Hepatitis C: global epidemiology and strategies for control.

It is estimated that globally there are approximately 100 million persons with serological evidence of current or past HCV infection, and that HCV causes about 700 000 deaths each year. The prevalence of infection is the highest in lower and middle income countries, in which a significant number of past infections were caused by iatrogenic transmission and sub-optimal injection safety. In contrast, in developed countries, infections are caused mainly by high-risk exposures and behaviours among specific populations, such as persons who inject drugs. Recently, new direct antiviral activity (DAA) oral drugs with high rates of cure over short duration, which are well tolerated, have made chronic hepatitis C a curable condition. The extraordinary clinical performance of DAAs and recent substantial price reductions and expansion in access in resource-limited settings has provided new impetus for potential control and elimination of hepatitis C as a public health threat. We review the global epidemiology of HCV and the opportunities for preventative and treatment interventions to achieve global control of HCV infection. We also summarize the key elements of the World Health Organization's first-ever global health sector strategy for addressing the viral hepatitis pandemic.

Wide variation in estimates of global prevalence and burden of chronic hepatitis B and C infection cited in published literature.

To evaluate the extent of heterogeneity in global estimates of chronic hepatitis B (HBV) and C (HCV) cited in the published literature, we undertook a systematic review of the published literature. We identified articles from 2010 to 2014 that had cited global estimates for at least one of ten indicators [prevalence and numbers infected with HBV, HCV, HIV-HBV or HIV-HCV co-infection, and mortality (number of deaths annually) for HBV and HCV]. Overall, 488 articles were retrieved: 239 articles cited a HBV-related global estimate [prevalence (n = 12), number infected (n = 193) and number of annual deaths (n = 82)]; 280 articles had HCV-related global estimates [prevalence (n = 86), number infected (n = 203) and number of annual deaths (n = 31)]; 31 had estimates on both HBV and HCV; 54 had HIV-HBV co-infection estimates [prevalence (n = 42) and number co-infected (n = 12)]; and 68 had estimates for HIV-HCV co-infection [prevalence (n = 40) and number co-infected (n = 28)]. There was considerable heterogeneity in the estimates cited and also a lack of consistency in the terminology used. Although 40% of 488 articles cited WHO as the source of the estimate, many of these were from outdated or secondary sources. Our findings highlight the importance of clear and consistent communication from WHO and other global health agencies on current consensus estimates of hepatitis B and C burden and prevalence, the need for standardisation in their citation, and for regular updates.

Sexual risk behaviours and sexual health outcomes among heterosexual black Caribbeans: comparing sexually transmitted infection clinic attendees and national probability survey respondents.

We compared sociodemographic characteristics, sexual risk behaviours and sexual health experiences of 266 heterosexual black Caribbeans recruited at a London sexual health clinic between September 2005 and January 2006 with 402 heterosexual black Caribbeans interviewed for a British probability survey between May 1999 and August 2001. Male clinic attendees were more likely than men in the national survey to report: ≥10 sexual partners (lifetime; adjusted odds ratio [AOR]: 3.27, 95% confidence interval [CI]: 1.66-6.42), ≥2 partners (last year; AOR: 5.40, 95% CI: 2.64-11.0), concurrent partnerships (AOR: 3.26, 95% CI: 1.61-6.60), sex with partner(s) from the Caribbean (last 5 years; AOR: 7.97, 95% CI: 2.42-26.2) and previous sexually transmitted infection (STI) diagnosis/diagnoses (last 5 years; AOR: 16.2, 95% CI: 8.04-32.6). Similar patterns were observed for women clinic attendees, who also had increased odds of termination of pregnancy (AOR: 3.25, 95% CI: 1.87-5.66). These results highlight the substantially higher levels of several high-risk sexual behaviours among UK black Caribbeans attending a sexual health clinic compared with those in the general population. High-risk individuals are under-represented in probability samples, and it is therefore important that convenience samples of high-risk individuals are performed in conjunction with nationally representative surveys to fully understand the risk behaviours and sexual health-care needs of ethnic minority communities.

Patterns and predictors of the use of different antiretroviral drug regimens at treatment initiation in the UK.

