AIDS THERAPY – THE INFLUENCE OF NEW DRUGS

AIDS THERAPY – THE INFLUENCE OF NEW DRUGS

Sabna KottaHH,
Stephen Varghese,
Anoop Philip

National College of Pharmacy, Manassery, Calicut 

Cite this: Sabna Kotta,Stephen Varghese, Anoop Philip, "AIDS THERAPY – THE INFLUENCE OF NEW DRUGS", B. Pharm Projects and Review Articles, Vol. 1, pp. 1303-1342, 2006. (http://farmacists.blogspot.in/)

 


INTRODUCTION

 

    The acquired immune deficiency syndromes (AIDS) is the state of profound immuno-suppression produced by chronic infection with the human immune deficiency virus (HIV)¹

 

    It is characterized by profound immunosuppression that leads to opportunistic infections, secondary neoplasm and neurologic manifestations³⁶.

 

FIRST CASES OF AIDS

 

    The original description of AIDS appeared in USA in June 1981. researchers believe that HIV the virus that causes AIDS is rooted in the Congo. Until June of 1981 the disease was not known in America. The centre for disease control reported five young gay men in Los Angeles had a new, mysterious illness resembled pneumonia, attacking the immune system. In 1982, the health community coined the term AIDS to refer this illness⁶.

 

HISTORY

 

    Quite simply, HIV was probably a mutation of an African monkey virus. The presence of related retrovirus in African monkeys and Apes and the close relationship of HIV to a chimpanzee immune deficiency virus all suggest that central Africa may have been the site of evolution of HIV⁵.

 

CROSSING OF HIV AMONG SPECIES

 

    It has been known that certain viruses can pass between species. When a viral transfer between animals and humans takes place, it is known as 'Zoonosis'.
    The most common theories about zoonosis are:-

 

1. The hunter theory
    in this scenario, SIV (Simian immuno deficiency virus) was transferred to humans as a result of chimps being killed and eaten or their blood getting into cuts or wounds on the hunter.

 

2. The oral polio vaccine (OPV) theory:
    HIV was transferred iatrogenically (i.e., via medical experiments)

 

3. The contaminated needle theory

 

4. The conspiracy theory
    OR i.e., 'man-made' number of African Americans believe that HIV was manufactured as part of a biological warfare programme, designed to wipe out a large number of black and homosexual people.

 

REASON FOR SUDDEN SPREADING OF THE EPIDEMIC

 

• Travel
  
   
• The blood industry
      The blood form hundreds of individual donors had to be pooled to produce factors VIII (coagulant). This meant that a single donation of HIV + blood could contaminate a batch of Factor VIII. This put thousands of haemophiliacs all over the world at risk of HIV.
  
  
   
• Drug Use
      Growth in intravenous drug use together with the development of disposable plastic syringes and the establishment of 'shooting galleries' where people could buy drugs and rent equipment, provided another route through which the virus could be passed on⁶.
  
  
   
  WHO CLASSIFICATION SYSTEM
  
   
  WHO Asymptomatic
• WHO Stage 1
  This includes the acute retroviral syndrome of initial infection, the asymptomatic and those with persistent generalised lymphadenopathy.
  
   
  WHO Symptomatic
  This has been divided into two areas;
• WHO Stage 2
  Weight loss < 10% of body weight
  Muco-cutaneous manifestations such as seborrhoeic dermatitis, fungal nail infections, recurrent oral ulcerations, angular cheilitis.
  Recurrent upper respiratory tract infections such as bacterial sinusitis.
  
   
• WHO Stage 3
  Weight loss > 10% of body weight
  Unexplained chronic diarrhoea > 1 month.
  Unexplained prolonged fever (intermittent or constant > 1 month).
  Candidiasis, oral.
  Candidiasis, vulvovaginal for > 1 month
  Oral hairy leukoplakia.
  Pulmonary tuberculosis.
  Severe bacterial infections such as pneumonia or pyomyositis.
  Bed ridden for < 50% ofthe day during the last month.
  
   
  WHO - AIDS
• WHO stage 4
  Bed ridden for > 50% of the day during the last month.
  Candidiasis of the oesophagus, trachea, bronchi or lungs.
  Cryptococcus, extrapulmonary
  Cryptosporidiosis with diarrhoea for > 1 month.
  Cytomegalovirus disease of an organ other than the liver, spleen or lymph nodes.
  Herpes simplex infection, mucocutaneous for > 1 month or visceral for any duration.
  HIV dementia (encephalopathy).
  Isosporiasis with diarrhoea for > 1 month.
  Kaposi's sarcoma
  Lymphoma
  Mycobacterium tuberculosis - extrapulmonary
  Mycobacteriosis- atypical and disseminated.
  Mycosis - disseminated histoplasmosis or coccidioidomycosis.
  Pneumocystis carinii pneumonia.
  Progressive multifocal leukoencephalopathy.
  Salmonella septicaemia (non-typhoidal)
  Toxoplasmosis of the brain.
  Wasting syndrome due to HIV.
  
   
  AGE/NUMBER OF CASES - 2004
  
  (under 13) - 9,443
  (13-14) - 959
  (15-19) – 4,936
  (20-24) - 34,164
  (25-29) - 114,642
  (30-34) - 195,404
  (35-39) - 208,199 (highest)
  (40-44) - 161,964
  (45-49) - 99,644
  (50-59) - 29,553
  (60-64) - 16,119
  (over 65) - 14,410
  RACE/ETHNICITY NUMBER OF CASES - 2004
  
  Black - 379,155
  White - 375,155
  Hispanic - 177,164
  Asian/Pacific Islander - 7,317
  Alaskan/Native America - 3,084
  
   
  CONTRACTION OF HIV
  
      If you greet a person with HIV with a friendly handshake, you are not going to catch the disease. But there are still many ways one can contract HIV, which will then likely develop into AIDS.
  
   
  
  • Unprotected sexual intercourse (male/female or male/male) - Use protection, but remember, nothing is 100%: Condoms can break.
  • Oral sex - Some believe this to be a safe substitute to sex. However, HIV can be contracted through semen, menstrual blood or to the receiving person through mouth/gum/tongue sores.
  • IV drug use - Sharing a needle/syringe with an HIV positive person is a surefire way to contract HIV. If this is the lifestyle you choose, do not reuse or share materials.
  • Blood transfusions - Today, blood supplies are tested, and in turn, transfusions are generally safe. If you had a transfusion before 1985, you might still want to get an HIV test.
  • Birth and breast feeding - Although there are medications HIV-positive pregnant women can take to reduce the risk of their baby contracting the disease, HIV/AIDS can be passed on. All pregnant women should be tested for HIV.
  • Sharing a toothbrush/razors with an infected person - Ever get nicked and bleed while shaving? Don't share razors. And, while saliva does not pass the virus, there is a risk of blood being transferred through a toothbrush.
  
