Management of Acute HIV-1 Infection

2,092 views

Published on

Published in: Health & Medicine
0 Comments
3 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
2,092
On SlideShare
0
From Embeds
0
Number of Embeds
1
Actions
Shares
0
Downloads
62
Comments
0
Likes
3
Embeds 0
No embeds

No notes for slide

Management of Acute HIV-1 Infection

  1. 1. Treatment of Acute HIV-1 Infection Piyapan Peepanich, MD Rongpong Plongla, MD
  2. 2. <ul><li>An estimated 40%–90% of patients acutely infected with HIV will experience symptoms of acute retroviral syndrome </li></ul><ul><ul><li>fever, lymphadenopathy, pharyngitis, skin rash, myalgias/arthralgias, and other symptoms </li></ul></ul><ul><li>However, acute HIV infection is often not recognized by primary care clinicians </li></ul><ul><ul><li>symptoms are similar to those for influenza, infectious mononucleosis, or other illnesses. </li></ul></ul><ul><ul><li>can occur asymptomatically. </li></ul></ul>Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults andadolescents. Department of Health and Human Services. January 10, 2011; 1–166. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
  3. 3. Suspecting acute HIV infection <ul><li>Signs or symptoms of acute HIV infection with recent (within 2–6 weeks) high risk of exposure to HIV* </li></ul><ul><ul><li>Signs/symptoms/laboratory findings may include but are not limited to one or more of the following: </li></ul></ul><ul><ul><ul><li>fever, lymphadenopathy, skin rash, myalgia/arthralgia, headache, diarrhea, oral ulcers, leucopenia, thrombocytopenia, transaminase elevation. </li></ul></ul></ul><ul><ul><li>High-risk exposures include sexual contact with a person infected with HIV or at risk of HIV, sharing of injection drug use paraphernalia, or contact of potentially infectious blood with mucous membranes or breaks in skin.* </li></ul></ul>Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults andadolescents. Department of Health and Human Services. January 10, 2011; 1–166. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. * In some settings, behaviors conducive to acquisition of HIV infection might not be ascertained or might not be perceived as “high risk” by the health care provider or the patient or both. Thus, symptoms and signs consistent with acute retroviral syndrome should motivate consideration of this diagnosis even in the absence of reported high-risk behaviors.
  4. 4. Differential diagnosis <ul><li>Epstein-Barr virus (EBV)- and non-EBV (e.g., cytomegalovirus [CMV])-related infectious mononucleosis syndromes </li></ul><ul><li>Influenza </li></ul><ul><li>viral hepatitis </li></ul><ul><li>streptococcal infection </li></ul><ul><li>syphilis </li></ul>Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults andadolescents. Department of Health and Human Services. January 10, 2011; 1–166. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
  5. 5. Evaluation/diagnosis of acute/primary HIV infection <ul><li>HIV antibody enzyme immunoassay (EIA) (rapid test if available) </li></ul><ul><ul><li>Reactive EIA must be followed by Western blot. </li></ul></ul><ul><ul><li>Negative EIA or reactive EIA with negative or indeterminate Western blot should be followed by a virologic test.† </li></ul></ul><ul><li>Positive virologic test† in this setting is consistent with acute HIV infection. </li></ul><ul><li>When acute HIV infection is diagnosed by a positive virologic test (such as HIV RNA or p24 antigen) that was preceded by a negative HIV antibody test, a confirmatory HIV antibody test should be performed over the next 3 months to confirm seroconversion. </li></ul>Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults andadolescents. Department of Health and Human Services. January 10, 2011; 1–166. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. † p24 antigen or HIV RNA assay. The p24 antigen is less sensitive but more specific than HIV RNA tests; HIV RNA tests are generally preferred. HIV RNA tests include quantitative branched DNA (bDNA), reverse transcriptase-polymerase chain reaction (RT-PCR), or qualitative transcription-mediated amplification (APTIMA, GenProbe).
  6. 6. <ul><li>When acute retroviral syndrome is suspected, a plasma HIV RNA test is typically used in conjunction with an HIV antibody test to diagnose acute infection (BII). </li></ul><ul><li>Acute HIV infection is often defined by detectable HIV RNA in plasma in the setting of a negative or indeterminate HIV antibody test. </li></ul><ul><ul><li>A low-positive HIV RNA level (<10,000 copies/mL) may represent a false-positive test because values in acute infection are generally very high (>100,000 copies/mL) ANN INTERN MED2011 </li></ul></ul><ul><ul><li>A qualitative HIV RNA test can also be used in this setting. </li></ul></ul><ul><li>Interest in routine screening for antibody-negative acute infection has led to select centers performing virologic testing on all antibody-negative specimens, including the use of pooled HIV RNA testing on all seronegative serum samples NEJM2005 </li></ul><ul><li>In addition, a combination HIV antigen/antibody test January 10, 2011 Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents Page 90 (ARCHITECT), recently licensed by the Food and Drug Administration (FDA), could be used for this purpose. </li></ul><ul><li>Patients diagnosed with acute HIV infection by a virologic test while still antibody negative or indeterminate should have confirmatory serologic testing performed over the next 3 months (AI). </li></ul>Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults andadolescents. Department of Health and Human Services. January 10, 2011; 1–166. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
  7. 7. Treatment for Acute HIV Infection <ul><li>Clinical trials information regarding treatment of acute HIV infection is limited. </li></ul><ul><li>Ongoing trials are addressing the question of the long-term benefit of potent treatment regimens initiated during acute infection. </li></ul><ul><li>The health care provider and the patient should be fully aware that the rationale for therapy for acute HIV infection is based on theoretical considerations, and the potential benefits should be weighed against the potential risks. </li></ul>Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults andadolescents. Department of Health and Human Services. January 10, 2011; 1–166. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
  8. 8. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults andadolescents. Department of Health and Human Services. January 10, 2011; 1–166. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Potential Benefits Potential Risks beneficial effect on laboratory markers of disease progression exposure to ART without a known clinical benefit <ul><li>Theoretically , early intervention could </li></ul><ul><li>decrease the severity of acute disease </li></ul><ul><li>alter the initial viral setpoint, which can affect disease progression rates </li></ul><ul><li>reduce the rate of viral mutation as a result of suppression of viral replication </li></ul><ul><li>preserve immune function </li></ul><ul><li>reduce the risk of viral transmission during this highly infectious stage of disease. </li></ul>could result in drug toxicities <ul><li>Additionally, although data are limited and the clinical relevance is unclear </li></ul><ul><li>the profound loss of gastrointestinal lymphoid tissue that occurs during the first weeks of infection may be mitigated by the early initiation of ART </li></ul>development of drug resistance continuous need for therapy with strict adherence adverse effect on quality of life.
