HIV: 1999 Treatment Update

HIV infection has three phases: acute infection, clinical latency, and chronic infection. A flulike syndrome that can be accompanied by a fever, rash, and swollen lymph nodes characterizes acute HIV infection in many patients. Because these symptoms are nonspecific and common in many other illnesses, the likelihood that HIV may go undiagnosed in this stage is high. Viral burden is high and a dramatic immune response occurs in this phase of seroconversion. The immune response that is generated is generally enough to decrease the amount of virus in circulation and shift it into the lymphatic system but not enough to eliminate the virus from the body.

 

In the clinical latency phase, the patient has no outward signs and symptoms of disease, but the virus continues to replicate in the lymphatic system at a high rate (>10⁶ particles/day). The body is able to mount a partial immune response, but eventually viral production outpaces the ability of the immune system to control the virus.

 

The stage of chronic infection is characterized by progressive deterioration of the immune system, which results in increased viral burden, the appearance of OIs, and death if left untreated. Patients may suffer from such symptoms as fevers, night sweats, weight loss, and chronic diarrhea. Numerous other serious complications related to other organ systems (lung, liver, gastrointestinal [GI], endocrine, and hematologic) are more likely to develop in the later stages of infection.

 

 

Advances in the ability to detect the presence of HIV have resulted in earlier diagnosis and treatment. HIV can be diagnosed by antigen or antibody detection, recovery of the virus, or detection of viral nucleotide sequences. Most cases of HIV are diagnosed by detection of antibodies specific for HIV-1 or HIV-2. These antibodies are usually detectable within 6 weeks to 6 months after primary infection. The HIV enzyme-linked immunoabsorbent assay (ELISA) is the most commonly used serologic test for HIV. Because of the risk of false-positive results, all positive ELISA tests are confirmed with western blot assay. Patients with more advanced disease are often diagnosed during the course of a work-up for an acute clinical presentation of an OI such as pneumocystis carinii pneumonia.

 

The use of surrogate markers of disease, CD4 count and HIV RNA quantification (viral load), has enabled clinicians to determine the stage of disease and the likelihood of progression.

 

The CD4 count was the first surrogate marker of disease to be used. Early in the epidemic, patients in the early stages of disease were generally followed with serial CD4 measurements until the CD4 count decreased substantially or clinical signs and symptoms suggested that treatment should be initiated. Research over the period of the HIV epidemic has demonstrated that CD4 count is not a reliable predictor of disease progression or response to antiretroviral therapy. Because the risk of certain OIs is associated with certain levels of immunosuppression, the CD4 count is primarily used to determine when to institute or discontinue prophylaxis for OIs.

 

In recent years, measurement of plasma HIV RNA (viral load) has emerged as an important surrogate marker for determining when to begin therapy. It is also used to assess a patient's response to pharmacotherapy and provide an indicator of the need to change treatment. Two methods of measuring viral load are approved by the FDA. These are the polymerase chain reaction (PCR) and the branched chain DNA (b-DNA) amplification method. Researchers have discovered a relationship between the amount of circulating virus and the severity of disease. A higher viral load indicates a higher risk of disease progression and a higher risk of death.¹ Experts agree that viral load is the essential parameter to use regarding the decision to initiate or change therapy.^2,3 The relationship between viral load and CD4 count has been described as follows. The viral load is the speed at which a car approaches a cliff (OI or death). The CD4 count is the length of the road the car must travel before it goes over the cliff. A higher viral burden equals high speed and a faster progression toward the cliff. If viral burden is low, the car will not reach the cliff nearly as quickly. The role of pharmacotherapy in HIV is to slow the speed of the car as much as possible.

Antiretroviral medications for treatment of HIV infection are designed to interrupt the life cycle of the virus at various stages. Drug classes include reverse transcriptase inhibitors (RTIs), protease inhibitors (PIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Medications that are currently available for treatment of HIV are listed in Table 1. The goal of therapy is suppression of viral replication to an extent that renders the virus undetectable in plasma while minimizing adverse effects and maintaining the patient's quality of life. These drugs are especially effective at reducing viral load when used in combinations. The long-term prognosis of patients with fully suppressed virus is unknown.

