision, light flashes, and floaters. A therapy specific for CMV retinitis is surgical implantation of a ganciclovir pellet (Vitrasert) in the affected eye together with oral Ganciclovir. The implant is effective for several months, but will not protect the other eye from CMV (Princeton, 2003). CMV colitis presents with abdominal pain, diarrhea, anorexia, weight loss, and fever. CMV encephalopathy is usually seen as radiculopathy. This occurs as a spinal cord syndrome with lower-extremity weakness, spasticity, areflexia, urinary retention, and hypoesthesia. Subacute encephalitis caused by CMV also occurs in AIDS patients. Personality changes, difficulty concentrating, headaches, and sleepiness frequently are present. The best prophylaxis is effective ARV therapy to restore the immune system. Initial acute therapy is with IV Ganciclovir. Maintenance therapy throughout the life of the patient is critical for CMV retinitis because the virus is only suppressed by Ganciclovir and not eliminated. Oral Ganciclovir is nearly as effective as IV Ganciclovir was at delaying reactivation of CMV retinitis. Toxicity and viral resistance may limit Ganciclovir therapy. Foscarnet and Cidofovir may provide alternate therapies (Sande & Volberding, 1999).
Herpes viruses cause a number of symptoms in immunocompetent people and are responsible for substantial morbidity in immunosuppressed HIV/AIDS patients where their symptoms are more severe and of longer duration. This family of viruses includes CMV, described previously, as well as herpes simplex viruses I and II and herpes zoster. Herpes simplex virus I produces cold sores or fever blisters primarily around the mouth, but they can also occur on the genitalia. Other symptoms include fever, fatigue, swollen glands, and muscle pain. Herpes simplex virus II produces painful ulcers on the genitals or anus. Symptoms preceding an outbreak are similar to influenza. Herpes zoster (shingles) causes a painful rash along a particular dermatome, which is a reactivation of previous chicken pox infection. Suppression and treatment are accomplished with acyclovir (Zovirax), famciclovir (Famvir), or valacyclovir (Valtrex).
Toxoplasma gondii is associated with cerebral toxoplasmosis in the majority of patients. It is the second most common OI of the eye. It may also cause pneumonia. T. gondii is one of the most common tissue parasites found in humans and is hosted by the domestic cat as well as many
other mammals and bird species. Humans can become infected by coincidental exposure to cat feces or by eating raw or undercooked meat. In an immunocompetent individual, the parasite is usually dormant, causing no signs or symptoms; however, in the patient with depressed cellular immunity, the parasite may become activated and cause full-blown disease. Among individuals with AIDS, 3% to 40% develop toxoplasmic encephalitis (Smith, 1994). Persons with T gondii are at risk for developing toxoplasmosis and should begin suppressive therapy when their CD4+ count falls below 100. The most common regimens are TMP/SMX (Bactrim or Septa), pyrimethamine in combination with sulfadiazine, and Dapsone plus pyrimethamine (Daraprim). Patients with toxoplasmosis encephalitis must be on chronic suppressive therapy for life.
Cryptosporidium parvum is a serious parasitic OI. Cryptosporidiosis causes profuse, watery diarrhea with cramping, abdominal pain, fatigue, anorexia, and nausea/vomiting. CD4+ cell counts under 200 facilitate this illness. The infection is easily transmitted by contact with feces. Handwashing is the best protection against contamination. Cryptosporidiosis is not cured, only suppressed, and is more likely to reappear as the immune system is progressively impaired. Symptoms may be reduced by paromomycin, spiramycin, or erythromycin and other antidiarrheal agents.
Kaposi’s sarcoma, non-Hodgkin’s lymphomas (NHLs), and invasive cervical cancer are malignancies indicative of AIDS in HIV-infected individuals (Krown, 1996). Squamous carcinoma conjunctiva is known as an AIDS-associated cancer. Other neoplasms that are likely AIDS associated include Hodgkin’s disease, plasmacytoma, leiomyosarcoma (pediatric), and seminoma (Sande & Volberding, 1999). Both males and females with prolonged immunodeficiency exhibit a high frequency of noninvasive intraepithelial lesions (warts) of the anogenital squamous epithelium that may be precursors to invasive cancer. The sexually transmitted human papillomaviruses (HPVs) are suspected of causing these lesions and neoplasms. AIDS-associated malignancies may increase in frequency as their long latency periods are exceeded by prolonged survival provided by HAART.