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Initiating Antiretroviral Therapy: When and What to Start

Dr Lichtenstein received research support or honoraria from Abbott, Gilead, Merck, Pfizer, and TaiMed. He served as a consultant to Abbott, Bristol-Myers Squibb, Gilead, Merck, and Tibotec. (Updated 04/30/08). . . Disclosure Information. When to Start Treatment. . When to Start Treatment. Available at: http://aidsinfo.nih.gov/Default.aspx. Revision May 4, 2006.Hammer SM, et al. JAMA. 2006;296:827-843..

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Initiating Antiretroviral Therapy: When and What to Start

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    3. When to Start Treatment

    4. When to Start Treatment Slide: When to Start The October 6, 2005 DHHS treatment guidelines and the IAS-USA guidelines recommend antiretroviral therapy for all patients with history of an AIDS-defining illness or severe symptoms of HIV infection regardless of CD4 cell count.1,2 Antiretroviral therapy is also recommended for asymptomatic patients with <200 CD4 cells/mm3.1,2 Asymptomatic patients with CD4 cell counts of 201 to 350 cells/mm3 should be offered treatment.1,2 Antiretroviral therapy should be considered for asymptomatic patients with a CD4 cell count of >350 cells/mm3 and HIV RNA >100,000 copies/mL; and deferred for those with <100,000 copies/mL.1,2 References Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/Default.aspx. Revision: May 4, 2006. Hammer SM, Saag MS, Schechter M, et al. Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA panel. JAMA. 2006;296:827-843.Slide: When to Start The October 6, 2005 DHHS treatment guidelines and the IAS-USA guidelines recommend antiretroviral therapy for all patients with history of an AIDS-defining illness or severe symptoms of HIV infection regardless of CD4 cell count.1,2 Antiretroviral therapy is also recommended for asymptomatic patients with <200 CD4 cells/mm3.1,2 Asymptomatic patients with CD4 cell counts of 201 to 350 cells/mm3 should be offered treatment.1,2 Antiretroviral therapy should be considered for asymptomatic patients with a CD4 cell count of >350 cells/mm3 and HIV RNA >100,000 copies/mL; and deferred for those with <100,000 copies/mL.1,2 References Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/Default.aspx. Revision: May 4, 2006. Hammer SM, Saag MS, Schechter M, et al. Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA panel. JAMA. 2006;296:827-843.

    5. DHHS Guidelines: When To Start 2007

    6. Potential Benefits and Risks of Early Therapy Maintain higher CD4 count and prevent potentially irreversible damage to the immune system Decreased risk for HIV-associated complications Tuberculosis, non-Hodgkins lymphoma, Kaposis sarcoma, peripheral neuropathy, HPV-associated malignancies, and HIV-associated cognitive impairment Decreased risk of nonopportunistic conditions Cardiovascular disease, renal disease, liver disease, and nonAIDS-associated malignancies and infections Decreased risk of HIV transmission Treatment-related side effects and toxicities Development of drug resistance due to incomplete viral suppression Loss of future treatment options Less time for patient adjustment to disease and treatment requirements Increased total time on medication Premature use of therapy before potentially better/safer future options are available Transmission of drug-resistant virus in patients who do not maintain full virologic suppression Slide: Potential Benefits and Risks of Early Therapy The potential benefits of early initiation of antiretroviral therapy are to:1 Maintain higher CD4 count and prevent potentially irreversible damage to the immune system. Decrease the risk for HIV-associated complications (ie, tuberculosis, non-Hodgkins lymphoma, Kaposis sarcoma, peripheral neuropathy, HPV-associated malignancies, and HIV-associated cognitive impairment). Decrease the risk of nonopportunistic conditions such as cardiovascular disease, renal disease, liver disease, and nonAIDS-associated malignancies and infections. Decrease the risk of HIV transmission. The potential benefits need to be weighed against the potential risks, which include:1 Treatment-related side effects and toxicities. Development of drug resistance due to incomplete viral suppression (ie, loss of future treatment options). Less time for patient adjustment to disease and treatment requirements. Increased total time on medication. Premature use of therapy before potentially better/safer future options are available. Transmission of drug-resistant virus in patients who do not maintain full virologic suppression. Reference DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/Default.aspx. Revision: December 1, 2007.Slide: Potential Benefits and Risks of Early Therapy The potential benefits of early initiation of antiretroviral therapy are to:1 Maintain higher CD4 count and prevent potentially irreversible damage to the immune system. Decrease the risk for HIV-associated complications (ie, tuberculosis, non-Hodgkins lymphoma, Kaposis sarcoma, peripheral neuropathy, HPV-associated malignancies, and HIV-associated cognitive impairment). Decrease the risk of nonopportunistic conditions such as cardiovascular disease, renal disease, liver disease, and nonAIDS-associated malignancies and infections. Decrease the risk of HIV transmission. The potential benefits need to be weighed against the potential risks, which include:1 Treatment-related side effects and toxicities. Development of drug resistance due to incomplete viral suppression (ie, loss of future treatment options). Less time for patient adjustment to disease and treatment requirements. Increased total time on medication. Premature use of therapy before potentially better/safer future options are available. Transmission of drug-resistant virus in patients who do not maintain full virologic suppression. Reference DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/Default.aspx. Revision: December 1, 2007.

    7. Risk of Progression After 3 Years1 by Pretreatment CD4+ Count/HIV RNA The DHHS committee relied on this study to formulate the cut-off criteria shown in the previous slide. Data were taken from a large subset of patients <50 years old without a history of an AIDS-defining illness or injection-drug use. Based on an observational cohort, they provide strong support for the recommendation that therapy be initiated before the CD4+ T-cell count drops to <200 cells/mm3. Conversely, differences in risk for CD4+ T-cell counts between 200 and 350 and >350 cells/mm3 are based on too few events and too short a follow-up period to make reliable statements about when to initiate treatment. Consequently, the DHHS Committee did not know if there were a difference in risk between patients with 200 to 349 T-cells and >350 T-cells. This is an important point important to emphasize, especially because the data are presented subsequently. References Egger M et al. Lancet. 2002;360:119-29; DHHS Guidelines; Revision October 10, 2006. Available at: http://aidsinfo.nih.gov. Accessed December 13, 2006.The DHHS committee relied on this study to formulate the cut-off criteria shown in the previous slide. Data were taken from a large subset of patients <50 years old without a history of an AIDS-defining illness or injection-drug use. Based on an observational cohort, they provide strong support for the recommendation that therapy be initiated before the CD4+ T-cell count drops to <200 cells/mm3. Conversely, differences in risk for CD4+ T-cell counts between 200 and 350 and >350 cells/mm3 are based on too few events and too short a follow-up period to make reliable statements about when to initiate treatment. Consequently, the DHHS Committee did not know if there were a difference in risk between patients with 200 to 349 T-cells and >350 T-cells. This is an important point important to emphasize, especially because the data are presented subsequently. References Egger M et al. Lancet. 2002;360:119-29; DHHS Guidelines; Revision October 10, 2006. Available at: http://aidsinfo.nih.gov. Accessed December 13, 2006.

    8. Prognosis From Starting HAART Slide: Prognosis From Starting HAART The Antiretroviral Therapy Collaborative Group assessed the time to an AIDS defining event or death in a series of cohorts comprising 12,574 patients from 13 centers worldwide.1 They found that there was a continuum of risk according to the CD4 cell counts at the time of initiating HAART.1 They also found a significant differentiation of risk among patients who initiated HAART with a viral load of 100,000 copies/mL or higher compared with a viral load below 100,000 copies/mL.1 Reference Egger M, May M, Chene G, et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet. 2002;360:119-129. Slide: Prognosis From Starting HAART The Antiretroviral Therapy Collaborative Group assessed the time to an AIDS defining event or death in a series of cohorts comprising 12,574 patients from 13 centers worldwide.1 They found that there was a continuum of risk according to the CD4 cell counts at the time of initiating HAART.1 They also found a significant differentiation of risk among patients who initiated HAART with a viral load of 100,000 copies/mL or higher compared with a viral load below 100,000 copies/mL.1 Reference Egger M, May M, Chene G, et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet. 2002;360:119-129.

    9. Timing of Initiation of HAART HIV Outpatient Study (HOPS) cohort >7800 pts prospectively followed 8-year follow-up Lower CD4 at HAART initiation related to: Increased drug toxicity Risk of mortality and OIs Also in this same study is another reason for deferring therapy, ie, patients with higher T-cells are not necessarily at risk for mortality or OIs as a result of their HIV infection. The bar graph shows a trend toward patients who started with lower T-cells having higher mortality and opportunistic infections; it does not appear that this trend plateaus at any point. When you compare patients with 200 to 349 T-cells to those with 350 to 499 or =500 cells, you can see that the risk of mortality and opportunistic infection is decreased with the higher T-cell patients. Although the differences are not significant, they form a continuum of increased risk of mortality and opportunistic infections within T-cell ranges. Although arbitrary cut-off points are applied, there is no particular cut-off point where patients are without risk. They can remain at increased risk even in higher T-cell levels. [Although it is not directly on point with this issue, you might consider the SMART data just presented at the World AIDS Conference, which also might have some relevance on this topic.] Reference Lichtenstein K et al. 13th Annual Conference on Retroviruses and Opportunistic Infections; 2006. Abstract #769. Also in this same study is another reason for deferring therapy, ie, patients with higher T-cells are not necessarily at risk for mortality or OIs as a result of their HIV infection. The bar graph shows a trend toward patients who started with lower T-cells having higher mortality and opportunistic infections; it does not appear that this trend plateaus at any point. When you compare patients with 200 to 349 T-cells to those with 350 to 499 or =500 cells, you can see that the risk of mortality and opportunistic infection is decreased with the higher T-cell patients. Although the differences are not significant, they form a continuum of increased risk of mortality and opportunistic infections within T-cell ranges. Although arbitrary cut-off points are applied, there is no particular cut-off point where patients are without risk. They can remain at increased risk even in higher T-cell levels. [Although it is not directly on point with this issue, you might consider the SMART data just presented at the World AIDS Conference, which also might have some relevance on this topic.] Reference Lichtenstein K et al. 13th Annual Conference on Retroviruses and Opportunistic Infections; 2006. Abstract #769.

