Impact of nurse-delivered community-based CD4 services on facilitating pre-ART care in rural South Africa.

BACKGROUND: HIV testing, diagnosis and treatment programs have expanded globally, particularly in resource-limited settings. Diagnosis must be followed by determination of treatment eligibility and referral to care prior to initiation of antiretroviral treatment (ART). However, barriers and delays along these early steps in the treatment cascade may impede successful ART initiation. New strategies are needed to facilitate the treatment cascade. We evaluated the role of on site CD4+ T cell count phlebotomy services by nurses in facilitating pre-ART care in a community-based voluntary counseling and testing program (CBVCT) in rural South Africa. METHODS: We retrospectively evaluated CBVCT services during five continuous time periods over three years: three periods when a nurse was present on site, and two periods when the nurse was absent. When a nurse was present, CD4 count phlebotomy was performed immediately after HIV testing to determine ART eligibility. When a nurse was absent, patients were referred to their local primary care clinic for CD4 testing. For each period, we determined the proportion of HIV-positive community members who completed CD4 testing, received notification of CD4 count results, as well as the time to test completion and result notification. RESULTS: Between 2010 and 2013, 7213 individuals accessed CBVCT services; of these, 620 (8.6 %) individuals were HIV-positive, 205 (33.1 %) were eligible for ART according to South African national CD4 count criteria, and 78 (38.0 % of those eligible) initiated ART. During the periods when a professional nurse was available to provide CD4 phlebotomy services, HIV-positive clients were significantly more likely to complete CD4 testing than during periods when these services were not available (85.5 % vs. 37.3 %, p < 0.001). Additionally, when nurses were present, individuals were significantly more likely to be notified of CD4 results (60.6 % vs. 26.7 %, p <0.001). The time from HIV screening to CD4 test completion was also significantly shorter during nurse presence than nurse absence (median 8 days (IQR 4-19) vs. 35 days (IQR 15-131), p < 0.001). CONCLUSIONS: These findings indicate that in addition to CBVCT, availability of on site CD4 phlebotomy may reduce loss along the pre-ART care cascade and facilitate timely entry into HIV care.

'Cough officer' nurses in a general medical clinic successfully detect drug-susceptible and -resistant tuberculosis.

SETTING: Intensive case finding (ICF) for tuberculosis (TB) is recommended by the World Health Organization among known human immunodeficiency virus (HIV) patients. However, ICF may also be appropriate in generalized patient populations. OBJECTIVE: To evaluate the yield of ICF in a general medical clinic in a high HIV prevalence setting. METHODS: A nurse designated as a 'cough officer' identified clinic attendees with cough of >2 weeks and collected sputum for evaluation at the hospital and provincial referral laboratories. We retrospectively evaluated the number and proportion of patients with microbiologically confirmed TB identified in 2007-2008. RESULTS: Among 56 207 clinic attendees, 1442 (2.6%) TB suspects were identified and 122 (8.5%) were sputum Ziehl-Neelsen (ZN) positive. Of 389 available results, 72 (18.5%) were auramine-positive and 99 (25.4%) were culture-positive; multidrug-resistant and extensively drug-resistant TB were identified in 16 (16.2%). The number needed to screen was 11.8 patients to identify one ZN-positive case and 3.9 to identify one culture-positive case. CONCLUSIONS: A nurse-facilitated cough officer program successfully identified TB suspects and drug-susceptible and drug-resistant TB. Culture was more sensitive for TB screening and critical for identifying drug resistance. ICF is operationally feasible, and should be expanded to general medical clinics in high HIV and TB prevalence, resource-limited settings.

Integrated, home-based treatment for MDR-TB and HIV in rural South Africa: an alternate model of care.

SETTING: Treatment outcomes for multidrug-resistant tuberculosis (MDR-TB) in South Africa have suffered as centralized, in-patient treatment programs struggle to cope with rising prevalence and human immunodeficiency virus (HIV) co-infection rates. A new treatment model is needed to expand treatment capacity and improve MDR-TB and HIV outcomes. OBJECTIVE: To describe the design and preliminary results of an integrated, home-based MDR-TB-HIV treatment program created in rural KwaZulu-Natal. METHOD: In 2008, a decentralized center was established to provide out-patient MDR-TB and HIV treatment. Nurses, community health workers and family supporters have been trained to administer injections, provide adherence support and monitor adverse reactions in patients' homes. Physicians assess clinical response, adherence and the severity of adverse reactions to MDR-TB and HIV treatment at monthly follow-up visits. Treatment outcomes are assessed by monthly cultures and CD4 and viral load every 6 months. RESULTS: Of 80 patients initiating MDR-TB treatment from February 2008 to April 2010, 66 were HIV-co-infected. Retention has been high (only 5% defaults, 93% of visits attended), and preliminary outcomes have been favorable (77% cured/still on treatment, 82% undetectable viral load). Few patients have required escalation of care (9%), had severe adverse events (8%) or died (6%). CONCLUSION: Integrated, home-based treatment for MDR-TB and HIV is a promising treatment model to expand capacity and achieve improved outcomes in rural, resource-poor and high HIV prevalent settings.