  9. 9. <ul><li>Interpretation of acute infection studies is further hampered by the lack of standardized definitions for acute and early infection. </li></ul><ul><li>Many studies use different definitions and criteria, often including treatment within 3–6 months after infection, seroconversion, or trial enrollment as treatment during “acute” infection. </li></ul>Bell SK , Little SJ , Rosenberg ES . J Infect Dis. 2010 Oct 15;202 Suppl 2:S278-88. Divisions of Infectious Diseases, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  10. 10. Cohort Study
  11. 11. <ul><li>Assessed whether initiation of HAART within 2 weeks of (acute treatment) or between 2 weeks and 6 months after (early treatment) HIV seroconversion was associated with improvements in the viral load and the CD4+ T cell count after discontinuation of treatment in an observational cohort. </li></ul><ul><li>Subjects were enrolled in the present study within 6 months of HIV seroconversion and self-selected whether to initiate HAART. </li></ul><ul><ul><li>acute ( n=13) or early (n=45) treatment received HAART for at least 12 weeks and then subsequently stopped treatment </li></ul></ul><ul><ul><li>whereas untreated subjects (n=337) declined treatment. </li></ul></ul><ul><li>HIV RNA levels and CD4+ T cell counts at 24, 48, and 72 weeks after treatment cessation in the 2 treatment groups were compared with those noted in the untreated group during the same periods of observation after enrollment . </li></ul>The Journal of Infectious Diseases 2006; 194:725–733
  12. 12. <ul><li>(1) a negative or indeterminate result of an antibody test and an HIV RNA load of > 5000 copies/mL </li></ul><ul><li>(2) a documented negative result of an HIV antibody test performed within 12 months of enrollment of a participant in whom the current HIV antibody test result is positive, or </li></ul><ul><li>(3) a history consistent with recent HIV infection and an optical density of <1.0, as determined by a less-sensitive EIA antibody test </li></ul><ul><li>A history consistent with recent HIV infection meant that a subject had no prior positive result of HIV antibody tests or had not previously received treatment for HIV infection, had a CD4+ T cell percentage of >14%, and had self-reported a recent negative HIV antibody test result or a recent illness consistent with an acute retroviral syndrome. </li></ul>The Journal of Infectious Diseases 2006; 194:725–733
  13. 13. The Journal of Infectious Diseases 2006; 194:725–733
  14. 14. The Journal of Infectious Diseases 2006; 194:725–733
  15. 15. <ul><li>Initiation of HAART within 2 weeks of antibody seroconversion was associated with viral load and CD4+ T cell count benefits for 24 weeks after termination of HAART, with there being trends toward a longer term benefit. </li></ul><ul><li>Later initiation of HAART was associated with a persistent but decreasing CD4+ T cell count benefit and a loss of the viral load benefit by week 72 after discontinuation of treatment. </li></ul>The Journal of Infectious Diseases 2006; 194:725–733
  16. 16. <ul><li>To modelize the rate of CD4+ cell count decline and its determinants after cessation of combination antiretroviral therapy (cART) started during primary HIV infection (PHI) and compare it with never-treated patients. </li></ul><ul><li>PRIMO </li></ul><ul><ul><li>170 individuals who started cART within 3 months after PHI diagnosis, who had a virological response (defined as HIV RNA <500 copies/mL within 6 months on cART), who interrupted cART for at least 3 months , and who had at least 2 CD4 + T-cell counts during the interruption. </li></ul></ul><ul><li>SEROCO </li></ul><ul><ul><li>123 were selected for the current study if they would have been enrolled in the PRIMO cohort had this cohort been implemented at that time, using the PRIMO inclusion criteria detailed above. </li></ul></ul><ul><li>The interval between the estimated date of infection and enrollment could not exceed 6 months. </li></ul>J Acquir Immune Defic Syndr 2008;49:251–258
  17. 17. J Acquir Immune Defic Syndr 2008;49:251–258