Nucleoside analog RTIs were the first class of antiretroviral agents to be approved for treating HIV infection. They inhibit the ability of the virus to use reverse transcriptase to incorporate its RNA into the host cell's DNA, thereby preventing replication.

 

Several factors need to be considered when selecting any drugs for a particular regimen. These include the mechanism of action, synergy, pharmacokinetics, adverse effects, resistance patterns, drug interactions, laboratory monitoring, and drug costs. Nucleoside reverse transcriptase inhibitors (NRTIs) are relatively well tolerated and do not have extensive problems with drug interactions. Resistance patterns among the NRTIs have some overlap, but there are no primary mutations that are common to all drugs in the class. It is therefore possible to use other NRTIs after failure of a primary regimen. NRTIs are excreted renally and require adjustment in patients with renal dysfunction.⁴ Laboratory monitoring is required for zidovudine because of bone marrow toxicity. NRTIs are generally used in three drug regimens. Zidovudine should not be combined with stavudine because of concerns related to antagonism. Combinations that are not recommended are also included in Table 2.

The development of PIs revolutionized HIV treatment. Clinical trials with PIs in patients with advanced HIV directly showed a decrease in death and time to the first AIDS-defining illness.^5,6 PIs are indicated only for use in combination therapy. The three-drug PI- containing "cocktails" that are now standard of care are also known as HAART (highly active antiretroviral therapy). PIs work by preventing the "packaging" of immature viral particles into mature virions that can go on to infect other host cells.

 

A significant problem with PIs is overlapping resistance profiles, which may render the entire class useless should a patient develop resistance to one of the medications. Research related to development of new drugs in this class is focusing on finding compounds that have different resistance profiles. According to the manufacturer, amprenavir, the newest PI, appears to have a resistance pattern that differs from the others in in vitro testing. There is insufficient data to suggest clinical benefit related to these different mutations.

 

Double PI therapy is currently under study. The combination that has been most extensively studied and used clinically is ritonavir/ saquinavir. This combination takes advantage of the drug interaction between these two medications whereby low doses of ritonavir increase the levels of low doses of saquinavir to therapeutic concentrations. Use of lower doses of both of these medications decreases side effects and cost. The same phenomenon occurs when indinavir is combined with ritonavir. A small study of 24 patients found this combination to be effective.⁷ The most commonly used combination regimen is 400 mg of each drug twice daily (in addition to NRTIs). The addition of ritonavir to indinavir eliminates the food requirements related to indinavir (empty stomach) and may decrease the incidence of nephrolithiasis because of lower peak indinavir concentrations. Further studies of this combination are underway.

 

The potential benefits of dual PI therapy include increased adherence (reduced doses and numbers of pills), increased viral suppression, and increased options for salvage therapy if a patient fails a single PI regimen. Concerns with this type of regimen include possible drug antagonism, loss of future therapeutic options, and a higher rate of adverse effects, especially hepatotoxicity in patients who are co-infected with HIV and hepatitis C. Despite these concerns, many patients have responded to therapy with two PIs.^4,8,9 Other combinations of PIs are currently being investigated. Saquinavir and indinavir should not be combined because of antagonism. Dual PI therapy is used in conjunction with two NRTIs or one NRTI plus one NNRTI.