   
  METHODS OF CONTRACTION OF AIDS
  
   
  According to a CDC 2004 surveillance report:
  
  • Male to male sex - 402,722 (44%)
  • Injection drugs - 219,053 (24%)
  • Heterosexual sex - 117,887 (13%)
  • Male to male and IV drugs - 60,038 (7%)
  • Hemophilia - 5,427 (1%)
  • Transfusion - 9,274 (1%)
  • Other Risk/not identified - 94,504 (10%)
  
   
  
  ETIOLOGY
  
   
      There is no doubt that AIDS is caused by HIV, a human retrovirus belongs to the lentivirus family.
  
   
      Two genetically different, but related forms of HIV, called HIV - 1, and HIV - 2 have been isolated from patients with AIDS.
  
   
  • HIV-1 is the most common type associated with AIDS in U.S, Europe and Central Africa.
  • HIV-2 causes a similar disease principally in West Africa.
      
  
  Although distinct HIV-1 and HIV-2 share some antigens.
  
   
      Similar to most retrovirus, the HIV-1 virion is spherical and contains an electrone-dense, cone shaped core surrounded by a lipid envelop derived from the host cell membrane. The virus core contains:

1. the major capsid protein p^24.
2. nucleoscapsid protein p7/p9
3. two copies of genomic RNA and
4. the three viral enzymes (protease, reverse transcriptase and integrase).
   
    
   
    
   
    
   
    
   
    
   
    
   
    
   
    
   
    
   
   Figure: structure of HIV 1
   
    
   
   Figure. 1. Structure of HIV 1
   PATHOGENESIS
   
   
    
   1. Attachment
   2. Reverse transcription
   3. Integration
   4. Translation
   5. Viral protease
   6. Assembly and budding.
   
   
    
   
    
   
    
   
    
   
    
   
    
   
    
   
    
   
    
   
    
   
    
   
    
   
    
   
    
   
    
   
    
   
    
   
    
   
   
    
       Figure. 2. Pathogenesis
   
   CLINICAL MANIFESTATIONS
   
    
       Clinical presentation of primary HIV infection may vary but patients often have an acute retroviral syndrome. The most common symptoms are fever, sore throat, fatigue, weight loss and myalgia. Approximately 40% to 80% of patients also exhibit a macula popular rash, usually involving the trunk. Other common manifestations (>50%) include diarrhea, lymphadenopathy, nausea, night sweats and vomiting. Aseptic meningitis (fever, headache, photophobia, and stiff neck) may be present in a quarter of presenting cases.
   
    

• A persistent decrease in CD₄ lymphocytes is the most measurable aspect of immune system estruction³.
• Multiple opportunistic infections:
• Protozoal and Helminthic infections
• Fungal infections
• Bacterial infections
• Viral infections
• Neurologic disease
• Secondary neo plasms
• Kaposi sarcoma
• B-cell non-Hodgkin lymphomas
• Primary lymphoma of brain
• Invasive cancer of uterine cervix
  DIAGNOSIS
  
   
• CD₄ count

 

The level of immuno-suppresion is most easily estimated by monitoring a patient's CD₄ count. This measures the number of CD₄ positive t-lymphocytes in a sample of peripheral blood. The normal range can vary between 500-1500 cells/mm³. as HIV disease progresses, the number of cells falls. Both physician and patient are likely to use the CD₄ count as one indicator of when to consider starting anti retroviral therapy and how effective such therapy is.

 

• Viral load

 

The measurement of HIV viral load estimates the amount of circulating virus in the blood plasma. This can be correlate with prognosis, a high viral load predicting faster disease progression.

 

    Four methods for determing HIV DNA

• Reverse transcriptase – coupled polymerase chain reaction (RT-PCR)
• Branched DNA (b DNA)
• Transcription-mediated amplification and
• Nucleic acid sequence-based assay (NASBA)
  
   
• ELISA (Enzyme linked Immuno Sorbent Assay)
  Convenient methods for obtaining ELISA sample:
• Oral collection device (Ora sure)
• Over-the-counter home finger-stick blood-collectin test system (Home Access)
• Urine test (calpyte)
• Western blot
• Indirect Immunofluorescence Assay (IFA)
  Viral load is a better predictor of disease progression than the absolute CD₄ lymphocyte count, but prognosis is much more accurate when the two are used together.³
  
   
  TREATMENT GOALS
  
   
• Keeping the amount of HIV in blood as low as possible for as long as possible.
• Increasing or stabilizing the number of CD4 cells.
• Lowering the risk of HIV developing resistance.
  
   
  Three primary methods of approach in the treatment
• Inhibition of viral replication.
• Vaccination to stimulate a more effective immune response.
• Restoration of the immune system with immuno modulators.
  HIV TREATMENT
  
   
      HIV treatment is the use of HIV meds (antiretroviral drug or ARVs) to target the virus's ability to make copies of itself, slow it down and therefore help to keep an HIV-positive person healthy.
  
   
      To reduce the amount of virus in the blood stream, HIV meds from different classes target the virus in different ways and at different stages of its replication cycle. The four classes of HIV meds are:
  
   
• Fusion inhibitors (FIs)
• Nucleoside reverse transcriptase inhibitors
• Non-nucleoside reverse transcriptase inhibitors
• Protease inhibitors (PIs)
  
   
  Fusion Inhibitors(FIs)
  
   
  
  Stops virus from entering the cell.
  Only one fusion inhibitor –Enfuvirtide-approved by FDA
  
   
  Nucleoside Analogs (nukes, NRTIs)
  
   
  Mechanism of Action
  
   
      Nucleoside analogs (slang: "nukes") are also referred to as nucleoside reverse transcriptase inhibitors. Their target is the HIV enzyme reverse transcriptase. Acting as alternative substrates or "false building blocks", they compete with physiological nucleosides, differing from them only by a minor modification in the sugar (ribose) molecule. The incorporation of nucleoside analogs aborts DNA synthesis, as phosphodiester bridges can no longer be built to stabilize the double strand.
      Nucleoside analogs are converted to the active metabolite only after endocytosis, whereby they are phosphorylated to triphosphate derivatives. AZT and d4T are thymidine analogs, while ddC, FTC and 3TC are cytidine analogs. Combinations containing AZT plus d4T, ddC plus 3TC or FTC plus 3TC are therefore pointless, since both drugs would compete for the same bases. ddI is an inosine analog, which is converted to dideoxyadenosine; abacavir is a guanosine analog. There is a high degree of cross resistance between nucleoside analogs.
  
   
      Nucleoside analogs are easy to take, and once-daily dosing is sufficient for most of these drugs. Overall tolerability is fairly good. Frequent complaints during the first weeks are fatigue, headache and gastrointestinal problems, which range from mild abdominal discomfort to nausea, vomiting and diarrhea. The gastrointestinal complaints are easily treated symptomatically.
  