  18. 18. <ul><li>PRIMO </li></ul><ul><li>After cART interruption in the PRIMO cohort, the CD4+ cell count fell rapidly during the first 5 months and more slowly thereafter. </li></ul><ul><li>The timing of treatment initiation had no influence on the rate of CD4+ cell decline. </li></ul><ul><li>In contrast, a larger increase in CD4+ cell counts during cART was associated with a steeper decline and a larger loss of CD4+ cells after treatment interruption. </li></ul><ul><li>The mean CD4+ cell loss 3 years postinterruption was 383 cells per microliter. </li></ul><ul><li>SEROCO </li></ul><ul><li>the CD4+ T-cell decline was less steep (3-year CD4+ loss 239 cells/mL). </li></ul><ul><li>As a result, the mean CD4+ cell counts were similar (416 cells/mL) 3 years after cART interruption (PRIMO) or after infection (SEROCO). </li></ul><ul><li>These data question the benefit of a limited course of cART even when initiated within 3 months after PHI diagnosis. ?? interruption </li></ul>J Acquir Immune Defic Syndr 2008;49:251–258 PRIMO SEROCO
  19. 19. <ul><li>58 patients from the PRIMO cohort (1996–2003) treated during primary infection (with sustained virological responses until HAART interruption) and </li></ul><ul><li>116 untreated patients enrolled in the SEROCO cohort within 6 months following infection (1988–1995). </li></ul><ul><li>Viral loads were estimated in PRIMO patients 36 months after infection (12 months after treatment interruption) and were estimated for the SEROCO patients 36 months after infection, after adjustment for gender and age. </li></ul><ul><li>Results: HIV RNA levels 12 months after HAART interruption were independently associated with levels at HAART initiation and with the CD4 cell count at HAART interruption, but not with the precocity of HAART or the duration of virological response to HAART. </li></ul><ul><li>Thirty-six months after infection, mean HIV RNA levels were 3.95 log10 copies/ml 12 months after stopping HAART and 4.11 log10 copies/ml in never-treated patients. </li></ul><ul><li>Conclusion: Viral load 12 months after withdrawal of transient effective HAART started during primary infection is similar to viral load at the same time after infection in never-treated patients, suggesting that early HAART initiation does not lower the virological set-point </li></ul>AIDS 2004, 18:2361–2369
  20. 20. <ul><li>To compare immunological, virological and clinical outcomes in persons initiating combination antiretroviral therapy (cART of different durations within 6 months of seroconversion (early treated) with those who deferred therapy (deferred group). 675 patients VS 348 patients </li></ul><ul><ul><li>age of at least 15 years at seroconversion </li></ul></ul><ul><ul><li>Seroconversion interval (interval between last negative and first positive antibody test dates) of less than 6 months or laboratory evidence of acute infection (e.g., PCR positivity in the absence of antibody, evolving antibody response or indeterminate result) </li></ul></ul><ul><ul><li>follow-up (with known cART status) of at least 6 months; and availability of at least 2 CD4 cell and at least 2 HIV-RNA measurements during follow-up. </li></ul></ul><ul><ul><li>Exclude: Individuals with at least 2 CD4 cell measurements less than 350 cells/ml or who developed clinical AIDS within 6 months of estimated seroconversion were excluded as they most likely consist of a special subgroup more likely to initiate cART. </li></ul></ul>AIDS 2008, 22:2441–2450
  21. 21. <ul><li>Of 348 ‘early treated’ patients </li></ul><ul><li>147 stopped cART following treatment for </li></ul><ul><ul><li>At least 6 (n=38 ), more than 6–12 (n= 40) or more than 12 months (n= 69). </li></ul></ul><ul><li>CD4 cell loss was steeper for the first 6 months following cART cessation, but subsequent loss rate was similar to the ‘deferred’ group (n= 675, P= 0.26). </li></ul><ul><li>Although those treated for more than 12 months appeared to maintain higher CD4 cell counts following cART cessation, those treated for 12 months or less had CD4 cell counts 6 months after cessation comparable to those in the ‘deferred’ group. </li></ul><ul><li>There was no difference in HIV-RNA set points between the ‘early’ and ‘deferred’ groups (P= 0.57). </li></ul><ul><li>AIDS rates were similar but death rates, mainly due to non-AIDS causes, were higher in the ‘deferred’ group (P= 0.05). </li></ul>AIDS 2008, 22:2441–2450 Conclusion: Transient cART, initiated within 6 months of seroconversion, seems to have no effect on viral load set point and limited beneficial effect on CD4 cell levels in individuals treated for more than 12 months. Its long-term effects remain inconclusive and need further investigation.
