Highly active antiretroviral therapy (HAART)

Has led to major improvements in morbidity and mortality among patients with HIV/AIDS.

With its use age-adjusted death rate as a result of HIV/AIDS declined by more than 70%.

From 1996 and 2012 an estimated 6.6 million AIDS related deaths have been averted by ART therapy.

HIV-infected individuals on ART therapy have a life expectancy at diagnosis, that is approximating that of uninfected individuals.

ART therapy results in viral suppression with decreased HIV transmission on individual and population levels, and when used consistently by HIV uninflected persons provides protection against HIV infection.

No randomized study defines optimal time of initiation.

Evidence is increasing to support initiation of ART regardless of CD4 feel count.

Presently life-long therapy with ART is required.

The choice of initial therapy has been streamlined with guidelines suggesting the use of integrase  strain transfer inhibitor based therapy and tenofovir formulations and either lamivudine or emitricitabine.

If ART is prescribed before a baseline laboratory tests are available the first visit should be limited to-bicittegravir-tenfovir formulation- emitricitabine or dolutegravir  plus a fixed dose of tenofovir, lamiduvine or emitricitabine.

Studies have shown that viral control is maintained in some patients who received a short course of anti-retro viral therapy during primary HIV infection, even after int2242upting such therapy, suggesting that viral reservoir may not be replenished after interruption.

The Short Pulse Anti-retro viral Therapy at Seroconversion (SPARTAC) trial Randomly assigned adults with primary HIV infection to ART for 48 weeks, 12 weeks, or standard care (no rx):a 48 week course of ART in patients with primary HIV infection delayed disease progression, although not significantly longer than the duration of the treatment.

In the above study 48 week course of treatment delayed disease progression and the need for long-term ART therapy:It was no benefit for 12 week therapy during primary HIV infection.

In the above study higher overall average CD4+ positive count with 48 week ART therapy may confer clinical benefit.

There is a significant and steady decrease in AIDS free survival as the CD4 cell count threshold for initiation of therapy decreases.

The best evidence of benefit from HIV anti-retro viral therapy is for people with a CD4 cell count below 350/µL.

After HIV acquisition immunologic damage occurs rapidly and is not fully reversible by later ART.

Obervation studies suggest a short course of ART therapy during primary HIV infection may preserve immune function, decrease viral reservoir and decrease viral evolution.

Anti-retroviral therapy is associated with reduction of transmission of HIV in high-risk men who have sex with men, although viral suppression is not guarantee suppression of the virus in semen, especially in the presence of inflammatory disease.

About one in three hundred patients antiretroviral medications are not necessary as patients may have disease without developing progressive disease and have maintained low to undetectable levels of the virus without taking antiretroviral drugs.

These elite controllers maintain an HIV viral load below 50 virus particles per milliliter of blood, and viremia controllers maintain a viral load level ranging between 50 and 2000 particles.

CASCADE seroconversion study with more than 9000 study participants confirm the benefits of starting anti-retro viral therapy below 500 CD4 cells per microliter.

The COHERE study of 75,336 patients found the prognostic value of the CD4 cell count after virologic suppression by antiretrovirals therapy and noted higher CD4 cell counts were associated with incremental decrease in the risk of new AIDS events, all cause mortality and non AIDS mortality.

The higher the CD4 cell count achieved after ART, the greater the survival benefit, implying that starting antiretroviral therapy earlier may lead to improved outcomes.

Morbidity and mortality from non-AIDS illness does not differ from that of the general population if CD4 cell counts of greater than 500 µL are achieved.

Initiating ART in all adults with HIV infection has been demonstrated to have no harm with early initiation of therapy and reduces the likelihood of HIV transmission while providing clinical benefit to the patient.

Supporting early ART, a registry of 20,775 HIV-infected patients and 215,158 uninfected persons, the incidence of most cancers was either no longer elevated in HIV-infected persons with CD4 counts at or above 500 µL compared with HIV uninfected persons or was greatly decreased.

There is an estimated 38% increase in the hazard of AIDS or death when therapy is initiated below CD4 cell count of 350/microL with 500 µL.

After six months of highly active antiretroviral therapy (HAART) systolic blood pressure increases of 10 mmHg or more may be noted.

Athena cohort found that older age, lower CD4 cell nadir, and lower plasma HIV-1 RNA at the start of ART therapy are independent predictors of poor immunologic recovery with increased morbidity and mortality.

HIV Prevention Trials Network of 1763 HIV couples with CD4 cell counts between 350 µL and 550 µL showed immediate initiation of treatment resulted in 41% reduction in serious stage 4 events such as pulmonary TB, serious bacterial infections and death.

Trial HPTN 052 demonstrated that providing antiretroviral therapy to be infected partner in HIV-discordant heterosexual couples early in the course of the disease, the risk of HIV transmission to uninfected partners is significantly reduced when compared to def2242ing therapy until the disease is more advanced.

Treatment with 2 nucleoside reverse transcriptase inhibitors (NRTIs) and a nonnucleoside reverse transcriptase inhibitor (NNRTI) appears to be better than starting treatment with 2 NRTIs and a protease inhibitor (PI) or starting with all 4 drugs.

Vast majority of patients receive treatment with a 3-drug combination of efavinenz, emitricitabine, and tenofovir available as a single pill, taken once daily (Atripla).

