Initiating Antiretroviral Therapy in HIV-Infected Patients

Initiating Antiretroviral Therapy in HIV-Infected Patients
Yumi Lee, PharmD, BCPS NYSCHP- Royal Counties September 14, 2011

Objectives Identify the CD4 cell parameters where initiation of therapy is appropriate Recognize the advantages and disadvantages of early versus deferred therapy Identify the preferred regimens as per treatment guidelines Understand the benefits and detriments of recommended treatment regimens

History of HIV 1981- Beginning of HIV/AIDS epidemic
Outbreak of rare cancer and pneumonia in homosexuals (Kaposi’s sarcoma and PCP) Blood sample of African man who died of mysterious illness in 1959 later confirmed to be HIV 1984- Patient “zero” Canadian flight attendant died of AIDS 8,000 confirmed cases in US and 3,700 deaths 1987- Treatment arrives FDA approved Zidovudine (Retrovir®) 100,000 – 150,000 cases of HIV and AIDS

History of HIV (cont’d…)
1992- Combination therapy arrives Addition of Zalcitabine (Hivid®) marks beginning of combination therapy 1996- Protease inhibitors arrive Triple therapy introduced 2000’s- More antiretrovirals released 4.9 million people newly infected in 2005 40.3 million people worldwide living with HIV/AIDS 2006- Origins of HIV discovered Simian form of HIV (SIV) entered humans by monkey bites or ingesting monkey meat and brains

HIV Life Cycle Binding and fusion Reverse transcription Integration
Assembly Budding Free virus binds and fuses to host cd4 cell.. Empties rna contents into the host. The enzyme reverse transcriptase converts the viral rna to dna The viral dna enters the host’s nucleus where the enzyme integrase hides the viral dna in the host dna. When the infected cell receives the signal to replicate, copies of HIV genetic material and HIV protein chains are produced Another enzyme called protease cuts the long HIV protein chains and together with the HIV genetic material, a new virus particle is assembled The newly assembled virus then buds out from the host cell and goes on to infecting other cells.

Clinical Progression of HIV
Relationship of CD4 and viral load Relation of cd4 and viral load See that viral load increases, it devastates the immune system decreasing the cd4 count During the acute phase of a primary infection, the viral load is high and spreading throughout the body. During this phase, patients often experience this acute HIV syndrome of flu like symptoms. In 2-4 weeks after the initial exposure, the immune system fights back and the viral load goes down while the cd4 rebounds The pt then enters the clinical latency phase where they remain free of any symptoms for a period of time. However, the immune system eventually deteriorates to the point where the body can no longer fight infections. The viral load at this point is very high, cd4 drops significantly. This is the phase where people develop opportunistic infections.

Goals of Antiretroviral Therapy (ART)
Durable suppression of HIV viral load Restoration of immune function Prevention of HIV transmission Prevention of drug resistance Improvement in quality of life

Initiation of Antiretroviral Therapy:
What is the recommended CD4 threshold?

DHHS 2009: When to Start? CD4 (cells/mm3 ) Recommendation <350
Start ART Start ART* >500 Panel divided◊ Clinical Conditions Favoring Initiation of Therapy Regardless of CD4 History of AIDS-defining illness Certain acute opportunistic infections Pregnancy HIV-associated nephropathy Hepatitis B co-infection when HBV treatment is indicated CD4 count decline >100 cells/mm3 per year HIV RNA >100,000 copies/mL This slide lists the DHHS guidelines released on World AIDS Day, December 1, The guidelines state that HAART should be initiated at CD4+ cell counts between 350 and 500 cells/mm^3. The asterisk indicates that 55% of panel members strongly recommended initiation at these CD4+ cell counts and 45% moderately recommended it. Essentially, all members of the panel at least moderately recommended initiating therapy when the CD4+ count is ≤ 500 cells/mm^3. The final category is CD4+ cell counts > 500 cells/mm^3, and on this issue, the panel was equally divided. One half of the members favored initiating therapy regardless of CD4+ cell count—that is, even in those patients with CD4+ cell counts > 500 cells/mm^3—whereas the remaining one half thought that the recommendations should view this number as an optional threshold for initiation of therapy. There are some conditions listed that favor initiation of antiretroviral therapy regardless of the CD4+ cell count, including history of an AIDS-defining illness, certain opportunistic infections, pregnancy, HIV-associated nephropathy, hepatitis B coinfection when hepatitis B treatment is indicated, rapid CD4+ cell count decline, and a high HIV-1 RNA level. The trend clearly is toward increased numbers of people falling into the category for which recommendations to start therapy are positive. DHHS: US Department of Health and Human Services *Panel divided: 55% strongly recommend and 45% moderately recommend ◊50% favor initiating therapy at this stage; 50% view initiating therapy at this stage at optional

