Showing papers in "AIDS in 1998"

A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors.

Abstract: Objective: To describe a syndrome of peripheral lipodystrophy (fat wasting of the face, limbs and upper trunk), hyperlipidaemia and insulin resistance in patients receiving potent HIV protease inhibitor therapy. Design: Cross-sectional study. Setting: Outpatient clinic of a university teaching hospital. Patients: HlV-infected patients either receiving at least one protease inhibitor (n = 116) or protease inhibitor-naive (n = 32), and healthy men (n = 47). Interventions and main outcome measures: Lipodystrophy was assessed by physical examination and questionnaire and body composition by dual-energy X-ray absorptiometry. Fasting triglyceride, cholesterol, free fatty acid, glucose, insulin, C-peptide and fructosamine levels, other metabolic parameters, CD4 lymphocyte counts, and HIV RNA load were also assessed. Results: HIV protease inhibitor-naive patients had similar body composition to healthy men. HIV protease inhibitor therapy was associated with substantially lower total body fat (13.2 versus 18.7 kg in protease inhibitor-naive patients; P = 0.005), and significantly higher total cholesterol and triglyceride levels. Lipodystrophy was observed clinically in 74 (64%) protease inhibitor recipients after a mean 13.9 months and 1(3%) protease inhibitor-naive patient (P = 0.0001). Fat loss occurred in all regions except the abdomen after a median 10 months. Patients with lipodystrophy experienced a relative weight loss of 0.5 kg per month and had significantly higher triglyceride, cholesterol, insulin and C-peptide levels and were more insulin-resistant than protease inhibitor recipients without lipodystrophy. Patients receiving ritonavir and saquinavir in combination had significantly lower body fat, higher lipids and shorter time to lipodystrophy than patients receiving indinavir. Three (2%) patients developed new or worsening diabetes mellitus. Conclusion: A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance is a common complication of HIV protease inhibitors. Diabetes mellitus is relatively uncommon.

Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway.

Abstract: After zidovudine (ZDV), a 3′-azido analogue of thymi-dine, was found to be an effective antiretroviral drugagainst HIV [1,2], other nucleoside analogues inhibit-ing reverse transcriptase (RT) soon followed: didano-sine (ddI), zalcitabine (ddC), lamivudine (3TC),stavudine (D4T), and recently abacavir (1592U89)[3–7]. These drugs have demonstrated efficacy inreduction of morbidity and mortality, especially incombination therapy [8–10]. A special feature of someof these drugs is the protection against AIDS dementiacomplex, which appears to be related to good penetra-tion of the blood–brain barrier [11–13]. Although theintroduction of protease inhibitors has changed themanagement of HIV infection drastically, this cerebro-protective property will assert the role of these nucleo-side RT inhibitors (NRTI) as a cornerstone ofantiretroviral therapy [9,10].More than 10 years of experience with NRTI therapyhas revealed important adverse effects ranging frommild (myopathy) to fatal in some cases (pancreatitis,liver failure and lactic acidosis). Behind most of theseside-effects there appears to be a common mechanism:a decreased mitochondrial energy-generating capacity.In this review we will summarize the literature inwhich this mechanism is analysed and will emphasizethe importance of acquired mitochondrial dysfunctionthat will accumulate during long-term treatment withantiretroviral nucleoside analogues.

Bacterial vaginosis and disturbances of vaginal flora: association with increased acquisition of HIV.

Abstract: Background Cross-sectional studies suggest an association between bacterial vaginosis (BV) and HIV-1 infection. However, an assessment of a temporal effect was not possible. Objectives To determine the association of BV and other disturbances of vaginal flora with HIV seroconversion among pregnant and postnatal women in Malawi, Africa. Design Longitudinal follow-up of pregnant and postpartum women. Methods Women attending their first antenatal care visit were screened for HIV after counselling and obtaining informed consent. HIV-seronegative women were enrolled and followed during pregnancy and after delivery. These women were again tested for HIV at delivery and at 6-monthly visits postnatally. Clinical examinations and collection of laboratory specimens (for BV and sexually transmitted diseases) were conducted at screening and at the postnatal 6-monthly visits. The diagnosis of BV was based on clinical criteria. Associations of BV and other risk factors with HIV seroconversion, were examined using contingency tables and multiple logistic regression analyses on antenatal data, and Kaplan-Meier proportional hazards analyses on postnatal data. Results Among 1196 HIV-seronegative women who were followed antenatally for a median of 3.4 months, 27 women seroconverted by time of delivery. Postnatally, 97 seroconversions occurred among 1169 seronegative women who were followed for a median of 2.5 years. Bacterial vaginosis was significantly associated with antenatal HIV seroconversion (adjusted odds ratio = 3.7) and postnatal HIV seroconversion (adjusted rate ratio = 2.3). There was a significant trend of increased risk of HIV seroconversion with increasing severity of vaginal disturbance among both antenatal and postnatal women. The approximate attributable risk of BV alone was 23% for antenatal HIV seroconversions and 14% for postnatal seroconversions. Conclusions This prospective study suggests that progressively greater disturbances of vaginal flora, increase HIV acquisition during pregnancy and postnatally. The screening and treating of women with BV could restore normal flora and reduce their susceptibility to HIV.

