Geographic distribution of risk ("Hotspots") for HIV, HCV, and drug overdose among persons who use drugs in New York City: the importance of local history.

AIMS: To identify geographic "hotspots" for potential transmission of HIV and HCV and for drug overdose among persons who use heroin and cocaine in New York City and to examine historical continuities in problem drug use hotspots in the city. METHODS: A total of 2714 study participants were recruited among persons entering Beth Israel substance use treatment programs. A structured questionnaire was administered and blood samples for HIV and HCV testing were collected. Hotspots for potential virus transmission were defined as ZIP codes with 10+ participants, 2+ persons infected with the virus and engaging in transmission behavior, and 2+ persons not infected and engaging in acquisition behavior. ZIP codes with 3+ persons with previous overdoses were considered potential hotspots for future overdoses. RESULTS: Participants resided in 166/178 (93%) of the ZIP codes in New York City. Injecting drug use was reported in 150/178 (84%) of the ZIP codes. No zip codes were identified for injecting-related HIV transmission, 5 zip codes were identified for sexual HIV transmission, 3 for HCV transmission, and 8 for drug overdose. Many of the ZIP code potential hotspots were in neighborhoods long associated with drug use: Lower Eastside and Harlem in Manhattan, the South Bronx, and Central Brooklyn. DISCUSSION: Heroin and cocaine use requiring treatment were reported from almost all ZIP codes in New York City, indicating needs for widely dispersed harm reduction services. Identified hotspots should be targeted for reducing sexual transmission of HIV, transmission of HCV, and drug overdoses. Some of the hotspots have persisted as problem drug use areas for 40 to over 100 years. Monitoring of drug use patterns in historical hotspot neighborhoods may permit early identification of and response to emerging drug use-related health problems. Persistent historical hotspots for problem drug use present a complex problem for implementing harm reduction services that deserve additional research.

The late-presenting HIV-infected patient 30 years after the introduction of HIV testing: spectrum of opportunistic diseases and missed opportunities for early diagnosis.

OBJECTIVES: The aim of the study was to describe the characteristics of HIV-infected late presenters, opportunistic diseases at diagnosis and missed opportunities to diagnose HIV infection earlier. METHODS: In a retrospective cohort study, we reviewed the medical records of all adults with newly diagnosed HIV infection admitted to the Department of Infectious Diseases of the Vivantes Auguste-Viktoria Hospital, Berlin, Germany. RESULTS: In the 5-year period from 2009 to 2013, 270 late presenters were identified. The most common AIDS-defining conditions were oesophageal candidiasis (n = 136; 51%), wasting syndrome (n = 106; 40%) and pneumocystis pneumonia (n = 91; 34%). Fifty-five patients (21%) had presented with at least one HIV indicator condition on prior contact with health care services without being offered testing for HIV. Female patients and heterosexual men [not men who have sex with men ('non-MSM')] had a significantly higher chance of being among patients previously presenting with indicator conditions and not being tested [odds ratio (OR) 4.7; 95% confidence interval (CI) 2.2-10.0; P < 0.001; and OR 2.4; 95% CI 1.2-5.1; P < 0.01, respectively]. The most commonly missed indicator conditions were leucocytopenia (n = 13; 24%), thrombocytopenia (n = 12; 22%), oral candidiasis (n = 9; 16%), unexplained weight loss (n = 7; 13%), herpes zoster (n = 5; 9%) and cervical dysplasia/cancer (n = 4; 20% of women). The median time between presentation with an indicator condition and the diagnosis of HIV infection was 158.5 days [interquartile range (IQR) 40-572 days]. Patients with oral candidiasis and unexplained weight loss had the shortest time between the "missed opportunity" and the diagnosis of HIV infection. Fifty-five hospital admissions with a total cost of over EUR 500 000 and - most importantly - six in-hospital deaths might have been prevented if HIV testing had been performed in patients with documented indicator conditions. CONCLUSIONS: Indicator conditions are still missed by clinicians. Women and 'non-MSM' are at highest risk of presenting with an indicator condition but not being tested for HIV infection.