   
      However, nucleoside analogs can cause a wide variety of long-term side effects, including myelotoxicity, lactate acidosis, polyneuropathy and pancreatitis. Although lipodystrophy was initially linked exclusively to treatment with protease inhibitors, may disorders of lipid metabolism (especially lipoatrophy) are now also attributed to nucleoside analogs. Long-term side effects that are probably related to mitochondrial toxicity were first described in 1999 . Mitochondrial function requires nucleosides. The metabolism of these important organelles is disrupted by the incorporation of false nucleosides, leading to mitochondrial degeneration. More recent clinical and scientific data indicates that there are probably considerable differences between individual drugs with regard to mitochondrial toxicity: d4T, for example, is more toxic than abacavir.
  
   
      Nucleoside analogs are eliminated mainly by renal excretion and do not interact with drugs that are metabolized by hepatic enzymes. There is therefore, little potential for interaction. However, substances such as ribavirin, which is also activated by intracellular phosphorylation, may interact with nucleoside analogs of AZT, d4T and ddI.
  
   
  Individual agents: Special features and problems
  
   
      Abacavir (Ziagen^®) is a guanosine analog with good CNS penetration. Earlier studies have shown that this drug can lower viral load by approximately 1.4 logs within 4 weeks, but that resistance develops relatively rapidly. Abacavir is phosphorylated intracellularly to carbovir triphosphate, which has a long half-life. In October 2004, abacavir was licensed for once daily therapy. The nucleoside backbone of abacavir + 3TC is about as effective as AZT + 3TC (DeJesus 2004) and d4T + 3TC (Podzamczer 2004), although it causes less lipodystrophy than the latter.
  
   
      With respect to mitochondrial toxicity, abacavir seems to compre favorably to d4T. However, switching from d4T to abacavir led to moderate changes at best and sometimes only subclinical effects in cases with existing lipodystrophy. Most in vitro data confirms that improvement of lipoatrophy is associated with an increase in mitochondrial DNA.
  
   
      One drawback to the use of abacavir is the risk of a hypersensitivity reaction (HSR). HSR occurs in approximately 4-6% of patients, almost always (93%) within the first six weeks of treatment. Every treating physician should be familiar with this syndrome. In acutely infected HIV patients, the risk seems significantly higher (up to 18%), and abacavir should be avoided in these cases. HSR can be fatal after rechallenges in individual cases. Cases of severe HSR have been reported after only a single abacavir tablet or even after treatment interruption despite prior tolerability. The combination of strongly worded warnings contained in the package insert and the often unspecific symptoms of the HSR poses a constant challenge to the treating physician. Several reports have now suggested that patients with HLA type B5701 may be genetically predisposed and therefore at a higher risk than others.
  
   
      AZT –Zidovudine (Retrovir^®) was the first antiretroviral agent to be put on the market, in 1987. Even very early studies still testing AZT monotherapy were able to show a significant survival benefit – at lest in significantly immuno compromised patients. It showed that there was no long-term benefit of AZT treatment. In addition, the higher doses that were given in these first few years led to considerable myelotoxicity.
  
   
      Even with the standard doses given today, monitoring of blood count is obligatory. Long-term tretmetn almost always increases MCV, and there is also a limited use of monitoring adherence to AZT. Initial gastrointestinal complaints may present a short-term problem. AZT-related myopathy or even cardiomyopathy are quite rare. AZT seems to have a more favorable profile with regard to long-term toxicity. Lack of neurotoxicity and good CNS penetration are important advantages of this drug, which has remained the cornerstone of many HAART regimens and transmission prophylaxis.
  
   
      AZT is a component of both Combivir^® and Trizivir^®, at a slightly higher dose (300mg instead of 250mg). This may occasionally lead to higher myelotoxicity and therefore anemia.
      ddC – Zalcitabine (Hivid^®) was the third nucleoside analog to reach the market in 1992. Studies such as Delta 1, ACTG 175 and CPCRA007 showed a significant survival benefit of the AZT + ddC combination compared to AZT monotherapy in treatment-naïve patients. In AZT-pretreated patients, however, addition of ddC showed hardly any benefit. AZT + ddI is more effective than AZT + ddC. The drug has become marginalized in the last years due to cross resistance with ddI and 3TC problems with pheripheral neuropathy, painful stomatitis, the three times daily dosing requirement, and lack of data in the HAART era. For these reasons, ddC is by far the least used nucleoside analog at the present time. Although twice daily dosing does seem possible, there is now no rationale for the use of ddC. It therefore, seems likely that this drug will disappear from antiretroviral therapy altogether.
  
   
      ddI – Didanosine (Videx^®) is a nucleoside analog with proven efficacy in numerous randomized studies. The introduction of acid-resistant tablets in 2000, replacing the chewable tablets used for many years, has done much to improve tolerability. ddI remains a component of many HAART regimens. Randomized studies showed significant improvement in survival rates of treatment-native patients with AZT + ddI compared to AZT monotherapy. As with ddC, this effect was less marked in AZT-pretreated patients. In ACTG 175, monotherapy with ddI was more potent than AZT, even with regard to disease progression. However, this advantage for ddI could not be shown in other studies. Following failure with AZT, ddI is probably more effective than d4T.
  
   
      Gastrointestinal complaints and polyneuropathy are the main side effects. Pancreatitis is a specific side effect occurring in up to 10% of cases, and an be fatal in individual cases. This toxicity is probably dose-dependent. The cause for this is unclear, but could possibly be related to ddI-specific disorders of purine metabolism. Special caution should be given to combinations with d4T, hydroxyurea or tenofovir. Patients with a history of pancreatitis or even chronic pancreatitis should not be treated with ddI. In patients weighing less than 60 kg, the dose should be reduced from 400 mg to 300mg, and a dose reduction to 250 mg is necessary when administered n combination with tenofovir. However, combination with tenofovir seems to be unfavorable for various reasons.
  
   
      One advantage of using ddI is simple once-daily dosing, which is possible due to the long intracellular half-life; it is counterbalanced by the need to take the drug under fasting conditions. In addition, most other nucleoside analogs are now also licensed for once-daily dosing.
  
   
      d4T – Stavudine (Zerit^®) was the second thymidine analog to be introduced after AZT. It is often initially better tolerated than AZT, producing less gastrointestinal side effects and limited myelotoxicity. It is definitely just as effective and used to be one of the most frequently prescribed antiretroviral agents of all. However, several randomized studies have recently discredited the drug. d4T was tested in a double blind design against tenofovir (both combined with 3TC + efavirenz) in treatment-naïve patients. Both drugs showed comparable virological efficacy, but tenofovir was tolerated significantly better than d4T, particularly with respect to mitochondrial toxicity and lipid changes. In fact, the FTC-301 Study, in which d4T was again tested in a randomized, double blind design against FTC (both combined with ddI + efavirenz) had to be prematurely terminated, because d4T was not only more toxic, but also showed significantly lower virological efficacy.
  