    10. ART Cohort Collaboration: Optimum CD4 Threshold for Starting HAART Slide: ART Cohort Collaboration: Optimum CD4 Threshold for Starting HAART Is the when to start pendulum swinging back towards earlier treatment? In the largest megacohort of 12 large HIV cohorts that is likely ever to be assembled, Sterne and colleagues assessed the likelihood of HIV disease progression among 10,855 people (AIDS- free, treatment- nave) who began treatment with HAART after 1996.1 Baseline CD4 strata (cells/mm3) distribution of patients: <200: 40%. 201-350: 37%. 351-500: 23%. Median follow-up: 2.7 years. The overall rate for the progression to AIDS or death was 8.6%. A total of 934 cases of progression to AIDS or death were recorded over the 5-year observation period.1 Those who started HAART with CD4 cell counts <200 cells/mm3 had a 3.68 times higher risk of AIDS and a 2.93 times higher risk of AIDS and death compared with those starting HAART with CD4 cell counts 201 to 350 cells/mm3. Baseline CD4 cell count strata associated with significantly lower risk of progression 201-350 versus <200 cells/mm3. <350 versus 351-500 cells/mm3. Patients who began HAART with a CD4 cell count of 200 to 350 cells/mm3 had a greater risk of progression to AIDS than those starting with a cell count >350 cells/mm3.1 Reference Sterne J, May M, Costagliola D, et al. Estimating the optimum CD4 threshold for starting HAART in antiretroviral-nave HIV-infected individuals. Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections. February 5-8, 2006. Denver, CO. Abstract 525.Slide: ART Cohort Collaboration: Optimum CD4 Threshold for Starting HAART Is the when to start pendulum swinging back towards earlier treatment? In the largest megacohort of 12 large HIV cohorts that is likely ever to be assembled, Sterne and colleagues assessed the likelihood of HIV disease progression among 10,855 people (AIDS- free, treatment- nave) who began treatment with HAART after 1996.1 Baseline CD4 strata (cells/mm3) distribution of patients: <200: 40%. 201-350: 37%. 351-500: 23%. Median follow-up: 2.7 years. The overall rate for the progression to AIDS or death was 8.6%. A total of 934 cases of progression to AIDS or death were recorded over the 5-year observation period.1 Those who started HAART with CD4 cell counts <200 cells/mm3 had a 3.68 times higher risk of AIDS and a 2.93 times higher risk of AIDS and death compared with those starting HAART with CD4 cell counts 201 to 350 cells/mm3. Baseline CD4 cell count strata associated with significantly lower risk of progression 201-350 versus <200 cells/mm3. <350 versus 351-500 cells/mm3. Patients who began HAART with a CD4 cell count of 200 to 350 cells/mm3 had a greater risk of progression to AIDS than those starting with a cell count >350 cells/mm3.1 Reference Sterne J, May M, Costagliola D, et al. Estimating the optimum CD4 threshold for starting HAART in antiretroviral-nave HIV-infected individuals. Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections. February 5-8, 2006. Denver, CO. Abstract 525.

    11. ART Cohort Collaboration: Optimum CD4 Threshold for Starting HAART Previously treatment-nave patients (n=20,379) 12 HIV cohorts in North America and Europe Baseline CD4 strata (cells/mm3) <200: 44% 200-350: 27% >350: 28% Follow-up: 61,798 person-years Death (n=1005) AIDS (n=1303) Baseline CD4 cell count strata was associated with a significantly lower risk of progression Slide: ART Cohort Collaboration: Optimum CD4 Threshold for Starting HAART May and colleagues assessed the likelihood of HIV disease progression among 20,379 people (AIDS-free, treatment-nave) who began treatment with HAART after 1996.1 Baseline CD4 strata (cells/mm3) distribution of patients: <200: 40%. 201-350: 27%. >350: 28%. Median follow-up: 61,798 person-years. A total of 1005 and 1303 cases of death and progression to AIDS, respectively, were recorded.1 The most strongly prognostic factor for 5-year disease progression from the start of HAART was baseline CD4 cell count. Reference May M, Sterne JA, Sabin C, et al. Prognosis of HIV-1-infected patients up to 5 years after initiation of HAART: collaborative analysis of prospective studies. AIDS. 2007;21:1185-1197.Slide: ART Cohort Collaboration: Optimum CD4 Threshold for Starting HAART May and colleagues assessed the likelihood of HIV disease progression among 20,379 people (AIDS-free, treatment-nave) who began treatment with HAART after 1996.1 Baseline CD4 strata (cells/mm3) distribution of patients: <200: 40%. 201-350: 27%. >350: 28%. Median follow-up: 61,798 person-years. A total of 1005 and 1303 cases of death and progression to AIDS, respectively, were recorded.1 The most strongly prognostic factor for 5-year disease progression from the start of HAART was baseline CD4 cell count. Reference May M, Sterne JA, Sabin C, et al. Prognosis of HIV-1-infected patients up to 5 years after initiation of HAART: collaborative analysis of prospective studies. AIDS. 2007;21:1185-1197.

    12. ART Cohort Collaboration: Prognosis for Starting HAART Slide: ART Cohort Collaboration: Prognosis for Starting HAART These data further illustrate the impact of baseline CD4 as a predictor of 5-year disease progression from the start of HAART.1 Reference May M, Sterne JA, Sabin C, et al. Prognosis of HIV-1-infected patients up to 5 years after initiation of HAART: collaborative analysis of prospective studies. AIDS. 2007;21:1185-1197. Slide: ART Cohort Collaboration: Prognosis for Starting HAART These data further illustrate the impact of baseline CD4 as a predictor of 5-year disease progression from the start of HAART.1 Reference May M, Sterne JA, Sabin C, et al. Prognosis of HIV-1-infected patients up to 5 years after initiation of HAART: collaborative analysis of prospective studies. AIDS. 2007;21:1185-1197.

    13. Impact of Age on Risk of HIV Progression One piece of information required when deciding to initiate antiretroviral therapy is the risk of AIDS before the next clinic visit. This slide, drawn from a study cited in the DHHS guidelines, looks at the risk of progression to AIDS across age groups. Data were taken from the CASCADE Collaboration, a combination of 20 cohorts based in clinics in Europe and Australia. In this study, risk of AIDS was assessed in 3226 patients with viral loads and CD4-cell counts that were known before initiation of antiretroviral therapy or during the zidovudine monotherapy era. During 5126.0 person-years of follow-up, 219 individuals developed AIDS. In those with current CD4-cell counts <200 x 10 cells/L, 6-month risks were 4.9%, 12.7%, 17.7%, and 22.4% for viral load groups <10 000, 10 000 to 29 999, 30 000 to 99 999 and =100 000 copies/mL, respectively. For CD4-cell counts 200 to 349 x 10 cells/L, risks were 0.5%, 1.6%, 3.2%, and 4.7%, respectively, for the 4 viral-load groups. The corresponding values for groups with CD4-cell count =350 x 10 cells/L were 0.2%, 0.5%, 0.9%, and 2.2%, respectively. Results were similar in an analysis of those with no antiretroviral drug experience. Older people had a higher risk of AIDS for a given CD4-cell count and viral load than younger people. Note that regardless of CD4 count, an older age conferred an increased risk of disease progression over the ensuing 6 months. This might be a point to raise regarding when to start therapy. Perhaps older patients could benefit from earlier therapy given their increased risk of progression. Reference Phillips A et al. AIDS. 2004;18:51-58.One piece of information required when deciding to initiate antiretroviral therapy is the risk of AIDS before the next clinic visit. This slide, drawn from a study cited in the DHHS guidelines, looks at the risk of progression to AIDS across age groups. Data were taken from the CASCADE Collaboration, a combination of 20 cohorts based in clinics in Europe and Australia. In this study, risk of AIDS was assessed in 3226 patients with viral loads and CD4-cell counts that were known before initiation of antiretroviral therapy or during the zidovudine monotherapy era. During 5126.0 person-years of follow-up, 219 individuals developed AIDS. In those with current CD4-cell counts <200 x 10 cells/L, 6-month risks were 4.9%, 12.7%, 17.7%, and 22.4% for viral load groups <10 000, 10 000 to 29 999, 30 000 to 99 999 and =100 000 copies/mL, respectively. For CD4-cell counts 200 to 349 x 10 cells/L, risks were 0.5%, 1.6%, 3.2%, and 4.7%, respectively, for the 4 viral-load groups. The corresponding values for groups with CD4-cell count =350 x 10 cells/L were 0.2%, 0.5%, 0.9%, and 2.2%, respectively. Results were similar in an analysis of those with no antiretroviral drug experience. Older people had a higher risk of AIDS for a given CD4-cell count and viral load than younger people. Note that regardless of CD4 count, an older age conferred an increased risk of disease progression over the ensuing 6 months. This might be a point to raise regarding when to start therapy. Perhaps older patients could benefit from earlier therapy given their increased risk of progression. Reference Phillips A et al. AIDS. 2004;18:51-58.

