Browsing by Author "Friedland, Gerald H."

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Antiretroviral switching and bedaquiline treatment of drug-resistant tuberculosis HIV co-infection.
(Elsevier., 2019) Padayatchi, Nesri.; Daftary, Amrita.; Orrell, Catherine.; Dooley, Kelly E.; O'Donnell, Max Roe.; Amico, Kathy Rivet.; Friedland, Gerald H.
Abstract available in PDF.
Chest radiograph findings and time to culture conversion in patients with multidrug-resistant tuberculosis and HIV in Tugela Ferry, South Africa.
(Plos., 2013) Brust, James C. M.; Berman, Andrew R.; Zalta, Benjamin.; Haramati, Linda B.; Ning, Yuming.; Heo, Moonseong.; Van der Merwe, Theo L.; Bamber, Sheila.; Moll, Anthony P.; Friedland, Gerald H.; Shah, N. Sarita.; Gandhi, Neel R.
Background: The majority of patients with multidrug-resistant tuberculosis (MDR-TB) in South Africa are co-infected with HIV, but the radiographic features of MDR-TB and their relationship with time to sputum culture conversion in the antiretroviral therapy era have not been described. Methods: We reviewed baseline chest radiographs for 56 patients with MDR-TB from a rural area of South Africa. We analyzed the association of cavities, consolidation, pleural effusion and hilar lymphadenopathy with time to sputum culture conversion, adjusting for HIV status, baseline sputum smear and CD4 count. Results: Of the 56 subjects, 49 (88%) were HIV-positive, with a median CD4 count of 136 cells/mm³ (IQR 65-249). Thirty-two (57%) patients were sputum smear positive. Twenty-two (39%) patients had a cavity and 37 (66%) patients had consolidations. Cavitary disease and consolidations were each associated with longer time to culture conversion on bivariate analysis but not after adjusting for sputum smear status (aORs 1.79 [0.94-3.42] and 1.09 [0.67-1.78], respectively). Positive baseline sputum smear remained independently associated with longer time to conversion (aOR 3.45 [1.39-8.59]). We found no association between pleural effusion or hilar lymphadenopathy and time to conversion. Seventy-nine percent of patients were cured at the end of treatment. Conclusions: Despite high rates of HIV co-infection and advanced immunodeficiency, the majority of patients had severe pathology on baseline chest radiograph. Nevertheless, culture conversion rates were high and treatment outcomes were favorable. Cavitation and consolidation do not appear to have an independent association with time to culture conversion beyond that of baseline sputum smear status.
The immune reconstitution inflammatory syndrome after antiretroviral therapy initiation in patients with tuberculosis: findings from the SAPiT trial.
(American College of Physicians., 2012) Naidoo, Kogieleum.; Yende Zuma, Nonhlanhla.; Padayatchi, Nesri.; Naidoo, Kasavan.; Jithoo, Niraksha.; Nair, Gonasagrie.; Bamber, Sheila.; Gengiah, Santhanalakshmi.; El-Sadr, Wafaa M.; Friedland, Gerald H.; Abdool Karim, Salim Safurdeen.
Background: Concerns about the immune reconstitution inflammatory syndrome (IRIS) remain a barrier to antiretroviral therapy (ART) initiation during antituberculosis treatment in co-infected patients. Objective: To assess IRIS incidence, severity, and outcomes relative to the timing of ART initiation in patients with HIV-related tuberculosis. Design: Randomized, open-label clinical trial. (ClinicalTrials.gov registration number: NCT00398996) Setting: An outpatient clinic in Durban, South Africa. Patients: 642 patients co-infected with HIV and tuberculosis. Measurements: In a secondary analysis of the SAPiT (Starting Antiretroviral Therapy at Three Points in Tuberculosis) trial, IRIS was assessed in patients randomly assigned to initiate ART within 4 weeks of tuberculosis treatment initiation (early integrated treatment group), within 4 weeks of completion of the intensive phase of tuberculosis treatment (late integrated treatment group), or within 4 weeks after tuberculosis therapy completion (sequential treatment group). The syndrome was defined as new-onset or worsening symptoms, signs, or radiographic manifestations temporally related to treatment