Colin N. Menezes

Early treatment outcomes and HIV status of patients with extensively drug-resistant tuberculosis in South Africa: a retrospective cohort study

BACKGROUND Data from Kwazulu Natal, South Africa, suggest that almost all patients with extensively drug-resistant (XDR) tuberculosis are HIV-positive, with a fatal outcome. Since, there are few data for the treatment-related outcomes of XDR tuberculosis in settings with a high HIV prevalence, we investigated the associations of these diseases in such settings to formulate recommendations for control programmes. METHODS In a retrospective cohort study, we analysed the case records of patients (>16 years old) with XDR tuberculosis (culture-proven at diagnosis) between August, 2002, and February, 2008, at four designated provincial treatment facilities in South Africa. We used Cox proportional hazards regression models to assess risk factors associated with the outcomes-mortality and culture conversion. FINDINGS 195 of 227 patients were analysed. 21 died before initiation of any treatment, and 174 patients (82 with HIV infection) were treated. 62 (36%) of these patients died during follow-up. The number of deaths was not significantly different in patients with or without HIV infection: 34 (41%) of 82 versus 28 (30%) of 92 (p=0.13). Treatment with moxifloxacin (hazard ratio 0.11, 95% CI 0.01-0.82; p=0.03), previous culture-proven multidrug-resistant tuberculosis (5.21, 1.93-14.1; p=0.001), and number of drugs used in a regimen (0.59, 0.45-0.78, p<0.0001) were independent predictors of death. Fewer deaths occurred in patients with HIV infection given highly active antiretroviral therapy than in those who were not (0.38, 0.18-0.80; p=0.01). 33 (19%) of 174 patients showed culture conversion, of which 23 (70%) converted within 6 months of initiation of treatment. INTERPRETATION In South Africa, patients with XDR tuberculosis, a substantial proportion of whom are not infected with HIV, have poor management outcomes. Nevertheless, survival in patients with HIV infection is better than previously reported. The priorities for the country are still prevention of XDR tuberculosis, and early detection and management of multidrug-resistant and XDR tuberculosis through strengthened programmes and laboratory capacity. FUNDING South African Medical Research Council, European Union Framework 7 program, and European Developing Countries Clinical Trials Partnership.

A longitudinal study of stavudine-associated toxicities in a large cohort of South African HIV infected subjects

BackgroundThere has been major improvement in the survival of HIV-1 infected individuals since the South African Government introduced highly active anti-retroviral therapy (HAART) in the public sector in 2004. This has brought new challenges which include the effects of stavudine-related toxicities.MethodsProspective analysis of a cohort of 9040 HIV-infected adults who were initiated on HAART at the Themba Lethu Clinic (TLC) in Johannesburg between April 1, 2004 to December 31, 2007, and followed up until June 30, 2008.ResultsAmongst the 9040 study subjects, 8497(94%) were on stavudine based therapy and 5962 (66%) were women. The median baseline CD4 count was 81 cells/mm3 (IQR 29-149). Median follow up on HAART was 19 months (IQR: 9.1-31.6). The proportion of HAART-related side effects for stavudine compared to non-stavudine containing regimens were, respectively: peripheral neuropathy,17.1% vs. 11.2% (p < 0.001); symptomatic hyperlactataemia, 5.7% vs. 2.2% (p < 0.0005); lactic acidosis, 2.5 vs. 1.3% (p = 0.072); lipoatrophy, 7.3% vs. 4.6% (p < 0.05). Among those on stavudine-based regimens, incidence rates for peripheral neuropathy were 12.1 cases/100 person-years (95%CI 7.0-19.5), symptomatic hyperlactataemia 3.6 cases/100 person-years (95%CI 1.2-7.5), lactic acidosis 1.6 cases/100 person-years (95%CI 0.4-5.2) and lipoatrophy 4.6 cases/100 person-years (95%CI 2.1-9.6). Females experienced more toxicity when compared to males in terms of symptomatic hyperlactataemia (p < 0.0001), lactic acidosis (p < 0.0001), lipoatrophy (p < 0.0001) and hypertension (p < 0.05).ConclusionsWe demonstrate significant morbidity associated with stavudine. These data support the latest WHO guidelines, and provide additional evidence for other resource limited HAART rollout programs considering the implementation of non-stavudine based regimens as first line therapy.