Tuberculosis infection control in a high drug-resistance setting in rural South Africa: information, motivation, and behavioral skills.

BACKGROUND: Tuberculosis (TB) is transmitted in resource-limited facilities where TB infection control (IC) is poorly implemented. Theory-based behavioral models can potentially improve IC practices. METHODS: The present study used an anonymous questionnaire to assess healthcare worker (HCW) TB IC information, motivation, and behavioral skills (IMB) and implementation in two resource-limited rural South African hospitals with prevalent drug-resistant TB. RESULTS: Between June and August 2010, 198 surveys were completed. Although the respondents demonstrated information proficiency and positive motivation, 22.8% did not consider TB IC to be worthwhile. Most tasks were rated as easy by survey participants, but responding HCWs highlighted challenges in discrete behavioral skills. The majority of responding HCWs reported that they always wore respirators (54.3%), instructed patients on cough hygiene (63.0%), and ensured natural ventilation (67.4%) in high-risk areas. Most respondents (74.0%) knew their HIV status. Social support items correlated with the implementation of the first three aforementioned practices but not with the respondents' knowledge of their HIV status. In most cases, motivation and behavioral skills, but not information, were associated with implementation. CONCLUSION: HCWs in rural South African hospitals with high drug-resistance demonstrated moderate IMB and implementation of TB IC. Improvement efforts should emphasize the development of HCW motivation and behavioral skills as well as social support from colleagues and supervisors. Such interventions should be informed by baseline IMB assessments. In the present study, a trimmed/modified IMB model helped characterize TB IC implementation.

Risk factors for mortality among MDR- and XDR-TB patients in a high HIV prevalence setting.

SETTING: Recent studies suggest that the prevalence of drug-resistant tuberculosis (TB) in sub-Saharan Africa may be rising. This is of concern, as human immunodeficiency virus (HIV) co-infection in multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB has been associated with exceedingly high mortality rates. OBJECTIVE: To identify risk factors associated with mortality in MDR- and XDR-TB patients co-infected with HIV in South Africa. DESIGN: Case-control study of patients who died of all causes within 2 years of diagnosis with MDR- or XDR-TB. RESULTS: Among 123 MDR-TB patients, 78 (63%) died following diagnosis. CD4 count ≤ 50 (HR 4.64, P = 0.01) and 51-200 cells/mm(3) (HR 4.17, P = 0.008) were the strongest independent risk factors for mortality. Among 139 XDR-TB patients, 111 (80%) died. CD4 count ≤ 50 cells/mm(3) (HR 4.46, P = 0.01) and resistance to all six drugs tested (HR 2.54, P = 0.04) were the principal risk factors. Use of antiretroviral therapy (ART) was protective (HR 0.34, P = 0.009). CONCLUSIONS: Mortality due to MDR- and XDR-TB was associated with greater degree of immunosuppression and drug resistance. Efforts to reduce mortality must focus on preventing the amplification of resistance by strengthening TB treatment programs, as well as reducing the pool of immunosuppressed HIV-infected patients through aggressive HIV testing and ART initiation.

Tuberculosis infection control in rural South Africa: survey of knowledge, attitude and practice in hospital staff.