NNRTIs have a mechanism of action similar to NRTIs, but, because of their chemical structure, have less toxicity. NNRTIs vary greatly relative to the magnitude of viral suppression that is seen when they are combined with other antiretroviral agents. Nevirapine and delavirdine have demonstrated a less durable effect on HIV replication than PIs; therefore, they are recommended as second-line therapy.¹⁰ Both drugs have numerous drug interactions and overlapping mutation patterns that confer cross-resistance. Efavirenz, the newest NNRTI, is extremely potent and has demonstrated viral suppression and durability similar to the combination of zidovudine/lamivudine/ indinavir.¹¹ The Department of Health and Human Services (DHHS) guidelines have been changed this year to reflect the recommendation of efavirenz (in a three-drug regimen) as a first-line treatment option.² This option offers an opportunity to reserve PIs until later stages of disease as well as offering a potent regimen for patients who cannot take PIs.

Hydroxyurea (HU), a ribonucleotide reductase inhibitor, has been shown to increase the available concentration of nucleoside analogs, particularly didanosine, and to increase antiretroviral activity. The mechanism of action relates to interference with the RT pathway and inhibition of HIV replication.¹² Small studies have demonstrated adequate viral suppression in combination with didanosine and stavudine, but long-term durability in large numbers of patients has not been established.^13,14 CD4 counts may not increase during therapy, but the clinical significance of this is not known. HU is associated with neutropenia, and patients with a baseline absolute neutrophil count of less than 1,700 cells/mm³ should not receive the drug because of the risk of drug-induced neutropenia. In the most recent update of guidelines for treatment, the Expert Panel made no recommendations regarding the place in therapy of HU citing lack of data and toxicity as drawbacks to its use. Other drugs in this class are currently under development and appear to have greater potency and less toxicity.

The International AIDS Society and the DHHS have developed treatment guidelines for initiation of therapy based on CD4 and viral load measurements (Table 2). Therapy should be considered for all patients who have detectable viral RNA and are willing to commit to a lifelong regimen.

 

The preferred regimens for starting antiretroviral therapy include two NRTIs and a PI or efavirenz.¹ Table 2 includes suggested regimens for initial therapy. The goal of the primary regimen is suppression of viral RNA below the limit of detection since levels of viral RNA correlate with disease progression. Patients will generally respond best to their first regimen. An assessment of the patient's understanding of the regimen and willingness to commit to excellent adherence must be made prior to institution of drug therapy. Failure to take medications as prescribed may lead to increases in viral replication and resistance as well as clinical progression of disease. Nonadherence may also limit future therapeutic options because of cross-resistance among agents in a particular drug class.

 

Monotherapy may be used in the case of pregnant women where use of zidovudine has been proven to reduce the maternal-fetal transmission rate from 25% to 8%.¹⁵ The DHHS recommendations suggest that pregnant women be treated more aggressively; however, zidovudine treatment is the minimum therapy that should be instituted.¹

Baseline viral load measurements should be obtained prior to starting therapy. A follow-up measurement should be done after 4 weeks of therapy to determine if the patient is responding. The majority of patients will demonstrate optimal response within 3 months, but a few individuals may take 4 to 6 months to achieve maximal response, especially if the initial viral load is very high. Viral load measurements should be obtained every 3 to 4 months once a patient has achieved an acceptable response to therapy. CD4 counts should be determined with each viral load measurement. If therapy is changed, viral load measurements should be made within 4 weeks of initiation of the new regimen. Other lab tests should be obtained as needed to monitor for drug toxicity (eg, anemia) or if the patient reports symptoms of any side effects that require laboratory confirmation (eg, pancreatitis).

Because each change in drug regimen limits future choices, decisions regarding therapy changes must be made carefully. Treatment failure may occur for a variety of reasons, including viral resistance, altered drug absorption, drug interactions, or poor adherence. A failing regimen may be defined as follows: (1) less than a 0.5 to 0.75 log drop in viral load by 4 weeks, or less than a 1 log reduction by 8 weeks of therapy; (2) failure to achieve undetectable viral load by 4 to 6 months after start of therapy; (3) detection of virus after a previously undetectable viral load; (4) any significant increase (threefold) in viral load not attributable to another factor, such as acute infection or vaccination (flu vaccine can increase viral load); (5) progression of disease as defined by a new OI or further decrease in CD4 cell count.¹