BACKGROUND: We describe the patterns of antiretroviral drug use at treatment initiation from 1996 to 2005 in a large UK multicentre cohort. METHODS: We examined trends over time and across 10 clinical sites in stage of disease and type of antiretroviral therapy (ART). Multivariable regression was used to identify factors associated with the CD4 cell count at ART initiation, and with the choice of a protease inhibitor (PI) over a nonnucleoside reverse transcriptase inhibitor (NNRTI), and use of nevirapine over efavirenz. RESULTS: A total of 14 252 patients initiated ART, of whom 54% had a CD4 count <200 cells/microL. The most important predictors of starting ART at a lower CD4 cell count were being male, nonwhite, and heterosexual or an injecting drug user (P<0.0001). Among those starting ART, the use of highly active ART increased from 23% in 1996 to >96% from 2000 onwards. There were differences over time and across the clinics in the use of PIs vs. NNRTIs, in the choice of specific PIs, NNRTIs and nucleoside reverse transcriptase inhibitor (NRTI) backbone, and in the rate at which prescribing practices changed. CONCLUSIONS: Clinic site and calendar year were important determinants of choice of drug at ART initiation, whereas clinical and demographic characteristics were more important in influencing the CD4 cell count at initiation of ART.

Incidence and risk factors for immune reconstitution inflammatory syndrome in an ethnically diverse HIV type 1-infected cohort.

BACKGROUND: It is estimated that 10%-25% of patients who start highly active antiretroviral therapy (HAART) experience immune reconstitution inflammatory syndrome (IRIS). Our objective was to determine the incidence, clinical spectrum, and predictors of IRIS in an ethnically diverse cohort of patients initiating HAART. METHODS: A retrospective study of all patients starting HAART between 1 January 2000 and 31 August 2002 at a human immunodeficiency virus (HIV) clinic in London was performed. All laboratory measurements and data on antiretroviral therapies were obtained from the clinic database. Medical records were reviewed to identify clinical events consistent with IRIS during the 6 months after HAART was initiated. RESULTS: A total of 199 patients were included, of whom 50.8% were male, 59.3% were black African, 29.1% were white, and 10.5% were black Caribbean. The median baseline CD4 cell count and HIV RNA load were 174x10(6) cells/L (interquartile range [IQR], 82-285x10(6) cells/L) and 37,830 copies/mL (IQR, 4809-149,653 copies/mL), respectively. Forty-four patients (22.7%) experienced an IRIS event at a median of 12 weeks after HAART initiation (IQR, 4-24 weeks after initiation); 22 events (50%) involved genital herpes, 10 (23%) involved genital warts, 4 (9.0%) involved molluscum contagiosum, and 4 (9.0%) involved varicella zoster virus infection. Five patients had mycobacterial infections, 4 had hepatitis B, 1 had Pneumocystis jirovecci infection, and 1 had Kaposi sarcoma. The strongest independent predictors of IRIS were younger age at initiation of HAART (P=.003), baseline CD4 cell percentage of <10% (odds ratio [OR], 2.97; IQR, 1.17-7.55) compared with >15%, and ratio of CD4 cell percentage to CD8 cell percentage of <0.15 (OR, 3.45; 95% confidence interval, 1.27-9.1) compared with >0.3. CONCLUSIONS: Approximately one-quarter of patients who start HAART experience an IRIS event. The majority are dermatological, in particular genital herpes and warts. Patients with advanced immunodeficiency at HAART initiation are at greatest risk of developing IRIS and should be appropriately screened and monitored.

Prevalence of hepatitis C in an ethnically diverse HIV-1-infected cohort in south London.

