NYC CHAIN Report (Update Report # 12) Trends in Use Of HIV Antiretroviral Therapy. Peter Messeri

NYC CHAIN Report 1998-2 (Update Report # 12) Trends in Use Of HIV Antiretroviral Therapy Peter Messeri Columbia University Mailman School of Public Health In collaboration with Medical and Health Research Association of New York, the NYC Department of Health and Mental Hygiene, the Westchester Department of Health, and the NY Health & Human Services HIV Planning Council HRSA Contract BRH890015-07 and BRX620002-97 Final submitted April 15, 1998 1998 The Trustees of Columbia University C.H.A.I.N. Report

C P H P A P I P N P Community Health Advisory and Information Network Update Report #12 April 15, 1998 Trends in Use of HIV Antiretroviral Therapy Prepared by Peter Messeri Columbia School of Public Health This research was supported by grant numbers BRH890015-07 and BRX620002-97 from the U.S. Health Resources and Services Administration (HRSA). This grant is funded through Title I of the Ryan White Comprehensive AIDS Resources Emergency Act of 1990 through the New York City Department of Health to the Medical and Health Research Association of New York City, Inc. Its contents are solely the responsibility of the Columbia University School of Public Health and do not necessarily represent the views of the funders.

Trends in Use of HIV Antiretroviral Therapy Prepared by Peter Messeri Introduction An earlier report in this series (CHAIN Project Update #1-Introduction of Combination Therapy) documented the rapid rise in the use of combination antiretroviral therapies during 1996 among CHAIN project participants--a representative cohort of HIV infected New York City residents. By the end of that year about one-half of the CHAIN participants were taking a combination of antiretroviral medications and one in five reported that their combination included a protease inhibitor. Use of combination therapy was higher among whites than among either blacks or Latinos. Its use was associated with higher educational attainment and current income. Lower use of combination therapy was associated with current problem drug use or an unstable housing condition. Finally characteristics of participants medical care was unrelated to combination therapy in general, but receiving care in a private physician s office rather than in a clinic was associated with higher use of protease inhibitors. This report draws on fourth round interviews with CHAIN participants to extend the findings of the earlier report in several respects. Trends in use of antiretroviral therapies are extended through the first 9 months of 1997. Findings from the fourth round of interviews are compared with those from the third to examine trends in the association between use of antiretroviral therapies and characteristics of participants and the medical care they receive. This report extends this earlier analysis by including additional measures of social support and characteristics of medical care providers as possible correlates of combination therapy. This report continues the earlier report s emphasis on use of any combination therapy, but use of more potent combinations including a protease inhibitor are broken out as well. Finally the analysis compares sources of payment for antiretroviral therapies for the two rounds of interviews. A companion Update report examines individual changes in antiretroviral therapy between the third and fourth interviews in conjunction with participant reports about reasons for starting and stopping medications. Key Findings Use of combination antiretroviral therapies that included protease inhibitors increased sharply during 1997. C In the 6 to 9 month time interval between the third and fourth rounds of CHAIN interviews, use of combination therapy has increased by 50 percent and use of protease inhibitors more than doubled. C 61 percent of CHAIN participants were taking a combination of antiretroviral medications at Time 4 interviews C 41 percent were taking triple therapy that included a protease inhibitor.

C The increased use of protease inhibitor marks a shift away from both monotherapy and two-drug regimens involving combinations of the older generation of nucleoside reverse transcriptase inhibitors. Increased use of any combination therapy was associated with C C C Declining CD4 T-cell counts Number of friends and family aware of participant s HIV status Current medical care that was comprehensive, coordinated and provided 24 hour coverage. Increased used of combination therapy that included a protease inhibitor was associated with C C C Declining CD4 T-cell counts Higher educational attainment Continuity of medical care Racial-ethnic disparities in use of combination therapies evident at the time of the third round of interviews were greatly reduced by the time of the fourth round of interviews. C C There were no statistically significant differences in use of any combination therapy between White, Latino and African Americans Observed race and ethnic differences in use of protease inhibitors are largely explained by higher educational attainment of white participants. The cost of these medications does not appear to be a major barrier to obtaining antiretroviral medications. C C C Virtually all CHAIN participants are enrolled in medical plans that cover all approved antiretroviral medications. Medicaid is by far the single largest payor of these medications; it paid for the medications taken by 77 percent of CHAIN participants using protease inhibitors. Only for the small number of white CHAIN participants do we find that ADAP and private insurance cover the medication costs of a substantial fraction CHAIN participant medication costs. The CHAIN Survey and Data The Columbia School of Public Health is responsible for conducting the CHAIN Project surveys and reporting on findings from the survey data in collaboration with the New York City Department of Health and Medical and Health Research Association of New York City, Inc. (MHRA). The purpose of the survey is to provide longitudinal information on study participants needs for health and human services, their use of health care and social service organizations, their 2