 

Recommendations for changes vary according to the reason for the change. If therapy has suppressed viral load but is causing toxicity, then the offending agent may be replaced with another drug. Ideally, the new drug would be in the same class but have a different toxicity profile. Virologic rebound should be confirmed by a second viral load measurement before changing therapy. In general, all drugs in a failing regimen should be replaced if possible. For example, a regimen with two NRTIs plus a PI could be replaced with two new RTIs and a new PI, or two new RTIs plus two PIs. There is very limited data suggesting that subsequent regimens will provide durable viral suppression after the initial regimen fails. Failure of an initial PI-containing regimen is of particular concern since many PIs have overlapping resistance patterns. For example, ritonavir and indinavir have identical resistance patterns, so failure of treatment with one of these agents eliminates the ability to use the other in a salvage regimen (unless ritonavir is being used for pharmacokinetic advantage). Other PIs have different primary mutations, but the long-term clinical benefits of using another PI after failure of primary PI therapy have not been demonstrated.

Drug interactions with antiretroviral medications are numerous. If a significant interaction is likely, an alternative regimen should be selected to avoid toxicity or treatment failure. PIs are most likely to have drug interactions because of extensive metabolism by the CYP450-3A4 isoenzyme. Ritonavir, in particular, is a potent inhibitor of this isoenzyme and is associated with many more interactions than other medications. Many of these interacting medications are psychoactive medications (antipsychotics, antidepressants, benzodiazepines) and have the potential to cause significant adverse effects when combined with ritonavir. Other examples include rifampin, which should not be used at all with PIs, and rifabutin, which should be used in reduced doses. Birth control pills are also rendered ineffective by a number of these medications (ritonavir, nelfinavir, amprenavir, nevirapine), so it is imperative that pharmacists share this information with patients.

 

Pharmacists can play an important role in the identification of drug interactions. Because information regarding reactions is changing rapidly based on postmarketing surveillance, it important to keep abreast of changing recommendations regarding drug combinations. The Internet can provide valuable information on the most current information regarding these medications. Table 3 lists Internet sites that are helpful in maintaining a current knowledge base.

 

Antiretroviral agents are associated with a number of side effects, many of which may cause patients to discontinue therapy. PIs have a number of side effects that are common to the drug class. All PIs have GI side effects, some of which may be severe. Ritonavir causes severe nausea and vomiting. Dose escalation may help alleviate this problem. Nelfinavir has been reported to cause diarrhea in greater than 10% of patients.¹⁶ This is generally manageable with antimotility agents such as loperamide. Other PIs cause varying degrees of GI distress.

 

Metabolic abnormalities are common with PIs. Hyperglycemia and hyperlipidemia may develop during therapy. New-onset hyperglycemia or worsening of diabetic control has been estimated to occur in 1% to 2% of patients.^17,18 Patients receiving PIs should have periodic blood glucose determinations and receive instruction on the signs and symptoms of hyperglycemia. Treatment of PI-associated hyperglycemia is similar to that of type 2 diabetes mellitus (insulin or oral hypoglycemic agents). Elevated cholesterol and triglyceride levels have both been reported with PI therapy. Studies suggest that these abnormalities are more common with ritonavir or ritonavir/saquinavir. Pancreatitis and vascular disease are associated with PI-induced hyperlipidemia.¹⁹ Gemfibrozil and HMG-CoA reductase inhibitors are the drugs of choice for management of elevated triglycerides and cholesterol, respectively. Treatment principles and goals are similar to those of the general population.¹⁹

 

All PIs have the potential to cause lipodystrophy or "protease paunch." This phenomenon occurs when fat from the face and extremities is redistributed to the patient's trunk. The mechanism for this redistribution is not clear. It occurs in less than 10% of patients, but may be enough of a problem to cause the patient to discontinue therapy.¹⁶

 

Non-nucleoside medications are all likely to cause a rash that can range in severity from benign to a Stevens-Johnson­type reaction. NRTIs (except zidovudine) may cause peripheral neuropathy. Individual medications may have other significant side effects in addition to the class effects. Abacavir, in particular, is associated with a hypersensitivity reaction that is potentially fatal if the patient is rechallenged. Nausea, lethargy, and rash characterize this reaction. The medication should be discontinued immediately if these symptoms appear. Combinations of medications with overlapping toxicities should be avoided or carefully monitored.

