Effectiveness of a community-based intervention to prevent childhood TB in Lesotho.

BACKGROUND: Child contact management (CCM) is a recognized strategy to prevent TB; however, implementation is suboptimal. PREVENT was a cluster-randomized trial that evaluated the effectiveness and acceptability of a community-based intervention (CBI) to improve CCM in Lesotho.METHODS: Ten health facilities (HFs) were randomized to CBI or standard-of-care (SOC). CBI included nurse training/mentorship, health education by village health workers (VHW), adherence support, and multidisciplinary team meetings. Information on TB cases registered from February 2016 to June 2018 and their child contacts was abstracted. Outcomes were TB preventive treatment (TPT) initiation, TPT completion, and CBI acceptability. Generalized linear mixed models were used to test for differences between study arms and qualitative interview thematic analysis for acceptability.RESULTS: Among 547 registered children (CBI: n = 399; SOC: n = 148) of 426 adult TB patients, 46% were <2 years, 48% female, and 3% HIV-exposed/positive, with no significant differences between study arms. A total of 501 children initiated TPT-98% at CBI and 88% at SOC HFs (P < 0.0001). TPT completion was 82% in CBI vs. 59% in SOC sites (P = 0.048). Caregivers and providers reported that CBI was acceptable.CONCLUSION: The CBI was acceptable and significantly improved TPT initiation and completion in Lesotho, offering the opportunity to mitigate the threat of TB among children.

Individual and poly-substance use and condomless sex among HIV-uninfected adults reporting heterosexual sex in a multi-site cohort.

BACKGROUND: We analyzed the association between substance use (SU) and condomless sex (CS) among HIV-negative adults reporting heterosexual sex in the Seek, Test, Treat, and Retain (STTR) consortium. We describe the impact of SU as well as person/partner and context-related factors on CS, identifying combinations of factors that indicate the highest likelihood of CS. METHODS: We analyzed data from four US-based STTR studies to examine the effect of SU on CS using two SU exposures: 1) recent SU (within 3 months) and 2) SU before/during sex. Behavioral data were collected via 1:1 or self-administered computerized interviews. Adjusted individual-study, multivariable relative risk regression was used to examine the relationship between CS and SU. We also examined interactions with type of sex and partner HIV status. Pooled effect estimates were calculated using traditional fixed-effects meta-analysis. We analyzed data for recent SU (n = 6781; 82% men, median age = 33 years) and SU before/during sex (n = 2915; 69% men, median age = 40 years). RESULTS: For both exposure classifications, any SU other than cannabis increased the likelihood of CS relative to non-SU (8-16%, p-values< 0.001). In the recent SU group, however, polysubstance use did not increase the likelihood of CS compared to single-substance use. Cannabis use did not increase the likelihood of CS, regardless of frequency of use. Type of sex was associated with CS; those reporting vaginal and anal sex had a higher likelihood of CS compared to vaginal sex only for both exposure classifications (18-21%, p < 0.001). Recent SU increased likelihood of CS among those reporting vaginal sex only (9-10%, p < 0.001); results were similar for those reporting vaginal and anal sex (5-8%, p < 0.01). SU before/during sex increased the likelihood of CS among those reporting vaginal sex only (20%; p < 0.001) and among those reporting vaginal and anal sex (7%; p = 0.002). Single- and poly-SU before/during sex increased the likelihood of CS for those with exclusively HIV-negative partners (7-8%, p ≤ 0.02), and for those reporting HIV-negative and HIV-status unknown partners (9-13%, p ≤ 0.03). CONCLUSION: Except for cannabis, any SU increased the likelihood of CS. CS was associated with having perceived HIV-negative partners and with having had both anal/vaginal sex.

Adherence to Pre-exposure Prophylaxis in Black Men Who Have Sex with Men and Transgender Women in a Community Setting in Harlem, NY.