OBJECTIVES: There is limited information on the prevalence of and risk factors for hepatitis C virus (HCV) infection among HIV-1-infected patients in the UK. Our objective was to determine the prevalence of HCV infection among an ethnically diverse cohort of HIV-infected patients in south London, and to extrapolate from these data the number of co-infected patients in the UK. METHODS: A total of 1017 HIV-1-infected patients who had attended King's College Hospital HIV clinic between September 2000 and August 2002 were screened for HCV antibody using a commercial enzyme-linked immunosorbent assay (ELISA). Positive results were confirmed by polymerase chain reaction (PCR) or recombinant immunoblot assay. Demographic, clinical and laboratory data were obtained from the local computerized database and medical records. We applied our HCV prevalence rates in the different HIV transmission groups to the estimated number of HIV-infected persons in these groups in the UK, to obtain a national estimate of the level of HIV-HCV co-infection. RESULTS: Of the 1017 HIV-1-infected patients, 407 (40%) were white men, 158 (15.5%) were black African men, 268 (26.3%) were black African women, and 61 (6%) and 26 (2.6%) were black Caribbean men and women, respectively. Heterosexual exposure was the most common route of HIV acquisition (53.5%), followed by men having sex with men (36.9%), and current or previous injecting drug use (IDU) (7.2%). The overall prevalence of HCV co-infection was 90/1017 (8.9%), but this varied substantially according to route of transmission, from 82.2% among those with a history of IDU (which accounted for 67% of all HCV infections), to 31.8% in those who had received blood products, to 3.5% and 1.8% in those with homosexually and heterosexually acquired infection, respectively. Multivariate logistic regression analysis identified several independent risk factors for HCV infection: a history of IDU [odds ratio (OR) = 107.2; 95% confidence interval (CI) = 38.5-298.4], having received blood products (OR = 16.5; 95% CI = 5.1-53.7), and either being from a white ethnic group (OR = 4.3; 95% CI = 1.5-12.0) or being born in Southern Europe (OR = 6.7; 95% CI = 1.5-30.7). Based on the 35,473 known HIV-1-infected persons in the UK and the 10 997 estimated to be unaware of their status, we projected that there are at least 4136 HIV-HCV co-infected individuals in the UK and 979 who are unaware of their status. CONCLUSIONS: Overall, 9% of our cohort was HIV-HCV co-infected. The prevalence was highest among intravenous drug users (82%), who accounted for most of our HCV cases, and lowest among heterosexual men and women from sub-Saharan Africa and the Caribbean [< 2%]. Our estimate that a significant number of co-infected persons may be unaware of their HIV and HCV status, highlights an urgent need to increase the uptake of HCV and HIV testing, particularly among injecting drug users, to reduce the risk of onward transmission.

Ethnic differences in stage of presentation of adults newly diagnosed with HIV-1 infection in south London.

OBJECTIVES: To establish whether there were ethnic differences in demographic characteristics, the stage at HIV diagnosis and reasons for and location of HIV testing between 1998 and 2000 in a large ethnically diverse HIV-1-infected clinic population in south London in the era of highly active antiretroviral therapy. METHODS: A retrospective review was carried out of all persons >18 years old attending King's College Hospital with a first positive HIV-1 test between 1 January 1998 and 31 October 2000, and of a random sample of patients attending St Thomas' hospital with a first positive HIV-1 test in the same period. Demographic data, details of reasons for and site of HIV test, clinical stage, CD4 lymphocyte count and HIV-1 viral load at HIV diagnosis were abstracted from the local database and medical records. Comparisons were made according to ethnic group (white, black African and black Caribbean) and over time (1998, 1999 and 2000). RESULTS: Of the 494 patients with new HIV-1 diagnoses between January 1998 and December 2000, 179 (36.2%) were white, 270 (54.7%) were black African and 45 (9.1%) were black Caribbean. There were significant differences across the ethnic groups in HIV risk group, reasons for and site of HIV testing, and clinical and CD4 stage at diagnosis. Among whites, 72.6% were men who had sex with men, 3.4% injecting drug users and 21.2% heterosexuals, compared to 2.2%, 0.4% and 93.3% among black Africans, and 28.9%, 0% and 68.9% among black Caribbeans (P<0.001). Black Africans were more likely to present with an AIDS diagnosis (21.3%) and a lower CD4 cell count [223 cells/microL; interquartile range (IQR) 88-348] compared to both whites (9.9%; 358 cells/microL; IQR 151-508) and black Caribbeans (17.9%; 294 cells/microL; IQR 113-380), who were intermediate between whites and black Africans in their stage of presentation. There was a statistically nonsignificant trend with time, between 1998 and 2000, towards earlier diagnosis based on the CD4 cell count in whites (323 and 403 cells/microL) and black Caribbeans (232 and 333 cells/microL), but a later diagnosis in black Africans (233 and 175 cells/microL). The majority of black Africans were HIV-tested as a result of suggestive symptoms or antenatal screening (58.4%) rather than because of perceived risk (40.5%), in contrast to the situation in whites (24.1% vs. 71.7%, respectively) or black Caribbeans (34.5% vs. 65.5%, respectively) (P<0.001). We found no significant differences across ethnic groups in age, HIV-1 viral load or year of HIV diagnosis. CONCLUSIONS: Black Africans continue to present with more advanced HIV disease than whites or black Caribbeans, with no evidence of any trend towards earlier diagnosis. Future educational campaigns designed to promote the uptake of HIV testing among black Africans and black Caribbeans will need to address the multiple barriers to testing, including misperception of risk, stigma and ready access to testing.

