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  • On this slide, the red bars represent the % of subjects with VL <400 c/mL and the yellow bars represent % with VL <50 c/mL At week 24, 79% of subjects achieved VL <400 c/mL and 67% of subjects achieved VL <50 c/mL. In the low baseline VL group, 84% of subjects were below 400 c/mL and 79% were below 50 c/mL. In the high baseline VL group, 74% were below 400 c/mL and 60% were below 50 c/mL.
  • Finally, data were presented on an induction/maintenance strategy using fixed-dose zidovudine/lamivudine/abacavir. In this study, approximately 450 treatment-naive patients were given zidovudine/lamivudine/abacavir plus efavirenz for 48 weeks as induction therapy. Those patients who had viral loads < 50 copies/mL at 48 weeks were then randomized to either maintenance therapy with just zidovudine/lamivudine/abacavir or continued therapy with efavirenz plus zidovudine/lamivudine/abacavir. At 48 weeks, only 282 of the original 448 patients were available for randomization, and were then monitored for an additional 48-week period. The results demonstrated that zidovudine/lamivudine/abacavir maintenance therapy was not inferior—in other words, it was quite similar—to continued therapy with zidovudine/lamivudine/abacavir plus efavirenz. At 96 weeks, 79% of the patients who received zidovudine/lamivudine/abacavir and efavirenz and 77% of the patients who received zidovudine/lamivudine/abacavir only had viral loads < 50 copies/mL in an intention to treat, missing = failure analysis. There were more virologic failures in the zidovudine/lamivudine/abacavir-only arm, but this difference did not reach statistical significance, and there were more dropouts in the arm in which patients continued both efavirenz and zidovudine/lamivudine/abacavir. In addition to having similar antiviral activity, the zidovudine/lamivudine/abacavir arm demonstrated reductions in fasting total cholesterol and fasting LDL cholesterol, with a 22 mg/dL reduction in fasting cholesterol between 48 and 96 weeks. There was also a trend toward improved self-reported adherence in the patients who were maintained on zidovudine/lamivudine/abacavir alone.

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  • 1. HAVE WE PREMATURELY DISCARDED TRIPLE NRTI REGIMENS? YES Diane V. Havlir, MD University of California, San Francisco, USA
  • 2. Available and emerging data suggest that select triple NRTI regimens are: •Simple to administer •Associated with respectable HIV RNA reductions and CD4 increases •Safe •Favorable drug interaction profile ZDV + 3TC + ABC ZDV + 3TC + TDF
  • 3. From a global perspective, these combinations may represent some of the best options in some rather large populations: •HIV+TB •Women • Child bearing age, pregnant •Breastfeeding •Persons with HIV-2
  • 4. HIV and TB: How large is this problem? •4 fold increase in TB in some parts of Africa •50-70% TB cases HIV+ •Case fatality rates 20% smear +, 50% smear – •Mean CD4 may be lower than previously thought •Lower penetration of ART in TB patients than meet treatment criteria
  • 5. AT HIGH RISK FOR TB, AND WILL NEED TB AND HIV TREATMENT HAVE CONFIRMED OR SUSPECTED TB,AND NEED TB AND HIV TREATMENT OR
  • 6. Antiretroviral Treatment Challenges with HIV and TB: Drug Interactions and Toxicity • Rifamycin containing regimens are associated with best TB treatment outcome. • Rifampin is the only affordable rifamycin option in most of the world. • Rifampin has significant drug interactions with NNRTIs and PIs. • Drug toxicity may be higher when rifampin is administered with NNRTIs or ritonavir boosted- PIs.
  • 7. Regimen Nevirapine +2 NRTI Disadvantages Decrease in NVP by rifampin Cannot give if CD4 >250 in women Hepatoxicity Rash FIRST LINE HIV TREATMENT REGIMENS* *WHO Guidelines for Resource Limited Settings March 2005: Severe, life threatening and sometimes fatal hepatoxicity in the first 18 weeks has been reported in patients treated with viramune. Women with CD4> 250 cells/mm3 are at greatest risk.
