Interpretationof Guidelines to ARV Therapy

The unprecedented benefits resulting from highly active antiretroviral therapy (HAART) have been well described. (1) Therapeutic options continue to expand with the development of new drugs and new strategies for using them. The benefit of HAART extends beyond the patients and to issues around public health. The correlation between HIV-1 RNA and HIV transmission has been well established,and it is assumed that by suppressing HIV replication, antiretroviral therapy (ARV) also decreases the risk of transmission. (2) However, this benefit must be weighed against the potential risk for transmission of drug-resistant virus by patients failing therapy. In an adherent patient population, the benefits of therapy would likely outweigh this risk.

HIV has beco me a chro nic dise ase that almos t always will require antiretroviral medications.Given our cur ren t know led ge and lim ite d alt ern ati ve interventions, antiretroviral therapy is likely to be lifelong and once started should not be stopped.
The mana geme nt of HIV-inf ect ed pat ien ts has become increasingly complex not only because of expanding choices for therapy but also because of the emergence of resist ance and the longer-te rm toxicity of antiretroviral agents.
The unprecedented benefits resulting from highly active antiretroviral therapy (HAART) have been well described.(1) Therapeutic options continue to expand with the development of new drugs and new strategies for using them.The benefit of HAART extends beyond the patients and to issues around public health.The correlation between HIV-1 RNA and HIV transmission has been well established,and it is assumed that by suppressing HIV replication, antiretroviral therapy (ARV) also decreases the risk of transmission.(2) However, this benefit must be weighed against the potential risk for transmission of drug-resistant virus by patients failing therapy.In an adherent patient population, the benefits of therapy would likely outweigh this risk.
A broad array of antiretroviral combinations is likely to be need ed to addr ess obst acle s to achi eving sustained virologic suppression for decades.Some of these obstacles includeadherence, tolerability, drug resis tance, cost, and issues relat ed to parti cular subgroups of patients such as women who desire pregnancy and those co-infected with tuberculosis, he pa ti ti s B, or he pa ti ti s C. Ne w agen ts an d combinations of new and recently approved agents are likelyto play an important role in addressing many of these issues, providingpotent alternativesfor HIVinfected patients.

Interpretationof Guidelines to ARV Therapy
Harindra V 1indicated primarily by the CD4+ cell count and the risk of disease progression, and to a lesser degree by the plasma HIV-1 RNA and rate of CD4+ cell count decline.(3) Patients should not begin therapy until they understand the reason for treatment, appreciate the importance of adherence, and are motivated to begin.There is growing rationale for considering earlier therapy in motivated patients who are likely to be adherent.
Studies continue to demonstrate a higher mortality rate in HIV-infected patients, even when the CD4+ cell counts are between 200 -350.The guidelines from USA-DHHS (4) ISA -USA (5) and UK were recently revised following evidence from thesestudies showingthe benefit of early treatment.These benefits include decreased mortality and morbidity from both opportunistic and non-opportunistic conditions such as cardiovascular, renal, (6) hepatic diseases, and malignancies (7).(SMART study, (8) STACCATO trial, PISCIS Spanish cohort (9)) Earlier initiation of therapy is also associated with a better response to therapy, including a greater likelihood of CD4+ cell count normalization.
There is widespread agreement that symptomatic patie nts, patie nts with AIDS, and asympto matic patients with CD4+ cell count below 200 require antiretroviral therapy.The timing of antiretroviral therapyin chronically infected asymptomatic patients remai ns unclear, but the late st guide lines move aggressivelytowards earlierinitiation of antiretroviral therapy, prior to a decline in CD4 cell count to less than350/μ L (10).Initiation of therapy in asymptomatic patients with CD4 cell count above 350/μ L should be strongly considered where there are correlates of faster HIV disease progression such as high viral loads >100,000copies/mL or rapid CD4 decline,over 10 0 pe r ye ar.Pa ti en ts wi th hi gh ri sk fo r cardiovascular disease, co-infected with hepatitis B or C, HIV-associated nephropathy and pregna nt women should be treated irrespective of CD4 cell The Sri Lanka Journal of Venereology count.Treatment of acute HIV infect ion is only considered for special circumstances.(11) Currentoptions for initialtherapy are highlyeffective, durable, convenient, and well tolerated and show minimal evidence of long-termtoxicity.The simplicity of the regim en furt her enhances adhe rence and thereforediminishes resistance.The 3 drugs approved since 2006, maraviroc, the first drug to target the CCR5 co-receptor, raltegravir, the first drug in the integrase inhibitor class and (12, 13) etravirine, (14,15) a secon d-generation non-nucleos ide reverse transcriptase inhibitor (NNRTI) with clear activity against some NNRTI-resistant viruses has presented us with more treatment options, for the second, third, and fourth lines of treatment.
There is little change in the recommendations for an initial regimen in patients who are not infected with resistant virus.The first-line choice is a backbone of either an NNRTI (efavirenz) (16) or a ritonavirboosted protease inhibitor (PI), ( 17) combined with a dual nucleoside reversetranscriptase inhibitor(NRTI) (tenofovir/emtr icitabine or abacavir /lamivudine).Prescribingcomplex regimensdosed more frequently than twice daily is no longer necessary and oncedaily regimens are now standar d.The choice of regimenshould be based on consideration of potency, tolerability, convenience,long-term toxicity, baseline drug resistance and co-morbid conditions.The goal of therapy in both treatment-naive and experience patients is to maintain an undetectable HIV-1 RNA with an ultrasensitive assay (less than 50 copies/ml) because anything less is associated with decreased durability and the development of drug resistance.Treatment failure should be promptly identified and managed to reduce building up of mutations, which will further compromise options for management.
First-line failure of a NNRTI-based regimen should be treated with two active NRTIs plus a ritonavirboosted protease inhibitor (PI).Depending on the NNRTI mutations present,one mightwant to consider use of etravirine.Failure of a PI-based regimen can be more complicated, depending upon the genetic barr ie rs .If ca ugh t ea rl y, chan ging th e NRTI component to two active drugs might be sufficient to save the regimen.However, as resist ance points accumulate, one should consider use of darunavir or tipranavir.The new class of drugs such as Maraviroc and raltegravir ads to the choice of drugs in PI failures or in mult ic la ss fa il ur es .On e chan ge in th e recommendations is a greater emphasis on virologic sup pre ssion bel ow 50 copies/ ml in treat men t experienced patients.This is only achievable due to the availability of new classes of ARV and drugs with higher genetic barrier and different mutation patterns in existing classes.
Broader application of these guidelines in resourcelimited countries is hampered by the availability of dr ug s, mo ni to ri ng of HIV ma ke rs , la ck of infrastructure and the cost of follow-up regimens.Ability to sequence therapy is depende nt on the availability of entire regimens.Unless these issues are addressed it will not be possible to implement the current guidelines and the gap between the developed countriesand resource limitedcountries will continue widen