HIV-positive men who have sex with men are at high risk of development of significant liver fibrosis after an episode of acute hepatitis C.

Acute hepatitis C virus infection remains a major health concern in human immunodeficiency virus(HIV)-infected men who have sex with men (MSM). New direct-acting antiviral agent (DAA) combination therapy has not yet been approved for the treatment for acute hepatitis C virus(HCV), thereby potentially causing deferral of HCV treatment. Therefore, we aimed to study the course of liver disease after an episode of acute HCV. This study is a retrospective single-centre cohort of HIV-positive MSM with acute HCV infection. Liver fibrosis was estimated by Fibroscan® and Fibrotest® . Liver-related and non-liver-related outcomes were documented. Overall 213 episodes of acute HCV infection in 178 men were documented. Median follow-up for all included patients was 38.7 months. Spontaneous HCV clearance was found in 10.8% of patients, which was significantly associated with older age, lower HCV RNA levels, and higher ALT levels upon initial acute HCV diagnosis. Treatment with interferon-based therapy was initiated in 86.3% of cases, resulting in a sustained virological response(SVR) rate of 70.7%. After 3 years' follow-up, significant liver fibrosis of METAVIR F2 stage or higher was found in 39.4% of patients after first acute HCV diagnosis. Higher age, physician-declared alcoholism, and nonresponse to acute HCV therapy were independently associated with higher fibrosis stages. Ten patients died during the observation period (IR 1.4/100 patient-years) and four during interferon treatment. Significant liver fibrosis is a common finding in HIV-positive MSM following acute HCV infection despite high treatment uptake and cure rates, suggesting the need for close liver disease monitoring particularly if HCV treatment is deferred.

Baseline cardiovascular risk in the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial.

OBJECTIVES: The Strategic Timing of AntiRetroviral Treatment (START) trial has recruited antiretroviral-naïve individuals with high CD4 cell counts from all regions of the world. We describe the distribution of cardiovascular disease (CVD) risk factors, overall and by geographical region, at study baseline. METHODS: The distribution of CVD risk factors was assessed and compared by geographical region among START participants who had a baseline electrocardiogram (n = 4019; North America, 11%; Europe/Australia/Israel, 36%; South America, 26%; Asia, 4%; Africa, 23%; median age 36 years; 26% female). RESULTS: About 58.3% (n = 2344) of the participants had at least one CVD risk factor and 18.9% (n = 761) had two or more. The most common CVD risk factors were current smoking (32%), hypertension (19.3%) and obesity (16.5%). There were significant differences in the prevalence of CVD risk factors among geographical regions. The prevalence of at least one risk factor across regions was as follows: North America, 70.0%; Europe/Australia/Israel, 65.1%; South America, 49.4%; Asia, 37.0%; Africa, 55.8% (P-value < 0.001). Significant regional differences were also observed when risk factors were used as part of the Framingham and Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) risk scores or used to define a favourable risk profile. CONCLUSIONS: CVD risk factors are common among START participants, and their distribution varies by geographical region. Better understanding of how and why CVD risk factors develop in people with HIV infection and their geographical distributions could shed light on appropriate strategies for CVD prevention and may inform the interpretation of the results of START, as CVD is expected to be a major fraction of the primary endpoints observed.

[A 55-year old Thai male patient with acute right upper quadrant abdominal pain]. / Akute rechtsseitige Oberbauchschmerzen bei einem 55-jährigen thailändischen Patienten.

We report on a 55-year-old Thai male who presented during a visit to Germany with acute abdominal pain in the right upper quadrant and signs of cholestasis. The diagnosis of liver fluke infection (opisthorchiasis) was confirmed by the detection of the characteristic eggs of Opisthorchis viverrini in stool microscopy. The patient was treated with praziquantel. Opisthorchiasis is a common parasitic disease and major public health problem in Southeast Asia and in Eastern Europe.

Combined HIV prevention, the New York City condom distribution program, and the evolution of safer sex behavior among persons who inject drugs in New York City.

