Prospective Study of Infective Endocarditis among Injection Drug Users
[Wilson LE et al. JID 2002;185:1761]:
Date Posted:07-01-2002 | The authors report an analysis of cases of endocarditis from 1988-1998 among participants in the "AIDS Link to Intravenous Experiences" (ALIVE) cohort, which has 2,946 participants. Cases were matched with up to five randomly selected controls. Results showed that there were 2,529 subjects followed for 16,469 patient-years, with 117 cases of endocarditis, for an incidence of 7.1 cases/1,000 patient-years. The incidence was four-fold higher among those with HIV infection: 13.8 cases/1,000 patient-years vs. 3.3 cases/1,000 patient years. The risk was inversely correlated with CD4 cell count: with a count >500 cells/mm3, there was no increased risk, but the odds ratio was 1.8 with a CD4 cell count of 200-500 cells/mm3, and it was 3.8 with a CD4 cell count <200 cells/mm3. With regard to etiology, blood cultures yielded S. aureus in 73%, staph species that were not otherwise classified in 7%, strep species in 13%, Pseudomonas in 2%, and other organisms in 5%.
COMMENT: The risk of endocarditis in the general population is about 1/100,000/year. The results of this study suggest that the risk with injection drug use is nearly 1,000 times greater and possibly comparable to that associated with prosthetic heart valves. The additional risk associated with HIV infection in this population has been variable according to prior reports, but most have found that HIV confers additional risk (AIDS 1996;10:1407; Epidemiology 1996;7:566; JID 1990;162:967). Other variables that significantly affected risk in the study summarized above include active vs. inactive drug use (OR 3.3), frequent injection drug use (OR 4.0 for daily use), and female sex (OR 3.3).
By John Bartlett MD |
In Vitro Antiviral Interaction of Lopinavir with Other Protease Inhibitors
[Molla A et al. AAC 2002;46:2249]:
Date Posted:07-01-2002 | This is a report from Abbott Laboratories on the activity of lopinavir combined with other protease inhibitors vs. HIV-1 in vitro. The companion drugs tested were indinavir, amprenavir, tipranavir, and BMS-232632. All of these PIs in combination with lopinavir showed an additive effect, except for saquinavir plus lopinavir, which showed a statistically significant synergy over a broad range of combination ratios.
By John Bartlett MD |
Evaluation of Initial CD4 T Cell Counts in Individuals with Newly Diagnosed Human Immunodeficiency Virus Infection, by Sex, and Race, in Urban Settings
[Dybul M et al. JID 2002;185:1818]:
Date Posted:07-01-2002 | The authors report a study of initial CD4 cell counts in 2,223 patients with newly diagnosed HIV infection at four community-based clinics. The results showed that 1,261 (57%) had an initial CD4 count <350 cells/mm3, and 796 (36%) had CD4 counts <200 cells/mm3. There were no important differences based on race or sex. The authors express concern that this many patients learn of HIV infection relatively late in the course of the disease and emphasize the need for educational efforts in HIV testing, particularly those that target those at HIV risk.
By John Bartlett MD |
Effect of Highly Active Antiretroviral Therapy on Incidence of Tuberculosis in South Africa: A Cohort Study
[Badri M et al. Lancet 2002;359:2059]:
Date Posted:07-01-2002 | This is a report from New Somerset Hospital HIV Clinic, University of Cape Town, South Africa which has a clinical trials program for HIV-infected persons including 12 trials conducted from 1995-2001. The current report concerns 264 participants who received HAART as compared with 770 controls in terms of impact on TB rates. The results showed that HAART treatment reduced the incidence of tuberculosis from 9.7 cases/100 patient-years to 2.4 cases/100 patient-years (p = 0.0001). This represents a reduction of more than 80%. The reduction was greatest in those with more advanced disease as indicated by CD4 cell count and by WHO stage. These results are summarized in the following table:
|
| HAART
n = 264
| Non-HAART
n = 770
| | Cases of TB
| 9
| 82
| | Incidence (/100 pt-yrs)
| 2.4
| 9.7
| | CD4 < 200
| 3.4
| 17.5
| | CD4 > 350
| 2.0
| 3.6
|
By John Bartlett MD |
Tenofovir DF in Antiretroviral-Experienced Patients: Results from a 48-Week, Randomized, Double-Blind Study
[Schooley RT et al. AIDS 2002;16:1257]:
Date Posted:07-09-2002 | This is a phase II study (GS-98-902) in which 189 patients with HIV RNA levels of 400-100,000 c/ml on stable antiretroviral regimens were randomized to receive intensification with tenofovir in doses of 75 mg, 150 mg or 300 mg/day or placebo. Efficacy was analyzed by changes in viral load at 4, 24 and 48 weeks. The results showed that the optimal results were achieved with the 300 mg dose; the average decrease in viral load in this group was 0.6 log10 c/mL at each of the time intervals examined. This result was significantly better than with both the lower dose and placebo. The increase in CD4 cell count in the 300 mg/day group was an 11 cells/mm3 at 48 weeks. Toxicity monitoring showed little: diarrhea was the only side effect that appeared more common in tenofovir recipients compared with controls (21-25% vs. 14%). The frequency of proteinuria was 14% in placebo recipients compared with 7% in tenofovir recipients at 24 weeks. The authors conclude that tenofovir added to a failing antiretroviral regimen has a significant antiviral affect, is well tolerated, has the simplicity of a single pill once daily, and is rarely associated with the emergence of drug resistant mutations.
By John Bartlett MD |
Genotypic and Phenotypic Analyses of HIV-1 in Antiretroviral-Experienced Patients Treated with Tenofovir DF
[Margot NA et al. AIDS 2002;16:1227]:
Date Posted:07-09-2002 | This is a report on resistance testing in the study summarized above , the phase II dose-finding study of tenofovir added to a stable antiretroviral regimen with persistent viremia. The addition of tenofovir at 300 mg/day was associated with a sustained reduction in viral load of at least 0.5 log10 c/ml in most of the patients who had sensitivity tests at baseline which showed TAMs, M184V mutations and resistance mutations to NNRTI or PIs. There was no evidence of novel resistance to tenofovir by genotypic or phenotypic testing. The authors conclude that the addition of tenofovir to an existing regimen with virologic failure is effective over a wide range of genotypic resistance patterns and the antiviral effect is sustained through at least 48 weeks.