While oral pre-exposure prophylaxis (PrEP) has proven efficacious for HIV prevention, consistent use is necessary to achieve its intended impact. We compared effectiveness of enhanced PrEP (enPrEP) adherence support to standard of care (sPrEP) among Black MSM and TGW attending a community clinic in Harlem, NY. EnPrEP included peer navigation, in-person/online support groups, and SMS messages. Self-reported adherence over previous 30 days, collected in quarterly interviews, was defined as ≥ 57%. Crude and adjusted analyses examined factors associated with adherence. A total of 204 participants were enrolled and randomized; 35% were lost to follow-up. PrEP adherence was 30% at 12-months; no intervention effect was observed (p = 0.69). Multivariable regression analysis found that lower adherence was associated with low education and depressive symptoms. We found that an enhanced adherence intervention did not improve PrEP adherence. Findings point to the need for innovative methods to improve PrEP adherence among Black MSM and TGW.Clinical Trial Registration NCT02167386, June 19, 2014.

Leveraging differentiated HIV service delivery to expand tuberculosis preventive treatment: a call to action.

Tuberculosis (TB) is the leading cause of death among people living with human immunodeficiency virus (PLHIV), and sub-Saharan Africa has a particularly heavy burden of HIV-associated TB. Although effective TB preventive treatment (TPT) has been available for decades and shorter regimens are newly available in some settings, TPT coverage among PLHIV is suboptimal, leading to preventable illness and death. In 2018, the United Nations High-Level Meeting on Ending Tuberculosis called for ambitious new targets for TPT coverage among PLHIV and many countries in sub-Saharan Africa have redoubled their efforts to take TPT to scale. Importantly, however, this push to expand TPT among PLHIV is taking place in the context of a changing HIV treatment delivery landscape. Countries in sub-Saharan Africa are at the forefront of innovative changes in HIV program design, including a shift towards less-intensive differentiated service delivery (DSD) models for stable patients doing well on antiretroviral therapy. Understanding the opportunities and challenges that DSD presents for TB diagnosis, prevention and linkage to care among PLHIV will be critical to success.

Tuberculosis preventive treatment preferences among care givers of children in Lesotho: a pilot study.

BACKGROUND: Shorter-duration regimens for preventing drug-susceptible tuberculosis (TB) have been shown to be safe and efficacious in children, and may improve acceptability, adherence, and treatment completion. While these regimens have been used in children in low TB burden countries, they are not yet widely used in high TB burden countries. SETTING: Five health facilities in one district in Lesotho, a high TB burden country. OBJECTIVE: Assess the preventive treatment preferences of care givers of child TB contacts. DESIGN: Qualitative data were collected using in-depth interviews with 12 care givers whose children completed preventive treatment, and analyzed using grounded theory. FINDINGS: Care givers were interested in being involved in the children's treatment decisions. Pill burden, treatment duration and related frequency of dosing were identified as important factors that influenced preventive treatment preferences among care givers. CONCLUSION: Understanding care giver preferences and involving them in treatment decisions may facilitate efforts to implement successful preventive treatment for TB among children in high TB burden countries.

Sexual Behaviors of US Women at Risk of HIV Acquisition: A Longitudinal Analysis of Findings from HPTN 064.

We describe the sexual behaviors of women at elevated risk of HIV acquisition who reside in areas of high HIV prevalence and poverty in the US. Participants in HPTN 064, a prospective HIV incidence study, provided information about individual sexual behaviors and male sexual partners in the past 6 months at baseline, 6- and 12-months. Independent predictors of consistent or increased temporal patterns for three high-risk sexual behaviors were assessed separately: exchange sex, unprotected anal intercourse (UAI) and concurrent partnerships. The baseline prevalence of each behavior was >30 % among the 2,099 participants, 88 % reported partner(s) with >1 HIV risk characteristic and both individual and partner risk characteristics decreased over time. Less than high school education and food insecurity predicted consistent/increased engagement in exchange sex and UAI, and partner's concurrency predicted participant concurrency. Our results demonstrate how interpersonal and social factors may influence sustained high-risk behavior by individuals and suggest that further study of the economic issues related to HIV risk could inform future prevention interventions.

