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Some ages are defined by their epidemics. Today, we live in the shadow of Acquired Immunodeficiency syndrome (AIDS), the terrifying modern epidemic. Recent developments have brought about what looks like some hope in the form of therapy and prophylaxis in the HIV infected.
The first anti-retroviral drug to be licensed was zidovudine (AZT) in 1987  in the form of monotherapy. In a very short period of time, availability of anti retroviral drugs has increased from one drug with a modest activity to twelve approved drugs with remarkable potency, particularly when used in combination . AZT is a synthetic pyrimidine, a nucleoside analog and a reverse transcriptase inhibitor (NRTI). What did the monotherapy with AZT offer? In a multicentric study  monotherapy with AZT resulted in reduced death rate, significant difference in occurrence of opportunistic infections (OIs), improvement in Karnofsky's functional capability scores, weight gain, increased CD4 counts (although falling back after 5 months), and gain in skin test reactivity. These initial encouraging results reflected diminished viral replication in vivo. The mode of action of AZT is well elicited. Within the cytoplasm of HIV infected cells AZT gets phosphorylated to its active form, AZT-TP (AZT-triphosphate) by cellular protein kinases. This compound has got a 100-fold greater affinity for viral reverse transcriptase (RT) in comparison to affinity for cellular DNA polymerase. Thus, AZT-TP serves as a substrate for viral RT and gets incorporated into growing DNA chains in preference to thymidine, resulting in premature DNA chain termination and inhibition of viral replication . Notwithstanding these benefits offered by AZT, HIV isolates from patients who received AZT for 6 months or more, showed increasing resistance to the drug in vitro. Such resistance often paralleled clinical deterioration in time , vindicating relationship between the two parameters. Mechanism of resistance to AZT is not clear as yet.
Thus emerged an intense investigation into other possible targets for antiviral action in the HIV replication cycle. These included potential agents to counter viral binding to cells, other inhibitors of RT besides AZT (non-nucleoside RT inhibltors-NNRTI which act to inhibit RT by non competitive inhibition at the pyrophosphate binding site of the enzyme), inhibitors of viral integration in to host cell genome, inhibitors of viral gene expression (transcription and translation), posttranslational processing inhibitors-protease inhibitors which inhibit the processing of the polyprotein products of gag and gag-pol genes in to the functional core proteins and viral enzymes, inhibitors of viral budding and release from the infected cell .
Many important advances have been made in the understanding of the biology and treatment of HIV infection during the past 24 months. In July 1996, at an International AIDS Conference in Vancouver, Canada, David Ho, a virologist reported on his most promising experiment. He and his team administered protease inhibitor cocktail therapy to HIV infected patients earliest possible in their course of disease. They came tantalisingly close to eliminating the virus from blood and body tissues. The mathematical models broached by them suggested that patients caught early enough following infection may be rendered virus free within 2-3 years with cocktail therapy . This virological ‘holy grail’ dawned the concept: AIDS is not invincible. For helping lift a death sentence-for a few years or perhaps longer-on tens and thousands of AIDS patients and for pioneeering a treatment that just might lead to a cure, David Ho was awarded a Nobel prize in Medicine for the year 1997.
Many randomised clinical trials [7, 8], have suggested combination anti-retroviral therapy is superior to nucleoside analog (NRTI) monotherapy. There is a need to consider some of the broad principles which have gained a wide consensus  amongst HIV treating physicians:
The pharmacokinetics, toxicity, dose and approximate cost of anti-retroviral agents belonging to three broad groups are presented in Table-1
Measurement of HIV RNA plasma load and CD4 counts are mandatory before initiation of anti-retroviral therapy, because these two parameters determine the risk of disease progression and response to therapy. Early initiation of therapy is vital as reduction of plasma HIV RNA to below levels of detection by this approach is viewed as optimal response to therapy. This stems from the rationale that early suppression of HIV replication limits the potential for selection of diverse HIV variants resistant to antiviral drugs. And also failure to suppress HIV replication adequately early in disease is likely to lead to virological and clinical failure besides preventing cumulative damage to the immune system . Thus the considerations for initiation of therapy are:-
Selected options for initial therapy are :
Both the above regimens are able to achieve plasma HIV RNA levels below the limit of detection in large majority of patients. The second regimen also permits deferral of use of a PI. However, this regimen is not recommended for patients with advanced disease. A prototype regimen as per (a) above is as follows:
(Note: The approximate present cost for the above mentioned regimen is Rs.5,20,000/- per year).