By John Bartlett MD |
Interventions to Reduce Unintended Pregnancies Among Adolescents: Systematic Review of Randomized Controlled Trials
[DiCenso A et al. BMJ 2002;324:1426]:
Date Posted:07-10-2002 | The authors reviewed 12 electronic bibliographic databases, ten key journals, citations of relevant articles, and contacted authors to identify 26 trials in 22 published and unpublished reports in which adolescents were randomized to an intervention vs. control group designed to reduce sexual intercourse, improve use of birth control, and reduce pregnancies. Pooled results showed that these interventions did not delay the initiation of sexual intercourse (OR 1.1 for women and 1.0 for men) and did not improve birth control (OR 0.95-1.25). Furthermore, four abstinence programs showed a significant increase in the number of pregnancies. The authors concluded that "primary prevention strategies evaluated to date do not delay the initiation of sexual intercourse, improve use of birth control ...or reduce the number of pregnancies."
COMMENT: Although this meta-analysis was primarily intended for studies designed to avoid unintended pregnancies, the observations are highly relevant in issues pertaining to infectious diseases, primarily STDs including HIV.
By John Bartlett MD |
Association of a Pool of HIV-1 with Erythrocytes In Vivo: A Cohort Study
[Hess C et al. Lancet 2002;359:2230]:
Date Posted:07-10-2002 | The investigators from Switzerland examined erythrocytes for evidence of HIV RNA by RT-PCR in 82 chronically infected patients. The results showed erythrocyte-associated HIV in 80 (98%), including 23 who had no detectable virus with <20 c/ml for up to 32 months. The median concentration of erythrocyte-associated HIV RNA was 1,587 c/ml and for the subgroup with no detectable virus with standard testing it was a median of 566 c/ml. The HIV was in immune complexes bound to erythrocytes and proved replication competent. The authors conclude that this HIV in immune complexes bound to erythrocytes represents a significant and previously unrecognized viral pool and that the observations further emphasize the failure of current treatment strategies to eradicate this virus.
COMMENT: The accompanying commentary by J. Levy [Lancet 2002;359:2212] concludes that the study showed "convincingly that HIV-1 RNA and infectious virus can be found, bound to erythrocytes and circulating in the blood of the vast majority of HIV-infected individuals." The concentration in WBCs is much larger, but the RBC pool is much greater, making these cells a potentially important source of viral RNA. This erythrocyte-bound HIV is potentially transmissible and can transport HIV to other cellular targets. Dr. Levy also raises the question about the use of this newly detected pool of HIV to measure virologic outcomes, although this approach may lead to treatment that is unnecessary or even dangerous.
By John Bartlett MD |
Randomized, Open-Label, Comparative Trial to Evaluate the Efficacy and Safety of Three Antiretroviral Drug Combinations Including Two Nucleoside Analogues and Nevirapine for Previously Untreated HIV-1 Infection: The OzCombo 2 Study
[French M et al. HIV Clin Trials 2002;3:177]:
Date Posted:07-10-2002 | This is a report of a study from Australia in which treatment-na ve patients with early HIV infection were randomized to receive three different combinations of NRTIs with nevirapine. The results showed comparable outcome in terms of viral load suppression, CD4 cell count increase and frequency of adverse reactions, as summarized in the table below:
|
| NVP + AZT + 3TC
(n = 20)
| NVP + d4T+ 3TC
(n = 22)
| NVP + d4T + ddI
(n = 23)
| | Completed 52 weeks
| 80%
| 73%
|
70%
| | ADR-Grade 3 or 4
| 20%
| 23%
|
22%
| | Decrease VL (wk 52)
| -1.64*
| -1.1*
|
-2.0*
| | VL < 500 c/ml
| 70%
| 68%
| 87%
| | CD4 count increase
| 172/mm3
| 201/mm3
| 190/mm3
| | * Log 10 c/ml
|
COMMENT: This is an interesting and important study. The main limitation is the small sample size and the need for a longer follow-up for long-term toxicity results. Nevertheless, the results in the short haul look comparable for the three most commonly used dual NRTI combinations.
By John Bartlett MD |
SENC (Spanish Efavirenz vs. Nevirapine Comparison) Trial: A Randomized, Open-Label Study in HIV-Infected Na ve Individuals
[Nunez M et al. HIV Clin Trials 2002;3:186]:
Date Posted:07-10-2002 | This is a report from Spain in which treatment na ve patients with CD4 counts >100 cells/mm3 were randomized to receive d4T + ddI combined with either nevirapine or efavirenz. Patients with a viral load >100,000 c/ml were excluded. The results showed comparable outcomes in terms of virologic results and adverse reactions as summarized in the following table:
|
| EFV
n= 36
| NVP
n= 31
| | VL < 500 c/ml 48 weeks
| 74%
| 64%
| | Adverse reactions
|
|
| | Rash
| 3 (10%)
| 4 (11%)
| | CNS toxicity
| 12 (41%)
| --
| | Transaminase
| 5 (17%)
| 9 (26%)
| | Cholesterol > 300 mg/dL
| 5 (17%)
| 1 (3%)
|
COMMENT: This study addresses the ongoing debate over the relative merits of nevirapine and efavirenz. An obvious limitation is the small numbers. The outcome was similar in the two groups, but there were some differences in this and other studies that should be acknowledged. With regard to potency, a prior observational study has suggested superior outcome for efavirenz compared to nevirapine [AIDS 2001;15:2385], and this report includes three virologic failures, all in the nevirapine arm. In regard to toxicity, there was the expected difference in the two drugs with respect to CNS toxicity. The frequency of hepatotoxicity was greater in the nevirapine arm, but it was also relatively high with efavirenz as previously noted by others [Hepatology 2002;35:182]. Hypercholesterolemia was more frequent with efavirenz in this study as it has been in others as well [Clin Infect Dis 2000;31:1266; J Acquir Immune Defic Syndr 2001;28:496).
