In less than two decades, human immunodeﬁciency virus (HIV) has dramatically progressed from a little-known or understood infection to the cause of a major global epidemic. In 1998, 36 million people were infected worldwide (1). Today, more than 46 million people are infected worldwide, with 16,000 new infections occurring in the world each day. Ninety-ﬁve percent of the HIV-infected population lives in the undeveloped-to-developing world where adequate treatment and prevention programs are lacking. For instance, the major- ity of new HIV infections in 2003 occurred in sub-Saharan Africa, where even monotherapy for HIV is lacking.
While the rate of new infections in the United States has been stabilizing overall in past years, this infection is becom- ing disproportionately concentrated in the lower socioeconomic class as well as the African-American community. Currently, African Americans are more than eight times as likely as whites to be infected with HIV, and AIDS is now the leading cause of death in black males between the ages of 25 and 44 (1).
Prior to the availability of highly active antiretroviral ther- apy (HAART), more than 90% of HIV-infected patients devel- oped cutaneous manifestations at some time during the course of disease (2). In some of these individuals, disorders of the skin are the ﬁrst presenting sign of HIV infection (3). A wide variety of skin conditions may arise in this immunosuppressed popula- tion, such as molluscum contagiosum (4), bacillary angiomatosis (5,6), Kaposi’s sarcoma (7), eosinophilic folliculitis (8), candidia- sis (7), mycobacterial infections (9–11), and a litany of others.
Because health care workers, in addition to those special- izing in infectious diseases, will increasingly be involved in the collaborative management of these patients, it is impera- tive that we become familiar not only with the clinical mani- festations of HIV, associated opportunistic infections, and their treatments, but also with the general antiviral therapies used for HIV infection. In addition, due to the rapid develop- ment of new antiretroviral drugs (Figure 2.1) and the need for
Fig. 2.1 Current antiretrovirals approved by the FDA (2004).
Antiretroviral Drugs to Treat Human Immunodeﬁciency Virus Infections
multiple medications in these patients, a plethora of drug interactions and adverse effects have complicated the issues of treatment Table 2.1. The goals of antiretroviral therapy are to decrease morbidity and mortality via suppression of viral load and maintenance of CD4(+) cell counts. Other objectives are to prevent the emergence of viral resistance, to capitalize on complementary drug actions, and to attack the virus in acti- vated and in resting immune cells. Furthermore, antiretrovi- ral treatment should attack HIV at multiple stages of reproduction, target viral compartments (e.g., lymph nodes), minimize side effects, and maximize patient compliance.
HUMAN IMMUNODEFICIENCY VIRUS
Antriretroviral drugs are used primarily to treat the patients with HIV infection which has become a major global scourge with little relief in sight for developing nations. The virus is transmitted through exposure to infected semen, cervical or vaginal secretions, or infected blood. Intravenous drug users who share contaminated needles are most at risk for contracting HIV. Unprotected sex between partners is a worldwide cause of transmission. Children born to HIV-infected women contract the disease during pregnancy through cross-contamination with the mother’s body secretions or blood during delivery, or during breast-feeding.
When initially infected, patients usually have normal CD4 cell numbers, a low viral load, and an immunological response that indicates a prevalence of Th 1 lymphocytes. With advanced infection, CD4 levels fall, viral loads rise, and Th 2 lymphocytes are predominant. The Th 2 lymphocytes enhance humoral immunity and produce IL-4, IL-5, IL-10, and allergic responses. As CD4 levels fall, patients are bombarded with a variety of organisms as immunological responses decline. Many patients develop previously “rare” diseases due to viruses, bacteria, parasites, and fungi as well as neoplastic and other noninfectious disorders.