Treatment with protease inhibitors associated with peripheral insulin resistance and impaired oral glucose tolerance in HIV-1-infected patients

Abstract: Background: The use of protease inhibitors in the treatment of HIV-1 infection is associated with the new onset of diabetes mellitus, hyperlipidaemia and lipodystrophy. It is unclear whether these findings are coincidental or whether they reflect a causative effect of protease inhibitors. Objective: To evaluate the effect of treatment with protease inhibitors on insulin sensitivity, oral glucose tolerance and serum lipids in HIV-infected patients in order to determine whether treatment with protease inhibitors can cause peripheral insulin resistance. Design: Cross-sectional controlled study in HIV-infected patients treated with protease inhibitors to assess insulin sensitivity, oral glucose tolerance and changes in serum lipids. Methods: Sixty-seven patients treated with protease inhibitors, 13 therapy-naive patients and 18 HIV-negative control subjects were tested for insulin sensitivity (intravenous insulin tolerance test). In a subgroup of 24 treated patients, oral glucose tolerance was determined. Serum lipids prior to and under treatment with protease inhibitors were compared. Results: Patients on protease inhibitors had a significantly decreased insulin sensitivity when compared with therapy-naive patients (median, 75 and 156 μmol/l/min, respectively; P < 0.001). All treated patients with impaired (n = 4) or diabetic (n = 9) oral glucose tolerance, and four out of 11 patients with normal glucose tolerance showed peripheral insulin resistance; all therapy-naive patients had normal insulin sensitivity. Treatment with protease inhibitors led to a significant increase in total triglycerides and cholesterol in the 67 treated patients (median increase, 113 and 37 mg/ml, respectively). Conclusion: Treatment with protease inhibitors is associated with peripheral insulin resistance, leading to impaired or diabetic oral glucose tolerance in some of the patients, and with hyperlipidaemia. Overall, there is a large variation in the severity and clinical presentation of protease inhibitor-associated metabolic side-effects.

High incidence of anal high-grade squamous intra-epithelial lesions among HIV-positive and HIV-negative homosexual and bisexual men.

Abstract: Objective The incidence of anal cancer among homosexual men exceeds that of cervical cancer in women, and HIV-positive homosexual men may be at even higher risk than HIV-negative men. Cervical cancer is preceded by high-grade squamous intra-epithelial lesions (HSIL) and anal HSIL may similarly be the precursor to anal cancer. In this study, we describe the incidence of and risk factors for HSIL in HIV-positive and HIV-negative homosexual and bisexual men. Design Prospective cohort study of HIV-positive and HIV-negative homosexual men. Setting The University of California, San Francisco. Patients 346 HIV-positive and 262 HIV-negative men enrolled at baseline, 277 HIV-positive and 221 HIV-negative homosexual men followed after baseline. Study design A questionnaire was administered detailing lifestyle habits, medical history and sexual practices. Anal swabs for cytology and human papillomavirus studies were obtained, followed by biopsies of visible lesions. Human papillomavirus testing was performed using polymerase chain reaction (PCR) and 'hybrid capture'. Blood was obtained for HIV testing and measurement of CD4 levels. Main outcome measures Incident HSIL. Results HIV-positive men were more likely to develop HSIL than HIV-negative men relative risk (RR), 3.7; 95% confidence interval (CI), 2.6-5.7. Life-table estimates of the 4-year incidence of HSIL was 49% (95% CI, 41-56) among HIV-positive men and 17% (95% CI, 12-23) among HIV-negative men. Among HIV-positive men, those with lower baseline CD4 counts (P = 0.007) and persistent infection with one or more human papillomavirus types, determined using PCR (P = 0.0001), were more likely to develop HSIL. Conclusions HIV infection, lower CD4 levels and human papillomavirus infection were associated with high rates of incident HSIL among homosexual men. However, high rates were found at all CD4 levels among HIV-positive men and among HIV-negative men.

Haptoglobin polymorphism, iron metabolism and mortality in HIV infection.

Abstract: Background: Three phenotypes of the antioxidant protein haptoglobin are known: Hp 1-1, Hp 2-1 and Hp 2-2. Objectives: To investigate the outcome of HIV infection according to haptoglobin type. Design and methods: Haptoglobin phenotypes were determined using starch gel electrophoresis in serum obtained from 653 HIV-infected Caucasians in the AIDS reference centers of Gent (n = 184), Antwerp (n = 309), and Luxembourg (n = 160). Survival was compared between haptoglobin types using Kaplan-Meier curves. Plasma HIV-1 RNA was quantified by reverse transcriptase PCR. Serum iron, transferrin saturation, ferritin, and vitamin C were assayed to evaluate iron-driven oxidative stress in 184 HIV-infected patients and 204 controls. Results: The haptoglobin type distribution amongst the patients (17.6% Hp 1-1, 49.9% Hp 2-1, 32.5% Hp 2-2) corresponded to that of the controls. Kaplan-Meier curves showed a higher mortality for the Hp 2-2 group (P = 0.0001; adjusted mortality risk ratio, 1.78; 95% confidence interval, 1.25-2.54). Median survival time was 11.0 years (Hp 1-1 and Hp 2-1) versus 7.33 years (Hp 2-2). Plasma HIV-1 RNA levels prior to antiviral therapy and their increase over 1 year were highest in Hp 2-2 patients (P = 0.03 and 0.003, respectively). The Hp 2-2 type was associated with higher serum iron, transferrin saturation, and ferritin levels and with low vitamin C concentrations. Furthermore, ferritin concentrations were higher in HIV-infected patients than in controls (P < 0.0001). Conclusion: HIV-infected patients carrying the Hp 2-2 phenotype show a worse prognosis, which is reflected by a more rapid rate of viral replication (in the absence of antiviral treatment). They also accumulate more iron and oxidize more vitamin C, suggesting that less efficient protection against haemoglobin/iron-driven oxidative stress may be a direct mechanism for stimulating viral replication.