Examine long term sexual risk behaviors among persons who inject drugs (PWID) in New York City following implementation of "combined" prevention programming, including condom social marketing. Quantitative interviews and human immunodeficiency virus (HIV) testing were conducted among PWID entering Beth Israel Medical Center drug treatment programs 1990-2012. Data were analyzed by four time periods corresponding to the cumulative implementation of HIV prevention interventions. 7,132 subjects were recruited from 1990 to 2012; little change in sexual behavior occurred among HIV seronegative subjects, while HIV seropositive subjects reported significant decreases in being sexually active and significant increases in consistent condom use. HIV transmission risk (being HIV positive and engaging in unprotected sex) declined from 14 % in 1990-1995 to 2 % in 2007-2012 for primary sexual partners and from 6 to 1 % for casual partners. Cumulative implementation of combined prevention programming for PWID was associated with substantial decreases in sexual risk behavior among HIV seropositives.

Effect of gender and race on the week 48 findings in treatment-naïve, HIV-1-infected patients enrolled in the randomized, phase III trials ECHO and THRIVE.

OBJECTIVES: A week 48 efficacy and safety analysis with respect to gender and race was conducted using pooled data from the phase III, double-blind, double-dummy efficacy comparison in treatment-naïve, HIV-infected subjects of TMC278 and efavirenz (ECHO) and TMC278 against HIV, in a once-daily regimen versus efavirenz (THRIVE) trials. METHODS: Treatment-naïve, HIV-1-infected adults were randomized to receive rilpivirine (RPV; TMC278) 25 mg once a day (qd), or efavirenz (EFV) 600 mg qd, plus tenofovir/emtricitabine (ECHO) or tenofovir/emtricitabine, zidovudine/lamivudine or abacavir/lamivudine (THRIVE). RESULTS: A total of 1368 participants (76% male and 61% White, of those with available race data) were randomized and treated. No gender-related differences in response rate (percentage of patients with HIV-1 viral load < 50 HIV-1 RNA copies/mL, using an intent-to-treat, time-to-loss-of-virological-response algorithm) were observed (RPV: men, 85%; women, 83%; EFV: men, 82%; women, 83%). Response rates were lower in Black compared with Asian and White participants (RPV: 75% vs. 95% and 85%, respectively; EFV: 74% vs. 93% and 83%, respectively); this finding was mostly a result of higher discontinuation and virological failure rates in Black patients. Safety findings were generally similar across race and gender subgroups. However, nausea occurred more commonly in women than in men in both treatment groups. In men, diarrhoea was more frequent in the EFV group, and abnormal dreams/nightmares were more frequent in men in both the EFV and RPV groups. CONCLUSIONS: Overall response rates were high for both RPV and EFV. No gender differences were observed. However, response rates were lower among Black patients, regardless of treatment group. Gender appeared to influence the incidence of gastrointestinal adverse events and abnormal dreams/nightmares for both treatments.

Twenty-four-week efficacy and safety of switching virologically suppressed HIV-1-infected patients from nevirapine immediate release 200 mg twice daily to nevirapine extended release 400 mg once daily (TRANxITION).