initiation, accompanied by a treatment response. Severity of IRIS, hospitalization, and time to resolution were monitored. Results: Incidence of IRIS was 19.5 (n = 43), 7.5 (n = 18), and 8.1 (n = 19) per 100 person-years in the early integrated, late integrated, and sequential treatment groups, respectively. Among patients with a baseline CD4+ count less than 0.050 × 10.9 cells/L, IRIS incidence was 45.5, 9.7, and 19.7 per 100 person-years in the early integrated, late integrated, and sequential treatment groups, respectively. Incidence of IRIS was higher in the early integrated treatment group than in the late integrated (incidence rate ratio, 2.6 [95% CI, 1.5 to 4.8]; P < 0.001) or sequential (incidence rate ratio, 2.4 [CI, 1.4 to 4.4]; P < 0.001) treatment groups. More severe IRIS cases occurred in the early integrated treatment group than in the other 2 groups (35% vs. 19%; P = 0.179), and patients in the early integrated treatment group had significantly higher hospitalization rates (42% vs. 14%; P = 0.007) and longer time to resolution (70.5 vs. 29.0 days; P = 0.001) than patients in the other 2 groups. Limitations: It was not possible to assess IRIS in more patients in the sequential treatment group (n = 74) than in the late integrated (n = 50) and early integrated (n = 32) treatment groups because of loss to follow-up, withdrawal, or death within 6 months of scheduled ART initiation. This study did not assess IRIS risk in nonambulatory patients or in those with extrapulmonary and smear-negative tuberculosis. Conclusion: Initiation of ART in early stages of tuberculosis treatment resulted in significantly higher IRIS rates, longer time to resolution, and more severe cases of IRIS requiring hospitalization. These findings are particularly relevant to patients initiating ART with a CD4+ count less than 0.050 × 10.9 cells/L, given the increased survival benefit of early ART initiation in this group.
Improved survival in multidrug-resistant tuberculosis patients receiving integrated tuberculosis and antiretroviral treatment in the SAPiT trial.
(International Journal of Tuberculosis and Lung Disease., 2014) Padayatchi, Nesri.; Naidoo, Kogieleum.; Grobler, Anna Christina.; Abdool Karim, Salim Safurdeen.; Friedland, Gerald H.
BACKGROUND: The therapeutic effects of antiretroviral treatment (ART) in patients with multidrug-resistant tuberculosis (MDR-TB) and human immunodeficiency virus (HIV) infection have not been established. Objective : To assess therapeutic outcomes of integrating ART with treatment for MDR-TB. Design: A subgroup of MDR-TB patients from a randomised controlled trial, the SAPiT (Starting Antiretroviral Therapy at Three Points in Tuberculosis) study, conducted in an out-patient clinic in Durban, South Africa, from 2008 to 2012. Methods : Clinical outcomes at 18 months were compared in patients randomised to receive ART within 12 weeks of initiating standard first-line anti-tuberculosis treatment with those who commenced ART after completing anti-tuberculosis treatment. Results : Mycobacterium tuberculosis drug susceptibility results were available in 489 (76%) of 642 SAPiT patients: 23 had MDR-TB, 14 in the integrated treatment arm and 9 in the sequential treatment arm. At 18 months, the mortality rate was 11.9/100 person-years (py; 95%CI 1.4–42.8) in the combined integrated treatment arm and 56.0/100 py (95%CI 18.2–130.8) in the sequential treatment arm (hazard ratio adjusted for baseline CD4 count and whether MDR-TB treatment was initiated: 0.14; 95%CI 0.02–0.94, P " 0.04). Conclusion: Despite the small sample size, the 86% reduction in mortality due to early initiation of ART in MDR-TB patients was statistically significant.
Integration of antiretroviral therapy with tuberculosis treatment.
(Massachusetts Medical Society., 2011) Abdool Karim, Salim Safurdeen.; Naidoo, Kogieleum.; Grobler, Anna Christina.; Padayatchi, Nesri.; Baxter, Cheryl.; Gray, Andrew Lofts.; Gengiah, Tanuja Narayansamy.; Gengiah, Santhanalakshmi.; Naidoo, Anushka.; Jithoo, Niraksha.; Nair, Gonasagrie.; El-Sadr, Wafaa M.; Friedland, Gerald H.; Abdool Karim, Quarraisha.