CD4 responses to conserved HIV-1 T helper epitopes show both negative and positive associations with virus load in chronically infected subjects.

Characterization of immune responses to immunodominant CD4 epitopes in HIV-1 that are associated with control of HIV infection could be used to strengthen the efficacy of polyepitope HIV vaccines. We measured both the proliferative and the CD4 interferon (IFN)-gamma and interleukin (IL)-2 cytokine responses specific for 11 previously identified HIV-1 T helper epitopes in 10 HIV-infected non-progressors (LTNPs) (infected for a median of 15 years with a stable CD4 count of >500 cells x 10(6)/l), and seven slow progressors (SPs) (infected for a median of 15 years with a CD4 count that had declined to <500 cells x 10(6)/l). Both groups were antiretroviral treatment-naive at the time of evaluation. The median virus load of SP group was higher than that of the LTNP group (P = 0.0002). The CD4 response to a peptide pool representing all potential CD4 Gag epitopes and to Gag p24 protein was also studied. Compared to SPs, LTNPs had higher numbers of Gag-specific IFN-gamma+IL-2+ CD4s (P = 0.0059). The Gag-specific cytokine and proliferative responses correlated inversely with virus load (P = 0.03 and 0.0002, respectively), highlighting the potential importance of this response in immunity to HIV. A direct correlation was noted between proliferation and the Gag-specific IL-2 (P = 0.0053) rather than IFN-gamma response (P = 0.1336), demonstrating that the proliferation assay reflected the IL-2 rather than the IFN-gamma secreting capacity of CD4 cells. Several subjects with diverse class II DRB1 alleles responded, confirming the 11 selected peptides to be both antigenic and conserved. CD4 cytokine responses to one Gag and two conserved Pol peptides correlated negatively with virus load. The cytokine response to two additional Pol peptides correlated positively with virus load. The data indicate that there is not an absolute correlation between the CD4 immune response to conserved and broadly antigenic helper T cell epitopes in HIV non-progression.

Epidemiological risk factors for hypersensitivity reactions to abacavir.

We investigated risk factors for hypersensitivity reactions (HSR) to abacavir in a case-control study. In a multivariate analysis, white race [odds ratio (OR), 5.16; 95% confidence interval (CI), 1.16-22.97] and a higher CD8 cell count at initiation of abacavir (>850 vs. < or =850 cells: OR, 3.74; 95% CI, 1.19-11.77) were found to be significantly associated with the development of HSR. Age, gender, stage of disease, prior antiretroviral exposure and type of concurrent antiretroviral therapy were not associated with HSR. Differences in predisposition to HSR according to ethnicity and baseline CD8 cell count may be explained by the reported MHC genetic associations with HSR.

Impact of human immunodeficiency virus (HIV) infection on the progression of liver fibrosis in hepatitis C virus infected patients.

OBJECTIVES: To compare the rate of hepatic fibrosis progression in hepatitis C virus (HCV) infected and human immunodeficiency virus (HIV)-HCV coinfected patients, and to identify factors that may influence fibrosis progression. PATIENTS AND METHODS: A total of 153 HCV infected and 55 HCV-HIV coinfected patients were identified from two London hospitals. Eligible patients had known dates of HCV acquisition, were HCV-RNA positive, and had undergone a liver biopsy, which was graded using the Ishak score. Univariate and multivariate logistic regression analyses were used to identify factors associated with fibrosis progression rate and the development of advanced fibrosis (stages 3 and 4). RESULTS: The estimated median fibrosis progression rate was 0.17 units/year (interquartile range (IQR) 0.10-0.25) in HIV-HCV coinfected and 0.13 (IQR 0.07-0.17) in HCV monoinfected patients (p=0.01), equating to an estimated time from HCV infection to cirrhosis of 23 and 32 years, respectively. Older age at infection (p<0.001), HIV positivity (p=0.019), higher alanine aminotransferase (ALT) level (p=0.039), and higher inflammatory activity (p<0.001) on first biopsy were all independently associated with more rapid fibrosis progression. ALT was correlated with histological index (r=0.35, p<0.001). A CD4 cell count < or =250 x 10(6)/l was independently associated with advanced liver fibrosis (odds ratio 5.36 (95% confidence interval 1.26-22.79)) and was also correlated with a higher histological index (r=-0.42, p=0.002). CONCLUSION: HIV infection modifies the natural history of HCV by accelerating the rate of fibrosis progression by 1.4 fold, and the development of advanced fibrosis threefold. A low CD4 cell count was independently associated with advanced disease and correlated with higher histological index, which suggests that early antiretroviral therapy may be of benefit in slowing HCV progression in coinfected patients.