Echinococcosis in sub-Saharan Africa: emerging complexity.

Cystic echinococcosis occurs in most regions of sub-Saharan Africa, but the frequency of this zoonosis differs considerably among and within countries. Especially human cases seem to be focally distributed. A number of environmental and behavioural factors partially explain this pattern, i.e. density of livestock, presence of dogs, uncontrolled slaughter, and hygiene. In addition, the various taxa of Echinococcus spp. are known to differ considerably in infectivity to different host species including humans. Genetic characterizations of isolates, which are necessary to evaluate the impact of this factor - so far done in only a few countries - indicate that the diversity of Echinococcus spp. in Sub-Saharan Africa is greater than on any other continent. The very incomplete data which are available show that sympatrical taxa may infect different hosts, others may be geographically restricted, some life cycles involve livestock, others wild animals. Possible implications of this complexity for public health, livestock economy and conservation are briefly discussed.

Cystic echinococcosis in sub-Saharan Africa

Cystic echinococcosis is regarded as endemic in sub-Saharan Africa; however, for most countries only scarce data, if any, exist. For most of the continent, information about burden of disease is not available; neither are data for the animal hosts involved in the lifecycle of the parasite, thus making introduction of preventive measures difficult. Available evidence suggests that several species or strains within the Echinococcus granulosus complex are prevalent in sub-Saharan Africa and that these strains might be associated with varying virulence and host preference. Treatment strategies (chemotherapy, percutaneous radiological techniques, but mainly surgery) predominantly target active disease. Prevention strategies encompass anthelmintic treatment of dogs, slaughter hygiene, surveillance, and health-educational measures. Existing data are suggestive of unusual clinical presentations of cystic echinococcosis in some parts of the continent, for which the causes are speculative.

First insights into species and genotypes of Echinococcus in South Africa

Cystic echinococcosis is a serious and neglected parasitic zoonosis that is regarded as an emerging disease world-wide. Effective control of the disease is based on understanding the variability of Echinococcus granulosus (sensu lato), as genotypic characteristics may influence lifecycle patterns, development rate, and transmission. No molecular epidemiological research has previously been conducted to shed light on genotypes responsible for the disease in South Africa. To identify strains circulating in the country, parasite material was collected from patients between August 2010 and September 2012 and analyzed by PCR/RFLP methods. A total of 32 samples was characterized as E. granulosus sensu stricto (G1-G3) (81%), E. canadensis (G6/7) (16%) and E. ortleppi (G5) (3%). Furthermore, two co-amplifying G6/7 genotypes were confirmed as G7 by sequencing. This is the first report on genotyping of Echinococcus species in South Africa, and, to the best of our knowledge, the first report of the G5 and G7 genotypes from humans in Africa.

Lamivudine-induced red cell aplasia

Anaemia is frequent in patients with human immunodeficiency virus infection, and antiretroviral drugs have been implicated. Whilst therapy-induced anaemia is more readily attributed to zidovudine, lamivudine-associated, potentially life-threatening, pure red cell aplasia (PRCA) has been less recognized in the past and is only infrequently documented in the literature. We report on a patient suffering from what turned out to be lamivudine-induced PRCA who required 15 units of blood within 3 weeks before recovering swiftly following lamivudine (3TC) treatment withdrawal. As reviewed here, the nature of this condition is not well described in general, the onset appears to be variable and occurs at any CD4(+) count, but rapid improvement after cessation of drug administration appears to be a consistent feature.

Linkage to Care and Treatment for TB and HIV among People Newly Diagnosed with TB or HIV-Associated TB at a Large, Inner City South African Hospital