    14. SMART Study: Benefits of Early Treatment of HIV Disease Open-label study CD4-guided intermittent therapy (deferred therapy) Stop: CD4 >350 cells/mm3 Resume: CD4 <250 cells/mm3 Continuous therapy (immediate therapy) There was a 5.7% reduction in absolute risk of opportunistic disease and serious non-AIDS events (CVD, hepatic and renal diseases, non-AIDS cancers and death) with immediate versus deferred antiretroviral therapy Slide: SMART Study: Benefits of Early Treatment of HIV Disease Emery and colleagues presented data on 477 patients who were not on antiretroviral therapy upon entry into the SMART study; of whom 228 initiated treatment and 249 deferred therapy until their CD4 cell count fell below 250 cells/mm3.1 The SMART investigators found a 3 to 5 times greater incidence of HIV-related disease progression or death in the deferred treatment group compared with the viral suppression group, as expected. However, what was unexpected was a 5 to 8 times greater risk of non-HIV-related serious events such as cardiovascular events, liver failure, and renal failure in the deferred group compared with the viral suppression group (ie, immediate antiretroviral therapy), and a 5.7% difference in absolute risk of opportunistic disease and serious non-HIV events.1 There was a renewed call from many investigators for a large prospective trial on when to start therapy.1 Reference Emery S, SMART Study Group. Major clinical outcomes in patients not treated with antiretroviral therapy at baseline in SMART; a rationale for a trial to examine early treatment of HIV disease. In: Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WePeB018. Slide: SMART Study: Benefits of Early Treatment of HIV Disease Emery and colleagues presented data on 477 patients who were not on antiretroviral therapy upon entry into the SMART study; of whom 228 initiated treatment and 249 deferred therapy until their CD4 cell count fell below 250 cells/mm3.1 The SMART investigators found a 3 to 5 times greater incidence of HIV-related disease progression or death in the deferred treatment group compared with the viral suppression group, as expected. However, what was unexpected was a 5 to 8 times greater risk of non-HIV-related serious events such as cardiovascular events, liver failure, and renal failure in the deferred group compared with the viral suppression group (ie, immediate antiretroviral therapy), and a 5.7% difference in absolute risk of opportunistic disease and serious non-HIV events.1 There was a renewed call from many investigators for a large prospective trial on when to start therapy.1 Reference Emery S, SMART Study Group. Major clinical outcomes in patients not treated with antiretroviral therapy at baseline in SMART; a rationale for a trial to examine early treatment of HIV disease. In: Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WePeB018.

    15. HOPS Cohort: Early Initiation of HAART Decreases Risk of Toxicities Prospective, dynamic cohort (>8000 patients) 8-year follow-up Incidence of nucleoside analogue-associated toxicities was significantly reduced when HAART was initiated at progressively higher CD4 cell counts These data suggest that a delay in initiating HAART increases the risk of toxicities Slide: HOPS Cohort: Early Initiation of HAART Decreases Risk of Toxicities The HOPS cohort is a prospective, dynamic cohort with >8000 patients and 8 years of follow-up. Lichtenstein and colleagues analyzed 1969 patients for 3 outcomes (peripheral neuropathy, anemia, and renal insufficiency) based on baseline pre-HAART CD4 cell count (0-49, 50-199, 200-349, 350-499, and >500 cells/mm3).1 The incidence of nucleoside analogue-associated toxicities was significantly reduced when HAART was initiated at progressively higher CD cell counts and was lowest when starting at or above 350 CD4 cells/mm3. The incidence of nucleoside analogue-associated toxicities was low and usually occurred within 6 to 12 months of initiating therapy.1 These data suggest that a delay in initiating HAART increases the risk of toxicities.1 Reference Lichtenstein KA, Armon C, Buchacz K, et al. Initiation of antiretroviral therapy at CD4 cell counts >/=350 cells/mm3 does not increase incidence or risk of peripheral neuropathy, anemia, or renal insufficiency. J Acquir Immune Defic Syndr. 2007;Oct 25; [Epub ahead of print]. Slide: HOPS Cohort: Early Initiation of HAART Decreases Risk of Toxicities The HOPS cohort is a prospective, dynamic cohort with >8000 patients and 8 years of follow-up. Lichtenstein and colleagues analyzed 1969 patients for 3 outcomes (peripheral neuropathy, anemia, and renal insufficiency) based on baseline pre-HAART CD4 cell count (0-49, 50-199, 200-349, 350-499, and >500 cells/mm3).1 The incidence of nucleoside analogue-associated toxicities was significantly reduced when HAART was initiated at progressively higher CD cell counts and was lowest when starting at or above 350 CD4 cells/mm3. The incidence of nucleoside analogue-associated toxicities was low and usually occurred within 6 to 12 months of initiating therapy.1 These data suggest that a delay in initiating HAART increases the risk of toxicities.1 Reference Lichtenstein KA, Armon C, Buchacz K, et al. Initiation of antiretroviral therapy at CD4 cell counts >/=350 cells/mm3 does not increase incidence or risk of peripheral neuropathy, anemia, or renal insufficiency. J Acquir Immune Defic Syndr. 2007;Oct 25; [Epub ahead of print].

    16. When to Start: Conclusion Data clearly support starting before CD4 <200 cells/mm3 DHHS guidelines now recommend starting patients at <350 cells/mm3 DHHS guidelines recommend treatment for: pregnancy, HIV-associated nephropathy, Hepatitis B, regardless of CD4 count Patients with high viral loads (eg, >100,000 c/mL) may benefit from therapy regardless of CD4 count Less toxic regimens may justify earlier initiation in some patients Starting at higher CD4 counts may further decrease risk of morbidity, mortality, and HAART toxicity Increasing viral load associated with an increased risk of transmission; earlier therapy may decrease transmission DHHS and IAS-USA guidelines recommend starting between 200 and 350 cells/mm3 in an asymptomatic patient. Simpler, less toxic regimens might justify earlier initiation in some patients; as we get to 1 pill once a day with limited toxicity regimens and forgiving pharmacokinetics, certainly it becomes more appealing to start patients earlier on therapy. Increased viral load is associated with increased risk of transmission, and earlier therapy might decrease transmission. This is especially important in the developed world, notably with serodiscordant couples. It is now also important in the developing world, where there is an effort to decrease the risk of transmission, as well. [Also note and perhaps mention other reasons to consider earlier therapy: (1) maintain R5-tropism, (2) possibly prevent some of less CD4-dependent conditions (PML, cognitive dysfunction, NHL, neuropathy, HPV, HCV progression, etc); (3) earlier therapy associated with better virologic response (HOPS) and better immunologic response (Hopkins, ATHENA).] DHHS and IAS-USA guidelines recommend starting between 200 and 350 cells/mm3 in an asymptomatic patient. Simpler, less toxic regimens might justify earlier initiation in some patients; as we get to 1 pill once a day with limited toxicity regimens and forgiving pharmacokinetics, certainly it becomes more appealing to start patients earlier on therapy. Increased viral load is associated with increased risk of transmission, and earlier therapy might decrease transmission. This is especially important in the developed world, notably with serodiscordant couples. It is now also important in the developing world, where there is an effort to decrease the risk of transmission, as well. [Also note and perhaps mention other reasons to consider earlier therapy: (1) maintain R5-tropism, (2) possibly prevent some of less CD4-dependent conditions (PML, cognitive dysfunction, NHL, neuropathy, HPV, HCV progression, etc); (3) earlier therapy associated with better virologic response (HOPS) and better immunologic response (Hopkins, ATHENA).]

    17. What to Start

    18. DHHS Guidelines Recommendations for Treatment Nave Patients

    19. Updated Regimen Recommendations for Treatment-Nave Patients: DHHS 2008 Slide #11: Updated Regimen Recommendations for Treatment-Nave Patients: DHHS 2008 On January 29, 2008, the Panel on Antiretroviral Guidelines for Adult and Adolescents, sponsored by the Department of Health and Human Services, updated its recommendations for the use of antiretroviral agents in treatment-nave HIV-infected patients.1 This approach now uses a simplified selection of either a PI or NNRTI from column A, combining it with a 2-NRTI combination from column B. Preferred agents include:1 PI: lopinavir/ritonavir bid, fosamprenavir + ritonavir bid, and atazanavir + ritonavir. NNRTI: efavirenz. 2-NRTI combinations: tenofovir DF/emtricitabine or abacavir/lamivudine (for patients who test negative for HLAB*5701). Reference Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 29, 2008; 1-128. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.Slide #11: Updated Regimen Recommendations for Treatment-Nave Patients: DHHS 2008 On January 29, 2008, the Panel on Antiretroviral Guidelines for Adult and Adolescents, sponsored by the Department of Health and Human Services, updated its recommendations for the use of antiretroviral agents in treatment-nave HIV-infected patients.1 This approach now uses a simplified selection of either a PI or NNRTI from column A, combining it with a 2-NRTI combination from column B. Preferred agents include:1 PI: lopinavir/ritonavir bid, fosamprenavir + ritonavir bid, and atazanavir + ritonavir. NNRTI: efavirenz. 2-NRTI combinations: tenofovir DF/emtricitabine or abacavir/lamivudine (for patients who test negative for HLAB*5701). Reference Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 29, 2008; 1-128. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.

    20. The Pros and Cons of Initial NRTI Options Slide: Which NRTI to Use With Emtricitabine or Lamivudine? The DHHS guidelines recommends the use of zidovudine or tenofovir DF + lamivudine or emtricitabine as the 2 NRTI backbone of choice as part of some combination regimen for initial treatment of HIV infection. The advantages and disadvantages of zidovudine, abacavir, tenofovir DF, and didanosine as potential options for combination with either emtricitabine or lamivudine are listed on this slide. Slide: Which NRTI to Use With Emtricitabine or Lamivudine? The DHHS guidelines recommends the use of zidovudine or tenofovir DF + lamivudine or emtricitabine as the 2 NRTI backbone of choice as part of some combination regimen for initial treatment of HIV infection. The advantages and disadvantages of zidovudine, abacavir, tenofovir DF, and didanosine as potential options for combination with either emtricitabine or lamivudine are listed on this slide.