OBJECTIVES: Once-daily (qd) antiretroviral therapies improve convenience and adherence. If found to be effective, nevirapine extended release (NVP XR) will confer this benefit. The TRANxITION trial examined the efficacy and safety of switching virologically suppressed patients from NVP immediate release (NVP IR) 200 mg twice daily to NVP XR 400 mg qd. METHODS: An open-label, parallel-group, noninferiority, randomized (2:1 NVP XR:NVP IR) study was performed. Adult HIV-1-infected patients receiving NVP IR plus a fixed-dose nucleoside reverse transcriptase inhibitor (NRTI) combination of lamivudine (3TC)/abacavir (ABC), tenofovir (TDF)/emtricitabine (FTC) or 3TC/zidovudine (ZDV) with undetectable viral load (VL) were enrolled in the study. The primary endpoint was continued virological suppression with VL < 50 HIV-1 RNA copies/mL up to week 24 (calculated using a time to loss of virological response algorithm). Cochran's statistic (background regimen adjusted) was used to test noninferiority. Adverse events (AEs) were recorded. RESULTS: Among 443 randomized patients, continued virological suppression was observed in 93.6% (276 of 295) of NVP XR- and 92.6% (137 of 148) of NVP IR-treated patients, an observed difference of 1% [95% confidence interval (CI) -4.3, 6.0] at 24 weeks of follow-up. Noninferiority (adjusted margin of -10%) of NVP XR to NVP IR was robust and further supported by SNAPSHOT analysis. Division of Acquired Immunodeficiency Syndrome (DAIDS) grade 3 and 4 events were similar for the NVP XR and NVP IR groups (3.7 vs. 4.1%, respectively), although overall AEs were higher in the NVP XR group (75.6 vs. 60.1% for the NVP-IR group). CONCLUSIONS: NVP XR administered once daily resulted in continued virological suppression at week 24 that was noninferior to that provided by NVP IR, with similar rates of moderate and severe AEs. The higher frequency of overall AEs with NVP XR may be a consequence of the open-label design.

Hepatitis C virus-specific immune responses in noninjecting drug users.

Noninjection drug use, although recognized as an emerging risk factor for acquisition of other blood-born pathogens, is still unconfirmed as a route of hepatitis C virus (HCV) transmission. Our goal was to measure HCV exposure and prevalence in noninjection drug users (NIDUs). Fifty-seven NIDUs were screened by extensive questionnaire to exclude prior injection drug use and evaluated for HCV-specific serologic and cellular immune responses. HCV-specific T-cell responses were measured using interferon-gamma (IFN-γ) enzyme-linked immunospot (ELISpot) assay with overlapping HCV peptides covering the entire HCV genome. Fifteen individuals who never used illicit drugs served as negative controls. Eleven people with no history of injecting drug use (19.3%) were HCV seropositive: seven with chronic HCV infection and four with previously resolved infection. Of 51 NIDUs with ELISpot results, HCV-specific cellular immunity was detected in 5 (9.8%). These responses were relatively weak and narrow. We did not find significant associations between HCV-specific immune responses and noninjection drug use practices. Subjects with HCV-specific immunity, however, were significantly more likely to have bought sex in the past 6 months, to have had more casual partners of the opposite sex in the last 6 months, and those partners were more likely to have ever injected drugs compared to subjects without HCV-specific immunity. In summary, we found serologic or cellular HCV-specific immune responses in 27.5% of NIDUs. Our results suggest that sexual behaviour associated with noninjection drug use might be a risk factor for HCV acquisition. Additional studies are needed to precisely determine the practices that lead to HCV exposure among this population.

The effects of enfuvirtide therapy on body composition and metabolic parameters over 48 weeks in the TORO body imaging substudy.

OBJECTIVE: The aim of the study was to compare the metabolic and morphological effects of enfuvirtide plus an optimized background (OB) regimen vs. OB alone (control group) in treatment-experienced patients in the T-20 vs. Optimized Regimen Only (TORO) studies. METHODS: Body composition and metabolic changes were investigated in patients over 48 weeks, based on fasting chemistries, body weight, and other anthropometric measurements. Dual-energy X-ray absorptiometry (DEXA) and computed tomography (CT) scans were performed in a patient subgroup (n=155) at baseline and at weeks 24 and 48. RESULTS: At week 48, mean changes from baseline were similar between treatment groups for glucose, insulin, C-peptide, total cholesterol, low-density lipoprotein (LDL) cholesterol, very low density lipoprotein (VLDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels. The enfuvirtide group experienced a significant increase in body weight [mean change from baseline +0.99 kg; 95% confidence interval (CI) +0.54, +1.44] and, in those who had body scans, there was a significant increase in truncal fat (by DEXA: median change +419.4 g; 95% CI+71.3, +767.5) and total fat [visceral adipose tissue (VAT)+subcutaneous adipose tissue (SAT) by single-slice abdominal CT scan: median change +25.5 cm(2) ; 95% CI+8.9, +42.0] over 48 weeks; significant increases in these parameters were not seen in the control group. There was no significant change in truncal:peripheral fat ratio in either the enfuvirtide or the control group. CONCLUSION: The addition of enfuvirtide to an OB regimen does not appear to have unfavourable effects on fat distribution or metabolic parameters.