satisfaction with services, and the impact of these services on changes in physical, mental and social well being. This information is prepared specifically for the NYC HIV Health and Human Services Planning Council to assess the full spectrum of services for HIV infected persons in NYC. The study is conducted under a subcontract from MHRA to Columbia University with the authorization of the NYC Department of Health and the HIV Planning Council. CHAIN sample design, participant recruitment and follow-up interviews The CHAIN Project followed a recruitment procedure designed to yield a broadly representative sample of people living with HIV in New York City. Study recruitment was conducted in 43 agencies that were selected so that there would be roughly equal numbers of medical care and social service sites and representation from sites that were and were not recipients of Title I grants. At 30 sites, staff contacted a random sample of clients. The names of clients who indicated an interest in participating were turned over to CHAIN staff for interviews. An open enrollment procedure was implemented at the remaining 13 agencies. All eligible clients present on a small number of recruitment days were invited by agency providers and CHAIN staff to participate in the CHAIN study. were then scheduled with interested clients. A total of 648 individuals recruited from participating agencies completed baseline interviews. The agency-based sample was supplemented with 50 interviews conducted with HIV+ individuals with little or no connection to medical and social services. These individuals were contacted at outreach sites and through nominations from CHAIN participants. More detailed information on sampling strategy and recruitment may be obtained upon request from MHRA (CHAIN Technical Report #1). Subsequent interviews were conducted at approximately 6 to 9 month intervals. Round two interviews were completed with 568 participants, 92 percent of the cohort still alive and not known to have moved outside of New York City. Round three interviews were conducted with 480 of CHAIN participants, 88 percent of the cohort who were alive and still residing in New York City. Round four interviews were conducted between October 1996 through September 1997 with 419 CHAIN participants or 82 percent of the surviving cohort. Sample loss for reasons other than death or migration out of New York City was minimal. About 3 percent of the original cohort has refused to participate in follow-up interviews and contact has been lost with another 10 percent. Comparison with the limited data on citywide characteristics of AIDS cases indicates that the CHAIN cohort corresponds closely to the sociodemographic composition of people living with HIV in New York City. Table 1 shows that age, ethnicity and risk behavior profiles are very similar for New York City surviving cases as of December 1994, for the subset of CHAIN participants reporting an AIDS diagnosis or an AIDS defining health condition at baseline, as well as for the full cohort of CHAIN participants. The over representation of women in the CHAIN cohort is intentional. CHAIN participants were sampled so as to yield roughly one female for every two 3

Table 1: Chain Sample Compared to Surviving New York City AIDS Cases New York City AIDS Cases 12/31/94 Time 1 CHAIN AIDS Cases 10/94-9/95 Total Time 1 10/94-9/95 Total Time 4 10/96-9/97 (N=) (427) (698) (419) Age 20-29 30-39 40-49 >49 14% 45% 30% 10% 11% 45% 35% 9% 11% 45% 35% 9% 11% 44% 35% 10% Sex Female Male 24% 75% 33% 67% 37% 63% 40% 60% Race/Ethnicity White Black Latino Other 23% 43% 33% <1% 20% 45% 35% <1% 17% 50% 33% <1% 16% 53% 31% <1% Risk Males MSWM IDU MSWM/IDU Hetero/Other 38% 48% 3% 11% 39% 32% 18% 11% 35% 35% 17% 13% 38% 36% 18% 8% Females IDU Other 58% 42% 60% 40% 59% 41% 60% 40% Source: New York State AIDS Institute, AIDS Surveillance data 4

males recruited. The much higher percentage of CHAIN males who report both same sex activity and injection drug use, when compared to the NYC AIDS case data, probably reflects the CHAIN project decision to ask about risk behaviors relevant to service delivery without asking about source of HIV infection. CHAIN participants interviewed at Time 4 do not differ from the full cohort on any of the characteristics presented in Table 1. CHAIN interviews All CHAIN interviews are conducted in person by trained interviewers. Interview topics include sociodemographic characteristics, the full range of experiences with access to and use of medical and social services, and quality of life. At each round of interviews participants are shown a card with a list of the generic and trade names of prescription drugs used to treat HIV-related conditions. These cards include the FDA approved nucleoside reverse transcriptase inhibitors (ZDV, ddi, ddc, d4t and 3TC), protease inhibitors (saquinavir, ritonavir, nelfinavir and indinavir), and nevirapine, a non-nucleoside reverse transcriptase inhibitor At baseline interviews, participants were asked tell me which of these drugs [on the card] you have taken in the last six months. If you are unsure of a drug name, please tell me the specific condition that it is prescribed for. For subsequent interviews, the phrasing of the question was changed to elicit information on medications currently being taken: Please look at this card and tell me which of these drugs, if any, you are taking right now?... Are you currently taking any other prescription medicines or drugs [not listed on the card]?. Participants were also asked for the names of other medications a doctor prescribed that were not on the card. CHAIN Technical Report 7R contains a more detailed description of data collected in the survey and profile of CHAIN participants. Classifying antiretroviral therapies-- DHHS clinical guidelines The release of federal (Department of Health and Human Services) clinical guidelines 1 for use of antiretroviral medications is among the most important developments since the first CHAIN Update report on antiretroviral therapies. The panel responsible for the guidelines concluded that antiretroviral therapy provided clinical benefits at all stages of infection. It recommended that: C All patients with symptomatic HIV infection should be treated with antiretroviral therapy. C Physicians should discuss antiretroviral therapy with asymptomatic patients, but a physician's recommendation to treat should depend on a complex set of considerations that include CD4 T cell count, viral load, the potential long term risks and benefits of initiating therapy in asymptomatic patients, and the willingness of the patient to begin therapy. 1 Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents (Department of Health and Human Services, November 5, 1997). 5