Objective To assess the outcomes of linkage to TB and HIV care and identify risk factors for poor referral outcomes. Design Cohort study of TB patients diagnosed at an urban hospital. Methods Linkage to care was determined by review of clinic files, national death register, and telephone contact, and classified as linked to care, delayed linkage to care (>7 days for TB treatment, >30 days for HIV care), or failed linkage to care. We performed log-binomial regression to identify patient and referral characteristics associated with poor referral outcomes. Results Among 593 TB patients, 23% failed linkage to TB treatment and 30.3% of the 77.0% who linked to care arrived late. Among 486 (86.9%) HIV-infected TB patients, 38.3% failed linkage to HIV care, and 32% of the 61.7% who linked to care presented late. One in six HIV-infected patients failed linkage to both TB and HIV care. Only 20.2% of HIV-infected patients were referred to a single clinic for integrated care. A referral letter was present in 90.3%, but only 23.7% included HIV status and 18.8% CD4 cell count. Lack of education (RR 1.85) and low CD4 count (CD4≤50 vs. >250cells/mm3; RR 1.66) were associated with failed linkage to TB care. Risk factors for failed linkage to HIV care were antiretroviral-naïve status (RR 1.29), and absence of referral letter with HIV or CD4 cell count (RR1.23). Conclusions Linkage to TB/HIV care should be strengthened by communication of HIV and CD4 results, ART initiation during hospitalization and TB/HIV integration at primary care.

A case of community-acquired Acinetobacter baumannii meningitis - has the threat moved beyond the hospital?

Acinetobacter baumannii is a prolific nosocomial pathogen renowned for its multidrug-resistant nature. We report a case of community-acquired meningitis due to A. baumannii. The case highlights the potential pathogenicity of this organism and raises concerns that this highly adaptable organism may soon evolve into a significant community pathogen, too.

High tuberculosis and HIV coinfection rate, Johannesburg.

To the Editor: Tuberculosis (TB) is the leading cause of illness and death among HIV-1–infected patients in sub-Saharan Africa (1–3), but valid data on the population-level interaction between the TB and HIV epidemics are scarce (4). Our objective was to determine the extent of this dual epidemic in our setting, a hospital in Johannesburg, South Africa. We did this by introducing bedside TB and HIV counseling. We also intended to increase the use of voluntary counseling and testing for our TB patients and facilitate referral to our antiretroviral clinic. From February to April 2006, 2 volunteers from Community AIDS Response (CARE) counseled patients admitted to the medical wards of the Helen Joseph Hospital. This regional hospital serves a catchment population of >500,000 people, predominantly low-income black Africans. Counselors provided TB and HIV wellness and adherence information, HIV pretest counseling, and referral to the Themba Lethu Clinic for rapid testing that used standard CARE modules. Basic demographic, TB, and HIV data from patient records were documented on standard data collection forms. Missing data were extracted from the hospital database and Therapy Edge-HIV, the data management system used by the HIV clinic. HIV testing was conducted with a fourth-generation ELISA or rapid finger prick antibody test, according to World Health Organization guidelines. Most admissions were for pulmonary TB. A total of 467 patients receiving TB treatment were counseled; 8 of these patients refused the TB counseling service, and 2 refused voluntary counseling and testing for HIV. These 467 patients constituted 13% of medical admissions and excluded the 1,075 patients seen at the hospital’s outpatient clinic with suspected TB for this 3-month period. Our impression is that this figure constitutes an underrepresentation of the total TB admissions because TB counselors were not able to see every patient with TB. Laboratory data were retrievable for 373 inpatients. For 301 (81%) of the 373 patients, TB blood culture, smear, or culture results could be traced. Hence, 72 (19%) of 373 patients who were receiving TB treatment had no record of a diagnostic effort to confirm TB. A total of 284 (76%) HIV test results could be traced; 270 (95%) of the 284 accessible TB patients had concurrent HIV infection (Table). Table Method of HIV diagnosis, Johannesburg, South Africa Most (123 [89%]) documented HIV results were from ELISAs performed during admission. Rapid testing performed in the ward was unacceptable to patients because confidentiality was compromised in large, busy wards and patients were often too ill to move to a side room. The system of making an appointment with the HIV clinic at the time of discharge failed because few patients (5%) actually had the rapid test after admission or began antiretroviral therapy. Those who began such therapy would have been captured on our database. The level of concurrent TB and HIV coinfection at the hospital was 95%. To the best of our knowledge, this is the highest level ever described in the peer-reviewed English-language literature (5). This finding may reflect the selection bias for our inpatients, who generally would have more coexisting conditions than outpatients do. Also, HIV data were missing for 24% of the 373 patients, a fact that may also influence this finding. The peak age incidence of TB in our population corresponds with previously published data and is similar to the peak age incidence of the HIV epidemic in South Africa (6). In one third of the admitted patients, no TB investigations were undertaken. This may be because patients provided a history of TB diagnosed elsewhere, or it may reflect the high rate of sputum smear negativity in the HIV-infected population, which lowers the clinician’s threshold for empiric TB treatment. Mycobacteremia appeared to be less common (14%) than reported in other African studies (7). However, we did not have a complete dataset—only 195 (52%) of the 373 patients could be evaluated. TB and HIV have reached unprecedented levels in our urban inpatient population. TB and HIV must be viewed as different sides of the same coin, and services and staff must change accordingly. We need to use the opportunity of hospital admission to educate patients on the interaction between these 2 epidemics and facilitate patient referral for long-term management. Such management would include voluntary counseling and testing, as well as antiretroviral medication. The latter is a recognized strategy of TB control because it reduces the risk for TB by 70%–90% (8). In addition, all inpatient procedures in our TB/HIV control programs need to be strengthened. Infection control interventions to limit the high rates of nosocomial transmission of TB to other vulnerable patients and staff need to be instituted. At our hospital, we are committed to these approaches. To this end, we have secured a Presidents Emergency Plan for AIDS Relief Grant via the nongovernmental organization Right to Care, which shares our vision. Urgent and extraordinary measures are indeed required in our combined control programs to achieve the Millennium Development Goals for TB/HIV.