Background. We previously reported that integrating antiretroviral therapy (ART) with tuberculosis treatment reduces mortality. However, the timing for the initiation of ART during tuberculosis treatment remains unresolved. Methods. We conducted a three-group, open-label, randomized, controlled trial in South Africa involving 642 ambulatory patients, all with tuberculosis (confirmed by a positive sputum smear for acid-fast bacilli), human immunodeficiency virus infection, and a CD4+ T-cell count of less than 500 per cubic millimeter. Findings in the earlier- ART group (ART initiated within 4 weeks after the start of tuberculosis treatment, 214 patients) and later-ART group (ART initiated during the first 4 weeks of the continuation phase of tuberculosis treatment, 215 patients) are presented here. Results. At baseline, the median CD4+ T-cell count was 150 per cubic millimeter, and the median viral load was 161,000 copies per milliliter, with no significant differences between the two groups. The incidence rate of the acquired immunodeficiency syndrome (AIDS) or death was 6.9 cases per 100 person-years in the earlier-ART group (18 cases) as compared with 7.8 per 100 person-years in the later-ART group (19 cases) (incidence-rate ratio, 0.89; 95% confidence interval [CI], 0.44 to 1.79; P = 0.73). However, among patients with CD4+ T-cell counts of less than 50 per cubic millimeter, the incidence rates of AIDS or death were 8.5 and 26.3 cases per 100 person-years, respectively (incidence-rate ratio, 0.32; 95% CI, 0.07 to 1.13; P = 0.06). The incidence rates of the immune reconstitution inflammatory syndrome (IRIS) were 20.1 and 7.7 cases per 100 person-years, respectively (incidence-rate ratio, 2.62; 95% CI, 1.48 to 4.82; P<0.001). Adverse events requiring a switching of antiretroviral drugs occurred in 10 patients in the earlier-ART group and 1 patient in the later-ART group (P = 0.006). Conclusions. Early initiation of ART in patients with CD4+ T-cell counts of less than 50 per cubic millimeter increased AIDS-free survival. Deferral of the initiation of ART to the first 4 weeks of the continuation phase of tuberculosis therapy in those with higher CD4+ T-cell counts reduced the risks of IRIS and other adverse events related to ART without increasing the risk of AIDS or death.
Managing multiple and extensively drug-resistant tuberculosis and HIV.
(Informa Healthcare., 2007) Padayatchi, Nesri.; Friedland, Gerald H.
Global increases in multi-drug-resistant and extensively drug-resistant tuberculosis (TB), are threatening both TB and HIV treatment programs worldwide. Together, they raise concerns of a global epidemic of untreatable TB. In the developing world, the directly observed treatment, short course (DOTS) strategy is proving ineffective as available resources are being outstripped by the large number of patients needing treatment. Thus, TB treatment and outcomes are sub-optimal, and multi-drug resistant and extensively drug-resistant TB are on the rise.
Pilot evaluation of a second-generation electronic pill box for adherence to Bedaquiline and antiretroviral therapy in drug-resistant TB/HIV co-infected patients in KwaZulu-Natal, South Africa.
(BioMed Central., 2018) Bionghi, Neda.; Daftary, Amrita.; Maharaj, Bhavna.; Msibi, Zama Princess N.; Rivet Amico, K.; Friedland, Gerald H.; Orrell, Catherine.; Padayatchi, Nesri.; O'Donnell, Max Roe.
Abstract available in pdf.
A pilot study of once-daily antiretroviral therapy integrated with Tuberculosis directly observed therapy in a resource-limited setting.
(Lippincott Williams & Wilkins., 2003) Jack, Christopher.; Lalloo, Umesh Gangaram.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.; El-Sadr, Wafaa M.; Cassol, Sharon.; Friedland, Gerald H.
To determine the feasibility and effectiveness of integrating highly active antiretroviral therapy (HAART) into existing tuberculosis directly observed therapy (TB/DOT) programs, we performed a pilot study in an urban TB clinic in South Africa. Patients with smear-positive pulmonary TB were offered HIV counseling and testing. Twenty HIV-positive patients received once-daily didanosine (400 mg) plus lamivudine (300 mg) plus efavirenz (600 mg) administered concomitantly with standard TB therapy Monday to Friday and self-administered on weekends. After completing TB therapy, patients were referred to an HIV clinic for continued treatment. At baseline, patients had a mean CD4 count of 230 cells/mm3 (range: 24–499 cells/mm3) and a mean viral load of 5.75 log10 (range: 3.81–7.53 log10). Seventeen completed combined standard TB and HIV therapy; 16 of 20 (80%) patients enrolled and 15 of 17 (88%) patients completing standard TB therapy achieved a viral load <50 copies/mL and mean CD4 count increase of 148 cells/mm3. TB was cured in 17 of 20 (85%) enrolled patients and 17 of 19 (89%) patients with drug-sensitive TB. Treatment was well tolerated, with minimal gastrointestinal, hepatic, skin, or neurologic toxicity. The project was well accepted and integrated into the daily TB clinic functions. This pilot study demonstrates that TB/DOT programs can be feasible and effective sites for HIV identification and the introduction and monitoring of a once-daily HAART regimen in resource-limited settings.