   
      Mitochondrial toxicity of d4T also causes problems beyond lipodystrophy. It is a risk factor for lactic acidosis, hyperlactacidemia and Guillain-Barre-like syndromes, particularly in combination with ddI or 3TC. Whether these problems will be lessened by the introduction of the new d4T PRC capsules is questionable.
  
   
      FTC – Emtricitabine (Emtriva^®) is a new cytidine analog, which was originally developed under the name Coviracil. It is biochemically very similar to 3TC, but has a longer half-life. Once-daily dosing with 200 mg is possible, and the drug also has HBV efficacy. Tolerability is good, although hyperpigmentation occurred in one study. FTC is more effective than 3TC in vitro, which was recently demonstrated in a small in vivo study. However, as with 3TC, efficacy is limited by the M184V point mutation. Subsequent to data from the FTC-301 Study, which was prematurely discontinued, the drug was swiftly licensed in 2003. This randomized, double blind trial showed that FTC was clearly more effective and tolerable than d4T (both in combination wit ddI and efavirenz). The combination of tenofovir + FTC was superior to AZT + 3TC in the 24 week analysis of another study, as there was better tolerability. AZT + FTC are as effective as AZT + 3TC. FTC seems to have a low affinity for the mitochondrial polymerase, so the risk of mitochondrial toxicity is likely to be relatively low. The ALIZE study has since confirmed the good long-term tolerability and efficacy of a once-daily combination of FTC + ddI + efavirenz. FTC is already an important HAART component, particularly of once-daily regimens. In 2005, a fixed-dose combination of FTC and tenofovir (Truvada^®) was licensed in Europe.
  
   
      3TC – Lamivudine (Epivir^®) is a well tolerated nucleoside analog. Its main disadvantage is rapid development of resistance, and a single point mutation is sufficient for loss of effectiveness. As a result, 3TC is weaker than other nucleoside analogs for monotherapy, since resistance is likely to develop after only a few weeks. The full effect of 3TC only emerges in combination with other nucleoside analogs. As a component of Combivir^®) and Trizivir^®), 3TC is the most frequently used antiretroviral drug. The N184V point mutation even has advantages: not only does it improve the susceptibility of certain AZT resistant viruses in some patients, but it also impairs viral fitness. Keeping 3TC as part of a combination despite proven resistance is therefore sensible to conserve the M184V mutation and thus reduce the replicative capacity of HIV. This has now been demonstrated in a study of monotherapy in treatment experienced patients with the M184V mutation: maintaining 3TC monotherapy was associated with a lower increase in viral load and fall in CD4 cell levels than completely stopping HAART.
  
   
      In the Atlantic Study, 3TC in combination with d4T + ddI proved significantly weaker virologically than indinavir or nevirapine (Van Leeuwen 2003). Combination with abacavir and tenofovir is also not good, as recently published data from the ESS30009 Study has shown.
  
   
      Once-daily dosing is now possible and has been licensed. 3TC is therefore likely to continue to play an important role in many once-daily combinations. A pleasant effect of 3TC is also its good efficacy against hepatitis B viruses, although this is again limited by the relatively rapid development of restance.
  
   
      Tenofovir (Viread^®) acts as a false building block similar to nrcleoside analogs, targeting the enzyme reverse transcriptase. However, in addition to the pentose and nucleic base, it is monophosphorylated and therefore referred to as a nucleotide analog. The accurate description of the substance is tenofovir DF, referring to the phosphonate form from which the phosphonate component is only removed by a serum esterase, and which is activated intracellulrly in two phosphorylation steps.
  
   
      In the 902 and 907 studies, in which tenofovir was added to existing HAART, tenofovir decreased viral load by approximately 0.62 logs after 48 weeks. The 903 Study was a double blind study in which treatment-naïve patients were given tenofovir or d4T (with a backbone regimen of 3TC + efavoremz). Results showed at least equivalent potency. However, tolerability was better in the tenofovir group, especially with regard to polyneuropathy and lipid changes. This is consistent with in vitro data, showing that phosphorylated tenofovir has a low affinity for mitochondrial polymerases. As a result of this convincing clinical data and its licensing in 2001, the drug is now very widely used in antiretroviral therapies.
  
   
  The choice of nuke backbones
  
   
      Until now, all classical HAART regimens have contained two nucleoside analogs as the "backbone" of treatment. This has mainly historical reasons: nucleoside analogs were the first available drugs for HIV therapy, and when protease inhibitors appeared on the scene, treatment with two nucleoside analogs was standard. As knowledge has grown about the mitochondrial toxicity of nucleoside analogs, this concept is now being questioned by an increasing number of experts. In comparison, nucleoside analogs and their combinations have been well investigated-countless studies over the years, especially before the introduction of PIs and NNRTIs, concentrated on figuring out the optimal combination of two nucleoside analogs.
  Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
  
  Mechanism of action and efficacy
  As with the nucleoside analogs, the target enzyme of NNRTIs is reverse transcriptase. NNRTIs were first described in 1990. In contrast to the NRTIs, they are not "false" building blocks, but rather bind directly and non-competitively to the enzyme, at a position in close proximity to the substrate binding site for nucleosides. The resulting complex blocks the catalyst-activated binding site of the reverse transcriptase, which can thus bind fewer nucleosides, slowing polymerization down significantly. In contrast to NRTIs, NNRTIs do not require activation within the cell.
  The three currently available NNRTIs - nevirapine, delavirdine and efavirenz - were introduced between 1996 and 1998.
  
   
  This was due to the early observation that functional monotherapy with NNRTIs, i.e. the mere addition of an NNRTI to a failing regimen, showed practically no effect. There were also initial difficulties in dealing with the problematic resistance profile of NNRTIs. The risk of cross-resistance is very high, and it can develop very rapidly; one point mutation at position 103 (K103N) of the hydrophobic binding site is enough to eliminate the entire drug class! Resistance has now even been described in mothers taking a single dose of nevirapine at birth for maternal transmission prophylaxis. This phenomenon is not rare. In two large studies, the frequency of NNRTI mutations following perinatal nevirapine prophylaxis was between 14 and 32 % (Cunningham 2002, Jourdain 2004).
  
   
  It is therefore important to always remember that NNRTI-containing regimens are very vulnerable - waiting too long to switch with insufficient suppression of viral load is almost certain to lead to complete resistance to this class of drugs. Subsequent withdrawal of the NNRTI does not induce any immunological or virological changes. This is because NNRTI mutations do not reduce the replicative capacity of HIV to the extent seen with PI or NRTI mutations.
  