A baseline assessment of tuberculosis infection control (TB IC) knowledge, attitude and practice (KAP) was conducted among staff in a resource-limited rural South African hospital where nosocomially transmitted multi- and extensively drug-resistant (M/XDR) TB had been reported. Assessment consisted of anonymous questionnaires and direct observation during July-September 2007, soon after the report of M/XDR-TB. Data were obtained from 57 questionnaires and 10h of direct observation. While knowledge and attitudes were generally supportive of TB IC implementation, 49.1% of staff felt that the hospital did not care about them and/or was not working to prevent staff TB infections, and 42.9% were less willing to continue as a healthcare worker because of staff TB/MDR-TB/XDR-TB deaths. Practices were variable. The recent appointment of an IC officer and implementation of natural ventilation were strengths, but the facility lacked a TB IC policy, the patient TB screening process was inadequate, and 41.5% of respondents were unaware of their personal human immunodeficiency virus (HIV) status. Respondents reported a number of barriers to TB IC implementation such as concerns about the confidentiality of staff health information, the stigma of TB and HIV, inadequate resources, and patient non-compliance. Assessment of staff KAP provided useful data regarding deficits and barriers to TB IC, and helped to focus subsequent IC strategies. Given the critical importance of reducing nosocomial TB transmission, it is recommended that facilities should conduct simplified TB IC assessment, ensure the confidentiality of staff health information, address the stigma of TB/HIV, and implement multi-faceted TB IC facility and behavioural change interventions. Behavioural science methods have the potential to improve TB IC research and implementation.

Characteristics of HIV-1-associated Kaposi's sarcoma among women and men in South Africa.

Despite the increase of HIV-1-associated Kaposi's sarcoma (KS), little is known about HIV-associated KS in the African setting, particularly among women. A descriptive study of the demographic, clinical, immunological and virological features of AIDS-associated KS from KwaZulu-Natal, South Africa was undertaken. Consecutively, recruited patients were clinically staged; CD4/CD8 cell counts, HIV-1 viral loads and clinical parameters were evaluated. Of the 152 patients (77 male and 75 female) 99% were black. Females were significantly younger (P = 0.02) and had poorer disease prognosis (odds ratio [OR] = 2.7, 95% confidence interval [CI] = 1.4-5.4, P = 0.003) and were more likely to have extensive cutaneous KS when compared with males (OR = 3.1, 95% CI = 1.4-6.7, P = 0.003). One-third of patients had coexisting HIV-related disease, most commonly tuberculosis, and these were more frequent in females (56.7 vs. 43.3%). In conclusion, HIV-associated KS in South Africans has an equal female-to-male ratio. Females are younger and have more severe disease than males.

Trust and the acceptance of and adherence to antiretroviral therapy.

BACKGROUND: Antiretroviral therapy (ART) has resulted in reduced AIDS incidence and mortality. Socially marginalized individuals with HIV infection, particularly injection drug users (IDUs), have received less ART and derived less benefit than others. Little is known about the therapeutic process necessary to promote acceptance of and adherence to ART among marginalized HIV-infected populations. We report on the correlates of both acceptance of and adherence to ART among HIV infected prisoners, most of whom are IDUs. DESIGN: Using a cross-sectional survey design within four ambulatory prison HIV clinics, 205 HIV-infected prisoners eligible for ART were recruited between March and October 1996. MEASUREMENTS: Detailed interviews were conducted that included personal characteristics, health status and beliefs, and validated standardized scales measuring depression, health locus of control, social desirability and trust in physician, medical institutions and society. Acceptance and adherence were documented by self-report and validated for a subset by pharmacy review. Clinical information was obtained from standardized chart review. Adherence was defined as having taken > or = 80% of ART. RESULTS: The acceptance of (80%) and adherence to (84%) ART among this group of prisoners was high. Multiple regression models demonstrated that correlates of acceptance of and adherence to ART differed. Acceptance was associated with trust in physician (8% increase for each unit increase with trust in physician scale) and trust in HIV medications (threefold reduction for those mistrustful of medication). Side effects (OR = 0.09), social isolation (OR = 0.08), and complexity of the antiretroviral regimen (OR = 0.33) were associated with decreased adherence. The prevalence of health beliefs suggesting an adverse relationship between ART and drugs of abuse was high (range 59 to 77%). Adherence did not differ among those receiving directly observed therapy (82%) or self-administration (85%). CONCLUSIONS: ART can be successfully administered within a correctional setting. Trust and the therapeutic relationship between patient and physician remain central in the ART initiation process. Characteristics of the therapeutic agents and the degree of social isolation predict adherence. These results may inform the design of interventions to improve both acceptance of and adherence to ART particularly among marginalized populations who have not derived full benefit from these potent new therapies.

Public health consequences of screening patients for adherence to highly active antiretroviral therapy.