Comparison between HIV- and CMV-specific T cell responses in long-term HIV infected donors.

The mechanisms underlying non-progression in HIV-1 infection are not well understood; however, this state has been associated previously with strong HIV-1-specific CD8+ T cell responses and the preservation of proliferative CD4+ T cell responses to HIV-1 antigens. Using a combination of interferon-gamma (IFN-gamma) ELISpot assays and tetramer staining, the HIV-1-specific CD8+ T cell populations were quantified and characterized in untreated long-term HIV-1-infected non-progressors and individuals with slowly progressive disease, both in relation to CD4+ T cell responses, and in comparison with responses to cytomegalovirus (CMV) antigens. High levels of CD8+ T cell responses specific for HIV-1 or CMV were observed, but neither their frequency nor their phenotype seemed to differ between the two patient groups. Moreover, while CMV-specific CD4+ T cell responses were preserved in these donors, IFN-gamma release by HIV-1-specific CD4+ T cells was generally low. These data raise questions with regard to the role played by CD8+ T cells in the establishment and maintenance of long-term non-progression.

Low prevalence of antiretroviral drug resistance among HIV-1 seroconverters in London, 1984-1991.

OBJECTIVES: To examine the prevalence of resistance mutations and natural polymorphisms to reverse transcriptase (RT) and protease inhibitors in a cohort of patients with defined seroconversion dates. METHODS: Eligible patients were those attending an HIV centre in North London who seroconverted from HIV negative to positive status between 01/01/85 and 31/12/91 (n=104). Genotypic resistance analysis was performed on the first positive serum sample after seroconversion and before use of antiretroviral therapy using population-based sequencing of RT-PCR fragments and rule-based sequence interpretation (Vircogen). RESULTS: Protease and RT sequences were successfully amplified from only 37 (35.6%) of the 104 seroconverters. Only one patient who seroconverted in August 1991 showed any evidence of significant mutations in the RT region, and this was associated with resistance to zidovudine (ZDV) (215Y and 210W). An additional patient who seroconverted in July 1991 had a TOR mutation and was classified as having intermediate resistance to ZDV. No spontaneous mutations were detected in the protease region. CONCLUSIONS: Overall only 2 (5%) of these treatment-naïve individuals were infected with HIV variants resistant to ZDV. Although the data at present do not support the need for pretreatment genotyping, there is a need for continued surveillance of the frequency of resistance mutations in antiretroviral naïve patients since the introduction of highly active antiretroviral therapy.

Variable fate of virus-specific CD4(+) T cells during primary HIV-1 infection.

Impairment of CD4(+) T lymphocyte responses to human immunodeficiency virus (HIV)-derived antigens is the classic immunological defect observed during the chronic phase of HIV-1 infection. Early intervention with potent antiretroviral therapy (ART) can preserve HIV-specific CD4(+) T lymphocyte reactivity, providing indirect evidence that such responses are mounted during primary infection and subsequently lost in the majority of infected individuals. Here, we demonstrate early and dramatic expansions of functional HIV-specific CD4(+) T lymphocyte frequencies directly ex vivo. These responses are initially of broad specificity, and can disappear rapidly during the natural course of primary infection. This process of loss is variable, such that the rapidity and extent of functional compromise differs between individuals. Institution of ART during these early phases of HIV-1 infection preserves patterns of functional reactivity within the HIV-specific CD4(+) T lymphocyte population. However, there was no evidence for the restoration of deleted responses. These findings indicate that, in some individuals at least, ART must be administered within a narrow window of opportunity during primary HIV-1 infection to effect substantial immune preservation.

Does an HIV clinical trial information booklet improve patient knowledge and understanding of HIV clinical trials?