   
  In the 2NN Study ("The Double Non-Nucleoside Study"), both NNRTIs were compared for the first time in a large-scale randomized study (Van Leth 2004). A total of 1216 patients received a nuke backbone of d4T+3TC with either nevirapine 1 x 400 mg, nevirapine 2 x 200 mg, efavirenz 1 x 600 mg or efavirenz 1 x 800 mg plus nevirapine 1 x 400 mg. The proportion of patients with a viral load below 50 copies/ml after 48 weeks was 56 %, 56 %, 62 % and 47 %, respectively. The only significant virological difference was an advantage of the efavirenz arm over the double NNRTI arm, mainly due to higher toxicity in the latter. In the nevirapine arm with 1 x 400 mg, severe hepatic side effects occurred more frequently than in the efavirenz arm; on the other hand, lipids were more favorably influenced in the nevirapine group. The 2NN Study and numerous other switch studies (Fisac 2002, Martinez 2003) demonstrate that the choice of treatment regimen should be based mainly on the different side effect profiles of nevirapine and efavirenz (see below).
  Nevirapine and efavirenz are both metabolized by cytochrome P450 enzymes (Miller 1997). Nevirapine is an inductor, whereas efavirenz is both an inductor and an inhibitor of the cytochrome P450 isoenzyme. The combination of efavirenz with saquinavir or lopinavir leads to strong interactions that require dose adjustments.
  
   
  Individual agents: Special features and problems
  
   
  Nevirapine (Viramune^®) was the first licensed NNRTI. Nevirapine with AZT+ddI is probably the oldest HAART combination of all. It has been investigated since 1993, starting with the ACTG 193A Study, and proved superior to monotherapy and dual therapy in severely immunocompromised patients. This was true for both survival and progression - although the difference in survival was not significant (Henry 1998). The AZT+ddI+nevirapine combination has been well investigated since the INCAS and ACTG 241 Studies. INCAS demonstrated a suppression of the viral load to below 20 copies/ml after one year with AZT+ddI+nevirapine in 51 % of patients - compared to 12 % of those on AZT+ddI and 0 % on AZT+nevirapine. Clinical progression rates were at 12 %, compared to 25 % and 23 %, which was not a significant difference due to the small sample size (p=0.08). In pretreated patients in ACTG 241 (AZT+ddI plus nevirapine or placebo), however, no trend could be shown in favor of this combination.
  Nevirapine has also been tested against protease inhibitors in randomized studies. In the Atlantic Study, combination with d4T+ddI was comparable to combination with indinavir (van Leeuwen 2003). Given with AZT+3TC in the Combine Study, there was at least a trend towards higher virological efficacy in comparison to nelfinavir (Podzamczer 2002).
  
   
  Nevirapine causes elevation of liver enzymes in up to 16 % of patients, which may be severe in rare cases. Lead-in dosing is always required. A recently published study showing that lead-in dosing is not required if efavirenz was previously administered (Winston 2004) still requires confirmation. During the first eight weeks on nevirapine, biweekly monitoring of transaminases is recommended. A rash develops in 15-20 % of cases and leads to discontinuation in up to 7 % of patients (Miller 1997). In the case of an isolated rash or isolated elevation of transaminases (up to five times the upper limit of normal), treatment may usually be continued. Prophylactic administration of antihistamines or steroids does not prevent the rash (GESIDA26/02 2004, Launay 2004). However, it is recommended to stop treatment if a rash occurs together with even slight elevation of transaminases (>2-fold of norm). Patients with chronic hepatitis are at a higher risk (Sulkowski 2000); in addition, there seems to be a correlation to drug plasma levels (Gonzalez 2002). However, other studies have not been able to confirm this (Almond 2004, Dailly 2004). An increased risk has also been reported for patients with good immune status. Women with CD4 cell counts above 250/µl have a 12-fold elevated risk (11 % versus 0.9 %); the US FDA even issued a warning relating to this in 2004. It is important to note that hepatic toxicity may occur even after several months (Sulkowski 2002). Permanent and significant g-GT elevations are very common, which may subject patients to false suspicions of excess alcohol consumption.
  
   
  Nevirapine has a good lipid profile. In studies such as Atlantic or 2NN, patients receiving nevirapine had favorable lipid changes for cholesterol and triglycerides, increasing HDL (Van der Valk 2001, Van Leth 2004). The Spanish Nefa Study demonstrated this too, as well with efavirenz, albeit to a lesser extent (Fisac 2002). Whether these positive effects will have clinical relevance over time and really help to prevent cardiovascular events remains to be seen.
  The pharmacokinetics of nevirapine seem to allow once-daily dosing (Van Heeswijk 2000). Various studies such as 2NN, SCAN, VIRGO or Atlantic have already successfully used 400 mg once daily (Garcia 2000, Raffi 2000, van Leeuwen 2003, Van Leth 2004).
  
   
  Protease Inhibitors (PIs)
  Mechanism of action and efficacy
  The HIV protease cuts the viral gag-pol polyprotein into its functional subunits. Inhibition of the protease, preventing proteolytic splicing and maturation, leads to the release of virus particles that are unable to infect new cells. With knowledge of the molecular structure of the protease encoded by the virus, the first protease inhibitors were designed in the early nineties; these substances were modified in such a way that they fit exactly into the enzyme active site of the HIV protease.
  
   
  Since 1995, protease inhibitors have revolutionized the treatment of HIV infection. At least three large studies with clinical endpoints proved the efficacy of indinavir, ritonavir and saquinavir. Although PIs have been criticized in recent years due to their high pill burden and side effects (see below), they remain an essential component of HAART, especially for treatment-experienced patients. With growing knowledge of the mitochondrial toxicity of nucleoside analogs and the introduction of easy-to-take PIs, this class of drugs is currently experiencing something of a renaissance - now even PI-only regimens are being investigated.
  
   
  As with the NNRTIs, there has been competition among pharmaceutical companies to establish which PI has superior efficacy. However, there have been few comparative randomized studies, which is not just the fault of the pharmaceutical industry, but also the result of restrictive regulations in many countries preventing the conduct of such studies, or at least making them very difficult.
  But even in the case of PIs, the differences are not so significant as to completely compromise individual members of this class. Two exceptions have to be mentioned: the hard gel capsule saquinavir-HGC and ritonavir on its own. Boosted PI regimens are presumably more effective.
  
   
  Apart from gastrointestinal side effects and high pill burden, all PIs used in long-term therapy can be implicated in lipodystrophy and dyslipidemia (review in Nolan 2003). Smaller randomized studies have shown that elevation of lipid levels is more pronounced in ritonavir-containing regimens (full, not booster dose) than with saquinavir or nelfinavir (Roge 2001, Wensing 2001). In addition, there may be significant drug interactions on ritonavir and with boosted regimens. Sexual dysfunction has also been attributed to PIs (Schrooten 2001), although data is inconclusive (Lallemand 2002).
  
   
  There is a high degree of cross-resistance between protease inhibitors, which was described even before PIs were put on the market (Condra 1995). All PIs are inhibitors of the CYP3A4 system and interact with numerous other drugs. Ritonavir is by far the strongest inhibitor, saquinavir probably the weakest.
  