- "... no patient should automatically be excluded from consideration for antiretroviral therapy simply because he or she exhibits a behavior or other characteristic judged by some to lend itself to noncompliance." C The guidelines divided antiretroviral therapies into four categories 1. A preferred category of antiretroviral regimens with [at least] one protease inhibitor (PI) and two nucleoside reverse transcriptase inhibitors (NRTI). 2. An alternative recommended category combinations that include two NRTIs and a non-nucleoside reverse transcriptase inhibitors (NNRTI) or the protease inhibitor Saquinavir with 2 NRTIs. 3. A not generally recommended category that contained 2 NRTI combinations 4. A not recommended category that contained monotherapy (except ZDV for pregnant women) and a small number of 2-NRTI combinations that have overlapping toxicities The grouping of antiretroviral therapies presented in this report follows the Guideline s organization of therapies. For several reasons it would be inappropriate to draw strong conclusions about best clinical practices based only on conformity to preferred and alternative DHHS recommended categories. First, most of the interviews were completed before the guidelines were distributed in draft version in July 1997 and the release of a revised version in November 1997. It is entirely possible that physicians using available clinical findings at the time of round four interviews may have prescribed what, in hindsight, the guidelines judged to be suboptimal treatments. Second, the guidelines make clear that the decisions about initiation of treatment and the choice of drug combinations are complex. To establish whether a choice of combination therapy is appropriate for an individual patient requires details that are incomplete or not available from the interview data about a patient s prior treatment history, failure of particular drug combinations, continued success of less potent combinations, medication interactions, patient reaction to drug toxicity, and consideration of a patient s social circumstances and psychological readiness to follow complex dosing instructions. Third, Time 4 interviews provide only incomplete information on how many participants were offered or prescribed medication by their physicians but chose not to take it. More complete information is now being gathered for the fifth round of interviews. Therefore compliance with the DHHS guidelines should not be taken as a direct quality of care measure. Nonetheless examination of the time 4 patterns of antiretroviral medication with respect to the guideline categories does provide policy relevant information for comparing the extent to which different subgroups of HIV patients are receiving what today we would regard as recommended antiretroviral therapy. 6

Findings Trends in Antiretroviral Therapy Figure 1 and Table 2 display trends in antiretroviral therapy among CHAIN participants. Reports of antiretroviral medication at all four rounds of interviews were pooled and then grouped by the quarter year in which they were conducted. This generated twelve quarters of data beginning with the final quarter of 1994 through the third quarter of 1997. The graph separately plots percentages of participants who report current use of any antiretroviral medication, and three underlying grouping of antiretroviral therapies: (1) monotherapy, (2) drug combinations without a protease inhibitor and (3)drug combinations including a protease inhibitor. Figure 1 displays both the actual quarterly percentages and a smoothed trend line for each of the four therapy groupings. Table 2 presents a tabular display of trends in antiretroviral therapy. For this table, interviews conducted for second through fourth round of interviews are grouped into three time periods: the first and second halves of 1996 and the first nine months of 1997 (relatively few interviews were conducted after June 1997, however). 7

Table 2: Trends in Antiretroviral Combination Therapy (January 1996-September 1997) Type of Antiretroviral Therapy 1/96-6/96 7/96-12/96 1/97-9/97 (N=) (405) (262) (358) None 49% 40% 30% Monotherapy 17% 9% 9% 2 Nucleoside Reverse Transcriptase Inhibitor(NRTI) drug Combination 21% 25% 16% 1 or 2 Drug Combination with a Protease Inhibitor. 3% 6% 9% 3 or more Drug Combination with a P.I. 8% 19% 33% Combination with Non-nucleoside reverse transcriptase inhibitor (NNRTI) 0% 0% 3% Total 100% 100% 100% Source: Time 2, Time 3 and Time 4 CHAIN Survey For the first five quarters of the study, from October 1994 through the last quarter of 1995, current use of antiretroviral medications fluctuated between 30 and 40 percent. Since FDA approval of combination therapies and protease inhibitors during the final months of 1995 and the winter of 1996, there has been a sustained rise in antiretroviral therapies, such that use of antiretroviral medications had expanded to about 60 percent of the CHAIN cohort interviewed during the last quarter of 1996 and to over 70 percent of those interviewed during the third quarter of 1997. The overall increase in antiretroviral therapy was accompanied by a sharp decline in monotherapy and a rapid increase in combination therapy. Monotherapy dropped sharply from over 30 percent during the first year of the study to under 10 percent in 1997. Meanwhile combination therapy without a protease inhibitor peaked at about 25 percent during the latter half of 1996 and has declined by half by the close of the study period. In contrast drug combinations involving protease inhibitors have steadily increased since they were approved during the winter of 1996; about half of those interviewed during the second and third quarters of 1997 were currently taking protease inhibitors. The trend in antiretroviral therapy shows a general conformity to the DHHS clinical guidelines outlined above. Nonetheless Table 2 indicates that 34 percent of CHAIN participants 8

during 1997 interviews were not taking the DHHS recommended protease inhibitor based combination of three or more drugs. To assess more precisely the extent to which the CHAIN cohort's use of antiretroviral therapies conforms to DHHS recommendations, we grouped the antiretroviral drug combinations reported at fourth round interviews according to recommendation categories summarized in Table VI of the Guidelines. Table 3 lists the most frequent antiretroviral regimens reported at the fourth round of interviews. Table 4 shows the distribution of antiretroviral therapies following the four groupings used by the DHHS guidelines. A fifth category is added to Table 4 that includes combination therapies that do not fit into the guidelines categories; these are for the most part two-drug combinations of a PI and one NRTI. 9

Table 3: Most Frequent Antiretroviral Therapies at Time 4 (October 1996-September 1997) Type of Therapy (n) % None (132) 32% Single Nucleoside Reverse Transcriptase Inhibitor (33) 8% ZDV (17) 3TC (10) d4t (4) ddc (1) ddi (1) 2 Drug NRTI Combinations (73) 17% ZDV/3TC (37) d4t/3tc (22) d4t/ddi Other (7) (7) Combinations with Protease Inhibitor (180) 44% Indinavir/3TC/zdv Indinavir/3TC/d4T Saquinavir/3TC/zdv Saquinavir/3TC/d4T Ritonavir/3TC/zdv Saquinavir/3TC Indinavir/3TC Saquinavir/3TC/ddC Ritonavir/3TC/d4T Indinavir/zdv Ritonavir/3TC Others (30) (24) (18) (10) ( 9) (8) (6) (4) (4) (4) (4) (59) Source: Time 4 CHAIN Survey 10