Chemokines and receptors in HIV encephalitis.

Abstract: Background:Chemokines are involved in the migration of leukocytes and have been implicated in several inflammatory diseases of the central nervous system. Some of their receptors have been proposed to mediate HIV infection.Objective:To determine changes in chemokine and receptor expression in HIV en

Effects of vitamin E and C supplementation on oxidative stress and viral load in HIV-infected subjects.

Abstract: OBJECTIVES The HIV-infected population is known to be oxidatively stressed and deficient in antioxidant micronutrients. Since in vitro replication of HIV is increased with oxidative stress, this study assessed the effect of antioxidant vitamin supplementation on lipid peroxidation, a measure of oxidative stress, and viral load in humans. DESIGN A randomized placebo-controlled, double-blind study. METHODS Forty-nine HIV-positive patients were randomized to receive supplements of both DL-alpha-tocopherol acetate (800 IU daily) and vitamin C (1000 mg daily), or matched placebo, for 3 months. Plasma antioxidant micronutrient status, breath pentane output, plasma lipid peroxides, malondialdehyde and viral load were measured at baseline and at 3 months. New or recurrent infections for the 6-month period after study entry were also recorded. RESULTS The vitamin group (n = 26) had an increase in plasma concentrations of alpha-tocopherol (P < 0.0005) and vitamin C (P < 0.005) and a reduction in lipid peroxidation measured by breath pentane (P < 0.025), plasma lipid peroxides (P < 0.01) and malondialdehyde (P < 0.0005) when compared with controls (n = 23). There was also a trend towards a reduction in viral load (mean +/- SD changes over 3 months, -0.45 +/- 0.39 versus +0.50 +/- 0.40 log10 copies/ml; P = 0.1; 95% confidence interval, -0.21 to -2.14). The number of infections reported was nine in the vitamin group and seven in the placebo group. CONCLUSION Supplements of vitamin E and C reduce oxidative stress in HIV and produce a trend towards a reduction in viral load. This is worthy of larger clinical trials, especially in HIV-infected persons who cannot afford new combination therapies.

Hepatitis C virus-associated hepatitis following treatment of HIV-infected patients with HIV protease inhibitors: an immune restoration disease?

Abstract: Objective To report observations from case studies on the pathogenic mechanisms underlying the acute hepatitis that sometimes occurs in hepatitis C virus (HCV) and HIV coinfected patients following treatment with potent antiretroviral therapy that includes a HIV protease inhibitor. Methods Cases of acute hepatitis were identified from a group of 133 patients enrolled in a retrospective study of pathogen-associated inflammatory disease following the use of potent antiretroviral therapy. Data on serum alanine aminotransferase concentrations, clinical events, HCV antibodies, and liver biopsies were collected from medical records. HCV RNA assays and additional HCV antibody assays were undertaken on stored plasma or sera. Results Three of the 133 patients (2%) developed symptomatic hepatitis. One was HCV antibody-positive prior to commencing antiretroviral therapy and developed hepatitis subsequent to an episode of Mycobacterium avium complex disease associated with immune restoration. However, the other two patients had previously undiagnosed HCV infection for up to 2 years prior to antiretroviral therapy, with HCV RNA detected but anti-HCV antibody repeatedly undetectable in stored plasma or sera. HCV antibody was only detectable after antiretroviral therapy-induced decrease in plasma HIV RNA and immunological reconstitution. Plasma HCV RNA increased after therapy in one of these patients, but in the other the level was not increased at a time of active hepatitis demonstrated by liver biopsy. Conclusions Hepatitis in HCV-HIV-coinfected patients following treatment with potent antiretroviral therapy may reflect restoration of anti-HCV immune responses rather than increased HCV replication or a hepatotoxic effect of antiretroviral therapy.

HIV risk behavioral surveillance: a methodology for monitoring behavioral trends.

Abstract: Objective: This article summarizes issues and recommendations for conducting HIV risk behavioral surveillance surveys (BSS) based on experiences from ten BSS projects in eight countries in Asia and Africa. Background: BSS consists of systematic and repeated cross-sectional surveys of HIV and sexually transmitted disease-related behaviors, with other knowledge and attitudinal variables added where appropriate. Its major purpose and utility is in detecting trends among selected vulnerable and high-risk population groups whose behavioral change can have the most impact on the epidemic. BSS is also useful for tracking trends in behaviors over time in regions exposed to HIV prevention activities, as a contributing component to the comprehensive monitoring and evaluation of interventions. Recommendations: (i) implement BSS as an essential adjunct to HIV/STD epidemiological surveillance; (ii) use BSS for evaluation purposes in combination with process data and triangulate results with qualitative research; (iii) choose sentinel groups based on epidemiological considerations, evaluation and monitoring needs, representative sampling frames, and political and cultural considerations; (iv) maintain 1-year intervals between survey waves for most groups in order to provide yearly updates on behavioral trends for programmatic adjustments; (v) use internationally standardized indicators and question wording; (vi) maintain strict quality control standards to enhance data validity and reliability; and (vii) develop a clear dissemination strategy during BSS design to increase the likelihood of utilization of BSS results. Conclusion: BSS represents a cost-effective way to determine whether programmatic behavioral targets and goals are being met, to identify persisting risk behaviors over time, and to indicate whether new intervention approaches are necessary.

