Antiretroviral Drugs to Treat Human Immunodeficiency Virus Infections

1 Jun

INTRODUCTION

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.

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