A randomized controlled trial of HAART versus HAART and chemotherapy in therapy-naïve patients with HIV-associated Kaposi sarcoma in South Africa.
(Lippincott Williams & Wilkins., 2011) Mosam, Anisa.; Shaik, Fahmida.; Uldrick, Thomas S.; Esterhuizen, Tonya.; Friedland, Gerald H.; Scadden, David T.; Aboobaker, Jamila B.; Coovadia, Hoosen Mahomed.
Background: The optimal approach to HIV-associated Kaposi sarcoma (HIV-KS) in sub-Saharan Africa is unknown. With large-scale rollout of highly active antiretroviral therapy (HAART) in South Africa, we hypothesized that survival in HIV-KS would improve and administration of chemotherapy in addition to HAART would be feasible and improve KS-specific outcomes. Methods: We conducted a randomized, controlled, open-label trial with intention-to-treat analysis. Treatment-naive patients from King Edward VIII Hospital, Durban, South Africa, a public-sector tertiary referral center, with HIV-KS, but no symptomatic visceral disease or fungating lesions requiring urgent chemotherapy, were randomized to HAART alone or HAART and chemotherapy (CXT). HAART arm received stavudine, lamivudine, and nevirapine (Triomune; CXT arm received Triomune plus bleomycin, doxorubicin, and vincristine every 3 weeks. When bleomycin, doxorubicin, and vincristine were not available, oral etoposide (50–100 mg for 1–21 days of a 28-day cycle) was substituted. Primary outcome was overall KS response using AIDS Clinical Trial Group criteria 12 months after HAART initiation. Secondary comparisons included time to response, progression-free survival, overall survival, adverse events, HIV control, CD4 reconstitution, adherence, and quality of life. Results: Fifty-nine subjects were randomized to HAART and 53 to CXT; 12-month overall KS response was 39% in the HAART arm and 66% in the CXT arm (difference, 27%; 95% confidence interval, 9%–43%; P = 0.005). At 12 months, 77% were alive (no survival difference between arms; P = 0.49), 82% had HIV viral load <50 copies per milliliter without difference between the arms (P = 0.47); CD4 counts and quality-of-life measures improved in all patients. Conclusions: HAART with chemotherapy produced higher overall KS response over 12 months, whereas HAART alone provided similar improvement in survival and select measures of morbidity. In Africa, with high prevalence of HIV and human herpes virus-8 and limited resources, HAART alone provides important benefit in patients with HIV-KS.
Re-inventing adherence : toward a patient-centered model of care for drug-resistant tuberculosis and HIV.
(International Union against Tuberculosis and Lung Disease., 2016) O’Donnell, Max Roe.; Daftary, Amrita.; Frick, Mike Watson.; Hirsch-Moverman, Yael.; Amico, Kathy Rivet.; Senthilingam, Meera.; Wolf, Allison.; Metcalfe, John Z.; Isaakidis, Petros.; Davis, Luke J.; Zelnick, Jennifer R.; Brust, James C. M.; Naidu, Naressa.; Garretson, Marné.; Bangsberg, David R.; Padayatchi, Nesri.; Friedland, Gerald H.
Abstract available in PDF file.
The SAPIT trial provides essential evidence on risks and benefits of integrated and sequential treatment of HIV and tuberculosis.
(Health and Medical Publications Group., 2010) Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.; Baxter, Cheryl.; Friedland, Gerald H.; Gengiah, Tanuja Narayansamy.; Gray, Andrew Lofts.; Grobler, Anna Christina.; Naidoo, Kogieleum.; Padayatchi, Nesri.; El-Sadr, Wafaa M.