Can a peer-based intervention impact adherence to the treatment of latent tuberculous infection?

OBJECTIVE: To assess the effectiveness of a peer-based intervention on adherence to and completion of latent tuberculous infection (LTBI) treatment. METHODS: Patients prescribed self-administered LTBI treatment were enrolled in a randomized controlled trial of an experimental, peer-based adherence support intervention. Primary outcomes were treatment adherence and completion. Adherence was assessed through self-report, electronic monitoring devices and clinic visits. RESULTS: Of 250 participants, 70% were male; 71% were Black and 20% Latino; the mean age was 40 years; 67% were foreign-born and 39% were married. No significant baseline differences were noted between the intervention groups. Treatment completion was 61% in the intervention group compared to 57% in the controls (P = 0.482). The corresponding completion rate for other clinic patients was 44%. Foreign birth, marriage and history of mental illness were associated with non-completion of treatment after controlling for the intervention group; increased completion rates were found among foreign-born married persons and older participants. A substantial difference in adherence rates was observed between the intervention groups. Adherence among non-completers decreased early, while adherence among completers remained constant. CONCLUSIONS: The peer-based intervention was not significantly associated with LTBI treatment completion, but was associated with greater adherence. Findings suggest the importance of interventions to support adherence that target early non-adherence with LTBI treatment, particularly in the first 2 months, when there is a substantial risk of default.

Lessons from a randomised clinical trial for multidrug-resistant tuberculosis.

BACKGROUND: The treatment of multidrug-resistant tuberculosis (MDR-TB) is currently based upon expert opinion and findings from case series, rather than upon randomised clinical trials (RCTs). OBJECTIVE: To describe the challenges encountered during an RCT for the treatment of MDR-TB. METHODS: Tuberculosis Trials Consortium Study 30 was a pilot, Phase I/II, double-blind, placebo-controlled, RCT of the safety and tolerability of 16 weeks of daily, low-dose linezolid treatment for MDR-TB. RESULTS: A total of 36 patients, 56% of the target of 64 patients, consented to participate, for an average of 0.69 enrolments per week. Of the 36 patients enrolled, only 25 (69%) completed at least 90 doses of study treatment. Among the 12 (33%) patients who did not complete all 112 doses of the study treatment, the median time to study withdrawal was 15 days (range 0-92). After the study, we discovered discordance between treatment assignment and study drug for at least 9 (25%) of the 36 patients. CONCLUSIONS: Recruitment and retention in this MDR-TB clinical trial posed substantial challenges, suggesting the need for a large, multidisciplinary group of study staff to support the participants. Withdrawal tended to occur early in study treatment. The discrepancy in assigned study medication reflects the need for stronger administrative controls for study drugs.

Implementing family-focused HIV care and treatment: the first 2 years' experience of the mother-to-child transmission-plus program in Abidjan, Côte d'Ivoire.

OBJECTIVES: To describe a family-focused approach to HIV care and treatment and report on the first 2 years experience of implementing the mother-to-child transmission (MTCT)-plus program in Abidjan, Côte d'Ivoire. PROGRAM: The MTCT-plus initiative aims to enroll HIV-infected pregnant and postpartum women in comprehensive HIV care and treatment for themselves and their families. MAIN OUTCOMES: Between August 2003 and August 2005, 605 HIV-infected pregnant or postpartum women and 582 HIV-exposed infants enrolled. Of their 568 male partners reported alive, 52% were aware of their wife's HIV status and 30% were tested for HIV; 53% of these tested partners were found to be HIV-infected and 78% enrolled into the program. Overall only 10% of the women enrolled together with their infected partner. On the other hand, the program involved half of the seronegative men who came for voluntary counselling and testing (VCT) in the care of their families. Of 1624 children <15 years reported alive by their mothers (excluding the last newborn infants of the most recent pregnancy systematically screened for HIV), only 10.8% were brought in for HIV testing, of whom 12.3% were found to be HIV-infected. LESSONS LEARNED AND CHALLENGES: The family-focused model of HIV care pays attention to the needs of families and household members. The program was successful in enrolling HIV women, their partners and infants in continuous follow-up. However engaging partners and family members of newly enrolled women into care involves numerous challenges such as disclosure of HIV status by women to their partners and family members. Further efforts are required to understand barriers for families accessing HIV services as strategies to improve partner involvement and provide access to care for other children in the households are needed in this West African urban setting.