   
  Individual agents: Special features and problems
  
   
  Amprenavir (Agenerase^®) was the fifth PI to enter the European market, in June 2000, and is to date only licensed for treatment-experienced patients. This drug is weak when not boosted (Goodgame 2000, Fetter 2000), and not acceptable due to the high pill burden (8 pills bid). Boosting with ritonavir improves efficacy (Nadler 2002), although it remains inferior to the NNRTI efavirenz (Bartlett 2002). Important side effects include gastrointestinal disorders and, in contrast to other PIs, rashes in up to 30 %, which may be severe in rare cases. Whether the incidence of lipodystrophy and dyslipidemia under boosted amprenavir is reduced in comparison to other Pis - in line with theoretical suggestions (Furfine 2000) and some laboratory studies (Lenhard 2000) - remains to be clearly proven (Noble 2000). The resistance profile of the drug is particularly interesting, as it only partially overlaps with that of other PIs (Schmidt 2000). It has shown fairly good results in salvage settings (Eron 2001, Lastere 2003, Corbett 2004). It is possible that Agenerase^® will be removed from the market after licensing of the follow-on drug fosamprenavir. Patients should be switched to Telzir^® (Rodriguez 2004).
  
   
  Atazanavir (Reyataz ^®) was the first once-daily PI to be licensed in 2004. Two Phase II studies, AI424-007 and AI424-008 (Murphy 2003), demonstrated better tolerability in comparison to nelfinavir. In contrast to other PIs, atazanavir does not have a negative influence on lipid levels (Robinson 2000, Piliero 2002, Sanne 2003), which is its main advantage besides the once-daily dosing; it also does not induce insulin resistance Whether this will be reflected clinically (with less lipodystrophy), as suggested in some clinical case reports , remains to be confirmed. One problem with atazanavir is that more than half the treated patients experience elevated bilirubin levels, which can reach grade 3-4 in approximately one third of all cases (Squires 2004). Some patients even develop jaundice. The mechanism for this resembles that of Gilbert's syndrome (and the increased levels with indinavir - do not combine these two drugs!); there is reduced conjugation in the liver. Although this effect is harmless according to the manufacturer and only few cases of serious hepatic disorders have been described to date , liver function should be monitored and treatment discontinued in cases of significantly elevated bilirubin (>5-6 times the upper limit of normal).
  
   
  In the early Phase II studies, the antiretroviral potency of atazanavir, in combination with d4T+3TC, was comparable to nelfinavir (Murphy 2003, Sanne 2003). In a large Phase III study (AI424-034), atazanavir (with a nuke backbone of AZT+3TC) showed comparable virological efficacy to efavirenz (Squires 2004). Lipid levels were clearly better in the atazanavir arm than in the efavirenz arm. Data from other studies is now available showing that lipids improve when nelfinavir or other PIs are replaced by atazanavir. Boosting of atazanavir with ritonavir does not seem to have negative effects on lipid levels and is now generally recommended, particularly for combinations with NNRTIs or tenofovir, which significantly lower atazanavir levels (Preston 2002, Taburet 2004). Unfavorable interactions occur particularly in combination with proton pump inhibitors.
  
   
  Atazanavir is slightly less effective than lopinavir in treatment-experienced patients, at least when it is not boosted . This does not seem to be the case if ritonavir is added (DeJesus 2004). The primary resistance mutation for this drug is I50L, which does not impair sensitivity to other PIs (including amprenavir), and possibly even increases it . On the other hand, there are a number of cross-resistance mutations, and susceptibility to many virus isolates with moderate PI resistance is reduced . Currently, atazanavir is only licensed for treatment-experienced patients .
  
   
  Fosamprenavir (Telzir®, Lexiva®) is a calcium phosphate ester of amprenavir. Fosamprenavir has better solubility and absorption than the parent compound. This means that a significantly lower number of pills have to be taken. Fosamprenavir was licensed for treatment-naive and -experienced patients in 2004. The recommended doses are either a) 1400 mg bid (2 pills bid), b) 700 mg bid plus 100 mg ritonavir bid (2 pills bid) or c) 1400 mg plus 200 mg ritonavir once daily (4 pills qd). Once-daily dosing is not recommended for treatment-experienced patients. One advantage of the drug is that there are no restrictions with respect to food intake, and it can be taken on an empty stomach or with a meal.
  
   
  Three pivotal studies have investigated fosamprenavir: NEAT, SOLO and CONTEXT. In the NEAT Study, unboosted fosamprenavir was slightly more effective virologically and had better tolerability than nelfinavir in treatment-naive patients (Rodriguez-French 2004). However, this study was limited by a relatively heterogeneous study population and high dropout rates in both arms. In the SOLO licensing study, boosted once-daily fosamprenavir was about as effective as nelfinavir (Gathe 2004). No resistance was found on boosted fosamprenavir even after 48 weeks (MacManus 2004). In the CONTEXT Study, fosamprenavir was almost as effective as lopinavir/r in PI-experienced patients; the difference was not significant (Elston 2004). As a potent inductor of amprenavir metabolism, efavirenz can significantly (probably with clinical relevance) lower plasma levels, as can nevirapine. This does not occur when fosamprenavir is boosted with ritonavir (Wire 2002, DeJesus 2004). Beware of the combination with lopinavir - plasma levels (AUC, Cmin) of both drugs are lowered! This seems to eliminate what would otherwise have been an interesting salvage option.
  
   
  Indinavir (Crixivan^®) is one of the oldest and now most extensively tested PIs. In large, widely received studies in treatment-naive and -experienced patients, it was initially very successful . Later, indinavir had mixed success, at least in the unboosted form. In the Atlantic Study, indinavir was about as effective as nevirapine (Van Leeuwen 2003), but in the 006 Study it was clearly weaker than efavirenz (Staszewski 1999). In the double blind, randomized CNAAB3005 Study, indinavir was more effective than abacavir, particularly with high viral load . The large amount of available data is currently probably the most important argument in favor of this drug. Low protein binding (60 %) seems to allow better CNS penetration than with other PIs (Martin 1999). Whether this is clinically significant remains to be seen.
  There are, however, a number of problems associated with indinavir. Firstly, it causes nephrolithiasis in approximately 5-25 % of patients (Meraviglia 2002), and thus requires good hydration (at least 1.5 liters daily). Unboosted indinavir must be taken three times daily on an empty stomach (Hass 2000), a form of dosing that is unacceptable today. For this reason, boosting with ritonavir is recommendable, although this can increase the rate of side effects (Harley 2001, Arnaiz 2004). In the MaxCmin1 Trial, the dropout rate in the indinavir group was clearly higher than among patients receiving saquinavir (Dragstedt 2003). Beyond PI-specific side effects such as lipodystrophy and dyslipidemia, other problems that are relatively specific to indinavir include mucocutaneous side effects reminiscent of retinoid therapy, with alopecia, dry skin and lips, and ingrown nails. Many patients may also develop asymptomatic hyperbilirubinemia. Although it seems that the dose and thus toxicity can be reduced in most patients by boosting and monitoring plasma levels, indinavir has come to play a lesser role for all of these reasons.
  HOW TO START WITH HAART
  
   
  Once the decision has been made that HAART is necessary, the next question is: what to start with? More than two dozen drugs are now available, and the number of possible combinations is almost infinite. Of course, it is preferable that every treatment-naïve patient participates in a clinical study. This is the only way that differences between the various combinations can be established in the future, which will ultimately further improve the quality of treatment. In the past year, several combinations turned out to be suboptimal, which would never have emerged without the conduction of controlled studies. However, in practice it is not always possible to treat patients in clinical trials. For information regarding the treatment of these patients, the following summarizes the data available to date.
  
