Claudia Hawkins

Sex differences in antiretroviral treatment outcomes among HIV-infected adults in an urban Tanzanian setting.

Objective:To determine the relationship between sex and antiretroviral therapy (ART) outcomes in an urban Tanzanian setting. Design:Longitudinal analysis of a cohort of HIV-infected adult men and women on ART enrolled at the Management and Development for Health (MDH)-Presidents Emergency Plan For AIDS Relief (PEPFAR) HIV care and treatment program in Dar es Salaam, Tanzania. Methods:Clinical and immunologic responses to ART were compared between HIV-infected men and women enrolled from November 2004 to June 2008. Cox regression analyses were used to study sex differences with regard to mortality, immunologic failure (WHO, 2006) and loss to follow-up, after adjusting for other risk factors for the outcomes. Results:Four thousand, three hundred and eighty-three (34%) men and 8459 (66%) women were analyzed. Men were significantly more immunocompromised than women at enrollment in terms of stage IV disease (27 vs. 23%, P < 0.001) and mean CD4+ cell count (123 vs. 136 cells/μl, P < 0.001). In multivariate analyses, men had a significantly higher risk of overall mortality [hazard ratio 1.19, 95% confidence interval (CI) 1.05–1.30, P < 0.001], immunologic nonresponse defined as CD4 cell count less than 100 cells/μl after at least 6 months of initiating ART (hazard ratio 1.74, 95% CI 1.44–2.11, P < 0.001) and loss to follow-up (hazard ratio 1.19, 95% CI 1.10–1.30, P < 0.001) than that in women. Associations did not change significantly when restricting analyses to the period of good adherence for all patients. Conclusion:Nonadherence to care and advanced immunodeficiency at enrollment explained only 17% of the inferior mortality in HIV-infected men in this resource-limited setting. Additional study of behavioral and biologic factors that may adversely impact treatment outcomes in men is needed to reduce these sex disparities.

Impact of Hepatitis B Virus Infection on Human Immunodeficiency Virus Response to Antiretroviral Therapy in Nigeria

BACKGROUND As highly active antiretroviral therapy (ART) is introduced into areas of the world in which hepatitis B virus (HBV) infection is highly endemic, it is important to determine the influence of HBV on persons with human immunodeficiency virus (HIV) and HBV coinfection who are receiving ART. METHODS We studied 1564 HIV-infected patients in Jos, Nigeria, who initiated ART. Participants with HIV-HBV coinfection had hepatitis B e antigen (HBeAg) and HBV DNA status determined. CD4+ T cell count and HIV load at ART initiation were compared between individuals with HIV monoinfection and those with HIV-HBV coinfection with use of univariate methods. Regression analyses were used to determine if HBeAg status or HBV DNA at ART initiation were associated with baseline HIV parameters or ART response. RESULTS The median CD4+ T cell count of the 262 participants with HIV-HBV coinfection (16.7%) was 107 cells/mL, compared with 130 cells/mL for participants with HIV monoinfection at ART initiation (P = .001). Participants with HIV-HBV coinfection also had higher HIV loads than did patients with HIV monoinfection (4.96 vs 4.75 log10 copies/mL; p = .02 ). Higher HBV DNA and detectable HBeAg levels were independently associated with lower CD4+ T cell counts at ART initiation but not with higher HIV loads. In a multivariable model, HBeAg-positive patients were less likely than HBeAg-negative patients to suppress HIV replication to <or= 400 copies/mL (odds ratio, 0.54; P = .03 ) at 24 weeks, but they had similar CD4+ T cell increases. At 48 weeks, there was no significant effect of HBeAg status on ART response. CONCLUSIONS Among HIV-infected Nigerian individuals, HBV coinfection, especially among those with high levels of HBV replication, was associated with lower CD4+ T cell counts at ART initiation, independent of HIV RNA level. Patients with HBeAg-positive status had a slower virological response to ART, compared with HBeAg-negative patients. Further work is needed to understand the effects of HBV on CD4+ T cells.