Clinical and biological impact of antiretroviral therapy with protease inhibitors on HIV-related Kaposi's sarcoma.

Abstract: Objective To evaluate the clinical and biological impact of protease inhibitors on HIV-associated Kaposi's sarcoma. Design and setting A cohort of 10 patients included prospectively from April 1996 to June 1997 were studied in one institutional centre after initiation of protease inhibitors. Patients and methods All patients but one (stable disease) had progressive Kaposi's sarcoma. Three out of 10 patients had stopped specific chemotherapy for Kaposi's sarcoma for more than 4 weeks, three were still under chemotherapy, and four had never received specific treatment of Kaposi's sarcoma. Plasma HIV viral load, human herpesvirus (HHV)-8 viraemia in peripheral blood mononuclear cells (PBMC), and CD4 cell count were sequentially assessed from the beginning of therapy. For six patients, a semiquantitative evaluation of HHV-8 viral load in the Kaposi's sarcoma lesions was performed during treatment using polymerase chain reaction. Results After initiation of HIV triple therapy with protease inhibitors, we observed six complete responses, two partial responses, and two patients with progressive disease. All patients had undetectable plasma HIV viral load within 2 months of treatment. Undetectable HHV-8 viraemia in PBMC occurred in seven out of eight patients with partial or complete response and in none of the progressive patients. A decrease or negation of HHV-8 viral load in Kaposi's sarcoma lesions was observed in two complete responders. Conclusion Our results suggest that antiviral therapy with protease inhibitors are clinically efficient in HIV-associated Kaposi's sarcoma and that there exists a correlation between clinical response and negation of HHV-8 viraemia.

Social network dynamics and HIV transmission.

Abstract: The objective of this study was to prospectively study the changes in the social networks of persons at presumably high risk for HIV in a community with low prevalence and little endogenous transmission. From a cohort of 595 persons at high risk (prostitutes injecting drug users and sexual partners of these persons) and nearly 6000 identified contacts we examined the social networks of a subset of 96 persons who were interviewed once per year for 3 years. We assessed their network configuration network stability and changes in risk configuration and risk behavior using epidemiologic and social network analysis and visualization techniques. Some significant decrease in personal risk-taking was documented during the course of the study particularly with regard to needle-sharing. The size and number of connected components (groups that are completely connected) declined. Microstructures (small subgroups of persons that interact intensely) were either not present or declined appreciably during the period of observation. In this area of low prevalence the lack of endogenous transmission of HIV may be related in part to the lack of a network structure that fosters active propagation despite the continued presence of risky behaviors. Although the relative contribution of network structure and personal behavior cannot be ascertained from these data the study suggests an important role of network configuration in the transmission dynamics of HIV. (authors)

Elevated cerebrospinal fluid levels of monocyte chemotactic protein-1 correlate with HIV-1 encephalitis and local viral replication.

Abstract: OBJECTIVE To investigate whether the CC-chemokine monocyte chemotactic protein (MCP)-1 could play a role in the pathogenesis of HIV infection of the central nervous system. This hypothesis was suggested by previous observations, including our finding of elevated cerebrospinal fluid (CSF) levels of this chemokine in patients with cytomegalovirus (CMV) encephalitis. DESIGN AND METHODS CSF levels of MCP-1 were determined in 37 HIV-infected patients with neurological symptoms, and were compared with both the presence and severity of HIV-1 encephalitis at post-mortem examination and CSF HIV RNA levels. MCP-1 production by monocyte-derived macrophages was tested after in vitro infection of these cells by HIV. RESULTS CSF MCP-1 levels were significantly higher in patients with (median, 4.99 ng/ml) than in those without (median, 1.72 ng/ml) HIV encephalitis. Elevated CSF MCP-1 concentrations were also found in patients with CMV encephalitis and with concomitant HIV and CMV encephalitis (median, 3.14 and 4.23 ng/ml, respectively). HIV encephalitis was strongly associated with high CSF MCP-1 levels (P = 0.002), which were also correlated to high HIV-1 RNA levels in the CSF (P = 0.007), but not to plasma viraemia. In vitro, productive HIV-1 infection of monocyte-derived macrophages upregulated the secretion of MCP-1. CONCLUSIONS Taken together, these in vivo and in vitro findings support a model whereby HIV encephalitis is sustained by virus replication in microglial cells, a process amplified by recruitment of mononuclear cells via HIV-induced MCP-1.