OBJECTIVES: To evaluate the impact of an information booklet on HIV clinical trials, Clinical Trials in HIV and AIDS: Information For People Who Are Thinking About Joining a Trial, in addition to the standard trial information (SI) on patients' knowledge; understanding and attitudes about clinical trials; and to investigate patients' motivations and reasons for enrolling or not enrolling in a clinical trial. METHODS: Fifty HIV-1 positive patients who attended the HIV clinic at a west London hospital were randomized to receive either SI alone (n = 27) or SI and a 16 page information booklet explaining the principles and procedures of HIV clinical trials (n = 23). A self-administered questionnaire was used at baseline to assess past experience and attitudes to clinical trials (10 questions), knowledge and understanding of HIV treatments (8 questions) and clinical trials (11 questions). At 2-6 months after randomization, a second interviewer-administered questionnaire addressed the patient's assessment of the usefulness and comprehensiveness of the information provided by the SI and information booklet, whether or not the patient had enrolled in a clinical trial and reasons for enrolling/not enrolling, knowledge of specific aspects of the trial protocol the patient was eligible to join (13 questions) and general knowledge of clinical trial procedures (repeat of 11 baseline questions). Changes in the attitudes and scores on knowledge and understanding of clinical trials were compared for the two groups. RESULTS: In both groups, patient knowledge of clinical trial procedures improved significantly over the study period. The median score increased from 30 at baseline to 35/44 at follow-up (SI only) vs. 24-31/44 (SI plus booklet), but this did not differ significantly between the two groups. However, knowledge of the specific trial protocol was poor [median score 13/25, interquartile range (IQR) 8-14], and there was no difference in the scores for the two groups. The prime motivations for joining a clinical trial were to benefit personal health and to gain access to new treatments. Potential side-effects were the main concern of prospective trial participants. CONCLUSIONS: This small trial shows that, while the patients' general knowledge and understanding of clinical trials improved over time, this was not improved by the information booklet and recollection of the details of the relevant trial protocol remained poor.

The changing pattern of AIDS-defining illnesses with the introduction of highly active antiretroviral therapy (HAART)in a London clinic.

OBJECTIVES: To quantify the progressive impact of combination antiretroviral therapy (ART) on the incidence of AIDS-defining illnesses (ADIs) over a 9-year period. METHODS: Retrospective cohort study. Eligible patients were 1538 AIDS-free, HIV-1-positive patients attending a large HIV clinic in west London who were at risk of developing AIDS because their CD4 count had declined to < or =350 x 10(6)/l cells during the period 1 January 1990 and 31 December 1998. Incidence rates for the 12 most frequent ADIs were compared for two time periods, 1990-1995 (pre-HAART) and 1996-1998 (post-HAART), using Poisson regression methods. Multivariate Poisson regression models were used to examine the contribution of ART and HAART to any observed temporal trends in incidence rates. RESULTS: After a median follow-up of 35 months, 450 (29%) patients had developed AIDS. Between the two time periods there was a significant decrease in the incidence of Pneumocystis carinii pneumonia (PCP) by 35% (4.11 per 100 person-years in 1990-1995 vs. 2.67 in 1996-1998;P= 0.007), Kaposi's sarcoma by 34% (3.27 vs. 2.17;P= 0.022) and cryptosporidiosis by 60% (0.76 vs. 0.31;P= 0.029). A non-significant reduction in incidence was observed for cryptococcosis by 45% (0.81 vs. 0.45;P= 0.11), oesophageal candidiasis by 29% (3.34 vs. 2.39;P= 0.053) and mycobacterium avium complex by 18% (1.58 vs. 1.29;P= 0.4), and a non-significant increase was observed for tuberculosis by 17% (0.62 vs. 0.73;P= 0.66) and non-Hodgkins lymphoma (NHL) by 51% (0.43 vs. 0.65;P= 0.31). The incidence of cerebral toxoplasmosis, cytomegalovirus, recurrent bacterial chest infections and dementia remained stable. There was a clear stepwise reduction in the incidence of PCP, Kaposi's sarcoma and cryptosporidiosis with the use of non-H AART and HAART regimens relative to no ART. In a multivariate analysis, the use of ART and HAART explained the progressive decrease in incidence of PCP and Kaposi's sarcoma. CONCLUSIONS: The incidence of most ADIs has decreased over the last 9 years. The striking reduction in the inci-dence of PCP and Kaposi's sarcoma since 1996 can be attributed to the use of combination ART and particularly HAART. The non-significant increase in the incidence of NHL and tuberculosis needs confirmation in other patient cohorts.

