HIV care need not hamper maternity care: a descriptive analysis of integration of services in rural Malawi.

OBJECTIVE: To evaluate the use of reproductive health care and incidence of paediatric HIV infection during the expansion of antiretroviral therapy and services for the prevention of mother-to-child transmission in rural Malawi, and the influence of integration of these HIV-related services into general health services. DESIGN: Descriptive analysis. SETTING: Thyolo District, with a population of 600,000, an HIV prevalence of 21% and a total fertility rate of 5.7 in 2004. POPULATION: Women attending reproductive health services care in 2005 and 2010. METHODS: Review of facility records and databases for routine monitoring. MAIN OUTCOME MEASURES: Use of antenatal, intrapartum, postpartum, family planning and sexually transmitted infection services; incidence of HIV infection in infants born to mothers who received prevention of mother-to-child transmission care. RESULTS: There was a marked increase in the uptake of perinatal care: pregnant women in 2010 were 50% more likely to attend at least one antenatal visit (RR 1.50, 95% CI 1.48-1.51); were twice as likely to deliver at a healthcare facility (RR 2.05, 95% CI 2.01-2.08); and were more than four times as likely to present for postpartum care (RR 4.40, 95% CI 4.25-4.55). Family planning consultations increased by 40% and the number of women receiving treatment for sexually transmitted infections doubled. Between 2007 and 2010, the number of HIV-exposed infants who underwent testing for HIV went up from 421 to 1599/year, and the proportion testing positive decreased from 13.3 to 5.0%; infants were 62% less likely to test HIV positive (RR 0.38, 95% CI 0.27-0.52). CONCLUSIONS: During the expansion and integration of HIV care, the use of reproductive health services increased and the outcomes of infants born to HIV-infected mothers improved. HIV care may be successfully integrated into broader reproductive health services.

Nevirapine-associated hepatotoxicity was not predicted by CD4 count ≥250 cells/µL among women in Zambia, Thailand and Kenya.

OBJECTIVE: The aim of the study was to determine risk factors for developing severe hepatotoxicity (grade 3 or 4 hepatotoxicity) and rash-associated hepatotoxicity (rash with ≥ grade 2 hepatotoxicity) among women initiating nevirapine-based antiretroviral therapy (ART). METHODS: The Non-Nucleoside Reverse Transcriptase Inhibitor Response Study was a prospective cohort study carried out in Zambia, Thailand and Kenya. Between May 2005 and January 2007, we enrolled antiretroviral-naïve HIV-infected women initiating nevirapine-based ART. At enrollment and at weeks 2, 4, 8, 16 and 24, participants had serum alanine transferase (ALT) and aspartate transaminase (AST) measured and were evaluated clinically for hepatitis and rash. RESULTS: Nevirapine-based ART was initiated in 820 women and baseline ALT or AST results were abnormal (≥ grade 1) in 113 (14%) women. After initiating nevirapine-based ART, severe hepatotoxicity occurred in 41 (5%) women and rash-associated hepatotoxicity occurred in 27 (3%) women. In a multivariate logistic regression model, severe hepatotoxicity and rash-associated hepatotoxicity were both associated with baseline abnormal (≥ grade 1) ALT or AST results, but not with a baseline CD4 cell count ≥250 cells/µL. Three participants (0.4%) died with symptoms suggestive of fatal hepatotoxicity; all three women had baseline CD4 count <100 cells/µL and were receiving anti-tuberculosis therapy. CONCLUSION: Among women taking nevirapine-based ART, severe hepatotoxicity and rash-associated hepatotoxicity were predicted by abnormal baseline ALT or AST results, but not by a CD4 count ≥250 cells/µL. In resource-limited settings where transaminase testing is available, testing should focus on early time-points and on women with abnormal baseline ALT or AST results.

The impact of project closure on HIV incidence and mortality in a cohort of couples in Lusaka, Zambia.