    21. Study 934: Emtricitabine + Tenofovir DF Versus Fixed-Dose Zidovudine/Lamivudine Treatment-nave patients (n=509) Open-label, non-inferiority trial Baseline HIV RNA: 5.0 log10 copies/mL CD4: 237 cells/mm3 Regimens Emtricitabine + tenofovir DF qd Zidovudine/lamivudine bid All patients received efavirenz 600 mg qd At week 96, FTC + TDF arm Significantly greater virologic suppression and CD4 cell gain Similar proportion <50 copies/mL Significantly fewer discontinuations due to adverse events Slide: Study 934: Emtricitabine + Tenofovir DF Versus Fixed-Dose Zidovudine/Lamivudine Gallant and colleagues reported the 96-week results of the use of two NRTI backbones in treatment-nave patients in Study 934, an open-label, non-inferiority trial.1 509 patents are enrolled. Randomized regimens included the use of the following NRTIs with efavirenz 600 mg qd:1 Emtricitabine + tenofovir DF qd. Zidovudine/lamivudine bid. At 96 weeks:1 Significantly greater proportion of patients in the emtricitabine + tenofovir DF arm achieved a >1 log10 reduction in HIV RNA compared with zidovudine/lamivudine (P=0.004). The emtricitabine + tenofovir DF patients had significantly fewer virologic failures (<1% versus 5%; P=0.007) and discontinuations due to adverse events (5% versus 12%; P=0.036). compared with zidovudine/lamivudine. Reference Gallant JE, Pozniak A, DeJesus E, et al. Efficacy and safety of tenofovir DF, emtricitabine and efavirenz compared to fixed dose zidovudine/lamivudine through 96 weeks in antiretroviral treatment-nave patients. Program and abstracts of the 16th International AIDS Conference. August 13-18, 2006. Toronto, Canada. Abstract TuPE0064.Slide: Study 934: Emtricitabine + Tenofovir DF Versus Fixed-Dose Zidovudine/Lamivudine Gallant and colleagues reported the 96-week results of the use of two NRTI backbones in treatment-nave patients in Study 934, an open-label, non-inferiority trial.1 509 patents are enrolled. Randomized regimens included the use of the following NRTIs with efavirenz 600 mg qd:1 Emtricitabine + tenofovir DF qd. Zidovudine/lamivudine bid. At 96 weeks:1 Significantly greater proportion of patients in the emtricitabine + tenofovir DF arm achieved a >1 log10 reduction in HIV RNA compared with zidovudine/lamivudine (P=0.004). The emtricitabine + tenofovir DF patients had significantly fewer virologic failures (<1% versus 5%; P=0.007) and discontinuations due to adverse events (5% versus 12%; P=0.036). compared with zidovudine/lamivudine. Reference Gallant JE, Pozniak A, DeJesus E, et al. Efficacy and safety of tenofovir DF, emtricitabine and efavirenz compared to fixed dose zidovudine/lamivudine through 96 weeks in antiretroviral treatment-nave patients. Program and abstracts of the 16th International AIDS Conference. August 13-18, 2006. Toronto, Canada. Abstract TuPE0064.

    22. Study 934: Emtricitabine + Tenofovir DF Versus Fixed-Dose Zidovudine/Lamivudine Slide: Study 934: Emtricitabine + Tenofovir DF Versus Fixed-Dose Zidovudine/Lamivudine Gallant and colleagues reported that at 96 weeks, patients in the emtricitabine + tenofovir DF arm had numerically greater suppression of HIV replication (% with HIV <50 copies/mL: 67% versus 61%; P=0.16) and a significantly greater CD4 cell gain (270 versus 237 cells/mm3; P=0.036) compared with zidovudine/lamivudine.1 Reference Gallant JE, Pozniak A, DeJesus E, et al. Efficacy and safety of tenofovir DF, emtricitabine and efavirenz compared to fixed dose zidovudine/lamivudine through 96 weeks in antiretroviral treatment-nave patients. Program and abstracts of the 16th International AIDS Conference. August 13-18, 2006. Toronto, Canada. Abstract TuPE0064. Slide: Study 934: Emtricitabine + Tenofovir DF Versus Fixed-Dose Zidovudine/Lamivudine Gallant and colleagues reported that at 96 weeks, patients in the emtricitabine + tenofovir DF arm had numerically greater suppression of HIV replication (% with HIV <50 copies/mL: 67% versus 61%; P=0.16) and a significantly greater CD4 cell gain (270 versus 237 cells/mm3; P=0.036) compared with zidovudine/lamivudine.1 Reference Gallant JE, Pozniak A, DeJesus E, et al. Efficacy and safety of tenofovir DF, emtricitabine and efavirenz compared to fixed dose zidovudine/lamivudine through 96 weeks in antiretroviral treatment-nave patients. Program and abstracts of the 16th International AIDS Conference. August 13-18, 2006. Toronto, Canada. Abstract TuPE0064.

    23. Study 934: Emtricitabine + Tenofovir DF Versus Fixed-Dose Zidovudine/Lamivudine Metabolics at week 96 Total limb fat Zidovudine/lamivudine: 5.5 kg Emtricitabine + tenofovir DF: 8.1 kg (P=0.01) Change in body weight Zidovudine/lamivudine: +0.5 kg Emtricitabine + tenofovir DF: +2.7 kg (P<0.001) No discontinuations due to renal events Glomerular filtration rate (Cockcroft-Gault) at week 96 (P=0.51) Zidovudine/lamivudine: 118 mL/min (baseline 121) Emtricitabine + tenofovir DF: 119 (baseline 121) Slide: Study 934: Emtricitabine + Tenofovir DF Versus Fixed-Dose Zidovudine/Lamivudine Gallant and colleagues reported the 96-week results of the use of two NRT backbones in treatment-nave patients in Study 934, an ongoing open-label, non-inferiority trial. A metabolic substudy assessed lipids and regional body fat by DXA scanning.1 Randomized regimens included the use of the following NRTIs with efavirenz 600 mg qd:1 Emtricitabine + tenofovir DF qd. Zidovudine/lamivudine bid. At 96 weeks:1 In a subgroup of 51 patients who had data at week 48, median total limb fat at week 96 was 5.5 kg in the zidovudine/lamivudine group versus that of 8.1 kg (P=0.01) in the emtricitabine + tenofovir DF group. No discontinuations occurred due to renal events. There was not difference between the two groups with regard to glomerular filtration rate. Reference Gallant JE, Pozniak A, DeJesus E, et al. Efficacy and safety of tenofovir DF, emtricitabine and efavirenz compared to fixed dose zidovudine/lamivudine through 96 weeks in antiretroviral treatment-nave patients. Program and abstracts of the 16th International AIDS Conference. August 13-18, 2006. Toronto, Canada. Abstract TuPE0064. Slide: Study 934: Emtricitabine + Tenofovir DF Versus Fixed-Dose Zidovudine/Lamivudine Gallant and colleagues reported the 96-week results of the use of two NRT backbones in treatment-nave patients in Study 934, an ongoing open-label, non-inferiority trial. A metabolic substudy assessed lipids and regional body fat by DXA scanning.1 Randomized regimens included the use of the following NRTIs with efavirenz 600 mg qd:1 Emtricitabine + tenofovir DF qd. Zidovudine/lamivudine bid. At 96 weeks:1 In a subgroup of 51 patients who had data at week 48, median total limb fat at week 96 was 5.5 kg in the zidovudine/lamivudine group versus that of 8.1 kg (P=0.01) in the emtricitabine + tenofovir DF group. No discontinuations occurred due to renal events. There was not difference between the two groups with regard to glomerular filtration rate. Reference Gallant JE, Pozniak A, DeJesus E, et al. Efficacy and safety of tenofovir DF, emtricitabine and efavirenz compared to fixed dose zidovudine/lamivudine through 96 weeks in antiretroviral treatment-nave patients. Program and abstracts of the 16th International AIDS Conference. August 13-18, 2006. Toronto, Canada. Abstract TuPE0064.

    24. Study 903E: Impact on Metabolics After Stavudine-to-Tenofovir DF Switch Slide: Study 903E: Impact on Metabolics After Stavudine-to-Tenofovir DF Switch Zhong and colleagues presented 48-week metabolic outcomes among patients who switched from efavirenz + lamivudine + stavudine to efavirenz + lamivudine + tenofovir DF as part of the extension to study 903 (n=82).1 48-weeks after the switch from stavudine to tenofovir DF found that total limb fat increased 0.4 kg (P<0.001). In addition, bone mineral density of the spine did not change, but there was a 1.5% decrease in hip bone mineral density.1 There was a significant decrease in total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride levels (P<0.001), and decrease in high-density lipoprotein cholesterol (HDL-C) levels (P=0.048) 48 weeks following the switch. Reference Zhong L, Enejosa J, Cheng AK. Improvement in lipoatrophy and lipid abnormalities following switch from stavudine to tenofovir DF in combination with lamivudine and efavirenz in HIV-infected patients: a 48-week follow-up from study 903e. Program and abstracts of the 10th European AIDS Conference. November 17-20, 2005. Dublin, Ireland. Abstract PE9.3/5. Slide: Study 903E: Impact on Metabolics After Stavudine-to-Tenofovir DF Switch Zhong and colleagues presented 48-week metabolic outcomes among patients who switched from efavirenz + lamivudine + stavudine to efavirenz + lamivudine + tenofovir DF as part of the extension to study 903 (n=82).1 48-weeks after the switch from stavudine to tenofovir DF found that total limb fat increased 0.4 kg (P<0.001). In addition, bone mineral density of the spine did not change, but there was a 1.5% decrease in hip bone mineral density.1 There was a significant decrease in total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride levels (P<0.001), and decrease in high-density lipoprotein cholesterol (HDL-C) levels (P=0.048) 48 weeks following the switch. Reference Zhong L, Enejosa J, Cheng AK. Improvement in lipoatrophy and lipid abnormalities following switch from stavudine to tenofovir DF in combination with lamivudine and efavirenz in HIV-infected patients: a 48-week follow-up from study 903e. Program and abstracts of the 10th European AIDS Conference. November 17-20, 2005. Dublin, Ireland. Abstract PE9.3/5.