Incidence and risk factors for the development of indinavir-associated renal complications.

OBJECTIVES: To describe the incidence and risk factors for the development of indinavir-associated renal complications (IRC), and subsequent clinical outcome. PATIENTS AND METHODS: This was a retrospective cohort study based on two large HIV centres in London. Eligible patients received indinavir for at least 1 week between 1 December 1995 and 28 February 1999. Development of IRC was ascertained by case-note review. Multivariate logistic regression and Cox Proportional Hazard's model analysis were used to determine independent risk factors for the development of IRC. RESULTS: 781 patients were eligible. Median CD4 count and viral load at indinavir initiation were 117 x 10(6) cells/L and 47 332 copies/mL, respectively. Median indinavir exposure was 53 weeks (IQR: 20-83). Many patients received other potentially nephrotoxic drugs during indinavir treatment: co-trimoxazole (46%), aciclovir (33%) or both (20%). Overall IRC incidence was 7.3% (6.7 per 100 person-years indinavir exposure). Cases presented with loin pain (58%), renal colic (42%) or dysuria (19%). Identified precipitating events (26%) included fluid depletion or altered indinavir regimen. In the majority of cases indinavir therapy was continued and there was no progressive rise in creatinine levels. In the multivariate analysis, for indinavir treatment >74 weeks there was a reduced risk of developing IRC (OR = 0.23, 95% CI 0.09-0.57, P = 0.001). Concomitant aciclovir increased the IRC risk (OR = 1.99, 95% CI 1.14-3.51, P = 0.016). Factors not associated with outcome were age, gender, ethnicity, baseline CD4 count and viral load, concomitant co-trimoxazole, or use of specific antiretrovirals. CONCLUSION: An overall IRC incidence of 7.3% was identified. Concomitant aciclovir doubled the risk of IRC and we therefore recommend careful monitoring when prescribing aciclovir with indinavir. A precipitating event was identified in 26% of IRC cases, many of which could have been avoided.

The metabolic toxicities of antiretroviral therapy.

Since the adoption of highly active antiretroviral therapy (HAART) in the mid-1990s, certain metabolic toxicities have been increasingly recognized. These include a fat redistribution syndrome (lipohypertrophy, lipoatrophy), hyperlipidaemia, altered glucose metabolism and insulin resistance, mitochondrial toxicity (presenting as anaemia, myopathy, pancreatitis, neuropathy, hepatic steatosis and lactic acidosis), and bone density abnormalities (osteoporosis and osteonecrosis). Metabolic complications are principally reported with protease inhibitors and nucleoside reverse transcriptase inhibitors, but may be seen with all classes of antiretroviral therapy. In this review, we summarize the epidemiology, pathogenesis and management of these various toxicities.

An association of disseminated Mycoplasma fermentans in HIV-1 positive patients with non-Hodgkin's lymphoma.

We examined the relationship between the haematogenous dissemination of Mycoplasma fermentans and non-Hodgkin's lymphoma (NHL) in 265 HIV-1 positive patients. A polymerase chain reaction (PCR) assay was used to detect M. fermentans in peripheral blood mononuclear cells (PBMCs) from 50 patients enrolled consecutively from an HIV outpatient clinic in 1991 (cohort 1), 56 patients with lower respiratory tract infection who underwent bronchoscopy in 1992 (cohort 2), and 159 patients who were enrolled into a natural history cohort study in 1994 (cohort 3). The incidence of NHL among the patients was determined in 1998. The PBMCs of 29 patients (10.9%) were positive for M. fermentans (8 in cohort 1, 13 in cohort 2 and 8 in cohort 3) and 11 patients (4.2%) developed NHL which was confirmed histologically (3 in cohort 1, 4 in cohort 2 and 4 in cohort 3). We found a statistically significant association between the presence of M. fermentans and the development of NHL in the combined cohort (risk ratio [RR]=6.78 [95% confidence interval (CI) 2.21--20.84], P=0.003 Fisher's exact test [FET]). This association remained significant even after adjustment in a multivariate analysis for CD4 cell count and HIV disease status at the time of M. fermentans testing (RR=7.97 [95% CI=2.16--29.47], P=0.002).