  22. 22. <ul><li>A prospective trial of treatment stratified by acute versus recent HIV-1 infection. </li></ul><ul><ul><li>Acute infection was defined as having a plasma HIV RNA concentration more than 2000 copies/ ml within 14 days of study entry and either a negative ELISA or a positive ELISA but a negative or indeterminate western blot (CDC/ASTPHLD criteria) or a positive ELISA and western blot in conjunction with either a negative ELISA or a plasma HIV RNA concentration less than 2000 copies/ml in the 30 days prior to entry. : WITHIN 4 WEEKS </li></ul></ul><ul><ul><li>Recent infection was defined as a positive ELISA and western blot within the 14 days prior to entry but a negative ELISA or plasma HIV RNA concentration less than 2000 copies/ml within the 31–90 days before entry or a positive ELISA and western blot and a nonreactive detuned ELISA in patients with more than 200 CD4 cells/ml all within the 21 days before study entry. : >14 DAYS-6 MONTHS </li></ul></ul><ul><li>If HIV viral load <50 copies/ml after at least 52 weeks, treatment was interrupted. </li></ul><ul><ul><li>The standard regimen included stavudine, lamivudine, abacavir, ritonavir and amprenavir. </li></ul></ul><ul><li>If viremia rebounded, treatment and interruption were repeated. </li></ul><ul><li>The primary endpoint was maintaining viral load less than 5000 copies/ml for 24 weeks following treatment interruption. </li></ul>AIDS 2009, 23:1987–1995
  23. 23. <ul><li>Forty percent of patients treated during acute HIV-1 infection or recent HIV-1 infection sustained a viral load less than 5000 copies/ml after 24 weeks of treatment interruption </li></ul>AIDS 2009, 23:1987–1995
  24. 24. Randomized Controlled Trial
  25. 25. <ul><li>multicenter, double-blind, placebo- controlled trial 1991-1994, 27 centres, 8 countries </li></ul><ul><li>77 patients with primary HIV infection </li></ul><ul><ul><li>Patients 18 years of age or older were enrolled in the study if they met at least one clinical criterion and one laboratory criterion. </li></ul></ul><ul><ul><ul><li>The clinical criteria </li></ul></ul></ul><ul><ul><ul><ul><li>the presence of an acute retroviral syndrome and known exposure to HIV within the previous three months. </li></ul></ul></ul></ul><ul><ul><ul><li>The laboratory criteria </li></ul></ul></ul><ul><ul><ul><ul><li>p24 antigenemia and a negative or low positive result of an antibody test with an indeterminate result of a Western blot. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Confirmation of seroconversion was obtained at follow-up visits, with the use of Western blot analysis. </li></ul></ul></ul></ul><ul><li>randomly assigned to receive either </li></ul><ul><ul><li>zidovudine (250 mg twice daily; n=39) or </li></ul></ul><ul><ul><li>placebo (n=38) for six months. </li></ul></ul><ul><ul><li>Clinical assessment and laboratory testing were performed weekly from the day of enrollment until week 6, then every six weeks until the end of the trial period. </li></ul></ul><ul><ul><li>Subsequent assessments were performed every 2 weeks for 4 weeks after the discontinuation of the trial medication, then every 12 weeks until the end of the first year, and then every 6 months for the next 2 years. </li></ul></ul><ul><li>The main end points of the study </li></ul><ul><ul><li>the duration of the acute retroviral syndrome </li></ul></ul><ul><ul><li>the change in the CD4 lymphocyte count at six months, and </li></ul></ul><ul><ul><li>the occurrence of opportunistic infections </li></ul></ul><ul><li>Additional outcome variables </li></ul><ul><ul><li>the CD4 lymphocyte counts after the trial period </li></ul></ul><ul><ul><li>the CD8 lymphocyte counts </li></ul></ul><ul><ul><li>p24 antigenemia, and viremia </li></ul></ul>N Engl J Med 1995;333:408-13.
  26. 26. <ul><li>The mean time from the onset of symptoms until enrollment in the study was 25.1 days (23.9 in the zidovudine group and 26.6 in the placebo group). </li></ul><ul><li>Among the 43 patients who were still symptomatic at the time of enrollment, </li></ul><ul><ul><li>there was no appreciable difference in the mean ( +/-SE) duration of the retroviral syndrome between the zidovudine group (15.0 +/- 4.1 days) and the placebo group (15.8 +/- 3.6 days). </li></ul></ul><ul><li>During a mean follow-up period of 15 months, minor opportunistic infections developed in eight patients: oral candidiasis in four, herpes zoster in two, and oral hairy leukoplakia in two. </li></ul><ul><ul><li>The mean CD4 count for this group was 310 cells per cubic millimeter (range, 48 to 645). </li></ul></ul><ul><ul><li>1 patient had mutation codon </li></ul></ul><ul><li>Disease progression was significantly less frequent in the zidovudine group (one opportunistic infection) than in the placebo group (seven opportunistic infections; P =0.009 by the log-rank test). </li></ul>N Engl J Med 1995;333:408-13.
  27. 27. <ul><li>After adjustment for the base-line CD4 cell count, </li></ul><ul><ul><li>the patients treated with zidovudine had an average gain of 8.9 CD4 cells per cubic millimeter per month (95 %CI, 1.4 to 19.1) during the first six months of the study, whereas </li></ul></ul><ul><ul><li>those receiving placebo had an average loss of 12.0 CD4 cells per cubic millimeter per month (95 %CI, 5.2 to 18.7) </li></ul></ul><ul><ul><li>for a between-group difference of 20.9 CD4 cells per cubic millimeter per month (95 percent confidence interval, 8.5 to 33.2; P =0.001) </li></ul></ul><ul><li>In this study, treatment with zidovudine during primary HIV infection </li></ul><ul><ul><li>reduced the frequency of minor opportunistic infections during a mean follow-up period of 15 months </li></ul></ul><ul><ul><li>substantially increased the CD4 lymphocyte count during the trial period. </li></ul></ul><ul><ul><li>did not seem to affect the duration of the acute retroviral syndrome. </li></ul></ul>N Engl J Med 1995;333:408-13.