Trends of HIV-1 and Sexually Transmitted Diseases Among Pregnant and Postpartum Women in Urban Malawi

Abstract: Prevalence rates of HIV-1 and other sexually transmitted diseases (STDs) among pregnant and postpartum women were investigated in sequential cross-sectional studies (1990 1993 and 1994-95) conducted at Queen Elizabeth Central Hospital in Blantyre Malawi. Annual anonymous unlinked testing revealed a linear increase in HIV-1 prevalence among antenatal patients from 2.0% in 1985 to 32.8% in 1996. Analysis of demographic attributes of women enrolled in the 1990 and 1993 surveys of consecutive first-visit antenatal women (n = 6603 and 2161 respectively) and the 1994-95 study of all women giving birth at the hospital during a 6-month period (n = 6964) indicated that HIV-infected women were most likely to be young with fewer pregnancies and be more educated. The highest age-specific HIV prevalence shifted from 20-24 years in 1990 to 30-34 years in 1996 indicating an aging cohort of women who became infected at a younger age. Reported lifetime use of condoms increased from 5.6% in 1990 to 17.5% in 1993 then declined to 4.9% in 1995; condom use was consistently higher among HIV-positive than HIV-negative women. The prevalence of all STDs (syphilis trichomoniasis gonorrhea and genital warts and ulcers) declined significantly during 1990-96 with the most consistent decreases recorded among HIV-positive women. In a follow-up study of 1173 HIV-seronegative postpartum women evaluated for 2302 person-years (average duration 30.9 months) 97 seroconverted (4.21/100 person-years). The seroconversion rate declined steadily from 21.26/100 person-years in 1990 to 1.11/100 person-years in 1994-95. These findings are consistent with those from other sub-Saharan African countries indicating a rapid increase in HIV prevalence followed by stabilization within about 10 years of the onset of the epidemic. The large decline in STD prevalence in the antenatal population suggests that Malawis national AIDS prevention program is having an impact either through improved STD diagnosis and treatment or reduced risk behaviors.

Measuring the impact of HIV on fertility in Africa.

Abstract: Growing evidence indicates that HIV-1 infection is having a measurable impact upon fertility in the countries of sub-Saharan Africa which have been seriously affected by the epidemic. The impact is due to the direct biological effects of HIV on the fecundity of infected women as well as to its indirect effects upon behavior in the general population. Data from case-control studies and theoretical predictions from a model of the proximate determinants of fertility and HIV incidence were used to assess the impact of HIV upon fertility in Africa. Analysis of the data shows that the fertility of HIV-positive women is lower than that of HIV-negative women in all but the youngest age group with the differential increasing with womens age and epidemic duration. Selection for the early start of sexual activity explains the reverse pattern at younger ages. Lower fertility among HIV-positive women causes a population attributable decline in total fertility of 0.4% for each percentage point HIV prevalence in the general female population.

Mechanisms and timing of mother-to-child transmission of HIV-1

Abstract: A growing body of clinical and laboratory evidence supports several possible mechanisms of vertical HIV transmission including maternal disease state and viral load fetal exposure to infected maternal body fluids during pregnancy and delivery and breast feeding. More precise knowledge of the timing of maternal-infant transmission would help identify the periods of greatest risk and suggest approaches to reduce this risk. This article reviews the research literature on intrauterine transmission intrapartum transmission breast feeding and the hypothesized timing of HIV transmission. The research evidence suggests that transmission during late pregnancy and the intrapartum period contributes relatively more to the overall rate of vertical HIV transmission than the early intrauterine period even in populations where breast feeding is the norm and that postnatal transmission through breast feeding confers a substantial additional risk of infection.

Antiretroviral therapies in pregnancy: maternal, fetal and neonatal effects. Swiss HIV Cohort Study, the Swiss Collaborative HIV and Pregnancy Study, and the Swiss Neonatal HIV Study.

Abstract: BACKGROUND: Therapies containing two reverse transcriptase inhibitors (RTI) with or without protease inhibitors are used with increasing frequency in pregnant HIV-infected women. OBJECTIVE: To assess the safety of antiretroviral therapy in pregnant women and their newborns. METHODS: All clinical events and laboratory abnormalities in pregnant women on RTI with or without protease inhibitors and in their newborns were collected through an observational study. RESULTS: A total of 37 HIV-infected pregnant women have given birth to 30 children (by 30 April 1998). All received RTI, which were combined with protease inhibitors in 16 cases. Twelve women became pregnant while on treatment. Drugs used were as follows: zidovudine (n = 33), lamivudine (n = 33), stavudine (n = 4), indinavir (n = 9), ritonavir (n = 4), nelfinavir (n = 2) and saquinavir (n = 2). Adverse events during pregnancy were anaemia (n = 15), elevation of transaminases (n = 4), nausea/vomiting (n = 4), glucose intolerance (n = 2), nephrolithiasis (n = 2), diarrhoea (n = 2), hypertension (n = 1), insulin-requiring diabetes (n = 1). Adverse events in neonates were prematurity (n = 10), anaemia (n = 8), cutaneous angioma (n = 2), cryptorchidism (n = 2), transient hepatitis (n = 1). Non-life-threatening intracerebral haemorrhage occurred in a premature baby (33 weeks gestation) exposed during fetal life to zidovudine-lamivudine-indinavir, and in a term baby exposed to stavudine-lamivudine-indinavir. Extrahepatic biliary atresia occurred in one newborn exposed to zidovudine-lamivudine-indinavir. Maternal viral load was below 400 copies/ml in 18 out of 30 patients who delivered. One case of mother-to-child HIV transmission was identified. CONCLUSIONS: In HIV-infected pregnant women treated with two RTI with or without protease inhibitors, one or more adverse events occurred in 29 out of 37 women and in 14 out of 30 babies. In newborns, frequent prematurity, one case of biliary malformation and one intracerebral haemorrhage in a term baby are of concern. These observations do not preclude combination therapies during pregnancy but emphasize the necessity to maintain updated registers on their safety.