Treatment of HIV-related primary central nervous system lymphoma with AZT high dose, HAART, interleukin-2 and foscarnet in three patients.

PURPOSE: Combined immunomodulatory and antiviral treatment was administered to three patients with newly diagnosed HIV-associated primary central nervous system lymphoma (PCNSL) in an attempt to improve outcomes. PATIENTS AND METHODS: Three patients from our institution who were recently diagnosed with HIV-associated PCNSL received intravenous azidothymidine (AZT) 1.6 gr. bid for two weeks, followed by oral AZT 250mg bid from day 15. In addition, complementary highly active antiretroviral therapy (HAART) with a second nucleoside reverse transcriptase inhibitor (NRTI) plus one protease inhibitor (PI) and interleukin 2 (IL-2) subcutaneously 2 million units twice daily (bid) plus foscarnet 90mg/kg bid were administered on days 1-14. One patient received anti-Epstein-Barr virus (EBV)-maintenance therapy with ganciclovir, followed by cidofovir. RESULTS: All patients experienced progressive disease while on induction therapy, and switched early to whole-brain radiation therapy (WBRT) as second line-treatment. No grade 3 or 4 toxicities were observed. Two patients died on days 50 and 166 respectively due to progressive disease. The third patient with histo?logically proven lymphoproliferation and only suspected PCNSL remained alive at 53 months. He was on HAART and remained clinically and neurologically stable. CONCLUSION: Although IL-2, HAART, high-dose AZT and foscarnet are used for other HIV-related conditions, they did not demonstrate benefit in lymphoma remission for 2 HIV- associated PCNSL patients. The third patient went into delayed remission after additional radiotherapy and was in good clinical and neurological health status over 53 months after diagnosis.

Potential geographic "hotspots" for drug-injection related transmission of HIV and HCV and for initiation into injecting drug use in New York City, 2011-2015, with implications for the current opioid epidemic in the US.

OBJECTIVE: We identified potential geographic "hotspots" for drug-injecting transmission of HIV and hepatitis C virus (HCV) among persons who inject drugs (PWID) in New York City. The HIV epidemic among PWID is currently in an "end of the epidemic" stage, while HCV is in a continuing, high prevalence (> 50%) stage. METHODS: We recruited 910 PWID entering Mount Sinai Beth Israel substance use treatment programs from 2011-2015. Structured interviews and HIV/ HCV testing were conducted. Residential ZIP codes were used as geographic units of analysis. Potential "hotspots" for HIV and HCV transmission were defined as 1) having relatively large numbers of PWID 2) having 2 or more HIV (or HCV) seropositive PWID reporting transmission risk-passing on used syringes to others, and 3) having 2 or more HIV (or HCV) seronegative PWID reporting acquisition risk-injecting with previously used needles/syringes. Hotspots for injecting drug use initiation were defined as ZIP codes with 5 or more persons who began injecting within the previous 6 years. RESULTS: Among PWID, 96% injected heroin, 81% male, 34% White, 15% African-American, 47% Latinx, mean age 40 (SD = 10), 7% HIV seropositive, 62% HCV seropositive. Participants resided in 234 ZIP codes. No ZIP codes were identified as potential hotspots due to small numbers of HIV seropositive PWID reporting transmission risk. Four ZIP codes were identified as potential hotspots for HCV transmission. 12 ZIP codes identified as hotspots for injecting drug use initiation. DISCUSSION: For HIV, the lack of potential hotspots is further validation of widespread effectiveness of efforts to reduce injecting-related HIV transmission. Injecting-related HIV transmission is likely to be a rare, random event. HCV prevention efforts should include focus on potential hotspots for transmission and on hotspots for initiation into injecting drug use. We consider application of methods for the current opioid epidemic in the US.