Antiretroviral durability and tolerability in HIV-infected adults living in urban Kenya

Background:Insufficient data exist on the durability and tolerability of first-line antiretroviral therapy (ART) regimens provided by HIV treatment programs implemented in developing countries. Methods:Longitudinal observation of clinical, immunologic, and treatment parameters of all HIV-infected adult patients initiated on ART was performed at Saint Marys Mission Hospital in Nairobi, Kenya from September 2004 until August 2006. Results:A total of 1286 patients were analyzed (59.1% female). Initial ART regimens were primarily stavudine, lamivudine, and nevirapine (62.1%). Median ART duration was 350 days (11.6 months). Significant improvements in clinical and immunologic status were noted after 12 months of therapy. ART switches occurred in 701 (54.5%) patients. The cumulative incidence of ART switch at 12 months was 78.4%. Concurrent ART-related toxicities (40.6%) and tuberculosis treatment interactions (28.1%) were the most frequent reasons for ART switch. Baseline AIDS symptoms (hazard rate [HR] = 1.59, 95% confidence interval [CI]: 1.28 to 1.98; P < 0.01) and a CD4 count ≤100 cells/mm3 (HR = 1.20, CI: 1.01 to 1.43; P = 0.04) were independent predictors of ART switch. ART-related clinical toxicity occurred in 341 (26.5%) patients. Peripheral neuropathy was reported most frequently (20.7%). A CD4 count ≤100 cells/mm3 was an independent predictor of clinical toxicity. Conclusions:Excellent clinical and immunologic responses to ART were observed in this urban Kenyan population; however, frequent switches in ART among medication classes because of toxicity or drug interactions may limit the durability of these responses.

Nutritional Status and Mortality Among HIV-Infected Patients Receiving Antiretroviral Therapy in Tanzania

BACKGROUND Poor nutritional status is associated with immunologic impairment and adverse health outcomes among adults infected with human immunodeficiency virus (HIV). METHODS We investigated body mass index (BMI), middle upper arm circumference (MUAC), and hemoglobin (Hgb) concentrations at initiation of antiretroviral therapy (ART) in 18,271 HIV-infected Tanzanian adults and their changes in the first 3 months of ART, in relation to the subsequent risk of death. RESULTS Lower BMI, MUAC, and Hgb concentrations at ART initiation were strongly associated with a higher risk of death within 3 months. Among patients who survived >3 months after ART initiation, those with a decrease in weight, MUAC, or Hgb concentrations by 3 months had a higher risk of death during the first year. After 1 year, only a decrease in MUAC by 3 months after ART initiation was associated with a higher risk of death. Weight loss was associated with a higher risk of death across all levels of baseline BMI, with the highest risk observed among patients with BMI <17 kg/m(2) (relative risk, 7.9; 95% confidence interval, 4.4-14.4). CONCLUSIONS Poor nutritional status at ART initiation and decreased nutritional status in the first 3 months of ART were strong independent predictors of mortality. The role of nutritional interventions as adjunct therapies to ART merits further investigation.

Effect of High-Dose vs Standard-Dose Multivitamin Supplementation at the Initiation of HAART on HIV Disease Progression and Mortality in Tanzania A Randomized Controlled Trial

CONTEXT Large randomized trials have previously shown that high-dose micronutrient supplementation can increase CD4 counts and reduce human immunodeficiency virus (HIV) disease progression and mortality among individuals not receiving highly active antiretroviral therapy (HAART); however, the safety and efficacy of such supplementation has not been established in the context of HAART. OBJECTIVE To test the hypothesis that high-dose multivitamin supplementation vs standard-dose multivitamin supplementation decreases the risk of HIV disease progression or death and improves immunological, virological, and nutritional parameters in patients with HIV initiating HAART. DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blind, controlled trial of high-dose vs standard-dose multivitamin supplementation for 24 months in 3418 patients with HIV initiating HAART between November 2006 and November 2008 in 7 clinics in Dar es Salaam, Tanzania. INTERVENTION The provision of daily oral supplements of vitamin B complex, vitamin C, and vitamin E at high levels or standard levels of the recommended dietary allowance. MAIN OUTCOME MEASURE The composite of HIV disease progression or death from any cause. RESULTS The study was stopped early in March 2009 because of evidence of increased levels of alanine transaminase (ALT) in patients receiving the high-dose multivitamin supplement. At the time of stopping, 3418 patients were enrolled (median follow-up, 15 months), and there were 2374 HIV disease progression events and 453 observed deaths (2460 total combined events). Compared with standard-dose multivitamin supplementation, high-dose supplementation did not reduce the risk of HIV disease progression or death. The absolute risk of HIV progression or death was 72% in the high-dose group vs 72% in the standard-dose group (risk ratio [RR], 1.00; 95% CI, 0.96-1.04). High-dose supplementation had no effect on CD4 count, plasma viral load, body mass index, or hemoglobin level concentration, but increased the risk of ALT elevations (1239 events per 1215 person-years vs 879 events per 1236 person-years; RR, 1.44; 95% CI, 1.11-1.87) vs standard-dose supplementation. CONCLUSION In adults receiving HAART, use of high-dose multivitamin supplements compared with standard-dose multivitamin supplements did not result in a decrease in HIV disease progression or death but may have resulted in an increase in ALT levels. TRIAL REGISTRATION Clinicaltrials.gov Identifier: NCT00383669.