By John Bartlett MD |
China and AIDS -- The Time to Act is Now
[Kaufman J and Jing J. Science 2002;296:2339]:
Date Posted:07-10-2002 | This report from the "Policy Forum" in Science reviews the recent reports regarding HIV in China. The sentinel surveillance reports indicate 250,000 cases [China Daily, April 12, 2002]. This represents <0.1% of the population, but there is also a 67% increase in incidence rate compared to results for 2000. Projections are for 10 million cases by 2010.
By John Bartlett MD |
Human Immunodeficiency Virus (HIV) Type 1 Reverse Transcriptase Resistance Mutations in Hepatitis B Virus (HBV)-HIV-Coinfected Patients Treated for HBV Chronic Infection Once Daily with 10 Milligrams of Adefovir Dipivoxil Combined with Lamivudine
[Delaugerre C et al. Antimicrob Agents Chemother 2002;46:1586]:
Date Posted:07-10-2002 | Adefovir is highly active against hepatitis B, but a concern is that its use in HIV-HBV-coinfected patients might result in mutations at codons 65 and 70 or other HIV-1 RT resistant mutations. A prior report showed excellent activity of adefovir plus lamivudine in terms of inhibition of HBV [Lancet 2001;358:718]. The present study analyzed HIV isolates from 13 participants in this trial to determine genotypic resistance patterns for HIV. This failed to show evolution of resistance despite the low dose (10 mg/day) of adefovir for up to one year of treatment.
COMMENT: Lamivudine is highly active against HBV, making it very attractive for co-infected patients. The problem is the high rates of resistance by HBV, which are 15-30% in immunocompetent HBV-infected patients with one year of treatment, and 90% in those with HIV co-infection. The use of adefovir either alone or in combination with lamivudine is an attractive option, and the initial results with seven months of combination treatment showed good tolerance and significant activity against lamivudine-resistant HBV. The paper summarized above provides additional assurance regarding another potential concern with this combination. Nevertheless, much of the enthusiasm for adefovir has been blunted by the extraordinarily good activity of tenofovir.
By John Bartlett MD |
Impact of Active Drug Use on Antiretroviral Therapy Adherence and Viral Suppression in HIV-Infected Drug Users
[Arnsten JH et al. J Gen Intern Med 2002;17:377]:
Date Posted:07-10-2002 | This is a report from the Bronx HIV Epidemiologic Research on Outcomes (HERO) cohort at Montefiore Medical Center to determine the correlation between adherence, drug abuse behavior, and viral suppression. HIV-infected patients were selected if they were currently receiving antiretroviral therapy and were willing to use MEMS caps. There were 85 participants followed a median of 157 days. The overall adherence rate was 53%, the mean percent of days in which at least one dose was taken was 64%, and the mean percent of days on which the correct number of doses was taken was 38%. Virologic results showed that 31 participants (37%) maintained a mean viral load of <500 c/ml during the six months of observation. The strongest predictor for poor adherence and virologic failure was active cocaine use. Among this group, adherence was 27% in cocaine users compared to 68% in those with no cocaine use. Viral suppression was achieved in 13% of active cocaine users and 46% of non-users.
COMMENT: This study shows a relatively poor virologic result, but all of the patients were either active or prior injection drug users, and most (85%) were antiretroviral experienced. As with other studies, the results with both adherence monitoring and virologic outcome for those not actively using cocaine is similar to that of other populations [AIDS 2000;14:357; AIDS 1998;12:2295].
By John Bartlett MD |
Cost-Effectiveness of HIV/AIDS Interventions in Africa: A Systematic Review of the Evidence
[Creese A et al. Lancet 2002;359:1635]:
Date Posted:07-10-2002 | This is a systematic review of databases and consultations with over 60 reports measuring cost effectiveness of HIV/AIDS interventions in Africa. The report is based on 24 studies, with results reported for the cost/case of HIV prevented and the cost per disability-adjusted life-year (DALY) gained. The results are summarized in the following table:
| Issue
| Cost/HIV Case
Prevented
| Cost/DALY
Gained
| Comment
| | Condom distribution
| $11-$2188
| $1-$99
| Variation by target population
| | Blood safety screening
| $18-$107
| $1-$5
| Defer high risk donors or rapid serology
| Perinatal tx
NVP regimen
AZT regimen
|
$20-$268
$949-$2356
|
$1-$12
$33-$81
|
Breast feeding-separate issue
| | Treatment STDs
| $271
| $12
|
| | Voluntary testing & counseling
| $393-$482
| $18-$22
|
| Short source active TB Rx
DOT
|
-
-
|
$2-$16
$14-$21
|
Ambulatory care
| | TMP-SMX prophylaxis
| -
| $6
| HIV pos. TB pts.
| | Rx latent TB
| -
| $169-$288
|
| | Antiretroviral Rx
| -
| $1100-$1800
|
|
COMMENT: This report is highly topical due to the availability of the Global Fund, which now has $2,082,000 in pledges ( www.globalfundatm.org ). There was substantial variation among different interventions, including some that have not received high priorities in planning. Nevertheless, use of these data exclusively for planning decisions could be a mistake. For example, antiretroviral treatment appears to be a relatively inefficient method to apply resources, but may be effective in attempts to achieve other interventions (such as counseling), for prevention of new cases (by reduction in viral load), and by prevention of other morbid conditions (such as tuberculosis as recently demonstrated).