Interventions for HIV. Mechanistic analyses of the replica- tion of HIV infection within a patient have revealed several
Fig. 2.2 Sites of action of antiretroviral drugs. Nucleoside, nucle- otide and non-nucleoside reverse transcriptase (RT) inhibitors act at the same step in the replication of HIV. Nucleoside analogues, when phosphorylated, competitively inhibit RT by acting as an alternative substrate for the enzyme. Non-nucleoside analogues do not require phosphorylation but noncompetitively bind directly to the active site of RT. Protease inhibitors prevent the cleavage of viral polyproteins in the ﬁnal stage of viral protein processing, thus preventing the assembly of mature HIV virions. Fusion inhibitors prevent binding to the surface of the cell and subsequent infection of the cell.
avenues for therapy. These include inhibitors that are active during the binding, fusion, and entry of the viral capsid into the cell. Then, during RNA replication, reverse transcriptase drugs interfere with RNA replication. Viral integrase drugs (of which there are none approved at this writing) interfere with entry into the nucleus. Another potential, but not yet having any approved drugs, target would be the viral zinc- ﬁnger nucleocapsid proteins. Finally, viral protease inhibi- tors attack the virus as it leaves the cell to infect other cells. (See Fig. 2.2)
Treatments for HIV. There is no known “cure” for HIV dis- ease. The initial regimen programs for HIV began with nucleo- side reverse transcriptase inhibitors (NRTIs) in 1987 and therapy was with one drug, zidovudine Over time, it became obvious that as HIV replicated, it also mutated. This meant that therapy began to fail. Progress (rising CD4+ counts and lowered HIV RNA levels) began to unravel. Other drugs, administered individually, were no better. However, combinations of antiret- roviral drugs provided a “cocktail” that attacked the virus at multiple points (12). This HAART became the standard of care in 1996 in developed countries where insurance or government health care pays for the nearly $20,000 bill for drugs prescribed for a patient each year. In developing countries, however, mono- therapy may be the only option, if any antiretroviral therapy is available. Figures 2.1 and 2.2 illustrate the available therapies that can be used in HAART and their sites of action.
Typically HAART consists of two nucleoside analogues and a protease inhibitor (PI) or a non-nucleoside reverse tran- scriptase inhibitor (NNRTI). Today there is an armada of anti- retrovirals in the arsenal with many more being developed (Fig. 2.2). Nucleotide and nucleoside reverse transcriptase inhibitors, PIs, and NNRTIs have been joined by fusion inhib- itors. Selecting the appropriate therapy, however, is no longer a simple matter.
There have been several suggested therapy cocktails con- sisting of three or even four antiretrovirals taken concur- rently. The “original combination therapy” called for two NRTIs administered with one NNRTI or a PI. (13,14) Recent studies indicate that a combination of three anti- virals appears most efﬁcacious and that efavirenz, lamivu- dine, and zidovudine provide the best combination for patients receiving their ﬁrst HIV medication. At this time, lamivudine and zidovudine are available as a combination pill (Com- bivir®). This combination drug, administered with efavirenz, means patients take only three pills/day with a concomitant increase in patient compliance.
If resistance is detected, the patient and doctor must con- sider other antiretroviral drugs as alternative therapy. The options may appear numerous, but many factors enter into the picture. Once resistance occurs, other related drugs may demonstrate cross-resistance. Allergies to one drug usually transfer to other drugs in the same category. Concomitant non-antiretroviral drugs also must be considered. For exam- ple, prescribing a drug known to cause hepatic toxicity might prove to be risky to a patient with any type of hepatitis. Like- wise, any drug that affects liver metabolism must be used with extreme care if given along with other agents metabo- lized by the liver.
Controversy still exists regarding the optimal time to initiate therapy due to the cost of treatment, the side effects, and the difﬁculty with compliance which results in potential resistance. Newly revised guidelines on treating adults and adolescents with HIV and AIDS provide suggestions for regi- mens that are more deﬁnitive. The guidelines were prepared by the Panel on Clinical Practices for Treatment of HIV Infec- tion, convened by the Department of Health and Human Ser- vices. For the ﬁrst time, the guidelines include lists of “preferred” and “alternative” regimens. These lists are avail- able at http://aidsinfo.nih.gov; the document also lists regi- mens or components that should never be offered.
The preferred regimen based on NNRTIs calls for a com- bination of efavirenz, lamivudine, and zidovudine, tenofovir or stavudine, except for women who are pregnant or may become pregnant. Patients on this regimen take three to ﬁve pills per day.