The objective of this study was to assess the impact of temporary closure of an HIV research clinic on the health of study participants. Primary data were collected quarterly from couples enrolled in research studies at an established HIV study site. There were 632 participating couples enrolled when the project closed, 475 of whom returned when it re-opened six months later. HIV sero-incidence, mortality rates and risk-taking behaviours were compared before and during the closure. Perceived impact of the closure was measured in returning participants. Demographic data collected at the last pre-closure study visit were used to look at the differences between returning and non-returning study participants. Serologic data from those who returned were compared pre- and post-closure to examine changes in HIV incidence. Mortality rates were estimated from reported deaths, and were compared pre- and during project closure. Perceptions of the impact of the closure among returning participants were examined through an interviewer administered questionnaire. It was found that couples who returned were not demographically different from couples who did not return. Most participants reported no problems with finding alternate sources of condoms and the incidence of HIV did not change significantly during the closure. Eighty-four percent respondents reported that the closure had a negative impact on them, 87% of whom rated loss of medical care as the main impact. The mortality rate among HIV-positive participants doubled from 6.7/100 person years to 12.4/100 person years during the closure (p=0.01). Results indicate that couples voluntary counselling and testing (CVCT) established durable risk-reduction behaviours that persisted during project closure. ThIn ae loss of healthcare was perceived as the most negative impact on participants, reflected in increased mortality rates. Research projects should make transition plans and budget for mechanisms to reduce the negative impact on participants of project closures.

Nitazoxanide for persistent diarrhoea in Zambian acquired immune deficiency syndrome patients: a randomized-controlled trial.

BACKGROUND: Adults with acquired immune deficiency syndrome and persistent diarrhoea in Zambia have intestinal infection, predominantly protozoa. AIM: To search for treatment which can be offered with minimal investigation, we carried out a double-blind, randomized-controlled trial of nitazoxanide (a drug with a range of activity against parasites and bacteria). METHODS: Patients with diarrhoea of 1 month duration or longer were randomized to receive nitazoxanide (1000 mg twice daily) or placebo for 2 weeks. End-points were clinical response, parasitological clearance and mortality. RESULTS: Two hundred and seven adults were randomized; 42 died during the study. The primary assessment of efficacy was made after 17 days. Clinical response was observed in 56 (75%) of 75 patients receiving nitazoxanide and 45 (58%) of 77 patients receiving placebo (P = 0.03). The rate of improvement was markedly higher in patients with CD4 counts under 50 cells/microL receiving nitazoxanide (P = 0.007). The benefit was largely restricted to the period when the drug was being administered. No difference was seen in parasitological clearance between the two groups. Mortality was 19% by 4 weeks of follow-up and did not differ with treatment allocation. CONCLUSIONS: Nitazoxanide given orally for 14 days was associated with clinical improvement in Zambian acquired immune deficiency syndrome patients with diarrhoea, especially those with very low CD4 counts.

Impaired bioavailability of vitamin A in adults and children with persistent diarrhoea in Zambia.

BACKGROUND: We have previously demonstrated a strong relationship between low serum retinol concentration and mortality in Zambian AIDS patients with diarrhoea, but were unable to detect any benefit from oral micronutrient supplementation. AIM: To test the hypothesis that this is related to impaired availability of vitamin A, we analysed serum retinol concentration changes over 6 h following oral mega-dose therapy (60, 120 or 180 mg retinol). METHODS: Twenty-four men without diarrhoea, 15 adults with persistent diarrhoea and 11 children (six girls, five boys) with persistent diarrhoea were studied. RESULTS: Men with persistent diarrhoea had lower baseline serum retinol concentrations (median 0.39 micromol/L, interquartile range 0.21-0.56) than controls (median 1.16 micromol/L, interquartile range 0.84-1.47; P=0.0003). After 60 mg retinol, the rise in serum retinol in HIV seropositive controls (median 0.63 micromol/L, interquartile range 0.35-0.77) did not differ significantly from that observed in HIV seronegative controls (median 0.35 micromol/L, interquartile range - 0.04-0.56; P=0.20). Increasing the dose to 120 mg or 180 mg retinol did not enhance the increase in serum retinol concentration. The increase in serum retinol was less in adults with persistent diarrhoea (median 0.25 micromol/L, interquartile range 0.04-0.35) and in children (median 0.11 micromol/L, interquartile range 0.04-0.46) than in men without diarrhoea (median 0.44 micromol/L, interquartile range 0.26-0.74; P=0.03). Adults and children with diarrhoea had greater losses of retinol in urine over a 24-h period than controls, but less than 1% of the ingested dose was excreted. CONCLUSIONS: These results suggest that persistent diarrhoea in this population is associated with reduced bioavailability of retinol. Further work is required to determine the metabolic fate of therapeutic doses of retinol and to determine appropriate replacement strategies for HIV infected individuals.