By John Bartlett MD |
The Global Fund to Fight AIDS, Tuberculosis and Malaria
[www.globalfundatm.org accessed 7/5/02 Global Fund 2002;website]:
Date Posted:07-10-2002 | Total funds and pledges now total approximately $2,082,000. The major donors, with donations of at least $50 million, are tabulated below in rank order:
| Global Fund: Major Donors (7/5/02)
| | Country
| Pledge (x $1,000)
| | United States
| 500,000
| | Japan
| 200,000
| | Italy
| 200,000
| | U.K.
| 200,000
| | France
| 131,200
| | Germany
| 131,200
| | Netherlands
| 118,100
| | European commission
| 105,000
| | Canada
| 100,000
| | Gates Foundation
| 100,000
| | Sweden
| 58,000
| | Spain
| 50,000
| | Total
| 2,081,888
|
By John Bartlett MD |
Long-Term Metabolic Consequences of Switching from Protease Inhibitors to Efavirenz in Therapy for Human Immunodeficiency Virus-Infected Patients with Lipoatrophy
[Estrada V et al. Clin Infect Dis 2002;35:69]:
Date Posted:07-17-2002 | This is the report of a study from Madrid in which 41 patients with prolonged viral suppression and metabolic complications of PI-based HAART were switched to efavirenz-based HAART. Results were available for a one year follow-up in 28 participants. All 28 maintained an HIV viral load less than 50 c/ml. The mean CD4 count increased 94 cells/mm3 (mean of 483 to 577 cells/mm3). However, there was essentially no change in lipid profile, insulin resistance, or abdominal or subcutaneous fat. Details are provided in the following table:
|
| Entry
| Wk 48
| | Body mass index (kg/m2)
| 23.7
| 23.8
| | Waist-hip ratio (cm)
| 0.96
| 0.98
| | Fasting glucose (mg/dh)
| 93.8
| 99
| | Fasting insulin (uU/mL)
| 13.2
| 15.3
| | 2 hr. OGTT (mg/dL)
| 105
| 112.5
| | Cholesterol (mg/dL)
| 230.7
| 228
| | LDL cholesterol (mg/dL)
| 122
| 128
| | Triglyceride
| 346
| 311
|
COMMENT: Given the interest in PI-sparing regimens for patients with metabolic consequences ascribed to PIs, these results are disappointing. Prior switch studies with abacavir for the PI have shown a reduction in cholesterol and triglyceride levels, and a switch to nevirapine has shown reduction in triglyceride levels and variable effects on cholesterol. Perhaps the biggest surprise with the efavirenz switch is the lack of an effect on insulin resistance, which seems to be most clearly associated with PI use. The good news here is the continual viral suppression and the increase in CD4 cell count to the point where therapeutic discontinuation would represent an alternative strategy for many or most of the participants.
By John Bartlett MD |
High Prevalence of Osteonecrosis of the Femoral Head in HIV-Infected Adults
[Miller KD et al. Ann Intern Med 2002;137:17]:
Date Posted:07-17-2002 | In this study from the NIH Clinical Center, 339 asymptomatic HIV-infected adults underwent MRI to determine the frequency of osteonecrosis of the hip. There were 118 age and sex matched HIV negative controls. The results showed osteonecrosis in 15 of 339 (4.4%) with HIV infection compared to 0/118 controls. The difference is highly significant. Comparison of HIV-infected patients with or without osteonecrosis showed no difference by age, sex, race, risk factor, CD4 cell count, viral load, antiretroviral therapy, blood lipids or CBC. The risk was increased for those who had received corticosteroids, lipid-lowering agents or testosterone. The authors conclude that patients infected with HIV have an increased rate of osteonecrosis of the hip.
COMMENT: This report seems to clearly identify HIV infection as a risk for osteonecrosis of the hip. The confounding variable was the use of selected medications that could be implicated, including steroids, testosterone or lipid-lowering agents. The practical application of the information was the author s recommendation to avoid routine MRI screening simply due to low frequency and high cost of MRIs, but to consider this diagnostic possibility in patients who complain of groin or hip pain.
By John Bartlett MD |
Hepatitis C and Progression of HIV Disease
[Sulkowski MS et al. JAMA 2002;288:199]:
Date Posted:07-17-2002 | This is a report from the Johns Hopkins Moore Clinic using the Moore Clinic database to assess the impact of HCV co-infection on the rate of progression of HIV. The analysis involved 873 patients with HCV-HIV co-infection and 1082 with only HIV infection. The median duration of follow-up was 2.2 years. The results showed no significant difference in the rate of HIV infection in terms of the number of AIDS-defining events, deaths, or the rate of progression to a CD4 count less than 200 cells/mm3 when adjusted for therapy and baseline CD4 cell count. The authors conclude that HCV infection does not substantially alter the risk of dying, developing AIDS or responding to HAART. Results are shown in the following table for baseline data and outcome according to AIDS-defining events and mortality.
|
| HCV infection
n = 873
| No HCV infection
n = 1082
| | Baseline
|
|
| | - CD4 <200/mm3
| 55%
| 59%
| | - HIV RNA > 10K c/ml
| 63%
| 66%
| | - IDU
| 13%
| 85%
| | Outcome
|
|
| | - AIDS defining events
| 26%
| 24%
| | - Death
| 18%
| 16%
|
COMMENT: The fact that HIV infection notably augments the rate of progression of HCV appears well established. There are controversial or conflicting data about the affect of HCV on the rate of HIV infection. This large study supports the impression that there is little or no impact.