The laboratory tool that has contributed most to the increased understanding of viral pathogenesis and anti-retroviral efficacy is quantitation of HIV RNA in plasma. The level of HIV RNA in plasma has been shown to be the strongest predictor of outcome over 1-10 years period of observation . The level of HIV RNA expression in lymphoid tissue may be higher and more intense than suggested by plasma concentration. Thus, even moderate levels of HIV RNA appear to reflect very active HIV replication in tissue. Decline in plasma HIV RNA concentrations during therapy are strongly associated with a decrease in risk of subsequent disease progression . Despite the strength of plasma viral load quantification as a prognostic and therapeutic marker certain caveats are important:-
In view of the above independent predictors of clinical cure, although less powerful than viral load, have been identified and adhered to. These include CD4 counts and if feasible, biological phenotype (syncytium inducing-SI strains) .
Indications for changing therapy are:
In the case of treatment failure the guiding principle should be to try and change all drugs in the regimen or at least to include a minimum of two new drugs in the revised regimen. The practice of adding a single drug to a prior insufficiently suppressive regimen is strongly deplored. Thus, failure with two NRTIs + one PI entails switching over to two newer NRTIs and one newer PI, or to two newer NRTIs and NNRTI, or to two newer PIs and one newer NRTI .
Stopping anti-retroviral therapy may be the recourse in patients with very advanced disease in whom there is significant drug toxicity that consequently affects the quality of life. However, efforts should be made to manage drug related toxicity before all therapy is abandoned.
Without anti-retroviral intervention, 15-35% of infants born to HIV positive mothers  will acquire HIV infection through mother-to-child-transmission (MTCT). Reported rates of MTCT differ significantly between developed and developing countries. Breast feeding may be largely responsible for the higher rates in developing countries [17, 18]. Zidovudine prophylaxis is recommended for prevention of perinatal transmission of HIV. The regimen followed by American Control Trial Group (ATCG 076) using zidovudine monotherapy aims to intervene at all possible stages of transmission i.e, antenatal, intrapartum, postpartum & neonatal. Zidovudine has consistently resulted in reductions of 65-75% in infant infections with no immediate serious consequences to the mother, infant, or child development during the first two years of life . Zidovudine significantly decreases the likelihood of vertical tranmission at all observed levels of maternal HIV viral load . Since no other anti-retroviral drug has yet demonstrated to significantly reduce vertical HIV transmission, zidovudine should be included as a component of any anti-retroviral regimen during pregnancy as far as possible . Zidouvudine regimen used and recommended by US Public Health Service  for use in HIV infected pregnant women and their newborn is as follows:-
A recently recommended  short course zidovudine regimen (Thailand trial) is as follows:-
HCWs are potentially at risk for HIV infection through occupational exposure. The estimated risk for HIV infection after a percutaneous exposure to HIV infected blood is 0.3% . After controlling for all factors associated with HIV transmission risk in HCWs in a large study , use of zidovudine prophylaxis reduced HIV transmission by 79%. In view of the proven disregard for zidovudine monotherapy, the recommendations (in detail) for chemoprophylaxis after occupational exposure to HIV, by type of exposure and source material are presented in Table 2 [24, 25].
Starting anti-retroviral therapy is a major decision and careful thought and consideration are needed by both patient and physician if success is to be achieved. Several factors would determine the common ground on which individual patient would make an informed decision on his/her willingness to start therapy. These factors would include regimen adherence, cost, tolerability, psychological morbidity, and limitation of future therapeutic options in patients commencing early treatment. Physicians and patients when considering therapy must set realistic and achievable therapeutic goals.
Further advances will ensue and recent advances are to be applauded. We anticipate further updates will be forthcoming and many caveats will be filled up. One such caveat is anti-retroviral prophylaxis for high risk sexual exposures on which Centre for Disease Control (CDC), Atlanta is in the process of developing recommendations. However, in view of increasing complexity of treatment it is imperative that all clinicians involved with the care of HIV infected patients continue to remain abreast of a rapidly changing knowledge base. Guidelines are useful summary statements of current knowledge and thinking and cannot substitute a well informed clinician fully aware of current data and their interpretation.