Albendazole chemotherapy for AIDS-related diarrhoea in Zambia--clinical, parasitological and mucosal responses.

BACKGROUND: Albendazole reduces diarrhoea in African AIDS patients, but it is unclear if the clinical response to treatment reflects pathogen eradication and/or mucosal recovery. METHODS: Adults with HIV-related persistent diarrhoea were treated with albendazole 800 mg twice daily for 14 days. Clearance of parasites was evaluated at 3 and 6 weeks by stool microscopy. At baseline and at 6 weeks duodenal biopsies were taken for electron microscopy (EM) and morphometry. RESULTS: Ten (7%) of 153 patients had cryptosporidiosis, 54 (37%) had isosporiasis and 23 (16%) had microsporidiosis. By 3 weeks, these protozoa were cleared in 27 (46%) of 59 patients initially positive. By 6 weeks, 34 (39%) of 87 patients experienced complete clinical response, 18 (21%) partial response and 35 (40%) no response. Crypt depth increased by 15% over 6 weeks (P < 0.001), but villous height increased only in patients with complete response (median + 50 microm, interquartile range (IQR) 2-90, compared to patients with partial (+ 4 microm, IQR -15,41) or no response (-13 microm, IQR -2,12; P=0.008)). Fifteen patients died: body mass index < 17.5 kg/m(2) and crypt depth < 180 microm independently predicted death. CONCLUSIONS: Albendazole therapy reduced the burden of protozoal infection and promoted mucosal recovery in patients with a complete clinical response.

Tropical enteropathy: a T-cell-mediated crypt hyperplastic enteropathy.

OBJECTIVE: Tropical enteropathy is widespread throughout the tropics, but its pathogenesis is unknown. T-cell activation has been demonstrated to result in enteropathy in vitro and in animal models, and occurs in untreated patients with coeliac disease. We have therefore examined the hypothesis that T-cell activation is important in the pathogenesis of tropical enteropathy. PATIENTS AND METHODS: Healthy black Zambian subjects were compared with black and white South Africans. Quantitative microscopy was conducted on distal duodenal biopsies. Mucosal T-cell activation was quantitated by dual colour immunofluorescence staining for CD3 plus CD69 or HLA-DR. Crypt proliferation was measured by direct counting of Feulgen-stained mitotic figures, and systemic immune activation by assay of serum tumour necrosis factor alpha (TNF-alpha). RESULTS: Villous height was reduced (P = 0.0004), crypt depth increased (P < 0.0001), and mitoses per crypt increased (P = 0.014) in black Zambians compared with black and white South Africans. Mucosal thickness was similar. Intraepithelial lymphocyte count was increased in the black groups compared with whites (P = 0.03). CD3+CD69+ (P = 0.0007) and CD3+HLA-DR+ (P < 0.0001) expression was increased in black Zambians compared with black and white South Africans. Serum TNF-alpha was similar in all groups. CONCLUSIONS: Tropical enteropathy is associated with mucosal T-cell activation and crypt hyperplasia. Tropical enteropathy occurs in the absence of malnutrition, diarrhoea or systemic illness.

Lack of evidence for small intestinal mucosal T-cell activation as a pathogenic mechanism in African HIV-associated enteropathy.