SMART Study Immediate arm: ART immediately after randomization
HIV-infected with CD4 >350 (n=5472) Immediate Continuous Arm (n=2752; 249 not on ART) Deferred Intermittent Arm (n=2270; 228 not on ART) Immediate arm: ART immediately after randomization Deferred arm: CD4 250 and 350 as on and off switch Primary endpoints Opportunistic infection (OI) or death from any cause Fatal or nonfatal OI Serious non-AIDS events Fatal and non-fatal OI plus serious non-AIDS events We will now review some of the data that support this more aggressive approach of starting therapy earlier. One of the most important studies in this regard is the prospective SMART study. This was a large trial involving more than 5000 persons who were randomized to one of 2 treatment strategies. The first treatment strategy involved initiating therapy as soon as patients enrolled in the study and staying on continuous antiretroviral therapy throughout the study duration. The other patient group was assigned to defer the initiation of therapy until the CD4+ count decreased to < 250 cells/mm^3. If the CD4+ cell count increased after therapy was administered and reached > 350 cells/mm^3, then therapy would again be interrupted, and consequently, the CD4+ cell count levels of 350 cells/mm^3 and 250 cells/mm^3 served as an on/off switch for holding or starting antiretroviral therapy. Within this large group of 5472 patients in the overall SMART study, there were approximately 500 patients who were either not receiving antiretroviral therapy at the time they enrolled in the study or who had never received antiretroviral therapy and, therefore, were eligible to be included in this subset analysis investigating the optimal threshold for initiating antiretroviral therapy. Emery S, et al. J Infect Dis. 2008;197:

SMART: Subgroup Analysis
Subgroup analysis investigated optimal threshold for initiating ART (n= 477) Immediate group experienced substantially fewer events compared with deferred group Event n, (Rate per 100 person yrs) Deferred Arm (n=228) Immediate Arm (n=249) HR 95% CI P-value OI/ Death 15 (4.8) 5 (1.3) 3.5 .02 OI only 11 (3.5) 4 (1.1) 3.3 .04 Serious non-AIDS events 12 (3.9) 2 (0.5) 7.0 .01 Composite* 21 (7.0) 6 (1.6) 4.2 .002 This slide shows that the patients who were randomized to the immediate therapy arm had a reduced risk of opportunistic disease and serious non-AIDS events relative to patients who deferred therapy until reaching lower CD4+ cell counts. The first row in the table includes data on opportunistic disease or death. In the deferred arm, there were 15 events, representing 4.8 events per 100 person-years of follow-up compared with only 5 events among patients who initiated and maintained therapy in the immediate arm, representing 1.3 events per 100 person-years and demonstrating a 3.5-fold increased risk among patients who deferred therapy with a statistically significant P value of .02. In addition, opportunistic disease alone or serious non-AIDS events alone were also statistically significantly in favor of initiating therapy, with fewer events occurring in the group that started and sustained therapy compared with patients who deferred and interrupted therapy. Finally, for the composite endpoint there were 21 outcomes among the 228 patients in the deferred arm, or 7.0 per 100 person-years, vs only 6 outcomes among 249 patients in the immediate arm, or 1.6 per 100 person-years, reflecting a statistically significant difference in favor of those who initiated therapy. This was a very important result that has advanced the field. Clinicians who have advocated initiating therapy earlier certainly have found much support for that approach in these data. However, there are also other data, predominantly cohort data, that inform the issue of when to start antiretroviral therapy. *Fatal and nonfatal OI plus serious non-AIDS events. (OI= opportunistic infection) Emery S, et al. J Infect Dis. 2008;197:

Kitahata MM, et al. N Engl J Med. 2009;360:1815-1826.
NA-ACCORD Study Established in 2006, examining 22 HIV research cohorts (n=17,517) Two analyses comparing Initiation of ART in CD4 >350 – 500 vs. CD4 ≤350 (n=8,362) Initiation of ART in CD4 >500 vs. CD4 ≤500 (n=9,155) Adjusted for lead-time bias allowed ART to be initiated within 1.5 yrs after baseline CD4 Primary outcome: All cause mortality *Cohort study not randomized trial* The NA-ACCORD study examined 22 different HIV research cohorts beginning in The investigators conducted 2 analyses within this larger cohort. The first analysis was a comparison of patients who initiated therapy when the CD4+ cell count was between 351 cells/mm^3 and 500 cells/mm^3 vs the population that did not initiate therapy at the earlier threshold and instead waited until the CD4+ cell count was < 351 cells/mm^3. A second analysis in a separate population within this cohort examined patients who initiated therapy at CD4+ cell counts > 500 cells/mm^3 vs individuals who initiated therapy at CD4+ cell counts ≤ 500 cells/mm^3. The investigators controlled for lead-time bias by considering individuals as having initiated antiretroviral therapy if they did so within 1.5 years after their CD4+ cell count reached the ranges under investigation. The primary outcome in this study was death from any cause. One must remember that this is a cohort study—not a randomized trial of starting vs not starting therapy. Therefore, the reasons why patients might have started therapy at any particular CD4+ cell count can be highly variable. In addition, decisions made by providers based on other factors could also have had an important impact on when patients initiated therapy; therefore, one must interpret these findings with caution. Kitahata MM, et al. N Engl J Med. 2009;360:

Kitahata MM, et al. N Engl J Med. 2009;360:1815-1826.
NA-ACCORD Study This slide depicts data from the 2 different comparisons with the upper series showing the 350 cells/mm^3 CD4+ threshold and the lower series indicating the 500 cells/mm^3 threshold. The relative hazard for death is shown by the bars on the right-hand side of the slide with the assessed categories indicated, as well as the statistical significance of the difference. Comparing patients who deferred therapy until the CD4+ cell count decreased to ≤ 350 cells/mm^3 with patients who started therapy at CD4+ cell counts between 351 cells/mm^3 and 500 cells/mm^3, the relative hazard of death was 1.69; that is, there was a 69% increased likelihood of death occurring among patients who deferred therapy to lower CD4+ cell counts compared with patients who started therapy within the range of cells/mm^3 (P < .001). In this cohort, older age also was associated with a greater risk of death. This finding has been seen in many other cohorts, but it seems to validate the statistical methodology in this study. Patients experienced a statistically significant 68% increased likelihood of death per 10 years of older age (P < .001). Baseline CD4+ cell count or sex seemed to have no impact on mortality risk. For the second population, comparison between patients with a CD4+ cell count > 500 cells/mm^3 at therapy initiation and patients who waited until their CD4+ cell count decreased to ≤ 500 cells/mm^3 before starting therapy, there was also a statistically significant outcome favoring the earlier initiation of therapy; in this case, the hazard ratio was 1.94 (P < .001). Age was also an important parameter in this group with a hazard ratio of 1.83 (P < .001). Similar to the first comparison, baseline CD4+ cell count did not appear to be a predictor of death, and this finding is likely related to the fact that in both of these instances the baseline CD4+ cell count was quite high and the period of follow-up was relatively short. In the second comparison, female sex was associated with a higher rate of death (hazard ratio: 1.85; P < .001), although the reasons for this outcome are not entirely clear. Therefore, the NA-ACCORD study provides a second, very meticulously analyzed dataset that also appears to favor starting antiretroviral therapy earlier in the course of the disease at higher CD4+ cell counts. In this case, beginning therapy above CD4+ cell count thresholds of either 350 cells/mm^3 or 500 cells/mm^3 appeared to be associated with a lower risk of death relative to deferring therapy until reaching the CD4+ cell count threshold. Kitahata MM, et al. N Engl J Med. 2009;360:

ART Cohort Collaboration
Analysis of 15 cohorts from US and Europe (n=24,444) The next study had a slightly different outcome. This is the ART Cohort Collaboration study from the When to Start Consortium that also examined CD4+ cell count thresholds of therapy initiation. This study involved a large cohort with 24,444 patients included in the analysis, but the methodology was different from the NA-ACCORD study. The scientists in the ART Cohort Collaboration compared outcomes for patients who initiated therapy within specific CD4+ cell count strata spanning 100 cells/mm^3 with patients who initiated therapy in adjacent CD4+ cell count strata. For example, comparing patients who started therapy at a CD4+ cell count between 1 cell/mm^3 and 100 cells/mm^3 with patients who started at a CD4+ cell count between 101 cells/mm^3 and 200 cells/mm^3 showed a 3.35-fold significantly higher risk of an AIDS-defining condition or death (95% confidence interval: ). With each comparison, there continued to be a significant difference favoring earlier initiation of therapy until CD4+ cell counts reached the range of cells/mm^3 compared with cells/mm^3. In this case, the outcomes did not appear to differ in a statistically significant way and the hazard ratio was 0.99 (95% confidence interval: ), meaning that the risk of death or new AIDS-defining condition was equivalent in the 2 strata. The graph on the left-hand side of this slide shows the point estimates for various CD4+ cell count ranges. As the CD4+ cell count threshold at which therapy was initiated increases, the risk of death or an AIDS-defining condition is reduced, but the curve plateaus above CD4+ cell counts of 350 cells/mm^3. Therefore, these data clearly support the idea of starting therapy when CD4+ counts are < 350 cells/mm^3, but they do not show reduced rates of new AIDS-defining conditions or death when comparing treatment initiation at different CD4+ cell count strata > 350 cells/mm^3. Therefore, the results differ somewhat from the NA-ACCORD findings and instead suggest that a CD4+ cell count threshold of 350 cells/mm^3 may be appropriate for the initiation of antiretroviral therapy. The Lancet 2009;373:

Panel Split: CD4 >500 cells/mm3
Arguments in Favor Arguments Against Cohort data showing survival benefit Available data do not definitively establish benefit of ART in all patients with CD4 >500 Untreated HIV infection may be associated with higher risk of non-AIDS conditions Benefits of earlier initiation may be outweighed by: Risks of short or long term drug-related adverse events Risk of non-adherence in asymptomatic patients Potential for development of drug resistance Availability of newer regimens with improved efficacy, convenience, and tolerability Growing evidence that treatment reduces HIV transmission What do these findings mean in terms of the DHHS panel recommendations? As discussed previously, there was an approximately 50/50 split between panel members who thought that treatment initiation at higher CD4+ cell counts (ie, > 500 cells/mm^3) should be recommended and members who felt that approach should be considered optional. This slide lists some of the arguments that were offered both in favor of and against earlier initiation. As the quality, tolerability, and adherence likelihood of therapy improves, the risks of treatment failure and resistance are diminished and the potential for long-term success is enhanced. Such improvements in available antiretroviral regimens over the last few years have helped support the notion of earlier initiation of therapy. DHHS. Available at:

START : Enrolling Patients
Treatment-naive patients with CD4+ cell count > 500 cells/mm³ (N = 4000) Immediate Treatment Deferred Treatment to CD4 ≤350 cells/mm3 Randomize trial underway Follow up period for 4 – 5 years Study endpoints: Fatal AIDS or non-fatal serious AIDS events (cardiovascular, liver, renal, and cancer), and all-cause mortality Is it possible to investigate this question using the gold-standard method of a prospective, randomized, placebo-controlled, double-blind study? Perhaps not entirely, but there is an effort under way to examine the question of when to start antiretroviral therapy in a prospective fashion. This slide depicts the START study. This study is under way and has begun enrolling patients. The investigators are identifying HIV-infected persons with CD4+ cell counts > 500 cells/mm^3 and randomizing them to immediately initiate therapy or to defer therapy until the CD4+ cell count decreases to < 350 cells/mm^3. The endpoints include fatal AIDS events, non-fatal serious AIDS events, such as cardiovascular disease, hepatic disease, renal disease, and cancer, and all-cause mortality. This is an ambitious study with the intention to enroll 4000 patients and follow them for 4-5 years. As yet, the pace of enrollment is not quite as brisk as had been hoped. It is hoped that this study will succeed in enrolling the proper population and that it will provide more definitive data on the question of when to initiate antiretroviral therapy, but it will be a challenge because this is a difficult study to enroll. ClinicalTrials.gov. NCT

What are the preferred ART regimens?

Antiretroviral Agents

Antiretroviral Agents
NRTIs PIs Abacavir (ABC, Ziagen®) Atazanavir (ATV, Reyataz®) Didanosine (ddI, Videx®) Darunavir (DRV, Prezista®) Emtricitabine (FTC, Emtriva®) Fosamprenavir (FPV, Lexiva®) Lamivudine (3TC, Epivir®) Lopinavir/ritonavir (LPV/r, Kaletra®) Stavudine (d4T, Zerit®) Nelfinavir (NFV, Viracept®) Tenofovir (TDF, Viread®) Ritonavir (RTV, Norvir®) Zidovudine (ZDV, Retrovir®) Saquinavir (SQV, Invirase®) NNRTIs Tipranavir (TPV, Aptivus®) Delavirdine (DLV, Rescriptor®) Entry Inhibitors Efavirenz (EFV, Sustiva®) Enfuvirtide (ENV, Fuzeon®) Etravirine (ETV, Intelence®) Maraviroc (MVC, Selzentry®) Nevirapine (NVP, Viramune®) Integrase Inhibitors Raltegravir (RAL, Isentress®)

DHHS: Preferred Regimens
Preferred regimens: those with optimal and durable efficacy, favorable tolerability and toxicity profile, and ease of use NNRTI based Efavirenz* + Tenofovir/Emtricitabine Boosted PI based Atazanavir/R◊ + Tenofovir/Emtricitabine Darunavir/R + Tenofovir/Emtricitabine INSTI based Raltegravir + Tenofovir/Emtricitabine *Should not be used in first trimester of pregnancy or women in child-bearing age ◊ Should not be used in patients who require >20mg omeprazole equivalent per day US Department of Health and Human Services guidelines

Efavirenz-Based Regimen
Why? Why not? Long track record Unbeaten clinical trial Convenience Forgiving missed doses CNS adverse events Teratogenic in 1st trimester Low genetic barrier to resistance Lower CD4 increase than other drug classes Advantages: Long track record- long clinical experience with efavirenz with good efficacy Unbeaten clinical trial- no other agents has been found to be superior Convenience- once daily dosing – Atripla Forgiving missed doses- Drugs have long half life Disadvantages: CNS effects- Dizziness, vivid dreams. 1st weeks of therapy Teratogenic in 1st trimester Risk of resistance with treatment interruption- takes just a single mutation to confer total resistance to the NNRTIs. Forgiving doses but EFV has longest half life. Lower CD4 increase- tends to increase less when compared to other classses