  28. 28. <ul><li>28 patients </li></ul><ul><ul><li>>/=13 years </li></ul></ul><ul><ul><ul><li>p24 antigenemia confirmed by neutralization assay and either HIV EIA–negative or HIV EIA–positive and HIV Western blot–negative or –indeterminate (</=2 HIV-specific bands corresponding to gag, env, or pol gene product) or </li></ul></ul></ul><ul><ul><ul><li>documented EIA seroconversion within the prior 30 days and HIV Western blot–negative or –indeterminate. </li></ul></ul></ul><ul><li>1000 mg daily (200 mg 5 times/day) or placebo for 24 weeks </li></ul><ul><li>prematurely closed to accrual because of slow enrollment and waning acceptance of zidovudine monotherapy </li></ul><ul><li>Median time from exposure-symtomps 16 days (1-284) </li></ul><ul><li>Median time from onset of symptoms to study entry 4.5 days (0-29) </li></ul>The Journal of Infectious Diseases 1998;178:80–91
  29. 29. <ul><li>At week 48, compared with placebo patients </li></ul><ul><ul><li>no significant differences between study arms with regard to clinical events </li></ul></ul><ul><ul><li>zidovudine-treated patients had significantly higher CD4 cell counts (zidovudine, 666 cells/mm3; placebo, 362; P = .004) </li></ul></ul><ul><ul><li>lower peripheral blood mononuclear cell (PBMC) culture titers (zidovudine, 0.58 log infectious units per million cells; placebo, 1.68; P = .02) </li></ul></ul><ul><ul><li>no difference in plasma RNA (zidovudine, 3.93 log copies/ mL; placebo, 4.00; P = .83). </li></ul></ul><ul><li>Serious adverse events and minor clinical events were infrequent and comparable in both arms. </li></ul><ul><li>Six months of high-dose zidovudine initiated during PHI results in higher CD4 cell counts and lower PBMC culture titers but no difference in plasma HIV-1 RNA. </li></ul><ul><li>Further studies with more potent antiretroviral combination therapies are warranted. </li></ul>The Journal of Infectious Diseases 1998;178:80–91
  30. 30. <ul><li>prospective, randomized-controlled trial </li></ul><ul><li>to assess the effect of 36 weeks of ART given during early HIV-1 infection on virologic set point at week 72 </li></ul><ul><li>enrolled recently infected adults—newly seropositive or detuned-EIA consistent with infection <6 months’ duration. </li></ul><ul><ul><li>randomized 1:1 in step 1 to receive 36 weeks of ART and then discontinue treatment (arm A) vs no therapy (arm B). </li></ul></ul><ul><ul><li>Subjects were advised to start ART (step 2) if they met disease progression criteria consistent with current treatment guidelines. </li></ul></ul><ul><li>Primary endpoint </li></ul><ul><ul><li>a composite of meeting criteria for step 2 and log 10 HIV-1 RNA at week 72 (arms A and B) and at week 36 (arm B). </li></ul></ul><ul><ul><li>Difference in viral set point between the arms was assessed using the Wilcoxon rank-sum 1-sided test; </li></ul></ul><ul><ul><li>those meeting criteria for step 2 were considered ”failures” and assigned an unfavorable rank. </li></ul></ul><ul><ul><li>Time-to-failure was assessed via KM plot and log-rank test.  </li></ul></ul>the 17 th Conference on Retroviruses and Opportunistic Infections; 2010; San Francisco, CA.
  31. 31. <ul><li>Results:   </li></ul><ul><li>At the June 2009 Data and Safety Monitoring Board (DSMB) interim review </li></ul><ul><li>130 of 150 subjects had been enrolled, 52 still on study. </li></ul><ul><li>Baseline characteristics: 90% male, median age 33 years, CD4 count 540 cells/mm 3 and HIV-1 RNA 4.4 log 10 copies/mL. </li></ul><ul><li>The DSMB recommended stopping the study because of a significant advantage for arm A by week 76 , driven mostly by a higher rate of progression to Step 2 eligibility criteria in arm B, and their expectation that further enrollment would not yield additional conclusions. </li></ul><ul><li>Efficacy analysis included 79 subjects randomized at least 72 weeks prior to the DSMB review. </li></ul><ul><li>Arm A had a better outcome on the primary endpoint ( P  =0.005) at week 72, as well as at week 72 (Arm A) vs week 36 (arm B) ( P  =0.002), due primarily to the higher rate of progression in arm B — 4 of 66 (6%) on arm A vs 22 of 64 (34%) on arm B met step 2 eligibility criteria by week 76, 13 (20%) on arm B by week 36. </li></ul><ul><li>Time-to-progression was significantly shorter in arm B vs A, whether the time origin was study entry for both arms ( P  <0.001) or time of scheduled discontinuation of ART for arm A ( P  =0.035). </li></ul><ul><li>Conclusions:   Progression to meeting criteria for initiation of ART occurred more frequently than anticipated, limiting our ability to evaluate HIV-1 RNA levels at study endpoint. </li></ul><ul><li>However, a limited period of ART during early HIV-1 infection modestly delayed the need for subsequent initiation of ART. </li></ul>
  32. 32. <ul><li>assessed the clinical benefit of temporary cART during PHI. </li></ul><ul><li>multicentre, open-label, randomized trial including patients with laboratory evidence of PHI.   </li></ul><ul><li>randomized over 3 study arms (no treatment, 24 or 60 weeks of cART); if therapy was favored, they were randomized over the 2 treatment arms. </li></ul><ul><li>Primary endpoint was the total time that patients could remain off therapy, defined as the time between randomization and start of cART in the untreated arm, or as the time between treatment interruption (TI) and restart of cART (subtracting time spent on early cART) in the treatment arms. </li></ul><ul><ul><li>cART was (re)started in case of an AIDS diagnosis or a confirmed CD4 count <350 cells/mm 3 . </li></ul></ul><ul><ul><li>Time off therapy was compared across the study arms using KM plots and Cox survival analysis adjusted for age, baseline CD4 count, protective HLA types, and presence of X4-tropic viruses at baseline. </li></ul></ul><ul><ul><li>Viral set point was defined as pVL 36 weeks after randomization/TI in the untreated/treated arms. </li></ul></ul>the 18 th Conference on Retroviruses and Opportunistic Infections; 2011; Boston, CA.