The protease inhibitor lopinavir with its pharmacological booster ritonavir is now the most widely prescribed ritonavir boosted protease inhibitor in children.

Lopinavir-ritonavir Is approved for HIV infected newborns older than 14 days.

Among the newborn children of HIV-1-infected mothers exposed in utero lopinavir-rotonavir, and postnatal treatment with exam agents compared with a zidoovudine-based regimen, was associated with transient adrenal dysfunction (Simon A et al).

Resistance to NRTIs frequently confers variable cross resistance within this class of agents.

Long-term use of NRTI associated with mitochondrial toxicities and lipoatrophy.

EuroSIDA study of 6814 patients with 22767 person-years of follow-up revealed that the rate of AIDS or deaths were not altered for different combinations of antiretroviral drugs in patients with similar CD4 cell counts and HIV RNA concentrations.

The FIRST trial compared 1397 treatment naïve patients with three treatment strategies of a protease inhibitor, plus a nucleoside reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor or a three class strategy of a protease inhibitor or a nucleoside reverse transcriptase inhibitor and a non-nucleoside reverse transcriptase inhibitor with defining end points of death, CD4 cell count decline to less than 200 cells per m/L with results showing no difference between PI and NNRTI strategy. Furthermore, the three class strategy did not increase CD4 counts anymore than did two-class strategy and is associated with more toxic effects.

Randomized controlled trials in immunocompromised patients with CD4 cell counts of 200/microL or lower demonstrated that the rate of AIDS or death were halved in patients starting HAART compared with rates in patients with drugs from only one class during approximately one year.

In a observational cohort study of HIV type I seroconverters from CASCADE ( Concerted Action on SeroConversion to AIDS and Death In Europe) HAART treatment initiation at CD4 cell counts of 350- 499/microL was associated with slower disease progression, and no benefit to treatment initiated at 500-799/microL (CASCADE Collaboration).

Consensus presently is HAART should be offered to HIV infected patients with CD4 cell counts lower than 350/microL, and for those with symptomatic HIV infection or AIDS conditions regardless of CD4 cell count.

All patients with HIV may benefit from ART therapy by reducing HIV transmission while providing clinical benefit.

No CD4 cell count threshold exists at which ART therapy is contraindicated.

Repeated long cycle intermittent therapy may not be an advantage over continuous antiviral treatment.

Over three fourths of patients receiving HAART with achieve a plasma HIV RNA level below the limit of detection and most will experience concomitant CD4 cell increases.

Associated with nausea, vomiting, diarrhea, lactic acidosis, fat redistribution, osteopenia, dyslipidemia, insulin resistance and accelerated atherosclerosis.

Suppressing HIV levels to below 50 copies/mL of HIV-RNA prevents drug resistance.

Many patients experience intermittent episodes of increasing viremia, blips, which may raise the concern of resistance

Continuous use of antiviral therapy is felt to be superior to episodic use guided by CD4+ counts in which antiviral therapy was held until CD4+ counts fell to less than 250 cells per cubic millimeter.

With continuous vs. int2242upted therapy the risk of opportunistic disease, as well as death from any other cause is decreased.

Viral load testing is available to ensure antiviral treatment is fully suppressant.

With full viral suppression it is likely that opportunustic infections and malignancies will not develop.

Today, the most common reason for lack of viral suppression is nonadherence of antiviral meds.

Long term treatment may result in dyslipidemia, alterations in body fat, possibly increased cardiovascular disease and hepatitis.

Decreases viremia, increases CD34 cell counts, delays clinical progression of disease and delays death.

Current treatment guidelines suggest initial therapy with one or more protease inhibitors, or a nonnucleoside reverse-transcriptase inhibitor inhibitors.

After HIV-1 infection begins a transient, spontaneous restoration of CD4 positive T-cell counts occurs in the four-month time window and initiation of anti-retroviral therapy during this period is associated with enhanced likelihood of recovery CD4positive counts (Le T et al).

Associated with increased visceral fat, loss of subcutaneous fat, dyslipidemia and insulin resistance.

Complications including insulin resistance, glucose intolerance, lactic academia, osteopenia and hypertension.

Penile and anal cancers have increased in HIV patients despite HAART treatment.

In a randomized double blind controlled trial of high-dose versus standard dose multivitamin supplementation for 24 months and 3418 patients with HIV initiating HAART therapy: there was no decrease in HIV disease progression or death, but they may have been an increase in ALT levels (Isanaka S et al).

Anti-retro therapy is indicated for all pregnant women with HIV to prevent HIV transmission to the infant and for the mother’s health.

Antiretrovirals therapy has helped to prevent 350,000 infant infections worldwide from 2005-2010.

Early initiation of antiretroviral therapy is recommended after starting treatment of active opportunistic infections.

Anti-retroviral treatment can be adjusted once the HIV RNA level, CD4 count, and renal, liver, HPV, hepatitis C virus, and HIV genotypic data are known.

Subsequent treatment may be simplified to a two drug regimen of dolutegravir-3TC single tablet.

ART treatments have yielded greater than 90% sustained virologic suppression in trials.

Follow up visits after initiation of a RT therapy occur at 4 to 6 week intervals, and then every 3 to 4 months until virologic suppression.

Once virologic suppression occurs for over a year follow up visits occur every six months.

More than 85% of patients who consistently receive ART care have sustained virologic suppression, indefinitely.