Table 4: Antiretroviral Therapies & DHHS Recommended Antiretroviral Agents for Treatment of HIV(November 5, 1997) DHHS Recommendations N % of All T4 (N=419) Preferred anti-retroviral combinations PI+2 NRTI s Alternative 1 NNRTI + 2 NRTIs Saquinavir + 2 NRTIs Not generally recommended 2 NRTIs Not recommended Montherapy Some 2 NRTI combinations Combinations not classified PI+NRTI 89 21% 36 9% 70 18% 44 11% 35 8% Source: Time 4 CHAIN Survey Table 4 indicates that at the time of the fourth round interviews (October 1996 to July 1997), the largest grouping of CHAIN participants were those taking antiretroviral therapies reported combinations conforming to DHHS recommendations. Thirty percent of the CHAIN cohorts, were taking drug combinations that fell within DHHS categories for first-line antiretroviral regimens (the DHHS preferred and alternative categories). Approximately 20 percent of Time 4 participants were taking two NRTI drug combinations that were not generally recommended, but may have short-term clinical benefits, and only 11 percent of CHAIN participants reported taking an antiretroviral therapy that was clearly not recommended. An additional 8 percent reported taking a PI with a single NRTI, combinations that did not fall into any of the DHHS recommendation categories. Based on these results, findings in the rest of this report are divided into two groups. The first encompasses all combinations of two or more antiretroviral medications; virtually all combinations are believed to have some clinical benefit. The second focuses more narrowly on the most potent antiretroviral therapies that fall within the preferred and alternative categories and are regarded to have sustained clinical benefit when taken as prescribed. 11

Factors Associated with Use of Antiretroviral Therapies The next series of tables present CHAIN data that explore potential participant and provider influences on the use of combination therapy. The factors examined for this analysis are grouped into six domains: (1) clinically relevant criteria, (2) participant social characteristics, (3) current social circumstances, (4) social support, (5) characteristics of medical care, and (6) insurance coverage. The findings for this analysis are presented in two parts. First a series of tables show how each factor is related to percent differences in use of any combination of antiretroviral therapy and use of combinations that include protease inhibitors. Because there are strong inter- relationships between the various factors examined for this analysis, we cannot tell from looking at these tables alone, which are the most important influences that shape use of combination therapy. Therefore a multiple regression analysis was performed that was used to identify the most salient influences on use of combination therapy. The results of the multiple regression analysis are summarized at the end of this section. A more complete presentation of the findings of the multiple regression analysis are presented in the appendix to this report. Clinical relevant criteria: Antiretroviral Therapies and Stage of Disease The relatively large percentage of CHAIN participants not taking a DHHS preferred regimen is partly due to cohort members in the early stages of HIV infection, for whom the decision to delay initiation may be clinically appropriate. As further basis for assessing the extent of appropriate antiretroviral therapy, Table 5 displays the percentages of CHAIN participants who were currently taking (1) any combination antiretroviral therapy and (2) a DHHS recommended therapy grouped by CD4 T-cell count at the previous round of interviews 2 by self reported stage of HIV disease. 3 Comparable data are present for Time 3 and Time 4 interviews to permit analysis of short-term trends. 2 CD4 T-cell counts are used from the preceding interview to avoid the confounding therapeutic benefit of the medication on increasing CD4 T-cell counts. 3 Viral load reports were neither sufficiently complete or reliable at fourth round interviews to include this as a further clinical marker for initiation of antiretroviral therapy. 12

Table 5: Antiretroviral Therapy and Stage of Disease Any Combination Therapy 1 DHHS Recommended Therapies 2 All Participants 3 (N=479/419) Time 3 3/96-12/96 Time 4 10/96-9/97 Time 3 3/96-12/96 40% 59% 14% 34% Time 4 10/96-9/97 CD4 T-Cell Counts 4 >500 (90/85) 301-500 (121/98) 201-300 (61/53) 101-200 (73/67) 0-100 (96/83) 20% 40% 31% 45% 60% *** 34% 58% 57% 69% 87% *** 8% 12% 8% 16% 26% ** 14% 32% 30% 36% 59% ** Stage of Disease 5 Asymptomatic (56/43) Symptomatic (42/38) AIDS (381/338) 27% 36% 43% 40% 34% 64% *** 5% 5% 17% 28% 16% 37% * Source: Time 2, Time 3 and Time 4 CHAIN Surveys *p #.05 **p #.01 ***p #.001 1 Currently taking two or more antiretroviral medications 2 Currently taking a preferred or alternative antiretroviral therapy according DHHS Guidelines 3 Time 3 sample size/time 4 sample size 4 CD4 T-cell counts are measured for the preceding interview (e.g. Time 3 CD4 counts used for Time 4 data). 5 In staging disease, individuals stay in the same stage or progress to more advanced stage. Thus, once diagnosed with AIDS, CHAIN participants stay in this category regardless of subsequent improvement in T-cell counts or absence of symptoms. 13

