Treatment of HIV
Contents Introduction HIV Prevention Sexual transmission Injection drug users Blood transfusions Human tissue transplants Artificial insemination Transmission of HIV to health care workers Vaccination Barriers to AIDS vaccine development Prophylaxis against infections Antiretroviral therapy     Definition of HAART     Resistance Protease Inhibitors (PI) Combination therapy Long term complication Drugs currently available Nucleoside Reverse Transcriptase Inhibitors (NRTI) Combination therapy Drugs currently available Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) Drugs currently available Other antiretroviral drugs Prospect of immune reconstitution

Introduction

Managing patients with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) is becoming increasingly more complex as newer medication and technologies are approved. New approaches to monitoring and treating patients with HIV infection and AIDS have been developed over the last two years, offering additional options for managing these conditions. These recent advances include: (100)

1. a better understanding of the replication kinetics of HIV throughout all stages of the disease
2. the development of quantitative viral assays and the demonstration of their ability to predict progression and treatment response
3. the availability of new effective antiretroviral drugs
4. clinical data documenting the superiority of combination therapy over zidovudine monotherapy

HIV is spread as much through ignorance and societal inequities as through physical modes of transmission. With the average age at infection falling and with half of new infections occurring in individuals under the age of 25, any comprehensive plan should handle how we can improve HIV prevention efforts for young people. (101)

Sexual transmission

Other than abstinence, latex-rubber condoms are the best protection against sexual transmission of HIV. (102) A meta-analysis of several studies of HIV transmission found that condom efficacy was 69% overall. (18,24) Condom efficacy is greatly increased by proper use. (18) Condoms should always be used for oral, anal and vaginal sex in any relationship that isn't mutually monogamous, and if there is any other chance that either partner may be infected. (102) The polyurethane Reality Female Condom, which is a product available for women, provides limited protection against sexually transmitted diseases. (102)

Injection drug users

An effective approach to preventing transmission of HIV among  injection drug users must encompass multiple interventions based on realistic assessment of different levels of risk. The first goal must be to reduce the number of people injecting. Despite the best preventive efforts, however, some level of injection drug use will inevitably persist. The next goal must therefore be to reduce the frequency of needle use and of risky injection practices, such as needle sharing. Finally, as these practices will never be eliminated, a harm education approach requires making each injection episode less risky and reducing the risks of sexual transmission. (27)

Blood transfusions (28)

Transfusion transmitted HIV-1 has become rare since the beginning of voluntary deferral of donors at risk for HIV-1 infection and the routine HIV antibody testing of all donations. Continued improvement in donor recruitment practices, donor education, donor screening, and blood testing result in continued decrease in risk of transfusion transmission.

Human tissue transplants

In December 1993, FDA issued a requirement that potential donors of all human tissues for transplantation, including tendons, bone, skin and corneas, be tested for HIV-1, HIV-2 and hepatitis B and C viruses and screened  for symptoms of AIDS, hepatitis and high risk behaviors such as sex between males and intravenous drug abuse. (102)

Artificial insemination

Current Center of Disease Control guidelines recommend screening semen donors for HIV antibody on the day of semen donation, freezing the semen, and not using it until the donor is tested again 6 months later and found to be HIV antibody-negative. (28)

Transmission of HIV to health care workers (103)

Transmission of HIV infection to health-care workers in an occupational setting is fortunately not a common event. Data from several large studies indicate, on average, a 0,3% risk of HIV infection after a needlestick or similar percutaneous exposure to HIV infected blood. (104) HIV infection after mucocutaneous exposure to HIV infected blood is so infrequent that the risk can not be estimated from published series, but does occur rarely, as evidenced by reports describing anecdotal cases. (104) The cumulative risk to a health-care provider for occupational HIV infection depends on three probabilities:

1. That the exposure will occur
2. That the exposure will involve HIV
3. That infection of the health worker will result

Vaccination (105)

The continued spread of the HIV epidemic in both the industrialized countries and the developing world provides compelling evidence for the need for an AIDS vaccine. Although HIV transmission is in theory largely preventable, in practice, without the development of an effective vaccine, HIV will continue to infect millions throughout the world. As of 1997, the United Nations Global Program on AIDS estimates that more than 30 million people worldwide are currently infected with HIV, and that more than 5 million new infections occurred in the past year. While programs to reduce transmission of HIV have achieved some success in both developed and developing countries,  it is unlikely that widespread application of these programs will be able to achieve a sustained decrease in HIV transmission. Similarly, although the advent of highly effective antiretroviral therapy has resulted in significant increases in survival for HIV infected individuals, the impact of combination antiretroviral therapy will be largely confined to the industrialized world, which at present constitutes less than 10% of the worldwide HIV infected population. Finally, historically, vaccines have been the most efficient and cost effective means for the control of infectious diseases, resulting in the eradication of smallpox and the control of polio, yellow fever, and measles.