    25. Tenofovir DF Renal Safety 4-year safety data Incidence of serious renal events: 0.5% Tenofovir DF expanded access program 10,343 patients (3700 person-years) No increased risk of renal dysfunction with tenofovir DF in patients with normal renal function Risk factors for increased serum creatinine Concomitant nephrotoxic medications Higher baseline serum creatinine Lower baseline CD4 cell count and body weight Older age In patients with compromised renal function FDA advised dose reductions and close monitoring of patients Slide: Tenofovir DF Renal Safety Nelson and colleagues presented the 4-year renal safety data with tenofovir DF drawing on data from the international expanded access program for tenofovir DF (n=10,343).1 The incidence of serious renal events was 0.5%. They found no increased risk of renal dysfunction with tenofovir DF in patients with normal renal function.1 Risk factors for increased serum creatinine included use of concomitant nephrotoxic medications, a higher baseline serum creatinine, lower baseline CD4 cell count and body weight, and older age.1 These data support the FDA-advised dose reductions and monitoring procedures for patients with compromised renal function who are receiving tenofovir DF.1 Reference Nelson M, Cooper D, Schooley R, et al. The safety of tenofovir DF for the treatment of HIV infection: the first 4 years. Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections. February 5-8, 2006. Denver, CO. Abstract 781. Slide: Tenofovir DF Renal Safety Nelson and colleagues presented the 4-year renal safety data with tenofovir DF drawing on data from the international expanded access program for tenofovir DF (n=10,343).1 The incidence of serious renal events was 0.5%. They found no increased risk of renal dysfunction with tenofovir DF in patients with normal renal function.1 Risk factors for increased serum creatinine included use of concomitant nephrotoxic medications, a higher baseline serum creatinine, lower baseline CD4 cell count and body weight, and older age.1 These data support the FDA-advised dose reductions and monitoring procedures for patients with compromised renal function who are receiving tenofovir DF.1 Reference Nelson M, Cooper D, Schooley R, et al. The safety of tenofovir DF for the treatment of HIV infection: the first 4 years. Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections. February 5-8, 2006. Denver, CO. Abstract 781.

    26. CNA30024: Abacavir Versus Zidovudine in Combination With Lamivudine Randomized, double-blind, trial 649 treatment-nave patients HIV RNA 4.79 log10 copies/mL CD4: 264 cells/mm3 21% Black Efavirenz-based arms Abacavir + lamivudine (n=324) Zidovudine/lamivudine (n=325) Zidovudine/lamivudine arm Most common adverse events Nausea, vomiting, fatigue Abacavir arm Hypersensitivity reactions in 9% Conclusion Abacavir not inferior to zidovudine Slide: CNA30024: Abacavir Versus Zidovudine in Combination With Lamivudine DeJesus and colleagues evaluated the use of either zidovudine or abacavir with lamivudine and efavirenz in 649 treatment-nave patients.1 Baseline HIV RNA was 4.79 log10 copies/mL and CD4 cell count was 264 cells/mm3. At week 48:1 70% and 69% of patients in the abacavir and zidovudine groups, respectively, maintained a HIV RNA level <50 copies/mL. Patients in the abacavir group had a significantly greater increase in CD4 cell counts compared with the zidovudine group (P=0.005). The most common adverse events in the zidovudine/lamivudine arm were nausea, vomiting, and fatigue.1 Hypersensitivity reactions occurred in 9% of the abacavir treated patients.1 These data demonstrated that abacavir was not inferior to zidovudine when used a part of a n NRTI backbone in combination with lamivudine + efavirenz.1 Reference DeJesus E, Herrera G, Teofilo E, et al. Abacavir versus zidovudine combined with lamivudine and efavirenz, for the treatment of antiretroviral-naive HIV-infected adults. Clin Infect Dis. 2004;39:1038-1046. Slide: CNA30024: Abacavir Versus Zidovudine in Combination With Lamivudine DeJesus and colleagues evaluated the use of either zidovudine or abacavir with lamivudine and efavirenz in 649 treatment-nave patients.1 Baseline HIV RNA was 4.79 log10 copies/mL and CD4 cell count was 264 cells/mm3. At week 48:1 70% and 69% of patients in the abacavir and zidovudine groups, respectively, maintained a HIV RNA level <50 copies/mL. Patients in the abacavir group had a significantly greater increase in CD4 cell counts compared with the zidovudine group (P=0.005). The most common adverse events in the zidovudine/lamivudine arm were nausea, vomiting, and fatigue.1 Hypersensitivity reactions occurred in 9% of the abacavir treated patients.1 These data demonstrated that abacavir was not inferior to zidovudine when used a part of a n NRTI backbone in combination with lamivudine + efavirenz.1 Reference DeJesus E, Herrera G, Teofilo E, et al. Abacavir versus zidovudine combined with lamivudine and efavirenz, for the treatment of antiretroviral-naive HIV-infected adults. Clin Infect Dis. 2004;39:1038-1046.

    27. HEAT Study: Abacavir/Lamivudine Versus Emtricitabine/Tenofovir DF Treatment-nave patients (n=688) Double-blind, 96-week phase 4 study Once-daily regimens Abacavir/lamivudine Emtricitabine/tenofovir DF All patients: lopinavir/r qd Week 0-48: soft-gel capsules Week 48-96: tablets Non-inferiority Lower confidence interval <12% Primary efficacy endpoint HIV RNA <50 copies/mL Slide #13: HEAT Study: Abacavir/Lamivudine Versus Emtricitabine/Tenofovir DF The HEAT study is an ongoing prospective, double-blind, 96-week, phase 4 study comparing the once-daily NRTI combinations of abacavir/lamivudine and emtricitabine/tenofovir DF, both in combination with lopinavir/ritonavir qd, in 688 treatment-nave patients.1 Similar baseline characteristics between treatment arms. All patients received lopinavir/ritonavir qd soft-gel capsules for weeks 0-48; and will switch to once-daily tablets for the remainder of the study. The primary efficacy endpoint is the proportion of patients achieving HIV RNA <50 copies/mL. Non-inferiority is <12% of the lower confidence interval. Week 48 data are presented.1 Reference Smith K, Fine D, Patel P, et al. Efficacy and safety of abacavir/lamivudine compared to tenofovir/emtricitabine in combination with once-daily lopinavir/ritonavir through 48 weeks in the HEAT study. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 774.Slide #13: HEAT Study: Abacavir/Lamivudine Versus Emtricitabine/Tenofovir DF The HEAT study is an ongoing prospective, double-blind, 96-week, phase 4 study comparing the once-daily NRTI combinations of abacavir/lamivudine and emtricitabine/tenofovir DF, both in combination with lopinavir/ritonavir qd, in 688 treatment-nave patients.1 Similar baseline characteristics between treatment arms. All patients received lopinavir/ritonavir qd soft-gel capsules for weeks 0-48; and will switch to once-daily tablets for the remainder of the study. The primary efficacy endpoint is the proportion of patients achieving HIV RNA <50 copies/mL. Non-inferiority is <12% of the lower confidence interval. Week 48 data are presented.1 Reference Smith K, Fine D, Patel P, et al. Efficacy and safety of abacavir/lamivudine compared to tenofovir/emtricitabine in combination with once-daily lopinavir/ritonavir through 48 weeks in the HEAT study. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 774.

    28. HEAT Study: Virologic and Immunologic Outcomes at Week 48 Slide #14: HEAT Study: Virologic and Immunologic Outcomes at Week 48 At week 48, 68% and 67% of patients in the abacavir/lamivudine and emtricitabine/tenofovir DF arms, respectively, achieved HIV RNA <50 copies/mL (ITT, M=F); meeting the criteria for non-inferiority. The results were similar regardless of baseline HIV RNA level.1 CD4 cell gains in the two arms were statistically similar.1 Reference Smith K, Fine D, Patel P, et al. Efficacy and safety of abacavir/lamivudine compared to tenofovir/emtricitabine in combination with once-daily lopinavir/ritonavir through 48 weeks in the HEAT study. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 774. Slide #14: HEAT Study: Virologic and Immunologic Outcomes at Week 48 At week 48, 68% and 67% of patients in the abacavir/lamivudine and emtricitabine/tenofovir DF arms, respectively, achieved HIV RNA <50 copies/mL (ITT, M=F); meeting the criteria for non-inferiority. The results were similar regardless of baseline HIV RNA level.1 CD4 cell gains in the two arms were statistically similar.1 Reference Smith K, Fine D, Patel P, et al. Efficacy and safety of abacavir/lamivudine compared to tenofovir/emtricitabine in combination with once-daily lopinavir/ritonavir through 48 weeks in the HEAT study. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 774.

    29. HEAT Study: 48-Week Tolerability Results Slide #15: HEAT Study: 48-Week Tolerability Results Discontinuations due to adverse events were low and similar between the two groups.1 Diarrhea and nausea were the most frequent adverse events and 4% of patients in the abacavir/lamivudine arm had suspected abacavir hypersensitivity reaction.1 Both arms had similar and expected changes in lipid levels.1 Reference Smith K, Fine D, Patel P, et al. Efficacy and safety of abacavir/lamivudine compared to tenofovir/emtricitabine in combination with once-daily lopinavir/ritonavir through 48 weeks in the HEAT study. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 774.Slide #15: HEAT Study: 48-Week Tolerability Results Discontinuations due to adverse events were low and similar between the two groups.1 Diarrhea and nausea were the most frequent adverse events and 4% of patients in the abacavir/lamivudine arm had suspected abacavir hypersensitivity reaction.1 Both arms had similar and expected changes in lipid levels.1 Reference Smith K, Fine D, Patel P, et al. Efficacy and safety of abacavir/lamivudine compared to tenofovir/emtricitabine in combination with once-daily lopinavir/ritonavir through 48 weeks in the HEAT study. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 774.