Risk for opportunistic disease and death after reinitiating continuous antiretroviral therapy in patients with HIV previously receiving episodic therapy: a randomized trial.

BACKGROUND: Episodic use of antiretroviral therapy guided by CD4+ cell counts is inferior to continuous antiretroviral therapy. OBJECTIVE: To determine whether reinitiating continuous antiretroviral therapy in patients who received episodic treatment reduces excess risk for opportunistic disease or death. DESIGN: Randomized, controlled trial. SETTING: Sites in 33 countries. PATIENTS: 5472 HIV-infected individuals with CD4(+) cell counts greater than 0.350 x 10(9) cells/L enrolled from January 2002 to January 2006. INTERVENTION: Episodic or continuous antiretroviral therapy initially, followed by continuous therapy in participants previously assigned to episodic treatment. MEASUREMENTS: Opportunistic disease or death was the primary outcome. RESULTS: Eighteen months after the recommendation to reinitiate continuous therapy, mean CD4+ cell counts were 0.152 x 10(9) cells/L (95% CI, 0.136 to 0.167 x 10(9) cells/L) less in participants previously assigned to episodic treatment (P < 0.001). The proportion of follow-up time spent with CD4+ cell counts of 0.500 x 10(9) cells/L or more and HIV RNA levels of 400 copies/mL or less was 29% for participants initially assigned to episodic therapy and 66% for those assigned to continuous therapy. Participants who reinitiated continuous therapy experienced rapid suppression of HIV RNA levels (89.7% with HIV RNA levels < or =400 copies/mL after 6 months), but CD4+ cell counts after 6 months remained 0.140 x 10(9) cells/L below baseline. The hazard ratio (episodic versus continuous treatment) for opportunistic disease or death decreased after the recommendation to reinitiate continuous therapy (from 2.5 [CI, 1.8 to 3.5] to 1.4 [CI, 1.0 to 2.0]; P = 0.033 for difference). The residual excess risk was attributable to failure to reinitiate therapy by some participants and slow recovery of CD4+ cell counts for those who reinitiated therapy. LIMITATION: Follow-up was too short to assess the full effect of switching from episodic to continuous antiretroviral therapy. CONCLUSION: Reinitiating continuous antiretroviral therapy in patients previously assigned to episodic treatment reduced excess risk for opportunistic disease or death, but excess risk remained. Episodic antiretroviral therapy, as used in the SMART study, should be avoided.

Changes over time in risk factors for cardiovascular disease and use of lipid-lowering drugs in HIV-infected individuals and impact on myocardial infarction.