By John Bartlett MD |
Time Trends in Primary HIV-1 Drug Resistance Among Recently Infected Persons
[Grant RM et al. JAMA 2002;288:181]:
Date Posted:07-17-2002 | The authors report their experience with 225 consecutive patients referred for evaluation of recent HIV infection in San Francisco. Eligible patients were untreated, with acute HIV or seroconversion within 12 months. HIV strains were tested by genotypic and phenotypic analysis for resistance, and resulted were compared for 1996-97, 1998-99 and 2000-01. Results for NRTI showed a 25% rate of a resistance mutation in the early period of review, which decreased in the second period, and then went back to baseline in the third period. The results with NNRTI showed an increase from 0 in 1996-97 to 13% in 2000-01 (p = 0.01). For PIs, genotypic resistance was noted for two classes in 1/40 (2%) isolates in 1996-97 and in 12/91 (13%) in 2000-01. There was only one strain resistant to all three classes in the last period of study. Results with phenotypic analysis showed similar trends. These results are summarized in the following table:
|
| 1996-97
n = 40
| 1998-99
n = 94
| 2000-01
n = 91
| Resistance-genotypic
- NRTI-any
|
25%
|
7%
|
21%
| | - M184V
| 10%
| 2%
| 8%
| | NNRTI-any
| 0
| 6%
| 13%
| | PI-any primary
| 3%
| 5%
| 8%
| | Any
| 25%
| 18%
| 27%
| | Two classes
| 3%
| 1%
| 13%
| | Three classes
| 0
| 0
| 1%
| | Resistance-phenotypic
|
|
|
| | - NRTIs
| 21%
| 3%
| 6%
| | - NNRTIs
| 0
| 4%
| 10%
| | - PIs
| 3%
| 2%
| 6%
|
COMMENT: This report shows an anticipated increase in primary drug resistance. Nevertheless, resistance to two or more classes is unusual, and resistance to all three classes is extraordinarily rare.
By John Bartlett MD |
Dual vs. Single Protease Inhibitor Therapy Following Antiretroviral Treatment Failure: A Randomized Trial
[Hammer SM et al. JAMA 2002;288:169]:
Date Posted:07-17-2002 | This is a report of ACTG 398 which examined the relative merits of amprenavir combined with one of three PIs or placebo. All participants received abacavir, efavirenz and adefovir. There were 481 HIV-infected persons; all had prior exposure to HAART with virologic failure defined as a viral load exceeding 1000 c/ml. The PI regimens were saquinavir (1600 mg bid), indinavir (1200 mg bid), nelfinavir (1250 mg bid) or placebo. The results at 24 weeks based on intent-to-treat analysis showed virologic success (viral load < 200 c/ml) in 31%, with the best results in patients who received 2 PIs, and in patients who were naive to prior exposure to NNRTIs. The results are summarized in the table below:
| Salvage therapy with APV, ABC, EFV and Adefovir
| |
| SQV
| IDV
| NFV
| Placebo
| | No. enrolled
| 116
| 69
| 139
| 157
| | No. w/ VL <200 c/mL at week 24
| 40 (34%)
| 25 (36%)
| 47 (34%)
| 36 (23%)
| | Decrease in VL log10 c/mL
| -1.9
| -1.8
| -1.6
| -1.0
| | ADRs gr ?
| 20%
| 22%
| 19%
| 15%
|
COMMENT: ACTG 398 is the largest, prospective, randomized trial of salvage therapy for PI failure reported to date. It is disappointing that only 31% of the patients had virologic suppression to less than 200 c/ml at 24 weeks. Nevertheless, the average viral load decrease was 1.4 log10 c/ml at 24 weeks. As perhaps expected, there was a significant benefit with dual PIs and benefit in those who were NNRTI-na ve, presumably because all patients received efavirenz. Thus, the rate of virologic suppression to <200 c/mL was 43% in the NNRTI-naive group compared to 16% in the NNRTI experienced group. Abacavir was also given to all patients, and is the most potent of the nucleosides, although this activity is substantially reduced in patients who have multiple nucleoside resistance mutations.
By John Bartlett MD |
Antiretroviral Treatment for Adult HIV Infection in 2002
[Yeni PG et al. JAMA 2002;288:222]:
Date Posted:07-17-2002 | The IAS-USA has released its annual guidelines for management of HIV infection. The following tables summarize the issue of when to start therapy, the initial regimen and toxicity monitoring:
| When To Start Antiretroviral Therapy: IAS-USA
| | Status
| Recommendation
| | Symptomatic HIV
| Treatment recommended
| | Asymptomatic with CD4 200 cells/mm3
| Treatment recommended
| | Asymptomatic CD4 >200 cells/mm3
| Treatment individualized based on
- CD4 count (some use 350/mm3)
- CD4 rate of decline >100/mm3/year
- HIV VL > 50-100,000 c/ml
- Risk of toxicity and drug-drug interactions
|
| Recommendations for Initial Therapy: IAS-USA
| 2 NRTIs + one PI + low dose RTV boost
2 NRTIs + and one NNRTI
3 NRTIs
Special circumstance: PI (+ low dose RTV) + NNRTI + 1-2 NRTI
|
| Adverse Reactions
| | ADR
| Cause
| Signs
| Monitoring
| Rx
| | Lactic acidosis
| NRTI
| GI, fatigue,
wt loss
lactate 
| Lactate levels not recommended
| D/C ART if lactate > 5 + sx or > 10
| | Lipids
| PIs esp RTV
| --
| Lipids at baseline +
gq 3-6 mos.
| NCEP guidelines
| | Diabetes
| PI s (?)
| --
| FBS baseline and
q 3-6 mos.
| Diet, exercise,
wt control metformin, etc.
| | Fat redistribution
| Complex issue
| --
| CT, MRI, DXA research tools only waist/hip
| None
| | Hepatitis
| All ART esp NVP,  risk w/HCV or HBV or d4T + ddI in pregnancy
| --
| LFTs with NVP at baseline
+ q 2 wks
| Avoid d4T
+ ddI in pregnancy
| | Bone necrosis osteoporosis
| Assoc w/ART unclear
|
| CT with sx
| As with gen. Population
| | Hypersensitivity
| NNRTI, ABC and AMP
| NNRTI-rash
ABC-fever
GI sx
| Warn
| Severe-stop drug
|
By John Bartlett MD |
Predictive Value of HIV-1 Viral Load on Risk for Opportunistic Infection
[Swindells S et al. JAIDS 2001;30:154]:
Date Posted:07-29-2002 | This is a report from AACTG 722 which was a substudy of AACTG 323 designed to determine relative efficacy of intermittent vs. continuous fluconazole for thrush in patients with a CD4 cell count <150/mm3 and prior thrush. Participants had viral load determinations every 16 weeks and were monitored for opportunistic infections. There were 518 participants and 45 events including 33 opportunistic infections and 12 cases of refractory thrush. There were two controls for each of the 45 with an "event." A multivariate analysis showed four important variables for the risk of an opportunistic infection: baseline HIV viral load, baseline CD4 cell count, a previous opportunistic infection, and a decline in viral load by at least one log at any time. The risk ratio for these variables is shown on the following table:
| Variable
| Risk ratio
| | Prior OI
| 5.2
| Baseline HIV RNA
- (/log10 c/mL increase)
| 2.2
| Change in HIV RNA
- (failure to achieve > 1 log decrease)
| 14.9
| Baseline CD4
- Baseline CD4 (/50/mm3 decrease)
| 6.0
|
COMMENT: The authors claim this to be the first prospective study to examine the role of viral load in predicting opportunistic infections. The relationships between risk and a prior OI and CD4 cell count are anticipated on the basis of prior studies. Failure to decrease viral load by at least one log conferred a risk of OI that was increased 15-fold. The authors note that current recommendations for discontinuing prophylaxis are based exclusively on the CD4 cell count and possibly should also consider viral load on the basis of these observations.