    30. HEAT Study: Abacavir/Lamivudine Versus Emtricitabine/Tenofovir DF No new safety findings in either arm Few discontinuations due to adverse events (<6% in both arms) Similar virologic failure rates Abacavir/lamivudine versus emtricitabine/tenofovir DF Overall (HIV RNA >200 copies/mL): 12% versus 11% Leading to discontinuation: 1% each arm Virologic outcome (HIV RNA <50 copies/mL) Abacavir/lamivudine was non-inferior to emtricitabine/tenofovir DF No difference in outcome with baseline HIV RNA <100K or >100K copies/mL Slide #16: HEAT Study: Abacavir/Lamivudine Versus Emtricitabine/Tenofovir DF In summary, there were no new safety findings in either arm at week 48 and there were few discontinuations in both arms due to adverse events (<6%).1 Both treatment arms had similar virologic failure rates with 12% and 11% of patients experiencing virologic failure in the abacavir/lamivudine and emtricitabine/tenofovir DF arms, respectively. Only 1% of patients in both arms discontinued the study due to virologic failure.1 Further, abacavir/lamivudine was non-inferior to emtricitabine/tenofovir DF with regard to the proportion of patients achieving HIV RNA <50 copies/mL. There was no difference in outcome in patients with baseline HIV RNA <100K versus those with HIV RNA >100K copies/mL.1 Reference Smith K, Fine D, Patel P, et al. Efficacy and safety of abacavir/lamivudine compared to tenofovir/emtricitabine in combination with once-daily lopinavir/ritonavir through 48 weeks in the HEAT study. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 774. Slide #16: HEAT Study: Abacavir/Lamivudine Versus Emtricitabine/Tenofovir DF In summary, there were no new safety findings in either arm at week 48 and there were few discontinuations in both arms due to adverse events (<6%).1 Both treatment arms had similar virologic failure rates with 12% and 11% of patients experiencing virologic failure in the abacavir/lamivudine and emtricitabine/tenofovir DF arms, respectively. Only 1% of patients in both arms discontinued the study due to virologic failure.1 Further, abacavir/lamivudine was non-inferior to emtricitabine/tenofovir DF with regard to the proportion of patients achieving HIV RNA <50 copies/mL. There was no difference in outcome in patients with baseline HIV RNA <100K versus those with HIV RNA >100K copies/mL.1 Reference Smith K, Fine D, Patel P, et al. Efficacy and safety of abacavir/lamivudine compared to tenofovir/emtricitabine in combination with once-daily lopinavir/ritonavir through 48 weeks in the HEAT study. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 774.

    31. Pros and Cons of Initial NNRTI Options Slide: Pros and Cons of Initial NNRTI Options This slide lists the advantages and disadvantages of using either efavirenz or nevirapine as part of a combination regimen for initial antiretroviral therapy. Slide: Pros and Cons of Initial NNRTI Options This slide lists the advantages and disadvantages of using either efavirenz or nevirapine as part of a combination regimen for initial antiretroviral therapy.

    32. Efficacy of Efavirenz-Based Regimens in Treatment-Nave Patients Study 0061,2 Efficacy: efavirenz > unboosted indinavir-based regimen ACTG 3843 Efficacy: efavirenz > unboosted nelfinavir-based regimen NRTI combination of zidovudine/lamivudine provided best response 2NN Study4 Similar efficacy among NNRTI regimens, fewer toxicities with efavirenz Study 9035 Similar efficacy: efavirenz + lamivudine + (tenofovir DF or stavudine) Study 9346 Better efficacy and safety of efavirenz when used with emtricitabine + tenofovir DF versus zidovudine/lamivudine Slide: Efficacy of Efavirenz-Based Regimens in Treatment-Nave Patients Five key studies define the potent and durable efficacy associated with efavirenz-based regimens in treatment-nave patients. Study 006, an open-label study with data from up to 144 weeks of follow-up.1,2 The 160-week ACTG 384 study.3 The 2NN study which compared 2 NNRTI-based regimens.4 The 144-week results from study 903.5 The 48-week results from study 934.6 References Staszewski S, Morales-Ramirez J, Tashima KT, et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N Engl J Med. 1999;341:1865-1873. Tashima K, Staszewski S, Morales-Ramirez J, et al. 3-year durability of response with an efavirenz-containing regimen: 144 week follow-up of study 006. Program and abstracts of the 1st International AIDS Society Conference on HIV Pathogenesis and Treatment. July 2001. Buenos Aires, Argentina. Abstract 224. Robbins GK, De Gruttola V, Shafer RW, et al. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med. 2003;349:2293-2303. van Leth F, Hassink E, Phanuphak P, et al. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet. 2004;363:1253-1263. Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA. 2004;292:191-201. Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med. 2006;354:251-260. Slide: Efficacy of Efavirenz-Based Regimens in Treatment-Nave Patients Five key studies define the potent and durable efficacy associated with efavirenz-based regimens in treatment-nave patients. Study 006, an open-label study with data from up to 144 weeks of follow-up.1,2 The 160-week ACTG 384 study.3 The 2NN study which compared 2 NNRTI-based regimens.4 The 144-week results from study 903.5 The 48-week results from study 934.6 References Staszewski S, Morales-Ramirez J, Tashima KT, et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N Engl J Med. 1999;341:1865-1873. Tashima K, Staszewski S, Morales-Ramirez J, et al. 3-year durability of response with an efavirenz-containing regimen: 144 week follow-up of study 006. Program and abstracts of the 1st International AIDS Society Conference on HIV Pathogenesis and Treatment. July 2001. Buenos Aires, Argentina. Abstract 224. Robbins GK, De Gruttola V, Shafer RW, et al. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med. 2003;349:2293-2303. van Leth F, Hassink E, Phanuphak P, et al. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet. 2004;363:1253-1263. Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA. 2004;292:191-201. Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med. 2006;354:251-260.

    33. Pros and Cons of Initial Boosted-PI Options Slide: Pros and Cons of Initial Boosted-PI Options The advantages and disadvantages of the various boosted PI options as initial therapy are listed on this slide. Slide: Pros and Cons of Initial Boosted-PI Options The advantages and disadvantages of the various boosted PI options as initial therapy are listed on this slide.

    34. Efficacy of Lopinavir/Ritonavir-Based Regimens in Treatment-Nave Patients Study 8631,2 Lopinavir/ritonavir-based regimen demonstrated superior efficacy and durability of response compared with nelfinavir-based regimen Study 7203 Lopinavir/ritonavir-based regimen demonstrated potent and durable antiretroviral activity and CD4 responses through 7 years Study 4184 Similar efficacy between once-daily and twice-daily lopinavir/ritonavir-based regimens Slide: Efficacy of Lopinavir/Ritonavir-Based Regimen in Treatment-Nave Patients Two key studies define the potent and durable efficacy associated with lopinavir/ritonavir-based regimens in treatment-nave patients.1-3 Study 863 is a 48-week double-blind comparison with follow-up data at 60 weeks.1,2 Study 720 is an open-label study showing efficacy for up to 7 years.3 Study 418 showed similar efficacy between once-daily and twice-daily lopinavir/ritonavir-based regimens.4 References Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med. 2002;346:2039-2046. Ruane R, Cimoch PJ, Mathews C, et al. Kaletra vs. nelfinavir in antiretroviral-nave subjects: week 60 comparison in a phase III, blinded, randomized clinical trial. Program and abstracts of the 1st International AIDS Society Conference on HIV Pathogenesis and Treatment. July 2001. Buenos Aires, Argentina. Abstract 6. Murphy R, da Silva B, McMillan F, et al. Seven year follow-up of a lopinavir/ritonavir-based regimen in antiretroviral-nave subjects. Program and abstracts of the 10th European AIDS Conference. November 17-20, 2005. Dublin, Ireland. Abstract PE7.9/3. Molina JM, Wilkin A, Domingo P, et al. Once-daily vs. twice-daily lopinavir/ritonavir in antiretroviral-nave patients: 96-week results. Program and abstracts of the 3rd International AIDS Conference on HIV Pathogenesis and Treatment. July 24-27, 2005. Rio de Janeiro, Brazil. Abstract WePe12.3C12. Slide: Efficacy of Lopinavir/Ritonavir-Based Regimen in Treatment-Nave Patients Two key studies define the potent and durable efficacy associated with lopinavir/ritonavir-based regimens in treatment-nave patients.1-3 Study 863 is a 48-week double-blind comparison with follow-up data at 60 weeks.1,2 Study 720 is an open-label study showing efficacy for up to 7 years.3 Study 418 showed similar efficacy between once-daily and twice-daily lopinavir/ritonavir-based regimens.4 References Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med. 2002;346:2039-2046. Ruane R, Cimoch PJ, Mathews C, et al. Kaletra vs. nelfinavir in antiretroviral-nave subjects: week 60 comparison in a phase III, blinded, randomized clinical trial. Program and abstracts of the 1st International AIDS Society Conference on HIV Pathogenesis and Treatment. July 2001. Buenos Aires, Argentina. Abstract 6. Murphy R, da Silva B, McMillan F, et al. Seven year follow-up of a lopinavir/ritonavir-based regimen in antiretroviral-nave subjects. Program and abstracts of the 10th European AIDS Conference. November 17-20, 2005. Dublin, Ireland. Abstract PE7.9/3. Molina JM, Wilkin A, Domingo P, et al. Once-daily vs. twice-daily lopinavir/ritonavir in antiretroviral-nave patients: 96-week results. Program and abstracts of the 3rd International AIDS Conference on HIV Pathogenesis and Treatment. July 24-27, 2005. Rio de Janeiro, Brazil. Abstract WePe12.3C12.