BACKGROUND: Because of the known relationship between exposure to combination antiretroviral therapy and cardiovascular disease (CVD), it has become increasingly important to intervene against risk of CVD in human immunodeficiency virus (HIV)-infected patients. We evaluated changes in risk factors for CVD and the use of lipid-lowering therapy in HIV-infected individuals and assessed the impact of any changes on the incidence of myocardial infarction. METHODS: The Data Collection on Adverse Events of Anti-HIV Drugs Study is a collaboration of 11 cohorts of HIV-infected patients that included follow-up for 33,389 HIV-infected patients from December 1999 through February 2006. RESULTS: The proportion of patients at high risk of CVD increased from 35.3% during 1999-2000 to 41.3% during 2005-2006. Of 28,985 patients, 2801 (9.7%) initiated lipid-lowering therapy; initiation of lipid-lowering therapy was more common for those with abnormal lipid values and those with traditional risk factors for CVD (male sex, older age, higher body mass index [calculated as the weight in kilograms divided by the square of the height in meters], family and personal history of CVD, and diabetes mellitus). After controlling for these, use of lipid-lowering drugs became relatively less common over time. The incidence of myocardial infarction (0.32 cases per 100 person-years [PY]; 95% confidence interval [CI], 0.29-0.35 cases per 100 PY) appeared to remain stable. However, after controlling for changes in risk factors for CVD, the rate decreased over time (relative rate in 2003 [compared with 1999-2000], 0.73 cases per 100 PY [95% CI, 0.50-1.05 cases per 100 PY]; in 2004, 0.64 cases per 100 PY [95% CI, 0.44-0.94 cases per 100 PY]; in 2005-2006, 0.36 cases per 100 PY [95% CI, 0.24-0.56 cases per 100 PY]). Further adjustment for lipid levels attenuated the relative rates towards unity (relative rate in 2003 [compared with 1999-2000], 1.06 cases per 100 PY [95% CI, 0.63-1.77 cases per 100 PY]; in 2004, 1.02 cases per 100 PY [95% CI, 0.61-1.71 cases per 100 PY]; in 2005-2006, 0.63 cases per 100 PY [95% CI, 0.36-1.09 cases per 100 PY]). CONCLUSIONS: Although the CVD risk profile among patients in the Data Collection on Adverse Events of Anti-HIV Drugs Study has decreased since 1999, rates have remained relatively stable, possibly as a result of a more aggressive approach towards managing the risk of CVD.

Integrating tuberculosis and HIV care in rural Rwanda.

SETTING: Rwanda has generalised human immunodeficiency virus (HIV) and tuberculosis (TB) epidemics. The Rwandan Ministry of Health approved a policy on TB-HIV collaborative activities in 2005. The present study is a report on the results of the integrated TB and HIV activities at a rural health care site between July 2005 and June 2006. METHODS: Activities included provider-initiated HIV testing and counselling (PITC) of TB patients and the implementation of a standardised TB screening questionnaire for in-patients on medical wards and HIV-infected out-patients. RESULTS: Of a total 259 TB patients registered, 87% with unknown HIV status or who were HIV-negative accepted PITC. Overall, 48% (125/259) of TB patients were HIV-infected. The proportion of TB patients ever tested for HIV increased from 82% (138/169) in 2004-2005 to 93% (240/259) in 2005-2006 (P < 0.001). Of the 770 in-patients screened for TB, 162 (21%) tested positive, of whom 53 (33%) were diagnosed with TB; 39 (76%) of these were HIV co-infected. Three hundred out-patients with HIV were screened for TB; 80 (27%) tested positive, of whom 11 (14%) were diagnosed with TB. DISCUSSION: Activities integrating TB and HIV were feasible in a rural health care setting. PITC was successful in TB patients and unrecognised TB was common, particularly among HIV-infected in-patients.

CD4+ count-guided interruption of antiretroviral treatment.