Hepatitis C virus prevalence and estimated incidence among new injectors during the opioid epidemic in New York City, 2000-2017: Protective effects of non-injecting drug use.

OBJECTIVE: Assess hepatitis C virus (HCV) prevalence and incidence among person who began injecting drugs during the opioid epidemic in New York City (NYC) and identify possible new directions for reducing HCV infection among persons who inject drugs. METHODS: 846 persons who began injecting drugs between 2000 and 2017 were recruited from persons entering Mount Sinai Beth Israel substance use treatment programs. A structured interview was administered and HCV antibody testing conducted. Protective effects of non-injecting drug use were examined among persons who "reversed transitioned" to non-injecting drug use and persons who used non-injected heroin in addition to injecting. RESULTS: Participants were 79% male, 41% White, 15% African-American, 40% Latinx, with a mean age of 35. Of those who began injecting in 2000 or later, 97 persons (11%) "reverse transitioned" back to non-injecting drug use. Reverse transitioning was strongly associated with lower HCV seroprevalence (30% versus 47% among those who continued injecting, p < 0.005). Among those who continued injecting, HCV seropositivity was inversely associated with current non-injecting heroin use (AOR = 0.72, 95%CI 0.52-0.99). HCV incidence among persons continuing to inject was estimated as 13/100 person-years. HCV seropositive persons currently injecting cocaine were particularly likely to report behavior likely to transmit HCV. CONCLUSIONS: Similar to other locations in the US, NYC is experiencing high rates of HCV infection among persons who have begun injecting since 2000. New interventions that facilitate substitution of non-injecting for injecting drug use and that reduce transmission behavior among HCV seropositives may provide additional methods for reducing HCV transmission.

Randomized comparative trial of pegylated liposomal doxorubicin versus bleomycin and vincristine in the treatment of AIDS-related Kaposi's sarcoma. International Pegylated Liposomal Doxorubicin Study Group.

PURPOSE: Cytotoxic chemotherapy is frequently required for the more severe manifestations of human immunodeficiency virus (HIV)-related Kaposi's sarcoma. Combinations of bleomycin and vincristine (BV) or BV with the addition of doxorubicin (ABV) are the most commonly used regimens against which new treatments may be compared. We report a multicenter phase III study that compared pegylated liposomal doxorubicin (PLD) to the BV combination. PATIENTS AND METHODS: We conducted a randomized study that compared PLD 20 mg/m2 with a combination of bleomycin 15 IU/m2 and vincristine 2 mg in 241 patients with HIV-related Kaposi's sarcoma. Both regimens were administered by intravenous infusion every 3 weeks for six cycles. RESULTS: A total of 121 patients received PLD and 120 patients the BV combination. The response to PLD was superior to BV: 58.7% versus 23.3% (P < .001). Patients who were randomized to receive BV, however, were more likely to terminate treatment early because of an adverse event (26.7% v 10.7%), and fewer completed the full six cycles of treatment (30.8% v 55.4%). Treatment with BV was associated with a significantly higher incidence of peripheral neuropathy (P < .001), whereas PLD treatment was more commonly associated with neutropenia and delays in receiving treatment (P < or = .001). CONCLUSION: Pegylated liposomal doxorubicin is an effective treatment for HIV-related Kaposi's sarcoma with a higher response rate than the BV combination. It is well tolerated but more myelosuppressive.

[New drugs--hope for salvage patients?]. / Ein Blick in die Pipeline. Die nächste Generation der antiretroviralen Medikamente.

New and potent drugs are urgently needed for the salvage therapy of HIV-infected patients. The protease inhibitors Tipranavir and TMC114, which have high potency against multidrug-resistant viral strains, are the most promising drugs for the near future. How important they will be in salvage therapy cannot be predicted at this time. New points of attack in the viral replication cycle have been defined. Substances belonging to the groups of integrase and maturation inhibitors are in the early stages of clinical development.

The role of abacavir (ABC, 1592) in antiretroviral therapy-experienced patients: results from a randomized, double-blind, trial. CNA3002 European Study Team.