  33. 33. <ul><li>173 patients were randomized. The modified ITT-analysis consisted of 168 patients: </li></ul><ul><li>Mean (SD) viral set point (log 10  c/mL) 36 weeks after randomization/TI was 4.8 (0.6) in the untreated arm, and 3.9 (1.1) and 4.2 (1.0) in the 24- and 60-week treated arms ( p  <0.001). </li></ul><ul><li>Mean (SD) CD4 count (cells/mm 3 ) 8 weeks after randomization/TI in the untreated arm was 470 (167), and 670 (249) and 611 (231) in the 24- and 60-week treated arms ( p  = 0.001). </li></ul><ul><li>The median time off therapy in the untreated arm was 0.7 (95%CI 0.2 to 1.2) years compared to 3.1 (2.3 to 3.8) and 2.1 (0.4 to 3.8) years in the 24- and 60-week treated arms, respectively ( p  <0.001). </li></ul><ul><li>Combining all treated patients, the median time off therapy did not differ significantly between the 24- and 60-week arms ( p  = 0.14). </li></ul><ul><li>In the adjusted Cox analysis, temporary early cART was independently associated with total time off therapy (HR for (re)start 0.26,  p  <0.001). </li></ul><ul><li>Conclusions:   Temporary cART during PHI lowers the viral set point and defers the moment of initiation of cART during chronic HIV infection. </li></ul>the 18 th Conference on Retroviruses and Opportunistic Infections; 2011; Boston, CA.
  34. 34. <ul><li>randomized 40 newly infected patients (mean estimated duration of infection: 48-54 days) </li></ul><ul><li>1:2 to </li></ul><ul><ul><li>3-drug therapy with TDF/FTC with AZT or DRV/r once daily (n = 14/11) or </li></ul></ul><ul><ul><li>5-drug therapy with TDF/FTC/PI/r once daily with raltegravir/maroviroc (RAL/MVC) twice daily (n = 26/23) </li></ul></ul><ul><li>The primary endpoints were the as-treated percentage of subjects with undetectable plasma HIV-1 levels using Roche Amplicor/Taqman1.0 (detection limit 50/48 copies/mL) and the single copy assay (SCA) after 48 weeks. </li></ul>the 18 th Conference on Retroviruses and Opportunistic Infections; 2011; Boston, CA.
  35. 35. <ul><li>mean log 10 HIV-1 RNA 6.3 and 5.6 ( p = 0.17) </li></ul><ul><li>mean CD4 + T cells; 405 and 539 cells/mm 3 ( p = 0.15). </li></ul><ul><li>At week 48 11 of 11 (100%) vs 20 of 23 (86.9%) in the 3-drug and 5-drug arms, respectively, were considered complete responders by standard assay ( p = 0.53 Fisher’s exact test). </li></ul><ul><li>There were 3 virologic failures in the 5-drug arm; 2 failed to reach virologic failure <50/48 copies/mL by week 36, 1 subject reached viral load <50 copies/mL at week 12 but had confirmed low-level rebound at week 48. </li></ul><ul><li>All 3 patients with virologic failure had regimen-susceptible virus at baseline and random PI levels consistent with patient’s dosing histories. </li></ul><ul><li>Excluding patients with virologic failure, 29 of 31 were quantifiable by SCA; 3 of 11 in the 3-drug and 9 of 18 in the 5-drug arm were undetectable ( p = 0.21, Fisher’s exact test) at week 48. </li></ul><ul><li>Per planned as-treated analysis, we failed to demonstrate a 50% treatment effect of 5-drug over 3-drug therapy. </li></ul><ul><ul><li>The changes in CD4 cell counts at week 48 were comparable; +299 cells/mm 3 versus +328 cells/mm 3 in the 3-drug and 5-drug arms, respectively ( p = 0.5) </li></ul></ul><ul><ul><li>mean changes in naïve CD4 + T cells; +152 vs +150  ( p = 0.98) </li></ul></ul><ul><ul><li>Levels of CD8 + CD38 + T cells were 27.1% and 29.7% ( p = 0.82) at week 48 in the 3-drug and 5-drug arms, respectively. </li></ul></ul><ul><li>Conclusions:  Intensified ART initiated during acute and early infection fails to significantly impact as-treated response rates, residual plasma viremia by SCA, degree of immune reconstitution in peripheral blood or levels of CD8 + CD38 + T cells, a marker of immune activation. Studies to determine its impact on the gastrointestinal tract and the latent reservoir are in progress. Virologic failure in 3 of 26 reportedly adherent patients on the 5-drug arm was unanticipated and reasons remain obscure. </li></ul>the 18 th Conference on Retroviruses and Opportunistic Infections; 2011; Boston, CA.