Comparison of virologic, immunologic, and clinical response to five different initial protease inhibitor-containing and nevirapine-containing regimens.

CONTEXT: The effectiveness of different protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors outside the setting of clinical trials has not been well described. OBJECTIVES: To compare five different PI-and nevirapine (NVP)-containing regimens on virologic, immunologic, and clinical outcomes and treatment discontinuation. DESIGN AND SETTING: Observational cohort study based on an HIV clinic in London. PATIENTS: A total of 690 patients who received either saquinavir hard gel (SQV HG) (n = 183), indinavir (IDV) (n = 189), nelfinavir (NFV) (n = 109), ritonavir (RTV) (n = 42), ritonavir with saquinavir hard gel (RTV/SQV HG) (n = 45), or NVP (n = 122) as part of an initial PI-or NVP-containing treatment regimen between November 1994 and December 1998. A total of 351 (51%) patients had prior exposure to nucleoside reverse transcriptase inhibitors (NRTIs). MAIN OUTCOME MEASURES: The main outcome measures were virologic undetectability, subsequent virologic rebound, CD4 cell count rise, development of AIDS, and treatment discontinuation. All analyses were stratified for year of initiation of the PI-or NVP-containing regimen. RESULTS: Overall, 63% of patients attained an undetectable viral load (VL) within 6 months of starting their PI or NVP regimen. The adjusted relative hazard (95% confidence interval [CI]) for an undetectable VL relative to SQV HG was (in rank order): 2.77 (CI: 1.84-4.17) for NFV, 2.54 (CI: 1.81-3.57) for IDV, 2.43 (CI: 1.52-3.87) for RTV, 2.08 (CI: 1.28-3.37) for RTV/SQV HG, and 1.96 (CI: 1.35-2.85) for NVP. Forty-nine percent of patients experienced VL rebound within 12 months of initial attainment of undetectability, but relative to SQV HG, this did not differ significantly across the different PI and NVP regimens. The CD4 cell count response and rate of AIDS events were also similar across the different regimens. No independent predictors of VL undetectability were identified, but prior NRTI exposure was associated with VL rebound, and a lower baseline VL and CD4 cell count were associated with a reduced CD4 count response. The frequency (95% CI) of treatment discontinuation differed across the regimens; at 6 months, it was lowest for NFV (18% [CI: 13%-24%]), IDV (25% [CI: 22%-29%]), and NVP (28% [CI: 22%-34%]) and highest for RTV (41% [CI: 31%-52%]) and SQV HG (52% [CI: 48%-57%]). CONCLUSIONS: Although PI- and NVP-containing regimens were similar in their CD4 cell count response and rates of subsequent VL rebound, differences were observed in time to VL undetectability and discontinuation rates relative to SQV HG. SQV HG was consistently inferior to the other PIs and NVP. The use of NFV and IDV was associated with the highest rates of undetectability, and together with NVP, the lowest rates of discontinuation.

Direct ex vivo analysis reveals distinct phenotypic patterns of HIV-specific CD8(+) T lymphocyte activation in response to therapeutic manipulation of virus load.

Therapeutic intervention with antiretroviral therapy (ART) enables the modulation of HIV virus load and hence provides a unique opportunity to study the consequences of varying antigen load on the phenotype of virus-specific CD8(+) T lymphocytes in a persistent human viral infection. The recent advent of tetrameric peptide / HLA class I complexes has enabled the direct phenotypic characterization of antigen-specific T cell populations ex vivo. Here, we use this technology to examine directly ex vivo the consequences of therapeutic manipulation of HIV virus load on the phenotype of HIV-specific CTL. Our observations show that: (1) distinct sequential activation patterns of CD8(+) T cells are associated with increasing virus load; (2) T cell receptor (TCR) down-regulation without apoptosis represents an early event during the generation of a T cell response in a natural infection and precedes the emergence of two distinct antigen-specific CD8(+) T cell populations which differ in TCR and CD8 expression levels. Clear differences in surface Annexin V staining were observed between these populations. The observation that CTL activation, demonstrated by TCR and CD8 down-regulation, in response to rising levels of virus load, co-segregates with apoptosis only during later stages of the response indicates that antigen-associated cell death is restricted to distinct subpopulations of CTL.