OBJECTIVE: To compare the antiviral activity of abacavir (ABC) with stable background therapy (SBG) and SBG alone in antiretroviral therapy-experienced subjects as demonstrated by the proportion of subjects with plasma HIV-1 RNA < or = 400 copies/ml, plasma HIV-1 RNA and CD4 cell count profiles, and safety and tolerance of the two regimens over 16 weeks. DESIGN: One-hundred and eighty-five HIV-1 infected adults, with CD4 cell counts > or = 100 x 10(6)/l and plasma HIV-1 RNA of 400-50,000 copies/ml and who had received SBG therapy for at least 12 weeks, were randomized to receive ABC (300 mg twice daily) or placebo in a double blind, multi-centre study. METHODS: Antiretroviral activity was assessed by measuring changes in plasma HIV-1 RNA levels and CD4 cell counts. Genotypic and phenotypic resistance was determined at baseline and week 16. Evaluation of safety and tolerance was based on clinical adverse events and laboratory analyses. RESULTS: At week 16 significantly more subjects receiving ABC + SBG had plasma HIV-1 RNA < or = 400 copies/ml (36/92, 39%) than subjects receiving SBG alone (7/93, 8%; P < 0.001). A similar response was observed in both the lamivudine naive and lamivudine-experienced subjects. The presence of the M184V mutation did not preclude an antiviral response to ABC; 73% of subjects with the M184V mutation alone experienced a > or = 1.0 log10 copies/ml reduction in plasma HIV-1 RNA or had a value of < or = 400 copies/ml by week 16. CONCLUSIONS: ABC was generally well tolerated and exerted significant antiviral effect when added to combination antiretroviral therapy over 16 weeks.

A dose comparison study of didanosine in patients with very advanced HIV infection who are intolerant to or clinically deteriorate on zidovudine. German ddI Trial Group.

OBJECTIVE: Zidovudine (ZDV) is the only antiretroviral drug which has been shown to reduce mortality in patients with symptomatic HIV disease, but its use is restricted by intolerance in a significant proportion of patients. Additionally, the efficacy of ZDV therapy appears to decrease after prolonged treatment particularly in the advanced stage of HIV disease. Therefore, alternative antiretroviral regimens for patients are needed. In this study, didanosine (ddI; 2',3'-dideoxyinosine), another HIV reverse transcriptase inhibitor, was evaluated. DESIGN: A total of 426 patients with AIDS or AIDS-related complex (ARC) who were intolerant to or clinically progressing on ZDV therapy and who had CD4+ cell counts < or = 150 x 10(6)/l were randomized to receive either a high (750 mg for bodyweight > or = 60 kg or 500 mg for bodyweight < 60 kg) or a low (200 mg and 134 mg, respectively) dose of ddI daily. SETTING: The patients were recruited from 31 German and Austrian AIDS clinical primary-care centres. RESULTS: The study was stopped after the second interim analysis due to a statistically significant difference in the incidence of pancreatitis (nine versus 26; relative risk, 2.92; P = 0.003) and neuropathy (28 versus 43; relative risk, 1.55; P = 0.05) in favour of the low dose. There was no difference between the low and high dosage groups in survival rate at 6 (80 versus 80%) and 12 months (61 versus 65%), number of deaths [82 (43.6 per 100 patient-years) versus 84 (44.4 per 100 patient-years)], progression from ARC to AIDS or to AIDS or death, or average number of new/recurrent opportunistic infections (2.8 versus 3.0 per patient). CONCLUSIONS: This study cannot conclude on ddI efficacy but it shows that in patients with advanced HIV disease for whom no alternative antiretroviral therapy is available and ddI therapy is considered, daily doses < 750 mg should be administered.

Pharmacokinetic optimisation in the treatment of Pneumocystis carinii pneumonia.