Clinical and genotypic findings in HIV-infected patients with the K65R mutation failing first-line antiretroviral therapy in Nigeria.

Introduction:The HIV-1 epidemic in African countries is largely due to non-B HIV-1 subtypes. Patterns and frequency of antiretroviral drug resistance mutations observed in these countries may differ from those in the developed world, where HIV-1 subtype B predominates. Methods:HIV-1 subtype and drug resistance mutations were assayed among Nigerian patients with treatment failure on first-line therapy (plasma HIV RNA >1000 copies/mL). Sequence analysis of the reverse transcriptase and protease gene revealed drug resistance mutations and HIV-1 viral subtype. Specific patterns of mutations and clinical characteristics are described in patients with the K65R mutation. Results:Since 2005, 338 patients were evaluated. The most prevalent subtypes were CRF02_AG [152 of 338 (44.9%)] and G [128 of 338 (37.9%)]. Three hundred seven of 338 (90.8%) patients had previously received stavudine and/or zidovudine + lamivudine + efavirenz or nevirapine; 41 of 338 (12.1%) had received tenofovir (TDF). The most common nucleoside reverse transcriptase inhibitor mutations observed were M184V (301, 89.1%) and K70R (91, 26.9%). The K65R mutation was present in 37 of 338 patients (10.9%). The Q151M (P < 0.05), K219R, and T69del (P < 0.01) mutations were more common in patients with K65R who had not received TDF. Conclusions:The K65R mutation is increasingly recognized and is a challenging finding among patients with non-B HIV subtypes, whether or not they have been exposed to TDF.

Prevalence of hepatitis B co-infection and response to antiretroviral therapy among HIV-infected patients in Tanzania.

Objectives:To evaluate the prevalence of HIV/hepatitis B virus (HBV) co-infection and relationship between HIV/HBV and health outcomes in a cohort of HIV-infected adults receiving antiretroviral treatment (ART) in urban Tanzania. Design/methods:Clinical and immunologic responses to ART were compared longitudinally between HIV mono (HIV) and HIV/HBV co-infected (HIV/HBV) adults enrolled between November 2004 and September 2011 at the Management and Development for Health (MDH)-PEPFAR HIV Care and Treatment program in Dar es Salaam, Tanzania. Results:The prevalence of HIV/HBV co-infection was 6.2% (1079/17 539). Compared to HIV patients, HIV/HBV patients were more likely to be male, younger, and more immunosuppressed at ART initiation. Median ART duration was 18.6 [interquartile range (IQR) 4.9–29.5] and 18.2 (IQR 4.2–27.2) months in HIV and HIV/HBV patients, respectively. In multivariate analyses, a trend towards a higher risk of mortality was observed in HIV/HBV patients {hazard ratio 1.18 [95% confidence interval (CI) 0.98–1.42], P = 0.07} as well as lower CD4+ cell counts throughout recovery (P < 0.01) and higher risk of moderate-to-severe hepatotoxicity (P values  < 0.01 for alanine transaminase > 120 and >200 IU/l). There was a higher risk of mortality in HIV/HBV patients vs. HIV patients on non-tenofovir (TDF)-containing ART [hazard ratio 1.28 (95% CI 1.02–1.61), P < 0.03], whereas there was no difference in the risk of mortality observed in HIV/HBV patients vs. HIV patients on TDF-containing ART [hazard ratio 0.70 (95% CI 0.34–1.44), P < 0.33]; interaction P = 0.30. Conclusions:HBV co-infection significantly impacted ART outcomes in this Tanzanian HIV-infected population. Further research is needed to confirm the potential beneficial effects of TDF on mortality in HIV/HBV co-infected individuals in these settings.