    35. CASTLE Study: Atazanavir + Ritonavir Versus Lopinavir/Ritonavir + FTC/TDF Treatment-nave patients (n=883) Open-label, 96-week study Once-daily regimens Atazanavir + RTV 300 + 100 mg qd Lopinavir/r 400/100 mg bid (soft-gel capsules) All patients received emtricitabine/tenofovir DF Non-inferiority Lower confidence interval <10% Primary efficacy endpoint HIV RNA <50 copies/mL at week 48 Slide #21: CASTLE Study: Atazanavir + Ritonavir Versus Lopinavir/Ritonavir + FTC/TDF Molina and colleagues presented the 48-week results from the ongoing 96-week CASTLE study, a randomized, open-label non-inferiority comparison of atazanavir + ritonavir (300/100 mg qd) with lopinavir/ritonavir (400/100 mg bid, soft-gel capsules) in 883 treatment-nave patients. All patients received emtricitabine/tenofovir DF.1 Baseline HIV RNA 5 log10 copies/mL and CD4 205 cells/mm3. The primary efficacy point is the proportion of patients achieving HIV RNA <50 copies/mL. Non-inferiority is <10% of the lower confidence interval. Week 48 data are presented.1 Reference Molina JM, Andrade-Villanueva J, Echevarria J, et al. Efficacy and safety of once-daily atazanavir/ritonavir compared to twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine in ARV-naive HIV-1-infected subjects: the CASTLE study, 48-week results. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 37.Slide #21: CASTLE Study: Atazanavir + Ritonavir Versus Lopinavir/Ritonavir + FTC/TDF Molina and colleagues presented the 48-week results from the ongoing 96-week CASTLE study, a randomized, open-label non-inferiority comparison of atazanavir + ritonavir (300/100 mg qd) with lopinavir/ritonavir (400/100 mg bid, soft-gel capsules) in 883 treatment-nave patients. All patients received emtricitabine/tenofovir DF.1 Baseline HIV RNA 5 log10 copies/mL and CD4 205 cells/mm3. The primary efficacy point is the proportion of patients achieving HIV RNA <50 copies/mL. Non-inferiority is <10% of the lower confidence interval. Week 48 data are presented.1 Reference Molina JM, Andrade-Villanueva J, Echevarria J, et al. Efficacy and safety of once-daily atazanavir/ritonavir compared to twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine in ARV-naive HIV-1-infected subjects: the CASTLE study, 48-week results. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 37.

    36. CASTLE Study: Virologic and Immunologic Outcomes at Week 48 Slide #22: CASTLE Study: Virologic and Immunologic Outcomes at Week 48 At week 48, HIV RNA <50 copies/mL was achieved by 78% and 76% of patients in the boosted atazanavir and lopinavir/ritonavir arms, respectively, meeting the criteria for non-inferiority.1 The results were similar regardless of baseline HIV RNA level. CD4 cell gains in the two arms were statistically similar.1 Reference Molina JM, Andrade-Villanueva J, Echevarria J, et al. Efficacy and safety of once-daily atazanavir/ritonavir compared to twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine in ARV-naive HIV-1-infected subjects: the CASTLE study, 48-week results. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 37.Slide #22: CASTLE Study: Virologic and Immunologic Outcomes at Week 48 At week 48, HIV RNA <50 copies/mL was achieved by 78% and 76% of patients in the boosted atazanavir and lopinavir/ritonavir arms, respectively, meeting the criteria for non-inferiority.1 The results were similar regardless of baseline HIV RNA level. CD4 cell gains in the two arms were statistically similar.1 Reference Molina JM, Andrade-Villanueva J, Echevarria J, et al. Efficacy and safety of once-daily atazanavir/ritonavir compared to twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine in ARV-naive HIV-1-infected subjects: the CASTLE study, 48-week results. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 37.

    37. CASTLE Study 48-Week Tolerability Results Slide #23: CASTLE Study: 48-Week Tolerability Results Both treatment arms were well tolerated with few discontinuations due to adverse events (2% and 3%).1 Jaundice (4% versus 0%) and hyperbilirubinemia (34% versus <1%) were more common in the boosted atazanavir arm. Nausea (8% versus 4%) and diarrhea (11% versus 2%) occurred with greater frequency in the lopinavir/ritonavir arm. Lipid changes favored patients in the atazanavir + ritonavir arm. Fewer patients in the boosted atazanavir arm required lipid-lowering therapy than in the lopinavir/ritonavir arm (2% versus 7%).1 Reference Molina JM, Andrade-Villanueva J, Echevarria J, et al. Efficacy and safety of once-daily atazanavir/ritonavir compared to twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine in ARV-naive HIV-1-infected subjects: the CASTLE study, 48-week results. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 37.Slide #23: CASTLE Study: 48-Week Tolerability Results Both treatment arms were well tolerated with few discontinuations due to adverse events (2% and 3%).1 Jaundice (4% versus 0%) and hyperbilirubinemia (34% versus <1%) were more common in the boosted atazanavir arm. Nausea (8% versus 4%) and diarrhea (11% versus 2%) occurred with greater frequency in the lopinavir/ritonavir arm. Lipid changes favored patients in the atazanavir + ritonavir arm. Fewer patients in the boosted atazanavir arm required lipid-lowering therapy than in the lopinavir/ritonavir arm (2% versus 7%).1 Reference Molina JM, Andrade-Villanueva J, Echevarria J, et al. Efficacy and safety of once-daily atazanavir/ritonavir compared to twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine in ARV-naive HIV-1-infected subjects: the CASTLE study, 48-week results. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 37.

    38. CASTLE Study: Atazanavir + Ritonavir Versus Lopinavir/Ritonavir Resistance data not reported at this time No new safety findings Atazanavir + RTV: jaundice and hyperbilirubinemia Lopinavir/r: nausea and diarrhea Atazanavir + RTV had significantly better lipid profile Few discontinuations leading to withdrawal Adverse events: <3% Virologic failure: <2% Virologic outcome (HIV RNA <50 copies/mL) Atazanavir + RTV qd was non-inferior to lopinavir/r bid Slide #24: CASTLE Study: Atazanavir + Ritonavir Versus Lopinavir/Ritonavir Resistance data were not reported at this time.1 No new safety findings were found in this 48-week analysis.1 Atazanavir + RTV: jaundice and hyperbilirubinemia. Lopinavir/r: nausea and diarrhea. Atazanavir + RTV had significantly better lipid profile Few discontinuations leading to withdrawal (adverse events: <3% and virologic failure: <2%).1 Virologic outcome (HIV RNA <50 copies/mL) with atazanavir + RTV qd was non-inferior to lopinavir/r bid.1 Reference Molina JM, Andrade-Villanueva J, Echevarria J, et al. Efficacy and safety of once-daily atazanavir/ritonavir compared to twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine in ARV-naive HIV-1-infected subjects: the CASTLE study, 48-week results. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 37. Slide #24: CASTLE Study: Atazanavir + Ritonavir Versus Lopinavir/Ritonavir Resistance data were not reported at this time.1 No new safety findings were found in this 48-week analysis.1 Atazanavir + RTV: jaundice and hyperbilirubinemia. Lopinavir/r: nausea and diarrhea. Atazanavir + RTV had significantly better lipid profile Few discontinuations leading to withdrawal (adverse events: <3% and virologic failure: <2%).1 Virologic outcome (HIV RNA <50 copies/mL) with atazanavir + RTV qd was non-inferior to lopinavir/r bid.1 Reference Molina JM, Andrade-Villanueva J, Echevarria J, et al. Efficacy and safety of once-daily atazanavir/ritonavir compared to twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine in ARV-naive HIV-1-infected subjects: the CASTLE study, 48-week results. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 37.

    39. ACTG 5142: Efavirenz Versus Lopinavir/Ritonavir Regimens Treatment-nave patients (n=753) CD4: 182 cells/mm3 HIV RNA >100,000 copies/mL: 51% Randomized arms Lopinavir/ritonavir (soft-gel; 400/100 mg bid) + 2 NRTIs Efavirenz + 2 NRTIs Efavirenz + lopinavir/ritonavir Selected NRTIs in combination with lamivudine: zidovudine (42%), stavudine XR (24%), tenofovir DF: (34%) 96-week tolerability No difference between efavirenz + 2 NRTIs and lopinavir/ritonavir + 2 NRTIs with regard to incidence of grade 3/4 adverse events or laboratory abnormalities Slide: ACTG 5142: Efavirenz Versus Lopinavir/Ritonavir Regimens ACTG 5142 was a phase 3, randomized, open-label, prospective trial comparing the efficacy and safety of lopinavir/ritonavir and efavirenz-containing regimens in 753 treatment-nave patients.1 Patients in this trial had fairly advanced HIV disease (baseline median CD4 182 cells/mm3 and HIV RNA >100,000 copies/mL. Treatment arms:1 Lopinavir/ritonavir (soft-gel bid) + 2 NRTIs. Efavirenz + 2 NRTIs. Lopinavir/ritonavir + efavirenz. NRTIs were selected before randomization and included lamivudine with either zidovudine, stavudine XR, or tenofovir DF. No difference between efavirenz + 2 NRTIs and lopinavir/ritonavir + 2 NRTIs with regard to incidence of grade 3/4 adverse events or laboratory abnormalities.1 Reference Riddler SA, Haubrich R, DiRienzo G, et al. A prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV-1 infection. Program and abstracts of the 16th International AIDS Conference. August 13-18, 2006. Toronto, Canada. Abstract ThLB0204.Slide: ACTG 5142: Efavirenz Versus Lopinavir/Ritonavir Regimens ACTG 5142 was a phase 3, randomized, open-label, prospective trial comparing the efficacy and safety of lopinavir/ritonavir and efavirenz-containing regimens in 753 treatment-nave patients.1 Patients in this trial had fairly advanced HIV disease (baseline median CD4 182 cells/mm3 and HIV RNA >100,000 copies/mL. Treatment arms:1 Lopinavir/ritonavir (soft-gel bid) + 2 NRTIs. Efavirenz + 2 NRTIs. Lopinavir/ritonavir + efavirenz. NRTIs were selected before randomization and included lamivudine with either zidovudine, stavudine XR, or tenofovir DF. No difference between efavirenz + 2 NRTIs and lopinavir/ritonavir + 2 NRTIs with regard to incidence of grade 3/4 adverse events or laboratory abnormalities.1 Reference Riddler SA, Haubrich R, DiRienzo G, et al. A prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV-1 infection. Program and abstracts of the 16th International AIDS Conference. August 13-18, 2006. Toronto, Canada. Abstract ThLB0204.