Boosted PI-Based Regimen
Why? Why not? Long track record Greater CD4 increase vs. Efavirenz Boosted Atazanavir as good as Efavirenz with less resistance risk at failure Preferred in pregnancy GI adverse effects Greater pill burden Lipid elevation Lipohypertrophy Increased tenofovir renal toxicity? Advantages: Long track record with ATV and DRV for efficacy and safety Greater CD4 increase vs Efavirenz Boosted ATV shown non-inferior to EFV and less risk of resistance Forgiving of nonadherence because a single mutation or resistance to PI will not knock out the whole PI class. Preferred in pregnancy- Kaletra Disadvantages: GI effects Less convenient because no one pill combination Lipid elevation and lipodystrophy Increase renal tox of tenofovir with PIs

Raltegravir-Based Regimen
Why? Why not? Very well tolerated As effective as EFV with better tolerability No lipid effects Not known to be teratogenic Rapid virologic suppression Greater CD4 increase vs EFV No long-term data Twice daily dosing Resistance risk at virologic failure similar to EFV RAL newest addition to guidelines Excellent tolerability- have not heard of any pts complain Non-inferior to efv without side effect profile No lipid effects like the Pis Not known to be teratogenic Studies shown to cause rapid decline in viral load and greater cd4 increase Disadvantages: No long term data approved in 2007 Twice daily dosing Like efv, resistance happen rapidly once virlogic failure occurs

DHHS: Alternative Regimens
Alternative regimens: those that are effective and tolerable but have potential disadvantages compared with preferred regimens; an alternative regimen may be the preferred regimen for some patients NNRTI based Efavirenz + (Abacavir or Zidovudine) + Lamivudine Nevirapine* + Zidovudine/Lamivudine Boosted PI based Atazanavir/R + (Abacavir◊ or Zidovudine) + Lamivudine Fosamprenavir/R + [(Abacavir or Zidovudine) + Lamivudine] or Tenofovir/Emtricitabine Lopinavir/R~ + [(Abacavir or Zidovudine) + Lamivudine] or Tenofovir/Emtricitabine Saquinavir/R + Tenofovir/Emtricitabine There are several other categories of regimens in the DHHS guidelines. Alternative regimens include the more traditional model: 2 NRTIs plus an NNRTI or boosted PI. There are many options listed. It should be noted that the alternative regimens may be in fact preferred for some patients based on patient characteristics. These are combinations that have been proven to be effective and tolerable but have potential disadvantages when compared with the preferred regimens. *Should not be used in females with CD4 >250 and males with CD4 >400 ◊Associated with increased MI risk ~LPV/r + ZDV/3TC recommended in pregnancy US Department of Health and Human Services guidelines

US Department of Health and Human Services guidelines. 2009.
DHHS: Others Regimens Acceptable regimens: those that may be selected for some patients but are less satisfactory than preferred of alternative regimens NNRTI based Efavirenz + Didanosine + (Lamivudine or Emtricitabine) Unboosted PI based Atazanavir + (Abacavir or Zidovudine) + Lamivudine Regimens that may be acceptable but more data are needed CCR5 antagonist based Maraviroc* + Zidovudine + Lamivudine INSTI based Raltegravir + (Abacavir + Zidovudine) + Lamivudine Boosted PI based Darunavir/R + (Abacavir + Zidovudine) + Lamivudine Saquinavir/R + (Abacavir + Zidovudine) + Lamivudine The acceptable regimens also consist of 2 NRTIs and an NNRTI or PI, specifically efavirenz and unboosted atazanavir. Again, these regimens may be selected for some patients but have characteristics that make them less satisfactory than preferred or alternative regimens for most patients. There is a new category of regimens in the DHHS guidelines that has been termed “acceptable but more data are needed.” This category includes 2 regimens incorporating drugs from the novel classes: maraviroc combined with zidovudine/lamivudine (the regimen studied in the MERIT study) and raltegravir combined with NRTIs with which it has not been specifically studied, namely zidovudine/lamivudine or abacavir/lamivudine. It is important to remember that before using maraviroc, the tropism of the patient’s virus must be determined. Maraviroc is active only if the patient’s virus is CCR5 tropic only. *CCR5 tropism assay necessary US Department of Health and Human Services guidelines

What standard tests should be preformed?