The preferred regimen based on PIs calls for a combina- tioin of lopinavir/ritonavir (coformulated as Kaletra®) together with lamivudine and either zidovudine or stavudine. Patients on this regimen take 8 to 10 pills per day.
Triple NRTI regimens should be used only when an NNRTI- or PI-based regimen cannot be used as ﬁrst-line ther- apy. The panel’s preferred triple-NRTI regimen calls for a com- bination of abacavir, lamivudine, and either zidovudine or stavudine. Patients on this regimen take two to six pills per day. Regimens listed as “alternative” in the guidelines, how- ever, may actually be the preferred regimen for a speciﬁc patient.
The panel listed 12 regimens or components that should never be offered. Several, including monotherapy and dual nucleoside therapy, had been listed as contraindicated in previ- ous versions of the guidelines. The newly listed contraindicated regimens are a three-NRTI regimen with abacavir, tenofovir, and lamivudine (because of early virologic nonresponse); a three-NRTI regimen with didanosine, tenofovir, and lamivu- dine (because of a high rate of virologic failure); the combination of didanosine and stavudine (because of a high incidence of tox- icities, including several deaths); the combination of atazanavir and indinavir (both of which can cause high-grade hyperbiliru- binemia and jaundice); and emtricitabine plus lamivudine as a two-NRTI backbone (since both drugs have similar resistance proﬁles and minimal additive antiviral activity).
The guidelines found at www.hivatis.org recommend ini- tiation of treatment for all HIV-infected persons who have symptoms of HIV infection, a rapidly declining CD4 count, a CD4 count <200–350 cells/mm3, or a viral load >30,000 RNA copies/ml (bDNA assay) or 55,000 RNA copies ml (RT-PCR assay) (regardless of the CD4 count) (15).
Guidelines are less established for pediatric patients, but it is generally recommended that therapy be initiated in chil- dren with clinical symptoms of HIV infection or evidence of immunosuppression, regardless of viral load. However, any child with HIV RNA levels >100,000 copies/ml is at a high risk for mortality, and antiretroviral therapy should be started. Others recommended starting therapy in children at HIV RNA levels >10,000–20,000 copies/ml. Zidovudine (AZT) monotherapy is indicated only for infants of indeterminate HIV status during the ﬁrst six weeks of life to prevent perin- atal HIV transmission (16).
Even combination therapy has many side effects that HIV-infected persons must tolerate. Side effects and the required number of pills to be taken daily affect patient com- pliance. Even missing 5% of one’s pills may put a patient at risk for drug resistance. These factors have led to the develop- ment of more potent and safer antiretroviral agents. Although resistance is less likely with HAART than with monotherapy, it remains a problem.
Combination therapies. To address the need for fewer pills, pharmaceutical companies have begun to market com- bination therapies. Three of these are currently marketed. Zidovudine and lamivudine are marketed as Combivir. A combination of abacavir, zidovudine, and lamivudine is mar- keted as Trizivir®. Lopinavir, which was approved only as a combination drug with ritonavir, is marketed in this combi- nation as Kaletra.
Maintenance therapy after combination therapy. One study of maintenance therapy of HIV infection (after an ini- tial response to combination therapy) showed that suppres- sion of plasma HIV RNA was better sustained with a combination of indinavir, zidovudine, and lamivudine than either indinavir alone or zidovudine and lamvudine (17). A similar study also found that three-drug therapy (zidovu- dine, lamivudine, and indinavir) was more effective than two-drug maintenance therapy (zidovudine plus lamivudine or zidovudine plus indinavir) in sustaining a reduced viral load in HIV-1–infected patients after three months of induc- tion therapy (18).
These studies and others have led to the current thera- peutic approach to HIV, which involves HAART. These treat- ment guidelines suggest early and aggressive drug therapy with three antiretroviral drugs from different classes of drugs. In previously untreated patients, this approach is expected to reduce the plasma HIV virus levels to levels below the limits of detection (19). However, studies have shown that even with effective HAART therapy and unde- tectable plasma HIV virus levels, virus is still present in lymph nodes, semen, or possibly elsewhere. Furtado et al. (20) showed that despite treatment with potent antiretroviral drugs and suppression of plasma HIV-1 RNA, HIV transcrip- tion was actively present in peripheral blood mononuclear cells. Zhang et al. (21) found that several HIV-1–infected men on HAART therapy continued to have virus present in seminal cells, which may still allow for sexual transmission of the virus. Moreover, combination antiretrovirals appear to suppress HIV-1 replication in some, but not all, patients (22).