  36. 36. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults andadolescents. Department of Health and Human Services. January 10, 2011; 1–166. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Potential Benefits Potential Risks beneficial effect on laboratory markers of disease progression exposure to ART without a known clinical benefit <ul><li>Theoretically , early intervention could </li></ul><ul><li>decrease the severity of acute disease </li></ul><ul><li>alter the initial viral setpoint, which can affect disease progression rates </li></ul><ul><li>reduce the rate of viral mutation as a result of suppression of viral replication </li></ul><ul><li>preserve immune function </li></ul><ul><li>reduce the risk of viral transmission during this highly infectious stage of disease. </li></ul>could result in drug toxicities <ul><li>Additionally, although data are limited and the clinical relevance is unclear </li></ul><ul><li>the profound loss of gastrointestinal lymphoid tissue that occurs during the first weeks of infection may be mitigated by the early initiation of ART </li></ul>development of drug resistance continuous need for therapy with strict adherence adverse effect on quality of life.
  37. 37. Considerations for antiretroviral therapy <ul><li>All pregnant women with acute or recent HIV infection should start on a combination ARV regimen as soon as possible because of the high risk of MTCT of HIV (AI). </li></ul><ul><ul><li>Following delivery, considerations regarding continuation of the ARV regimen as therapy for the mother are the same as for treatment of other nonpregnant individuals. </li></ul></ul><ul><li>Treatment of acute and early HIV infection in nonpregnant persons is considered optional (CIII). </li></ul><ul><li>Potentially unique benefits associated with ART during acute and early infection exist, although they remain unproven. </li></ul><ul><li>The risks of ART during acute and early infection are consistent with those for initiating ART in chronically infected asymptomatic patients with high CD4 counts. </li></ul><ul><li>If therapy is initiated, the goal should be for maintenance of maximal viral suppression. </li></ul><ul><li>Enrollment in a clinical trial should be considered. </li></ul>Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults andadolescents. Department of Health and Human Services. January 10, 2011; 1–166. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
  38. 38. Performance of Resistance Testing <ul><li>Data from the United States and Europe demonstrate that transmitted virus may be resistant to at least one ARV drug in 6%–16% of patients </li></ul><ul><li>If the decision is made to initiate therapy </li></ul><ul><ul><li>genotypic resistance testing at baseline to guide the selection of an ARV regimen will likely optimize virologic response; this strategy is therefore recommended (AIII). </li></ul></ul><ul><li>If therapy is deferred </li></ul><ul><ul><li>resistance testing should still be performed because the result may be useful in optimizing the virologic response when therapy is ultimately initiated (AIII). </li></ul></ul>Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults andadolescents. Department of Health and Human Services. January 10, 2011; 1–166. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
  39. 39. Treatment for Recent but Nonacute HIV Infection or Infection of Undetermined Duration <ul><li>some HIV clinicians also recommend consideration of therapy for patients in whom seroconversion has occurred within the previous 6 months (CIII). </li></ul><ul><ul><li>Although the initial burst of viremia among infected adults usually resolves in 2 months </li></ul></ul><ul><ul><li>rationale for treatment during the 2- to 6-month period after infection is based on the probability that virus replication in lymphoid tissue is still not maximally contained by the immune system during this time </li></ul></ul>Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults andadolescents. Department of Health and Human Services. January 10, 2011; 1–166. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
  40. 40. Treatment for Recent but Nonacute HIV Infection or Infection of Undetermined Duration <ul><li>In the case of pregnancy </li></ul><ul><ul><li>use of a combination ARV regimen to prevent MTCT of HIV is recommended (AI). </li></ul></ul><ul><li>For nonpregnant patients </li></ul><ul><ul><li>CD4 count between 350 and 500 cells/mm3 as well as a recommendation to consider therapy for those with CD4 count >500 cells/mm3. </li></ul></ul><ul><ul><ul><li>Although these recommendations are primarily based upon data from patients with chronic infection, the potential benefit of early treatment on immune recovery and on attenuation of the pathologic effects of viremia-associated inflammation and coagulation could apply to those with early HIV infection as well. </li></ul></ul></ul><ul><ul><ul><li>Based upon all of these considerations it is reasonable that clinicians share with patients the potential rationale for initiating ART during early HIV infection and offer treatment to those who are willing and able to commit to lifelong treatment. </li></ul></ul></ul>Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults andadolescents. Department of Health and Human Services. January 10, 2011; 1–166. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
  41. 41. Treatment Regimen for Acute or Recent HIV Infection <ul><li>the goal of therapy is to suppress plasma HIV RNA levels to below detectable levels (AIII). </li></ul><ul><li>Data are insufficient to draw firm conclusions regarding specific drug combinations to use in acute HIV infection. </li></ul><ul><ul><li>Potential combinations of agents should be those used in chronic infection. </li></ul></ul><ul><ul><li>However, because clinically significant resistance to PIs is less common than resistance to NNRTIs in ART-naïve persons </li></ul></ul><ul><ul><ul><li>an RTV-boosted PI-based regimen should be used if therapy is initiated before drug-resistance test results are available (AIII) </li></ul></ul></ul><ul><ul><ul><li>If resistance test results or resistance pattern of the source virus are known, this information should be used to guide the selection of the ARV regimen. </li></ul></ul></ul>Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults andadolescents. Department of Health and Human Services. January 10, 2011; 1–166. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
  42. 42. <ul><li>prospective, single-arm evaluation of once-daily, co-formulated FTC/TDF/EFV initiated during AHI. </li></ul><ul><li>61 patients 2005-2009 </li></ul><ul><li>The primary endpoint is the proportion of responders with HIV RNA less than 200 copies/ml by week 24. </li></ul><ul><li>92% achieved viral suppression to less than 200 copies/ml by week 24, and 35 of 41 (85.4%) to less than 50 copies/ml by week 48 </li></ul><ul><li>Once-daily emtricitabine/tenofovir/efavirenz initiated during AHI achieves rapid and sustained HIV suppression during this highly infectious period. </li></ul>AIDS 2011, 25 :941–949
  43. 43. <ul><li>The RV254/SEARCH 010 study </li></ul><ul><li>Subjects who fit the AHI laboratory criteria for Fiebig stages I to IV </li></ul><ul><li>Initiation of MegaHAART was voluntary and done as part of enrollment in an accompanying local protocol </li></ul><ul><ul><li>Tenofovir (TDF) 300mg/Emtricitabine (FTC) 200mg once daily </li></ul></ul><ul><ul><li>Efavirenz (EFV) 600mg once daily </li></ul></ul><ul><ul><li>Raltegravir (RAL) 400mg twice daily </li></ul></ul><ul><ul><li>Maraviroc (MVC) 600mg twice daily </li></ul></ul><ul><li>30 subjects enrolled, 15 subjects with 24-weeks of MegaHAART </li></ul>the 18 th Conference on Retroviruses and Opportunistic Infections; 2011; Boston, CA.