Patient Evaluation Tests administered to all patients
Tests administered to selected patients HIV RNA CD4 cell count Viral resistance test Complete blood count Blood chemistry profile Liver enzymes Bilirubin Blood urea nitrogen Creatinine Urinalysis Fasting blood glucose Fasting serum lipids Screening for syphilis Hepatitis A, B, C Coinfection screening Tuberculosis Toxoplasma gondii Cervical Pap smear (women) Pregnancy (women) HLA-B*5701 Tropism assay When a patient enters care, there is a series of evaluations that should be performed. On this slide, some of the standard tests that should be done for all patients are listed. In addition, there are tests that clinicians might perform on selected patients. Certainly screening for tuberculosis is extremely important. Obtaining a Toxoplasma antibody is standard of care, although now that treatment is initiated earlier and HAART is more effective, we are seeing much less toxoplasmosis. Women should have a Pap smear; they represent a selected population based on sex. Men should probably have an anal Pap smear, although there is still some debate about that issue. Testing for pregnancy in women of the appropriate age and menstrual status is logical. Many would advocate doing an HLA-B*5701 test at baseline—the presence of this allele is associated with increased risk of abacavir hypersensitivity. Some would suggest performing HLA-B*5701 testing on all patients whereas others would only perform the test in patients for whom abacavir is being actively considered.

Viral Resistance Test Resistance testing recommended for all antiretroviral-naive patients, regardless of infection duration *Test source patient especially if treated with antiretroviral drugs. DHHS1 IAS-USA2 European3 Primary/acute Recommend Post-exposure prophylaxis -- Recommend* Chronic, tx naïve Failure Pregancy Pediatric Should a resistance test be ordered for every patient when they first present for care? 1.)DHHS guidelines. January 12, ) Hirsch MS, et al. Clin Infect Dis. 2008;47: ) EACS Guidelines Version 3.

Genotype vs. Phenotype Genotype Phenotype Basis of test
Detects drug resistance mutations present in viral genes Measures ability of virus to grow in different concentrations of ART Interpretation Requires knowledge of mutations selected by individual ART and potential for cross-resistance conferred by certain mutations Visual interpretation by bars indicating susceptibility to individual agents Sensitivity Enhanced sensitivity for detecting mixtures of wild-type and resistance virus Results reflect susceptibility of dominant viral species Availability of results 1-2 weeks 2-3 weeks Relative cost Lower cost Higher cost

Patient Case

HIV Screening MS is a 33-yr-old woman visiting you, her new primary care physician. As you take her medical history, she mentions that she had an abnormal Pap smear a few yrs ago. You ask her if she has ever been tested for HIV. She says no and also says that she is confident that she has not acquired HIV. Is there a basis for you to encourage her to be tested at this time? Yes, she is in a high-risk group Yes, all adults up to 64 yrs of age should be tested No, I do not think that she needs testing CDC Recommendations for HIV Testing of Adult Patients In all healthcare settings, screening for HIV infection should be performed routinely for all patients aged yrs of age unless local prevalence has been documented to be < 0.1% All patients initiating treatment for TB should be screened All patients seeking treatment for STDs, including all patients attending STD clinics, should be screened routinely during each visit for a new complaint

HIV Screening CDC recommends HIV screening for all patients:
Yes, all adults up to 64 yrs of age should be tested CDC recommends HIV screening for all patients: 13-64 years old unless local prevalence has been documented to be <0.1% Initiating TB treatment Seeking treatment for STDs CDC Recommendations for HIV Testing of Adult Patients In all healthcare settings, screening for HIV infection should be performed routinely for all patients aged yrs of age unless local prevalence has been documented to be < 0.1% All patients initiating treatment for TB should be screened All patients seeking treatment for STDs, including all patients attending STD clinics, should be screened routinely during each visit for a new complaint