Table 5 indicates that the percentage of the CHAIN participants taking a combination therapy at Time 4 interviews increased significantly with declining a CD4 T-Cell count and an AIDS diagnosis. Current use of combination therapy reaches a very high level of coverage for people at the end stages of the disease. Among CHAIN participants with a CD4 T-Cell count below 100 at Time 3 interview, 87 percent were taking some combination of medications and 59 percent were taking a combination that included a protease inhibitor. At the other end of the disease spectrum, a much smaller, but a still sizable minority of CHAIN participants, who were asymptomatic or had a CD4 T-Cell count above 500, were taking combination antiretroviral medications. It is also of interest that with the exception of people with a CD4 T-Cell count below 100, a roughly constant proportion of participants taking a drug combination, about half, are taking one that conforms to DHHS recommended therapies regardless of CD4 T-cell count or stage of disease. Despite the substantial increase in use of combination therapy between the third and fourth round of interviews, a substantial fraction of CHAIN participants, according to DHHS guidelines, would benefit from initiation of triple-drug therapy. Between 30 and 40 percent of CHAIN participants with depressed CD4 T-Cell counts between 100 and 300 at Time 3 were not on any form of combination therapy at Time 4 interviews and another 30 percent were taking a not generally recommended NRTI combination that did not include a protease inhibitor. Social Characteristics: Race/ethnic differences Third round interviews found large race and ethnic differences in use of antiretroviral therapy during 1996. Table 6 combines interview data from the second through fourth rounds to examine trends in ethnic differences through the first nine months of 1997. Table 6 indicates that race and ethnic differences have greatly diminished between the first half of 1996 and more recent time periods. For interviews conducted during 1997, about the same percentage of whites and Latinos (approximately 70%) report taking some form of combination therapy. Blacks, during 1997, continued to lag behind the other two groups, as only 50 percent of this groups was on a combination therapy. All three major ethnic groups have experienced large increases in use of protease inhibitors from 1996 to 1997. While blacks and Latinos experienced proportionately larger increases than whites, the latter group continues to enjoy higher rates of use of 3-drug combinations with a protease inhibitor. Whereas 56 percent of whites were taking a 3-drug combination with a protease inhibitor in 1997, only 35 percent of Latinos and 31 percent of blacks were on such regimens. 14

Table 6: Use of Combination Antiretroviral Therapies by Race/Ethnicity CHAIN Conducted Between January 1996 and June 1996 Type of Antiretroviral Therapy White Black Latino (N=) (68) (202) (132) None 34% 57% 46% Monotherapy 10% 19% 18% 2 drug Combination without a Protease Inhibitor 26% 17% 25% 1 or 2 Drug Combination with a P.I. 7% 2% 3% 3+ Drug Combination with a P.I. 22% 3% 8% Total 100% 100% 100% Pearson Chi Square (8)= 38.5 p<.001 CHAIN Conducted between July 1996 to December 1996 Type of Antiretroviral Therapy White Black Latino (N=) (38) (142) (80) None 34% 50% 28% Monotherapy 5% 8% 14% 2 Drug Combination Therapy without a Protease Inhibitor 24% 22% 32% 1 or 2 Drug Combination with a P.I. 5% 6% 5% 3+ Combination with a P. I. 32% 14% 23% Total 100% 100% 100% Pearson Chi Square (8)=17 p<.05 15

TABLE 6 (Cont.) Use of Combination Antiretroviral Therapies by Race/Ethnicity CHAIN Conducted between January 1997 to September 1997 Type of Antiretroviral Therapy White Black Latino (N=) (54) (183) (120) None 22% 35% 27% Monotherapy 7% 13% 3% 2 Drug Combination Therapy without a Protease Inhibitor 9% 15% 22% 1 or 2 Drug Combination with a P.I. 6% 7% 13% 3+ Combination with a P. I. 56% 31% 35% Total 100% 100% 100% Pearson Chi Square (8)=26 p<.005 Other Social Characteristics Examination of a range of social characteristics in Table 7 indicate the declining importance of social status with respect to the use of any combination therapy between the third and fourth round of interviews. In contrast social status differences persist with respect to use of the more potent DHHS recommended therapies. Education, annual income, which were significantly related to combination therapy at time 3, are no longer statistically significant factors at time 4. Neither gender or borough of residence were strongly related to use of combination therapy at either round of interviews. Sociodemographic characteristics are more important influences on use of the DHHS recommended three - drug combinations. The differences at Time 4 interviews largely replicated patterns present at Time 3. At Time 4 higher levels of use were most strongly associated with being male, college educated and of higher family income. Borough differences were also present. In a pattern similar at both interviews, the highest level of use of a DHHS recommended therapy was found among Queens participants and the lowest among Bronx residents. 16

Table 7: Antiretroviral Therapy and Social Characteristics Any Combination Therapy 1 DHHS Recommended Therapies 2 Time 3 3/96-12/96 Time 4 10/96-9/97 Time 3 3/96-12/96 Time 4 10/96-9/97 All Participants (N=479/419) (T3/T4) 40% 59% 14% 34% Gender Male (293/250) Female (186/169) 41% 40% 59% 59% 17% 11 % 38% 28%* Years of Education Less than H.S. (163/148) H.S. Grad (148/126) Some College (117/101) College Grad (50/43) 31% 35% 51% 62%*** 53% 60% 61% 70% 6% 12% 20% 36%*** 23% 34% 43% 53%*** Current Annual Income ($) >5,000 (93/72) 5,000-7,499 (177/163) 7,500-9,999 (58/52) 10,000-14,999 (77/62) 15,000-24,999 (40/38) 25,000+ (30/24) 28% 35% 33% 55% 60% 67%*** 47% 61% 63% 60% 61% 71% 4% 12% 7% 26% 18% 40%*** 19% 33% 25% 45% 47% 58%** Borough of Residence Bronx (145/128) Brooklyn (114/94) Manhattan (152/130) Queens (40/39) Staten Island ( 26/23) 33% 44% 39% 58% 54% 52% 66% 58% 69% 61% 7% 14% 17% 38% 8%*** 23% 36% 35% 61% 30%** Source: Time 3 and Time 4 CHAIN Surveys *p #.05 **p #.01 ***p #.001 1 Currently taking two or more antiretroviral medications 2 Currently taking a preferred or alternative antiretroviral therapy according DHHS Guidelines Current Social Circumstances 17