Regardless of these dilemmas, the leading problem with HAART therapy is its cost and availability. With the extremely high expense of daily combination treatment (i.e., $15,000 to $20,000 per year), more than 95% of the 46 million HIV- infected people worldwide cannot afford it. Further progress in the battle against HIV will require a more economic and accessible means of treatment that can reach the population in the developing world.
Prophylactic antiretroviral drugs. Another advance in the treatment of HIV is the potential to administer prophylac- tic antiretroviral drugs to exposed individuals in order to decrease the risk of acquiring infection. Although large-scale, placebo-controlled clinical trials are not logistically possible, one study has found that zidovudine prophylaxis reduced HIV seroconversion after percutaneous exposure (23,24). Current basic recommendations for postexposure prophylaxis (PEP) include a four-week regimen of zidovudine and lamivudine, begun as soon as possible after exposure (25). For occupational HIV exposure with additional risk for transmission (e.g., higher virus titers or larger blood exposure), indinavir or nelﬁ- navir is added to the basic regimen.
Zidovudine chemoprophylaxis is also effective in the reduction of perinatal transmission, in some studies decreas- ing the risk of vertical transmission from mother to child by
66 to nearly 70% (26,27). This regimen consists of daily oral zidovudine given during the last six weeks of pregnancy, fol- lowed by intravenous zidovudine during labor (28). Thereaf- ter, the newborn is given oral zidovudine for the ﬁrst six weeks of life. Implementation of this regimen in the United States and Europe has dropped the rate of perinatal trans- mission to 6% or less (29). However, the high expense of treatment is cost-prohibitive for developing countries. Three recent studies have evaluated the efﬁcacy of short-term zidovudine in decreasing the risk of HIV-1 perinatal transmis- sion. The trial regimens generally consisted of oral zidovudine given during the last four weeks of pregnancy, some with additional doses during labor. Results revealed a 37 to 38% decrease in vertical transmission of HIV-1 in subjects who breastfed (30,31). In a similar study without breastfeeding, the reduction in the rate of transmission was 50% (32). While a shorter course of zidovudine is considerably cheaper, ($50 for the shorter course vs. $800 for the longer course), the cost of therapy remains too high for most developing countries. Musoke et al. (33) found that a single dose of nevirapine administered to HIV-positive women during labor and another dose given to their infants during the ﬁrst week of life may be a safe and well-tolerated treatment that is helpful in reduc- ing perinatal transmission of HIV. This treatment would be a low-cost and accessible alternative for poor and developing countries with high rates of HIV infection and limited funds for treatment.
Guidelines for therapy. The National Institutes of Health has deﬁned general principles for the therapy of HIV (34). Both plasma HIV RNA levels (viral load) and CD4+ T cell counts should be followed for monitoring of response to treat- ment. The combination of these values has been determined to be a more accurate assessment of prognosis (35). In addition, they are a useful tool in determining the efﬁcacy of antiretro- viral treatment while the patient is awaiting clinical response. CD4+ counts indicate the extent of immune system damage and the risk for opportunistic infections. Although HIV RNA levels are more predictive of the risk for disease progression, CD4+ counts are a more accurate measurement of the effect of antiretroviral therapy.
HIV RNA levels should begin to decline within days of effective treatment and ideally should progressively fall to below the limits of detection within eight weeks, although complete suppression is seen in a maximum of only 60–80% of previously untreated patients. A more realistic eight-week target is a one-log reduction of the viral load. Rebound of viral load levels during consistent treatment may indicate resistant HIV variants and may likely require changes in the current antiretroviral regimen. It should be noted that if one of the drugs in the antiretroviral regimen must be stopped, they all should be stopped and that a single-drug substitu- tion can be made only if the patient’s viral load is completely suppressed.