Improvements in HIV antiretroviral therapy (ART) have been accompanied by increasing recognition of the importance of adherence to treatment regimens for maximizing patient benefits while minimizing the emergence of drug-resistant virus. Whether clinicians should screen patients for adherence and only administer therapy to those believed likely to adhere has not been resolved. We first examine the implications of data drawn from a recent study reporting physicians' ability to predict whether patients will adhere to highly active antiretroviral therapy (HAART) or not. We then extend previously developed mathematical models of ART to include screening for adherence and focus on resulting drug resistance as well as on HIV and AIDS incidence at the population level. We show that although screening for adherence is likely to reduce the level of drug resistance compared with a policy of treating all HIV patients with HAART, rates of new HIV infections and AIDS cases in the population would likely increase unless screening accuracy is extremely (perhaps implausibly) high.

Interactions between methadone and medications used to treat HIV infection: a review.

BACKGROUND: It is critical for providers caring for HIV-positive methadone recipients to have accurate information on pharmacologic interactions between methadone and antiretroviral therapy. If providers do not have these data, symptoms of narcotic withdrawal or excess due to medication interactions may be mismanaged, and antiretroviral regimens may be suboptimal in efficacy or associated with increased side effects and toxicities. This review was undertaken to clarify what is known about interactions between pharmacotherapies of opiate dependence and HIV-related medications, to suggest clinically useful approaches to these issues, and to outline areas which need further study. METHOD: A search for relevant published papers and abstracts presented at scientific meetings was conducted using electronic databases. These documents were obtained and reviewed, and additional publications referenced in them were also reviewed. RESULTS: Pharmacokinetic interactions between methadone and zidovudine, didanosine, stavudine, abacavir, nevirapine, efavirenz and nelfinavir have been documented. The mechanisms, clinical implications and management of these interactions are reviewed. CONCLUSIONS: Interactions between methadone and some HIV-related medications are known to occur, yet their characteristics cannot reliably be predicted based on current understanding of metabolic enzyme induction and inhibition, or through in vitro studies. Only carefully designed and conducted pharmacologic studies involving human subjects can help us define the nature of the interactions between methadone (and other pharmacotherapies for opiate dependence) and specific HIV-related medications. Clinicians must be aware of known interactions and be alert to the possibility that interactions which are still undocumented may be present among their patients.

In vivo antagonism with zidovudine plus stavudine combination therapy.

Human immunodeficiency virus (HIV)-infected subjects receiving zidovudine were randomized either to add stavudine (d4T) or didanosine (ddI) to their current regimen or to switch to ddI or d4T monotherapy. After 16 weeks of therapy, the mean reduction in HIV RNA from baseline was 0.14 log(10) copies/mL in patients receiving d4T or zidovudine plus d4T. In subjects receiving ddI or ddI plus zidovudine, reductions were 0.39 and 0.56 log(10), respectively. CD4 cell counts remained stable or showed modest increases in all arms except the zidovudine plus d4T arm. Patients receiving zidovudine plus d4T showed progressive declines in CD4 cell counts with a median of 22 cells/mm(3) below baseline by 16 weeks. Examination of intracellular levels of d4T-triphosphate in 6 subjects was consistent with previous in vitro studies demonstrating pharmacologic antagonism between zidovudine and d4T. Analysis of these data suggests that zidovudine and d4T should not be prescribed in combination and that ddI provides greater antiviral activity than d4T in zidovudine-treated patients.

Attaining higher goals in HIV treatment: the central importance of adherence.

In recent years, advances in HIV therapeutics have changed the nature of HIV/AIDS disease, so that it has now assumed some of the characteristics of a 'chronic' disease. Several factors have, however, qualified these advances. Social, economic, and clinical variables have confounded universal therapeutic success. Access to the highly active antiretroviral therapy is limited among marginalized populations, such as the homeless, or absent in many nations that have poor resources. In addition, study populations are often not fully representative of those actually cared for in clinical practice, who may respond differently to the study medications. Moreover, physiologic differences between patients may alter drug plasma levels, resulting in varying efficacy levels in different patients. Finally, and crucial among determinants of effective therapy, is a patient's level of adherence to the antiretroviral regimen. The magnitude of 'error-prone' viral replication makes resistance to antiretroviral agents invariable. In the presence of partially suppressive therapy, viral replication will select for viral variants with resistance mutations. Therefore, potent and continuous suppressive therapy for the duration of viral replicative capability is necessary for therapy to be effective. Factors that have an impact on adherence include characteristics of the treatment regimen, of patients and clinicians, and of the clinical setting. Successful adherence to therapeutic regimens is the responsibility of clinicians as well as patients. Many patient- and clinician-focused strategies and interventions that can improve adherence exist. The simplification of current antiviral regimens, without the loss of potency, is essential to achieving the goal of complete adherence. Maximizing the long-term benefit of highly active antiretroviral therapy requires knowledge of the technical and biologic aspects of HIV therapeutics, but necessitates an understanding of the behavioral aspects of therapeutics as well.