Table 8 summarizes findings for two measures of current social circumstances, problem drug use and unstable housing situation. that are believed by many to complicate adherence, and therefore may be reasons not to prescribe these medications. The CHAIN data suggest, perhaps contrary to conventional thinking, that neither unstable housing or current drug use are strong deterrents to starting patients on combination therapy or more potent combinations, for that matter. To be sure both current problem drug users and those living in unstable housing situations were less likely than other participants to be taking more potent combinations, but the differences for these two variables were not statistically significant. Table 8: Current Social Circumstances Any Combination Therapy 1 DHHS Recommended Therapies 2 All Participants (N=479/419) Time 3 3/96-12/96 Time 4 10/96-9/97 Time 3 3/96-12/96 40% 59% 14% 34% Time 4 10/96-9/97 Problem Drug Use Current Problem (89/78) Past Problem (151/137) No Problem (239/204) 29% 35% 48% 51% 63% 59% 7% 12% 19% 23% 34% 38% Housing Situation Stable (426/379) Unstable (53/40) 43% 21%** 60% 48% 16% 4% 35% 20% Source: Time 3 and Time 4 CHAIN Surveys *p #.05 **p #.01 ***p #.001 1 Currently taking two or more antiretroviral medications 2 Currently taking a preferred or alternative antiretroviral therapy according DHHS Guidelines 18

Social Support For our analysis of participant characteristics, we have included two measures of social support, a factor many believe facilitates adherence to drug regimens. Providers may be more inclined to recommend combination therapy if they know that their patients have family and friends who can assist them in taking their medications. The presence of a large circle of supportive family and friends may also have a more direct influence on initiation of combination therapy. Caring family and friends may encourage people to take these medications, who may otherwise have concerns about their safety and efficacy. 4 By contrast, people who have not disclosed their HIV status to many family and friends may not want to start therapy for fear that heavy medication regimen may reveal their HIV status to others. Drawing from the CHAIN study s rich information on social support, a household composition variable was constructed that ordered study participants with respect to the presence of the adult in a participant s household. Among participants who lived in households with other adult members, we distinguished participants who lived with a partner or spouse from those did not have a partner or spouse but lived with a parent or another adult. We also constructed a broader measure of supportive HIV social networks based on the number of relatives and friends aware of the CHAIN participant s HIV infection. Findings from Time 3 and Time 4 interviews are presented side by side in Table 9 to permit comparison of short-term trends. From Table 9 we see that household structure was unrelated to use of combination therapy, however use of combination therapy increased with the number of friends and family who are aware of a participant s HIV status. Neither measure of social support was significantly related to use of the more potent combinations, but use did increase with the number of friends or families who were aware of a participant s HIV status. 4 There is also anecdotal evidence that friends and family, particularly those with HIV, may also be sources of influence for discouraging use of combination therapy. 19

Table 9: HIV Social Support Networks Any Combination Therapy 1 DHHS Recommended Therapies 2 All Participants (N=479/419) Time 3 3/96-12/96 Time 4 10/96-9/97 Time 3 3/96-12/96 40% 59% 14% 34% Time 4 10/96-9/97 Household Composition Lives with Partner or Spouse (125/104) Lives with parent (33/31) Lives with other adult (35/26) No other adult in household (268/258) 35% 24% 49% 44% 56% 58% 54% 61% 14% 0% 17% 16% 35% 29% 31% 35% Number of Friends or Family who know you are HIV+ 0 (30/30) 1 (36/33) 2-4 (118/100) 5-9 (98/83) 10+ (195/169) 27% 42% 36% 42% 45% 53% 42% 54% 58% 67%* 7% 8% 10% 16% 18% 23% 21% 29% 39% 39% Source: Time 3 and Time 4 CHAIN Surveys *p #.05 **p #.01 ***p #.001 1 Currently taking two or more antiretroviral medications 2 Currently taking a preferred or alternative antiretroviral therapy according DHHS Guidelines 20

Medical Care and Insurance coverage Tables 10 and 11 summarize the relationship between use of combination therapy and the source of medical and type of insurance coverage. These tables are similar in layout to previous tables. Besides the organization setting in which participants received their medical care, several measures of the character of medical care and satisfaction with the provider-patient interaction are examined. A measure of the continuity of medical care was constructed by comparing whether the facility where medical care was provided had changed between interviews. About half the sample reported receiving their medical care at the same facility at each of the four rounds of interviews. We also considered whether participants current medical care embodied three attributes associated with primary care: comprehensiveness, coordination and 24-hour access. Two characteristics were examined that measured the quality of the patient-provider relationship. The first combines answers to three items and is an indication of possible barriers to obtaining medical care either because the participant felt the staff at the office or clinic where they received their medical care were disrespectful or insensitive to their needs, didn t understand their problems, or were not good at listening to their problems or needs. For the second measure, two questions measuring patient satisfaction were combined such that participants were regarded as being satisfied with their interaction if they felt that their current medical provider both understood very well what was bothering them and showed a high level of concern or interest in their problems and needs. Not surprisingly the most important medical care characteristic related to use of combination therapy was current access to medical care. Although virtually all CHAIN participants report having a current provider, a very small number (n=22 at Time 4) did not report a physician visit within six months of the interviews. Very few of these participants reported current use of any antiretroviral combination (18%) or use of a combination that included a protease inhibitor (9%). Higher levels of use of combination therapy were associated with participants who had access to comprehensive primary care. Use of combination therapy was unrelated to the source of medical care, continuity of medical care, reported problems in obtaining medical care or satisfaction with provider interaction. By contrast, the organizational setting of medical care was the single most important provider variable related to use of DHHS recommended therapies. There was a more than 20 percent difference in use of the more potent therapies between participants who received care in a private practice (57%) compared to those receiving care in a clinic setting (percentages from 19% to 34%). Small but nonsignificant increases in use of more potent regimens were associated with longer continuity of medical care and access to comprehensive primary care. 21