Catheter-related bloodstream infections caused by rapidly growing nontuberculous mycobacteria : a case series including rare species

Rapidly growing nontuberculous mycobacteria (RGMs) are responsible for a variety of clinical syndromes in humans including catheter-related blood stream infections (CRBSIs). Recently, we identified a cluster of RGM-associated CRBSI at our institution. We describe the epidemiologic and clinical patterns associated with these infections. We conducted a retrospective single-center review of RGM CRBSI between May 2004 and June 2005. RGMs isolated from blood cultures of 6 patients included Mycobacterium mucogenicum (2), Mycobacterium fortuitum (2), and the rare RGM species, Mycobacterium neoaurum (1) and Mycobacterium septicum (1). All of the patients had a long-term intravascular catheter (mean duration, 6.5 months). Bacteremia was resolved in all patients after catheter removal and appropriate antibiotics. None of the patients suffered a relapse of RGM CRBSI, and all survived to 1 year. RGMs are causative pathogens in both immunosuppressed and immunocompetent individuals with long-term intravascular catheters and blood stream infections. Recent trends at our center suggest that infections with these pathogens are rising.

Nucleoside Reverse Transcriptase Inhibitor Resistance Mutations Associated with First-Line Stavudine-Containing Antiretroviral Therapy: Programmatic Implications for Countries Phasing Out Stavudine

BACKGROUND The World Health Organization Antiretroviral Treatment Guidelines recommend phasing-out stavudine because of its risk of long-term toxicity. There are two mutational pathways of stavudine resistance with different implications for zidovudine and tenofovir cross-resistance, the primary candidates for replacing stavudine. However, because resistance testing is rarely available in resource-limited settings, it is critical to identify the cross-resistance patterns associated with first-line stavudine failure. METHODS We analyzed HIV-1 resistance mutations following first-line stavudine failure from 35 publications comprising 1,825 individuals. We also assessed the influence of concomitant nevirapine vs. efavirenz, therapy duration, and HIV-1 subtype on the proportions of mutations associated with zidovudine vs. tenofovir cross-resistance. RESULTS Mutations with preferential zidovudine activity, K65R or K70E, occurred in 5.3% of individuals. Mutations with preferential tenofovir activity, ≥ two thymidine analog mutations (TAMs) or Q151M, occurred in 22% of individuals. Nevirapine increased the risk of TAMs, K65R, and Q151M. Longer therapy increased the risk of TAMs and Q151M but not K65R. Subtype C and CRF01_AE increased the risk of K65R, but only CRF01_AE increased the risk of K65R without Q151M. CONCLUSIONS Regardless of concomitant nevirapine vs. efavirenz, therapy duration, or subtype, tenofovir was more likely than zidovudine to retain antiviral activity following first-line d4T therapy.

High rates of hepatitis C virus (HCV) cure using direct-acting antivirals in HIV/HCV-coinfected patients: a real-world perspective

OBJECTIVES There are few data on the real-world experience of FDA-approved oral hepatitis C virus (HCV) direct-acting antiviral (DAA) drug combinations in HIV/HCV-coinfected patients. We evaluated the safety and efficacy of DAA therapies in a cohort of HIV/HCV patients in a large urban clinic in Chicago. METHODS HIV/HCV-coinfected adults (≥18 years) enrolled in the Northwestern University Viral Hepatitis Registry between January 2013 and June 2015 were analysed. Treated patients received one of the following DAA combinations: sofosbuvir/ledipasvir, sofosbuvir/ribavirin, sofosbuvir/simeprevir or paritaprevir/ritonavir/ombitasvir/dasabuvir ± ribavirin. The primary outcome was sustained virological response at 12 weeks after DAA completion (SVR12). RESULTS Seventy-seven HIV/HCV patients were evaluated for DAA therapy. Most patients were male (62/77, 81%) and infected with HCV genotype 1 (67/77, 87%). Some 32/77 (42%) were cirrhotic and 29/77 (38%) had received prior treatment with an IFN-containing regimen. DAA therapy was more likely to be started in Caucasians than persons of other ethnicities (P = 0.01). The overall SVR12 rate was 92% in 52 patients who completed therapy and had follow-up by the end of the study: sofosbuvir/simeprevir, 32/33 (97%); sofosbuvir/ribavirin, 4/7 (57%); sofosbuvir/ledipasvir, 11/11 (100%); and paritaprevir/ritonavir/ombitasvir/dasabuvir, 1/1 (100%). Four patients relapsed after therapy with sofosbuvir/simeprevir (n = 1) or sofosbuvir/ribavirin (n = 3). Adverse events were uncommon and did not result in DAA treatment interruption or discontinuation. CONCLUSIONS The HCV DAA combinations of sofosbuvir/ledipasvir and sofosbuvir/simeprevir were highly effective and well tolerated in this diverse population of HIV/HCV-coinfected patients, many of whom had advanced liver disease. HIV coinfection should not be considered a barrier to successful HCV treatment with DAAs.