  44. 44. <ul><li>All 15 subjects showed good immunologic and virologic response to megaHAART indicated by the CD4 count and the plasma HIV RNA respectively </li></ul><ul><li>Mega-HAART in early Fiebig stage AHI may prevent CD4 depletion of the sigmoid colon and render gut and peripheral HIV RNA undetectable. </li></ul><ul><li>Mega-HAART may reduce viral burden and promote mucosal immune restoration, indicated by the increased frequency of CD4 + CCR5 +  T cells in the sigmoid colon and could be a crucial component of a functional cure. </li></ul>the 18 th Conference on Retroviruses and Opportunistic Infections; 2011; Boston, CA.
  45. 45. Patient Follow-up <ul><li>Testing for plasma HIV RNA levels and CD4 count and toxicity monitoring should be performed as described in Laboratory Testing for Initial Assessment and Monitoring While on Antiretroviral Therapy (i.e., HIV RNA at initiation of therapy, after 2–8 weeks, then every 4–8 weeks until viral suppression, then every 3–4 months thereafter) (AII). </li></ul>Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults andadolescents. Department of Health and Human Services. January 10, 2011; 1–166. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
  46. 46. Duration of Therapy for Acute or Recent HIV Infection <ul><li>Unknown </li></ul><ul><ul><li>Difficulties inherent in determining the optimal duration and therapy composition for acute or recent infection (and the potential need for lifelong treatment) should be considered when counseling patients prior to initiation of therapy. </li></ul></ul><ul><ul><ul><li>Plasma viral load and CD4 dynamics after a single interruption of highly active antiretroviral therapy were different for primary HIV infection and chronic HIV infection patients. </li></ul></ul></ul><ul><ul><ul><li>Viral rebound is delayed or absent and early CD4 cell count decline after treatment interruption is less pronounced in primary HIV infection patients. </li></ul></ul></ul><ul><ul><ul><li>Radjin Steingrover, et al. AIDS 2008, 22 :1583–1588 </li></ul></ul></ul><ul><ul><li>Patients need to know that there are limited data regarding the benefits of stopping treatment, whereas strong data from studies in patients with chronic HIV infection show that stopping ART may be harmful </li></ul></ul>Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults andadolescents. Department of Health and Human Services. January 10, 2011; 1–166. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
  47. 47. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults andadolescents. Department of Health and Human Services. January 10, 2011; 1–166. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Rating of Recommendations : A = Strong; B = Moderate; C = Optional Rating of Evidence : I = data from randomized controlled trials; II = data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = expert opinion Panel’s Recommendations Rating of Recommendations/Evidence It is unknown if treatment of acute HIV infection results in long-term virologic, immunologic, or clinical benefit; treatment should be considered optional at this time CIII Therapy should also be considered optional for patients with HIV seroconversion in the previous 6 months CIII All pregnant women with acute or recent HIV infection should start a combination antiretroviral (ARV) regimen as soon as possible to prevent mother-to-child transmission (MTCT) of HIV AI If the clinician and patient elect to treat acute HIV infection, treatment should be implemented with the goal of suppressing plasma HIV RNA to below detectable levels AIII For patients with acute HIV infection in whom therapy is initiated, testing for plasma HIV RNA levels and CD4 count and toxicity monitoring should be performed as described for patients with established, chronic HIV infection AII If the decision is made to initiate therapy in a person with acute HIV infection, genotypic resistance testing at baseline will be helpful in guiding the selection of an ARV regimen that can provide the optimal virologic response; this strategy is therefore recommended. If therapy is deferred, genotypic resistance testing should still be performed because the result may be useful in optimizing the virologic response when therapy is ultimately initiated AIII Because clinically significant resistance to protease inhibitors (PIs) is less common than resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) in antiretroviral therapy (ART)-naïve persons who harbor drug-resistant virus, a ritonavir (RTV)-boosted PI-based regimen should be used if therapy is initiated before drug-resistance test results are available. AIII
  48. 48. Thank You

×