Barriers to AIDS vaccine development

Obstacles to the development of an effective AIDS vaccine include factors related to the biology of HIV-1 infection and practical realities of developing and testing an AIDS vaccine.

• The extensive sequence variation of HIV isolates poses a considerable barrier to vaccine development.
• The lack of information regarding what types of immune responses may protect against HIV infection.
• Like other retroviruses, HIV integrates into the host genome where it can remain in a latent form that does not express HIV structural proteins and is thus less likely to be eliminated by host cellular and humoral immune responses.
• HIV-1 is predominantly transmitted by mucosal routes, yet our knowledge of the events occurring during mucosal infection and the immune responses responsible for defending against mucosal infection are quite limited.
• In addition, HIV transmission may occur by both cell-free and cell-associated viral particles. Cell-associated virus is thought to be resistant to neutralizing antibodies and will not be recognized by host CTL responses, unless there is a fortuitous match between the HLA molecules between the host and donor.

Routine prescription of anti-microbial medication is now widely used for prevention or clinical suppression of Pneumocystis carinii pneumonia and Mycobacteriun avium complex infections, and there is evidence that certain regimens in selected patients are beneficial against toxoplasmosis, bacterial infections, cytomegalovirus, herpes simplex, Mycobacterim tuberculosis, and fungal infections. Although it is difficult to statistically prove an impact on survival time or progression of underlying HIV disease, there is evidence that appropriate regimens can significantly decrease the incidence of each infection.

Antiretroviral therapy

Dramatic progress has been made in the ability to suppress HIV replication, leading to wide spread enthusiasm that HIV is now a manageable disease. With 11 antiretroviral drugs which have a price and are reimbursable in Belgium, however, and more in development, HIV medicine has become increasingly complex, a situation complicated by the fact that many of these drugs received accelerated approval by the Food and Drug Administration (FDA). Clinicals and patients must develop rational strategies with limited long term data. The current state of knowledge indicates that the combination of three drugs, rather than any monotherapy, should always be used, as it is the best strategy to combat the rapid replication of viruses and to enhance development of viral resistance. (100,106)
Potential benefits of combination antiviral therapy include drug synergy and toxicity profiles that may allow the use of certain drugs to counteract the toxicity of others. In addition, different drugs may have different tissue distributions or cell tropism's. (107)

Definition of HAART:

Striking subjective and objective clinical improvement is common in patients with clinically significant HIV disease, including many with AIDS and CD4+ counts below 100 cells/microliter, who begin an appropriate HAART regimen, adhere successfully to it, and do not experience significant adverse medication effects. In patients who respond well to HAART, subjective signs often include increased appetite, weight gain, increased energy, improved sleep, and a general feeling of greatly improved well being. Often, there is resolution or significant improvement of minor problems, (108) such as seborrheic dermatitis, molluscum contagiosum, (or recurrent thrush, and reports describe resolution of more significant conditions such as progressive multifocal leucoencephalopathy, cytomegalovirus retinitis, Kaposi's sarcoma, microsporidiosis, and cryptosporidiosis. In patients with advanced disease, CD4+ counts commonly rise dramatically, often by several hundred cells per microliter, to levels characteristic of the clinically quiescent middle stage of HIV disease. HIV RNA levels drop to levels undetectable by standard commercial assays. The potential duration of this response is unknown because the therapy is relatively new, but many patients have maintained this state after 2 years. In patients with middle stage disease, the changes may be less dramatic, although some increase in CD4+ T cells and subjective sense of well being is common.
Unfortunately, the desired response to HAART does not occur or does not endure in all patients. (109) In some patients, an initial response occurs, but eventually signs of advancing HIV disease reemerge. In others, the response is minimal.