A gardener who coughed up blood

In April, 2006, a 32-year-old man was referred to us by his local primary health-care clinic, with a cough that had been present for 2 weeks, accompanied by mild haemoptysis and diff use pleuritic chest pain. He was from Mozambique, but had been working in Johannesburg—initially as a labourer on building sites, and then as a gardener. He did not smoke. He had been diagnosed as HIV positive in 2005. On examination, the patient was not underweight or short of breath. He had cervical, axillary, and inguinal lymphadenopathy. We heard coarse crackles over both lungs, and palpated the liver edge 8 cm below the costal margin. We found no splenomegaly or ascites. Chest radiography (fi gure) showed many round opacities. Ultrasonography of the abdomen showed many hypoechogenic lesions in the liver. Blood tests showed that the patient was mildly anaemic, with a normal white-cell count. However, the CD4 cell count was only 27 per μL. Serum concentrations of alkaline phos phatase and γ-gluta myltransferase were raised, at 335 U/L and 228 U/L respectively. Serological testing gave a positive result for hepatitis C. CT of the chest and abdomen showed many cystic lesions in the lungs and in the liver; an indirect haemagglutination assay was positive for Echinococcus spp, at a titre of 1:512; a titre of 1:20 is regarded as diagnostic. We prescribed albendazole, at a dose of 400 mg twice daily, and prednisolone. The patient was discharged after 2 weeks, and completed the course of albendazole, which consisted of three 4-week periods of medication, separated by 1-week intervals intended to reduce the risk of liver damage. In August 2006, repeat CT of the chest and abdomen revealed that the cysts had decreased in size and number. We did not start treatment with highly active antiretroviral drugs while the patient was taking albendazole, because of the possible drug interaction, the risk of iatrogenic liver damage, and the risk of immune reconstitution syndrome. The patient was counselled about the risks and management of HIV; we intended to prescribe antiretroviral drugs after he completed the course of albendazole. However, the patient did not attend follow-up appointments, and attempts to trace him were unsuccessful. Echinococcus is a tapeworm carried by dogs. As a gardener, our patient was at increased risk of unwittingly swallowing the tapeworm’s eggs, by which means people become infected; the peak age of infection is 30–40 years. After being swallowed, the eggs release embryos, which travel in the bloodstream before lodging in organs such as the liver and lungs, where the embryos develop into cysts containing larvae. Echinococcus cysts are also known as hydatid cysts. Most cysts are asymptomatic; indeed, they are often found serendipitously, on radiological testing. Patients with AIDS are more likely to have echinococcal disease that develops rapidly and manifests early. However, our patient presented with mild symptoms, despite disseminated cystic disease and infection with hepatitis C. We speculate that perhaps the mildness of the symptoms was caused by the impairment of his immune response. Although our patient accepted treatment for tapeworm infestation and HIV counselling, he did not attend appointments for HIV treatment. He may have feared unemployment; his health beliefs may have caused him to doubt the diagnosis or treatment of AIDS; the grief or stigma of the diagnosis may have prevented him from accepting it.