Suppression of plasma viral load below 20 copies/ml is required to achieve a long-term response to therapy.

Abstract: BACKGROUND: Current guidelines state that the goal of antiretroviral therapy for HIV-infected individuals is to suppress plasma viral load (pVL) to below 400 copies/ml. METHODS: Predictors of achieving and maintaining pVL suppression were examined in a randomized trial of combinations of zidovudine, nevirapine and didanosine in patients with CD4+ T cell counts of between 200 and 600 x 10(6) cells/l who were naive to antiretroviral therapy and AIDS-free at enrolment. RESULTS: One hundred and four patients had pVL > 500 copies/ml at baseline and a pVL nadir below 500 copies/ml. Of these, 77 patients experienced an increase in pVL above 500 copies/ml. The median number of days of pVL suppression to below 500 copies/ml was 285 (42) for patients with pVL nadir ) 20 copies/ml (P = 00.0001). The relative risk of an increase in pVL above 500 copies/ml associated with a pVL nadir below 20 copies/ml was 0.11 (P = 0.0001). The relative risks of an increase in pVL above 5000 copies/ml associated with a pVL nadir below 20 copies/ml or between 20 and 400 copies/ml were 0.05 [95% confidence interval (CI), 0.02-0.12] and 0.37 (95% CI, 0.23-0.61) respectively, compared with individuals with a pVL nadir > 400 copies/ml. Individuals with a pVL nadir

Twice weekly tuberculosis preventive therapy in HIV infection in Zambia

Abstract: Figures show that in 1994 25-32% of childbearing women in Zambias urban areas were infected with HIV. Latent tuberculosis (TB) infection is also common in the region. TB is an HIV-associated infection which is both curable and preventable. Evidence also indicates that TB may precipitate the progression of HIV disease through immune activation. A randomized double-blind placebo-controlled trial was conducted to estimate the efficacy of preventive therapy for TB in HIV-infected adults in Lusaka. During a 2-year period 1053 HIV-positive individuals with no evidence of clinical TB were randomly assigned to receive 6 months of isoniazid twice weekly (H) or 3 months of rifampicin twice per week (R) plus pyrazinamide (Z) or a placebo. Therapy was taken twice per week and was self-administered. Study subjects were followed for 1631 person-years for a median of 1.8 years. The treatment of 29 subjects was stopped due to adverse drug reactions. 59 cases of TB and 37 of probable TB were diagnosed during the study period and 185 deaths were reported. 115 subjects (11%) failed to return to the study clinic at any time after enrollment. The incidence of TB was lower among subjects in the H and RZ groups than it was among those receiving placebo as was the incidence of TB/probable TB. The effect of preventive therapy was greater among subjects with a tuberculin skin test (TST) of 5 mm or greater among those with a lymphocyte count of 2x10(9)/l or higher and in those with hemoglobin of 10 g/dl or higher. There was no difference in mortality rates between the preventive therapy and placebo groups. The effect of preventive therapy declined after the first year of the study so that by 18 months the rates of TB in the treated groups were similar to those in the placebo group.

A randomized, community trial of intensive sexually transmitted disease control for AIDS prevention, Rakai, Uganda.

Abstract: An ongoing (1994-98) randomized community-based trial in Ugandas Rakai District is assessing the assumption that intensive sexually transmitted disease (STD) control efforts result in marked declines in HIV/AIDS prevalence. Described in this article are the project design and findings of the first-round baseline survey. 56 communities were grouped into 10 clusters designed to encompass social/sexual networks and clusters within blocks were randomly assigned to the intervention or control arm. All consenting permanent residents of the district are visited in their homes at 10-month intervals where they are administered extensive questionnaires provide urine and vaginal swab samples and are offered mass treatment regardless of symptoms or laboratory testing (single oral dose STD treatment in the intervention arm and anthelmintics and iron folate in the control arm). Both groups receive identical health education condom promotion and serologic counseling services. In the first round of home visits 5834 intervention and 5784 control arm subjects were enrolled representing about 90% of eligible adults. The groups were comparable in terms of sociodemographic and behavioral characteristics and baseline rates of HIV and STDs. 16.9% of subjects were HIV-positive 10.0% had syphilis 23.8% of women had trichomonas and 50.9% had bacterial vaginosis. Detailed STD assessment is expected not only to document the relationship between STD control and HIV but also to identify which STDs confer the greatest population attributable risk for HIV transmission facilitating targeted control efforts in the future.

Discrepant responses to triple combination antiretroviral therapy in advanced hiv disease