Patient Evaluation MS does test positive for HIV-1 infection. After informing the patient about her diagnosis, which tests related to HIV should be performed immediately, in addition to CD4+ count and HIV-1 RNA? Genotypic resistance testing Genotypic and phenotypic resistance testing Resistance testing and viral tropism testing Resistance testing and hepatitis B serology

Additional Patient Information
33 yrs old Weight: 232 lbs Height: 5'6" BP: 145/90 mm Hg Fasting glucose: 126 mg/dL (6.99 mmol/L) Taking oral contraceptives, no other medications No baseline resistance on genotypic resistance test 33 yrs old Weight: 232 lbs Height: 5'6" BP: 145/90 mm Hg Fasting glucose: 126 mg/dL (6.99 mmol/L) Taking oral contraceptives, no other medications No baseline resistance on genotypic resistance test

Initiation of Therapy The patient has HIV-1 RNA of 7000 copies/mL and a CD4+ cell count of 495 cells/mm³. What would you recommend about starting antiretroviral therapy? Start therapy as soon as she has had time to adjust to her diagnosis Defer therapy until CD4+ cell count declines to < 350 cells/mm³ Start therapy as soon as she has had time to adjust to her diagnosis Defer therapy until CD4+ cell count declines to < 350 cells/mm³

Initiation of Therapy Conditions Favoring Delay of Therapy
Start therapy as soon as she has had time to adjust to her diagnosis Conditions Favoring Delay of Therapy Significant barriers to adherence Presence of comorbidities that complicate or prohibit antiretroviral therapy (eg, scheduled surgery that might force treatment interruption) Elite controllers or long-term nonprogressors Delay of antiretroviral initiation suggested only for patients with higher CD4+ cell counts Conditions Favoring Delay of Therapy Significant barriers to adherence Presence of comorbidities that complicate or prohibit antiretroviral therapy (eg, scheduled surgery that might force treatment interruption or other medications that may have interactions with antiretroviral medications) Elite controllers or long-term nonprogressors Delay of antiretroviral initiation suggested only for patients with higher CD4+ cell counts

Pre-Treatment Evaluation
You have consulted with the patient and agree that she should start therapy. Would you obtain any additional testing at this time? Renal function tests Pregnancy test All of the above Something else

Results of Tests UA: trace proteinuria CLCr 70 mg/mL/1.73 m²
Pregnancy test negative UA: trace proteinuria CLCr 70 mg/mL/1.73 m² Pregnancy test negative

Initiating Therapy Which initial regimen would you choose?
Efavirenz + tenofovir/emtricitabine Atazanavir/ritonavir + tenofovir/emtricitabine Darunavir/ritonavir + tenofovir/emtricitabine Raltegravir + tenofovir/emtricitabine

Initial Regimen Chosen
Atazanavir/ritonavir + tenofovir/emtricitabine Patient tolerated this regimen well and viral suppression was maintained for 1.5 yrs However, renal function has declined slowly Current CrCl: 48 mg/mL Patient tolerated this regimen well and viral suppression was maintained for 1.5 yrs However, renal function has declined slowly Current creatinine clearance: 54 mg/mL/1.73 m² Tenofovir/emtricitabine + atazanavir/ritonavir

Modification of Initial Regimen
Would you consider modifying her regimen? I would change her NRTIs I would continue her NRTIs and change the dosage I would stop NRTIs and proceed with atazanavir/ritonavir monotherapy I would change to a whole new regimen I would NOT change her regimen at this time Would you consider modifying her regimen?

Useful Websites www.aidsinfo.nih.gov www.clinicaloptions.com

Thank you! Any questions?

Initiating Antiretroviral Therapy in HIV-Infected Patients

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