   
  Recommended Initial Regimens at a Glance
  Combinations that we recommend for first-line therapy (December 2004) are shown in the table below.
  
   
  
   
  
   
  It should be noted that many other combinations are possible. These may be acceptable in individual cases or in investigational studies, but general recommendations for their use cannot be given.
  
   
  First-line therapies that are currently completely unacceptable include full dosage ritonavir (because of side effects) or unboosted saquinavir (high pill burden). There is also insufficient data on boosted amprenavir as an initial therapy. It is therefore not licensed for first-line therapy, likewise delavirdine, T-20 and atazanavir. The same is true for the old formulation of nelfinavir and indinavir/ritonavir due to the high number of pills and relatively poor tolerability. Similarly, the nuke backbones of d4T+ddI and TDF+ddI are not recommended for first-line therapy.
  
   
  A Practical Approach to the First Regimen – Important Rules
  
   
  It consist of two nucleoside analogs, combined with either a (possibly boosted) PI, an NNRTI or a third nucleoside analog. No single combination has clearly been shown to be superior to another, and in a 2001 meta-analysis of 23 clinical studies in 3,257 patients, virological and immunological effects were comparable for most regimens. An important factor was simply the number of pills – the fewer pills, the better. Pill burden is therefore an important consideration when choosing a treatment regimen (Bartlett 2001). However, the simplest therapy may not necessarily be the best. In fact, some differences in efficacy have recently started to emerge. These are considered later in the text.
  
   
  The choice of the initial regimen should always be adapted to the individual situation with respect to compliance, concurrent illnesses and concomitant medications, and the needs of the patient. The following are important points to consider for the initial regimen.
  
   
  Practical tips for first-line therapy:
  • The first regimen offers the patient the best chance of long-term success; this regimen should therefore be potent and endurable.
  • The pros and cons of different combinations should be discussed with the patient there is usually enough time for this.
  • The initial regimen ideally should be dosed at no more then twice daily. Once-daily combinations should be considered.
  • First-line therapy should not consist of all three drug classes, in order to keep further options open for later.
  • Care should be taken to avoid overlapping toxicities.
  • Don't insist on theoretically superior combinations if reality requires a different choice.
  • Each patient should receive the ART he is able to take!
  • All drugs should be started on the same day – no lead-in mono- or dual therapy.
  • Be sure to check whether the patient would be eligible for a clinical study! All patients, especially if treatment-naïve, should be encouraged to participate in clinical trials.
  
   
  Two Nucleoside Analogs Plus a PI
  
   
  The combination of two nukes plus one protease inhibitor is the only HAART to date that is supported by efficacy data from randomized studies with clinical endpoints (Hammer 1997, Cameron 1998, Stellbrink 2000). Most importantly, data is available over longer periods than for other combinations. Some studies have been ongoing for over five or six years (Gulick 2003, Hicks 2003). Many experts still like to use these combinations today, particularly in patients with AIDS or high viral load, as another advantage is the relatively robust efficacy with respect to viral resistance. These regimens, however, often involve a considerable pill burden and relatively frequent side effects, which makes compliance difficult. The following briefly describes the most common combinations:
  
   
  Two nukes plus lopinavir/r
  
   
  These combinations are now among those most frequently used for initial therapy, and categorized in many guidelines as preferred regimens. Long-term efficacy seems to be good (Hicks 2003). No resistance has been described for such therapy to date. The combination of d4T+3TC+lopinavir/r seemed to show better efficacy than d4T+3TC+nelfinavir in the only comparative study described to date. At week 48, 67 % versus 52 % of patients had a viral load below 50 copies/ml (Walmsley 2002). Whether this drug is really more effective for initial therapy than other boosted PIs remains uncertain at the moment. It is also not clear what treatment would be effective if lopinavir/r fails. The most frequently used nuke backbone has been d4T+3TC. There is also positive data on TDF+FTC (Molina 2004).
  
   
  Two nukes plus saquinavir/r
  
   
  The combination of AZT+ddC+saquinavir-HGC was the first PI-combination for which survival benefit was shown in a randomized study; in fact this was the largest randomized HIV study ever (Stellbrink 2000). Today, however, saquinavir is generally given in its boosted form (saquinavir/r) and with other NRTIs. Pill burden would be too high without the addition of ritonavir, as the bioavailability of saquinavir is too low. Tolerability is probably better than for indinavir/r, which is no longer recommended for first-line therapy (Dragstedt 2003). The boosted combination of 1,000 mg saquinavir with 100 mg ritonavir, both twice daily, has been licensed. Saquinavir is now available as 500 mg tablets.
  
   
  ABC+3TC plus fosamprenavir
  
   
  With the end of the patent protection of AZT looming ahead, GSK has started a number of studies in recent years testing its other two nukes ABC+3TC as a backbone. The fixed combination tablet Kivexa^® is now providing a new once-daily option. In the NEAT and SOLO studies, ABC+3TC showed good efficacy in combination with fosamprenavir (Gathe 2004, Rodriguez-French 2004). There is only little data on other PI combinations. We would therefore recommend fosamprenavir as the best option for combination with the ABC+3TC backbone. Despite relatively good data on efavirenz (Gazzard 2003, DeJesus 2004, Podzamczer 2004), we do not recommend the combination of ABC+3TC plus an NNRTI for first-line therapy, due to the potentially problematic occurrence of allergy , which can unnecessarily jeopardize future treatment options.
  Two nukes plus nelfinavir
  
   
  Nelfinavir combinations have long been among the most frequently used ART regimens. The licensing studies tested nelfinavir mainly with AZT+3TC (Saag 2001, Gartland 2001). In the Combine Study, nelfinavir seemed slightly weaker than nevirapine (Podczamzer 2002). In CPCRA042, nelfinavir was as effective as ritonavir, but with significantly better tolerability (Perez 2002). However, nelfinavir is less potent when compared directly to other PIs such as fosamprenavir (boosted or not) or lopinavir/r .
  
   
  Nelfinavir-containing combinations have a high pill burden and are associated with unpleasant diarrhea, so that we generally no longer recommend it for first-line therapy.
  