Abstract: Objectives To determine the clinical, virological and immunological outcome in a cohort of unselected patients receiving triple combination therapy for more than 1 year. Methods Prospective follow-up of a cohort of 162 unselected, protease inhibitor-naive, antiretroviral-experienced patients with advanced HIV disease, treated with indinavir combined with two nucleoside analogues. Results The mean CD4 cell count and plasma HIV RNA level in the study group at baseline were 69+/-5 x 10(6)/l and 4.75+/-0.07 log10 copies/ml, respectively. Five per cent of patients died prematurely or were lost to follow-up. Fifty-seven per cent of patients responded to therapy, as assessed by a sustained increase in CD4 cell counts above 50 x 10(6)/l and a decrease in plasma HIV RNA greater than 1 log10 copies/ml, throughout 12.1 months of follow-up. Seventeen per cent of patients were immunological and virological non-responders. Twenty-one per cent of patients exhibited discrepant virological and immunological responses to treatment, of whom one-half failed to exhibit significant increases in CD4 cells despite a virological response to therapy and one-half exhibited increased CD4 cell counts in the absence of significant decrease in plasma viral load. The incidence of AIDS-defining events in the latter group of patients was similar to that of responder patients, whereas their incidence was higher in patients who failed to exhibit a virological and immunological response and those who failed to increase CD4 cells despite a significant decrease in viral load. Conclusion Our observations of discrepant immunological and virological responses to treatment raise the issue of the significance of persistent elevated levels of plasma HIV RNA and of the relevance of measurements of plasma viral load for assessing the efficacy of antiretroviral therapy in patients whose CD4 cell counts increase despite the absence of significant decrease in plasma HIV viral load.

The incidence of HIV infection among women using family planning methods in Dar es Salaam Tanzania.

Abstract: A prospective cohort study (1992-95) investigated risk factors for HIV seroconversion among 2471 HIV-negative women attending three large family planning clinics in Dar es Salaam Tanzania. 78.1% of respondents reported only one sexual partner during the follow-up period. Of the 1370 women who completed the study 75 (5.5%) seroconverted. The overall seroconversion incidence rate was 3.4/100 person-years. The risk of HIV seroconversion decreased with age. Significant risk factors for seroconversion included 3 or more sex partners during the study period (age-adjusted relative risk (RR) 4.89; 95% confidence interval (CI) 2.61-9.17); having an uncircumcised husband (adjusted RR 3.60; 95% CI 1.12-11.59); gonorrhea at baseline (adjusted RR 3.51; 95% CI 1.60-7.71); candidiasis at baseline (adjusted RR 1.98; 95% CI 1.17-3.33); and alcohol consumption during the follow-up period (adjusted RR 2.43; 95% CI 1.54-3.82). After controlling for other risk factors the risk of HIV infection was not significantly increased among users of oral contraceptives injectable contraception or the IUD and there was no significant trend associated with increasing duration of use of any of these methods. Despite continued education and counseling condom use remained low in the study population (11.1% at baseline and 23.0% at follow up). These findings suggest a need for interventions aimed at reducing the large number of new HIV infections that continue to occur among women in Tanzania.

The duration of viral suppression during protease inhibitor therapy for HIV-1 infection is predicted by plasma HIV-1 RNA at the nadir

Abstract: Objective: To determine markers that are associated with the durability of virologic response to therapy with HIV protease inhibitors in HIV-infected individuals. Design: This study encompassed two retrospective analyses of the duration of virologic response to protease inhibitor therapy. The first analysis included 29 patients receiving either monotherapy or combination therapy with the protease inhibitor ritonavir whose plasma HIV RNA levels rebounded from the point of greatest decline with mutations associated with resistance to ritonavir. The second analysis included a cohort of 102 patients who initially responded to randomized treatment with either monotherapy with ritonavir or combination therapy with ritonavir and zidovudine. Methods: Durability of response was defined as the time from the initiation of therapy to the point at which plasma HIV RNA displayed a sustained increase of at least 0.6 log 10 copies/ml from the nadir value. In the first analysis, durability of response was analyzed with respect to baseline HIV RNA, HIV RNA at the nadir, and the drop in HIV RNA from baseline to the nadir. In the second analysis, time to rebound was examined using Kaplan-Meier analysis, stratifying by either baseline HIV RNA or HIV RNA at the nadir. Results: In both analyses, the durability of response was not highly associated with either baseline RNA or the magnitude of RNA decline from baseline. Instead, a strong relationship was observed between the durability of response and the nadir plasma HIV-1 RNA value (P < 0.01). The nadir in viral load was generally reached after 12 weeks of randomized therapy. Conclusions: Viral RNA determinations at intermediate timepoints may be prognostic of impending virologic failure of protease inhibitor therapy. Therapeutic strategies that allow intensification of initial antiretroviral regimens in the subset of patients with incomplete virological response before the emergence of high level resistance should be investigated.

HIV-1 genetic subtype A/B recombinant strain causing an explosive epidemic in injecting drug users in Kaliningrad.

Abstract: The objectives were to investigate the molecular epidemiology and genetic structure of the virus strain(s) causing an outbreak of HIV-1 infection in the Kaliningrad province of the Russian Federation and to investigate the relationship of this outbreak to some other emerging HIV-1 epidemics in the countries of the former Soviet Union. A molecular epidemiological investigation was conducted in the city of Kaliningrad amongst individuals recently diagnosed as HIV-1-positive. Samples were also collected from neighbouring Lithuania and from the Ukraine. Incident and population data was collected from official health statistics in Kaliningrad. A standardized questionnaire was administered to newly diagnosed individuals to assess risk factors for HIV-1 infection. For genotyping two regions of the virus (env C2-V3 and gag NCp7) were directly sequenced. The number of newly diagnosed individuals testing seropositive for HIV-1 infection in Kaliningrad rose from less than one per month to more than 100 per month during the period of July--October 1996. A total of 1335 new infections were identified between 1 July 1996 and 30 June 1997. The main reported risk factor for HIV-1 infection (80%) was injecting drug use in particular with a locally produced opiate. Sequence analysis of patient viruses in Kaliningrad (n = 50) showed that the epidemic was caused by a highly homogenous HIV-1 strain recombinant between the genetic subtypes A and B. Comparison with subtype A strains prevalent amongst injecting drug users (IDU) in the Ukraine showed that one of these strains was the direct subtype A parent of the epidemic A/B recombinant strain in Kaliningrad. The HIV-1 epidemic in Kaliningrad probably started from a single source with rapid spread of the virus through the IDU population. The origin of the epidemic strain is a recombination event occurring between the subtype A strain virus prevalent among IDU in some southern CIS countries and a subtype B strain of unknown origin. (authors)

Prevention of vertical HIV transmission: additive protective effect of elective Cesarean section and zidovudine prophylaxis. Swiss Neonatal HIV Study Group.