Boulle et al.(1) queried whether a clinical trial was needed to provide the evidence for the mortality benefits of antiretroviral therapy (ART) initiation during tuberculosis (TB) treatment. While several experts, including foremost TB-HIV scientists from South Africa (2) and the USA,(3) senior World Health Organization (WHO) (4) and UNAIDS (5) officials at the time the study was initiated, the 2003 WHO AIDS Treatment Guidelines Committee Chair (3), the Chair of the Ethics Committee (6) and the researchers,(7) have previously addressed the points raised, the SAPIT (Starting Antiretroviral Therapy at Three Points in Tuberculosis) research team welcomes the opportunity also to address the comments. We hold Boulle and his colleagues in high regard and appreciate their contributions to the field of HIV and tuberculosis co-infection. More importantly, we share with them the common goal of rigorously and relentlessly seeking answers to critically important research questions as we confront the devastating dual AIDS and tuberculosis epidemics. The SAPIT trial,(8) which was developed in 2004, set out to assess whether integrating tuberculosis and AIDS treatment would lead to improved outcomes compared with the widely practised approach of treating them sequentially. The trial’s Safety Monitoring Committee halted the sequential treatment arm in September 2008 because of a 56% lower mortality rate in the integrated treatment arm. We systematically address the queries on equipoise and standard of care.
Timing of initiation of antiretroviral drugs during tuberculosis therapy.
(Massachusetts Medical Society., 2010) Abdool Karim, Salim Safurdeen.; Naidoo, Kogieleum.; Grobler, Anna Christina.; Padayatchi, Nesri.; Baxter, Cheryl.; Gray, Andrew Lofts.; Gengiah, Tanuja Narayansamy.; Nair, Gonasagrie.; Bamber, Sheila.; Singh, Aarthi.; Khan, Munira.; Pienaar, Jacqueline C.; El-Sadr, Wafaa M.; Friedland, Gerald H.; Abdool Karim, Quarraisha.
Background. The rates of death are high among patients with coinfection with tuberculosis and the human immunodeficiency virus (HIV). The optimal timing for the initiation of antiretroviral therapy in relation to tuberculosis therapy remains controversial. Methods. In an open-label, randomized, controlled trial in Durban, South Africa, we assigned 642 patients with both tuberculosis and HIV infection to start antiretroviral therapy either during tuberculosis therapy (in two integrated-therapy groups) or after the completion of such treatment (in one sequential-therapy group). The diagnosis of tuberculosis was based on a positive sputum smear for acid-fast bacilli. Only patients with HIV infection and a CD4+ cell count of less than 500 per cubic millimeter were included. All patients received standard tuberculosis therapy, prophylaxis with trimethoprim–sulfamethoxazole, and a once-daily antiretroviral regimen of didanosine, lamivudine, and efavirenz. The primary end point was death from any cause. Results. This analysis compares data from the sequential-therapy group and the combined integrated-therapy groups up to September 1, 2008, when the data and safety monitoring committee recommended that all patients receive integrated antiretroviral therapy. There was a reduction in the rate of death among the 429 patients in the combined integrated-therapy groups (5.4 deaths per 100 person-years, or 25 deaths), as compared with the 213 patients in the sequential-therapy group (12.1 per 100 person-years, or 27 deaths); a relative reduction of 56% (hazard ratio in the combined integrated-therapy groups, 0.44; 95% confidence interval, 0.25 to 0.79; P = 0.003). Mortality was lower in the combined integrated-therapy groups in all CD4+ count strata. Rates of adverse events during follow-up were similar in the two study groups. Conclusions. The initiation of antiretroviral therapy during tuberculosis therapy significantly improved survival and provides further impetus for the integration of tuberculosis and HIV services. (Clinical Trials.gov number, NCT00398996.)
Utility of Tuberculosis directly observed therapy programs as sites for access to and provision of antiretroviral therapy in resource-limited countries.
(The Infectious Diseases Society of America., 2004) Friedland, Gerald H.; Abdool Karim, Salim Safurdeen.; Abdool Karim, Quarraisha.; Jack, Christopher.; Gandhi, Neel R.; El-Sadr, Wafaa M.; Lalloo, Umesh Gangaram.
The overwhelming share of the global human immunodeficiency virus (HIV) infection and disease burden is borne by resource-limited countries. The explosive spread of HIV infection and growing burden of disease in these countries has intensified the need to find solutions to improved access to treatment for HIV infection. The epidemic of HIV infection and acquired immune deficiency syndrome (AIDS) has been accompanied by a severe epidemic of tuberculosis. Tuberculosis has become the major cause of morbidity and mortality in patients with HIV disease worldwide. Among the various models of provision of HIV/AIDS care, one logical but unexplored strategy is to integrate HIV/AIDS and tuberculosis care and treatment, including highly active antiretroviral therapy, through existing tuberculosis directly observed therapy programs. This strategy could address the related issues of inadequate access and infrastructure and need for enhanced adherence to medication and thereby potentially improve the outcome for both diseases.