 

Pharmacists should be aware of potential side effects, counsel patients about them prior to starting therapy, and encourage reporting of any adverse event. Some may be managed with over-the-counter medications and often tend to improve over time. Telling patients what to expect and how to manage problems in advance may help with medication adherence. Table 4 lists common adverse effects with antiretroviral agents.

Medication adherence is one of the largest issues in HIV therapy today. Drug regimens are complex and have many side effects and potential drug interactions. In addition, there are medication-specific considerations that may affect the efficacy of a regimen. HIV is one of the few disease states where partial adherence nearly always guarantees therapeutic failure and limits future options.

 

Literature on adherence shows a direct association between poor adherence and the number of medications in the regimen, the complexity of the regimen, and the extent to which medication administration interferes in the patient's daily activities.²⁰ Adherence tends to be better if treatment alleviates symptoms, and worse if treatment creates side effects. Unfortunately, HIV medication regimens are extremely complex, involve large numbers of pills, create inconvenience, and produce side effects. All of these problems create a huge barrier to therapeutic success.

 

Numerous small studies related to medication adherence have been conducted in the past few years, the results of which have been reported in abstract form. A study by Paterson and colleagues at the University of Pittsburgh examined the relationship between adherence and suppression of viral load.²¹ The investigators studied only the PI component of the patient's regimen, but the results were striking. At an adherence level of >95%, viral load was suppressed in 81% of patients, but at a level of 70% adherence or less, viral suppression was achieved in only 6% of patients. No patients had perfect adherence to their regimen. Many factors have been purported to predict a patient's ability to adhere to a regimen, but active depression and substance abuse have been consistently shown to predict nonadherence.²⁰ In situations where these factors are present, it may be best to delay treatment until these issues are addressed instead of risking nonadherence and limiting future therapeutic options. Factors that are likely to help with adherence include a good support system and belief that medications are likely to be of benefit.

 

It is extremely important that care providers assess the patient's ability to manage a regimen before prescribing it. An organized, highly motivated patient is much more likely to be able to handle a regimen that involves medication administration several times a day than is the patient who can barely handle the tasks of day-to-day living. Many antiretroviral regimens require 10 or more pills a day in addition to any other medications the patient may be taking and may be administered two to three times a day.

 

Many approaches have been suggested regarding assessment of a patient's readiness to begin therapy. For example, a new clinic patient may be required to attend a certain number of clinic visits, where extensive education regarding HIV and medication taking are addressed before a conversation regarding therapy for that patient is had. Another approach that has been used is the use of a medication organizer and jelly beans to simulate the regimen the patient will receive. The patient is given a "trial run" of the regimen before the drugs are started so he or she will have an idea of the commitment involved.

The development of potent antiretroviral medications has revolutionized the care of patients with HIV. The HIV-infected individual may now expect to have a much longer life span than individuals who were infected at the beginning of the epidemic. Therapy can be difficult to manage for many patients, however, and it takes a team approach to care to ensure success. The major obstacle to long-term success with antiretrovirals is patient adherence. Regimens are complex and have significant side effects. Pharmacists can have a key role in educating patients, helping them manage their medications, and monitoring for adverse effects and drug interactions. Performing these activities will increase the chances for therapeutic success while maintaining the patient's quality of life.

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References

A copy of this article’s references can be obtained by sending a stamped, self-addressed envelope to References Dept., Pharmacy Times, 1065 Old Country Road, Westbury, NY 11590.

 

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