Abstract: To study the effect of elective Cesarean section and zidovudine prophylaxis on vertical HIV transmission.

Early regression of cervical lesions in HIV-seropositive women receiving highly active antiretroviral therapy.

Abstract: Objective: Advanced HIV disease is associated with a high prevalence of cervical squamous intra-epithelial lesions (SIL) and of infection with oncogenic human papillomavirus (HPV) genotypes. Triple-combination antiretroviral therapy results in decreased plasma HIV viral load, increased CD4 cell counts and partial restoration of immune functions in patients with severe HIV disease. This study investigated the outcome of SIL in HIV-seropositive women undergoing triple combination antiretroviral treatment. Methods: Forty-nine women who started triple-combination antiretroviral therapy, including a protease inhibitor, were examined prior to and after a median 5-month treatment. We collected cytological, colposcopic and histologic data and assessed the presence of HPV DNA in cervical smears by PCR and Southern blot hybridization (SBH). Results: The prevalence of SIL decreased from 69 to 53% during follow-up (P < 0.0001). Among 13 women who initially presented with high-grade SIL, conversion to lower grade was observed in two women and a full regression to normality was observed in one. Cytology also returned to normality in nine out of 21 women who initially presented with low-grade SIL. The high prevalence of HPV infection as detected by SBH and PCR was similar at the first and second examinations and the same high-risk viral genotypes were identified at both examinations in all infected patients but one. There was a higher increase in absolute CD4 cells in the subgroup of patients whose lesions regressed (99 versus 50 × 10 6 /l, P = 0.03). Conclusion: Our observations demonstrate that active antiretroviral therapy may result in a reduced prevalence of cervical squamous intra-epithelial lesions despite the absence of clearance of HPV infection.

Two doses of PMPA protect newborn macaques against oral simian immunodeficiency virus infection.

Abstract: Background:A G-to-A transition in the 3′ untranslated region (UTR) of stromal cell-derived factor (SDF)-1 gene (SDF1-3′A) has recently been described, which in the homozygous state was associated with delayed disease progression.Objective:To analyse the effect of the SDF-1 polymorphism on AIDS-free

Decreasing incidence of HIV and sexually transmitted diseases in young Thai men: evidence for success of the HIV/AIDS control and prevention program.

Abstract: A program promoting 100% condom use has been in place in Thailand since 1991 in an attempt to reduce the incidence and prevalence of HIV/AIDS and other sexually transmitted diseases (STDs). 2 cohorts of men aged 19-23 years conscripted by lottery for military service in northern Thailand were enrolled in longitudinal studies of HIV and STD infections in 1991 and 1993 and followed at 6-month intervals for incident HIV and STD through May 1995. The 1991 and 1993 cohorts were comprised of 2417 and 1669 men respectively. HIV incidence was determined by serology while incident STD was reported by conscripts as diagnosed by health care providers. Between 1991-93 and 1993-95 HIV incidence fell from 2.48 infections per 100 person-years to 0.55/100 and STD incidence declined by a factor of 10. Behavioral risk factors for incident STD infections included a history of prior STD and sex with girlfriends and sex workers. Inconsistent condom use remained a strong predictor of incident STD among brothel visitors. Previously-reported risk factors in 1991-93 such as illicit drug use the frequency and cost of brothel visits and low socioeconomic status were not associated with incident STD or HIV in 1993-95.

Protease inhibitor combination therapies and perceptions of gay men regarding AIDS severity and the need to maintain safer sex.

Abstract: Background Advances in the treatment of HIV disease with protease inhibitor combination therapies have been widely documented in the media. Objectives To investigate perceptions concerning the severity of HIV/AIDS and the need to maintain safer sex practices in the light of recent HIV treatment advances. Methods A survey eliciting demographic characteristics, HIV serostatus and treatment information, and HIV/AIDS severity and safer sex perceptions was administered to a community sample of 379 homo-/bisexual men who reported awareness of combination therapy regimens. Results Ten per cent of all respondents agreed or strongly agreed with the statement that 'AIDS is now very nearly cured' and 13% felt that the threat of AIDS is less serious than in the past. HIV-positive men were more likely to perceive AIDS as a less serious threat or as very nearly cured. Overall, 8% of men in the sample indicated that they practice safer sex less often since new AIDS treatments came along; 18% of HIV-positive men on combination therapy regimens said they practice safer sex less frequently since treatments have advanced. Regardless of serostatus, nearly 20% of men indicated they would stop practicing safer sex if an AIDS cure was announced. Conclusion It is essential to integrate behavior change counseling into HIV treatment programs and to temper optimism concerning treatment advances with recognition that the threat of HIV/AIDS remains great.