By John Bartlett MD |
Viral Replication Under Combination Antiretroviral Therapy: A Comparison of Four Different Regimens
[Ghani AC et al. JAIDS 2002;30:167]:
Date Posted:07-29-2002 | The authors compared the virologic outcome in four groups of patients who participated in clinical trials containing two to five antiretroviral drugs and then developed a mathematical model based on observations of viral load decreases at 7, 14 and 28 days. The results demonstrated that the regimen of two nucleosides was inferior to the regimens that contained a PI or a NNRTI. Results are shown in the following table:
|
| Change in HIV viral load:Median decrease (log10 c/mL)
| | 7d
| 14d
| 28d
| | AZT/3TC/RTV
| 1.5
| 1.9
|
2.5
| | AZT/3TC/ABC/IDV/NVP
| 1.5
| 1.8
|
2.1
| | AZT/ddI
|
1.2
| 1.9
|
2.1
| | AZT/ddI/NVP
| 1.1
|
1.7
| 2.4
|
COMMENT: The results are not surprising and are somewhat suspect on the basis of no information about adherence and low numbers with 10-12 patients/group. Nevertheless, a potentially important observation is that measurement of viral load after 7 days provided the most accurate measure of viral suppression.
By John Bartlett MD |
Incidence of and Risk Factors for Severe Hepatotoxicity Associated with Antiretroviral Combination Therapy
[Wit FWNM et al. JID 2002;186:23]:
Date Posted:07-29-2002 | The authors examined results of HAART as initial treatment for 560 patients treated at the Academic Medical Center at the University of Amsterdam for 1996-2000. Of the 560 participants followed a median of 3.0 years, 44 (8%) developed grade 4 hepatotoxicity as indicated by an ALT over 10 times the upper limits of normal. Risk factors that were statistically significant included female sex, elevated baseline ALT levels, chronic hepatitis due to HCV or HBV, recent discontinuation of 3TC (HBV subgroup), or recent initiation of nevirapine or ritonavir. Of the 44, nine were related to other factors such as acute hepatitis A, syphilis, alcohol abuse, etc. Of the 35 remaining patients, six (17%) were symptomatic, all 35 patients had resolution of grade 4 changes to grade 2 (2.5-5 times upper limit of normal) or less, none died of hepatotoxicity, and the median time to improvement to grade two was nine weeks. Of the 35 with hepatotoxicity, 23 continued treatment, and 12 discontinued or interrupted therapy for reasons unrelated to hepatotoxicity. A separate analysis of patients receiving low dose ritonavir showed risk of hepatotoxicity occurred only with doses of at least 300 mg twice daily. The results regarding risk expressed as odds ratio are summarized in the following table:
| Risk of Grade 4 Hepatotoxicity
| |
| Odds Ratio*
| | Female sex
| 2.8
| | Baseline ALT increase
| 1.1
| | Chronic HCV
| 5.0
| | Chronic HBV
| 9.2
| | Discontinue 3TC
| 6.8
| | Nevirapine
| 9.6
| | Ritonavir
| 4.9
| | *Multivariate analysis, all values are statistically significant (p = <0.05)
|
COMMENT: This report tends to confirm the observations of others concerning the risk of hepatotoxicity in patients with HIV infection who have chronic hepatitis with HCV or HBV and the risks associated with three specific antiretroviral agents: 3TC, nevirapine or ritonavir. For 3TC, the risk was discontinuation in the presence of chronic HBV infection, and the authors urge restraint from discontinuing this drug in that setting even with HIV resistance. Of interest is the observation that most of the patients had continued treatment through the episode and all had spontaneous improvement. Also of interest is the observation that the risk associated with ritonavir in the 372 patients who received this agent was dose-related.