   
  Two Nucleoside Analogs Plus an NNRTI
  
   
  NNRTIs have an equal, if not presumably even superior effect on surrogate markers as PI combinations. NNRTIs have done well in numerous randomized studies: efavirenz-based regimens in studies such as 006, ACTG 384, ACTG 5095 or CLASS were superior to indinavir, nelfinavir, amprenavir/r or triple nukes . The nevirapine-containing regimens in Combine or Atlantic were at least equivalent to nelfinavir and indinavir, and better than triple nukes (Podzamczer 2002, van Leeuwen 2003). A direct comparison in the 2NN Study showed no major differences between efavirenz and nevirapine .
  
   
  Advantages of NNRTI-regimens include the low pill burden and good tolerability. In contrast to PIs, however, data with clinical endpoints is unavailable. Neither is there any long-term data or studies on severely immunocompromised patients. A disadvantage of NNRTI combinations is the rapid development of cross-resistance.
  HIV VACCINES
  
   
  Vaccines stimulate the body's immune system to provide protection against infection or disease. Vaccines against HIV are being developed, and they are in various stages of clinical trial but at present none have proven effective.
  
   
  Why it is Important
  It is important to conduct research to find an effective vaccine because:
• The availability of a safe, highly effective and accessible preventive HIV vaccine would be a valuable complement to other preventive interventions, significantly contributing to the interruption of the chain of transmission of HIV.
• Well conceived HIV immunization strategies could reach populations where other interventions are not sufficiently effective.
• Research on preventive HIV vaccines is providing new information on the possible use of vaccines as therapeutic interventions, to be used in association with antitretroviral therapies, which could lead to a lowering in the cost of the treatments and to an increase on their long-term efficacy.
  
   
  How it is Done
  
   
  Vaccine research is a long process that begins with basic laboratory research and product development, including animal experiments, mostly performed in academic laboratories and by the pharmaceutical industry.
  
   
  The next step is to test these products (candidate vaccines) on healthy human volunteers through sequential phases. Phase I and II trials provide data on the safety of the candidate vaccines and on their ability to induce immune responses specific to HIV. These trials are done among small numbers of volunteers (50-200 per trial). Depending of the results obtained, candidate vaccines can proceed to large-scale Phase III trials, to obtain definitive information about their efficacy in inducing protection against HIV infection or AIDS. For scientific reasons, Phase III trials are done in populations with a high incidence of HIV infection, involving thousands of volunteers.
  
   
  Since 1987, more than 30 HIV candidate vaccines have been tested in approximately 60 Phase I/II trails, involving more than 10,000 healthy volunteers. Most of these trials have been conducted in the United States and Europe, but several have also been conducted in developing countries (Brazil, China, Cuba, Haiti, Kenya, Peru, Thailand, Trinidad, and Uganda). The results have confirmed the safety of the vaccines, and have provided important scientific information to develop newer generations of candidate vaccines with better ability to induce anti-HIV specific immune responses.
  
   
  At the present time, there are only two related candidate vaccines being evaluated in Phase III efficacy trials. The first trial started in 1998 in the United States (with sites in Canada and the Netherlands), enrolling 5,400 volunteers, mostly homosexual men. The trial is evaluating the efficacy of an envelope gp120 candidate vaccine based on the HIV subtype circulating in North America (subtype B), and the definitive results will be available early in 2003. The second Phase III trial started in 1999 in Thailand, and is testing the efficacy of a gp120 candidate vaccine based on the subtypes B and E prevalent in Thailand, enrolling a total of 2,500 volunteers, the majority of which are recovering intravenous drug users. Results from this trial will be available late in 2003.
  
   
  The "simultaneous" development and evaluation of multiple vaccine concepts require that vaccine evaluation "sites" are identified and strengthened in multiple developing countries. This process requires intense national, regional and international coordination and collaboration. An example is the WHO-UNAIDS driven "African AIDS Vaccine Programme (AAVP)", a network of African experts working to facilitate the development and evaluation of AIDS vaccines for Africa through regional and international collaboration and capacity building
  SUCCESS AND FAILURE OF TREATMENT
  
   
      Both success and failure of treatment can be evaluated by using different criteria:
• Virological
• Immunological
• Clinical
  
   
  Earliest indicator is virological success or failure. Virological treatment success is usually monitored by the suppression of viral load to below the level of detection of 50 copies/ml.
  
   
      Immunological success is generally defined as an increase in the CD₄ cell count.
  
  
      Clinical treatment success is dependent on virologic and immunological therapeutic success. Clinical success is almost always evaluated via the endpoints, although improvement on HAART in a patient with considerable constitutional symptoms should also be seen as a success. Clinical failure is usually defined as the development of AIDS-associated condition or even death.
  
  
   
  
   
  
  
   
      
   
  
   
  
   
  
   
  
   
  PATIENT CARE:
  
   
      AIDS is a multi system disorder that presents numerous challenges to the infected individual, their loved ones and their health care workers.
  
   
  • Be treated as individuals, recognizing the various life style factors that may affect their choice of treatment and ability to adhere to it.
  • Be given appropriate information to empower them to participate in their own health care decision-making process and adhere to the chosen treatment regimen.
  • Be monitored regularly for signs of treatment failure, low adherence and drug toxicity.
  • Be given appropriate advice regarding prevention of transmission and re infection (eg: safer sex, safer drug use).
  DISCUSSION
  
  
   
      The HIV reverse transcriptase is highly error prone since it lacks 3' exonuclease activity needed to correct transcription errors. Since all patients infected with HIV hartor such mutants prior to therapy, monotherapy with a non nucleo side reverse transcriptase inhibitor will cause an initial plasma HIV RNA decline followed within weeks by virologic failure.
  
   
      Extra ordinary patients with HIV infection have no evidence of viral replication or immunodeficiency in the absence of therapy and it has been suggested that their immune system can control HIV. Current clinical trials are testing this hypothesis.
  
   
      As per the therapy adherence is crucial to the success of anti retroviral regimens and in the treatment and prophylaxis of opportunistic infections.
  CONCLUSION
  
   
  The only cure: Prevention
  
   
      The estimate of December 1 2006 shows that around 39.5 million people world wide have AIDS. Though millions of dollars are spent on AIDS research, a cure has still not been discovered. Every researcher involved in this field conclude with the opinion that the only way to hinder this disease is prevention.
  REFERENCE
  
  
   

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18. Clotet B, Negredo E, Bonjoch A, Paredes R. Concurrent administration of tenofovir (TDF) and didanosine (ddI) compromises immunologic recovery in treatment-experienced patients. Results from the TORO studies. Abstract P3, 7th Int Congress Drug Therapy HIV Inf 2004, Glasgow.
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Cite this: Sabna Kotta,Stephen Varghese, Anoop Philip, "AIDS THERAPY – THE INFLUENCE OF NEW DRUGS", B. Pharm Projects and Review Articles, Vol. 1, pp. 1303-1342, 2006. (http://farmacists.blogspot.in/)