  • 8. Regimen Nevirapine +2 NRTI Efavirenz+2 NRTI Disadvantages Decrease in NVP by rifampin Cannot give if CD4 >250 in women Hepatoxicity Rash Decrease in EFV by rifampin Teratogenic FIRST LINE HIV TREATMENT REGIMENS* March 2005: Severe, life threatening and sometimes fatal hepatoxicity in the first 18 weeks has been reported in patients treated with viramune. Women with CD4> 250 cells/mm3 are at greatest risk. March 2005: SUSTIVA may cause fetal harm when administered during the first trimester to a pregnant woman, pregnancy should be avoided in women receiving SUSTIVA *WHO Guidelines for Resource Limited Settings
  • 9. Regimen PI +2 NRTI Boosted PI +2 NRTI Disadvantages PI levels decrease by >70%, cannot use Toxicity Drug interactions Cost Cold chain /Refrigeration ALTERNATIVE REGIMENS
  • 10. Ritonavir-Saquinavir and Rifampin interaction • Recent drug interaction warning issued • HIV- volunteers received 100/1000 rit/SQV and rifampin 600 mg • Study stopped prematurely • 39% developed hepatocellular toxicity • Elevations up to 20 times upper normal of limit of liver tests were observed Rifampin SHOULD NOT be administered to patients receiving saquinavir/ritonavir as part of combination antiretroviral therapy for HIV infection* *Roche, Dear Doctor letter, Feb , 2005
  • 11. TRIPLE NRTI REGIMEN FOR PATIENTS RECEIVING TB TREATMENT ZDV + 3TC + ABC ZDV + 3TC + TDF ADVANTAERegimen Advantage •NO DRUG INTERACTIONS WITH TB MEDS •NOT TERATOGENIC •LESS RISK THAN NNRTI FOR HIV RESISTANCE WITH TREATMENT INTERRUPTIONS •FAMILY BASED CARE •NO DRUG INTERACTIONS WITH TB MEDS •NO RASH •LESS RISK THAN NNRTI FOR HIV RESISTANCE WITH TREATMENT INTERRUPTIONS
  • 12. WOMEN: SIGNIFICANT LIMITATIONS OF FIRST LINE REGIMENS Courtesy of Dr. El Sadr
  • 13. 1. Women at risk for pregnancy who need ART 2. Pregnant and breastfeeding women who need ART 3. Pregnant and breastfeeding women who need ART to prevent perinatal transmission only 4. Women who need chronic ART who harbor nevirapine resistant virus SIGNIFICANT LIMITATIONS OF FIRST LINE REGIMENS : 4 GROUPS
  • 14. PREGNANCY RISK PREGNANCY BREAST FEEDING EFAVIRENZ Women with CD4<250 who need ART EFAVIRENZ March 2005: SUSTIVA may cause fetal harm when administered during the first trimester to a pregnant woman, pregnancy should be avoided in women receiving SUSTIVA
  • 15. PREGNANCY RISK PREGNANCY BREAST FEEDING EFAVIRENZ Women with CD4>250 who need ART EFAVIRENZ NEVIRAPINE NEVIRAPINENEVIRAPINE March 2005: Severe, life threatening and sometimes fatal hepatoxicity in the first 18 weeks has been reported in patients treated with viramune. Women with CD4> 250 cells/mm3 are at greatest risk.
  • 16. PREGNANCY RISK PREGNANCY BREAST FEEDING EFAVIRENZ WOMEN WITH CD4>250:TREATMENT OPTIONS EFAVIRENZ NEVIRAPINE NEVIRAPINENEVIRAPINE TRIZIVIR TRIZIVIR TRIZIVIR
  • 17. Triple NRTI may be good option for chronic treatment in women who have received single dose nevirapine Jourdain, NEJM, 2004
  • 18. HIV-2 HIGH PREVALENCE In WEST AFRICA
  • 19. Current WHO Guidelines: First Line ART Regimens and HIV-2 First Line Regimen D4T/3TC/NVP ZDV/3TC/NVP D4T//3TC/EFV ZDV/3TC/EFV Usage in HIV-2 No No No No
  • 20. Regimens For HIV-2 Regimen PI (boosted or unboosted) +2 NRTI ZDV/3TC/TDF ZDV/3TC/ ABC Usage in HIV-2 Yes Yes Yes
  • 21. Research Agenda NRTI Only Regimens • Quadruple NRTI • Induction Maintenance • Refining target population
  • 22. QUAD NRTI : Abacavir, 3TC, ZDV and Tenofovir 79 84 74 67 79 60 0 20 40 60 80 100 Overall VL<100,000 VL>100,000 %ofSubjects <400 c/mL <50 c/mL % % % % % % No of 54 19 35 Subjects Elion, CROI 2004
  • 23. ESS40013: Intensified Induction/Trizivir maintenance Markowitz, JAIDS, 2005 Trizivir + EFV (N = 448) Trizivir (n = 121) VL < 50 at Week 48 “Intensified Induction” Maintenance Trizivir +EFV (n = 121) Control Maintenance Control 77% 79% Virologic suppression 48 weeks
  • 24. Identifying predictors of success in induction/maintenance 19/19 (100%) with DNA/RNA below median succeeded in maintenance •ACTG 343 •Patients remaining on maintenance therapy with either IDV or ZDV/3TC •N= 105
  • 25. 200 Pneumocystis pneumonia Deep fungal infections CMV retinitis M. avium CD4CellCount Thrush Kaposi’s Sarcoma Lymphoma 50 TIME IN YEARS 10 US, EUROPEAN AND AUSTRALIAN GUIDELINES WERE MADE FOR THIS HIV COURSE Toxoplasmosis
  • 26. TRIZIVIR IS CONSIDERED AN ALTERNATIVE REGIMEN FOR SELECT CIRCUMSTANCES Gulick, NEJM, 2004
  • 27. 200 Pneumocystis Deep fungal infections CMV retinitis Penicillium CD4CellCount Thrush Kaposis Sarcoma Lymphoma 50 TIME IN YEARS 10 Toxoplasmosis Tuberculosis Malaria STI HEPATITIS HIV DISEASE PROGRESSION: Global View
  • 28. SELECT TRIPLE NRTI REGIMENS PROVIDE NEEDED OPTIONS FOR A GLOBAL HIV TREATMENT APPROACH AND SHOULD NOT BE DISCARDED