    40. ACTG 5142: Summary of 96-Week Efficacy Results Slide: ACTG 5142: Summary of 96-Week Efficacy Results Significant trends favoring the efavirenz + 2 NRTI arm over lopinavir/ritonavir + 2 NRTI arm included:1 Virologic failure rate (24% versus 33%; P=0.006). HIV RNA level <200 copies/mL (93% versus 86%, P=0.041). HIV RNA level <50 copies/mL (89% versus 77%; P=0.003). There were no statistically significant difference between the treatment arms in the proportion of patients completing the regimen.1 The lopinavir/ritonavir arm had significantly greater increases in CD4 cells compared with the efavirenz arm after 96 weeks (285 versus 239 cells/mm3; P=0.01).1 Reference Riddler SA, Haubrich R, DiRienzo G, et al. A prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV-1 infection. Program and abstracts of the 16th International AIDS Conference. August 13-18, 2006. Toronto, Canada. Abstract ThLB0204.Slide: ACTG 5142: Summary of 96-Week Efficacy Results Significant trends favoring the efavirenz + 2 NRTI arm over lopinavir/ritonavir + 2 NRTI arm included:1 Virologic failure rate (24% versus 33%; P=0.006). HIV RNA level <200 copies/mL (93% versus 86%, P=0.041). HIV RNA level <50 copies/mL (89% versus 77%; P=0.003). There were no statistically significant difference between the treatment arms in the proportion of patients completing the regimen.1 The lopinavir/ritonavir arm had significantly greater increases in CD4 cells compared with the efavirenz arm after 96 weeks (285 versus 239 cells/mm3; P=0.01).1 Reference Riddler SA, Haubrich R, DiRienzo G, et al. A prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV-1 infection. Program and abstracts of the 16th International AIDS Conference. August 13-18, 2006. Toronto, Canada. Abstract ThLB0204.

    41. Systematic Overview of 49 Clinical Trials: HAART in Treatment-Nave Patients Slide: Systematic Overview of HAART Regimens in Treatment-Nave Patients Bartlett and colleagues updated their previous systematic review of triple combination therapy of treatment-nave patients.1 49 clinical trials with triple combination therapy conducted between 1994 to March 2004. 13,147 treatment-nave patients. 48-week outcomes:1 Boosted protease inhibitor (PI)- and non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens had superior virologic response versus nucleoside reverse transcriptase inhibitor (NRTI) and PI regimens. Boosted PIs had greater increases in CD4 cell counts versus all drug classes. Lower pill burden was not associated with virologic response. Compared with the 2001 systematic review, this updated version demonstrates that virologic response rates have improved over time and that the primary driver of virologic response is regimen potency. Pill count was not consistently associated with virologic response.1 These results support the DHHS treatment recommendations for preferred regimens.1 Reference Bartlett JA, Fath MJ, DeMasi R, et al. An updated systematic overview of triple combination therapy in antiretroviral-nave HIV-infected adults. Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections. February 22-25, 2005. Boston, MA. Abstract 586. Slide: Systematic Overview of HAART Regimens in Treatment-Nave Patients Bartlett and colleagues updated their previous systematic review of triple combination therapy of treatment-nave patients.1 49 clinical trials with triple combination therapy conducted between 1994 to March 2004. 13,147 treatment-nave patients. 48-week outcomes:1 Boosted protease inhibitor (PI)- and non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens had superior virologic response versus nucleoside reverse transcriptase inhibitor (NRTI) and PI regimens. Boosted PIs had greater increases in CD4 cell counts versus all drug classes. Lower pill burden was not associated with virologic response. Compared with the 2001 systematic review, this updated version demonstrates that virologic response rates have improved over time and that the primary driver of virologic response is regimen potency. Pill count was not consistently associated with virologic response.1 These results support the DHHS treatment recommendations for preferred regimens.1 Reference Bartlett JA, Fath MJ, DeMasi R, et al. An updated systematic overview of triple combination therapy in antiretroviral-nave HIV-infected adults. Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections. February 22-25, 2005. Boston, MA. Abstract 586.

    42. DHHS Guidelines: Predictors of Successful ARV Therapy Predictors of long-term virologic success include Potency of antiretroviral regimen Adherence to treatment regimen Low baseline viremia Higher baseline CD4+ cell count Rapid (ie, >1 log10 in 1 to 4 months) reduction of viremia in response to treatment The predictors of long-term virologic suppressors are shown in this slide. [You might just touch on some of these very quickly. The intent is not to have this slide read, rather to highlight certain points in it that you think might interest the audiencesuch as the rapid reduction of viremia in the last bullet point, which is a predictor of response to therapy.] Reference DHHS Guidelines; Revision October 10, 2006. Available at: http://aidsinfo.nih.gov. Accessed December 13, 2006.The predictors of long-term virologic suppressors are shown in this slide. [You might just touch on some of these very quickly. The intent is not to have this slide read, rather to highlight certain points in it that you think might interest the audiencesuch as the rapid reduction of viremia in the last bullet point, which is a predictor of response to therapy.] Reference DHHS Guidelines; Revision October 10, 2006. Available at: http://aidsinfo.nih.gov. Accessed December 13, 2006.

    43. The New Antiretroviral Agents Antiretroviral Nave Patients Tipranavir Darunavir Maravaroc Raltegravir Etravirine

    44. Conclusion DHHS Guidelines: Factors to Consider When Selecting an Initial Regimen Co-morbidity or conditions: TB, liver disease, depression or mental illness, CVD, chemical dependency, or pregnancy Adherence potential Dosing convenience: pill burden, dosing frequency, food and fluid considerations Potential adverse drug effects Potential drug interactions with other medications Pretreatment CD4+ cell count Gender Age Pregnancy potential Results of genotypic resistance testing This slide shows a long list of considerations when selecting an initial regimen. [It is intended to provide a comprehensive list; you can decide if it is appropriate for your audience. This might be a slide that you cover quickly, or if your audience is less sophisticated, that you spend more time on. You might pick a particular bullet point out and emphasize what is important, For example, dosing convenience is generally given particular weight by most physicians when selecting a regimen.] Reference DHHS Guidelines; Revision October 10, 2006. Available at: http://aidsinfo.nih.gov. Accessed December 13, 2006. This slide shows a long list of considerations when selecting an initial regimen. [It is intended to provide a comprehensive list; you can decide if it is appropriate for your audience. This might be a slide that you cover quickly, or if your audience is less sophisticated, that you spend more time on. You might pick a particular bullet point out and emphasize what is important, For example, dosing convenience is generally given particular weight by most physicians when selecting a regimen.] Reference DHHS Guidelines; Revision October 10, 2006. Available at: http://aidsinfo.nih.gov. Accessed December 13, 2006.

    45. D:A:D Study: NRTI Use and Risk of MI D:A:D study 33,347 HIV patients on HAART 517 patients developed MI over 157,912 person-years of follow-up Recent didanosine use (n=124) Recent abacavir use (n=192) Recent other NRTI use (n=237) Recent use of abacavir and didanosine (but not cumulative or past use) associated with increased risk of MI Risk persists regardless of length of use Risk was reversible with discontinuation of drugs Most MIs occurred in patients with existing cardiovascular risk factors Slide #43: D:A:D Study: NRTI Use and Risk of MI D:A:D study (n= 33,347 on HAART).1 517 patients developed MI over 157,912 person-years of follow-up. Analysis adjusted for demographic factors (age, sex, HIV risk and ethnicity), cardiovascular risk factors that are not modified greatly by antiretroviral therapy (smoking status, family history of cardiovascular disease, previous cardiovascular event, body mass index), and cumulative exposure to other antiretroviral drugs (tenofovir DF, main Pis and NNRTIs),. Recent abacavir and didanosine use associated with increased risk of MI.1 No association with cumulative or past use. Excess risk most pronounced in patients with underlying cardiovascular risk. Risk appears reversible with discontinuation of drugs. Reference Sabin C, Worm S, Weber R, et al. Do thymidine analogues, abacavir, didanosine and lamivudine contribute to the risk of myocardial infarction? The D:A:D study. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 957C. Slide #43: D:A:D Study: NRTI Use and Risk of MI D:A:D study (n= 33,347 on HAART).1 517 patients developed MI over 157,912 person-years of follow-up. Analysis adjusted for demographic factors (age, sex, HIV risk and ethnicity), cardiovascular risk factors that are not modified greatly by antiretroviral therapy (smoking status, family history of cardiovascular disease, previous cardiovascular event, body mass index), and cumulative exposure to other antiretroviral drugs (tenofovir DF, main Pis and NNRTIs),. Recent abacavir and didanosine use associated with increased risk of MI.1 No association with cumulative or past use. Excess risk most pronounced in patients with underlying cardiovascular risk. Risk appears reversible with discontinuation of drugs. Reference Sabin C, Worm S, Weber R, et al. Do thymidine analogues, abacavir, didanosine and lamivudine contribute to the risk of myocardial infarction? The D:A:D study. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 957C.

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