Table 10: Source and Characteristics of Medical Care Any Combination Therapy 1 DHHS Recommended Therapies 2 Time 3 3/96-12/96 Time 4 10/96-9/97 Time 3 3/96-12/96 Time 4 10/96-9/97 All Participants (N=479/419) 40% 59% 14% 34% Source of Medical Care Private Practice (59/60) HHC Clinic (90/76) Voluntary Hospital Clinic (202/178) Freestanding Clinic (71/55) Other (36/36) 66% 31% 43% 42% 25%*** 68% 64% 56% 57% 64% 41% 12% 14% 7% 3%*** 57% 34% 31% 33% 19%*** Continuity of Medical Care Has Same Provider Since Time 4 interview (NA/125) Time 3 Interview (108/44) Time 2 Interview (58/35) Time 1 Interview (294/203) -- 37% 43% 43% 58% 61% 60% 61% -- 10% 21% 16% 30% 32% 34% 38% Saw a Physician Six months Before interview Yes (449/397) No (30/22) 43% 10%*** 61% 18%** 15% 0% 35% 9% Has Access to Comprehensive & Coordinated Medical Care Yes (263/249) No (216/170) 49% 30%*** 66% 56%*** 17% 11%* 37% 29%* Experienced Problems in Obtaining Medical Care Yes (63/42) No (416/377) 51% 39% 55% 59% 14% 14% 33% 34% Satisfied with interaction with MD Yes (334/312) No (145/85) 41% 40% 62% 49% 15% 12% 34% 31% Source: Time 3 and Time 4 CHAIN Surveys *p #.05 **p #.01 ***p #.001 1 Currently taking two or more antiretroviral medications 2 Currently taking a preferred or alternative antiretroviral therapy according DHHS Guidelines 22

Table 11: Insurance Coverage and Antiretroviral Therapy Any Combination Therapy 1 DHHS Recommended Therapies 2 All Participants (N=479/419) Time 3 3/96-12/96 Time 4 10/96-9/97 Time 3 3/96-12/96 40% 59% 14% 34% Time 4 10/96-9/97 Type of Insurance Private (46/41) Medicaid (332/284) Other Public Insurance(87/82) Uninsured (14/12) 59% 35% 53% 29%** 70% 56% 66% 42% 33% 11% 21% 7%** 59% 27% 48% 17%*** Enrolled in ADAP+ Yes (52/43) No (427/376) 60% 38%** 74% 57%* 23% 13% 56% 31%** Enrolled in a Managed Care Plan Yes (49/48) No (430/371) 47% 40% 65% 58% 22% 13% 46% 32% Source: Time 3 and Time 4 CHAIN Surveys *p #.05 **p #.01 ***p #.001 1 Currently taking two or more antiretroviral medications 2 Currently taking a preferred or alternative antiretroviral therapy according DHHS Guidelines Even fewer participants were currently uninsured than lacked access to medical care, but here too absence of insurance more than the type of insurance coverage was a key determinant of use of combination therapy. What is perhaps surprising is that even among the very small number of uninsured participants at Time 4 interviews, 42 percent or 5 of 12 participants said they were currently taking a combination therapy. Participants receiving Medicaid are less likely than those with private insurance or enrolled in another public sector insurance program (mainly Medicare) to be taking a combination therapy and significantly less likely to be on a DHHS recommended therapy. Enrollment in ADAP+ is also associated with increased use of combination therapy. Enrollment in managed care plans slightly increases in use of combination therapy, but the 23

difference is not statistically significant. Interpretation of these findings is further complicated by the fact that almost all the managed care plans are private insurers. A Multiple Regression Analysis: Summary of Participant and Provider Characteristics that Influence Use of Combination Therapy Multiple regression analysis was performed to distill the most salient influences on use of combination therapy from the large number of participant and provider characteristics examined above. This analysis estimated the simultaneous influence of all characteristics except those few which exhibited no discernable association with Time 4 use of combination therapies. 5 A small number of CHAIN participants (n=22) who had not seen a physician during the six months prior to time 4 interviews were drop from this analysis, as recent contact with a medical provider was virtually a prerequisite for use of combination therapy. Regression equations, which adjusted for stage of disease (CD4 T-Cell count), were estimated to select the most important correlates of the use of any combination therapy and then use of a DHHS recommended therapy (essentially three or more medications that included a protease inhibitor). Table 12 summarizes the results of the analysis. The interested reader is directed to the appendix to this report for a more detailed presentation of the regression methodology and findings. Table 12 lists all factors included in the regression analysis. The middle column identifies the most important correlates of the use of combination therapy and the right most column identifies those for combinations with protease inhibitors. Table 12 highlights these characteristics that were highly (++,.p<.01) and moderately ++.(p<.05) correlated with the combination therapy outcomes after adjusting for CD4 T-cell counts and all other explanatory factors. A third category covers influences that fell below conventional levels of statistical significant + (p<.2); nonetheless exert relatively large influence on use of combination therapy. Declining CD4 T-cell count was the strongest predictor of use of combination therapy whether or not it included a protease inhibitor. After taking into account disease progression, having medical care, which participants regarded as comprehensive, coordinated and accessible 24- hours-a-day, exerted the strongest influence on use of any combination therapy. To a lesser extent current social circumstances of CHAIN participants also directly influenced use of any combination therapy. CHAIN participants were less likely to use combination therapy if they had disclosed their HIV status to only a small number of friends and family and their housing situation was unstable. 5 Household composition, satisfaction with medical care provider, and barriers to medical care were dropped for this reason. Stage of HIV disease was also dropped as its influence could be entirely explained by CD4 T-cell count. 24

Table 12: Summary of Most Important Patient and Provider Characteristics Associated with Use of Combination Therapy at Wave 4 October 1996 to September 1997 (All Results Adjusted for CD4 Counts and Date of Interview) Any Combination CD4 T-Cell Count --- --- Gender Ethnicity (Compared to Whites) Black Latino + DHHS recommended Therapies Educational Attainment (Grades Completed) +++ Annual Income Unstable housing Conditions - - Current Problem Drug Use # of friends or family know R has HIV ++ + Private Practice Medical Care Continuity ++ Private Insurance Coverage + Covered by ADAP+ + + Comprehensive, Coordinated and Accessible Medical care +++ (N=392) (N=392) +/- Marginal influence ++/-- Moderate influence +++/--- Strong Influence - category/higher values associated with lower use of antiretroviral Medications. See Appendix for underlying logistic regression coefficients used in constructing this table. 25