Resistance:
 
The emerge of HIV resistance has been described for all antiretroviral therapies. The high replication rate of HIV and the error prone nature of HIV reverse transcriptase results in the rapid development of mutations.Recombination events also contribute to substantial genetic variation. In the presence of the selective pressure of an antiretroviral therapy, drug resistant HIV variants emerge. On the basis of these observations, clinical guidelines are based on strategies aimed at completely suppressing viral replication, thereby delaying or preventing the selection of drug resistant strains. (106)

HIV-1 protease activity is critical for the terminal maturation of infectious virions. Protease inhibitors specific for HIV-1 competitively inhibit this enzyme, thereby  preventing the maturation of virions capable of infecting other cells. All four available drugs are potent inhibitors of HIV-1 protease in vitro. It is this class of drugs that has created the greatest optimism since the beginning of the AIDS epidemic. (100) To achieve long-term viral suppression, protease inhibitor therapy must be managed carefully. (106,110)

Combination therapy:
 
Several compelling arguments support the use of dual protease inhibitor regimens. The use of two drugs with distinct, non overlapping mutation patterns may delay or prevent the onset of resistance. As a class, protease inhibitors have potent effects on their own metabolism, which, with specific combinations, may allow for dose reductions, more convenient dosing regimens, less toxicity, and less cost. (106)
Long-term complications:
 
The long-term safety of protease inhibitors is unknown. Anecdotal information continues to emerge that protease inhibitors may be associated with various complications, particularly after long-term dosing. Hair loss, premature coronary arterial disease, diabetes mellitus, abnormal distributions of body fat, increased spontaneous bleeding episodes for hemophilia patients and other complications may prove to be related to protease inhibitor therapy. (106)


Drugs currently available:
 

1. indinavir:      Crixivan®
2. nelfinavir:     Viracept®
3. ritonavir:      Norvir®
4. saquinavir:   Invirase® (The new formulation Fortovase® has not yet a price is not yet reimbusable in Belgium.)

amprenavir: Agenerase® (not yet a price neither reimbusable in Belgium)


Other drugs are under investigation. (for more information click here)

Nucleoside Reverse Transcriptase Inhibitors (NRTI)

Despite the recent introduction of potent new classes of antiretroviral therapies, nucleoside analogues continue to be crucial drugs in therapeutic strategies aimed at controlling HIV infection, this class of NRTI drugs was the mainstay of antiretroviral therapy for the first 10 years of the AIDS epidemic. These drugs are safe, generally well tolerated, and effective in prolonging life, particularly when used in combination with other therapies. They also delay or prevent the development of HIV resistance to protease inhibitors and non-nucleoside reverse transcriptase inhibitors. NRTI drugs are phosphorylated intracellulary to their active metabolites. The primary mechanism of action of this class is  inhibition of viral RNA dependent DNA polymerase (reverse transcriptase). All  drugs in this class are nucleoside analogs with antiretroviral activity against HIV-1. (100,106)

Combination therapy:
 
Combination therapy often involves two nucleoside analogues and either a protease inhibitor or an NNRTI. Five dual nucleoside analogues combinations are recommended as part of a potent antiretroviral regimen: zidovudine/didanosine, zidovudine/zalcitabine, zidovudine/lamivudine, stavudine/lamivudine, and stavudine/didanosine. (106)
Drugs currently available:
 
1. didanosine: Vidix®
2. lamivudine: Epivir®
3. stavudine:   Zerit®
4. zalcitabine: Hivid®
5. zidovudine: Retrovir®

abacavir:    Ziagen® (not yet a price neither reimbusable in Belgium)


Other drugs are under investigation. (for more information click here)

As a class, the non-nucleoside reverse transcriptase inhibitors (NNRTI's) are heterogeneous with respect to chemical structure. NNRTI's bind non competitively to the HIV reverse transcriptase enzyme, causing a disruption in the enzyme's catalytic site. In contrast to the nucleoside analogues, NNRTI's do not require intracellular phosphorylation to become active. Although the two antiretroviral classes inhibit the same enzyme, there is no evidence for cross-resistance between the two classes. (106)
Because resistance to these drugs develops rapidly, especially when used alone, monotherapy with this class of antiretrovirals should never be attempted.

Drugs currently available:

1. nevirapine:  Viramune®

delavirdine: Rescriptor® (not yet a price neither reimbusable in Belgium)
efavirenz:    Sustiva® (not yet a price neither reimbusable in Belgium)

Other drugs are under investigation. (for more information click here)

• Nucleotide Reverse Transcriptase Inhibitors
• Zinc Finger Inhibitors
• Fusion Inhibitors
• Antisense antivirals
• Cellular Inhibitors

Prospect of immune reconstitution (8)

In controlling HIV disease, the most striking successes to date have been with drugs to suppress HIV replication. Reconstitution of immune system function, however, is clearly a necessary step to recovery and is thus an obvious goal of research and therapy. Information to date offers some hope of achieving this goal, but also indicates problems to be overcome. At present, there is some evidence of partial immune reconstitution following response to HAART. It is still far from clear whether responding individuals can progress to broad restored immune competence, and whether or how additional interventions might promote restoration.