The role of mucosal T-cell activation in HIV-associated enteropathy is uncertain. Twenty Zambian patients with AIDS and chronic diarrhea were studied, as were nine controls. Distal duodenal biopsies were taken at endoscopy. Morphometric analysis and dual color immunofluorescence staining were performed. Villous height was reduced [177 (118-228) vs 305 (244-358) microm P = 0.002] and crypt depth increased [220 (164-202) vs 194 (164-202) microm P = 0.008] in AIDS patients compared to controls. CD3+CD4+ T cells were reduced in AIDS patients compared to controls [12.9 (5.7-25.2) vs 47.6 (33.4-65.5)% P = 0.04]. There was no significant difference in expression of CD8, CD25, CD69, HML-1, or HLA-DR on T cells between the AIDS patients and controls, with the exception of CD3+HML-1+ cells, which were increased in AIDS patients (P = 0.05). Small intestinal T-cell activation was similar between AIDS patients and controls. We conclude, therefore, that this mechanism is not likely to be important in the pathogenesis of HIV-associated enteropathy.

Helicobacter pylori infection in an urban African population.

We have studied 221 adults drawn from an impoverished urban population with high human immunodeficiency virus (HIV) seroprevalence (35%) to determine the prevalence of gastroduodenal pathology and its relationship to serological markers of Helicobacter pylori virulence proteins and other potential environmental and immunological determinants of disease including HIV infection. Eighty-one percent were H. pylori seropositive, and 35% were HIV seropositive. Urban upbringing and low CD4 count were associated with a reduced likelihood of H. pylori seropositivity, as was current Ascaris infection, in keeping with recent evidence from an animal model. One hundred ninety-one adults underwent gastroduodenoscopy, and 14 had gastroduodenal pathology. Mucosal lesions were a major cause of abdominal pain in this population. While the majority of patients with gastroduodenal pathology (12 of 14) were seropositive for H. pylori, none were seropositive for HIV. Smoking was associated with increased risk of macroscopic pathology, and a history of Mycobacterium bovis BCG immunization was associated with reduced risk. Antibodies to H. pylori lipopolysaccharide were associated with pathology. HIV infection was associated with protection against mucosal lesions, suggesting that fully functional CD4 lymphocytes may be required for the genesis of gastroduodenal pathology.

Enteropathy in Zambians with HIV related diarrhoea: regression modelling of potential determinants of mucosal damage.

BACKGROUND: AIDS is characterised by small intestinal mucosal damage, but its aetiopathogenesis is poorly understood. Enteric infections in Africa differ from those in northern countries, where protozoan infections have been associated with severe enteropathy in AIDS patients. AIMS: To characterise enteropathy in Zambian AIDS patients compared with local controls, and to assess relative contributions of enteric infection, nutritional impairment, and immune dysfunction. METHODS: Computer aided mucosal morphometry of small intestinal biopsy specimens from 56 HIV infected Zambians with persistent diarrhoea and 26 diarrhoea free controls, followed by regression modelling. RESULTS: Patients with HIV related diarrhoea had reduced villous height and increased crypt depth compared with controls. There was no difference between HIV positive and negative controls. In regression models applied to AIDS mucosal measurements, villous height and crypt depth were related to nutritional parameters and to serum soluble tumour necrosis factor receptor p55 concentration. Crypt depth was also related to lamina propria plasma cell count. Intestinal infection was found in 79%, which consisted predominantly of microsporidia in 34%, Isospora belli in 24%, and Cryptosporidium parvum in 21%, but detection of these enteropathogens was not related to severity of enteropathy. CONCLUSIONS: Nutritional and immune disturbances were associated with enteropathy, accounting for over one third of the variation in mucosal morphometric parameters.

PIP: The relative contributions of enteric infection, nutritional impairment, and immune dysfunction to AIDS-related enteropathy were investigated in a comparative study of small intestinal biopsy specimens from 56 HIV-positive patients from Lusaka, Zambia, with persistent diarrhea and 26 diarrhea-free controls. Compared with both HIV-positive and HIV-negative controls, patients with HIV-related diarrhea had a 40% reduction in mean villous height and a 19% increase in mean crypt depth. In regression models applied to AIDS mucosal measurements, villous height and crypt depth were related to nutritional parameters and to the serum soluble tumor necrosis factor receptor p55 concentration. Crypt depth also was related to lamina propria plasma cell count. Intestinal infection, primarily microsporidia, was detected in 79% of cases; however, the presence of enteropathogens was not related to the severity of enteropathy. These findings suggest that nutritional and immune disturbances account for more than 33% of the variation in mucosal morphometric parameters in AIDS-related enteropathy.