Finally, coverage by ADAP+ was marginally associated with use of combination therapy independent of the characteristics of one s medical provider. 6 A somewhat different set of factors was associated with use of more potent combination therapies that included a protease inhibitors. Educational attainment was the single most important factor predicting use of antiretroviral combinations that included protease inhibitor. Although blacks and Latinos have significantly lower rates of use of DHHS recommended antiretroviral therapies than whites, the regression analysis attributes these ethnic differences largely to the higher educational attainment of whites. Current social circumstances as measured by unstable housing conditions and size of social network aware of participants HIV status continued to be important if now secondary influences on use of combination therapies with protease inhibitors. Among features related to medical care, continuity is the most important influence. To a lesser degree, private insurance and ADAP+ coverage are associated with increased use of protease inhibitors. Third Party reimbursement Tables 13 and 14 summarize CHAIN participant third party reimbursement for antiretroviral therapy. There are two important finding from these tables. First, Medicaid continues to be, by far, the single most common source of payment for antiretroviral therapy. Medicaid pays for medication for about 90 percent of people on monotherapy or an NRTI combination. Private insurance and ADAP cover a larger share of the emerging demand for protease inhibitor. Nonetheless, 77 percent of CHAIN participants who use protease inhibitors are covered by Medicaid. Table 14 shows the other important finding: there are large ethnic differences in who pays for these medications. Although Medicaid is the single largest payer for all three race/ethnic groups, white participants are much more likely than either blacks or Latinos to obtain reimbursement through either private insurance prescription programs or ADAP. These patterns are essentially unchanged from Time 3 interviews, although a much larger portion of the CHAIN cohort are now taking these medications. 6 The marginal positive influence of Latinos on use of combination therapy after adjusting for other factors, underscores that Latinos had achieved relative parity with whites regarding use of combination therapy despite tending to access types of medical care that were associated with lower use of combination therapy. 26

Table 13: Third Party Reimbursement for Antiretroviral Therapy Fourth Round (10/96 to 9/97) Reimbursement for Monotherapy (n=) Medicaid Private Insurance ADAP Reimbursement for Combinations with Reverse Transcriptase Inhibitors (n=) Medicaid Private Insurance ADAP Reimbursement for Combinations with Protease Inhibitor (n=) Medicaid Private Insurance ADAP (34) 88% 3% 6% (73) 90% 3% 8% (180) 77% 12% 12% Source: Time 4 CHAIN Survey Table 14: Third Party Reimbursement for Antiretroviral Therapy and Ethnicity Fourth Round (10/96 to 9/97) White Black Latino Reimbursement for Reverse Transcriptase Inhibitors (n=) Medicaid Private Insurance ADAP (11) 64% 18% 27% (62) 95% 0% 3% (34) 88% 3% 9% Reimbursement for Combinations with Protease Inhibitor (n=) Medicaid Private Insurance ADAP (40) 53% 35% 20% (77) 84% 6% 10% (62) 85% 5% 6% Source: Time 4 CHAIN Survey 27

Conclusion and Policy Implications In a relatively short period of time combination antiretroviral therapy has become standard practice in New York City. At the time of the fourth round of interviews, approximately 60 percent of CHAIN participants were taking a combination therapy and one-third were taking more potent combinations that included a protease inhibitor. However, these percentages give at best a crude idea as to the extent to which drugs are reaching all those who would gain demonstrable clinical benefits from state-of-the-art antiretroviral therapy. DHHS guidelines allow for broad clinical discretion when it comes to deciding when to initiate antiretroviral therapy, but the guidelines unequivocally recommend that all people with low CD4 T-cell counts should be treated with triple drug therapy. To obtain a more accurate sense of how many people not taking a potent antiretroviral therapy would, following current clinical guidelines, be strongly advised to initiate such therapy, we calculate the percentage of CHAIN participants interviewed at Time 4 (N=419) who are both not taking the more potent antiretroviral combinations and have CD4 T-cell counts below 300. Roughly a quarter of the CHAIN participants were currently not taking a triple drug combination at time 4 interviews but were likely to obtain immediate clinical benefits because of a low CD4 T-cell count. About 13 percent of the CHAIN cohort had CD4 T-cell counts below 300 but were not on any antiretroviral therapy; an equal number were candidates for an upgrade from a two-drug to three-drug combination. There remains approximately 40 percent of the cohort (100%-34% [currently on triple drug inhibitors] - 25% [Low CD4 not on triple drug therapy]) who would fall into what we might term a watch and wait status. These are people with relatively high CD4 T-cell counts (above 300), who are on no anti-retroviral therapy or on a two-drug combination. Some caution should be taking in interpreting the above breakdowns as a strict measure of need. They should be treated as order of magnitude estimates of the upper bound of the current and future unmet demand for these medications. Undoubtedly some proportion of people will not find success with these drugs. They may have tried and have stopped using them either because of adverse reaction or difficulties in adhering to the regimen. The CHAIN data indicate that all segments of the HIV positive community shared in the large increase in access to the new therapies between the third and fourth interviews. Although there are disparities in use of combination therapies, there appears to be no identifiable subgroup that can be singled out as being at an extreme disadvantage in obtaining these medications. In fact, comparison between third and fourth rounds of interview suggest that the influence of sociodemographic characteristics and current social circumstances appears to be diminishing with time. It would appear from the CHAIN data that the social attributes of patients do not loom large in decisions about the use of combination therapy, but they continue to influence who is taking protease inhibitors. 28