BACKGROUND: Despite declines in morbidity and mortality with the use of combination antiretroviral therapy, its effectiveness is limited by adverse events, problems with adherence, and resistance of the human immunodeficiency virus (HIV). METHODS: We randomly assigned persons infected with HIV who had a CD4+ cell count of more than 350 per cubic millimeter to the continuous use of antiretroviral therapy (the viral suppression group) or the episodic use of antiretroviral therapy (the drug conservation group). Episodic use involved the deferral of therapy until the CD4+ count decreased to less than 250 per cubic millimeter and then the use of therapy until the CD4+ count increased to more than 350 per cubic millimeter. The primary end point was the development of an opportunistic disease or death from any cause. An important secondary end point was major cardiovascular, renal, or hepatic disease. RESULTS: A total of 5472 participants (2720 assigned to drug conservation and 2752 to viral suppression) were followed for an average of 16 months before the protocol was modified for the drug conservation group. At baseline, the median and nadir CD4+ counts were 597 per cubic millimeter and 250 per cubic millimeter, respectively, and 71.7% of participants had plasma HIV RNA levels of 400 copies or less per milliliter. Opportunistic disease or death from any cause occurred in 120 participants (3.3 events per 100 person-years) in the drug conservation group and 47 participants (1.3 per 100 person-years) in the viral suppression group (hazard ratio for the drug conservation group vs. the viral suppression group, 2.6; 95% confidence interval [CI], 1.9 to 3.7; P<0.001). Hazard ratios for death from any cause and for major cardiovascular, renal, and hepatic disease were 1.8 (95% CI, 1.2 to 2.9; P=0.007) and 1.7 (95% CI, 1.1 to 2.5; P=0.009), respectively. Adjustment for the latest CD4+ count and HIV RNA level (as time-updated covariates) reduced the hazard ratio for the primary end point from 2.6 to 1.5 (95% CI, 1.0 to 2.1). CONCLUSIONS: Episodic antiretroviral therapy guided by the CD4+ count, as used in our study, significantly increased the risk of opportunistic disease or death from any cause, as compared with continuous antiretroviral therapy, largely as a consequence of lowering the CD4+ cell count and increasing the viral load. Episodic antiretroviral therapy does not reduce the risk of adverse events that have been associated with antiretroviral therapy. (ClinicalTrials.gov number, NCT00027352 [ClinicalTrials.gov].).

Results of a tuberculosis-specific IFN-gamma assay in children at high risk for tuberculosis infection.

The specificity of the tuberculin skin test (TST) for the diagnosis of latent tuberculosis infection (LTBI) is adversely affected by bacille Calmette-Guérin (BCG) vaccination and infection with non-tuberculous mycobacteria. Interferon-gamma release assays (IGRAs) using TB-specific antigens promise higher specificity. We compared a new IGRA and TST in 184 schoolchildren at high risk for LTBI. The IGRA and TST were positive in 33.2% and 43.5% of the children, respectively (P < 0.001). If studies confirm that this difference is due to higher specificity of this IGRA, it may have an important role to play in the diagnosis of LTBI and identification of children at true risk for TB.

The use of the Framingham equation to predict myocardial infarctions in HIV-infected patients: comparison with observed events in the D:A:D Study.

BACKGROUND: The D:A:D (Data Collection on Adverse Events of Anti-HIV Drugs) Study, a prospective observational study on a cohort of 23 468 patients with HIV infection, indicated that the incidence of myocardial infarction (MI) increased by 26% per year of exposure to combination antiretroviral treatment (CART). However, it remains unclear whether the observed increase in the rate of MI in this population can be attributed to changes in conventional cardiovascular risk factors. OBJECTIVE: To compare the number of MIs observed among participants in the D:A:D Study with the number predicted by assuming that conventional cardiovascular risk equations apply to patients with HIV infection. METHODS: The Framingham equation, a conventional cardiovascular risk algorithm, was applied to individual patient data in the D:A:D Study to predict rates of MI by duration of CART. A series of sensitivity analyses were performed to assess the effect of model and data assumptions. Predictions were extrapolated to provide 10-year risk estimates, and various scenarios were modelled to assess the expected effect of different interventions. RESULTS: In patients receiving CART, the observed numbers of MIs during D:A:D follow up were similar to or somewhat higher than predicted numbers: 9 observed vs 5.5 events predicted, 14 vs 9.8, 22 vs 14.9, 31 vs 23.2 and 47 vs 37.0 for<1 year, 1-2 years, 2-3 years, 3-4 years and >4 years CART exposure, respectively. In patients who had not received CART, the observed number of MIs was fewer than predicted (3 observed vs 7.6 predicted). Nine per cent of the study population have a predicted 10-year risk of MI above 10%, a level usually associated with initiation of intervention on risk factors. CONCLUSIONS: A consistent feature of all analyses was that observed and predicted rates of MI increased in a parallel fashion with increased CART duration, suggesting that the observed increase in risk of MI may at least in part be explained by CART-induced changes in conventional risk factors. These findings provide guidance in terms of choosing lifestyle or therapeutic interventions to decrease those risk factors in much the same way as in persons without HIV infection.