Several drugs and drug combinations are currently used in the treatment of patients with Pneumocystis carinii pneumonia (PCP)--pentamidine and cotrimoxazole (trimethoprim plus sulphamethoxazole), which are indicated for this usage, dapsone/trimethoprim and clindamycin/primaquine, which are not licensed for PCP, and trimetrexate/calcium folinate (leucovorin), eflornithine and BW-566C (566 C80) as investigational drugs. For most of these agents, recommendations regarding the use of pharmacokinetic parameters to establish individualised therapy cannot be made. The pharmacokinetics of antipneumocystis drugs are not well documented and clinical trials evaluating the relationship between the individual plasma pharmacokinetic profiles and responses to treatment are sparse. In clinical trials, the reduction of the daily dose of pentamidine to 3 or 2 mg/kg/day and of cotrimoxazole to 15 mg/kg of the trimethoprim component resulted in a substantial reduction of frequency and severity of adverse drug effects without diminishing efficacy. For pentamidine, a long half-life of > or = 4 days implies the need for a loading dose. Plasma concentrations of the parent drug at steady-state varied between 30 and 100 micrograms/L. The elimination pharmacokinetics are characterised by several elimination slopes indicating the existence of a deep peripheral compartment. Due to its very low renal clearance, dosage adjustments are not necessary in patients with renal impairment. The pharmacokinetics of cotrimoxazole follow first-order kinetics in PCP and the particular parameters are similar to those reported in the treatment of bacterial infection. Steady-state plasma concentrations of both trimethoprim and sulphamethoxazole are attained within 2 to 3 days, but the range of 'therapeutic' plasma concentrations must be newly defined, since elevated trimethoprim concentrations could not be correlated with the frequency and severity of adverse drug reactions. The concentrations of sulphamethoxazole may be at least as important as those of trimethoprim in defining a toxic range. With dapsone/trimethoprim, clindamycin/primaquine and BW-566C (566 C 80) good clinical response rates were found in groups of patients with mild to moderate PCP. Comparative trials with standard drugs are still ongoing. Therapeutic to toxic concentration ratios have not been established in patients with PCP. Pharmacokinetic data pertaining to patients with PCP are either nonexistent or incomplete, or are complicated by a drug interaction between dapsone and trimethoprim suggesting an inhibition of metabolism of dapsone. Eflornithine and trimetrexate/calcium folinate have been used under specific research protocols, showing partial success as salvage agents for desperately ill patients with AIDS. Regarding all antipneumocystis drugs, additional clinical and pharmacokinetic data are needed to optimise and more fully individualise the treatment regimens for this severe infection.

GW420867X administered to HIV-1-infected patients alone and in combination with lamivudine and zidovudine.

PURPOSE: GW420867X is a nonnucleoside inhibitor of HIV-1 reverse transcriptase. The primary objective was to assess the safety of GW420867X in HIV-1-infected patients. The secondary objectives were to assess the effect of GW420867X on plasma HIV-1 RNA and viral genotype and phenotype and to examine the pharmacokinetics of GW420867X in HIV-1-infected patients. METHOD: HIV-1-infected patients were randomized to GW420867X 50 mg/day, 100 mg/day, or 200 mg/day from days 1-28 (n = 15 per group). Lamivudine (3TC) plus zidovudine (ZDV) was added from days 8-28. A control group (n = 15) received GW420867X, 3TC, and ZDV placebos. RESULTS: Plasma HIV-1 RNA and CD4+ counts improved in the GW420867X groups at days 8 and 28. No significant development of drug resistance was detected. Median observed peak GW420867X concentration (C(max)) generally occurred at 2 hours. The area under the curve over the dosing interval (AUCtau)on day 14 increased less than proportionally to dose, suggesting there was increased clearance and/or decreased absorption. Mean trough GW420867X concentrations were many fold above the in vitro IC(50) in the presence of human serum proteins. Seven of 15 patients on 50 mg GW420867X, 8/15 on 100 mg GW420867X, 12/15 on 200 mg GW420867X, and 8/15 on placebo reported drug-related adverse events. CONCLUSION: GW420867X was well tolerated and has potent antiretroviral activity alone and in combination with 3TC plus ZDV.