By John Bartlett MD |
Spending on the HIV/AIDS Epidemic --Trends in U.S. Spending on HIV/AIDS
[Alagiri P et al. The Henry J. Kaiser Family Foundation 2002;July]:
Date Posted:07-31-2002 | This is a "policy brief" developed as a component of the "AIDS at 20: A National HIV/AIDS Policy Initiative" jointly sponsored by the Kaiser Family Foundation and the Ford Foundation. Since the beginning of the epidemic in 1981, the US government has invested over $100 billion for HIV-related research, education and medical care. Funding for FY02 totaled $14.7 billion; the budget request from President Bush totals $15.8 billion for FY03. The breakdown of the $14.7 billion allocated in FY02 showed the majority (94%) was for domestic activities, most (82%) was administered by DHHS, and most (59%) was for clinical care. The largest increase in recent years has been the allocation for global AIDS, but this increased to a total of only 6% of the total HIV budget for FY02 spending. A breakdown of the numbers is shown in the following three tables, which include a summary of the federal spending in FY02, by category (Table 1), a sequential analysis of total spending (Table 2), and a breakdown of sequential spending by category (Table 3):
| Table 1: HIV/AIDS Federal Spending for FY02
| | Category
| Amount (x $1 million)
| | Medical care
| $8,700 (59%)
| | Research
| $2,600 (18%)
| | Assistance
| $1,600 (11%)
| | Prevention
| $1,000 (7%)
| | Global*
| $800 (6%)
| | Total
| $14,700
| | * CDC - $144 million (14%), NIH - $188 million (19%), USAID - $435 million (43%) and Global Fund - $200 million (20%)
|
| Table 2: Sequential Total Spending
| | Year
| Amount*
| | 1985
| 0.2
| | 1990
| 3.1
| | 1995
| 6.8
| | 2000
| 11.8
| | 2001
| 13.9
| | 2002
| 14.7
| | * x $1 billion, rounded off
|
| Table 3: Sequential Spending by Category 1995-02*
| | Year
| Care (US)
| Ryan White
| Research
| Prevention
| International
| | 1995
| 3.5
| 0.7
| 1.4
| 0.7
| 0.1
| | 1996
| 4.1
| 0.7
| 1.5
| 0.6
| 0.1
| | 1997
| 4.9
| 1.0
| 1.6
| 0.7
| 0.1
| | 1998
| 5.6
| 1.2
| 1.7
| 0.7
| 0.1
| | 1999
| 6.3
| 1.4
| 1.9
| 0.8
| 0.1
| | 2000
| 7.1
| 1.6
| 2.1
| 0.8
| 0.2
| | 2001
| 8.5
| 1.8
| 2.3
| 0.9
| 0.6
| | 2002
| 8.7
| 1.9
| 2.6
| 1.0
| 0.8
| | * x $1 billion, rounded off
|
By John Bartlett MD |
Spending on the HIV/AIDS Epidemic -- Global Spending on HIV/AIDS in Resource-Poor Settings
[Alagiri P et al. Kaiser Family Foundation 2002;July]:
Date Posted:07-31-2002 | This is a summary of the "Global Spending on HIV/AIDS in Resource-Poor Settings," the third part of the three-part series sponsored by the Kaiser Family Foundation and the Ford Foundation. The UNAIDS reports that spending for HIV and other sexually transmitted diseases by 20 major countries other than the US and Europe totaled $402 million in 2000. Spending relative to gross national income was highest for the UK at $116/$1 million; for the US it was $36/$1 million. The breakdown for spending in resource-poor countries for 2001 is estimated at $800 million for prevention, and $1 billion for medical care and research. The research component was limited to NIH-funded research, which is the major sponsor of international HIV research at $188 million for FY02. Philanthropic contributions from US-based foundations total an estimated $312.4 million for 2000. The major contributors are the Gates, Ford and Kaiser Foundations. There are also substantial contributions from pharmaceutical companies. Again, many of these are multi-year donations making it difficult to define annual totals. These data are summarized in the following table:
Philanthropic Contributions
Global Fund 2000
U.S. based foundations: $312.4 million
 | Gates: $465 million in multiyear grants
|
| Ford Foundation: $89 million multiyear
|
| Kaiser: $62 million over 5 years
|
| Rockefeller: $5.1 million for 2001
|
Pharmaceutical companies:
| Company
| Activity
| | Abbott
| "Step Forward": AIDS orphans & children*
| | Bristol
| "Secure the Future": $100 million over 5 years* for
women and children in south and west Africa
| | Merck
| "Enhancing Care Initiation": $50 million in Botswana;
other projects in Thailand, Brazil & S. Africa
| | Glaxo
| "Positive Action": $55 million multiyear projects with 49 countries*
| | Pfizer
| Uganda project for treatment and education plus $315,000
study of best practices*
| | * Additional support includes pharmaceutical company's HIV-related drugs either donated (BI-nevirapine and Pfizer-fluconazole) or provided at "no profit" or "at reduced price."
|
By John Bartlett MD |
Changes in Bloodstream Infections in HIV-Positive Patients in a University Hospital in Spain (1995-1997)
[Pedro-Botet ML et al. Int J Infect Dis 2002;6:17]:
Date Posted:07-31-2002 | This is a review of the experience in a 600-bed medical center in Catalonia serving 1,800 patients with HIV infection. The analysis included a review of 186 episodes of bloodstream infections in 1995-97. HAART became available in late 1996. In 1997 there was a substantial decrease in the recovery rate of Gram-negative bacilli and Myobacteria with an increase in the relative frequency of S. aureus and enterococci. The entire three-year experience with 186 episodes is summarized in the following table:
| Etiologic Agents in 186 Episodes of Bacteremia in HIV-Infected Persons
| |
|
| | Gram-positive cocci
| 67 (36%)
| | S. aureus
| 20
| | Coag. Neg. Staph.
| 16
| | S. pneumoniae
| 15
| | Enterococcus
| 8
| | Other
| 7
| | Gram-negative bacteria
| 51 (27%)
| | Salmonella
| 16
| | P. Aeruginosa
| 14
| | E. coli
| 9
| | Coliforms (other)
| 7
| | Mycobacteria
| 52 (28%)
| | M. avium
| 23
| | M. tuberculosis
| 20
| | Fungi
| 12 (6%)
| | C. neoformans
| 9
|
COMMENT: This is one of the relatively few large series dealing with bacteremia in patients with AIDS. The most frequent portals of entry were indwelling IV catheters (27%), respiratory tract (23%), and the GI tract (19%). The predominant pathogens are summarized above and will not surprise those who are experienced in HIV care. The review serves to illustrate the extraordinary experience here compared to other patients with similar defects in cell-mediated immunity (transplant recipients, chronic corticosteroids, cancer chemotherapy, etc.), especially with respect to the high frequency of M. avium, M. tuberculosis, S. pneumoniae, Salmonella and C. neoformans. This distinction in the HIV-infected population is striking.