Effects of HIV disease on lipid, glucose and insulin levels: results from a large antiretroviral-naive cohort.

OBJECTIVES: With the use of potent antiretroviral therapy in patients with HIV disease, changes in lipid parameters and glucose homeostasis have been noted. However, these effects have been difficult to interpret because of the varied demographic and treatment characteristics of the cohorts and the complexity of differentiating the effect of HIV disease from that of the drugs used in its treatment. This study was designed to explore these issues. METHODS: Demographic information and fasting blood samples were collected from 419 antiretroviral-naive HIV-1-infected patients. RESULTS: The average age of the participants was 38.2 years, with 21% being female, 60% being African American, and 14% having a history of injection drug use. The mean CD4 lymphocyte count was 216 cells/microL, the mean baseline log10 HIV viral load was 4.98 HIV-1 RNA copies/mL, and 26% of patients had a history of AIDS-defining events. Women and African Americans had significantly higher levels of high-density lipoprotein (HDL) cholesterol, and older age was associated with higher total cholesterol levels. Lower CD4 lymphocyte counts and higher HIV RNA levels were independently associated with lower HDL cholesterol levels. Additionally, higher HIV RNA level was associated with lower levels of low-density lipoprotein (LDL) cholesterol and higher levels of very-low-density lipoprotein (VLDL) cholesterol and triglycerides. A history of AIDS-defining events was associated with higher total cholesterol, VLDL cholesterol and triglyceride concentrations. With respect to glucose homeostasis, a higher CD4 lymphocyte count was associated with less evidence of insulin resistance. However, a higher body mass index was associated with higher lipid levels and with more evidence of insulin resistance. CONCLUSIONS: Both HIV disease and demographic characteristics were found to influence lipid values and glucose homeostasis in the absence of antiretroviral treatment. More advanced HIV disease was associated with less favourable lipid and glucose homeostatic profiles. The independent association between HIV RNA levels and various lipid parameters suggests that viral replication had a direct effect on lipid levels. Interpretation of the effects of various HIV treatment regimen and drugs on metabolic parameters must take into account the stage of HIV disease and the demographic characteristics of the population studied.

The safety and efficacy of adefovir dipivoxil in patients with advanced HIV disease: a randomized, placebo-controlled trial.

OBJECTIVE: Efficacy and safety of adefovir dipivoxil (adefovir) added to background antiretroviral therapy in advanced HIV disease. DESIGN: Randomized, double-blind, placebo-controlled multicenter trial. SETTING: Fifteen clinical trial units providing HIV primary care. PARTICIPANTS: Adults with CD4 cell count < or = 100 x 10(6)/l, or 101-200 x 10(6)/l with prior nadir < or = 50 x 10(6)/l. INTERVENTIONS: Oral adefovir or placebo 120 mg once daily. MAIN OUTCOME MEASURES: Survival, cytomegalovirus (CMV) disease, plasma HIV-RNA, CD4 cell count, grade 4 drug toxicity, permanent drug discontinuation due to toxicity. RESULTS: Among the 253 patients assigned adefovir and the 252 assigned placebo, respectively, 17 and 16 died (P = 0.88), and four and eight experienced CMV disease (P = 0.25). Mean change in log(10) plasma HIV-RNA in the adefovir and placebo groups, respectively, was 0.09 and -0.03 copies/ml at 6 months (P = 0.22) and 0.06 and -0.02 at 12 months (P = 0.87). Changes in CD4 cell counts were not different between groups. At 12 months the cumulative percent with proximal renal tubular dysfunction (PRTD) was 17% in the adefovir group and 0.4% in the placebo group (P < 0.0001, log rank test). Median time to resolution of PRTD was 15 weeks among patients assigned adefovir, and 16% of patients did not resolve completely 41 weeks after onset. More drug discontinuations occurred in the adefovir group than in the placebo group. CONCLUSIONS: No virologic or immunologic benefit was observed when adefovir was added to background antiretroviral therapy in advanced HIV disease, and adefovir was associated with considerable nephrotoxicity. This study does not support the use of adefovir for treatment of advanced HIV disease in pretreated patients.