Efficacy and safety of delavirdine mesylate with zidovudine and didanosine compared with two-drug combinations of these agents in persons with HIV disease with CD4 counts of 100 to 500 cells/mm3 (ACTG 261). ACTG 261 Team.

To evaluate the antiretroviral activity of delavirdine mesylate, a non-nucleoside reverse transcriptase inhibitor of HIV-1, we performed a phase II, randomized, double-blind, multicenter trial comparing the three-drug combination of delavirdine with zidovudine and didanosine to two-drug combinations of these drugs. Patients with CD4 cell counts between 100 and 500 cells/mm3 without prior or <6 months of monotherapy with zidovudine or didanosine were randomized to one of four arms and observed on a follow-up basis for 48 weeks. In total, 544 patients were evaluated. In those assigned to the three-drug regimen, mean short-term (weeks 4-12) and long-term (weeks 40-48) change in CD4 cells from baseline were 49.3+/-8.1 and 65.4+/-13.4 cells/mm3, respectively; mean short-term and long-term HIV-1 RNA changes from baseline were -1.13 log10+/-0.12 and -0.73+/-0.12 copies/ml, respectively. These responses in CD4 cell counts and HIV-1 RNA levels were better in comparisons with each of the two-drug arms at all study points; however, differences were not consistently significant. Gastrointestinal side effects were experienced by 33% of patients (178 of 544), and 30% (121 of 407) receiving delavirdine experienced rash, only one case of which was severe. In this study, therapy with delavirdine + zidovudine + didanosine was safe and showed modest, but not always significant, antiviral activity and CD4 cell count benefit compared with two-drug regimens with these agents. Key

Nevirapine induced opiate withdrawal among injection drug users with HIV infection receiving methadone.

BACKGROUND: Pharmacokinetic interactions complicate and potentially compromise the use of antiretroviral and other HIV therapeutic agents in patients with HIV disease. This may be particularly so among those receiving treatment for substance abuse. OBJECTIVE: We describe seven cases of opiate withdrawal among patients receiving chronic methadone maintenance therapy following initiation of therapy with the non-nucleoside reverse transcriptase inhibitor, nevirapine. DESIGN: Retrospective chart review. RESULTS: In all seven patients, due to the lack of prior information regarding a significant pharmacokinetic interaction between these agents, the possibility of opiate withdrawal was not anticipated. Three patients, for whom methadone levels were available at the time of development of opiate withdrawal symptoms, had subtherapeutic methadone levels. In each case, a marked escalation in methadone dose was required to counteract the development of withdrawal symptoms and allow continuation of antiretroviral therapy. Three patients continued nevirapine with methadone administered at an increased dose; however, four chose to discontinue nevirapine. CONCLUSION: To maximize HIV therapeutic benefit among opiate users, information is needed about pharmacokinetic interactions between antiretrovirals and therapies for substance abuse.

Methadone and antiretroviral medications, part II.

AIDS: The second installment in a two-part series on Methadone and antiretroviral medications is presented. The use of methadone and potential drug interactions between Methadone and anti-HIV medications are reviewed. Several studies about drug interactions, other substance-abuse therapies and opiates, and the future direction of antiretroviral and opiate interaction studies are discussed. Physicians are advised to consider the potential effects of Methadone on HIV-related medications when designing a treatment regimen.^ieng

Methadone and antiretroviral medications, part I.

AIDS: The interactions of Methadone with NRTIs and NNRTIs are presented in the first of a two-part article. Methadone is an effective treatment for heroin addiction; however, insufficient information is available on its interactions with HAART. Methadone is metabolized by the cytochrome P450 system, and NRTIs do not appear to be inducers or inhibitors of the cytochrome P450 system. Pharmacokinetics between Methadone and AZT have been studied in detail, and AZT appears to have no effect on plasma Methadone levels. However, NNRTIs do share metabolic pathways with Methadone, indicating that important interactions between Methadone and these drugs are possible, but formal study is still needed. A table of current information is presented on NRTI and NNRTI interactions with Methadone.^ieng