By John Bartlett MD |
Antiretroviral Guidelines for Resource-Limited Settings: WHO Public Health Approach
[Hammer SM et al. Nat Med 2002;8:649]:
Date Posted:07-31-2002 | This is a "Commentary" in Nature Medicine addressing the WHO guidelines for antiretroviral drugs released in April 2002 and summarized previously in this literature review series. The authors of the commentary include the first author of the guidelines (S. Hammer) and coauthors from WHO (T. Turmen, B. Vareldzis and J. Perriens). The authors explain that the guidelines are designed for use by clinicians, but their primary targets are the National Treatment Advisory Board and senior level policy makers who assist in program development. The rationale for the guidelines is based on several converging factors: 1) the price of antiretroviral drugs for developing countries has substantially decreased making purchase more realistic; 2) the Global Fund also makes purchase more realistic; and 3) WHO has placed these drugs on the "Essential Drug List." Those who have read the guidelines know that they are very precise in terms of the recommendations for specific regimens in different settings such as pregnancy, probability of pregnancy, availability of refrigeration, concurrent treatment of tuberculosis, probability of adherence, pediatric cases, and injecting drug users. It is explained in this commentary that the limitations in trained manpower and limitations in infrastructure in resource-poor countries make "a defined treatment program most feasible." The authors describe this as "the public health approach" designed to expand antiretroviral treatment programs by standardization and simplification. They also use an approach that accounts for limited laboratory monitoring with the probability of non-availability of CD4 cell count and viral load determinations. It is stated that the WHO guidelines will be reviewed and updated at regular intervals, but the mechanism and frequency of doing this is not mentioned.
By John Bartlett MD |
Clinical Efficacy of Early Initiation of HAART in Patients with Asymptomatic HIV Infection and CD4 Cell Count > 350 x 106/l
[Opravil M et al. AIDS 2002;16:1371]:
Date Posted:07-31-2002 | This is a retrospective analysis from the Swiss HIV Cohort Study in which all asymptomatic patients starting HAART from 1996-99 with a CD4 cell count >350/mm3 were compared to a similar untreated group matched for age, sex, CD4 cell count, viral load, and HIV risk category. The resulting analysis included 283 pairs of treated and untreated patients, and the median duration of follow-up was about three years. The results showed that early treatment was associated with a statistically significant delay in rates of clinical progression as measured by "events" or death. There was also substantial benefit in terms of CD4 cell count and viral load. The authors conclude that early therapy when the CD4 cell count is above 350/mm3 is associated with significant benefit in terms of the delay in clinical progression, but "the risk of severe clinical events with deferred therapy was low and must be counterbalanced against the burden and toxicity of HAART." The results are summarized in the following table:
| Variable
| Treated
| Untreated
| P
| | Last CD4 (median)
| 731/mm3
| 415/mm3
| < 0.001
| | Last VL (log 10/ml)
| 2.6
| 3.7
| < 0.001
| | Clinical event
| 6.4%
| 21.2%
| < 0.001
| | Death
| 2.1%
| 6.4%
| 0.01
|
COMMENT: The authors point out that the risk of clinical events in the untreated group was relatively low over median observation period of 2.7 years and the modest benefit shown must be interpreted in the context of a 35% frequency of treatment-related adverse events that required a change in the HAART regimen and a 24% frequency of discontinuing treatment because of toxicity. The debate regarding the threshold for initiating therapy is not settled by this study because early therapy provided a small but significant benefit without consideration of long-term toxicity. It is unfortunate that viral loads were not also considered since this is an important prognostic variable. For example, the DHHS guidelines do support the initiation of antiretroviral drugs in patients with a CD4 cell count above 350/mm3 if the viral load exceeds 55,000 c/ml, and it also endorses the delay in initiation of therapy for those with a CD4 cell count of 200-350/mm3 if the viral load is below 20,000 c/ml. It seems clear that the decision to initiate therapy "must be individualized."
By John Bartlett MD |
Varicella Pneumonia in Patients with HIV/AIDS
[Popara M et al. Int J Infect Dis 2002;6:6]:
Date Posted:07-31-2002 | This is a report from Johannesburg, South Africa concerning 12 patients with HIV infection who were hospitalized with severe chicken pox. The mean age was 29 years, 7 (58%) developed severe varicella pneumonia, and three of the seven died. All 12 patients received antiviral therapy for VZV, and six received systemic corticosteroids including all four who survived with varicella pneumonia.
COMMENT: Chicken pox is an infrequent infection in patients with HIV infection although there is substantial concern about the possible deleterious effects of transmission of the vaccine strain in HIV-infected patients who are seronegative. Current recommendations for exposures include use of immune globulin (VZIG) to immunologically naive HIV-infected patients. This report is modest in numbers, but does seem to justify the current recommendations.
By John Bartlett MD |
Risk Factors for Urological Symptoms in a Cohort of Users of the HIV Protease Inhibitor Indinavir Sulfate
[Dieleman JP et al. Arch Intern Med 2002;162:1493]:
Date Posted:07-31-2002 | This is a report from the ATHENA Cohort in the Netherlands to determine the incidence rate of urologic symptoms among 1219 patients who initiated PI-based HAART. The symptoms reviewed were nephrolithiasis, renal colic, flank pain, hematuria, renal insufficiency, and nephropathy. The incidence of urologic symptoms was 8.3/100 treatment-years for indinavir. The relative risk was significantly increased for the 644 patients taking indinavir 1000 mg twice daily versus 800 mg t.i.d. (RR = 3.1), treatment change due to intolerance (RR = 2.4), low weight (RR = 2.1), low lean body mass (RR = 1.7), and warm climate (RR = 3.9). Risk was highest among patients with low lean body mass. The authors conclude that there should be alertness to urologic symptoms in patients receiving indinavir, particularly for those with low mean body mass and those receiving at least one gram twice daily in warm climates.
COMMENT: Urologic symptoms are well known complications of indinavir. With the standard dose of 800 mg thrice daily, the frequency of urologic symptoms was 4% in initial registration clinical trials and it was 8-16% in several subsequent reports. This analysis calls attention to certain risk factors for this complication including some that seem relatively obvious: low body mass, high dose and warm climate. Unfortunately, the number taking indinavir in combination with ritonavir was too small for meaningful analysis. The authors warn that the current recommendation of 1.5 liters of fluid/day may not be adequate for persons in warm climates.
By John Bartlett MD |
|
