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Anti-HIV drugs

Generic names (other names)

Side effects

Indinavir (Crixivan) Kidney stones, nausea, headache, blurred vision, dizziness, rash, glucose intolerance

Nelfinavir (Viracept) Diarrhea, glucose intolerance, abnormal distribution o f fat, elevated cholesterol level Ritonavir (Norvir) Nausea, vomiting, diarrhoea, abdominal pain,

headache, hepatitis, weakness, elevated cholesterol levels, glucose intolerance

Saquinavir (Invirase, Fortovase) Nausea, diarrhoea, headache, elevated cholesterol levels, glucose tolerance

Amprenavir (Agenerase) Rash, nausea, diarrhoea, dyspepsia, depression, fatigue, elevated amylase

HIV replicates prolifically from the start, but HIV levels remain fairly stable for several years and this is

because the body responds for a time by manufacturing extremely high numbers o f CD4^ T cells to

replenish those lost. In addition, in untreated patients the strength o f the immune response (in acute stage)

has a decisive influence on the rate o f progression to AIDS. Some patients show strong CD8^ T cell

activity and those patients achieve greater suppression o f viral replication, and a lower viral set point. The

disease progresses more slowly than in individuals with weak immune response. The amount o f the virus

in the system plays a major role in determining the fate of patient. Therefore, therapy must aim to shut down

viral reproduction.

The emergence o f resistant mutants was originally countered by the use o f two or three drug combinations

despite the fact that these only extended the survival o f AIDS patients by one or two years and also had

More recently, Highly Active Anti Retroviral Therapy (HAART) has been shown to control replication of

HIV-1 in vivo so effectively that the virus becomes undetectable in the plasma. This could be the best way to achieve maximum viral suppression. At the moment, HAART consists o f triple therapy, including two

nucleoside analogues and a proteinase inhibitor (Hermankova et a l, 2001).

HAART has some problems such as side effects, complicated regimens and resistance. Inability to adhere

strictly to medication schedules by missing doses can cause incomplete suppression of viral replication and

a rise in resistance.

It has been shown that Virus- induced immunosuppression is stopped and partially reversed with HAART

and therapeutic strategies directed at activated CD4^ T cells might benefit patients by helping to contain the

low level o f viral replication that continues in patients on HAART (Chun et a l, 2000). This led to a study o f the effects o f immunosuppressive agents such as mycophenolic acid (MPA) on HIV-1 replication in vitro and in vivo. MPA selectively inhibits lymphocyte proliferation by inhibiting cellular DNA synthesis in lymphocytes. It actually causes the death of activated CD4^ T cells, reducing the number o f susceptible

target cells for HIV-1 replication. Because the resting CD4^ T cells that contain latent provims are not likely

to be affected by MPA, the observed reductions may reflect a decrease in the number o f activated CD4^

T cells that maintain very low level o f active replication that continues in patients on HAART (Domatula,

1999). Furthermore, addition o f other compounds such as Mycophenolate mofetil (MMF) results in a

considerable reduction in the number o f proliferating CD4^ and CD8^ T cells in patients on HAART

(Chapuis et a l, 2000).

There are other agents that could halt replication in other ways. Some would block the integrase enzyme

from inserting HIV DNA into a cell’s chromosome. Other ways to stop infected cells from making critical

viral proteins include the use of antisense DNA to inactivate two genes {tat & rev) that normally give rise to proteins needed for the efficient production o f other viral proteins. This therapy resulted in limited viral

replication and CD4^ T cell depletion in rhesus macaques exposed to the simian version o f HIV (McCune,

2001 ). In addition, many groups are examining compounds that might shield the HlV-docking site on co­

receptors to prevent cell attachment. (O ’Brien & Dean, 1997).

Dmgs targeting the other essential viral enzyme, integrase, and dmgs targeting the initial step in the virus life

cycle, may eventually become part o f HAART regimens.

Efforts to improve therapy o f HIV-induced immune deficiency will involve three strategies: better anti-HIV

dmgs and combinations o f dmgs aimed at slowing the replication of HIV, immune-based therapies intended

to stimulate the immune system, and multiple opportunistic pathogen prophylaxis strategies to prevent HIV-

related opportunistic infections (Henry & Schwebke., 1993). This approach will involve considerable cost

and polypharmacy. In 2001, the best strategy is prevention, which is where physicians can have the greatest

impact on the epidemic.

1.8.2 Vaccines and the Immune Response

Vaccines in general are cheap and easy to administer, but no effective vaccine is yet available for HIV. Even

experimental SIV vaccines have problems. The objective o f an AIDS vaccine is to prevent infection. The

A major problem arises due to the sequence dis-similarity (approximately 45%) between HIV-1 and

SIVmac. This work therefore may involve extensive HIV-1 vaccine development in the chimpanzee.

In the case of HIV, a successful vaccine should be able to eliminate incoming virus and destroy quickly any

cells that become infected. HIV stimulates two kinds o f immune responses. In the humoral response, a

macrophage or related cell degrades HIV particles and presents antigens to white blood cells such as

CD4^, or helper, T lymphocytes. After contact with antibodies to antigens on the viral surface, B lymphocytes mature and produce antibody molecules able to mark HIV particles for destruction. In

addition, helper, or CD4^, Tlymphocytes direct B cells to produce more antibodies or to form memory B cells.

Cellular response begins after an HIV-infected macrophage that displays viral fi’agments is recognized by

activated white blood cells called cytotoxic Tlymphocytes (CD8^ T cells) which multiply and move through

the bloodstream and tissues, to eliminate vims infected cells. However, cytotoxic Tcells are activated in part by signals from T cells. Some of the B and T cells eventually become long-lived memory cells that react promptly to future exposures to HIV. The most effective HIV vaccines maybe the ones that stimulate both

the humoral and cellular arms o f the immune system, generating antibodies and activated cytotoxic T cells. The ideal target would be a protein which does not change as the vims mutates. However, no such target

has been noted.

Table 1.5: Vaccine strategies for HIV (A dapted from Baltim ore & H eilm an, 1998).