A review of efficacy studies of 6-month short-course therapy for tuberculosis among patients infected with human immunodeficiency virus: differences in study outcomes.

Six-month regimens that include rifampin for the treatment of tuberculosis in patients without human immunodeficiency virus (HIV) infection are recommended because of low percentage of relapses. Whether a similar duration of therapy should be used to treat tuberculosis in HIV-infected patients is unclear. Six studies of patients with HIV-infection and 3 of patients without HIV infection were reviewed and compared. The studies differed in terms of design, eligibility criteria, site of disease, frequency of dosing, dose administration methods, and outcome definitions. Among HIV-infected patients, the following percentages were found: cure, 59.4%--97.1%; treatment success, 34.0%--100%; effective treatment, 29.4%--88.2%; and relapse, 0%--10%. In those without HIV infection, percentages were as follows: cure, 62.3%--88.0%; treatment success, 91.2%--98.8%; effective treatment, 70.6%--83.8%; and relapse, 0%--3.4%. Although the rate of relapse appeared to be higher in some studies of HIV-infected patients with tuberculosis, this review demonstrates the limitation in the use of relapse as the exclusive outcome of interest when comparing studies.

Discontinuation of prophylaxis against Mycobacterium avium complex disease in HIV-infected patients who have a response to antiretroviral therapy. Terry Beirn Community Programs for Clinical Research on AIDS.

BACKGROUND: Several agents are effective in preventing Mycobacterium avium complex disease in patients with advanced human immunodeficiency virus (HIV) infection. However, there is uncertainty about whether prophylaxis should be continued in patients whose CD4+ cell counts have increased substantially with antiviral therapy. METHODS: We conducted a multicenter, double-blind, randomized trial of treatment with azithromycin (1200 mg weekly) as compared with placebo in HIV-infected patients whose CD4+ cell counts had increased from less than 50 to more than 100 per cubic millimeter in response to antiretroviral therapy. The primary end point was M. avium complex disease or bacterial pneumonia. RESULTS: A total of 520 patients entered the study; the median CD4+ cell count at entry was 230 per cubic millimeter. In 48 percent of the patients, the HIV RNA value was below the level of quantification. The median prior nadir CD4+ cell count was 23 per cubic millimeter, and 65 percent of the patients had had an acquired immunodeficiency syndrome-defining illness. During follow-up over a median period of 12 months, there were no episodes of confirmed M. avium complex disease in either group (95 percent confidence interval for the rate of disease in each group, 0 to 1.5 episodes per 100 person-years). Three patients in the azithromycin group (1.2 percent) and five in the placebo group (1.9 percent) had bacterial pneumonia (relative risk in the azithromycin group, 0.60; 95 percent confidence interval, 0.14 to 2.50; P=0.48). Neither the rate of progression of HIV disease nor the mortality rate differed significantly between the two groups. Adverse effects led to discontinuation of the study drug in 19 patients assigned to receive azithromycin (7.4 percent) and in 3 assigned to receive placebo (1.1 percent; relative risk, 6.6; P=0.002). CONCLUSIONS: Azithromycin prophylaxis can safely be withheld in HIV-infected patients whose CD4+ cell counts have increased to more than 100 cells per cubic millimeter in response to antiretroviral therapy.